Clinical trial NCT02215096
Conditions: Neoplasms
Keywords: enzalutamide metastatic castration-resistant prostate cancer GSK2636771 PI3K-beta PTEN deficiency
Sponsor: GlaxoSmithKline
Start date: 2014-11-13; Completion date: 2019-10-03
Enrollment: 37 participants; Allocation: NON_RANDOMIZED; Intervention model: SINGLE_GROUP

Brief summary:
This Phase I, open-label, dose-finding, multicenter study is designed to determine the recommended Phase II dose (RP2D) for the combination of an orally administered Phosphatidylinositol-4,5-bisphosphate 3-kinase beta (PI3K-beta) inhibitor (GSK2636771) with enzalutamide. Subjects with phosphatase and tensin homolog (PTEN)-deficient metastatic castration-resistant prostate cancer (mCRPC) who are receiving a stable dose of enzalutamide with a recently demonstrated progression (either by RECIST \[Response Evaluation Criteria In Solid Tumors\] version 1.1, prostate-specific antigen \[PSA\] progression, and/or progression in bone) per the Prostate Cancer Working Group 2 (PCWG2) criteria will be enrolled. Eligible subjects will be enrolled in the Dose-Escalation Phase to determine the maximum tolerated dose (MTD) of the combination therapy using a modified 3+3 dose escalation procedure. The safety, pharmacokinetics (PK) and clinical efficacy will also be assessed to guide the selection of the RP2D. The starting dose will be GSK2636771 300 mg once daily in combination with the recommended dose (160 milligram \[mg\] once daily) of oral enzalutamide. Once the RP2D has been established, additional subjects will be enrolled in the Dose Expansion Phase to further evaluate the safety, PK and preliminary clinical activity. Safety assessments will be performed throughout the study including physical examinations, vital signs, clinical laboratory tests, 12 lead electrocardiograms and monitoring of adverse events. Blood samples will be collected for pharmacokinetic analysis. Subjects will continue treatment until an unacceptable toxicity, disease progression, withdrawal of consent or death occurs. A post-treatment follow-up visit will be performed within 30 days of the last dose of study treatment. Xtandi is a registered trademark of Astellas Pharma Inc

Detailed description:

Arms: arm 1: Subject receiving a stable dose of enzalutamide 160 mg once daily will receive GSK2636771 following a modified 3+3 dose escalation procedure (Cohort -1: 200 mg, Cohort 1: 300 mg and Cohort 2: 400 mg) to evaluate the safety and PK for each combination dose level and to guide selection of the RP2D of the combination. If the combination doses in Cohort 1 are not tolerable, lower doses as defined in the de-escalation cohort (Cohort -1) will be evaluated. If the de-escalation cohort (Cohort -1) is not tolerable, further dose-escalation using a continuous daily dosing schedule for both compounds simultaneously will be terminated. Additional dose levels of GSK2636771 or alternative dosing schedules may be explored based upon ongoing assessment of safety and PK. Dose modification decisions will be made utilizing all available data at the end of each DLT determination period (28 days). arm 2: Additional 20 subjects will be assigned to receive GSK2636771 at the MTD or RP2D determined in the Dose-Escalation Phase while continuing treatment with enzalutamide to evaluate the long-term safety of the combination as well as the 12-week non-PD rate
Interventions: intervention 1: GSK2636771 intervention 2: Enzalutamide
Intervention descriptions: intervention 1: GSK is available as 100 mg hard gelatin oral capsule to be taken once daily/continuous until treatment withdrawal under fasting conditions for at least 1hour (h) before and 2h after dosing with approximately 200 mL of water intervention 2: Enzalutamide will be sourced locally from commercial stock for sites in countries where it is approved

Protocol documents:
Prot_000.pdf: 
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TITLE PAGE
Division: Worldwide Development
Information Type: Protocol Amendment
Title:
A Phase I, Open-Label, Dose-Finding Study of GSK2636771 
Administered in Combination with Enzalutamide (Xtandi) in 
Male Subjects with Metastatic Castration-Resistant Prostate 
Cancer (mCRPC)
Compound Number:
GSK2636771
Development Phase:
I
Effective Date:
27-JAN-2017
Protocol Amendment Number:  04
Author (s):
 
 
Copyright 2017 the GlaxoSmithKline group of companies.  All rights reserved.  
Unauthorised copying or use of this information is prohibited.
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Revision Chronology
GlaxoSmithKline 
Document Number
Date
Version
2013N172718_00
2014-MAY-22
Original
2013N172718_01
2014-SEP-08
Amendment No. 1
Amendment 1 incorporates changes to Section 5.2, Permanent Discontinuation of Study 
Treatment(s) for clarification as requested by the Medicines and Healthcare products 
Regulatory Agency (MHRA) in the United Kingdom
2013N172718_02
2015-FEB-26
Amendment No. 2
Amendment 2 was completed to include the following changes:

Allow 30 days rather than 14 days of drug holiday from enzalutamide treatment 
prior to initiation enzalutimde as investigational product within the study to 
ensure sufficient time for completion of pre-screening and screening assessments

Clarify and define the 14-day treatment with enzalutamide monotherapy prior to 
the addition of GSK263771 as the “Enzalutamide Run-In Period”, that the 
Enzalutamide Run-In Period is to follow completion of pre-screening and 
screening rather than be concurrent with screening, and other administrative 
changes needed as a result of defining the Enzalutamide Run-in Period (e.g., 
specify collection of adverse events [AEs] during the Enzalutamide Run-In Period 
and that enzaluitmide will be provided during the Enzalutamide Run-In Period)

Added an assessment for genetic research

Add parathyroid hormone assessments at baseline and in the event of Grade 2 or 
higher hypocalcemia or hypophosphatemia 

Add updated standard GlaxoSmithKline protocol language for specific AEs (i.e., 
liver chemistry stopping criteria).

Removed androgen receptor antagonists from the list of prohibited medications 
and other changes to lists of medications to avoid or use with caution
The remaining changes are largely administrative, and intended to provide additional 
clarification or to correct inadvertent errors
2013N172718_03
2016-JUN-24
Amendment No.3 
Amendment 3 was completed to update the risk assessment section and to include 
additional requirements for monitoring of renal events.  Optional pharmacodynamics 
paired biopsies as well as clarifications around biomarker assessments were added to the
Time and Events tables for the Dose Escalation and Dose Expansion Phases.  Additional 


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language was added to clarify that:

Subjects with disease progression defined by PSA progression alone or for the 
worsening of an isolated disease site that is not clinically significant are not 
required to discontinue treatment in the study,

The decision to terminate the Dose Expansion Phase will take into account all 
relevant factors, including but not soley based upon the statistical methodogy and 
futility criterion.

Other minor clarifications were also added.   
2013N172718_04
2017-JAN-27
Amendment No. 4
Amendment 4 was completed to include the following: 

Additional requirements for monitoring of events related to calcium results. This 
includes revisions to the Table & Events to clarify additional laboratory testing 
requirements

Clarification of secondary clinical activity endpoints and update to associated 
statistical section(s)

Revision of clinical activity population to allow analyses to occur using a 
combination of dose escalation and dose expansion populations

Revision of dose escalation and dose expansion wording to move into dose 
expansion with a MTD or lower dose level and to clarify that multiple dose levels 
may be examined in the dose expansion phase to establish RP2D after dose 
expansion phase

Adjustment to Week 12 visit window to assist correct timing of disease 
assessments for this visit after actual 12 weeks on combination treatment

Revision to reflect current indication for enzalutamide throughout the document

Clarification of study populations

Clarification of bone progression definition

Other minor clarifications and corrections of inadvertent errors were also added


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SPONSOR INFORMATION PAGE
Sponsor Legal Registered Address:
GlaxoSmithKline Research & Development Limited
Iron Bridge Road 
Stockley Park West, Uxbridge, Middlesex, UB11 1BU, UK
Telephone: 
 
GlaxoSmithKline Research & Development Limited
1250 South Collegeville Road
Collegeville, PA 19426, USA
Telephone:
GlaxoSmithKline Research & Development Limited
Five Moore Drive 
P.O. 13398
Research Triangle Park, NC 27709-3398, USA
Telephone:
In some countries, the clinical trial sponsor may be the local GlaxoSmithKline affiliate 
company (or designee). Where applicable, the details of the Sponsor and contact person 
will be provided to the relevant regulatory authority as part of the clinical trial 
submission.
Sponsor Medical Monitor Contact Information
Role
Name
Day Time 
Phone 
Number
After-
hours 
Phone/ 
Cell/
Pager 
Number
Fax 
Number
GSK Address
Primary 
Medical 
Monitor
, 
MD, PhD
GlaxoSmithKline
1250 S. Collegeville Road
Collegeville, PA 19426, USA
Secondary 
Medical 
Monitor
, MD, 
PhD
NA
GlaxoSmithKline
1250 S. Collegeville Road
Collegeville, PA 19426, USA
Regulatory Agency Identifying Numbers:
Investigational New Drug (IND) No:
113058
EudraCT No:
2013-005111-27
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INVESTIGATOR PROTOCOL AGREEMENT PAGE
For protocol 200331
I confirm agreement to conduct the study in compliance with the protocol, as amended by 
this protocol amendment.
I acknowledge that I am responsible for overall study conduct. I agree to personally 
conduct or supervise the described study.
I agree to ensure that all associates, colleagues and employees assisting in the conduct of 
the study are informed about their obligations. Mechanisms are in place to ensure that site 
staff receives the appropriate information throughout the study. 
Investigator Name:
Investigator Address:
Investigator Phone Number:
Investigator Signature
Date


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TABLE OF CONTENTS
PAGE
LIST OF ABBREVIATIONS...........................................................................................12
PROTOCOL SYNOPSIS...............................................................................................16
1.
INTRODUCTION....................................................................................................32
1.1.
Metastatic Castration-Resistant Prostate Cancer........................................32
1.2.
GSK2636771..............................................................................................33
1.2.1.
Clinical Safety, Pharmacokinetic Data, and Clinical Activity 
of GSK2636771 ...........................................................................33
1.3.
Enzalutamide (Xtandi).................................................................................34
1.3.1.
Clinical Safety, Pharmacokinetic Data, and Clinical Activity 
of Enzalutamide...........................................................................34
1.4.
Summary of Risk Management...................................................................35
1.4.1.
Risk Assessment .........................................................................36
1.4.1.1.
GSK2636771..............................................................36
1.4.1.2.
Enzalutamide..............................................................38
1.4.1.3.
Potential Overlapping Toxicities..................................38
1.4.1.4.
Risk of Drug-Drug Interaction .....................................38
1.4.2.
Benefit Assessment.....................................................................39
1.4.3.
Overall Benefit:Risk Conclusion...................................................39
1.5.
Rationale ....................................................................................................40
1.5.1.
Rationale for Study ......................................................................40
1.5.2.
Rationale for Study Population.....................................................40
1.5.3.
Dose Rationale ............................................................................40
1.5.4.
Endpoint Rationale ......................................................................41
2.
OBJECTIVES AND ENDPOINTS...........................................................................41
2.1.
Hypothesis..................................................................................................41
2.2.
Objectives and Endpoints ...........................................................................42
3.
INVESTIGATIONAL PLAN.....................................................................................43
3.1.
Pre-Screening and Screening.....................................................................45
3.2.
Treatment Periods ......................................................................................45
3.2.1.
Enzalutamide Run-In Period ........................................................45
3.2.2.
Combination Treatment Period ....................................................46
3.2.3.
Treatment Continuation Period ....................................................46
3.2.4.
Post-Treatment Follow up............................................................46
3.3.
Discussion of Study Design ........................................................................46
3.4.
Dose Escalation Phase...............................................................................47
3.4.1.
Cohort Expansion ........................................................................48
3.4.2.
Alternative Dosing Schedules ......................................................48
3.4.3.
Definition of Dose Limiting Toxicity ..............................................48
3.4.4.
Maximum Tolerated Dose............................................................49
3.5.
Dose Expansion Phase...............................................................................49
3.6.
Recommended Phase II Dose ....................................................................49
3.7.
Intra-subject Dose Escalation .....................................................................50
3.7.1.
Evaluation of Futility.....................................................................50
3.8.
Continued Treatment ..................................................................................51


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3.9.
Treatment Assignment................................................................................51
3.10.
Blinding.......................................................................................................51
4.
STUDY POPULATION...........................................................................................51
4.1.
Subject Selection Criteria............................................................................51
4.1.1.
Number of Subjects .....................................................................51
4.1.2.
Inclusion Criteria..........................................................................51
4.1.3.
Exclusion Criteria.........................................................................53
5.
COMPLETION OR WITHDRAWAL OF SUBJECTS...............................................56
5.1.
Screen Failures...........................................................................................56
5.2.
Permanent Discontinuation of Study Treatment(s)......................................56
5.3.
Subject Completion.....................................................................................57
5.4.
Study Completion .......................................................................................58
5.5.
Treatment after the End of the Study ..........................................................58
6.
INVESTIGATIONAL PRODUCT.............................................................................58
6.1.
GSK2636771 GSK Investigational Product.................................................58
6.2.
Enzalutamide Non-GSK Product.................................................................59
6.3.
Administration of Study Treatments ............................................................59
6.3.1.
GSK2636771...............................................................................61
6.3.2.
Enzalutamide...............................................................................62
6.4.
Handling and Storage of Study Treatments ................................................62
6.5.
Product Accountability ................................................................................62
6.6.
Treatment Compliance................................................................................63
6.7.
Treatment of Study Treatment Overdose....................................................63
7.
DOSE MODIFICATIONS, STOPPING CRITERIA AND MANAGEMENT 
GUIDELINES .........................................................................................................63
7.1.
Dose Modifications .....................................................................................64
7.1.1.
GSK2636771...............................................................................64
7.1.2.
Enzalutamide...............................................................................64
7.2.
Stopping Criteria.........................................................................................65
7.2.1.
QTc Stopping Criteria ..................................................................65
7.2.2.
Liver Chemistry Stopping Criteria ................................................65
7.2.2.1.
Liver Chemistry Stopping and Increased 
Monitoring Algorithm for Subjects WITH entry 
criteria ALT ≤2.5xULN ................................................65
7.2.2.2.
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 .........................................67
7.2.2.3.
Liver Safety Required Actions and Follow-up .............68
7.2.3.
Left Ventricular Ejection Fraction (LVEF) Stopping Criteria..........70
7.2.4.
Valvular Toxicity Stopping Criteria ...............................................71
7.3.
Management Guidelines for Specific Events Associated with 
GSK2636771..............................................................................................72
7.3.1.
Renal Insufficiency or Other Renal Events...................................72
7.3.1.1.
Parathyroid Hormone (PTH).......................................75
7.3.2.
Cardiac-related Toxicities ............................................................75
7.3.2.1.
Hypertension ..............................................................75


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7.3.3.
Rash............................................................................................76
7.3.4.
Diarrhea.......................................................................................77
7.3.5.
Vomiting ......................................................................................83
8.
STUDY ASSESSMENTS AND PROCEDURES .....................................................83
8.1.
Time and Events Tables .............................................................................84
8.2.
Consent ......................................................................................................97
8.2.1.
Consent for Pre-Screening ..........................................................97
8.2.2.
Consent for Screening .................................................................97
8.3.
Pre-Screening and Screening.....................................................................97
8.3.1.
Pre-Screening:  Determination of PTEN Deficiency Status ..........97
8.3.2.
Screening ....................................................................................98
8.4.
Demographics and Medical History.............................................................98
8.5.
Critical Baseline Assessment......................................................................98
8.6.
Safety .........................................................................................................98
8.6.1.
Physical Examination...................................................................98
8.6.2.
Vital Signs....................................................................................99
8.6.3.
ECOG Performance Status..........................................................99
8.6.4.
Electrocardiogram........................................................................99
8.6.5.
Echocardiogram and/or Multi-gated Acquisition (MUGA) 
Scans ..........................................................................................99
8.6.6.
Laboratory Assessments ...........................................................100
8.7.
Pharmacokinetic Assessments .................................................................101
8.7.1.
PK Assessments: Dose Escalation Phase .................................101
8.7.2.
PK Assessments:  Dose Expansion Phase................................102
8.7.3.
PK Blood Sample Collection ......................................................102
8.7.3.1.
Additional PK Blood Sample Collection ....................103
8.7.4.
Pharmacokinetic Sample Analysis .............................................104
8.7.5.
Meals, Alcohol, Tobacco and Activity Restrictions .....................104
8.8.
Clinical Activity..........................................................................................104
8.8.1.
Clinical Activity Endpoints..........................................................105
8.8.2.
Disease Assessment .................................................................105
8.8.2.1.
PSA Response per PCWG2 Criteria.........................105
8.8.2.2.
Radiographic Response per PCWG2 Criteria...........105
8.8.2.3.
Disease Progression Endpoint .................................106
8.9.
Translational Research.............................................................................106
8.9.1.
Predictive Biomarkers................................................................106
8.9.2.
Tumor Biopsies for PD and Disease Progression ......................107
8.9.3.
Circulating Tumor Cells..............................................................107
8.9.3.1.
CTC Conversion Rate ..............................................107
8.9.4.
Circulating Cell Free DNA, RNA and Soluble Markers ...............107
8.10.
Genetic Research.....................................................................................108
8.11.
Exploratory Pharmacokinetic and Pharmacodynamic Analysis .................108
9.
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS...................................108
9.1.
Definition of an AE....................................................................................108
9.2.
Definition of an SAE..................................................................................109
9.2.1.
Sentinel Events..........................................................................110
9.3.
Laboratory and Other Safety Assessment Abnormalities Reported 
as AEs and SAEs .....................................................................................111
9.3.1.
Cardiovascular Events...............................................................111
9.3.2.
Death Events.............................................................................112


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9.4.
Disease-Related Events and/or Disease-Related Outcomes Not 
Qualifying as SAEs...................................................................................112
9.5.
Time Period and Frequency of Detecting AEs and SAEs..........................112
9.5.1.
Method of Detecting AEs and SAEs...........................................113
9.5.2.
Prompt Reporting of SAEs and Other Events to GSK ................113
9.5.3.
Regulatory Reporting Requirements for SAEs ...........................115
9.6.
Reporting of Pregnancy ............................................................................115
10. CONCOMITANT MEDICATIONS AND NON-DRUG THERAPIES .......................115
10.1.
Permitted Medications ..............................................................................116
10.2.
Prohibited Medications and Non-Drug Therapies......................................116
10.2.1.
Potential Drug Interactions with GSK2636771 ...........................117
10.2.1.1.
GSK2636771 as Perpetrator of Drug-Drug 
Interactions...............................................................117
10.2.1.2.
GSK2636771 as Victim of Drug-Drug 
Interactions...............................................................118
10.2.2.
Potential Drug Interactions with Enzalutamide ...........................118
11. LIFESTYLE RESTRICTIONS...............................................................................120
11.1.
Contraception Requirements ....................................................................120
11.2.
Other:  Light Sensitivity and Allergens ......................................................120
11.3.
Other: Hydration .......................................................................................121
12. DATA MANAGEMENT .........................................................................................121
13. DATA ANALYSIS AND STATISTICAL CONSIDERATIONS.................................121
13.1.
Hypotheses...............................................................................................121
13.1.1.
Dose Escalation Phase..............................................................121
13.1.2.
Dose Expansion Phase..............................................................121
13.2.
Sample Size Determination ......................................................................122
13.2.1.
Dose Escalation Phase..............................................................122
13.2.2.
Dose Expansion Phase..............................................................122
13.3.
Data Analysis Considerations ...................................................................123
13.3.1.
Analysis Populations..................................................................123
13.3.2.
Analysis Data Sets.....................................................................123
13.3.3.
Interim Analysis .........................................................................123
13.3.3.1.
Dose Escalation Phase ............................................123
13.3.3.2.
Dose Expansion Phase ............................................123
13.3.4.
Key Elements of Analysis Plan ..................................................124
13.3.4.1.
Efficacy Analyses .....................................................124
13.3.4.2.
Safety Analyses........................................................126
13.3.4.2.1.
Extent of Exposure ...............................126
13.3.4.2.2.
Adverse Events ....................................126
13.3.4.2.3.
Clinical Laboratory Evaluations.............126
13.3.4.2.4.
Other Safety Measures.........................127
13.3.4.3.
Pharmacokinetic Analyses........................................127
13.3.4.4.
Pharmacokinetic/Pharmacodynamic Analyses .........127
13.3.4.5.
Translational Research Analyses .............................128
14. STUDY CONDUCT CONSIDERATIONS .............................................................128
14.1.
Posting of Information on Publicly Available Clinical Trial Registers..........128


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14.2.
Regulatory and Ethical Considerations, Including the Informed 
Consent Process ......................................................................................129
14.3.
Urgent Safety Measures ...........................................................................129
14.4.
Quality Control (Study Monitoring) ............................................................129
14.5.
Quality Assurance.....................................................................................130
14.6.
Study and Site Closure .............................................................................130
14.7.
Records Retention....................................................................................131
14.8.
Provision of Study Results to Investigators, Posting of Information 
on Publicly Available Clinical Trials Registers and Publication..................131
15. REFERENCES.....................................................................................................132
16. APPENDICES......................................................................................................135
16.1.
Appendix 1:  ECOG Performance Status ..................................................135
16.2.
Appendix 2:  NYHA Functional Classification System ...............................136
16.3.
Appendix 3:  CKD-EPI equation................................................................137
16.4.
Appendix 4:  Disease Assessment per RECIST 1.1..................................138
16.5.
Appendix 5:  Urine Protein Creatinine (UPC) Ratio...................................146
16.6.
Appendix 6:  Liver Safety Drug Restart/Rechallenge Guidelines...............147
16.7.
Appendix 7:  Genetic Research ................................................................150
16.8.
Appendix 8:  Country Specific Requirements............................................153
16.9.
Appendix 9:  Protocol Amendment Changes.............................................154
16.9.1.
Protocol Changes for Amendment 1 (08-Sep-2014) from 
Original Protocol (22-May-2014)................................................154
16.9.2.
Protocol Changes for Amendment 2 (26-Feb-2015) from 
Protocol Amendment 1 (08-Sep-2014).......................................154
16.9.3.
Protocol changes for Amendment 3 (24-Jun-2016) from 
Protocol Amendment 2 (26-Feb-2015).......................................208
16.9.4.
Protocol changes for Amendment 4 (27-Jan-2017) from 
Protocol Amendment 3 (24-Jun-2016) .......................................216


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LIST OF ABBREVIATIONS
C
Degrees Celsius
F
Degrees Fahrenheit
ADP
Adenosine diphosphate
AE
Adverse Event
ALT
Alanine aminotransferase
ANC
Absolute neutrophil count
AR
Androgen receptor
ASCO
American Society of Clinical Oncology
AST
Aspartate aminotransferase
ATP
Adenosine triphosphate
AUC
Area under the concentration-time curve
AUC(0-t)
Area under the concentration-time curve from zero over the dosing 
interval
AUC(0-τ)
Area under the concentration-time curve from zero to the last quantifiable 
blood or plasma concentration
AUC(0-24)
Area under the concentration-time curve from zero (pre-dose) to 24 hrs
BBB
Bundle branch block
BCRP
Breast cancer resistant protein
BP
Blood pressure
BUN
Blood urea nitrogen
C24
Trough concentration
CBC
Complete blood count
cfDNA
Circulating-free tumor DNA
CI
Confidence Interval
CL/F
Oral clearance
Cmax
Maximum observed concentration
CO2
Carbon dioxide
CR
Complete response
CRPC
Castrate-resistant prostate cancer
CSR
Clinical study report
CT
Computed tomography
CTA
Clinical Trial Application
CTC
Circulating tumor cells
CTCAE
Common Terminology Criteria for Adverse Events
CYP
Cytochrome
DBP
Diastolic blood pressure
DDI
Drug-drug interaction
DHT
Dihydrotestosterone
DILI
Drug induced liver injury
dL
Deciliter
DLT
Dose-limiting toxicity
DNA
Deoxyribonucleic acid
ECG
Electrocardiogram
ECHO
Echocardiogram


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ECOG
Eastern Cooperative Oncology Group
eCRF
Electronic Case Report Form
Emax
Maximum effect
FDA
Food and Drug Administration
FDG-PET
Fluorodeoxyglucose-positron emission tomography
FISH
Fluorescent in situ hybridization
ft
Foot
FTIH
First time in human
g
Gram
GCP
Good Clinical Practice
GI
Gastrointestinal
GnRH
Gonadotropin releasing hormone
GSK
GlaxoSmithKline
h/hr
Hour(s)
HBsAg
Hepatitis B surface antigen
HIV
Human immunodeficiency virus
HLA
Human leukocyte antigen
HPLC
High performance liquid chromatography
IB
Investigator’s Brochure
IBW
Ideal body weight
ICF
Informed consent form
ICH
International Conference on Harmonization 
IDSL
International Data Standards Library
IEC
Independent Ethics Committee
IgG or M
Immunoglobulin G or M
IHC
Immunohistochemistry
IMP
Investigational medicinal product
IND
Investigational New Drug
INPP4B
Inositol polyphosphate-4-phosphatase type II
INR
International Normalized Ratio
IP
Investigational product
IR
Immediate release
IRB
Institutional Review Board
IV
Intravenous
ka
Absorption rate constant
kg
Kilogram
L
Liter
LCH
Langerhans cell histiocytosis
LDH
Lactate dehydrogenase
LHRH
Luteinizing hormone releasing hormone
LLN
Lower limit of normal
LOH
Loss of heterozygosity
LVEF
Left ventricular ejection fraction
M
Mandatory
MCH
Mean corpuscular hemoglobin
mCRPC
Metastatic castration-resistant prostate cancer


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MCV
Mean corpuscular volume
MedDRA
Medical Dictionary for Regulatory Activities
mg
Milligrams
mL
Milliliter
mm
Millimeter
mmHg
Millimeters of mercury
mmol
Millimolar
MRI
Magnetic resonance imaging
mRNA
Messenger RNA
MSDS
Material Safety Data Sheet
msec
Milliseconds
MTD
Maximum tolerated dose
mTOR
Mammalian Target of Rapamycin
MUGA
Multigated acquisition scan
N, n
Number
NA
Not available or not applicable
NE
Not evaluable
ng
Nanogram
NLCB
No longer clinically benefitting
nM
Nanomolar
NYHA
New York Heart Association
O
Optional
OATP
Organic anionic transferase peptide
OCT
ORR
Objective Response Rate
OTC
Over-the-counter
P-gp
P-glycoprotein
pAKT
Phosphorylated AKT
PCR
Polymerase chain reaction
PCWG2
Prostate Cancer Working Group 2
PCWG3
Prostate Cancer Working Group 3
PD
Pharmacodynamic or progressive disease
PET
Positron emission tomography or probability of early termination
Pgp
P-glycoprotein
PHLPP
PH and leukine-rich repeat protein phosphatase (a negative regulator of 
AKT)
PI3K
Phosphoinositide 3-kinase
PI3KCA
Phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha
PI3KR1
Phosphoinositide-3-kinase, regulatory subunit 1 (alpha)
PI3KR3
Phosphoinositide-3-kinase, regulatory subunit 3 (gamma)
PI3Kβ
Phosphoinositide 3-kinase beta
PK
Pharmacokinetic
PR
Partial response
PRP
Platelet rich plasma
PSA
Prostate-specific antigen
PSA50
Prostate-specific antigen decrease from baseline ≥50%


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PT
Prothrombin time
PTEN
Phosphatase and tensin homolog
PTH
Parathyroid hormone
PTS-DMPK
Platform Technology and Science – Drug Metabolism and 
Pharmacokinetics
PTT
Partial thromboplastin time
QTc
Corrected QT interval 
QTcB
QT interval corrected by Bazett’s formula
QTcF
QT interval corrected by Fridericia’s formula
RAP
Reporting and Analysis Plan
RBC
Red blood cell
RECIST
Response Evaluation Criteria In Solid Tumors
RNA
Ribonucleic acid
RP2D
Recommended Phase II dose
rPFS
Radiological progression free survival
RR
Response rate
SAE
Serious adverse event(s)
SBP
Systolic blood pressure
SD
Stable disease or standard deviation
SRM
Study Reference Manual
t1/2
Half-life
Tmax
Time of occurrence of maximum observed concentration
TMF
Trial Master File
UGT
UDP-glucuronosyltransferase
UK
United Kingdom
ULN
Upper limit of normal
UPC
Urine protein to creatinine 
US
United States
V/F
Oral volume of distribution
WBC
White blood cells
Wk(s)
Week(s)
WNL
Within normal limits
Yr
Year
Trademark Information
Trademarks of the GlaxoSmithKline 
group of companies
Trademarks not owned by the 
GlaxoSmithKline group of companies
NONE
InForm
NONMEM
Xtandi


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PROTOCOL SYNOPSIS
TITLE
A Phase I, Open-Label, Dose-Finding Study of GSK2636771 Administered in 
Combination with Enzalutamide (Xtandi) in Male Subjects with Metastatic 
Castration-Resistant Prostate Cancer (mCRPC)
PROTOCOL 
NUMBER
200331
CLINICAL PHASE
I
COMPOUND
GSK2636771
STUDY 
RATIONALE
Despite recent advances in the treatment of advanced prostate cancer, 
relapses are inevitable and metastatic castration-resistant prostate cancer 
(mCRPC) carries considerable morbidity along with shortened survival.  
Previous studies have indicated the importance of the phosphoinositide 
3-kinase (PI3K) pathway in prostate cancer.  A common event in prostate 
cancer progression is the loss of tumor suppressor phosphatase and tensin 
homolog (PTEN) in 40-50% of mCRPC patients that results in the activation of 
the PI3K pathway.  The choice of subject populations represented in this 
study is based on the hypothesis that activation of the PI3K pathway in 
mCRPC will result in increased sensitivity to the combination and thus 
subjects will be selected on the basis of PTEN deficiency.
Therapeutic approaches that simultaneously inhibit both the androgen 
receptor (AR) pathway and the PI3K pathway may be more effective than 
inhibition of either pathway alone in mCRPC.  Enzalutamide is an AR inhibitor 
indicated for the treatment of patients with mCRPC.  The proposed Phase I 
study will evaluate the safety and tolerability, pharmacokinetics (PK), and 
clinical activity to determine the recommended Phase II dose (RP2D) and 
regimen of GSK2636771 in combination with enzalutamide given orally in 
adult male subjects with mCRPC.
STUDY 
OBJECTIVES, 
ENDPOINTS 
AND 
HYPOTHESES
Primary Hypothesis:  The addition of a targeted PI3K pathway inhibitor 
(GSK2636771) to enzalutamide treatment can be safely administered with 
ongoing enzalutamide treatment.
Secondary Hypothesis:  The addition of a targeted PI3K pathway inhibitor 
(GSK2636771) to enzalutamide can limit mCPRC progression in a clinically 
meaningful way for at least 12 weeks.  The null hypothesis is that the 12-week 
non-progressive disease (PD) rate is not attractive (≤5%).  The alternative 
hypothesis is that the rate is clinically meaningful and, therefore, the 
compound warrants further development (≥30%).  This hypothesis will be 
tested for Part 2 of the study, combining eligible subjects from Part 1. 


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STUDY 
OBJECTIVES, 
ENDPOINTS 
AND 
HYPOTHESES 
continued
Objectives
Endpoints
Primary

To assess the safety and 
tolerability of GSK2636771 + 
enzalutamide administered 
orally once daily continuously 
in subjects with mCRPC.

Adverse Events (AE), 
Serious Adverse Events
(SAE), Dose Limiting 
Toxicities (DLTs), and 
changes in laboratory values, 
Electrocardiograms (ECGs), 
and vital signs (Blood 
Pressue [BP], temperature 
and heart rate)

To determine the RP2D of 
orally administered 
GSK2636771 + enzalutamide 
in subjects with mCRPC.

Safety and tolerability as 
assessed by AEs, SAEs, 
DLTs, and changes in 
laboratory values, ECGs, and 
vital signs (BP, temperature 
and heart rate)

To evaluate lack of 
progression in the dose 
expansion subjects with  
mCPRC by rate of subjects 
who do not progress for 
12 weeks

Non-PD rate for 12 weeks 
according to PCWG2 criteria 
(either by Response 
Evaluation Criteria In Solid 
Tumors [RECIST] 1.1, or 
progression in bone or 
Prostate Specific Antigen 
[PSA] progression with 
accompanying progression 
by RECIST 1.1 or bone scan
when baseline radiological or 
bone disease present or PSA 
progression if no other 
baseline disease).
Secondary

To evaluate the clinical 
activity of oral GSK2636771 
+ enzalutamide in the 
treatment of mCRPC (PTEN 
deficient)

PSA50 response rate defined 
as the percent of subjects 
achieving PSA50 at 12 
weeks or thereafter (PSA50
is ≥50% decrease in PSA 
from baseline)

Objective Response Rate 
(ORR) defined as complete 
response (CR) rate plus 
partial response (PR) rate 
per RECIST 1.1 

Time to PSA progression 
according to PCWG2 criteria


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STUDY 
OBJECTIVES, 
ENDPOINTS 
AND 
HYPOTHESES 
continued

Time to radiological 
progression according to 
PCWG2 criteria (either by 
RECIST 1.1, and/or 
progression in bone)

Radiological progression free 
survival (rPFS) per 
RECIST1.1 and/or bone 
scans

To determine the effect of 
GSK2636771 on 
enzalutamide PK following 
repeat-dose oral 
administration.

Plasma concentrations of 
enzalutamide and 
N-desmethyl enzalutamide.

To determine the PK of 
GSK2636771 in the presence 
of enzalutamide.

Blood GSK2636771 
concentrations.
Exploratory

To determine the frequency 
of PTEN deficiency in 
subjects with mCRPC

Frequency of PTEN-deficient 
mCRPC reported in subjects 
based on pre-screened 
tumors

To determine the mechanism 
of PTEN deficiency

PTEN deletion, mutation or 
promoter methylation

To identify additional 
biomarkers (DNA, RNA or 
protein based) in tumor or in 
circulation that may predict 
response to oral 
GSK2636771 + enzalutamide 

Response prediction 
biomarkers based on 
analysis of DNA, RNA, and 
proteins from surrogate 
tissues (e.g., cfDNA) and/or 
tumor tissue

To determine the effect of 
enzalutamide with 
GSK2636771 on the kinetics 
of tumor growth

Longitudinal tumor size 
measurements; serum PSA 
levels, change from baseline 
in CTCs

Evaluation of biomarkers in 
CTCs that may predict 
response to combination

AR expression, PTEN FISH 
and other genomic 
evaluations in CTCs

Evaluation of tumor tissue to 
explore explanation for the 
mechanism of resistance to 
combination therapy

Based on analysis of DNA, 
RNA and proteins from tumor 
tissue obtained at time of 
progression after initially 
responding to combination 
therapy

To determine 
pharmacodynamic effects of 
drug treatment

RNA/protein analysis of 
pre/post treatment tumor 
biopsies 


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Abbreviations: AEs, adverse events; AR, androgen receptor; BP, blood pressure; cfDNA, 
circulating-free deoxyribonucleic acid; CTC, circulating tumor cells; DLTs, dose limiting 
toxicities; DNA, deoxyribonucleic acid; ECG, electrocardiogram; FISH, fluorescent in situ 
hybridization; mCRPC, metastatic castration-resistant prostate cancer; PCWG2, Prostate 
Cancer Working Group 2; PD, progressive disease; PK, pharmacokinetics; PSA, prostate-
specific antigen; PTEN, phosphatase and tensin homolog; RECIST, Response Evaluation in 
Solid Tumors; RNA, ribonucleic acid; RP2D, recommended Phase II dose; SAE, serious 
adverse event(s)
STUDY DESIGN
This is a Phase I, open-label, non-controlled, non-randomized, dose-finding, 
multicenter study to determine the RP2D of the oral PI3K beta (PI3K) 
inhibitor, GSK2636771 in combination with enzalutamide in subjects with 
mCRPC.
Pre-Screening and Screening:  Subjects will be required to undergo pre-
screening to determine the PTEN status of their tumor.  Details regarding the 
PTEN requirements are provided in the Study Reference Manual.  Subjects 
will sign a separate Informed Consent Form (ICF) to allow for pre-screening of 
archived tumor tissue or tumor tissue from a fresh tumor biopsy.
Subjects will be required to sign another ICF for the main study at Screening 
prior to initiation of any screening procedures or assessments. Screening 
assessments will be conducted to determine subject eligibility for enrollment 
into the study.
Dose Escalation Phase
Enzalutamide Run-In Period (Days 1-14):  Approximately 24 subjects will be 
enrolled in the 14-day run-in period and receive enzalutamide monotherapy at 
the approved dose of 160 mg once daily.
Combination Treatment Period (Weeks 1-4):  Subjects who complete the 
Enzalutamide Run-In Period will begin oral GSK2636771 treatment on 
Week 1, Day 1 of the Combination Treatment Period while continuing to 
receive enzalutamide to evaluate safety of the combination therapy.
The combination dose will be studied following a 3+3 dose modification 
procedure.  Additional doses may be explored based upon ongoing 
assessment of safety and PK.  Dose escalation decisions will be made 
utilizing all available data at the end of the Dose Limiting Toxicity (DLT) 
reporting period (the first 28 days of combination treatment).
The starting dose of GSK2636771 is 300 mg once daily.  The enzalutamide 
dose will remain fixed at 160 mg once daily.  Additional dose levels of each 
study treatment may be explored based upon ongoing assessment of safety 
and PK.  Dose modification decisions will be made utilizing all available safety 
and PK data at the end of the DLT reporting period (the first 28 days of 
combination treatment).
A minimum of 3 subjects may be enrolled in each subsequent cohort until the 
maximum tolerated dose (MTD) is defined.  Evaluation of at least 3 subjects 


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STUDY DESIGN
continued
who have completed 28 days of combination treatment is required prior to 
dose escalation to the next cohort.  Dose escalation will proceed with the 
increment of the GSK2636771 dose increase determined by toxicity rules.
3+3 Dose Escalation Guidelines Based on Toxicity
Number of 
Subjects with a 
DLT 
Action
0 out of 3 subjects
Escalate to next dose level.
1 out of 3 subjects
Accrue 3 additional subjects at current dose 
level for a total of 6 subjects
1 out of 6 subjects
Escalate to the next dose level. 
2 or more subjects in 
a dosing cohort (up 
to 6 subjects)
Dose escalation will be stopped.  At this 
dose level, the MTD has been exceeded 
(highest dose administered).  Either evaluate 
at a lower intermediate dose (3+3 dosing) or 
expand a prior cohort up to approximately 
20 subjects per treatment arm.
Abbreviations: DLT, dose limiting toxicity; MTD, maximum tolerated dose
If the combination doses in Cohort 1 are not tolerable, lower doses as defined 
in the de-escalation cohort (Cohort -1) will be evaluated.  If the de-escalation 
cohort (Cohort -1) is not tolerable, further dose escalation using a continuous 
daily dosing schedule for both compounds simultaneously will be terminated.
Dose escalation will proceed until the MTD of the combination regimen is 
identified.  If the dose(s) administered to a given cohort exceeds the MTD, 
intermediate doses may be explored.  Dose escalation decisions will take into 
account all available data, including the safety profile and PK data of prior 
cohorts throughout the time subjects are on study, which will be reviewed by 
the investigator(s), GlaxoSmithKline (GSK) Medical Monitor, 
pharmacokineticist and statistician.  In the absence of DLTs, the dose of 
GSK2636771 may be escalated to the MTD of 400 mg as determined in the 
first-time-in-human study (P3K115717).
If diarrhea (in the absence of aggressive diarrhea management), fatigue or 
rash defines the MTD, the cohort in which the toxicity is observed may be 
expanded by at least 3 subjects and the efficacy of supportive care evaluated 
prior to further dose escalation.  If supportive care measures ameliorate the 
toxicity without recurrence of the toxicity, further dose escalation may be 
conducted in the presence of appropriate supportive care.
Treatment Continuation Period (Week 5 and thereafter):  Subjects will 
continue to receive the combination treatment of GSK2636771 + 
enzalutamide until criteria are met for discontinuation of study treatment.


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STUDY DESIGN
continued
Dose Escalation Cohorts
Cohort
N
GSK2636771
Enzalutamide
-1
3 - 6
200 mg once daily
160 mg once daily
1
3 - 6
300 mg once daily
160 mg once daily
2
3 - 6
400 mg once daily
160 mg once daily
Cohort Expansion:  Selected dose levels may enroll up to 12 additional 
subjects to ensure a sufficient number of subjects enrolled to assess PK 
and/or safety.  The MTD may be the recommended dose combination for 
future Phase II studies unless there is a lower dose of GSK2636771 that 
provides adequate PK exposure and biologic activity with superior tolerability.
The final decision will be based on the totality of data. 
Alternate dose levels and schedules may also be explored based on 
emerging safety, PK or PD data.
Definition of DLT:  An event will be considered a DLT if the event is 
attributed (definitely, probably or possibly) to study treatment, occurs within 
the first 28 days of combination treatment (DLT reporting period), and meets 
one of the following criteria:

Grade 3 or greater non-hematologic toxicity that cannot be controlled 
with routine supportive measures (e.g., anti-emetics, anti-diarrheals)

Grade 4 neutropenia lasting >5 days

Febrile neutropenia, of any grade or duration as defined by Common 
Terminology Criteria for Adverse Events version 4.0 (CTCAE v4.0)

Grade 4 thrombocytopenia

Alanine aminotransferase (ALT) ≥3 times upper limit of normal (ULN) 
(or ALT ≥3 times ULN and ≥1.5 times baseline ALT value, if enrolled 
with liver metastases/tumor infiltration at baseline) and bilirubin 
≥2 times ULN
Any Grade 2 or greater toxicity per CTCAE v4.0 that that occurs beyond the 
28-day DLT reporting period which in the judgment of the investigator and 
GSK Medical Monitor would be considered dose limiting
NOTE: Subjects who fail to receive at least 75% of protocol-specified study 
treatment during the DLT reporting period (the first 28 days of combination 
treatment), for reasons OTHER than toxicity, will be replaced if data from the 


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STUDY DESIGN
continued
replacement subject could impact the dose selection criteria. 
Subjects who experience an intolerable toxicity causing a dose interruption or 
dose reduction during the Enzalutamide Run-In Period (before the start of 
GSK2636771 combination treatment) will require approval from the GSK 
Medical Monitor in order to continue in the study.  Those subjects not eligible 
for treatment in the Combination Treatment Period will not be considered in 
the evaluation of DLTs and may be replaced.
Dose Expansion Phase
This phase of the study will evaluate the long term safety of the combination 
treatment as well as the 12-week non-progressive disease (PD) rate of the 
combination treatment in subjects with mCPRC.  To confirm dose(s) identified 
during dose escalation, multiple dose levels of GSK2636771 in combination 
with enzalutamide may be examined during dose expansion, with each dose 
level cohort enrolling up to 20 subjects. Using the totality of safety, PK and 
clinical activity data, the RP2D will be confirmed from the dose level(s) which 
are examined in the dose expansion phase. 
Enzalutamide Run-In Period (Days 1-14):  Following pre-screening and 
screening, approximately 20 subjects will be enrolled and receive 
enzalutamide monotherapy at the approved dose of 160 mg once daily for 
14 days.
Combination Treatment Period (Weeks 1-4):  Subjects who complete the 
Enzalutamide Run-In Period will begin oral GSK2636771 treatment on 
Week 1, Day 1 of the Combination Treatment Period at the RP2D dose 
established in the Dose Escalation Phase of the study while continuing to 
receive enzalutamide to evaluate safety of the combination therapy.
Treatment Continuation Period (Week 5 and thereafter):  Subjects will 
continue to receive the combination treatment of GSK2636771 + 
enzalutamide until criteria are met for discontinuation of study treatment.
PK:  Blood and plasma samples for PK analysis of GSK2636771 and 
enzalutamide (including its active metabolite, N-desmethyl enzalutamide) will 
be collected on specified PK days in the Dose Escalation and Dose 
Expansion Phase.
Genetic Research: A single blood sample will be collected after Screening, 
preferably on Week 1, Day 1 of the Combination Treatment Period, if 
informed consent has been obtained for genetic research. 
NUMBER OF 
SUBJECTS
A total of approximately 44 to 64 subjects will be enrolled in this study.  
In the Dose Escalation Phase, the number of dose levels and the level at 
which the MTD is reached cannot be determined in advance.  An adequate 
number of subjects will be enrolled to establish the MTD.  It is estimated that 
approximately 24 subjects will be enrolled to allow assessment of safety and 
preliminary efficacy in PTEN-deficient mCRPC with disease progression on 


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enzalutamide.
In the Dose Expansion Phase, it is estimated that approximately 20 subjects 
will be enrolled, with evaluation for futility after the first 10 subjects have 
completed 12 weeks of treatment. This analysis may occur using the 
combination of the dose escalation and dose expansion population. If multiple 
dose levels of GSK2636771 are examined during dose expansion to 
establish the RP2D, each dose level cohort will enrol approximately 20 
subjects, increasing the overall number of subjects targeted for enrolment in 
this study. The sample size planned for the Dose Expansion Phase is not 
driven by statistical considerations as the cohort is meant to further 
understand the safety implications of enrolling subjects to combination 
therapy for an extended period of time.  
INCLUSION/
EXCLUSION
CRITERIA
Key Inclusion Criteria 
1.
Signed written informed consent provided
NOTE: Separate ICFs must be signed prior to the pre-screening and 
screening procedures.
2.
Males 18 years of age (at the time written consent is obtained for pre-
screening)
3.
Histologically or cytologically confirmed diagnosis of prostate 
adenocarcinoma, surgically castrated or continuous medical castration 
(for 8 weeks prior to Screening)
4.
Serum testosterone <50 ng/dL (1.7 nM/L)
5.
PTEN-deficient tumor as documented from archived or fresh (from pre-
treatment biopsy) tumor tissue analyzed by a GSK selected laboratory
6.
Eastern Cooperative Oncology Group (ECOG) performance status of 0 
or 1
7.
Has completed at least 12 weeks of prior continuous therapy with 
enzalutamide
8.
Has not been without enzalutamide treatment for >30 days prior to 
enrollment
9.
Has documented disease progression following treatment with 
enzalutamide at time of Screening
NOTE: Disease progression is defined by one or more of the following 
criteria:

PSA progression defined by PCWG2 criteria (see Section 
8.8.2.1), or

Soft tissue disease progression defined by RECIST 1.1 (see 
Appendix 4), or

Bone disease progression defined by PCWG2 criteria (see 


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INCLUSION/
EXCLUSION 
CRITERIA 
continued
Section 8.8.2.2)
10. Able to swallow and retain orally administered medication.
11. Adequate baseline organ function at time of Screening defined as:
Hematologic
ANC
1.5 x 109/L
Hemoglobin
9 g/dL 
Platelets
100 x 109/L
PT/INR and PTT
1.3 x ULN
Hepatic
Albumin
2.5 g/dL
Total bilirubin1
1.5 x ULN
AST
ALT1
2.5 x ULN
2.5 x ULN or >2.5 x 
ULN but 5 x ULN with 
documented liver 
metastases or tumor 
infiltration
Renal
Urine Protein (via dipstick)2
0/+1
UPC3,4
<0.2
Serum Creatinine
OR
Estimated Serum Creatinine Clearance5
OR
24-hr Urine Creatinine Clearance
ULN
60 mL/min
60 mL/min
Cardiac
LVEF
50% by ECHO or 
MUGA
Other
Serum Phosphate
WNL
Serum Calcium6 (corrected)
Ionized Calcium6
Vitamin D6: 25-OH D and 1,25-OH2 D
WNL
WNL
WNL
Abbreviations: ANC, absolute neutrophils count; ALT, alanine aminotransferase; 
AST, aspartate aminotransferase; CTCAE, Common Terminology Criteria for 
Adverse Events; ECHO, echocardiogram; INR, international normalization ratio; LLN, 
lower limit of normal; LVEF, left ventricular ejection fraction; MUGA, multigated 
acquisition scan; PT, prothrombin time; PTT, partial thromboplastin time; ULN, upper 
limit of normal; UPC, urine protein to creatinine ratio; WNL, within normal limits
1. If ALT or bilirubin values are outside range listed due to Gilbert’s syndrome or 
asymptomatic gallstones, subject remains eligible.
2. If subject’s urine protein is >1+ (via dipstick), then UPC ratio will be calculated.  
Subject will be considered eligible for study if UPC ratio is <0.2.
3. UPC ratio is only to be calculated if subject’s urine protein is >1+ via dipstick.
4. The UPC value will not be used to determine eligibility for subjects who are 
unable to obtain uncontaminated urine samples due to their disease.
5. Estimated by the CKD-EPI equation (see Appendix 3) 


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6. Vitamin D supplementation may be added to achieve values WNL. Calcium 
supplements should be added for subjects with calcium values near the lower 
normal limit. 
NOTE:  Laboratory results obtained during Screening should be used 
to determine eligibility criteria.  In situations where laboratory results are 
outside the permitted range, the investigator may opt to retest the 
subject and the subsequent within range screening result may be used 
to confirm eligibility.  
12. Male subject with a female partner of childbearing potential or 
pregnant must agree to use two acceptable methods of contraception 
from time of Screening until 3 months after the last dose of study 
treatments (see Section 11.1).
INCLUSION/ 
EXCLUSION
CRITERIA 
continued
Key Exclusion Criteria
1.
Prior treatment with:

Anti-cancer therapy (e.g., chemotherapy with delayed toxicity, 
immunotherapy, biologic therapy or chemoradiation) within 21 days 
(or within 42 days if prior nitrosourea or mitomycin C containing 
therapy) prior to enrollment and/or daily or weekly chemotherapy 
without the potential for delayed toxicity within 14 days prior to 
enrollment
Exception: Subjects may remain on luteinizing hormone releasing 
hormone (LHRH) agonists (i.e., leuprolide, goserelin, triptorelin or 
histrelin) and AR antagonists (e.g., bicalutamide, flutamide, 
nilutamide; but not abiraterone).
Exception: Subjects must have received prior treatment with 
enzalutamide.

Any PI3K, AKT or mammalian target of rapamycin (mTOR) inhibitors

Investigational drug(s) (other than enzalutamide) within 30 days or 
5 half-lives, whichever is longer, prior to enrollment
2.
Prior malignancy other than CRPC.
Exception:  Subjects who have been disease-free for 5 years, or 
subjects with a history of completely resected non-melanoma skin 
cancer or successfully treated in situ carcinoma are eligible.
3.
Current use of or anticipated requirement during the study of any 
prohibited medication(s) (see Section 10.2)
4.
Any unresolved Grade 2 toxicity (per CTCAE 4.0) from previous anti-
cancer therapy at time of enrollment, except alopecia or Grade 2 anemia 
(if hemoglobin is >9.0 g/dL)
5.
Presence of any clinically significant GI abnormality or other condition(s) 
that may alter absorption such as malabsorption syndrome or major 
resection of the stomach or substantial portion of the small intestine
NOTE:  If clarification is needed as to whether a GI abnormality, 


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INCLUSION/ 
EXCLUSION
CRITERIA 
continued
condition or resection will significantly affect the absorption of study 
treatment, contact the GSK Medical Monitor.
6.
Active peptic ulcer disease or history of abdominal fistula, GI perforation, 
or intra- abdominal abscess within 28 days prior to enrollment
7.
Previous major surgery within 28 days prior to enrollment
8.
Known active infection requiring intravenous (IV) or oral anti-infective 
treatment
9.
Presence of hepatitis B surface antigen (HBsAg), positive hepatitis C 
antibody test result at time of Screening or within 3 months prior to 
enrollment
10. A positive pre-study drug/alcohol screening (testing at time of Screening 
is not required).
11. A positive test for human immunodeficiency virus (HIV) antibody (testing 
at time of Screening is not required).
12. Evidence of severe or uncontrolled systemic diseases (e.g., unstable or 
uncompensated respiratory, hepatic, renal or cardiac disease)
13. History of seizure or any condition that may predispose subject to 
seizure (e.g., prior cortical stroke or significant brain trauma).  
14. History of loss of consciousness or transient ischemic attack within 12 
months prior to enrollment
15. Has a QTc >450 msec or QTc >480 msec for subjects with bundle 
branch block (BBB)
NOTES: The QTc is the QT interval corrected for heart rate by Bazett’s 
formula (QTcB), Fridericia’s formula (QTcF), and/or another method, 
machine-read or manually over-read.
The specific formula that will be used to determine eligibility and 
discontinuation for an individual subject should be determined prior to 
initiation of the study. In other words, several different formulae cannot 
be used to calculate the QTc for an individual subject and then the 
lowest QTc value used to include or discontinue the subject from the 
trial.
For purposes of data analysis, QTcB, QTcF, another QT correction 
formula, or a composite of available values of QTc will be used as 
specified in the Reporting and Analysis Plan (RAP).
16. History or evidence of cardiovascular risk including any of the following:

Clinically significant ECG abnormalities including second degree 
(Type II) or third degree atrioventricular block

History of myocardial infarction, acute coronary syndromes (including 
unstable angina), coronary angioplasty, stenting, or bypass grafting 
within the past 6 months prior to enrollment


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INCLUSION/ 
EXCLUSION
CRITERIA 
continued

Class III or IV heart failure as defined by the NYHA functional 
classification system (Appendix 2)

Left ventricular ejection fraction (LVEF) below 50% 

Known cardiac metastases
17. Poorly controlled hypertension (defined as systolic blood pressure [SBP] 
of ≥150 mmHg or diastolic blood pressure [DBP] of >100 mmHg based 
on a mean of three measurements at approximately 2-minute intervals)
NOTE:  Initiation or adjustment of antihypertensive medication(s) is 
permitted if done 30 or more days prior to enrollment.
18. History of congenital platelet function defect (e.g., Bernard-Soulier 
syndrome, Chediak-Higashi syndrome, Glanzmann thrombasthenia, 
storage pool defect)
19. Have a known immediate or delayed hypersensitivity reaction or 
idiosyncrasy to drugs chemically related to GSK2636771or 
enzalutamide or excipients.
20. Any serious and/or unstable pre-existing medical, psychiatric disorder or 
other conditions that could interfere with subject’s safety, obtaining 
informed consent or compliance to the study procedures.
21. Exposure to more than 4 investigational medicinal products (IMPs)
within 12 months prior to enrollment
STUDY 
TREATMENT 
DOSE/ROUTE/
REGIMEN
The planned starting dose of study treatment will be GSK2636771 300 mg 
orally once daily in combination with enzalutamide 160 mg orally once daily.
Additional doses of each study treatment regimen may be explored based 
upon ongoing assessment of safety, PK or PD.
SAFETY 
ASSESSMENTS
Safety assessments will include physical examination, vital signs, ECOG 
performance status, 12-lead ECGs, echocardiogram/multigated acquisition 
scan and monitoring for AEs.
The following clinical laboratory tests will be conducted:
Hematology:  platelet count, red blood cell (RBC) count with RBC indices, 
white blood cell (WBC) count with automated WBC differential, hemoglobin, 
hematocrit and reticulocyte count.
Clinical chemistry: blood urea nitrogen, creatinine, glucose (fasting), sodium, 
potassium, chloride, carbon dioxide, calcium (serum and ionized), vitamin D, 
aspartate aminotransferase (AST), ALT, alkaline phosphatase, total protein, 
albumin, uric acid and total/direct bilirubin, phosphorus, and magnesium.
Urinalysis: specific gravity, pH, glucose, protein, blood and ketones by 
dipstick, and microscopic examination (if blood or protein is abnormal).  
Urine-protein-creatinine (UPC) will also be included if urine protein is >1+ by 


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SAFETY 
ASSESSMENTS
continued
dipstick.
Other tests:  PSA, serum testosterone, parathyroid hormone, and coagulation 
tests (prothrombin time, partial thromboplastin time and international 
normalization ratio).
PK/PD
ASSESSMENTS
PK:  In the Dose Escalation and the Dose Expansion Phase, blood and 
plasma samples for PK analysis of GSK2636771 and enzalutamide 
(including its active metabolite, N-desmethyl enzalutamide) will be collected.  
Each PK sample should be collected as close as possible to the planned 
time relative to the dose (i.e., time zero) administered to the subject on 
specified PK days.
PK Analysis:  Concentrations of GSK2636771 and enzalutamide (including 
its active metabolite, N-desmethyl enzalutamide) will be determined from 
blood and plasma samples obtained during PK sampling using currently 
approved bioanalytical methodology.  Once the blood and plasma have been 
analyzed for GSK2636771 and enzalutamide any remaining blood and 
plasma may be analyzed for other compound-related metabolites and the 
results reported under a separate GSK PTS-DMPK protocol.
Tumor size assessments, expressed as linear tumor dimensions, will be 
described as a function of time.
CLINICAL 
ACTIVITY 
ASSESSMENT
Disease assessment will be performed every 8 weeks in all subjects.  
Response will be determined according to the PCWG2 criteria (either by 
RECIST 1.1, PSA progression, and/or progression in bone).  Subjects whose 
disease responds should have a confirmatory disease assessment(s) 
performed at least 4 weeks after the date of assessment during which the 
response was first demonstrated.
Disease progression will be defined according to the definitions established 
in RECIST 1.1 for soft tissue lesions, or progression in PSA or bone lesions 
per PCWG2 criteria.
TRANSLATIONAL 
RESEARCH
Tumor tissue:  Archived tumor tissue or remaining tumor tissue from the 
sample submitted for PTEN testing will be utilized to identify potential 
predictive biomarkers (protein, DNA and RNA based markers).  If additional 
tumor tissue is not available, no new biopsy procedure is required for 
predictive biomarker analysis.  
Optional progression biopsies for subjects who have initially responded to 
the combination therapies and then progressed will also be requested.  
Genetic and protein based biomarkers will be evaluated to understand the 
mechanism of resistance/progression.


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TRANSLATIONAL 
RESEARCH 
continued
Circulating Tumor Cells (CTC):  Blood will be collected to enumerate CTCs 
in circulation.  The isolated CTCs may also be evaluated for alterations in 
AR, PTEN or other genes.  Additional blood samples will be collected to 
isolate CTCs using an EPIC Sciences platform and analyzed for RNA 
expression (e.g. AR variants), protein markers and/or potential genomic 
alterations (PTEN loss, PIK3CB mutations, AR amplifications, etc.).
Plasma Collection for Circulating-free DNA (cfDNA) and soluble marker 
analysis:  Plasma will be collected and analyzed for circulating DNA or RNA 
markers related to disease or the PI3K/Ras/Raf/AR pathway.  The samples 
may also be used to analyze soluble markers of immune response or other 
markers that may predict response.  Other biomarkers identified via 
emerging science relevant to disease or study treatments related pathways 
will also be evaluated.
STATISTICAL
METHODS
Hypothesis:  
Dose Escalation Phase: The total number of subjects to be enrolled in the 
Dose Escalation Phase is not driven by hypothesis testing. The sample 
size of 24 subjects for the Dose Escalation Phase will provide the following 
95% Clopper-Pearson confidence interval (CI) for safety events.
Safety Events
Frequency of Safety Events (95% CI)
1
4.2% (0.1% – 21.1%)
2
8.3% (1.0% - 27.0%)
3
12.5% (2.7% - 32.4%)
4
16.7% (4.7% - 37.4%)
8
33.3% (15.6% - 55.3%)
12
50.0% (29.1% - 70.9%)
16
66.7% (44.7% - 84.4%)
20
83.3% (62.6% – 95.3%)
21
87.5% (67.6% - 97.3%)
22
91.7% (73.0% - 99.0%)
23
95.8% (78.9% - 99.9%)
Abbreviation: CI, confidence interval
For the Dose Expansion Phase, clinical activity will be evaluated per dose 
level if more than one dose is examined (combing data from Dose Escalation 
Phase). A targeted PI3K pathway inhibitor (GSK2636771) added to 
enzalutamide will be tested to see if mCPRC progression can be limited in a 
clinically meaningful way for at least 12 weeks.  The null hypothesis is that 
the 12-week non-PD rate is not attractive (≤5%).  The alternative hypothesis 
is that the rate is clinically meaningful and therefore, the compound warrants 
further development (≥30%). A maximum of 20 subjects per dose level may 
be enrolled, with a minimum enrollment of 10 subjects. With an actual type I 
error rate (α) of 0.065 and 94.2% power, the design has stopping criteria 
defined for futility as follows.  


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STATISTICAL
METHODS 
continued
The trial is designed to stop early for futility if the predictive probability of 
success is less than 6%.  The type I error rate, power, and predictive 
probability of success to stop early for futility were derived from explicitly 
stating the minimum and maximum sample size, futility stopping rate, and 
selection of the optimizing criterion as the maximization of power under the 
alternative hypothesis.  The Bayesian prior probability used in determining 
the design was Beta (0.10, 0.90), a distribution with a mean response rate 
(defined as lack of disease progression at 12 weeks according to PCWG2 
criteria [either by RECIST 1.1, PSA progression, and/or progression in bone]) 
of 10%. Under the null hypothesis, if the true response rate is 5%, the 
expected sample size of the design is 13.1 subjects and probability of early 
termination (PET) is 83.0%. Under the alternative hypothesis, if the true 
response rate is 30%, the expected sample size of the design is 
19.7 subjects and PET is 4.3%.
Number of Subjects 
Enrolled
This Number of  
Responses1 to Stop Early 
for Futility
10
0
11
0
12
0
13
0
14
0
15
0
16
1
17
1
18
1
19
1
20
2
Abbreviation: PCWG2, Prostate Cancer Working Group 2
1.
Response for the purpose of futility is defined as lack of disease progression at 12 
weeks according to PCWG2 criteria. PSA progression in subjects with baseline 
radiological or bone disease will require RECIST or bone progression in addition 
to PSA progression to be determined a disease progressor. 
Study Populations:
The All Treated Safety Population is defined as all subjects who receive at 
least one dose of GSK2636771 or Enzalutamide.  Safety will be evaluated 
based on this analysis population. 
The All Treated Clinical Activity Population is defined as all subjects who 
received at least one dose of GSK2636771. Clinical activity and evaluation of 
non-PD rate will be based on this analysis population. This will include 
subjects from both dose escalation and dose expansion. 
The All Evaluable Population is defined as all subjects from All Treated 
Clinical Activity Population who have at least one post-dose disease 
assessment and have been exposed to study drug for at least 12 weeks or 
have progressed or have died or have withdrawn from the study for any 


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STATISTICAL 
METHODS 
continued
reason. Dose Expansion futility analyses will be based on this population. 
The PK Population will consist of all subjects from the All Treated 
Population for whom at least one PK sample is obtained and analyzed.
Efficacy Analyses:  The All Treated Clinical Activity Population will be used 
for the analysis of efficacy data, and will be summarized separately per dose 
level. Response data per PCWG2 and RECIST 1.1 guidelines will be 
reported.  Further details about efficacy analyses will be outlined in detail in 
the RAP.
Safety Analyses:  The All Treated Safety Population will be used for the 
analysis of safety data. All serially collected safety endpoints (e.g., laboratory 
tests, vital signs, 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.
Additional details of the statistical analysis plan will be provided in the RAP.


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1.
INTRODUCTION
1.1.
Metastatic Castration-Resistant Prostate Cancer
Prostate cancer is the most frequently diagnosed cancer among men and the second-
leading cause of cancer-related death in men [American Cancer Society, 2013].  Over the 
past decades the primary target of treatment has been focused on depleting or blocking 
androgen activity as the growth of prostate cancer is dependent on androgens.  Hormonal 
therapy has included the use of gonadotropin-releasing hormone (GnRH) analogues, 
androgen receptor (AR) antagonists, ketoconazole and estrogenic compounds.  Despite 
early sensitivity to hormonally directed therapies and while maintaining castrate levels of 
serum testosterone, these tumors often eventually progress as castration-resistant prostate 
cancer (CRPC).  Once metastatic CPRC (mCPRC) develops, the mean survival time in 
these patients is approximately 16 to 18 months [Karantanos, 2013].
The AR signaling axis frequently remains active despite castration therapy in CRPC, as is 
clinically evident by the rise in prostate-specific antigen (PSA) and hypersensitivity to 
even low levels of residual androgens, suggesting that continued treatment directed at the 
AR signaling axis may provide benefit.  Overexpression of AR is seen in over 50% of 
CRPC and is thought to be a significant contributor to progression.  Despite recent 
advances in the development of therapeutic options (e.g., abiraterone acetate, 
enzalutamide, etc.), disease progression is inevitable and is seen in the form of resistant 
tumors with PSA expression that suggests an active AR axis.
The phosphoinositide 3-kinase (PI3K)-AKT pathway is among the most commonly 
activated pathways in human cancer and is active in the majority of metastatic prostate 
cancer [Taylor, 2010; Bitting, 2013]. Activation of the PI3K-AKT pathway can occur 
due to several different aberrations: decreased expression of the inhibitory phosphatase 
and tensin homolog (PTEN), inositol polyphosphate-4-phosphatase type II (INPP4B), 
and pH and leukine-rich repeat protein phosphatase (PHLPP; a negative regulatory of 
AKT); activating mutations in the PI3K catalytic gene phosphatidylinositol-4,5-
bisphosphate 3-kinase catalytic subunit alpha (PIK3CA); and decreased expression of the 
PI3K regulatory genes phosphoinositide-3-kinase regulatory subunit 1 (PI3KR1) and 
phosphoinositide-3-kinase regulatory subunit 3 (PI3KR3) [Taylor, 2010]. Loss of PTEN 
protein is observed in 40 to 50% of mCRPC tumors.  Both PTEN loss per se and AKT 
activation regardless of mechanism have been associated with poor clinical outcome 
[Yoshimoto, 2008] and recurrence following radical prostatectomy [Ayala, 2004; 
Bedolla, 2007].
Cross-talk between AR and PI3K-AKT pathways has been observed in models of CRPC 
as evidenced by activation of AKT signalling with AR inhibition [Carver, 2011].  
Conversely, AR transcriptional activity is decreased in PTEN-deficient tumor cells and 
increased by pharmacological inhibition of PI3K-AKT pathway [Carver, 2011; Martin, 
2010].
The concurrent interruption of the AR and PI3K pathways by the combination of 
enzalutamide with GSK2636771 may provide additive benefit by limiting prostate tumor 
growth and the development or reversal of AR resistance to enzalutamide.


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1.2.
GSK2636771
GSK2636771 is a potent, orally bioavailable, adenosine triphosphate (ATP) competitive 
inhibitor of the PI3Kisoforms. It inhibits anchorage-independent growth of the majority 
of PTEN-deficient, but not PTEN wild-type tumor cell lines.  In a PTEN-negative human 
prostate cancer xenograft mouse model, treatment results in dose-dependent inhibition of 
AKT phosphorylation and stable disease or tumor growth delays.
A detailed summary of in vitro and in vivo non-clinical pharmacology studies is provided 
in the GSK2636771 Investigator Brochure (IB) [GlaxoSmithKline Document Number 
2011N117133_01].
1.2.1.
Clinical Safety, Pharmacokinetic Data, and Clinical Activity of 
GSK2636771
To date, the administration of GSK2636771 has been limited to subjects with PTEN 
deficient tumor as determined by immunohistochemistry (IHC) analysis who were 
enrolled in the first-time-in-human (FTIH) study P3B115717.  Doses of GSK2636771 
evaluated have ranged from 25 mg to 500 mg once daily.  The maximum tolerated dose 
(MTD) has been defined as 400 mg orally once daily.  Dose-limiting toxicities (DLTs) 
observed were hypophosphatemia and hypocalcemia. This study is completed and 
enrolled 65 subjects.
Dose-limiting toxicity (DLT) of hypophosphatemia was identified at 500 mg daily dose 
level, occurring in 3 of 4 subjects, and resulting in dose reductions and or 
discontinuations.  The hypophosphatemia improved upon discontinuation of 
GSK2636771.  The mechanism(s) of hypophosphatemia is under investigation.
Safety.  The most frequent adverse events (AEs) with GSK2636771 were Grade 1 or 
Grade 2 gastrointestinal (GI) toxicities, with the most frequently reported AEs being 
diarrhea (42%), nausea (40%), fatigue (30%), vomiting (30%), abdominal pain (26%), 
decreased appetite (23%), anemia (21%), constipation (17%), headache (17%), 
hypokalemia (15%), cough (13%), dyspnea (13%), edema peripheral (13%), and urinary 
tract infection (11%).
Pharmacokinetics.  Preliminary pharmacokinetic (PK) results from study P3B115717 
indicate that GSK2636771 is absorbed orally with a median time to achieve the peak 
blood concentration (Tmax) of 4 to 5 hrs after single doses of 25 to 500 mg.  The median 
half-life (t1/2) of GSK2636771 ranged from 17.1 to 38.6 hrs across the dose range of 
25 mg to 500 mg once daily.  Mean maximum observed concentration (Cmax) and area 
under the concentration-time curve from zero (pre-dose) to 24 hrs [AUC(0-24)] values on 
Day 22 were greater than the mean values observed after a single dose, demonstrating 
that GSK2636771 accumulated in plasma after repeated doses.
Clinical Activity.  There are limited data available to assess the clinical activity of 
GSK2636771.  In the FTIH study P3B115717, one subject with mCRPC who received 
200 mg GSK2636771 once daily had a partial response (PR) per Response Evaluation 
Criteria in Solid Tumors (RECIST) 1.1.  There were 20 (N=65) subjects who had stable 
disease, 8 of whom were on study for at least 6 months. Refer to the GSK2636771 IB 


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[GlaxoSmithKline Document Number 2011N117133_01] for additional details on 
available safety, PK and clinical activity data.
1.3.
Enzalutamide (Xtandi)
Testosterone and its active metabolite dihydrotestosterone (DHT) are normally ligands 
for AR.  Binding to AR causes changes in the composition and conformation, leading to 
nuclear translocation from the cytoplasmic compartment.  Once in the nucleus, the AR 
binds to androgen response elements on target genes (e.g., PSA) and leads to 
transcription of messenger ribonucleic acid (mRNA).  Traditional androgen deprivation 
therapy reduces intracellular concentrations of DHT and results in tumor regression in 
prostate cancer.  However, androgen deprivation therapy does not completely inhibit 
intratumoral androgens or the expression of AR target genes.
The AR is central to the biology of mCRPC.  The mechanisms that explain resistance to 
traditional androgen deprivation therapy include, but are not limited to, AR amplification 
or point mutations, ligand-independent activation of the AR, and alternative signalling 
pathways that no longer involve the AR.
Enzalutamide (Xtandi) is an orally bioavailable, AR signalling inhibitor approved in the 
United States (US) and the European Union for the treatment of patients with mCRPC 
[Xtandi, 2016].  Enzalutamide acts on several steps in the AR signaling pathway, 
including competitive inhibition of androgen binding to ARs and inhibition of AR 
nuclear translocation and its interaction with deoxyribonucleic acid (DNA).  A major 
metabolite, N-desmethyl enzalutamide, exhibited similar in vitro activity to enzalutamide.
Refer to to the approved US Food and Drug Administration (FDA) prescribing 
information [Xtandi, 2016] or the Xtandi Prescribing Information for the area where it is 
approved for further details.].
1.3.1.
Clinical Safety, Pharmacokinetic Data, and Clinical Activity of 
Enzalutamide
Safety.  Generally, treatment with enzalutamide has been well tolerated in subjects with 
CRPC.  Based upon the comparison of safety data from the randomized Phase III study of 
CRPC subjects treated with enzalutamide 160 mg once daily to placebo, the most 
common AEs were reported in >5% of subjects:  asthenia/fatigue, back pain, diarrhea, 
arthralgia, hot flush, peripheral edema, musculoskeletal pain, headache, upper respiratory 
infection, muscular weakness, dizziness, insomnia, lower respiratory infection, spinal 
cord compression and cauda equine syndrome, hematuria, paresthesia, anxiety, and 
hypertension.  Grade 3 or higher AEs were reported in 47% of subjects receiving 
enzalutamide compared to 53% in placebo-treated subjects.  The most common AE 
leading to discontinuation of treatment was seizure.
Seizure is a risk associated with enzalutamide treatment.  In a randomized Phase III study 
of subjects with CRPC, seizures occurred in 7 of 800 (0.9%) enzalutamide subjects 
(160 mg once daily) compared to no seizures experienced by subjects receiving placebo.  
The onset of seizures was seen 31 to 603 days from the initiation of treatment.  All 
seizures resolved with discontinuation of enzalutamide.  The safety of enzalutamide in 


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subjects with predisposing factors for seizures has not been evaluated as these subjects 
were excluded from the study.
Pharmacokinetics.  Oral absorption of enzalutamide is rapid and independent of dose 
with Cmax achieved 1 to 2 hrs post-dose.  It is 97 to 98% bound to plasma proteins, 
primarily albumin.  N-desmethyl enzalutamide is 95 to 97% bound to plasma proteins.  
Enzalutamide is metabolized by CYP3A4 and CYP2C8 to an active metabolite 
N-desmethyl enzalutamide and primarily eliminated by hepatic metabolism (CYP3A4 
and CYP2C8).  The mean t1/2 is 5.8 days in patients.  With daily administration, steady 
state is reached after approximately 30 days. In order to achieve near-steady state 
enzalutamide exposure, a 14-day run-in period has been included in the study design 
(Section 1.5.3 and Section 3).  Enzalutamide accumulates approximately 8.3-fold relative 
to a single dose with a mean peak-to-trough ratio of 1.25. A high-fat meal did not alter 
the area under the concentration-time curve (AUC) of enzalutamide or its active 
metabolite, N-desmethyl enzalutamide.
Clinical Response.  In a randomized, double-blinded, Phase III clinical trial comparing 
enzalutamide with placebo in subjects with mCRPC who had progressed following 
docetaxel-based chemotherapy, enzalutamide prolonged overall survival by 5 months 
(median survival of 18.4 months with enzalutamide [n=800] compared to 13.6 months 
with placebo [N=399])  which is statistically and clinically significant [Xtandi, 2016].  
Enzalutamide is approved in the US, Canada, the European Union and others (refer to 
Xtandi Prescribing Information in the relevant jurisdiction).  Recently, enzalutamide has 
also been shown to improve survival (32.4 months vs. 30.2 months) in chemotherapy-
naïve subjects with advanced prostate cancer in a separate Phase III, randomized, 
placebo-controlled study [Beer, 2014].
Refer to the approved US FDA prescribing information [Xtandi, 2016] or the Xtandi 
Prescribing Information for the area where it is approved for further details.
1.4.
Summary of Risk Management
The risk of administration of GSK2636771 with enzalutamide has not been assessed in 
clinical trials or in non-clinical toxicology studies.  In the placebo-controlled Phase III 
clinical trial (AFFIRM) of subjects with mCRPC who had received docetaxel therapy, 
enzalutamide was administered at a dose of 160 mg daily (N = 800) versus placebo 
(N = 399). The median duration of treatment with enzalutamide was 8.3 months while it 
was 3.0 months with placebo. Subjects were allowed, but not required, to take 
prednisone.  GSK2636771 has demonstrated activity in solid tumor cell lines.  Clinical 
efficacy data for GSK2636771 in mCRPC are not currently available.
Enrollment criteria and dose modification guidelines will be followed to minimize the 
risk of identified or potential risks.  In the event that any AEs are reported or observed, 
supportive treatment will be provided according to standard medical practice and/or as 
specified in the protocol, including dose modification if specified.
Refer to the GSK2636771 IB [GlaxoSmithKline Document Number 2011N117133_01] 
for detailed information concerning the biology, pharmacology, PK and safety.  Refer to 


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approved US FDA prescribing information [Xtandi, 2016] or the Xtandi Prescribing 
Information for the area where it is approved for additional information.
1.4.1.
Risk Assessment
The assessment of the risk of GSK2636771 combination therapy, and suggestions for 
management of risk, is based on non-clinical data and clinical data from GSK2636771 
monotherapy studies in adults.  In the event that any AEs are reported or observed, 
supportive treatment will be provided according to standard medical practice.  Subjects 
will be withdrawn from the study if a clinically significant toxicity is reported or 
observed.
1.4.1.1.
GSK2636771
Renal and electrolytes: Degenerative changes were observed in the kidneys of rats and 
dogs at 100 mg/kg/day or 1000 mg/kg/day, including cellular and tubular changes, with 
chemistry and urinalysis findings.  There have been serious, treatment-related reports of 
acute kidney injury, hypophosphatemia and hypocalcaemia in GSK2636771 clinical 
trials.  Renal events should be closely monitored.  It is recommended that patients be 
well-hydrated and avoid the use of NSAIDs.  Calcium and Vitamin D levels will be 
monitored.  Consider supplements in those with calcium levels at or near the lower 
normal limit and those with low Vitamin D levels.  Medical history will be collected and, 
physical examination and clinical laboratory tests will be measured frequently during 
therapy to monitor for potential toxicity.  Guidelines will be implemented including dose 
modification and discontinuation (Section 7.3.1) for the management of renal 
insufficiency, renal-related events or electrolyte abnormalities considered to be related to 
study treatment.  
Gastrointestinal (GI) toxicity: Data from rats receiving GSK2636771 showed 
microscopic focal erosions or ulcerations in the stomach at 1000 mg/kg/day.  Grade 3 
treatment-related nausea and vomiting and non-serious diarrhea have been observed in 
the FTIH study (P3B115717).  Eligibility criteria will exclude any subject with active 
peptic ulcer disease (see Section 4.1.3).  Medical history, physical examination and 
clinical laboratory assessments will be used to identify and assess toxicity in the GI tract.  
Supportive therapy will be provided according to standard medical practice.  Treatment 
with GSK2636771 will be withheld for any clinically significant GI toxicity.
Liver toxicity: In dogs, liver changes including minimal to mild single cell, perivascular 
hepatocellular necrosis, perivascular mixed inflammatory cell infiltrate, pigmented 
macrophages and Kupffer cells in the liver have been observed.  Individual animals with 
liver changes had associated increased in serum alanine aminotransferase (ALT) and 
aspartate aminotransferase (AST).  In the FTIH study (P3B115717), no serious (Grade 
3) treatment-related elevations in liver function tests (e.g., AST, total bilirubin) have been 
observed.  Eligibility criteria (see Section 4.1) will prevent any subject with significant 
liver dysfunction from enrolling on the study.  Liver function laboratory tests will be 
measured frequently during therapy to monitor for potential toxicity and stopping criteria 
will be implemented, including dose reduction or discontinuation for clinically significant 
toxicity.


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Rash:  Events of Grade 1 or 2 rash (no grade ≥3) have been observed in 15% of subjects 
during the dose escalation phase in the FTIH study (P3B115717).  Grade 3 rash was 
observed in 2 subjects in the ongoing expansion cohort of this study.  Both improved with 
supportive care and interruption of study treatment.  Both subjects restarted GSK2636771 
at a lower dose.  Medical history will be collected and physical exam will be conducted 
frequently during therapy to monitor for potential toxicity. Guidelines including dose 
modification and discontinuation (see Section 7.3.3) for the management of rash events 
are included in the protocol.
Cardiac effects:  Increased heart weight and marked hypertrophy of the intramural 
coronary arteries characterized by thickening of the tunica intima and media was 
observed in one male dog.  No microscopic evidence of myocardial damage was 
observed in this dog.  However, reversible increases in mean arterial pressure, decreases 
in heart rate, and cardiac contractility that appeared to be secondary to elevation in blood 
pressure (BP) were observed in a single-dose safety pharmacology study in dogs 300 
mg/kg.  In the FTIH study (P3B115717), no serious (Grade 3) cardiac events have been 
observed.  Subjects with a history of uncontrolled hypertension, heart failure, or known 
significant coronary artery disease will be excluded from studies of GSK2636771.  
Cardiac monitoring, including assessment of BP and heart rate, along with 12-lead 
electrocardiograms (ECGs) will be performed. Specific corrected QT interval (QTc) (see 
Section 7.2.1) and/or withdrawal criteria as well as guidance for the management of 
hypertension (see Section 7.3.2.1) are included in the protocol.
Hematopoietic effects:  In dogs given 1000 mg/kg/day, lymphoid necrosis was observed 
in the spleen, lymph nodes, and gut associated lymphoid tissues with no associated 
changes in peripheral white blood cell (WBC) counts.  Decreased thymus weights were 
observed in rats given 1000 mg/kg/day, with mildly increased mean total WBC, 
neutrophil, monocyte, and lymphocyte counts in female rats, likely due to GI and kidney 
inflammation.  In the FTIH study (P3B115717), no Grade 3 treatment-related 
hematopoietic changes have been observed.  Eligibility criteria (see Section 4.1) will 
exclude a subject with clinically significant, abnormal hematology laboratory parameters.  
Complete blood counts with differential will be monitored frequently to identify and 
assess hematologic toxicity.  Supportive therapy will be provided according to local 
standard medical practice.  Treatment with GSK2636771 will be withheld for a clinically 
significant toxicity.
Because of published non-clinical data indicating that p110β plays an important role in 
adenosine diphosphate (ADP)-induced platelet aggregation [Martin, 2010; Nylander, 
2012], subjects with a history of congenital platelet function defects will not be eligible.  
In addition, concomitant usage of anti-platelet agents that act at platelet purinergic 
receptors is prohibited.  Caution is recommended when GSK2636771 and aspirin are 
used concomitantly.
Reproductive effects: To reduce the risk of reproductive effects from GSK2636771 
based upon a bursal hemorrhage noted in the ovary of 3 rats (two after 4 weeks dosing 
and one following a 2-week recovery period) given 1000 mg/kg/day, specific guidelines 
and precautions for male subjects (and their female partners of childbearing potential) are 
provided in the protocol (see Section 11.1).


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1.4.1.2.
Enzalutamide
Seizure.  In the placebo-controlled Phase III clinical trial (AFFIRM) of subjects with 
mCRPC who had received docetaxel therapy, enzalutamide was administered at a dose of 
160 mg daily (N = 800) versus placebo (N = 399).  Seizure occurred in 0.9% of subjects 
receiving enzalutamide.
Caution should be used in administering enzalutamide to subjects with a history of 
seizures or other predisposing factors including, but not limited to, underlying brain 
injury, stroke, primary brain tumors or brain metastases, or alcoholism. In addition, the 
risk of seizure may be increased in subjects receiving concomitant medicinal products 
that lower the seizure threshold and therefore, subjects requiring such products should be 
excluded (Section 10.2).  Enzalutamide should be discontinued if a seizure occurs while 
on treatment.
Cardiovascular effect.  The AFFIRM study excluded subjects with recent myocardial 
infarction (within 6 months of study enrollment) or unstable angina (within 3 months of 
study enrollment), New York Heart Association (NYHA) Class III or IV heart failure 
(Appendix 2) except if left ventricular ejection fraction (LVEF) ≥45%, long QT, QT 
interval corrected by Fridericia’s formula (QTcF) >470 msec, bradycardia or 
uncontrolled hypertension. Eligibility criteria will prevent any subject with significant 
cardiovascular disease from enrolling on the study.
1.4.1.3.
Potential Overlapping Toxicities
Diarrhea:  According to the prescribing information for enzalutamide, Grade 1 to 4 
diarrhea was reported in 22% of subjects (N=800) with Grade 3 or 4 diarrhea reported 
among 1% of these subjects (versus 0.3% of placebo treated subjects).  Diarrhea is an 
observed AE with GSK2636771 monotherapy (reported in 42% of subjects overall, 
regardless of causality; Grade 2 events in 6% of subjects and Grade 1 in all others; no 
Grade 3 or 4 events), diarrhea would be considered a potential overlapping event for 
GSK2636771 in combination with enzalutamide.
Fatigue: Based upon data reported for the integrated safety population for enzalutamide, 
fatigue was reported in 40.5% (422/1043) of subjects, resulting in 0.8% (8/1043) subjects 
from discontinuing treatment with enzalutamide.  Fatigue may also be seen as an 
expected adverse effect due to androgen deficiency in this subject population.  With 
GSK2636771 monotherapy, fatigue has been reported in 30% of subjects (N=53), mostly 
Grade 1 or 2 with 4% of subjects reporting Grade 3 or higher events.  Given the potential 
of occurrence of fatigue from any of the study treatments, it is considered a potential 
overlapping event for the combination treatment of GSK2636771 with enzalutamide.
1.4.1.4.
Risk of Drug-Drug Interaction
The risk for GSK2636771 to affect enzalutamide via enzymes of CYP3A4 and CYP2C8 
is low but not fully discharged.  It is unknown if enzalutamide could potentially affect the 
exposure of GSK2636771 via UDP-glucuronosyltransferase (UGT) inhibition or
induction, while the drug-drug interaction (DDI) risk on GSK2636771 via organic 


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anionic transferase protein (OATP) transporter inhibition by enzalutamide is considered 
low due to high permeability of GSK2636771.
1.4.2.
Benefit Assessment
This is the initial clinical experience with GSK2636771 in combination with 
enzalutamide, therefore, the benefit:risk has yet to be established.  The benefit:risk should 
be favorable if the anticipated level of efficacy is demonstrated.
There is a risk of lack of efficacy with the combination as subjects entering the study will 
have progressed after receiving enzalutamide.  Such a risk may be acceptable given the 
following:

Further treatment with enzalutamide may continue to provide benefit as seen from 
the limited data suggesting some evidence of response in patients receiving 
abiraterone following abiraterone, enzalutamide following abiraterone, and from 
abiraterone following enzalutamide.  Rate of growth may still be lower with 
enzalutamide than without enzalutamide (precedent from trastuzumab beyond 
progression).  A 14-day run-in period of treatment with enzalutamide 
monotherapy will be continuous with prior enzalutamide therapy, with the 
exception of an allowed 30 day drug holiday from enzalutamide treatment, in 
order to achieve near-steady state enzalutamide exposure.

Mechanisms of resistance to enzalutamide may provide less growth activity 
relative to unrestrained AR stimulation upon withdrawal of enzalutamide

Mechanism of response may rely upon activation of the PI3K pathway and 
inhibition of the PI3K pathway while maintaining AR inhibition may be 
efficacious.
Additional considerations for subjects who participate in this study may include:

Potential benefit of receiving GSK2636771 in combination with enzalutamide 
treatment during study duration that may have clinical utility

Contribution to the process of developing a new treatment in mCRPC

Medical evaluations/assessments associated with study procedures (e.g., physical 
examinations, ECGs, clinical laboratory tests, etc.)
1.4.3.
Overall Benefit:Risk Conclusion
Taking into account the measures to be taken to minimize the risk to subjects 
participating in this study, the potential risks identified in association with GSK2636771 
in combination with enzalutamide are justified by the anticipated benefits that may be 
afforded to subjects with mCRPC.


