Clinical trial NCT01587703
Conditions: Carcinoma, Midline
Keywords: BRD3 GSK525762 NUT Midline Carcinoma MYCN-amplified Solid Tumor BRD4 BET inhibitor bromodomains NMC Colorectal C ancer Small Cell Lung Cancer Multiple Myeloma Neuroblastoma Oncology
Sponsor: GlaxoSmithKline
Start date: 2012-03-28; Completion date: 2019-07-29
Enrollment: 196 participants; Allocation: NON_RANDOMIZED; Intervention model: SINGLE_GROUP

Brief summary:
This study is divided into two parts; Part 1 of the study is a dose escalation phase to select the recommended dose for Part 2 based on the safety, pharmacokinetic, and pharmacodynamic profiles observed after oral administration of GSK525762 in the following subjects: NMC, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), colorectal cancer (CRC), neuroblastoma (NB), castration resistant prostate cancer (CRPC), triple negative breast cancer (TNBC), estrogen receptor positive (ER positive) breast cancer, and MYCN driven solid tumor subjects. Part 2 of the study will explore the safety, tolerability, pharmacokinetics, pharmacodynamics, and clinical activity of the recommended dose from Part 1 in cohorts comprised of NMC, small cell lung cancer (SCLC), castration resistant prostate cancer (CRPC), triple negative breast cancer (TNBC), and estrogen receptor positive (ER positive) breast cancer subjects. Approximately 60 subjects will be enrolled in the Part 1 and approximately 150 subjects will be enrolled in Part 2. A sub-study will be opened in Part 1 to approximately 10-12 subjects in the United States to investigate the relative bioavailability of the besylate tablet compared to the amorphous free-base tablet at the maximum tolerated dose (MTD) or recommended phase 2 dosing (RP2D), the effect of high-fat high-calorie meal on the bioavailability of the besylate tablet at the MTD or RP2D and the dose proportionality of 2 doses of GSK525762 administered as besylate tablet.

Detailed description:

Arms: arm 1: All subjects will follow a 3+3 dose escalation design for GSK525762 and the dose will be escalated based on all available data, including PK data and the safety profile of prior cohorts, as well as the recommended dose from the Neuenschwander- Continuous Reassessment Method (N-CRM) design. arm 2: Up to 150 additional subjects with NMC and other solid tumors may be enrolled in expansion cohorts. The recommended Phase 2 (Part 2) dose (RP2D) of GSK525762 will be determined based on the MTD or biologically active dose (example: clinical response), the safety profile and available pharmacodynamic data generated from all subjects in Parts 1 arm 3: Tablet and amorphous tablet in one of the two sequences (ABCD or BACD). Where Treatment A: RP2D/MTD as amorphous free-base tablet + low dose stable isotope in solution, fasted Treatment B: RP2D/MTD as besylate tablet + low dose stable isotope in solution, fasted. Treatment C: half to one-third of RP2D/MTD as besylate tablet + low dose stable isotope in solution, fasted. Treatment D: RP2D/MTD as besylate tablet, fed
Interventions: intervention 1: GSK525762
Intervention descriptions: intervention 1: Begin at Dose Level 1 and increase up to 2 fold

Protocol documents:
Prot_000.pdf: 
2 0 1 1 N 1 1 8 5 9 9 _ 0 9
C O N FI D E N TI A L
T h e Gl a x o S mit h Kli n e gr o u p of c o m p a ni e s
B E T 1 1 5 5 2 1
1
TI T L E P A G E
Di visi o n: W orl d w i de De vel o p me nt
I nf or m ati o n T y pe: Pr ot oc ol A me n d me nt
Title:
A p hase I/II o pe n -la bel, d ose escalati o n st u d y t o i n vesti gate t he 
safety, p har mac o ki netics, p har mac o d y n a mics a n d cli nical 
acti vit y of G S K 5 2 5 7 6 2 i n s u bjects wit h N U T mi dli ne carci n o ma 
( N M C) a n d ot her ca ncers
C o m p o u n d N u m ber:
G S K 5 2 5 7 6 2
De vel o p me nt P h ase:
I
Effecti ve D ate:
2 4 -F E B - 2 0 1 7
A ut h or (s):
P P D
 
C o p y ri g ht 2 0 1 7 t he Gla x o S mit h Kli ne gr o u p of c o m pa nies.  All ri g hts reser ve d.  
U na ut h orise d c o p yi n g or use of t his i nf o r mati o n is pr o hi bite d.


2011N118599_09
CONFIDENTIAL
The GlaxoSmithKline group of companies
BET115521
2
Revision Chronology
GlaxoSmithKline 
Document Number
Date
Version
2011N118599_00
2011-NOV-11
Original
2011N118599_01
2012-JAN-09
Amendment No. 1
Amendment 1 applies to all study sites.  Modifications include updated medical 
monitoring information due to a personnel change on the GSK team. In addition, the 
following review of the protocol by the FDA, the following changes are made: For Part 1, 
the starting dose of GSK525762 is reduced from 5 mg/day to 2 mg/day. Cardiac troponin 
T level assessments are required as a part of the inclusion criteria and thereafter.   An 
observation of CTCAE Grade 2 drug related toxicity, including grade 2 troponin T 
elevation, in one subject will end accelerated dose titration in Part 1.  Subjects with a
history of gastrointestinal bleeding or active bleeding (positive guaiac fecal occult blood 
monitoring) will be excluded.  In addition, wording for dose escalation decisions has 
been modified to state that no more than a 2-fold increase in dose will occur between 
successive cohorts.  A staggered dosing approach will be implemented in the 3+3 dosing 
design to minimize potential for toxicity in multiple subjects. Alternative dosing 
regimens will not be implemented without consultation with FDA and a protocol
amendment.  For Part 2 of the trial, stopping rules based on lack of efficacy and the 
futility rule have been modified. Additionally the disease assessment scans may be 
reviewed retrospectively by an independent radiologist.  Finally, multiple Time and 
Event Tables have been revised for consistency across Part 1 and Part 2 of the protocol.
2011N118599_02
2012-AUG-29
Amendment No. 2
Amendment 02 applies to all study sites.  Changes via Amendment 02 include the 
addition of subjects with tumor types other than NMC [including multiple myeloma 
(MM), small cell lung cancer (SCLC), colorectal cancer (CRC), neuroblastoma (NB), and 
any solid tumor that demonstrates N-Myc amplification or over expression (such as 
NSCLC with N-myc amplification)] and associated changes in the study design and 
inclusion criteria; definition of adult subjects as those 16 and older; addition of pediatric 
subjects 12 to ≤15 years old; modification of the initial staggered dosing schedule to 
shorten the dose escalation period from 6 weeks to 4 weeks; allowance for treatment 
beyond tumor progression (decision made in consultation with GSK Medical Monitor); 
minor clarifications to the Risk Assessment section; updates to Exploratory 
Objectives/Endpoints to ensure adequate assessment of the effect of drug on tumor 
biology; and addition of drug preparation guidelines for GSK525762 administered via an 
enteral feeding tube.
2011N118599_03
2014-FEB-04
Amendment No. 03
Amendment 3 applies to all study sites and includes the addition of the NMC 
Pharmacodynamic (PD) Expansion Cohort to evaluate the pharmacodynamic effects of 


2011N118599_09
CONFIDENTIAL
The GlaxoSmithKline group of companies
BET115521
3
GSK525762 across the predicted efficacious dose range at doses that have been 
previously cleared during 3+3 dose escalation.  The collection of ECGs, PK samples and 
liver chemistry were clarified or corrected. The inclusion of a pediatric cohort in Part1B, 
implemented in protocol amendment 2, was clarified and emphasis was added regarding 
the preservation of reproductive capacity.
2011N118599_04
2014-OCT-06
Amendment No 04
Amendment 4 applies to all study sites and includes the addition of subjects with the 
following solid tumor types: castration-resistant prostate cancer (CRPC), triple negative 
breast cancer (TNBC), estrogen receptor positive breast cancer (ER positive), and non-
small cell lung cancer (NSCLC).  Multiple myeloma (MM), a haematological malignancy 
previously included in the trial, is now removed from this trial as it is included in a 
separate trial open for hematologic malignancies with dose escalation to better define the 
benefit/risk balance. Additional details of twice daily (BID) dosing during dose escalation 
have been included. A Besylate Sub-Study has been added to determine the relative 
bioavailability (BA), food effect, and dose proportionality of the besylate formulation of 
GSK525762 at or near the MTD. An update to inclusion criteria has been made to allow 
subjects with evaluable disease to be enrolled in the NMC PD cohort. An updated 
imaging schedule for NMC subjects has been included.
2011N118599_05
2015-MAR-24
Amendment No. 5
Amendment 5 applies to all study sites and includes the following additional expansion 
cohorts for Part 2 of the trial: castration-resistant prostate cancer (CRPC), triple negative 
breast cancer (TNBC), estrogen receptor positive breast cancer (ER positive) and small 
cell lung cancer (SCLC). An update was included regarding the Besylate Sub-Study to 
clarify that this sub-study would only be conducted at centers in the United States. The 
pediatric cohort in Part 1B was removed for further evaluation in a separate study. An 
update to the QTc management guidelines has been included.  
2011N118599_06
2015-JUN-19
Amendment No. 6
Amendment 6 applies to all study sites and includes updated guidance on contraception 
use based on emerging data from preclinical studies. Section 6.4.6 was updated to clarify 
how the Holter monitoring data will be reviewed and analyzed. Additionally, updates 
were made throughout to correct minor inconsistencies and provide further clarification, 
specifically with the Time and Events Tables. Furthermore, the dosing schedule was 
updated from a staggered (1,3,5,7) dosing schedule in the first two weeks to a continuous 
daily dosing schedule. Finally, after an internal QTc analysis and evaluation of cardiac 
safety data collected from all subjects up to the 100 mg QD cohort available by May 15 
2015, the 48-hour telemetry requirement has been removed for all parts of the study and 
the frequency of Holter monitoring has been decreased in Part 1.
2011N118599_07
2016-MAR-10
Amendment No. 7
Amendment 07 updates were made, to include the final dose and regimen for Part 2, 
which was determined to be 75 mg once daily based on emerging data from Part 1 and 


2011N118599_09
CONFIDENTIAL
The GlaxoSmithKline group of companies
BET115521
4
Besylate Sub-Study; to clarify that the besylate salt tablets will be the formulation used 
for subjects enrolled in Part 2 (and potentially for ongoing or newly enrolled subjects in 
Part 1); to update required number of subjects to be enrolled in the Part 1; to update the 
subject and study completion details; to update the Visit window for Discontinuation and 
End of Treatment; to update diagnosis criteria of NMC for Part 1 and 2 for NMC 
subjects; to update dosing, handling and storage instruction for GSK525762 Besylate 
tablet; to modify the meals and dietary restrictions based on the results of the besylate 
sub-study, the fasting requirement is being lifted , except on Serial PK sampling days in 
Part 2 (Week 1 and Week 4); to include the details about interim and final analysis. 
Additionally, following updates were in the time and event table, 12-lead ECGs 
monitoring for prolonged QTcF for Part 1 and 2 was updated, tumor sampling time point 
was updated for Part 1 and 2; optional Sweat PK sampling for Part1 was removed; 
optional saliva sampling for time points for part 1 was updated; pain assessments was 
included for Part 2; W1D1, ECHO was made optional for Part 2; and CT Scan, MRI and 
PET scan detail were updated for Part 2.
2011N118599_08
2016-DEC-02
Amendment No. 8
Amendment 8 includes changes as the result of the Dear Investigator Letter, dated 16 
November 2016 which outlines the updated thrombocytopenia management guidelines, 
as outlined in the Dear Investigator Letter, dated 16 November 2016. This amendment 
also includes increased coagulation monitoring for Part 2 (added at W2D1, W3D1 and 
changed from q8W to q4W after Week 13), addition of Factor VII monitoring in Part 2 
(at Screening, W3D1 and reflex testing if PT or INR are ≥1.5XULN) and addition of 
laboratory values required prior to performing the post-dose biopsy. 
2011N118599_09
2017-FEB-24
Amendment No. 9
Amendment 9 applies to all global sites. Updates were made throughout the protocol to 
correct minor inconsistencies, spelling errors and provide further clarification. The 
following changes have been made based on comments from regulatory agencies during 
review of this protocol and other GSK525762 protocols: addition of exclusion criteria for 
exclusionary medications; updated exclusion of bleeding to include all history of 
bleeding and added known bleeding disorders; addition of laboratory monitoring required 
prior to surgeries, as described in Section 6.4.6.2 and Section 6.8.1; addition of guidance 
for dose reduction levels, as described in Section 7.7.1; updated dose adjustment/stopping 
safety criteria, as described in Table 24 and Table 25; updated prohibited medications in 
Section 8.2.1. In addition, other changes include: addition of a GIST cohort in Part 2, 
including background information, updated endpoints, overall Part 2 sample size, futility 
information, eligibility criteria and Section 11, Data Analysis and Statistical 
Considerations; updated Section 1.5 Risk Assessment to include current available data; 
removal of cytokines throughout protocol; updated sample size for MTD dose level in 
Part 1; update to contraception use in Inclusion 9 and 10 and clarifications in Section 9 
Lifestyle Requirements; removal of Holter monitoring; changes to Part 1 Time and 
Events Tables which includes removal of certain ECG time points, change from required 
to optional for urine PK samples and certain PK/ECG/biomarker tests (see Table 12 to 
Table 14), addition of Factor VII assay testing, additional lab samples at Week 7 and 
Week 11, change in timing of on-treatment biopsy; changes to Part 2 Time and Events 


2011N118599_09
CONFIDENTIAL
The GlaxoSmithKline group of companies
BET115521
5
Tables which includes additional lab samples at Week 7 and 11 and increase in Factor 
VII testing, addition of pregnancy/testosterone test at W1D1; change in timing of on-
treatment biopsy and removal of an ECHO time point; change to the pregnancy reporting 
guidelines to 24 hours; addition of wording that subjects are to abstain from consuming 
certain fruits in Section 7.3; updates to Section 8, Concomitant Medications and Non-
Drug Therapies to reorganize and update the prohibited, cautionary medication tables and 
drug interaction information; removal of fever and diarrhea information from Appendix 
3. Additionally, Appendix 3 was updated with the current GSK Liver Event and follow-
up information, but the liver event criteria did not change.


P P D
P P D
P P D


2 0 1 1 N 1 1 8 5 9 9 _ 0 9
C O N FI D E N TI A L
B E T 1 1 5 5 2 1
7
S P O N S O R/ M E DI C A L M O NI T O R I N F O R M A T I O N P AG E
Me dic al M o nit or a n d
S p o ns or C o nt act I nf or m ati o n:
R ol e
N a m e
D a y 
Ti m e 
P h o n e 
N u m b er
Aft er -h o ur s 
P h o n e/ C ell/
P a g er 
N u m b er
F a x 
N u m b er
G S K A d dr e s s
Pri m ary 
M e dic al 
M o nit or
 
M D, P h D
 
Gl ax o S mit h Kli n e
1 2 5 0 S o ut h C oll e g evill e R o a d, 
U P 4 4 1 0
C oll e g evill e, P A 1 9 4 2 6, U S A
S ec o n d ary 
M e dic al 
M o nit or
 
M D, 
P h D
Gl ax o S mit h Kli n e
1 2 5 0 S o ut h C oll e g evill e R o a d
M ailst o p U P 4 4 1 0
C oll e g evill e, P A 1 9 4 2 6, U S A
S p o ns or Re gistere d A d dress:
P P D
Gla x o S mit h Kli ne Researc h & De vel o p me nt Li mite d
9 8 0 Great West R oa d
Bre ntf or d
Mi d dlese x, T W 8 9 G S
U K
Gla x o S mit h Kli ne
Fi ve M o ore Dri ve 
P. O. 1 3 3 9 8
Researc h Tria n gle Par k, N C 2 7 7 0 9 -3 3 9 8, U S A
Tele p h o ne: 
I n s o me c o u ntries, t he cli nical trial s p o ns or ma y be t he l ocal Gla x o S mit h Kli ne affiliate 
c o m pa n y ( or desi g nee). If a p plica ble, t he details of t he alter nati ve S p o ns or a n d c o ntact 
pers o n i n t he territ or y  will be pr o vi de d t o t he rele va nt re g ulat or y a ut h orit y as part of the 
cli nical trial a p plicati o n.
Re g ulat or y  A ge nc y Ide ntif y i n g N u m ber(s):  I n vesti gati o nal Ne w Dr u g (I N D) # 
I ND 1 1 2 9 4 2
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D


2011N118599_09
CONFIDENTIAL
BET115521
8
INVESTIGATOR PROTOCOL AGREEMENT PAGE
For protocol number BET115521
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


2011N118599_09
CONFIDENTIAL
BET115521
9
TABLE OF CONTENTS
PAGE
ABBREVIATIONS .........................................................................................................14
PROTOCOL SYNOPSIS...............................................................................................17
1.
INTRODUCTION....................................................................................................21
1.1.
Background ................................................................................................21
1.2.
Study Population Rationale.........................................................................21
1.2.1.
NUT midline carcinoma................................................................21
1.2.2.
Other tumor types........................................................................22
1.3.
Dose Rationale ...........................................................................................25
1.3.1.
Human Pharmacokinetics............................................................25
1.3.2.
Starting dose ...............................................................................25
1.3.3.
Predicted therapeutic dose range ................................................28
1.3.4.
Dose escalation steps..................................................................28
1.3.5.
BID Dose Cohort..........................................................................28
1.3.5.1.
Preclinical Rationale...................................................28
1.3.5.2.
Clinical Rationale........................................................28
1.3.6.
Doses for Besylate Bioavailability/Food Effect/Dose 
Proportionality Sub-Study ............................................................29
1.4.
Rationale for Study and Endpoints..............................................................29
1.5.
Risk Assessment ........................................................................................30
2.
OBJECTIVES, ENDPOINTS, HYPOTHESES FOLLOWING QD AND/OR 
BID DOSING SCHEDULES ...................................................................................34
3.
INVESTIGATIONAL PLAN.....................................................................................36
3.1.
Study Design/Schematic.............................................................................36
3.2.
Discussion of Design ..................................................................................37
3.2.1.
Part 1 Dose Escalation ................................................................37
3.2.2.
Dose Escalation and Schedule ....................................................38
3.2.2.1.
Accelerated Dose Escalation in Part 1........................39
3.2.2.2.
3+3 Dose Escalation in Part 1 ....................................39
3.2.2.3.
Biopsy and PET Cohorts during Dose 
Escalation Phase........................................................40
3.2.2.4.
Alteration of Schedule ................................................40
3.2.2.5.
BID Dosing Cohort......................................................41
3.2.2.6.
Intra-Subject Dose Escalation ....................................41
3.2.3.
Dose Limiting Toxicity (DLT)........................................................42
3.2.4.
Maximum Tolerated Dose (MTD) and Recommended 
Phase 2 Dose (RP2D) .................................................................42
3.2.5.
Part 1...........................................................................................43
3.2.5.1.
NMC Pharmacodynamic Expansion Cohort................43
3.2.6.
Bioavailability, Food Effect, and Dose Proportionality 
Besylate Sub-Study .....................................................................43
3.2.7.
Part 2 Expansion Cohort..............................................................44
4.
STUDY POPULATION...........................................................................................51
4.1.
Number of Subjects ....................................................................................51


2011N118599_09
CONFIDENTIAL
BET115521
10
4.2.
Eligibility Criteria .........................................................................................51
4.2.1.
Inclusion Criteria..........................................................................51
4.2.1.1.
Specific Eligibility Criteria for Part 2 CRPC 
Expansion Cohort.......................................................54
4.2.1.2.
Specific Eligibility Criteria for Part 2 GIST 
Cohort ........................................................................55
4.2.2.
Exclusion Criteria.........................................................................55
4.2.3.
Screen Failures............................................................................57
4.2.4.
Permanent Discontinuation from Study Treatment and 
Subject Completion Criteria .........................................................57
4.2.4.1.
Permanent Discontinuation from Study 
Treatment...................................................................57
4.2.4.2.
Subject and Study Completion ...................................58
5.
TIME AND EVENTS TABLES ................................................................................59
6.
STUDY ASSESSMENTS AND PROCEDURES .....................................................83
6.1.
Study Visits.................................................................................................83
6.1.1.
Assessments ...............................................................................83
6.1.2.
Visit Windows ..............................................................................83
6.2.
Baseline Assessment for NMC Subjects.....................................................84
6.3.
Baseline Assessment for Non-NMC Subjects .............................................84
6.4.
Safety .........................................................................................................85
6.4.1.
Physical Examinations.................................................................85
6.4.2.
ECOG..........................................................................................85
6.4.3.
Vital Signs....................................................................................85
6.4.4.
Echocardiogram (ECHO).............................................................85
6.4.5.
Safety Electrocardiograms...........................................................85
6.4.6.
Clinical Laboratory Assessments .................................................87
6.4.6.1.
Troponin.....................................................................88
6.4.6.2.
Clinical Laboratory Assessments Required 
Prior to Scheduled Surgeries......................................88
6.5.
Efficacy.......................................................................................................88
6.5.1.
Disease Assessment ...................................................................88
6.6.
Pharmacokinetics .......................................................................................88
6.6.1.
Blood Sample Collection..............................................................88
6.6.2.
Plasma Sample Analysis .............................................................89
6.6.3.
Urine Collection ...........................................................................89
6.6.4.
Caffeine, Alcohol, and Tobacco ...................................................89
6.6.5.
Activity .........................................................................................89
6.7.
Pharmacodynamics ....................................................................................89
6.7.1.
Rationale for 18FDG-PET .............................................................89
6.7.2.
Assessments for PET ..................................................................90
6.8.
Translational Research...............................................................................90
6.8.1.
Tumor Tissue Collection ..............................................................90
6.8.2.
Whole blood LPS-induced IL-6, Plasma Cytokines, and 
Plasma Protein Biomarkers..........................................................91
6.8.2.1.
LPS-induced (Stimulated) Whole Blood Ex 
Vivo ............................................................................91
6.8.2.2.
Systemic (Unstimulated) Plasma for Cytokines, 
Chemokines, and Acute Phase Proteins.....................91
6.8.2.3.
Whole Blood mRNA....................................................92