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1.5.
Rationale
1.5.1.
Rationale for Study
Despite recent advances in the treatment of advanced prostate cancer, relapses are 
inevitable and mCRPC carries considerable morbidity along with shortened survival.  
Previous studies have indicated the importance of the PI3K pathway in prostate cancer.  
Therapeutic approaches that simultaneously inhibit both the AR and PI3K pathways may 
be more effective than inhibition of either pathway alone in mCRPC.  Enzalutamide is an 
AR inhibitor indicated for the treatment of patients with mCRPC.  This study is designed 
to investigate whether the PI3K pathway inhibitor can be co-administered safely with 
enzalutamide, thus allowing further investigation of their ability to reverse resistance to 
this AR inhibitor.  Future studies may also assess whether the combination can delay the 
onset of resistance in enzalutamide-naïve CRPC or increase the response rate to 
enzalutamide.
1.5.2.
Rationale for Study Population
A common event in prostate cancer progression is the loss of tumor suppressor PTEN in 
40 to 50% of mCRPC patients that results in the activation of the PI3K pathway.  
Subjects with PTEN-deficient tumors are selected for this study as these tumors are more 
likely to have activation of the PI3K pathway and to potentially benefit from specific 
inhibition of this pathway.  Tumors of subjects who have progressive disease following 
prior AR pathway inhibition with enzalutamide are likely to be reliant on resistance 
pathways, such as the PI3K pathway.  In addition, these two pathways (PI3K and AR) are 
believed to modulate each other.  Continued suppression of the AR pathway is a hallmark 
of treatment in mCRPC, and thus, this treatment approach is included in this study.
1.5.3.
Dose Rationale
This study will be the first clinical experience with the combination of GSK2636771 + 
enzalutamide.  Therefore this study will evaluate the safety of the combination regimen in 
order to determine its future development.  Based on current clinical experience, 
overlapping toxicities, other than diarrhea and fatigue, are not anticipated with the 
combination.  Subjects will be enrolled only if they are currently tolerating a full dose of 
enzalutamide.  Enzalutamide will be administered at the approved dose of 160 mg once 
daily and should remain fixed during treatment.
Results from a study of inhibition of PI3Kin PC-3 human prostate tumors grown 
subcutaneously in female nude mice suggest that GSK2636771 concentrations must be 
above a target level to maintain inhibition of the target enzyme.  After treatment with 
GSK2636771, inhibition of phosphorylated AKT (pAKT) occurred rapidly (within 1 hr) 
with the maximum inhibition (80%) occurring 2 hrs after administration of 10 mg/kg in 
the mice.  Doses of 25 mg to 500 mg GSK2636771 have been investigated in Study 
P3B115717. The range of blood GSK2636771 trough concentrations (C24) at steady-
state in the 200 mg once daily cohort of Study P3B115717 (2.62 – 13.4 g/mL) exceeded 
the largest Cmax observed in mice after administration of 10 mg/kg/day (1.093 g/mL).  
Therefore, preliminary PK results from Study P3B115717 demonstrate that doses of 


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200 mg or greater once daily achieved systemic exposure to GSK2636771 that resulted in 
pharmacologic effects consistent with inhibition of PI3Kin preclinical models.
Changes in phosphorylated and total protein levels of AKT, GSK3β and p70S6K in the 
platelet rich plasma (PRP) collected at various time points on Day 1 and Day 22 of 
treatment with GSK2636771 were quantified to assess the PI3K pathway inhibition.  Of 
the 23 subjects treated with 25 to 500 mg GSK2636771, the data from pre- and post-dose 
on Day 1 revealed that 19 subjects had a >50% decrease in phospho (Ser473)/total AKT 
at 2 hrs.  Thirteen of the 20 subjects treated with 100 to 500 mg GSK2636771 had >80% 
decrease in phospho (Ser473)/total AKT between pre-treatment and 1 to 10 hrs post-dose 
on Day 1.  A similar decrease in phospho-GSK3β (Ser9), an AKT substrate, was also 
observed.  These data suggest that treatment with GSK2636771 at the explored doses 
results in pathway inhibition (a surrogate to target engagement) in PRP.
A dose of 400 mg of GSK2636771 once daily was determined to be the MTD and was 
selected as the recommended Phase II dose (RP2D) for GSK2636771 monotherapy 
treatment based on safety, PK, and pharmacodynamic (PD) data from Study P3B115717.  
The proposed starting dose of GSK2636771 in the present study will be 300 mg once 
daily which is 75% of the RP2D as a single agent determined in Study P3B115717.  The 
starting dose for the present study is lower than the monotherapy RP2D to decrease the 
probability of overlapping toxicities with GSK2636771 and enzalutamide.  Preliminary 
results from Study P3B115717 indicate that 300 mg once daily of GSK2636771 will 
result in systemic exposure that resulted in effects consistent with pathway inhibition.
For enzalutamide, the approved dose of 160 mg once daily was selected.  Given the long 
t1/2 of enzalutamide, a run-in period of 14 days is included in the study design.  The 
intent of this run-in period is to achieve near-steady state plasma concentrations of 
enzalutamide prior to initiating combination therapy with GSK2636771.
1.5.4.
Endpoint Rationale
This study has been designed to fully explore the safety of the combination as this 
represents the first clinical experience for the combination.  The dose-finding cohorts are 
large enough that less common but important safety risks may be identified.  Any clinical 
efficacy seen will also be described as the population under study has great unmet need 
for active therapies, and will be assessed through the use of response criteria defined in 
the Prostate Cancer Working Group 2 (PCWG2) guidelines.
In the dose expansion phase, the cohorts are large enough to analyze the 12-week non-
progressive disease (PD) rate.
2.
OBJECTIVES AND ENDPOINTS
2.1.
Hypothesis
Primary Hypothesis:  The addition of a targeted PI3K pathway inhibitor (GSK2636771) 
to enzalutamide can be safely administered with ongoing enzalutamide treatment.


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Secondary Hypothesis:  The addition of a targeted PI3K pathway inhibitor 
(GSK2636771) to enzalutamide can limit mCPRC progression in a clinically meaningful 
way for at least 12 weeks.  The null hypothesis is that the 12-week non-PD rate is not 
attractive (≤5%).  The alternative hypothesis is that the rate is clinically meaningful and, 
therefore, the compound warrants further development (≥30%).  This hypothesis will be 
tested using a combination of data provided in both the dose escalation and dose 
expansion phases.
2.2.
Objectives and Endpoints
Objectives
Endpoints
Primary

To assess the safety and 
tolerability of GSK2636771 + 
enzalutamide administered orally 
once daily continuously in subjects 
with mCRPC.

AEs, SAEs, DLTs, and changes in laboratory 
values, ECGs, and vital signs (BP, 
temperature and heart rate)

To determine the RP2D of orally 
administered GSK2636771 + 
enzalutamide in subjects with 
mCRPC.

Safety and tolerability as assessed by AEs, 
SAEs, DLTs, and changes in laboratory 
values, ECGs, and vital signs (BP, 
temperature and heart rate)

To evaluate lack of progression in 
the dose expansion subjects with  
mCPRC by rate of subjects who 
do not progress for 12 weeks

Non-PD rate for 12 weeks according to 
PCWG2 criteria (either by RECIST 1.1, or 
progression in bone or PSA progression with 
accompanying progression by RECIST 1.1 
or bone scan when baseline radiological or 
bone disease present or PSA progression if 
no other baseline disease).
Secondary

To evaluate the clinical activity of 
oral GSK2636771 + enzalutamide 
in the treatment of mCRPC (PTEN 
deficient)

PSA50 response rate defined as the percent 
of subjects achieving PSA50 at 12 weeks or 
thereafter (PSA50 is ≥50% decrease in PSA 
from baseline)

Objective Response Rate (ORR) defined as 
complete response (CR) rate plus partial 
response (PR) rate per RECIST 1.1 

Time to PSA progression according to 
PCWG2 criteria

Time to radiological progression according to 
PCWG2 criteria (either by RECIST 1.1, PSA 
progression and/or progression in bone)

Radiological progression free survival (rPFS) 
per RECIST1.1 and/or bone scans


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Objectives
Endpoints

To determine the effect of 
GSK2636771 on enzalutamide PK 
following repeat-dose oral 
administration.

Plasma concentrations of enzalutamide and 
N-desmethyl enzalutamide.

To determine the PK of 
GSK2636771 in the presence of 
enzalutamide.

Blood GSK2636771 concentrations.
Exploratory

To determine the frequency of 
PTEN deficiency in subjects with 
mCRPC

Frequency of PTEN-deficient mCRPC 
reported in subjects based on pre-screened 
tumors

To determine the mechanism of 
PTEN deficiency

PTEN deletion, mutation or promoter 
methylation

To identify additional biomarkers 
(DNA, RNA or protein based) in 
tumor or in circulation that may 
predict response to oral 
GSK2636771 + enzalutamide 

Response prediction biomarkers based on 
analysis of DNA, RNA, and proteins from 
surrogate tissues (e.g., cfDNA) and/or tumor 
tissue

To determine the effect of 
enzalutamide with GSK2636771 
on the kinetics of tumor growth

Longitudinal tumor size measurements; 
serum PSA levels, change from baseline in 
CTCs

Evaluation of biomarkers in CTCs 
that may predict response to 
combination

AR expression, PTEN FISH and other 
genomic evaluations in CTCs

Evaluation of tumor tissue to 
explore explanation for the 
mechanism of resistance to 
combination therapy

Based on analysis of DNA, RNA and 
proteins from tumor tissue obtained at time 
of progression after initially responding to 
combination therapy

To determine pharmacodynamic 
effects of drug treatment

RNA/protein analysis of pre/post treatment 
tumor biopsies 
Abbreviations: AEs, adverse events; AR, androgen receptor; BP, blood pressure; cfDNA, circulating-free 
deoxyribonucleic acid; CTC, circulating tumor cells; DLTs, dose limiting toxicities; DNA, deoxyribonucleic acid; ECG, 
electrocardiogram; FISH, fluorescent in situ hybridization; mCRPC, metastatic castration-resistant prostate cancer; 
PCWG2, Prostate Cancer Working Group 2; PD, progressive disease; PK, pharmacokinetics; PSA, prostate-specific 
antigen; PTEN, phosphatase and tensin homolog; RECIST, Response Evaluation in Solid Tumors; RNA, ribonucleic 
acid; RP2D, recommended Phase II dose; SAE, serious adverse event(s)
3.
INVESTIGATIONAL PLAN
This is a Phase I, open-label, non-controlled, non-randomized dose finding, dose 
escalation, multicenter study to determine the RP2D of the oral PI3Kinhibitor, 
GSK2636771 in combination with enzalutamide in subjects with mCRPC.  The study 
will be conducted in two phases: the Dose Escalation Phase and the Dose Expansion 
Phase.  Each phase of the study will consist of a pre-screening period, a screening period, 


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three treatment periods (Enzalutamide Run-In Period, Combination Treatment Period and 
Treatment Continuation Period), and a post-treatment follow-up visit.
Subjects with PTEN deficient mCRPC (determined during pre-screening), who have 
documented progression per Prostate Cancer Working Group 2 (PCWG2) criteria (either 
by Response Evaluation Criteria in Solid Tumors [RECIST] 1.1, prostate-specific antigen 
[PSA] progression, and/or progression in bone), will be enrolled in the Dose Escalation 
Phase and Dose Expansion Phase of the study.  
In the Dose Escalation Phase, subjects will be enrolled into dose-finding cohorts to 
evaluate the safety and PK to guide the selection of the MTD of GSK2636771.  Dosing 
decisions will be based on all available data at the end of each DLT reporting period (the 
first 28 days of combination treatment).  Decisions for dose determination for subsequent 
cohorts will be documented and maintained by each site and in the GSK Trial Master 
Files (TMF).
In the Dose Expansion Phase, subjects will be assigned to receive GSK2636771 at doses 
identified at or below the MTD in the Dose Escalation Phase while continuing treatment 
with enzalutamide to evaluate the long-term safety of the combination as well as the 12-
week non-PD rate. This may include multiple dose levels in order to establish the RP2D 
of the combination treatment at the conclusion of combination treatment in any dose 
level. 
Safety Assessments: Throughout the study, safety will be assessed through standard 
measures, including physical examinations, vital signs, clinical laboratory tests, 12-lead 
ECGs and monitoring of AEs.  Efficacy will be assessed by physical examination,
computed tomography (CT) scan or magnetic resonance imaging (MRI), radionuclide 
bone scans, circulating tumor cells (CTC) enumeration, and PSA.  Pharmacokinetic (PK) 
blood samples will be collected from all subjects to evaluate if there is an effect of 
GSK2636771 on the PK of enzalutamide and to quantify the systemic exposure to 
GSK2636771.
Clinical Response Assessments: The determination of clinical response, including 
disease progression, will be assessed by the PCWG2 criteria (see Section 8.8.2).  The 
assessment of the 12 week non-PD-rate will also be determined by PCWG2 criteria 
(either by RECIST 1.1, PSA progression, and/or progression in bone).
Biomarker Assessments:  Planned biomarker assessments include: 1) Identify potential 
predictive biomarkers (protein, DNA, ribonucleic acid [RNA] based) in archived tumor 
tissue/pre-treatment biopsies; 2) enumeration of CTCs in circulation and evaluation of 
genetic alterations or expression of AR, PTEN or other genes in isolated CTCs; 3) 
Assessment of circulating DNA/RNA and other soluble markers in plasma to better 
understand clonal evolution and other predictive circulating biomarkers; and 4) 
understand the mechanism of resistance in tumor tissues biopsies (optional) at time of 
progression 5) assess pharmacodynamic effects by collecting pre/post treatment tumor 
biopsies
Protocol waivers or exemptions are not allowed.  Therefore, adherence to the study 
design requirements, including those specified in the Time and Events Tables 
(Section 8.1) are essential.


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Supplementary study conduct information not mandated to be present in this protocol is 
provided in the accompanying Study Reference Manual (SRM).  The SRM will provide 
the site personnel with administrative and detailed technical information that does not 
impact subject safety.
3.1.
Pre-Screening and Screening
All subjects will be required to undergo pre-screening to determine the PTEN deficiency 
status of their tumor at the GSK selected laboratory.

Pre-screening may be performed prior to confirmation of progression on 
enzalutamide 

Subjects will be required to sign a separate Pre-Screening Informed Consent 
Form (ICF) to allow for pre-screening of archived or fresh tumor biopsy 
samples

Details of the PTEN requirements are provided in SRM.
Only subjects who have completed pre-screening and who have been confirmed to have 
PTEN-deficient tumor will be eligible to enter into screening.  Subjects will be required 
to sign another Informed Consent Form (ICF) for the main study at Screening prior to 
initiation of any screening procedures or assessments.
Screening assessments will be conducted to determine subject eligibility for enrollment 
into the study.  Enrollment is defined as the first dose of enzalutamide monotherapy on 
Day 1 of the Enzalutamide Run-In Period.  The screening assessments should be 
completed within 14 days of the planned first dose of enzalutamide in the Enzalutamide 
Run-In Period, but may be shorter if all entry criteria have been evaluated and met.   
3.2.
Treatment Periods
3.2.1.
Enzalutamide Run-In Period
Subjects will be enrolled in the 14-day run-in period and receive enzalutamide 
monotherapy at the approved dose of 160 mg once daily.  The intent of the Run-in period 
is to achieve near-steady-state plasma concentrations of enzalutamide prior to initiating 
combination therapy with GSK2636771.
Subjects who experience an intolerable toxicity causing a dose interruption or dose 
reduction during the Enzalutamide Run-In Period will require approval from the GSK 
Medical Monitor in order to continue in the study.  Those subjects not eligible for 
treatment in the Combination Treatment Period will not be considered in the evaluation 
of DLTs and may be replaced.
Subjects who discontinue the study during the Enzalutamide Run-In Period will be asked 
to complete the post-treatment follow-up visit within 30 days of the last dose of 
enzalutamide.


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3.2.2.
Combination Treatment Period
Subjects who complete the Enzalutamide Run-In Period will begin oral GSK2636771 
treatment on Week 1, Day 1 of the Combination Treatment Period while continuing to 
receive enzalutamide to evaluate safety of the combination therapy.
3.2.3.
Treatment Continuation Period
Subjects will continue to receive the combination treatment of GSK2636771 + 
enzalutamide from Week 5 and thereafter will be seen in the clinic every 4 weeks.  
Subjects will continue study treatment until clinical benefit is no longer apparent (see 
Section 5.2 ), in the opinion of the treating physician, or until unacceptable AE, 
withdrawal of consent, permanent discontinuation of treatment or death.
The study will be considered completed approximately 6 months after the last subject 
begins study treatment. However, based on emerging data, the study may continue to 
collect further efficacy data if warranted.
3.2.4.
Post-Treatment Follow up
A post-treatment follow-up visit will be performed within 30 days of the last dose of 
study treatment(s) for all subject who permanently discontinue study treatments, during 
the Enzalutamide Run-In Period (and/or do not enter the Combination Treatment Period), 
or for those who permanently discontinue study treatments during the Combination 
Treatment or Treatment Continuation Period due to disease progression.  
Subjects who withdraw from the study during the Combination Treatment or Treatment 
Continuation Period without disease progression should complete the Extended 
Follow-up Visits where they will be contacted every 3 months (14 days) until disease
progression, death, withdrawal of consent, or subject is lost to follow-up.  Contact may 
include a clinic visit, a telephone contact, or an e-mail.  The initiation of any new anti-
cancer treatments and date of last contact should be documented.  Subjects who 
discontinue the Extended Follow-Up Visits for reasons other than death, loss to follow-
up, or withdrawal of consent should have a Post-Extended Follow-Up/EOS Visit 
performed.
3.3.
Discussion of Study Design
This is the first clinical experience with the combination of GSK2636771 with 
enzalutamide.  The study is designed to provide a robust evaluation of the safety for the 
combination treatment.  Additional doses and/or dosing schedules of GSK2636771 with 
enzalutamide may be explored in each of the cohorts, if necessary.
The dosing of enzalutamide will be administered at the US FDA approved dose (refer to 
the Prescribing Information for enzalutamide [Xtandi, 2016].  Study treatment will 
continue until there is no longer clinical benefit (see Section 5.2), in the opinion of the 
investigator, or until an unacceptable AE (including stopping criteria outlined in Section 
7.2), withdrawal of consent, permanent discontinuation of study treatment, or death 


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occurs.  Investigators will use the PCWG2 criteria to determine clinical response to each 
treatment.
3.4.
Dose Escalation Phase
In the Dose Escalation Phase, the dose of GSK2636771 will follow a modified 3+3 dose 
escalation procedure to evaluate the safety and PK for each combination dose level and to 
guide selection of the combination dose for dose expansion.  
A minimum of 3 subjects may be enrolled in each subsequent cohort until the MTD (see 
Section 3.4.4) is defined.  Evaluation of at least 3 subjects who have completed 28 days 
of treatment with the combination is required prior to dose escalation to the next cohort.  
Dose escalation decisions will be by the investigator(s), GSK Medical Monitor, 
pharmacokineticist, and statistician following review of all available data.  Dose 
escalation will proceed with the increment of dose increase or decrease as determined by 
toxicity rules outlined in Table 1.
Table 1
3+3 Dose Escalation Guidelines Based on Toxicity
Number of Subjects with a DLT 
Action
0 out of 3 subjects
Escalate to next dose level.
1 out of 3 subjects
Accrue 3 additional subjects at current dose level for a total 
of 6 subjects
1 out of 6 subjects
Escalate to the next dose level. 
2 or more subjects in a dosing cohort (up to 
6 subjects)
Dose-escalation will be stopped.  At this dose level, the 
MTD has been exceeded (highest dose administered).  
Either evaluate at a lower intermediate dose (3+3 dosing) or 
expand a prior cohort up to approximately 20 subjects per 
treatment arm.
Abbreviations: DLT, dose limiting toxicity; MTD, maximum tolerated dose
If the combination doses in Cohort 1 are not tolerable, lower doses will be evaluated.  If 
the de-escalation cohort (Cohort -1) is not tolerable, additional dose levels of 
GSK2636771 or alternative dosing schedules may be explored based upon ongoing 
assessment of safety, PD and PK.  Dose modification decisions will be made utilizing all 
available data at the end of each DLT reporting period (the first 28 days of combination 
treatment).
Dose escalation will proceed until the MTD of the combination regimen is identified.  If 
the dose(s) administered to a given cohort exceeds the MTD as defined in Section 3.4.4, 
intermediate doses may be explored.  Dose escalation decisions will take into account all 
available data, including the safety profile and PK data of prior cohorts throughout the 
time subjects are on study, which will be reviewed by the investigator(s), GSK Medical 
Monitor, pharmacokineticist and statistician.  The dose escalation decision for the 
subsequent cohort and rationale will be documented in writing with copies maintained in 
the site’s study files and the TMF at GSK.  In the absence of DLTs, the dose of 
GSK2636771 may be escalated to the MTD of 400 mg as determined in the FTIH study 
(P3K115717).


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If diarrhea (in the absence of aggressive diarrhea management), fatigue, or rash defines 
the MTD, the cohort in which the toxicity is observed may be expanded by at least 
3 subjects and the efficacy of supportive care evaluated prior to further dose escalation.  
If supportive care measures ameliorate the toxicity without recurrence of the toxicity, 
further dose escalation may be conducted in the presence of appropriate supportive care.
Table 2
Dose Escalation Cohorts
Cohort
N
GSK2636771
Enzalutamide
-1
3 - 6
200 mg once daily
160 mg once daily
1
3 - 6
300 mg once daily
160 mg once daily
2
3 - 6
400 mg once daily
160 mg once daily
3.4.1.
Cohort Expansion
Any cohort may be expanded up to 12 subjects in order to collect adequate data on safety, 
PD or PK.  Subjects may be enrolled at previously completed dose levels for the purpose 
of obtaining additional PK and/or PD data.
3.4.2.
Alternative Dosing Schedules
Alternative schedules may be evaluated if emerging data suggest that continuous daily 
dosing will result in excessive toxicity.  Only those alternative schedules exploring 
dosing less frequent than current dosing schedule will be evaluated.  If alternative dosing 
schedules are explored, PK sampling times will be modified to reflect the new dosing 
schedule.
3.4.3.
Definition of Dose Limiting Toxicity
The DLT criteria apply only during the Dose Escalation Phase, and impacts the decisions 
around whether the MTD has been determined, and/or decisions around whether to 
escalate or de-escalate the next dose level, but do not apply to the mandated management 
of an individual subject as with the liver stopping criteria.
Subjects who fail to receive at least 75% of the protocol-specified study treatment during 
the DLT reporting period (the first 28 days of combination treatment) for reasons 
OTHER than toxicity will be replaced if data from the replacement subject could impact 
the dose selection criteria.  
An event will be considered a DLT if the event is attributed (definitely, probably or 
possibly) to study treatment, occurs within the first 28 days of combination treatment 
(DLT reporting period), and meets one of the following criteria:

Grade 3 or greater non-hematologic toxicity that cannot be controlled with routine
supportive measures (e.g., antiemetics, antidiarrheals)

Grade 4 neutropenia lasting >5 days


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
Febrile neutropenia, of any grade or duration as defined by Common Terminology 
Criteria for Adverse Events version 4.0 (CTCAE v4.0)

Grade 4 thrombocytopenia

Alanine aminotransferase (ALT) >3 times upper limit of normal (ULN) with
bilirubin >2 times ULN or ALT ≥3 times ULN and ≥1.5 times baseline ALT 
value, if enrolled with liver metastases/tumor infiltration at baseline), together 
with bilirubin ≥2 times ULN)
Any Grade 2 or greater toxicity (per CTCAE v4.0) that occurs beyond the 28-day DLT 
reporting period which in the judgment of the investigator and GSK Medical Monitor 
would be considered dose limiting will also be considered a DLT.
Subjects who experience an intolerable toxicity causing a dose interruption or dose 
reduction during the Enzalutamide Run-In Period (before the start of GSK2636771 
combination treatment) will require approval from the GSK Medical Monitor in order to 
continue in the study.  Those subjects not eligible for the combination phase will not be 
considered in the evaluation of DLTs and may be replaced.
3.4.4.
Maximum Tolerated Dose
The MTD is defined as the highest dose at which no more than one of 6 subjects 
experience a DLT during the first 28 days of combination therapy.  The MTD will be 
exceeded if 2 or more subjects in a cohort of up to 6 subjects experience a DLT.
3.5.
Dose Expansion Phase
Enrollment in the Dose Expansion Phase of the study may begin once a suspected MTD 
has been determined in the Dose Escalation Phase. Up to 20 additional subjects per dose 
level may be enrolled to better characterize the safety profile, PK, and clinical activity of 
the recommended doses of the combination of GSK2636771 + enzalutamide for future 
studies. One or more combination doses may be explored in the Dose Expansion Phase 
based on the MTD identified in the Dose Escalation Phase of the study. To fully evaluate 
additional combination doses, up to 20 additional subjects per dose level may be enrolled. 
In the Dose Expansion Phase, final analyses will occur 6 months after the last subject is 
enrolled to allow for adequate collection of safety information.  Those subjects that have 
not completed the treatment phase of the study (see Section 5.2) at the time of the final 
analysis may be transferred to a continued access study, if available.
3.6.
Recommended Phase II Dose
The RP2D will be considered the lowest dose of GSK2636771 explored (at or below 
MTD) that provides adequate PK exposure and biologic activity with a superior 
tolerability profile. If multiple dose levels are explored in dose expansion, the RP2D will 
be based on the totality of data. 


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3.7.
Intra-subject Dose Escalation
Subjects enrolled in a lower combination cohort may be subsequently escalated to a 
higher dose combination once safety has been established and after consultation with the 
GSK Medical Monitor.
3.7.1.
Evaluation of Futility
Futility will be evaluated when there is adequate enrollment. The methodology for 
evaluation of futility is based on the predictive probability of success if enrollment 
continues to 20 subjects per dose level [Lee, 2008]. The predictive probability design is 
similar to a Green-Dahlberg design in that it allows for early stopping for futility. The 
differences are that the predictive probability design allows for evaluation of stopping 
rules after each subject, rather than at only two stages, once a minimum number of 
subjects are evaluable. In this particular study, we will stop only for futility. While the 
two designs have similar type I and type II error rates, the probability of early termination 
is greater with the predictive probability design.
After 10 subjects have been enrolled to examine safety and 12-week non-PD rate, the 
number of subjects who have not progressed in 12 weeks will guide further enrollment 
according to the rules summarized in Table 3.  The decision to terminate the Dose 
Expansion Phase will not depend solely on the results of the statistical methodology, but 
will take all factors into account. These factors include the representation of predictive 
biomarkers, such as Androgen receptors, in the subjects treated at the time of interim 
analysis; and the totality of the safety, tolerability, PK, and PD data. Additional subjects 
targeting a specific biomarker profile may be enrolled in the cohort at the discretion of 
the study team, even if the predictive probability suggests a low likelihood of clinical 
activity in this cohort.
Table 3
Stopping Rules for Predictive Probability Design
Number of Subjects 
Enrolled
This Number of  
Responses1 to Stop Early 
for Futility
10
0
11
0
12
0
13
0
14
0
15
0
16
1
17
1
18
1
19
1
20
2
Abbreviations: PCWG2, Prostate Cancer Working Group 2; PSA, prostate-
specific antigen; RECIST, Response Evaluation Criteria in Solid Tumors
1.
Response for the purpose of futility is defined as lack of disease 
progression at 12 weeks according to PCWG2 criteria. PSA 


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progression in subjects with baseline radiological or bone disease 
will require RECIST or bone progression in addition to PSA 
progression to be determined a disease progressor.
3.8.
Continued Treatment
A subject may continue study treatment until the treatment discontinuation criteria are 
met (see Section 5.2).  Additional guidelines regarding dose modifications are provided 
in Section 7.1.  
3.9.
Treatment Assignment
Each subject will be assigned a unique subject number that will remain consistent for the 
duration of the study.  This number will be assigned sequentially from a range of subject 
numbers provided for each site in the SRM.  Upon completion of all required pre-
screening and screening procedures and assessments, eligible subjects must be approved 
for enrollment by a member of the GSK central study team according to the procedures 
detailed in the SRM.
3.10.
Blinding
This is an open-labeled study.
4.
STUDY POPULATION
4.1.
Subject Selection Criteria
4.1.1.
Number of Subjects
A total of between approximately 44 and 64 subjects will be enrolled in this study.  
Dose Escalation Phase:  The number of dose levels and the level at which the MTD is 
reached cannot be determined in advance.  An adequate number of subjects will be 
enrolled to establish the recommended dose for further study.  It is estimated that 
approximately 24 subjects will be enrolled in the Dose Escalation Phase.
Dose Expansion Phase:  In the Dose Expansion Phase, it is estimated that approximately 
20 subjects will be enrolled, with evaluation for futility after the first 10 subjects have 
completed 12 weeks of treatment (see Section 3.7.1). This analysis may occur using the 
combination of the dose escalation and dose expansion population. If multiple dose levels
of GSK2636771 are examined during dose expansion to establish the RP2D, each dose 
level cohort will enrol approximately 20 subjects, increasing the overall number of 
subjects targeted for enrolment in this study.
4.1.2.
Inclusion Criteria
Specific information regarding warnings, precautions, contraindications, AEs, and other 
pertinent information on GSK2636771 or enzalutamide that may impact subject 
eligibility is provided in the IB for GSK2636771 [GlaxoSmithKline Document Number 
2011N117133_01] and the Prescribing Information for enzalutamide [Xtandi, 2016].


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Deviations from inclusion criteria are not allowed because they can potentially jeopardize 
the scientific integrity of the study, regulatory acceptability or subject safety.  Therefore, 
adherence to the criteria as specified in the protocol is essential.
To be eligible for this study, subjects must meet ALL of the following criteria:
1.
Signed written informed consent provided
NOTE: Separate ICFs must be signed prior to the pre-screening and screening 
procedures.
2.
Males 18 years of age (at the time written consent is obtained for pre-screening)
3.
Histologically or cytologically confirmed diagnosis of prostate adenocarcinoma, 
surgically castrated or continuous medical castration (for 8 weeks prior to 
Screening)
4.
Serum testosterone <50 ng/dL (1.7 nM/L)
5.
PTEN-deficient tumor as documented from archived or fresh (from pre-treatment 
biopsy) tumor tissue analyzed by a GSK selected laboratory
6.
Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
7.
Has completed at least 12 weeks of prior continuous therapy with enzalutamide
8.
Has not been without enzalutamide treatment for >30 days prior to enrollment
9.
Has documented disease progression following treatment with enzalutamide at time 
of Screening
NOTE: Disease progression is defined by one or more of the following criteria:

PSA progression defined by PCWG2 criteria (see Section 8.8.2.1), or

Soft tissue disease progression defined by RECIST 1.1 (see Appendix 4), or

Bone disease progression defined by PCWG2 criteria (see Section 8.8.2.2)
10. Able to swallow and retain orally administered medication.
11. Adequate baseline organ function at time of Screening defined as:
Hematologic
ANC
1.5 x 109/L
Hemoglobin
9 g/dL 
Platelets
100 x 109/L
PT/INR and PTT
1.3 x ULN
Hepatic
Albumin
2.5 g/dL
Total bilirubin1
1.5 x ULN
AST
ALT1
2.5 x ULN
2.5 x ULN or >2.5 x ULN but 
5 x ULN with documented liver 
metastases or tumor infiltration


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Renal
Urine Protein (via dipstick)2
0/+1
UPC3,4
<0.2
Serum Creatinine
OR
Estimated Serum Creatinine Clearance5
OR
24-hr Urine Creatinine Clearance
ULN
60 mL/min
60 mL/min
Cardiac
LVEF
50% by ECHO or MUGA
Other
Serum Phosphate
WNL
Serum Calcium6 (corrected)
Ionized Calcium6
Vitamin D6: 25-OH D and 1,25-OH2 D
WNL
WNL
WNL
Abbreviations: ANC, absolute neutrophils count; ALT, alanine aminotransferase; AST, aspartate 
aminotransferase; CTCAE, Common Terminology Criteria for Adverse Events; ECHO, echocardiogram; INR, 
international normalization ratio; LLN, lower limit of normal; LVEF, left ventricular ejection fraction; MUGA, 
multigated acquisition scan; PT, prothrombin time; PTT, partial thromboplastin time; ULN, upper limit of 
normal; UPC, urine protein to creatinine ratio; WNL, within normal limits
1.
If ALT or bilirubin values are outside range listed due to Gilbert’s syndrome or asymptomatic gallstones, 
subject remains eligible.
2.
If subject’s urine protein is >1+ (via dipstick), then UPC ratio will be calculated.  Subject will be 
considered eligible for study if UPC ratio is <0.2.
3.
UPC ratio is only to be calculated if subject’s urine protein is >1+ via dipstick.
4.
The UPC value will not be used to determine eligibility for subjects who are unable to obtain 
uncontaminated urine samples due to their disease.
5.
Estimated by the CKD-EPI equation (see Appendix 3).
6.
Vitamin D supplementation may be added to achieve values WNL.  Calcium supplements should be 
added for subjects with calcium values near the lower normal limit.
NOTE:  Laboratory results obtained during Screening should be used to determine 
eligibility criteria.  In situations where laboratory results are outside the permitted 
range, the investigator may opt to retest the subject and the subsequent within range 
screening result may be used to confirm eligibility.  
12. Male subject with a female partner of childbearing potential or pregnant must agree 
to use two acceptable methods of contraception from time of Screening until 
3 months after the last dose of study treatments (see Section 11.1).
4.1.3.
Exclusion Criteria
Deviations from exclusion criteria are not allowed because they can potentially 
jeopardize the scientific integrity of the study, regulatory acceptability or subject safety.  
Therefore, adherence to the criteria as specified in the protocol is essential.
Subjects meeting ANY of the following criteria must not be enrolled in the study:
1.
Prior treatment with:


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
Anti-cancer therapy (e.g., chemotherapy with delayed toxicity, immunotherapy, 
biologic therapy or chemoradiation) within 21 days (or within 42 days if prior 
nitrosourea or mitomycin C containing therapy) prior to enrollment and/or daily 
or weekly chemotherapy with the potential for delayed toxicity within 14 days 
prior to enrollment
Exception: Subjects may remain on luteinizing hormone releasing hormone 
(LHRH) agonists (i.e., leuprolide, goserelin, triptorelin or histrelin) and AR 
antagonists (e.g., bicalutamide, flutamide, nilutamide), except abiraterone.
Exception: Subjects must have received prior treatment with enzalutamide.

Any PI3K, AKT or mammalian target of rapamycin (mTOR) inhibitors

Investigational drug(s) (other than enzalutamide) within 30 days or 5 half-lives, 
whichever is longer, prior to enrollment
2.
Prior malignancy other than CRPC.
Exception:  Subjects who have been disease-free for 5 years, or subjects with a 
history of completely resected non-melanoma skin cancer or successfully treated in 
situ carcinoma are eligible.
3.
Current use of or anticipated requirement during the study of any prohibited 
medication(s) (see Section 10.2)
4.
Any unresolved Grade 2 toxicity (per CTCAE 4.0) from previous anti-cancer 
therapy at time of enrollment, except alopecia or Grade 2 anemia (if hemoglobin is 
>9.0 g/dL)
5.
Presence of any clinically significant GI abnormality or other condition(s) that may 
alter absorption such as malabsorption syndrome or major resection of the stomach 
or substantial portion of the small intestine
NOTE:  If clarification is needed as to whether a GI abnormality, condition or 
resection will significantly affect the absorption of study treatment, contact the GSK 
Medical Monitor.
6.
Active peptic ulcer disease or history of abdominal fistula, GI perforation, or intra-
abdominal abscess within 28 days prior to enrollment
7.
Previous major surgery within 28 days prior to enrollment
8.
Known active infection requiring intravenous (IV) or oral anti-infective treatment
9.
Presence of hepatitis B surface antigen (HBsAg), positive hepatitis C antibody test 
result at time of Screening or within 3 months prior to enrollment
10. A positive pre-study drug/alcohol screening (testing at time of Screening is not 
required).
11. A positive test for human immunodeficiency virus (HIV) antibody (testing at time of 
Screening is not required).
12. Evidence of severe or uncontrolled systemic diseases (e.g., unstable or 
uncompensated respiratory, hepatic, renal or cardiac disease)


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13. History of seizure or any condition that may predispose subject to seizure (e.g., prior 
cortical stroke or significant brain trauma).  
14. History of loss of consciousness or transient ischemic attack within 12 months prior 
to enrollment
15. Has a QTc >450 msec or QTc >480 msec for subjects with bundle branch block 
(BBB)
NOTES: The QTc is the QT interval corrected for heart rate by Bazett’s formula 
(QTcB), Fridericia’s formula (QTcF), and/or another method, machine-read or 
manually over-read.
The specific formula that will be used to determine eligibility and discontinuation for 
an individual subject should be determined prior to initiation of the study. In other 
words, several different formulae cannot be used to calculate the QTc for an 
individual subject and then the lowest QTc value used to include or discontinue the 
subject from the trial.
For purposes of data analysis, QTcB, QTcF, another QT correction formula, or a 
composite of available values of QTc will be used as specified in the Reporting and 
Analysis Plan (RAP).
16. History or evidence of cardiovascular risk including any of the following:

Clinically significant ECG abnormalities including second degree (Type II) or 
third degree atrioventricular block

History of myocardial infarction, acute coronary syndromes (including unstable 
angina), coronary angioplasty, stenting, or bypass grafting within the past 
6 months prior to enrollment

Class III or IV heart failure as defined by the NYHA functional classification 
system (Appendix 2)

Left ventricular ejection fraction (LVEF) below 50% 

Known cardiac metastases
17. Poorly controlled hypertension (defined as systolic blood pressure [SBP] of 
≥150 mmHg or diastolic blood pressure [DBP] of >100 mmHg based on a mean of 
three measurements at approximately 2-minute intervals)
NOTE:  Initiation or adjustment of antihypertensive medication(s) is permitted if 
done 30 or more days prior to enrollment.
18. History of congenital platelet function defect (e.g., Bernard-Soulier syndrome, 
Chediak-Higashi syndrome, Glanzmann thrombasthenia, storage pool defect)
19. Have a known immediate or delayed hypersensitivity reaction or idiosyncrasy to 
drugs chemically related to GSK2636771or enzalutamide or excipients.
20. Any serious and/or unstable pre-existing medical, psychiatric disorder or other 
conditions that could interfere with subject’s safety, obtaining informed consent or 
compliance to the study procedures.


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21. Exposure to more than 4 investigational medicinal products (IMPs) within 12 months 
prior to enrollment
5.
COMPLETION OR WITHDRAWAL OF SUBJECTS
5.1.
Screen Failures
A subject will be considered a screen failure if:

subject signs the pre-screening ICF but does not complete pre-screening, or

subject completes the pre-screening, signs the screening ICF but does not 
complete screening or does not meet the eligibility criteria for enrollment, or

subject is withdrawn from the study before receiving any study treatment
Minimal core data for screen failures will be collected from source documentation at the 
site, entered into the electronic case report forms (eCRFs), and transmitted to GSK.  The 
minimal core data includes the following:

Reason(s) for screen failure

Demography

Eligibility

SAE (if applicable)
5.2.
Permanent Discontinuation of Study Treatment(s)
Study treatment(s) will be permanently discontinued for any of the following reasons:

Disease progression defined with regards to termination of study treatment 
as: Radiographic progression in soft tissue or bone by RECIST 1.1 for 
subjects with measurable disease, OR

Bone progression on bone scan according to the PCWG2 criteria (Section 
8.8.2.2), OR

When it is determined in the opinion of the treating physician in collaboration 
with the subject that the subject is no longer clinically benefitting (NLCB) 
from treatment.
NOTE: Subjects who are tolerating therapy and meet criteria for disease 
progression solely on the basis of rising PSA or for the worsening of an isolated 
disease site that is not clinically significant will NOT be required to discontinue 
treatment and can continue treatment until they are NLCB from treatment 
[Scher, 2016].
NOTE:  Subjects must meet the PCWG2 guidelines for disease progression 
to avoid premature discontinuation of study treatment(s).

Unacceptable toxicity (including meeting liver chemistry stopping criteria as 
defined in Section 7.2)


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NOTE: If the subject voluntarily discontinues from treatment due to toxicity, 
‘adverse event’ will be recorded as the primary reason for permanently 
discontinuation on the eCRF.

Substantial protocol deviation(s)

Death 

Investigator’s discretion

Lost to follow-up

Intercurrent illness that prevents further administration of study treatment(s)

Withdrawal of consent by subject or proxy for further treatment and/or data 
collection

If subject withdraws consent for further treatment, the subject should return 
for Post-Treatment Follow-up Visit as indicated in the Time and Events 
Tables (Section 8.1).

If subject withdraws consent for further treatment and data collection, then no 
additional study visits, including a post-treatment follow-up visit, or data 
collection should occur.  All samples collected for the biomarker analysis at 
the time of withdrawal will proceed for analysis to meet the intended 
objectives defined in this protocol, unless consent for further analyses is 
withdrawn by the subject.

Study closure or termination
If study treatment(s) is/are permanently discontinued, the subject will not be allowed to 
be retreated.  The primary reason for permanently discontinuing study treatment(s) must 
be documented in the subject’s medical records and eCRF.
All subjects who have study treatment(s) permanently discontinued will have safety 
assessments at the time of discontinuation and during post-study treatment follow-up as 
specified in Time and Events Tables (Section 8.1).
Treatment Discontinuation without Disease Progression: All subjects who permanently 
discontinue study treatment(s) without disease progression should be followed for 
progression according to the protocol schedule until:

A new anti-cancer therapy is initiated, or

Disease progression occurs, or

Death
5.3.
Subject Completion
A subject will be considered to have completed the study if the subject dies or otherwise 
progresses during the study treatment or post-treatment follow-up period. All other 
subjects will be considered to have withdrawn from the study.


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5.4.
Study Completion
The study will be considered completed, having met the study objectives, approximately 
6 months after the last subject begins study treatment. However, based on emerging data, 
the study may continue to collect further efficacy data if warranted.  Per the European 
Union Clinical Trial Directive, the end of the study is defined as the last subject’s last 
visit.
5.5.
Treatment after the End of the Study
The investigator is responsible for ensuring that consideration has been given for the 
post-study care of the subject’s medical condition whether or not GSK is providing 
specific post-study treatment.  For this study, post-study treatment will not be provided.
Upon discontinuation from the assigned study treatment, subject should complete the 
required withdrawal and follow-up evaluations prior to transitioning to a rollover study if 
one is available, initiating further anti-cancer therapy or treatment with any 
investigational agent.
Refer to the Time and Events Tables (Section 8.1) for follow-up assessments and 
procedures.
6.
INVESTIGATIONAL PRODUCT
The term ‘study treatment’ is used throughout the protocol to describe any combination 
of investigational products (IP) received by the subject as per the protocol design.  Study 
treatment may therefore refer to the individual study treatments or the combination of 
those study treatments.
A description of each IP is provided in the following sections.
6.1.
GSK2636771 GSK Investigational Product
GSK2636771 will be provided to sites by GSK.  
The contents of the label will be in accordance with all applicable regulatory and/or legal 
requirements.
Product name:
GSK2636771
Formulation description:
Each 100 mg capsule contains GSK2636771B (tromethamine, tris salt) 
equivalent to 100 mg of GSK2636771A 
Shell composition: gelatin, red iron oxide (E172) and titanium dioxide 
(E171)
Dosage form:
Capsule (gelatin)
Unit dose strength(s):
100 mg
Physical description:
100 mg: Pink, size 0 hard gelatin capsule
Route/Frequency/Duration:
Oral/once daily/continuous until treatment withdrawal
Dosing Instructions:
See Section 6.3.1 for dosing instructions.


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6.2.
Enzalutamide Non-GSK Product
Initially, in countries where it is approved (i.e., US), sites will need to obtain 
enzalutamide (Xtandi) from local commercial stock in order to provide enrolled subjects 
with an adequate supply of enzalutamide while on study. 
In countries where regulatory authorities mandate that the Sponsor must supply all study 
treatment(s) required for study participation, GSK will provide an adequate supply of 
enzalutamide (from commercial stock) directly to the site for enrolled subjects.  
Enzalutamide will be provided to subjects at no cost to begin taking enzalutamide on the 
first day (Day 1) of the Enzalutamide Run-In Period and throughout their participation in 
the study.  If a subject does not qualify for entry into the study based on the tests or 
assessments performed during pre-screening and screening, then enzalutamide will not be 
provided to them.
The sourcing of enzalutamide from commercial stock will continue until which time 
(estimate within the first quarter of 2015) GSK will begin supplying all sites with an 
adequate inventory of commercial US sourced enzalutamide; an appropriate amendment 
will be made to the Quality section of the Investigational New Drug (IND) and Clinical 
Trials Application (CTA).
The contents of the label will be in accordance with all applicable regulatory 
requirements.
Product name:
Enzalutamide (Xtandi)
Formulation description:
Each capsule contains fill solution: enzalutamide, caprylocaproyl 
macrogolglycerides, butylhydroxyanisole, and butylhydroxytoluene
Dosage form:
Capsule (soft gelatin)
Unit dose strength(s):
40 mg 
Physical description:
White to off-white oblong liquid filled soft gelatin capsule imprinted in 
black ink with ENZ
Route/Administration/
Duration:
Oral/once daily, within 5 minutes of GSK2636771 administration/ 
continuous until treatment withdrawal
Dosing Instructions:
See Section 6.3.2 for dosing instructions.
6.3.
Administration of Study Treatments
Dosing Time: Subjects will be instructed to take their doses of study treatment 
(GSK2636771 and enzalutamide) at the same time each day if possible (24 hr intervals).  
Morning dosing is required until the last serial PK blood and plasma sample are obtained 
on Day 29 of Week 5 (Treatment Continuation Period).  Once the last serial PK sample is 
obtained, dosing of study treatments can occur anytime during the day.  For subjects who 
wish to switch to evening dosing, the subject is to delay their next doses of study 
treatments by 12 hrs.  


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Dosing at Home: On days when subjects do not have a scheduled study visit in the clinic 
subjects will be instructed to self-administer their doses of study treatments at home 
under fasted conditions, at least 1 hr before or 2 hrs after a meal.
Dosing during the Enzalutamide Run-In Period (Days 1-14): Enzalutamide is the only 
study treatment taken during the Run-In Period. The intent of this Enzalutamide Run-In 
Period is to achieve near-steady state plasma concentrations of enzalutamide prior to 
initiating combination therapy with GSK2636771.  Subjects should be instructed to take 
their once daily dose of enzalutamide every morning at the same time each day if 
possible (24-hr intervals) during the Enzalutamide Run-In Period. Specific instructions 
for the administration of enzalutamide on Day 14 of the Enzalutamide Run-In Period are 
provided in the Dosing on PK Sampling Days during the Dose Escalation Phase section 
below.
Dosing on Scheduled Study Visit Days: Most of the scheduled study visit days during 
the first 5 weeks of combination treatment will require a pre-dose blood, plasma, and/or 
urine sample for analysis of PK, CTC, and/or urine electrolytes. On Day 1 of Weeks 8 
and 12 during the Treatment Continuation Period, pre-dose blood and plasma samples for 
analysis of PK are required. On Day 1 of Week 8 and every 8 weeks thereafter during the 
Treatment Continuation Period, pre-dose blood and urine samples for analysis of CTC 
(through Week 32 only) and urine electrolytes are also required. Subjects should be 
instructed to withhold their doses of study treatments on mornings of these scheduled 
study visits as follows:
Dosing on PK Sampling Days during the Dose Escalation Phase: 

Day 14 (Enzalutamide Run-In Period); the day prior to administration of the 
first dose of GSK2636771):  Subjects will fast overnight (at least 8 hrs) and 
remain fasting the morning of this study visit.  Subjects will be instructed to 
withhold their dose of enzalutamide on the morning of this study visit.  After the 
pre-dose PK plasma sample is drawn, subjects will be administered their doses of 
enzalutamide in the clinic and will to continue fasting for an additional 2 hrs.  

Day 29, Week 5 (Treatment Continuation Period): Subjects will fast overnight 
(at least 8 hrs) and remain fasting the morning of this study visit.  Subjects will be 
instructed to withhold their doses of study treatment on the morning of this study 
visit.  After the pre-dose PK blood and plasma samples are drawn, subjects will be 
administered their doses of study treatments in the clinic and will continue fasting 
for an additional 2 hrs. 

Weeks 8 and 12 (Treatment Continuation Period): Subjects will be instructed 
to withhold their doses of study treatment prior to these study visits. After the pre-
dose PK blood and plasma samples are drawn, subjects will be administered their 
doses of study treatments in the clinic under fasted conditions, at least 1 hr before 
or 2 hrs after a meal (an overnight fast is not required).
Dosing on PK Sampling Days during the Dose Expansion Phase:  

Day 29, Week 5 (Treatment Continuation Period) :  


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o
Subjects scheduled for a morning clinic visit will be instructed to withhold 
the doses of study treatments prior to this study visit.  After the pre-dose 
PK blood and plasma samples are drawn, subjects will be administered 
their doses of study treatments in the clinic under fasted conditions, at 
least 1 hr before or 2 hrs after a meal (an overnight fast is not required). 
o
Subjects scheduled for an afternoon clinic visit will be instructed to take 
their doses of study treatments at the usual time on the morning of this 
study visit, at least 1 hr before or 2 hrs after a meal (an overnight fast is 
not required).  

Weeks 8 and 12 (Treatment Continuation Period): Subjects will be instructed 
to withhold the doses of study treatment prior to the study visit during Weeks 8 
and 12. Subjects will have their doses of study treatments administered in the 
clinic after the pre-dose blood draw is completed and under fasted conditions, at 
least 1 hr before or 2 hrs after a meal.
Dosing on CTC and Urine Electrolyte Sampling Days:  Subjects will be instructed to 
withhold their doses of study treatments on the morning of study visits when a blood or 
urine sample is to be obtained for analysis of CTCs and/or urine electrolytes, 
respectively.  After the pre-dose blood sample is drawn and/or the pre-dose urine sample 
is collected, subjects will have their doses of study treatments administered in the clinic, 
at least 1 hr before or 2 hrs after a meal (an overnight fast is not required).
Vomiting: If a subject vomits after taking study treatment(s), the subject should be 
instructed NOT to retake the dose and should take the next scheduled dose of study 
treatment(s).  If vomiting persists, the subject should contact the investigator.
Missed Doses: If subject misses a dose of study treatment(s), the subject should be 
instructed to take the missed dose as soon as they realize it was missed, but not take the 
missed dose if there are less than 12 hrs until the next dose.  The missed dose should be 
recorded in the subject diary for either GSK2636771 or enzalutamide and in the eCRF.
Capsules: GSK2636771 and enzalutamide capsules should be swallowed whole and not 
chewed, opened, or dissolved.
6.3.1.
GSK2636771
For this study, the starting dose of GSK2636771 is 300 mg taken orally once daily.  
GSK2636771 is to be administered within 5 minutes prior to enzalutamide and under 
fasted conditions, either 1 hr before or 2 hrs after a meal and with approximately 200 mL 
of water (unless otherwise instructed in Section 6.3.1 for study visit days when PK, CTC, 
or urine electrolyte sampling is required). 
Subjects shall abstain from ingestion of any food or drink containing grapefruit and 
grapefruit juice, Seville oranges or pomelos within 7 days prior to the first dose of 
GSK2636771 (Week 1, Day 1 of Combination Treatment Period) until the last dose of 
study treatment.


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6.3.2.
Enzalutamide
Per the product prescribing information for enzalutamide [Xtandi, 2016], the 
recommended dose of enzalutamide 160 mg (four 40 mg capsules) taken orally once 
daily will be administered during this study.  
Enzalutamide may be taken with or without food on each day of the Enzalutamide Run-In 
Period (Days 1-13).  Specific instructions for the administration of enzalutamide on 
Day 14 of Enzalutamide Run-In Period may be found in Section 6.3.2.  Once 
combination therapy (GSK2636771 + enzalutamide) begins on Week 1, Day 1 of the 
Combination Treatment Period of both the Dose Escalation Phase and the Dose 
Expansion Phase, enzalutamide is to be administered within 5 minutes after the 
administration of GSK2636771 and under fasted conditions, either 1 hr before or 2 hrs 
after a meal (unless otherwise instructed in Section 6.3.2 for study visit days when PK, 
CTC, or urine electrolyte sampling is required). 
6.4.
Handling and Storage of Study Treatments
Handling: Under normal conditions of handling and administration, the study treatments 
are not expected to pose significant safety risks to site staff.  Material Safety Data Sheets 
(MSDS) for GSK2636771 and enzalutamide describing the occupational hazards and 
recommended handling precautions will be provided to site staff within the SRM.
Adequate precautions must be taken to avoid direct contact with the investigational 
product.  In the case of unintentional occupational exposure notify the study monitor, the 
GSK Medical Monitor and/or the study manager.
Storage: All study treatments (GSK2636771 and enzalutamide) must be stored in a 
secure area under the following conditions for each product:  

GSK2636771:  Store under appropriate physical conditions for the product as 
stated on the label.  Refer to the SRM regarding temperature excursions.

Enzalutamide (Xtandi):  Store under appropriate physical conditions for the 
product as stated on the label. Refer to the SRM regarding temperature 
excursions.
Access to and administration of study treatments will be limited to the investigator and 
authorized site staff.  Study treatments must be dispensed or administered only to subjects 
who qualify for entry in this study and in accordance with the protocol.  Subjects should 
be reminded that all study treatments should be stored at home out of the reach of 
children.
6.5.
Product Accountability
In accordance with local regulatory requirements, the investigator, designated site staff, 
or head of the medical institution (where applicable) must document the amount of 
investigational product dispensed and/or administered to study subjects, the amount 


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returned by study subjects, and the amount received from and returned to GSK, when 
applicable. Product accountability records must be maintained throughout the course of 
the study. Refer to the SRM for further detailed instructions on product accountability.
6.6.
Treatment Compliance
Compliance with study treatments will be assessed through querying the subject during 
the site visits and documented in the source documents and eCRF.
A record of the number of GSK2636771 capsules and enzalutamide capsules dispensed to 
and taken by each subject must be maintained and reconciled with study treatment and 
compliance records.  Treatment start and stop dates including dates for treatment delays 
and/or dose reductions will also be recorded in the eCRF.
6.7.
Treatment of Study Treatment Overdose
In the event of a GSK2636771 or enzalutamide overdose (defined as administration of 
more than the protocol-specified dose), the investigator should contact the GSK Medical 
Monitor immediately and closely monitor the subject for AEs/SAEs and laboratory 
abnormalities.
Subjects suspected of overdose should be monitored at least until through five t1/2 of 
each study treatment, and resolution of all AEs and laboratory abnormalities suspected to 
be related to study treatment.
In the case of treatment overdose, decisions regarding dose interruptions or modifications 
will be made by the investigator in consultation with the GSK Medical Monitor.
A plasma or blood sample for PK analysis of one or more study treatments may be 
requested by the GSK Medical Monitor on a case-by-case basis.  This plasma or blood 
sample should be collected as soon as possible, but within 7 days from the date of the last 
dose of study treatment (or suspected overdose).
Information regarding the suspected overdose administered should be documented in the 
eCRF.
7.
DOSE MODIFICATIONS, STOPPING CRITERIA AND 
MANAGEMENT GUIDELINES
The following dose modifications, stopping criteria, and management guidelines for 
specific events associated with GSK2636771 are provided as guidance and should not act 
as a replacement for sound clinical judgment.  The investigator should use clinical 
judgment to determine which study treatment may be contributing to the toxicity 
necessitating dose adjustment, and make the appropriate change for that agent.  The 
severity of AEs will be graded utilizing the CTCAE v4.0.  
If a given toxicity is considered to be related to one specific study treatment by the 
investigator but not both, then dose modification should only occur with the study 
treatment associated with the specific toxicity or event of clinical concern.


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7.1.
Dose Modifications
7.1.1.
GSK2636771
Dose modification guidelines for GSK2636771 are outlined in Table 4 for clinically 
significant toxicities that are deemed related to study treatment but are not addressed 
specifically in Section 7.3.  
Dose re-escalation of GSK2636771 may be considered for some subjects who are clearly 
benefiting from treatment but must be discussed and agreed with the GSK Medical 
Monitor.
Table 4
Dose Modification for GSK2636771
Toxicity Grade
Dose Modification of GSK2636771
Grade 1
Continue at current dose level.  Consider supportive care.
Grade 2
Consider withholding dose until toxicity resolves to Grade 1 or baseline.  Upon 
resolution, then restart at current dose level.  Consider supportive care.
Grade 3
Withhold dose until toxicity resolves to Grade 1 or baseline.  Upon resolution, 
then consider dose reducing by next lower dose level. Consider supportive 
care. 
Grade 4
Permanently discontinue study treatment.
GSK2636771:  The dose of GSK2636771 should be adjusted in increments of 100 mg.  
Table 5 below illustrates an example using the starting dose of 300 mg once daily.
Table 5
Dose Levels for GSK2636771
Dose Level
GSK2636771 Dose (mg)
Starting dose
300
Dose Level -1
200
Dose Level -2
100
7.1.2.
Enzalutamide
If a subject experiences a Grade 3 or greater toxicity or an intolerable side effect, 
treatment with enzalutamide should be held for 7 days or until the event resolves to 
Grade 2 or less.  Then, treatment with enzalutamide may be resumed at the same dose 
level (160 mg [4 capsules]) or at a reduced dose of 120 mg (3 capsules) or 80 mg 
(2 capsules) or per local prescribing information, if warranted.


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7.2.
Stopping Criteria
7.2.1.
QTc Stopping Criteria

QTc >500 msec 
OR

Change from baseline of QTc >60 msec
For subjects with underlying BBB, follow the discontinuation criteria listed below:
Baseline QTc with BBB
Discontinuation QTc with BBB
<450 msec
>500 msec
450 – 480 msec
≥530 msec
7.2.2.
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 US FDA 
premarketing clinical liver safety guidance).  
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM174090.pdf.
7.2.2.1.
Liver Chemistry Stopping and Increased Monitoring Algorithm for 
Subjects WITH entry criteria ALT ≤2.5xULN


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Table 6
Liver Chemistry Stopping Criteria – Liver Stopping Event for 
Subjects WITH Entry Criteria ALT ≤2.5xULN
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
Abbreviations: ALT, alanine aminotransferase; INR, international normalization ratio; SAE, serious adverse event; 
ULN, upper limit of normal
1.
Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin fractionation is not 
immediately available, discontinue study treatment for that subject if ALT 3xULN and bilirubin 2xULN. 
Additionally, if serum bilirubin fractionation testing is unavailable, record presence of detectable urinary bilirubin on 
dipstick, indicating direct bilirubin elevations and suggesting liver injury.
2.
All events of ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin) or ALT 3xULN and INR>1.5, if INR 
measured which may indicate severe liver injury (possible ‘Hy’s Law’), must be reported as an SAE (excluding 
studies of hepatic impairment or cirrhosis); INR measurement is not required and the threshold value stated will 
not apply to subjects receiving anticoagulants.
3.
New or worsening symptoms believed to be related to liver injury (such as fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, or jaundice) or believed to be related to hypersensitivity (such as fever, rash or 
eosinophilia).


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7.2.2.2.
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


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Table 7
Liver Chemistry Stopping Criteria – Liver Stopping Event for 
Subjects with Documented Liver Metastases/Tumor Infiltration at 
Baseline AND Entry Criteria ALT>2.5xULN but ≤5xULN
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
Abbreviations: ALT, alanine aminotransferase; INR, international normalization ratio; SAE, serious adverse event; 
ULN, upper limit of normal
1.
Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin fractionation is not 
immediately available, discontinue study treatment for that subject if ALT 3xULN and bilirubin 2xULN. 
Additionally, if serum bilirubin fractionation testing is unavailable, record presence of detectable urinary 
bilirubin on dipstick, indicating direct bilirubin elevations and suggesting liver injury.
2.
All events of ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin) or ALT 3xULN and INR>1.5, if INR 
measured which may indicate severe liver injury (possible ‘Hy’s Law’), must be reported as an SAE (excluding 
studies of hepatic impairment or cirrhosis); INR measurement is not required and the threshold value stated 
will not apply to subjects receiving anticoagulants.
3.
New or worsening symptoms believed to be related to liver injury (such as fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, or jaundice) or believed to be related to hypersensitivity (such as fever, rash or 
eosinophilia).
7.2.2.3.
Liver Safety Required Actions and Follow-up
Table 8
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 hrs

Complete the liver event eCRF and complete 
an SAE data collection tool if the event also 
meets the criteria for an SAE2

Perform liver event follow-up assessments 

Monitor the subject until liver chemistries
resolve, stabilize, or return to within baseline 
(see MONITORING below)

Do not restart/rechallenge subject with 
study treatment unless allowed per protocol 

Viral hepatitis serology1

Only in those with underlying chronic hepatitis B at 
study entry (identified by positive hepatitis B 
surface antigen) quantitative hepatitis B DNA and 
hepatitis delta antibody3

Blood sample for PK analysis, obtained 24-72 hrs
after last dose4

Serum creatine phosphokinase and lactate 
dehydrogenase.

Fractionate bilirubin, if total bilirubin 2xULN


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Actions
Follow-Up Assessments
and GSK Medical Governance approval is 
granted (refer to Appendix 6)

If restart/rechallenge not allowed per 
protocol or 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 and 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

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 eCRF

Record use of concomitant medications on the 
concomitant medications eCRF including 
acetaminophen, herbal remedies, other OTC 
medications

Record alcohol use on the liver event alcohol 
intake eCRF
For bilirubin or INR criteria:

Anti-nuclear antibody, anti-smooth muscle 
antibody, Type 1 anti-liver kidney microsomal 
antibodies, and quantitative total IgG or gamma 
globulins.

Serum acetaminophen adduct HPLC assay 
(quantifies potential acetaminophen contribution to 
liver injury in subjects with definite or likely 
acetaminophen use in the preceding week 
[James, 2009]).

Liver imaging (ultrasound, MRI or CT) and /or liver 
biopsy to evaluate liver disease; complete Liver 
Imaging and/or Liver Biopsy eCRFs
Abbreviations: AE, adverse event; ALT, alanine aminotransferase; AST, aspartate aminotransferase; CT, computed 
tomography; DNA, deoxyribonucleic acid; eCRF, electronic case report form; GSK, GlaxoSmithKline; HPLC, high 
performance liquid chromatography; hrs, hours; IgG/IgM, immunoglobulin G or M; INR, international normalization 
ratio; MRI, magnetic resonance imaging; OTC, over-the-counter; PCR, polymerase chain reaction; PK, 
pharmacokinetic; RNA, ribonucleic acid; SAE, serious adverse event; SRM, Study Reference Manual; ULN, upper 
limit of normal
1.
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
2.
All events of ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin) or ALT 3xULN and INR>1.5, if INR 
measured which may indicate severe liver injury (possible ‘Hy’s Law’), must be reported as an SAE (excluding 
studies of hepatic impairment or cirrhosis); INR measurement is not required and the threshold value stated 
will not apply to subjects receiving anticoagulants
3.
If hepatitis delta antibody assay cannot be performed, it can be replaced with a PCR of hepatitis D RNA virus 
(where needed) [Le Gal, 2005].
4.
Record the date/time of the PK blood sample draw and the date/time of the last dose of study treatment prior to 
blood sample draw on the eCRF. If the date or time of the last dose is unclear, provide the subject’s best 
approximation. If the date/time of the last dose cannot be approximated OR a PK sample cannot be collected in 
the time period indicated above, do not obtain a PK sample. Instructions for sample handling and shipping are in 
the SRM.


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Table 9
Liver Chemistry Increased Monitoring Criteria with Continued 
Therapy
Criteria
Actions
Subject with entry criteria ALT≤2.5xULN
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>2.5xULN but ≤5xULN
ALT ≥3xULN and 1.5x baseline value but ALT 
<5xULN and 2x baseline value and bilirubin 
<2xULN, without symptoms believed to be 
related to liver injury, or hypersensitivity and
who can be monitored weekly for 4 weeks

Notify the GSK Medical Monitor within 24 hrs 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, stabilize or return to 
within baseline 

If at any time subject meets the liver chemistry 
stopping criteria, proceed as described above
For subjects with entry criteria ALT≤2.5xULN

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>2.5xULN but ≤5xULN

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
Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; GSK, GlaxoSmithKline; hrs, hours; 
ULN, upper limit of normal
Refer to Appendix 6 for liver safety drug restart or rechallenge guidelines.
7.2.3.
Left Ventricular Ejection Fraction (LVEF) Stopping Criteria
Echocardiography (or multigated acquisition [MUGA] scan) must be performed at 
Screening and as clinically indicated as outlined in the Time and Events Tables 
(Section 8.1).  Subjects who have an absolute decrease of >10% in LVEF compared with 
baseline and the ejection fraction is below the institution’s lower limit of normal (LLN) 
should temporarily discontinue treatment with GSK2636771 and have a repeat evaluation 
of LVEF within 1 week.  Echocardiogram (ECHO) or MUGA should be repeated every 
1 to 2 weeks for 4 weeks or until LVEF recovery to above institutional LLN and within 
10% of baseline.

If the LVEF recovers (defined as LLN and absolute decrease 10% compared 
with baseline) at any time during the next 4 weeks, after consultation and 
approval of the GSK Medical Monitor, the subject may be restarted on 
GSK2636771 at a reduced dose.  For such subjects, monitoring of LVEF will be 


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performed 2 and 4 weeks after re-challenge, and every 4 weeks thereafter for a 
total of 16 weeks and then per protocol.

If repeat LVEF does not recover within 4 weeks, treatment with GSK2636771 
should be permanently discontinued.  Ejection fraction should be monitored 
every 4 weeks for a total of 16 weeks or until resolution.
Subjects with Grade 3 or 4 (symptomatic) left ventricular systolic dysfunction must 
discontinue treatment with GSK2636771.  Ejection fraction should be monitored every 
4 weeks for a total of 16 weeks or until resolution.  If recovery occurs (LVEF 
>institutional LLN and symptom resolution) within 4 weeks, treatment with 
GSK2636771 may be restarted at a reduce dose in consultation with the GSK Medical 
Monitor.
Copies of all ECHOs (or MUGA 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 ECHOs (or MUGA scans) are provided in the SRM.
7.2.4.
Valvular Toxicity Stopping Criteria
Subjects who have a new asymptomatic, moderate regurgitation or stenosis by ECHO or 
MUGA scan (Grade 2 mitral/tricuspid/aortic valvular toxicity per CTCAE v4.0 should 
temporarily discontinue treatment with GSK2636771 and have a repeat evaluation by 
ECHO within 1 week.  An ECHO (or MUGA scan) 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 GSK Medical Monitor, the subject may be 
restarted on GSK2636771 at a reduced dose(s).  For such subjects, monitoring of 
the valve via ECHO (or MUGA scan) will then be performed 2 and 4 weeks 
after re-challenge, and every 4 weeks thereafter for 8 weeks and then per 
protocol.

If repeat ECHO (or MUGA scan) does not reveal valve recovery to baseline 
within 4 weeks, then the subject should permanently discontinue GSK2636771.  
The valve should continue to be monitored via ECHO (or MUGA scan) every 
4 weeks for 8 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 
GSK2636771.  Valvular toxicity should continue to be monitored every 4 weeks for 
8 weeks or until resolution.  If recovery occurs (return to baseline via imaging AND 
symptom resolution) within 4 weeks, the subject may restart GSK2636771 at a reduced 
dose after consultation and approval of the GSK Medical Monitor.
Copies of all ECHO(s) (or MUGA scan) and cardiology consultations performed on 
subjects who experience valvular toxicity will be required by GSK for review.  
Instructions for submitting qualifying ECHOs (or MUGA scans) are provided in the 
SRM.


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7.3.
Management Guidelines for Specific Events Associated with 
GSK2636771
If a subject experiences an AE during the Enzalutamide Run-In Period resulting in a dose 
interruption that precludes the subject from completing the run-in period within 14 days
or a dose reduction, the GSK Medical Monitor should be contacted as approval will be 
required in order for the subject to continue in the study (refer to the SRM).  
7.3.1.
Renal Insufficiency or Other Renal Events
Prior to start of study treatment, concomitant medications should be reviewed for the 
potential risk of inducing nephrotoxicity and concomitant medications should be 
modified if clinically possible.
Close monitoring of serum creatinine, calcium and phosphate and treatment interruption 
for increased serum creatinine >2 mg/dL (or >0.5 mg/dL above baseline), hypocalcemia, 
and hypophosphatemia, respectively, should occur.  Nephrology consultation should also 
be considered.
Calcium should be carefully managed in all subjects and especially in subjects with bone 
lesions/metastases and in those on treatments that are associated with hypocalcemia, 
including but not limited to, bisphosphanates (e.g., zoledronic acid) or denosumab 
(RANK-L inhibitor). Subjects with baseline calcium levels at or near the lower normal 
limit and those with Vitamin D below the normal limit should be treated with 
supplements.  Subjects who develop hypocalcemia should be closely monitored and 
managed per Table 10. 
Guidelines regarding the management of renal insufficiency or renal-related events 
considered to be related to study treatment are provided in Table 10.
Table 10
Management and Dose Modifications for Renal Events
Assessment
Action and Dose Modification
Urine dipstick 
protein 2+

Monitor for concomitant medications (e.g., NSAIDs) or medical conditions 
(e.g., urinary tract infection) associated with positive urinary protein dipstick 
test (see SRM for further details)

Assess BP and ensure it is well-controlled (<140/90 mmHg)

Obtain a random UPC ratio (see Appendix 5)
UPC ratio 3

Repeat UPC within 24 hrs of previous result

If repeat UPC confirms UPC ratio 3, permanently discontinue treatment 
with GSK2636771

Consult with GSK Medical Monitor
UPC ratio >0.5 
but <3

Repeat UPC within 24 hrs of previous result

If repeat UPC confirms UPC >0.5 but <3, interrupt treatment with 
GSK2636771

Evaluate urine sediment (rule out RBC casts)

Consider consult with nephrologist regarding further management

Reassess UPC ratio at least weekly or more frequently if clinically indicated

If UPC ratio improves to 0.5 within 14 days:


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Assessment
Action and Dose Modification

Restart treatment with GSK2636771 with dose reduced one dose level

Continue monitoring UPC ratio weekly for 4 weeks

Resume urinalysis testing at frequency indicated in Time and Events 
Tables (Section 8.1)

If UPC ratio fails to improve to 0.5 within 14 days:

Discontinue treatment with GSK2636771

Consult with a nephrologist regarding further management

Consult with GSK Medical Monitor

If UPC ratio elevation recurs after one dose level reduction:

Discontinue treatment with GSK2636771; withdraw subject from study 
unless there is agreement between investigator and GSK Medical 
Monitor that subject will benefit from continued treatment following 
recovery of UPC ratio to 0.5
UPC 0.5

Continue treatment with GSK2636771 at same dose level without 
interruption
Serum creatinine 
0.3 mg/dL 
(26.5 µmol/L) 
increase from 
baseline

Repeat serum creatinine level within 24 hrs of previous result

If repeat value confirms serum creatinine 0.3 mg/dL (26.5 µmol/L) 
increase from baseline:

Immediately interrupt treatment with GSK2636771

Evaluate and treat possible causes for elevated serum creatinine (e.g., 
renal outflow obstruction, sepsis, dehydration, hypotension, GI bleed, 
medications [e.g., trimethoprim, ketoconazole or cimetidine] that 
increase serum creatinine level)

Obtain blood sample for PK analysis , if within 24-72 hrs after the last 
dose (refer to Section 8.7.3.1 for details on PK sample collection)

Obtain serum chemistries for calcium, phophorus and magnesium

Obtain UA, UPC and urine electrolytes

Consider oral or IV hydration, if clinically indicated; and 24-hour Urine 
Creatinine Clearance assessment, where feasible

Repeat serum creatinine level every 7 days or more frequently if 
clinically indicated

If serum creatinine fails to improve (0.3 mg/dL [26.5 µmol/L] increase 
persists) within 14 days following dose interruption:

Permanently discontinue treatment with GSK2636771

Consult with GSK Medical Monitor

If serum creatinine improves (<0.3 mg/dL [<26.5 µmol/L] increase from 
baseline) within 14 days following dose interruption:

Restart treatment with GSK2636771 with dose reduced by one dose 
level

Repeat serum creatinine level every 4 weeks or more frequently if 
clinically indicated

If elevated serum creatinine recurs after one dose reduction (0.3 mg/dL 
[26.5 µmol/L] increase from baseline):

Repeat serum creatinine within 24 hrs to confirm result

If repeat serum creatinine confirms increase, withdraw subject 
from treatment/study unless there is agreement between 
investigator and GSK Medical Monitor that subject will benefit from 
continued treatment following recovery of serum creatinine 
(0.3 mg/dL [<26.5 µmol/L] increase from baseline)


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Assessment
Action and Dose Modification

If repeat serum creatinine fails to confirm increase, continue 
treatment with GSK2636771 at same dose level without 
interruption and obtain blood sample for PK analysis , within 24-72 
hrs after the last dose (refer to Section 8.7.3.1 for details on PK 
sample collection)
Hypocalcemia
(serum calcium 
Grade 1)
or
Hypophosphatemia
(serum phosphate 
Grade 3 or 
symptomatic 
Grade 2)

Administration of oral calcium supplements to subjects with calcium levels at or 
near the lower limit of normal should be considered

For subjects with Grade1 hypocalcemia, administer oral calcium supplements 
and evaluate the need for Vitamin D supplementation.

For hypocalcemia > Grade 1, repeat serum calcium and Vitamin D, and 
phosphate level within 24 hrs of previous result

If repeat value confirms > Grade 1 serum calcium, or symptomatic 
Grade 2 serum phosphate.

Immediately interrupt treatment with GSK2636771

Treat as clinically indicated by local institutional standards or 
administer i.v. calcium gluconate (1 g/10 ml) and evaluate the need for 
Vitamin D supplementation.

Obtain serum PTH level

Obtain blood sample for PK analysis, if requested (see SRM), within 
24-72 hrs after the last dose(refer to Section 8.7.3.1 for details on PK 
sample collection)

Obtain urine samples for urine creatinine, calcium, phosphate, and 
protein at treatment interruption; repeat every 7 days

Repeat serum calcium or phosphate level every 7 days or more 
frequently if clinically indicated

If serum calcium fails to improve to WNL or if serum phosphate fails to 
improve to asymptomatic Grade 2 within 14 days following dose 
interruption:

Permanently discontinue treatment with GSK2636771

Consult with GSK Medical Monitor

If serum calcium improves to WNL or serum phosphate improves to 
asymptomatic Grade 2 within 14 days following dose interruption:

Restart treatment with GSK2636771 with dose reduced by one dose 
level

Repeat serum calcium or phosphate level per Time and Events Tables 
(Section 8.1) or more frequently if clinically indicated

If decreased serum calcium or phosphate levels reoccurs after one dose 
reduction :

Repeat serum calcium or phosphate levels within 24 hrs to confirm 
result

If repeat serum calcium or phosphate levels confirm decrease, 
withdraw subject from treatment/study unless there is agreement 
between investigator and GSK Medical Monitor that subject will 
benefit from continued treatment following recovery of serum 
calcium or phosphate to baseline with dose of GSK2636771 
further reduced one dose level.

If repeat serum calcium or phosphate fails to confirm a decrease, continue 
treatment with GSK2636771 at same dose level without interruption


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Abbreviations:  BP, blood pressure; GI, gastrointestinal; GSK, GlaxoSmithKline; IV, intravenous; mmHg, millimeters of 
mercury; NSAIDs, non-steroidal anti-inflammatory drugs; PK, pharmacokinetics; PTH, parathyroid hormone; RBC, red 
blood cell; SRM, Study Reference Manual; UPC, urine/protein/creatinine ratio
Details regarding collection and testing of urine specimens are provided in the SRM.
7.3.1.1.
Parathyroid Hormone (PTH)
Serum parathyroid hormone (PTH) level will be assessed on the first day of combination 
treatment (Week 1, Day 1 of Combination Treatment Period).  Subsequently a serum 
PTH level should be obtained for any subject who experiences Grade 2 or greater 
hypocalcemia or hypophosphatemia while on study (refer to Table 10).
7.3.2.
Cardiac-related Toxicities
Reversible increases in mean arterial pressure and decreases in heart rate and cardiac 
contractility that were considered secondary to an elevation in blood pressure were 
observed in a single dose safety pharmacology study in dogs administered 300 mg/kg of 
GSK2636771.  In the ongoing FTIH study, no Grade 3 or higher cardiac events have 
been observed.  Subjects with a history of uncontrolled hypertension, heart failure, or 
known significant coronary artery disease are excluded from this study.  Cardiac 
monitoring, including assessment of BP and heart rate, along with 12-lead ECGs, will be 
performed.
7.3.2.1.
Hypertension
Hypertension is defined as a pathological increase in BP; a repeatedly elevated BP 
exceeding 140/90 mmHg.  Hypertension has been reported with GSK2636771; however, 
the mechanism by which it may cause hypertension has not been established.  It should 
be noted that hypertension may resolve as the study treatment is cleared and that there 
may be a risk for rebound hypotension.  Any time antihypertensive medication(s) is/are 
adjusted, ambulatory BP monitoring should be considered.


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Table 11
Management and Dose Modification for Hypertension
Grade1
Action and Dose Modification
Grade 1:
SBP 120 - 139 mmHg or DBP 80 - 89 mmHg
1) No interruption in treatment with GSK2636771; 
maintain current dose. 
2) Careful monitoring of BP. Ambulatory BP monitoring 
should be considered.
Grade 2:
SBP 140 - 159 mmHg or DBP 90 -99 mmHg, 
medical intervention may be indicated
1) No interruption in treatment with GSK2636771; 
maintain current dose.
2) Begin antihypertensive medication(s), adjust dose of 
current antihypertensive medication(s), or begin an 
additional antihypertensive medication(s). 
3) Titrate antihypertensive medication(s) during next 
2 weeks until hypertension Grade 1.
4) If hypertension is not Grade 1 within 2 weeks, follow 
steps outlined for Grade 3.
Grade 3:
SBP 160 mmHg or DBP 100 mmHg, 
medical intervention indicated
1) Interrupt treatment with GSK2636771.
2) Begin antihypertensive medication, or adjust dose of 
current antihypertensive medication(s), or begin an 
additional antihypertensive medication(s).
3) Titrate antihypertensive medication(s) during next 
2 weeks as indicated until hypertension Grade 1. Restart 
study treatment at a previously evaluated dose with at 
least a with a 25% dose reduction.
5) If hypertension is not Grade 1 within 2 weeks, 
permanently discontinue treatment with GSK2636771 and 
follow-up per protocol.
Grade 4:
Life-threatening, malignant hypertension, 
urgent intervention indicated
Permanently discontinue treatment with GSK2636771 and 
follow-up per protocol.
Abbreviations:  BP, blood pressure; CTCAE, Common Terminology Criteria for Adverse Events; DBP, diastolic blood 
pressure; mmHg, millimeters of mercury; SBP, systolic blood pressure
1. Grading is based on CTCAE v4.0.
7.3.3.
Rash
Subjects should be informed to protect themselves against direct sun exposure and to 
avoid exposure to known allergens.  Subjects should contact the investigator immediately 
upon onset of a rash.  Full supportive care should be provided to subjects who experience 
a rash while on study.  Information contained in this section is a guideline. The 
investigator’s best medical judgment should determine medical intervention for rash.


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Table 12
Management and Dose Modification for Rash
1st Occurrence
2nd Occurrence
3rd Occurrence
Grade 13

Symptomatic care1

Consider oral steroids if multiple occurrences2
Grade 23

Consider oral 
steroids2

Consider oral 
steroids2

Hold study treatment 
until <Grade 1, then 
resume at full dose

Administer oral 
steroids2

Hold study treatment 
until Grade 1 then 
restart treatment with 
GSK2636771 with 
dose reduced one
dose level.
Grade 33, 
4

Consider oral 
steroids2

Hold study 
treatment until 
Grade 1, then 
resume at full 
dose

Administer oral 
steroids2

Hold study treatment 
until Grade 1 then 
restart treatment with
GSK2636771 with 
dose reduced one
dose level.

Administer oral 
steroids2

Hold study treatment 
until Grade 1 then 
restart treatment with 
GSK2636771 with 
dose reduced 2 dose 
levels.
Grade 43, 
4

Administer oral 
steroids2

Hold study 
treatment until 
Grade 1 then 
restart 
treatment with 
GSK2636771 
with dose 
reduced one
dose level.

Administer oral 
steroids2

Hold study treatment 
until Grade 1 then 
restart treatment with 
GSK2636771 with 
dose reduced 2 dose 
levels.

Discontinue treatment 
with GSK2636771.
1.
Recommended symptomatic measures (for all grades) includes topical steroids (e.g., hydrocortisone 1% or 2.5% 
cream), antihistamines, hypoallergenic moisturizers and emollients for dry skin (e.g., 5 -10% urea in cetomacrogel 
cream or soft paraffin).
2.
Oral steroid therapy should follow institutional standard of care (e.g., short course of tapering dose of 
methylprednisolone or prednisone).
3.
Dermatology consult should be considered for Grade 3 rash or multiple occurrences of Grade 2.
4.
Obtain blood sample for PK analysis, if within 24-72 hours after the last dose (see Section 8.7.3.1). 
7.3.4.
Diarrhea
Episodes of diarrhea have occurred in subjects receiving GSK2636771 monotherapy. 
Other frequent causes for diarrhea, including concomitant medications (e.g., stool 
softeners, laxatives, antacids, etc.), infections by C. difficile or other pathogens, partial 
bowel obstruction, should be clinically excluded.


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Standardized and universal guidelines have been developed by an American Society of 
Clinical Oncology (ASCO) panel for treating chemotherapy-induced diarrhea [Benson, 
2004].  Presented in the sections below are the recommended guidelines for the 
management of diarrhea in subjects receiving GSK2636771.  These guidelines were 
derived from the recommendations published by the ASCO panel [Benson, 2004].
Early identification and intervention is critical for the optimal management of diarrhea.  
A subject’s baseline bowel patterns should be established so that changes in patterns can 
be identified while subject is on treatment.
An assessment of frequency, consistency and duration as well as knowledge of other 
symptoms such as fever, cramping, pain, nausea, vomiting, dizziness and thirst should be 
taken at baseline.  Consequently subjects at high risk of diarrhea can be identified.  
Subjects should be educated on signs and symptoms of diarrhea with instructions to 
report any changes in bowel patterns to the physician.
It is recommended that subjects keep a diary and record the number of diarrhea episodes 
and its characteristics.  They should also include information on any dietary changes or 
other observations that may be useful in the evaluation of their diarrhea history.
If subjects present with diarrhea of any grade, check they are receiving the study 
treatment correctly (i.e., single dose, rather than splitting it through the day).  Obtain 
information on food (solid and liquid) and over-the-counter (OTC) medication(s),
including herbal supplements, taken during the treatment period.
Guidelines regarding management and dose reduction for diarrhea considered to be 
related to study treatments by the investigator are provided in Table 13.  Also, see 
guidance on hydration in Section 11.3.


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Table 13
Management and Dose Modification Guidelines for Diarrhea
Grade
Management
Action and Dose 
Modification
Uncomplicated 
Diarrhea -
Grade 1
1. Instruct subject to start supportive care immediately 
at the first episode of diarrhea (i.e., unformed stool) 
and contact the investigator.

Administer loperamide: Initial dose: 4 mg. 
Subsequent doses: 2 mg after each unformed 
stool
1.
Re-evaluate after 24 hrs:
2.
If diarrhea is resolving: continue 
loperamide treatment at 2 mg dose after each 
unformed stool until diarrhea-free (i.e., bowel 
patterns return to baseline) for 12 hrs.  If 
diarrhea recurs, re-initiate loperamide as 
needed to maintain normal bowel pattern.
3.
If diarrhea is NOT resolving: continue 
loperamide 2 mg every 4 hrs for the next 
24 hrs; re-evaluate after 24 hrs.  If not 
resolving, administer loperamide 2 mg after 
each unformed stool until diarrhea free 
(i.e., bowel patterns return to baseline) for 
12 hrs.  If diarrhea is not resolving, continue 
loperamide 2 mg every 4 hrs and re-evaluate 
every 24 hrs.
2. Dietary modifications:
4.
Stop all lactose containing products and eat 
small meals
5.
Avoid spicy, fried and fatty foods, raw 
vegetables and other foods high in fiber
6.
Avoid caffeine and alcohol (can irritate bowel 
and increase motility)
7.
Hydration:  Drink 8 to 10 large glasses of clear 
liquids (e.g., water, electrolyte drink) daily.  
Avoid acidic drinks such as tomato juice and 
fizzy soft drinks
8.
Supplement diet to include food rich in 
potassium (e.g., bananas, potatoes, apricots; 
evaluate their impact on diarrhea due to fiber 
content (e.g., apricots)

Continue study 
treatments at current 
dose.

Continue supportive care 
until diarrhea resolves 
(diarrhea free for 12 hrs 
and bowel pattern 
returns to baseline)

If diarrhea recurs after 
stopping loperamide 
treatment, resume 
loperamide treatment, 
re-introduce diet 
modifications, and 
continue study 
treatments at current 
dose.


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Grade
Management
Action and Dose 
Modification
Uncomplicated 
Diarrhea -
Grade 1
continued
3. If Grade 1 diarrhea persists for >1 week with
loperamide treatment, consider treatment with 
second-line agents (i.e., octreotide, budesonide or 
tincture of opium).
4. If Grade 1 diarrhea persists for ≥2 weeks, refer to 
Persistent Grade 2 diarrhea management 
guidelines.
Uncomplicated 
Diarrhea –
Grade 2
1. Instruct subject to start supportive care immediately 
at the first episode of diarrhea (i.e., unformed stool) 
and contact the investigator.
9.
Administer loperamide: Initial dose: 4 mg.  
Subsequent doses: 2 mg every 4 hrs or after 
each unformed stool
10. Re-evaluate after 24 hrs:
11.
If diarrhea is resolving: continue 
loperamide treatment at 2 mg dose after each 
unformed stool until diarrhea free (i.e., bowel 
patterns return to baseline) for 12 hrs.  If 
diarrhea recurs, re-initiate loperamide as 
needed to maintain normal bowel pattern.
12.
If diarrhea is NOT resolving: consider 
loperamide 2 mg every 2 hrs for the next 
24 hrs.  If Grade 2 diarrhea persists after 48 
hrs of loperamide treatment, start treatment 
with second-line agents (i.e., octreotide, 
budesonide or tincture of opium).  Consider 
performing stool work-up, CBC, electrolytes 
and other tests as appropriate.
2.Dietary modifications:
13. Stop all lactose containing products and eat 
small meals
14. Avoid spicy, fried and fatty foods, bran, raw 
vegetables and other foods high in fiber.  Eat 
foods low in fiber (i.e., lean meat, rice, skinless 
chicken or turkey, fish, eggs, canned or cooked 
skinless fruits, cooked/pureed vegetables)
15. Avoid caffeine and alcohol (can irritate bowel 
and increase motility)
16. Hydration:  Drink 8 to 10 large glasses of clear 
liquids (e.g., water, electrolyte drink) daily.  
Avoid acidic drinks such as tomato juice and 
fizzy soft drinks

Continue study 
treatments at current 
dose.