2011N118599_09
CONFIDENTIAL
BET115521
11
6.8.3.
Biomarker Blood Sample Timing and Schedule ...........................92
6.8.4.
Exploratory Safety Biomarker Blood Samples..............................92
6.9.
Adverse Events (AE) and Serious Adverse Events (SAE)...........................92
6.9.1.
Definition of an AE.......................................................................92
6.9.2.
Definition of a SAE.......................................................................93
6.9.3.
Laboratory and Other Safety Assessment Abnormalities 
Reported as AEs and SAEs.........................................................94
6.9.4.
Time Period and Frequency of Detecting AEs and SAEs.............95
6.9.5.
Prompt Reporting of SAEs and Other Events to GSK ..................95
6.9.6.
Regulatory reporting requirements for SAEs................................96
6.10.
Pregnancy ..................................................................................................97
6.10.1.
Time period for collecting pregnancy information.........................97
6.10.2.
Action to be taken if pregnancy occurs ........................................97
6.10.3.
Action to be taken if pregnancy occurs in a female partner 
of a male study subject ................................................................97
6.11.
Pharmacogenetics......................................................................................98
7.
STUDY TREATMENTS..........................................................................................98
7.1.
GSK525762 Investigational Product Dosage/Administration.......................98
7.2.
Handling and Storage of Study Treatment ................................................100
7.3.
Meals and Dietary Restrictions .................................................................101
7.4.
Treatment Assignment..............................................................................101
7.5.
Product Accountability ..............................................................................102
7.6.
Treatment Compliance..............................................................................102
7.7.
Dose Modifications ...................................................................................102
7.7.1.
Dose and Safety Management Guidelines.................................102
7.7.2.
Dose Adjustments for Toxicity....................................................108
8.
CONCOMITANT MEDICATIONS AND NON-DRUG THERAPIES .......................109
8.1.
Permitted Medications and Non-Drug Therapies.......................................109
8.2.
Prohibited Medications and Non-Drug Therapies......................................110
8.2.1.
Prohibited Medications...............................................................110
8.2.2.
Cautionary Medications .............................................................111
8.3.
Treatment after Discontinuation of Study Treatment or Withdrawal 
from/Completion of Study .........................................................................113
8.4.
Treatment of Study Treatment Overdose..................................................113
9.
LIFESTYLE REQUIREMENTS (CONTRACEPTION)...........................................113
9.1.
Female Subjects.......................................................................................113
9.2.
Male Subjects...........................................................................................114
10. DATA MANAGEMENT .........................................................................................115
11. DATA ANALYSIS AND STATISTICAL CONSIDERATIONS.................................115
11.1.
Sample Size Assumptions ........................................................................115
11.1.1.
Part 1.........................................................................................115
11.1.2.
Besylate Sub-Study ...................................................................115
11.1.3.
Part 2.........................................................................................115
11.1.4.
Sensitivity Analysis ....................................................................117
11.1.5.
Sample Size Re-estimation........................................................117
11.1.6.
Subset Analysis for NMC Population .........................................117
11.2.
Analysis Populations.................................................................................117


2011N118599_09
CONFIDENTIAL
BET115521
12
11.3.
Data Analysis Considerations ...................................................................118
11.3.1.
Interim Analysis .........................................................................118
11.3.2.
Final Analyses ...........................................................................118
11.3.3.
Analysis Datasets ......................................................................118
11.3.4.
Withdrawal.................................................................................118
11.3.5.
Missing Data..............................................................................119
11.3.6.
Derived and Transformed Data..................................................119
11.3.7.
Assessment Windows................................................................119
11.3.8.
Other Issues ..............................................................................119
11.4.
Efficacy Analyses......................................................................................119
11.4.1.
Primary Analysis........................................................................119
11.4.2.
Secondary Analyses ..................................................................120
11.5.
Safety Analyses........................................................................................120
11.5.1.
Extent of Exposure ....................................................................121
11.5.2.
Adverse Events..........................................................................121
11.5.3.
Clinical Laboratory Evaluations..................................................122
11.6.
Pharmacokinetic Analyses........................................................................122
11.6.1.
Pharmacokinetic Parameters.....................................................122
11.6.2.
Statistical analysis of pharmacokinetic parameters....................122
11.6.3.
Population Pharmacokinetic Analysis ........................................124
11.7.
Pharmacokinetic/Pharmacodynamic Analyses..........................................124
11.8.
Translational Research Analyses..............................................................124
11.9.
Pharmacogenetic Analyses ......................................................................125
12. STUDY CONDUCT CONSIDERATIONS .............................................................125
12.1.
Posting of Information on Clinicaltrials.gov................................................125
12.2.
Regulatory and Ethical Considerations, Including the Informed 
Consent Process ......................................................................................125
12.3.
Urgent Safety Measures ...........................................................................125
12.4.
Quality Control (Study Monitoring) ............................................................126
12.5.
Quality Assurance.....................................................................................126
12.6.
Study and Site Closure .............................................................................126
12.7.
Records Retention....................................................................................127
12.8.
Provision of Study Results to Investigators, Posting to the Clinical 
Trials Register and Publication .................................................................127
12.9.
Safety Review...........................................................................................127
12.9.1.
Dose Escalation Decisions ........................................................127
13. REFERENCES.....................................................................................................129
14. APPENDICES......................................................................................................132
14.1.
Appendix 1 : Pharmacogenetic Research .................................................132
14.2.
Appendix 2 : Cockcroft-Gault Formula ......................................................137
14.3.
Appendix 3: Liver Events ..........................................................................138
14.3.1.
Liver Safety Stopping Criteria and Required Actions and 
Follow Up Assessments.............................................................138
14.3.2.
Liver Safety Drug Restart Guidelines.........................................140
14.3.2.1.
Rechallenge Following Liver Stopping Events 
that are Possibly Related to Study Treatment...........141
14.3.2.2.
Restart Following Transient Resolving Liver 
Stopping Events NOT Related to Study 
Treatment.................................................................142


2011N118599_09
CONFIDENTIAL
BET115521
13
14.4.
Appendix 4: Pain Assessment ..................................................................144
14.5.
Appendix 5: RECIST 1.1...........................................................................145
14.6.
Appendix 6: Response Criteria for Neuroblastoma ...................................152
14.7.
Appendix 7: NYHA Functional Classification System for Heart 
Failure ......................................................................................................155
14.8.
Appendix 8: Country Specific Requirements.............................................156
14.8.1.
Investigational Product Label.....................................................156
14.8.2.
Medical Devices Used in the Study............................................157
14.9.
Appendix 9: Protocol Amendment Changes..............................................158


2011N118599_09
CONFIDENTIAL
BET115521
14
ABBREVIATIONS
1,5 AG
1,5-Anhydroglucitol
AE
Adverse Event
ALT
Alanine aminotransferase (SGPT)
aPTT
Activated partial thromboplastin time 
AST
Aspartate aminotransferase (SGOT)
AUC
Area under concentration-time curve
BCS
Bio-pharmaceutics Classification System 
BET
Bromodomain and extra-terminal
BID
Twice Daily
BP
Blood pressure
BQL
Below the quantitative limit
BRD
Bromodomains
CBC
Complete blood count
CL/F
Apparent clearance following oral dosing
Cmax
Maximum observed concentrations
CPK
Creatine phosphokinase
CR
Complete response
CRC
Colorectal cancer
CRF
Case Report Form
CRP
C reactive protein
CRPC
Castrate-Resistant Prostate Cancer
CV
Coefficient of variance
DLT
Dose limiting toxicity
DMPK
Drug Metabolism and Pharmacokinetics
DNA
Deoxyribonucleic acid
ECG
Electrocardiogram
ECHO
Echocardiogram
EIAC
Enzyme-inducing anticonvulsant
ER positive
Estrogen receptor positive (breast cancer)
FDA
Food and Drug Administration
FISH
Fluorescence in situ hybridization 
FSH
Follicle Stimulating Hormone
FTIH
First time in humans
Fu
Fraction unbound
GCP
Good Clinical Practice
GIST
Gastrointestinal Stromal Tumor
GSK
GlaxoSmithKline
HbA1C
Hemoglobin A1C
HBsAg
Hepatitis B surface antigen
hERG
Human ether a go-go-related gene
HIV
Human Immunodeficiency Virus
HNSTD
Highest non-severely toxic dose 
hr
Hour(s)
HR
Heart rate


2011N118599_09
CONFIDENTIAL
BET115521
15
ICH
International Conference on Harmonization of Technical Requirements 
for Registration of Pharmaceuticals for Human Use
IEC
Independent Ethics Committee
IgM
Immunoglobulin M
IHC
Immunohistochemistry
IL-6
Interleukin 6
IND
Investigational New Drug
INR
International Normalized Ratio
IRB
Institutional Review Board
IVRS
Interactive voice response system
Kg
Kilogram
L
Liter
LCNEC
Large cell neuroendocrine carcinoma tumor
LFTs
Liver function tests
LLN
Lower limit of normal
LO(A)EL
Lowest observed (adverse) effect level
LPS
Lipopolysaccharide
µg
Microgram
MABEL
Minimum anticipated biological effect level
MedDRA
Medical Dictionary for Regulatory Activities
mg
Milligrams
Mins
Minute(s)
mL
Milliliter
MM
Multiple Myeloma
MSDS
Material Safety Data Sheet
msec
Milliseconds
MTD
Maximum tolerated dose
N-CRM
Neuenschwander- Continuous Reassessment Method 
nT-proBNP
N-terminal pro–B-Type natriuretic peptide
NMC
NUT Midline Carcinoma 
NO(A)EL
No observed (adverse) effect level
NSAIDs
Non-Steroidal Anti-Inflammatory Drugs
NSCLC
Non-small cell lung cancer
OS
Overall Survival
PD
Progressive disease
PGx
Pharmacogenetics
PK
Pharmacokinetic
PSA
Prostate-Specific Antigen
PT
Prothrombin time
QD
Once Daily
QTcF
QT duration corrected for heart rate by Fridericia’s formula
RAMOS
Registration and Medication Ordering System
RAP
Reporting and Analysis Plan
Resp
Respiration rate
RP2D
Recommended Phase II Dose
RR
Response rate 


2011N118599_09
CONFIDENTIAL
BET115521
16
RNA
Ribonucleic acid
SAE
Serious adverse event(s)
SCLC
Small cell lung cancer
SD
Stable disease
SPM
Study Procedures Manual
STD 10
10% mortality over the duration of the study 
T
Temperature
τ
Dosing interval
t1/2
Terminal phase half-life
tmax
Time of occurrence of Cmax
TNBC
Triple Negative Breast Cancer
TSH
Thyroid stimulating hormone
ULN
Upper limit of normal
UK
United Kingdom
USA
United States
V/F
Apparent Volume of distribution following oral dosing
Trademark Information
Trademarks of the GlaxoSmithKline 
group of companies
Trademarks not owned by the 
GlaxoSmithKline group of companies
NONE
WinNonlin


2011N118599_09
CONFIDENTIAL
BET115521
17
PROTOCOL SYNOPSIS
PRODUCT: GSK525762
PROTOCOL TITLE: A Phase I/II Open-Label, Dose Escalation Study to Investigate 
the Safety, Pharmacokinetics, Pharmacodynamics, and Clinical Activity of GSK525762 
in Subjects with NUT Midline Carcinoma (NMC) and Other Cancers
PROTOCOL NO.: BET115521
U.S. IND NO.:
IND112942
CLINICAL PHASE: I/II
Primary
Objective

To determine the safety, tolerability and maximum tolerated dose (MTD) of 
GSK525762 in subjects 16 years or older following Once Daily (QD) and/or BID 
dosing schedules.

To evaluate the clinical activity of GSK525762 in NMC and other solid tumors.

To evaluate, after single dose administration, the relative bioavailability of the 
GSK525762 besylate tablet compared to the amorphous free-base tablet, the 
effect of high-fat high-calorie meal on the bioavailability of the besylate tablet 
and the dose proportionality of two doses of GSK525762 administered as the 
besylate tablets.
Endpoints

AEs, SAEs, dose reductions or delays, withdrawals due to toxicities and 
changes in safety assessments (e.g., laboratory parameters, vital signs,
Electrocardiogram (ECG), cardiotoxicity, gastrointestinal, etc.) to determine the 
MTD in subjects 16 years or older

Assess overall response rate (RR) using RECIST 1.1 in NMC and other solid 
tumors or PSA50 response rate using PCWG2 guidelines in CRPC or DCR
(CR+PR+ SD ≥16 weeks in duration) in GIST.

Pharmacokinetic (PK) parameter values for GSK525762 following single oral 
administration as amorphous free-base or besylate tablet
Hypothesis

No formal statistical hypotheses will be tested in Part 1. Analysis will be 
descriptive and exploratory. 

The primary goal of Part 2 is to demonstrate a clinically meaningful response, 
defined as follows: 
NMC: this will be determined by testing the null hypothesis that the 
response rate is ≤5%, with about 80% power when the true response rate 
is 20%.
Small cell lung cancer (SCLC) and Castrate-Resistant Prostate Cancer 
(CRPC): this will be determined by testing the null hypothesis that the 
response rate is ≤10%, with about 80% power when the true response 
rate is 30%.
ER+BC: this will be determined by testing the null hypothesis that the 
response rate is ≤15%, with about 80% power when the true response 
rate is 30%.
Triple Negative Breast Cancer (TNBC): this will be determined by testing the 
null hypothesis that the response rate is ≤10%, with about 80% power 
when the true response rate is 25%.


2011N118599_09
CONFIDENTIAL
BET115521
18
Gastrointestinal stromal tumor (GIST): this will be determined by testing the 
null hypothesis that the disease control rate is ≤15%, with about 80% 
power when the true disease control rate is 40%.
Secondary (Objectives and Endpoints only)
Objectives

To characterize the pharmacokinetics (PK) of GSK525762 in subjects 16 years 
or older following QD and/or BID dosing schedules. 

To evaluate cardiac safety, including the potential for QT duration corrected for 
heart rate by Fridericia’s formula (QTcF) changes with GSK525762 and to 
assess PK/QTcF relationship following QD and/or BID dosing schedules.

To evaluate the exposure response (pharmacokinetic/pharmacodynamic 
[PK/PD]) relationship between GSK525762 and safety and efficacy parameters 
following QD and/or BID dosing schedules.

To evaluate the effect of treatment with GSK525762 on tumor growth and 
survival.
Endpoints

PK parameter values for GSK525762 following single and repeat-dose oral 
administration in subjects 16 years or older.

Changes in cardiac safety including QTcF following single and repeat-dose oral 
administration GSK525762.

Progression free survival (PFS), time to response, duration of response, overall 
survival (OS), and exploratory analysis for antitumor response by various 
imaging modalities.
Exploratory (Objectives and Endpoints only)
Objectives

To evaluate the effect of GSK525762 on tumor biology.

Correlation of GSK525762 exposure to changes in PD markers in tumor and/or 
surrogate tissue.

To identify potential indicators of sensitivity or response to GSK525762.

To evaluate systemic and ex vivo on-target BET inhibitory effects.
Endpoints

Dose related changes in markers of cell proliferation and/or cell differentiation 
in tumor and/or surrogate tissue.

Dose related changes in transcription of genes and/or changes in expression of 
proteins regulated by BRD proteins in tumor and/or surrogate tissue.

PK/PD parameter values for exposure response (by RECIST and 18FDG-PET
[if data allows]) relationship between GSK525762 exposure and QTcF, troponin 
and tumor response following single and repeat-dose oral administration.

Changes from baseline and dose/response relationship in ex vivo 
Lipopolysaccharide (LPS) induced cytokines including Interleukin 6 (IL-6) in 
whole blood and systemic cytokines including IL-6.


2011N118599_09
CONFIDENTIAL
BET115521
19

STUDY DESIGN AND DURATION: This study is divided into 2 parts: 

Part 1 of the study is a dose escalation phase to determine the maximum 
tolerated dose (MTD) and select a recommended dose for Part 2 or a 
recommended Phase 2 dose (RP2D) based on the safety, pharmacokinetic, 
and pharmacodynamic profiles observed after oral administration of 
GSK525762. Eligible subjects with NUT midline carcinoma (NMC), small 
cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), colorectal 
cancer (CRC), neuroblastoma (NB), castration resistant prostate cancer 
(CRPC), triple negative breast cancer (TNBC), estrogen receptor positive 
(ER positive) breast cancer, and any other MYCN-amplified solid tumor will
be enrolled in the dosing cohorts until a maximum tolerated dose (MTD) is 
established. Subjects with NMC will also be enrolled in a pharmacodynamic 
dose expansion cohort during Part 1. Subjects may continue treatment in the 
study until disease progression, unacceptable toxicity, or withdrawal of 
consent.   

Part 1 besylate sub-study will explore the relative bioavailability, food effect 
and dose proportionality of besylate formulation. The sub-study will be 
conducted at active centers in the United States in subjects eligible for Part 1 
at the MTD or a dose near the MTD or RP2D. This will be an open-label, 
randomized, single dose, four period, cross over sub-study to investigate the 
relative bioavailability of the besylate tablet compared to the amorphous free-
base tablet, the effect of high-fat high-calorie meal on the bioavailability of 
the besylate tablet and the dose proportionality of two doses of GSK525762 
administered as besylate tablets.

Part 2 is an expansion cohort planned to further explore clinical activity at the 
MTD in NMC, SCLC, CRPC, TNBC, ER positive BC and GIST subjects.

Duration of study will depend on recruitment rates, and timing of subjects’ 
duration on study (withdrawal rates due to toxicity or progression).

SUBJECT SAMPLE: Worldwide approximately 110 subjects will be enrolled 
in Part 1, and approximately 170 subjects will be enrolled in Part 2. 

DOSAGE/DOSAGE FORM, ROUTE AND DOSE REGIMEN: Starting dose 
will be 2 mg, orally (tablets), once a day. Dose escalations will be performed in 
Part 1 and dose adjustments are allowed to address tolerability and safety issues. 
Alternate dosing schedules (BID or intermittent dosing) may be used based on 
PK and safety. 

PHARMACOKINETIC/PHARMACODYNAMIC MEASUREMENTS: 
There is extensive pharmacokinetic (PK) sampling in Part 1 and limited PK 
sampling in Part 2 for this study. Single safety PK blood draws may be collected 
for subjects with severe adverse events or adverse events of concern. Blood 
samples will be collected for analysis of protein biomarkers (cytokines and acute 
phase proteins) and mRNA. Ex-vivo LPS induction of cytokines in whole blood 
will be assessed. In addition, pre-treatment and post-treatment tumor samples 
will also be collected from selected subjects to be evaluated for target 
engagement and effects of GSK525762 on tumor biology. 


2011N118599_09
CONFIDENTIAL
BET115521
20

EFFICACY MEASUREMENTS: Response Rate (RR), Disease Control Rate 
(DCR), PSA50 response rate, Progression Free Survival (PFS) and Overall 
Survival (OS), time to response and duration of response. 

SAFETY MEASUREMENTS: Routine physical examinations, vital sign 
measurements, echocardiograms, and monitoring of adverse events. Cardiac 
safety monitoring will be required, consisting of triplicate 12-lead ECGs in Part 
1 prior to dosing on selected days and prior to drawing PK samples on serial PK 
sampling days (overnight stays in research facility may be necessary in Part 1). 
Extensive laboratory testing includes, in addition to standard hematology, 
clinical chemistry, pancreatic, coagulation, and liver chemistry panels, testing 
for troponin, c-peptide, 1,5-Anhydroglucitol (1,5 AG), HbA1c, and thyroid 
monitoring. Additional safety assessments may be necessary if a combination 
treatment regimen is administered to address specific safety concerns with the 
other agent(s) being administered.

DATA ANALYSIS: Subject demographic and safety data will be collected on 
electronic case report forms (eCRFs). All data will be pooled and descriptive 
safety analyses summarized and listed by cohort at conclusion of Part 2 
expansion cohorts. Additional analyses may occur between Part 1 and Part 2 and 
details will be included in the Reporting Analysis Plan (RAP). Part 2 of the 
study is powered to test overall Response Rate (RR). A futility assessment will 
be conducted after data are available from the first 10 subjects in each expansion 
cohort in Part 2.


2011N118599_09
CONFIDENTIAL
BET115521
21
1.
INTRODUCTION
1.1.
Background
Bromodomains: Bromodomains (BRDs) are small protein domains found in a variety of 
proteins that recognize and bind to acetylated histone tails. This binding affects 
chromatin structure, and thereby regulates epigenetically controlled processes including 
gene transcription and mRNA elongation [Nicodeme, 2010; French, 2008]. The 
bromodomain extra-terminal (BET) family of bromodomain proteins includes the BRD2, 
BRD3, BRD4 and BRDT [testes] proteins. 
Investigational Product: GSK525762 is an orally bioavailable small molecule that is a 
potent inhibitor of the binding of BET proteins to acetylated histones. Binding of 
GSK525762 induces squamous differentiation and inhibits proliferation of patient-
derived NMC cell lines both in culture and in murine xenografts. The phenotypic changes 
induced in vitro (flattening, keratin production, and the loss of proliferation markers) 
persist for more than 2 weeks after washout of GSK525762.
Nonclinical data suggest a narrow therapeutic window relative to reproductive, cardiac, 
and gastrointestinal toxicities which may be observed clinically with GSK525762 (see 
Section 1.5). However, the major cardiac and gastrointestinal toxicities observed in the 
animal studies can be clinically monitored and are largely reversible.
1.2.
Study Population Rationale
1.2.1.
NUT midline carcinoma
Nuclear protein in testis (NUT) midline carcinoma (NMC) is a newly described 
aggressive carcinoma that arises from a NUT gene translocation that generates a fusion 
protein with BRD proteins (BRD4 or BRD3) that is retained strictly in the cell nucleus 
via interactions with chromatin [Stelow, 2008; French, 2004]. NMC is a poorly 
differentiated malignant neoplasm, often with squamous differentiation, without 
pathognomonic features. As a newly described disease, and without specific histology, it 
is not surprising that NMC is often not diagnosed, or mistaken for other entities, 
including thymic carcinoma, squamous cell carcinoma of the head and neck, lung 
carcinoma, and Ewing sarcoma. NMCs are invariably lethal and despite aggressive 
chemotherapeutic regimens, subjects have a median life expectancy of only 6.7 months 
(N=63 patients) [Bauer, 2012].
Functional studies in subject-derived NMC cell lines have validated the essential role of 
the BRD4–NUT oncoprotein in maintaining the characteristic proliferation advantage and 
differentiation block of this uniformly fatal malignancy. The siRNA-mediated BRD 
knockdown arrests the proliferation and prompts terminal squamous differentiation in 
subject-derived NMC cells [French, 2008]. Additionally, BET inhibitors induce 
differentiation and growth arrest in NMC, and possess anti-tumor activity in NMC mouse 
xenograft models [Filippakopoulos, 2010].