Continue supportive care 
until diarrhea resolves 
(diarrhea free for 12 hrs / 
bowel pattern returns to 
baseline)

Once diarrhea has 
resolved, subject may 
gradually re-introduce 
foods from their normal 
diet.

If diarrhea recurs after 
stopping loperamide 
treatment, resume 
loperamide treatment, re-
introduce diet 
modifications, and 
continue study 
treatments at current 
dose.


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Grade
Management
Action and Dose 
Modification
Uncomplicated 
Diarrhea –
Grade 2
continued
17. Supplement diet to include food rich in 
potassium (e.g., bananas, potatoes, apricots); 
evaluate their impact on diarrhea due to fiber 
content (e.g., apricots) 
18. If diarrhea recurs, refer to Recurrent Diarrhea 
management guidelines.
Persistent  
(≥3 days/ 
72 hrs) 
Diarrhea –
Grade 2
1.
If Grade 2 diarrhea persists for ≥3 days or 72 
hrs, resume loperamide treatment and re-
introduce diet modifications.
2.
If supportive care measures and interruption of 
study treatments are ineffective in treatment of 
persistent Grade 2 diarrhea, perform stool 
work-up, CBC, electrolytes, and other tests as 
appropriate.  Consider consultation with GI 
specialist.

Hold treatment with 
GSK2636771 and 
enzalutamide until 
symptoms have resolved 
to Grade 1 or baseline 
bowel pattern.

Once diarrhea has 
resolved, continue 
treatment with 
GSK2636771 and 
enzalutamide at reduced 
dose.
Recurrent 
Diarrhea (>1 
occurrence) -
(Grade 2)
If second occurrence of Grade 2 diarrhea recurs, 
resume loperamide treatment and re-introduce diet 
modifications.

Once diarrhea resolves 
to Grade 1 or baseline, 
consider re-starting study 
treatments 
(GSK2636771 +  
enzalutamide) at a 
reduced dose
Complicated 
Diarrhea2 –
Grade 3 or 
Grade 1 or 2 
with 
complicating 
factors
1.
Instruct subject that they must call investigator 
immediately for any complicated severe 
diarrhea event.
2.
If loperamide has not been initiated, initiate 
loperamide immediately.  Initial dose: 4 mg.  
Subsequent doses: 2 mg every 2 hrs or after 
each unformed stool.
3.
Refer to the dietary modifications for Grade 1 
and 2 uncomplicated diarrhea (above).
4.
For dehydration use IV fluids as appropriate.  If 
subject presents with severe dehydration, 
administer octreotide.
5.
Perform stool work-up, complete blood count, 
electrolytes and other tests as appropriate
6.
Administer antibiotics (i.e., fluoroquinolones) as 
needed, especially if diarrhea is persistent 
beyond 24 hrs or if fever or Grade 3 or 4 
neutropenia is present

Hold treatment with 
GSK2636771 and 
enzalutamide until 
symptoms have resolved 
to Grade 1 or baseline 
bowel pattern and 
without complicating 
factors present.

Once diarrhea resolves 
to Grade 1 or baseline, 
consider re-starting study 
treatments 
(GSK2636771 
+enzalutamide) at a 
reduced dose 

Continue supportive care 
until diarrhea resolves 
(diarrhea free for 24 hrs 
and bowel pattern 
returns to baseline)


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Grade
Management
Action and Dose 
Modification
Complicated 
Diarrhea2 –
Grade 3 or 
Grade 1 or 2 
with 
complicating 
factors
continued
7.
Instruct subject that they must call investigator 
immediately for any complicated severe 
diarrhea event.
8.
If loperamide has not been initiated, initiate 
loperamide immediately.  Initial dose: 4 mg.  
Subsequent doses: 2 mg every 2 hrs or after 
each unformed stool.
9.
Refer to the dietary modifications for Grade 1 
and 2 uncomplicated diarrhea (above).
10. For dehydration use IV fluids as appropriate.  If 
subject presents with severe dehydration, 
administer octreotide.
11. Perform stool work-up, complete blood count, 
electrolytes and other tests as appropriate
12. Administer antibiotics (i.e., fluoroquinolones) as 
needed, especially if diarrhea is persistent 
beyond 24 hrs or if fever or Grade 3 or 4 
neutropenia is present
13. Intervention may require hospitalization for 
subjects most at risk for life threatening 
complications.
Complicated 
Diarrhea –
Grade 4
1.
Instruct subject that they must call investigator 
immediately for any complicated Grade 4 
diarrhea event.
2.
If loperamide has not been initiated, initiate 
loperamide immediately.  Initial dose: 4 mg.  
Subsequent doses: 2 mg every 2 hrs or after 
each unformed stool.
3.
For dehydration use IV fluids as appropriate.  If 
subject presents with severe dehydration, 
administer octreotide.
4.
Perform stool work-up, CBC, electrolytes and 
other tests as appropriate
5.
Consider consultation with GI specialist.
6.
Administer antibiotics (i.e., fluoroquinolones) as 
needed, especially if diarrhea is persistent 
beyond 24 hrs or if fever or Grade 3 or 4 
neutropenia is present
7.
Intervention may require hospitalization for 
subjects most at risk for life threatening 
complications.

Hold treatment with 
GSK2636771 and 
enzalutamide

Consult with GSK 
Medical Monitor to 
discuss subject’s event 
history, re-initiation of 
study treatments, and 
dose modifications, once 
symptoms have resolved 
to Grade 1 or baseline 
bowel pattern

Continue supportive care 
until diarrhea resolves 
(diarrhea free for 24 hrs 
and bowel pattern 
returns to baseline)
Abbreviations: CBC, complete blood count; GI, gastrointestinal; hrs, hours; IV, intravenous; mg, milligram(s)


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7.3.5.
Vomiting
Table 14
Management and Dose Modification for Events of Vomiting
Grade
Action and Dose Modification
≤Grade 1
Continue study treatments at current dose.
Grade 2
Hold until ≤Grade 1.  Resume study treatments at same dose level.
Grade 3
Hold1 until <Grade 2.  Resume study treatments at one dose level lower, if 
indicated.2
Grade 4
Withdraw study treatments.
1.
Subjects requiring a delay of >14 days should be withdrawn from treatment and/or study.
2.
Subjects requiring >2 dose reductions should be withdrawn from treatment and/or study.
It is recommended that any event of vomiting should be managed with the use of 
antiemetics.  Also, see guidance on hydration in Section 11.3.
8.
STUDY ASSESSMENTS AND PROCEDURES
This section lists the parameters of each planned study assessment.  The timing of each 
assessment for the Dose Escalation Phase is listed in the Time and Events Table 
(Section 8.1).  Further details for study procedures and assessments can be found in the 
SRM.
The timing and number of planned study assessments, including safety, PK, and 
biomarker assessments, may be altered during the course of the study based on newly 
available data (e.g., to obtain data closer to the time of peak blood concentrations) to 
ensure appropriate monitoring.  Any addition or deletion of a study assessment, including 
any significant change in the timing or frequency of an assessment, must be approved and 
documented by GSK, and will require a protocol amendment, except in a situation where 
additional assessments are required to immediately address any safety concerns.  The 
institutional review board (IRB)/independent ethics committee (IEC) will be informed of 
any safety issues that require alteration of the safety monitoring scheme.  No more than 
500 mL of blood will be collected over a period of 30 days, including any extra 
assessments that may be required.
Whenever vital signs, 12-lead ECGs and blood draws are scheduled for the same nominal 
time, the assessments should occur in the following order: 12-lead ECG, vital signs, and 
then blood draws (see SRM for additional details).
Procedures conducted as part of the subject’s routine clinical management (e.g., blood 
count, imaging study) and obtained prior to signing of informed consent may be utilized 
for screening or baseline purposes provided the procedure meets the protocol-defined 
criteria and has been performed in the timeframe of the study.


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8.1.
Time and Events Tables
This section consists of the Time and Events Tables and supplemental footnotes to 
describe the assessment windows and sequencing of study-specific assessments and 
procedures.
Additional unplanned blood, plasma and/or optional tumor samples may be requested 
with patient consent and investigator agreement as needed to better characterize safety 
and response(s) in subjects.


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Table 15
Time and Events Table for Dose Escalation Phase
Study 
Assessments1,2
Pre-Screening
Screening
Enzalutamide 
Run-In Period
Combination Treatment Period 
(DLT Reporting Period)
Treatment Continuation Period
Time of Discontinuation of 
Treatment due to Disease 
Progression31
Post-Treatment
Follow-Up Visit28
Extended
Follow-Up  
Visits29
Post-
Extended 
Follow-
Up
/EOS 
Visit30
Day    
-14 to
Day -1
Day 1
to
Day 13
Day 
14
Wk 1, 
Day 1
Wk 2, 
Day 8
Wk 3, 
Day 
15
Wk 4, 
Day 
22
Wk 5, 
Day 
29
Week 8 and every 4 
weeks thereafter
Every 3 
months
Visit Window
+1 day
1 
day
1
day
1
day
1
day
+5 days Week 12 only; 
3 days for all other visits
+1
day
-2/+7 
days
14 
days
3 
days
Clinical Assessments
Informed Consent
X3
X4
Demographics
X
Medical History
X
Determination of 
PTEN Deficiency 
Status
M5
Safety Assessments
ECOG PS
X
X
X
X
X
Week 8 and then Q8wks
X
X
X
Physical Exam
X
X
Week 8 and then Q8wks
X
X
Height8
X
Weight
X
X
Week 8 and then Q8wks
X
X
Vital Signs9
X
X
X
X
X
X
X
X
X
12-Lead ECG10
X6
X
Week 8 and then Q8wks
X
X
ECHO/MUGA
X6,7
As clinically indicated
AE Monitoring
Continuous
X11
X11
Concomitant 
Medications
X
Continuous
X


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Study 
Assessments1,2
Pre-Screening
Screening
Enzalutamide 
Run-In Period
Combination Treatment Period 
(DLT Reporting Period)
Treatment Continuation Period
Time of Discontinuation of 
Treatment due to Disease 
Progression31
Post-Treatment
Follow-Up Visit28
Extended
Follow-Up  
Visits29
Post-
Extended 
Follow-
Up
/EOS 
Visit30
Day    
-14 to
Day -1
Day 1
to
Day 13
Day 
14
Wk 1, 
Day 1
Wk 2, 
Day 8
Wk 3, 
Day 
15
Wk 4, 
Day 
22
Wk 5, 
Day 
29
Week 8 and every 4 
weeks thereafter
Every 3 
months
Visit Window
+1 day
1 
day
1
day
1
day
1
day
+5 days Week 12 only; 
3 days for all other visits
+1
day
-2/+7 
days
14 
days
3 
days
Laboratory Assessments12    
Hematology/
Clinical Chemistry
X6
X33
X
X
X
X
X
X
X
Ionized Calcium
X6
X
X
X
X
X
X
X
X
Vitamin D34
X6
X
X
X
Coagulation: 
PT, PTT, INR
X6
X
X
Liver Function Tests
X6
X
X
X
X
X
X
X
X
Urinalysis13
Urine Microscopy13
UPC14
X6
X
X
X
X
X
Urine Electrolytes15
X6
X33
X
X
X
Week 8 and then Q8wks
X
Parathyroid 
Hormone
X
As clinically indicated16
Bone Markers35
X
X
Weeks  12 and  24
X
X
PSA and LDH32
X6
X
X
X
X
X
Serum Testosterone
X6
X
X
PK Assessments
PK Blood 
Sampling17
X
X
Weeks 8 and 12
Disease Assessments18
CT Scan or MRI19
X6,7
Week 8 and then Q8wks 
to Week 48; then 
Q12wks
X
X


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Study 
Assessments1,2
Pre-Screening
Screening
Enzalutamide 
Run-In Period
Combination Treatment Period 
(DLT Reporting Period)
Treatment Continuation Period
Time of Discontinuation of 
Treatment due to Disease 
Progression31
Post-Treatment
Follow-Up Visit28
Extended
Follow-Up  
Visits29
Post-
Extended 
Follow-
Up
/EOS 
Visit30
Day    
-14 to
Day -1
Day 1
to
Day 13
Day 
14
Wk 1, 
Day 1
Wk 2, 
Day 8
Wk 3, 
Day 
15
Wk 4, 
Day 
22
Wk 5, 
Day 
29
Week 8 and every 4 
weeks thereafter
Every 3 
months
Visit Window
+1 day
1 
day
1
day
1
day
1
day
+5 days Week 12 only; 
3 days for all other visits
+1
day
-2/+7 
days
14 
days
3 
days
Disease Assessments18 continued
Chest X-Ray or 
Chest CT Scan
X6,7
Bone Scan20
X6,7
Week 12 and then 
Q12wks
X
X
Biomarker Assessments
CTC –- Janssen21
X
X
X
Weeks 8, 16, 24, and 32
X
CTC – EPIC22
X
Week 8 only
X
Predictive 
Biomarker: Tumor 
Tissue23
X
Progression Tumor 
Biopsy24
X
Tumor Biopsies for 
Pharmaco-
dynamics24
X
X24
cfDNA/RNA/Soluble 
Markers25
X
X
X
Weeks 8, 16, 24, and 32
X
Blood Sample for 
Genetic Research26
X
Study Treatments27
Enzalutamide
Continuous
Continuous
GSK2636771
Continuous


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Abbreviations: AE, adverse event; cfDNA, circulating-free tumor DNA; CT, computed tomography; CTC, circulating tumor cells; ECG, electrocardiogram; ECHO, echocardiogram; 
ECOG, Eastern Cooperative Oncology Group; EOS, End of Study; HbA1C, hemoglobin A1C; INR, international normalization ratio; M, mandatory; MRI, magnetic resonance imaging; 
MUGA, multigated acquisition scan; O, optional; PD, pharmacodynamics; PK, pharmacokinetics; PS, performance status; PSA, prostate-specific antigen; PT, prothrombin time; PTEN, 
phosphatase and tensin homolog; PTH, parathyroid hormone; PTT, partial thromboplastin time; Q4wks, every 4 weeks; Q8wks, every 8 weeks; Q12wks, every 12 weeks; UPC, 
urine:protein:creatinine; Wk(s), week(s)
1.
Study Assessments: All assessments may be performed more frequently if clinically appropriate. Assessments scheduled on days of dosing should be completed prior to the 
administration of study treatments, unless otherwise specified
2.
Study Assessments: Assessments throughout the study are calendar based starting from Week 1, Day 1 of the Combination Treatment Period (the first dose of combination 
treatment).  Dose interruptions should not alter the assessment schedule for any subsequent treatment period.
3.
Pre-Screening Informed Consent: Separate pre-screening informed consent must be obtained prior to initiation of any pre-screening procedures or assessments.
4.
Screening Informed Consent: Informed consent must be obtained prior to initiation of any screening procedures or assessments..
5.
PTEN Deficiency Status (Mandatory): Tumor tissue samples (archived or fresh tumor tissue obtained by pre-treatment biopsy) will be collected to determine PTEN deficiency 
status of the tumor by the designated central laboratory.  Refer to the SRM for details about the number of slides to be submitted, preparation, handling and shipping.  Results of 
the PTEN deficiency testing from the central laboratoryonly will be used to determine if the subject is eligible to continue Screening.  Only subjects with PTEN deficient tumor 
based on central laboratorytesting results will be screened.  Any remaining tumor tissue may be used for other predictive biomarker analyses if consent has been obtained.
6.
Screening: When possible, screening assessments that require imaging, ECG, ECHO/MUGA, or laboratory studies should be performed AFTER PTEN status has been 
determined.
7.
Screening: All screening assessments must be completed and all entry criteria must be met prior to assessments on Day 1 of Enzalutamide Run-In Period.  EXCEPTION:  
ECHO/MUGA must be completed within 28 days of enrollment (Day 1 of Enzalutamide Run-In Period), and disease assessment must be completed within 28 days (35 days if MRI 
is used) prior to enrollment (Day 1 of the Enzalutamide Run-In Period).
8.
Height is only measured at Screening.
9.
Vital Signs:  Blood pressure, temperature and heart rate will be measured.  Vital signs may be measured more frequently if clinically warranted.
10. ECG: A single 12-lead ECG is to be performed before vital signs are measured and any blood draws, if assessments are planned at the same nominal time point.
11. AE Monitoring: Continued monitoring of AEs applies only to ongoing events at time of treatment discontinuation.
12. Laboratory Assessments: Refer to Section 8.6.6 (Table 17) for list of specific laboratory tests to be performed.  Assessments may be performed within 24 hrs prior to scheduled 
visit (liver function tests and urine tests for UPC may be performed up to 72 hrs prior to a scheduled visit) to ensure availability of results.
13. Urinalysis and Urine Microscopy:  Urinalysis and urine microscopy will be performed at the time points indicated. Assessments may be performed within 24 hrs prior to a 
scheduled visit to ensure availability of results.
14. UPC:  Urine sample for UPC is to be collected at the time points indicated. Perform UPC with the first morning urine specimen (if possible) when urine dipstick protein 2+.  Urine 
samples for UPC may be collected up to 72 hrs prior to a scheduled visit to ensure that results are available at time of visit.  If the urine sample collected at Screening is 
contaminated with other bodily fluids, UPC will not be determined and subject will remain eligible for the study.
15. Urine Electrolytes:  Urine samples will be obtained at Screening, pre-dose on Day 1 (Week 1), Day 3 OR Day 4, Day 15 (Week 3), Day 22 (Week 4) of the Combination 
Treatment Period, Week 8 and then every 8 weeks (3 days) thereafter during the Treatment Continuation Period, and at the post-treatment follow-up visit to determine urine 
electrolytes (magnesium, phosphorus and calcium) and urine creatinine.
16. Parathyroid Hormone (PTH): Assessment of PTH will be performed if a Grade 2 or higher hypocalcemia or hypophosphatemia is reported.


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17. PK Blood Sampling:  Day 14 (Enzalutamide Run-In Period): Plasma samples for analysis of enzalutamide and N-desmethyl enzalutamide will be collected at pre-dose and 0.5, 
1, 2, 3, 4, and 6 hrs post-dose on Day 14 of Enzalutamide Run-In Period, the day prior to administration of the first dose of combination study treatment (GSK2636771 and 
enzalutamide). Week 5, Day 29 (Treatment Continuation Period): Blood and plasma samples for analysis of GSK2636771, enzalutamide and N-desmethyl enzalutamide will be 
collected at pre-dose and 0.5, 1, 2, 3, 4, and 6 hrs post-dose. Actual date and time of sample collection and dosing of study treatments must be recorded.  Explanations are 
required for any deviations of more than 5 minutes from the planned time during the first 2 hrs and for deviations of more than 20 minutes from the planned time for samples 
collected at 3 hrs up to 6 hrs post-dose.  Week 8 and Week 12 (Treatment Continuation Period): Blood and plasma samples for analysis of GSK2636771, enzalutamide and N-
desmethyl enzalutamide will be collected pre-dose only.
18. Disease Assessments: Disease assessments at Screening must be performed within 28 days prior to enrollment (Day 1 of the Enzalutamide Run-In Period), or within 35 days 
prior to enrollment (Day 1 of the Enzalutamide Run-In Period if disease assessment is performed by MRI, to identify target and non-target lesions.
19. CT scan or MRI:  Scans should be performed at Screening, Week 8 and then every 8 weeks (7 days) during the first 48 weeks of the Treatment Continuation Period and then 
every 12 weeks (7 days) thereafter in the Treatment Continuation Period, and at the time of disease progression.  All confirmatory scans are to be performed within 4 weeks 
(3 days) of a CR or PR.  If a subject discontinues treatment for reasons other than disease progression, disease assessments should continue every 3 months until disease 
progression, initiation of new anti-cancer treatment, subject withdrawal of consent, or death.
20. Bone Scan:  A bone scan is required for all subjects at Screening.  For subjects without bone disease at baseline, subsequent bone scans should be performed as clinically 
indicated.  Subjects with bone metastases at baseline should have a bone scan performed at Week 12 and then every 12 weeks (7 days) thereafter in the Treatment 
Continuation Period, or as clinically indicated, and at the time of disease progression.  If a subject discontinues treatment for reasons other than disease progression, bone scans 
should continue every 3 months until disease progression, initiation of new anti-cancer treatment, subject withdrawal of consent, or death.
21. CTC-Janssen:  Whole blood samples will be obtained at Screening; pre-dose on Day 1 (Week 1) and Day 22 (Week 4) of the Combination Treatment Period; pre-dose on Day 1 
of Weeks 8, 16, 24 and 32 of the Treatment Continuation Period; and at time of disease progression.
22. CTC-EPIC:  Whole blood samples will be obtained at Screening, pre-dose on Day 1 of Week 8 of the Treatment Continuation Period, and at the time of disease progression for 
protein and genomic analysis.
23. Predictive Biomarkers Tumor Tissue:  For subjects enrolled into the study, additional slides of tumor tissue samples will be collected and submitted to the designated laboratory 
for analysis once a subject has received their first dose of GSK2636771 on Week 1, Day 1 of the Combination Treatment Period.  Tumor tissue may be obtained from archived 
tissue samples or fresh tumor tissue submitted for the PTEN testing.  If additional tumor tissue is not available, no new biopsy procedure is required for predictive biomarker 
analysis.  Refer to the SRM for details about the number of slides to be submitted, preparation, handling and shipping.
24. Tumor Biopsies for PD and progression: These biopsies are optional and may be undertaken in select cases upon agreement with the investigator and when consent is 
provided by the subject. For pharmacodynamic biomarker analyses, fresh tissue biopsies would be collected between Day 12 of the Enzalutamide Run-in Period and Week 
1/Day 1, prior to any treatment with GSK2636771, and 2-4 hours post dose between Days 8 and 15 of the Combination Treatment Period (post-treatment).  For subjects who 
consent to the optional progression biopsy, a fresh tumor biopsy should be completed if the subject initially responded to combination treatment and then progressed.
25. cfDNA/RNA/Soluble Markers:  Plasma samples will be obtained from collected blood samples at Screening, pre-dose on Weeks 1, 4, 8, 16, 24, and 32 of the Combination 
Treatment Period, and at the time of treatment discontinuation due to disease progression.  Plasma will be analyzed for genomic changes in the circulating tumor DNA, RNA, and 
soluble markers.
26. Genetic Research: A 6-mL blood sample should be collected after Screening, preferably on Week 1, Day 1 of the Combination Treatment Period, if informed consent has been 
obtained for genetic research.
27. Study Treatment: Enzalutamide monotherapy should be taken once daily during the Enzalutamide Run-In Period.  Enzalutimide will be self adiministered in the clinic on Day 14 
of the Enzalutamide Run-In Period.  GSK2636771 and enzalutamide will be administered in the clinic on Week 1, Day 1 of the Combination Treatment Period and on days when 
blood, plasma, and/or urine samples are collected for analysis of PK, CTC, and/or urine electrolytes.


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28. Post-Treatment Follow-Up Visit: ONLY subjects who withdraw during the Enzalutamide Run-In Period or withdraw from study treatment due to  disease progression (see 
Section 5.2) should have a post-treatment follow-up visit conducted within approximately 30 days (-2/+7 days) of last dose of study treatment(s).  If a subject is unable 
to return to the clinic due to hospitalization, site staff is encouraged to call subject for assessment of AEs.  
29. Extended Follow-Up Visits:  Subjects who withdraw from study treatment without disease progression should be contacted every 3 months (14 days) until disease 
progression, death, withdrawal of consent, or subject is lost to follow-up.  Contact may include a clinic visit, a telephone contact, or an e-mail.  The initiation of any new anti-cancer 
treatments and date of last contact should be documented.
30. Post-Extended Follow-Up/EOS Visit:  ONLY subjects who discontinue the Extended Follow-Up Visits should have a Post-Extended Follow-Up/EOS Visit performed.
31. Subjects are not required to discontinue treatment on the basis of PSA progression alone or for the worsening of an isolated disease site that is not clinically significant (see 
Section 5.2).
32. When collected as part of the routine standard of care for a subject, LDH will be reported.
33. Complete clinical chemistries laboratory assessments at Week1/Day 1 and again on either Day 3 or Day 4.  The Day 3 or Day 4 assessments can be completed at a local 
laboratory and does not require a clinic visit.  The hematology panel does NOT need to be collected on Day 3/ Day.4. Review of these labs must occur before Week 2, Day 1 visit. 
34. Includes assessments for 25-OH D and 1,25-OH2 D.
35. Includes urine and blood and/or serum samples.  Must be collected at the same time of day (1 hour) to eliminate diurnal effects, and after fasting.  See SRM for additional details 
on the specific assessments and sample collection.  


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Table 16
Time and Events Table for Dose Expansion Phase
Study Assessments1,2
Pre-Screening
Screening
Enzalutamide 
Run-In 
Period
Combination Treatment Period 
(DLT Reporting Period)
Treatment Continuation 
Period
Time of Discontinuation of 
Treatment due to Disease 
Progression31
Post-Treatment Follow-Up 
Visit28
Extended
Follow-Up  
Visits29
Post-
Extende
d Follow-
Up
/EOS 
Visit30
Day -14 
to
Day -1
Day 1 to Day 
14
Wk 1, 
Day 1
Wk 2, 
Day 8
Wk 3, 
Day 
15
Wk 4, 
Day 
22
Week 
5, Day 
29
Week 8 and every 4 
weeks thereafter
Every 3 
months
Visit Window
+1 
day
1 
day
1
day
1
day
1
day
+5days Week 12 only; 
3 days for all other 
visits
+1
day
-2/+7 
days
14 
days
3 
days
Clinical Assessments
Informed Consent
X3
X4
Demographics
X
Medical History
X
Determination of PTEN 
Deficiency Status
M5
Safety Assessments
ECOG PS
X
X
X
X
X
Week 8 and then 
Q8wks
X
X
X
Physical Exam
X
X
Week 8 and then 
Q8wks
X
X
Height8
X
Weight
X
X
Week 8 and then 
Q8wks
X
X
Vital Signs9
X
X
X
X
X
X
X
X
X
12-Lead ECG10
X6
X
Week 8 and then 
Q8wks
X
X
ECHO/MUGA
X6,7
As clinically indicated
AE Monitoring
Continuous
X11
X11


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Study Assessments1,2
Pre-Screening
Screening
Enzalutamide 
Run-In 
Period
Combination Treatment Period 
(DLT Reporting Period)
Treatment Continuation 
Period
Time of Discontinuation of 
Treatment due to Disease 
Progression31
Post-Treatment Follow-Up 
Visit28
Extended
Follow-Up  
Visits29
Post-
Extende
d Follow-
Up
/EOS 
Visit30
Day -14 
to
Day -1
Day 1 to Day 
14
Wk 1, 
Day 1
Wk 2, 
Day 8
Wk 3, 
Day 
15
Wk 4, 
Day 
22
Week 
5, Day 
29
Week 8 and every 4 
weeks thereafter
Every 3 
months
Visit Window
+1 
day
1 
day
1
day
1
day
1
day
+5days Week 12 only; 
3 days for all other 
visits
+1
day
-2/+7 
days
14 
days
3 
days
Concomitant Medications
X
Continuous
X
Laboratory Assessments12
Hematology/
Clinical Chemistry
X6
X
X
X
X
X
X
X
X
Ionized Calcium
X6
X33
X
X
X
X
X
X
X
Vitamin D34
X6
X
X
X
Coagulation: 
PT, PTT, INR
X6
X
X
Liver function Tests
X6
X
X
X
X
X
X
X
X
Urinalysis13
Urine Microscopy13
UPC14
X6
X
X
X
X
X
Urine Electrolytes15
X6
X33
X
X
Week 8 and then 
Q8wks
X
Parathyroid Hormone
X
As clinically indicated16
Bone Markers35
X
X
Weeks  12 and  24
X
X
PSA and LDH32
X6
X
X
X
X
X
Serum Testosterone
X6
X
X
PK Assessments
PK Blood Sampling17
X
Weeks 8 and 12


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Study Assessments1,2
Pre-Screening
Screening
Enzalutamide 
Run-In 
Period
Combination Treatment Period 
(DLT Reporting Period)
Treatment Continuation 
Period
Time of Discontinuation of 
Treatment due to Disease 
Progression31
Post-Treatment Follow-Up 
Visit28
Extended
Follow-Up  
Visits29
Post-
Extende
d Follow-
Up
/EOS 
Visit30
Day -14 
to
Day -1
Day 1 to Day 
14
Wk 1, 
Day 1
Wk 2, 
Day 8
Wk 3, 
Day 
15
Wk 4, 
Day 
22
Week 
5, Day 
29
Week 8 and every 4 
weeks thereafter
Every 3 
months
Visit Window
+1 
day
1 
day
1
day
1
day
1
day
+5days Week 12 only; 
3 days for all other 
visits
+1
day
-2/+7 
days
14 
days
3 
days
Disease Assessments18
CT scan or MRI19
X6,7
Week 8 and then 
Q8wks to Week 48; 
then Q12wks
X
X
Chest X-ray or Chest CT 
scan
X6,7
Bone Scan20
X6,7
Week 12 and then 
Q12wks
X
X
Biomarker Assessments
CTC – Janssen21
X
X
X
Weeks 8, 16, 24, and 
32
X
CTC – EPIC22
X
Week 8 only
X
Predictive Biomarker: 
Tumor Tissue23
X
Progression Tumor 
Biopsy24
X
Tumor Biopsies for 
Pharmacodynamics24
X (Day 14)
X24
cfDNA/RNA/Soluble 
Markers25
X
X
X
Weeks 8, 16, 24, and 
32
X


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Study Assessments1,2
Pre-Screening
Screening
Enzalutamide 
Run-In 
Period
Combination Treatment Period 
(DLT Reporting Period)
Treatment Continuation 
Period
Time of Discontinuation of 
Treatment due to Disease 
Progression31
Post-Treatment Follow-Up 
Visit28
Extended
Follow-Up  
Visits29
Post-
Extende
d Follow-
Up
/EOS 
Visit30
Day -14 
to
Day -1
Day 1 to Day 
14
Wk 1, 
Day 1
Wk 2, 
Day 8
Wk 3, 
Day 
15
Wk 4, 
Day 
22
Week 
5, Day 
29
Week 8 and every 4 
weeks thereafter
Every 3 
months
Visit Window
+1 
day
1 
day
1
day
1
day
1
day
+5days Week 12 only; 
3 days for all other 
visits
+1
day
-2/+7 
days
14 
days
3 
days
Biomarker Assessments continued
Blood Sample for 
Genetic Research26
X
Study Treatments27
Enzalutamide
Continuous
Continuous
GSK2636771
Continuous
Abbreviations: AE, adverse event; cfDNA, circulating-free tumor DNA; CT, computed tomography; CTC, circulating tumor cells; ECG, electrocardiogram; ECHO, echocardiogram; 
ECOG, Eastern Cooperative Oncology Group; EOS, End of Study; HbA1C, hemoglobin A1C; INR, international normalization ratio; M, mandatory; MRI, magnetic resonance imaging; 
MUGA, multigated acquisition scan; O, optional; PD, pharmacodynamics; PK, pharmacokinetics; PS, performance status; PSA, prostate-specific antigen; PT, prothrombin time; PTEN, 
phosphatase and tensin homolog; PTH, parathyroid hormone; PTT, partial thromboplastin time; Q4wks, every 4 weeks; Q8wks, every 8 weeks; Q12wks, every 12 weeks; UPC, 
urine:protein:creatinine; Wk(s), week(s)
1.
Study Assessments: All assessments may be performed more frequently if clinically appropriate. Assessments scheduled on days of dosing should be completed prior to the 
administration of study treatments, unless otherwise specified
2.
Study Assessments: Assessments throughout the study are calendar based starting from Week 1, Day 1 of the Combination Treatment Period (the first dose of combination 
treatment).  Dose interruptions should not alter the assessment schedule for any subsequent treatment period.
3.
Pre-Screening Informed Consent: Separate pre-screening informed consent must be obtained prior to initiation of any pre-screening procedures or assessments.
4.
Screening Informed Consent: Informed consent must be obtained prior to initiation of any screening procedures or assessments..
5.
PTEN Deficiency Status (Mandatory): Tumor tissue samples (archived or fresh tumor tissue obtained by pre-treatment biopsy) will be collected to determine PTEN deficiency 
status of the tumor by the designated central laboratory.  Refer to the SRM for details about the number of slides to be submitted, preparation, handling and shipping.  Results of 


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the PTEN deficiency testing from the central laboratoryonly will be used to determine if the subject is eligible to continue Screening.  Only subjects with PTEN deficient tumor 
based on central laboratorytesting results will be screened.  Any remaining tumor tissue may be used for other predictive biomarker analyses if consent has been obtained.
6.
Screening: When possible, screening assessments that require imaging, ECG, ECHO/MUGA, or laboratory studies should be performed AFTER PTEN status has been 
determined.
7.
Screening: All screening assessments must be completed and all entry criteria must be met prior to assessments on Day 1 of Enzalutamide Run-In Period.  EXCEPTION:  
ECHO/MUGA must be completed within 28 days of enrollment (Day 1 of Enzalutamide Run-In Period), and disease assessment must be completed within 28 days (35 days if MRI 
is used) prior to enrollment (Day 1 of the Enzalutamide Run-In Period).
8.
Height is only measured at Screening.
9.
Vital Signs:  Blood pressure, temperature and heart rate will be measured.  Vital signs may be measured more frequently if clinically warranted.
10. ECG: A single 12-lead ECG is to be performed before vital signs are measured and any blood draws, if assessments are planned at the same nominal time point.
11. AE Monitoring: Continued monitoring of AEs applies only to ongoing events at time of treatment discontinuation.
12. Laboratory Assessments: Refer to Section 8.6.6 (Table 17) for list of specific laboratory tests to be performed.  Assessments may be performed within 24 hrs prior to scheduled 
visit (liver function tests and urine tests for UPC may be performed up to 72 hrs prior to a scheduled visit) to ensure availability of results.
13. Urinalysis and Urine Microscopy:  Urinalysis and urine microscopy will be performed at the time points indicated. Assessments may be performed within 24 hrs prior to a 
scheduled visit to ensure availability of results.
14. UPC:  Urine sample for UPC is to be collected at the time points indicated. Perform UPC with the first morning urine specimen (if possible) when urine dipstick protein 2+.  Urine 
samples for UPC may be collected up to 72 hrs prior to a scheduled visit to ensure that results are available at time of visit.  If the urine sample collected at Screening is 
contaminated with other bodily fluids, UPC will not be determined and subject will remain eligible for the study.
15. Urine Electrolytes:  Urine samples will be obtained at Screening, pre-dose on Day 1 (Week 1), Day 3 OR Day 4, Day 15 (Week 3), Day 22 (Week 4) of the Combination 
Treatment Period, Week 8 and then every 8 weeks (3 days) thereafter during the Treatment Continuation Period, and at the post-treatment follow-up visit to determine urine 
electrolytes (magnesium, phosphorus and calcium) and urine creatinine.
16. Parathyroid Hormone (PTH): Assessment of PTH will be performed if a Grade 2 or higher hypocalcemia or hypophosphatemia is reported.
17. PK Blood Sampling:  Week 5, Day 29 (Treatment Continuation Period): Blood and plasma samples for analysis of GSK2636771, enzalutamide and N-desmethyl enzalutamide 
will be collected at pre-dose and 1, 2, and 3 hrs post-dose if a morning clinic visit is scheduled, or at approximately 5 to 6, 6 to 7, and 7 to 8 hrs post-dose if an afternoon clinic visit 
is scheduled.  Actual date and time of sample collection and dosing of study treatments must be recorded.  Explanations are required for any deviations of more than 5 minutes 
from the planned time during the first 2 hrs and for deviations of more than 20 minutes from the planned time for samples collected at 3 hrs up to 8 hrs post-dose.  Week 8 
and Week 12 (Treatment Continuation Period): Blood and plasma samples for analysis of GSK2636771, enzalutamide and N-desmethyl enzalutamide will be collected pre-
dose only.
18. Disease Assessments: Disease assessments at Screening must be performed within 28 days prior to enrollment (Day 1 of the Enzalutamide Run-In Period), or within 35 days 
prior to enrollment (Day 1 of the Enzalutamide Run-In Period if disease assessment is performed by MRI, to identify target and non-target lesions.
19. CT scan or MRI:  Scans should be performed at Screening, Week 8 and then every 8 weeks (7 days) during the first 48 weeks of the Treatment Continuation Period and then 
every 12 weeks (7 days) thereafter in the Treatment Continuation Period, and at the time of disease progression.  All confirmatory scans are to be performed within 4 weeks 
(3 days) of a CR or PR.  If a subject discontinues treatment for reasons other than disease progression, disease assessments should continue every 3 months until disease 
progression, initiation of new anti-cancer treatment, subject withdrawal of consent, or death.
20. Bone Scan:  A bone scan is required for all subjects at Screening.  For subjects without bone disease at baseline, subsequent bone scans should be performed as clinically 
indicated.  Subjects with bone metastases at baseline should have a bone scan performed at Week 12 and then every 12 weeks (7 days) thereafter in the Treatment 


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Continuation Period, or as clinically indicated, and at the time of disease progression.  If a subject discontinues treatment for reasons other than disease progression, bone scans 
should continue every 3 months until disease progression, initiation of new anti-cancer treatment, subject withdrawal of consent, or death.
21. CTC-Janssen:  Whole blood samples will be obtained at Screening; pre-dose on Day 1 (Week 1) and Day 22 (Week 4) of the Combination Treatment Period; pre-dose on Day 1 
of Weeks 8, 16, 24 and 32 of the Treatment Continuation Period; and at time of disease progression.
22. CTC-EPIC:  Whole blood samples will be obtained at Screening, pre-dose on Day 1 of Week 8 of the Treatment Continuation Period, and at the time of disease progression for 
protein and genomic analysis.
23. Predictive Biomarkers Tumor Tissue:  For subjects enrolled into the study, additional slides of tumor tissue samples will be collected and submitted to the designated laboratory 
for analysis once a subject has received their first dose of GSK2636771 on Week 1, Day 1 of the Combination Treatment Period.  Tumor tissue may be obtained from archived 
tissue samples or fresh tumor tissue submitted for the PTEN testing.  If additional tumor tissue is not available, no new biopsy procedure is required for predictive biomarker 
analysis.  Refer to the SRM for details about the number of slides to be submitted, preparation, handling and shipping.
24. Tumor Biopsies for PD and progression: These biopsies are optional and may be undertaken in select cases upon agreement with the investigator and when consent is 
provided by the subject. For pharmacodynamic biomarker analyses, fresh tissue biopsies would be collected between Day 12 of the Enzalutamide Run-in Period and Week 
1/Day 1, prior to any treatment with GSK2636771, and 2-4 hours post dose between Days 8 and 15 of the Combination Treatment Period (post-treatment).  For subjects who 
consent to the optional progression biopsy, a fresh tumor biopsy should be completed if the subject initially responded to combination treatment and then progressed..
25. cfDNA/RNA/Soluble Markers:  Plasma samples will be obtained from collected blood samples at Screening, pre-dose on Weeks 1, 4, 8, 16, 24, and 32 of the Combination 
Treatment Period, and at the time of discontinuation of treatment due to disease progression.  Plasma will be analyzed for genomic changes in the circulating tumor DNA, RNA, 
and soluble markers.
26. Genetic Research: A 6-mL blood sample should be collected after Screening, preferably on Week 1, Day 1 of the Combination Treatment Period, if informed consent has been 
obtained for genetic research.
27. Study Treatment: Enzalutamide monotherapy should be taken once daily during the Enzalutamide Run-In Period.  Enzalutimide will be self adiministered in the clinic on Day 14 
of the Enzalutamide Run-In Period.  GSK2636771 and enzalutamide will be administered in the clinic on Week 1, Day 1 of the Combination Treatment Period and on days when 
blood, plasma, and/or urine samples are collected for analysis of PK, CTC, and/or urine electrolytes.
28. Post-Treatment Follow-Up Visit: ONLY subjects who withdraw during the Enzalutamide Run-In Period or withdraw from study treatment due to disease progression see 
Section 5.2) should have a post-treatment follow-up visit conducted within approximately 30 days (-2/+7 days) of last dose of study treatment(s).  If a subject is unable to return to 
the clinic due to hospitalization, site staff is encouraged to call subject for assessment of AEs.  
29. Extended Follow-Up Visits:  Subjects who withdraw from study treatment without disease progression should be contacted every 3 months (14 days) until disease 
progression, death, withdrawal of consent, or subject is lost to follow-up.  Contact may include a clinic visit, a telephone contact, or an e-mail.  The initiation of any new anti-cancer 
treatments and date of last contact should be documented.
30. Post-Extended Follow-Up/EOS Visit:  ONLY subjects who discontinue the Extended Follow-Up Visits should have a Post-Extended Follow-Up/EOS Visit performed.
31. These assessments should be completed at the time of disease progression that leads to discontinuation of treatment.  Subjects are not required to discontinue treatment on the 
basis of PSA progression alone or for the worsening of an isolated disease site that is not clinically significant (see Section 5.2).
32. When collected as part of the routine standard of care for a subject, LDH will be reported.
33. Complete clinical chemistries laboratory assessments at Week1/Day 1 and again on either Day 3 or Day 4.  The Day 3 or Day 4 assessments can be completed at a local 
laboratory and does not require a clinic visit.  The hematology panel does NOT need to be collected on Day 3/ Day.4. Review of these labs must occur before Week 2, Day 1 visit.
34. Includes assessments for 25-OH D and 1,25-OH2 D. 
35. Includes urine and blood and/or serum samples.  Must be collected at the same time of day (1 hour) to eliminate diurnal effects, and after fasting.  See SRM for additional details 
on the specific assessments and sample collection


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8.2.
Consent
A signed, written ICF must be obtained from the subject prior to any study-specific 
procedures or assessments.
Each subject will have adequate time to provide written informed consent of his or her 
own free will and prior to conducting any study procedures according to International 
Conference on Harmonization (ICH) and applicable local regulations and guidelines.  
Each subject will be provided a copy of their signed ICF prior to the initiation of any 
study procedures.
8.2.1.
Consent for Pre-Screening
The subject will be asked to provide written informed consent for pre-screening prior to 
any of the pre-screening assessments outlined in the Time and Events Tables 
(Section 8.1) being performed.
8.2.2.
Consent for Screening
If, during pre-screening, the subject is determined to have a PTEN deficient tumor, the 
subject will be asked to provide written informed consent prior to screening for 
enrollment in the study.  The investigator or other designated study personnel will 
determine if the subject is eligible for enrollment in the study by reviewing the eligibility 
criteria and completing all of the Screening assessments outlined in the Time and Events 
Tables in Section 8.1.
8.3.
Pre-Screening and Screening
8.3.1.
Pre-Screening:  Determination of PTEN Deficiency Status
A pre-screening assessment must be completed to determine the PTEN deficiency status 
of the subject’s tumor. 
After written informed consent is provided by the subject, archived tissue will be 
submitted to determine the PTEN deficiency status of the subject’s tumor.  If archival 
tumor tissue is not available, fresh tumor tissue should be obtained by a pre-treatment 
biopsy to determine PTEN deficiency.  The PTEN testing will be performed at a GSK 
selected laboratory or laboratories and the tumor specimen should be provided to that 
laboratory or laboratories.  The PTEN status will be communicated to sites by GSK 
authorized personnel.
If analysis of the archival tumor tissue specimen is not PTEN-deficient, fresh tumor 
tissue may be submitted to determine PTEN deficiency.
Details regarding pre-screening assessment and procedures with handling, processing and 
shipping tumor tissue samples are provided in the SRM.


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8.3.2.
Screening
Subjects with confirmed PTEN deficiency and have provide written informed consent for 
screening will be eligible to undergo specific screening assessments to determine 
eligibility for the study.
Screening assessments and procedures will be performed as indicated in the Time and 
Events Tables (Section 8.1).  Screening assessments may be carried out over one or more 
days but should be completed within 14 days prior to the first planned dose of 
enzalutamide monotherapy (Day 1 of Enzalutamide Run-In Period), unless otherwise 
indicated.
Details regarding screening assessments and procedures are provided in the SRM.
8.4.
Demographics and Medical History
Demographic data will include gender, year of birth, height, weight, ethnicity and 
geographic ancestry.
Medical, surgical, and treatment history including date of first diagnosis, histology, 
current sites of disease as well as cardiovascular risk factors, alcohol and tobacco history, 
plus family history will be taken as part of the medical history and disease status.
8.5.
Critical Baseline Assessment
Cardiovascular medical history/risk factors will be assessed at baseline.
8.6.
Safety
Measurements used to evaluate safety will include physical examinations, vital sign (BP, 
temperature and heart rate) measurements, ECOG performance status, 12-lead ECGs, 
ECHO/MUGA, clinical laboratory tests and monitoring for AEs.  Planned time points for 
all safety assessments are listed in the applicable Time and Events Tables (Section 8.1).
Additional time points for safety tests (such as vital signs, physical examinations or 
laboratory tests) may be added during the course of the study based on newly available 
data to ensure appropriate safety monitoring.
8.6.1.
Physical Examination
A complete physical examination will be performed by a qualified physician according to 
local practices.  At minimum, the examination should include assessments of the head 
and neck, eyes, ears, nose, throat, skin, thyroid, neurological, lungs, cardiovascular, 
abdomen (liver and spleen), lymph nodes and extremities.  Complete physical 
examinations will be performed as indicated in the Time and Events Tables (Section 8.1) 
and as medically indicated throughout the study.
Height and weight will be measured and recorded as indicated in the Time and Event 
Tables (Section 8.1).


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8.6.2.
Vital Signs
Vital sign measurements will include BP, temperature, and heart rate.  Vital signs may be 
measured as indicated in the Time and Event Tables (Section 8.1) or more frequently if 
warranted by clinical condition of the subject.  Refer to the SRM for details regarding 
measurement of vital signs.
8.6.3.
ECOG Performance Status
A subject’s performance status will be assessed using the ECOG performance status scale 
(Appendix 1) as indicated in the Time and Events Tables (Section 8.1).
8.6.4.
Electrocardiogram
Electrocardiograms (12-Lead ECGs) will be performed as indicated in the Time and 
Events Tables (Section 8.1) and obtained using an ECG machine that automatically 
calculates the heart rate and measures PR, QRS, QT, and QTc intervals.

At each assessment, a 12-lead ECG will be performed by qualified personnel at the 
site after the subject has rested at least 5 minutes in a semi-recumbent or supine 
position.

If there are any clinically significant abnormalities including, but not limited to, 
QTcF >500 msec, confirm with two additional ECGs taken at least 5 minutes apart.

Refer to Section 7.2.1 for QTc stopping criteria and additional QTc readings that 
may be necessary.

Results of the ECG will be transmitted to a central storage facility.  Any duplicate 
ECGs performed will be collected and evaluated, transmitted and stored in the same 
manner.
Electrocardiograms (ECGs) may be centrally reviewed during the study on a post-
hoc basis in response to any potential ECG safety concerns or at the end of the study.  
Any findings will be summarized and shared with study investigators but are not 
intended for individual subject safety management.
Refer to the SRM for further details on submission of ECGs.
8.6.5.
Echocardiogram and/or Multi-gated Acquisition (MUGA) Scans
Echocardiograms (ECHOs) or MUGA scans will be performed at baseline to assess 
cardiac ejection fraction and cardiac valve morphology for the purpose of study 
eligibility, as specified in the Time and Events Tables (Section 8.1).  Additional ECHO 
assessments may be performed if clinically warranted.  The evaluation of the 
echocardiographer should include an evaluation for LVEF and both right and left-sided 
valvular lesions.
Copies of all ECHOs or MUGA scans performed on subjects who experience an absolute 
decrease >10% in LVEF compared to baseline concurrent with LVEF < institutional LLN 
may be required by GSK for review.


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Refer to the SRM for further details on submission of ECHOs or MUGA scans.
8.6.6.
Laboratory Assessments
Laboratory tests may be done up to 24 hrs prior to the scheduled visit.  Laboratory test 
results are to be reviewed prior to the administration of study treatment.
Liver function tests and urine tests for UPC may be performed up to 72 hrs prior to the 
scheduled visit in order to have results available for review by investigator prior to the 
scheduled visit date.
Any laboratory test with a value outside the normal range may be repeated during 
Screening at the discretion of the investigator.  A subject with a laboratory value outside 
the reference range(s) may be included only if the investigator and GSK Medical Monitor 
agree that it is unlikely to introduce additional risk factors and will not interfere with 
study procedures.
All laboratory tests with values that are significantly abnormal during participation in the 
study or within 30 days after the last dose of study treatments should be repeated until the 
values return to normal or baseline.  If such values do not return to normal within a 
period judged reasonable by the investigator, the etiology should be identified and the 
sponsor notified.
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 (i.e., AE, SAE or dose modification) 
the results must be recorded in the subject’s eCRF.
All laboratory samples must be appropriately labelled and submitted with the applicable 
laboratory requisition form(s) according to central or local laboratory guidelines.  
Reference ranges will be provided to the site for each laboratory used by the site during 
the course of the study.
Refer to the SRM for details on the appropriate processing, handling and shipping of 
samples to avoid duplicate and/or additional blood draws.


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Table 17
Clinical Laboratory Assessments
Hematology
Platelet Count
RBC Indices:
Automated WBC Differential:
WBC Count (absolute)
MCV
Neutrophils
Hemoglobin
MCH
Lymphocytes
Hematocrit
Monocytes
Eosinophils
Clinical Chemistry
BUN
Potassium
AST 
Total and direct bilirubin1
Creatinine 
Chloride2
ALT
Uric Acid2
Glucose
Total CO2
Alkaline phosphatase
Albumin
Sodium
Calcium
Lactate dehydrogenase4
Total Protein
Magnesium
Phosphate
Urine Testing
Urinalysis
Specific gravity
pH, glucose, protein, blood and ketones by dipstick
with microscopy (if clinically warranted or protein >1)
UPC3
Urine electrolytes
Urinary calcium, magnesium and phosphorus; urine creatinine from same urine 
specimen
Other tests
PSA 
Serum Testosterone
Coagulation Tests: PT/PTT/INR
Serum Parathyroid Hormone (PTH)
Ionized Calcium
25-OH D and 1,25-OH2 D
Bone Markers5
Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; BUN, blood urea nitrogen; INR, 
international normalization ratio; MCH, mean corpuscular hemoglobin; MCV, mean corpuscular volume; PSA, prostate-
specific antigen; PT, prothrombin time; PTH, parathyroid hormone; PTT, partial thromboplastin time; RBC, red blood 
cell; ULN, upper limit of normal; UPC, urine/protein/creatinine ratio; WBC, white blood cell
1.
Direct bilirubin is required only if the total bilirubin is elevated (2 times ULN)
2.
Chemistry evaluation of chloride or uric acid is not required where there are logistical constraints.
3.
See Appendix 5.
4.
For sites that routinely collect this information.
5.
Refer to SRM
8.7.
Pharmacokinetic Assessments
8.7.1.
PK Assessments: Dose Escalation Phase
Plasma samples for PK analysis of enzalutamide and N-desmethyl enzalutamide will be 
collected from all subjects on Day 14 of the Enzalutamide Run-In Period.  Blood and 
plasma samples for the analysis of GSK2636771, enzalutamide and N-desmethyl 
enzalutamide will be collected from all subjects on Week 5, Day 29 and during Weeks 8 
and 12 of the Treatment Continuation Period.  These PK samples will be collected to 
evaluate if there is an effect of GSK2636771 on the PK of enzalutamide and to quantify 
the systemic exposure to GSK2636771, enzalutamide and N-desmethyl enzalutamide.


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8.7.2.
PK Assessments:  Dose Expansion Phase
A reduced PK sampling strategy will be used for subjects in the Dose Expansion Phase 
(on Day 29 of Week 5).  Pre-dose blood and plasma samples will also be collected on 
Day 1 of Weeks 8 and 12 of the Treatment Continuation Period) to quantify the systemic 
exposure to GSK2636771, enzalutamide and N-desmethyl enzalutamide.
8.7.3.
PK Blood Sample Collection
Blood and/or plasma samples for PK analysis of GSK2636771 and/or enzalutamide and 
N-desmethyl enzalutamide will be collected at the time points indicated in the Time and 
Events Tables (see Section 8.1).  Whenever possible, blood for PK samples should be 
drawn from the peripheral arm vein or from a central IV port.  Each PK sample should be 
collected as close as possible to the planned time relative to the dose (i.e., time zero) 
administered to the subject on serial PK days.  Once preliminary PK data have been 
reviewed, the planned sample collection times or study day may be revised based on 
newly available data (i.e., to obtain data closer to the time of peak plasma concentration) 
to ensure appropriate monitoring.  These changes must be approved and documented by 
GSK, but will not constitute a protocol amendment.  
For Dose Escalation Phase:  Blood and/or plasma samples for analysis of GSK2636771, 
enzalutamide and N-desmethyl enzalutamide will be collected according to a serial 
sampling scheme in the Dose Escalation Phase.  

Day 14 (Enzalutamide Run-In Period); the day prior to administration of the 
first dose of GSK2636771):  Subjects will be instructed to fast overnight (at least 
8 hrs) and withhold their dose of enzalutamide prior to the study visit on Day 14.  
Study treatments will be administered in the clinic after the pre-dose blood draw 
is completed.  Subjects will continue to fast for 2 hrs post-dose.  Plasma samples 
for analysis of enzalutamide and N-desmethyl enzalutamide will be collected at 
pre-dose and 0.5, 1, 2, 3, 4, and 6 hrs post-dose of enzalutamide (total of 
7 samples).

Day 29, Week 5 (Treatment Continuation Period): Subjects will be instructed 
to fast overnight (at least 8 hrs) and withhold the doses of study treatment prior to 
the study visit. Study treatments will be administered in the clinic after the pre-
dose blood draws are completed.  Subjects will continue to fast for 2 hrs post-
dose.  Blood and plasma samples for the analysis of GSK2636771, enzalutamide 
and N-desmethyl enzalutamide will be collected at pre-dose and 0.5, 1, 2, 3, 4, 
and 6 hrs post-dose (total of 14 samples).

Weeks 8 and 12 (Treatment Continuation Period):  Subjects will be instructed 
to withhold the doses of study treatment prior to the study visit (no overnight fast 
is necessary). Study treatments will be administered in the clinic after the pre-
dose blood draws are completed, either 1 hr before or 2 hrs after a meal. Blood 
and plasma samples for the analysis of GSK2636771, enzalutamide and N-
desmethyl enzalutamide will be collected pre-dose only (total of 2 samples per 
visit).


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For Dose Expansion Phase:  Blood and plasma samples for analysis of GSK2636771, 
enzalutamide and N-desmethyl enzalutamide will be collected according to a sparse 
sampling scheme in the Dose Expansion Phase.  Overnight fast is not necessary for any 
of these PK days. Study treatments should be administered either 1 hr before or 2 hrs 
after a meal.

Day 29, Week 5 (Treatment Continuation Period):  
o
Subjects scheduled for a morning clinic visit will be instructed to withhold 
the doses of study treatments prior to the study visit.  Study treatments will 
be administered in the clinic after the pre-dose blood draws are completed 
(either 1 hr before or 2 hrs after a meal). Blood and plasma samples for
analysis of GSK2636771, enzalutamide and N-desmethyl enzalutamide 
will be collected at pre-dose and 1, 2, and 3 hrs post-dose (total of 
8 samples).
o
Subjects scheduled for an afternoon clinic visit will take their doses of 
study treatments at the usual time in the morning (either 1 hr before or 
2 hrs after a meal).  Blood and plasma samples for analysis of 
GSK2636771, enzalutamide and N-desmethyl enzalutamide will be 
collected approximately 5 to 6, 6 to 7, and 7 to 8 hrs post-dose (total of 
6 samples).

Weeks 8 and 12 (Treatment Continuation Period):  Subjects will be instructed 
to withhold the doses of study treatment prior to the study visit. Study treatments 
will be administered in the clinic after the pre-dose blood draw is completed 
(either 1 hr before or 2 hrs after a meal). Blood and plasma samples for the 
analysis of GSK2636771, enzalutamide and N-desmethyl enzalutamide will be 
collected pre-dose only (total of 2 samples per visit). 
Details of PK blood and plasma sample collection (including volume to be collected), 
processing, storage and shipping procedures are provided in the SRM.
8.7.3.1.
Additional PK Blood Sample Collection
Blood and plasma samples for PK analysis will also be collected within 24-72 hrs after 
the last dose of study treatment(s) at the time of a treatment-emergent AE of special 
interest unless the event occurs on the same day that the Day 14 (Enzalutamide Run-In 
Period) and/or Week 5, Day 29 (Treatment Continuation Period) PK samples are 
obtained.
The date/time of the PK blood and plasma sample draw and the date/time of the last dose 
of study treatments prior to the PK blood and plasma sample draws will be recorded on 
the eCRF.  If the date or time of the last dose of study treatment is unclear, provide the 
subject’s best approximation.  If the date/time of the last dose of study treatment cannot 
be approximated OR PK blood or plasma samples cannot be collected in the time period 
indicated above, do not obtain a PK samples.  Refer to the SRM for instructions on 
sample handling and shipping of the PK samples.


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8.7.4.
Pharmacokinetic Sample Analysis
Blood and plasma analysis will be performed under the control of GSK Platform 
Technology and Science-Drug Metabolism and Pharmacokinetics (PTS-DMPK)/Scinovo, 
the details of which will be included in the SRM. Concentrations of GSK2636771, 
enzalutamide and N-desmethyl enzalutamide will be determined in blood and plasma 
samples using the currently approved bioanalytical methodology. Raw data will be 
archived at the bioanalytical site (detailed in the SRM).
Once the blood and plasma has been analyzed for GSK2636771, enzalutamide and N-
desmethyl enzalutamide any remaining blood or plasma may be analyzed for other 
compound-related metabolites and the results reported under a separate GSK PTS-DMPK 
protocol.
8.7.5.
Meals, Alcohol, Tobacco and Activity Restrictions
Meals
Subjects will be instructed to take study treatments at least 1 hr before or 2 hrs after a 
meal unless otherwise instructed due to PK, CTC and/or urine electrolyte sampling (see 
Section 6.3 for details).
Alcohol
During each dosing session in which serial PK samples are collected, subjects will 
abstain from ingesting alcohol for 24 hrs prior to dosing until collection of the final PK 
sample.
Tobacco
Smoking while in the clinical unit will not be permitted. Subjects who use tobacco 
products may use nicotine patches while they are in the clinical unit.
Activity
All subjects will abstain from strenuous exercise for 48 hrs prior to each blood collection 
for PK and/or clinical laboratory tests.  Subjects may participate in light recreational 
activities during studies (e.g., watch television, reading).
8.8.
Clinical Activity
Refer to the Time and Events Tables (Section 8.1) for the schedule of disease 
assessments to be performed to assess the clinical activity of the combination therapy.  
Assessments must be performed on a calendar schedule and should not be affected by 
dose interruptions or delays.  For post-baseline assessments, a window of 7 days is 
permitted to allow for flexible scheduling.  Additional assessments may be performed as 
clinically indicated.
Refer to the SRM for further details on submission of CT scans, MRIs and bone scans.


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8.8.1.
Clinical Activity Endpoints
The secondary endpoint to evaluate the clinical activity of oral GSK2636771 + 
enzalutamide will be assessed using the disease progression endpoint (see Section 
8.8.2.3) which differs from the disease progression criteria that lead to discontinuation of 
treatment (see Section 5.2).  CTC response will also be determined and reported as an 
exploratory endpoint.
8.8.2.
Disease Assessment
The primary endpoint is to evaluate the 12 week non-PD rate of oral GSK2636771 + 
enzalutamide according to PCWG2 guidelines (either by RECIST 1.1, PSA progression, 
and/or progression in bone). These assessments at Week 12 should occur at least 12 
weeks (+5day window) after start of combination treatment.
For this study, the disease assessment will include the assessment of multiple parameters: 
RECIST 1.1 (see Appendix 4), PSA values per PCWG2 criteria (see Section 8.8.2.1), and 
radiographic response per PCGW2 criteria (see Section 8.8.2.2).
8.8.2.1.
PSA Response per PCWG2 Criteria
Only subjects who have a baseline PSA value and at least one post-baseline assessment 
will be included in the analysis of PSA response.
PSA Response Rate is defined as proportion of subjects with a decrease of ≥50% in the 
PSA concentration from the baseline PSA value determined at least 12 weeks after start 
of treatment and confirmed after ≥4 weeks by an additional PSA evaluation.
PSA progression [Scher, 2008] is defined as:

If there has been a decline from baseline: time from start of therapy to first PSA 
increase that is 25% and 2 ng/mL in absolute value from the nadir, and which is 
confirmed by a second value 3 or more weeks later (i.e., a confirmed rising trend) at 
least 12 weeks after the start of combination treatment

If there has NOT been a decline from baseline: time from start of therapy to first 
PSA increase that is 25% and 2 ng/mL in absolute value from the baseline value, 
determined at least 12 weeks after start of combination treatment
8.8.2.2.
Radiographic Response per PCWG2 Criteria
Bone progression [Scher, 2008] is defined as the appearance of ≥2 new lesions, and, for 
the first reassessment only, a confirmatory bone scan performed 6 or more weeks later 
that shows a minimum of 2 or more additional new lesions.  The first post-treatment bone 
scan (Week 12) will be used as the baseline scan with which all future bone scans are 
compared. The date of progression is the date of the first scan that shows a minimum of 2 
additional new lesions.  Subjects should not be discontinued from study treatment(s) due 
to the occurrence of bone scan changes in the first 12 weeks of combination treatment 
that do not meet PCWG2 guidelines for progression.


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8.8.2.3.
Disease Progression Endpoint
The disease progression endpoint is defined by 1 or more of the following criteria:

PSA progression according to the PCWG2 criteria (Section 8.8.2.1) with 
accompanying progression by RECIST 1.1 or bone scan for subjects with 
measeurable baseline disease OR PSA progression if no measurable baseline 
disease

Radiographic progression in soft tissue or bone by RECIST 1.1 for subjects with 
measurable disease

Bone progression on bone scan according to the PCWG2 criteria 
(Section 8.8.2.2).
Subjects are not required to discontinue treatment on the basis of meeting PSA 
progression alone or for the worsening of an isolated disease site that is not clinically 
significant (see Section 5.2) 
8.9.
Translational Research
The analysis of biomarkers may depend on emerging pre-clinical and clinical biomarker 
data.  All collected samples will be retained for a maximum of 15 years after the last 
subject completes the study. If subject withdraws consent for further treatment and data 
collection, all samples collected for the biomarker analysis at the time of withdrawal will 
still proceed for analysis to meet the intended objectives defined in this protocol. Details 
on sample collection, processing, storage and shipping procedures for all plasma samples 
are provided in the SRM.
8.9.1.
Predictive Biomarkers
For subjects enrolled into the study, additional slides of tumor tissue samples will be 
collected and submitted to the designated central laboratory for analysis once a subject 
has received their first dose of GSK2636771 on Week 1, Day 1 of the Combination 
Treatment Period.  The remaining tumor tissue submitted for the PTEN testing may be 
utilized for predictive biomarker analysis.  If additional tumor tissue is not available, no 
newy biopsy procedure is required in order to obtain tumor tissue for predictive 
biomarker analysis.  
Genetic changes known to alter or regulate PTEN function including mutation, loss of 
heterozygosity (LOH), silencing due to promoter methylation may be assessed.  
Additional proteins, DNA, RNA, or microRNA, related to activity of GSK2636771and 
enzalutamide or prostate cancer may also be analyzed.  Any remaining tumor tissue may 
also be utilized to further develop a diagnostic assay.
Details on sample collection, processing, storage and shipping procedures are provided in 
the SRM.


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8.9.2.
Tumor Biopsies for PD and Disease Progression
If consent is provided by the subject, optional fresh tumor biopsies may be collected prior 
to combination treatment and 2 to 4 hours post dose on day 8 or 15 of combination 
treatment to understand target engagement and pharmacodyamic effects.  It is preferable 
to repeat biopsy the same lesion to get a clearer picture of pre- and post-treatment effects. 
For subjects who initially responded to combination therapy and then progress, an 
optional progression tumor biopsy is requested in order to better understand the 
mechanism of resistance. It is preferable to obtain this biopsy from a new lesion or a 
lesion which had previously responded and then progressed.  Biopsy samples from other 
lesions will be accepted as well.  Both soft tissue and bone biopsies will be accepted.
Details on sample collection, processing, storage and shipping procedures for all samples 
are provided in the SRM.
8.9.3.
Circulating Tumor Cells
Blood samples will be collected and analyzed to enumerate CTCs in circulation at the 
time points indicated in the Time and Events Tables (Section 8.1).  The enumerated 
CTCs may also be utilized for additional analysis like alterations in AR or PTEN genes 
and may include additional genes implicated in the prostate cancer or related to AR/PI3K 
signalling pathway.  If baselines CTCs are not observed in a subject, GSK may ask to 
terminate the further sampling for CTC enumeration in those subjects.
Additional blood samples will be collected at the time points indicated in the Time and 
Events Tables (Section 8.1) to isolate CTCs using an EPIC Sciences platform.  The 
isolated CTCs will be analyzed for AR variants or other protein markers and potential 
genomic alterations (e.g., PTEN allele loss, AR amplifications, etc.).
If subject withdraws consent for further treatment and data collection, all samples 
collected for the biomarker analysis at the time of withdrawal will still proceed for 
analysis to meet the intended objectives defined in this protocol.
Details on sample collection, processing, storage and shipping procedures for all blood 
and tissue samples are provided in the SRM.
8.9.3.1.
CTC Conversion Rate
CTC enumeration will be performed at a central laboratory using the analytically valid 
CellSearch system (Veridex LLC).  For subjects with baseline CTC counts of 5 cells per 
7.5 mL of blood, a conversion is defined as a decline in the CTC count to <5 cells per 
7.5 mL of blood.  Genetic analysis of CTCs may also be performed by other laboratories.
8.9.4.
Circulating Cell Free DNA, RNA and Soluble Markers
Tumor-specific cfDNA levels detected in plasma or serum have been found to correlate 
with increasing tumor burden and decline following therapy.  Furthermore, cfDNA in 
cancer subjects can harbor many genetic alterations (mutations, copy number changes, 
aberrant methylation), which are generally consistent with the tumor of origin. Thus, 
tumor-specific circulating cfDNA has the potential to be a useful biomarker of 


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therapeutic response as well as offering a less invasive blood based technique for 
identifying predictive biomarkers.
Plasma samples for analysis of cfDNA, RNA and soluble markers will be collected at the 
time points provided in the Time and Events Tables in Section 8.1.
If subject withdraws consent for further treatment and data collection, all samples 
collected for the biomarker analysis at the time of withdrawal will still proceed for 
analysis to meet the intended objectives defined in this protocol.
Details on sample collection, processing, storage and shipping procedures for all plasma 
samples are provided in the SRM.
8.10.
Genetic Research
Information regarding genetic research is included in Appendix 7.
8.11.
Exploratory Pharmacokinetic and Pharmacodynamic 
Analysis
Tumor size assessments, expressed as sum of longest diameters or the sum of the 
products of the two largest perpendicular diameters, described as a function of time using 
a 2-parameter model may be explored.  Model parameters will be determined after 
administration of enzalutamide + GSK2636771.
The effect of GSK2636771 and enzalutamide on PSA levels also may be explored.  
Models including a linear model and a maximum effect model (Emax) may be fit to the 
change in PSA levels versus blood or plasma concentrations of GSK2636771, 
enzalutamide, and/or N-desmethyl enzalutamide.
This study will also include biopsies in subjects who consent to these optional 
procedures.  Evaluation of pre and post treatment tumor tissue will be explored to 
determine pharmacodynamic effects.  The mechanism of resistance to combination 
therapy will be explored in subjects who have progressed after initially responding to the 
combination therapy.  
9.
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS
The investigator or site staff will be responsible for detecting, documenting and reporting 
events that meet the definition of an AE or SAE as outlined in Section 9.1 and 
Section 9.2, respectively.
9.1.
Definition of an AE
An AE is any untoward medical occurrence in a subject or clinical investigation subject, 
temporally associated with the use of a medicinal product, whether or not considered 
related to the medicinal product.
Note: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 


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associated with the use of a medicinal product.  For marketed medicinal products, this 
also includes failure to produce expected benefits, abuse, or misuse.
Examples of events meeting the definition of an AE include:

Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or grade of the condition

New conditions detected or diagnosed after study treatment administration even 
though it may have been present prior to the start of the study

Signs, symptoms, or the clinical sequelae of a suspected interaction

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
treatment or a concomitant medication (overdose per se will not be reported as an 
AE/SAE).
“Lack of efficacy” or “failure of expected pharmacological action” per se is not to be 
reported as an AE or SAE.  However, any signs and symptoms and/or clinical sequelae 
resulting from “lack of efficacy” will be reported as an AE or SAE, if they fulfill the 
definition of an AE or SAE. 
Events that do not meet the definition of an AE include:

Medical or surgical procedure (e.g., endoscopy, appendectomy); the condition that 
leads to the procedure is an AE.

Situations where an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).

Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present 
or detected at the start of the study that do not worsen.

The disease/disorder being studied or expected progression, signs, or symptoms of 
the disease/disorder being studied, unless more severe than expected for the subject’s 
condition. 
9.2.
Definition of an SAE
A serious adverse event (SAE) is any untoward medical occurrence that, at any dose:
a.
Results in death
b.
Is life-threatening
NOTE:  The term 'life-threatening' in the definition of 'serious' refers to an event in 
which the subject was at risk of death at the time of the event.  It does not refer to an 
event, which hypothetically might have caused death, if it were more severe.
c.
Requires hospitalization or prolongation of existing hospitalization
NOTE:  In general, hospitalization signifies that the subject has been detained 
(usually involving at least an overnight stay) at the hospital or emergency ward for 
observation and/or treatment that would not have been appropriate in the physician’s 
office or outpatient setting. Complications that occur during hospitalization are AEs. 


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If a complication prolongs hospitalization or fulfills any other serious criteria, the 
event is serious.  When in doubt as to whether “hospitalization” occurred or was 
necessary, the AE should be considered serious.
Hospitalization for elective treatment of a pre-existing condition that did not worsen 
from baseline is not considered an AE.
d.
Results in disability/incapacity, or
NOTE:  The term disability means a substantial disruption of a person’s ability to 
conduct normal life functions.  This definition is not intended to include experiences 
of relatively minor medical significance such as uncomplicated headache, nausea, 
vomiting, diarrhea, influenza, and accidental trauma (e.g. sprained ankle) which may 
interfere or prevent everyday life functions but do not constitute a substantial 
disruption.
e.
Is a congenital anomaly/birth defect. 
f.
Medical or scientific judgment should be exercised in deciding whether reporting is 
appropriate in other situations, such as important medical events that may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize 
the subject or may require medical or surgical intervention to prevent one of the 
other outcomes listed in the above definition. These should also be considered 
serious. Examples of such events are invasive or malignant cancers, intensive 
treatment in an emergency room or at home for allergic bronchospasm, blood 
dyscrasias or convulsions that do not result in hospitalization, or development of 
drug dependency or drug abuse.
g.
Protocol-Specific SAES:

All events of possible study treatment-induced liver injury with 
hyperbilirubinemia defined as ALT 3 times ULN, and

Bilirubin 2 times ULN (>35% direct) (or ALT ≥3 times ULN and INR >1.5 if 
INR is measured) or termed ‘Hy’s Law’ events (INR measurement is not 
required and the threshold value stated will not apply to patients receiving 
anticoagulants).
NOTE:  Bilirubin fractionation should be performed if testing is available.  If 
testing is not available, record presence of detectable urinary bilirubin on 
dipstick indicating direct bilirubin elevations and suggesting liver injury.  If 
testing is unavailable and a subject meets the criterion of total bilirubin ≥2 times 
ULN, then the event is still reported as a SAE.  If INR is obtained, include 
values on the SAE form.  INR elevations >1.5 suggest severe liver injury.

Any new primary cancer(s)
9.2.1.
Sentinel Events
A Sentinel Event is a GSK-defined SAE that is not necessarily drug-related but has been 
associated historically with adverse reactions for other drugs and is therefore worthy of 
heightened pharmacovigilance.  The GSK Medical Monitor is accountable for reviewing 
all SAEs for possible Sentinel Events which is mandated at GSK.  The GSK Medical 


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Monitor may request additional clinical information on an urgent basis if a possible 
Sentinel Event is identified on SAE review.  The current GSK-defined Sentinel Events 
are listed below:

Acquired Long QT Syndrome

Agranulocytosis/Severe Neutropenia 

Anaphylaxis & Anaphylactoid Reactions 

Hepatotoxicity

Acute Renal Failure

Seizure

Stevens-Johnson Syndrome/Toxic Epidermal Necrosis
9.3.
Laboratory and Other Safety Assessment Abnormalities 
Reported as AEs and SAEs
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis), or 
other safety assessments (e.g., ECGs, radiological scans, vital signs measurements) 
including those that worsen from baseline, and event 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 an SAE.
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.
9.3.1.
Cardiovascular Events
Investigators will be required to fill out event specific data collection tools for the 
following AEs and SAEs:  

Myocardial infarction/unstable angina

Congestive heart failure

Arrhythmias

Valvulopathy

Pulmonary hypertension


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
Cerebrovascular events/stroke and transient ischemic attack

Peripheral arterial thromboembolism

Deep venous thrombosis/pulmonary embolism

Revascularization
This information should be recorded in the specific cardiovascular eCRF within 1 week 
of when the AE/SAE(s) are first reported.
9.3.2.
Death Events
In addition, all deaths, whether or not they are considered SAEs, will require a specific 
death data collection tool to be completed.  The death data collection tool includes 
questions regarding cardiovascular (including sudden cardiac death) and non-
cardiovascular death.
This information should be recorded in the specific death eCRF within 1 week of when 
the death is first reported.
9.4.
Disease-Related Events and/or Disease-Related Outcomes 
Not Qualifying as SAEs
An event which is part of the natural course of the disease under study (i.e., disease 
progression or hospitalization due to disease progression) does not need to be reported as 
an SAE.
Death due to disease under study is to be recorded on the Death eCRF form.
However, if the underlying disease (i.e., progression) is greater than that which would 
normally be expected for the subject, or if the investigator considers that there was a 
causal relationship between treatment with study treatment(s) or protocol 
design/procedures and the disease progression, then this must be reported as an SAE.
9.5.
Time Period and Frequency of Detecting AEs and SAEs
The investigator or site staff is responsible for detecting, documenting and reporting 
events that meet the definition of an AE or SAE.
AEs will be collected from the time the first dose of enzalutamide is administered on 
Day 1 of the Enzalutamide Run-In Period until 30 days following discontinuation of 
study treatments regardless of initiation of a new cancer therapy or transfer to hospice.
SAEs will be collected over the same time period as stated above for AEs.  In addition, 
any SAE assessed as related to study participation (e.g., protocol-mandated procedures, 
invasive tests, or change in existing therapy), study treatment or GSK concomitant 
medication must be recorded from the time a subject consents to participate in the study 


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up to and including any follow-up contact. All SAEs will be reported to GSK within 
24 hrs, as indicated in Section 9.5.2.
After discontinuation of study treatment, the investigator will monitor all AEs/SAEs that 
are ongoing until resolution or stabilization of the event or until the subject is lost to 
follow-up.  At any time after 30 days the investigator may report any AE that they 
believe possibly related to study treatment.
9.5.1.
Method of Detecting AEs and SAEs
Care must be taken not to introduce bias when detecting AEs and/or SAEs.  Open-ended 
and non-leading verbal questioning of the subject is the preferred method to inquire about 
AE occurrence.  Examples of 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?”
9.5.2.
Prompt Reporting of SAEs and Other Events to GSK
SAEs, pregnancies (in female partner of male subject), and liver function abnormalities 
meeting pre-defined criteria will be reported promptly by the investigator to GSK as 
described in the following table once the investigator determines the event meets the 
protocol definition for that event.


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Initial Reports
Follow-up Information on a Previous 
Report
Type of Event
Time Frame
Documents
Time Frame
Documents
All SAEs
24 hrs
SAE data collection 
tool
24 hrs
Updated SAE data 
collection tool 
“Cardiovascular (CV) 
events” and/or 
“death”
Initial and 
follow-up 
reports to be 
completed 
within 1 week 
of when the 
CV event or 
death is 
reported
“CV events” 
and/or “death” 
data collection 
tool(s) if 
applicable
Initial and 
follow-up reports 
to be completed 
within 1 week of 
when the CV 
event or death is 
reported
Updated “CV 
events” and/or 
“death” data 
collection tool(s) if 
applicable
Pregnancy
2 Weeks
Pregnancy 
Notification Form
2 Weeks
Pregnancy 
Follow-up Form
Liver chemistry abnormalities:
ALT 3 times ULN and 
bilirubin 2 times ULN 
(>35% direct) (or ALT 
3 times ULN and INR 
>1.5, if INR is 
measured)3
24 hrs1
SAE data collection 
tool;
Liver Event eCRF 
and liver imaging 
and/or biopsy 
eCRFs if 
applicable2
24 hrs
Updated SAE data 
collection tool. 
Updated Liver Event 
eCRF2
ALT 5 times ULN; ALT 
3 times ULN with 
hepatitis or rash or 
3 times ULN 4 weeks
24 hrs1
Liver Event eCRF2
24 hrs
Updated Liver Event 
eCRF2
ALT 3 times ULN and 
<5 times ULN and 
bilirubin <2 times ULN
24 hrs1
Liver Event eCRF 
does not need to be 
completed unless 
elevations persist 
for 4 weeks or 
subject cannot be 
monitored weekly 
for 4 weeks2
Abbreviations: ALT, alanine aminotransferase; eCRF, electronic case report form; GSK, GlaxoSmithKline; hrs, hours; 
INR, international normalization ratio; SAE, serious adverse event; ULN, upper limit of normal
1.
GSK to be notified at onset of liver chemistry elevations to discuss subject safety.
2.
Liver Event Documents (i.e., “Liver Event eCRF” and “Liver Imaging eCRF” and/or “Liver Biopsy eCRF”, as 
applicable) should be completed as soon as possible
3.
INR measurement is not required; if measured, the threshold value stated will not apply to subjects receiving 
anticoagulants.
Methods for detecting, recording, evaluating, and following up on AEs and SAEs are 
provided in the SRM.


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9.5.3.
Regulatory Reporting Requirements for SAEs
Prompt notification of SAEs by the investigator to GSK is essential so that legal 
obligations and ethical responsibilities towards the safety of subjects are met.
GSK has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a product under clinical investigation.  GSK will 
comply with country specific regulatory requirements relating to safety reporting to the 
regulatory authority, IRB/IEC and investigators.
Investigator safety reports are prepared for suspected unexpected serious adverse 
reactions according to local regulatory requirements and GSK policy and are forwarded 
to investigators as necessary.
An investigator who receives an investigator safety report describing a SAE(s) or other 
specific safety information (e.g., summary or listing of SAEs) from GSK will file it with 
the IB and will notify the IRB/IEC, if appropriate according to local requirements.
9.6.
Reporting of Pregnancy
The investigator must attempt to collect pregnancy information on any female partners of 
male study subjects who become pregnant while the subject is enrolled in the study.  
Pregnancy information must be reported to GSK as described below.
Any pregnancy that occurs during study participation must be reported using a clinical 
trial pregnancy form.  To ensure subject safety, each pregnancy must be reported to GSK 
within 2 weeks of learning of its occurrence.  The pregnancy must be followed up to 
determine outcome (including premature termination) and status of mother and child.  
Pregnancy complications and elective terminations for medical reasons must be reported 
as an AE or SAE.  Spontaneous abortions must be reported as an SAE.
Any SAE occurring in association with a pregnancy brought to the investigator’s 
attention after the subject has completed the study and considered by the investigator as 
possibly related to the study treatment, must be promptly reported to GSK.
10.
CONCOMITANT MEDICATIONS AND NON-DRUG 
THERAPIES
Subjects will be asked to provide a complete list of prescription and OTC medications 
that have been taken within 4 weeks prior to Screening.  Subjects will be instructed to 
inform the investigator prior to starting any new medication(s), including herbal and OTC 
products, taken from the time of the first dose of enzalutamide monotherapy on Day 1 of 
the Enzalutamide Run-In Period until the end of the study (i.e., through the post-
treatment follow-up visit).  Any concomitant medication(s), including OTC and herbal 
product(s), taken during the study will be recorded in the eCRF. At a minimum, the drug 
name, dose and the dates of administration are to be recorded.  Additionally, a complete 
list of all prior cancer therapies will be recorded in the eCRF.


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Questions regarding concomitant medications should be directed to the GSK Medical 
Monitor for clarification.
If future changes to the list of permitted or prohibited medications are made as a result of 
emerging data, formal documentation will be provided to the investigative site by GSK.
Any such changes will be communicated to the investigative sites in the form of a letter, 
which should be stored in the study file.
Recommended guidelines for the use of concomitant medication(s) with the combination 
of GSK2636771 with enzalutamide are provided in the following sections.
10.1.
Permitted Medications
Supportive Care:  Subjects should receive full supportive care during the study, 
including transfusions of blood and blood products, and treatment with antibiotics, 
antiemetics, antidiarrheals, calcium supplements, Vitamin D supplements, and analgesics, 
and other care as deemed appropriate, and in accordance with local institutional 
guidelines.
Growth Factors and Bisphosphonates:  The use of growth factors and bisphosphonates 
(if on a stable dose for at least 4 weeks) is permitted while participating in this study.  
However, the initiation of growth factors and bisphosphonates is not allowed during the 
first 4 weeks of study treatment.
Steroids:  Use of steroids is discouraged while subject is undergoing treatment on this 
study.  However, steroids (up to a maximum of 10 mg of prednisone or equivalent) are 
permitted provided that the subject has been on a stable dose for at least 4 weeks prior to 
enrollment.
Anticoagulants:  Prophylactic doses of anticoagulants (i.e., heparin, warfarin) are 
permitted provided that the subject meets the prothrombin time (PTT)/International 
Normalization Ratio (INR) entry criteria (see Section 4.1.2) and INR is monitored in 
accordance with local institutional practice.  Therapeutic doses of warfarin (defined as a 
dose resulting in INR >1.5) are prohibited within 14 days prior to first dose of 
enzalutamide monotherapy on Day 1 of the Enzalutamide Run-In Period through the 
post-treatment follow-up visit.  Caution should be exercised if aspirin is used 
concomitantly with GSK2636771.
NSAIDs: Use of NSAIDs should be avoided during the study.
10.2.
Prohibited Medications and Non-Drug Therapies
The following medications are prohibited within 28 days prior to the first dose of 
enzalutamide monotherapy (Day 1 of the Enzalutamide Run-In Period); unless otherwise 
stated) and while on treatment in this study:

Any investigational drug(s)


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
Other anti-cancer therapy (chemotherapy, radiation therapy, immunotherapy, 
biologic therapy, or hormone therapy other than for replacement).
NOTE:  If administration of medically indicated anti-cancer therapy is required 
while on study, prior approval from a GSK Medical Monitor must be obtained.  
Study treatment must be held while the anti-cancer therapy is administered.  Re-
starting of study treatment following the completion of anti-cancer therapy also 
requires prior approval of the GSK Medical Monitor.

5-alpha reductase inhibitors (e.g., finasteride, dutasteride)

Androgens (e.g., testosterone, dihydroepiandrosterone)

Herbal medication(s) that may affect PSA levels (e.g., saw palmetto)

Other herbal medications including, but not limited to: St. John’s wort, kava, 
ephedra (ma huang), gingko biloba, yohimbe and ginseng.
10.2.1.
Potential Drug Interactions with GSK2636771
10.2.1.1.
GSK2636771 as Perpetrator of Drug-Drug Interactions
A preliminary study suggested the potential of CYP3A4 inhibition by GSK2636771; 
however, subsequent studies using human recombinant CYP3A4 and pooled human liver 
microsomes did not confirm this at concentrations tested (up to 100 M). The 
preliminary study indicated GSK2636771 did not inhibit CYP1A2, 2C8, 2C9, 2C19 and 
2D6 at up to 25 µM (10.8 g/mL), the risk is low but was not fully discharged at higher 
concentrations.  Medications that have a narrow therapeutic index and are substrates of 
CYP3A4 should be used with caution within 7 days or 5 half-lives (whichever is longer) 
prior to the first dose of GSK2636771 (Week 1, Day 1 of the Combination Treatment 
Period) and for the duration of study treatment through the post-treatment follow-up visit 
(Table 18).  Medications that have a narrow therapeutic index and are substrates of 
CYP1A2, CYP2C8, 2C9 and 2C19, CYP2D6 and CYP2B6 should be used with caution.  
GSK2636771 did not inhibit transporters OATP1B1, OATP1B3, breast cancer resistance 
protein (BCRP) and p-glycoprotein (P-gp) up to 23-30 µM in vitro. Due to high 
GSK2636771 concentrations (up to 100 M) observed in the FTIH study (P3B115717), 
there is a risk for renal transporter inhibition; however, in vitro data to discharge this risk 
is pending.  Therefore, medications that are sensitive substrates of renal transporters OAT 
and OCT2 should be used with caution when administered with GSK2636771 (example 
drugs are listed in Table 18). 


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Table 18
Drugs Potentially Affected by GSK2636771: Use with Caution
Drugs/Agents
Therapeutic Area
CYP3A4 Substrates
dihydroergotamine, ergonovine, ergotamine, methylergonovine
Ergot derivatives
Pimozide
Neuroleptic
bepridil, flecainide, lidocaine, mexilitine, amiodarone, quinidine, 
propafenone
Antiarrhythmics
tacrolimus, sirolimus
Immune modulators
quetiapine, risperidone, clozapine, atomoxetine
Miscellaneous
Antiplatelet agents
ticlopidine, prasugrel or ticagrelor
Antiplatelet
Renal Transporter (OAT, OCT2) Substrates 
Methotrexate
Antineoplastic
dofetilde, pilsicainide, procainamide
Antiarrhythmic
Metformin
Antidiabetic
10.2.1.2.
GSK2636771 as Victim of Drug-Drug Interactions
Pre-clinical and in vitro data suggested GSK2636771 is a substrate for UDP-
glucuronosyltransferase (UGT) enzymes, while CYP enzymes do not appear to mediate 
the major metabolism pathways of GSK2636771. Therefore, drugs that are inhibitors and 
inducers of UGT enzymes should be used with caution (Table 19).
Effect on GSK2636771 exposure due to inhibition of transporters OATP1B1 and 
OATP1B3 is low due to the high permeability of GSK2636771. 
Table 19
Drugs that may Potentially Affect GSK2636771: Use with Caution
Generic Drug Name
Therapeutic Area
Inducers of UGT enzymes
rifamycin class agents (e.g., rifampin, rifabutin, rifapentine)
Antibiotics
carbamazepine, phenobarbital, phenytoin, s-mephenytoin
Antiepileptic drugs
Inhibitors of UGT enzymes
Fluconazole
Antifungal
cisapride, probenecid, ranitidine, cyclosporine, diflunisal, sertraline, valproic 
acid, atavaquone, methadone, methsuximide, olanzapine, retigabine
Miscellaneous
Caution is also recommended when GSK2636771 and aspirin are used concomitantly.
10.2.2.
Potential Drug Interactions with Enzalutamide
The following information is provided as an initial reference, however, please refer to the 
approved US FDA prescribing information [Xtandi, 2016] or the Xtandi Prescribing 
Information for the area where it is approved for the most current DDI information and 
contraindicated medications.
Drugs that Inhibit or Induce CYP3A4:  Co-administration of enzalutamide with the 
strong CYP3A4 inhibitor itraconazole caused a slight increase (1.3-fold) in the composite 
AUC for enzalutamide plus N-desmethyl enzalutamide.  Strong CYP3A4 inducers (e.g., 


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carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin, or rifapentine) are likely to 
reduce the plasma exposure of enzalutamide.  Moderate CYP3A4 inducers (e.g., 
bosentan, efavirenz, etravirine, modafinil, nafcillin) and St. John’s Wort may also reduce 
the plasma exposure of enzalutamide.  Investigators should use clinical judgment as to 
whether or not to co-administer these agents.
Drugs that Inhibit or Induce CYP2C8:  Co-administration of enzalutamide with a strong 
CYP2C8 inhibitor (e.g., gemfibrozil) increased the AUC of enzalutamide plus N-
desmethyl enzalutamide by 2.2-fold in healthy volunteers.  Due to the potential for the 
change in enzalutamide exposure, co-administration with a strong CYP2C8 inhibitor is 
not recommended.  If co-administration of enzalutamide cannot be avoided, reduce the 
dose of enzalutamide to 80 mg (2 capsules) once daily.  If the administration of a strong 
CYP2C8 inhibitor is discontinued, the dose of enzalutamide should be increased to the 
previous dose level.
The effects of CYP2C8 inducers on the PK of enzalutamide have not been evaluated; 
therefore, co-administration of a strong or moderate CYP2C8 inducer (e.g., rifampin) 
should be avoided.  Use of concomitant medication(s) with no or minimal CYP2C8 
induction potential is recommended.
Effect of Enzalutamide on Drug Metabolizing Enzymes:  Enzalutamide is a strong 
CYP3A4 inducer and a moderate inducer of CYP2C9 and CYP2C19 in humans and may 
lead to loss of efficacy of many commonly used medicinal products.  Therefore, 
co-administration of enzalutamide with products with a narrow therapeutic range that are 
metabolized by CYP3A4 (e.g., alfentanil, cyclosporine, dihydroergotamine, pimozide, 
quinidine, sirolimus or tacrolimus), CYP2C9 (e.g., phenytoin, warfarin), and CYP2C19 
(e.g., S-mephenytoin) should be avoided as enzalutamide may decrease the plasma 
exposure of these drugs.  If enzalutamide is co-administered with an anticoagulant 
metabolized by CYP2C9 (such as warfarin or acenocoumarol) additional INR monitoring 
should be conducted.
Transporters:  Concomitant use of enzalutamide with medicinal products that are 
sensitive substrates or transporters should generally be avoided if their therapeutic effect 
is of large importance to the subject, and if dose adjustments cannot easily be performed 
based on monitoring of efficacy or plasma concentrations. 
Enzalutamide and N-desmethyl enzalutamide are potential inhibitors, but not substrates, 
of the efflux transporter P-gp.  Enzalutamide may also be an inhibitor of BCRP, MRP2 
and OAT3.  Medicinal products with a narrow therapeutic range that are substrates for 
P-gp (e.g., colchicine, dabigatran etexilate, digoxin), BCRP, MRP2 or OAT3 
(e.g., methotrexate) should be used with caution when administered concomitantly with 
enzalutamide and may require dose adjustment to maintain optimal plasma 
concentrations.  Enzalutamide and its major metabolites are unlikely to inhibit the in vivo 
transport of OATP1B1, OATP1B3, OCT1, OCT2 or OAT1 substrates at clinically 
relevant concentrations.


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11.
LIFESTYLE RESTRICTIONS
11.1.
Contraception Requirements
Male subjects with a female partner of childbearing potential or pregnant must agree to 
use two acceptable methods of contraception from time of Screening until 3 months after 
the last dose of study treatment.  The two acceptable methods of contraception are:
1. Condom (as barrier method) is required, and 
2. One of the following methods is also required:

Established use of oral, injected or implanted hormonal method by female 
partner

Use of intrauterine device or intrauterine system by female partner, or

Tubal ligation performed on female partner at least 6 months prior to the 
time of Screening of male subject

Use of additional barrier method including contraceptive sponge or 
occlusive cap (diaphragm or cervical/vault caps) plus spermicidal agent
(foam/gel/film/cream/suppository)

Vasectomy or other surgical castration of male subject at least 6 months 
prior to the time of Screening of male subject
Abstinence:  Male subjects may also elect abstinence, defined as sexual inactivity 
consistent with the preferred and usual lifestyle of the subject.  Periodic abstinence 
(e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are 
not acceptable methods of contraception.  Complete abstinence from sexual intercourse 
must occur for 14 days prior to the first dose of enzalutamide monotherapy on Day 1 of 
the Enzalutamide Run-In Period, through the dosing period, and until 3 months after the 
last dose of study treatments.
Sperm Donation:  Subjects must not donate sperm from the day of the first dose of 
enzalutamide monotherapy on Day 1 of the Enzalutamide Run-In Period through 
3 months after the last dose of study treatments.
11.2.
Other:  Light Sensitivity and Allergens
During this study, subjects should be instructed to protect themselves against direct sun 
exposure and to avoid exposure to known allergens.  Upon onset of any rash(es) during 
the study, subjects should be instructed to contact the investigator immediately and the 
rash management guidelines in Section 7.3.3 should be followed by investigators/sites.


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11.3.
Other: Hydration
Subjects are to be instructed to avoid dehydration while participating in the study.  
Subjects who have inadequate oral intake or who have difficulty maintaining hydration
should discontinue treatment with GSK2636771 until adequate oral intake can be 
maintained.  If the subject must discontinue treatment for more than 14 days due to 
inadequate oral intake, the subject should be withdrawn from the study.
12.
DATA MANAGEMENT
For this study, data will be collected using a GSK defined eCRF, transmitted 
electronically to GSK and combined with data provided from other sources in a validated 
data system.
Management of clinical data will be performed in accordance with applicable GSK 
standards and data cleaning procedures to ensure the integrity of the data, e.g., removing 
errors and inconsistencies in the data.  Adverse events and concomitant medications 
terms will be coded using the Medical Dictionary for Regulatory Activities (MedDRA)
and an internal validated medication dictionary, GSK Drug.  Electronic CRF (including 
queries and audit trails) will be retained by GSK, and copies will be sent to the 
investigator to maintain as the investigator copy.
When laboratory samples (i.e., hematology and clinical chemistry) are analyzed by a 
central laboratory the results will be stored in a database maintained by the central 
laboratory and transferred to GSK at agreed times.
In all cases, subject initials will not be collected or transmitted to GSK according to GSK 
policy.
13.
DATA ANALYSIS AND STATISTICAL CONSIDERATIONS
13.1.
Hypotheses
13.1.1.
Dose Escalation Phase
No formal statistical hypotheses will be tested.  All analyses will be descriptive and 
exploratory.
13.1.2.
Dose Expansion Phase
The hypothesized non-PD rate is provided in Section 13.2.2.  In this case, a test that non-
PD rate is less than or equal to the null hypothesis rate versus the non-PD rate is greater 
than or equal to the alternative rate is being performed using the stopping rules provided 
in Section 13.2.2.  Descriptive statistics will be used to describe the response data at the 
dose(s) used in the expanded cohort(s).


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13.2.
Sample Size Determination
13.2.1.
Dose Escalation Phase
The total number of subjects to be enrolled in the Dose Escalation Phase is not driven by 
statistical considerations, and will depend on the number of dose levels, number of 
subjects enrolled in each dose level, and the number of subjects enrolled at the 
recommended dose to evaluate long term safety.  It is estimated that 24 subjects will be 
enrolled for the Dose Escalation Phase.  The sample size of 24 subjects for the Dose 
Escalation Phase will provide the following 95% Clopper-Pearson confidence intervals 
(CI) for safety events as well as response data.
Safety Events
Frequency of Safety Events (95% CI)
1
4.2% (0.1% – 21.1%)
2
8.3% (1.0% - 27.0%)
3
12.5% (2.7% - 32.4%)
4
16.7% (4.7% - 37.4%)
8
33.3% (15.6% - 55.3%)
12
50.0% (29.1% - 70.9%)
16
66.7% (44.7% - 84.4%)
20
83.3% (62.6% – 95.3%)
21
87.5% (67.6% - 97.3%)
22
91.7% (73.0% - 99.0%)
23
95.8% (78.9% - 99.9%)
Abbreviation: CI, confidence interval
13.2.2.
Dose Expansion Phase
An initial dose finding will be used to establish the MTD for the combination arm.  Once 
the final dose is confirmed, at least 10 subjects will be enrolled at the appropriate dose 
level, using decision rules defined in Table 3.  The sample size and stopping rules are 
based on the methodology of Lee [Lee, 2008].
Utilizing a null and alternative hypothesis of 5% and 30% respectively, a maximum of 
20 subjects will be enrolled, with a minimum enrollment of 10 subjects. With an actual 
type I error rate (α) of 0.065 and 94.2% power, the design has stopping criteria defined 
for futility.  The trial is designed to stop early for futility if the predictive probability of 
success is less than 6%.  The type I error rate, power, and predictive probability of 
success to stop early for futility were derived from explicitly stating the minimum and 
maximum sample size, futility stopping rate, and selection of the optimizing criterion as 
the maximization of power under the alternative hypothesis.  The Bayesian prior 
probability used in determining the design was Beta (0.10, 0.90), a distribution with a 
mean response rate (defined as lack of disease progression at 12 weeks according to 
PCWG2 criteria) of 10%. Under the null hypothesis, if the true response rate is 5%, the 
expected sample size of the design is 13.1 subjects and probability of early termination 
(PET) is 83.0%. Under the alternative hypothesis, if the true response rate is 30%, the 
expected sample size of the design is 19.7 subjects and PET is 4.3%.


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However, the decision to terminate the Dose Expansion Phase will not depend solely on 
the results of the statistical methodology, but will take all factors into account. Additional 
subjects in a cohort may be enrolled even if the predictive probability suggests a low 
likelihood of activity in the Expansion Cohort (see Section 3.7.1).
13.3.
Data Analysis Considerations
13.3.1.
Analysis Populations
The All Treated Safety Population is defined as all subjects who receive at least one dose 
of GSK2636771 or Enzalutamide.  Safety will be evaluated based on this analysis 
population. 
The All Treated Clinical Activity Population is defined as all subjects who received at 
least one dose of GSK2636771. Clinical activity and evaluation of non-PD rate will be 
based on this analysis population.  This will include subjects from both dose escalation 
and dose expansion.
The All Evaluable Population is defined as all subjects from All Treated Clinical
Activity Population who have at least one post-dose disease assessment and have been 
exposed to study drug for at least 12 weeks or have progressed or have died or have 
withdrawn from the study for any reason. Dose Expansion futility analyses will be based 
on this population.
Pharmacokinetic (PK) 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.
13.3.2.
Analysis Data Sets
The construction of analysis data sets will be performed in accordance with all applicable 
GSK standards and procedures.
13.3.3.
Interim Analysis
13.3.3.1.
Dose Escalation Phase
In the Dose Escalation Phase, available safety data will be reviewed and summarized on 
an ongoing basis.  Review of preliminary safety data from all available dose cohorts will 
be performed in each study treatment combination before starting a new dose cohort and 
before selecting a dose level for expansion. Safety will be reviewed on an ongoing basis 
by the Safety Monitoring Team, composed of study investigators and key GSK personnel 
including the medical monitor, study manager, and study statistician. 
13.3.3.2.
Dose Expansion Phase
After the initial 10 subjects become evaluable at a dose level using a combination of dose 
escalation and dose expansion subjects, 12-week non-PD rate will be reviewed on an 


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ongoing basis and the number of responses observed will be compared with the stopping 
rules provided in Section 13.2.2.
13.3.4.
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.
As it is anticipated that accrual will be spread thinly across centers and summaries of data 
by center would be unlikely to provide valuable information, data from all participating 
centers will be pooled prior to analysis.
All data up to the time of study completion/withdrawal from study will be included in the 
analysis, regardless of duration of treatment.
As the duration of treatment for a given subject will depend on efficacy and tolerability, 
the duration of follow-up will vary between subjects. Consequently there will be no 
imputation for missing data.
Demographic and baseline characteristics will be summarized.
Summaries will generally be provided by cohort.
Details on the determination of tumor response are given in Appendix 4.  Additional 
details on efficacy and safety analyses are provided in Section 13.3.4.1 and 
Section 13.3.4.2, respectively.
13.3.4.1.
Efficacy Analyses
The All Treated Clinical Activity Population will be used for the analysis of efficacy 
data, and will be summarized separately for each dose level combining data from both 
dose escalation and does expansion.  Efficacy analyses will be provided separately for 
each dose level.
Primary Analyses
The primary analysis is to determine whether the 12-week non PD rate is greater than or 
equal to 5%.  The 12-week non PD rate is defined as the percentage of subjects without 
progression at Week 12. Progression is defined by RECIST 1.1 or progression in bone or 
PSA progression with accompanying progression by RECIST 1.1 or bone scan when 
baseline disease present or PSA progression solely if no other baseline disease. Subjects 
with unknown or missing response will not be treated as not having PD (i.e., subjects 
with NE will be included in the denominator when calculating the percentage of non-PD). 
Non-PD rate will be provided along with corresponding exact 95% CIs.


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Secondary Analyses
PSA and RECIST 1.1 response data will be reported.  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 tumor response data.  An exact 95% CI will be computed for the PSA50 
response rate and RECIST 1.1 confirmed response rate.
Further details about the efficacy analyses will be outlined in the RAP.
PSA Response Rate
PSA Response rate (RR) is defined as proportion of subjects with a decrease of 50% in 
the PSA concentration from the baseline PSA value determined at least 12 weeks after 
start of treatment and confirmed after ≥4 weeks by an additional PSA evaluation RR will 
be reported by dose level along with the exact 95% confidence interval. Waterfall plots 
will be presented that show the maximum percentage of change in PSA reduction from 
baseline.
Objective Response Rate
The objective response (ORR) rate is defined as the percentage of subjects with a 
confirmed complete response (CR) or a partial response (PR) at any time as per PCWG3-
modified RECIST 1.1 (Appendix 5). Subjects with unknown or missing response will be 
treated as non-responders, i.e. these subjects will be included in the denominator when 
calculating the percentage. The number and types of responses, as outlined in PCWG3-
modified RECIST 1.1, will be listed and summarized separately, as appropriate. The 
observed ORR, observed confirmed and unconfirmed ORR will be reported at the interim 
and final analysis for each cohort specified in treated dose, if data warrant. The estimates 
along with 95% exact confidence interval (CI) will be provided.
Radiographic Progression-free survival (rPFS) will be defined as the time from 
combination study treatment start until the first date of either disease progression or death 
due to any cause. The date of disease progression will be defined as the earliest date of
disease progression as assessed by the investigator using RECIST version 1.1 or 
progression on bone scan. For subjects who have not progressed or died at the time of the 
rPFS analysis, censoring will be performed using the date of the last adequate disease 
assessment. In addition, subjects with an extended loss to follow-up or who start a new 
anti-cancer therapy prior to a rPFS event will be censored at the date of the last adequate 
disease assessment (e.g. assessment where visit level response is CR, PR, or stable 
disease [SD]) prior to the extended loss to follow-up or start of new anti-cancer therapy, 
respectively. Further details on rules for censoring will be provided in the RAP. rPFS will 
be summarized by dose level specified in expansion cohort using Kaplan-Meier quantile 
estimates along with 2-sided 95% CIs 
Time to PSA progression

If there has been a decline from baseline: time from start of combination treatment to 
first PSA increase that is 25% and 2  ng/mL in absolute value from the nadir, and
which is confirmed by a second value 3 or more weeks later (i.e., a confirmed rising 
trend) at least 12 weeks after the start of treatment.


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
If there has NOT been a decline from baseline: time from start of therapy to first
PSA increase that is 25% and 2  ng/mL in absolute value from the baseline value, 
determined at least 12 weeks after start of treatment.
Time to PSA progression will be summarised using Kaplan-Meier methods by dose level.
Time to radiological progression will be defined as the time from combination study 
treatment start until the first radiological progression by RECIST 1.1 and/ or confirmed 
bone progression as defined in Section 8.8.2.2. Time to radiological progression will be 
summarised using Kaplan-Meier methods by dose level.
13.3.4.2.
Safety Analyses
The All Treated Safety Population will be used for the analysis of safety data. All serially 
collected safety endpoints (e.g., laboratory tests, vital signs, 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.
13.3.4.2.1. Extent of Exposure
The number of subjects administered study treatment will be summarized according to 
the duration of therapy. Details pertaining to dose interruptions or dose modification will 
also be listed.
13.3.4.2.2. Adverse Events
Adverse events (AEs) will be coded using Medical Dictionary for Regulatory Activities 
(MedDRA) and grouped by system organ class.  AEs will be graded by the investigator 
according to the CTCAE v4.0.
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, SAEs and AEs leading to discontinuation of study treatment.  Adverse 
events (AEs), if listed in the CTCAE v4.0, will be summarized by the maximum grade.  
Otherwise, the AEs will be summarized by maximum intensity
Dose-limiting toxicities (DLTs) will be listed for each subject and summarized by dose 
cohort according to International Data Standards Library (IDSL) standards.
The incidence of deaths and the primary cause of death will be summarized.
13.3.4.2.3. Clinical Laboratory Evaluations
Hematology and clinical chemistry data will be summarized at each scheduled 
assessment according to CTCAE v4.0 grade.  Laboratory data will also be summarized 
according to the subjects’ baseline grade and maximum grade post-dose.  The proportion 
of values lying outside the reference range will also be presented for laboratory tests that 
are not graded because there are no associated CTCAE 4.0 criteria.  Summaries will 
include data from scheduled assessments only, and all data will be reported according to 
the nominal visit date for which it was recorded (i.e., no visit windows will be applied).  


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Unscheduled data will be included in “overall” and “any post-screening” summaries 
which will capture a worst-case across all scheduled and unscheduled visits post first 
dose of study treatment.  Further details are provided in the RAP.
13.3.4.2.4. Other Safety Measures
The results of scheduled assessments of vital signs, 12-lead ECG and ECOG performance 
status will be summarized.  Summaries will include data from scheduled assessments 
only.  All data will be reported according to the nominal visit date for which it was 
recorded (i.e., no visit windows will be applied).  All data will be listed.  Further details 
are provided in the RAP.
13.3.4.3.
Pharmacokinetic Analyses
Pharmacokinetic analysis will be the responsibility of the Clinical Pharmacology 
Modeling and Simulation Department, GSK.  Statistical analyses of the PK parameter 
data will be the responsibility of GSK Discovery Biometrics and Clinical Statistics.
Concentration-time data for GSK2636771, enzalutamide and N-desmethyl enzalutamide 
from the Dose Escalation Phase will be analyzed via standard non-compartmental 
methods.  Parameters calculated include the area under the concentration-time curve from 
0 to the last quantifiable blood or plasma concentration [AUC(0-t)] and/or over the 
dosing interval [AUC(0-τ)], Cmax, and Tmax, if data permit.  Population PK parameters 
for GSK2636771 including oral clearance (CL/F), oral volume of distribution (V/F), and 
absorption rate constant (ka) will be estimated by pooling all data from this study with 
historical data, if data permit.  Dependent on the final structural PK model, additional PK 
parameters may also be estimated. Sources of variability in PK parameters will be 
investigated during population modeling.  Demographic parameters including, but not 
limited to age, sex, race, body weight, relevant laboratory parameters, will be evaluated 
as potential predictors of inter- and intra-subject variability for PK parameters.  
Population PK modeling will be performed using the non-linear mixed effects software 
NONMEM (Globomax LLC; Hanover, MD, US).  Population PK of the active 
metabolite(s) may be characterized as appropriate.
Further details of the PK analyses will be described in the RAP.
13.3.4.4.
Pharmacokinetic/Pharmacodynamic Analyses
Exploratory analyses will be performed to examine the relationship(s) between exposure 
(e.g., dose, plasma concentrations of GSK2636771, enzalutamide and N-desmethyl 
enzalutamide or other measure of exposure), and PD endpoints such as tumor size. 
Parameters describing the kinetics of tumor growth will be determined after 
administration of GSK2636771 + enzalutamide.  Model parameters generated with data 
will be compared to investigate differences in the effect on tumor growth kinetics after 
administration of GSK2636771 + enzalutamide.
Pharmacokinetic/PD models also may be applied to describe the relationship between PK 
parameters and endpoints of clinical efficacy and safety (PSA and RECIST response rate, 
change from baseline in PSA, change from baseline in CTCs), as determined appropriate. 
Graphical analysis will be used initially to determine if there are any apparent 


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relationships between PK parameters and clinical endpoint.  A simple linear model and 
Emax may be used to describe any apparent relationship(s). More complex models will 
be considered if appropriate.
Further details of PK/PD analyses will be described under a separate RAP.  Results of the 
PK/PD analyses may be included in a report separate from the clinical study report 
(CSR).
13.3.4.5.
Translational Research Analyses
All biomarker analyses will be conducted on the All Treated Population unless otherwise 
stated.  Translational research analyses may include evaluation of PD indicators to 
explore the kinetics of tumor growth and molecular markers that may be predictive of 
clinical benefit.
Circulating tumor cells (CTC) may be evaluated for AR expression and other genomic 
markers that may be predictive of clinical benefit, as well as decreases in CTC from 
baseline.
Plasma collection at baseline, post-treatment and at time of disease progression will be 
used to analyze cfDNA, RNA and other soluble markers to understand clonal evolution, 
monitor response and explore predictive biomarkers.  Archival or fresh biopy tissue may 
be utilized to identify potential predictive biomarkers (protein, DNA and RNA based 
markers).  Optional PD and progression biopsies for subjects who have progressed from 
initially responding to the combination therapy may also be requested to understand 
pharmacodynamic effects and mechanism(s) of resistance.
Select biomarker data may be reported for all subjects consenting to pre-screening, based 
on the All Screened Population. Frequency of PTEN negative mCRPC subjects during 
pre-screening, as well as evidence of PTEN deletion, mutation, and promoter 
methylation, may be examined to further understand the mechanism of PTEN deficiency.
The results of these biomarker investigations may be reported separately from the main 
CSR.  Analytic strategies for the final analysis of all biomarker data will be influenced by 
the data available (e.g., available material).  Generally, all endpoints will be descriptively 
and/or graphically summarized but may be further determined at the completion of data 
collection.
14.
STUDY CONDUCT CONSIDERATIONS
14.1.
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.


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14.2.
Regulatory and Ethical Considerations, Including the 
Informed Consent Process
Prior to initiation of a study site, GSK will obtain favorable opinion/approval from the 
appropriate regulatory agency to conduct the study in accordance with ICH Good Clinical 
Practice (GCP) and applicable country-specific regulatory requirements.
The study will be conducted in accordance with all applicable regulatory requirements.
The study will be conducted in accordance with ICH GCP, all applicable subject privacy 
requirements, and the ethical principles that are outlined in the Declaration of 
Helsinki 2008, including, but not limited to:

IRB/IEC review and favorable opinion/approval of study protocol and any 
subsequent amendments.

Subject informed consent.

Investigator reporting requirements.
GSK will provide full details of the above procedures, either verbally, in writing, or both.
Written informed consent must be obtained from each subject prior to participation in the 
study.
In approving the clinical protocol the IEC/IRB and, where required, the applicable 
regulatory agency are also approving the optional assessments, e.g. genetic research 
described in Appendix 7, unless otherwise indicated.  Where permitted by regulatory 
authorities, approval of the optional assessments can occur after approval is obtained for 
the rest of the study.  If so, then the written approval will clearly indicate approval of the 
optional assessments is being deferred and the study, except for the optional assessments, 
can be initiated.  When the optional assessments are not approved, then the approval for 
the rest of the study will clearly indicate this and therefore, the optional assessments will 
not be conducted.
14.3.
Urgent Safety Measures
If an event occurs that is related to the conduct of the study or the development of the IP,
and this new event is likely to affect the study of subjects, the Sponsor, and the 
investigator will take appropriate urgent safety measures to protect subjects against any 
immediate hazard.
The Sponsor will work with the investigator to ensure the IRB/IEC is notified.
14.4.
Quality Control (Study Monitoring)
In accordance with applicable regulations, Good Clinical Practice (GCP), and GSK 
procedures, the site will be contacted prior to the start of the study to review with the site 
staff the protocol, study requirements, and their responsibilities to satisfy regulatory, 
ethical, and GSK requirements.  When reviewing data collection procedures, the 


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discussion will include identification, agreement and documentation of data items for 
which the eCRF will serve as the source document.
The investigator and the head of the medical institution (where applicable) agrees to 
allow the monitor direct access to all relevant documents and to allocate their time and 
the time to their staff to monitor to discuss findings and any issues.
Monitoring visits will be conducted in a manner to ensure that the:

Data are authentic, accurate, and complete.

Safety and rights of subjects are being protected.

Study is conducted in accordance with the currently approved protocol and any other 
study agreements, ICH GCP, and all applicable regulatory requirements.
14.5.
Quality Assurance
To ensure compliance with ICH GCP and all applicable regulatory requirements, GSK 
may conduct quality assurance audits of the site. Regulatory agencies may conduct a 
regulatory inspection at any time during or after completion of the study. In the event of 
an audit or inspection, the investigator (and institution) must agree to grant the auditor(s) 
and inspector(s) direct access to all relevant documents and to allocate their time and the 
time of their staff to discuss any findings/relevant issues.
14.6.
Study and Site Closure
The end of the study is defined as the date of the last visit of the last subject enrolled.
Upon completion or termination of the study, the monitor will conduct site closure 
activities with the investigator or site staff (as appropriate), in accordance with applicable 
regulations, ICH GCP, and GSK Standard Operating Procedures.
GSK reserves the right to temporarily suspend or terminate the study at any time for 
reasons including (but not limited to) safety issues, ethical issues, or severe 
noncompliance.  If GSK determines that such action is required, GSK will discuss the 
reasons for taking such action with the investigator or head of the medical institution 
(where applicable).  When feasible, GSK will provide advance notice to the investigator 
or head of the medical institution of the impending action.
If a study is suspended or terminated for safety reasons, GSK will promptly inform all 
investigators, heads of the medical institutions (where applicable),and/or institutions 
conducting the study.  GSK will also promptly inform the relevant regulatory authorities 
of the suspension/termination along with the reasons for such action.  Where required by 
applicable regulations, the investigator or head of the medical institution must inform the 
IRB/IEC promptly and provide the reason(s) for the suspension/termination.


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14.7.
Records Retention
Following closure of the study, the investigator or head of the medical institution (where 
applicable) must maintain all site study records (except for those required by local 
regulations to be maintained elsewhere) in a safe and secure location.  The records must 
be easily accessible when needed (e.g., for a GSK audit or regulatory inspection) and 
must be available for review in conjunction with assessment of the facility, supporting 
systems, and relevant site staff.
Where permitted by local laws/regulations or institutional policy, some or all of the 
records may be maintained in a format other than hard copy (e.g., microfiche, scanned, 
electronic); however, caution must be exercised before such action is taken.  The 
investigator must ensure that all reproductions are legible and are a true and accurate 
copy of the original.  In addition, they must meet accessibility and retrieval standards, 
including regeneration of a hard copy, if required.  The investigator must also ensure that 
an acceptable back-up of the reproductions exists and that there is an acceptable quality 
control procedure in place for creating the reproductions.
GSK will inform the investigator of the time period for retaining the site records in order 
to comply with all applicable regulatory requirements.  The minimum retention time will 
meet the strictest standard applicable to a particular site, as dictated by local 
laws/regulations, GSK standard operating procedures, and/or institutional requirements.
The investigator must notify GSK of any changes in the archival arrangements, including, 
but not limited to archival of records at an off-site facility or transfer of ownership of the 
records in the event that the investigator is no longer associated with the site.
14.8.
Provision of Study Results to Investigators, Posting of 
Information on Publicly Available Clinical Trials Registers 
and Publication
Where required by applicable regulatory requirements, an investigator signatory will be 
identified for the approval of the clinical study report.  The investigator will be provided 
reasonable access to statistical tables, figures, and relevant reports and will have the 
opportunity to review the complete study results at a GSK site or other mutually-
agreeable location.
GSK will also provide the investigator with the full summary of the study results.  The 
investigator is encouraged to share the summary results with the study subjects, as 
appropriate.
The results summary will be posted to the Clinical Study Register no later than 8 months 
after the final primary completion date, the date that the final subject was examined or 
received an intervention for the purposes of final collection of data for the primary 
outcome.  In addition, a manuscript will be submitted to a peer reviewed journal for 
publication no later than 18 months after the last subject’s last visit.  When manuscript 
publication in a peer reviewed journal is not feasible, a statement will be added to the 
register to explain the reason for not publishing


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15.
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Devine, BJ.  Case Number 25 Gentamicin Therapy:  Clinical Pharmacology Case 
Studies.  Drug Intelligence and Clinical Pharmacy. 1974;8:650-655
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, 
Arbuck S, Gwyther S, Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, 
Lacombe D, Verweij J.  New response evaluation criteria in solid tumours:  Revised 
RECIST guidelines (version 1.1).  European Journal of Cancer. 2009;45:228-247.
GlaxoSmithKline Document Number 2011N117133_01. Investigator’s Brochure for 
GSK2636771. 04-Mar-2014.
Hunt, CM.  Mitochondrial and immunoallergic injury increase risk of positive drug 
rechallenge after drug-induced liver injury: A systematic review.  Hepatol. 
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James LP, Letzig L, Simpson PM, Capparelli E, Roberts DW, Hinson JA, Davern TJ, Lee 
WM. Pharmacokinetics of Acetaminophen-Protein Adducts in Adults with 
Acetaminophen Overdose and Acute Liver Failure. Drug Metab Dispos.
2009;37(8):1779-1784.
Karantanos T, Corn PG, Thompson TC.  Prostate cancer progression after androgen 
deprivation therapy: mechanisms of castrate resistance and novel therapeutic approaches. 
Oncogene. 2013;32:5501-5511.
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.
Lee JJ, Liu DD. A predictive probability design for Phase II cancer clinical trials.  Clin 
Trials. 2008;5(2); 93-106.
Martin V, Guillermet-Guibert J, Chicanne G, Cabou C, Jandrot-Perrus M, Plantavid M, 
Vanhaesebroeck B, Payrastre B, Gratacap MP. Deletion of the p110beta isoform of 
phosphoinositide 3-kinase in platelets reveals its central role in Akt activation and 
thrombus formation in vitro and in vivo. Blood. 2010;115:2008-2013.
NCI-CTCAE (NCI Common Terminology Criteria for Adverse Events), Version 4, 
DCTD, NCI, NIH, DHHS, May 28, 2009.
Nylander S, Kull B, Bjorkman JA, Ulvinge JC, Oakes N, Emanuelsson BM, Andersson 
M, Skarby T, Inghardt T, Fjellstrom O, Gustafsson D. Human target validation of 
phosphoinositide 3-kinase (PI3K)β: effects on platelets and insulin sensitivity, using 
AZD6482 a novel PI3Kβ inhibitor. J Thromb Haemost. 2012;10:2127-2136.
Oken MM, Creech RH, Tormey DC, et al. Toxicity and response criteria of the Eastern 
Cooperative Oncology Group. Am J Clin Oncol. 1982;5:649-655.
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. 
Scher HI, Halabi S, Tannock I, et al. Design and End Points of Clinical Trials for Patients 
With Progressive Prostate Cancer and Castrate Levels of Testosterone: 
Recommendations of the Prostate Cancer Clinical Trials Working Group. J Clin Oncol. 
2008;26:1148-1159.
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Resistant Prostate Cancer: Updated Recommendations From the Prostate Cancer Clinical 
Trials Working Group 3. J Clin Oncol. 2016;34:1402-1418.
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Kaushik P, Cerami E, Reva B et al. Integrative genomic profiling of human prostate 
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The Criteria Committee of the New York Heart Association (NYHA). Nomenclature and 
Criteria for Diagnosis of Diseases of the Heart and Great Vessels. 9th ed. Boston, Mass: 
Little, Brown & Co. 1994:253–256.
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1460.


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16.
APPENDICES
16.1.
Appendix 1:  ECOG Performance Status
Assessment of Eastern Cooperative Oncology Group (ECOG) performance status to 
evaluate daily living abilities is required at Screening as well as routinely throughout the 
treatment and at treatment discontinuation [Oken, 1982]: 
Reference:
Oken MM, Creech RH, Tormey DC, 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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16.2.
Appendix 2:  NYHA Functional Classification System
The New York Heart Association (NYHA) Functional Classification: Class I, II, III 
or IV Heart Failure [NYHA, 1994] provides a simple way of classifying the extent of 
heart failure.  It places subjects in one of 4 categories based on the level of limitation 
experienced during physical activity:
Class
Symptoms
Class I
(Mild)
No limitation of physical activity.  Ordinary physical activity does not cause 
undue fatigue, palpitation or dyspnea (shortness of breath).
Class II
(Mild)
Slight limitation of physical activity.  Comfortable at rest, but ordinary 
physical activity results in fatigue, palpitation or dyspnea.
Class III
(Moderate)
Marked limitation of physical activity.  Comfortable at rest, but less than 
ordinary physical activity results in fatigue, palpitation or dyspnea.
Class IV
(Severe)
Unable to carry out any physical activity without discomfort.  Symptoms of 
cardiac insufficiency at rest. If any physical activity is undertaken, discomfort 
is increased.
Reference:
The Criteria Committee of the New York Heart Association (NYHA). Nomenclature and 
Criteria for Diagnosis of Diseases of the Heart and Great Vessels. 9th ed. Boston, Mass: 
Little, Brown & Co. 1994:253–256.


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16.3.
Appendix 3:  CKD-EPI equation
https://www.qxmd.com/calculate/egfr-using-ckd-epi.


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16.4.
Appendix 4:  Disease Assessment per RECIST 1.1
Disease progression and response evaluations will be determined according to the 
definitions established in the Response Evaluation Criteria in Solid Tumors 
(RECIST) 1.1 [Eisenhauer, 2009].
Assessment Guidelines

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 computed tomography (CT) or magnetic 
resonance imaging (MRI) is required.
CT and MRI:  Contrast enhanced CT with 5 mm 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 optimized 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.
NOTE: If CT contrast is contraindicated, acquire and submit a contrast-enhanced 
MRI of the abdomen/pelvis and an unenhanced CT of the chest in place of the 
enhanced CT for complete lesion assessment.
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.
Brain Scan:  If brain scans are required, then contrast enhanced MRI is preferable to 
contrast enhanced CT.
Bone Scan (typically bone scintigraphy):  Refer to Prostate Cancer Working Group 2 
(PCWG2) guidelines.
Baseline Assessments
The following baseline disease (lesion) assessments must be performed within 28 days 
(or within 35 days if disease assessment is assessed by MRI) prior to first dose of 
enzalutamide (Day 1 of Enzalutamide Run-In Period) to identify target and non-target 
lesions:


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
CT/MRI:  A CT scan with contrast of the chest, abdomen, and/or pelvis, or other 
areas as indicated by the subject’s underlying disease, is required for assessment 
of baseline disease burden.
NOTE: Although CT scan is preferred, MRI may be used as an alternative 
method of baseline disease assessment for abdomen/pelvis, especially for those 
subjects where a CT scan is contraindicated due to allergy to contrast, provided 
that the method used to document baseline status is used consistently throughout 
study treatment to facilitate direct comparison.  An unenhanced CT of the chest 
can replace the enhanced CT of the chest, but MRI of the chest is not
recommended.

Bone Scan:  A baseline bone scan is required for all subjects.  For subjects 
without bone disease at baseline, subsequent bone scans should only be performed 
as clinically indicated (e.g., presentation of bone pain).  For subjects with bone 
disease at baseline, a bone scan is required every 12 weeks or as clinically 
indicated.  In addition, in order to confirm a complete response (CR) in a subject 
with bone disease at baseline, a bone scan must be performed 1 week prior to the 
first set of images showing CR to 4 weeks after the next protocol specified 
assessment.
For subjects with palpable/superficial lesions, clinical disease assessments by physical 
examination should be performed at baseline and throughout study treatment as clinically 
indicated.
Confirmation of CR and partial response (PR) are required per protocol.  Confirmation 
assessments must be performed no less than 4 weeks (±3 days) 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 time point regardless of unscheduled assessments).
Baseline documentation of target and non-target lesions 

All baseline lesion assessments must be performed within 28 days (or within 35 days 
if disease assessment is assessed by MRI) prior to the first dose of enzalutamide 
(Day 1 of the Enzalutamide Run-In Period).

Lymph nodes that have a short axis of <10 mm are considered non-pathological and 
should not be recorded or followed.

Pathological lymph nodes with <15 mm and but 10 mm short axis are considered 
non-measurable.

Pathological lymph nodes with 15 mm 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 


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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, fluorodeoxyglucose-positron emission tomography (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. 
Post-Baseline Assessments
For all subjects, post-baseline assessment should evaluate disease sites identified by 
baseline scans.  Post-baseline disease assessment (CT scan or MRI) is required every 
8 weeks (7 days) during the first 48 weeks of treatment and then every 12 weeks 
(7 days) thereafter or as clinically indicated.
For subjects with no bone disease at baseline, subsequent bone scans should only be 
performed as clinically indicated (e.g., presentation of bone pain).
For subjects with bone disease at baseline, a bone scan is required every 12 weeks 
(7 days) or as clinically indicated.
Follow-up Assessments for Subjects Permanently Discontinued from Study 
Treatment
Refer to Section 5.2 (Permanent Discontinuation from Study Treatment) and the Time 
and Events Tables (see Section 8.1) for follow-up assessment of subjects who are to be 
followed for disease progression after permanently discontinuing from study treatment.
Assessment of Subject Completion
If the last radiographic assessment was more than 4 weeks prior to withdrawal from study 
and progressive disease has not been documented, a disease assessment should be 
obtained at the time of withdrawal from study. 


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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 5 mm.  If 
the slice thickness is greater than 5 mm, 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:

15 mm in the short axis when assessed by CT or MRI (slice thickness 
recommended to be no more than 5 mm).  At baseline and follow-up, only the short 
axis will be measured.
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.
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 <10 mm) 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.

Progressive Disease (PD): Unequivocal progression of existing non-target lesions. 


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
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.

Sites of non-target lesions, which are not assessed at a particular time point 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
The table below 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.
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
Abbreviations:  CR, complete response, PR, partial response, SD, stable disease, PD, progressive disease, NA, Not 
applicable; NE, Not Evaluable
Note:

Subjects with a global deterioration of health status requiring discontinuation of 
treatment without objective evidence of disease progression at that time should 
be classified as having "symptomatic deterioration."  Objective response status 


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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 56 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 (±3 days) after the criteria for response are first met.
Confirmation of Response per RECIST 1.1
Confirmation of CR and PR are required per protocol.  Confirmation assessments must be 
performed at least 4 weeks (±3 days) 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-specified assessment, the next 
protocol-specified evaluation is still required (e.g., evaluations must occur at each 
protocol scheduled time point regardless of unscheduled assessments).
Bone disease:  To confirm a CR in a subject with bone disease at baseline, a bone scan 
that was obtained before the response assessment indicating a CR must have been 
obtained no earlier than 1 week prior to that response assessment scan.  Alternatively, a 
bone scan performed after a response assessment scan suggesting a CR must be done no 
more than 4 weeks after the next protocol specified assessment in order to confirm a CR.
Brain metastases:  To confirm a CR in a solid tumor subject with brain metastases at 
baseline, brain imaging that is obtained before the response assessment indicating a CR 
must have been obtained no earlier than 1 week prior to that response assessment 
imaging.  Alternatively, brain imaging performed after a response assessment imaging 
suggesting a CR in a solid tumor subject with brain metastases must be done no more 
than 4 weeks (±3 days) after the next protocol specified assessment in order to confirm a 
CR.


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Reference:
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, 
Arbuck S, Gwyther S, Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, 
Lacombe D, Verweij J.  New response evaluation criteria in solid tumours:  Revised 
RECIST guidelines (version 1.1).  European Journal of Cancer. 2009;45:228-247.


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16.5.
Appendix 5:  Urine Protein Creatinine (UPC) Ratio
Clinical meaning of UPC
There is a good correlation between the ratio of protein concentration to creatinine 
concentration in a random urine sample and the amount of protein excreted over 24 hrs.  
Creatinine excretion is fairly constant throughout the day regardless of changes in urine 
flow rate.
Normal protein excretion is <150 mg/24 hrs and is similar for men and women.
Men excrete 20 mg to 25 mg of creatinine/kg of body weight/day.
Women excrete 15 mg to 20 mg of creatinine/kg of body weight/day.
Calculating UPC
UPC ratio = Urine protein (mg/dL) / Urine creatinine (mg/dL). 
UPC ratio ≈ equivalent to grams of protein excreted in urine over 24 hrs. 
Example:  Subject has a urine protein = 90 mg/dL and urine creatinine = 30 mg/dL.  
UPC ratio= (90 mg/dL) / (30 mg/dL) =  3  
The calculated UPC ratio is 3, which correlates to roughly 3 g protein excretion in a 
24-hr period.
Units for UPC ratio
Note: To calculate UPC, protein and creatinine concentrations must be expressed in the 
same units (mg/dL, g/L, or μmol/L). If, for example, protein concentration is expressed 
in mg/dL and creatinine concentration is expressed in µmol/L, conversion of one of the 
concentration values is required.  Conversion factors are: 
From 
To 
Conversion Factor 
Conventional Units: mg/dL
SI Units: µmol/L
Multiply by 88.4
SI Units: µmol/L
Conventional Units: mg/dL
Divide 88.4 
References:
NKF: NKF KDOQI Guidelines [Internet].  National Kidney Foundation; nd.  KDOQI 
Clinical Practice Guidelines for Chronic Kidney Disease: Evaluation, Classification, and 
Stratification.  Available from 
http://www.kidney.org/professionals/KDOQI/guidelines_ckd/p5_lab_g5.htm
Xin G, Wang M, Jian L, Xu F, Wang H.  Protein-to-creatinine ratio in spot urine samples 
as a predictor of quantitation of proteinuria 2004. Clinica Chimica Acta 350:35-39.


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16.6.
Appendix 6:  Liver Safety Drug Restart/Rechallenge 
Guidelines
If subject meets liver chemistry stopping criteria do not restart/rechallenge subject with 
study treatment unless:

GlaxoSmithKline (GSK) Medical Governance approval is granted (as described 
below),

Independent ethics committee (IEC) and/or institutional review board (IRB) 
approval is obtained, if required, and

Separate consent for treatment restart/rechallenge is signed by the subject
If GSK Medical Governance approval to restart/rechallenge subject with study treatment 
is not granted, then subject must permanently discontinue study treatment and may 
continue in the study for protocol-specified follow-up assessments.
1. Rechallenge Following Liver Stopping Events that are Possibly Related to 
Study Treatment
Following drug-induced liver injury (DILI), 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 re-administered within 1 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 >2 x upper limit of normal (ULN) with initial liver injury 
(direct bilirubin >35% of total)

subject currently exhibits severe liver injury defined by: alanine 
aminotransferase (ALT) ≥3 x ULN, bilirubin ≥2 x ULN (direct bilirubin >35% 
of total), or international normalization ratio (INR)>1.5

serious adverse event or fatality has previously been observed with rechallenge 
of the drug [Papay, 2009; Hunt, 2010]

evidence of treatment-related preclinical liability (e.g., reactive metabolites; 
mitochondrial impairment) [Hunt, 2010]
Rechallenge refers to resuming study treatment following 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 favorable.


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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.

IEC or IRB approval for rechallenge with study treatment must be obtained, as 
required.

If the rechallenge is approved by GSK Medical Governance in writing, the subject 
must be provided with a clear description of the possible benefits and risks of study 
treatment administration, including the possibility of recurrent, more severe liver 
injury or death.  

The subject must also provide signed informed consent specifically for the 
rechallenge with study treatment.  Documentation of informed consent must be 
recorded in the study chart.  

Study treatment must be administered at the dose specified by GSK.

Subjects approved by GSK Medical Governance for rechallenge with study 
treatment must return to the clinic twice a week for liver chemistry tests until stable 
liver chemistries have been demonstrated and then standard laboratory monitoring 
may resume as per protocol.

If after study treatment rechallenge, subject meets protocol-defined liver chemistry 
stopping criteria, study treatment should be permanently discontinued. 

GSK Medical Monitor, and the IEC or IRB as required, must be informed of the 
subject’s outcome following study treatment rechallenge. 

GSK to be notified of any adverse events, as per Section 9.
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 human leukocyte antigen (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 


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HLA genetic marker associated with liver injury (e.g. lapatinib, abacavir, 
amoxicillin/clavulanate) are reviewed and excluded

IEC or IRB approval of study treatment restart must be obtained, as required.

If restart of study treatment is approved by GSK Medical Governance in writing, the 
subject must be provided with a clear description of the possible benefits and risks of 
study treatment administration, including the possibility of recurrent, more severe 
liver injury or death.

The subject must also provide signed informed consent specifically for the study 
treatment restart.  Documentation of informed consent must be recorded in the study 
chart.  

Study treatment must be administered at the dose specified by GSK.

Subjects approved by GSK Medical Governance for restarting study treatment must 
return to the clinic once a week for liver chemistry tests until stable liver chemistries 
have been demonstrated and then laboratory monitoring may resume as per protocol.

If after study treatment re-start, subject meets protocol-defined liver chemistry 
stopping criteria, follow usual stopping criteria instructions.

GSK Medical Monitor, and the IEC or IRB as required, must be informed of the 
subject’s outcome following study treatment restart.

GSK to be notified of any adverse events, as per Section 9 of the protocol.
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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16.7.
Appendix 7:  Genetic Research
Genetic Research Objectives and Analyses
The objectives of the genetic research are to investigate the relationship between genetic 
variants and: 

Response to medicine, including any treatment regimens under investigation in this 
study or any concomitant medicines;

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.
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 (Day 1 preferably for this study), after 
the subject has been randomized and provided informed consent for genetic research. 
If a subject initially declines to participate in genetic research and then changes their 
mind, a sample should be obtained at the earliest opportunity.  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.  


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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 GlaxoSmithKline (GSK) may destroy the samples sooner.  GSK 
or those working with GSK (for example, other researchers) will only use samples 
collected from the study for the purpose stated in this protocol and in the informed 
consent form.  Samples may be used as part of the development of a companion 
diagnostic to support the GSK medicinal product.
Subjects can request their sample to be destroyed at any time.
Informed Consent
Subjects who do not wish to participate in the genetic research may still participate in the 
clinical 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 
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 


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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.


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16.8.
Appendix 8:  Country Specific Requirements
United Kingdom (UK): The UK Specific QTc Stopping Criteria should be applied to 
subjects enrolled in this study in the UK.
In line with local requirements, a subject enrolled and participating in this study in 
the UK that meets the criteria QTc1 below will have study treatment withheld:
QTcB >500 msec
1Based on average QTc value of triplicate ECGs to include manual overread.  For 
example, if an ECG demonstrates a prolonged QT interval, obtain two more 
ECGs over a brief period, and then use the averaged QTc values of the three 
ECGs to determine whether the subjects should have study treatment withheld.
If the QTc prolongation resolves to Grade 1 or baseline, the subject may be re-
started on the study treatment if the investigator and GSK Medical Monitor agree 
that the subject will benefit from further treatment.
Abbreviations: ECG, electrocardiogram; GSK, GlaxoSmithKline; QTc, corrected QT 
interval; QTcB, corrected QT interval by Bazett’s formula; UK, United Kingdom


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16.9.
Appendix 9:  Protocol Amendment Changes
16.9.1.
Protocol Changes for Amendment 1 (08-Sep-2014) from Original 
Protocol (22-May-2014)
Where the Amendment Applies
This amendment applies to all sites and countries.
Summary of Amendment Changes with Rationale
Amendment 1 incorporates changes to Section 5.2, Permanent Discontinuation of Study 
Treatment(s) for clarification as requested by the Medicines and Healthcare products 
Regulatory Agency (MHRA) in the United Kingdom.
List of Specific Changes
Section 5.2, Permanent Discontinuation of Study Treatment(s)
REVISED TEXT
Subjects may receive study treatment until disease progression, unacceptable toxicity, 
including meeting stopping criteria for liver chemistry as defined in Section 7.2.2, or 
death.  Study treatment(s) maywill be permanently discontinued for any of the following 
reasons:

Disease progression

Death

Unacceptable AE (including meeting liver chemistry stopping criteria as defined 
in Section 7.2.2)

Substantial protocol deviation(s)
16.9.2.
Protocol Changes for Amendment 2 (26-Feb-2015) from Protocol 
Amendment 1 (08-Sep-2014)
Where the Amendment Applies
This amendment applies to all sites and countries.
Summary of Amendment Changes with Rationale
Amendment 2 incorporates changes to list of authors and primary medical monitor 
(contact information) due to changes in personnel assignment within GSK; list of 
abbreviations was revised appropriately based upon addition/deletion of abbreviated 
terms used throughout the protocol; Time and Events Tables were revised for 
clarification of assessments and procedures to be performed and to reflect changes made 
throughout the body of the protocol.


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List of Specific Changes
Sponsor Medical Monitor Contact Information
Role
Name
Day Time 
Phone 
Number
After-
hours 
Phone/ 
Cell/
Pager 
Number
Fax 
Number
GSK Address
Primary 
Medical 
Monitor
MD, PhD
GlaxoSmithKline
1250 S. Collegeville Road
Collegeville, PA 19426, 
USA
Secondary 
Medical 
Monitor
 
MD, PhD
GlaxoSmithKline
1250 S. Collegeville Road
Collegeville, PA 19426, USA
Section 1.2.1  Clinical Safety, Pharmacokinetic Data and Clinical Activity of 
GSK2636771, first paragraph
REVISED TEXT
This study is ongoing; and, as of February 2014, 53 subjects have been enrolled.the last 
subject was enrolled on 21-Aug-2014 for a total of 62 subjects.
Section 1.3.1  Clinical Safety, Pharmacokinetic Data, and Clinical Activity of 
Enzalutamide
REVISED TEXT
Pharmacokinetics.  Oral absorption of enzalutamide is rapid and independent of dose 
with Cmax achieved 1 to 2 hrs post-dose.  It is 97 to 98% bound to plasma proteins, 
primarily albumin.  N-desmethyl enzalutamide is 95 to 97% bound to plasma proteins.  
Enzalutamide is metabolized by CYP3A4 and CYP2C8 to an active metabolite 
N-desmethyl enzalutamide and primarily eliminated by hepatic metabolism (CYP3A4 
and CYP2C8).  The mean t1/2 is 5.8 days in patients.  With daily administration, steady 
state is reached after approximately 30 days. In order to achieve near-steady state 
enzalutamide exposure, a 14-day run-in period has been included in the study 
design (Section 1.5.3, and Section 3).  Enzalutamide accumulates approximately 8.3-
fold relative to a single dose with a mean peak-to-trough ratio of 1.25. A high-fat meal 
did not alter the area under the concentration-time curve (AUC) of enzalutamide or its 
active metabolite, N-desmethyl enzalutamide.
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


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Section 1.4.1.4  Risk of Drug-Drug Interaction (NEW SECTION)
NEW TEXT
The risk for GSK2636771 to affect enzalutamide via enzymes of CYP3A4 and 
CYP2C8 is low but not fully discharged.  It is unknown if enzalutamide could 
potentially affect the exposure of GSK2636771 via UGT inhibition or induction, 
while the drug-drug interaction (DDI) risk on GSK2636771 via OATP transporter 
inhibition by enzalutamide is considered low due to high permeability of 
GSK2636771.
Section 1.4.2  Benefit Assessment
REVISED TEXT
2nd paragraph, 1st bullet:

Further treatment with enzalutamide may continue to provide benefit as seen from 
the limited data suggesting some evidence of response in patients receiving 
abiraterone following abiraterone, enzalutamide following abiraterone, and from 
abiraterone following enzalutamide.  Rate of growth may still be lower with 
enzalutamide than without enzalutamide (precedent from trastuzumab beyond 
progression).  A 14-day run-in period of treatment with enzalutamide 
monotherapy will be continuous with prior enzalutamide therapy, with the 
exception of an allowed 30 day drug holiday from enzalutamide treatment, in 
order to achieve near-steady state enzalutamide exposure.
Section 1.5.3  Dose Rationale
REVISED TEXT
5th paragraph:  A dose of 400 mg of GSK2636771 once daily was determined to be the 
MTD and was selected as the recommended Phase II dose (RP2D) for GSK2636771 
monotherapy treatment based on safety, PK, and pharmacodynamic (PD) data from Study 
P3B115717.  The proposed starting dose of GSK2636771 in the present study will be 300 
mg once daily which is 75% of the RP2D as a single agent determined in Study 
P3B115717.  The starting dose for the present study is lower than the monotherapy RP2D 
to decrease the probability of overlapping toxicities with GSK2636771 and enzalutamide.  
Preliminary results from Study P3B115717 indicate that 300 mg once daily of 
GSK2636771 will result in systemic exposure that resulted in effects consistent with 
pathway inhibition.
NEW TEXT
6th paragraph:  For enzalutamide, the approved dose of 160 mg once daily was 
selected.  Given the long half-life of enzalutamide, a run-in period of 14 days is 
included in the study design.  The intent of this run-in period is to achieve near-
steady state plasma concentrations of enzalutamide prior to initiating combination 
therapy with GSK2636771.


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Section 2.2 Objectives and Endpoints
REVISED TEXT
Objectives
Endpoints
Primary

To assess the safety and 
tolerability of GSK2636771 + 
enzalutamide administered orally 
once daily continuously in 
subjects with mCRPC.

AEs, SAEs, DLTs, and changes in 
laboratory values, ECGs, and vital signs 
(BP, temperature and pulse heart rate)

To determine the RP2D of orally 
administered GSK2636771 + 
enzalutamide in subjects with 
mCRPC.

Safety and tolerability as assessed by 
AEs, SAEs, DLTs, and changes in 
laboratory values, ECGs, and vital signs 
(BP, temperature and heart rate)
Section 3 Investigational Plan
REVISED TEXT
This is a Phase I, open-label, non-controlled, non-randomized dose-escalation, 
multicenter study to determine the RP2D of the oral PI3Kinhibitor, GSK2636771 in 
combination with enzalutamide in subjects with mCRPC.  The study will be conducted in 
two phases: the Dose Escalation Phase and the Dose Expansion Phase.  Each phase of 
the study will consist of a pre-screening period and three treatment periods: 
Enzalutamide Run-In Period, Combination Treatment Period and Treatment 
Continuation Period. 
Subjects with PTEN deficient mCRPC (determined during pre-screening), who have 
documented progression per Prostate Cancer Working Group 2 (PCWG2) criteria 
(either by Response Evaluation Criteria in Solid Tumors [RECIST] 1.1, prostate-
specific antigen [PSA] progression, and/or progression in bone), will be enrolled in 
the Dose Escalation Phase and Dose Expansion Phase of the study.  
In the Dose-Escalation Phase, subjects will be enrolled to receive GSK2636771 + 
enzalutamide and will be approved based on review of available screening data by the 
GSK Medical Monitor and study manager.  Dosing will be conducted in 28 day treatment 
periods.  Decisions for dose determination for subsequent cohorts will be documented 
and maintained by each site and in the GSK Master Study Files.
In the Dose Escalation Phase, subjects will be enrolled into dose-finding cohorts to 
evaluate the safety and PK to guide the selection of the RP2D of GSK2636771.  
Dosing decisions will be based on all available data at the end of each DLT reporting 
period (the first 28 days of combination treatment).  Decisions for dose 
determination for subsequent cohorts will be documented and maintained by each 
site and in the GSK Trial Master Files (TMF).


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In the Dose Expansion Phase, subjects will be assigned to receive GSK2636771 at the 
MTD or RP2D determined in the Dose Escalation Phase while continuing treatment with 
enzalutamide to evaluate the long-term safety of the combination as well as the 12-week 
non-PD rate.
Safety Assessments:  Throughout the study, safety will be assessed through standard 
measures, including physical examinations, vital signs, clinical laboratory tests, 12-lead 
ECGs and monitoring of AEs.  Efficacy will be assessed by physical examination, 
computed tomography (CT) scan or magnetic resonance imaging (MRI), radionuclide 
bone scans, circulating tumor cells (CTC) enumeration, and PSA.  Pharmacokinetic (PK) 
blood samples will be collected from all subjects to evaluate if there is an effect of 
GSK2636771 on the PK of enzalutamide and to quantify the systemic exposure to 
GSK2636771.
Clinical Response Assessments: The determination of clinical response, including 
disease progression, will be assessed by both the PCWG2 criteria (see Section 8.8.2).  
The assessment of the 12 week non-PD-rate in the dose expansion phase will also be 
determined by PCWG2 criteria (either by RECIST 1.1, PSA progression, and/or 
progression in bone).
Biomarker Assessments: Planned biomarker assessments include:  1) Identify potential 
predictive biomarkers (protein, DNA, RNA based) in archival tumor tissue/pre-dose 
biopsies; 2) enumeration of CTCs in circulation and evaluation of alterations in AR or 
PTEN genes (or other genomic markers) in isolated CTCs; 3) Assessment of gene 
mutations in cfDNA and other soluble markers in plasma to better understand clonal 
evolution and other predictive circulating biomarkers; and 4) understand the mechanism 
of resistance in tumor tissues biopsies (optional) at time of progression.
Subjects will continue study treatment until clinical benefit is no longer apparent, in the 
opinion of the treating physician, or until unacceptable AE, withdrawal of consent, or 
death.  A post-treatment follow-up visit will be performed within 30 days of the last dose 
of study treatment(s).  The study will be considered completed approximately 6 months 
after the last subject begins study treatment. However, based on emerging data, the study 
may continue to collect further efficacy data if warranted.
Protocol waivers or exemptions are not allowed.  Therefore, adherence to the study 
design requirements, including those specified in the Time and Events Tables 
(Section 8.1) are essential.
Supplementary study conduct information not mandated to be present in this protocol is 
provided in the accompanying Study Procedures Reference Manual (SRPM).  The SPM 
will provide the site personnel with administrative and detailed technical information that 
does not impact subject safety.


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Section 3.1
Prescreening and Screening (New Section)
NEW TEXT (originally in Section 3.2):
All subjects will be required to undergo pre-screening to determine the PTEN 
deficiency status of their tumor at the GSK selected laboratory.

Pre-screening may be performed prior to confirmation of progression on 
enzalutamide 

Subjects will be required to sign a separate Pre-Screening Informed 
Consent Form (ICF) to allow for pre-screening of archived or fresh 
tumor biopsy samples

Details of the PTEN requirements are provided in SRM.
Subjects with PTEN-deficient tumors may enter into Screening for the study.  
Subjects meeting all screening criteria (Section 4.1.2 and Section 4.1.3) may enroll 
into the Treatment Periods of the study.
Section 3.2 Treatment Periods (New Section)
Section 3.2.1  Enzalutamide Run-In Period (New Section)
NEW TEXT
Subjects will be enrolled in the 14-day run-in period and receive enzalutamide 
monotherapy at the approved dose of 160 mg once daily.  The intent of this run-in 
period is to achieve near-steady state plasma concentrations of enzalutamide prior 
to initiating combination therapy with GSK2636771.
Subjects who experience an intolerable toxicity causing a dose interruption or dose 
reduction during the Enzalutamide Run-In Period will require approval from the 
GSK Medical Monitor in order to continue in the study.  Those subjects not eligible 
for treatment in the Combination Treatment Period will not be considered in the 
evaluation of DLTs and may be replaced.
Subjects who discontinue the study during the Enzalutamide Run-In Period will be 
asked to complete the post-treatment follow-up visit within 30 days of the last dose 
of enzalutamide.
Section 3.2.2  Combination Treatment Period (New Section)
NEW TEXT
Subjects who complete the Enzalutamide Run-In Period will begin oral 
GSK2636771 treatment on Week 1, Day 1 of the Combination Treatment Period 
while continuing to receive enzalutamide to evaluate safety of the combination 
therapy.


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Section 3.2.3  Treatment Continuation Period (New Section)
NEW TEXT
Subjects will continue to receive the combination treatment of GSK2636771 + 
enzalutamide from Week 5 and thereafter will be seen in the clinic every 4 weeks.  
Subjects will continue study treatment until clinical benefit is no longer apparent, in 
the opinion of the treating physician, or until unacceptable AE, withdrawal of 
consent, permanent discontinuation of treatment, or death.  
The study will be considered completed approximately 6 months after the last 
subject begins study treatment. However, based on emerging data, the study may 
continue to collect further efficacy data if warranted.
Section 3.3  Post-Treatment Follow-Up
REVISED TEXT, 2nd paragraph
The dosing of enzalutamide will be administered at the US FDA approved dose (refer to 
the Prescribing Information for enzalutamide [Xtandi, 2013].  Study treatment will 
continue until there is no longer clinical benefit, in the opinion of the investigator, or until 
an unacceptable AE (including stopping criteria outlined in Section 7.2), withdrawal of 
consent, permanent discontinuation of treatment, or death occurs.  Investigators will 
use the PCWG2 criteria to determine clinical response to each treatment.
NEW TEXT
A post-treatment follow-up visit will be performed within 30 days of the last dose of
study treatment(s) for all subject who permanently discontinue study treatments, 
during the Enzalutamide Run-In Period (and/or do not enter the Combination 
Treatment Period), or for those who permanently discontinue study treatments 
during the Combination Treatment or Treatment Continuation Period due to 
disease progression.  
Subjects who withdraw from the study during the Combination Treatment or 
Treatment Continuation Period without disease progression should complete the 
Extended Follow-up Visits where they will be contacted every 3 months (14 days) 
until disease progression, death, withdrawal of consent, or subject is lost to follow-
up.  Contact may include a clinic visit, a telephone contact, or an e-mail.  The 
initiation of any new anti-cancer treatments and date of last contact should be 
documented.  Subjects who discontinue the Extended Follow-Up Visits prior to 
disease progression, death, or withdrawal of consent should have a Post-Extended 
Follow-Up/EOS Visit performed.
Section 3.4  Dose Escalation Phase
REVISED TEXT
1st paragraph: In the Dose-Escalation Phase, the dose of GSK2636771 will follow a 
modified 3+3 dose-escalation procedure to evaluate the safety and PK for each 


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combination dose level and to guide selection of the RP2D of the combination.  Subjects 
with PTEN deficient mCRPC who are receiving a stable dose of enzalutamide with 
recent demonstrated progression per PCWG2 criteria (either by RECIST 1.1, PSA 
progression, and/or progression in bone) will be enrolled.
2nd paragraph, last sentence: Dose escalation will proceed with the increment of dose 
increase or decrease as determined by toxicity rules outlined in Table 1.
Section 3.4.2 Alternative Dosing Schedule
REVISED TEXT
Alternative schedules may be evaluated if emerging data suggest that continuous daily 
dosing will result in excessive toxicity.  Only those alternative schedules exploring 
dosing less frequent than current dosing schedule will be evaluated.  If alternative 
dosing schedules are explored, PK sampling times will be modified to reflect the new 
dosing schedule.
Section 3.4.3  Definition of Dose Limiting Toxicity
NEW TEXT
1st paragraph:  The DLT criteria apply only during the dose finding stage, and 
impacts the decisions around whether the MTD has been determined, and/or 
decisions around whether to escalate or de-escalate the next dose level, but do not 
apply to the mandated management of an individual subject as with the liver 
stopping criteria.
Last paragraph:  Subjects who experience an intolerable toxicity causing a dose 
interruption or dose reduction during the Enzalutamide Run-In Phase (before the 
start of GSK2636771 combination treatment) will require approval from the GSK 
Medical Monitor in order to continue in the study.  Those subjects not eligible for 
the combination phase will not be considered in the evaluation of DLTs and may be 
replaced.
REVISED TEXT
Subjects who fail to receive at least 75% of protocol-specified study treatment during the 
DLT reporting period (the first 28 days of combination treatment), for reasons OTHER 
than toxicity, will be replaced if data from the replacement subject could impact the dose 
selection criteria.  
An event will be considered a DLT if the event is attributed (definitely, probably or 
possibly) to study treatment, occurs within the first 28 days of combination treatment
(DLT reporting period), and meets one of the following criteria:


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Bullets 5 and 6:

Alanine aminotransferase (ALT) >3 times upper limit of normal (ULN) with
bilirubin >2 times ULN (or ALT >5 times ULN and 150% of baseline ALT, if 
enrolled with liver metastases/tumor infiltration at baseline) (or ALT ≥3 times 
ULN and ≥1.5 times baseline ALT value, if enrolled with liver 
metastases/tumor infiltration at baseline), together with bilirubin ≥2 times 
ULN)
Any Grade 2 or greater toxicity per CTCAE v4.0 that occurs beyond the 28-day DLT 
reporting period which in the judgment of the investigator and GSK Medical Monitor 
would be considered dose-limiting.
Section 3.4.4  Maximum Tolerated Dose
REVISED TEXT
The MTD is defined as the highest dose at which no more than one of one or fewer of 
up to 6 subjects experience a DLT during the first 28 days of combination therapy.  The 
MTD will be exceeded if 2 or more subjects in a cohort of up to 6 subjects experience a 
DLT.
Section 3.5  Dose Expansion Phase
REVISED TEXT
First sentence: Enrollment in the Dose Expansion Phase of the study may begin once the 
MTD and RP2D have been determined at the RP2D in the Dose Escalation Phase.  
Section 3.6.1  Evaluation of Futility
REVISED TEXT
Futility will be evaluated in the Dose Expansion Phase of the study.  The 
methodology is based on the predictive probability of success if enrollment continues to 
20 subjects [Lee, 2008]. The predictive probability design is similar to a Green-Dahlberg 
design in that it allows for early stopping for futility. The differences are that the 
predictive probability design allows for evaluation of stopping rules after each subject, 
rather than at only two stages, once a minimum number of subjects are evaluable. In this 
particular study, we will stop only for futility. While the two designs have similar type I 
and type II error rates, the probability of early termination is greater with the predictive 
probability design.
After 10 subjects have been enrolled to examine safety and 12-week non-PD rate, the 
number of subjects who have not progressed in 12 weeks will guide further enrollment 
according to the rules summarized in Table 3.  A maximum of 20 subjects will be 
enrolled at the RP2D.  All available data will be considered in making enrollment 
decisions.  


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Section 3.7  Continued Treatment
REVISED TEXT
A subject may continue study treatment until the treatment discontinuation criteria are 
met (see Section 5.2).  Additional guidelines regarding dose modifications are 
provided in Section 7.1.  Prior to administration of additional study treatment beyond 
the first 28 days (the DLT reporting period), clinically significant AEs should be resolved 
to baseline or Grade 1.
Section 3.8 Treatment Assignment
DELETED TEXT
Each site will be given a subject number range (range will be provided in the SRM).  
Upon completion of all required pre-screening and screening procedures and 
assessments, eligible subjects will be enrolled by the study team.  Subjects will be 
identified by a unique subject number that will remain consistent for the duration of the 
study.
NEW TEXT
Each subject will be assigned a unique subject number that will remain consistent 
for the duration of the study.  This number will be assigned sequentially from a 
range of subject numbers provided for each site in the SRM.  Upon completion of all 
required pre-screening and screening procedures and assessments, eligible subjects 
must be approved for enrollment by a member of the study team according to the 
procedures detailed in the SRM.
Section 4.1.1  Number of Subjects
REVISED TEXT
A total of approximately 44 subjects will be enrolled in this study.  In the Dose 
Escalation Phase, additional subjects/cohorts may be enrolled to allow for evaluation of 
additional dose levels. The sample size planned for the Dose Expansion Phase is not 
driven by statistical considerations as the cohort is meant to further understand the safety 
implications of enrolling subjects to combination therapy for an extended period of time.  
See Section 13.2 for sample size assumptions.
Dose Escalation Phase:  The number of dose levels and the level at which the MTD is 
reached cannot be determined in advance.  An adequate number of subjects will be 
enrolled to establish the recommended dose for further study.  It is estimated that 
approximately 24 subjects will be needed for the Dose Escalation Phase.
Dose Expansion Phase:  In the Dose Expansion Phase, it is estimated that approximately 
20 subjects will be enrolled, with evaluation for futility after the first 10 subjects have 
completed 12 weeks of treatment (see Section 3.5.1). although if the first 10 subjects 
progress with mCPRC, the dose expansion will be stopped.


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The sample size planned for the Dose Expansion Phase is not driven by statistical 
considerations as the cohort is meant to further understand the safety implications 
of enrolling subjects to combination therapy for an extended period of time.  See 
Section 13.2 for sample size assumptions.
Section 4.1.2 Inclusion Criteria #1, #2, #3, #5, #7, #8, #9, #11 and #12
NEW TEXT
New Inclusion Criteria #8 (all subsequent criteria have been renumbered):  Has not been 
without enzalutamide treatment for >30 days prior to enrollment
REVISED TEXT
1.  Signed written informed consent
NOTE:  Separate ICFs must be signed prior to the pre-screening and 
screening procedures.
2. Males ≥18 years of age (at the time written consent is obtained for pre-screening)
3. Histologically or cytologically confirmed diagnosis of prostate adenocarcinoma, 
surgically castrated or continuous medical castration (for ≥8 weeks prior to Screening)
5. PTEN-deficient tumor as documented from archived or fresh (from pre-treatment
biopsy) tumor tissue analyzed by a GSK selected laboratory
7. Has completed at least 12 weeks of prior continuous therapy with enzalutamide
NOTE: A 30 day or less treatment (enzalutamide) holiday will be permitted prior to 
Screening.
8. Most recent enzalutamide dose received is 160 mg once daily with no change in dose 
for at least 2 weeks prior to enrollment
9. Has documented disease progression progressive disease at time of enrollment 
following treatment with enzalutamide at a time of Screening.
NOTE: Disease progression is defined as one or more of the following criteria:
11.  Adequate baseline organ function at the time of Screening defined as:
Renal
Urine Protein (via dipstick)2
0/+1
UPC3,4
<0.2
Serum Creatinine
OR
Estimated Serum Creatinine Clearance5
OR
24-hr Urine Creatinine Clearance
ULN
60 mL/min
60 mL/min
Cardiac
LVEF
50% by ECHO or MUGA
Other
Serum Phosphate6
≤Grade 1
Serum Calcium (corrected)
WNL


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Abbreviations: ANC, absolute neutrophils count; ALT, alanine aminotransferase; AST, aspartate 
aminotransferase; CTCAE, Common Terminology Criteria for Adverse Events; ECHO, echocardiogram; 
INR, international normalization ratio; LLN, lower limit of normal; LVEF, left ventricular ejection fraction; 
MUGA, multigated acquisition scan; PT, prothrombin time; PTT, partial thromboplastin time; ULN, upper limit 
of normal; UPC, urine protein to creatinine ratio; WNL, within normal limits
1.
If ALT or bilirubin values are outside range listed due to Gilbert’s syndrome or asymptomatic gallstones, 
subject remains eligible.
2.
If subject’s urine protein is >1+ (via dipstick), then UPC ratio will be calculated.  Subject will be 
considered eligible for study if UPC ratio is <0.2.
3.
UPC ratio is only to be calculated if subject’s urine protein is >1+ via dipstick.
4.
The UPC value will not be used to determine eligibility for subjects who are unable to obtain 
uncontaminated urine samples due to their disease.
5.
Estimated by the Cockcroft and Gault Formula (see Appendix 3).
6.
Per CTCAE v4.0, Grade 1 hypophosphatemia is <LLN – 2.5 mg/dL (<LLN – 0.8 mmol/L)
NOTE:  Laboratory results obtained during Screening should be used to determine 
eligibility criteria.  In situations where laboratory results are outside the permitted 
range, the investigator may opt to retest the subject and the subsequent within range 
screening result may be used to confirm eligibility.  
12. Male subject with a female partner of childbearing potential or pregnant must have 
either a prior vasectomy or agree to use two acceptable methods effective of 
contraception as described in Section 11.1 from time of Screening until 3 months after 
the last dose of study treatment.
DELETED TEXT
12.
Must have a QT interval corrected for heart rate according to Fridericia’s formula 
(QTcF) <470 msec or <480 msec with bundle branch block (BBB).
NOTE:  For subject eligibility, withdrawal, and for purposes of data analysis, 
QTcF will be used.  The QTcF should be based on single or averaged QTc values 
of triplicate ECGs obtained over a brief recording period.
Section 4.1.3 Exclusion Criteria #1, #4, #5, #6, #11, #15, #16, #18 and #22
REVISED TEXT
1. Prior treatment with:
Exception: Subjects may remain on luteinizing hormone releasing hormone 
(LHRH) agonists (i.e., leuprolide, goserelin, triptorelin or histrelin) and AR 
antagonists (e.g., bicalutamide, flutamide, nilutamide).
Exception: Subjects must have received prior treatment with enzalutamide.

Any PI3K, AKT or mammalian target of rapamycin (mTOR) inhibitors

Investigational drug(s) (other than enzalutamide) within 30 days or 5 half-lives, 
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4.  Any unresolved Grade 2 toxicity (per CTCAE v4.0) toxicity from previous anti-
cancer therapy at the time of enrollment, except alopecia or Grade 2 anemia (if 
hemoglobin is >9.0 g/dL)
5. Hypophosphatemia Any Grade 2 hypophosphatemia (per CTCAE v4.0) at the time of 
enrollment
6. Serum calcium Grade 1 (per CTCAE v4.0) at time of enrollmenton Day -1, unless 
ionized calcium is within normal range
11. Presence of hepatitis B surface antigen (HBsAg), positive hepatitis C antibody test 
result at time of Screening or within 3 months prior to enrollment first dose of study 
treatment
15.  History of seizure or any condition that may predispose subject to seizure (e.g., prior 
cortical stroke or significant brain trauma).  History of loss of consciousness or transient 
ischemic attack within 12 months of randomizationenrollment
18. Poorly controlled hypertension (defined as systolic blood pressure [SBP] of 
≥150 mmHg or diastolic blood pressure [DBP] of >100 mmHg based on a mean of 
three measurements at approximately 2-minute intervals)
NOTE:  Initiation or adjustment of antihypertensive medication(s) is permitted if 
done within 30 or more days prior to enrollment.
22. Exposure to more than 4 investigational medicinal products (IMPs) within 12 
months prior to the first dose of study treatment enrollment
NEW TEXT
16. Has a QTc >450 msec or QTc >480 msec for subjects with bundle branch 
block (BBB)
NOTES: The QTc is the QT interval corrected for heart rate by Bazett’s 
formula (QTcB), Fridericia’s formula (QTcF), and/or another method, 
machine-read or manually over-read.
The specific formula that will be used to determine eligibility and 
discontinuation for an individual subject should be determined prior to 
initiation of the study. In other words, several different formulae cannot be 
used to calculate the QTc for an individual subject and then the lowest QTc 
value used to include or discontinue the subject from the trial.
For purposes of data analysis, QTcB, QTcF, another QT correction formula, 
or a composite of available values of QTc will be used as specified in the 
Reporting and Analysis Plan (RAP).
Section 5.2 Permanent Discontinuation of Study Treatment(s)
REVISED TEXT
Subjects may receive study treatment until disease progression, unacceptable toxicity, 
including meeting stopping criteria for liver chemistry as defined in Section 7.2.2, or 
death.  Study treatment(s) will be permanently discontinued for any of the following 
reasons:


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
Disease progression
NOTE:  Subjects must meet the PCWG2 guidelines for disease progression 
to avoid premature discontinuation of study treatment(s).
Treatment Discontinuation due to PSA rise:  Following PCWG2 
guidelines, subjects should not be discontinued from study 
treatment(s) solely due to PSA rise during the first 12 weeks of 
treatment (Section 8.8.2.1).
Treatment Discontinuation due to Bone Scan changes:  Subjects should 
not be discontinued from study treatment(s) due to the occurrence of 
bone scan changes in the first 12 weeks that do not meet PCWG2 
guidelines for progression (Section 8.8.2.2).

Unacceptable toxicity (including meeting liver chemistry stopping criteria as 
defined in Section 7.2.2)
NOTE: If the subject voluntarily discontinues from treatment due to 
toxicity, ‘adverse event’ will be recorded as the primary reason for 
permanently discontinuation on the eCRF.

Substantial protocol deviation(s)

Death 

Investigator’s discretion

Lost to follow-up

Intercurrent illness that prevents further administration of study treatment(s)

Withdrawal of consent by subject or proxy for further treatment and/or data 
collection

If subject withdraws consent for further treatment, the subject should return 
for Post-Treatment Follow-up Visit as indicated in the Time and Events 
Tables (Section 8.1).

If subject withdraws consent for further treatment and data collection, then no 
additional study visits, including a post-treatment follow-up visit, or data 
collection should occur.  All samples collected for the biomarker analysis at 
the time of withdrawal will proceed for analysis to meet the intended 
objectives defined in this protocol, unless consent for further analyses is 
withdrawn by the subject.

Study closure or termination
If study treatment(s) is/are permanently discontinued, the subject will not be allowed to 
be retreated.  The primary reason for permanently discontinuing study treatment(s) must 
be documented in the subject’s medical records and electronic case report form (eCRF).
All subjects who have study treatment(s) permanently discontinued will have safety 
assessments at the time of discontinuation and during post-study treatment follow-up as 
specified in Time and Events Tables (Section 8.1).


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Treatment Discontinuation without Disease Progression: All subjects who permanently 
discontinue study treatment(s) without disease progression should be followed for 
progression in the Extended Follow-Up Visits according to the protocol schedule until:

A new anti-cancer therapy is initiated, or

Disease progression occurs, or

Subject withdrawal, or

Death
Treatment Discontinuation due to PSA rise:  Following PCWG2 guidelines, subjects 
should not be discontinued from study treatment(s) solely due to PSA rise during the first 
12 weeks of treatment (Section 8.8.2.1).
Treatment Discontinuation due to Bone Scan changes:  Subjects should not be 
discontinued from study treatment(s) due to the occurrence of bone scan changes in the 
first 12 weeks that do not meet PCWG2 guidelines for progression (Section 8.8.2.2).
Section 5.3 Study Completion
REVISED TEXT
A subject will be considered to have completed the study if the subject dies or otherwise 
progresses during the study treatment or post-treatment follow-up period.
A subject will be considered to have withdrawn from the study if the subject has not died 
or progressed and is lost to follow-up, has withdrawn consent, or at the investigator’s 
discretion is no longer being followed.
Section 6.1 GSK2636771 GSK Investigational Product
REVISED TEXT
Dosing Instructions:
Dose with approximately 200 mL of water.  GSK2636771 should be taken 
prior to enzalutamide in the morning (once last PK sample is obtained 
morning dosing is not required).  Subjects should fast for at least 1hr 
before and 2 hrs after dosing.  See Section 6.3 for dosing instructions on 
days when PK blood draws will occur.
Section 6.2 Enzalutamide Non-GSK Product
DELETED TEXT
Enzalutamide (Xtandi) will be sourced locally from commercial stock for sites in 
countries where it is approved (e.g., US).  The contents of the label will be in accordance 
with all applicable regulatory requirements.


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Investigators are responsible for ensuring that subjects receive supplies of enzalutamide 
for the entire duration of the study, except in countries where Regulatory Authorities 
mandate that the Sponsor must supply all study treatment(s) required for study 
participation.
NEW TEXT
Initially, in countries where it is approved (i.e., US), sites will need to obtain 
enzalutamide (Xtandi) from local commercial stock in order to provide enrolled 
subjects with an adequate supply of enzalutamide while on study. 
In countries where regulatory authorities mandate that the Sponsor must supply all 
study treatment(s) required for study participation, GSK will provide an adequate 
supply of enzalutamide (from commercial stock) directly to the site for enrolled 
subjects.  
Enzalutamide will be provided to subjects at no cost to begin taking enzalutamide 
on the first day (Day 1) of the Enzalutamide Run-In Period and throughout their 
participation in the study.  If a subject does not qualify for entry into the study 
based on the tests or assessments performed during the pre-screening and screening 
periods, then no further supply of enzalutamide will be provided to them.
The sourcing of enzalutamide from commercial stock will continue until which time 
(estimate within first quarter of 2015) GSK will begin supplying all sites with an 
adequate inventory of commercial, US sourced enzalutamide; an appropriate 
amendment will be made to the Quality section of the IND and CTA.
The contents of the label will be in accordance with all applicable regulatory 
requirements.
Route/Administration/
Duration:
Oral/once daily, within 5 minutes of GSK2636771 administration/
continuous until treatment withdrawal
Section 6.3 Administration of Study Treatments
REVISED TEXT
Dosing Time: Subjects will be instructed to take their doses of study treatment 
(GSK2636771 and enzalutamide) at the same time each day if possible (24 hr intervals).  
Morning dosing is required until the last serial PK blood and plasma sample are 
obtained on Day 29 of Week 5 (Treatment Continuation Period.  Once the last serial 
PK sample is obtained, dosing of study treatments can occur anytime during the 
day.  For subjects who wish to switch to evening dosing may do so once the last PK 
blood sample is obtained.  To switch to evening dosing, the subject is to delay their next 
doses of study treatments by 12 hrs.  
Dosing at Homeon Non-PK Sampling Days: On days when subjects do not have a 
scheduled study visit in the clinic, subjects will be instructed to takeself-administer


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their doses of study treatments at home under fasted conditions, at least 1 hr before or 
2 hrs after a meal, on days when no PK blood samples are to be drawn.
Dosing during the Enzalutamide Run-In Period (Days 1 to 14): Enzalutamide is the 
only study treatment taken during the Enzalutamide Run-In Period.  The intent of 
this Enzalutamide Run-In Period is to achieve near-steady state plasma 
concentrations of enzalutamide prior to initiating combination therapy with 
GSK2636771.  Subjects should be instructed to take their once daily dose of 
enzalutamide every morning at the same time each day if possible (24-hr intervals) 
during the Enzalutamide Run-In Period. Specific instructions for the administration 
of enzalutamide on Day 14 of the Enzalutamide Run-In Period are provided in the 
Dosing on PK Sampling Days during the Dose Escalation Phase section below.
Dosing on Scheduled Study Visit Days: Most of the scheduled study visit days during 
the first 5 weeks of combination treatment will require a pre-dose blood, plasma, 
and/or urine sample for analysis of PK, CTC, and/or urine electrolytes. On Day 1 of 
Weeks 8 and 12 during the Treatment Continuation Period, pre-dose blood and 
plasma samples for analysis of PK are required. On Day 1 of Week 8 and every 8 
weeks thereafter during the Treatment Continuation Period, pre-dose blood and 
urine samples for analysis of CTC (through Week 32 only) and urine electrolytes 
are also required. Subjects should be instructed to withhold their doses of study 
treatments on mornings of these scheduled study visits as follows:
Dosing on PK Sampling Days: For dense serial PK days, subjects should fast overnight 
(at least 8 hrs) and remain fasting the morning of dosing until study treatment is 
administered.  After dosing of study treatment, subjects will continue to fast for an 
additional 2 hrs.  On days when sparse PK samples are collected, subjects should fast for 
at least 1 hr before and 2 hrs after administration of study treatment.
Dosing on PK Sampling Days during the Dose Escalation Phase: 

Day 14 (Enzalutamide Run-In Period): the day prior to administration of the 
first dose of GSK2636771:  Subjects will fast overnight (at least 8 hrs) and remain 
fasting the morning of this study visit.  Subjects will be instructed to withhold 
their dose of enzalutamide on the morning prior to the of this study visit. on Day 
-1.  After the pre-dose PK plasma sample is drawnblood draw is completed, 
subjects will be administered their doses of enzalutamide in the clinic and will 
asked to continue fasting for an additional 2 hrs. 

Day 29, Week 5 (Treatment Continuation Period): Subjects will fast overnight 
(at least 8 hrs) and remain fasting the morning of this study visit.  Subjects will be 
instructed to withhold the doses of study treatment on the morning of this prior
to the study visit.on Day 29 of Wk 5. After the pre-dose pK blood and plasma 
samples are drawn draw is completed, subjects will be administered their doses 
of study treatments in the clinic and asked to will continue fasting for an 
additional 2 hrs. 


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
Weeks 8 and 12 (Treatment Continuation Period): Subjects will be instructed 
to withhold their doses of study treatment prior to these study visits. After the 
pre-dose PK blood and plasma samples are drawn, subjects will have be 
administered their doses of study treatments administered in the clinic after the 
pre-dose blood draw is completed and under fasted conditions, at least 1 hr before 
or 2 hrs after a meal (an overnight fast is not required).
Dosing on PK Sampling Days during the Dose Expansion Phase:  

Day 29, Week 5 (Treatment Continuation Period):  
o
Subjects scheduled for a morning clinic visit will be instructed to withhold 
the doses of study treatments prior to this study visit on Day 29 of Wk 5.  
After the pre-dose PK blood and plasma samples are drawn, subjects 
Study treatments will be administered their doses of study treatments in 
the clinic after the pre-dose blood draw is completed and under fasted 
conditions, at least 1 hr before or 2 hrs after a meal (an overnight fast is 
not required). 
o
Subjects scheduled for an afternoon clinic visit will be instructed to take 
their doses of study treatments at the usual time on the morning of this 
study visit and under fasted conditions, at least 1 hr before or 2 hrs after a 
meal (an overnight fast is not required).  