2011N118599_09
CONFIDENTIAL
BET115521
22
NMC tumors may occur in multiple organ sites and are histologically indistinguishable 
from other undifferentiated squamous cell carcinomas. Subjects for the study will be 
selected based on the ectopic expression of NUT protein by Immunohistochemistry 
(IHC) [Haack, 2009] rather than on tumor histopathology or organ site. Fluorescence in 
situ hybridization (FISH) can also be used as a method to detect the presence of BRD-
NUT fusion protein in NMC diagnosis. However, due to the fast progression of NMC, 
there is a practical limitation to the extent of FISH testing that can be completed, 
especially for delineating cryptic BRD rearrangements, prior to patient inclusion. 
Recent studies have delineated the NUT variant sub population (n=4) through bespoke 
FISH experiments to, in all but one case, a cryptic rearrangement of the BRD3 locus. 
Retrospective analysis of the survival data observed in the NUT variant sub-population 
has indicated there is no apparent difference in progression free or overall survival based 
on this variant diagnosis compared to BRD4 or BRD3.
NMC is extremely rare with approximately 20 cases being reported in the United States 
annually, however due to misdiagnosis or underdiagnosis, the exact incidence and 
frequency of NMC are not well established (http://www.nmcregistry.org/). NMC may 
affect subjects of all ages (age range 0-78 yrs). The only known long-term survivor had a 
complete tumor resection. Therefore, patients with this rare tumor have a significant 
unmet medical need for more effective therapy.
1.2.2.
Other tumor types
Recently published data as well as data generated internally at GlaxoSmithKline (GSK) 
and by collaborators have demonstrated the potential application of BRD extra-terminal
(BET) inhibitors in tumor types other than NMC, including small cell lung cancer 
(SCLC), non-small cell lung cancer (NSCLC), colorectal cancer (CRC), castration 
resistant prostate cancer (CRPC), triple negative breast cancer (TNBC);  estrogen 
receptor positive (ER positive) breast cancer, neuroblastoma (NB), acute leukemias, 
gastrointestinal stromal tumors (GIST), and other N-Myc driven tumors. Studies in 
leukemia and Multiple Myeloma (MM) have shown that small molecule inhibition of 
BET protein binding to chromatin can directly block both c-Myc expression and its 
downstream transcriptional functions, resulting in significant anti-tumor effects 
[Delmore, 2011; Mertz, 2011]. Myc family proteins play a central role in the regulation 
of gene expression and cell cycle control. Their enhanced expression has been implicated 
in all aspects of tumor cell biology [Adhikary, 2005]. 
Based on the preclinical findings within GSK and with collaborators, subjects with small 
cell lung cancer, non-small cell lung cancer (NSCLC), colorectal cancer, castration 
resistant prostate cancer (CRPC), triple negative breast cancer (TNBC), estrogen receptor 
positive (ER positive) breast cancer, neuroblastoma, and N-Myc amplified solid tumors 
will be enrolled to the dose finding part of the study. In addition, Part 2 expansion cohorts 
will enrol subjects with NMC, SCLC, CRPC, TNBC, ER+BC and GIST.
Small Cell Lung Cancer
GSK525762 was found to inhibit growth in a subset of SCLC cell lines, with 46% (18 of 
39) of cell lines possessing a gIC50 < 1 µM. It was confirmed in several of the cell lines 


2011N118599_09
CONFIDENTIAL
BET115521
23
that apoptosis (assessed by caspase cleavage) is induced at concentrations above the 
gIC100.  Additionally, significant tumor growth inhibition was observed in a subset of cell 
line and patient-derived subcutaneous xenograft models of SCLC. 
No correlation between status of c-Myc or L-Myc and sensitivity was found. N-Myc 
amplified cell lines were found to be sensitive, though the low number (N=2) of lines 
tested with this amplification does not allow for a firm conclusion to be drawn. Although 
no predictive marker of GSK525762 sensitivity in SCLC has been identified and 
considering the high percentage of cell lines that are sensitive, enrolment will be opened 
to all relapsed refractory SCLC patients in the dose escalation part of the study while 
collecting data retrospectively on potential predictive biomarkers from the available 
tissues.
Non-Small Cell Lung Cancer
GSK525762 inhibited cell growth in a subset of NSCLC cell lines, with 46% (33/72) of 
cell lines tested exhibiting a gIC50 <1µM. Median gIC50 across the NSCLC cell line panel 
was 1.1µM. MYCN amplified cell lines and large cell neuroendocrine carcinoma 
(LCNEC) cell lines were among the most sensitive to GSK525762, with a median gIC50 
of 0.17µM and 0.24µM (n=4 for each sub-type). A subset of NSCLC cell lines, including 
MYCN-amplified and LCNEC lines, exhibited a cytotoxic response to GSK525762. 
Given the broad sensitivity of NSCLC cell lines to GSK525762, a selection marker will 
not be used for entry into the dose escalation part of the study.
Colorectal Cancer
In colorectal cell lines, initial data using the same criterion of sensitivity indicates that 
GSK525762 inhibits growth in a high percentage of lines tested (58%, 25/43 with gIC50 < 
1 µM). No markers of sensitivity in these lines has been identified yet and, as with SCLC, 
enrolment will be opened to all relapsed refractory CRC patients without a selection 
marker in an initial clinical trial.
Neuroblastoma
NB cell lines are sensitive to GSK525762, with 83% of cell lines tested (15/18) 
exhibiting a gIC50 < 1µM. Median gIC50 across the NB cell line panel was 0.48µM, with a 
subset of cell lines exhibiting a cytotoxic response to GSK525762. The agent is sensitive 
in MYCN amplified cell lines, as 10 of the 15 sensitive cell lines possess the copy number 
increase. As with SCLC, NSCLC, and CRC, a selection marker will not be used in NB 
patients for entry into the dose escalation part of the study.
Castration-Resistant Prostate Cancer
A subset of prostate cancer cell lines were found to be sensitive to GSK525762, with 
57% (4/7) of cell lines exhibiting a gIC50 <1µM. Apoptosis was observed in a subset of 
prostate cancer cell lines as measured by poly ADP ribose polymerase (PARP) cleavage 
and accumulation of cells in sub-G1 phase of cell cycle. Prostate cancer lines cell lines, 
including models of CRPC, with high androgen receptor (AR) and high c-Myc protein 
expression were found to be the most sensitive (lowest gIC50) to GSK525762A. 


2011N118599_09
CONFIDENTIAL
BET115521
24
Consistent with in vitro observations, significant tumor growth inhibition was observed in 
a subcutaneous patient-derived xenograft model of CRPC expressing high levels of AR
and MYC. In contrast, no significant inhibition of tumor growth was observed in a second 
model expressing low levels of AR and MYC. Given the limited availability of pre-
clinical prostate models and the broad sensitivity of prostate cancer cell lines to 
GSK525762, no selection marker will be used for entry into the dose escalation part of 
the study.
Triple Negative and ER-positive Breast Cancer
A subset of breast cancer cell lines representing the ER-positive and triple negative sub-
types were found to be sensitive to GSK525762, with 55% (17/31) cell lines tested 
exhibiting a gIC50 < 1µM. Median gIC50 across the breast cancer cell line panel was 
980nM, with a subset of cell lines exhibiting a cytotoxic response to GSK525762. 
The activity observed with GSK525762 in ER+ breast cancer cell lines is consistent with 
data reported in two recent publications using the tool BET inhibitor JQ1 [Feng Q, 2014; 
Nagarajan, 2014]. Given the broad activity of BET inhibitors across the ER+ and triple 
negative subtypes, no selection marker will be used for entry into the dose escalation part 
of the study for ER-positive and TNBC patients.
N-Myc amplified solid tumors
A large majority of N-Myc amplified cell lines from various tumor types, including 
SCLC, NSCLC, and neuroblastoma, are highly sensitive to GSK525762. Across the three 
tumor types, 16 of 19 (84%) MYCN-amplified cell lines possess a gIC50 < 1µM, and 11 of 
19 (58%) exhibit a cytotoxic response to GSK525762. Expression of MYCN was 
suppressed by GSK525762 in SCLC and NB cell lines, which is consistent with 
published reports [Puissant, 2013; Wyce, 2013]. 
Given the high percentage of responsive cell lines in small cell lung cancer, non-small 
cell lung cancer, colorectal, castration-resistant prostate cancer, triple-negative breast 
cancer, ER-positive breast cancer, and neuroblastoma it is appropriate to include 
refractory patients who have failed prior treatments regimens into the dose escalation 
phase of this study where this medicine may prolong survival. In addition subjects with 
any solid tumor that demonstrates N-Myc amplification will be eligible for the dose 
escalation phase of the study.
GIST (Gastrointestinal Stromal Tumor)
The super-enhancer profiling of sarcoma tumor samples and cell lines identified 
conserved super-enhancer program in GIST tumors. Some of the genes associated with 
super-enhancers in GIST tumors include well-established drivers, such as KIT and 
PDGFRA, but also potential novel targets, such as ETV1 and HAND1. GIST-specific KIT
super-enhancer regulating KIT gene activity is remarkably sensitive to bromodomain 
inhibition. KIT-dependent GIST cell lines have an IC50 to the prototypical bromodomain 
inhibitor, JQ1, ranging from 150 – 470nM (Matthew Hemming, personal communication, 
December 2016). Other bromodomain inhibitors, including GSK525762, demonstrate 
similar selective toxicity in KIT-dependent GIST cell lines. At the gene and protein 


2011N118599_09
CONFIDENTIAL
BET115521
25
expression levels, BET bromodomain inhibitors attenuate the expression of genes, 
associated with superenhancers, such as KIT, ETV1 and HAND1, suggesting that BET 
proteins are required for the maintenance of GIST super-enhancer associated 
transcriptional program and are critical regulators of GIST growth and survival. In 
support of this mechanism, uncoupling KIT expression from its native super-enhancer 
leads to resistance to bromodomain inhibition. In KIT-dependent GIST cells, 
bromodomain inhibition shows synergistic toxicity with KIT-inhibition, further 
suggesting an independent and complimentary mechanism of action in GIST (Matthew 
Hemming, personal communication, December 2016). These evolving data have driven 
strong enthusiasm in developing bromodomain inhibitors in GIST. 
1.3.
Dose Rationale
1.3.1.
Human Pharmacokinetics
Whole blood human clearance was predicted from three species (mouse, rat and dog) 
using simple power-law allometry (in the absence of detectable in vitro metabolism) to be 
2.8 mL/min/kg. Volume of distribution was predicted from Gastroplus to be 2.6 L/kg and 
half-life 10 hours (GlaxoSmithKline Document Number 2010N108204_00, 2011). As the 
in vitro blood to plasma ratio was 0.86, a 70 kg adult therefore had a predicted total 
clearance of 10.1 L/hr and a total plasma volume of distribution of 157 L.
Information on the pharmacokinetics of GSK525762 in humans can be found in the 
Investigator’s Brochure (GlaxoSmithKline Document Number 2011N113741_05, 2016). 
In summary, GSK525762 pharmacokinetics are characterized by a rapid absorption with 
maximum concentration occurring mostly within the first hour after dosing. GSK525762 
is eliminated rapidly with an average terminal phase half-life of 3 to 7 hours, leading to a 
lack of accumulation following once daily oral administration. Following single oral 
administration and repeated once daily administration of 2 mg to 100 mg of GSK525762, 
Maximum observed concentrations (Cmax) and Area under concentration-time curve
(AUC) tended to increase in a dose proportional fashion with a large overlap for 
individual AUC between 30, 60, 80 and 100 mg cohorts. 
1.3.2.
Starting dose
Four approaches have been considered to establish the starting dose for GSK525762:

One tenth of the rat 10% mortality over the duration of the study (STD) 10 as per 
International Conference on Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use (ICH) S9 guidance
For GSK525762, the STD10 was defined as 30 mg/kg in the rat following ICH S9 
guidelines. 1/10 rat STD10 is 18 mg/m2; this dose is not severely toxic to dogs; therefore 
starting dose is 1/10 rat STD10 which translates to a starting dose in man of 30 mg, 
assuming a 70 kg adult and adult surface area of 1.7 m2. 

One sixth of the dog Highest non-severely toxic dose (HNSTD) as per ICH S9 
guidance


2011N118599_09
CONFIDENTIAL
BET115521
26
Based on tolerability and QT prolongation, the HNSTD was defined as 0.3 mg/kg in the 
dog. 1/6 dog HNSTD is 1 mg/m2 which translates to a starting dose in man of 1.7 mg 
(rounded to a starting dose of 2 mg based on tablet strength), assuming a 70 kg adult and 
adult surface area of 1.7 m2.

Average exposure at the QTc NOEL in the dog 
Average exposure at the QTc NOEL (0.3 mg/kg) was as follows: AUC 642 ng.hr/ml 
(total), 167 ng.hr/ml (free), Cmax 80 ng/ml (total), 20.8 ng/ml (free). Extrapolating the 
AUC to humans, the dose required for parity is given by Dose = AUC x CL/Fu, where Fu 
is fraction unbound in humans (22%). Using this expression, the predicted starting dose 
would be 167 ng.hr/ml x 11.8 (L/hr)/0.22 = 9 mg, assuming 100% absolute 
bioavailability. Using an absorption rate of 1/hr predicted from Gastroplus, the predicted 
free drug Cmax is 8.2 ng/ml.

The dose predicted to deliver a Cmax of less than the IC20 for the most sensitive 
known human pharmacology (Minimum anticipated biological effect level
[MABEL] dose)
The most sensitive human pharmacology is defined as the inhibition of growth in patient 
derived NMC cells. Free drug IC50 is approximately 40 ng/ml with maximal inhibition at 
1000 ng/ml. IC20 for this pharmacology, defined as MABEL, is 10 ng/ml. The dose to 
achieve this MABEL concentration at Cmax is 11mg (MABEL dose).
Taking all four approaches into consideration, a starting dose of 2 mg is proposed. This 
dose will provide a 5-fold safety margin to the QTc prolongation observed on repeat 
dosing in the dog. Table 1 provides the predicted safety cover for the proposed 2 mg 
starting dose.


2011N118599_09
CONFIDENTIAL
BET115521
27
Table 1
Predicted Safety Cover for proposed 2mg starting dose (data from 
most sensitive NOAEL/NOEL from 4 week toxicology studies)
Clinical starting dose
Dose (2 mg)
Total AUC
Free AUC
Total Cmax
Free Cmax
Predicted human exposure
197 ng.h/mL
36.6 ng.h/mL
9.80 ng/mL
36.6 ng.h/mL
Cardiotoxicity
QTc from single dose*
94.1x (NOEL)
130x (NOEL)
336x (NOEL)
130x (NOEL)
QTc on repeat dosing
3.97x (NOEL)
10.7x (LOEL)
5.45x (NOEL)
14.8x (LOEL)
10.9x (NOEL)
32.7x (LOEL)
5.45x (NOEL)
14.8x (LOEL)
Troponin
No cover
No cover
Gastrointestinal toxicity
In life changes
0.863x (NOAEL)
9.44x (LOAEL)
8.25x (NOAEL)
121x (LOAEL)
Microscopic changes
9.44x (NOAEL)
45.3x (LOAEL)
32.7x (NOAEL)
134x (LOAEL)
Hepatic toxicity (single rat)
9.44x (NOAEL)
62.6x (LOAEL)
121x (NOAEL)
337x (LOAEL)
Hematopoietic toxicity
1.64x (NOAEL)
9.44x (LOAEL)
14.7x (NOAEL)
121x (LOAEL)
Lymphoid toxicity
9.44x (NOAEL)
62.6x (LOAEL)
121x (NOAEL)
337x (LOAEL)
Hemolysis (rat specific)
9.44x (NOAEL)
62.6x (LOAEL)
121x (NOAEL)
337x (LOAEL)
Clotting effects
10.7x (NOAEL)
45.3x (LOAEL)
32.7x (NOAEL)
134x (LOAEL)
Pancreatic toxicity (male rat 
specific)
7.39x (NOAEL)
62.3x (LOAEL)
64.2x (NOAEL)
338x (LOAEL)
Pulmonary effects (rat 
specific)
1.64x (NOEL)
9.44x (LOEL)
14.7x (NOEL)
121x (LOEL)
Testicular toxicity
No cover
No cover
NO(A)EL = No observed (adverse) effect level
LO(A)EL = Lowest observed (adverse) effect level
*Calculated from single dose GLP dog Coefficient of variance (CV) study


2011N118599_09
CONFIDENTIAL
BET115521
28
1.3.3.
Predicted therapeutic dose range
The potential therapeutic dose for GSK525762 in human was derived using available 
preclinical PK, in vitro data, and efficacy data from several tumor xenograft studies. 
Based on modeling, maximal efficacy of GSK525762 may require ≥ 50% target 
inhibition. The predicted human effective daily dose is 25 to 100 mg assuming 50 to 
100% oral bioavailability.
1.3.4.
Dose escalation steps
Human PK predictions suggest that exceeding the systemic exposure of the preclinical 
4 week MTD (1 mg/kg in dogs and 10 mg/kg in rats) may be required to achieve ≥ 50% 
target inhibition in the majority of subjects. The start of the predicted therapeutic range in 
humans is at parity with the 4 week MTD exposure range in preclinical species. The 
toxicities observed at exposures greater than the preclinical MTD are clinically 
monitorable and largely reversible (excluding testicular effects), therefore semi-semi-log 
(≤ 2-fold) dose escalation above this preclinical MTD, conditional on acceptable 
tolerability, is permitted until the clinical MTD is established. 
1.3.5.
BID Dose Cohort
1.3.5.1.
Preclinical Rationale
Pre-clinical pharmacokinetic and pharmacodynamic data suggests a potential benefit of a 
BID dosing regimen compared to QD dosing. In mice, GSK525762 has a short half-life 
of about 1.5 hours. Single dose pharmacodynamic experiments were performed in three 
SCLC and one CRC mouse xenograft model. Dose-dependent changes in gene expression 
were observed in all models at early time points post-dose; however, expression returned 
to pre-treatment levels within 8-12 hours. Additionally, in a subcutaneous multiple 
myeloma cell line xenograft study, c-Myc protein levels were significantly reduced 2 and 
5 hours post-dose, and returned to baseline by 8 hours. The transient effects on gene 
expression observed in these studies with QD dosing highlights the potential benefit of 
BID dosing by extending the duration of gene silencing within a 24 hour period.
QD and BID dosing have been further explored in efficacy studies in the above-
mentioned SCLC and CRC xenograft models. In a subcutaneous, patient-derived model 
of SCLC, BID dosing at 12.5mg/kg resulted in improved tumor growth inhibition 
compared to 25 mg/kg QD (74% versus 60%, respectively).  Improved efficacy with BID 
dosing was also observed in the cell line xenograft model of CRC. BID dosing at 
12.5 mg/kg resulted in 48% tumor growth inhibition, whereas 25 mg/kg QD dosing 
resulted in 34% inhibition.  In a third model, a cell line xenograft of SCLC, there was no 
significant difference in tumor growth inhibition resulting from 12.5mg/kg BID versus 
25mg/kg QD dosing. Thus, we observed equivalent or improved efficacy with BID 
dosing in all xenograft models tested.
1.3.5.2.
Clinical Rationale
Based on the pharmacokinetics of GSK525762 observed to date, with  the short half-life 
of about 5 hours, it is predicted that even 100 mg QD doses would result in the trough 


2011N118599_09
CONFIDENTIAL
BET115521
29
concentrations falling below the average in vitro IC50 (0.08 uM to 1.3 uM) for the tumor 
types selected for this study. Dividing the daily dose into two doses administered about 
12 hours apart would maintain the concentrations above the lower in vitro IC50 for doses 
around 30 mg BID.  
1.3.6.
Doses for Besylate Bioavailability/Food Effect/Dose 
Proportionality Sub-Study
A dose at or near the maximum tolerated dose or the recommended Phase 2 dose will be 
used to evaluate the relative bioavailability of the besylate salt tablet compared to the 
amorphous free-base tablet.
As GSK525762 is a compound with high solubility but low permeability, it is expected 
that administration with food will have no effect or possibly a negative effect on its 
absorption [C-H Gu, 2007] and a dose at or near the MTD or RP2D will be used to 
evaluate the effect of food on the relative BA of GSK525762 administered as the besylate 
salt tablet.  
In addition, to evaluate the dose proportionality of the PK of GSK525762 after fasted 
administration as besylate salt tablet, a lower dose of half to one-third of the MTD or 
RP2D will be evaluated. 
1.4.
Rationale for Study and Endpoints
Safety and efficacy (RR) are being assessed to address the primary objectives of the 
study. The safety assessments along with the PK will be important for determining the 
MTD of once daily and/or twice daily dosing. The pharmacodynamic assessments will 
further support the recommended Phase II doses (RP2D) and expand the understanding 
regarding mechanism of action. The response rate hurdle of 20% in NMC was
determined based on 3 parameters: NMC is a rare population, there is currently no 
standard of care therapy for NMC, and NMC carries a poor prognosis (median survival of 
6.7 months [Bauer, 2012].
Given the poor prognosis and high unmet medical need of NMC, as well as in other 
tumor types such as relapsed/refractory SCLC, NSCLC, CRC, CRPC, TN and ER+ BC, 
GIST, NB and N-Myc amplified tumors and the exceptional drug-to-target alignment of 
GSK525762, a combined Phase I/II study (BET115521) is proposed. The BET115521 
study comprises an accelerated dose titration (Part 1), which will include subjects with 
NMC and other tumor types that are predicted to be responsive to GSK525762, to 
determine a maximum tolerated dose (MTD). The besylate sub-study will be an open-
label, randomized, single dose, four period, crossover sub-study to investigate the relative 
bioavailability of the besylate salt tablet compared to the amorphous free-base tablet at a 
dose at or near the MTD or RP2D, the effect of high-fat high-calorie meal on the 
bioavailability of the besylate salt tablet at or near the MTD or RP2D and the dose 
proportionality of two doses of GSK525762 administered as besylate salt tablets. Results 
of the besylate sub-study will enable the use of the besylate salt tablet formulation later in 
this study and provide recommendation around the need for fasting status when 
administering GSK525762. The besylate sub-study will be conducted at centers in the 
United States.  