Weeks 8 and 12 (Treatment Continuation Period): Subjects will be instructed 
to withhold the doses of study treatment prior to the study visit during Wks 8 and 
12. Subjects will have their doses of study treatments administered in the clinic 
after the pre-dose blood draw is completed and under fasted conditions, at least 1 
hr before or 2 hrs after a meal.
Dosing on CTC and Urine Electrolyte Sampling Days:  Subjects will be instructed 
to withhold their doses of study treatments on the morning of study visits when a 
blood or urine sample is to be obtained for analysis of CTCs and/or urine 
electrolytes, respectively.  After the pre-dose blood sample is drawn and/or the 
pre-dose urine sample is collected, subjects will have their doses of study 
treatments administered in the clinic, at least 1 hr before or 2 hrs after a meal
(an overnight fast is not required).
Vomiting: If a subject vomits after taking study treatment(s), the subject should be 
instructed NOT to retake the dose and should take the next scheduled dose of study 
treatment(s).  If vomiting persists, the subject should contact the investigator.
Missed Doses: If subject misses a dose of study treatment(s), the subject should be 
instructed to take the missed dose as soon as they realize it was missed, but not take the 
missed dose if there are less than 12 hrs until the next dose.  The missed dose should be 
recorded in the subject diary for either GSK2636771 or enzalutamide and in the 
eCRF.


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Section 6.3.1 GSK2636771
REVISED TEXT
For this study, the starting dose of GSK2636771 is 300 mg taken orally once daily.  
GSK2636771 should is to be administered within 5 minutes prior to enzalutamide and 
under fasted conditions, either 1 hr before or 2 hrs after a meal and with approximately 
200 mL of water (unless otherwise instructed in Section 6.3 for study visit days when 
PK, CTC, or urine electrolyte sampling is required).
Subjects shall abstain from ingestion of any food or drink containing grapefruit and 
grapefruit juice, Seville oranges or pomelos within 7 days prior to the first dose of 
GSK2636771 (Week 1, Day 1 of Combination Treatment Period) until the last dose of 
study treatment.
Section 6.3.2 Enzalutamide
REVISED TEXT
Per the product prescribing information for enzalutamide [Xtandi, 2013], the 
recommended dose of enzalutamide 160 mg (four 40 mg capsules) taken orally once 
daily will be administered during this study.  Enzalutamide may be taken with or without 
food except on days of PK sampling when enzalutamide should be administered under 
fasted conditions, either 1 hr before or 2 hrs after a meal.  
Enzalutamide may be taken with or without food on each day of the Enzalutamide 
Run-In Period (Days 1-13).  Specific instructions for the administration of 
enzalutamide on Day 14 of the Enzalutamide Run-In Period may be found in 
Section 6.3.  Once combination therapy (GSK2636771 + enzalutamide) begins on 
Week 1, Day 1 of the Combination Treatment Period,  enzalutamide should is to be 
administered within 5 minutes after of the administration of GSK2636771.  When 
administered with GSK2636771, enzalutamide should be administered and under fasted 
conditions, either 1 hr before or 2 hrs after a meal (unless otherwise instructed due to PK 
sampling; see Section 6.3). in Section 6.3 for study visit days when PK, CTC, or urine 
electrolyte sampling is required).
Section 6.4  Handling and Storage of Study Treatments
REVISED TEXT
Handling: Under normal conditions of handling and administration, the study treatments 
are not expected to pose significant safety risks to site staff.  Material Safety Data Sheets 
(MSDSs) for GSK2636771 and enzalutamide describing the occupational hazards and 
recommended handling precautions will be provided to site staff if required by local laws 
or will otherwise be available from GSK upon request.
Storage: All study treatments (GSK2636771 and enzalutamide) must be stored in a 
secure area under the appropriate physicalfollowing conditions for each product:  Access 


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to and administration of study treatments will be limited to the investigator and 
authorized site staff.  Study treatments must be dispensed or administered only to subjects 
enrolled in the study and in accordance with the protocol.

GSK2636771:  Store under appropriate physical conditions for the product as 
stated on the label. Refer to the SRM regarding temperature excursions.

Enzalutamide:  Recommended storage is 20C to 25C (68F to 77F) in a dry 
place.  Excursions permitted from 15C to 30C (59F to 86F). Store under 
appropriate physical conditions for the product as stated on the label.  Refer 
to the SRM regarding temperature excursions.
Access to and administration of study treatments will be limited to the investigator 
and authorized site staff.  Study treatments must be dispensed or administered only 
to subjects who qualify for entry in this study and in accordance with the protocol.  
Subjects should be reminded that all study treatments should be stored at home out 
of the reach of children.
All study treatments should be stored out of the reach of children.
Section 6.7 Treatment of Study Treatment Overdose, 4th paragraph
REVISED TEXT
A plasma or blood sample for PK analysis of one or more study treatments may be 
requested by the GSK Medical Monitor on a case-by-case basis.  This plasma or blood
sample should be collected as soon as possible, but within 7 days from the date of the last 
dose of study treatment (or suspected overdose).
Section 7  Dose Modifications, Stopping Criteria, and Management Guidelines for 
Specific Events Associated with GSK2636771
REVISED TEXT
The following dose modifications, stopping criteria, and management guidelines for 
specific events associated with GSK2636771 are provided as guidance and should not 
act as a replacement for sound clinical judgment.  The investigator should use clinical 
judgment to determine which study treatment may be contributing to the toxicity 
necessitating dose adjustment, and make the appropriate change for that agent.  The 
severity of AEs will be graded utilizing the CTCAE v4.0.  Guidelines for dose 
modifications and interruptions for management of specific toxicities are provided in this 
section.
If a given toxicity is considered to be related to one specific study treatment by the
investigator but not both, then dose modification should only occur with the study 
treatment associated with the specific toxicity or event of clinical concern.


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Section 7.1.1  GSK2636771 (NEW Section Header)
Text moved from Section 7.1 to Section 7.1.1
REVISED TEXT
Dose modification guidelines for GSK2636771 are outlined in Table 4 for clinically 
significant toxicities that are deemed related to study treatment but are not addressed 
specifically in Section 7.2 7.3.  If a given toxicity is considered to be related to one 
specific study treatment by the investigator but not both, then dose modification should 
only occur with the study treatment associated with the specific toxicity or event of 
clinical concern.
Section 7.2.1 QTc Stopping Criteria
DELETED TEXT
If QTcF >500 msec (Grade 3 or 4 QTc prolongation) or uncorrected QT >600 msec 
(averaged manual overread of 3 ECGs over at least 15 minutes), then the following 
guidelines should be followed:

Hold study treatments

Discuss with GSK Medical Monitor

Correct any electrolyte abnormalities

If QTcF resolves to 470 msec, study treatment may be restarted with dose 
reduction to the next dose level if the investigator and GSK Medical Monitor 
agree that the subject will benefit from further treatment.

If QTcF does NOT resolve to 470 msec, discontinue study treatments 
permanently.
NEW TEXT

QTc >500 msec 
OR

Change from baseline of QTc >60 msec
For subjects with underlying bundle branch block (BBB), follow the 
discontinuation criteria listed below:
Baseline QTc with BBB
Discontinuation QTc with BBB
<450 msec
>500 msec
450 – 480 msec
≥530 msec


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Section 7.2.2 Liver Chemistry Stopping Criteria
DELETED TEXT
Liver chemistry threshold stopping criteria have been designed to assure subject safety 
and to evaluate liver event etiology during administration of study treatments and the 
follow-up period. The liver chemistry stopping criteria for subjects with ALT 2.5 times 
ULN at study entry is provided in Section 7.2.2.1 and for subjects with documented liver 
metastases or tumor infiltration at baseline AND entry criteria ALT>2.5 x ULN but ≤5 x 
ULN in Section 7.2.2.2.
NEW TEXT
Liver chemistry stopping and increased monitoring criteria have been designed to 
assure subject safety and evaluate liver event etiology (in alignment with the US 
FDA premarketing clinical liver safety guidance).  
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/
Guidances/UCM174090.pdf.
Section 7.2.2.1 Liver Chemistry Stopping and Increased Monitoring Algorithm for 
Subjects WITH entry criteria ALT ≤2.5 x ULN
DELETED TEXT
Liver Safety Required Actions and Follow-up Assessments can be found in Appendix 6.


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NEW TEXT
Table 6
Liver Chemistry Stopping Criteria – Liver Stopping Event for Subjects 
WITH Entry Criteria ALT ≤2.5xULN
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
Abbreviations: ALT, alanine aminotransferase; INR, international normalization ratio; SAE, serious adverse 
event; ULN, upper limit of normal
1.
Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin fractionation is 
not immediately available, discontinue study treatment for that subject if ALT 3xULN and bilirubin 
2xULN. Additionally, if serum bilirubin fractionation testing is unavailable, record presence of detectable 
urinary bilirubin on dipstick, indicating direct bilirubin elevations and suggesting liver injury.
2.
All events of ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin) or ALT 3xULN and INR>1.5, if INR 
measured which may indicate severe liver injury (possible ‘Hy’s Law’), must be reported as an SAE 


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(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).
Section 7.2.2.2 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
DELETED TEXT
Liver Safety Required Actions and Follow-up Assessments can be found in Appendix  7.


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NEW TEXT
Table 7
Liver Chemistry Stopping Criteria – Liver Stopping Event for Subjects 
with Documented Liver Metastases/Tumor Infiltration at Baseline AND 
Entry Criteria ALT>2.5xULN but ≤5xULN
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
Abbreviations: ALT, alanine aminotransferase; INR, international normalization ratio; SAE, serious adverse 
event; ULN, upper limit of normal
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.


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2.
All events of ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin) or ALT 3xULN and INR>1.5, if INR 
measured which may indicate severe liver injury (possible ‘Hy’s Law’), must be reported as an SAE 
(excluding studies of hepatic impairment or cirrhosis); INR measurement is not required and the 
threshold value stated will not apply to subjects receiving anticoagulants.
3.
New or worsening symptoms believed to be related to liver injury (such as fatigue, nausea, vomiting, right 
upper quadrant pain or tenderness, or jaundice) or believed to be related to hypersensitivity (such as 
fever, rash or eosinophilia).
Section 7.2.2.3 Liver Safety Required Actions and Follow-up (NEW SECTION)
NEW TEXT
Table 8
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 hrs

Complete the liver event eCRF and 
complete an SAE data collection tool if 
the event also meets the criteria for an 
SAE2

Perform liver event follow-up 
assessments 

Monitor the subject until liver chemistries
resolve, stabilize, or return to within 
baseline (see MONITORING below)

Do not restart/rechallenge subject with 
study treatment unless allowed per 
protocol and GSK Medical Governance 
approval is granted (refer to Appendix 6)

If restart/rechallenge not allowed per 
protocol or 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 and 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

Viral hepatitis serology1

Only in those with underlying chronic hepatitis 
B at study entry (identified by positive hepatitis 
B surface antigen) quantitative hepatitis B DNA 
and hepatitis delta antibody3

Blood sample for PK analysis, obtained 24-72 
hrs after last dose4

Serum creatine phosphokinase and lactate 
dehydrogenase.

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 eCRF

Record use of concomitant medications on the 
concomitant medications eCRF including 
acetaminophen, herbal remedies, other OTC 
medications

Record alcohol use on the liver event alcohol 
intake eCRF
For bilirubin or INR criteria:

Anti-nuclear antibody, anti-smooth muscle 
antibody, Type 1 anti-liver kidney microsomal 
antibodies, and quantitative total IgG or 
gamma globulins.

Serum acetaminophen adduct HPLC assay 
(quantifies potential acetaminophen 


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Actions
Follow-Up Assessments

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
contribution to liver injury in subjects with 
definite or likely acetaminophen use in the 
preceding week [James, 2009]).

Liver imaging (ultrasound, MRI or CT) and /or 
liver biopsy to evaluate liver disease; complete 
Liver Imaging and/or Liver Biopsy eCRFs
Abbreviations: AE, adverse event; ALT, alanine aminotransferase; AST, aspartate aminotransferase; CT, 
computed tomography; DNA, deoxyribonucleic acid; eCRF, electronic case report form; GSK, 
GlaxoSmithKline; HPLC, high performance liquid chromatography; hrs, hours; IgG/IgM, immunoglobulin 
G or M; INR, international normalization ratio; MRI, magnetic resonance imaging; OTC, over-the-counter; 
PCR, polymerase chain reaction; PK, pharmacokinetic; RNA, ribonucleic acid; SAE, serious adverse 
event; SRM, Study Reference Manual; ULN, upper limit of normal
1.
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
2.
All events of ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin) or ALT 3xULN and INR>1.5, if INR 
measured which may indicate severe liver injury (possible ‘Hy’s Law’), must be reported as an SAE 
(excluding studies of hepatic impairment or cirrhosis); INR measurement is not required and the 
threshold value stated will not apply to subjects receiving anticoagulants
3.
If hepatitis delta antibody assay cannot be performed, it can be replaced with a PCR of hepatitis D RNA 
virus (where needed) [Le Gal, 2005].
4.
PK sample may not be required for subjects known to be receiving placebo or non-GSK comparator 
treatments.  Record the date/time of the PK blood sample draw and the date/time of the last dose of study 
treatment prior to blood sample draw on the eCRF. If the date or time of the last dose is unclear, provide 
the subject’s best approximation. If the date/time of the last dose cannot be approximated OR a PK 
sample cannot be collected in the time period indicated above, do not obtain a PK sample. Instructions 
for sample handling and shipping are in the SPM.


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Table 9
Liver Chemistry Increased Monitoring Criteria with Continued Therapy
Criteria
Actions
Subject with entry criteria ALT≤2.5xULN
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>2.5xULN but ≤5xULN
ALT ≥3xULN and 1.5x baseline value but
ALT <5xULN and 2x baseline value and 
bilirubin <2xULN, without symptoms 
believed to be related to liver injury, or 
hypersensitivity and who can be monitored 
weekly for 4 weeks

Notify the GSK Medical Monitor within 24 hrs 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, stabilize or return to 
within baseline 

If at any time subject meets the liver chemistry 
stopping criteria, proceed as described above
For subjects with entry criteria ALT≤2.5xULN

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>2.5xULN but ≤5xULN

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
Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; GSK, GlaxoSmithKline; hrs, 
hours; ULN, upper limit of normal
Refer to Appendix 6 for liver safety drug restart or rechallenge guidelines.
Section 7.2.3 Events Associated with GSK2636771 – renamed Left Ventricular 
Ejection Fraction (LVEF) Stopping Criteria
NEW TEXT
Echocardiography (or multigated acquisition [MUGA] scan) must be performed at 
Screening and as clinically indicated as outlined in the Time and Events Tables 
(Section 8.1).  Subjects who have an absolute decrease of >10% in LVEF compared 
with baseline and the ejection fraction is below the institution’s lower limit of 
normal (LLN) should temporarily discontinue treatment with GSK2636771 and 
have a repeat evaluation of LVEF within 1 week.  Echocardiogram or MUGA 
should be repeated every 1 to 2 weeks for 4 weeks or until LVEF recovery to above 
institutional LLN and within 10% of baseline.


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
If the LVEF recovers (defined as LLN and absolute decrease 10% 
compared with baseline) at any time during the next 4 weeks, after 
consultation and approval of the GSK Medical Monitor, the subject may be 
restarted on GSK2636771 at a reduced dose.  For such subjects, monitoring 
of LVEF will be performed 2 and 4 weeks after re-challenge, and every 4 
weeks thereafter for a total of 16 weeks and then per protocol.

If repeat LVEF does not recover within 4 weeks, treatment with 
GSK2636771 should be permanently discontinued.  Ejection fraction should 
be monitored every 4 weeks for a total of 16 weeks or until resolution.
Subjects with Grade 3 or 4 (symptomatic) left ventricular systolic dysfunction must 
discontinue treatment with GSK2636771.  Ejection fraction should be monitored 
every 4 weeks for a total of 16 weeks or until resolution.  If recovery occurs (LVEF 
>institutional LLN and symptom resolution) within 4 weeks, treatment with 
GSK2636771 may be restarted at a reduce dose in consultation with the GSK 
Medical Monitor.
Copies of all ECHOs (or MUGA 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 ECHOs (or MUGA scans) are provided in the 
SRM.
Section 7.2.4 Valvular Toxicity Stopping Criteria (NEW SECTION)
NEW TEXT
Subjects who have a new asymptomatic, moderate regurgitation or stenosis by 
ECHO or MUGA scan (Grade 2 mitral/tricuspid/aortic valvular toxicity per 
CTCAE v4.0 should temporarily discontinue treatment with GSK2636771 and have 
a repeat evaluation by ECHO within 1 week.  An ECHO (or MUGA scan) 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 GSK Medical Monitor, the subject may be 
restarted on GSK2636771 at a reduced dose(s).  For such subjects, 
monitoring of the valve via ECHO (or MUGA scan) will then be performed 
2 and 4 weeks after re-challenge, and every 4 weeks thereafter for 8 weeks 
and then per protocol.

If repeat ECHO (or MUGA scan) does not reveal valve recovery to baseline 
within 4 weeks, then the subject should permanently discontinue 
GSK2636771.  The valve should continue to be monitored via ECHO (or 
MUGA scan) every 4 weeks for 8 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 GSK2636771.  Valvular toxicity should continue to be monitored every 
4 weeks for 8 weeks or until resolution.  If recovery occurs (return to baseline via 


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imaging AND symptom resolution) within 4 weeks, the subject may restart 
GSK2636771 at a reduced dose after consultation and approval of the GSK Medical 
Monitor.
ECHO (or MUGA scan) must be performed within 28 days of Day -1 and at the End 
of Study visit (see Time and Events Tables in Section 8.1).  Copies of all ECHO(s) 
(or MUGA scan) and cardiology consultations performed on subjects who 
experience valvular toxicity will be required by GSK for review.  Instructions for 
submitting qualifying ECHOs (or MUGA scans) are provided in the SRM.
Section 7.3 Management Guidelines for Specific Events Associated with 
GSK2636771 (NEW SECTION)
NEW TEXT
If a subject experiences an AE during the Enzalutamide Run-In Period resulting in 
a dose interruption that precludes the subject from completing the run-in period 
within 14 days or a dose reduction, the GSK Medical Monitor should be contacted 
as approval will be required in order for the subject to continue in the study (refer 
to the SRM).  
Section 7.3.1 Renal Insufficiency or Other Renal Events – Table 10
REVISED TEXT
Table 10  Management and Dose Modification of Renal Events
Assessment
Action and Dose Modification
Urine dipstick protein 2+

Monitor for concomitant medications (e.g., NSAIDs) or medical 
conditions (e.g., menstruation, urinary tract infection) associated 
with positive urinary protein dipstick test (see SRM for further 
details)

Assess BP and ensure it is well-controlled (<140/90 mmHg)

Obtain a random UPC ratio (see Appendix  5)
Serum creatinine 
0.5 mg/dL (44.2 µmol/L) 
increase from baseline

Repeat serum creatinine level within 24 hrs of previous result

If repeat value confirms serum creatinine 0.5 mg/dL 
(44.2 µmol/L) increase from baseline:

Immediately interrupt treatment with GSK2636771

Evaluate and treat possible causes for elevated serum 
creatinine (e.g., renal outflow obstruction, sepsis, dehydration, 
hypotension, GI bleed, medications [e.g., trimethoprim, 
ketoconazole or cimetidine] that increase serum creatinine 
level)

Obtain blood sample for PK analysis, if requested (see 
SRM),  within 24-72 hrs after the last dose ( refer to Section 
8.7.3.1 for details on PK sample collection)

Consider oral or IV hydration, if clinically indicated

Repeat serum creatinine level every 7 days or more frequently 
if clinically indicated


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Assessment
Action and Dose Modification

If serum creatinine fails to improve (0.5 mg/dL [44.2 µmol/L] 
increase persists) within 14 days following dose interruption:

Permanently discontinue treatment with GSK2636771

Consult with GSK Medical Monitor

If serum creatinine improves (<0.5 mg/dL [<44.2 µmol/L] increase 
from baseline) within 14 days following dose interruption:

Restart treatment with GSK2636771 with dose reduced by one 
dose level

Repeat serum creatinine level every 4 weeks or more 
frequently if clinically indicated

If elevated serum creatinine recurs after one dose reduction 
(0.5 mg/dL [44.2 µmol/L] increase from baseline):

Repeat serum creatinine within 24 hrs to confirm result

If repeat serum creatinine confirms increase, withdraw 
subject from treatment/study unless there is agreement 
between investigator and GSK Medical Monitor that 
subject will benefit from continued treatment following 
recovery of serum creatinine (0.5 mg/dL [<44.2 µmol/L] 
increase from baseline)

If repeat serum creatinine fails to confirm increase, 
continue treatment with GSK2636771 at same dose level 
without interruption
Hypocalcemia
(serum calcium Grade 2)
or
Hypophosphatemia
(serum phosphate Grade 3 
or symptomatic Grade 2)

Repeat serum calcium or phosphate level within 24 hrs of previous 
result

If repeat value confirms Grade 2 serum calcium, or 
symptomatic Grade 2 serum phosphate.

Immediately interrupt treatment with GSK2636771

Treat as clinically indicated by local institutional standards

Obtain serum PTH level

Obtain blood sample for PK analysis, if requested (see 
SRM),  within 24-72 hrs after the last dose (refer to Section 
8.7.3.1 for details on PK sample collection)

Obtain urine samples for urine creatinine, calcium, phosphate, 
and protein at treatment interruption; repeat every 7 days

Repeat serum calcium or phosphate level every 7 days or more 
frequently if clinically indicated

If serum calcium fails to improve to Grade 1 or if serum phosphate 
fails to improve to asymptomatic Grade 2 within 14 days following 
dose interruption:

Permanently discontinue treatment with GSK2636771

Consult with GSK Medical Monitor

If serum calcium improves to Grade 1 or serum phosphate 
improves to asymptomatic Grade 2 or baseline, whichever is more 
improved within 14 days following dose interruption:

Restart treatment with GSK2636771 with dose reduced by one 
dose level

Repeat serum calcium or phosphate level per Time and Events 
Tables (Section 8.1) or more frequently if clinically indicated

If decreased serum calcium or phosphate levels reoccurs after one 
dose reduction :


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Assessment
Action and Dose Modification

Repeat serum calcium or phosphate levels within 24 hrs to 
confirm result

If repeat serum calcium or phosphate levels confirm 
decrease, withdraw subject from treatment/study unless 
there is agreement between investigator and GSK Medical 
Monitor that subject will benefit from continued treatment 
following recovery of serum calcium or phosphate to 
baseline with dose of GSK2636771 further reduced one 
dose level.

If repeat serum calcium or phosphate fails to confirm a decrease, 
continue treatment with GSK2636771 at same dose level without 
interruption
Abbreviations:  BP, blood pressure; GI, gastrointestinal; GSK, GlaxoSmithKline; IV, intravenous; mmHg, millimeters of 
mercury; NSAIDs, non-steroidal anti-inflammatory drugs; PK, pharmacokinetics; PTH, parathyroid hormone; RBC, 
red blood cell; SRM, Study Reference Manual; UPC, urine/protein/creatinine ratio
Section 7.3.1.1. (New Section)
NEW TEXT
Serum parathyroid hormone (PTH) level will be assessed on the first day of 
combination treatment (Week 1, Day 1 of Combination Treatment Period).  
Subsequently a serum PTH level should be obtained for any subject who 
experiences Grade 2 or greater hypocalcemia or hypophosphatemia while on study 
(refer to Table 10).
Section 7.3.2  Cardiac-related Toxicities
REVISED TEXT
Reversible increases in mean arterial pressure and decreases in heart rate and cardiac 
contractility that were considered secondary to an elevation in blood pressure were 
observed in a single dose safety pharmacology study in dogs administered 300 mg/kg of 
GSK2636771.  In the ongoing FTIH study, no Grade 3 or higher cardiac events have 
been observed.  Subjects with a history of uncontrolled hypertension, heart failure, or 
known significant coronary artery disease are excluded from this study.  Cardiac 
monitoring, including assessment of blood pressure and heart rate, along with 12-lead 
ECGs, will be performed.
Section 7.3.2.1  Hypertension
REVISED TEXT 
Table 6
Management and Dose Modification for Hypertension


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Section 7.3.3 Rash
REVISED TEXT
Table 7
Management and Dose Modification for Rash
Section 7.3.4  Diarrhea (NEW SECTION)
NEW TEXT
Episodes of diarrhea have occurred in subjects receiving GSK2636771 
monotherapy. Other frequent causes for diarrhea, including concomitant 
medications (e.g., stool softeners, laxatives, antacids, etc.), infections by C. difficile or 
other pathogens, partial bowel obstruction, should be clinically excluded.
Standardized and universal guidelines have been developed by an American Society 
of Clinical Oncology (ASCO) panel for treating chemotherapy-induced diarrhea 
[Benson, 2004].  Presented in the sections below are the recommended guidelines for 
the management of diarrhea in subjects receiving GSK2636771.  These guidelines 
were derived from the recommendations published by the ASCO panel [Benson, 
2004].
Early identification and intervention is critical for the optimal management of 
diarrhea.  A subject’s baseline bowel patterns should be established so that changes 
in patterns can be identified while subject is on treatment.
An assessment of frequency, consistency and duration as well as knowledge of other 
symptoms such as fever, cramping, pain, nausea, vomiting, dizziness and thirst 
should be taken at baseline.  Consequently subjects at high risk of diarrhea can be 
identified.  Subjects should be educated on signs and symptoms of diarrhea with 
instructions to report any changes in bowel patterns to the physician.
It is recommended that subjects keep a diary and record the number of diarrhea 
episodes and its characteristics.  They should also include information on any 
dietary changes or other observations that may be useful in the evaluation of their 
diarrhea history.
If subjects present with diarrhea of any grade, check they are receiving the study 
treatment correctly (i.e., single dose, rather than splitting it through the day).  
Obtain information on food (solid and liquid) and over-the-counter (OTC) 
medication(s), including herbal supplements, taken during the treatment period.
Guidelines regarding management and dose reduction for diarrhea considered to be 
related to study treatments by the investigator are provided in Table 13.


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Table 13
Management and Dose Modification Guidelines for Diarrhea
Grade
Management
Action and Dose Modification
Uncomplicated 
Diarrhea -
Grade 1
1. Instruct subject to start supportive care 
immediately at the first episode of diarrhea 
(i.e., unformed stool) and contact the 
investigator.

Administer loperamide: Initial dose: 4 mg. 
Subsequent doses: 2 mg after each 
unformed stool
19. Re-evaluate after 24 hrs:
20. If diarrhea is resolving: continue 
loperamide treatment at 2 mg dose after 
each unformed stool until diarrhea-free 
(i.e., bowel patterns return to baseline) for 
12 hrs.  If diarrhea recurs, re-initiate 
loperamide as needed to maintain normal 
bowel pattern.
21. If diarrhea is NOT resolving:
continue loperamide 2 mg every 4 hrs for 
the next 24 hrs; re-evaluate after 24 hrs.  
If not resolving, administer loperamide 2 
mg after each unformed stool until 
diarrhea free (i.e., bowel patterns return 
to baseline) for 12 hrs.  If diarrhea is not 
resolving, continue loperamide 2 mg 
every 4 hrs and re-evaluate every 24 hrs.
2. Dietary modifications:
22. Stop all lactose containing products and 
eat small meals
23. Avoid spicy, fried and fatty foods, raw 
vegetables and other foods high in fiber
24. Avoid caffeine and alcohol (can irritate 
bowel and increase motility)
25. Hydration:  Drink 8 to 10 large glasses of 
clear liquids (e.g., water, electrolyte drink) 
daily.  Avoid acidic drinks such as tomato 
juice and fizzy soft drinks
26. Supplement diet to include food rich in 
potassium (e.g., bananas, potatoes, 
apricots; evaluate their impact on 
diarrhea due to fiber content 
(e.g., apricots)

Continue study 
treatments at current 
dose.

Continue supportive care 
until diarrhea resolves 
(diarrhea free for 12 hrs 
and bowel pattern 
returns to baseline)

If diarrhea recurs after 
stopping loperamide 
treatment, resume 
loperamide treatment, 
re-introduce diet 
modifications, and 
continue study 
treatments at current 
dose.
3. If Grade 1 diarrhea persists for >1 week with 
loperamide treatment, consider treatment with 
second-line agents (i.e., octreotide, 


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Grade
Management
Action and Dose Modification
budesonide or tincture of opium).
4. If Grade 1 diarrhea persists for ≥2 weeks, refer 
to Persistent Grade 2 diarrhea management 
guidelines.
Uncomplicated 
Diarrhea –
Grade 2
1. Instruct subject to start supportive care 
immediately at the first episode of diarrhea 
(i.e., unformed stool) and contact the 
investigator.
27. Administer loperamide: Initial dose: 4 mg.  
Subsequent doses: 2 mg every 4 hrs or 
after each unformed stool
28. Re-evaluate after 24 hrs:
29.
If diarrhea is resolving: continue 
loperamide treatment at 2 mg dose after 
each unformed stool until diarrhea free 
(i.e., bowel patterns return to baseline) for 
12 hrs.  If diarrhea recurs, re-initiate 
loperamide as needed to maintain normal 
bowel pattern.
30.
If diarrhea is NOT resolving:
consider loperamide 2 mg every 2 hrs for 
the next 24 hrs.  If Grade 2 diarrhea 
persists after 48 hrs of loperamide 
treatment, start treatment with second-
line agents (i.e., octreotide, budesonide 
or tincture of opium).  Consider 
performing stool work-up, CBC, 
electrolytes and other tests as 
appropriate.
2.Dietary modifications:
31. Stop all lactose containing products and 
eat small meals
32. Avoid spicy, fried and fatty foods, bran, 
raw vegetables and other foods high in 
fiber.  Eat foods low in fiber (i.e., lean 
meat, rice, skinless chicken or turkey, 
fish, eggs, canned or cooked skinless 
fruits, cooked/pureed vegetables)
33. Avoid caffeine and alcohol (can irritate 
bowel and increase motility)
34. Hydration:  Drink 8 to 10 large glasses of 
clear liquids (e.g., water, electrolyte drink) 
daily.  Avoid acidic drinks such as tomato 
juice and fizzy soft drinks

Continue study 
treatments at current 
dose.

Continue supportive care 
until diarrhea resolves 
(diarrhea free for 12 hrs / 
bowel pattern returns to 
baseline)

Once diarrhea has 
resolved, subject may 
gradually re-introduce 
foods from their normal 
diet.

If diarrhea recurs after 
stopping loperamide 
treatment, resume 
loperamide treatment, re-
introduce diet 
modifications, and 
continue study 
treatments at current 
dose.


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Grade
Management
Action and Dose Modification
35. Supplement diet to include food rich in 
potassium (e.g., bananas, potatoes, 
apricots); evaluate their impact on 
diarrhea due to fiber content 
(e.g., apricots) 
36. If diarrhea recurs, refer to Recurrent 
Diarrhea management guidelines.
Persistent  
(≥3 days/ 
72 hrs) 
Diarrhea –
Grade 2
1.If Grade 2 diarrhea persists for ≥3 days or 72 
hrs, resume loperamide treatment and re-
introduce diet modifications.
2.If supportive care measures and interruption 
of study treatments are ineffective in treatment 
of persistent Grade 2 diarrhea, perform stool 
work-up, CBC, electrolytes, and other tests as 
appropriate.  Consider consultation with GI 
specialist.

Hold treatment with 
GSK2636771 and 
enzalutamide until 
symptoms have resolved 
to Grade 1 or baseline 
bowel pattern.

Once diarrhea has 
resolved, continue 
treatment with 
GSK2636771 and 
enzalutamide at reduced 
dose.
Recurrent 
Diarrhea (>1 
occurrence) -
(Grade 2)
If second occurrence of Grade 2 diarrhea recurs, 
resume loperamide treatment and re-introduce 
diet modifications.

Once diarrhea resolves 
to Grade 1 or baseline, 
consider re-starting 
study treatments 
(GSK2636771 +  
enzalutamide) at a 
reduced dose
Complicated 
Diarrhea2 –
Grade 3 or 
Grade 1 or 2 
with 
complicating 
factors
1.Instruct subject that they must call 
investigator immediately for any complicated 
severe diarrhea event.
2.If loperamide has not been initiated, initiate 
loperamide immediately.  Initial dose: 4 mg.  
Subsequent doses: 2 mg every 2 hrs or after 
each unformed stool.
3.Refer to the dietary modifications for Grade 1 
and 2 uncomplicated diarrhea (above).
4.For dehydration use IV fluids as appropriate.  
If subject presents with severe dehydration, 
administer octreotide.
5.Perform stool work-up, complete blood count, 
electrolytes and other tests as appropriate
6.Administer antibiotics (i.e., fluoroquinolones) 
as needed, especially if diarrhea is persistent 
beyond 24 hrs or if fever or Grade 3 or 4 
neutropenia is present
7.Intervention may require hospitalization for 
subjects most at risk for life threatening 

Hold treatment with 
GSK2636771 and 
enzalutamide until 
symptoms have resolved 
to Grade 1 or baseline 
bowel pattern and 
without complicating 
factors present.

Once diarrhea resolves 
to Grade 1 or baseline, 
consider re-starting 
study treatments 
(GSK2636771 
+enzalutamide) at a 
reduced dose 

Continue supportive care 
until diarrhea resolves 
(diarrhea free for 24 hrs 
and bowel pattern 
returns to baseline)


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Grade
Management
Action and Dose Modification
complications.
Complicated 
Diarrhea –
Grade 4
1.Instruct subject that they must call 
investigator immediately for any complicated 
Grade 4 diarrhea event.
2.If loperamide has not been initiated, initiate 
loperamide immediately.  Initial dose: 4 mg.  
Subsequent doses: 2 mg every 2 hrs or after 
each unformed stool.
3.For dehydration use IV fluids as appropriate.  
If subject presents with severe dehydration, 
administer octreotide.
4.Perform stool work-up, CBC, electrolytes and 
other tests as appropriate
5.Consider consultation with GI specialist.
6.Administer antibiotics (i.e., fluoroquinolones) 
as needed, especially if diarrhea is persistent 
beyond 24 hrs or if fever or Grade 3 or 4 
neutropenia is present
7.Intervention may require hospitalization for 
subjects most at risk for life threatening 
complications.

Hold treatment with 
GSK2636771 and 
enzalutamide

Consult with GSK 
Medical Monitor to 
discuss subject’s event 
history, re-initiation of 
study treatments, and 
dose modifications, once 
symptoms have resolved 
to Grade 1 or baseline 
bowel pattern

Continue supportive care 
until diarrhea resolves 
(diarrhea free for 24 hrs 
and bowel pattern 
returns to baseline)
Abbreviations: CBC, complete blood count; GI, gastrointestinal; hrs, hours; IV, intravenous; mg, milligram(s)
Section 7.3.5 Vomiting (NEW SECTION)
NEW TEXT
Table 14
Management and Dose Modification for Events of Vomiting
Grade
Action and Dose Modification
≤Grade 1
Continue study treatments at current dose.
Grade 2
Hold until ≤Grade 1.  Resume study treatments at same dose 
level.
Grade 3
Hold1 until <Grade 2.  Resume study treatments at one dose 
level lower, if indicated.2
Grade 4
Withdraw study treatments.
1Subjects requiring a delay of >14 days should be withdrawn from treatment and/or study.
2Subjects requiring >2 dose reductions should be withdrawn from treatment and/or study.
It is recommended that any event of vomiting should be managed with the use of 
antiemetics.


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Section 8.2.1  Consent for Pre-Screening
REVISED TEXT
The subject will be asked to provide written informed consent for pre-screening prior to 
any of the he investigator or other designated study personnel will determine if the 
subject is eligible for pre-screening by reviewing the eligibility criteria and completing all 
of The pre-screening assessments outlined in the Time and Events Tables (Section 8.1) 
are performed.
Section 8.2.2 Consent for Screening
REVISED TEXT
If, during pre-screening, the subject is determined during pre-screening to have a PTEN 
deficient tumor, the subject will be asked to provide written informed consent prior to 
screening for enrollment in the study.  The investigator or other designated study 
personnel will determine if the subject is eligible for enrollment in the study by reviewing 
the eligibility criteria and completing all of the Screening assessments outlined in the 
applicable Time and Events Tables in Section 8.1.
Section 8.3.1  Pre-Screening: Determination of PTEN Deficiency Status, 2nd
paragraph
REVISED TEXT
After written informed consent is provided by the subject archived tissue will be 
submitted to determinethe PTEN deficiency status of the subject’s tumor.  If archived 
tumor tissue is not available, fresh tumor tissue should be obtained by pre-treatment
biopsy to determine PTEN deficiency.  The PTEN testing will be performed at a GSK 
selected laboratory and the tumor specimen should be provided to that laboratory.  The 
PTEN status will be communicated to sites by GSK authorized personnel.
Section 8.3.2  Screening
REVISED TEXT
Subjects with confirmed PTEN deficiency and who have provide written informed 
consent for screening will be eligible to undergo specific screening assessments to 
determine eligibility for the study.
Section 8.4 Demographics and Medical History
REVISED TEXT
Demographic data will include gender, date year of birth, race, height, weight, ethnicity 
and geographic ancestry.
Medical, surgical, and treatment history including date (month and year) of first 
diagnosis, histology, current sites of disease as well as cardiovascular risk factors, alcohol 


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and tobacco history, plus family history will be taken as part of the medical history and 
disease status.
Section 8.6 Safety 
REVISED TEXT
Measurements used to evaluate safety will include physical examinations, vital sign (BP, 
temperature and pulse heart rate) measurements, ECOG performance status, 12-lead 
ECGs, ECHO/MUGA, clinical laboratory tests and monitoring for AEs.  Planned time 
points for all safety assessments are listed in the applicable Time and Events Tables 
(Section 8.1).
Section 8.6.2 Vital Signs
REVISED TEXT
Vital sign measurements will include BP, temperature, and pulseheart rate.  Vital signs 
may be measured as indicated in the Time and Event Tables (Section 8.1) or more 
frequently if warranted by clinical condition of the subject.  Refer to the SRM for details 
regarding measurement of vital signs.
Section 8.6.5 Echocardiogram and/or Multi-gated Acquisition (MUGA) Scans 
(NEW SECTION)
NEW TEXT
Echocardiograms (ECHOs) or MUGA scans will be performed at baseline to assess 
cardiac ejection fraction and cardiac valve morphology for the purpose of study 
eligibility, as specified in the Time and Events Tables (Section 8.1).  Additional 
ECHO assessments may be performed if clinically warranted.  The evaluation of the 
echocardiographer should include an evaluation for LVEF and both right and left-
sided valvular lesions.
Copies of all ECHOs or MUGA scans performed on subjects who experience an 
absolute decrease >10% in LVEF compared to baseline concurrent with LVEF < 
institutional LLN may be required by GSK for review.
Refer to the SRM for further details on submission of ECHOs or MUGA scans.
Section 8.6.6. Laboratory Assessments, 1st, 2nd, 3rd paragraphs
REVISED TEXT
Laboratory tests may be done up to 24 hrs prior to the scheduled visit.  Laboratory test 
results are to be reviewed prior to administration of the first dose of study treatment.
Liver function tests and urine tests for UPC protein/creatinine may be performed up to 
72 hrs prior to the scheduled visit in order to have results available for review by 
investigator prior to the scheduled visit date.


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Any laboratory test with a value outside the normal range may be repeated during 
Screening (prior to the first dose) at the discretion of the investigator.  A subject with a 
laboratory value outside the reference range(s) may be included only if the investigator 
and GSK Medical Monitor agree that it is unlikely to introduce additional risk factors and 
will not interfere with study procedures.
Table 17  Laboratory Assessments
Other tests
PSA 
Serum Testosterone
Coagulation Tests: PT/PTT/INR
Serum Parathyroid Hormone (PTH)
Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; BUN, blood urea nitrogen; INR, 
international normalization ratio; MCH, mean corpuscular hemoglobin; MCV, mean corpuscular volume; PSA, prostate-
specific antigen; PT, prothrombin time; PTH, parathyroid hormone; PTT, partial thromboplastin time; RBC, red blood 
cell; ULN, upper limit of normal; UPC, urine/protein/creatinine ratio; WBC, white blood cell
1.
Direct bilirubin is required only if the total bilirubin is elevated (2 times ULN)
2.
Chemistry evaluation of chloride or uric acid is not required where there are logistical constraints.
3.
See Appendix 5
Section 8.7.1 PK Assessments: Dose Escalation Phase
REVISED TEXT
Blood Plasma samples for PK analysis of enzalutamide and N-desmethyl 
enzalutamide will be collected from all subjects on Day 14 of the Enzalutamide Run-
In Period.  Blood and plasma samples for the analysis of GSK2636771, 
enzalutamide, and N-desmethyl enzalutamide will be collected from all subjects on 
Week 5, Day 29 and during Weeks 8 and 12 of the Treatment Continuation Period.  
These PK samples will be collected to evaluate if there is an effect of GSK2636771 on 
the PK of enzalutamide and to quantify the systemic exposure to GSK2636771, 
enzalutamide and N-desmethyl enzalutamide. 
Section 8.7.2  PK Assessments: Dose Expansion Phase
REVISED TEXT
A sparse reduced PK sampling strategy will be used for subjects in the Dose Expansion 
Phase (on Day 29, Week 5 and during Weeks 8 and 12) to quantify the systemic 
exposure to study treatments GSK2636771, enzalutamide and N-desmethyl 
enzalutamide.
Section 8.7.3 PK Blood Sample Collection
REVISED TEXT
Serial Blood and/or plasma samples for PK analysis of GSK2636771 and/or
enzalutamide and N-desmethyl enzalutamide will be collected at the time points indicated 


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in the Time and Events Tables (see Section 8.1).  Whenever possible, blood for PK 
samples should be drawn from the peripheral arm vein or from a central IV port.  Each 
PK sample should be collected as close as possible to the planned time relative to the 
dose (i.e., time zero) administered to the subject on serial PK days.  Once preliminary PK 
data have been reviewed, the planned sample collection times or study day may be 
revised based on newly available data (i.e., to obtain data closer to the time of peak 
plasma concentration) to ensure appropriate monitoring.  These changes must be 
approved and documented by GSK, but will not constitute a protocol amendment.  
For Dose-Escalation Phase:  Blood samples for analysis of enzalutamide and 
N-desmethyl enzalutamide will be collected pre-dose and 0.5, 1, 2, 3, 4, and 6 hrs post-
dose on the day prior to administration of the first dose of GSK2636771 (Day -1).
Blood samples for the analysis of GSK2636771 + enzalutamide should be collected on 
Day 29 at pre-dose and 0.5, 1, 2, 3, 4, and 6 hrs post-dose. Blood and/or plasma 
samples for analysis of GSK2636771 and/or enzalutamide and N-desmethyl 
enzalutamide will be collected according to a serial sampling scheme in the Dose 
Escalation Phase.  

Day 14 (Enzalutamide Run-In Period): the day prior to administration of the 
first dose of GSK2636771:  Subjects will be instructed to fast overnight (at 
least 8 hrs) and withhold their dose of enzalutamide prior to the study visit 
on Day 14.  Study treatments will be administered in the clinic after the pre-
dose blood draw is completed.  Subjects will continue to fast for 2 hrs post-
dose.  Plasma samples for analysis of enzalutamide and N-desmethyl 
enzalutamide will be collected pre-dose and 0.5, 1, 2, 3, 4, and 6 hrs post-dose 
of enzalutamide (total of 7 samples).

Day 29, Week 5 (Treatment Continuation Period): Subjects will be instructed 
to fast overnight (at least 8 hrs) and withhold the doses of study treatment 
prior to the study visit. Study treatments will be administered in the clinic 
after the pre-dose blood draws are completed. Subjects will continue to fast 
for 2 hrs post-dose.  Blood and plasma samples for the analysis of 
GSK2636771, enzalutamide and N-desmethyl enzalutamide will be collected 
at pre-dose and 0.5, 1, 2, 3, 4, and 6 hrs post-dose (total of 14 samples).

Weeks 8 and 12 (Treatment Continuation Period):  Subjects will be 
instructed to withhold the doses of study treatment prior to the study visit 
(no overnight fast is necessary). Study treatments will be administered in the 
clinic after the pre-dose blood draws are completed, either 1 hr before or 
2 hrs after a meal. Blood and plasma samples for the analysis of 
GSK2636771, enzalutamide and N-desmethyl enzalutamide will be collected 
pre-dose only (total of 2 samples per visit).
For Dose Expansion Phase:  Blood samples for analysis of enzalutamide and 
N-desmethyl enzalutamide will be collected according to a sparse sampling scheme in 
subjects in the Dose Expansion Phase.  Subjects with morning clinic visits will be 
instructed to withhold the doses of study treatment prior to the Week 5 visit.  A pre-dose 


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blood sample for analysis of enzalutamide, N-desmethyl enzalutamide, and GSK2636771 
will be collected prior to administration of study treatment at the clinic.  Additional blood 
samples for analysis of enzalutamide, N-desmethyl enzalutamide, and GSK2636771 will 
be collected 1, 2, and 3 hrs post-dose.  Subjects with afternoon clinic visits will take 
study treatments at the usual time.  Blood samples for analysis of enzalutamide, N-
desmethyl enzalutamide, and GSK2636771 will be collected at approximately 5 to 6, 6 to 
7, and 7 to 8 hrs after administration of study treatments. Blood and plasma samples for 
analysis of GSK2636771, enzalutamide and N-desmethyl enzalutamide will be 
collected according to a sparse sampling scheme in the Dose Expansion Phase.  
Overnight fast is not necessary for any of these PK days. Study treatments should be 
administered either 1 hr before or 2 hrs after a meal.  

Day 29, Week 5 (Treatment Continuation Period):  
o
Subjects scheduled for a morning clinic visit will be instructed to 
withhold the doses of study treatments prior to the study visit.  Study 
treatments will be administered in the clinic after the pre-dose blood 
draws are completed (either 1 hr before or 2 hrs after a meal). Blood
and plasma samples for analysis of GSK2636771, enzalutamide and 
N-desmethyl enzalutamide will be collected at pre-dose and 1, 2, and 
3 hrs post-dose (total of 8 samples).
o
Subjects scheduled for an afternoon clinic visit will take their doses of 
study treatments at the usual time in the morning (either 1 hr before 
or 2 hrs after a meal).  Blood and plasma samples for analysis of 
GSK2636771, enzalutamide and N-desmethyl enzalutamide will be 
collected approximately 5 to 6, 6 to 7, and 7 to 8 hrs post-dose (total of 
6 samples).

Weeks 8 and 12 (Treatment Continuation Period):  Subjects will be 
instructed to withhold the doses of study treatments prior to the study visit. 
Study treatments will be administered in the clinic after the pre-dose blood 
draw is completed (either 1 hr before or 2 hrs after a meal). Blood and 
plasma samples for the analysis of GSK2636771, enzalutamide and N-
desmethyl enzalutamide will be collected pre-dose only (total of 2 samples 
per visit). 
Details of PK blood and plasma sample collection (including volume to be 
collected), processing, storage and shipping procedures are provided in the SRM.
Section 8.7.3.1  Additional PK Blood Sample Collection
NEW TEXT
Blood and plasma samples for PK analysis will also be collected within 24-72 hrs 
after the last dose of study treatment(s) at the time of a treatment-emergent AE of 
special interest unless the event occurs on the same day that the Day 14 
(Enzalutamide Run-In Period) and/or Week 5, Day 29 (Treatment Continuation 
Period) PK samples are obtained.


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The date/time of the PK blood and plasma sample draw and the date/time of the last 
dose of study treatments prior to the PK blood and plasma sample draws will be 
recorded on the eCRF.  If the date or time of the last dose of study treatment is 
unclear, provide the subject’s best approximation.  If the date/time of the last dose 
of study treatment cannot be approximated OR PK blood or plasma samples cannot 
be collected in the time period indicated above, do not obtain a PK samples.  Refer 
to the SRM for instructions on sample handling and shipping of the PK samples.
Section 8.7.4 Pharmacokinetic Sample Analysis
REVISED TEXT
Blood and plasma analysis will be performed under the control of GSK Platform 
Technology and Science-Drug Metabolism and Pharmacokinetics (PTS-DMPK)/Scinovo, 
the details of which will be included in the SRM. Concentrations of GSK2636771, 
enzalutamide and N-desmethyl enzalutamide will be determined in blood and plasma 
samples using the currently approved bioanalytical methodology. Raw data will be 
archived at the bioanalytical site (detailed in the SRM).
Once the blood and plasma has been analyzed for GSK2636771, enzalutamide and N-
desmethyl enzalutamide any remaining blood or plasma may be analyzed for other 
compound-related metabolites and the results reported under a separate GSK PTS-DMPK 
protocol.
Section 8.7.5 Meals, Alcohol, Tobacco and Activity Restrictions
REVISED TEXT
Meals
On serial PK sampling days subjects will fast for 4 hrs before and 2 hrs after dosing of 
the study treatments.
Subjects will be instructed to take study treatments at least 1 hr before or 2 hrs after 
a meal unless otherwise instructed due to PK, CTC, and/or urine electrolyte 
sampling (see Section 6.3 for details).
Tobacco
Subjects who use tobacco products will be instructed that use of nicotine-containing 
products (including nicotine patches) will not be permitted while they are in the clinical 
unit.
Smoking while in the clinical unit will not be permitted. Subjects who use tobacco 
products may use nicotine patches while they are in the clinical unit.
Section 8.8  Clinical Activity


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NEW TEXT
Refer to the SRM for further details on submission of CT scans, MRIs and bone 
scans.
Section 8.9.1  Predictive Biomarkers, first paragraph
REVISED TEXT
For subjects entered in the study, additional slides of tumor tissue samples will be 
collected and submitted to the designated central laboratory for analysis once a 
subject has received their first dose of GSK2636771 on Week 1, Day 1 of the 
Combination Treatment Period.  The remaining tumor tissue submitted for the PTEN 
testing may be utilized for retrospective analysis as detailed belowpredictive biomarker 
analysis.  Additional archival or pre-dose biopsy tumor tissue samples will also be 
requested for the enrolled subjects to complete the intended analysis.  .  If additional 
tumor tissue is not available, no new biopsy procedure is required in order to obtain 
tumor tissue for predictive biomarker analysis.  
Genetic changes known to alter or regulate PTEN function including mutation, loss of 
heterozygosity (LOH), silencing due to promoter methylation may also be assessed.  
Additional proteins, DNA, RNA, or microRNA, related to activity of GSK2636771and 
enzalutamide or prostate cancer may also be analyzed.  Any remaining tumor tissue may 
also be utilized to further develop a PTEN diagnostic assay.
Section 8.9.3  Circulating Tumor Cells
NEW TEXT
Additional blood samples will be collected at the time points indicated in the Time 
and Events Tables (Section 8.1) to isolate CTCs using an EPIC Biosciences 
platform.  The isolated CTCs will be analyzed for AR variants or other protein 
markers and potential genomic alterations (e.g., PTEN allele loss, AR 
amplifications, etc.).
If subject withdraws consent for further treatment and data collection, all samples 
collected for the biomarker analysis at the time of withdrawal will still proceed for 
analysis to meet the intended objectives defined in this protocol.
Details on sample collection, processing, storage and shipping procedures for all 
blood and tissue samples are provided in the SRM.
Section 8.9.3.1  CTC Conversion Rate
REVISED TEXT
CTC enumeration will be performed at a central laboratory using the analytically valid 
CellSearch system (Veridex LLC).  For subjects with baseline CTC counts of 5 cells per 
7.5 mL of blood, a conversion is defined as a decline in the CTC count to <5 cells per 


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7.5 mL of blood.  Genetic analysis of CTCs may also be performed by other 
laboratories.
Section 8.9.4  Circulating Free Tumor DNA and Soluble Markers
REVISED TEXT
Assessment of gene mutations in circulating free tumor DNA (cfDNA) and other soluble 
markers will be performed to better understand clonal evolution and other predictive 
circulating biomarkers.  Soluble markers may include cytokines or other immune 
response markers.  DNA analysis includes mutation analysis of genes implicated in the 
PI3K/Ras/Raf or AR pathway.
Tumor-specific cfDNA levels detected in plasma or serum have been found to 
correlate with increasing tumor burden and decline following therapy.  
Furthermore, cfDNA in cancer subjects can harbor many genetic alterations 
(mutations, microsatellite alterations, aberrant methylation), which are generally 
consistent with the tumor. Thus, tumor-specific circulating cfDNA has the potential 
to be a useful biomarker of therapeutic response as well as offering a less invasive 
blood based technique for identifying predictive biomarkers.
Plasma samples for analysis of cfDNA and soluble markers will be collected at the time 
points provided in the Time and Events Tables in Section 8.1.during Screening, at 
Week 4 (pre-dose) and at time of disease progression for soluble markers and DNA 
analysis for all subjects enrolled in the study (see Time and Event Tables in Section 8.1).  
Section 8.10  Appendix 8:  Genetic Research
NEW TEXT
Information regarding genetic research is included in Appendix 8.
Section 9.5 Time Period and Frequency of Detecting AEs and SAEs
REVISED TEXT
2nd paragraph: AEs will be collected from the time the first dose of enzalutamide is 
administered on Week 1, Day 1 of the Enzalutamide Run-In Phase 14 during the 
Screening Period until 30 days following discontinuation of study treatments regardless 
of initiation of a new cancer therapy or transfer to hospice.
Section 10  Concomitant Medications and Non-Drug Therapies
REVISED TEXT
Subjects will be asked to provide a complete list of prescription and OTC medications 
that have been taken within 4 weeks prior to Screening.  Subjects will be instructed to 
inform the investigator prior to starting any new medication(s), including herbal 
preparations and OTC products, taken from the time of the first dose of study treatment
enzalutamide monotherapy on Day 1 of the Enzalutamide Run-In Period until the 


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end of the study (i.e. through the final post-treatment follow-up visit).  Any 
concomitant medication(s), including OTC and herbal product(s), taken during the 
study will be recorded in the eCRF. At a minimum, the drug name, dose and the 
dates of administration are to be recorded.  Additionally, a complete list of all prior 
cancer therapies will be recorded in the eCRF.
Questions regarding concomitant medications should be directed to the GSK Medical 
Monitor for clarification.
If future changes to the list of permitted or prohibited medications are made as a result of 
emerging data, formal documentation will be provided to the investigative site by GSK.
Any such changes will be communicated to the investigative sites in the form of a letter, 
which should be stored in the study file. Sites may also refer to the SRM for updates 
regarding changes to the list of permitted or prohibited medications.
Section 10.1 Permitted Medications, 3rd and 4th paragraphs
REVISED TEXT
Steroids:  Use of steroids is discouraged while subject is undergoing treatment on this 
study.  However, steroids (up to a maximum of 10 mg of prednisone or equivalent) are 
permitted provided that the subject has been on a stable dose for at least 4 weeks prior to 
enrollmentfirst dose of study treatments.
Anticoagulants:  Prophylactic doses of anticoagulants (i.e., heparin, warfarin) are 
permitted provided that the subject meets the PTT/INR entry criteria (see Section 4.1.2) 
and INR is monitored in accordance with local institutional practice.  Therapeutic doses 
of warfarin (defined as a dose resulting in INR >1.5) are prohibited within 14 days prior 
to first dose of study treatments Day 1 of the Enzalutamide Run-In Period through the 
post-treatment follow-up visit.  Caution should be exercised if aspirin is used 
concomitantly with GSK2636771.
Section 10.2  Prohibited Medications and Non-Drug Therapies
DELETED TEXT

AR antagonists (e.g., bicalutamide, flutamide, nilutamide)
Section 10.2.1.1 GSK2636771 as Perpetrator of Drug-Drug Interactions (section 
header added)
DELETED TEXT
A preliminary study suggested the potential of CYP3A4 inhibition; however, subsequent 
studies did not confirm this.  Use of medications that have a narrow therapeutic index and 
are substrates of CYP3A4 should be avoided within 7 days or 5 half-lives (whichever is 
longer) prior to the first dose of study treatment and for the duration of study treatment 
through the post-treatment follow-up visit.


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Drug(s) that are strong inducers of CYPs and UGTs as they may decrease the 
concentration of GSK2636771 (see Table 11).  CYP3A4 substrates with a narrow 
therapeutic index, strong inducers of CYP3A4 and UGTs, and anti-platelet agents to 
avoid include, but are not limited to, those listed in Table 11 below.  Consider therapeutic 
substitutions for these medications.
NEW TEXT
A preliminary study suggested the potential of CYP3A4 inhibition by GSK2636771; 
however, subsequent studies using human recombinant CYP3A4 and pooled human 
liver microsomes did not confirm this at concentrations tested (up to 100 M). The 
preliminary study indicated GSK2636771 did not inhibit CYP1A2, 2C8, 2C9, 2C19 
and 2D6 at up to 25 µM (10.8 g/mL), the risk is low but was not fully discharged at 
higher concentrations.  Medications that have a narrow therapeutic index and are 
substrates of CYP3A4 should be used with caution within 7 days or 5 half-lives 
(whichever is longer) prior to the first dose of GSK2636771 (Week 1, Day 1 of the 
Combination Treatment Period) and for the duration of study treatment through 
the post-treatment follow-up visit (Table 18).  Medications that have a narrow 
therapeutic index and are substrates of CYP1A2, CYP2C8, 2C9 and 2C19, CYP2D6 
and CYP2B6 should be used with caution.  GSK2636771 did not inhibit transporters 
OATP1B1, OATP1B3, BCRP and P-gp up to 23-30 µM in vitro.  Due to high 
GSK2636771 concentrations (up to 100 M) observed in the FTIH study 
(P3B115717), there is a risk for renal transporter inhibition; however, in vitro data 
to discharge this risk is pending.  Therefore, medications that are sensitive 
substrates of renal transporters OAT and OCT2 should be used with caution when 
administered with GSK2636771 (example drugs are listed in Table 18).
Table 18
Drugs Potentially Affected by GSK2636771: Avoid Use with Caution
Drugs/Agents
Therapeutic Area
CYP3A4 Substrates
dihydroergotamine, ergonovine, ergotamine, methylergonovine
Ergot derivatives
pimozide
Neuroleptic
bepridil, flecainide, lidocaine, mexilitine, amiodarone, quinidine, 
propafenone
Antiarrhythmics
tacrolimus, sirolimus
Immune modulators
quetiapine, risperidone, clozapine, atomoxetine
Miscellaneous
CYP Inducers and/or UGT enzymes
rifamycin class agents (e.g., rifampin, rifabutin, rifapentine)
Antibiotics
carbamazepine, phenobarbital, phenytoin, s-mephenytoin
Antiepileptic drugs
Antiplatelet agents
ticlopidine, prasugrel or ticagrelor
Antiplatelet
Renal Transporter (OAT, OCT2) Substrates 
methotrexate
Antineoplastic
dofetilde, pilsicainide, procainamide
Antiarrhythmic
metformin
Antidiabetic


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Section 10.2.1.2  GSK2636771 as Victim of Drug-Drug Interactions (section header 
added)
REVISED TEXT
Based on pre-clinical and in vitro data, CYP enzymes do not appear to mediate the 
metabolism of GSK2636771.  However, strong inhibitors or inducers of CYP enzymes 
should be used with caution in the case that they may alter the PK of GSK2636771 
(Table 12).
Based on pre-clinical and in vitro data GSK2636771 is a substrate for UDP-
glucuronosyltransferase (UGT) enzymes.  Therefore, drugs that are inhibitors of UGT 
enzymes should be used with caution (Table 12).
Based on pre-clinical and in vitro data, GSK2636771 is an in vitro substrate for 
UDP-glucuronosyltransferase (UGT) enzymes, while CYP enzymes did not appear 
to be the major pathways for metabolism of GSK2636771. Therefore, drug(s) that 
are strong inhibitors or inducers of CYPs and UGTs may increase or decrease the 
concentration of GSK2636771.  Medications that are strong inhibitor/inducers of 
CYP3A4 and UGTs, including, but not limited to, those listed in Table 19, should be 
used with caution.  Consider therapeutic substitutions for these medications.
Table 19
Drugs that may Potentially Affect GSK2636771: Use with Caution
Generic Drug Name
Therapeutic Area
Inducers of UGT enzymes
rifamycin class agents (e.g., rifampin, rifabutin, rifapentine)
Antibiotics
carbamazepine, phenobarbital, phenytoin, s-mephenytoin
Antiepileptic drugs
CYP Inhibitors
clarithromycin, telithromycin, troleandomycin
Antibiotics
itraconazole, ketoconazole, posaconazole, voriconazole
Antifungals
nefazodone
Antidepressants
gemfibrozil 
Hyperlipidemia
bosentan, mibefranil, conivaptan
Miscellaneous
cyclosporine
Immunosuppressive agents
Inhibitors of UGTenzymes inhibitors
fluconazole
Antifungal
cisapride, probenecid, ranitidine, cyclosporine, diflunisal, sertraline, valproic 
acid, atavaquone, methadone, methsuximide, olanzapine, retigabine
Miscellaneous
Caution is also recommended when GSK2636771 and aspirin are used 
concomitantly.
Section 10.2.2 Potential Drug Interactions with Enzalutamide


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NEW TEXT
The following information is provided as an initial reference, however, please refer 
to the approved US FDA prescribing information [Xtandi, 2013] or the Xtandi 
Prescribing Information for the area where it is approved for the most current 
drug-drug interaction (DDI) information and contraindicated medications.
Section 11.1 Contraception Requirements
REVISED TEXT
Abstinence:  Male subjects may also elect abstinence, defined as sexual inactivity 
consistent with the preferred and usual lifestyle of the subject.  Periodic abstinence 
(e.g. calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not
acceptable methods of contraception.  Complete abstinence from sexual intercourse must 
occur for 14 days prior to first dose of study treatment enzalutamide monotherapy on 
Day 1 of the Enzalutamide Run-In Period, through the dosing period, and until 3 
months after the last dose of study treatments.
Sperm Donation:  Subjects must not donate sperm from the time day of the first dose of 
study treatment enzalutamide monotherapy on Day 1 of the Enzaluatmide Run-In 
Period through 3 months after the last dose of study treatments.
Section 13.3.4.3 Pharmacokinetic Analyses
REVISED TEXT
Pharmacokinetic analysis will be the responsibility of the Clinical Pharmacology 
Modeling and Simulation Department, GSK.  Statistical analyses of the PK parameter 
data will be the responsibility of GSK Discovery Biometrics and Clinical Statistics.
Non-compartmental analysis will be conducted on Concentration-time data for 
GSK2636771, enzalutamide and N-desmethyl enzalutamide from the Dose-Escalation 
Phase will be analyzed via standard non-compartmental methods.  Parameters 
calculated include the area under the concentration-time curve from 0 to the last 
quantifiable blood or plasma concentration (AUC(0-t)), the maximum plasma or blood 
concentration (Cmax), and the time of the maximum concentration (tmax) if data permit.  
Population PK parameters for GSK2636771 including oral clearance (CL/F), oral 
volume of distribution (V/F), and absorption rate constant (ka) will be estimated pooling 
all data from this study with historical data, if data permit.  Dependent on the final 
structural PK model, additional PK parameters may also be estimated. Sources of 
variability in PK parameters will be investigated during population modeling.  
Section 14.2 Regulatory and Ethical Considerations, Including the Informed 
Consent Process


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NEW TEXT
In approving the clinical protocol the IEC/IRB and, where required, the applicable 
regulatory agency are also approving the optional assessments, e.g. genetic research 
described in Appendix 7, unless otherwise indicated.  Where permitted by 
regulatory authorities, approval of the optional assessments can occur after 
approval is obtained for the rest of the study.  If so, then the written approval will 
clearly indicate approval of the optional assessments is being deferred and the 
study, except for the optional assessments, can be initiated.  When the optional 
assessments are not approved, then the approval for the rest of the study will clearly 
indicate this and therefore, the optional assessments will not be conducted.
Section 16.1  Appendix 1: ECOG Performance Status
REVISED TEXT
5
Death
Section 16.4  Appendix 4: Disease Assessment per RECIST 1.1
NEW TEXT
Assessment Guidelines – CT and MRI:
NOTE: If CT contrast is contraindicated, acquire and submit a contrast-
enhanced MRI of the abdomen/pelvis and an unenhanced CT of the chest in 
place of the enhanced CT for complete lesion assessment.
REVISED TEXT
Baseline Assessments – CT and MRI:
NOTE: Although CT scan is preferred, MRI may be used as an alternative method of 
baseline disease assessment for abdomen/pelvis, especially for those subjects where a 
CT scan is contraindicated due to allergy to contrast, provided that the method used to 
document baseline status is used consistently throughout study treatment to facilitate 
direct comparison.  An unenhanced CT of the chest can replace the enhanced CT of 
the chest, but MRI of the chest is not recommended.
Confirmation of CR and PR are required per protocol.  Confirmation assessments must be 
performed no less than 4 weeks (±3 days) 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 time point regardless of unscheduled assessments).
Baseline Assessments
The following baseline disease (lesion) assessments must be performed within 28 days 
prior to enrollment (or within 35 days if disease assessment is assessed by MRI) prior to 


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the first dose of enzalutamide (Day 1 of Enzalutamide Run-In Period) to identify 
target and non-target lesions:
Baseline documentation of target and non-target lesions 

All baseline lesion assessments must be performed within 28 days prior to 
enrollment (or within 35 days if disease assessment is assessed by MRI) prior to the 
first dose of enzalutamide (Day 1 of Enzalutamide Run-In Period).
Confirmation Criteria:
To be assigned a status of PR or CR, a confirmatory disease assessment should be 
performed no less than 4 weeks (±3 days) after the criteria for response are first 
met.
Confirmation of Response per RECIST 1.1
Confirmation of CR and PR are required per protocol.  Confirmation assessments must be 
performed at least 4 weeks (±3 days) 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-specified assessment, the next 
protocol-specified evaluation is still required (e.g., evaluations must occur at each 
protocol scheduled time point regardless of unscheduled assessments).
Brain metastases:  To confirm a CR in a solid tumor subject with brain metastases at 
baseline, brain imaging that is obtained before the response assessment indicating a CR 
must have been obtained no earlier than 1 week prior to that response assessment 
imaging.  Alternatively, brain imaging performed after a response assessment imaging 
suggesting a CR in a solid tumor subject with brain metastases must be done no more 
than 4 weeks (±3 days) after the next protocol specified assessment in order to confirm a 
CR.
Section 16.6  Appendix 6: Liver Safety Required Actions and Follow-up 
Assessments (Section deleted; subsequent sections renumbered)
DELETED TEXT
Phase I 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 Oncology Liver Chemistry Increased Monitoring Criteria with continued therapy –
Liver Monitoring Event
Criteria
Actions
ALT 3 x ULN but <5 x ULN 
and bilirubin <2 x ULN, 
without symptoms believed 
to be related to liver injury or 

Notify the GSK Medical Monitor within 24 hrs of learning of the 
abnormality to discuss subject safety

Subject can continue study treatment


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hypersensitivity and who can 
be monitored weekly for 4 
weeks

Subject must return weekly for repeat liver chemistries (ALT, AST, 
alkaline phosphatase, bilirubin) until they resolve, stabilise or return to 
within baseline

If at any time subject meets the liver chemistry stopping criteria, 
proceed as described above

If, after 4 weeks of monitoring, ALT <3 x ULN and bilirubin <2 x ULN, 
monitor subjects twice monthly until liver chemistries normalize or 
return to within  baseline.
Subject with documented
liver metastases/tumor 
infiltration at baseline AND 
entry criteria ALT>2.5 x 
ULN but ≤5 x ULN
ALT ≥3 x ULN and 1.5 x 
baseline value but ALT <5 x 
ULN and 2 x baseline value
and bilirubin <2 x ULN, 
without symptoms believed 
to be related to liver injury, or 
hypersensitivity and who can 
be monitored weekly for 4 
weeks
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 <3 x ULN and <1.5 x baseline 
value, and bilirubin <2 x ULN, monitor subjects twice monthly until liver 
chemistries normalize or return to within baseline
References:
James LP, Letzig L, Simpson PM, Capparelli E, Roberts DW, Hinson JA, Davern TJ, Lee 
WM. Pharmacokinetics of Acetaminophen-Protein Adducts in Adults with 
Acetaminophen Overdose and Acute Liver Failure. Drug Metab Dispos.
2009;37(8):1779-1784. 
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.
Section 16.6  Appendix 6: Liver Safety Drug Restart/Rechallenge Guidelines
REVISED TEXT
1. Rechallenge Following Liver Stopping Events that are Possibly Related to 
Study Treatment (third bullet)

subject currently exhibits severe liver injury defined by: alanine aminotransferase 
(ALT) >≥3xULN, bilirubin ≥>2xULN (direct bilirubin >35% of total), or 
international normalization ratio (INR) >1.5
Section 16.7  Appendix 7: Genetic Research (new section; subsequent sections were 
renumbered)


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NEW TEXT
Genetic Research Objectives and Analyses
The objectives of the genetic research are to investigate the relationship between 
genetic variants and: 

Response to medicine, including any treatment regimens under investigation in 
this study or any concomitant medicines;

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.
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 (Day 1 preferably for this study), 
after the subject has been randomized and provided informed consent for 
genetic research. If a subject initially declines to participate in genetic research 
and then changes their mind, a sample should be obtained at the earliest 
opportunity.  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.  


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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 GlaxoSmithKline (GSK) may destroy the samples 
sooner.  GSK or those working with GSK (for example, other researchers) will only 
use samples collected from the study for the purpose stated in this protocol and in 
the informed consent form.  Samples may be used as part of the development of a 
companion diagnostic to support the GSK medicinal product.
Subjects can request their sample to be destroyed at any time.
Informed Consent
Subjects who do not wish to participate in the genetic research may still participate 
in the clinical 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 
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 


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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.
16.9.3.
Protocol changes for Amendment 3 (24-Jun-2016) from Protocol 
Amendment 2 (26-Feb-2015)
Where the Amendment Applies
This amendment applies to all sites and countries.
Summary of Amendment Changes with Rationale
Amendment 3 incorporates changes to update the risk assessment section and to include 
additional requirements for monitoring of renal events following an INDSR report for 
Acute Renal Failure in a subject enrolled in this study.
In addition, it was clarified that subjects with disease progression defined by PSA 
progression alone or for the worsening of an isolated disease site that is not clinically 
significant are not required to discontinue treatment in the study.   Separate definitions 
for disease progression as a study endpoint and disease progression mandated by the 
protocol to result in a subject being withdrawal from treatment is clarified. 
Optional pharmacodynamics paired biopsies as well as clarifications around biomarker 
assessments were added to the Time and Events tables for the Dose Escalation and Dose 
Expansion Phases.  
Additional language was added to clarify that the decision to terminate the Dose 
Expansion Phase will take into account all relevant factors, including but not solely based 
upon the statistical methodology and futility criterion.
Other minor clarifications and corrections of inadvertent errors were also added.   


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List of Specific Changes:
Throughout this section, added text has been bolded and deleted text had been shown 
with strikethrough.  The remaining text has been shown to provide context for the 
changes.
Changes associated with renal assessments:
Section 1.4.1.1, Risk assessment for GSK2636771:
Renal: Degenerative changes were observed in the kidneys of rats and dogs at 
100 mg/kg/day or 1000 mg/kg/day, including cellular and tubular changes, with 
chemistry and urinalysis findings.  Grade 3, treatment-related hypophosphatemia and 
hypocalcaemia have been observed in the FTIH study P3B115717.  There have been 2 
reports of acute kidney injury (grade 2 and 3) in subjects who received GSK2636771 
in Study 200331.  Since it is possible that GSK2636771 may contribute to acute 
kidney injury, renal events should be closely monitored.  Medical history will be 
collected and, physical examination and clinical laboratory tests will be measured 
frequently during therapy to monitor for potential toxicity.  Guidelines will be 
implemented including dose modification and discontinuation (Section 7.3.1) for the 
management of renal insufficiency or renal-related events considered to be related to 
study treatment, will be implemented.  It is recommended that patients be well 
hydrated and avoid the use of NSAIDs.
Section 4.1.2, Inclusion Criterion 11:
Changes to requirements for adequate baseline organ function at time of Screening to 
include serum phosphate within normal limits, rather than Grade 1; and to require 
the use of the CKD-EPI equation rather than by the Cockcroft-Gault formula when 
estimating serum creatinine clearance. 
Section 7.3.1, Management Guidelines for Renal Insufficiency:
Management guidelines for renal insufficiency or other renal events are to be followed 
when serum creatinine 0.3 mg/dL (26.5 µmol/L) rather than when serum creatinine 
0.5 mg/dL (44.2 µmol/L), and are to include an assessment of 24-hour urine 
creatinine clearance, where feasible.   
In addition,

If repeat serum creatinine fails to confirm increase, continue treatment with GSK2636771
at same dose level without interruption and obtain blood sample for PK analysis , 
within 24-72 hrs after the last dose (refer to Section 8.7.3.1 for details on PK sample 
collection)
Section 7.3.4 and Section 7.3.5, Management Guidelines for Diarrhea and Vomiting
A cross reference to Section 11.3 on hydration was added to this section on the 
management of diarrhea and the section on vomiting.


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Section 10.1, Permitted Medications:
Concomitant medication and non-drug therapies was updated to note, Use of NSAIDs 
should be avoided during the study.
Section 11.3 Other Lifestyle Restrictions:
Lifestyle restrictions was updated to include the addition, Subjects are to be instructed 
to avoid dehydration while participating in the study.  Subjects who have 
inadequate oral intake or who have difficulty maintaining hydration should 
discontinue treatment with GSK2636771 until adequate oral intake can be 
maintained.  If the subject must discontinue treatment for more than 14 days due to 
inadequate oral intake, the subject should be withdrawn from the study.
Appendix 3:
Updated to remove the Cockcroft-Gault Formula and to add the web address for the 
CKD-EPI equation.
Change associated with clarification of the distinction between disease 
progression as and endpoint and as a criterion for the discontinuation of 
treatment
Section 5.2, Permanent Discontination of Study Treatment:
Study treatment(s) will be permanently discontinued for any of the following reasons:

Disease progression defined with regards to termination of study 
treatment as: Radiographic progression in soft tissue or bone by 
RECIST 1.1 for subjects with measurable disease, OR

Bone progression on bone scan according to the criteria (Section 8.8.2.2), 
OR

When it is determined in the opinion of the treating physician in 
collaboration with the subject that the subject is no longer clinically 
benefitting (NLCB) from treatment.
NOTE: Subjects who are tolerating therapy and meet criteria for disease 
progression solely on the basis of rising PSA or for the worsening of an 
isolated disease site that is not clinically significant will NOT be required to 
discontinue treatment and can continue treatment until they are NLCB 
from treatment [Scher, 2016].
NOTE:  Subjects must meet the PCWG2 guidelines for disease progression to 
avoid premature discontinuation of study treatment(s).
Treatment Discontinuation due to PSA rise:  Following PCWG2 
guidelines, subjects should not be discontinued from study treatment(s) 
solely due to PSA rise during the first 12 weeks of treatment 
(Section 8.8.2.1).


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Treatment Discontinuation due to Bone Scan changes:  Subjects should 
not be discontinued from study treatment(s) due to the occurrence of 
bone scan changes in the first 12 weeks that do not meet PCWG2 
guidelines for progression (Section 8.8.2.2).
Section 5.3, Subject Completion:
A subject will be considered to have completed the study if the subject dies or 
discontinues treatment due to disease progression otherwise progresses during the 
study treatment or post-treatment follow-up period. All other subjects will be considered 
to have withdrawn from the study.
Section 8.1, Change in the column heading for Table 15 Time and Event Table for 
the Dose Escalation Phase and Table 16 Time and Event Table for the Dose 
Expansion Phase and addition of explanatory footnote 31:
Time of Discontinuation of Treatment due to Disease Progression31
31.
Subjects are not required to discontinue treatment on the basis of PSA 
progression alone or for the worsening of an isolated disease site that is not clinically 
significant (see Section 5.2).
Section 8.8.1, Clinical Activity Endpoint:
The secondary endpoint to evaluate the clinical activity of oral GSK2636771 + 
enzalutamide will be assessed using the disease progression endpoint (see Section 
8.8.2.3) which differs from the disease progression criteria that lead to 
discontinuation of treatment (see Section 5.2).  is the PSA and RECIST response rate 
as per PCWG2 guidelines.  CTC response will also be determined and reported as an 
exploratory endpoint.
Section 8.8.2.3, Disease Progression Endpoint:
The disease progression endpoint is defined by 1 or more of the following criteria:

PSA progression according to the PCWG2 criteria (Section 8.8.2.1)

Radiographic progression in soft tissue or bone by RECIST 1.1 for subjects with 
measurable disease

Bone progression on bone scan according to the PCWG2 criteria 
(Section 8.8.2.2).
Subjects are not required to discontinue treatment on the basis of meeting PSA 
progression alone or for the worsening of an isolated disease site that is not clinically 
significant (see Section 5.2) 


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References:
Citation for the Prostate Cancer Clinical Trials Working Group 3 [Scher, 2016] was 
added. 
Other minor changes:
To conform to changes added in Section 5.2 regarding when treatment is to be 
discontinued

A cross reference to Section 5.2 was added to Section 3.2.3 and Section 3.3, and

Clarifications were added to Section 3.5 and Section 8.1 (Time and Events Table 
15 and Table 16). 
Changes associated with the addition of optional paired biopsies for  
pharmacodynamics analysis as well as clarifications around biomarkers, 
including assessments added to the Time and Events tables for the Dose 
Escalation and Dose Expansion Phases.  
Section 2.2 Objective and Endpoints:
Addition of the following study objective and endpoint:

To determine pharmacodynamic effects of 
drug treatment

RNA/protein analysis of pre/post 
treatment tumor biopsies 
Section 3.0, Investigational Plan:
Biomarker Assessments:  Planned biomarker assessments include:  1) Identify potential 
predictive biomarkers (protein, DNA, ribonucleic acid [RNA] based) in archived tumor 
tissue/pre-treatment biopsies; 2) enumeration of CTCs in circulation and evaluation of 
genetic alterations or expression of inAR,orPTEN or other genes (or other genomic 
markers) in isolated CTCs; 3) Assessment of gene mutations in circulatingfree
DNA/RNA (cfDNA) and other soluble markers in plasma to better understand clonal 
evolution and other predictive circulating biomarkers; and 4) understand the mechanism 
of resistance in tumor tissues biopsies (optional) at time of progression 5) assess 
pharmacodynamic effects by collecting pre/post treatment tumor biopsies
Section 3.4 Dose Escalation Plan
If the combination doses in Cohort 1 are not tolerable, lower doses as defined in the de-
escalation cohort (Cohort -1) will be evaluated.  If the de-escalation cohort (Cohort -1) is 
not tolerable, further dose escalation using a continuous daily dosing schedule for both 
compounds simultaneously will be terminated.additional dose levels of GSK2636771 or 
alternative dosing schedules may be explored based upon ongoing assessment of safety, 


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PD and PK.  Dose modification decisions will be made utilizing all available data at the 
end of each DLT reporting period (the first 28 days of combination treatment).
Section 8.1, Time and Events Tables:
Additional unplanned blood, plasma and/or optional tumor samples may be requested 
with patient consent and investigator agreement as needed to better characterize safety 
and response(s) in subjects.
Table 15 Time and Events Table for the Dose Escalation Phase and Table 16 Time 
and Events Table for the Dose Expansion Phase:
cfDNA/RNA/Soluble Marker updated to include plasma samples collected pre-dose at 
Weeks 1, 8, 16, 24, and 32.
Footnote 24:
24. Tumor Biopsies for PD and progression: These biopsies are optional and may be 
undertaken in select cases upon agreement with the investigator and when consent is 
provided by the subject. For pharmacodynamic biomarker analyses, fresh tissue 
biopsies would be collected between Day 12 of the Enzalutamide Run-in Period and 
Week 1/Day 1, prior to any treatment with GSK2636771, and 2-4 hours post dose 
between Days 8 and 15 of the Combination Treatment Period (post-treatment).  For 
subjects who consent to the optional progression biopsy, a fresh tumor biopsy 
should be completed if the subject initially responded to combination treatment and 
then progressed.  
LDH assessments added, along with a footnote 32
32. When collected as part of the routine standard of care for a subject, LDH will be 
reported.
Section 8.9.2, Tumor Sample Biopsies:
If consent is provided by the subject, optional fresh tumor biopsies may be collected 
prior to combination treatment and 2 to 4 hours post dose on day 8 or 15 of 
combination treatment to understand target engagement and pharmacodyamic 
effects. It is preferable to repeat biopsy the same lesion to get a clearer picture of 
pre and post treatment effects. For subjects who initially responded to combination 
therapy and then progressed, an optional progression tumor biopsy is requested in order 
to better understand the mechanism of resistance.  It is preferable to obtain this biopsy 
from a new lesion or a lesion which had previously responded and then progressed.  
Biopsy samples from other lesions will be accepted as well.  Both soft tissue and bone 
biopsies will be accepted.


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Section 8.9.4, Circulating Cell Free Tumor DNA, RNA and Soluble Markers:
Furthermore, cfDNA in cancer subjects can harbor many genetic alterations (mutations, 
copy number changes microsatellite alterations, aberrant methylation), which are 
generally consistent with the tumor of origin.
Section 8.11, Explorator PK and PD Analysis:
Evaluation of pre and post treatment tumor tissue may also be explored to determine 
pharmacodynamic effects and the mechanism of resistance to combination therapy in 
subjects who have progressed after initially responding to the combination therapy.
Section 13.3.4.5, Translational Research Analyses:
Plasma collection at baseline, post-treatment and at time of disease progression will be 
used to analyze cfDNA, RNA and other soluble markers to understand clonal evolution, 
monitor response and explore and other predictive circulating biomarkers.  Archival 
tissue/pre-dose or fresh biopy tissue may be utilized to identify potential predictive 
biomarkers (protein, DNA and RNA based markers).  Optional PD and progression 
biopsies for subjects who have progressed from initially responding to the combination 
therapy may also be requested to understand pharmacodynamic effects and
mechanism(s) of resistance.
Changes associated with the futility criterion for the Dose Expansion Phase
Section 3.6.1, Evaluation of Futility
All available data will be considered in making enrollment decisions.
The decision to terminate the Dose Expansion Phase will not depend solely on the 
results of the statistical methodology, but will take all factors into account. These 
factors include the representation of predictive biomarkers, such as Androgen 
receptors, in the subjects treated at the time of interim analysis; and the totality of 
the safety, tolerability, PK, and PD data. Additional subjects targeting a specific 
biomarker profile may be enrolled in the cohort at the discretion of the team even if 
the predictive probability suggests a low likelihood of clinical activity in this cohort
Section 13.2.2, Dose Expansion Phase
However, the decision to terminate the Dose Expansion Phase will not depend solely 
on the results of the statistical methodology, but will take all factors into account. 
Additional subjects in a cohort may be enrolled even if the predictive probability 
suggests a low likelihood of activity in the Expansion Cohort (see Section 3.6.1).


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Other changes to provide additional clarifications or to correct inadvertent 
errors in previous versions of the protocol:
Section 1.2.1, Introduction:
Updated status of study P3B115717 to note the study is completed and enrolled 65 
subjects.
Section 3.0 Cohort Expansion, 4th paragraph
In the Dose Expansion Phase, subjects will be assigned to receive GSK2636771 at doses 
identified at or below the MTD or RP2D determined in the Dose Escalation Phase while 
continuing treatment with enzalutamide to evaluate the long-term safety of the 
combination as well as the 12-week non-PD rate.
Section 3.2.4, Post Treatment Follow up
Subjects who discontinue the Extended Follow-Up Visits prior to disease progression, for 
reasons other than death, loss to follow-up, or withdrawal of consent should have a 
Post-Extended Follow-Up/EOS Visit performed.
Section 3.4.1, Cohort Expansion:
Subjects may be enrolled at previously completed dose levels for the purpose of 
obtaining additional PK and/or PD data
Section 3.5 Dose Expansion Phase
Enrollment in the Dose Expansion Phase of the study may begin once the MTD and 
RP2D have been determined in the Dose Escalation Phase.  Up to 20 additional subjects 
may be enrolled to better characterize the safety profile, PK, and clinical activity of the 
recommended doses of the combination of GSK2636771 + enzalutamide for future 
studies. One or more combination doses may be explored in the Dose Expansion 
Phase based the MTD and RP2D identified in the Dose Escalation Phase of the 
study.
Section 4.1.3, Exclusion Criteria 1:
Added clarification that treatment with abiraterone during the study is exclusionary to 
enrollment. 
Section 7.3.3 Management Guidelines for Rash:
An error in previous versions of the protocol was corrected in the rash management 
guidelines to indicate that treatment can be restarted following rash events when rash 
returns to Grade 1, rather than < Grade 1. 
A note was also added to include PK samples for Grade 3 and Grade 4 dose limiting 
toxicity rash events. 


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Section 8.1, Time and Events Tables:
Table 15 Time and Events Table for the Dose Escalation Phase and Table 16 Time 
and Events Table for the Dose Expansion Phase:
CTC- Janssen
Section 8.6.6, Table 17, Laboratory Assessments:
Added Hematocrit to the list of laboratory assessments.
Section 8.8.2.1 and Section 8.8.2.2:
Clarification was added to note that PSA response and response in bone is to be assessed 
following 12 weeks of combination treatment with enzalutamide plus GSK2636771.
16.9.4.
Protocol changes for Amendment 4 (27-Jan-2017) from Protocol 
Amendment 3 (24-Jun-2016)
Where the Amendment Applies
This amendment applies to all sites and countries.
Summary of Amendment Changes with Rationale
Amendment 4 was completed to include additional requirements for monitoring of events 
related to calcium results, including revisions to the Table & Events to clarify additional 
laboratory testing requirements; clarification of secondary clinical activity endpoints and 
update to associated statistical section(s); revision of clinical activity population allowing 
the combination of dose escalation and dose expansion populations; revision of dose 
escalation and dose expansion wording to allow multiple dose levels in dose expansion to 
establish RP2D after dose expansion phase; adjustment to Week 12 visit window and 
clarification for Week 12 assessment timing; revision to reflect current indication for 
enzalutamide throughout; clarification of study populations; clarification of bone 
progression definition. 
Other minor clarifications and corrections of inadvertent errors were also added.   
List of Specific Changes:
Throughout this section, added text has been bolded and deleted text had been shown 
with strikethrough.  The remaining text has been added to provide context for changes.
Synopsis – Study Rationale: 
Rationale for Change: 
Revision to reflect currently approved indication for enzalutamide.