2011N118599_09
CONFIDENTIAL
BET115521
30
The recommended phase II dose (RP2D) of GSK525762 with possible adjustment based 
on the relative bioavailability of the besylate salt formulation, will be studied in the 
cohort expansion (Part 2) to determine efficacy, safety and tolerability in NMC and other 
tumor types including SCLC, CRPC, TNBC, ER+BC and GIST.
1.5.
Risk Assessment
Toxicology studies performed in dogs, rats and mice suggest that the primary toxicities of 
GSK525762 are gastrointestinal, cardiovascular, pancreatic, hematologic and 
reproductive (see GlaxoSmithKline Document Number 2011N113741_05, 2016, Section 
3.4). These toxicities are addressed below, together with the proposed safety monitoring 
and risk mitigation activities that are included in the planned study.
Gastrointestinal: Evidence of degeneration/regeneration and/or erosion/ulceration in the 
gastrointestinal tract was seen at non-tolerated doses in 7 and 14 day studies in rat and 
dog, respectively.  Microscopic examination included degenerative changes in the 
esophagus, stomach, small and large intestine, including erosion or ulceration, mucosal 
congestion, hemorrhage and edema, crypt dilatation and focal inflammatory cell 
infiltration in the toxicology studies of up to 3 month duration in the dog and rat. 
Recovery was evident after a minimum of 3 weeks off dose. During clinical studies, 
medical history, physical examination (including weight) and clinical laboratory 
assessments will be used to identify and assess toxicity in the GI tract.  Supportive 
therapy will be provided as per standard medical practice.  In the event of clinically 
significant toxicity, treatment will be withheld and supportive therapy provided according 
to standard medical practice.
Cardio-vascular:  Although there were minimal effects of GSK525762 on current 
density and no effects on trafficking in HEK-293 cells or on ECG rhythms or arrhythmias 
in the ex vivo rabbit wedge assay, QT and QTc prolongation (maximum 41 milliseconds 
at 3 mg/kg for 12 days) was seen in dogs after a single oral dose of 30 mg/kg or repeat 
dosing at 1 mg/kg/day in toxicology studies of up to 3 month duration.  No effect was 
seen in the dog at 0.3 mg/kg (6 mg/m2) where exposure is estimated to be approximately 
equivalent to that achieved by a 10 mg dose in humans if 100% bioavailability is 
assumed.  However, the starting dose in this First time in humans (FTIH) study is 2 mg.  
Increases in biomarkers of cardiac damage (cardiac troponin I and T, myosin light chain
and NT-proANP) were also seen in the rat and cardiac troponin I in the dog.  Despite 
these QTc and cardiac biomarker changes, there was no evidence of compound-related 
myocardial necrosis or other histopathological changes in cardiac tissue of either species.  
No significant arrhythmias were detected in preclinical studies. 
Given the risks of long QTc associated arrhythmias, and of compound associated 
cardiomyopathy, subjects will be monitored closely for changes in QTc with triplicate 
12-lead ECGand for elevations in plasma Troponin.  Inpatient 48-hour telemetry was 
originally required for all subjects following the first dose of study drug, as part of the 
cardiac monitoring. Evaluation of cardiac safety data from subjects treated up to the 100 
mg QD cohort by the cut-off date of May 15, 2015 demonstrated no significant QTc 
prolongation after single and repeat dose administration. Therefore, the 48-hour telemetry 
requirement was removed and the frequency of Holter monitoring was reduced with 


2011N118599_09
CONFIDENTIAL
BET115521
31
Protocol Amendment 6 and upon further review of the totality of data, Holter monitoring 
was removed in Amendment 9. Specific stopping criteria and management guidelines are 
provided for cardiac toxicities.
Electrolytes, including potassium and magnesium will be checked at baseline and at 
regular intervals or when clinically indicated. Appropriate medical management will be 
instituted to assure that electrolytes are kept within the normal range.
Safety ECGs
Safety ECGs will be performed at the time points specified in Time and Events Tables 
using a standard 12-lead ECG machine that automatically calculates the HR and 
measures PR, QRS, QT and QTcF intervals. The mean from triplicate ECGs (when 
indicated) will be evaluated at each time point. Safety ECGs will be reviewed by the 
investigator and a Cardiologist on an ongoing basis for safety purposes and will be over-
read at a central site (eRT). The dosing for each new week in the first cycle should not 
begin until the safety ECG has been reviewed and no significant abnormalities have been 
detected.
Serum Markers 
In addition to the safety ECGs performed during the study, laboratory evaluations for 
cardiac troponins and electrolytes will be performed and NT-pro-brain natriuretic peptide 
(BNP) will be checked at baseline, regular intervals (as specified in the Time and Events
Tables), and when clinically warranted during the study treatment.  Troponin I or T 
(based on availability) levels will be tested by a local laboratory and monitoring for 
troponin T at a central laboratory.  Appropriate medical therapy will be provided by the 
investigator for any clinically significant increase in troponins including withholding or 
discontinuing the study medication.
Pancreatic:  Islet cell fibrosis/fibroplasias and peri-islet hemorrhage, pigmented 
macrophages and inflammation were seen at 30 mg/kg in male rats and acinar cell 
apoptosis, vacuolation and/or degranulation were seen at 3 mg/kg in female dogs. 
Glucose (serum and urine), insulin, 1,5-AG and c-peptide will be monitored clinically for 
changes associated with islet cell toxicity and signs of gastric distress or abdominal pain 
that may serve as a sign and/or symptom of acinar cell dysfunction.  In addition, amylase 
and lipase levels will be obtained.  Subjects will be monitored for clinical signs of 
malabsorption.
Hematologic and lymphoid:  Lymphoid toxicity was observed in rats and dogs 
manifested by bone marrow hypo-cellularity and variable and inconsistent changes in 
total white cell lymphocyte and decreased platelet counts.  There were variable and 
inconsistent changes in multiple red blood cell parameters and reticulocytes in the 
periphery, and decreased organ weight, thymus, spleen, and lymph node hypocellularity.  
Higher activated partial thromboplastin time (aPTT) and increased fibrinogen were seen 
at 3 mg/kg in dogs indicative of abnormal clotting.  In clinical studies, the complete 
blood count (CBC) and coagulation factors (INR, prothrombin time [PT], aPTT) will be 
measured frequently to monitor for these toxicities.  Supportive therapy will be provided 


2011N118599_09
CONFIDENTIAL
BET115521
32
according to standard medical practice, and treatment will be held for clinically 
significant toxicity.
Pulmonary: Aggregates of foamy macrophages in peri-bronchiolar areas were evident in 
rats given ≥10 mg/kg/day for 28 days. Following the 3 week off-dose period, these 
changes were decreased in incidence. This effect may be a result of unintended lung 
exposure due to the dosing procedure and an exacerbation of the finding by GSK525762. 
This finding is unlikely to affect pulmonary function; no effects were observed in the 3 
month studies in rats and dogs.
In the study, patients will have pulmonary function assessments at baseline and as 
clinically appropriate. In addition, a chest x-ray will be obtained at baseline along with 
physical exams that will be performed throughout the study (see Section 5).
Hepatic Toxicity: Non-adverse liver changes were observed in rats and dogs including 
increases in bilirubin levels and transient increases in AST in rats. Necrosis was observed 
in one rat at 30 mg/kg/day in the 4 week study. GSK525762 has been demonstrated to 
undergo bioactivation in vitro which indicates potential for idiosyncratic hepatotoxicity. 
The precursor metabolite has been observed in clinical plasma samples.
The BET115521 protocol includes frequent monitoring of liver biochemistry along with 
stopping criteria for dose limiting toxicity (DLT), liver monitoring guidelines and 
management (see Section 3.2.3, Section 7.7.2, and Appendix 3).
Reproductive and Developmental: In toxicology studies of up to 3 month duration, 
bilateral sperm retention, germ cell degeneration and tubular vacuolization, and depletion 
of testicular germinal epithelium occurred in male dogs receiving ≥ 0.01 mg/kg and male 
rats receiving ≥ 10 mg/kg doses of GSK525762.  Exposures associated with reproductive 
toxicity in male dogs overlap with the proposed 5 mg starting dose in this FTIH 
study. These changes were accompanied in rats and dogs by changes in sperm 
morphology, motility and number and hormonal changes (decreased testosterone and 
Inhibin B in rats and increased FSH in rats and dogs).  Reduced prostate weight and 
secretory content was also evident in the rat.  An effect on spermatogenesis is anticipated. 
Full or partial reversibility of the testicular effects was observed in the 3 month rat and 
dogs studies following a 17 week off dose period.
GSK525762 at 0, 1, 3, 10, or 30 mg/kg/day (total dose; doses expressed as parent 
compound) was given orally by gavage BID (doses given 6 hours apart) to pregnant rats 
on Days 0 through 17 post-coitus. Dose-dependent maternal toxicity (reduced body 
weight gain and reduced food consumption) was evident at ≥10 mg/kg/day. Embryo-fetal 
toxicity was evident as both pre-implantation loss and increased fetal resorptions leading 
to complete loss of litters at 30 mg/kg/day, and dose-dependent increased fetal 
resorptions at doses ≥1 mg/kg/day. Developmental toxicity was evident as decreased fetal 
weights at 10 mg/kg/day and fetal malformations and/or variations at all doses 
(membranous ventricular septal defects in the heart ≥1 mg/kg/day; great vessel, heart, 
kidney, ovary, uterus, and ureter malformations and/or variations at 10 mg/kg/day). The 
AUC0-t and Cmax at 1 mg/kg/day (the lowest dose tested) in non-mated female rats after 
5 doses were 54 ng.h/mL and 18 ng/mL, respectively.


2011N118599_09
CONFIDENTIAL
BET115521
33
No ovarian histologic changes were observed in the 4 week toxicology studies, however 
female fertility (disrupted estrous cyclicity, delays to mating and/or reduced fertility 
index) was affected in rats given 30 mg/kg/day GSK525762 for 15 days prior to mating 
and 15 days prior to mating through to Day 6 post coitus (pc). Systemic exposure in rats 
was approximately 2-fold higher than current exposure in late stage cancer patients (at 60 
mg/day). No fertility effects were observed when 30 mg/kg/day was given for 6 weeks 
followed by 6 weeks off-dose prior to mating.
Reproductive and developmental toxicity (decreased fetal body weight, fetal 
malformations or variations and / or pre- and post-implantation loss) occurred in rats 
given GSK525762 ≥1mg/kg/day from conception through gestation day 17 (of 21 days) 
and when dosed at ≥10 mg/kg/day for 14 days and dosing stopped prior to mating or 
continued until Day 6 pc. Systemic exposure in rats was approximately 80-fold lower 
than current exposure in late stage cancer patients (at 60 mg/day). These results are 
consistent with observations that BRD2, BRD3, BRD4 and BRDT have crucial roles in 
reproduction and development [see the GSK525762 IB, GlaxoSmithKline Document 
Number 2011N113741_05, 2016]] for references.
Based on the findings in these reproductive and developmental toxicity studies in rats 
with GSK525762, there is a substantiated risk for adverse effects on embryofetal 
development and impacts on female fertility.
In the BET11521 study, specific contraceptive guidelines and precautions for males and 
females are provided in the protocol.  In addition, the informed consent will include 
potential reproductive risks and precautions in addition to recommendations for the 
preservation of reproductive capacity.
Potential drug-drug interactions based on nonclinical studies: There is low potential 
for GSK525762 to induce or inhibit cytochrome P450 (CYP) enzymes or to inhibit Pgp 
or BCRP.  Use of concurrent drugs with potential to prolong QTcF will be used with 
extreme caution or prohibited (as outlined in Section 8.2.2 of the protocol).  Regarding 
drugs for hyperemesis, palonosetron (administered per the prescribing information) and 
ondansetron (at a maximum oral dose of 8 mg TID) will be the only allowed serotonin 5-
HT3 receptor antagonist drugs. 


2011N118599_09
CONFIDENTIAL
BET115521
34
2.
OBJECTIVES, ENDPOINTS, HYPOTHESES FOLLOWING 
QD AND/OR BID DOSING SCHEDULES
Primary
Objective

To determine the safety, tolerability and maximum tolerated dose (MTD) of 
GSK525762 in subjects 16 years or older following QD and/or BID dosing 
schedules.

To evaluate the clinical activity of GSK525762 in NMC and other solid tumors.

To evaluate, after single dose administration, the relative bioavailability of the 
GSK525762 besylate tablet compared to the amorphous free-base tablet, the 
effect of high-fat high-calorie meal on the bioavailability of the besylate tablet 
and the dose proportionality of two doses of GSK525762 administered as the 
besylate tablets.
Endpoints

AEs, SAEs, dose reductions or delays, withdrawals due to toxicities and 
changes in safety assessments (e.g., laboratory parameters, vital signs, ECG, 
cardiotoxicity, gastrointestinal, etc.) to determine the MTD in subjects 16 years 
or older

Assess overall response rate (RR) using RECIST 1.1 in NMC and other solid 
tumors or PSA50 response rate using PCWG2 guidelines in CRPC or DCR
(CR+PR+SD ≥16 weeks in duration) in GIST. 

PK parameter values for GSK525762 following single oral administration as 
amorphous free-base or besylate tablet.
Hypothesis

No formal statistical hypotheses will be tested in Part 1. Analysis will be 
descriptive and exploratory. 

The primary goal of Part 2 is to demonstrate a clinically meaningful response, 
defined as follows: 
NMC: this will be determined by testing the null hypothesis that the 
response rate is ≤5%, with about 80% power when the true response rate 
is 20%.
SCLC and CRPC: this will be determined by testing the null hypothesis that 
the response rate is ≤10%, with about 80% power when the true response 
rate is 30%.
ER+BC: this will be determined by testing the null hypothesis that the 
response rate is ≤15%, with about 80% power when the true response 
rate is 30%.
TNBC: this will be determined by testing the null hypothesis that the 
response rate is ≤10%, with about 80% power when the true response 
rate is 25%.
GIST: this will be determined by testing the null hypothesis that the disease 
control rate is ≤15%, with about 80% power when the true disease control 
rate is 40%.


2011N118599_09
CONFIDENTIAL
BET115521
35
Secondary (Objectives and Endpoints only)
Objectives

To characterize the pharmacokinetics (PK) of GSK525762 in subjects 16 years 
or older following QD and/or BID dosing schedules. 

To evaluate cardiac safety, including the potential for QTcF changes with 
GSK525762 and to assess PK/QTcF relationship following QD and/or BID 
dosing schedules.

To evaluate the exposure response (pharmacokinetic/pharmacodynamic 
[PK/PD]) relationship between GSK525762 and safety and efficacy parameters 
following QD and/or BID dosing schedules.

To evaluate the effect of treatment with GSK525762 on tumor growth and 
survival.
Endpoints

PK parameter values for GSK525762 following single and repeat-dose oral 
administration in subjects 16 years or older

Changes in cardiac safety including QTcF following single and repeat-dose oral 
administration GSK525762.

Progression free survival (PFS), time to response, duration of response, overall 
survival (OS), and exploratory analysis for antitumor response by various 
imaging modalities.
Exploratory (Objectives and Endpoints only)
Objectives

To evaluate the effect of GSK525762 on tumor biology.

Correlation of GSK525762 exposure to changes in PD markers in tumor and/or 
surrogate tissue.

To identify potential indicators of sensitivity or response to GSK525762.

To evaluate systemic and ex vivo on-target BET inhibitory effects.
Endpoints

Dose related changes in markers of cell proliferation and/or cell differentiation 
in tumor and/or surrogate tissue.

Dose related changes in transcription of genes and/or changes in expression of 
proteins regulated by BRD proteins in tumor and/or surrogate tissue.

PK/PD parameter values for exposure response (by RECIST and 18FDG-PET
[if data allows]) relationship between GSK525762 exposure and QTcF, troponin 
and tumor response following single and repeat-dose oral administration.

Changes from baseline and dose/response relationship in ex vivo LPS induced 
cytokines including IL-6 in whole blood and systemic cytokines including IL-6.


2011N118599_09
CONFIDENTIAL
BET115521
36
3.
INVESTIGATIONAL PLAN
3.1.
Study Design/Schematic
Protocol waivers or exemptions are not allowed. Therefore, adherence to the study design 
requirements, including those specified in the Time and Events Tables, is essential.
This is an open-label, single and repeat dose, 2-part study to determine the maximum 
tolerated dose (MTD) and the recommended Phase 2 dose (RP2D) for GSK525762 given 
once-daily orally. Twice daily dosing may also be explored upon evaluation of safety, 
PK, and PD data from once-daily dosing.  Part 1 will be conducted in adult subjects with 
NMC, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), colorectal 
cancer (CRC), neuroblastoma (NB), castration resistant prostate cancer (CRPC), triple 
negative breast cancer (TNBC), estrogen receptor positive (ER positive) breast cancer, 
and MYCN  driven solid tumors.  During the dose escalation of Part 1, additional 
subjects with NMC will be enrolled in a Pharmacodynamic (PD) Expansion Cohort to 
evaluate the pharmacodynamic effects of GSK525762 at lower doses that have been 
previously cleared during dose escalation.  This will enable collection of 
pharmacodynamic data across the predicted efficacious dose range and contribute to the 
evaluation of a biologically efficacious dose.  A sub-study will be opened to 
approximately 10 to 12 subjects in the United States to investigate the relative 
bioavailability of the besylate tablet compared to the amorphous free-base tablet at the 
MTD or RP2D, the effect of high-fat high-calorie meal on the bioavailability of the 
besylate tablet at the MTD or RP2D and the dose proportionality of two doses of 
GSK525762 administered as besylate tablet. This sub-study will also use a stable isotope 
of GSK525762 in order to reduce the variability in the measurement of drug exposure 
caused by day-to-day biologic variations. Expansion cohorts (Part 2) are planned to 
further explore clinical activity of GSK525762 in subjects with NMC, SCLC, CRPC, 
TNBC, ER+BC and GIST as shown in Figure 1. The expansion cohorts will enroll adult 
(16 years old and above) subjects at the appropriate R2PD dose. 
In Part 1, an accelerated dose titration will be employed with one subject per dose level 
until the first instance of a Grade 2 drug related toxicity occurs. Thereafter, subjects will 
be enrolled in a standard 3+3 design. 
After the MTD has been determined in Part 1, Part 2 will be opened for the SCLC, 
TNBC, ER+BC and CRPC expansion cohorts. The NMC expansion cohort will be 
opened with the pivotal besylate tablet after results from the besylate study are available.
The GIST expansion cohort is being added in Amendment 9 due to pre-clinical evidence 
for bromodomain inhibition in GIST.
In Part 1, all subjects will be evaluated for systemic and ex-vivo on-target BET inhibitory 
effects in blood. In addition, pre-treatment and post-treatment tumor samples will be 
collected from selected subjects to be evaluated for target engagement and effects of 
GSK525762 on tumor biology. 


2011N118599_09
CONFIDENTIAL
BET115521
37
Figure 1
Study Schema
A. Part 1 and 2
B. Besylate Sub-Study (N=up to 12 subjects in the United States)
After completion of either sequence all subjects enrolled in the sub-study will be allowed 
to continue in the study with a continuous daily schedule. 
3.2.
Discussion of Design
3.2.1.
Part 1 Dose Escalation
Part 1 will start with an accelerated dose escalation schema in subjects ≥16 years old with 
one subject per dose level.  Accelerated dose titration will stop once a single Grade 2 or 
higher drug-related adverse event is observed in one subject, at which point a standard 
3+3 dose escalation design will be implemented to define the MTD.  The details of these 
2 dose escalation strategies are in Figure 2.
In the accelerated dose escalation cohorts and the 3+3 dose escalation cohorts, the dose 
will be escalated based on all available data, including PK data and the safety profile of 
prior cohorts, as well as the recommended dose from the Neuenschwander- Continuous 
Reassessment Method (N-CRM) design [Neuenschwander, 2009].  N-CRM design is a 
type of Bayesian adaptive dose escalation scheme.  The method is fully adaptive and 


2011N118599_09
CONFIDENTIAL
BET115521
38
makes use of all the Dose Limiting Toxicity (DLT) information available at the time of 
each dose assignment.  The DLT information of all subjects enrolled in the trial are used 
to update the dose-toxicity relationship and provide supportive information in addition to 
3+3 design in the next escalation/de-escalation decision.
Dose escalation will continue until an MTD is determined or until a dose of 200mg per 
day is reached. 
Figure 2
Dose Escalation Schema
Dose Level 1 
Starting Dose = 2mg
Single Subject
Dose Level 2 
Treat Single Subject
Dose Level 3 
Treat Single Subject
Dose Level X 
Single Patient 
≥2 grade toxicity
Dose Level X 
Treat  3 Subjects 
(max 9 subjects) 
Dose Level X +1
Treat  3 Subjects 
(max 9 subjects) 
Dose Level X +2
Treat  3 Subjects
(max 9 subjects) 
Dose level X+1
Add  3 Subjects
(total =6 subjects) 
Declare MTD at 
previous dose level 
(max 18 subjects)
or test 
intermediate dose
Part 1, 
Accelerated Dose 
Escalation
Part 1, 
3+3 Dose Escalation
If DLT/Toxicity at dose level 1 then 
de-escalate to dose level -1 (dose 1mg)
One DLT
(1DLT in 3 
subjects)
One more DLT
(≥2 DLTs in 6 
subjects)
No DLT 
MTD 
Exceeded 
2 DLT
(≥2DLT in 3 subjects)
(Dose increase at any dose escalation will be < 2 fold) 
3.2.2.
Dose Escalation and Schedule
In Part 1, subjects will dose once or twice daily, depending on the cohort. Alternative 
dosing regimens and/or schedule may be implemented based on emerging PK and safety 
data.
Monitoring for cardiac safety signals will be performed, with triplicate 12-lead ECGs to 
be performed on the days indicated in the Time and Events Tables. 
Subjects will be evaluated for dose limiting toxicities (DLTs) during the first 4 weeks of 
treatment (Section 3.2.3).


2011N118599_09
CONFIDENTIAL
BET115521
39
3.2.2.1.
Accelerated Dose Escalation in Part 1
One subject per dose level in the accelerated dose escalation schema will be treated to 
minimize suboptimal drug exposures, starting with Dose Level 1 (Table 2) and 
continuing until one subject experiences a Grade 2 or higher (based on CTCAE v. 4.0) 
drug related adverse event or a DLT. Once this occurs, the accelerated dose escalation 
will terminate, and subjects will be enrolled under a standard 3+3 design (i.e., 3 subject 
cohorts) (Section 3.2.2.2).
Table 2
Accelerated Dose Escalation Procedures in Part 1
Dose Level
Change in Dose
Dose Level -1
Lower doses may be used if Dose Level 1 is not tolerated. This may be 
achieved by reducing the dose or by alternate dosing (e.g. every other 
day)
Dose Level 1
Starting Dose at 2 mg once daily 
Subsequent dose levels
Increase by 2-fold 
(No subjects with Grade 2 drug related toxicity AND no subjects with 
any DLTs in first 4 weeks of treatment)
End of Accelerated Titration 
Phase
Begin 3+3 Dose Escalation Phase
(1 subject Grade 2 drug related toxicity in the first 4 weeks of 
treatment)
NOTE: Route/Administration/Duration: Oral QD or BID (specific dosing instructions will be provided to each 
subject).
3.2.2.2.
3+3 Dose Escalation in Part 1
Two additional subjects will be enrolled to the dose level at which accelerated dose 
titration ends, for a total of at least 3 subjects at that dose level. If no DLTs are observed 
in any of the 3 patients then dosing will proceed to the next higher dose level (≤2 fold 
increase in dose). Subjects will be entered in a staggered approach with at least 3 days 
between each subject to minimize the risk of inadvertently exceeding the maximum 
tolerated dose in multiple subjects. Dose escalation decisions will be made as outlined in 
Table 3. Escalation to the next dose level will not increase greater than 2 fold from the 
previous dose level. If 2 or more DLTs are observed at any dose level, the MTD will 
have been exceeded.
Once the MTD is reached, up to 20 additional subjects may be enrolled at the MTD to 
further evaluate safety and tumor PD. Up to an additional 6 subjects may be enrolled at 
any dose level below the MTD in order to obtain additional dose/response information 
related to tumor PD.  Additional cohorts (with daily exposure not exceeding QD MTD 
exposure) may also be initiated to explore alternative dosing schedules to optimize the 
PK, safety and tolerability profile (see Section 3.2.2.4).  The enrolment of additional 
subjects as described could be in parallel with Part 2 enrolment.


2011N118599_09
CONFIDENTIAL
BET115521
40
Table 3
3+3 Dose Escalation Decision Process in Part 1
Number of subjects at given dose 
level with DLT
Action
0 out of 3 subjects
Escalate to next dose level 
1 out of 3 subjects
Accrue 3 additional evaluable subjects at current dose level for a 
total of 6 evaluable subjects
1 out of 6 subjects
Escalate to the next dose level (Increase by 2-fold)
2 or more subjects in a dosing cohort 
(up to 6 subjects)
Maximum tolerated dose has been exceeded. Either evaluate an 
intermediate dose lower than current dose or expand a prior 
cohort. 
3.2.2.3.
Biopsy and PET Cohorts during Dose Escalation Phase
During the accelerated dose escalation phase 18FDG-PET and biopsy assessments will be 
optional until the standard 3+3 design is implemented. At this point, the sites will be 
required to obtain biopsies (when accessible) and required to perform 18FDG-PET 
assessments when appropriate.  Additional details on biopsy collection are provided in 
Section 6.8.1.
3.2.2.4.
Alteration of Schedule
Alterations may be made to the schedule of administration and/or PK/PD sampling 
schedule based on the results of emerging PK and safety data.
Schedules that incorporate a recovery period may be explored (e.g. every other day or 
two weeks on treatment followed by one week off). This approach will be considered if 
the safety and PK data suggest that a therapeutic exposure cannot be achieved using the 
initial schedule without excessive toxicity. The starting dose for the alternate schedule 
will be the highest completed dose level (at or below MTD) with the initial schedule. 
Escalation can then proceed as described using 3 + 3 dose escalation.  If alternative 
dosing schedules are explored, PK sampling times and other safety assessments may be 
modified to reflect the new dosing schedule. 
On completion of the besylate sub-study for relative bioavailability of besylate 
formulation in tablet form, and having determined a dose for Part 2, all subjects in Part 1 
daily dosing cohorts and in Part 2 will be administered the besylate tablets at the 
recommended Part 2 dose of 75 mg once daily. Those subjects in Part 1 daily dosing 
cohort who were on amorphous tablet dosing before availability of besylate tablets, they 
will be switched to the equivalent besylate tablet dose and will have limited PK samples 
drawn after start on besylate tablets.
In Part 2, subjects approved to alter their current dose level with either a dose reduction 
or dose escalation may require additional limited PK sampling, after discussion with the 
GSK Medical Monitor.


2011N118599_09
CONFIDENTIAL
BET115521
41
3.2.2.5.
BID Dosing Cohort
BID dosing will be explored, based on the short half-life.  The initial dose level for BID 
will be 20mg BID or “x”mg BID (where 2x is equivalent to the last once daily dose 
cleared for dose escalation in Part 1) – whichever is lower.  Dosing will be separated by 
approximately 12 hours (± 1 hr). Escalation can then proceed as described using the 3 + 3 
dose escalation. Additional blood samples will be collected for PK, PD, and safety as 
described in Table 7. 
Subjects may need to undergo dose modification(s) to manage toxicities.  A dose 
adjustment (e.g., BID dose level with a minimum 25% reduction in total daily dosing or 
QD at the same or lower dose level) may be explored after consultation with GSK 
Medical Monitor. The investigator should use clinical judgment to determine whether the 
dosing scheduling may be contributing to any potential toxicity necessitating dose 
adjustment, and make the appropriate change after consultation with the GSK Medical 
Monitor.
3.2.2.6.
Intra-Subject Dose Escalation
Intra-subject dose escalations may be considered on a case-by-case basis, provided that 
the subject has not experienced any Grade 2 or higher drug related toxicity during the 
first 4 weeks of investigational therapy in the accelerated dose escalation phase or a DLT 
in the 3+3 dose escalation phase and contingent upon one of the following:

If additional subject(s) have been enrolled at a higher dose in the dose escalation 
phase and at least one subject has completed 4 weeks of dosing on that regimen 
without a DLT, and after review of all safety data and approval by a GSK Medical 
Monitor, a subject on a lower dose level may be increased up to the highest dose 
level tested.  In this case the subject may begin daily dosing at the higher dose level 
as it will have already been demonstrated to be tolerable.

If no further subjects have been identified for a subsequent higher dose level and 
after a subject has completed 4 weeks of dosing on that regimen without a DLT, that 
subject may be escalated to the next higher dose level after an additional 4 weeks of 
dosing (total of 8 weeks of dosing), review of all safety data and approval by a GSK 
Medical Monitor. In this case the subject must follow the dosing/monitoring 
schedule for the first 4-weeks as outlined in the Time and Events Tables, as he/she 
will be the first subject exposed to the higher dose. 
In Part 1, subjects approved for intra-subject dose escalation will require additional 
limited PK sampling (pre-dose, 0.5, 3 and 6-8 hours) at the higher dose, as determined by 
GSK Clinical Pharmacology.  Additional safety assessments such as insulin/glucose or 
cardiac monitoring may be specified at the time of dose escalation or schedule 
modification based on the safety profile in previous subjects at the higher dose level. 
Intra-subject dose escalations or schedule modification will be discussed with 
investigators and approved by the GSK Medical Monitor and safety monitoring required 
will be specified in writing.


2011N118599_09
CONFIDENTIAL
BET115521
42
3.2.3.
Dose Limiting Toxicity (DLT)
An event will be considered a DLT if it occurs within the first 4 weeks of therapy and 
meets one of the following criteria:

Neutropenia:
- Grade 4 neutropenia lasting 7days.
- Febrile neutropenia: as defined by CTCAE version 4.0 lasting for >24 hours despite 
adequate treatment.

Grade 4 thrombocytopenia.

Drug related Grade 3 or 4 non-hematologic toxicity (including QTcF) as described in 
the Common Terminology Criteria for Adverse Events v 4.0 (excluding 
abnormalities of alanine aminotransferase (ALT) or aspartate aminotransferase 
(AST) (see criteria below). In addition, the DLT exceptions include: rash, diarrhea, 
fatigue, mucositis, nausea, and vomiting that do respond to standard medical care 
within 72 hours or for electrolyte disturbances within 24 hours). 

Drug related Grade 2 non-hematological toxicity (at any time during treatment) that 
in the judgment of the investigator and GSK Medical Monitor is dose-limiting.

Grade 2 Troponin T elevation (central laboratory > Upper limit of normal [ULN]),
measured on two separate occasions within 48 hours in order to confirm elevation 
and with other clinical signs, symptoms, laboratory tests consistent with cardiac
toxicity. (In the event a troponin T (central laboratory assessment) is not performed 
or a laboratory error occurs, considerations for a DLT criteria will involve review of 
two separate local troponin (I or T) assays done within 48 hours at a local 
investigator site. Troponin I or T elevations greater than the upper limit of normal, 
and > 10% coefficient of variance (CV) for that assay will be considered as a grade 2 
elevation.)

Treatment delay of 14 days or greater due to unresolved drug-related toxicity.

ALT 3x ULN + bilirubin 2xULN (>35% direct) or ALT between 3-5 X ULN with 
bilirubin < 2xULN but with hepatitis symptoms or rash or ALT 5xULN.
3.2.4.
Maximum Tolerated Dose (MTD) and Recommended Phase 2 
Dose (RP2D)
The MTD will be exceeded if 2 or more subjects in a cohort of up to 6 subjects 
experience a DLT.
The recommended Phase 2 (Part 2) dose (RP2D) will be determined based on the MTD 
or biologically active dose (example: clinical response), the safety profile and available 
pharmacodynamic data generated from all subjects in Parts 1. The MTD will be the 
RP2D for Part 2 of the study unless there is a lower dose that provides a more favorable 
safety/tolerability profile while providing adequate exposure, biomarker inhibition or 
clinical activity. If necessary, alternate schedules can be explored to determine additional 
biologically active doses even after a RP2D is defined.


2011N118599_09
CONFIDENTIAL
BET115521
43
3.2.5.
Part 1
3.2.5.1.
NMC Pharmacodynamic Expansion Cohort
In the event there are no available enrollment slots during 3+3 dose escalation, eligible 
subjects with NMC (Section 6.2) may be enrolled in a Pharmacodynamic (PD) Expansion 
Cohort to evaluate the pharmacodynamics of GSK525762 at doses that have previously 
been cleared during 3+3 dose escalation.  Three subjects with NMC will be allowed to 
enroll at the last cleared dose level only if subjects with NMC or other solid tumor types 
(Section 4.2.1 Inclusion Criteria) have already enrolled in 3+3 dose escalation. 
Enrollment in the PD Expansion Cohort will continue until either 12 subjects with NMC 
are enrolled in the PD Expansion Cohort, or until the RP2D is determined in Part 1, 
whichever occurs first.  Eligibility criteria for subjects diagnosed with NMC to enroll in 
this cohort are described in Section 4.2 (Part 1). NMC subjects with non-measurable 
disease by RECIST 1.1 but clinically evaluable for progression or response may be 
considered for enrollment after discussion with the GSK Medical Monitor.  Biopsy 
collection will be mandatory as described in Section 3.2.2.3, unless a waiver is granted by 
the GSK medical monitor.  18FDG-PET will be required for all subjects in this cohort.
Subjects in the NMC PD Expansion Cohort will start with same dosing schedule 
described in Section 3.2.2 ; Monitoring for cardiac safety signals will be performed as 
required in Part 1 with triplicate 12-lead ECGs to be performed on the days indicated in 
the Time and Events Table.  All safety and PK evaluations will be performed as outlined 
in the Time and Events Tables for Part 1 (Section 5).  Safety data from subjects in the 
NMC PD Expansion Cohort will be reviewed on an ongoing basis by the GSK medical 
monitor, GSK Safety Review Team, and investigators for consideration during 3+3 dose 
escalation decisions.  
Subjects will be eligible for intra-subject dose escalation to a higher approved dose as 
described in Section 3.2.2.6, upon completion of the 4 week observation period, tumor 
biopsy collection, and approval by the investigator and GSK medical monitor in 
consultation with the GSK study team.  Subjects approved for intra-subject dose 
escalation will require additional limited PK sampling (pre-dose, 0.5, 3 and 6-8 hours) at 
the higher dose, as determined by GSK Clinical Pharmacology. Subjects may continue on 
daily administration of GSK525762 until permanent discontinuation or completion of the
study as described in Section 4.2.4.1.
3.2.6.
Bioavailability, Food Effect, and Dose Proportionality Besylate 
Sub-Study
Part 1 will include a besylate sub-study that will be an open-label, randomized, single 
dose, four period, cross over study to investigate the relative bioavailability of the 
besylate salt tablet compared to the amorphous free-base tablet at or near the MTD or 
RP2D, the effect of high-fat high-calorie meal on the bioavailability of the besylate salt 
tablet at or near the MTD or RP2D and the dose proportionality of two doses of 
GSK525762 administered as besylate salt tablets. GSK525762 dosing will be separated 
by at least 48 hours.  Up to 12 subjects in the United States may be enrolled in besylate 
sub-study. A subject requiring dose reduction or discontinuation from study before 
completion of the Besylate Sub-Study will be replaced by a new enrollment. All subjects 
enrolled to the Besylate Sub-Study, on completion of their participation in this segment 


2011N118599_09
CONFIDENTIAL
BET115521
44
of the study, will continue on a daily dosing schedule till disease progression or 
discontinuation due to investigational agent related toxicity or withdrawal of informed 
consent.  The high-fat (approximately 50% of the total caloric content of the meal), high-
calorie meal (approximately 800 to 1000 calories) will be the representative example 
given by the 2002 US Food and Drug Administration (FDA) guidance [FDA, 2002]. It 
includes the following: two eggs fried in butter, two strips of bacon, two slices of toast 
with butter, four ounces of hash brown potatoes and eight ounces of whole milk.
In order to reduce variability in measurement of drug exposure caused by day-to-day 
biologic variation, a small (<10% of total dose) liquid dose of a stable, non-radioactive 
13C isotope labeled version of GSK525762 besylate salt, will be coadministered orally 
with each fasted treatment in besylate sub-study to serve as an internal standard for 
quantitation purposes (Refer to Section 7.1 for additional information). Use of this stable 
isotope approach will allow better characterization of the impact of the besylate salt and 
dose on GSK525762 bioavailability, if any (Parr, 2012).
Table 4
Besylate Sub-Study Design: BA, Food Effect and Dose 
Proportionality Evaluation
Besylate Sub-Study: Single Dose PK Evaluation
Sample 
Size
Sequence
Period 1
(Week 1 Day 1)
Period 2
(Week 1 Day 3)
Period 3
(Week 2 Day 1)
Period 4
(Week 2 Day 3)
6
1
Treatment A2
Treatment B
Treatment C
Treatment D
6
2
Treatment B
Treatment A2
Treatment C
Treatment D
Treatment A2: RP2D (or MTD) as amorphous free-base tablet + low dose stable isotope in solution, fasted 
administration
Treatment B: RP2D (or MTD) as besylate tablet + low dose stable isotope in solution, fasted administration
Treatment C: half to one-third of RP2D (or MTD) as besylate tablet + low dose stable isotope in solution, 
fasted administration 
Treatment D: RP2D (or MTD) as besylate tablet, fed administration with FDA recommended high fat 
breakfast
3.2.7.
Part 2 Expansion Cohort
Based on the analysis and evaluation of the safety profile and available 
pharmacodynamic, pharmacokinetic and efficacy data generated from all subjects 
enrolled in Part 1 as of January 28, 2016, including the analysis of subjects enrolled in the 
Besylate Sub-Study, the final dose and regimen for Part 2 is determined to be 75 mg once 
daily. The besylate salt tablets will be the formulation used for subjects enrolled in Part 2 
(and potentially for ongoing or newly enrolled subjects in Part 1). Additional details and 
supporting information are provided under separate cover in a companion document and 
dose decision memo. Approximately 170 subjects with NMC, SCLC, CRPC, TNBC, 
ER+BC and GIST will be enrolled in expansion cohort at the RP2D to gather more safety 
data and to further assess anti-tumor activity. 


2011N118599_09
CONFIDENTIAL
BET115521
45
Subjects in Part 2 will start with a continuous daily dosing schedule unless safety, PK or 
PD data necessitate a different dosing schedule. 
The statistical design and number of subjects to be enrolled in a cohort is based on the 
predictive probability of success if enrollment continues until all planned subjects are 
recruited [Lee, 2008]. The predictive probability design allows for evaluation of stopping 
rules after each subject once a minimum number of subjects are evaluable. In this 
particular study, we will stop only for futility. Final decisions on stopping enrollment will 
depend on the totality of the data collected.
For NMC, to test for 20% ORR relative to a 5% ORR suggesting no activity with 0.1 
type I error and 80% power, first interim look may be conducted once 10 evaluable 
subjects have been enrolled into the expansion cohort or treated at the same dose level to 
examine safety and efficacy; if 0 responses are observed, further enrolment into this 
cohort may be terminated. The number of observed confirmed responses will guide 
further enrolment according to the rules summarized in Figure 3. A maximum of 25 
subjects in this cohort will be enrolled at the RP2D.  All available data will be considered 
in making enrollment decisions.
Figure 3
Diagram of Stopping Rules for NMC Cohort Expansion
Number of Responses
Number of 
Subjects
0
1
2
3
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25


2011N118599_09
CONFIDENTIAL
BET115521
46
Figure 3: The shaded regions are the specific regions for stopping enrollment for futility. For instance, if there is no 
response in 10 subjects, then the predictive probability for success will be 10% or less (the futility criterion) and further
enrollment into this cohort will be stopped.
For SCLC and CRPC, to test for 30% ORR relative to a 10% ORR suggesting no activity
with 0.1 type I error and 80% power, first interim look maybe conducted once 10 
evaluable subjects have been enrolled in either cohort or treated at the same dose level to 
examine safety and efficacy, if 0 responses are observed in either cohort, further 
enrolment into this cohort may be terminated. The number of observed confirmed 
responses will guide further enrolment according to the rules summarized in Figure 4. A 
maximum of 22 subjects will be enrolled at the RP2D.  All available data will be 
considered in making enrollment decisions.


2011N118599_09
CONFIDENTIAL
BET115521
47
Figure 4
Diagram of Stopping Rules for SCLC and CRPC Cohort Expansion
Number of Responses
Number of Subjects
0
1
2
3
4
10
11
12
13
14
15
16
17
18
19
20
21
22
Figure 4 Legend:  The shaded regions are the specific regions for stopping enrollment for futility.  For instance, if there 
is no response in 10 subjects, then the predictive probability for success will be 1% or less (the futility criterion) and 
further enrolment in this cohort will be stopped.
For TNBC, to test for 25% ORR relative to a 10% ORR suggesting no activity with 0.1 
type I error and 80% power, first interim look maybe conducted once 10 evaluable TNBC 
subjects have been enrolled in the cohort or treated at the same dose level to examine 
safety and efficacy, if 0 responses are observed in the cohort, Part 2 of the trial may be 
terminated with no further enrolment in this cohort. The number of observed confirmed 
responses will guide further enrolment according to the rules summarized in Figure 5. A 
maximum of 37 subjects will be enrolled at the RP2D.  All available data will be 
considered in making enrollment decisions.
Figure 5
Diagram of Stopping Rules for TNBC Cohort Expansion
Number of Responses
Number of Subjects
0
1
2
3
4
5
6
10
11
12
13
14


2011N118599_09
CONFIDENTIAL
BET115521
48
Number of Responses
Number of Subjects
0
1
2
3
4
5
6
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
Figure 5 Legend:  The shaded regions are the specific regions for stopping enrollment for futility.  For instance, if there 
is no response in 10 subjects, then the predictive probability for success will be 1% or less (the futility criterion) and 
further enrolment in this cohort will be stopped.
For ER+BC, to test for 25% ORR relative to a 10% ORR suggesting no activity with 0.1 
type I error and 80% power, first interim look maybe conducted once 10 evaluable 
ER+BC subjects have been enrolled in this cohort or treated at the same dose level to 
examine safety and efficacy, if 0 responses are observed, further enrolment into this 
cohort may be terminated. The number of observed confirmed responses will guide 
further enrolment according to the rules summarized in Figure 6. A maximum of 37 
subjects per cohort will be enrolled at the RP2D.  All available data will be considered in 
making enrollment decisions.


2011N118599_09
CONFIDENTIAL
BET115521
49
Figure 6
Diagram of Stopping Rules for ER+BC Cohort Expansion
Number of Responses
Number of 
Subjects
0
1
2
3
4
5
6
7
8
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
Figure 6 Legend:  The shaded regions are the specific regions for stopping enrollment for futility.  For instance, if there 
is no response in 10 subjects, then the predictive probability for success will be 1% or less (the futility criterion) and 
further enrolment in this cohort will be stopped.


2011N118599_09
CONFIDENTIAL
BET115521
50
For GIST, to test for 40% DCR relative to a 15% DCR suggesting no activity with 0.1 
type I error and 80% power, first interim look maybe conducted once 8 evaluable GIST 
subjects have been enrolled in this cohort or treated at the same dose level to examine 
safety and efficacy, if 0 confirmed response or SD with at least 16 weeks is observed, 
further enrolment into this cohort may be terminated. The number of observed confirmed 
responses will guide further enrolment according to the rules summarized in Table 5. A 
maximum of 25 subjects will be enrolled at the RP2D. All available data will be 
considered in making enrollment decisions.
Table 5
Decision Making Criteria for Futility of GIST 
Number of Evaluable 
Subjects 
This Number of 
Confirmed 
Responses/SD to Stop 
Early for Futility
Probability of 
continuing enrolling 
when DCR=0.4
Probability of 
continuing enrolling 
when DCR=0.15 
  8
0
0.0000
0.7275
  9
0
0.0000
0.7275
10
1
0.0000
0.4496
11
1
0.0000
0.4496
12
1
0.0000
0.4496
13
1
0.0000
0.4496
14
2
0.0000
0.3087
15
2
0.0000
0.3087
16
2
0.0000
0.3087
17
2
0.0000
0.3087
18
3
0.0000
0.2215
19
3
0.0000
0.2215
20
3
0.0000
0.2215
21
4
0.0000
0.1532
22
4
0.0000
0.1532
23
4
0.0000
0.1532
24
5
0.0000
0.1047
25
6
0.0585
0.0000
Additional safety assessments such as insulin/glucose or cardiac monitoring may be 
specified. Plasma samples for pharmacokinetic evaluation will be collected in all 
subjects. Plasma samples and tumor biopsies will be collected pre- and post-treatment for
the pharmacodynamic evaluation. 


2011N118599_09
CONFIDENTIAL
BET115521
51
4.
STUDY POPULATION
4.1.
Number of Subjects
The number of dose levels and the level at which the MTD will be reached cannot be 
determined in advance. An adequate number of subjects will be enrolled into the study to 
establish a recommended dose(s) and schedule(s) of GSK525762 for further study. To 
complete Part 1, it is estimated 90 to 110 evaluable subjects will be enrolled. The 
besylate sub-study will enroll approximately 10 to 12 subjects in the United States only. 
Part 2 will enroll approximately 170 subjects.
If a subject discontinues the study before completing Week 4 during Part 1 due to reasons 
other than toxicity, additional subjects may be enrolled at the discretion of the Sponsor in 
consultation with the investigator to ensure adequate population for DLT and MTD 
evaluations.
If subjects discontinue the study before completing Week 8 during Part 2, additional 
subjects may be enrolled at the discretion of the Sponsor in consultation with the 
investigator to ensure adequate population for determination of response within NMC
and other expansion cohorts.
4.2.
Eligibility Criteria
4.2.1.
Inclusion Criteria
Deviations from inclusion criteria are not allowed because they can potentially jeopardize 
the scientific integrity of the study, regulatory acceptability or subject safety. Therefore, 
adherence to the criteria as specified in the protocol is essential. Additional details 
regarding the enrollment and registration process for this study can be found in the Study 
Procedures Manual.
A subject will be eligible for inclusion in this study only if all of the following criteria 
apply and after consultation with GSK:
1.
Male or female 16 years or older, at the time of signing the informed consent.
2.
Capable of giving written informed consent, which includes compliance with the 
requirements and restrictions listed in the consent form. If the subject is less than 18 
years old, an Assent form and parental/guardian Consent form (replacing “you will” 
with “your child will” will be required).
3.
Diagnosis of one of the following:

Part 1 Only:

NUT Midline Carcinoma based on ectopic expression of NUT protein as 
determined by IHC and/or detection of NUT gene translocation as 
determined by FISH. Subjects may be treatment naïve or have had prior 
therapy.

SCLC, CRC, NB, TNBC, ER positive BC, CRPC, NSCLC, and any other 
solid tumor which has been confirmed by clinical testing to be MYCN 


2011N118599_09
CONFIDENTIAL
BET115521
52
amplified (defined as a MYCN gene copy number gain of ≥5).  Subjects 
should have tumor progression after receiving at least one prior 
standard/approved chemotherapy, or where there is no approved therapy, or 
where standard therapy is refused.

Part 2 Only: 

NUT Midline Carcinoma as diagnosed by the Central Laboratory. Subjects 
may be treatment naïve or have had prior therapy.

SCLC, CRPC, TNBC, ER+BC and GIST
4.
Subjects with solid tumors, with the exception of CRPC, must demonstrate 
measurable disease, per RECIST v1.1. NOTE: Subjects with NMC that do not meet 
the RECIST v1.1 criteria for measurable disease, but have evaluable disease may be 
considered for enrollment after discussion with the GSK medical monitor.
5.
All prior treatment- related toxicities must be CTCAE (Version 4.0) ≤ Grade 1 
(except alopecia and peripheral neuropathy) at the time of treatment allocation [NCI-
CTCAE, 2009]. 
6.
ECOG Performance Status score of 0-2 for subjects with NMC; 0-1 for subjects with 
other tumor types. 
7.
Adequate organ function as defined in Table 6.


2011N118599_09
CONFIDENTIAL
BET115521
53
Table 6
Definitions for Adequate Organ Function
System
Laboratory Values
Hematologic
Absolute neutrophil count (ANC)
1.5 X 109/L
Hemoglobin
9.5 g/dL (patients that required transfusion or 
growth factor need to demonstrate stable 
haemoglobin for 7 days of 9.5 g/dL)
Platelets
100 X 109/L 
PT/INR and PTT 
≤ 1.5 X ULN
Hepatic
Total bilirubin
≤1.5 x X ULN (isolated bilirubin >1.5 X ULN is 
acceptable if bilirubin is fractionated and direct 
bilirubin <35% or subject has a diagnosis of Gilbert’s 
syndrome)
ALT and AST
2.5 ULN
Renal
Creatinine
OR
Calculated creatinine clearance [calculated by 
Cockcroft Gault formula1]
OR
24-hour urine creatinine clearance 1
≤1.5 X ULN
≥ 50 mL/min
≥ 50 mL/min
Cardiac
Ejection fraction
≥ Lower limit of normal (LLN) by Echocardiogram
(ECHO) (minimum of 50%)
Troponin (T)
Potassium
Magnesium
ULN 
≥LLN and ≤ULN
≥LLN
Thyroid
Thyroid stimulating hormone (TSH)2
≥LLN and ≤ULN
Reproductive/Endocrine
Testosterone 
<50ng/dL (only for subjects with CRPC)
1. See Appendix 2 for Cockcroft Gault formula
2. If TSH is abnormal, but free T3 and/or free T4 are normal, then the subject may still be considered eligible for 
enrolment.
8.
Able to swallow and retain orally administered medication and does not have any 
clinically significant gastrointestinal abnormalities that may alter absorption such as 
malabsorption syndrome or major resection of the stomach or bowels.
9.
A female subject is eligible to participate if she is of:

Non-childbearing potential defined as pre-menopausal females with a 
documented tubal ligation or hysterectomy; or postmenopausal defined as 12 
months of spontaneous amenorrhea [in questionable cases a blood sample with 
simultaneous follicle stimulating hormone (FSH) >40 MIU/ml and estradiol <40 
pg/ml (<140 pmol/L) is confirmatory]. Females on hormone replacement 
therapy (HRT) and whose menopausal status is in doubt will be required to use 


2011N118599_09
CONFIDENTIAL
BET115521
54
one of the contraception methods if they wish to continue their HRT during the 
study. Otherwise, they must discontinue HRT to allow confirmation of post-
menopausal status prior to study enrollment. For most forms of HRT, at least 2 
to 4 weeks will elapse between the cessation of therapy and the blood draw; this 
interval depends on the type and dosage of HRT. Following confirmation of 
their post-menopausal status, they can resume use of HRT during the study 
without use of a contraceptive method.