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Previous text:
Therapeutic approaches that simultaneously inhibit both the androgen receptor (AR) pathway and 
the PI3K pathway may be more effective than inhibition of either pathway alone in mCRPC.  
Enzalutamide is an AR inhibitor indicated for the treatment of patients with mCRPC who have 
previously received docetaxel.  The proposed Phase I study will evaluate the safety and tolerability, 
pharmacokinetics (PK), and clinical activity to determine the recommended Phase II dose (RP2D) 
and regimen of GSK2636771 in combination with enzalutamide given orally in adult male subjects 
with mCRPC.
Revised text: 
Therapeutic approaches that simultaneously inhibit both the androgen receptor (AR) pathway and 
the PI3K pathway may be more effective than inhibition of either pathway alone in mCRPC.  
Enzalutamide is an AR inhibitor indicated for the treatment of patients with mCRPC who have 
previously received docetaxel.  The proposed Phase I study will evaluate the safety and tolerability, 
pharmacokinetics (PK), and clinical activity to determine the recommended Phase II dose (RP2D) 
and regimen of GSK2636771 in combination with enzalutamide given orally in adult male subjects 
with mCRPC.
Synopsis – Secondary Hypothesis: 
Rationale for Change: 
Update of study population in hypothesis wording
Previous text:
Secondary Hypothesis:  The addition of a targeted PI3K pathway inhibitor (GSK2636771) to 
enzalutamide can limit mCPRC progression in a clinically meaningful way for at least 12 weeks.  
The null hypothesis is that the 12-week non-progressive disease (PD) rate is not attractive (≤5%).  
The alternative hypothesis is that the rate is clinically meaningful and, therefore, the compound 
warrants further development (≥30%).  This hypothesis will be tested for Part 2 of the study only. 
Revised text: 
Secondary Hypothesis:  The addition of a targeted PI3K pathway inhibitor (GSK2636771) to 
enzalutamide can limit mCPRC progression in a clinically meaningful way for at least 12 weeks.  
The null hypothesis is that the 12-week non-progressive disease (PD) rate is not attractive (≤5%).  
The alternative hypothesis is that the rate is clinically meaningful and, therefore, the compound 
warrants further development (≥30%).  This hypothesis will be tested for Part 2 of the study, only 
combining eligible subjects from Part 1.
Synopsis – Primary Objectives: 
Rationale for Change: 
Changes to the abbreviations used in this section, by writing out all abbreviations s first 
instance in the synopsis. These included writing out AE (Adverse Events), SAEs (Serious 


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Adverse Events), DLTs (Dose Limiting Toxicities, ECGs (Electrocardiograms) and BP 
(Blood Pressure). Adjustment to efficacy endpoint wording. 
Previous text:

Non-PD rate for 12 weeks according to 2PCWG2 criteria (either by RECIST 1.1, PSA 
progression, and/or progression in bone).
Revised text: 

Non-PD rate for 12 weeks according to 2PCWG2 criteria (either by Response Evaluation
Criteria In Solid Tumors [RECIST] 1.1, or progression in bone or Prostate Specific
Antigen [PSA] progression with accompanying progression by RECIST 1.1 or bone 
scan when baseline radiological or bone disease present or PSA progression if no 
other baseline disease).
Synopsis – Secondary Objectives: 
Rationale for Change: 
Deletion of wording associated with how additional clinical activity was to be measured 
with less defined endpoints. Addition new secondary objective and endpoints. 
Previous text: 

To evaluate the clinical activity of oral 
GSK2636771 + enzalutamide in the 
treatment of mCRPC (PTEN deficient)

PSA as defined in PCWG2 guidelines 
and RECIST 1.1 response.
Revised text: 

To evaluate the clinical activity of oral 
GSK2636771 + enzalutamide in the 
treatment of mCRPC (PTEN deficient)

PSA50 response rate defined as the 
percent of subjects achieving PSA50 
at 12 weeks or thereafter (PSA50 is 
≥50% decrease in PSA from baseline)

Objective Response Rate (ORR) 
defined as complete response (CR) 
rate plus partial response (PR) rate 
per RECIST 1.1 

Time to PSA progression according 
to PCWG2 criteria

Time to radiological progression 
according to PCWG2 criteria (either 
by RECIST 1.1, and/or progression in 
bone)

Radiological progression free 
survival (rPFS) per RECIST1.1 and/or 
bone scans

PSA as defined in PCWG2 guidelines 
and RECIST 1.1 response.


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Synopsis – Dose escalation Cohort Expansion: 
Rationale for Change: 
Due to possibility of multiple doses being explored in dose expansion, updated wording 
to clarify dose escalation population and how maximum tolerated dose will be defined. 
Previous text: 
Cohort Expansion: Selected dose levels may enroll up to 12 additional subjects to ensure a 
sufficient number of subjects enrolled to assess PK and/or safety.  The MTD will be the 
recommended dose combination for future Phase II studies unless there is a lower dose of 
GSK2636771 that provides adequate PK exposure and biologic activity with superior tolerability.
Revised text: 
Cohort Expansion:  Selected dose levels may enroll up to 12 additional subjects to ensure a 
sufficient number of subjects enrolled to assess PK and/or safety.  The MTD may will be the 
recommended dose combination for future Phase II studies unless there is a lower dose of 
GSK2636771 that provides adequate PK exposure and biologic activity with superior tolerability. 
The final decision will be based on the totality of data.  
Synopsis – Dose Expansion Phase: 
Rationale for Change: 
Clarification that multiple doses may be explored in the dose expansion phase. 
Previous text: 
This phase of the study will evaluate the long term safety of the combination treatment as well as 
the 12-week non-progressive disease (PD) rate of the combination treatment in subjects with 
mCPRC.  Approximately 20 subjects will be enrolled with each subject assigned to receive 
GSK2636771 in combination with enzalutamide.
Revised text: 
This phase of the study will evaluate the long term safety of the combination treatment as well as 
the 12-week non-progressive disease (PD) rate of the combination treatment in subjects with 
mCPRC.  Approximately 20 subjects will be enrolled with each subject assigned to receive 
GSK2636771 in combination with enzalutamide.To confirm dose(s) identified during dose 
escalation, multiple dose levels of GSK2636771 in combination with enzalutamide may be 
examined during dose expansion, with each dose level cohort enrolling up to 20 subjects. 
Using the totality of safety, PK and clinical activity data, the RP2D will be confirmed from 
the dose level(s) which are examined in the dose expansion phase.
Synopsis – Number of Subjects Study Design: 


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Rationale for Change: 
Updated of the potential number of subjects due to possibility of multiple dose expansion 
cohorts and clarification of wording due to combination of dose escalation and expansion 
populations.
Previous text: 
A total of approximately 44 subjects will be enrolled in this study.  
In the Dose Escalation Phase, the number of dose levels and the level at which the MTD is 
reached cannot be determined in advance.  An adequate number of subjects will be enrolled to 
establish the RP2D.  It is estimated that approximately 24 subjects will be enrolled to allow 
assessment of safety and preliminary efficacy in PTEN-deficient mCRPC with disease progression 
on enzalutamide.
In the Dose Expansion Phase, it is estimated that approximately 20 subjects will be enrolled, with 
evaluation for futility after the first 10 subjects have completed 12 weeks of treatment. The sample 
size planned for the Dose Expansion Phase is not driven by statistical considerations as the cohort 
is meant to further understand the safety implications of enrolling subjects to combination therapy 
for an extended period of time.  
Revised text:
A total of approximately 44 to 64 subjects will be enrolled in this study.  
In the Dose Escalation Phase, the number of dose levels and the level at which the MTD is 
reached cannot be determined in advance.  An adequate number of subjects will be enrolled to 
establish the RP2D MTD.  It is estimated that approximately 24 subjects will be enrolled to allow 
assessment of safety and preliminary efficacy in PTEN-deficient mCRPC with disease progression 
on enzalutamide.
In the Dose Expansion Phase, it is estimated that approximately 20 subjects will be enrolled, with 
evaluation for futility after the first 10 subjects have completed 12 weeks of treatment. This 
analysis may occur using the combination of the dose escalation and dose expansion 
population. If multiple dose levels of GSK2636771 are examined during dose expansion to 
establish the RP2D, each dose level cohort will enrol approximately 20 subjects, increasing
the overall number of subjects targeted for enrolment in this study. The sample size planned 
for the Dose Expansion Phase is not driven by statistical considerations as the cohort is meant to 
further understand the safety implications of enrolling subjects to combination therapy for an 
extended period of time.  
Synopsis – Inclusion Criteria 11: 
Rationale for Change: 
Due to updated changes for calcium and bone markers adjusted the Other section of the 
tests in this criteria and updated footnote, by adding footnote 6.


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Previous text:
Other
Serum Phosphate6
WNL
Serum Calcium (corrected)
WNL
6.Per CTCAE v4.0, Grade 1 hypophosphatemia is <LLN – 2.5 mg/dL (<LLN - 0.8 mmol/L
Revised text: 
Other
Serum Phosphate6
WNL
Serum Calcium6 (corrected)
Ionized Calcium6
Vitamin D6: 25-OH D and 
1,25-OH2 D
WNL
WNL
WNL
6.
Per CTCAE v4.0, Grade 1 hypophosphatemia is <LLN – 2.5 mg/dL (<LLN   0.8 mmol/Vitamin D 
supplementation may be added to achieve values WNL. Calcium supplements should be added for 
subjects with calcium values near the lower normal limit. 
Synopsis – Safety Assessments: 
Rationale for change: 
Clarification of labs required for study based on emerging safety data. 
Previous text:
Clinical chemistry: blood urea nitrogen, creatinine, glucose (fasting), sodium, potassium, chloride, 
carbon dioxide, calcium, aspartate aminotransferase (AST), ALT, alkaline phosphatase, total 
protein, albumin, uric acid and total/direct bilirubin, phosphorus, and magnesium.
Revised text: 
Clinical chemistry: blood urea nitrogen, creatinine, glucose (fasting), sodium, potassium, chloride, 
carbon dioxide, calcium (serum and ionized), vitamin D, aspartate aminotransferase (AST), ALT, 
alkaline phosphatase, total protein, albumin, uric acid and total/direct bilirubin, phosphorus, and 
magnesium.
Synopsis – Statistical Methods: 
Rationale for change: 
Revision of hypotheses to allow analyses on combined dose escalation and expansion 
cohorts. 
Previous text:
Hypothesis:  No formal statistical hypotheses will be tested in the Dose Escalation Phase.  All 
analyses will be descriptive and exploratory for this phase.
A targeted PI3K pathway inhibitor (GSK2636771) added to enzalutamide will be tested to see if 
mCPRC progression can be limited in a clinically meaningful way for at least 12 weeks.  The null 


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hypothesis is that the 12-week non-PD rate is not attractive (≤5%).  The alternative hypothesis is 
that the rate is clinically meaningful and therefore, the compound warrants further development 
(≥30%). 
For the Dose Expansion Phase, utilizing a null and alternative hypothesis of 5% and 30% 
respectively, a maximum of 20 subjects will be enrolled, with a minimum enrollment of 10 subjects. 
With an actual type I error rate (α) of 0.065 and 94.2% power, the design has stopping criteria 
defined for futility.  
Number of Subjects 
Enrolled
This Number of  
Responses1 to Stop Early 
for Futility
10
0
11
0
12
0
13
0
14
0
15
0
16
1
17
1
18
1
19
1
20
2
Abbreviation: PCWG2, Prostate Cancer Working Group 2
1.
Response for the purpose of futility is defined as lack of disease progression at 12 weeks according to 
PCWG2 criteria.
Revised text: 
Hypothesis:  No formal statistical hypotheses will be tested in the Dose Escalation Phase.  All 
analyses will be descriptive and exploratory for this phase.
A targeted PI3K pathway inhibitor (GSK2636771) added to enzalutamide will be tested to see if 
mCPRC progression can be limited in a clinically meaningful way for at least 12 weeks.  The null 
hypothesis is that the 12-week non-PD rate is not attractive (≤5%).  The alternative hypothesis is 
that the rate is clinically meaningful and therefore, the compound warrants further development 
(≥30%). 
For the Dose Expansion Phase, clinical activity will be evaluated per dose level if more than 
one dose is examined. A targeted PI3K pathway inhibitor (GSK2636771) added to 
enzalutamide will be tested to see if mCPRC progression can be limited in a clinically 
meaningful way for at least 12 weeks.  The null hypothesis is that the 12-week non-PD rate 
is not attractive (≤5%).  The alternative hypothesis is that the rate is clinically meaningful 
and therefore, the compound warrants further development (≥30%). All evaluable subjects 
treated during dose escalation and in the dose expansion Phase will be included in 
analyses. utilizing a null and alternative hypothesis of 5% and 30% respectively, a A maximum of 
20 subjects per dose level will may be enrolled, with a minimum enrollment of 10 subjects. With an 
actual type I error rate (α) of 0.065 and 94.2% power, the design has stopping criteria defined for 
futility as follows.  


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Number of Subjects 
Enrolled
This Number of  
Responses1 to Stop Early 
for Futility
10
0
11
0
12
0
13
0
14
0
15
0
16
1
17
1
18
1
19
1
20
2
Abbreviation: PCWG2, Prostate Cancer Working Group 2
1.
Response for the purpose of futility is defined as lack of disease progression at 12 weeks according to 
PCWG2 criteria. PSA progression in subjects with baseline radiological or bone disease will require 
RECIST or bone progression in addition to PSA progression to be determined a disease progressor.
Synopsis – Statistical Methods Study Populations: 
Rationale for change: 
Revised and added population to clarify between safety and clinical activity populations 
and to define the evaluable population for endpoint analyses. 
Previous text: 
The All Treated Population is defined as all subjects who receive at least one dose of 
GSK2636771.  Safety, clinical activity, and evaluation of non-PD rate in the Dose Expansion Phase 
will be evaluated based on this analysis population. 
The PK Population will consist of all subjects from the All Treated Population for whom at least 
one PK sample is obtained and analyzed.
The All Screened Population is defined as all subjects for whom pre-screening consent is 
obtained.
Efficacy Analyses:  The All Treated Population will be used for the analysis of efficacy data, and 
summarized separately for each part of the study.  Response data per 2PCWG2 and RECIST 1.1 
guidelines will be reported.  Further details about efficacy analyses will be outlined in detail in the 
RAP.
Safety Analyses:  The All Treated Population will be used for the analysis of safety data. All 
serially collected safety endpoints (e.g., laboratory tests, vital signs, ECGs) will be summarized 
according to the scheduled, nominal visit at which they were collected and across all on-treatment 
time points using a “worst-case” analysis. 


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Revised text: 
The All Treated Safety Population is defined as all subjects who receive at least one dose of 
GSK2636771 or Enzalutamide.  Safety, clinical activity, and evaluation of non PD rate in the Dose 
Expansion Phase will be evaluated based on this analysis population. 
The All Treated Clinical Activity Population is defined as all subjects who received at least 
one dose of GSK2636771. Clinical activity and evaluation of non-PD rate will be based on 
this analysis population.  This will include subjects from both dose escalation and dose 
expansion. 
The All Evaluable Population is defined as all subjects from All Treated Clinical Activity 
Population who have at least one post-dose disease assessment and have been exposed to 
study drug for at least 12 weeks or have progressed or have died or have withdrawn from 
the study for any reason. Dose Expansion futility analyses will be based on this population. 
The PK Population will consist of all subjects from the All Treated Population for whom at least one 
PK sample is obtained and analyzed.
The All Screened Population is defined as all subjects for whom pre-screening consent is 
obtained.
Efficacy Analyses:  The All Treated Clinical Activity Population will be used for the analysis of 
efficacy data, and will be summarized separately for each part of the study per dose level. 
Response data per 2PCWG2 and RECIST 1.1 guidelines will be reported.  Further details about 
efficacy analyses will be outlined in detail in the RAP.
Safety Analyses:  The All Treated Safety Population will be used for the analysis of safety data. 
All serially collected safety endpoints (e.g., laboratory tests, vital signs, 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.
Section 1.3 – Enzalutamide (Xtandi): 
Rationale for change: 
Updated section to reflect currently approved indication for enzalutamide. Updated 
citation in the body of the text and added the citation in the Reference section. 
Previous text: 
Enzalutamide (Xtandi) is an orally bioavailable, AR signalling inhibitor approved in the 
United States (US) and the European Union for the treatment of patients with mCRPC 
who have previously received treatment with docetaxel [Xtandi, 2013].  Enzalutamide 
acts on several steps in the AR signaling pathway, including competitive inhibition of 
androgen binding to ARs and inhibition of AR nuclear translocation and its interaction 
with deoxyribonucleic acid (DNA).  A major metabolite, N-desmethyl enzalutamide, 
exhibited similar in vitro activity to enzalutamide.


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Refer to to the approved US Food and Drug Administration (FDA) prescribing 
information [Xtandi, 2013] or the Xtandi Prescribing Information for the area where it is 
approved for further details.].
Revised text: 
Enzalutamide (Xtandi) is an orally bioavailable, AR signalling inhibitor approved in the 
United States (US) and the European Union for the treatment of patients with mCRPC 
who have previously received treatment with docetaxel [Xtandi, 20136].  Enzalutamide 
acts on several steps in the AR signaling pathway, including competitive inhibition of 
androgen binding to ARs and inhibition of AR nuclear translocation and its interaction 
with deoxyribonucleic acid (DNA).  A major metabolite, N-desmethyl enzalutamide, 
exhibited similar in vitro activity to enzalutamide.
Refer to to the approved US Food and Drug Administration (FDA) prescribing 
information [Xtandi, 20136] or the Xtandi Prescribing Information for the area where it is 
approved for further details.].
Section 1.3.1 – Clinical Safety, Pharmacokinetic Data, and Clinical Activity of 
Enzalutamide: 
Rationale for change: 
Updated citation in the body of the text and added the citation in the Reference section. 
Previous text: 
Clinical Response.  In a randomized, double-blinded, Phase III clinical trial comparing 
enzalutamide with placebo in subjects with mCRPC who had progressed following 
docetaxel-based chemotherapy, enzalutamide prolonged overall survival by 5 months 
(median survival of 18.4 months with enzalutamide [n=800] compared to 13.6 months 
with placebo [N=399])  which is statistically and clinically significant [Xtandi, 2013].  
Enzalutamide is approved in the US, Canada, the European Union and others (refer to 
Xtandi Prescribing Information in the relevant jurisdiction).  Recently, enzalutamide has 
also been shown to improve survival (32.4 months vs. 30.2 months) in chemotherapy-
naïve subjects with advanced prostate cancer in a separate Phase III, randomized, 
placebo-controlled study [Beer, 2014].
Refer to the approved US FDA prescribing information [Xtandi, 2013] or the Xtandi 
Prescribing Information for the area where it is approved for further details.
Revised text: 
Clinical Response.  In a randomized, double-blinded, Phase III clinical trial comparing 
enzalutamide with placebo in subjects with mCRPC who had progressed following 
docetaxel-based chemotherapy, enzalutamide prolonged overall survival by 5 months 
(median survival of 18.4 months with enzalutamide [n=800] compared to 13.6 months 
with placebo [N=399])  which is statistically and clinically significant [Xtandi, 20136].  
Enzalutamide is approved in the US, Canada, the European Union and others (refer to 


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Xtandi Prescribing Information in the relevant jurisdiction).  Recently, enzalutamide has 
also been shown to improve survival (32.4 months vs. 30.2 months) in chemotherapy-
naïve subjects with advanced prostate cancer in a separate Phase III, randomized, 
placebo-controlled study [Beer, 2014].
Refer to the approved US FDA prescribing information [Xtandi, 20136] or the Xtandi 
Prescribing Information for the area where it is approved for further details.
Section 1.4 – Summary of Risk Management: 
Rationale for change: 
Updated citation in the body of the text and added the citation in the Reference section. 
Previous text: 
Refer to the GSK2636771 IB [GlaxoSmithKline Document Number 2011N117133_01] 
for detailed information concerning the biology, pharmacology, PK and safety.  Refer to 
approved US FDA prescribing information [Xtandi, 2013] or the Xtandi Prescribing 
Information for the area where it is approved for additional information.
Revised text: 
Refer to the GSK2636771 IB [GlaxoSmithKline Document Number 2011N117133_01] 
for detailed information concerning the biology, pharmacology, PK and safety.  Refer to 
approved US FDA prescribing information [Xtandi, 20136] or the Xtandi Prescribing 
Information for the area where it is approved for additional information.
Section 1.4.1.1 Risk Assessment - GSK2636771: 
Rationale for change: 
Section was updated to reflect updated information and to reflect changes in the core 
information sheet. 
Previous text: 
Renal: Degenerative changes were observed in the kidneys of rats and dogs at 
100 mg/kg/day or 1000 mg/kg/day, including cellular and tubular changes, with 
chemistry and urinalysis findings.  Grade 3, treatment-related hypophosphatemia and 
hypocalcaemia have been observed in the FTIH study P3B115717.  There have been 2 
reports of acute kidney injury (grade 2 and 3) in subjects who received GSK2636771 in 
Study 200331.  Since it is possible that GSK2636771 may contribute to acute kidney 
injury, renal events should be closely monitored.  Medical history will be collected and, 
physical examination and clinical laboratory tests will be measured frequently during 
therapy to monitor for potential toxicity.  Guidelines will be implemented including dose 
modification and discontinuation (Section 7.3.1) for the management of renal 
insufficiency or renal-related events considered to be related to study treatment.  It is 
recommended that patients be well hydrated and avoid the use of NSAIDs.


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Revised text: 
Renal and electrolytes: Degenerative changes were observed in the kidneys of rats and 
dogs at 100 mg/kg/day or 1000 mg/kg/day, including cellular and tubular changes, with 
chemistry and urinalysis findings.  There have been serious, treatment-related reports 
of acute kidney injury, hypophosphatemia and hypocalcaemia in GSK2636771 
clinical trials.  Renal events should be closely monitored.  It is recommended that 
patients be well-hydrated and avoid the use of NSAIDs.  Calcium and Vitamin D 
levels will be monitored.  Consider supplements in those with calcium levels at or 
near the lower normal limit and those with low Vitamin D levels.  Grade 3, treatment-
related hypophosphatemia and hypocalcaemia have been observed in the FTIH study 
P3B115717.  There have been 2 reports of acute kidney injury (grade 2 and 3) in subjects
who received GSK2636771 in Study 200331.  Since it is possible that GSK2636771 may 
contribute to acute kidney injury, renal events should be closely monitored. Medical 
history will be collected and, physical examination and clinical laboratory tests will be 
measured frequently during therapy to monitor for potential toxicity.  Guidelines will be 
implemented including dose modification and discontinuation (Section 7.3.1) for the 
management of renal insufficiency, or renal-related events or electrolyte abnormalities
considered to be related to study treatment. It is recommended that patients be well 
hydrated and avoid the use of NSAIDs.
Section 1.5.1 – Rationale for Study
Rationale for change: 
Updated citation in the body of the text and added the citation in the Reference section. 
Previous text: 
Despite recent advances in the treatment of advanced prostate cancer, relapses are 
inevitable and mCRPC carries considerable morbidity along with shortened survival.  
Previous studies have indicated the importance of the PI3K pathway in prostate cancer.  
Therapeutic approaches that simultaneously inhibit both the AR and PI3K pathways may 
be more effective than inhibition of either pathway alone in mCRPC.  Enzalutamide is an 
AR inhibitor indicated for the treatment of patients with mCRPC who have previously 
received docetaxel.  This study is designed to investigate whether the PI3K pathway 
inhibitor can be co-administered safely with enzalutamide, thus allowing further 
investigation of their ability to reverse resistance to this AR inhibitor.  Future studies may 
also assess whether the combination can delay the onset of resistance in enzalutamide-
naïve CRPC or increase the response rate to enzalutamide.
Revised text: 
Despite recent advances in the treatment of advanced prostate cancer, relapses are 
inevitable and mCRPC carries considerable morbidity along with shortened survival.  
Previous studies have indicated the importance of the PI3K pathway in prostate cancer.  
Therapeutic approaches that simultaneously inhibit both the AR and PI3K pathways may 
be more effective than inhibition of either pathway alone in mCRPC.  Enzalutamide is an 
AR inhibitor indicated for the treatment of patients with mCRPC who have previously 


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received docetaxel.  This study is designed to investigate whether the PI3K pathway 
inhibitor can be co-administered safely with enzalutamide, thus allowing further 
investigation of their ability to reverse resistance to this AR inhibitor.  Future studies may 
also assess whether the combination can delay the onset of resistance in enzalutamide-
naïve CRPC or increase the response rate to enzalutamide.
Section 2.1 – Hypothesis; Secondary Hypothesis: 
Rationale for Change: 
Update of study population in hypothesis wording
Previous text: 
Secondary Hypothesis:  The addition of a targeted PI3K pathway inhibitor 
(GSK2636771) to enzalutamide can limit mCPRC progression in a clinically meaningful 
way for at least 12 weeks.  The null hypothesis is that the 12-week non PD rate is not 
attractive (≤5%).  The alternative hypothesis is that the rate is clinically meaningful and, 
therefore, the compound warrants further development (≥30%).  This hypothesis will be 
tested for Part 2 of the study only. 
Revised text: 
Secondary Hypothesis:  The addition of a targeted PI3K pathway inhibitor 
(GSK2636771) to enzalutamide can limit mCPRC progression in a clinically meaningful 
way for at least 12 weeks.  The null hypothesis is that the 12-week non PD rate is not 
attractive (≤5%).  The alternative hypothesis is that the rate is clinically meaningful and, 
therefore, the compound warrants further development (≥30%).  This hypothesis will be 
tested for Part 2 of the study only using a combination of data provided in both the 
dose escalation and dose expansion phases. 
Section 2.2 Objectives and Endpoints – Primary Objectives: 
Rationale for Change: 
Adjustment to efficacy endpoint wording. 
Previous text:

Non-PD rate for 12 weeks according to PCWG2 criteria (either by RECIST 1.1, 
PSA progression, and/or progression in bone).
Revised text: 

Non-PD rate for 12 weeks according to PCWG2 criteria (either by RECIST 1.1, 
or progression in bone or PSA progression with accompanying progression by 
RECIST 1.1 or bone scan when baseline radiological or bone disease present 
or PSA progression if no other baseline disease).


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Section 2.2 Objectives and Endpoints – Secondary Objectives: 
Rationale for Change: 
Deletion of wording associated with how additional clinical activity was to be measured 
with less defined endpoints. Addition new secondary objective and endpoints. 
Previous text: 

To evaluate the clinical activity of oral 
GSK2636771 + enzalutamide in the 
treatment of mCRPC (PTEN deficient)

PSA as defined in PCWG2 guidelines 
and RECIST 1.1 response.
Revised text: 

To evaluate the clinical activity of oral 
GSK2636771 + enzalutamide in the 
treatment of mCRPC (PTEN deficient)

PSA50 response rate defined as the 
percent of subjects achieving PSA50 
at 12 weeks or thereafter (PSA50 is 
≥50% decrease in PSA from baseline)

Objective Response Rate (ORR) 
defined as complete response (CR) 
rate plus partial response (PR) rate 
per RECIST 1.1 

Time to PSA progression according 
to PCWG2 criteria

Time to radiological progression 
according to PCWG2 criteria (either 
by RECIST 1.1, and/or progression in 
bone)

Radiological progression free 
survival (rPFS) per RECIST1.1 and/or 
bone scans

PSA as defined in PCWG2 guidelines 
and RECIST 1.1 response.
Section 3 – Investigation Plan: 
Rationale for Change: 
Due to possibility of multiple doses being explored in dose expansion, updated wording 
to clarify dose escalation population and how maximum tolerated dose will be defined. 
Previous text: 
In the Dose Escalation Phase, subjects will be enrolled into dose-finding cohorts to 
evaluate the safety and PK to guide the selection of the RP2D of GSK2636771.  Dosing 
decisions will be based on all available data at the end of each DLT reporting period (the 
first 28 days of combination treatment).  Decisions for dose determination for subsequent 


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cohorts will be documented and maintained by each site and in the GSK Trial Master 
Files (TMF).
In the Dose Expansion Phase, subjects will be assigned to receive GSK2636771 at doses 
identified at or below the MTD in the Dose Escalation Phase while continuing treatment 
with enzalutamide to evaluate the long-term safety of the combination as well as the 12-
week non-PD rate.
Clinical Response Assessments: The determination of clinical response, including 
disease progression, will be assessed by the PCWG2 criteria (see Section 8.8.2).  The 
assessment of the 12 week non-PD-rate in the Dose Expansion Phase will also be 
determined by 2PCWG2 criteria (either by RECIST 1.1, PSA progression, and/or 
progression in bone).
Revised text: 
In the Dose Escalation Phase, subjects will be enrolled into dose-finding cohorts to 
evaluate the safety and PK to guide the selection of the MTD RP2D of GSK2636771.  
Dosing decisions will be based on all available data at the end of each DLT reporting 
period (the first 28 days of combination treatment).  Decisions for dose determination for 
subsequent cohorts will be documented and maintained by each site and in the GSK Trial 
Master Files (TMF).
In the Dose Expansion Phase, subjects will be assigned to receive GSK2636771 at doses 
identified at or below the MTD in the Dose Escalation Phase while continuing treatment 
with enzalutamide to evaluate the long-term safety of the combination as well as the 12-
week non-PD rate. This may include multiple dose levels in order to establish the 
RP2D of the combination treatment at the conclusion of combination treatment in 
any dose level. 
Clinical Response Assessments: The determination of clinical response, including 
disease progression, will be assessed by the PCWG2 criteria (see Section 8.8.2).  The 
assessment of the 12 week non-PD-rate in the Dose Expansion Phasewill also be 
determined by 2PCWG2 criteria (either by RECIST 1.1, PSA progression, and/or 
progression in bone).
Section 3.3 – Discussion of Study Design: 
Rationale for change: 
Updated citation in the body of the text and added the citation in the Reference section. 
Previous text:
The dosing of enzalutamide will be administered at the US FDA approved dose (refer to 
the Prescribing Information for enzalutamide [Xtandi, 2013].  Study treatment will 
continue until there is no longer clinical benefit (see Section 5.2), in the opinion of the 
investigator, or until an unacceptable AE (including stopping criteria outlined in Section 
7.2), withdrawal of consent, permanent discontinuation of study treatment, or death 
occurs.  Investigators will use the PCWG2 criteria to determine clinical response to each 
treatment.


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Revised text: 
The dosing of enzalutamide will be administered at the US FDA approved dose (refer to 
the Prescribing Information for enzalutamide [Xtandi, 20136].  Study treatment will 
continue until there is no longer clinical benefit (see Section 5.2), in the opinion of the 
investigator, or until an unacceptable AE (including stopping criteria outlined in Section 
7.2), withdrawal of consent, permanent discontinuation of study treatment, or death 
occurs.  Investigators will use the PCWG2 criteria to determine clinical response to each 
treatment.
Section 3.4 Dose Escalation Phase: 
Rationale for Change: 
Due to possibility of multiple doses being explored in dose expansion, updated wording 
to clarify dose escalation population and how maximum tolerated dose will be defined. 
Previous text:
In the Dose Escalation Phase, the dose of GSK2636771 will follow a modified 3+3 dose 
escalation procedure to evaluate the safety and PK for each combination dose level and to 
guide selection of the RP2D of the combination.  
Revised text: 
In the Dose Escalation Phase, the dose of GSK2636771 will follow a modified 3+3 dose 
escalation procedure to evaluate the safety and PK for each combination dose level and to 
guide selection of the RP2D of the combination dose for dose expansion.  
Sections 3.4.5, 3.5 and Section 3.6 (new section) – Recommended Phase II dose/Dose 
Expansion Phase: 
Rationale for change: 
Due to possibility of multiple doses being explored in dose expansion, updated wording 
to clarify dose escalation population and how maximum tolerated dose will be defined. 
Movement of Section 3.4.5. under new section 3.6, thereby updated all remaining Section 
3 heading numbers. 
Previous text: 
Section 3.4.5 Recommended Phase II Dose
The RP2D will be considered the lowest dose of GSK2636771 explored (at or below 
MTD) in the Dose Escalation Phase that provides adequate PK exposure and biologic 
activity with a superior tolerability profile.


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Section 3.5 Dose Expansion Phase
Enrollment in the Dose Expansion Phase of the study may begin once the MTD and 
RP2D have been determined in the Dose Escalation Phase.  Up to 20 additional subjects 
may be enrolled to better characterize the safety profile, PK, and clinical activity of the 
recommended doses of the combination of GSK2636771 + enzalutamide for future 
studies. One or more combination doses may be explored in the Dose Expansion Phase 
based the MTD and RP2D identified in the Dose Escalation Phase of the study.
In the Dose Expansion Phase, final analyses will occur 6 months after the last subject is 
enrolled to allow for adequate collection of safety information.  Those subjects that have 
not completed the treatment phase of the study (see Section 5.2) at the time of the final 
analysis may be transferred to a continued access study, if available.
Revised text: 
Section 3.4.5 Recommended Phase II Dose
The RP2D will be considered the lowest dose of GSK2636771 explored (at or below 
MTD) in the Dose Escalation Phase that provides adequate PK exposure and biologic 
activity with a superior tolerability profile.
Section 3.5 Dose Expansion Phase
Enrollment in the Dose Expansion Phase of the study may begin once a suspected the
MTD and RP2D hasve been determined in the Dose Escalation Phase. Up to 20 
additional subjects per dose level may be enrolled to better characterize the safety 
profile, PK, and clinical activity of the recommended doses of the combination of 
GSK2636771 + enzalutamide for future studies. One or more combination doses may be 
explored in the Dose Expansion Phase based on the MTD and RP2D identified in the 
Dose Escalation Phase of the study. To fully evaluate additional combination doses, 
up to 20 additional subjects per dose level may be enrolled. 
In the Dose Expansion Phase, final analyses will occur 6 months after the last subject is 
enrolled to allow for adequate collection of safety information.  Those subjects that have 
not completed the treatment phase of the study (see Section 5.2) at the time of the final 
analysis may be transferred to a continued access study, if available.
Section 3.6 Recommended Phase II Dose
The RP2D will be considered the lowest dose of GSK2636771 explored (at or below 
MTD) in the Dose Escalation Phase that provides adequate PK exposure and biologic 
activity with a superior tolerability profile. If multiple dose levels are explored in dose 
expansion, the RP2D will be based on the totality of data. 


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Section 3.7.1 – Evaluation of Futility: 
Rationale for Change: 
Update of timing of futility analysis to occur when adequate subjects are enrolled. Update 
to the efficacy endpoint wording used for futility predictive probability design. 
Previous text: 
Futility will be evaluated in the Dose Expansion Phase of the study.  The methodology is 
based on the predictive probability of success if enrollment continues to 20 subjects [Lee, 
2008]. The predictive probability design is similar to a Green-Dahlberg design in that it 
allows for early stopping for futility. The differences are that the predictive probability 
design allows for evaluation of stopping rules after each subject, rather than at only two 
stages, once a minimum number of subjects are evaluable. In this particular study, we 
will stop only for futility. While the two designs have similar type I and type II error 
rates, the probability of early termination is greater with the predictive probability design.
Number of Subjects 
Enrolled
This Number of  
Responses1 to Stop Early 
for Futility
10
0
11
0
12
0
13
0
14
0
15
0
16
1
17
1
18
1
19
1
20
2
Abbreviation: PCWG2, Prostate Cancer Working Group 2; PSA, prostate-specific antigen; RECIST, Response 
Evaluation Criteria in Solid Tumors
1.
Response for the purpose of futility is defined as lack of disease progression at 12 weeks according to 
PCWG2 criteria (either by RECIST 1.1, PSA progression and/or progression in bone).
Revised text: 
Futility will be evaluated when there is adequate enrollment in the Dose Expansion 
Phase of the study.  The methodology for evaluation of futility is based on the predictive 
probability of success if enrollment continues to 20 subjects per dose level [Lee, 2008] 
per dose level. The predictive probability design is similar to a Green-Dahlberg design in 
that it allows for early stopping for futility. The differences are that the predictive 
probability design allows for evaluation of stopping rules after each subject, rather than at 
only two stages, once a minimum number of subjects are evaluable. In this particular 
study, we will stop only for futility. While the two designs have similar type I and type II 
error rates, the probability of early termination is greater with the predictive probability 
design.


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Number of Subjects 
Enrolled
This Number of  
Responses1 to Stop Early 
for Futility
10
0
11
0
12
0
13
0
14
0
15
0
16
1
17
1
18
1
19
1
20
2
Abbreviations: PCWG2, Prostate Cancer Working Group 2; PSA, prostate-
specific antigen; RECIST, Response Evaluation Criteria in Solid Tumors
1.
Response for the purpose of futility is defined as lack of disease 
progression at 12 weeks according to PCWG2 criteria. (either by 
RECIST 1.1, PSA progression and/or progression in bone).PSA 
progression in subjects with baseline radiological or bone 
disease will require RECIST or bone progression in addition to 
PSA progression to be determined a disease progressor.
Section 4.1.1.  – Number of Subjects: 
Rationale for Change: 
Updated of the potential number of subjects due to possibility of multiple dose expansion 
cohorts and clarification of wording due to combination of dose escalation and expansion 
populations.
Previous text: 
A total of approximately 44 subjects will be enrolled in this study.  
Dose Expansion Phase:  In the Dose Expansion Phase, it is estimated that approximately 
20 subjects will be enrolled, with evaluation for futility after the first 10 subjects have 
completed 12 weeks of treatment (see Section 3.7.1). 
The sample size planned for the Dose Expansion Phase is not driven by statistical 
considerations as the cohort is meant to further understand the safety implications of 
enrolling subjects to combination therapy for an extended period of time.  See 
Section 13.2 for sample size assumptions.


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Revised text:
A total of between approximately 44 and 64 subjects will be enrolled in this study.  
Dose Expansion Phase:  In the Dose Expansion Phase, it is estimated that approximately 
20 subjects will be enrolled, with evaluation for futility after the first 10 subjects have 
completed 12 weeks of treatment (see Section 3.7.1). This analysis may occur using the 
combination of the dose escalation and dose expansion population. If multiple dose 
levels of GSK2636771 are examined during dose expansion to establish the RP2D, 
each dose level cohort will enrol approximately 20 subjects, increasing the overall 
number of subjects targeted for enrolment in this study.
The sample size planned for the Dose Expansion Phase is not driven by statistical 
considerations as the cohort is meant to further understand the safety implications of 
enrolling subjects to combination therapy for an extended period of time.  See 
Section 13.2 for sample size assumptions.
Section 4.1.2. - Inclusion Criteria
Rationale for change: 
Updated citation in the body of the text and added the citation in the Reference section. 
Previous text:
Specific information regarding warnings, precautions, contraindications, AEs, and other 
pertinent information on GSK2636771 or enzalutamide that may impact subject 
eligibility is provided in the IB for GSK2636771 [GlaxoSmithKline Document Number 
2011N117133_01] and the Prescribing Information for enzalutamide [Xtandi, 2013].
Revised text: 
Specific information regarding warnings, precautions, contraindications, AEs, and other 
pertinent information on GSK2636771 or enzalutamide that may impact subject 
eligibility is provided in the IB for GSK2636771 [GlaxoSmithKline Document Number 
2011N117133_01] and the Prescribing Information for enzalutamide [Xtandi, 20136].
Section 4.1.2. - Inclusion Criteria 11: 
Rationale for Change: 
Due to updated changes for calcium and bone markers adjusted the Other section of the 
tests in this criteria and updated footnote, by adding footnote 6.
Previous text:
Other
Serum Phosphate6
WNL
Serum Calcium (corrected)
WNL
6.Per CTCAE v4.0, Grade 1 hypophosphatemia is <LLN – 2.5 mg/dL (<LLN - 0.8 mmol/L


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Revised text: 
Other
Serum Phosphate6
WNL
Serum Calcium6 (corrected)
Ionized Calcium6
Vitamin D6: 25-OH D and 
1,25-OH2 D
WNL
WNL
WNL
6.   Per CTCAE v4.0, Grade 1 hypophosphatemia is <LLN – 2.5 mg/dL (<LLN   0.8 mmol/L Vitamin D 
supplementation may be added to achieve values WNL. Calcium supplements should be added for 
subjects with calcium values near the lower normal limit. 
Section 6.1 – GSK2636771 GSK Investigational Product
Rationale for Change:
In the event that there are legal changes to the way that GSK2636771 is interpreted, 
added additional wording to include this possibility. 
Previous text: 
The contents of the label will be in accordance with all applicable regulatory 
requirements.
Revised text: 
The contents of the label will be in accordance with all applicable regulatory and/or legal
requirements.
Section 6.3.2. – Enzalutamide
Rationale for Change: 
Updated citation in the body of the text and added the citation in the Reference section. 
Previous text: 
Per the product prescribing information for enzalutamide [Xtandi, 2013], the 
recommended dose of enzalutamide 160 mg (four 40 mg capsules) taken orally once 
daily will be administered during this study.  
Revised text: 
Per the product prescribing information for enzalutamide [Xtandi, 20136], the 
recommended dose of enzalutamide 160 mg (four 40 mg capsules) taken orally once 
daily will be administered during this study.  


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Section 7.3.1 – Renal Insufficiency or Other Renal Events
Rationale for Change: 
Based on emerging data and additional internal review, section adjusted and revised to 
adjust calcium management. 
Previous text: 
Prior to start of study treatment, concomitant medications should be reviewed for the 
potential risk of inducing nephrotoxicity and concomitant medications should be 
modified if clinically possible.
Close monitoring of serum creatinine, calcium and phosphate and treatment interruption 
for increased serum creatinine >2 mg/dL (or >0.5 mg/dL above baseline), hypocalcemia, 
and hypophosphatemia, respectively, should occur.  Nephrology consultation should also 
be considered.
Guidelines regarding the management of renal insufficiency or renal-related events 
considered to be related to study treatment are provided in Table 10.
Table 10 Management and Dose Modifications for Renal Events
Hypocalcemia
(serum calcium 
Grade 2)
or
Hypophosphatemia
(serum phosphate 
Grade 3 or 
symptomatic 
Grade 2)

Repeat serum calcium or phosphate level within 24 hrs of previous result

If repeat value confirms Grade 2 serum calcium, or symptomatic Grade 
2 serum phosphate.

Immediately interrupt treatment with GSK2636771

Treat as clinically indicated by local institutional standards

Obtain serum PTH level

Obtain blood sample for PK analysis, if requested (see SRM), within 
24-72 hrs after the last dose(refer to Section 8.7.3.1 for details on PK 
sample collection)

Obtain urine samples for urine creatinine, calcium, phosphate, and 
protein at treatment interruption; repeat every 7 days

Repeat serum calcium or phosphate level every 7 days or more 
frequently if clinically indicated

If serum calcium fails to improve to Grade 1 or if serum phosphate fails to 
improve to asymptomatic Grade 2 within 14 days following dose 
interruption:

Permanently discontinue treatment with GSK2636771

Consult with GSK Medical Monitor

If serum calcium improves to Grade 1 or serum phosphate improves to 
asymptomatic Grade 2 or baseline, whichever is more improved within 14 
days following dose interruption:

Restart treatment with GSK2636771 with dose reduced by one dose 
level

Repeat serum calcium or phosphate level per Time and Events Tables 
(Section 8.1) or more frequently if clinically indicated

If decreased serum calcium or phosphate levels reoccurs after one dose 
reduction :

Repeat serum calcium or phosphate levels within 24 hrs to confirm 


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result

If repeat serum calcium or phosphate levels confirm decrease, 
withdraw subject from treatment/study unless there is agreement 
between investigator and GSK Medical Monitor that subject will 
benefit from continued treatment following recovery of serum 
calcium or phosphate to baseline with dose of GSK2636771 
further reduced one dose level.

If repeat serum calcium or phosphate fails to confirm a decrease, continue 
treatment with GSK2636771 at same dose level without interruption
Revised text: 
Prior to start of study treatment, concomitant medications should be reviewed for the 
potential risk of inducing nephrotoxicity and concomitant medications should be 
modified if clinically possible.
Close monitoring of serum creatinine, calcium and phosphate and treatment interruption 
for increased serum creatinine >2 mg/dL (or >0.5 mg/dL above baseline), hypocalcemia, 
and hypophosphatemia, respectively, should occur.  Nephrology consultation should also 
be considered.
Calcium should be carefully managed in all subjects and especially in subjects with 
bone lesions/metastases and in those on treatments that are associated with 
hypocalcemia, including but not limited to, bisphosphanates (e.g., zoledronic acid) 
or denosumab (RANK-L inhibitor). Subjects with baseline calcium levels at or near 
the lower normal limit and those with Vitamin D below the normal limit should be 
treated with supplements.  Subjects who develop hypocalcemia should be closely 
monitored and managed per Table 10. 
Guidelines regarding the management of renal insufficiency or renal-related events 
considered to be related to study treatment are provided in Table 10.
Management and Dose Modifications for Renal Events
Hypocalcemia
(serum calcium 
Grade 21)
or
Hypophosphatemia
(serum phosphate 
Grade 3 or 
symptomatic 
Grade 2)

Administration of oral calcium supplements to subjects with calcium 
levels at or near the lower limit of normal should be considered

For subjects with Grade1 hypocalcemia, administer oral calcium 
supplements and evaluate the need for Vitamin D supplementation.

For hypocalcemia > Grade 1, Rrepeat serum calcium and Vitamin D,and or
phosphate level within 24 hrs of previous result

If repeat value confirms > Grade 21 serum calcium, or symptomatic 
Grade 2 serum phosphate.

Immediately interrupt treatment with GSK2636771

Treat as clinically indicated by local institutional standards or 
administer i.v. calcium gluconate (1 g/10 ml) and evaluate the 
need for Vitamin D supplementation.

Obtain serum PTH level

Obtain blood sample for PK analysis, if requested (see SRM), within 
24-72 hrs after the last dose(refer to Section 8.7.3.1 for details on PK 
sample collection)


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
Obtain urine samples for urine creatinine, calcium, phosphate, and 
protein at treatment interruption; repeat every 7 days

Repeat serum calcium or phosphate level every 7 days or more 
frequently if clinically indicated

If serum calcium fails to improve to Grade 1 WNL or if serum phosphate 
fails to improve to asymptomatic Grade 2 within 14 days following dose 
interruption:

Permanently discontinue treatment with GSK2636771

Consult with GSK Medical Monitor

If serum calcium improves to Grade 1 WNL or serum phosphate improves 
to asymptomatic Grade 2 or baseline, whichever is more improved within 
14 days following dose interruption:

Restart treatment with GSK2636771 with dose reduced by one dose 
level

Repeat serum calcium or phosphate level per Time and Events Tables 
(Section 8.1) or more frequently if clinically indicated

If decreased serum calcium or phosphate levels reoccurs after one dose 
reduction :

Repeat serum calcium or phosphate levels within 24 hrs to confirm 
result

If repeat serum calcium or phosphate levels confirm decrease, 
withdraw subject from treatment/study unless there is agreement 
between investigator and GSK Medical Monitor that subject will 
benefit from continued treatment following recovery of serum 
calcium or phosphate to baseline with dose of GSK2636771 
further reduced one dose level.

If repeat serum calcium or phosphate fails to confirm a decrease, continue 
treatment with GSK2636771 at same dose level without interruption
Section 8.1 – Time and Events Tables
Rationale for Changes: 
Visit window clarifications at Week 1, Day 1and Week 12 to clarify that assessments are 
to occur only after that visit timeframe has passed; updates to laboratory assessments 
section including additional footnotes 33, 34 and 35; update to footnotes 12 and 15. 


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Previous text: 
Table 15 Time and Events Table for Dose Escalation Phase
Study 
Assessments1,2
Pre-Screening
Screening
Enzalutamide 
Run-In 
Period
Combination Treatment Period 
(DLT Reporting Period)
Treatment Continuation 
Period
Time of Discontinuation of 
Treatment due to Disease 
Progression31
Post-Treatment
Follow-Up Visit28
Extended
Follow-
Up  
Visits29
Post-
Extended 
Follow-
Up
/EOS 
Visit30
Day 
-14 
to
Day 
-1
Day 
1 to
Day 
13
Day 
14
Wk 
1, 
Day 
1
Wk 2, 
Day 8
Wk 3, 
Day 15
Wk 4, Day 
22
Wk 5, Day 
29
Week 8 and 
every 4 weeks 
thereafter
Every 3 
months
Visit Window
1 
day
1 
day
1
day
1
day
1
day
3 days
for each visit
+1
day
-2/+7 
days
14 
days
3 
days
Clinical Assessments
Informed Consent
X3
X4
Demographics
X
Medical History
X
Determination of 
PTEN Deficiency 
Status
M5
Safety Assessments
ECOG PS
X
X
X
X
X
Week 8 and then 
Q8wks
X
X
X
Physical Exam
X
X
Week 8 and then 
Q8wks
X
X
Height8
X
Weight
X
X
Week 8 and then 
Q8wks
X
X
Vital Signs9
X
X
X
X
X
X
X
X
X
12-Lead ECG10
X6
X
Week 8 and then 
Q8wks
X
X
ECHO/MUGA
X6,7
As clinically indicated
AE Monitoring
Continuous
X11
X11


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Study 
Assessments1,2
Pre-Screening
Screening
Enzalutamide 
Run-In 
Period
Combination Treatment Period 
(DLT Reporting Period)
Treatment Continuation 
Period
Time of Discontinuation of 
Treatment due to Disease 
Progression31
Post-Treatment
Follow-Up Visit28
Extended
Follow-
Up  
Visits29
Post-
Extended 
Follow-
Up
/EOS 
Visit30
Day 
-14 
to
Day 
-1
Day 
1 to
Day 
13
Day 
14
Wk 
1, 
Day 
1
Wk 2, 
Day 8
Wk 3, 
Day 15
Wk 4, Day 
22
Wk 5, Day 
29
Week 8 and 
every 4 weeks 
thereafter
Every 3 
months
Visit Window
1 
day
1 
day
1
day
1
day
1
day
3 days
for each visit
+1
day
-2/+7 
days
14 
days
3 
days
Concomitant 
Medications
X
Continuous
X
Laboratory Assessments12
Hematology/
Clinical Chemistry
X6
X
X
X
X
X
X
X
X
Coagulation: 
PT, PTT, INR
X6
X
X
Liver Function 
Tests
X6
X
X
X
X
X
X
X
X
Urinalysis13
Urine Microscopy13
UPC14
X6
X
X
X
X
X
Urine Electrolytes15
X6
X
X
X
Week 8 and then 
Q8wks
X
Parathyroid 
Hormone
X
As clinically indicated16
Laboratory Assessments continued
PSA and LDH32
X6
X
X
X
X
X
Serum 
Testosterone
X6
X
X
PK Assessments
PK Blood 
Sampling17
X
X
Weeks 8 and 12
Disease Assessments18


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Study 
Assessments1,2
Pre-Screening
Screening
Enzalutamide 
Run-In 
Period
Combination Treatment Period 
(DLT Reporting Period)
Treatment Continuation 
Period
Time of Discontinuation of 
Treatment due to Disease 
Progression31
Post-Treatment
Follow-Up Visit28
Extended
Follow-
Up  
Visits29
Post-
Extended 
Follow-
Up
/EOS 
Visit30
Day 
-14 
to
Day 
-1
Day 
1 to
Day 
13
Day 
14
Wk 
1, 
Day 
1
Wk 2, 
Day 8
Wk 3, 
Day 15
Wk 4, Day 
22
Wk 5, Day 
29
Week 8 and 
every 4 weeks 
thereafter
Every 3 
months
Visit Window
1 
day
1 
day
1
day
1
day
1
day
3 days
for each visit
+1
day
-2/+7 
days
14 
days
3 
days
CT Scan or MRI19
X6,7
Week 8 and then 
Q8wks to Week 
48; then Q12wks
X
X
Chest X-Ray or 
Chest CT Scan
X6,7
Bone Scan20
X6,7
Week 12 and 
then Q12wks
X
X
Biomarker Assessments
CTC –- Janssen21
X
X
X
Weeks 8, 16, 24, 
and 32
X
CTC – EPIC22
X
Week 8 only
X
Biomarker Assessments continued
Predictive 
Biomarker: Tumor 
Tissue23
X
Progression Tumor 
yBiopsy24
X
Tumor Biopsies for 
Pharmaco-
dynamics24
X
X24
cfDNA/RNA/Soluble 
Markers25
X
X
X
Weeks 8, 16, 24, 
and 32
X
Blood Sample for 
Genetic Research26
X


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Study 
Assessments1,2
Pre-Screening
Screening
Enzalutamide 
Run-In 
Period
Combination Treatment Period 
(DLT Reporting Period)
Treatment Continuation 
Period
Time of Discontinuation of 
Treatment due to Disease 
Progression31
Post-Treatment
Follow-Up Visit28
Extended
Follow-
Up  
Visits29
Post-
Extended 
Follow-
Up
/EOS 
Visit30
Day 
-14 
to
Day 
-1
Day 
1 to
Day 
13
Day 
14
Wk 
1, 
Day 
1
Wk 2, 
Day 8
Wk 3, 
Day 15
Wk 4, Day 
22
Wk 5, Day 
29
Week 8 and 
every 4 weeks 
thereafter
Every 3 
months
Visit Window
1 
day
1 
day
1
day
1
day
1
day
3 days
for each visit
+1
day
-2/+7 
days
14 
days
3 
days
Study Treatments27
Enzalutamide
Continuous
Continuous
GSK2636771
Continuous
12. Laboratory Assessments: Refer to Section 8.6.5 for list of specific laboratory tests to be performed.  Assessments may be performed within 24 hrs prior to scheduled visit 
(liver function tests and urine tests for UPC may be performed up to 72 hrs prior to a scheduled visit) to ensure availability of results.
15. Urine Electrolytes:  Urine samples will be obtained at Screening, pre-dose on Day 1 (Week 1), Day 15 (Week 3), Day 22 (Week 4) of the Combination Treatment Period, 
Week 8 and then every 8 weeks (3 days) thereafter during the Treatment Continuation Period, and at the post-treatment follow-up visit to determine urine electrolytes 
(magnesium, phosphorus and calcium) and urine creatinine.


2013N172718_04
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Revised text: 
Table 15 Time and Events Table for Dose Escalation Phase
Study 
Assessments1,2
Pre-Screening
Screening
Enzalutamide 
Run-In 
Period
Combination Treatment Period 
(DLT Reporting Period)
Treatment Continuation 
Period
Time of Discontinuation of 
Treatment due to Disease 
Progression31
Post-Treatment
Follow-Up Visit28
Extended
Follow-
Up  
Visits29
Post-
Extended 
Follow-
Up
/EOS 
Visit30
Day 
-14 
to
Day 
-1
Day 
1 to
Day 
13
Day 
14
Wk 
1, 
Day 
1
Wk 2, 
Day 8
Wk 3, 
Day 15
Wk 4, Day 
22
Wk 5, Day 
29
Week 8 and 
every 4 weeks 
thereafter
Every 3 
months
Visit Window
+1 
day
1 
day
1
day
1
day
1
day
+5 days Week 
12 only; 3 days
for all other 
visits
for each visit
+1
day
-2/+7 
days
14
days
3 
days
Clinical Assessments
Informed Consent
X3
X4
Demographics
X
Medical History
X
Determination of 
PTEN Deficiency 
Status
M5
Safety Assessments
ECOG PS
X
X
X
X
X
Week 8 and then 
Q8wks
X
X
X
Physical Exam
X
X
Week 8 and then 
Q8wks
X
X
Height8
X
Weight
X
X
Week 8 and then 
Q8wks
X
X
Vital Signs9
X
X
X
X
X
X
X
X
X
12-Lead ECG10
X6
X
Week 8 and then 
X
X


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Study 
Assessments1,2
Pre-Screening
Screening
Enzalutamide 
Run-In 
Period
Combination Treatment Period 
(DLT Reporting Period)
Treatment Continuation 
Period
Time of Discontinuation of 
Treatment due to Disease 
Progression31
Post-Treatment
Follow-Up Visit28
Extended
Follow-
Up  
Visits29
Post-
Extended 
Follow-
Up
/EOS 
Visit30
Day 
-14 
to
Day 
-1
Day 
1 to
Day 
13
Day 
14
Wk 
1, 
Day 
1
Wk 2, 
Day 8
Wk 3, 
Day 15
Wk 4, Day 
22
Wk 5, Day 
29
Week 8 and 
every 4 weeks 
thereafter
Every 3 
months
Visit Window
+1 
day
1 
day
1
day
1
day
1
day
+5 days Week 
12 only; 3 days
for all other 
visits
for each visit
+1
day
-2/+7 
days
14
days
3 
days
Q8wks
ECHO/MUGA
X6,7
As clinically indicated
AE Monitoring
Continuous
X11
X11
Concomitant 
Medications
X
Continuous
X
Laboratory Assessments12    
Hematology/
Clinical Chemistry
X6
X33
X
X
X
X
X
X
X
Ionized Calcium
X6
X
X
X
X
X
X
X
X
Vitamin D34
X6
X
X
X
Coagulation: 
PT, PTT, INR
X6
X
X
Liver Function 
Tests
X6
X
X
X
X
X
X
X
X
Urinalysis13
Urine Microscopy13
UPC14
X6
X
X
X
X
X
Urine Electrolytes15
X6
X33
X
X
X
Week 8 and then 
Q8wks
X
Parathyroid 
Hormone
X
As clinically indicated16


2013N172718_04
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Study 
Assessments1,2
Pre-Screening
Screening
Enzalutamide 
Run-In 
Period
Combination Treatment Period 
(DLT Reporting Period)
Treatment Continuation 
Period
Time of Discontinuation of 
Treatment due to Disease 
Progression31
Post-Treatment
Follow-Up Visit28
Extended
Follow-
Up  
Visits29
Post-
Extended 
Follow-
Up
/EOS 
Visit30
Day 
-14 
to
Day 
-1
Day 
1 to
Day 
13
Day 
14
Wk 
1, 
Day 
1
Wk 2, 
Day 8
Wk 3, 
Day 15
Wk 4, Day 
22
Wk 5, Day 
29
Week 8 and 
every 4 weeks 
thereafter
Every 3 
months
Visit Window
+1 
day
1 
day
1
day
1
day
1
day
+5 days Week 
12 only; 3 days
for all other 
visits
for each visit
+1
day
-2/+7 
days
14
days
3 
days
Bone Markers35
X
X
Weeks  12 and  
24
X
X
Laboratory Assessments continued
PSA and LDH32
X6
X
X
X
X
X
Serum 
Testosterone
X6
X
X
PK Assessments
PK Blood 
Sampling17
X
X
Weeks 8 and 12
Disease Assessments18
CT Scan or MRI19
X6,7
Week 8 and then 
Q8wks to Week 
48; then Q12wks
X
X
Chest X-Ray or 
Chest CT Scan
X6,7
Bone Scan20
X6,7
Week 12 and 
then Q12wks
X
X
Biomarker Assessments
CTC –- Janssen21
X
X
X
Weeks 8, 16, 24, 
and 32
X
CTC – EPIC22
X
Week 8 only
X


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Study 
Assessments1,2
Pre-Screening
Screening
Enzalutamide 
Run-In 
Period
Combination Treatment Period 
(DLT Reporting Period)
Treatment Continuation 
Period
Time of Discontinuation of 
Treatment due to Disease 
Progression31
Post-Treatment
Follow-Up Visit28
Extended
Follow-
Up  
Visits29
Post-
Extended 
Follow-
Up
/EOS 
Visit30
Day 
-14 
to
Day 
-1
Day 
1 to
Day 
13
Day 
14
Wk 
1, 
Day 
1
Wk 2, 
Day 8
Wk 3, 
Day 15
Wk 4, Day 
22
Wk 5, Day 
29
Week 8 and 
every 4 weeks 
thereafter
Every 3 
months
Visit Window
+1 
day
1 
day
1
day
1
day
1
day
+5 days Week 
12 only; 3 days
for all other 
visits
for each visit
+1
day
-2/+7 
days
14
days
3 
days
Biomarker Assessments continued
Predictive 
Biomarker: Tumor 
Tissue23
X
Progression Tumor 
Biopsy24
X
Tumor Biopsies for 
Pharmaco-
dynamics24
X
X24
cfDNA/RNA/Soluble 
Markers25
X
X
X
Weeks 8, 16, 24, 
and 32
X
Blood Sample for 
Genetic Research26
X
Study Treatments27
Enzalutamide
Continuous
Continuous
GSK2636771
Continuous
12. Laboratory Assessments: Refer to Section 8.6.68.6.5 (Table 17) for list of specific laboratory tests to be performed.  Assessments may be performed within 24 hrs prior to 
scheduled visit (liver function tests and urine tests for UPC may be performed up to 72 hrs prior to a scheduled visit) to ensure availability of results.


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15.Urine Electrolytes:  Urine samples will be obtained at Screening, pre-dose on Day 1 (Week 1), Day 3 OR Day 4, Day 15 (Week 3), Day 22 (Week 4) of the Combination 
Treatment Period, Week 8 and then every 8 weeks (3 days) thereafter during the Treatment Continuation Period, and at the post-treatment follow-up visit to determine urine 
electrolytes (magnesium, phosphorus and calcium) and urine creatinine.
33.Complete clinical chemistries laboratory assessments at Week1/Day 1 and again on either Day 3 or Day 4.  The Day 3 or Day 4 assessments can be completed at a 
local laboratory and does not require a clinic visit.  The hematology panel does NOT need to be collected on Day 3/ Day 4. Review of these labs must occur before 
Week 2, Day 1 visit. 
34.Includes assessments for 25-OH D and 1,25-OH2 D. 
35.Includes urine and blood and/or serum samples.  Must be collected at the same time of day (1 hour) to eliminate diurnal effects, and after fasting.  See SRM for 
additional details on the specific assessments and sample collection.  
Previous text: 
Table 16 Time and Events Table for Dose Expansion Phase
Study 
Assessments1,2
Pre-Screening
Screening
Enzalutamide 
Run-In 
Period
Combination Treatment Period 
(DLT Reporting Period)
Treatment Continuation 
Period
Time of Discontinuation of 
Treatment due to Disease 
Progression31
Post-Treatment
Follow-Up Visit28
Extended
Follow-
Up  
Visits29
Post-
Extended 
Follow-
Up
/EOS 
Visit30
Day 
-14 
to
Day 
-1
Day 1 to Day 
14
Wk 
1, 
Day 
1
Wk 2, 
Day 8
Wk 3, 
Day 15
Wk 4, Day 
22
Wk 5, Day 
29
Week 8 and 
every 4 weeks 
thereafter
Every 3 
months
Visit Window
1 
day
1 
day
1
day
1
day
1
day
3 days
for each visit
+1
day
-2/+7 
days
14 
days
3 
days
Clinical Assessments
Informed Consent
X3
X4
Demographics
X
Medical History
X
Determination of 
PTEN Deficiency 
Status
M5
Safety Assessments
ECOG PS
X
X
X
X
X
Week 8 and 
then Q8wks
X
X
X


2013N172718_04
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Study 
Assessments1,2
Pre-Screening
Screening
Enzalutamide 
Run-In 
Period
Combination Treatment Period 
(DLT Reporting Period)
Treatment Continuation 
Period
Time of Discontinuation of 
Treatment due to Disease 
Progression31
Post-Treatment
Follow-Up Visit28
Extended
Follow-
Up  
Visits29
Post-
Extended 
Follow-
Up
/EOS 
Visit30
Day 
-14 
to
Day 
-1
Day 1 to Day 
14
Wk 
1, 
Day 
1
Wk 2, 
Day 8
Wk 3, 
Day 15
Wk 4, Day 
22
Wk 5, Day 
29
Week 8 and 
every 4 weeks 
thereafter
Every 3 
months
Visit Window
1 
day
1 
day
1
day
1
day
1
day
3 days
for each visit
+1
day
-2/+7 
days
14 
days
3 
days
Physical Exam
X
X
Week 8 and 
then Q8wks
X
X
Height8
X
Weight
X
X
Week 8 and 
then Q8wks
X
X
Vital Signs9
X
X
X
X
X
X
X
X
X
12-Lead ECG10
X6
X
Week 8 and 
then Q8wks
X
X
ECHO/MUGA
X6,7
As clinically indicated
AE Monitoring
Continuous
X11
X11
Concomitant 
Medications
X
Continuous
X
Laboratory Assessments12
Hematology/
Clinical Chemistry
X6
X
X
X
X
X
X
X
X
Coagulation: 
PT, PTT, INR
X6
X
X
Liver Function 
Tests
X6
X
X
X
X
X
X
X
X
Urinalysis13
Urine Microscopy13
UPC14
X6
X
X
X
X
X
Urine Electrolytes15
X6
X
X
X
Week 8 and 
then Q8wks
X


2013N172718_04
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250
Study 
Assessments1,2
Pre-Screening
Screening
Enzalutamide 
Run-In 
Period
Combination Treatment Period 
(DLT Reporting Period)
Treatment Continuation 
Period
Time of Discontinuation of 
Treatment due to Disease 
Progression31
Post-Treatment
Follow-Up Visit28
Extended
Follow-
Up  
Visits29
Post-
Extended 
Follow-
Up
/EOS 
Visit30
Day 
-14 
to
Day 
-1
Day 1 to Day 
14
Wk 
1, 
Day 
1
Wk 2, 
Day 8
Wk 3, 
Day 15
Wk 4, Day 
22
Wk 5, Day 
29
Week 8 and 
every 4 weeks 
thereafter
Every 3 
months
Visit Window
1 
day
1 
day
1
day
1
day
1
day
3 days
for each visit
+1
day
-2/+7 
days
14 
days
3 
days
Parathyroid 
Hormone
X
As clinically indicated16
Laboratory Assessments continued
PSA and LDH32
X6
X
X
X
X
X
Serum 
Testosterone
X6
X
X
PK Assessments
PK Blood 
Sampling17
X
Weeks 8 and 12
Disease Assessments18
CT Scan or MRI19
X6,7
Week 8 and 
then Q8wks to 
Week 48; then 
Q12wks
X
X
Chest X-Ray or 
Chest CT Scan
X6,7
Bone Scan20
X6,7
Week 12 and 
then Q12wks
X
X
Biomarker Assessments
CTC –- Janssen21
X
X
X
Weeks 8, 16, 
24, and 32
X
CTC – EPIC22
X
Week 8 only
X
Biomarker Assessments continued
Predictive 
X


2013N172718_04
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251
Study 
Assessments1,2
Pre-Screening
Screening
Enzalutamide 
Run-In 
Period
Combination Treatment Period 
(DLT Reporting Period)
Treatment Continuation 
Period
Time of Discontinuation of 
Treatment due to Disease 
Progression31
Post-Treatment
Follow-Up Visit28
Extended
Follow-
Up  
Visits29
Post-
Extended 
Follow-
Up
/EOS 
Visit30
Day 
-14 
to
Day 
-1
Day 1 to Day 
14
Wk 
1, 
Day 
1
Wk 2, 
Day 8
Wk 3, 
Day 15
Wk 4, Day 
22
Wk 5, Day 
29
Week 8 and 
every 4 weeks 
thereafter
Every 3 
months
Visit Window
1 
day
1 
day
1
day
1
day
1
day
3 days
for each visit
+1
day
-2/+7 
days
14 
days
3 
days
Biomarker: Tumor 
Tissue23
Progression Tumor 
yBiopsy24
X
Tumor Biopsies for 
Pharmaco-
dynamics24
X (Day 14)
X24
cfDNA/RNA/Soluble 
Markers25
X
X
X
Weeks 8, 16, 
24, and 32
X
Blood Sample for 
Genetic Research26
X
Study Treatments27
Enzalutamide
Continuous
Continuous
GSK2636771
Continuous
12.Laboratory Assessments: Refer to Section 8.6.5 for list of specific laboratory tests to be performed.  Assessments may be performed within 24 hrs prior to scheduled visit 
(liver function tests and urine tests for UPC may be performed up to 72 hrs prior to a scheduled visit) to ensure availability of results.
15.Urine Electrolytes:  Urine samples will be obtained at Screening, pre-dose on Day 1 (Week 1), Day 15 (Week 3), Day 22 (Week 4) of the Combination Treatment Period, 
Week 8 and then every 8 weeks (3 days) thereafter during the Treatment Continuation Period, and at the post-treatment follow-up visit to determine urine electrolytes 
(magnesium, phosphorus and calcium) and urine creatinine.


2013N172718_04
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Revised text: 
Table 16 Time and Events Table for Dose Expansion Phase
Study 
Assessments1,2
Pre-Screening
Screening
Enzalutamide 
Run-In 
Period
Combination Treatment Period 
(DLT Reporting Period)
Treatment Continuation 
Period
Time of Discontinuation of 
Treatment due to Disease 
Progression31
Post-Treatment
Follow-Up Visit28
Extended
Follow-
Up  
Visits29
Post-
Extended 
Follow-
Up
/EOS 
Visit30
Day 
-14 
to
Day 
-1
Day 
1 to
Day 
13
Day 
14
Wk 
1, 
Day 
1
Wk 2, 
Day 8
Wk 3, 
Day 15
Wk 4, Day 
22
Wk 5, Day 
29
Week 8 and 
every 4 weeks 
thereafter
Every 3 
months
Visit Window
+1 
day
1 
day
1
day
1
day
1
day
+5 days Week 
12 only; 3 days
for all other 
visits
for each visit
+1
day
-2/+7 
days
14 
days
3 
days
Clinical Assessments
Informed Consent
X3
X4
Demographics
X
Medical History
X
Determination of 
PTEN Deficiency 
Status
M5
Safety Assessments
ECOG PS
X
X
X
X
X
Week 8 and then 
Q8wks
X
X
X
Physical Exam
X
X
Week 8 and then 
Q8wks
X
X
Height8
X
Weight
X
X
Week 8 and then 
Q8wks
X
X
Vital Signs9
X
X
X
X
X
X
X
X
X
12-Lead ECG10
X6
X
Week 8 and then 
X
X


2013N172718_04
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Study 
Assessments1,2
Pre-Screening
Screening
Enzalutamide 
Run-In 
Period
Combination Treatment Period 
(DLT Reporting Period)
Treatment Continuation 
Period
Time of Discontinuation of 
Treatment due to Disease 
Progression31
Post-Treatment
Follow-Up Visit28
Extended
Follow-
Up  
Visits29
Post-
Extended 
Follow-
Up
/EOS 
Visit30
Day 
-14 
to
Day 
-1
Day 
1 to
Day 
13
Day 
14
Wk 
1, 
Day 
1
Wk 2, 
Day 8
Wk 3, 
Day 15
Wk 4, Day 
22
Wk 5, Day 
29
Week 8 and 
every 4 weeks 
thereafter
Every 3 
months
Visit Window
+1 
day
1 
day
1
day
1
day
1
day
+5 days Week 
12 only; 3 days
for all other 
visits
for each visit
+1
day
-2/+7 
days
14 
days
3 
days
Q8wks
ECHO/MUGA
X6,7
As clinically indicated
AE Monitoring
Continuous
X11
X11
Concomitant 
Medications
X
Continuous
X
Laboratory Assessments12    
Hematology/
Clinical Chemistry
X6
X33
X
X
X
X
X
X
X
Ionized Calcium
X6
X
X
X
X
X
X
X
X
Vitamin D34
X6
X
X
X
Coagulation: 
PT, PTT, INR
X6
X
X
Liver Function 
Tests
X6
X
X
X
X
X
X
X
X
Urinalysis13
Urine Microscopy13
UPC14
X6
X
X
X
X
X
Urine Electrolytes15
X6
X33
X
X
X
Week 8 and then 
Q8wks
X
Parathyroid 
Hormone
X
X
As clinically indicated16
X


2013N172718_04
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Study 
Assessments1,2
Pre-Screening
Screening
Enzalutamide 
Run-In 
Period
Combination Treatment Period 
(DLT Reporting Period)
Treatment Continuation 
Period
Time of Discontinuation of 
Treatment due to Disease 
Progression31
Post-Treatment
Follow-Up Visit28
Extended
Follow-
Up  
Visits29
Post-
Extended 
Follow-
Up
/EOS 
Visit30
Day 
-14 
to
Day 
-1
Day 
1 to
Day 
13
Day 
14
Wk 
1, 
Day 
1
Wk 2, 
Day 8
Wk 3, 
Day 15
Wk 4, Day 
22
Wk 5, Day 
29
Week 8 and 
every 4 weeks 
thereafter
Every 3 
months
Visit Window
+1 
day
1 
day
1
day
1
day
1
day
+5 days Week 
12 only; 3 days
for all other 
visits
for each visit
+1
day
-2/+7 
days
14 
days
3 
days
Bone Markers35
X
X
Weeks  12 and  
24
X
X
Laboratory Assessments continued
PSA and LDH32
X6
X
X
X
X
X
Serum 
Testosterone
X6
X
X
PK Assessments
PK Blood 
Sampling17
X
X
Weeks 8 and 12
Disease Assessments18
CT Scan or MRI19
X6,7
Week 8 and then 
Q8wks to Week 
48; then Q12wks
X
X
Chest X-Ray or 
Chest CT Scan
X6,7
Bone Scan20
X6,7
Week 12 and 
then Q12wks
X
X
Biomarker Assessments
CTC –- Janssen21
X
X
X
Weeks 8, 16, 24, 
and 32
X
CTC – EPIC22
X
Week 8 only
X


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Study 
Assessments1,2
Pre-Screening
Screening
Enzalutamide 
Run-In 
Period
Combination Treatment Period 
(DLT Reporting Period)
Treatment Continuation 
Period
Time of Discontinuation of 
Treatment due to Disease 
Progression31
Post-Treatment
Follow-Up Visit28
Extended
Follow-
Up  
Visits29
Post-
Extended 
Follow-
Up
/EOS 
Visit30
Day 
-14 
to
Day 
-1
Day 
1 to
Day 
13
Day 
14
Wk 
1, 
Day 
1
Wk 2, 
Day 8
Wk 3, 
Day 15
Wk 4, Day 
22
Wk 5, Day 
29
Week 8 and 
every 4 weeks 
thereafter
Every 3 
months
Visit Window
+1 
day
1 
day
1
day
1
day
1
day
+5 days Week 
12 only; 3 days
for all other 
visits
for each visit
+1
day
-2/+7 
days
14 
days
3 
days
Biomarker Assessments continued
Predictive 
Biomarker: Tumor 
Tissue23
X
Progression Tumor 
Biopsy24
X
Tumor Biopsies for 
Pharmaco-
dynamics24
X
X24
cfDNA/RNA/Soluble 
Markers25
X
X
X
Weeks 8, 16, 24, 
and 32
X
Blood Sample for 
Genetic Research26
X
Study Treatments27
Enzalutamide
Continuous
Continuous
GSK2636771
Continuous
12.Laboratory Assessments: Refer to Section 8.6.68.6.5 (Table 17) for list of specific laboratory tests to be performed.  Assessments may be performed within 24 hrs prior to 
scheduled visit (liver function tests and urine tests for UPC may be performed up to 72 hrs prior to a scheduled visit) to ensure availability of results.


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15.Urine Electrolytes:  Urine samples will be obtained at Screening, pre-dose on Day 1 (Week 1), Day 3 OR Day 4, Day 15 (Week 3), Day 22 (Week 4) of the Combination 
Treatment Period, Week 8 and then every 8 weeks (3 days) thereafter during the Treatment Continuation Period, and at the post-treatment follow-up visit to determine urine 
electrolytes (magnesium, phosphorus and calcium) and urine creatinine.
33.Complete clinical chemistries laboratory assessments at Week1/Day 1 and again on either Day 3 or Day 4.  The Day 3 or Day 4 assessments can be completed at a 
local laboratory and does not require a clinic visit.  The hematology panel does NOT need to be collected on Day 3/ Day 4. Review of these labs must occur before 
Week 2, Day 1 visit. 
34.Includes assessments for 25-OH D and 1,25-OH2 D. 
35.Includes urine and blood and/or serum samples.  Must be collected at the same time of day (1 hour) to eliminate diurnal effects, and after fasting.  See SRM for 
additional details on the specific assessments and sample collection.  


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Section 8.6.6. – Laboratory Assessments
Rationale for Change: 
Addition to Table of Laboratory Assessments of the new tests added to Other tests 
section of this amendment. 
Previous text: 
Other tests
PSA 
Serum Testosterone
Coagulation Tests: PT/PTT/INR
Serum Parathyroid Hormone (PTH)
Revised text:
Other tests
PSA 
Serum Testosterone
Coagulation Tests: PT/PTT/INR
Serum Parathyroid Hormone (PTH)
Ionized Calcium
25-OH D and 1,25-OH2 D
Bone Markers5
5..Refer to SRM
Section 8.8.2. – Disease Assessment
Rationale for Change: 
Added text to clarify the importance of completing these Week 12 assessments at the 
appropriate time after the start of combination treatment. 
Previous text: 
The primary endpoint is to evaluate the 12 week non-PD rate of oral GSK2636771 + 
enzalutamide according to PCWG2 guidelines (either by RECIST 1.1, PSA progression, 
and/or progression in bone).
Revised text: 
The primary endpoint is to evaluate the 12 week non-PD rate of oral GSK2636771 + 
enzalutamide according to PCWG2 guidelines (either by RECIST 1.1, PSA progression, 
and/or progression in bone). These assessments at Week 12 should occur at least 12
weeks (+5 day window) after start of combination treatment.
Section 8.8.2.1. – PSA Response per PCWG2 Criteria
Rationale for Change: 


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Adjusted the rate of PSA to include that PSA decrease can be equal to 50%. 
Previous text:
PSA Response Rate is defined as proportion of subjects with a decrease of >50% in the 
PSA concentration from the baseline PSA value determined at least 12 weeks after start 
of treatment and confirmed after ≥4 weeks by an additional PSA evaluation.
Revised text:
PSA Response Rate is defined as proportion of subjects with a decrease of ≥>50% in the 
PSA concentration from the baseline PSA value determined at least 12 weeks after start 
of treatment and confirmed after ≥4 weeks by an additional PSA evaluation.
Section 8.8.2.2. – Radiographic Response per PCWG2 Criteria
Rationale for Change: 
Revisions and additional wording to further clarify the bone progression definition. 
Previous text:
Bone progression [Scher, 2008] is defined as the appearance of ≥2 new lesions on bone 
scan, and a confirmatory scan performed 6 or more weeks later that shows a minimum of 
2 or more additional new lesions.  The date of progression is the date of the first scan that 
indicates the change.  Subjects should not be discontinued from study treatment(s) due to 
the occurrence of bone scan changes in the first 12 weeks of combination treatment that 
do not meet PCWG2 guidelines for progression.
Revised text: 
Bone progression [Scher, 2008] is defined as the appearance of ≥2 new lesionson bone 
scan, and, for the first reassessment only, a confirmatory bone scan performed 6 or 
more weeks later that shows a minimum of 2 or more additional new lesions.  The first 
post-treatment bone scan (Week 12) will be used as the baseline scan with which all 
future bone scans are compared. The date of progression is the date of the first scan 
that shows a minimum of 2 additional new lesions indicates the change.  Subjects 
should not be discontinued from study treatment(s) due to the occurrence of bone scan 
changes in the first 12 weeks of combination treatment that do not meet PCWG2 
guidelines for progression.
Section 8.8.2.3. – Disease Progression Endpoint 
Rationale for Change: 
Revisions to clarify update to PSA progression assessment for inclusion in disease 
progression analysis.  
Previous text:
PSA progression according to the PCWG2 criteria (Section 8.8.2.1)


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Revised text: 

PSA progression according to the PCWG2 criteria (Section 8.8.2.1) with 
accompanying progression by RECIST 1.1 or bone scan for subjects with 
measeurable baseline disease OR PSA progression if no measurable baseline 
disease
Section 10.1 – Permitted Medications
Rationale for Change: 
Revised Supportive Care section to allow the use of calcium supplements and Vitamin D 
supplements due to changes to inclusion minimums and management guidelines.
Previous text:
Supportive Care:  Subjects should receive full supportive care during the study, 
including transfusions of blood and blood products, and treatment with antibiotics, 
antiemetics, antidiarrheals, and analgesics, and other care as deemed appropriate, and in 
accordance with local institutional guidelines.
Revised text: 
Supportive Care:  Subjects should receive full supportive care during the study, 
including transfusions of blood and blood products, and treatment with antibiotics, 
antiemetics, antidiarrheals, calcium supplements, Vitamin D supplements, and 
analgesics, and other care as deemed appropriate, and in accordance with local 
institutional guidelines.
Section 10.2.2. – Potential Drug Interactions with Enzalutamide
Rationale for Change: 
Updated citation in the body of the text and added the citation in the Reference section. 
Previous text: 
The following information is provided as an initial reference, however, please refer to the 
approved US FDA prescribing information [Xtandi, 2013] or the Xtandi Prescribing 
Information for the area where it is approved for the most current DDI information and 
contraindicated medications.
Revised text: 
The following information is provided as an initial reference, however, please refer to the 
approved US FDA prescribing information [Xtandi, 20136] or the Xtandi Prescribing 
Information for the area where it is approved for the most current DDI information and 
contraindicated medications.
Section 13.1.2. – Dose Expansion Phase: 
Rationale for Change: 


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Clarifications to Dose Expansion phase section to clarify that multiple doses may be 
examined. 
Previous text: 
For the Dose Expansion Phase, the hypothesized non-PD rate is provided in 
Section 13.2.2.  In this case, a test that non-PD rate is less than or equal to the null 
hypothesis rate versus the non-PD rate is greater than or equal to the alternative rate is 
being performed using the stopping rules provided in Section 13.2.2.  Descriptive 
statistics will be used to describe the response data at the RP2D dose used in the 
expanded cohort.
Revised text: 
For the Dose Expansion Phase, tThe hypothesized non-PD rate is provided in 
Section 13.2.2.  In this case, a test that non-PD rate is less than or equal to the null 
hypothesis rate versus the non-PD rate is greater than or equal to the alternative rate is 
being performed using the stopping rules provided in Section 13.2.2.  Descriptive 
statistics will be used to describe the response data at the RP2D dose(s) used in the 
expanded cohort(s).
Section 13.2.2.  – Dose Expansion Phase: 
Rationale for Change: 
Clarifications to Dose Expansion phase section to clarify that multiple doses may be 
examined. 
Previous text:
An initial dose finding will be used to establish the RP2D for the combination arm.  Once 
the final dose is confirmed, at least 10 subjects will be enrolled at the appropriate RP2D, 
using decision rules defined in Table 3.  The sample size and stopping rules are based on 
the methodology of Lee [Lee, 2008].
Revised text: 
An initial dose finding will be used to establish the RP2D MTD for the combination arm.  
Once the final dose is confirmed, at least 10 subjects will be enrolled at the appropriate 
dose level RP2D, using decision rules defined in Table 3.  The sample size and stopping 
rules are based on the methodology of Lee [Lee, 2008].
Section 13.3.1 – Analysis Populations
Rationale for Change: 
Revised and added population to clarify between safety and clinical activity populations 
and to define the evaluable population for endpoint analyses. 
Previous text: 


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All Treated Population:  The All Treated Population is defined as all subjects who 
receive at least one dose of GSK2636771. This will be the main population for all 
analyses.  
Pharmacokinetic (PK) Population: The PK Population will consist of all subjects from 
the All Treated Population for whom at least one PK sample is obtained and analyzed.
All Screened Population: The All Screened Population is defined as all subjects for 
whom pre-screening consent is obtained.
Revised text: 
All Treated Population:  The All Treated Safety Population is defined as all subjects 
who receive at least one dose of GSK2636771 or Enzalutamide. This will be the main 
population for all analyses.  Safety will be evaluated based on this analysis population.
The All Treated Clinical Activity Population is defined as all subjects who received 
at least one dose of GSK2636771. Clinical activity and evaluation of non-PD rate 
will be based on this analysis population.  This will include subjects from both dose 
escalation and dose expansion 
The All Evaluable Population is defined as all subjects from All Treated Clinical
Activity Population who have at least one post-dose disease assessment and have 
been exposed to study drug for at least 12 weeks or have progressed or have died or 
have withdrawn from the study for any reason. Dose Expansion futility analyses will 
be based on this population.
Pharmacokinetic (PK) Population:  The PK Population will consist of all subjects from 
the All Treated Population for whom a PK sample is obtained and analyzed.
All Screened Population: The All Screened Population is defined as all subjects for 
whom pre-screening consent is obtained.
Section 13.3.3.2. – Dose Expansion Phase
Rationale for Change: 
Clarification on futility analysis timeframe and population for this analysis. 
Previous text:
After the initial 10 subjects have enrolled at the RP2D dose, 12-week non-PD rate will be 
reviewed on an ongoing basis and the number of responses observed will be compared 
with the stopping rules provided in Section 13.2.2.
Revised text: 
After the initial 10 subjects have enrolled at the RP2D become evaluable at a dose level 
using a combination of dose escalation and dose expansion subjects, 12-week non-PD 


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rate will be reviewed on an ongoing basis and the number of responses observed will be 
compared with the stopping rules provided in Section 13.2.2.
Section 13.3.4.1 – Efficacy Analyses
Rationale for Change: 
Updated of population to be used for analyses; added and revised secondary analyses.
Previous text: 
The All Treated Population will be used for the analysis of efficacy data.  Efficacy 
analyses will be provided separately for each cohort.
Primary Analyses
The primary analysis is to determine whether the 12-week non PD rate is greater than or 
equal to 5%.  The 12-week non PD rate is defined as the percentage of subjects without 
progression at Week 12. Subjects with unknown or missing response will not be treated 
as not having PD (i.e., subjects with NE will be included in the denominator when 
calculating the percentage of non-PD). Non-PD rate will be provided along with 
corresponding exact 95% CIs.
Secondary Analyses
PSA and RECIST response data will be reported.  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 tumor response data.  An exact 95% CI will be computed for the PSA and 
RECIST response rate.
Revised text: 
The All Treated Clinical Activity Population will be used for the analysis of efficacy 
data, and will be summarized separately for each dose level combining data from 
both dose escalation and does expansion.  Efficacy analyses will be provided separately 
for each dose levelcohort.
Primary Analyses
The primary analysis is to determine whether the 12-week non PD rate is greater than or 
equal to 5%.  The 12-week non PD rate is defined as the percentage of subjects without 
progression at Week 12. Progression is defined by RECIST 1.1 or progression in bone 
or PSA progression with accompanying progression by RECIST 1.1 or bone scan 
when baseline disease present or PSA progression solely if no other baseline disease.
Subjects with unknown or missing response will not be treated as not having PD (i.e., 
subjects with NE will be included in the denominator when calculating the percentage of 
non-PD). Non-PD rate will be provided along with corresponding exact 95% CIs.
Secondary Analyses


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PSA and RECIST 1.1 response data will be reported.  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 tumor response data.  An exact 95% CI will be computed for the PSA50 
response rate and RECIST 1.1 confirmed response rate.
New text: 
PSA Response Rate
PSA Response rate (RR) is defined as proportion of subjects with a decrease of 
50% in the PSA concentration from the baseline PSA value determined at least 12 
weeks after start of treatment and confirmed after ≥4 weeks by an additional PSA 
evaluation RR will be reported by dose level along with the exact 95% confidence 
interval. Waterfall plots will be presented that show the maximum percentage of 
change in PSA reduction from baseline.
Objective Response Rate
The objective response (ORR) rate is defined as the percentage of subjects with a 
confirmed complete response (CR) or a partial response (PR) at any time as per 
PCWG3-modified RECIST 1.1 (Appendix 5). Subjects with unknown or missing 
response will be treated as non-responders, i.e. these subjects will be included in the 
denominator when calculating the percentage. The number and types of responses, 
as outlined in PCWG3-modified RECIST 1.1, will be listed and summarized 
separately, as appropriate. The observed ORR, observed confirmed and 
unconfirmed ORR will be reported at the interim and final analysis for each cohort 
specified in treated dose, if data warrant. The estimates along with 95% exact 
confidence interval (CI) will be provided.
Radiographic Progression-free survival (rPFS) will be defined as the time from 
combination study treatment start until the first date of either disease progression 
or death due to any cause. The date of disease progression will be defined as the 
earliest date of disease progression as assessed by the investigator using RECIST 
version 1.1 or progression on bone scan. For subjects who have not progressed or 
died at the time of the rPFS analysis, censoring will be performed using the date of 
the last adequate disease assessment. In addition, subjects with an extended loss to 
follow-up or who start a new anti-cancer therapy prior to a rPFS event will be 
censored at the date of the last adequate disease assessment (e.g. assessment where 
visit level response is CR, PR, or stable disease [SD]) prior to the extended loss to 
follow-up or start of new anti-cancer therapy, respectively. Further details on rules 
for censoring will be provided in the RAP. rPFS will be summarized by dose level 
specified in expansion cohort using Kaplan-Meier quantile estimates along with 2-
sided 95% CIs 
Time to PSA progression 

If there has been a decline from baseline: time from start of combination 
treatment to first PSA increase that is 25% and 2  ng/mL in absolute value 
from the nadir, and which is confirmed by a second value 3 or more weeks later 
(i.e., a confirmed rising trend) at least 12 weeks after the start of treatment.