Child-bearing potential and agrees to use one of the contraception methods 
(described in Section 9.1) from the time of the screening pregnancy test until 7 
months after the last dose of study medication.

Negative serum pregnancy test ≤ 7 days prior to first study drug dose, for 
women of childbearing potential.

Female subjects who are lactating must discontinue nursing prior to the first 
dose of study treatment and must refrain from nursing throughout the treatment 
period and for 5 half-lives of GSK525762 or at least 28 days (whichever is 
longer) following the last dose of study treatment.
10. Male subjects with a female partner of childbearing potential must agree to use one 
of the methods of contraception specified in Section 9.2. This method must be used 
from the time of the first dose of study medication until 16 weeks after the last dose 
of study medication. 
11. Male subjects whose partners are or become pregnant while on study medication 
must continue to use condoms for 16 weeks following the last dose of study 
medication.
4.2.1.1.
Specific Eligibility Criteria for Part 2 CRPC Expansion Cohort
Subjects must meet all of the following additional inclusion criteria in order to be 
considered eligible for this cohort:
12. Histologically or cytologically confirmed diagnosis of prostate adenocarcinoma, 
surgically castrated or continuously medically castrated (for 8 weeks prior to pre-
screening)
13. Persistent disease with evidence of disease progression following standard 
therapy(ies) including prior treatment with androgen/androgen receptor directed 
therapy, including enzalutamide and/or abiraterone
14. Ongoing androgen deprivation therapy with a serum testosterone level <1.7 nmol/L 
or <50 ng/dL [Scher, 2008]
15. Prostate-Specific Antigen (PSA) levels 2.0 ng/mL [Scher , 2008]
NOTE:  If PSA level has been obtained within 14 days of Screening, this test does 
not need to be repeated and the result previously obtained may be used for the 
Screening value.


2011N118599_09
CONFIDENTIAL
BET115521
55
4.2.1.2.
Specific Eligibility Criteria for Part 2 GIST Cohort
16. Histopathologically confirmed diagnosis of advanced (metastatic and/or 
unresectable) GIST.
17. Subjects must have had failure of at least imatinib as therapy for advanced disease 
due to progression.  There is no limit on the number of prior TKI therapies. 
4.2.2.
Exclusion Criteria
Deviations from exclusion criteria are not allowed because they can potentially 
jeopardize the scientific integrity of the study, regulatory acceptability or subject safety. 
Therefore, adherence to the criteria as specified in the protocol is essential.
A subject will not be eligible for inclusion in this study if any of the following criteria 
apply:
1.
Primary malignancy of the central nervous system, or malignancies related to Human 
Immunodeficiency Virus (HIV) or solid organ transplant. History of known HIV. 
History of known Hepatitis B surface antigen or positive Hepatitis C antibody 
(confirmed by RIBA).
2.
Prior treatments usage as defined:
a.
Use of an investigational anti-cancer drug within 14 days or 5 half-lives,
whichever is longer, prior to the first dose of the study medication. Note 
that an investigational drug is defined as a drug without an approved 
oncologic indication.
b.
Any therapy related toxicities must also have resolved to Grade 1 or less. 
c.
Chemotherapy, radiotherapy, anti-neoplastic antibody or targeted therapy 
or immunotherapy within 14 days, major surgery within 28 days (or 42 
days for prior nitrosoureas or mitomycin C) prior to the first dose of the 
study medication. 
d.
Anti-androgen (e.g., bicalutamide) therapies for prostate cancer must be 
stopped 4 weeks prior to enrollment. Second line hormone therapies such 
as enzalutamide, abiraterone, or orteronel should be stopped 2 weeks prior 
to enrollment. Subjects with prostate cancer should remain on luteinizing 
hormone releasing hormone (LHRH) agonists or antagonists. Subjects 
with prostate cancer may also remain on low-dose prednisone or 
prednisolone (up to 10 mg/day) and still be eligible for this study.
3.
Current use of anticoagulants (e.g., warfarin, heparin) at therapeutic levels within 7 
days prior to the first dose of GSK525762. Low dose (prophylactic) low molecular 
weight heparin (LMWH) is permitted. In addition, INR must be monitored in 
accordance with local institutional practices.
4.
Current use of a prohibited medication or requires any of these medications during 
treatment with the investigational drugs (details will be available in Section 8.2). 
This includes excluding current medications known or suspected to be associated QT 


2011N118599_09
CONFIDENTIAL
BET115521
56
prolongation and strong inducers or inhibitors of CYP3A4. In addition, any subject 
who may require a QT prolonging medication while on trial should not be enrolled.
5.
Concurrent use of non-steroidal anti-inflammatory drugs (NSAIDs) except for cases 
where NSAIDs provide benefit over other analgesics or high dose aspirin (allowed 
up to 100 mg PO daily). Details are available in Section 8.2.
6.
Evidence of severe or uncontrolled systemic diseases (e.g., unstable or 
uncompensated respiratory, hepatic, renal, cardiac disease, or clinically significant 
bleeding episodes). Any serious and/or unstable pre-existing medical (aside from 
malignancy exception above), psychiatric disorder, or other conditions that could 
interfere with subject’s safety, obtaining informed consent or compliance to the 
study procedures, in the opinion of the Investigator.
7.
Symptomatic or untreated leptomeningeal or brain metastases or spinal cord 
compression.
NOTE: Subjects previously treated for these conditions that have had stable CNS 
disease (verified with consecutive imaging studies) for >1months, are asymptomatic 
and off corticosteroids, or are on stable dose of corticosteroids for at least 1 month 
prior to study Day 1 are permitted. Stability of brain metastases must be confirmed 
with imaging.  Subject treated with gamma knife the can be enrolled 2 weeks post-
procedure as long as there are no post-procedure complications/stable. In addition, 
subjects treated or currently taking enzyme-inducing anticonvulsant (EIAC) are 
allowed on study.
8.
Cardiac abnormalities as evidenced by any of the following:

History or current untreated clinically significant uncontrolled arrhythmias.

Clinically significant conduction abnormalities or arrhythmias or subjects with 
Bundle Branch Block

Presence of cardiac pacemaker

History or evidence of current ≥Class II congestive heart failure as defined by 
New York Heart Association (NYHA).

History of acute coronary syndromes (including unstable angina and myocardial 
infarction), coronary angioplasty, or stenting within the past 3 months. 
9.
Any of the following EKG findings:

Baseline QTcF interval ≥450 msec

Any clinically significant ECG assessments should be reviewed by the site 
cardiologist prior to study entry.
10. GSK525762 is a benzodiazepine class molecule. Any serious known immediate or 
delayed hypersensitivity reaction(s) to GSK525762 or idiosyncrasy to drugs 
chemically related to the investigational drug.
11. Hemoptysis > 1 teaspoon in 24 hours within the last 28 days. 
12. Subjects with a history of known bleeding disorder(s) or history of clinically 
significant hemorrhage (e.g., GI, neurologic) within the past 6 months.


2011N118599_09
CONFIDENTIAL
BET115521
57
13. Besylate Sub-Study only: unable or unwilling to eat the FDA recommended high-fat 
high-calorie breakfast (two eggs fried in butter, two strips of bacon, 4 oz. of hash 
brown potatoes and 8 oz of whole milk) within the recommended 30 minutes. 
4.2.3.
Screen Failures
Screen failures are defined as subjects who consent to participate in the clinical trial but 
are never subsequently dosed with study treatment.
4.2.4.
Permanent Discontinuation from Study Treatment and Subject 
Completion Criteria
4.2.4.1.
Permanent Discontinuation from Study Treatment
Subjects will receive study treatment until disease progression, death or unacceptable 
adverse event, including meeting stopping criteria for liver chemistry defined in 
Appendix 3 or for hematologic and other non-hematologic toxicity. After disease 
progression, subjects may be allowed to continue treatment with study drug if the 
Investigator strongly believes, and the Sponsor Medical Monitor concurs, that the subject 
could continue to receive benefit (for example in cases of an isolated new lesion, with the 
majority of the disease still under control).
In addition study treatment may be permanently discontinued for any of the following 
reasons:

deviation(s) from the protocol

request of the subject or proxy

investigator’s discretion

subject is lost to follow-up

study is closed or terminated.
The primary reason study treatment was permanently discontinued must be documented 
in the subject’s medical records and case report form (CRF). 
If the subject voluntarily discontinues from treatment due to toxicity, ‘adverse event’ will 
be recorded as the primary reason for permanently discontinuation on the CRF.  
Once a subject has permanently discontinued from study treatment, the subject will not 
be allowed to be retreated. 
All subjects who discontinue from study treatment will have safety assessments at the 
time of discontinuation and during post study treatment (End of Treatment) as specified 
in Time and Events Tables. 
All subjects who permanently discontinue study treatment without disease progression 
will be followed for progression according to the protocol schedule until:

progression


2011N118599_09
CONFIDENTIAL
BET115521
58

death, or

subject has been followed for 2 years after stopping treatment. 
All subjects who permanently discontinue study treatment for any reason will be 
followed for survival and new anti-cancer therapy [including radiotherapy] every 6 
months until death or until the subject has been followed for 2 years. Reporting of any 
pregnancies in female subjects and/or female partners of male subjects will also be 
collected until 7 months after the last dose of study drug. If subjects are unable or 
unwilling to attend clinic visits during follow-up, contact to assess survival may be made 
via another form of communication (e.g., telephone, email, etc.).
4.2.4.2.
Subject and Study Completion
In Part 1, a subject will be considered to have completed the study if:

they complete screening assessments, the 28-day DLT observation period, and the 
end-of-treatment follow-up visit,

they progress or die while receiving study treatment, or

are receiving ongoing study treatment at the time of the Sponsor’s decision to 
close the study.
In Part 2, a subject will be considered to have completed the study if:

they progressed or die while receiving study treatment, or

are receiving ongoing study treatment at the time of the Sponsor’s decision to 
close the study.
Subjects who have not died, and are no longer being followed for survival are considered 
to have discontinued the study.  The End of Study eCRF should only be completed when 
a subject is no longer being followed.  The study may be considered completed for 
purposes of a final analysis when 70% of subjects enrolled at part 2 have progressed or 
died.  If available, subjects continuing on treatment at the time of final analysis may be 
offered the option to continue in a rollover trial.


2011N118599_09
CONFIDENTIAL
BET115521
59
5.
TIME AND EVENTS TABLES
Table 7
Time and Events: Part 1
Part 1 
Assessments
Notes
S
C
R
Refer to Section 6.1.2 for visit windows.
Q4 and 
Q8W 
Initiated 
from 
Week 9
E
O
T
Week 1
Week 2
W3
W4
W5
W7
W9
W11
q4
W
q8
W
D
1
D
2
D
3
D
4
D
5
D
6
D
7
D
1
D
2
D
3
D
4
D
5
D
6
D
7
D
1
D
4
D
1
D
4
D
1
D
1
D
1
D1
D
1
D
1
Informed 
consent
Unless otherwise noted, 
screening assessments to be 
completed within 14 days of first 
dose.
X
Demography
X
Medical history
X
Disease 
characteristics
X
Cardiology 
evaluation
X
Prior therapy
X
Register subject
X
TREATMENT PHASE
Study Drug
Dispense study 
druga
Refer to SPM for further details.
X
X
X
X
X
X
X
Review 
compliance
X
X
X
X
X
X
X
Safety
Pregnancy testb/  
testosterone
Females: serum pregnancy test 
within 7 days of first dose; urine 
X
X
X
X
X
X


2011N118599_09
CONFIDENTIAL
BET115521
60
Part 1 
Assessments
Notes
S
C
R
Refer to Section 6.1.2 for visit windows.
Q4 and 
Q8W 
Initiated 
from 
Week 9
E
O
T
Week 1
Week 2
W3
W4
W5
W7
W9
W11
q4
W
q8
W
D
1
D
2
D
3
D
4
D
5
D
6
D
7
D
1
D
2
D
3
D
4
D
5
D
6
D
7
D
1
D
4
D
1
D
4
D
1
D
1
D
1
D1
D
1
D
1
or serum test thereafter. Males: 
complete and free testosterone 
at SCR; free testosterone 
thereafter.
Physical Exam
X
X
X
X
X
X
X
X
X
ECOG PS
X
X
X
X
X
X
X
X
X
X
Vital Signs
SBP, DBP, heart rate, 
respiratory rate, temp
X
X
X
X
X
X
X
X
X
X
X
X
X
Pain
X
X
X
X
X
X
X
X
X
X
X
X
X
Weight and 
height
Height at SCR only
X
X
X
X
X
X
X
X
X
X
Chest x-ray
X
Pulmonary 
function test
X
Adverse events
SAEs collected continuously from signing of informed consent; AEs collected continuously from time of first dose
Concomitant 
medications
Continuous from signing of informed consent
Laboratory assessments: For details please see following tables
Tests
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Cardiac Monitoring
Echocardiogram
Within 35 days of first dose
X
X
X
X
X
X
12-lead ECGs 
For timing of triplicate ECGs on 
X
O
O
O
O
X
O
X
X
O
X
X
X
O
X
X


2011N118599_09
CONFIDENTIAL
BET115521
61
Part 1 
Assessments
Notes
S
C
R
Refer to Section 6.1.2 for visit windows.
Q4 and 
Q8W 
Initiated 
from 
Week 9
E
O
T
Week 1
Week 2
W3
W4
W5
W7
W9
W11
q4
W
q8
W
D
1
D
2
D
3
D
4
D
5
D
6
D
7
D
1
D
2
D
3
D
4
D
5
D
6
D
7
D
1
D
4
D
1
D
4
D
1
D
1
D
1
D1
D
1
D
1
(Triplicate)
Oc days, see Table 9, Table 10, 
Table 11, Table 12 and Table 
13. Otherwise, triplicate ECGs 
at approximately same time of 
day, and prior to dose on 
dosing days. If QTcF increase 
>30msec, ECGs should be 
repeated Q2-3 days until QTcF 
is within 30msec from baseline.
Efficacy
CT/MRI Scansd
SCR assessment within 28
days of first dose. Target 
lesions to be identified at SCR 
and followed.
X
X
X
X
X
Tumor sample
Optional during rapid dose 
escalation; required during 3+3 
dose escalation. EOT sample 
should be collected at time of 
progression where feasible.
Subjects must have a platelet 
count of ≥75,000/mm3 and a 
PT, INR and aPTT that are 
WNL within 48 hours prior to 
the post-dose biopsye.
X
One post-
dose 
sample 
collected 
anytime 
between
W3D1-
W4D1 (4-
6h post-
dose). 
X
PET scand
Optional during rapid dose 
escalation; required during 3+3 
X
X
X


2011N118599_09
CONFIDENTIAL
BET115521
62
Part 1 
Assessments
Notes
S
C
R
Refer to Section 6.1.2 for visit windows.
Q4 and 
Q8W 
Initiated 
from 
Week 9
E
O
T
Week 1
Week 2
W3
W4
W5
W7
W9
W11
q4
W
q8
W
D
1
D
2
D
3
D
4
D
5
D
6
D
7
D
1
D
2
D
3
D
4
D
5
D
6
D
7
D
1
D
4
D
1
D
4
D
1
D
1
D
1
D1
D
1
D
1
dose escalation.
SCR assessment within 28
days of first dose.
Castrate-Resistant Prostate Cancer Assessments
PSA
PSA to be collected in line with 
PCWG2 guidelines. Levels may 
be checked more frequently if 
appropriate.
X
X
X
Neuroblastoma Assessments
CT/MRI
One or more tests should be 
used as appropriate for 
disease. The same modalities 
utilized at screening should be 
used throughout study. 
Screening Assessment within 
28 days of first dose can be 
used as screening assessment.
X
X
X
MIBG scanf
X
X
X
FDG-PET
X
X
X
99Tc scintigraphy 
for bone scan
X
X
X
Bilateral bone 
marrow 
aspirates and 
biopsy
X
X
X
Urine HVA, 
VMA, dopamine
X
X
X
X
X
Pharmacokinetics (PK) and Pharmacodynamics (PD): For details please see following tables
PK and 
biomarker 
samplesc
Fasting requirements apply for 
PK samples on W1D1 and 
W3D4.
X
X
X
X
X
X
X


2011N118599_09
CONFIDENTIAL
BET115521
63
Part 1 
Assessments
Notes
S
C
R
Refer to Section 6.1.2 for visit windows.
Q4 and 
Q8W 
Initiated 
from 
Week 9
E
O
T
Week 1
Week 2
W3
W4
W5
W7
W9
W11
q4
W
q8
W
D
1
D
2
D
3
D
4
D
5
D
6
D
7
D
1
D
2
D
3
D
4
D
5
D
6
D
7
D
1
D
4
D
1
D
4
D
1
D
1
D
1
D1
D
1
D
1
Samples for 
mRNAc
X
X
X
X
LPS blood 
sample
Not required with BID dosing 
schedule.
X
PK Urine 
samples 
These are optional as of 
Amendment 9.
X
X
Optional Saliva 
and Sample
Not collected with BID dosing 
schedule.
X
X
Blood samples 
for circulating 
exploratory 
biomarkers 
(cfDNA, etc.)
EOT circulating biomarker 
blood samples to be collected 
with lab assessments.
X
X
X
Pharmacogenomics (PGx)
PGx sample
Blood sample should be 
collected after screening 
(preferably on D1) if informed 
consent has been obtained for 
Genetic research.
X
FOLLOW-UP PHASE
Follow-up contact by clinic visit or other means (telephone contact, email, etc) for survival status and anticancer therapy every 6 months. Disease assessment will be collected for subjects who 
discontinue study medication due to any reason other than progression or death. Individual subjects will be considered to have completed the study 2 years after their last treatment or upon 
death, whichever is sooner. Document the cause of death. For the study, the Follow-up Phase ends after a minimum of 70% of subjects have died or 5 years after the last subject is enrolled in 
Phase 2.


2011N118599_09
CONFIDENTIAL
BET115521
64
Part 1 
Assessments
Notes
S
C
R
Refer to Section 6.1.2 for visit windows.
Q4 and 
Q8W 
Initiated 
from 
Week 9
E
O
T
Week 1
Week 2
W3
W4
W5
W7
W9
W11
q4
W
q8
W
D
1
D
2
D
3
D
4
D
5
D
6
D
7
D
1
D
2
D
3
D
4
D
5
D
6
D
7
D
1
D
4
D
1
D
4
D
1
D
1
D
1
D1
D
1
D
1
Abbreviations: CK=creatine kinase; CRP=c-reactive protein; D=day; DBP=diastolic blood pressure; ECG=electrocardiogram; ECOG PS=Eastern Cooperative Oncology Group Performance 
Status; EOT=End-of-Treatment; FLC=free light chain; HVA=homovanillic acid; LPS=lipopolysaccharide; MIBG=meta-iodo-benzyl-guanidine; q4W=every 4 weeks; q8W=every 8weeks; 
SBP=systolic blood pressure; SCR=Screening; SPEP=serum protein electrophoresis; UPEP=urine protein electrophoresis; VMA= vanillylmandelic acid; W=week; PT=Prothrombin Time; 
INR=International Normalized Ratio; aPTT=Activated partial thromboplastin time; WNL=Within normal limits 
a.
Suggested timing of study medication dispensing; may be altered at the discretion of the Investigator or designee, based on availability and visit schedule.  
b.
Not required for women of non-childbearing potential, as defined in Section 4.2, Inclusion Criterion 9.
c.
Some of these samples will be optional as of Amendment 9; please see Table 11, Table 12 and Table 13 for further details.
d.
Per RECIST 1.1 baseline (within 28 days of first dose) bone scans and brain scans are to be conducted for all subjects. Thereafter, scans should be conducted as clinically indicated. 
Subjects undergoing baseline full body PET/CT and/or brain MRI will not require these additional scans, unless clinically appropriate. Disease assessments should be performed 
no less than 4 weeks (28 days) after first dose and from previous on-treatment scan.
e.
If the post-dose biopsy is not performed during this timeframe due to lab abnormalities or subject status, it should be performed at the next agreed upon visit with the GSK Medical 
Monitor after subject recovery.
f.
Subjects with neuroblastoma will have MIBG and bone marrow biopsies after week 24 as clinical indicated to confirm complete remission.


2011N118599_09
CONFIDENTIAL
BET115521
65
Table 8
Time and Events: Part 1 Laboratory Assessments
NB: On dosing days, collect 
blood samples prior to dosing. 
W1D1 samples not needed if 
SCR sample collected within 
72h of first dose.
Notes
SCR
Refer to Section 6.1.2 for visit windows.
Q4 and Q8W 
Initiated from 
Week 9
EOTa
W1
W2
W3
W4
W5
W7
W9
W11
q4W
q8W
D1
D2
D6
D1
D6
D1
D1
D1
D1
D1
D1
D1
D1
Troponin, NT-proBNP
For Troponin: all time points, 
including unscheduled, collect 2 
samples: 1 for local, 1 for central 
lab
X
X
X
X
X
X
X
X
X
X
X
X
Hematology
X
X
X
X
X
X
X
X
X
X
X
X
X
Clinical chemistry
X
X
X
X
X
X
X
X
X
Pancreatic
X
X
X
X
X
X
X
X
X
Coagulation
X
X
X
X
X
X
X
X
X
X
Factor VII Assay
Also perform if PT, INR or aPTT 
are ≥1.5XULN, or in case of 
bleeding event
X
X
X
Creatine phosphokinase
X
X
X
X
X
X
X
X
X
Liver chemistry
X
X
X
X
X
X
X
X
X
X
Fasting blood glucose and 
insulin 
Will be performed at central lab if
not available at local lab
X
X
X
X
X
X
X
X
X
c-peptide and 1,5 AG
Will be performed at central lab if 
not available at local lab
X
X
X
X
X
HbA1c
X
X
X
X
X
X
X
Fasting lipids
X
X
X
X
X
X
Thyroid monitoring
TSH, free T3, free T4 at SCR 
and W1. If TSH is abnormal at 
W1D1, continue monitoring TSH, 
free T3 and free T4 going 
forward at time points indicated 
in this Table and at any time 
X
X
X
X
X
X


2011N118599_09
CONFIDENTIAL
BET115521
66
NB: On dosing days, collect 
blood samples prior to dosing. 
W1D1 samples not needed if 
SCR sample collected within 
72h of first dose.
Notes
SCR
Refer to Section 6.1.2 for visit windows.
Q4 and Q8W 
Initiated from 
Week 9
EOTa
W1
W2
W3
W4
W5
W7
W9
W11
q4W
q8W
D1
D2
D6
D1
D6
D1
D1
D1
D1
D1
D1
D1
D1
when clinically appropriate.
Urinalysis
X
X
X
X
X
X
Pregnancy testb, females
Serum pregnancy test within 7 
days of first dose; urine or serum 
test thereafter
X
X
X
X
X
X
Testosterone, males
Complete and free testosterone 
at SCR; free testosterone 
thereafter
X
X
X
X
X
X
CK, CK-MB
Pre-dose and 12-18 h post-dose
X
as clinically appropriate
HBsAg, HepC antibody
If hepatits C antibody positive, 
perform third generation 
immunoassay on  same sample 
to confirm results
X
C=cycle; D=day; EOT=End of Treatment Visit; q4W=Every 4 weeks; q8W=every 8 weeks; SCR=Screening; W=week
a.
EOT circulating biomarker blood samples to be collected with lab assessments.
b.
Not required for women of non-childbearing potential, as defined in Section 4.2, Inclusion Criterion 9.