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
If there has NOT been a decline from baseline: time from start of therapy to first
PSA increase that is 25% and 2  ng/mL in absolute value from the baseline 
value, determined at least 12 weeks after start of treatment.
Time to PSA progression will be summarised using Kaplan-Meier methods by dose 
level.
Time to radiological progression will be defined as the time from combination study 
treatment start until the first radiological progression by RECIST 1.1 and/ or 
confirmed bone progression as defined in Section 8.8.2.2.  Time to radiological 
progression will be summarised using Kaplan-Meier methods by dose level.
Section 13.3.4.2 – Safety Analyses
Rationale for Change: 
Clarification of the population used for safety analyses.
Previous text:
The All Treated Population will be used for the analysis of safety data. All serially 
collected safety endpoints (e.g., laboratory tests, vital signs, ECGs) will be summarized 
according to the scheduled, nominal visit at which they were collected and across all on-
treatment time points using a “worst-case” analysis. Complete details of the safety 
analyses will be provided in the RAP.
Revised text: 
The All Treated Safety Population will be used for the analysis of safety data. All serially 
collected safety endpoints (e.g., laboratory tests, vital signs, ECGs) will be summarized 
according to the scheduled, nominal visit at which they were collected and across all on-
treatment time points using a “worst-case” analysis. Complete details of the safety 
analyses will be provided in the RAP. 


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Other changes to provide additional clarifications or to correct inadvertent 
errors in previous versions of the protocol:
Title Page: 
Updated author list to include new authors:
 and 
and remove 
. 
Table of Contents: 
Revision to Table of Contents to reflect changes to Section 3 addressed earlier in this 
Appendix. 
List of Abbreviations: 
Addition of new abbreviations to table: ORR – Objective Response Rate, PSA50 –
Prostate-specific antigen decrease from baseline ≥50%, rPFS – Radiological progression 
free survival, and RR – Response rate
Protocol Synopsis and Section 3:
In multiple locations, revised an error in the abbreviation for PCWG2 guidelines, which 
was previously 2PCWG2 to PCWG2. 
Section 4.1.1. – Number of Subjects: 
Updated link for Section related to futility from 3.6.1 to 3.7.1.
Section 13.2.2 – Dose Expansion Phase: 
Updated link for Section related to futility from 3.6.1 to 3.7.1.
Section 15 – References: 
Updated date of most recent prescribing information reference for Xtandi (enzalutamide).
Appendix 9 – Protocol Amendment Changes:
For each Amendment, updated the section to provide heading numbers and dates of all 
protocol amendments. 
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SAP_001.pdf: 
 
CONFIDENTIAL 
 
The GlaxoSmithKline group of companies 
 
200331 
 
1 
 
 Division 
: Worldwide Development 
Information Type 
: Reporting and Analysis Plan (RAP) 
 
Title 
: Reporting and Analysis Plan for A Phase I, Open-Label, 
Dose-Finding Study of GSK2636771 Administered in 
Combination with Enzalutamide (Xtandi) in Male Subjects 
with Metastatic Castration-Resistant Prostate Cancer 
(mCRPC) 
Compound Number  : GSK2636771 
Effective Date  
: 03-MAR-2020 
 
Description: 
 
The purpose of this RAP is to describe the planned analyses and output to be 
included in the Clinical Study Report for Protocol 2013N172718_04. 
 
This RAP is intended to describe the safety, efficacy and pharmacokinetic analyses 
required for the study.  
 
This RAP will be provided to the study team members to convey the content of the 
Statistical Analysis Complete (SAC) deliverable. 
 
RAP Author(s):   
Author 
Date 
Lead 
 
Statistician (Oncology, Clinical Statistics) 
Co-Authors 
Clinical Pharmacology Manager (Oncology, CPMS) 
17-FEB-2020 
Clinical Biomarker Lead (Oncology, Biomarkers) 
17-FEB-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 
 
200331 
 
2 
 
RAP Team Review Confirmations (Method: E-mail) 
Reviewer 
Date 
 
17-FEB-2020 
Clinical Development Director (Oncology) 
 
18-FEB-2020 
Principal Programmer/Analyst (Oncology, Clinical Programming) 
Clinical Statistics and Clinical Programming Line Approvals 
(Method: Pharma TMF eSignatures) 
Approver 
Date 
e-signature 
Senior Statistics Director (Oncology, Clinical Statistics) 
e-signature 
Programming Manager (Oncology, Clinical Programming) 
  
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TABLE OF CONTENTS 
PAGE 
1. 
INTRODUCTION ...................................................................................................... 6 
1.1. 
RAP Amendments ........................................................................................ 7 
2. 
SUMMARY OF KEY PROTOCOL INFORMATION .................................................. 8 
2.1. 
Changes to the Protocol Defined Statistical Analysis Plan ............................ 8 
2.2. 
Study Objective(s) and Endpoint(s)............................................................... 8 
2.3. 
Study Design .............................................................................................. 11 
2.4. 
Statistical Hypotheses / Statistical Analyses ............................................... 12 
3. 
PLANNED ANALYSES .......................................................................................... 13 
3.1. 
Interim Analyses ......................................................................................... 13 
3.1.1. 
Dose Escalation Phase ................................................................ 13 
3.1.2. 
Dose Expansion Phase ................................................................ 13 
3.2. 
Final Analyses ............................................................................................ 13 
4. 
ANALYSIS POPULATIONS ................................................................................... 14 
4.1. 
Protocol Deviations ..................................................................................... 14 
5. 
CONSIDERATIONS FOR DATA ANALYSES AND DATA HANDLING 
CONVENTIONS ..................................................................................................... 16 
5.1. 
Study Treatment & Sub-group Display Descriptors ..................................... 16 
5.2. 
Baseline Definitions .................................................................................... 16 
5.3. 
Other Considerations for Data Analyses and Data Handling 
Conventions ................................................................................................ 17 
6. 
STUDY POPULATION ANALYSES ....................................................................... 18 
6.1. 
Overview of Planned Study Population Analyses ........................................ 18 
6.1.1. 
Disposition of Subjects ................................................................. 18 
6.1.2. 
Demographic and Baseline Characteristics .................................. 18 
6.1.3. 
Treatment Compliance ................................................................. 19 
6.1.4. 
Concomitant Medications ............................................................. 19 
6.1.5. 
Subsequent Anti-Cancer Therapies ............................................. 20 
7. 
EFFICACY ANALYSES .......................................................................................... 21 
7.1. 
Overview of Planned Efficacy Analyses ...................................................... 21 
7.2. 
Primary Efficacy Analyses .......................................................................... 21 
7.2.1. 
Endpoint / Variables ..................................................................... 22 
7.2.1.1. 
PSA Response (at week 12) ....................................... 22 
7.2.1.2. 
Bone Response (at week 12) ..................................... 24 
7.2.1.3. 
RECIST Response ..................................................... 25 
7.2.1.4. 
Overall Response (at week 12) .................................. 25 
7.2.2. 
Summary Measure ...................................................................... 27 
7.2.3. 
Population of Interest ................................................................... 27 
7.2.4. 
Statistical Analyses / Methods ..................................................... 28 
7.3. 
Secondary Efficacy Analyses ...................................................................... 28 
7.3.1. 
Endpoint / Variables ..................................................................... 28 
7.3.2. 
Summary Measure ...................................................................... 32 
7.3.3. 
Population of Interest ................................................................... 32 
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7.3.4. 
Statistical Analyses / Methods ..................................................... 32 
8. 
SAFETY ANALYSES ............................................................................................. 34 
8.1. 
Overview of Planned Analyses ................................................................... 34 
8.2. 
Extent of Exposure ..................................................................................... 34 
8.3. 
Adverse Events Analyses ........................................................................... 34 
8.4. 
Adverse Events of Special Interest (AESI) Analyses ................................... 34 
8.5. 
Clinical Laboratory Analyses ....................................................................... 35 
8.6. 
Other Safety Analyses ................................................................................ 35 
8.6.1. 
Deaths and Serious Adverse Events ............................................ 35 
8.7. 
Pregnancies ................................................................................................ 35 
9. 
PHARMACOKINETIC ANALYSES ......................................................................... 36 
9.1. 
Primary Pharmacokinetic Analyses ............................................................. 36 
9.2. 
Secondary Pharmacokinetic Analyses ........................................................ 36 
9.2.1. 
Endpoint / Variables ..................................................................... 36 
9.2.1.1. 
Drug Concentration Measures .................................... 36 
9.2.2. 
Population of Interest ................................................................... 36 
9.2.3. 
Statistical Analyses / Methods ..................................................... 36 
10. BIOMARKER ANALYSES ...................................................................................... 37 
10.1. 
Exploratory Biomarker Analyses ................................................................. 37 
10.1.1. 
Endpoint / Variables ..................................................................... 37 
10.1.1.1. Circulating Tumour Cells ............................................ 37 
10.1.1.2. Frequency of PTEN loss and Mechanism of 
PTEN Loss ................................................................. 37 
10.1.1.3. Mutational Analysis of Tumour Biopsy Sample ........... 37 
10.1.2. 
Summary Measure ...................................................................... 37 
10.1.3. 
Population of Interest ................................................................... 38 
10.1.4. 
Statistical Analyses / Methods ..................................................... 38 
11. PHARMACOKINETIC / PHARMACODYNAMIC ANALYSES ................................. 39 
12. REFERENCES ....................................................................................................... 40 
13. APPENDICES ........................................................................................................ 41 
13.1. 
Appendix 1: Protocol Deviation Management and Definitions for Per 
Protocol Population ..................................................................................... 41 
13.1.1. 
Exclusions from Per Protocol Population ..................................... 41 
13.2. 
Appendix 2: Schedule of Activities .............................................................. 42 
13.2.1. 
Protocol Defined Schedule of Events ........................................... 42 
13.3. 
Appendix 3: Assessment Windows ............................................................. 56 
13.3.1. 
Definitions of Assessment Windows for Analyses ........................ 56 
13.4. 
Appendix 4: Study Phases and Treatment Emergent Adverse 
Events ........................................................................................................ 57 
13.4.1. 
Study Phases for Concomitant Medication ................................... 57 
13.4.2. 
Treatment Emergent Flag for Adverse Events ............................. 57 
13.5. 
Appendix 5: Data Display Standards & Handling Conventions .................... 58 
13.5.1. 
Reporting Process ....................................................................... 58 
13.5.2. 
Reporting Standards .................................................................... 58 
13.5.3. 
Reporting Standards for Pharmacokinetic .................................... 59 
13.6. 
Appendix 6: Derived and Transformed Data ............................................... 60 
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5 
 
13.6.1. 
General ........................................................................................ 60 
13.6.2. 
Study Population .......................................................................... 61 
13.6.3. 
Efficacy ........................................................................................ 61 
13.6.4. 
Safety .......................................................................................... 63 
13.7. 
Appendix 7: Reporting Standards for Missing Data ..................................... 64 
13.7.1. 
Premature Withdrawals ................................................................ 64 
13.7.2. 
Handling of Missing Data ............................................................. 64 
13.7.2.1. Handling of Missing and Partial Dates ........................ 64 
13.8. 
Appendix 8: Values of Potential Clinical Importance ................................... 67 
13.8.1. 
Laboratory Values ........................................................................ 67 
13.8.2. 
ECG and Vital Signs .................................................................... 67 
13.9. 
Appendix 9: Population Pharmacokinetic (PopPK) Analyses ...................... 68 
13.10. Appendix 10: Pharmacokinetic / Pharmacodynamic Analyses .................... 69 
13.11. Appendix 11: Abbreviations & Trade Marks ................................................ 70 
13.11.1. Abbreviations ............................................................................... 70 
13.11.2. Trademarks ................................................................................. 72 
13.12. Appendix 12: List of Data Displays.............................................................. 73 
13.12.1. Data Display Numbering .............................................................. 73 
13.12.2. Mock Example Shell Referencing ................................................ 73 
13.12.3. Deliverables ................................................................................. 73 
13.12.4. Study Population Tables .............................................................. 74 
13.12.5. Efficacy Tables ............................................................................ 78 
13.12.6. Efficacy Figures ........................................................................... 79 
13.12.7. Safety Tables ............................................................................... 80 
13.12.8. Safety Figures ............................................................................. 87 
13.12.9. Pharmacokinetic Tables ............................................................... 88 
13.12.10. Pharmacokinetic Figures ............................................................. 89 
13.12.11. Biomarker Tables ......................................................................... 91 
13.12.12. Biomarker Figures ....................................................................... 91 
13.12.13. ICH Listings ................................................................................. 92 
13.12.14. Non-ICH Listings .......................................................................... 97 
13.13. Appendix 13: Example Mock Shells for Data Displays .............................. 100 
 
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1. 
INTRODUCTION 
The purpose of this reporting and analysis plan (RAP) is to describe the analyses to be 
included in the Clinical Study Report for Protocol 200331: 
Revision Chronology: 
2013N172718_00 
22-May-2014 
Original 
2013N172718_01 
08-Sep-2014 
Amendment 1 incorporates changes to Section 5.2, 
Permanent Discontinuation of Study 
Treatment(s) for clarification as requested by the Medicines 
and Healthcare products 
Regulatory Agency (MHRA) in the United Kingdom. 
2013N172718_02 
26-Feb-2015 
Amendment 2 incorporates changes to list of authors and 
primary medical monitor (contact information) due to changes 
in personnel assignment within GSK; list of abbreviations was 
revised appropriately based upon addition/deletion of 
abbreviated terms used throughout the protocol; Time and 
Events Tables were revised for clarification of assessments 
and procedures to be performed and to reflect changes made 
throughout the body of the protocol. 
2013N172718_03 
24-Jun-2016 
Amendment 3 incorporates changes to update the risk 
assessment section and to include additional requirements for 
monitoring of renal events following an INDSR report for  
Acute Renal Failure in a subject enrolled in this study.  
In addition, it was clarified that subjects with disease 
progression defined by PSA progression alone or for the 
worsening of an isolated disease site that is not clinically 
significant are not required to discontinue treatment in the 
study. Separate definitions for disease progression as a study 
endpoint and disease progression mandated by the protocol 
to result in a subject being withdrawal from treatment is 
clarified.  
Optional pharmacodynamics paired biopsies as well as 
clarifications around biomarker assessments were added to 
the Time and Events tables for the Dose Escalation and Dose 
Expansion Phases. 
Additional language was added to clarify that the decision to 
terminate the Dose Expansion Phase will take into account all 
relevant factors, including but not solely based upon the 
statistical methodology and futility criterion. 
Other minor clarifications and corrections of inadvertent errors 
were also added. 
2013N172718_04 
27-Jan-2017 
Amendment 4 was completed to include additional 
requirements for monitoring of events related to calcium 
results, including revisions to the Table & Events to clarify 
additional laboratory testing requirements; clarification of 
secondary clinical activity endpoints and update to associated 
statistical section(s); revision of clinical activity population 
allowing the combination of dose escalation and dose 
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Revision Chronology: 
expansion populations; revision of dose escalation and dose 
expansion wording to allow multiple dose levels in dose 
expansion to establish RP2D after dose expansion phase; 
adjustment to Week 12 visit window and clarification for Week 
12 assessment timing; revision to reflect current indication for 
enzalutamide throughout; clarification of study populations; 
clarification of bone progression definition. 
Other minor clarifications and corrections of inadvertent errors 
were also added. 
 
All data displays (Tables, Figures & Listings) will use the term “Subject” which reflects 
CDISC and GSK Data Display Standards terminology. 
1.1. 
RAP Amendments 
Revision chronology:   
RAP Section  
Amendment Details  
Reporting and Analysis Plan_200331_Final_V1 [02-Dec-2019]  
Reporting and Analysis Plan_200331_Amendment_Final_V1 
7.2. 
Removed references to PCWG2 modification of RECIST since it was not 
required in the protocol. 
 
Removed the text “PCWG2 modified” prior to “RECIST” throughout the 
section. 
 
Removed the text “Additional requirement (per PCWG2) that 
progression at first assessment be confirmed by a second scan 6 or 
more weeks later” from the RECIST response (at 16 weeks) in Table 2. 
7.2.1.2. 
 
Added the following text to Table 4 to clarify the definition of Bone 
Response (at week 12): “This algorithm assumes subjects had bone 
lesions identified via bone scan at baseline. For subjects without bone 
lesions identified via Bone Scan at baseline, the confirmed and 
unconfirmed bone responses are set to missing.” 
7.2.1.3. 
 
Removed the following text from the RECIST response as was not 
required in the protocol: “with the added PCWG2 requirement that 
progression at first assessment be confirmed by a second scan 6 or 
more weeks later.” 
7.2.1.4. 
 
Added additional 12 scenarios to Table 5 to clarify the Overall 
Response at week 12.These scenarios take into account subjects with 
no baseline bone lesions identified via bone scan. 
7.3.1. 
 
Removed the text “PCWG2 modified” prior to “RECIST” throughout the 
section as was not required in the protocol. 
9.2.1.1. 
 
Clarified the description of the how the secondary objectives will be 
displayed. 
13.12.9., 13.12.10., 
13.12.14. 
 
Added clarifying text to the titles of the PK tables/figures/listings 
 
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2. 
SUMMARY OF KEY PROTOCOL INFORMATION 
2.1. 
Changes to the Protocol Defined Statistical Analysis Plan 
Changes from the originally planned statistical analysis specified in the protocol 
amendment 4 (Dated: 27-Jan-2017) are outlined in Table 1. These exploratory endpoints 
were unlikely to provide any additional information to what would be provided by the 
other endpoints. 
Table 1 
Exploratory Endpoints Removed from Protocol Defined Analysis 
Plan 
Protocol 
Reporting & Analysis Plan 
objective 
endpoint 
Statistical Analysis 
Plan 
Rationale for Changes 
 Evaluation of 
biomarkers in 
CTCs that may 
predict response 
to combination 
 
AR expression, 
PTEN FISH and 
other genomic 
evaluations in 
CTCs 
 
removed 
 
analysis not 
performed since no 
response was 
identified 
 Evaluation of 
tumor tissue to 
explore 
explanation for the 
mechanism of 
resistance to 
combination 
therapy 
 
Based on analysis 
of DNA, RNA and 
proteins from 
tumour tissue 
obtained at time of 
progression after 
initially responding 
to combination 
therapy 
 
removed 
 
paired biopsies 
were not obtained 
 To determine 
pharmacodynamic 
effects of drug 
treatment 
 
RNA/protein 
analysis of 
pre/post treatment 
tumour biopsies  
 
removed 
 
paired biopsies 
were not obtained 
 
2.2. 
Study Objective(s) and Endpoint(s) 
Objectives 
Endpoints 
Primary Objectives 
Primary Endpoints 
 To assess the safety and 
tolerability of GSK2636771 + 
enzalutamide administered 
orally once daily continuously in 
subjects with mCRPC. 
 AEs, SAEs, DLTs, and changes in laboratory 
values, ECGs, and vital signs (BP, temperature 
and heart rate) 
 To determine the RP2D of 
orally administered 
GSK2636771 + enzalutamide 
in subjects with mCRPC. 
 Safety and tolerability as assessed by AEs, 
SAEs, DLTs, and changes in laboratory values, 
ECGs, and vital signs (BP, temperature and 
heart rate) 
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Objectives 
Endpoints 
 To evaluate lack of progression 
in the dose expansion subjects 
with mCRPC by rate of 
subjects who do not progress 
for 12 weeks 
 Non-Progressive Disease (Non-PD) rate for 12 
weeks according to PCWG2 criteria (either by 
RECIST 1.1, or progression in bone or PSA 
progression with accompanying progression by 
RECIST 1.1 or bone scan when baseline 
radiological or bone disease present or PSA 
progression if no other baseline disease). 
Secondary Objectives 
Secondary Endpoints 
 To evaluate the clinical activity 
of oral GSK2636771 + 
enzalutamide in the treatment 
of mCRPC (PTEN deficient) 
 PSA50 response rate defined as the percent of 
subjects achieving PSA50 at 12 weeks or 
thereafter (PSA50 is ≥50% decrease in PSA 
from baseline) 
 Objective Response Rate (ORR) defined as 
complete response (CR) rate plus partial 
response (PR) rate per RECIST 1.1  
 Time to PSA progression according to PCWG2 
criteria 
 Time to radiological progression according to 
PCWG2 criteria (either by RECIST 1.1, PSA 
progression and/or progression in bone) 
 Radiological progression free survival (rPFS) 
per RECIST1.1 and/or bone scans 
 
 To determine the effect of 
GSK2636771 on enzalutamide 
PK following repeat-dose oral 
administration. 
 Plasma concentrations of enzalutamide and 
N-desmethyl enzalutamide. 
 To determine the PK of 
GSK2636771 in the presence 
of enzalutamide. 
 Blood GSK2636771 concentrations. 
Exploratory Objectives 
Exploratory Endpoints 
 To determine the frequency of 
PTEN deficiency in subjects 
with mCRPC 
 Frequency of PTEN-deficient mCRPC reported 
in subjects based on pre-screened tumours 
 To determine the mechanism of 
PTEN deficiency 
 PTEN deletion, mutation or promoter 
methylation 
 To identify additional 
biomarkers (DNA, RNA or 
protein based) in tumour or in 
circulation that may predict 
response to oral GSK2636771 
+ enzalutamide  
 Response prediction biomarkers based on 
analysis of DNA, RNA, and proteins from 
surrogate tissues (e.g., cfDNA) and/or tumour 
tissue 
 To determine the effect of 
enzalutamide with 
GSK2636771 on the kinetics of 
tumour growth 
 Longitudinal tumour size measurements; serum 
PSA levels, change from baseline in CTCs 
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Objectives 
Endpoints 
 Evaluation of biomarkers in 
CTCs that may predict 
response to combination 
 AR expression, PTEN FISH and other genomic 
evaluations in CTCs 
 Evaluation of tumour tissue to 
explore explanation for the 
mechanism of resistance to 
combination therapy 
 Based on analysis of DNA, RNA and proteins 
from tumour tissue obtained at time of 
progression after initially responding to 
combination therapy 
 To determine 
pharmacodynamic effects of 
drug treatment 
 RNA/protein analysis of pre/post treatment 
tumour biopsies  
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2.3. 
Study Design 
Overview of Study Design and Key Features 
Design 
Features 
 Dose Escalation Phase of the study is to determine the maximum tolerated 
dose (MTD) and select a recommended dose for Dose Expansion Phase or a 
recommended Phase 2 dose (RP2D) based on the safety, pharmacokinetic, 
and pharmacodynamic profiles observed after combination therapy of 
GSK2636771 and enzalutamide. Any cohort may be expanded up to 12 
subjects in order to collect adequate data on safety, PD or PK. 
 Dose Expansion Phase: This phase of the study will evaluate the long-term 
safety of the combination treatment as well as the 12-week non-progressive 
disease (PD) rate of the combination treatment in subjects with mCPRC.  To 
confirm dose(s) identified during dose escalation, multiple dose levels of 
GSK2636771 in combination with enzalutamide may be examined during dose 
expansion, with each dose level cohort enrolling up to 20 subjects.  
Dosing 
The planned starting dose of study treatment will be GSK2636771 300 mg orally 
once daily in combination with enzalutamide 160 mg orally once daily. Participants 
will begin combination therapy only after completing a 14-day run-in period of 
enzalutamide monotherapy 160 mg orally once daily. Dose escalations will be 
performed in Dose Escalation Phase and dose adjustments are allowed to address 
tolerability and safety issues. 
Cohort 
N 
GSK2636771 
Enzalutamide 
-1 
3 - 6 
200 mg once daily 
160 mg once daily 
1 
3 - 6 
300 mg once daily 
160 mg once daily 
2 
3 - 6 
400 mg once daily 
160 mg once daily 
Treatment 
Assignment 
 This is a non-randomized open-label study.   
Interim 
Analysis 
 No formal interim analyses will be performed at Dose Escalation Phase. 
Available safety data will be reviewed and summarized on an ongoing basis.  
Review of preliminary safety data from all available dose cohorts will be 
performed in each study treatment combination before starting a new dose 
cohort and before selecting a dose level for expansion.  
 Futility will be evaluated when there is adequate enrolment; this analysis may 
occur using the combination of the dose escalation and dose expansion 
population.  
 
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2.4. 
Statistical Hypotheses / Statistical Analyses 
No formal statistical hypothesis will be tested during dose escalation phase. All analyses 
will be descriptive and exploratory.  
 
For dose expansion phase, the 12-week non-PD rate will be tested using the predictive 
probability design by Lee and Liu (Lee, 2008). The null and alternative hypotheses for 
the non-PD rate are as follows:  
 
H0: p≤ 5.0% 
HA: p>30%.  
 
This hypothesis will be tested using a combination of data provided in both the dose 
escalation and dose expansion phases. 
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3. 
PLANNED ANALYSES 
3.1. 
Interim Analyses 
3.1.1. 
Dose Escalation Phase 
In the Dose Escalation Phase, available safety data will be reviewed and summarized on 
an ongoing basis. Review of preliminary safety data from all available dose cohorts will 
be performed in each study treatment combination before starting a new dose cohort and 
before selecting a dose level for expansion. Safety will be reviewed on an ongoing basis 
by the Safety Monitoring Team, composed of study investigators and key GSK personnel 
including the medical monitor, study manager, and study statistician. 
3.1.2. 
Dose Expansion Phase 
After the initial 10 subjects become evaluable at a dose level using a combination of dose 
escalation and dose expansion subjects, 12-week non-PD rate will be reviewed on an 
ongoing basis and the number of responses observed will be compared with the stopping 
rules provided below. 
3.2. 
Final Analyses 
The final planned primary and secondary analyses will be performed after the completion 
of the following sequential steps: 
1. All participants have completed or withdrawn from the study as defined in the 
protocol.  
2. All required database cleaning activities have been completed and final database 
release (DBR) and database freeze (DBF) has been declared by Data Management. 
 
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4. 
ANALYSIS POPULATIONS 
Population 
Definition / Criteria 
Analyses Evaluated 
All Screened  
 This population will consist of all subjects who 
were screened for PTEN status and enrolment 
of study 
 Summary of study 
eligibility and PTEN 
status 
All Treated Safety   This population will consist of all subjects who 
receive at least one dose of GSK2636771 or 
Enzalutamide. 
 Safety 
All Treated 
Clinical Activity 
 This population will consist of all subjects who 
received at least one dose of GSK2636771. 
 Clinical Activity 
 
Modified All 
Treated Clinical 
Activity 
 
 This population will consist of all subjects in All 
Treated Clinical Activity who were treated at 
the same dose as the dose expansion cohort 
and have been on study drug for at least 12 
weeks or have discontinued study treatment 
due to disease progression, died, or withdrawn 
for any reason. 
 Evaluation of non-
PD rate 
All Evaluable 
Subjects  
 This population will consist of all subjects from 
All Treated Clinical Activity Population who 
have at least one post-dose disease 
assessment and have been exposed to study 
drug for at least 12 weeks or have progressed 
or have died or have withdrawn from the study 
for any reason 
 Dose Escalation & 
Expansion futility 
analyses 
PK Concentration 
Population 
 This population will consist of all subjects in 
the All Treated Safety Population for whom a 
blood sample for pharmacokinetics is obtained, 
analysed, and was measurable. 
 Listing, summary, 
and figures of PK 
concentration 
Biomarker 
Population 
 This population will consist of subjects in the 
All Treated Safety Population for whom a 
sample was obtained and analyzed for 
biomarkers 
 PTEN deletion and 
gene mutation  
 CTC conversion 
NOTES :  
 
Please refer to Appendix 12: List of Data Displays which details the population to be used for each display being 
generated. 
 
4.1. 
Protocol Deviations 
Important protocol deviations (including deviations related to study inclusion/exclusion 
criteria, conduct of the trial, patient management or patient assessment) will be 
summarised and listed. 
Protocol deviations will be tracked by the study team throughout the conduct of the study 
in accordance with the Protocol Deviation Management Plan. 
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o Data will be reviewed prior to freezing the database to ensure all important 
deviations and deviations which may lead to exclusion from the analysis are 
captured and categorised on the protocol deviations dataset.  
o This dataset will be the basis for the summaries and listings of protocol 
deviations. 
A separate summary and listing of all inclusion/exclusion criteria deviations will also be 
provided. This summary will be based on data as recorded on the inclusion/exclusion 
page of the eCRF. 
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5. 
CONSIDERATIONS FOR DATA ANALYSES AND DATA 
HANDLING CONVENTIONS 
5.1. 
Study Treatment & Sub-group Display Descriptors 
Participants will be listed and summarized based on their treatment group initially 
assigned regardless of any dose modifications that may occur following treatment 
initiation. 
Treatment Group Descriptions 
RandAll NG  
Data Displays for Reporting  
 
Code 
Description 
Description 
Data Display 
Order in TLF  
A 
Enzalutamide 
Run-in Enzalutamide 
Run-in Enza 
1 
B 
GSK2636771 + 
Enzalutamide 
GSK2636771 200mg/ 
Enzalutamide 160mg 
Escalation 
GSK 200mg / Enza 160mg 
Escalation 
2 
GSK2636771 200mg/ 
Enzalutamide 160mg 
Expansion 
GSK 200mg / Enza 160mg 
Expansion 
3 
GSK2636771 200mg/ 
Enzalutamide 160mg 
Overall 
GSK 200mg / Enza 160mg 
Overall 
4 
GSK2636771 300mg/ 
Enzalutamide 160mg 
Escalation 
GSK 300mg / Enza 160mg 
Escalation 
5 
GSK2636771 400mg/ 
Enzalutamide 160mg 
Escalation 
GSK 400mg / Enza 160mg 
Escalation 
6 
 
5.2. 
Baseline Definitions 
For all endpoints (except as noted in baseline definitions) the baseline value will be the 
latest GSK2636771 pre-dose assessment with a non-missing value, including those from 
unscheduled visits. If time is not collected, Day 1 assessments are assumed to be taken 
prior to first GSK2636771 dose and used as baseline. 
For laboratory data, baseline will be the latest non-missing pre-dose value from central 
lab. If no central lab value is available, the latest non-missing pre-dose value from local 
lab will be used. If there are multiple assessments on the same day, the mean will be used 
as the baseline value. 
Unless otherwise stated, if baseline data is missing no derivation will be performed and 
baseline will be set to missing. 
 
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5.3. 
Other Considerations for Data Analyses and Data Handling 
Conventions 
Other considerations for data analyses and data handling conventions are outlined in the 
appendices: 
Section 
Component 
13.4 
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 
 
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6. 
STUDY POPULATION ANALYSES 
6.1. 
Overview of Planned Study Population Analyses 
The study population analyses will be based on the All Treated Safety population, unless 
otherwise specified. 
Study population analyses including analyses of subject’s disposition, demographic and 
baseline characteristics, protocol deviations, substance use, past and current medical 
conditions, disease characteristics at initial diagnosis and at screening, prior and follow-
up anti-cancer therapy, cancer-related surgical procedures, concomitant medications, and 
exposure and treatment compliance will be based on GSK Core Data Standards. Details 
of the planned displays are presented in Appendix 12: List of Data Displays. 
6.1.1. 
Disposition of Subjects 
A summary of the number of subjects in each of the dosing groups/phases will be 
provided. A listing of subjects excluded from analysis populations will also be provided. 
A summary of subject status and reason for study withdrawal will be provided. This 
display will show the number and percentage of subjects who withdrew from the study, 
including primary reasons for study withdrawal. Reasons for study withdrawal will be 
presented in the order they are displayed in the eCRF.  
A summary of study treatment status will be provided. This display will show the number 
and percentage of subjects who are completed or discontinued study treatment and a 
summary of the primary reasons for discontinuation of study treatment. Reasons for study 
treatment discontinuation will be presented in the order they are displayed in the eCRF. A 
listing of study treatment discontinuation will be generated. The listing will include last 
dose date and reasons for study treatment discontinuation as well as study part of 
discontinuation.  
A table of study eligibility information will be provided based on All Pre-screened and 
Screened population. Number of subjects who were pre-screened for PTEN status and/or 
screened for enrolment, reasons of failure, subjects PTEN status etc. will be presented.  
6.1.2. 
Demographic and Baseline Characteristics 
The demographic characteristics (e.g. age, race, ethnicity, sex, baseline height, and 
baseline body weight) will be summarized and listed. In addition, age will also be 
categorized and summarized by two groups of categories, <18, 18-64, 65-74, >74 and 
<18-64, 65-84; >=85 for Development Safety Update Report and Europe Clinical Trial 
Registry disclosure, respectively.  The count and percentage will be computed for sex and 
ethnicity. 
Race and racial combinations will be summarized and listed. 
Medical conditions will be summarized by past and current categories. 
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Disease history and characteristics (primary tumor type, lesion status, time since initial 
diagnosis in weeks, stage at initial diagnosis and screening, time since last progression in 
weeks) will be listed. Separate summaries of disease characteristics at initial diagnosis 
and screening will be provided.  
Prior anti-cancer therapy will be coded using GSK Drug coding dictionary, then 
summarized by type of therapy and listed. A listing of prior anti-cancer therapy will show 
the relationship between Anatomical Therapeutic Chemical (ATC) Level 1, Ingredient, 
and verbatim text.  
A summary of prior anti-cancer therapies will be provided. The number of lines of prior 
anti-cancer therapies and radiotherapy will be tabulated.  Number of subjects who 
received Enzalutamide before or after chemotherapy will be provided.  Summary of 
cancer-related surgeries will be produced. A summary of the best response to the most 
recent prior anti-cancer therapy will also be provided. 
Substance use, including smoking history and alcohol use, will also be summarized and 
listed. 
6.1.3. 
Treatment Compliance 
A listing of planned and actual treatments will be produced including number of tablets 
prescribed per day and total number of tablets dispensed.  
In addition, summaries of study treatment exposure by Enzalutamide run in and 
combination treatment with GSK2636771 and dose modifications (e.g. number of dose 
reductions, number of dose interruptions) will further characterize compliance.  
6.1.4. 
Concomitant Medications 
Concomitant medications will be coded using GSK Drug coding dictionary, summarized, 
and listed. The summary of concomitant medications will show the number and 
percentage of subjects taking concomitant medications by Ingredient. Multi-ingredient 
products will be summarized by their separate ingredients rather than as a combination of 
ingredients.  
In the summary of concomitant medications, each subject is counted once within each 
unique ingredient. For example, if a subject takes Amoxycillin on two separate occasions, 
the subject is counted only once under the ingredient “Amoxycillin”. In the summary of 
concomitant medications, the ingredients will be summarized by the base only, using 
CMBASECD and CMBASE. 
A summary of the relationship between concomitant medications and reasons of the 
medications will be generated.   
Blood products or blood supportive care products will be listed.  
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6.1.5. 
Subsequent Anti-Cancer Therapies 
The number and percentage of subjects that received chemotherapy, immunotherapy, 
hormonal therapy, biologic therapy, radioactive therapy, small molecule targeted therapy, 
radiotherapy and cancer-specific surgery as post study treatment (see Section 13.4.1 for 
definition) anti-cancer therapy will be summarized. Time from study treatment 
discontinuation to the first post study anti-cancer therapy will also be included in this 
summary table.  
Follow-up anti-cancer therapy will be coded using GSK Drug coding dictionary, then 
summarized by ingredient. A listing of the type of follow-up anti-cancer therapy received 
(chemotherapy, immunotherapy, hormonal therapy, biologic therapy, radioactive therapy, 
small molecule targeted therapy, radiotherapy and cancer-specific surgery and details of 
the anticancer therapy for each subject will be provided.    
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7. 
EFFICACY ANALYSES 
7.1. 
Overview of Planned Efficacy Analyses 
The primary efficacy analyses will be based on the All Treated Clinical Activity 
Population, unless otherwise specified, and all summaries and data listings will use 
treatment labels as specified in Section 5.1. All summaries will be presented by dose, and 
overall. 
7.2. 
Primary Efficacy Analyses 
This analysis is to determine whether the 12-week non-PD rate is greater than 5%.  The 
12-week non-PD rate is defined as the percentage of subjects without progression (non-
PD) at Week 12 as determined from PSA results, radiographic assessment per RECIST 
1.1, and bone scan (see Section 7.2.1.4 for algorithm details). The PSA and bone scan 
results recorded at week 12 will be used for the evaluation of 12-week non-PD rate. 
Radiological assessments (CT/MRI) of target and non-target lesions at week 16 (instead 
of week 12) will be considered for the evaluation of week 12 non-PD rate since there 
were no week 12 radiological assessments scheduled for subjects during the study.   
The disease progression is defined by 1 or more of the following criteria:  
 PSA progression alone if no other baseline disease  
 PSA progression according to the PCWG2 criteria with accompanying 
progression by RECIST 1.1 or bone scan for subjects with soft tissue baseline 
disease 
 Bone progression on bone scan according to the PCWG2 criteria [measured by 
bone scan] 
 Radiographic progression in soft tissue or bone by RECIST 1.1 for subjects with 
baseline disease. 
The components of the 12 week non-PD rate primary efficacy endpoint are defined in 
Table 2. Additional details on these endpoints and composite 12-week non-PD rate are 
provided in Section 7.2.1 through Section 7.2.4. 
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Table 2 
Components of the 12 week Non-PD Rate 
Primary Efficacy endpoint 
Definition 
PSA Response (at 12 weeks) 
Progression Definition (per PCWG2)*: 
 
If there has been a decline from baseline: time from start of 
therapy to first PSA increase that is 25% and 2 ng/mL in 
absolute value from the nadir, and which is confirmed by a 
second value 3 or more weeks later (i.e., a confirmed rising trend) 
at least 12 weeks after the start of combination treatment 
 
If there has NOT been a decline from baseline: time from start of 
therapy to first PSA increase that is 25% and 2 ng/mL in 
absolute value from the baseline value, determined at least 12 
weeks after start of combination treatment 
 
See Section 7.2.1 for additional details on response 
Bone Response (at 12 weeks) 
 
Progression Definition (per PCWG2)*: 
The appearance of ≥2 new lesions, and, for the first reassessment 
only, a confirmatory bone scan performed 6 or more weeks later that 
shows a minimum of 2 or more additional new lesions.   
The date of progression is the date of the first scan that shows a 
minimum of 2 additional new lesions.  
 
See Section 7.2.2 for additional details on response. 
RECIST Response (at 16 
weeks) 
Progression Definition (per RECIST v1.1)*: 
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. The date of PD is the date of the first scan that shows 
progression. Progression is also defined as unequivocal progression in 
non-target lesions or identification of unequivocal new lesions. 
• 
See Section 7.2.3 for additional details on response. 
 
*[Scher, 2008] 
7.2.1. 
Endpoint / Variables 
7.2.1.1. 
PSA Response (at week 12) 
Determination of PSA response at week 12 is based on PCWG2 criteria. The algorithm is 
outlined in the Table 3. The response is categorized into progression (PD), non-PD, or 
not evaluable (NE). 
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Table 3 
Assessment of PSA Response 
Visit 
 
 
Week 8 (or any 
visit < 12 weeks) 
Week 12* 
Week 16 (or visit ≥3 
weeks after week 12) 
Response 
(Confirmed) 
Response 
(unconfirmed) 
 
PSA less than 
baseline 
PSA increase that is 
≥25% and ≥2 ng/mL in 
absolute value from the 
nadir (or week 8 visit) 
PSA ≥ week 12 visit 
PD 
PD 
PSA NOT less 
than baseline 
PSA increase that is 
≥25% and ≥2 ng/mL in 
absolute value from the 
baseline 
Any 
PD 
PD 
Missing 
PSA increase that is 
≥25% and ≥2 ng/mL in 
absolute value from the 
baseline 
PSA ≥ week 12 visit 
PD 
PD 
PSA less than 
baseline 
PSA increase that is 
≥25% and ≥2 ng/mL in 
absolute value from the 
nadir 
Results present, PSA < 
week 12 value (rising 
trend not confirmed by 
PSA) 
Non-PD 
PD 
PSA less than 
baseline 
PSA increase that is 
<25% or <2 ng/mL in 
absolute value from the 
nadir 
Any 
Non-PD 
Non-PD 
PSA NOT less 
than baseline or 
is missing 
PSA increase that is 
<25% or <2 ng/mL in 
absolute value from the 
baseline 
Any 
Non-PD 
Non-PD 
PSA less than 
baseline 
PSA increase that is 
≥25% and ≥2 ng/mL in 
absolute value from the 
nadir (or week 8 visit) 
missing 
NE 
PD 
Missing 
PSA increase that is 
≥25% and ≥2 ng/mL in 
absolute value from the 
baseline 
PSA < week 12 visit 
Non-PD 
PD 
Missing 
PSA increase that is 
≥25% and ≥2 ng/mL in 
absolute value from the 
missing 
NE 
PD 
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Visit 
 
 
Week 8 (or any 
visit < 12 weeks) 
Week 12* 
Week 16 (or visit ≥3 
weeks after week 12) 
Response 
(Confirmed) 
Response 
(unconfirmed) 
 
baseline 
Results available at week 8 and 12 but do not 
meet PD definition  
Any 
Non-PD 
Non-PD 
If conditions above not met  
Any 
NE 
NE 
* 12 week visit window is defined as follows: If visit occurred under amendment 3, use 78 days  3 days; if 
visit occurred under amendment 4, use window of 78 days + 5 days.  
Note: PSA response of “Any” includes scenarios where results are present and/or missing. 
 
7.2.1.2. 
Bone Response (at week 12) 
The determination of bone response at week 12 is based on PCWG2 criteria for bone 
progression (Table 2). The algorithm defining the response is outlined in Table 4. The 
response is categorized into progression (PD), non-PD, not evaluable (NE), and missing. 
Table 4 
Bone Response Algorithm (based on bone scan results) + 
First post-
baseline 
bone scan 
prior to 12 
weeks? 
Week 12 visit* 
Secondary 
Assessment (at least 
6 weeks after week 
12 visit) 
Bone Response 
(confirmed) 
Bone Response 
(unconfirmed) 
No 
≥ 2 new lesions 
≥ 2 new lesions 
PD 
PD 
No 
≥ 2 new lesions 
< 2 new lesions  
non-PD 
PD 
No 
< 2 new lesions 
≥ 2 new lesions 
non-PD 
Non-PD 
No 
< 2 new lesions 
< 2 new lesions 
non-PD 
Non-PD 
No 
not done/missing 
Any 
Not Evaluable 
Not Evaluable 
No 
≥ 2 new lesions 
not done/missing 
Not Evaluable 
PD 
No 
< 2 new lesions  
any 
Non-PD 
Non-PD 
No 
Not done/missing  
any 
Not Evaluable 
Not Evaluable 
No 
not done/missing 
not done/missing 
Not Evaluable 
Not Evaluable 
Yes 
≥ 2 new lesions 
Any (confirmation not 
required since first 
bone scan was prior 
to 12 weeks) 
PD 
PD 
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First post-
baseline 
bone scan 
prior to 12 
weeks? 
Week 12 visit* 
Secondary 
Assessment (at least 
6 weeks after week 
12 visit) 
Bone Response 
(confirmed) 
Bone Response 
(unconfirmed) 
Yes 
< 2 new lesions 
Any 
non-PD 
Non-PD 
Yes 
not done/missing 
Any 
Not Evaluable 
Not Evaluable 
* 12 week visit window is defined as follows: If visit occurred under amendment 3, use 78 days  3 days; if 
visit occurred under amendment 4, use window of 78 days + 5 days. 
+This algorithm assumes subjects had bone lesions identified via bone scan at baseline. For subjects 
without bone lesions identified via Bone Scan at baseline, the confirmed and unconfirmed bone responses 
are set to missing. 
 
7.2.1.3. 
RECIST Response  
The determination of confirmed (and unconfirmed) radiographic response (PR, CR, and 
PD) at week 12 is based on RECIST v1.1 criteria (Table 1). The algorithm is well defined 
in the RECIST guidelines (Eisenhauer, 2009). Categories for response include: PD, non-
PD (CR, PR, SD, or non-CR/non-PD), NE, and missing (only if no baseline 
measurable/non-measurable lesions present). The unconfirmed response will also be 
assessed. 
According to PCWG2 criteria, radiological response at week 12 for subjects with 
baseline disease will be determined by RECIST 1.1 criteria assessed 12 weeks following 
initiation of GSK2636771 and enzalutamide combination treatment. Since CT/MRI 
tumour assessments were not scheduled at week 12, the week 16 assessments or the 
closest unscheduled CT/MRI assessment after week 12 will be used for week 12 RECIST 
response evaluation. 
7.2.1.4. 
Overall Response (at week 12) 
The overall response at week 12 will be used to determine the 12-week non-PD rate. 
Table 5 provides the algorithm for the derivation of the overall response assessed at 12 
weeks post treatment for subjects with or without measurable disease at baseline.  
Table 5 
Algorithm for Overall Response at Week 12  
Measurable/Non-Measurable 
Disease Identified at 
baseline? 
RECIST 
Response 
(RECIST 1.1) 
Bone Response  
at Week 12  
PSA 
Response  
at Week 12 
Overall 
Response at 
Week 12  
(PD/non-
PD/NE) 
Yes 
PD 
PD  
PD 
PD 
Yes 
PD 
PD  
Non-PD 
PD 
Yes 
PD 
PD  
NE 
PD 
Yes 
PD 
Non-PD  
PD 
PD 
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Measurable/Non-Measurable 
Disease Identified at 
baseline? 
RECIST 
Response 
(RECIST 1.1) 
Bone Response  
at Week 12  
PSA 
Response  
at Week 12 
Overall 
Response at 
Week 12  
(PD/non-
PD/NE) 
Yes 
PD 
Non-PD  
Non-PD 
PD (via target 
lesion) 
Yes 
PD 
Non-PD  
NE 
PD (via target 
lesions) 
Yes 
PD 
NE (missing data) 
PD 
PD 
Yes 
PD 
NE (missing data) 
Non-PD 
PD (via target 
lesions) 
Yes 
PD 
NE (missing data) 
NE 
PD (via target 
lesions) 
Yes 
PD 
no baseline bone 
lesions 
PD 
PD 
Yes 
PD 
no baseline bone 
lesions 
Non-PD 
PD (via target 
lesions) 
Yes 
PD 
no baseline bone 
lesions 
NE 
PD (via target 
lesions) 
Yes 
Non-PD 
PD  
PD 
PD 
Yes 
Non-PD 
PD  
Non-PD 
PD 
Yes 
Non-PD 
PD  
NE 
PD 
Yes 
Non-PD 
Non-PD  
PD 
Non-PD 
Yes 
Non-PD 
Non-PD  
Non-PD 
Non-PD 
Yes 
Non-PD 
Non-PD  
NE 
Non-PD 
Yes 
Non-PD 
NE (missing data) 
PD 
NE 
Yes 
Non-PD 
NE (missing data) 
Non-PD 
NE 
Yes 
Non-PD 
NE (missing data) 
NE 
NE 
Yes 
Non-PD 
no baseline bone 
lesions 
PD 
Non-PD 
Yes 
Non-PD 
no baseline bone 
lesions 
Non-PD 
Non-PD 
Yes 
Non-PD 
no baseline bone 
lesions 
NE 
Non-PD 
Yes 
NE 
PD  
PD 
 PD 
Yes 
NE 
PD  
Non-PD 
 PD 
Yes 
NE 
PD  
NE 
 PD 
Yes 
NE 
Non-PD  
PD 
 NE 
Yes 
NE 
Non-PD  
Non-PD 
 NE 
Yes 
NE 
Non-PD  
NE 
 NE 
Yes 
NE 
NE (missing data) 
PD 
 NE 
Yes 
NE 
NE (missing data) 
Non-PD 
 NE 
Yes 
NE 
NE (missing data) 
NE 
 NE 
Yes 
NE 
no baseline bone 
PD 
 NE 
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Measurable/Non-Measurable 
Disease Identified at 
baseline? 
RECIST 
Response 
(RECIST 1.1) 
Bone Response  
at Week 12  
PSA 
Response  
at Week 12 
Overall 
Response at 
Week 12  
(PD/non-
PD/NE) 
lesions 
Yes 
NE 
no baseline bone 
lesions 
Non-PD 
 NE 
Yes 
NE 
no baseline bone 
lesions 
NE 
 NE 
No 
- 
PD  
PD 
 PD 
No 
- 
PD  
Non-PD 
 PD 
No 
- 
PD  
NE 
 PD 
No 
- 
Non-PD  
PD 
PD 
No 
- 
Non-PD  
Non-PD 
 non-PD 
No 
- 
Non-PD  
NE 
 non-PD 
No 
- 
NE (missing data) 
PD 
PD 
No 
- 
NE (missing data) 
Non-PD 
Non-PD 
No 
- 
NE (missing data) 
NE 
NE 
No 
- 
no baseline bone 
lesions 
PD 
PD 
No 
- 
no baseline bone 
lesions 
Non-PD 
Non-PD 
No 
- 
no baseline bone 
lesions 
NE 
NE 
 Note: “-“ = “missing response” 
For subjects without measurable/non-measurable disease in baseline, the overall response 
will be determined on PSA response alone. 
Subjects with unknown or missing responses will be treated as having PD (i.e., subjects 
with NE will be included in the denominator but will not be included in the numerator 
when calculating the percentage of non-PD).  
7.2.2. 
Summary Measure 
12 week Non-PD Rate  
The number and percentage of participants with the non-PD will be summarized by dose. 
The corresponding exact 95% Confidence Interval (CI) will also be provided. Subjects 
with unknown or missing response will be treated as having PD (i.e., subjects with NE 
will be included in the denominator when calculating the percentage of non-PD). 
7.2.3. 
Population of Interest 
The primary efficacy analyses will be based on the All Treated Clinical Activity 
population, unless otherwise specified. All summaries will be presented by dose, and 
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overall. The full details of data listings, tables, and figures are presented in Appendix 12: 
List of Data Displays. 
7.2.4. 
Statistical Analyses / Methods 
Details of the planned displays are provided in Appendix 12: List of Data Displays and 
will be based on GSK data standards and statistical principles. 
Unless otherwise specified, endpoints / variables defined in Section 7.2.1 will be 
summarised using descriptive statistics, graphically presented (where appropriate) and 
listed. 
7.3. 
Secondary Efficacy Analyses 
7.3.1. 
Endpoint / Variables 
PSA and RECIST 1.1 response data will be reported.  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 PSA response data.  An exact 95% CI will be computed for the PSA50 
response rate and RECIST 1.1 confirmed response rate. 
Due to the small sample size in the 400 mg cohort (n=2), the radiographic Progression 
Free Survival (rPFS), time to PSA progression, and time to radiological progression for 
this cohort will not be summarized separately, however, it will be included in the overall 
summary. The cohort will also be included in the associated listings. 
Details of the planned displays are provided in Appendix 12: List of Data Displays and 
will be based on GSK data standards and statistical principles. 
Secondary 
Efficacy 
Endpoint 
Definition 
Analysis / Display  
PSA50 
Response 
Rate 
 
defined as proportion of subjects 
with a decrease of ≥50% in the 
PSA concentration from the 
baseline PSA value determined at 
least 12 weeks after start of 
treatment until last post-treatment 
follow-up visit or initiation of new 
anti-cancer therapy and 
confirmed after 3 or more weeks 
by an additional PSA evaluation. 
 
Confirmed and unconfirmed PSA changes will be 
categorized as follows: decline >=50%, PSA 
increase >=25% (PSA progression per PCWG2), 
No significant PSA change, and Not Evaluable. 
 
Confirmed and unconfirmed PSA50 response 
rate will be reported by dose level along with 
the exact 95% confidence interval.  
 
See Section 13.6.3 for algorithm details. 
 
Waterfall plots will be presented that show the 
maximum percentage of change in PSA from 
baseline. 
 
Spider plots will be presented to show percent 
change in PSA from baseline over time 
Best Overall 
Response 
defined as the best 
confirmed/unconfirmed response 
 
Confirmed and unconfirmed best overall response 
will be reported 
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Secondary 
Efficacy 
Endpoint 
Definition 
Analysis / Display  
(BOR) 
(Complete Response [CR] > 
Partial Response [PR] > Stable 
Disease [SD] [or non-CR/non-PD] 
> Progressive Disease [PD] > Not 
Evaluable [NE]) from combination 
treatment start date until disease 
progression or initiation of new 
anti-cancer therapy, whichever is 
earlier, as assessed by the 
investigator per RECIST 1.1 
Criteria. 
o 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 56 days 
 
RECIST 1.1 criteria requires that progression at 
first assessment be confirmed by a second scan 6 
or more weeks later 
 
 
Objective 
Response 
Rate (ORR) 
 
defined as the percentage of 
subjects with a confirmed 
complete response (CR) or a 
partial response (PR) as the 
BOR, as assessed by the 
investigator per RECIST 1.1 
criteria. 
 
The number and types of responses, as outlined in 
RECIST 1.1, will be listed and summarized 
separately, as appropriate. The investigator 
observed ORR, confirmed and unconfirmed, will 
be reported at the interim and final analysis for 
each cohort specified in treated dose, if data 
warrant. The estimates along with 95% exact 
confidence interval (CI) will be provided. 
 
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. 
Radiographic 
Progression-
free survival 
(rPFS) 
defined as the interval of time (in 
weeks) between the date of first 
dose of GSK2636771 and the 
earlier of the date of disease 
progression as assessed by the 
investigator per RECIST 1.1 
criteria and the date of death due 
to any cause. Determination of 
dates of PFS events and dates 
for censoring are described in 
Table 6 
 
 
The date of disease progression will be defined as 
the earliest date of disease progression as 
assessed by the investigator using RECIST 1.1 
criteria or progression on bone scan. 
• 
RECIST 1.1 criteria requires that progression 
at first assessment be confirmed by a second 
scan 6 or more weeks later. If no scans are 
available after the first assessment, the 
subject should be censored on the date of 
their first assessment. 
• 
See Table 1, Bone Response, for definition of 
progression on bone scan. Bone progression 
at first assessment requires confirmation by a 
second scan 6 or more weeks later that 
shows a minimum of 2 or more additional new 
lesions. If no second scan is available, the 
subject should be censored on the date of 
their first assessment. 
 
rPFS will be summarized by dose level using 
Kaplan-Meier quantile estimates along with 2-
sided 95% CIs.  
Time to PSA 
defined as the time from 
combination study treatment start 
 
See Table 1 for definition of PSA progression per 
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Secondary 
Efficacy 
Endpoint 
Definition 
Analysis / Display  
progression  
 
until the first PSA progression 
(confirmed if there has been a 
PSA decline from baseline) 
 
PCWG2. 
 
Time to PSA progression will be summarised 
using Kaplan-Meier methods (plots and 
summarize table on medians and quartiles) by 
dose level. 
Time to 
radiological 
progression 
defined as the time from 
combination study treatment start 
until the first radiological 
progression by RECIST 1.1 and/ 
or confirmed bone progression. 
 
The date of disease progression will be defined as 
the earliest date of disease progression as 
assessed by the investigator using RECIST 1.1 
criteria or progression on bone scan. 
• 
RECIST 1.1 criteria requires that progression 
at first assessment be confirmed by a second 
scan 6 or more weeks later. If no scans are 
available after the first assessment, the 
subject should be censored on the date of 
their first assessment. 
• 
See Table 1, Bone Response, for definition of 
progression on bone scan. Bone progression 
at first assessment by bone scan requires 
confirmation by a second bone scan 6 or 
more weeks later that shows a minimum of 2 
or more additional new lesions. If no second 
scan is available, the subject should be 
censored 
on 
the 
date of 
their 
first 
assessment. 
 
Time to radiological progression will be 
summarised using Kaplan-Meier methods (plots 
and summary table on medians and quartiles) by 
dose level. 
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Table 6 
Censoring Rules for rPFS Analysis 
Censoring Rules 
Scenario 
Date of Event (Progression/Death) or Censoring 
Event 
(Progression/Death) 
or Censoring 
No adequate baseline tumour assessments (MRI/CT or Bone 
Scan) and the subject has not died 
First Dose Date  
Censored 
No post-baseline tumour assessments and the subject has not 
died (if the subject has died follow the rules for death indicted at 
the bottom of the table) 
First Dose Date 
Censored 
Progression documented between scheduled visits 
Date of assessment of progression1 
Event 
With adequate post-baseline assessment and no progression 
(or death)  
Date of last ‘adequate’ assessment of response2 
Censored 
No adequate post-baseline assessment before start of new 
anticancer therapy 
First dose date 
censored 
With adequate post-baseline assessment and new anticancer 
treatment started (prior to documented disease progression).  
Date of last ‘adequate’ assessment of response2 (on or prior to starting anti-
cancer therapy)  
Censored 
Death before first PD assessment (or Death at baseline or 
prior to any adequate assessments) 
Date of death 
Event 
Death between adequate assessment visits  
Date of death 
Event 
Death or progression after more than one missed visit 
Date of last ‘adequate’ assessment of response2 (prior to missed 
assessments)): Since the disease assessment is every 8 weeks, a window 
of 119 days (16 weeks + 3-day window) will be used to determine whether 
there is extended time without adequate assessment. If the time difference 
between PD/death and last adequate disease assessment is more than 119 
days, PFS will be censored at the last adequate disease assessment prior 
to PD/death. 
Censored 
NOTES : 
1 The earliest of (i) Date of radiological assessment showing new lesion (if progression is based on new lesion); or (ii) Date of radiological assessment showing unequivocal progression 
in non-target lesions, or (iii) Date of last radiological assessment of measured lesions (if progression is based on increase in sum of measured lesions) 
2 An adequate assessment is defined as an assessment where the response is CR, PR, or SD. 
3 If PD and New anti-cancer therapy occur on the same day, assume the progression was documented first (e.g. outcome is progression and the date is the date of the assessment of 
progression). If anti-cancer therapy is started prior to any adequate assessments, censoring date should be the date of randomization. 
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7.3.2. 
Summary Measure 
PSA50 Response Rate 
The proportion of subjects with a decrease of ≥50% in the PSA concentration from the 
baseline PSA value will be categorized as follows: decline >=50%, PSA increase >=25% 
(PSA progression per PCWG2), No significant PSA change, and Not Evaluable. 
Confirmed and unconfirmed PSA50 response rate will be reported by dose level and 
overall along with the exact 95% confidence interval. See Section 13.6.3 for algorithm 
details. 
ORR  
The number and percentage of participants with the BOR in the following response 
categories at [timepoint] will be summarized by dose and overall: CR, PR, overall 
response (CR+PR), SD or Non-CR/Non-PD, PD and NE. The corresponding exact 95% 
CI for ORR will also be provided. Participants with unknown or missing responses will 
be treated as non-responders, i.e., these participants will be included in the denominator 
when calculating percentages of response. 
Time to PSA Progression 
Time to progression will be summarized descriptively by dose (200 mg and 300 mg doses 
only) and overall using median(s) and quartiles in the subset of subjects with PSA 
progression.  
Time to Radiological Progression 
Time to progression at will be summarized descriptively by dose (200 mg and 300 mg 
doses only) and overall using median(s) and quartiles in the subset of subjects with 
radiological progression.  
Radiological Progression Free Survival (rPFS) 
The distribution of PFS for each dose (200 mg and 300 mg doses only) and overall will 
be estimated using the Kaplan-Meier method. The median, 25th and 75th percentiles of 
PFS will be estimated and corresponding 95% confidence intervals will be estimated 
using the Brookmeyer-Crowley method (1982). PFS rate and corresponding 95% CI will 
also be estimated from the Kaplan-Meier analysis.  
7.3.3. 
Population of Interest  
The secondary efficacy analyses will be based on the All Treated Clinical Activity 
population, unless otherwise specified. 
7.3.4. 
Statistical Analyses / Methods 
Details of the planned displays are provided in Appendix 12: List of Data Displays and 
will be based on GSK data standards and statistical principles. 
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Unless otherwise specified, endpoints / variables defined in Section 7.3.1 will be 
summarised using descriptive statistics, graphically presented (where appropriate) and 
listed. No additional statistical analysis will be performed. 
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8. 
SAFETY ANALYSES 
8.1. 
Overview of Planned Analyses 
The safety analyses will be based on the All Treated Safety population, unless otherwise 
specified, and all summaries and data listings will use treatment labels as specified in 
Section 5.1. All summaries will be presented by Enzalutamide run-in, combination 
treatment by dose level, and combination total. 
Details of data displays are presented in Appendix 12: List of Data Displays 
8.2. 
Extent of Exposure 
Dose intensity: Average daily dose on study, cumulative dose of the combination 
treatment will be summarised with mean, median, standard deviation, minimum, and 
maximum. The cumulative duration of exposure to the combination treatment in weeks 
(from first day to last day of   treatment plus 1 day) will also be summarised.  
Reductions, escalations, and interruptions will be summarised by number of 
modifications and reasons for modifications for Enzalutamide and GSK2636771 
separately. The summaries of dose modifications will be provided only if the data 
warrant. All the dose reductions, dose escalations and dose interruptions will be listed 
separately.  
8.3. 
Adverse Events Analyses 
Adverse events analyses including the analysis of adverse events (AEs), Serious (SAEs) 
and other significant AEs will be based on GSK Core Data Standards. Details on 
treatment emergent AEs are provided in Section 13.4.2. Dose modifications (, dose 
interruptions, dose reductions and dose escalations) and Dose limiting toxicity (DLT) will 
also be summarized and listed according to GSK Oncology Data Standards. 
In addition, a trellis display of subject profiles will be produced that displays individual 
subject data for renal function tests (correct calcium, magnesium, phosphorous, 
creatinine, PTH) over time within the same panel for all subjects, along with information 
regarding age, bone metastasis at baseline, denosumab received within 6 months prior to 
study, denosumab received during study. 
The full details of the planned displays are provided in Appendix 12: List of Data 
Displays.  
8.4. 
Adverse Events of Special Interest (AESI) Analyses 
A comprehensive list of MedDRA terms based on clinical review will be used to identify 
each type of event. Changes to the MedDRA dictionary may occur between the start of 
the study and the time of reporting and/or emerging data from on-going studies may 
highlight additional adverse events of special interest, therefore the list of terms to be 
used for each event of interest and the specific events of interest will be based on the 
safety review team (SRT) agreements in place at the time of reporting. The list is below: 
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 
Hypocalcaemia 
 
Increase in Creatinine 
8.5. 
Clinical Laboratory Analyses 
Laboratory evaluations including the analyses of Chemistry laboratory tests, 
Haematology laboratory tests, Urinalysis, and liver function tests will be based on GSK 
Core Data Standards. The details of the planned displays are in Appendix 12: List of Data 
Displays. 
8.6. 
Other Safety Analyses 
The analyses of non-laboratory safety test results including ECGs and vital signs will be 
based on GSK Core Data Standards, unless otherwise specified. LVEF and Performance 
status will be summarized and listed based on GSK Oncology Data Standard. The details 
of the planned displays are presented in Appendix 12: List of Data Displays. 
8.6.1. 
Deaths and Serious Adverse Events  
All deaths will be summarised based on the number and percentage of subjects. This 
summary will classify subjects by time of death relative to the last dose of medication 
(>30 days or 30 days) and primary cause of death (disease under study, SAE related to 
study treatment, or other). A supportive listing will be generated to provide subject-
specific details on subjects who died.  
All SAEs will be tabulated based on the number and percentage of subjects who 
experienced the event. The summary table will be displayed in descending order of total 
incidence by Preferred Term only. 
SAEs will also be summarized by maximum toxicity grade. Relevant serious adverse 
events will be displayed by preferred term and will be sorted in descending order based 
on total incidence in each treatment group. 
SAEs are included in the listing of all adverse events. Separate supportive listings with 
subject-level details will be generated for 
 
Fatal SAEs  
 
Non-Fatal SAEs. 
8.7. 
Pregnancies 
A listing of pregnancies will be generated if there was any female partner of the male 
subjects become pregnant during the study. 
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9. 
PHARMACOKINETIC ANALYSES 
Pharmacokinetic analysis will be the combined responsibility of GSK Clinical 
Pharmacology Modelling and Simulation Department and GSK Discovery Biometrics 
and Clinical Statistics.  
The merge of PK concentration data, randomisation and eCRF data will be performed by 
Clinical Statistics (Programmer).   
9.1. 
Primary Pharmacokinetic Analyses 
There were no primary pharmacokinetic endpoints defined in the objectives for this 
study. 
9.2. 
Secondary Pharmacokinetic Analyses 
9.2.1. 
Endpoint / Variables 
9.2.1.1. 
Drug Concentration Measures 
Refer to Appendix 5: Data Display Standards & Handling Conventions (Section 13.5.3 
Reporting Standards for Pharmacokinetic). 
Concentration-time data for GSK2636771, enzalutamide and N-desmethyl enzalutamide 
from the Dose Escalation Phase will be listed and summarized. In addition, 
concentration-time figures will be presented.   
 
The following secondary objectives will be displayed graphically:  
 The PK of enzalutamide and N-desmethyl enzalutamide following repeat-dose 
oral administration with and without GSK2636771, and 
 The PK of GSK2636771 in the presence of enzalutamide. 
 
9.2.2. 
Population of Interest  
The pharmacokinetic (PK) analyses will be based on the PK Concentration population, 
unless otherwise specified. 
 
9.2.3. 
Statistical Analyses / Methods 
No formal statistical analysis will be performed.  
   
 
 
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10. 
BIOMARKER ANALYSES 
10.1. 
Exploratory Biomarker Analyses 
10.1.1. 
Endpoint / Variables 
10.1.1.1. 
Circulating Tumour Cells 
CTC response rate will be performed, which is defined as percent of subjects having 
favourable (CTC <5/7.5 mL of blood) at nadir, if baseline is unfavourable 
(CTC≥5/7.5mL of blood). Conversions from baseline number of CTCs using the 
CellSearch platform in blood samples will be summarized and listed as part of this RAP.  
If data warrant, additional analysis of CTC will be discussed as part of a RAP 
supplement; i) Analysis of baseline CTC with clinical outcome (time on treatment and 
PSA changes  
10.1.1.2. 
Frequency of PTEN loss and Mechanism of PTEN Loss 
The frequency of PTEN loss is defined as the proportion of subjects that were tested by 
central PTEN testing that were identified as PTEN-deficient. The number of tumour 
biopsy samples with a Histo-score (H score) of 30 and less will be compared with the 
total number of tumour biopsy samples that were analysed by central PTEN testing to 
evaluate the frequency of PTEN loss in mCRPC for this study.  
The H-Score of all enrolled subjects will be compared to molecular sequencing of tumour 
biopsy sample to understand the mechanism(/s) of PTEN loss. 
10.1.1.3. 
Mutational Analysis of Tumour Biopsy Sample 
Mutational analysis of screening tumour biopsy samples will be analysed to understand 
gene mutations of mCRPC subjects enrolled in this study and to evaluate the frequency of 
PTEN homozygous loss. Gene mutations include, small nuclear variant (SNV), copy 
number variation (gene deletion and gene amplification) and gene fusions.  
10.1.2. 
Summary Measure 
1. CTC response rate is defined as any conversion from ≥5 at baseline to <5 over the 
course of the study. Data will be presented as a single line in a table, for each 
subject.  
2. PTEN:  
a. Frequency of PTEN loss by PTEN IHC (H-Score ≤ 30) in all screened 
subjects. 
b. Homozygous or heterozygous PTEN loss based on Foundation Medicine 
analysis 
3. Heatmap representation of all SNV, CNV, gene fusion and indels of genes in the 
475 gene panel from Foundation Medicine (n=16 subjects).   
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10.1.3. 
Population of Interest 
The exploratory biomarker analyses will be based on the  All Screened and/or Biomarker 
population, unless otherwise specified. 
10.1.4. 
Statistical Analyses / Methods 
Details of the planned displays are provided in Appendix 12: List of Data Displays and 
will be based on GSK Data Standards and statistical principles. 
Unless otherwise specified, endpoints / variables defined in Section 10.1.1 will be 
summarised using descriptive statistics, graphically presented (where appropriate) and 
listed. 
 
 
 
 
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11. 
PHARMACOKINETIC / PHARMACODYNAMIC 
ANALYSES 
For this study no on treatment biopsy samples were obtained for Pharmacodynamic 
analysis. Therefore, no PD analysis can be done for this study.  
If data warrant, the pharmacokinetic / pharmacodynamic relationship of GSK2636771 
administered in Male Subjects with Metastatic Castration-Resistant Prostate Cancer 
(mCRPC) may be explored. The influence of subject demographics and baseline 
characteristics, including disease activity in this population will be investigated. 
Further details of PK/PD analyses will be described under a separate RAP. Results of the 
PK/PD analyses may be included in a report separate from the clinical study report 
(CSR). 
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12. 
REFERENCES 
Brookmeyer R, Crowley J. A confidence interval for the median survival time. 
Biometrics, 1982; 38:29-41. 
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, 
Arbuck S, Gwyther S, Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, 
Lacombe D, Verweij J.  New response evaluation criteria in solid tumours:  Revised 
RECIST guidelines (version 1.1).  European Journal of Cancer. 2009;45:228-247. 
Lee JJ, Liu DD. A predictive probability design for phase II cancer clinical trials. Clinical 
Trials. 5(2):93-106. 2008 
Scher HI, Halabi S, Tannock I, et al. Design and End Points of Clinical Trials for Patients 
With Progressive Prostate Cancer and Castrate Levels of Testosterone: 
Recommendations of the Prostate Cancer Clinical Trials Working Group. J Clin Oncol. 
2008;26:1148-1159. 
 
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13. 
APPENDICES 
13.1. 
Appendix 1: Protocol Deviation Management and Definitions 
for Per Protocol Population 
13.1.1. 
Exclusions from Per Protocol Population 
No exclusions are noted. 
 
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13.2. 
Appendix 2: Schedule of Activities 
13.2.1. 
Protocol Defined Schedule of Events 
Table 7 
Time and Events Table for Dose Escalation Phase 
See following page. 
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Study Assessments1,2 
Pre-Screening 
Screening 
Enzalutamide 
Run-In 
Period 
Combination Treatment Period  
(DLT Reporting Period) 
Treatment Continuation 
Period 
Time of Discontinuation of 
Treatment due to Disease 
Progression31 
Post-Treatment Follow-Up 
Visit28 
Extended 
Follow-Up  
Visits29 
Post-
Extende
d Follow-
Up 
/EOS 
Visit30 
 
 
Day -14 
to 
Day -1 
Day 1 to Day 
14 
Wk 1, 
Day 1 
Wk 2, 
Day 8 
Wk 3, 
Day 
15 
Wk 4, 
Day 
22 
Week 
5, Day 
29 
Week 8 and every 4 
weeks thereafter 
 
 
Every 3 
months 
 
Visit Window 
 
 
 
+1 
day 
1 
day 
1 
day 
1 
day 
1 
day 
+5days Week 12 only; 
3 days for all other 
visits 
+1 
day 
-2/+7 
days 
14  
days 
3  
days 
Clinical Assessments 
Informed Consent 
X3 
X4 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Determination of PTEN 
Deficiency Status 
M5 
 
 
 
 
 
 
 
 
 
 
 
 
Safety Assessments 
ECOG PS 
 
X 
 
X 
 
X 
X 
X 
Week 8 and then 
Q8wks 
X 
X 
 
X 
Physical Exam 
 
X 
 
X 
 
 
 
 
Week 8 and then 
Q8wks 
 
X 
 
X 
Height8 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Weight 
 
X 
 
X 
 
 
 
 
Week 8 and then 
Q8wks 
 
X 
 
X 
Vital Signs9 
 
X 
 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
12-Lead ECG10 
 
X6 
 
 
 
 
X 
 
Week 8 and then 
Q8wks 
 
X 
 
X 
ECHO/MUGA 
 
X6,7 
 
As clinically indicated 
 
 
 
 
AE Monitoring 
 
 
Continuous 
X11 
X11 
 
 
Concomitant Medications 
 
X 
Continuous 
 
X 
 
 
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Study Assessments1,2 
Pre-Screening 
Screening 
Enzalutamide 
Run-In 
Period 
Combination Treatment Period  
(DLT Reporting Period) 
Treatment Continuation 
Period 
Time of Discontinuation of 
Treatment due to Disease 
Progression31 
Post-Treatment Follow-Up 
Visit28 
Extended 
Follow-Up  
Visits29 
Post-
Extende
d Follow-
Up 
/EOS 
Visit30 
 
 
Day -14 
to 
Day -1 
Day 1 to Day 
14 
Wk 1, 
Day 1 
Wk 2, 
Day 8 
Wk 3, 
Day 
15 
Wk 4, 
Day 
22 
Week 
5, Day 
29 
Week 8 and every 4 
weeks thereafter 
 
 
Every 3 
months 
 
Visit Window 
 
 
 
+1 
day 
1 
day 
1 
day 
1 
day 
1 
day 
+5days Week 12 only; 
3 days for all other 
visits 
+1 
day 
-2/+7 
days 
14  
days 
3  
days 
Laboratory Assessments12 
Hematology/ 
Clinical Chemistry 
 
X6 
 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
Ionized Calcium 
 
X6 
 
X33 
X 
X 
X 
X 
X 
 
X 
 
X 
Vitamin D34 
 
X6 
 
 
 
 
X 
 
 
 
X 
 
X 
Coagulation:  
PT, PTT, INR 
 
X6 
  
X 
 
 
X 
 
 
 
 
 
 
Liver function Tests 
 
X6 
 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
Urinalysis13 
Urine Microscopy13 
UPC14 
 
X6 
 
X 
 
 
X 
 
X 
 
X 
 
X 
Urine Electrolytes15 
 
X6 
 
X33 
 
X 
X 
 
Week 8 and then 
Q8wks 
 
X 
 
 
Parathyroid Hormone 
 
 
 
X 
As clinically indicated16 
 
 
 
 
Bone Markers35 
 
 
 
X 
 
 
 
X 
Weeks  12 and  24 
 
X 
 
X 
PSA and LDH32 
 
X6 
  
X 
 
 
  
 
X 
X 
X 
 
X 
Serum Testosterone 
 
X6 
  
 
 
 
 
 
 
 
X 
 
X 
PK Assessments 
 PK Blood Sampling17 
 
 
 
  
 
 
  
X 
Weeks 8 and 12 
 
 
 
 
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Study Assessments1,2 
Pre-Screening 
Screening 
Enzalutamide 
Run-In 
Period 
Combination Treatment Period  
(DLT Reporting Period) 
Treatment Continuation 
Period 
Time of Discontinuation of 
Treatment due to Disease 
Progression31 
Post-Treatment Follow-Up 
Visit28 
Extended 
Follow-Up  
Visits29 
Post-
Extende
d Follow-
Up 
/EOS 
Visit30 
 
 
Day -14 
to 
Day -1 
Day 1 to Day 
14 
Wk 1, 
Day 1 
Wk 2, 
Day 8 
Wk 3, 
Day 
15 
Wk 4, 
Day 
22 
Week 
5, Day 
29 
Week 8 and every 4 
weeks thereafter 
 
 
Every 3 
months 
 
Visit Window 
 
 
 
+1 
day 
1 
day 
1 
day 
1 
day 
1 
day 
+5days Week 12 only; 
3 days for all other 
visits 
+1 
day 
-2/+7 
days 
14  
days 
3  
days 
Disease Assessments18 
CT scan or MRI19 
 
X6,7 
 
 
 
 
 
 
Week 8 and then 
Q8wks to Week 48; 
then Q12wks 
X 
 
X 
 
Chest X-ray or Chest CT 
scan 
 
X6,7 
 
 
 
 
 
 
 
 
 
 
 
Bone Scan20 
 
X6,7 
 
 
 
 
 
 
Week 12 and then 
Q12wks 
X 
 
X 
 
Biomarker Assessments 
CTC – Janssen21 
 
X 
 
X 
 
 
X 
 
Weeks 8, 16, 24, and 
32 
X 
 
 
 
CTC – EPIC22 
 
X 
 
 
 
 
 
 
Week 8 only 
X 
 
 
 
Predictive Biomarker: 
Tumor Tissue23 
 
  
 
X 
 
 
 
 
 
 
 
 
 
Progression Tumor 
Biopsy24 
 
 
 
 
 
 
 
 
 
X 
 
 
 
Tumor Biopsies for 
Pharmacodynamics24 
 
 
X (Day 14) 
 
X24 
 
 
 
 
 
 
 
 
cfDNA/RNA/Soluble 
Markers25 
 
X 
 
X 
 
 
X 
 
Weeks 8, 16, 24, and 
32 
X 
 
 
 
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Study Assessments1,2 
Pre-Screening 
Screening 
Enzalutamide 
Run-In 
Period 
Combination Treatment Period  
(DLT Reporting Period) 
Treatment Continuation 
Period 
Time of Discontinuation of 
Treatment due to Disease 
Progression31 
Post-Treatment Follow-Up 
Visit28 
Extended 
Follow-Up  
Visits29 
Post-
Extende
d Follow-
Up 
/EOS 
Visit30 
 
 
Day -14 
to 
Day -1 
Day 1 to Day 
14 
Wk 1, 
Day 1 
Wk 2, 
Day 8 
Wk 3, 
Day 
15 
Wk 4, 
Day 
22 
Week 
5, Day 
29 
Week 8 and every 4 
weeks thereafter 
 
 
Every 3 
months 
 
Visit Window 
 
 
 
+1 
day 
1 
day 
1 
day 
1 
day 
1 
day 
+5days Week 12 only; 
3 days for all other 
visits 
+1 
day 
-2/+7 
days 
14  
days 
3  
days 
Biomarker Assessments continued 
Blood Sample for 
Genetic Research26 
 
 
 
X 
 
 
 
 
 
 
 
 
 
Study Treatments27 
Enzalutamide 
 
  
Continuous 
Continuous 
 
 
 
 
GSK2636771 
 
 
 
Continuous 
 
 
 
 
Abbreviations: AE, adverse event; cfDNA, circulating-free tumor DNA; CT, computed tomography; CTC, circulating tumor cells; ECG, electrocardiogram; ECHO, echocardiogram; 
ECOG, Eastern Cooperative Oncology Group; EOS, End of Study; HbA1C, hemoglobin A1C; INR, international normalization ratio; M, mandatory; MRI, magnetic resonance imaging; 
MUGA, multigated acquisition scan; O, optional; PD, pharmacodynamics; PK, pharmacokinetics; PS, performance status; PSA, prostate-specific antigen; PT, prothrombin time; PTEN, 
phosphatase and tensin homolog; PTH, parathyroid hormone; PTT, partial thromboplastin time; Q4wks, every 4 weeks; Q8wks, every 8 weeks; Q12wks, every 12 weeks; UPC, 
urine:protein:creatinine; Wk(s), week(s) 
 
1. 
Study Assessments: All assessments may be performed more frequently if clinically appropriate. Assessments scheduled on days of dosing should be completed prior to the 
administration of study treatments, unless otherwise specified 
2. 
Study Assessments: Assessments throughout the study are calendar based starting from Week 1, Day 1 of the Combination Treatment Period (the first dose of combination 
treatment).  Dose interruptions should not alter the assessment schedule for any subsequent treatment period. 
3. 
Pre-Screening Informed Consent: Separate pre-screening informed consent must be obtained prior to initiation of any pre-screening procedures or assessments. 
4. 
Screening Informed Consent: Informed consent must be obtained prior to initiation of any screening procedures or assessments.. 
5. 
PTEN Deficiency Status (Mandatory): Tumor tissue samples (archived or fresh tumor tissue obtained by pre-treatment biopsy) will be collected to determine PTEN deficiency 
status of the tumor by the designated central laboratory.  Refer to the SRM for details about the number of slides to be submitted, preparation, handling and shipping.  Results of 
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the PTEN deficiency testing from the central laboratory only will be used to determine if the subject is eligible to continue Screening.  Only subjects with PTEN deficient tumor 
based on central laboratory testing results will be screened.  Any remaining tumor tissue may be used for other predictive biomarker analyses if consent has been obtained. 
6. 
Screening: When possible, screening assessments that require imaging, ECG, ECHO/MUGA, or laboratory studies should be performed AFTER PTEN status has been 
determined. 
7. 
Screening: All screening assessments must be completed and all entry criteria must be met prior to assessments on Day 1 of Enzalutamide Run-In Period.  EXCEPTION:  
ECHO/MUGA must be completed within 28 days of enrollment (Day 1 of Enzalutamide Run-In Period), and disease assessment must be completed within 28 days (35 days if MRI 
is used) prior to enrollment (Day 1 of the Enzalutamide Run-In Period). 
8. 
Height is only measured at Screening. 
9. 
Vital Signs:  Blood pressure, temperature and heart rate will be measured.  Vital signs may be measured more frequently if clinically warranted. 
10. ECG: A single 12-lead ECG is to be performed before vital signs are measured and any blood draws, if assessments are planned at the same nominal time point. 
11. AE Monitoring: Continued monitoring of AEs applies only to ongoing events at time of treatment discontinuation. 
12. Laboratory Assessments: Refer to Section 8.6.6 in protocol for list of specific laboratory tests to be performed.  Assessments may be performed within 24 hrs prior to scheduled 
visit (liver function tests and urine tests for UPC may be performed up to 72 hrs prior to a scheduled visit) to ensure availability of results. 
13. Urinalysis and Urine Microscopy:  Urinalysis and urine microscopy will be performed at the time points indicated. Assessments may be performed within 24 hrs prior to a 
scheduled visit to ensure availability of results. 
14. UPC:  Urine sample for UPC is to be collected at the time points indicated. Perform UPC with the first morning urine specimen (if possible) when urine dipstick protein 2+.  Urine 
samples for UPC may be collected up to 72 hrs prior to a scheduled visit to ensure that results are available at time of visit.  If the urine sample collected at Screening is 
contaminated with other bodily fluids, UPC will not be determined and subject will remain eligible for the study. 
15. Urine Electrolytes:  Urine samples will be obtained at Screening, pre-dose on Day 1 (Week 1), Day 3 OR Day 4, Day 15 (Week 3), Day 22 (Week 4) of the Combination 
Treatment Period, Week 8 and then every 8 weeks ( 3 days) thereafter during the Treatment Continuation Period, and at the post-treatment follow-up visit to determine urine 
electrolytes (magnesium, phosphorus and calcium) and urine creatinine. 
16. Parathyroid Hormone (PTH): Assessment of PTH will be performed if a Grade 2 or higher hypocalcemia or hypophosphatemia is reported. 
17. PK Blood Sampling:  Day 14 (Enzalutamide Run-In Period): Plasma samples for analysis of enzalutamide and N-desmethyl enzalutamide will be collected at pre-dose and 0.5, 
1, 2, 3, 4, and 6 hrs post-dose on Day 14 of Enzalutamide Run-In Period, the day prior to administration of the first dose of combination study treatment (GSK2636771 and 
enzalutamide). Week 5, Day 29 (Treatment Continuation Period): Blood and plasma samples for analysis of GSK2636771, enzalutamide and N-desmethyl enzalutamide will be 
collected at pre-dose and 0.5, 1, 2, 3, 4, and 6 hrs post-dose. Actual date and time of sample collection and dosing of study treatments must be recorded.  Explanations are 
required for any deviations of more than 5 minutes from the planned time during the first 2 hrs and for deviations of more than 20 minutes from the planned time for samples 
collected at 3 hrs up to 6 hrs post-dose.  Week 8 and Week 12 (Treatment Continuation Period): Blood and plasma samples for analysis of GSK2636771, enzalutamide and N-
desmethyl enzalutamide will be collected pre-dose only. 
18. Disease Assessments: Disease assessments at Screening must be performed within 28 days prior to enrollment (Day 1 of the Enzalutamide Run-In Period), or within 35 days 
prior to enrollment (Day 1 of the Enzalutamide Run-In Period if disease assessment is performed by MRI, to identify target and non-target lesions. 
19. CT scan or MRI:  Scans should be performed at Screening, Week 8 and then every 8 weeks (7 days) during the first 48 weeks of the Treatment Continuation Period and then 
every 12 weeks (7 days) thereafter in the Treatment Continuation Period, and at the time of disease progression.  All confirmatory scans are to be performed within 4 weeks 
(3 days) of a CR or PR.  If a subject discontinues treatment for reasons other than disease progression, disease assessments should continue every 3 months until disease 
progression, initiation of new anti-cancer treatment, subject withdrawal of consent, or death. 
20. Bone Scan:  A bone scan is required for all subjects at Screening.  For subjects without bone disease at baseline, subsequent bone scans should be performed as clinically 
indicated.  Subjects with bone metastases at baseline should have a bone scan performed at Week 12 and then every 12 weeks (7 days) thereafter in the Treatment 
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Continuation Period, or as clinically indicated, and at the time of disease progression.  If a subject discontinues treatment for reasons other than disease progression, bone scans 
should continue every 3 months until disease progression, initiation of new anti-cancer treatment, subject withdrawal of consent, or death. 
21. CTC-Janssen:  Whole blood samples will be obtained at Screening; pre-dose on Day 1 (Week 1) and Day 22 (Week 4) of the Combination Treatment Period; pre-dose on Day 1 
of Weeks 8, 16, 24 and 32 of the Treatment Continuation Period; and at time of disease progression. 
22. CTC-EPIC:  Whole blood samples will be obtained at Screening, pre-dose on Day 1 of Week 8 of the Treatment Continuation Period, and at the time of disease progression for 
protein and genomic analysis. 
23. Predictive Biomarkers Tumor Tissue:  For subjects enrolled into the study, additional slides of tumor tissue samples will be collected and submitted to the designated laboratory 
for analysis once a subject has received their first dose of GSK2636771 on Week 1, Day 1 of the Combination Treatment Period.  Tumor tissue may be obtained from archived 
tissue samples or fresh tumor tissue submitted for the PTEN testing.  If additional tumor tissue is not available, no new biopsy procedure is required for predictive biomarker 
analysis.  Refer to the SRM for details about the number of slides to be submitted, preparation, handling and shipping. 
24. Tumor Biopsies for PD and progression: These biopsies are optional and may be undertaken in select cases upon agreement with the investigator and when consent is 
provided by the subject. For pharmacodynamic biomarker analyses, fresh tissue biopsies would be collected between Day 12 of the Enzalutamide Run-in Period and Week 
1/Day 1, prior to any treatment with GSK2636771, and 2-4 hours post dose between Days 8 and 15 of the Combination Treatment Period (post-treatment).  For subjects who 
consent to the optional progression biopsy, a fresh tumor biopsy should be completed if the subject initially responded to combination treatment and then progressed. 
25. cfDNA/RNA/Soluble Markers:  Plasma samples will be obtained from collected blood samples at Screening, pre-dose on Weeks 1, 4, 8, 16, 24, and 32 of the Combination 
Treatment Period, and at the time of treatment discontinuation due to disease progression.  Plasma will be analyzed for genomic changes in the circulating tumor DNA, RNA, and 
soluble markers. 
26. Genetic Research: A 6-mL blood sample should be collected after Screening, preferably on Week 1, Day 1 of the Combination Treatment Period, if informed consent has been 
obtained for genetic research. 
27. Study Treatment: Enzalutamide monotherapy should be taken once daily during the Enzalutamide Run-In Period.  Enzalutamide will be self-administered in the clinic on Day 14 
of the Enzalutamide Run-In Period.  GSK2636771 and enzalutamide will be administered in the clinic on Week 1, Day 1 of the Combination Treatment Period and on days when 
blood, plasma, and/or urine samples are collected for analysis of PK, CTC, and/or urine electrolytes. 
28. Post-Treatment Follow-Up Visit:  ONLY subjects who withdraw during the Enzalutamide Run-In Period or withdraw from study treatment due to  disease progression (see 
Section 5.2 in protocol) should have a post-treatment follow-up visit conducted within approximately 30 days (-2/+7 days) of last dose of study treatment(s).  If a subject 
is unable to return to the clinic due to hospitalization, site staff is encouraged to call subject for assessment of AEs.   
29. Extended Follow-Up Visits:  Subjects who withdraw from study treatment without disease progression should be contacted every 3 months (14 days) until disease 
progression, death, withdrawal of consent, or subject is lost to follow-up.  Contact may include a clinic visit, a telephone contact, or an e-mail.  The initiation of any new anti-cancer 
treatments and date of last contact should be documented. 
30. Post-Extended Follow-Up/EOS Visit:  ONLY subjects who discontinue the Extended Follow-Up Visits should have a Post-Extended Follow-Up/EOS Visit performed. 
31. Subjects are not required to discontinue treatment on the basis of PSA progression alone or for the worsening of an isolated disease site that is not clinically significant (see 
Section 5.2 in protocol) 
32. When collected as part of the routine standard of care for a subject, LDH will be reported. 
33. Complete clinical chemistries laboratory assessments at Week1/Day 1 and again on either Day 3 or Day 4.  The Day 3 or Day 4 assessments can be completed at a local 
laboratory and does not require a clinic visit.  The hematology panel does NOT need to be collected on Day 3/ Day.4. Review of these labs must occur before Week 2, Day 1 visit.  
34. Includes assessments for 25-OH D and 1,25-OH2 D.  
35. Includes urine and blood and/or serum samples.  Must be collected at the same time of day (1 hour) to eliminate diurnal effects, and after fasting.  See SRM for additional details 
on the specific assessments and sample collection.   
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Table 8 
Time and Events Table for Dose Expansion Phase  
See following page. 
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Study Assessments1,2 
Pre-Screening 
Screening 
Enzalutamide 
Run-In 
Period 
Combination Treatment Period 
(DLT Reporting Period) 
Treatment Continuation 
Period 
Time of Discontinuation of 
Treatment due to Disease 
Progression31 
Post-Treatment Follow-Up 
Visit28 
Extended 
Follow-Up  
Visits29 
Post-
Extended 
Follow-Up 
/EOS 
Visit30 
 