2011N118599_09
CONFIDENTIAL
BET115521
67
Table 9
QD Dosing Time and Events: Part 1 Pharmacokinetics and Biomarker Sampling, Week 1 and Week 2
W1D1 (fasting requirements apply)
W1D5
W2D4 + 1 day
pre 
dose
15 min 
± 5m 
30 
min 
±5m
1h 
±5m
2h 
±10m
4h 
±15m
8h 
±1h
12h 
±2h a
24h
±2h
48h ±2h
b, d
30 
min 
±5m
3h 
±15m
pre 
dose
30 min 
±5m
3h 
±15m
8h 
±1h
12-lead ECG, in 
triplicate, 5 minutes 
apart and within 10 
minutes prior to the 
15 min and 30 min 
PK draws and within 
15 minutes prior to 
the other PK draws.
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
PK and protein 
biomarker sample
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Optional Saliva 
Sample
X
X
X
X
X
Urine PK sampling 
(Part 1 only)c
X
0-2h
2-24h
mRNA whole blood 
sample
X
X
X
X
X
X
X
LPS whole blood 
sample
X
X
X
X
X
X
Plasma samples will be divided at the GSK DMPK facility where bioanalysis of PK is performed and shipped to a vendor for systemic cytokine assessment and acute phase protein 
assessment at pre-dose, 2, 4, 8, 12 and 24 hr post-dose.  The frequency of sampling may be changed based on data from the first few subjects assessed. 
a.
PK blood samples collected after-hours may be kept refrigerated at 4ºC in the event the PK lab is closed overnight (stable up to 12H)
b.
48h PK sample to be collected prior to dosing on W1D3
c.
Urine samples for quantitative analysis of GSK525762 are not required in the NMC PD Expansion Cohort.
d.
W1D1 48h assessments (ECG, PK and mRNA) are optional.


2011N118599_09
CONFIDENTIAL
BET115521
68
Table 10
QD Dosing Time and Events: Part 1 Pharmacokinetics and Biomarker Sampling, Week 3 and Week 9
W3D4 + 2 days (if dose has been altered (including held and resumed) serial PK sampling should occur 4 
to 7 days after dosing resumed) (fasting requirements apply)
W9D1 ±4 days
(if dose has been reduced or 
escalated, +4 to +7 days)
EOT
pre 
dose
15 min 
± 5m 
30 min 
±5m
1h 
±5m
2h 
±10m
4h 
±15m
8h 
±1h
12h 
±2h a
24h ±2h
b
48h ±2h
b, d
pre dose
0.5-2h
4 - 8h
12-lead ECG, in 
triplicate, 5 minutes 
apart and within 10 
min prior to the 15 
min and 30 min  PK 
draws and within 15 
minutes prior to the 
other PK draws
X
X
X
X
X
X
X
X
X
X
X
X
X
PK and protein 
biomarker sample
X
X
X
X
X
X
X
X
X
X
X
X
X
Urine PK sampling 
(Part 1 only)c
0-2h
2-24h
mRNA whole blood 
sample
X
X
X
X
Plasma samples will be divided at the GSK DMPK facility where bioanalysis of PK is performed and shipped to a vendor for systemic cytokine assessment and acute phase protein 
assessment at pre-dose and at 2, 4, 8, 12 and 24 hr post-dose.  The frequency of sampling may be changed based on data from the first few subjects assessed.
a.
PK blood samples collected after-hours may be kept refrigerated at 4ºC in the event the PK lab is closed overnight (stable up to 12H)
b.
24h and 48h PK samples to be collected prior to dosing on those days
c.
Urine samples for quantitative analysis of GSK525762 are not required in the NMC PD Expansion Cohort.
d.
W3D4 48h assessments (ECG, PK and mRNA) are optional.


2011N118599_09
CONFIDENTIAL
BET115521
69
Table 11
BID Dosing Time and Events: Part 1 Pharmacokinetics and Biomarker Sampling, Week 1
W1D1
W1D2  and 
W1D3
(relative to 
W1D1 
Morning 
Dose)
W1D5
ECG and 
PK 
samples 
after 
Morning 
Dose only
Morning Dose (fasting requirements apply)
Evening Dose (relative to W1D1 Morning Dose)
pre 
dose
0H
15 
min 
±5m
30 
min 
±5m
1h 
±5m
2h 
±10
m
4h 
±15
m
8h 
±1h
pre 
dose  
(12h-
15m)d
12h
d
15 
min(12.25h) 
± 5m d
30 min 
(12.5h) 
±5m d
1h 
(13h) 
±5m
d
2h 
(14h) 
±10
m d
4h 
(16h) 
±15
m d
8h 
(20h) 
±1h
d
12 h 
(24h) 
±1h
d
36 h 
(48h) 
(pre-
dose
) ±1h
d
30 
min 
±5m
3h 
±1
5
m
Administer/dose
Study 
Medication
X
X
X
12-lead ECG, in 
triplicatea
X
X
X
X
X
X
X
X
X
X
X
X
PK and protein 
biomarker 
sample b
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Urine PK 
sampling c
X
0-2h
2-12h
mRNA whole 
blood sample
X
X
X
Xd
X
X
X
X
X
X
The frequency of sampling may be changed based on data from the first few subjects assessed. 
a.
Triplicate ECGs should be collected 5 minutes apart and within 10 minutes prior to the 15 min and 30 min PK draws and within 15 minutes prior to the other PK draws.
b.
PK blood samples collected overnight may be kept refrigerated at 4ºC in the event the PK lab is closed overnight (stable up to 12H)
c.
Urine samples for quantitative analysis of GSK525762 are optional as of Amendment 9.
d.
These assessments are optional as of Amendment 9.


2011N118599_09
CONFIDENTIAL
BET115521
70
Table 12
BID Dosing Time and Events: Part 1 Pharmacokinetics and Biomarker Sampling, Week 2 and Week 3
W2D4 + 1 day ECG and PK 
samples after Morning Dose 
only
W3D4 +2 days
W3D5 and 
W3D6 
(relative to 
W3D4 
Morning 
Dose)
Morning Dose (fasting requirements apply)
Evening Dose (relative to W3D4 Morning Dose)
pre 
dose 
(Prior 
to 
Dosing)
30m 
± 
5m 
3h 
± 
15m
8 h 
±1h
pre 
dose 
0h
15m 
±5m
30m
±5m
1h 
±5m
2h 
±10m
4h 
±15m
8h 
±1h
pre 
dose
12h
15m 
±5m 
(12.25m)
d
30m 
±5m
d
1h 
(13h)
±5m
d
2h 
(14h)
±10m
d
4h 
(16h)
±15m
d
8h 
(20h)
±1h d
12h 
(24h) 
±1h
(pre 
dose)
d
36h 
(48h) 
±1h
(pre 
dose)
d
Administer 
Study 
Medication
X
X
X
X
X
12-lead 
ECG, in 
triplicate a
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
PK and 
protein 
biomarker 
sample b
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Urine PK 
sampling c
0-2h
2-12h
mRNA 
whole 
blood 
sample
X
X
X
The frequency of sampling may be changed based on data from the first few subjects assessed.
a.
Triplicate ECGs should be collected 5 minutes apart and within 10 minutes prior to the 15 min and 30 min PK draws and within 15 minutes prior to the other PK draws.
b.
PK blood samples collected overnight may be kept refrigerated at 4ºC in the event the PK lab is closed overnight (stable up to 12H)
c.
Urine samples for quantitative analysis of GSK525762 are optional as of Amendment 9.
d.
These assessments (ECG, PK and mRNA) are optional as of Amendment 9.


2011N118599_09
CONFIDENTIAL
BET115521
71
Table 13
BID Dosing Time and Events: Part 1 Pharmacokinetics and Biomarker Sampling, Week 9
W9D1 ±4 days
ECG and PK samples after Morning Dose only
EOT
Pre-dose
0.5-2h
4 - 8h
12-lead ECG, in triplicate, 5 minutes apart and within 10 min prior to the 15 
min and 30 min PK draws and within 15 minutes prior to the other PK draws
X
X
X
PK and protein biomarker sample
X
X
X
mRNA whole blood sample
X
Table 14
Time and Events: Part 2
Part 2 
Assessments
Notes
SCR
Refer to Section 6.1.2 for visit windows.
Q4, Q8 and Q12 Initiated 
from Week 13
EOT
W1
W2
W3
W4
W5
W7
W9
W11
W13
q4W
q8W
q12W
D1
D1
D1
D1
D1
D1
D1
D1
D1
D1
D1
D1
Informed consent
Unless otherwise noted, 
screening assessments to be 
completed within 14 days of first 
dose.
X
Demography
X
Medical history
X
Disease 
characteristics
X
Cardiology 
evaluation
X
Prior therapy
X
Register subject
X
TREATMENT PHASE


2011N118599_09
CONFIDENTIAL
BET115521
72
Part 2 
Assessments
Notes
SCR
Refer to Section 6.1.2 for visit windows.
Q4, Q8 and Q12 Initiated 
from Week 13
EOT
W1
W2
W3
W4
W5
W7
W9
W11
W13
q4W
q8W
q12W
D1
D1
D1
D1
D1
D1
D1
D1
D1
D1
D1
D1
Study Drug
Dispense study 
druga
Refer to SPM for further details. 
X
X
X
X
X
X
X
X
Review compliance
X
X
X
X
X
X
X
X
X
X
Safety
Pregnancy 
testb/testosterone
Females: serum pregnancy test 
within 7 days of first dose; urine 
or serum test thereafter. Males: 
complete and free testosterone 
at SCR; free testosterone 
thereafter.
X
X
X
X
X
X
X
Physical exam
X
X
X
X
X
X
X
X
X
X
ECOG 
X
X
X
X
X
X
X
X
X
X
Vital Signs and Pain 
Assessments
X
X
X
X
X
X
X
X
X
X
Weight and height
Height at SCR only
X
X
X
X
X
X
X
Chest x-ray
X
Pulmonary function 
test
X
Adverse events
SAEs collected continuously from signing of informed consent; AEs collected continuously from time of first dose
Concomitant 
medications
continuous from signing of informed consent
Laboratory assessments: For details please see Table 15
Tests
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Castrate-Resistant Prostate Cancer Assessments
PSA
X
X
X
X
X
X
X
X
X
X
Complete
X
X
X
X
X
X
X
X
X
X


2011N118599_09
CONFIDENTIAL
BET115521
73
Part 2 
Assessments
Notes
SCR
Refer to Section 6.1.2 for visit windows.
Q4, Q8 and Q12 Initiated 
from Week 13
EOT
W1
W2
W3
W4
W5
W7
W9
W11
W13
q4W
q8W
q12W
D1
D1
D1
D1
D1
D1
D1
D1
D1
D1
D1
D1
testosterone
Cardiac Monitoring
ECHO
If Baseline ECHO within 35 
days of first dose, the Week 1 
Day 1 ECHO is only required if 
clinically appropriate.
X
X
optional
X
X
X
X
X
12-lead ECGs 
(Single)
ECGs prior to dosing. If QTcF 
increase >30msec, ECGs 
should be repeated Q2-3 days 
until QTcF is within 30 msec 
from baseline.
X
X
X
X
X
X
X
X
X
X
Efficacy
Lesion  
assessments
X
X
X
X
CT scan or MRI c
Scans within 28 days of first 
dose may be used as screening 
assessment. Additional bone 
scans and brain scans not 
required unless clinically 
indicated.
X
X
X
X
PET scan (FDG or 
fluoride) c
Scans within 28 days of first 
dose may be used as screening 
assessment. Follow up scans 
conducted as clinically 
appropriate.
X
PK
PK 
Three samples to be collected 
each sampling day: During first 
4 weeks collect a pre-dose 
X
X
X
X


2011N118599_09
CONFIDENTIAL
BET115521
74
Part 2 
Assessments
Notes
SCR
Refer to Section 6.1.2 for visit windows.
Q4, Q8 and Q12 Initiated 
from Week 13
EOT
W1
W2
W3
W4
W5
W7
W9
W11
W13
q4W
q8W
q12W
D1
D1
D1
D1
D1
D1
D1
D1
D1
D1
D1
D1
within 60 minutes prior to dose, 
a single draw between 0.5-2h 
post-dose, and a single draw 
between 4-8h post-dose (fasting 
requirements apply).Thereafter 
only a Pre-dose and 0.5 hour 
post-dose sample are collected. 
NOTE: If dose level is adjusted, 
additional PK sampling may be 
requested.
Blood samples for 
circulating 
exploratory 
biomarkers (cfDNA, 
etc)
Baseline sample collected pre-
dose on W1D1 EOT circulating 
biomarker blood samples to be 
collected with lab assessments.
X
X
X
Translational Research
PGx sample
Blood sample should be 
collected after screening 
(preferably on W1D1) if 
informed consent has been 
obtained for Genetic research.
X
Tumor Sample
PK samples should be collected 
within 1 hour of on-treatment 
biopsy. EOT biopsy should be 
collected at time of disease 
progression where feasible. 
Subjects must have a platelet 
count of ≥75,000/mm3 and a 
PT, INR and aPTT that are 
WNL within 48 hours prior to the 
post-dose biopsyd.
X
One post-
dose 
sample 
collected 
anytime 
between
W3D1-
W4D1 (4-6h 
post-dose)e
X


2011N118599_09
CONFIDENTIAL
BET115521
75
Part 2 
Assessments
Notes
SCR
Refer to Section 6.1.2 for visit windows.
Q4, Q8 and Q12 Initiated 
from Week 13
EOT
W1
W2
W3
W4
W5
W7
W9
W11
W13
q4W
q8W
q12W
D1
D1
D1
D1
D1
D1
D1
D1
D1
D1
D1
D1
FOLLOW-UP PHASE
Follow-up contact by clinic visit or other means (telephone contact, email, etc) for survival status and anticancer therapy every 6 months. Disease assessment will be collected 
for subjects who discontinue study medication due to any reason other than progression or death. Individual subjects will be considered to have completed the study 2 years 
after their last treatment or upon death, whichever is sooner. Document the cause of death. For the study, the Follow-up Phase ends after a minimum of 70% of subjects have 
died or 5 years after the last subject is enrolled in Phase 2.
Abbreviations: CK=creatine kinase; D=day; ECG=electrocardiogram; ECOG PS=Eastern Cooperative Oncology Group Performance Status; EOT=End-of-Treatment; q4W=every 
4 weeks; q8W=every 8weeks; SCR=Screening; Wk=week; PT=Prothrombin Time; INR=International Normalized Ratio; aPTT=Activated partial thromboplastin time; WNL=Within 
normal limits
a.
Suggested timing of study medication dispensing; may be altered at the discretion of the Investigator or designee, based on availability and visit schedule.
b.
Not required for women of non-childbearing potential, as defined in Section 4.2, Inclusion Criterion 9.
c.
Per RECIST 1.1 baseline (within 28 days of first dose) bone scans and brain scans are to be conducted for all subjects. Thereafter, scans should be conducted as 
clinically indicated. Subjects undergoing baseline full body PET/CT and/or brain MRI will not require these additional scans, unless clinically appropriate. Disease 
assessments should be performed no less than 4 weeks (28 days) after first dose and from previous on-treatment scan.
d.
If the post-dose biopsy is not performed during this timeframe due to lab abnormalities or subject status, it should be performed at the next agreed upon visit with the 
GSK Medical Monitor after subject recovery.
e.
Timing may be further optimized based on tumor type and emerging data.


2011N118599_09
CONFIDENTIAL
BET115521
76
Table 15
Time and Events: Part 2 Laboratory Assessments
NB: On dosing days, 
collect blood samples 
prior to dosing. W1D1 
samples not needed 
if SCR sample is 
within 72h of first 
dose
Notes
SCR
Q4, Q8 and Q12W 
Initiated from Week 13
EOT
b
W1
W2
W3
W4
W5
W7
W9
W11
W13
q4W
q8W
q12W
D1
D4 a
D1
D4 a
D1
D1
D1
D1
D1
D1
D1
D1
D1
D1
Troponin, NT-proBNP
1 sample for 
local lab 
(troponin I or T), 
1 sample for 
central lab 
(troponin T) 
X
X
X
X
X
X
X
X
X
Hematology
X
X
X
X
X
X
X
X
X
X
X
X
Clinical chemistry
X
X
X
X
X
X
X
X
X
X
Pancreatic
X
X
X
X
X
X
X
X
X
X
Coagulation
X
X
X
X
X
X
X
X
X
X
X
X
Factor VII Assay
Also perform if 
PT, INR or aPTT 
are ≥1.5XULN, 
or in case of 
bleeding event
X
X
X
Liver chemistry
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Creatine 
phosphokinase
X
X
X
X
X
X
X
X
Fasting blood 
glucose and insulin
Will be 
performed at 
central lab if not 
available at local 
lab
X
X
X
X
X
X
X
X
X
X
c-peptide and 1,5 AG
Will be 
performed at 
X
X
X
X
X


2011N118599_09
CONFIDENTIAL
BET115521
77
NB: On dosing days, 
collect blood samples 
prior to dosing. W1D1 
samples not needed 
if SCR sample is 
within 72h of first 
dose
Notes
SCR
Q4, Q8 and Q12W 
Initiated from Week 13
EOT
b
W1
W2
W3
W4
W5
W7
W9
W11
W13
q4W
q8W
q12W
D1
D4 a
D1
D4 a
D1
D1
D1
D1
D1
D1
D1
D1
D1
D1
central lab if not 
available at local 
lab
HbA1c
X
X
X
X
Fasting lipids
X
X
X
X
X
X
X
X
Urinalysis
X
X
X
X
X
X
X
Thyroid monitoring
TSH, free T3, 
free T4 at SCR 
and W1. If TSH 
is abnormal 
W1D1, continue 
monitoring TSH, 
free T3 and free 
T4 going forward
at time points 
indicated in this
Table and at any 
time when 
clinically 
appropriate. 
X
X
X
X
X
X
X
HBsAg, HepC 
antibody
If hepatits C 
antibody 
positive, perform 
third generation 
immunoassay on  
same sample to 
confirm results
X
Abbreviations: D=day; EOT=End of Treatment Visit; q4W=Every 4 weeks; q8W=every 8 weeks; q12W=every 12 weeks; SCR=Screening Visit; W=week; ULN=Upper limit of normal


2011N118599_09
CONFIDENTIAL
BET115521
78
NB: On dosing days, 
collect blood samples 
prior to dosing. W1D1 
samples not needed 
if SCR sample is 
within 72h of first 
dose
Notes
SCR
Q4, Q8 and Q12W 
Initiated from Week 13
EOT
b
W1
W2
W3
W4
W5
W7
W9
W11
W13
q4W
q8W
q12W
D1
D4 a
D1
D4 a
D1
D1
D1
D1
D1
D1
D1
D1
D1
D1
a.
Optional Visits, should be conducted when additional monitoring of laboratory values is clinically appropriate.
b.
EOT circulating biomarker blood samples to be collected with lab assessments.
Table 16
Time and Events: Besylate Sub-Study
Besylate Sub-
Study 
Assessments
Notes
S
C
R
Q4 and Q8W 
Initiated 
from Week 9
E
O
T
Week 1
Week 2
W3
W4
W5
W7
W9
q4W
q8W
D
1
D
2
D
3
D
4
D
5
D
6
D
7
D
1
D
2
D
3
D
4
D
5
D
6
D
7
D
1
D
4
D
1
D
4
D
1
D
1
D
1
D
1
D
1
Informed consent
Unless otherwise noted, screening 
assessments to be completed 
within 14 days of first dose.
X
Demography
X
Medical history
X
Disease 
characteristics
X
Cardiology 
evaluation
X
Prior therapy
X
Register subject
X
TREATMENT PHASE
Study Drug
Administer study 
drug
Administer about same time of day.
No food or antacids 1h before and 
2h after.
X
X
X
X
Continuous dosing starting W2D5
Review subject 
Diary not required when dosed in 
X
X
X
X
X
X
X
X
X


2011N118599_09
CONFIDENTIAL
BET115521
79
Besylate Sub-
Study 
Assessments
Notes
S
C
R
Q4 and Q8W 
Initiated 
from Week 9
E
O
T
Week 1
Week 2
W3
W4
W5
W7
W9
q4W
q8W
D
1
D
2
D
3
D
4
D
5
D
6
D
7
D
1
D
2
D
3
D
4
D
5
D
6
D
7
D
1
D
4
D
1
D
4
D
1
D
1
D
1
D
1
D
1
diary
clinic.
Safety
Pregnancy test/  
testosterone
Females: serum pregnancy test 
within 7 days of first dose; urine or 
serum test thereafter. Males: 
complete and free testosterone at 
SCR; free testosterone thereafter.
X
X
X
X
X
X
Physical exam
X
X
X
X
X
X
X
X
X
X
ECOG PS
X
X
X
X
X
X
X
X
X
X
Vital Signs
SBP, DBP, heart rate, respiratory 
rate, temp
X
X
X
X
X
X
X
X
X
X
Pain
X
X
X
X
X
X
X
X
X
X
Weight and 
height
Height at SCR only
X
X
X
X
X
X
X
X
X
X
Chest x-ray
X
Pulmonary 
function test
X
Adverse events
SAEs collected continuously from signing of informed consent. AEs collected continuously from first dose.
Concomitant 
medications
Continuous from signing of informed consent
Laboratory assessments: For details please see corresponding days in Table 8
Tests
X
X
X
X
X
X
X
X
X
X
X
Cardiac Monitoring
Echocardiogram
Within 35 days of first dose
X
X
X
X
X
12-lead ECGs 
(Triplicate)
For timing of triplicate ECGs on O 
days, see Table 19and Table 20. 
X
O
X
X
X
X
X
X
X
X
O
X
X


2011N118599_09
CONFIDENTIAL
BET115521
80
Besylate Sub-
Study 
Assessments
Notes
S
C
R
Q4 and Q8W 
Initiated 
from Week 9
E
O
T
Week 1
Week 2
W3
W4
W5
W7
W9
q4W
q8W
D
1
D
2
D
3
D
4
D
5
D
6
D
7
D
1
D
2
D
3
D
4
D
5
D
6
D
7
D
1
D
4
D
1
D
4
D
1
D
1
D
1
D
1
D
1
Otherwise, triplicate ECGs at 
approximately same time of day, 
and prior to dose on dosing days. 
If QTcF increase >30msec, ECGs 
should be repeated Q2-3 days 
until QTcF is within 30msec from 
baseline.
Holter monitoring
At least 24 h, on dosing days start 
at least 60 min pre-dose.
X
X
Efficacy
CT/MRI Scans
SCR assessment within 35 days 
of first dose. Target lesions to be 
identified at SCR and followed.
X
X
X
X
X
PET scan
SCR assessment within 35 days 
of first dose.
X
X
X
Neuroblastoma Assessments
CT/MRI
One or more tests should be used 
as appropriate for disease. The 
same modalities utilized at 
screening should be used 
throughout study. Screening 
assessment within 35 days of first 
dose
X
X
X
MIBG scana
X
X
X
FDG-PET
X
X
X
99Tc scintigraphy 
for bone scan
X
X
X
Bilateral bone 
marrow aspirates 
and biopsy
X
X
X
Urine HVA, VMA, 
dopamine
X
X
X
X
X
Pharmacokinetics (PK) and Pharmacodynamics (PD): For details please see following tables
PK samples
X
X
X
X
X
X
X
X
X
X
X


2011N118599_09
CONFIDENTIAL
BET115521
81
Besylate Sub-
Study 
Assessments
Notes
S
C
R
Q4 and Q8W 
Initiated 
from Week 9
E
O
T
Week 1
Week 2
W3
W4
W5
W7
W9
q4W
q8W
D
1
D
2
D
3
D
4
D
5
D
6
D
7
D
1
D
2
D
3
D
4
D
5
D
6
D
7
D
1
D
4
D
1
D
4
D
1
D
1
D
1
D
1
D
1
Pharmacogenomics (PGx)
PGx sample
X
FOLLOW-UP PHASE
Follow-up contact by clinic visit or other means (telephone contact, email, etc) for survival status and anticancer therapy every 6 months. Disease assessment will be collected for 
subjects who discontinue study medication due to any reason other than progression or death. Individual subjects will be considered to have completed the study 2 years after their last 
treatment or upon death, whichever is sooner. Document the cause of death. For the study, the Follow-up Phase ends after a minimum of 70% of subjects have died or 5 years after 
the last subject is enrolled in Phase 2.
Abbreviations: CK=creatine kinase; CRP=c-reactive protein; D=day; DBP=diastolic blood pressure; ECG=electrocardiogram; ECOG PS=Eastern Cooperative Oncology Group 
Performance Status; EOT=End-of-Treatment; FLC=free light chain; HVA=homovanillic acid; LPS=lipopolysaccharide; MIBG=meta-iodo-benzyl-guanidine; q4W=every 4 weeks; 
q8W=every 8weeks; SBP=systolic blood pressure; SCR=Screening; SPEP=serum protein electrophoresis; UPEP=urine protein electrophoresis; VMA= vanillylmandelic acid; W=week
a.
Subjects with neuroblastoma will have MIBG and bone marrow biopsies after week 24 as clinical indicated to confirm complete remission.