 
Day -14 
to 
Day -1 
Day 1 to Day 
14 
Wk 1, 
Day 1 
Wk 2, 
Day 8 
Wk 3, 
Day 
15 
Wk 4, 
Day 
22 
Week 
5, Day 
29 
Week 8 and every 4 
weeks thereafter 
 
 
Every 3 
months 
 
Visit Window 
 
 
 
+1 
day 
1 
day 
1 
day 
1 
day 
1 
day 
+5days Week 12 only; 
3 days for all other 
visits 
+1 
day 
-2/+7 
days 
14  
days 
3  
days 
Clinical Assessments 
Informed Consent 
X3 
X4 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Determination of PTEN 
Deficiency Status 
M5 
 
 
 
 
 
 
 
 
 
 
 
 
Safety Assessments 
ECOG PS 
 
X 
 
X 
 
X 
X 
X 
Week 8 and then 
Q8wks 
X 
X 
 
X 
Physical Exam 
 
X 
 
X 
 
 
 
 
Week 8 and then 
Q8wks 
 
X 
 
X 
Height8 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Weight 
 
X 
 
X 
 
 
 
 
Week 8 and then 
Q8wks 
 
X 
 
X 
Vital Signs9 
 
X 
 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
12-Lead ECG10 
 
X6 
 
 
 
 
X 
 
Week 8 and then 
Q8wks 
 
X 
 
X 
ECHO/MUGA 
 
X6,7 
 
As clinically indicated 
 
 
 
 
AE Monitoring 
 
 
Continuous 
X11 
X11 
 
 
Concomitant Medications 
 
X 
Continuous 
 
X 
 
 
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Study Assessments1,2 
Pre-Screening 
Screening 
Enzalutamide 
Run-In 
Period 
Combination Treatment Period 
(DLT Reporting Period) 
Treatment Continuation 
Period 
Time of Discontinuation of 
Treatment due to Disease 
Progression31 
Post-Treatment Follow-Up 
Visit28 
Extended 
Follow-Up  
Visits29 
Post-
Extended 
Follow-Up 
/EOS 
Visit30 
 
 
Day -14 
to 
Day -1 
Day 1 to Day 
14 
Wk 1, 
Day 1 
Wk 2, 
Day 8 
Wk 3, 
Day 
15 
Wk 4, 
Day 
22 
Week 
5, Day 
29 
Week 8 and every 4 
weeks thereafter 
 
 
Every 3 
months 
 
Visit Window 
 
 
 
+1 
day 
1 
day 
1 
day 
1 
day 
1 
day 
+5days Week 12 only; 
3 days for all other 
visits 
+1 
day 
-2/+7 
days 
14  
days 
3  
days 
Laboratory Assessments12 
Haematology/ 
Clinical Chemistry 
 
X6 
 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
Ionized Calcium 
 
X6 
 
X33 
X 
X 
X 
X 
X 
 
X 
 
X 
Vitamin D34 
 
X6 
 
 
 
 
X 
 
 
 
X 
 
X 
Coagulation:  
PT, PTT, INR 
 
X6 
  
X 
 
 
X 
 
 
 
 
 
 
Liver function Tests 
 
X6 
 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
Urinalysis13 
Urine Microscopy13 
UPC14 
 
X6 
 
X 
 
 
X 
 
X 
 
X 
 
X 
Urine Electrolytes15 
 
X6 
 
X33 
 
X 
X 
 
Week 8 and then 
Q8wks 
 
X 
 
 
Parathyroid Hormone 
 
 
 
X 
As clinically indicated16 
 
 
 
 
Bone Markers35 
 
 
 
X 
 
 
 
X 
Weeks  12 and  24 
 
X 
 
X 
PSA and LDH32 
 
X6 
  
X 
 
 
  
 
X 
X 
X 
 
X 
Serum Testosterone 
 
X6 
  
 
 
 
 
 
 
 
X 
 
X 
PK Assessments 
 PK Blood Sampling17 
 
 
 
  
 
 
  
X 
Weeks 8 and 12 
 
 
 
 
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Study Assessments1,2 
Pre-Screening 
Screening 
Enzalutamide 
Run-In 
Period 
Combination Treatment Period 
(DLT Reporting Period) 
Treatment Continuation 
Period 
Time of Discontinuation of 
Treatment due to Disease 
Progression31 
Post-Treatment Follow-Up 
Visit28 
Extended 
Follow-Up  
Visits29 
Post-
Extended 
Follow-Up 
/EOS 
Visit30 
 
 
Day -14 
to 
Day -1 
Day 1 to Day 
14 
Wk 1, 
Day 1 
Wk 2, 
Day 8 
Wk 3, 
Day 
15 
Wk 4, 
Day 
22 
Week 
5, Day 
29 
Week 8 and every 4 
weeks thereafter 
 
 
Every 3 
months 
 
Visit Window 
 
 
 
+1 
day 
1 
day 
1 
day 
1 
day 
1 
day 
+5days Week 12 only; 
3 days for all other 
visits 
+1 
day 
-2/+7 
days 
14  
days 
3  
days 
Disease Assessments18 
CT scan or MRI19 
 
X6,7 
 
 
 
 
 
 
Week 8 and then 
Q8wks to Week 48; 
then Q12wks 
X 
 
X 
 
Chest X-ray or Chest CT 
scan 
 
X6,7 
 
 
 
 
 
 
 
 
 
 
 
Bone Scan20 
 
X6,7 
 
 
 
 
 
 
Week 12 and then 
Q12wks 
X 
 
X 
 
Biomarker Assessments 
CTC – Janssen21 
 
X 
 
X 
 
 
X 
 
Weeks 8, 16, 24, and 
32 
X 
 
 
 
CTC – EPIC22 
 
X 
 
 
 
 
 
 
Week 8 only 
X 
 
 
 
Predictive Biomarker: 
Tumor Tissue23 
 
  
 
X 
 
 
 
 
 
 
 
 
 
Progression Tumor 
Biopsy24 
 
 
 
 
 
 
 
 
 
X 
 
 
 
Tumor Biopsies for 
Pharmacodynamics24 
 
 
X (Day 14) 
 
X24 
 
 
 
 
 
 
 
 
cfDNA/RNA/Soluble 
Markers25 
 
X 
 
X 
 
 
X 
 
Weeks 8, 16, 24, and 
32 
X 
 
 
 
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Study Assessments1,2 
Pre-Screening 
Screening 
Enzalutamide 
Run-In 
Period 
Combination Treatment Period 
(DLT Reporting Period) 
Treatment Continuation 
Period 
Time of Discontinuation of 
Treatment due to Disease 
Progression31 
Post-Treatment Follow-Up 
Visit28 
Extended 
Follow-Up  
Visits29 
Post-
Extended 
Follow-Up 
/EOS 
Visit30 
 
 
Day -14 
to 
Day -1 
Day 1 to Day 
14 
Wk 1, 
Day 1 
Wk 2, 
Day 8 
Wk 3, 
Day 
15 
Wk 4, 
Day 
22 
Week 
5, Day 
29 
Week 8 and every 4 
weeks thereafter 
 
 
Every 3 
months 
 
Visit Window 
 
 
 
+1 
day 
1 
day 
1 
day 
1 
day 
1 
day 
+5days Week 12 only; 
3 days for all other 
visits 
+1 
day 
-2/+7 
days 
14  
days 
3  
days 
Biomarker Assessments continued 
Blood Sample for 
Genetic Research26 
 
 
 
X 
 
 
 
 
 
 
 
 
 
Study Treatments27 
Enzalutamide 
 
  
Continuous 
Continuous 
 
 
 
 
GSK2636771 
 
 
 
Continuous 
 
 
 
 
Abbreviations: AE, adverse event; cfDNA, circulating-free tumor DNA; CT, computed tomography; CTC, circulating tumor cells; ECG, electrocardiogram; ECHO, echocardiogram; 
ECOG, Eastern Cooperative Oncology Group; EOS, End of Study; HbA1C, hemoglobin A1C; INR, international normalization ratio; M, mandatory; MRI, magnetic resonance imaging; 
MUGA, multigated acquisition scan; O, optional; PD, pharmacodynamics; PK, pharmacokinetics; PS, performance status; PSA, prostate-specific antigen; PT, prothrombin time; PTEN, 
phosphatase and tensin homolog; PTH, parathyroid hormone; PTT, partial thromboplastin time; Q4wks, every 4 weeks; Q8wks, every 8 weeks; Q12wks, every 12 weeks; UPC, 
urine:protein:creatinine; Wk(s), week(s) 
 
1. 
Study Assessments: All assessments may be performed more frequently if clinically appropriate. Assessments scheduled on days of dosing should be completed prior to the 
administration of study treatments, unless otherwise specified 
2. 
Study Assessments: Assessments throughout the study are calendar based starting from Week 1, Day 1 of the Combination Treatment Period (the first dose of combination 
treatment).  Dose interruptions should not alter the assessment schedule for any subsequent treatment period. 
3. 
Pre-Screening Informed Consent: Separate pre-screening informed consent must be obtained prior to initiation of any pre-screening procedures or assessments. 
4. 
Screening Informed Consent: Informed consent must be obtained prior to initiation of any screening procedures or assessments.. 
5. 
PTEN Deficiency Status (Mandatory): Tumor tissue samples (archived or fresh tumor tissue obtained by pre-treatment biopsy) will be collected to determine PTEN deficiency 
status of the tumor by the designated central laboratory.  Refer to the SRM for details about the number of slides to be submitted, preparation, handling and shipping.  Results of 
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the PTEN deficiency testing from the central laboratory only will be used to determine if the subject is eligible to continue Screening.  Only subjects with PTEN deficient tumor 
based on central laboratory testing results will be screened.  Any remaining tumor tissue may be used for other predictive biomarker analyses if consent has been obtained. 
6. 
Screening: When possible, screening assessments that require imaging, ECG, ECHO/MUGA, or laboratory studies should be performed AFTER PTEN status has been 
determined. 
7. 
Screening: All screening assessments must be completed and all entry criteria must be met prior to assessments on Day 1 of Enzalutamide Run-In Period.  EXCEPTION:  
ECHO/MUGA must be completed within 28 days of enrollment (Day 1 of Enzalutamide Run-In Period), and disease assessment must be completed within 28 days (35 days if MRI 
is used) prior to enrollment (Day 1 of the Enzalutamide Run-In Period). 
8. 
Height is only measured at Screening. 
9. 
Vital Signs:  Blood pressure, temperature and heart rate will be measured.  Vital signs may be measured more frequently if clinically warranted. 
10. ECG: A single 12-lead ECG is to be performed before vital signs are measured and any blood draws, if assessments are planned at the same nominal time point. 
11. AE Monitoring: Continued monitoring of AEs applies only to ongoing events at time of treatment discontinuation. 
12. Laboratory Assessments: Refer to Section 8.6.6 in protocol) for list of specific laboratory tests to be performed.  Assessments may be performed within 24 hrs prior to scheduled 
visit (liver function tests and urine tests for UPC may be performed up to 72 hrs prior to a scheduled visit) to ensure availability of results. 
13. Urinalysis and Urine Microscopy:  Urinalysis and urine microscopy will be performed at the time points indicated. Assessments may be performed within 24 hrs prior to a 
scheduled visit to ensure availability of results. 
14. UPC:  Urine sample for UPC is to be collected at the time points indicated. Perform UPC with the first morning urine specimen (if possible) when urine dipstick protein 2+.  Urine 
samples for UPC may be collected up to 72 hrs prior to a scheduled visit to ensure that results are available at time of visit.  If the urine sample collected at Screening is 
contaminated with other bodily fluids, UPC will not be determined and subject will remain eligible for the study. 
15. Urine Electrolytes:  Urine samples will be obtained at Screening, pre-dose on Day 1 (Week 1), Day 3 OR Day 4, Day 15 (Week 3), Day 22 (Week 4) of the Combination 
Treatment Period, Week 8 and then every 8 weeks ( 3 days) thereafter during the Treatment Continuation Period, and at the post-treatment follow-up visit to determine urine 
electrolytes (magnesium, phosphorus and calcium) and urine creatinine. 
16. Parathyroid Hormone (PTH): Assessment of PTH will be performed if a Grade 2 or higher hypocalcemia or hypophosphatemia is reported. 
17. PK Blood Sampling:  Week 5, Day 29 (Treatment Continuation Period): Blood and plasma samples for analysis of GSK2636771, enzalutamide and N-desmethyl enzalutamide 
will be collected at pre-dose and 1, 2, and 3 hrs post-dose if a morning clinic visit is scheduled, or at approximately 5 to 6, 6 to 7, and 7 to 8 hrs post-dose if an afternoon clinic visit 
is scheduled.  Actual date and time of sample collection and dosing of study treatments must be recorded.  Explanations are required for any deviations of more than 5 minutes 
from the planned time during the first 2 hrs and for deviations of more than 20 minutes from the planned time for samples collected at 3 hrs up to 8 hrs post-dose.  Week 8 
and Week 12 (Treatment Continuation Period): Blood and plasma samples for analysis of GSK2636771, enzalutamide and N-desmethyl enzalutamide will be collected pre-
dose only. 
18. Disease Assessments: Disease assessments at Screening must be performed within 28 days prior to enrollment (Day 1 of the Enzalutamide Run-In Period), or within 35 days 
prior to enrollment (Day 1 of the Enzalutamide Run-In Period if disease assessment is performed by MRI, to identify target and non-target lesions. 
19. CT scan or MRI:  Scans should be performed at Screening, Week 8 and then every 8 weeks (7 days) during the first 48 weeks of the Treatment Continuation Period and then 
every 12 weeks (7 days) thereafter in the Treatment Continuation Period, and at the time of disease progression.  All confirmatory scans are to be performed within 4 weeks 
(3 days) of a CR or PR.  If a subject discontinues treatment for reasons other than disease progression, disease assessments should continue every 3 months until disease 
progression, initiation of new anti-cancer treatment, subject withdrawal of consent, or death. 
20. Bone Scan:  A bone scan is required for all subjects at Screening.  For subjects without bone disease at baseline, subsequent bone scans should be performed as clinically 
indicated.  Subjects with bone metastases at baseline should have a bone scan performed at Week 12 and then every 12 weeks (7 days) thereafter in the Treatment 
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Continuation Period, or as clinically indicated, and at the time of disease progression.  If a subject discontinues treatment for reasons other than disease progression, bone scans 
should continue every 3 months until disease progression, initiation of new anti-cancer treatment, subject withdrawal of consent, or death. 
21. CTC-Janssen:  Whole blood samples will be obtained at Screening; pre-dose on Day 1 (Week 1) and Day 22 (Week 4) of the Combination Treatment Period; pre-dose on Day 1 
of Weeks 8, 16, 24 and 32 of the Treatment Continuation Period; and at time of disease progression. 
22. CTC-EPIC:  Whole blood samples will be obtained at Screening, pre-dose on Day 1 of Week 8 of the Treatment Continuation Period, and at the time of disease progression for 
protein and genomic analysis. 
23. Predictive Biomarkers Tumor Tissue:  For subjects enrolled into the study, additional slides of tumor tissue samples will be collected and submitted to the designated laboratory 
for analysis once a subject has received their first dose of GSK2636771 on Week 1, Day 1 of the Combination Treatment Period.  Tumor tissue may be obtained from archived 
tissue samples or fresh tumor tissue submitted for the PTEN testing.  If additional tumor tissue is not available, no new biopsy procedure is required for predictive biomarker 
analysis.  Refer to the SRM for details about the number of slides to be submitted, preparation, handling and shipping. 
24. Tumor Biopsies for PD and progression: These biopsies are optional and may be undertaken in select cases upon agreement with the investigator and when consent is 
provided by the subject. For pharmacodynamic biomarker analyses, fresh tissue biopsies would be collected between Day 12 of the Enzalutamide Run-in Period and Week 
1/Day 1, prior to any treatment with GSK2636771, and 2-4 hours post dose between Days 8 and 15 of the Combination Treatment Period (post-treatment).  For subjects who 
consent to the optional progression biopsy, a fresh tumor biopsy should be completed if the subject initially responded to combination treatment and then progressed.. 
25. cfDNA/RNA/Soluble Markers:  Plasma samples will be obtained from collected blood samples at Screening, pre-dose on Weeks 1, 4, 8, 16, 24, and 32 of the Combination 
Treatment Period, and at the time of discontinuation of treatment due to disease progression.  Plasma will be analyzed for genomic changes in the circulating tumor DNA, RNA, 
and soluble markers. 
26. Genetic Research: A 6-mL blood sample should be collected after Screening, preferably on Week 1, Day 1 of the Combination Treatment Period, if informed consent has been 
obtained for genetic research. 
27. Study Treatment: Enzalutamide monotherapy should be taken once daily during the Enzalutamide Run-In Period.  Enzalutamide will be self-administered in the clinic on Day 14 
of the Enzalutamide Run-In Period.  GSK2636771 and enzalutamide will be administered in the clinic on Week 1, Day 1 of the Combination Treatment Period and on days when 
blood, plasma, and/or urine samples are collected for analysis of PK, CTC, and/or urine electrolytes. 
28. Post-Treatment Follow-Up Visit:  ONLY subjects who withdraw during the Enzalutamide Run-In Period or withdraw from study treatment due to disease progression see 
Section 5.2 in protocol) should have a post-treatment follow-up visit conducted within approximately 30 days (-2/+7 days) of last dose of study treatment(s).  If a subject is unable 
to return to the clinic due to hospitalization, site staff is encouraged to call subject for assessment of AEs.   
29. Extended Follow-Up Visits:  Subjects who withdraw from study treatment without disease progression should be contacted every 3 months (14 days) until disease 
progression, death, withdrawal of consent, or subject is lost to follow-up.  Contact may include a clinic visit, a telephone contact, or an e-mail.  The initiation of any new anti-cancer 
treatments and date of last contact should be documented. 
30. Post-Extended Follow-Up/EOS Visit:  ONLY subjects who discontinue the Extended Follow-Up Visits should have a Post-Extended Follow-Up/EOS Visit performed. 
31. These assessments should be completed at the time of disease progression that leads to discontinuation of treatment.  Subjects are not required to discontinue treatment on the 
basis of PSA progression alone or for the worsening of an isolated disease site that is not clinically significant (see Section 5.2 in protocol). 
32. When collected as part of the routine standard of care for a subject, LDH will be reported. 
33. Complete clinical chemistries laboratory assessments at Week1/Day 1 and again on either Day 3 or Day 4.  The Day 3 or Day 4 assessments can be completed at a local 
laboratory and does not require a clinic visit.  The hematology panel does NOT need to be collected on Day 3/ Day.4. Review of these labs must occur before Week 2, Day 1 visit. 
34. Includes assessments for 25-OH D and 1,25-OH2 D.  
35. Includes urine and blood and/or serum samples.  Must be collected at the same time of day (1 hour) to eliminate diurnal effects, and after fasting.  See SRM for additional details 
on the specific assessments and sample collection 
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13.3. 
Appendix 3: Assessment Windows 
13.3.1. 
Definitions of Assessment Windows for Analyses 
Analysis Set 
/ Domain 
Parameter      
(if applicable) 
Target  
Analysis Window 
Analysis 
Timepoint 
Beginning 
Timepoint 
Ending 
Timepoint 
Primary/Seco
ndary Efficacy 
 
For patients 
seen at week 
12 under 
protocol 
amendment 1-3 
 
Week 12  3 days 
78-3 days 
78 + 3 days 
Week 12 
Primary/Seco
ndary Efficacy 
 
For patients 
seen at week 
12 under 
protocol 
amendment 4 
 
Week 12 + 5 days 
78 days 
78+5 days 
Week 12 
 
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13.4. 
Appendix 4: Study Phases and Treatment Emergent 
Adverse Events 
13.4.1. 
Study Phases for Concomitant Medication 
Study Phase 
Definition 
Prior 
End Date < Combination Treatment Start Date 
Post-Treatment 
Start Date > Stop Date of GSK2636771 
For interim analyses when subjects are still on treatment, Study Treatment Stop Date 
will be imputed following rules specified in Section 13.7.2.1. 
Concomitant 
Any medication that is not a prior or post -treatment 
NOTES:  
 
Please refer to Section 13.7.2.1: Reporting Standards for Missing Data for handling of missing and partial dates 
for concomitant medication. Use the rules in this table if concomitant medication date is completely missing. 
 
13.4.2. 
Treatment Emergent Flag for Adverse Events 
Flag 
Definition 
Treatment 
Emergent 
 
If AE onset date is on or after treatment start date or missing &: 
o Treatment Start Date≤ AE Start Date AE start data is missing 
NOTES:  
 
Treatment start date refers to the time the first dose of enzalutamide is administered on Day 1 of the 
Enzalutamide Run-In Period 
 
Treatment stop date refers to the date of discontinuation of study treatments(s) 
 
If the 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 
: arprod\gsk2636771\mid200331\ 
Analysis Datasets  
 
Analysis datasets will be created according to IDSL standard.  
Generation of RTF Files 
 
RTF files will be generated for all tables 
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): 
 
4.03 to 4.23: General Principles 
 
5.01 to 5.08: Principles Related to Data Listings 
 
6.01 to 6.11: Principles Related to Summary Tables 
 
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 in the modular appendices as ICH or non-ICH listings 
Formats 
 
GSK IDSL Statistical Principles (5.03 & 6.06.3) for decimal places (DP’s) 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 DP’s.  
Planned and Actual Time 
 
Reporting for tables, figures and formal statistical analyses: 
 
Planned time relative to dosing will be used in figures, summaries, statistical analyses and 
calculation of any derived parameters, unless otherwise stated. 
 
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:  
 
Planned and actual time relative to study drug dosing will be shown in listings (Refer to IDSL 
Statistical Principle 5.05.1). 
 
Unscheduled or unplanned readings will be presented within the subject’s listings.  
Unscheduled Visits 
 
Unscheduled visits will not be included in summary tables and/or figures. 
For worst-case analysis, unscheduled visits will be included. 
 
All unscheduled visits will be included in listings. 
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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 
[Insert document name].  
Note: Concentration values will be imputed as per GUI_51487 
Descriptive Summary 
Statistics, Graphical 
Displays and Listings 
Refer to IDSL PK Display Standards. 
Refer to IDSL Statistical Principle 6.06.1. 
Note: Concentration values will be imputed as per GUI_51487 for descriptive 
summary statistics/analysis and summarized graphical displays only.  
NONMEM/Pop PK 
File 
Not applicable. 
NONMEM/PK/PD 
File 
Not applicable. 
 
 
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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 there are two values within a time window (as per Section 13.3.1), the value closest to the target day 
for that window will be used. If values are the same distance from the target, then the mean will be 
taken. 
 
Participants having both High and Low values for Normal Ranges at any post-baseline visit for safety 
parameters will be counted in both the High and Low categories of “Any visit post-baseline” row of 
related summary tables. This will also be applicable to relevant Potential Clinical Importance summary 
tables. 
Study Day for Safety 
 
Calculated as the number of days from First Dose Date: 
 
Ref Date = Missing              → Study Day = Missing  
 
Ref Date < First Dose Date → Study Day = Ref Date – First Dose Date 
 
Ref Date ≥ First Dose Date → Study Day = Ref Date – (First Dose Date) + 1     
Study Day for Efficacy 
 
Calculated as the number of days from First Dose Date: 
 
Ref Date = Missing                                                 → Study Day = Missing  
 
Ref Date < First Dose Date → Study Day = Ref Date – First Dose Date 
 
Ref Date ≥ First Dose Date → Study Day = Ref Date – First Dose Date + 1     
Change from Baseline 
 
Change from Baseline = Post-Baseline Visit Value – Baseline 
 
% Change from Baseline= 100 x (Post-Baseline Visit Value – Baseline) / Baseline 
 
Maximum Increase/Decrease from Baseline = maximum (Increase/Decrease from Baseline) 
 
If either the Baseline or Post-Baseline Visit Value is missing, Change from Baseline and % Change 
from Baseline is set to missing 
Date of Response 
 
For post-baseline disease assessments, the date of response (PR or better) is assigned to the latest 
date of disease assessments; for other response categories (SD or Non-CR/Non-PD, NE, PD), the date 
of response is assigned to the earliest date of disease assessments.    
Date of New Anti-Cancer Therapy 
 
Derived as the earliest date of new anti-cancer therapy, radiotherapy (where applicable) or cancer-
related surgical procedure (where applicable). Missing or partial dates will be imputed for derivation of 
new anti-cancer therapy following rules specified in Section 13.7.2.1. 
 
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13.6.2. 
Study Population 
Treatment Compliance 
 
Treatment compliance will be calculated based on the formula:   
Treatment Compliance = Number of Actual Doses / (Planned Treatment Duration in Days * 
Frequency) 
 
Frequency is 2 for BID and 1 for QD. Treatment compliance could be greater than 100% if there are 
events of overdose. Cumulative compliance (since Day 1) at each visit will be calculated. 
 
Planned Treatment Duration is defined as the time from start of study treatment until treatment end 
date. 
Extent of Exposure 
 
Missing treatment stop date will be imputed following rules specified in Section 13.7.2.1. 
 
Daily Oral Drugs   
o Extent of exposure will be calculated for each treatment component 
o Number of days of exposure (duration on study treatment) to study drug will be calculated based 
on the formula:   
Duration of Exposure in Days = Treatment Stop Date – Treatment Start Date + 1 
o Participants who were assigned a treatment but did not report a treatment start date will be 
categorised as having zero days of exposure.  
o The cumulative dose will be based on the formula: 
Cumulative Dose = Sum of (Number of Days x Total Daily Dose) 
 
If there are any treatment breaks during the study, exposure data will be adjusted accordingly. 
Time since Initial Diagnosis 
 
Calculated as the number of [Days] from the Date of Initial Diagnosis: 
o [Randomization/First Dose Date] = Missing           → Elapse Time = Missing  
o Date of Initial Diagnosis = Completely/partially Missing       → Elapse Time = Missing  
o Otherwise       → Elapse Time = [Randomization/First Dose Date] – Date of Initial Diagnosis + 1        
13.6.3. 
Efficacy 
PSA response (including PSA50 response) 
 
Using the following algorithm, the following 4 categories will be created: 
o [PSA] Decline>=50% from baseline [confirmed/unconfirmed] (PSA50) 
o No significant PSA change  
o PSA Progression (PSA increase >=25% from baseline) 
o Not Evaluable 
 For at least 12 weeks PSA: for visits under amendment 3, use week 12  3 days; for visits 
under amendment 4, use week 12 + 5 days  
PSA Response Algorithm – PSA50 unconfirmed 
 
Step 1: Within identified population define PSA Analysis Set 
 
If there is no post-baseline PSA visit with a non-missing result, output to [Not Evaluable] 
 
If there is no baseline PSA, output to [Not Evaluable] 
 
Output rest to [PSA evaluable Analysis Set] 
 
 
Step 2: within [PSA evaluable Analysis Set] create two subsets 
 
If any post-baseline visit PSA < baseline output to subset I (decline from baseline)  
 
Else if the visit is post-baseline output to Subset II (no decline from baseline)  
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PSA response (including PSA50 response) 
 
 
Step 3. Under Subset I:  
 
For each subject retain the response flag (urspflg). Find the first visit PSA <= 0.5*baseline, add 
urspflg (unconfirmed PSA response flag) =1; output to [Decline>=50% from baseline (unconfirmed] 
 
Else output to [temp set 1] 
 
 
Among [temp set 1], find nadir (lowest PSA value at this or any earlier visit through baseline) 
Retain nadir for each subject. 
o PSA >=1.25*nadir and (PSA-nadir)>=2ng/mL, add uprgflg (unconfirmed PSA progression 
flag)=1  
o If PSA >=1.25*nadir and (PSA-nadir)≥ 2ng/mL is confirmed by a second PSA value 
obtained >=21 days (3 weeks) from the initial increase, add cprgflg (confirmed PSA 
progression flag)=1  
 
If progression is confirmed [sum(uprgflg,cprgflg)=2] output to  [PSA progression] 
 
Else output to [No significant PSA change] 
 
 
Step 4. Under Subset II 
 
If any visit >=XX days (12 weeks) PSA >= 1.25*baseline and abs(increase from baseline) 
>=2ng/mL  output to [PSA progression] (no confirmation required). 
 
Else output to [No significant PSA change] 
PSA Response Algorithm – PSA50 Confirmed 
NOTE: Steps are very similar to unconfirmed PSA50 with differences indicated in Red. 
 
Step 1: Within identified population define PSA Analysis Set 
 
If there is no post-baseline PSA visit with a non-missing result, output to [Not Evaluable] 
 
If there is no baseline PSA, output to [Not Evaluable] 
 
Output rest to [PSA evaluable Analysis Set] 
 
 
Step 2: within [PSA evaluable Analysis Set] create two subsets 
 
If any post-baseline visit PSA < baseline output to subset I (decline from baseline)  
 
Else if the visit is post-baseline output to Subset II (no decline from baseline)  
 
 
Step 3. Under Subset I:  
 
For each subject retain the response flags (urspflg and crspflg). Find the first visit PSA <= 
0.5*baseline, add urspflg (unconfirmed PSA response flag) =1; 
 
Find the second visit PSA <= 0.5*baseline, if this visit time is >=21 days (3 weeks) from the first 
visit, add crspflg (confirmed PSA response flag)=1 
 
If the response is confirmed (urspflg+crspflg)=2, output to [Decline>=50% from baseline 
(confirmed] 
 
Else output to [temp set 1] 
 
 
Among [temp set 1], find nadir (lowest PSA value at this or any earlier visit through baseline) 
Retain nadir for each subject. 
o PSA >=1.25*nadir and (PSA-nadir)>=2ng/mL, add uprgflg (unconfirmed PSA progression 
flag)=1  
o If PSA >=1.25*nadir and (PSA-nadir)≥ 2ng/mL is confirmed by a second PSA value 
obtained >=21 days (3 weeks) from the initial increase, add cprgflg (confirmed PSA 
progression flag)=1  
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PSA response (including PSA50 response) 
 
If progression is confirmed [sum(uprgflg,cprgflg)=2] output to  [PSA progression] 
 
Else output to [No significant PSA change] 
 
 
Step 4. Under Subset II 
 
If any visit >=XX days (12 weeks) PSA >= 1.25*baseline and abs(increase from baseline) 
>=2ng/mL  output to [PSA progression] (no confirmation required). 
 
Else output to [No significant PSA change] 
 
13.6.4. 
Safety 
Adverse Events 
AE’S OF Special Interest 
 
Hypocalcaemia 
 
Increase in Creatinine 
Duration of AE 
 
Calculated as the number of [days] from AE Start Date to AE Stop Date: 
 
AE Start Date = Missing              → Elapse Time = Missing  
 
AE Stop Date = Missing              → Elapse Time = Missing 
o Otherwise                                    → Elapsed Time = AE Stop Date – AE Start Date + 1     
ECHO/MUGA 
 
Change from Baseline for cardiac data, e.g., Left Ventricular Ejection Fraction (LVEF), will be calculated 
based on the same modality (ECHO or MUGA) throughout the study for each subject. Post-baseline 
assessments with a different cardiac scan modality will not be used to calculate change from Baseline. 
 
 
 
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13.7. 
Appendix 7: Reporting Standards for Missing Data 
13.7.1. 
Premature Withdrawals 
Element 
Reporting Detail 
General 
Subject study completion (i.e. as specified in the protocol) was defined as below: 
 
A subject will be considered to have completed the study if the subject dies or 
otherwise progresses during the study treatment or post-treatment follow-up period.  All 
other subjects will be considered to have withdrawn from the study. 
 
Withdrawn subjects were not replaced in this study. 
 
All available data from participants who were withdrawn from the study will be listed 
and all available planned data will be included in summary tables and figures, unless 
otherwise specified.  
13.7.2. 
Handling of Missing Data 
Element 
Reporting Detail 
General 
 
Missing data occurs when any requested data is not provided, leading to blank fields on 
the collection instrument: 
o These data will be indicated using a “blank” in subject listing displays. Unless all 
data for a specific visit are missing in which case the data is excluded from the 
table.  
o Answers such as “Not applicable” and “Not evaluable” are not considered to be 
missing data and should be displayed as such. 
Outliers 
 
Any participants excluded from the summaries and/or statistical analyses will be 
documented along with the reason for exclusion in the clinical study report. 
13.7.2.1. 
Handling of Missing and Partial Dates 
Element 
Reporting Detail 
General 
 
Partial dates will be displayed as captured in subject listing displays. 
Adverse 
Events 
 
Imputations in the adverse events dataset are used for slotting events to the appropriate study time 
periods and for sorting in data listings. 
 
Partial dates for AE recorded in the CRF will be imputed using the following conventions: 
 
Missing start 
day 
 
If study treatment start date is missing (i.e. participant did not start 
study treatment), then set start date = 1st of month. 
 
Else if study treatment start date is not missing: 
o 
If month and year of start date = month and year of 
study treatment start date then 
 
If stop date contains a full date and stop date 
is earlier than study treatment start date then set start date= 
1st of month. 
 
Else set start date = study treatment start 
date. 
o Else set start date = 1st of month. 
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Element 
Reporting Detail 
Missing start 
day and month 
 
If study treatment start date is missing (i.e. participant did not start 
study treatment), then set start date = January 1. 
 
Else if study treatment start date is not missing: 
o 
If year of start date = year of study treatment start date 
then 
 
If stop date contains a full date and stop date 
is earlier than study treatment start date then set start date = 
January 1. 
 
Else set start date = study treatment start 
date.       
o 
Else set start date = January 1. 
Missing stop 
day  
Last day of the month will be used. 
Missing stop 
day and month 
No Imputation 
Completely 
missing 
start/end date 
No imputation 
Concomitant 
Medications/
Medical 
History/ 
Blood 
Supportive 
Products 
 
Partial dates for any concomitant medications recorded in the CRF will be imputed using the 
following convention: 
 
Missing start day 
 
If study treatment start date is missing (i.e. participant did not 
start study treatment), then set start date = 1st of month. 
 
Else if study treatment start date is not missing: 
o 
If month and year of start date = month and year of 
study treatment start date then 
 
If stop date contains a full date and stop 
date is earlier than study treatment start date then set start 
date= 1st of month. 
 
Else set start date = study treatment start 
date. 
o 
Else set start date = 1st of month. 
Missing start day 
and month 
 
If study treatment start date is missing (i.e. participant did not 
start study treatment), then set start date = January 1. 
 
Else if study treatment start date is not missing: 
o 
If year of start date = year of study treatment start 
date then 
 
If stop date contains a full date and stop 
date is earlier than study treatment start date then set start 
date = January 1. 
 
Else set start date = study treatment start 
date.       
 
Else set start date = January 1. 
Missing end day 
A '28/29/30/31' will be used for the day (dependent on the month and 
year)  
Missing end day 
and month 
A '31' will be used for the day and 'Dec' will be used for the month. 
Completely missing 
start/end date 
No imputation 
New Anti-
Cancer 
Start dates for follow-up anti-cancer therapy, radiotherapy (where applicable), and surgical 
procedures (where applicable) will be imputed in order to define event and censoring rules for 
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Element 
Reporting Detail 
Therapy/ 
Radiotherap
y/ 
Surgical 
Procedures 
for Efficacy 
Evaluation 
(e.g., 
response 
rate, time to 
event) 
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 following rules will be used to impute the date when partial start dates are present 
on anti-cancer therapy, radiotherapy, and/or surgical procedures dataset[s]: 
 
Completely missing start dates will remain missing, with no imputation applied; 
 
Partial start dates will be imputed using the following convention: 
 
If both month and day are missing, no imputation will be applied; 
 
If only day is missing:  
o 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; 
o 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; 
o If both conditions above are met, the later date will be used for the day; 
o Otherwise, a ‘01’ will be used for the day; 
 
Completely or partial missing end dates will remain missing, with no imputation applied; 
Treatment 
end date 
 
If there is more than one study treatment, imputation of missing treatment end date will be 
applied to all applicable treatments following rules below and treatment end date is the 
latest treatment end date across all study treatments. 
For daily oral treatment 
 
 
In general, completely missing end dates are not imputed, with the following exceptions for 
imputation of missing treatment end date at interim analyses. 
 
For imputation of missing exposure end date at an interim analysis when subjects are still 
on treatment, the following conventions will be applied: 
o If the missing end date is in the last exposure record, the earliest of: the date of the data 
cut-off, the date of withdrawal from the study, or the death date will be used  
o If the missing end date is not in the last exposure record, treatment start date for the 
record will be used 
 
The imputed treatment end date will be used to calculate cumulative dose and duration of 
treatment as specified in Section 13.6.2. For non-continual treatment 
 
 
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13.8. 
Appendix 8: Values of Potential Clinical Importance 
13.8.1. 
Laboratory Values 
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 for laboratory parameters including clinical chemistry, haematology, liver 
function tests, QTc (Bazett’s or Fridericia’s) values, vital signs (heart rate, blood 
pressure, temperature) and LVEF. 
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. 
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 and Vital Signs 
For ECG and vital signs, the most updated IDSL standard up to the RAP effective date 
will be followed. 
 
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13.9. 
Appendix 9: Population Pharmacokinetic (PopPK) Analyses 
Population PK analysis will be done under a separate RAP and reported outside of the 
CSR. 
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13.10. 
Appendix 10: Pharmacokinetic / Pharmacodynamic 
Analyses 
PK/PD analyses will be done under a separate RAP and reported outside of the CSR. 
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13.11. 
Appendix 11: Abbreviations & Trade Marks 
13.11.1. 
Abbreviations 
Abbreviation 
Description 
AE 
Adverse Event 
AESI 
Adverse Event of Special Interest 
ALT 
Alanine aminotransferase 
AR 
Androgen receptor 
ATC 
Anatomical Therapeutic Chemical 
AUC 
Area under the concentration-time curve 
AUC(0-t) 
Area under the concentration-time curve from zero over the dosing 
interval 
AUC(0-τ) 
Area under the concentration-time curve from zero to the last 
quantifiable blood or plasma concentration 
BID 
Twice daily 
BOR 
Best Overall Response 
BP 
Blood pressure 
cfDNA 
Circulating-free tumor DNA 
CI 
Confidence Interval 
CL/F 
Oral clearance 
Cmax 
Maximum observed concentration 
CNV 
Copy Number Variant 
CPMS 
Clinical Pharmacology Modeling & Simulation 
CR 
Complete response 
CSR 
Clinical study report 
CT 
Computed tomography 
CTC 
Circulating tumor cells 
CTCAE 
Common Terminology Criteria for Adverse Events 
DBR 
Database Release 
DBF 
Database Freeze 
DLT 
Dose-limiting toxicity 
DNA 
Deoxyribonucleic acid 
DP 
Decimal Places 
ECG 
Electrocardiogram 
ECHO 
Echocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic Case Report Form 
EOS 
End of Study 
EudraCT 
European Clinical Trials Database 
FDA 
Food and Drug Administration 
FDAAA 
Food and Drug Administration Amendments Act 
FISH 
Fluorescent in situ hybridization 
GSK 
GlaxoSmithKline 
ICH 
International Conference on Harmonization  
IDSL 
International Data Standards Library 
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Abbreviation 
Description 
IHC 
Immunohistochemistry 
INDSR 
Investigational New Drug Safety Report 
INR 
International Normalized Ratio 
ka 
Absorption rate constant 
LDH 
Lactate dehydrogenase 
LVEF 
Left ventricular ejection fraction 
M 
Mandatory 
mCRPC 
Metastatic castration-resistant prostate cancer 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
Milligrams 
MHRA 
Medicines and Healthcare Products Regulatory Agency 
mL 
Milliliter 
MRI 
Magnetic resonance imaging 
MTD 
Maximum tolerated dose 
MUGA 
Multigated acquisition scan 
N, n 
Number 
NCI 
National Cancer Institute 
NE 
Not evaluable 
O 
Optional 
ORR 
Objective Response Rate 
PCWG2 
Prostate Cancer Working Group 2 
PD 
Pharmacodynamic or progressive disease 
PI3Kβ 
Phosphoinositide 3-kinase beta 
PK 
Pharmacokinetic 
PR 
Partial response 
PopPK 
Population Pharmacokinetic 
PS 
Performance Status 
PSA 
Prostate-specific antigen 
PSA50 
Prostate-specific antigen decrease from baseline ≥50% 
PT 
Prothrombin time 
PTEN 
Phosphatase and tensin homolog 
PTH 
Parathyroid hormone 
PTT 
Partial thromboplastin time 
Q4wks 
Every 4 weeks 
Q8wks 
Every 8 weeks 
Q12wks 
Every 12 weeks 
QD 
Every day 
QTc 
Corrected QT interval  
QTcB 
QT interval corrected by Bazett’s formula 
QTcF 
QT interval corrected by Fridericia’s formula 
RAP 
Reporting and Analysis Plan 
RECIST 
Response Evaluation Criteria In Solid Tumors 
RNA 
Ribonucleic acid 
RP2D 
Recommended Phase II dose 
rPFS 
Radiological progression free survival 
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Abbreviation 
Description 
SAC 
Statistical Analysis Complete 
SAE 
Serious adverse event(s) 
SBP 
Systolic blood pressure 
SD 
Stable disease or standard deviation 
SNV 
Small Nuclear Variant 
SRM 
Study Reference Manual 
SRT 
Safety Review Team 
Tmax 
Time of occurrence of maximum observed concentration 
TMF 
Trial Master File 
UPC 
Urine protein to creatinine  
US 
United States 
V/F 
Oral volume of distribution 
Wk(s) 
Week(s) 
13.11.2. 
Trademarks 
Trademarks of the GlaxoSmithKline 
Group of Companies 
 
Trademarks not owned by the 
GlaxoSmithKline Group of Companies 
None 
 
NONMEM 
 
 
SAS 
 
 
WinNonlin 
 
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13.12. 
Appendix 12: List of Data Displays 
13.12.1. 
Data Display Numbering 
The following numbering will be applied for RAP generated displays: 
Section 
Tables 
Figures 
Study Population 
1.1 to 1.n 
1.1 to 1.n 
Efficacy 
2.1 to 2.n 
2.1 to 2.n 
Safety 
3.1 to 3.n 
3.1 to 3.n 
Pharmacokinetic 
4.1 to 4.n 
4.1 to 4.n 
Biomarker 
5.1 to 5.n 
5.1 to 5.n 
Section 
Listings 
ICH Listings;  
1 to x 
Other Listings 
y to z 
 
13.12.2. 
Mock Example Shell Referencing 
Non IDSL specifications will be referenced as indicated and if required example mock-up 
displays provided in Appendix 13: Example Mock Shells for Data Displays 
Section 
Figure 
Table 
Listing 
Study Population 
 
POP_T1 
 
Efficacy 
 
EFF_T1, EFF_T2, EFF_T3 
EFF_L1, EFF_L2 
Safety 
 
 
 
Pharmacokinetic 
 
 
 
Biomarker 
BIO_F1 
 
BIO_L1, BIO_L2, 
BIO_L3 
Non-ICH 
 
 
NICH_L1 
NOTES:  
 
Non-Standard displays are indicated in the ‘IDSL /  Example Shell’ or ‘Programming Notes’ column as ‘[Non-
Standard] + Reference.’ 
 
13.12.3. 
Deliverables 
Delivery [Priority] [1] 
Description 
SAC [X] 
Final Statistical Analysis Complete 
 
NOTES:  
1. 
Indicates priority (i.e. order) in which displays will be generated for the reporting effort 
 
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13.12.4. 
Study Population Tables 
Study Population Tables 
No. 
Population 
IDSL / Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Subject Disposition 
1.1. 
All Treated 
Safety 
ES8 
Summary of Subject Status and Reason for Study Withdrawal 
ICH E3, FDAAA, EudraCT 
 
SAC 
1.2. 
All Treated 
Safety 
SD1 
Summary of Treatment Status and Reasons for Discontinuation 
of Study Treatment 
ICH E3 
 
SAC 
1.3. 
All Screened 
ES6 
Summary of Screening Status and Reasons for Screen Failure 
EudraCT/Clinical Operations; for all 
subjects screened; 
SAC 
1.4. 
All Treated 
Safety 
NS1 
Summary of Number of Participant by Country and Site ID  
EudraCT/Clinical Operations 
SAC 
1.5. 
All Screened 
POP_T1 
Summary of Study Eligibility in Screening 
/arenv/arprod/gsk2636771/p3b115717/sac/ 
drivers/t_elig_prescn.sas 
SAC 
Protocol Deviation 
1.6. 
All Treated 
Safety 
DV1 
Summary of Important Protocol Deviations 
ICH E3 
SAC 
Population Analysed 
1.7. 
All Treated 
Safety 
SP1A 
Summary of Study Population 
IDSL 
SAC 
Demographic and Baseline Characteristics 
1.8. 
All Treated 
Safety 
DM1  
Summary of Demographic Characteristics 
ICH E3, FDAAA, EudraCT 
SAC 
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Study Population Tables 
No. 
Population 
IDSL / Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
1.9. 
All Treated 
Safety 
DM11 
Summary of Age Ranges 
EudraCT (<18-64, 65-84; >=85); DSUR 
(<18,18-64, 65- 74, >=75) 
SAC 
1.10.
All Treated 
Safety 
DM5 
Summary of Race and Racial Combinations 
ICH E3, FDA, FDAAA, EudraCT; include 
all races and race details 
SAC 
1.11.
All Treated 
Safety 
MH1 
Summary of Past Medical Conditions 
ICH E3  
SAC 
1.12.
All Treated 
Safety 
MH1 
Summary of Current Medical Conditions 
ICH E3  
SAC 
1.13.
All Treated 
Safety 
CM8 
Summary of Concomitant Medications 
ICH E3 
 
SAC 
Exposure and Treatment Compliance 
1.14.
All Treated 
Safety 
EX1 
Summary of Exposure to Study Treatment 
ICH E3 
 
SAC 
1.15.
 
 
 
 
 
1.16.
All Treated 
Safety 
COMP1 
Summary of Overall Compliance Based on Exposure 
 
SAC 
Disease Characteristics 
1.17.
All Treated 
Safety 
DC1 
Summary of Disease Characteristics at Initial Diagnosis  
ICH E3 ; See Table 1.4 from 
/arenv/arprod/gsk2636771/mid200331/ 
dsur_2018_01/drivers/t_dischar_init.sas 
SAC 
1.18.
All Treated 
Safety 
DC2 
Summary of Disease Characteristics at Screening  
See Table 1.5 from /arenv/arprod/ 
gsk2636771/mid200331/ 
SAC 
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Study Population Tables 
No. 
Population 
IDSL / Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
dsur_2018_01/drivers/ 
t_dischar_scr.sas  add  
Time on Enza prior study,  
1.19.
All Treated 
Safety 
LA1 
Summary of Disease Burden at Baseline 
ICH E3 
SAC 
Anti-Cancer Therapy 
1.20.
All Treated 
Safety 
AC2 
Summary of Prior Anti-Cancer Therapy 
IDSL; add "Enzalutamide received prior to 
chemotherapy", “Enzalutamide received 
following chemotherapy”  
SAC 
1.21.
All Treated 
Safety 
CM1 
Summary of Pre-Treatment Dictionary Coded Anti-Cancer 
Therapy 
IDSL  
SAC 
1.22.
All Treated 
Safety 
CM1 
Summary of Post-Treatment Dictionary Coded Anti-Cancer 
Therapy 
IDSL 
SAC 
1.23.
All Treated 
Safety 
AC3 
Summary of Number of Prior Anti-Cancer Therapy Regimens 
IDSL; include Biologic, chemotherapy, 
hormonal, immunotherapy, radioactive 
therapy, and small molecule targeted 
therapy along with radiotherapy and 
surgery  
SAC 
1.24.
All Treated 
AC4 
Summary of Best Response to Prior Enzalutamide Therapy 
 
SAC 
1.25.
All Treated 
Safety 
AC4 
Summary of the Most Recent Best Response to Prior Anti-
Cancer Therapies 
IDSL; By therapies 
SAC 
1.26.
All Treated 
Safety 
FAC1 
Summary of Post-Treatment Anti-Cancer Therapy 
IDSL; include Biologic, chemotherapy, 
hormonal, immunotherapy, radioactive 
therapy, and small molecule targeted 
therapy along with radiotherapy and 
SAC 
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Study Population Tables 
No. 
Population 
IDSL / Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
surgery 
Surgical and Medical Procedures 
1.27.
All Treated 
Safety 
OSP1  
Summary of Prior Cancer-Related Surgical Procedures  
IDSL, include follow-up surgeries 
separately if present 
SAC 
Substance Use 
1.28.
All Treated 
Safety 
SU1 
Summary of Substance Use 
IDSL, include Smoking history and alcohol 
use 
SAC 
 
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13.12.5. 
Efficacy Tables 
Efficacy: Tables 
No. 
Population 
IDSL /  
Example 
Shell 
Title  
Programming Notes 
Deliverabl
e [Priority] 
2.1.    
Modified All 
Treated Clinical 
Activity 
EFF_T1 
Summary of Confirmed and Unconfirmed Non-PD Response Rate at 
12 Weeks (PCWG2 Criteria) 
Include 95% exact confidence interval 
SAC 
2.2.  
All Treated 
Clinical Activity 
RE1a 
Summary of Investigator-Assessed Best Response (RECIST 1.1 
Criteria) (Confirmed) for Subjects with Target Lesion and/or Non-
Target Lesion at Baseline  
Including response without 
confirmation; (see Table 2.006 
present_2016_1 reporting effort) 
SAC 
2.3.  
All Treated 
Clinical Activity 
RE1a 
Summary of Investigator-Assessed Best Response (RECIST 1.1 
Criteria) (Unconfirmed) for Subjects with Target Lesion and/or Non-
Target Lesion at Baseline  
Including response with confirmation; 
(see Table 2.007 from 
present_2016_1 reporting effort) 
SAC 
2.4.  
All Treated 
Clinical Activity 
EFF_T2 
Summary of PSA50 Response for All Subjects (Confirmed) 
Including response with confirmation 
(see Table 2.008 from 
present_2016_1 reporting effort), 
provide overall results and results 
stratified by measurable vs. non-
measurable disease at baseline 
SAC 
2.5.  
All Treated 
Clinical Activity 
EFF_T2 
Summary of PSA50 Response for All Subjects (Unconfirmed) 
Including response without 
confirmation (see Table 2.009 from 
present_2016_1 reporting effort), 
provide overall results and results 
stratified by measurable vs. non-
measurable disease at baseline 
SAC 
2.6.  
All Treated 
Clinical Activity 
TTE1 
Summary of Time to PSA progression (PCWG2 criteria) 
Add footnote indicating 400 mg 
cohort not summarized individually 
due to small sample size (n=2) 
SAC 
2.7.  
All Treated 
Clinical Activity 
TTE1 
Summary of Time to radiological progression (PCWG2 criteria) 
Add footnote indicating 400 mg 
cohort not summarized individually 
due to small sample size (n=2) 
SAC 
2.8.  
All Treated 
Clinical Activity 
TTE1 
Summary of Investigator-Assessed Radiological Progression-Free 
Survival (PCWG2 Criteria) 
Add footnote indicating 400 mg 
cohort not summarized individually 
due to small sample size (n=2) 
SAC 
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13.12.6. 
Efficacy Figures 
Efficacy: Figures 
No. 
Population 
IDSL / 
Example 
Shell 
Title  
Programming Notes 
Deliverabl
e [Priority] 
2.1 
All Treated 
Clinical 
Activity 
 
Waterfall Plot of Maximum Reduction in PSA Values by Dose 
 
arenv/arprod/gsk2636771/mid2003
31/present_2018_01/drivers/f_wate
r_psa.sas 
SAC 
2.2 
All Treated 
Clinical 
Activity 
OLB12B 
Mean Change (95% CI) Change from Baseline in PSA by Time and 
Treatment 
 
 
SAC 
2.3 
All Treated 
Clinical 
Activity 
 
Spider Plot of Percent Change from Baseline in PSA values by Dose 
 
arenv/arprod/gsk2636771/mid2003
31/present_2018_01/drivers/f_spid
er_psa_1.sas 
SAC 
2.4 
All Treated 
Clinical 
Activity 
 
Waterfall Plot of Maximum Reduction in Target Lesion Diameter by 
Dose 
 
arenv/arprod/gsk2636771/mid2003
31/present_2018_01/drivers/f_delta
_p1.sas 
SAC 
2.5 
All Treated 
Clinical 
Activity 
 
Spider Plot of Percent Change from Baseline in Target Lesion 
Diameter by Dose 
 
arenv/arprod/gsk2636771/mid2003
31/present_2018_01/drivers/f_spid
er_nmc_2.sas 
SAC 
2.6 
All Treated 
Clinical 
Activity 
OEX12 
Swimming Lane Plot of Duration of Study Treatment by Dose 
 
One panel for each cohort; add labels 
of PR, PSA PD, Radiological PD, 
clinical PD, DLT, AEs leading to dose 
reduction/interruption etc. 
SAC 
2.7 
All Treated 
Clinical 
Activity 
TTE10 
Graph of Kaplan Meier Investigator-Assessed Radiological 
Progression-Free Survival Curves by dose 
Do not summarize results for the 400 
mg cohort 
SAC 
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Efficacy: Figures 
No. 
Population 
IDSL / 
Example 
Shell 
Title  
Programming Notes 
Deliverabl
e [Priority] 
2.8 
All Treated 
Clinical 
Activity 
TTE10 
Graph of Kaplan Meier Investigator-Assessed Radiological 
Progression-Free Survival Curves (overall) 
400 mg included in overall summary 
SAC 
2.9 
All Treated 
Clinical 
Activity 
TTE10 
Graph of Kaplan Meier Curves for Time to PSA Progression by dose 
Do not summarize results for the 400 
mg cohort 
SAC 
2.10 
All Treated 
Clinical 
Activity 
TTE10 
Graph of Kaplan Meier Curves for Time to PSA Progression (overall) 
400 mg included in overall summary 
SAC 
2.11 
All Treated 
Clinical 
Activity 
TTE10 
Graph of Kaplan Meier Curves for Time to Radiological Progression 
by dose 
Do not summarize results for the 400 
mg cohort 
SAC 
2.12 
All Treated 
Clinical 
Activity 
TTE10 
Graph of Kaplan Meier Curves for Time to Radiological Progression 
(overall) 
400 mg included in overall summary 
SAC 
 
13.12.7. 
 Safety Tables 
Safety: Tables 
No. 
Population 
IDSL / 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Adverse Events (AEs) 
3.1.  
All Treated 
Safety 
AE1 
 
Summary of All Adverse Events by System Organ Class and 
Preferred Term 
ICH E3 
SAC 
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Safety: Tables 
No. 
Population 
IDSL / 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
3.2.  
All Treated 
Safety 
AE3 
Summary of Common (>=5%) Adverse Events by Overall Frequency 
ICH E3 
SAC 
3.3.  
All Treated 
Safety 
AE3 
Summary of Common (>=5%) Grade 2-4 Adverse Events by Overall 
Frequency 
ICH E3 
SAC 
3.4.  
All Treated 
Safety 
AE3 
Summary of All Drug-Related Adverse Events by System Organ Class 
and Preferred Term and Maximum Grade 
ICH E3 
SAC 
3.5.  
All Treated 
Safety 
AE15 
Summary of Common (>=5%) Non-serious Adverse Events by System 
Organ Class and Preferred Term and Maximum Grade 
FDAAA, EudraCT 
 ‘ 
SAC 
3.6.  
All Treated 
Safety 
AE3 
Summary of Common (>=5%) Drug-Related Grade 2-4 Adverse 
Events by Overall Frequency 
ICH E3 
SAC 
3.7.  
All Treated 
Safety 
OAE07 
Summary of All Adverse Events by Maximum Grade  
 
SAC 
3.8.  
All Treated 
Safety 
OAE07 
Summary of Adverse Events Related to Study Treatment by Maximum 
Grade 
 
SAC 
3.9.  
All Treated 
Safety 
AE3 
Summary of Adverse Events Leading to Dose Reductions  
By preferred term 
SAC 
3.10. 
All Treated 
Safety 
AE3 
Summary of Adverse Events Leading to Dose Escalations 
By preferred term 
SAC 
3.11. 
All Treated 
Safety 
AE3 
Summary of Adverse Events Leading to Dose Interruptions  
By preferred term 
SAC 
Adverse Events of Special Interest  
3.12. 
All Treated 
Safety 
ESI1 
Summary of Characteristics of Hypocalcaemia 
 
SAC 
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Safety: Tables 
No. 
Population 
IDSL / 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
3.13. 
All Treated 
Safety 
ESI2a 
Summary of Onset and Duration of the First Occurrence of 
Hypocalcaemia 
 
SAC 
3.14. 
All Treated 
Safety 
OAE01  
Summary of Hypocalcaemia by Maximum Grade 
by AESI and preferred term 
SAC 
3.15. 
All Treated 
Safety 
AE17 
Summary of Exposure Adjusted Incidence Rate for Hypocalcaemia by 
Maximum Grade 
 
SAC 
3.16. 
All Treated 
Safety 
ESI1 
Summary of Characteristics of Increase in Creatinine 
 
SAC 
3.17. 
All Treated 
Safety 
ESI2a 
Summary of Onset and Duration of the First Occurrence of Increase in 
Creatinine 
 
SAC 
3.18. 
All Treated 
Safety 
OAE01  
Summary of Increase in Creatinine by Maximum Grade 
by AESI and preferred term 
SAC 
3.19. 
All Treated 
Safety 
AE17 
Summary of Exposure Adjusted Incidence Rate for Increase in 
Creatinine by Maximum Grade 
 
SAC 
Serious and Other Significant Adverse Events 
3.20. 
All Treated 
Safety 
AE16 
Summary of Serious Adverse Events by System Organ Class and 
Preferred Term (Number of Participants and Occurrences) 
FDAAA, EudraCT 
 
SAC 
3.21. 
All Treated 
Safety 
AE3 
Summary of Adverse Events Leading to Permanent Discontinuation of 
Study Treatment by Preferred Term 
 
SAC 
3.22. 
All Treated 
Safety 
AE3 
Summary of Serious Adverse Events by Maximum Grade 
By preferred term 
SAC 
3.23. 
All Treated 
Safety 
AE3 
Summary of Drug Related Serious Adverse Events by Maximum 
Grade 
By preferred term 
SAC 
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Safety: Tables 
No. 
Population 
IDSL / 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
3.24. 
All Treated 
Safety 
AE3 
Summary of Fatal Adverse Events  
If there are < 5 fatal AEs, only provide 
listing. 
SAC 
3.25. 
All Treated 
Safety 
AE3 
Summary of Drug Related Fatal Adverse Events 
If there are < 5 fatal AEs, only provide 
listing. 
SAC 
3.26. 
All Treated 
Safety 
AE3 
Summary of Non-Serious Drug-Related Adverse Events by 
Overall Frequency 
 
SAC 
3.27. 
All Treated 
Safety 
AE3 
Summary of Serious Drug-Related Adverse Events by Overall 
Frequency 
 
SAC 
Deaths 
3.28. 
All Treated 
Safety 
DTH1A 
Summary of Deaths  
IDSL; report time to death from last 
dose in weeks 
SAC 
3.29. 
All Treated 
Safety 
AE5 
Summary of Cardiovascular Events by maximum Grade 
See Section 8.6.1 for details. 
SAC 
Laboratory: Chemistry 
3.30. 
All Treated 
Safety 
LB1 
Summary of Chemistry Changes from Baseline 
ICH E3; include PSA, serum 
testosterone, and PTH, ionized 
calcium, vitamin D (total D, D1, D2, 
and D3), Serum Bone Markers 
(osteocalcin, Bone Specific Alk Phos, 
Serum N-telopeptide) 
SAC 
3.31. 
All Treated 
Safety 
LB1 
Summary of Percent Changes in Chemistry from Baseline 
include PSA, serum testosterone, and 
PTH, ionized calcium, vitamin D (total 
D, D1, D2, and D3), Serum Bone 
Markers (osteocalcin, Bone Specific 
Alk Phos, Serum N-telopeptide) 
SAC 
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Safety: Tables 
No. 
Population 
IDSL / 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
3.32. 
All Treated 
Safety 
OLB9C 
Summary of Worst Case Chemistry Results by Maximum Grade 
Increase Post-Baseline Relative to Baseline 
ICH E3; by visit summary rows are not 
needed 
SAC 
3.33. 
All Treated 
Safety 
OLB11B 
Summary of Worst Case Chemistry Results Relative to Normal Range 
Post-Baseline Relative to Baseline 
ICH E3 
SAC 
Laboratory: Haematology 
3.34. 
All Treated 
Safety 
LB1 
Summary of Haematology Changes from Baseline 
ICH E3; include PT, PTT, and INR 
SAC 
3.35. 
All Treated 
Safety 
LB1 
Summary of Percent Changes in Haematology from Baseline 
include PT, PTT, and INR 
SAC 
3.36. 
All Treated 
Safety 
OLB9C 
Summary of Worst Case Haematology Results by Maximum Grade 
Increase Post-Baseline Relative to Baseline 
ICH E3; by visit summary rows are not 
needed 
SAC 
3.37. 
All Treated 
Safety 
OLB11B 
Summary of Worst Case Haematology Results Relative to Normal 
Range Post-Baseline Relative to Baseline 
ICH E3 
SAC 
Laboratory: Urinalysis 
3.38. 
All Treated 
Safety 
LB1 
Summary of Urine Concentration Changes from Baseline 
ICH E3; include Urine Bone Marker 
(Urine C-telopeptide), 
SAC 
3.39. 
All Treated 
Safety 
LB1 
Summary of Percent Changes in Urine Concentration from Baseline 
include Urine Bone Marker (Urine C-
telopeptide), 
SAC 
3.40. 
All Treated 
Safety 
OUR1B 
Summary of Worst Case Urinalysis Results (Discrete or Character 
Values) Post-Baseline Relative to Baseline 
ICH E3 
 
Laboratory: Hepatobiliary (Liver) 
3.41. 
All Treated 
Safety 
LIVER1 
Summary of Liver Monitoring/Stopping Event Reporting 
IDSL 
SAC 
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Safety: Tables 
No. 
Population 
IDSL / 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
3.42. 
All Treated 
Safety 
LIVER10 
Summary of Hepatobiliary Laboratory Abnormalities 
IDSL 
SAC 
ECG 
3.43. 
All Treated 
Safety 
EG1 
Summary of ECG Findings  
IDSL 
 
SAC 
3.44. 
All Treated 
Safety 
OECG1B 
Summary of Maximum Fridericia’s QTc Values Post-Baseline 
Relative to Baseline by Category 
IDSL 
SAC 
3.45. 
All Treated 
Safety 
EG2 
Summary of Change from Baseline in ECG values by Visit 
IDSL 
SAC 
3.46. 
All Treated 
Safety 
OECG2B 
Summary of Maximum Increase in Fridericia’s QTc Values Post-
Baseline Relative to Baseline by Category 
IDSL 
SAC 
Vital Signs 
3.47. 
All Treated 
Safety 
VS1 
Summary of Change from Baseline in Vital Signs 
ICH E3 
SAC 
3.48. 
All Treated 
Safety 
OVT2B 
Summary of Worst Case Vital Signs Results by Maximum Grade 
Increase Post-Baseline Relative to Baseline 
IDSL 
SAC 
3.49. 
All Treated 
Safety 
OVTB 
Summary of Worst Case Vital Signs Results Relative to Normal 
Range Post-Baseline Relative to Baseline 
IDSL 
SAC 
LVEF 
3.50. 
All Treated 
Safety 
OLVEF1A  
Summary of Left Ventricular Ejection Fraction (%) Absolute Change 
from Baseline  
IDSL; Add "(%) Absolute" in title; 
remove column "LVEF (%)" 
SAC 
Dose Modifications 
3.51. 
All Treated 
Safety 
ODMOD1 
Summary of Dose Reductions of GSK2636771 
ICH E3 
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Safety: Tables 
No. 
Population 
IDSL / 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
3.52. 
All Treated 
Safety 
ODMOD1 
Summary of Dose Escalations of GSK2636771 
ICH E3 
SAC 
3.53. 
All Treated 
Safety 
ODMOD2 
Summary of Dose Interruptions of GSK2636771 
ICH E3 
SAC 
3.54. 
All Treated 
Safety 
ODMOD1 
Summary of Dose Reductions of Enzalutamide 
ICH E3 
SAC 
3.55. 
All Treated 
Safety 
ODMOD1 
Summary of Dose Escalations of Enzalutamide 
ICH E3 
SAC 
3.56. 
All Treated 
Safety 
ODMOD2 
Summary of Dose Interruptions of Enzalutamide 
ICH E3 
SAC 
Dose Limiting Toxicity (DLT) 
3.57. 
All Treated 
Safety 
DL1 
Summary of Dose-Limiting Toxicities during the Determinative Period 
ICH E3 
SAC 
Performance Status 
3.58. 
All Treated 
Safety 
PS1A  
Summary of ECOG Performance Status 
ICH E3 
SAC 
3.59. 
All Treated 
Safety 
PS4A  
Summary of Change in ECOG Performance Status from Baseline  
 
SAC 
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13.12.8. 
Safety Figures 
Safety: Figures 
No. 
Population 
IDSL / 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Adverse Events 
3.1.  
All Treated 
Safety 
AE10 
Plot of Common (>=5%) Adverse Events 
IDSL 
  
SAC 
Laboratory 
3.2.  
All Treated 
Safety 
LIVER9 
Scatter Plot of Maximum ALT vs. Maximum Total Bilirubin 
IDSL 
 
SAC 
3.3.  
All Treated 
Safety 
LB11 
Figure of LFT Patient Profiles for Possible Hy’s Law Subjects by Dose 
If there are subjects with 
liver events 
SAC 
3.4.  
All Treated 
Safety 
LB7 
Summary of change from Baseline in Calcium values by Dose 
(Hypocalcaemia, hypophosphatemia, creatinine increase) 
 
SAC 
ECG 
3.5.  
All Treated 
Safety 
OECG4 
Fridericia’s QTc Shifts from Baseline to Worst-case Post Baseline   
IDSL 
SAC 
 
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13.12.9. 
Pharmacokinetic Tables 
Pharmacokinetic: Tables 
No. 
Population 
IDSL / 
Example 
Shell 
Title  
Programming 
Notes 
Deliverable 
[Priority] 
PK Concentration 
4.1.  
PK concentration 
PK01 
Summary of GSK2636771 (in the presence of enzalutamide) Plasma 
Pharmacokinetic Concentration-Time Data by dose 
IDSL 
SAC 
4.2.  
PK concentration 
PK01 
Summary of Enzalutamide Plasma Pharmacokinetic Concentration-Time 
Data by Dose (with and without GSK2636771) 
IDSL 
SAC 
4.3.  
PK concentration 
PK01 
Summary of N-desmethyl enzalutamide Plasma Pharmacokinetic 
Concentration-Time Data by Dose (with and without GSK2636771) 
IDSL 
SAC 
 
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13.12.10. Pharmacokinetic Figures 
Pharmacokinetic: Figures 
No. 
Population 
IDSL / 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
PK 
4.1.  
PK concentration 
PK16a 
Individual GSK2636771 (in the presence of enzalutamide) 
Concentration-Time Plots (Linear and Semi-log) - Dose 
Escalation Phase only 
IDSL 
SAC 
4.2.  
PK concentration 
PK17 
Mean GSK2636771 (in the presence of enzalutamide) 
Concentration-Time Plots (Linear and Semi-log) by Dose - Dose 
Escalation Phase only 
IDSL 
SAC 
4.3.  
PK concentration 
PK18  
Median GSK2636771 (in the presence of enzalutamide) 
Concentration-Time Plots (Linear and Semi-log) by Dose - Dose 
Escalation Phase only 
IDSL 
SAC 
4.4.  
PK concentration 
PK16a 
Individual Enzalutamide Concentration-Time Plots (Linear and 
Semi-log) - Dose Escalation Phase only (with and without 
GSK2636771) 
IDSL 
SAC 
4.5.  
PK concentration 
PK17 
Mean Enzalutamide Concentration-Time Plots (Linear and Semi-
log) by Dose- Dose Escalation Phase only (with and without 
GSK2636771) 
IDSL 
SAC 
4.6.  
PK concentration 
PK18  
Median Enzalutamide Concentration-Time Plots (Linear and 
Semi-log) by Dose- Dose Escalation Phase only (with and 
without GSK2636771) 
IDSL 
SAC 
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Pharmacokinetic: Figures 
No. 
Population 
IDSL / 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
4.7.  
PK concentration 
PK16a 
Individual N-desmethyl enzalutamide Concentration-Time Plots 
(Linear and Semi-log) - Dose Escalation Phase only (with and 
without GSK2636771) 
IDSL 
SAC 
4.8.  
PK concentration 
PK17 
Mean N-desmethyl enzalutamide Concentration-Time Plots 
(Linear and Semi-log) by Dose- Dose Escalation Phase only 
(with and without GSK2636771) 
IDSL 
SAC 
4.9.  
PK concentration 
PK18  
Median N-desmethyl enzalutamide Concentration-Time Plots 
(Linear and Semi-log) by Dose- Dose Escalation Phase only 
(with and without GSK2636771) 
IDSL 
SAC 
4.10. 
PK Concentration 
PK19 
Mean enzalutamide and GSK2636771 (by dose) Concentration-
Time Plots (with and without GSK2636771) 
Plot GSK2636771 concentrations 
by dose 
SAC 
4.11. 
PK Concentration 
PK19 
Mean N-desmethyl enzalutamide and GSK2636771 (by dose) 
Concentration-Time Plots (with and without GSK2636771) 
Plot GSK2636771 concentrations 
by dose 
SAC 
 
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13.12.11. Biomarker Tables 
Biomarker: Tables 
No. 
Population 
IDSL / 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
5.1 
Biomarker 
BIO_T1 
 Summary of Conversion (>5 cells/mL dropping to ≤5 cells/mL) from Baseline 
in CTCs by Visit 
 
SAC 
5.2 
All Screened 
BIO_T2 
Summary of Frequency of PTEN Loss (H-Score ≤ 30) at Screening 
 
SAC 
5.3 
Biomarker 
BIO_T3 
Categorization of PTEN loss by Sequencing (homozygous vs 
heterozygous) 
 
SAC 
 
 
13.12.12. Biomarker Figures 
Biomarker: Tables 
No. 
Population 
IDSL / 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
 
5.1 
Biomarker 
BIO_F1 
Heatmap Display of 2 or More Gene Alterations by Subject 
 
SAC 
 
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13.12.13. ICH Listings 
ICH: Listings 
No. 
Population 
IDSL / Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Subject Disposition 
1.  
All Enrolled 
ES7 
Listing of Reasons for Screen Failure 
Journal Guidelines 
SAC 
2.  
All Treated Safety 
ES2  
Listing of Reasons for Study Withdrawal 
ICH E3 
SAC 
3.  
All Treated Safety 
SD2 
Listing of Reasons for Study Treatment 
Discontinuation 
ICH E3 
SAC 
4.  
All Treated Safety 
TA1  
Listing of Planned and Actual Treatments 
IDSL 
SAC 
Protocol Deviations 
5.  
All Treated Safety 
DV2 
Listing of Important Protocol Deviations  
ICH E3 
 
SAC 
6.  
All Treated Safety 
IE3 
Listing of Participants with Inclusion/Exclusion Criteria 
Deviations 
ICH E3 
SAC 
Populations Analysed 
7.  
All Treated Safety 
SP3 
Listing of Participants Excluded from Any Population 
ICH E3 
 
SAC 
Demographic and Baseline Characteristics 
8.  
All Treated Safety 
DM2  
Listing of Demographic Characteristics 
ICH E3 
SAC 
9.  
All Treated Safety 
DM9  
Listing of Race 
ICH E3 
SAC 
Prior and Concomitant Medications 
10.  
All Treated Safety 
CP_CM3  
Listing of Concomitant Medications 
IDSL 
 
SAC 
Exposure and Treatment Compliance 
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ICH: Listings 
No. 
Population 
IDSL / Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
11.  
All Treated Safety 
OEX3A 
Listing of Exposure to Enzalutamide 
ICH E3 
SAC 
12.  
All Treated Safety 
OEX3A 
Listing of Exposure to GSK2636771 
 
SAC 
13.  
All Treated Safety 
COMP2 
Listing of Study Treatment Compliance 
 
SAC 
14.  
All Treated Safety 
ODMOD10a  
Listing of Dose Reductions  
 
SAC 
15.  
All Treated Safety 
ODMOD10a  
Listing of Dose Escalations 
 
SAC 
16.  
All Treated Safety 
ODMOD11a  
Listing of Dose Interruptions  
 
SAC 
Response 
17.  
Modified All Treated 
Clinical Activity 
EFF_L1 
Listing of Overall Unconfirmed Response at Week 12 
List all data used for Table 2.1 by 
cohort and subject – see Listing 2.010 
from reporting effort present_2016_1 
SAC 
18.  
Modified All Treated 
Clinical Activity 
EFF_L1 
Listing of Overall Confirmed Response at Week 12 
List all data used for Table 2.1 by 
cohort and subject – see Listing 2.010 
from reporting effort present_2016_1 
SAC 
19.  
All Treated Clinical 
Activity 
LA2 
Listing of Investigator Assessed Target Lesion 
Assessments (RECIST 1.1 Criteria) 
 
SAC 
20.  
All Treated Clinical 
Activity 
LA3 
Listing of Investigator-Assessed Non-Target Lesion 
Assessments (RECIST 1.1 Criteria) 
 
SAC 
21.  
All Treated Clinical 
Activity 
LA4 
Listing of Investigator -Assessed New Lesions 
(RECIST 1.1 Criteria)  
 
SAC 
22.  
All Treated Clinical 
Activity 
 RE5 
Listing of Investigator -Assessed Tumour 
Responses(RECIST1.1 Criteria)  
Include with and without confirmation in 
same listing 
SAC 
23.  
All Treated Clinical 
Activity 
OLB7 
Listing of Subject PSA Value by Visit/Week 
 
SAC 
24.  
All Treated Clinical 
Activity 
LA2 
Listing of Subject Bone Scan Results by Visit/Week 
Use lesion dataset where lsorgcd=BE 
SAC 
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ICH: Listings 
No. 
Population 
IDSL / Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
25.  
All Treated Clinical 
Activity 
TTE9 
Listing of Time to PSA Progression 
 
SAC 
26.  
All Treated Clinical 
Activity 
TTE9 
Listing of Time to Radiological Progression 
 
SAC 
27.  
All Treated Clinical 
Activity 
TTE9 
Listing of Radiographic Progression-Free Survival 
 
SAC 
Adverse Events 
28.  
All Treated Safety 
AE8 
Listing of All Adverse Events 
ICH E3 
SAC 
29.  
All Treated Safety 
AE7 
Listing of Subject Numbers for Individual Adverse 
Events 
ICH E3 
SAC 
30.  
All Treated Safety 
AE2 
Listing of Relationship Between System Organ Class, 
Preferred Terms and Verbatim Text  
IDSL 
SAC 
Serious and Other Significant Adverse Events 
31.  
All Treated Safety 
AE8 
Listing of Fatal Serious Adverse Events 
ICH E3 
SAC 
32.  
All Treated Safety 
AE8 
Listing of Non-Fatal Serious Adverse Events 
ICH E3 
SAC 
33.  
All Treated Safety 
AE14 
Listing of Reasons for Considering as a Serious 
Adverse Event 
ICH E3 
SAC 
34.  
All Treated Safety 
AE8 
Listing of Adverse Events Leading to Permanent 
Discontinuation of Study Treatment 
ICH E3 
SAC 
35.  
All Treated Safety 
AE8 
Listing of Adverse Events Leading to Withdrawal from 
Study 
ICH E3 
SAC 
Dose Limiting Toxicities 
36.  
All Treated Safety 
DL3 
Listing of Dose-Limiting Toxicities (DLTs) During the 
Determinative Period 
 
SAC 
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ICH: Listings 
No. 
Population 
IDSL / Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Deaths 
37.  
All Treated Safety 
DTH3 
Listing of Deaths 
ICH E3 
SAC 
Hepatobiliary (Liver) 
38.  
All Treated Safety 
MH2 
Listing of Medical Conditions for Participants with 
Liver Stopping Events 
IDSL 
SAC 
39.  
All Treated Safety 
SU2 
Listing of Substance Use for Participants with Liver 
Stopping Events 
IDSL 
SAC 
All Laboratory 
40.  
All Treated Safety 
LB5A 
Listing of All Laboratory Data for Participants with Any 
Value Outside Normal Range 
ICH E3; include PSA, serum 
testosterone, parathyroid hormone, PT, 
PTT, INR 
SAC 
41.  
All Treated Safety 
LB5A 
Listing of All Bone Biomarker Laboratory Data 
Include ionized calcium, vitamin D 
(total D, D1, D2, and D3), Urine Bone 
Marker (Urine C-telopeptide), Serum 
Bone Markers (osteocalcin, Bone 
Specific Alk Phos, Serum N-
telopeptide) 
SAC 
42.  
All Treated Safety 
LB14 
Listing of Laboratory Data with Character Results 
ICH E3 
SAC 
43.  
All Treated Safety 
UR2A 
Listing of Urinalysis Data for Participants with Any 
Value of Potential Clinical Importance 
ICH E3 
SAC 
ECG 
44.  
All Treated Safety 
EG3  
Listing of All ECG Values for Participants with Any 
Value of Potential Clinical Importance 
IDSL 
SAC 
45.  
All Treated Safety 
EG5 
Listing of All ECG Findings for Participants with an 
Abnormal ECG Finding 
IDSL 
SAC 
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ICH: Listings 
No. 
Population 
IDSL / Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
46.  
All Treated Safety 
OECG5A 
Listing of Fridericia’s QTc Values of Potential Clinical 
Importance 
 
SAC 
Vital Signs 
47.  
All Treated Safety 
OVT7A 
Listing of Vital Signs with Values of Potential Clinical 
Importance 
 
SAC 
Performance Status 
48.  
All Treated Safety 
PS5A 
Listing of Performance Status 
 
SAC 
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13.12.14. Non-ICH Listings 
Non-ICH: Listings 
No. 
Population 
IDSL / 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Disease Characteristics 
49.  
All Treated 
Safety 
DC3 
Listing of Disease Characteristics at Initial Diagnosis         
 
SAC 
50.  
All Treated 
Safety 
DC4 
Listing of Disease Characteristics at Screening 
 
SAC 
51.  
All Treated 
Safety 
MD2 
Listing of Metastatic Disease at Screening  
 
SAC 
52.  
All Treated 
Safety 
MH2 
Listing of Current and Past Medical Conditions  
Only required is conditions are not 
MedDRA coded 
SAC 
Anti-Cancer Therapy 
53.  
All Treated 
Safety 
AC6 
Listing of Prior Anti-Cancer Therapy  
 
SAC 
54.  
All Treated 
Safety 
AC7 
Listing of Prior Anti-Cancer Radiotherapy  
 
SAC 
55.  
All Treated 
Safety 
AC6 
Listing of Follow-up Anti-Cancer Therapy  
 
SAC 
56.  
All Treated 
Safety 
AC7 
Listing of Follow-up Anti-Cancer Radiotherapy  
 
SAC 
Surgical Procedures 
57.  
All Treated 
Safety 
OSP3 
Listing of Prior/Post-Treatment Cancer Related Surgical Procedures  
 
SAC 
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Non-ICH: Listings 
No. 
Population 
IDSL / 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
Substance Use 
58.  
All Treated 
Safety 
SU2 
Listing of Substance Use  
 
SAC 
Responses 
59.  
All Treated 
Clinical 
Activity 
RE6 
Listing of Subjects with Progressive Disease Based on Clinical Assessment 
 
SAC 
LVEF 
60.  
All Treated 
Safety 
OLVEF2A  
Listing of Left Ventricular Ejection Fraction Results 
Option 
SAC 
PK 
61.  
PK 
Concentration 
PK07  
Listing of GSK2636771 (in the presence of enzalutamide)  
Pharmacokinetic Concentration-Time Data by Dose  
IDSL 
SAC 
62.  
PK 
Concentration 
PK07  
Listing of Enzalutamide Pharmacokinetic Concentration-Time Data by 
Dose  
IDSL 
SAC 
63.  
PK 
Concentration 
PK07  
Listing of N-desmethyl enzalutamide Pharmacokinetic Concentration-
Time Data by Dose  
IDSL 
SAC 
Other 
64.  
All Treated 
Safety 
NICH_L1 
Listing of Subjects Received Blood Product or Blood Supportive Care 
Including all data in BLDPROD dataset 
SAC 
65.  
All Treated 
Safety 
 
Listing of Circulating Tumour Cells (CTC) Concentrations 
arenv/arprod/gsk2636771/p3b115717/sac/
drivers/t_ctc.sas; add column indicating 
whether there have been conversion to < 
5 cells/7.5mL from week 1. 
SAC 
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Non-ICH: Listings 
No. 
Population 
IDSL / 
Example 
Shell 
Title  
Programming Notes 
Deliverable 
[Priority] 
66.  
All Treated 
Safety 
OLIVER5 
Listing of Liver Chemistry Assessments for Subjects with Liver Signal/Events 
 
SAC 
67.  
All Treated 
Safety 
PREG1a 
Listing of Pregnancies 
update for partners who became pregnant 
SAC 
adverse 
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13.13. 
Appendix 13: Example Mock Shells for Data Displays 
Data Display Specification will be made available on request 
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