2011N118599_09
CONFIDENTIAL
BET115521
82
Table 17
Time and Events: Besylate Sub-Study Pharmacokinetics Sampling, Week 1 and Week 2
W1D1, W1D3, W2D1 and W2D3
pre 
dose
15 min ± 
5m 
30 min 
±5m
1h ±5m
1.5h ± 
5m
2h ±10m
3h ±15m
4h ±15m
6h 
±15mn
8h ±30 
mn
24h ±2h
48h ±2h a
12-lead ECG, in triplicate, 5 
minutes apart and within 10 
minutes prior to the 30 min 
PK draws and within 15 
minutes prior to the other 
PK draws serial ECGs only 
W1D1
X
X
X
X
X
X
X
X
X
X
PK sample
X
X
X
X
X
X
X
X
X
X
X
X
a.
On W1D3 and W2D3, the 48 hour sample has to be taken prior to GSK525762 dosing. 
Table 18
Time and Events: Besylate Sub-Study Pharmacokinetics Sampling, Week 5 and Week 9
W5
W9D1 ±4 days
(if dose has been escalated, +4 to +7 days)
Pre-dose
30 min ±5m
3h ±15m
8h
±30m
Pre-dose
0.5-2h
4 - 8h
12-lead ECG, in triplicate, 5 minutes apart and within 10 min 
prior to the 15 min and 30 min PK draws and within 15 
minutes prior to the other PK draws
X
X
X
X
X
X
X
PK sample
X
X
X
X
X
X
X


2011N118599_09
CONFIDENTIAL
BET115521
83
6.
STUDY ASSESSMENTS AND PROCEDURES
A signed, written informed consent form must be obtained from the subject prior to any 
study-specific procedures or assessments.
Refer to the Time and Events Tables for the timing of all assessments (Section 5). 
Supplementary study conduct information not mandated to be present in this protocol is 
provided in the accompanying Study Procedures Manual (SPM). The SPM will provide 
the site personnel with administrative and detailed technical information that does not 
impact subject safety.
Procedures conducted as part of the subject’s routine clinical management (e.g., blood 
count, imaging study) and obtained prior to signing of informed consent may be utilized 
for screening or baseline purposes provided the procedure meets the protocol-defined 
criteria and has been performed in the timeframe of the study.
Investigators may be requested to perform additional safety tests during the course of the 
study based on newly available data to ensure appropriate safety monitoring. Appropriate 
local regulatory and ethical approvals should be obtained before any additional testing is 
performed.
Protocol waivers or exemptions are not allowed. Therefore, adherence to the study design 
requirements, including those specified in the Time and Events Tables, are essential.
6.1.
Study Visits
6.1.1.
Assessments
See Time and Events Tables for details on the specific assessments.
6.1.2.
Visit Windows
Screening (baseline to pre-dose): All assessments should be completed within 14 days 
prior to first dose, except for those specified in T&E tables (e.g. CT, MRI, ECHO). Note 
for females, pregnancy testing should be performed within 7 days prior to first dose. 
Also, clinical labs performed during screening within 72 hours of first dose do not need 
to be repeated on Day 1. In Part 2, testing by the central laboratory for NMC diagnosis 
must be completed within 3 months prior to signing the main consent (no other 
treatments may have been received after the central diagnosis through study enrollment).
Part 1 only - Week 1: Based on subject and clinic schedule, Week 1 Day 3 assessments 
can be 1 day. 
Part 1 only - Week 2 to Week 3: Based on subject and clinic schedule, assessments can 
be +3 days. 
Part 1 only - Week 3 to Week 4: Based on subject and clinic schedule, assessments can 
be +3 days. 


2 0 1 1 N 1 1 8 5 9 9 _ 0 9
C O N FI D E N TI A L
B E T 1 1 5 5 2 1
8 4
P art 2 o nl y – Wee k 1 t hr o u g h Wee k 3 : assess me nts ca n be +/- 2 da y s, wit h t he 
e xce pti o n of W 1 D 1 assess me nts, w hic h m ust occ ur o n W 1 D 1 .
P art 1 a n d P art 2 – Visits bet wee n Wee k 4 t o Wee k 9 (i ncl usi ve): V isits ca n be 
sc he d ule d 3 da y s.
P art 1 a n d P art 2 - Visits after Wee k 9 u ntil Wee k 5 2: After t he first disease 
assess me nt has bee n c o m plete d t he n t he visits ca n be sc he d ule d 5 da y s.
P art 1 a n d P art 2 - Visits after Wee k 5 2: V isits ca n be sc he d ule d 7 da ys.
Disc o nti n u ati o n / E n d of Tre at me nt visit – s h o ul d be wit hi n 1 4 da y s fr o m last d ose of 
st u d y dr u g. If a s u bject is u na ble t o ret ur n t o t he cli nic d ue t o h os pitalizati o n, site staff are 
e nc o ura ge d t o tele p h o ne t he s u bject f or assess me nt of a d verse e ve nts .
Bes yl ate S u b -St u d y –  + 1 da y wi n d o w is all o we d as l o n g as t here are at least 4 8 h o urs 
bet wee n t he si n gle d oses.
6. 2.
B a s eli n e A s s e s s m e nt f or N M C S u bj e ct s
F or N M C s u bjects i n Part 1, a dia g n osis of N M C base d o n a p ositi ve I H C test a n d/ or 
detecti o n of N U T ge ne tra nsl ocati o n as deter mi ne d b y  FI S H at scree ni n g will be re q uire d. 
I n Part 2, a dia g n osis of N M C base d o n a p ositi ve I H C test perf o r me d at a ce ntral 
la b orat or y will be re q uire d . A ≥2 0 % n uclei stai ni n g c ut off will be a p plie d f or a p ositi ve 
dia g n osis as a s u bset of ger m cell t u m ors (fr o m testis a n d o var y ) wea kly stai n f or t he 
N U T pr otei n ( 5 % ma xi mal n uclei stai ni n g, 
, pers onal c o m m u nicati o n). I n 
rare i nsta nces, w here a s u bject’s t u m or pre vi o usl y teste d p ositi ve f or N M C b y ot her 
met h o ds, a n d a false ne gati ve b y  ce ntral la b orat or y is s us pecte d d ue t o p o or q ualit y 
a n d/ or heter o ge neit y of t he tiss ue, retesti n g ma y  be c o nsi dere d o n a case -b y -case basis i n 
c o ns ultati o n wit h G S K Me dical M o nit or. If t he retest b y  t he ce ntral la b orat or y is p ositi ve 
f or N M C, t he s u bject ma y be c o nsi dere d eli gi ble f or e nr oll me nt.
I n Part 2, fl u oresce nce i n sit u h ybri dizati o n ( FI S H) or ne xt ge nerati o n se q ue nci n g ( N G S) 
ma y  be u n derta ke n retr os pecti vely t o c haracterize t he N U T ge ne f usi o n part ner a n d t o 
s u p p ort e x pl orat or y a nal ysis of differe ntial o utc o mes base d o n t he N U T f usi o n part ner.
6. 3.
B a s eli n e A s s e s s m e nt f or N o n -N M C S u bj e ct s
P P D
S u bjects dia g n ose d wit h S C L C, C R C, N B, C R P C, T N B C, E R + B C or N S C L C [ base d o n 
sta n dar d dia g n ostic criteria, s uc h as hist ol o g y, c yt ol o g y (i ncl u di n g b o ne marr o w 
e val uati o n)] or ser ol o gical criteria (s uc h as ser u m P S A) will be c o nsi dere d eli gi ble f or 
Part 1 of t he st u d y .  I n i nsta nces w here a s oli d t u m or s u bject’s M Y C N a m plificati o n 
stat us is k n o w n, t he n t hat s u bject will be c o nsi dere d eli gi ble.  N-M y c c o p y n u m ber gai n 
of ≥5 will be c o nsi dere d p ositi ve f or M Y C N a m plificati o n. N -M y c testi n g ma y be 
perf or me d usi n g a n y met h o d. S u bjects dia g n o se d wit h S C L C, C R P C, T N B C , E R + B C or 
GI S T will be eli gi ble f or Part 2 of t he st u d y . 


2 0 1 1 N 1 1 8 5 9 9 _ 0 9
C O N FI D E N TI A L
B E T 1 1 5 5 2 1
8 5
6. 4.
S af et y
6. 4. 1.
P h y si c al E x a mi n ati o n s
A r o uti ne p h y sical e xa mi nati o n will be perf or me d b y a q ualifie d p h ysicia n or desi g nee 
acc or di n g t o l ocal practice. Hei g ht a n d wei g ht will als o be meas ure d a n d rec or de d. 
Hei g ht o nl y nee ds t o be meas ure d at baseli ne.
Car di o vasc ular me dical hist or y /ris k fact ors will als o be assesse d at baseli ne.
6. 4. 2.
E C O G
6. 4. 3.
Vit al Si g n s
Vital si g n meas ure me nts will i ncl u de s y st olic a n d diast olic bl o o d press ure, p ulse rate, 
res pirati o n, te m perat ure. T he vital si g ns will be meas ure d after resti n g f or at least 5 
mi n utes i n a s u pi ne or se mi -rec u m be nt p ositi o n. Pai n will be assesse d usi n g a vis ual 
a nal o g scale (A p pe n di x 4 ).
6. 4. 4.
E c h o c ar di o gr a m ( E C H O)
F or all s u bjects, E C H Os will be perf or me d at scree ni n g a n d at assess me nt ti m es as 
o utli ne d i n Secti o n 5 . E C H Os s h o ul d be e val uate d a n d c o m pare d t o baseli ne b y t he sa me 
rea der. 
E C H O data will be tra nsferre d a n d re vie we d b y a n i n de pe n de nt car di ol o gist. Instr ucti o ns 
f or s u b missi o n of q ualif yi n g E C H O sca ns are pr o vi de d i n t he S P M. 
6. 4. 5.
S af et y  El e ctr o c ar di o gr a m s
C CI - T hi s s e cti o n c o nt ai n e d Cli ni c al O ut c o m e A s s e s s m e nt d at a c oll e cti o n q u e sti o n n air e s or i n di c e s, w hi c h ar e pr ot e ct e d b y 
t hir d p art y c o p yri g ht l a w s a n d t h er ef or e h a v e b e e n e x cl u d e d.
Safet y  E C Gs will be perf or me d at t he ti me p oi nts s pecifie d i n Ti me a n d E ve nts Ta bles 
usi n g a sta n dar d 1 2 -lea d E C G mac hi ne t hat a ut o maticall y calc ulates t he H R a n d 
meas ures P R, Q R S, Q T a n d Q Tc F i nter vals. Details will be pr o vi de d i n t he S P M. I n Part 


2011N118599_09
CONFIDENTIAL
BET115521
86
1, the investigator will review the ECG data manually, and should not rely solely on the 
automatic readings of the equipment, when making decisions regarding dosing of 
subjects.

During Part 1, a triplicate 12-lead ECG should be performed at Screening and at all 
other time points.  Triplicate ECGs should be done for all time points on Serial 
Pharmacokinetic sampling days. 

During Part 2, single 12-lead ECGs should be performed at the time points indicated 
in the Time and Events Tables. Standard 12-lead ECGs (Safety ECGs) will be 
performed as part of the real-time assessment of subjects and may not be included in 
the primary QT analysis. Safety ECGs should be reviewed by the investigator on an 
ongoing basis for safety purposes. The dosing for each new week in the first cycle 
should not begin until the safety ECG has been reviewed and no significant 
abnormalities have been detected
If a subject meets the corrected QT (QTc) interval duration criteria below, study 
treatment(s) will be withheld.

QTc interval ≥ 500 msec OR interval increase from baseline 60 msec: IP 
will be discontinued unless the benefits of therapy outweigh the risk of 
rechallenge in the opinion of the Investigator, the GSK Medical Monitor, as 
well as the GSK medical governance. In this situation, rechallenge may be 
permitted (see Table 24 for rechallenge guidelines).
NOTE: QT interval duration criteria should be based on the average QTc value of 
triplicate electrocardiograms (ECGs) to include manual over-read. For example, if an 
ECG demonstrates a prolonged QT interval, obtain 2 additional ECGs over a brief period 
(e.g., within approximately 10 minutes of the abnormal ECG, if possible, and 
approximately 10 minutes apart from each other), and then use the averaged QTc values 
of the 3 ECGs to determine whether the subjects should have study treatment 
discontinued.
The QTc is the QT interval corrected for heart rate according to Fridericia’s formula 
(QTcF). 

For eligibility and withdrawal, QTcF will be used for all subjects. 

For purposes of data analysis, QTcF will be used.
Baseline results are defined by the nearest timepoint prior to first dose. For this trial, 
when triplicate ECGs are indicated at baseline, the baseline QTcF value is determined by 
the mean of the triplicate W1D1 pre-dose QTcF results. If these results are not available, 
then the mean QTcF of the screening triplicate ECG results would be used.
Abnormal ECGs should be evaluated manually prior to final decision making. ECG data 
may be transferred and reviewed by an independent central reviewer. 


2011N118599_09
CONFIDENTIAL
BET115521
87
6.4.6.
Clinical Laboratory Assessments
All protocol required safety laboratory assessments, as defined in Table 19, are 
performed at the institution’s local laboratory. All non-safety assessments (example: 
pharmacokinetic samples, biopsy, translational samples) will be assessed by a central 
laboratory. Please refer to the Study Procedures Manual (SPM) for appropriate 
processing and handling of samples to avoid duplicate and/or additional blood draws.
Some laboratory assessments can vary throughout the day such as testosterone.  It is 
recommended but not mandated that laboratory assessments are collected at 
approximately the same time on each clinic day. If abnormal testosterone levels are 
observed, repeat measurements should occur at the approximate baseline timing to ensure 
this is a trend and not a single outlying event.
Table 19
Clinical Laboratory Tests
Serum Chemistry
Blood urea nitrogen
Sodium
Magnesium 
Potassium
aspartate aminotransferase
Total and direct bilirubin
Uric acid
Creatinine
Chloride
alanine aminotransferase
Albumin
Fasting Glucose
Total carbon dioxide
alkaline phosphatase
Total protein
Creatine phosphokinase
Ionized calcium
gamma-glutamyltransferase
Total calcium
Hematology
Platelet count
Automated White Blood Cell 
Red blood cell count
Differential:
White blood cell count (absolute)
Neutrophils (absolute)
Hemoglobin
Lymphocytes (absolute)
Monocytes (absolute)
Eosinophils (absolute)
Basophils (absolute)
Routine Urinalysis
Specific gravity
pH, glucose, protein, blood, and ketones by dipstick
Microscopic examination (if blood or protein is abnormal)
Other Tests
Coagulation tests (prothrombin time, partial thromboplastin time, international normalized ratio, and fibrinogen)
Factor VII Assay
Pancreatic markers (amylase and lipase)
Fasting Lipid panel (triglycerides and total cholesterol, LDL, HDL)
C-Peptide
Troponin (I or T at local laboratory, Troponin T at central laboratory]
Insulin
Hemoglobin A1C
1,5 –Anhydroglucitol (1,5 AG)
NT-proBNP
Thyroid-stimulating hormone (TSH)
Free Thyroxine 3 (Free T3)
Free Thyroxine 4 (Free T4)
Creatine kinase (CK)
Creatine Kinase-MB (CK-MB)
Testosterone for males (free and complete testosterone at prior to first dose, free testosterone after first dose and as 
indicated in the Time and Events tables for CRPC subjects)
Pregnancy test for females (serum at screening, Urine or serum post-dose)
Cytokine samples (collected as part of PK sample for plasma cytokines)


2011N118599_09
CONFIDENTIAL
BET115521
88
Subjects should be instructed to fast (no food and only water allowed) for 10 hours prior 
to any fasting laboratory assessments (example: fasting glucose, fasting lipid panel, etc). 
Abnormal laboratory results that are considered by the investigator to be clinically 
significant should be recorded on the eCRF as AEs. In addition, these clinically 
significant abnormal laboratory results should be followed until the abnormality resolves 
or is determined to be stable.
6.4.6.1.
Troponin
Two samples for troponin will be collected at each time-point as outlined in Time and 
Events Tables. Troponin T will be assessed at a central laboratory as a means of 
consistent evaluation across all subjects. A second sample will be assessed at a local 
laboratory for purposes of subject management. Whenever possible, troponin T will be 
assayed by the local laboratory. However, either troponin I or troponin T may be assessed 
at a local laboratory. The same local laboratory test (troponin I or troponin T) should be 
used consistently for an individual subject throughout the study. 
6.4.6.2.
Clinical Laboratory Assessments Required Prior to Scheduled 
Surgeries
Subjects must have a platelet count of ≥75,000/mm3 and a PT, INR and aPTT that are 
within normal limits within 48 hours prior to the post-dose biopsy and any scheduled 
surgical procedures.
6.5.
Efficacy
6.5.1.
Disease Assessment
Tumor response will be assessed as outlined in Time and Event Tables by the investigator 
using RECIST 1.1 (Appendix 6) or the Prostate Cancer Working Group 2 (PCWG2) 
guidelines [Scher, 2008] and documented in the eCRF as: progressive disease (PD), 
stable disease (SD), partial response (PR), and complete response (CR).  For subjects 
with NB the appropriate tests and criteria will be followed (See Time and Events Tables, 
Appendix 6). See the SPM for additional instructions.
GSK requires sites to provide electronic copies (upload digital images or images on CD) 
of scans for all subjects for central storage which may be transferred to a central 
independent imaging center. This includes baseline scans and all scans performed during 
the course of the study. GSK may request an independent review of scans. See SPM for 
additional details.  
6.6.
Pharmacokinetics
6.6.1.
Blood Sample Collection
Blood samples to enable quantification of GSK525762 in plasma will be collected at the 
time points indicated in Time and Events Tables. The actual date and time of each blood 


2011N118599_09
CONFIDENTIAL
BET115521
89
sample collection will be recorded. The timing of PK samples may be altered and/or PK 
samples may be obtained at additional time points to ensure thorough PK monitoring. 
Details of PK sample collection, processing, storage and shipping procedures are 
provided in the Study Procedures Manual (SPM). 
6.6.2.
Plasma Sample Analysis
Plasma analysis will be performed under the management of Worldwide Bioanalysis, 
Drug Metabolism and Pharmacokinetics (DMPK), GlaxoSmithKline. Concentrations of 
GSK525762 will be determined in plasma samples using the currently approved 
analytical methodology. In addition, selected metabolites of GSK525762 may also be 
quantified using approved analytical methodology. Raw data will be stored in the GLP 
Archives, GlaxoSmithKline. 
In addition, plasma may be analyzed qualitatively for other circulating compound-related 
material and the results will be reported under a separate DMPK protocol.
6.6.3.
Urine Collection
Urine samples for quantitative analysis of GSK525762 may be collected at the time
points noted in the Time and Events Tables for Part 1 of the study (these samples are 
optional as of Amendment 9). 
Selected urine samples may be analyzed qualitatively and/or quantitatively for 
GSK525762 metabolites and the results will be reported under a separate DMPK 
protocol.
Details of urine sample collection, processing, storage and shipping procedures are 
provided in the SPM.
6.6.4.
Caffeine, Alcohol, and Tobacco
During serial PK sampling days (as outlined in Section 5), subjects will abstain from 
ingesting alcohol, tobacco products, caffeine- or xanthine-containing products (e.g. 
coffee, tea, cola drinks, chocolate) for 24 hours prior to the start of dosing until collection 
of the final pharmacokinetic and/or pharmacodynamic sample during each session. 
6.6.5.
Activity
Subjects will abstain from strenuous exercise for 48 hours prior to each blood collection 
for clinical laboratory tests. 
6.7.
Pharmacodynamics
6.7.1.
Rationale for 18FDG-PET
The inclusion of 18F-FDG PET is based on the limited past experience with this modality 
of imaging in NUT Midline Carcinoma. In an small study (n=1) conducted at the Dana 
Farber Cancer Institute, an intolerable dose of Vorinostat demonstrated marked reduction 


2011N118599_09
CONFIDENTIAL
BET115521
90
in glucose uptake in a 28 day period, which correlated with a smaller reduction in tumor 
volume by CT. On this basis, it would appear that at least in this case NMC is highly 
metabolically active, and thus glucose uptake may be a sensitive surrogate marker of 
tumor inhibition. 
6.7.2.
Assessments for PET
During the dose escalation phase in Part 1, 18F-FDG PET assessments will be optional 
until the standard 3+3 design is implemented. At this point, the sites will be required to 
perform 18F-FDG PET assessments for all NMC subjects and other solid tumors as 
appropriate.
During Part 2, PET (FDG or fluoride) scans should be performed at baseline, with follow 
up scans conducted as clinically appropriate (as outlined in the T&E Table 16).
Additional details will be provided in the SPM. 
Additional analysis may be conducted by an independent central reviewer. Instructions 
for submission of data are provided in the SPM. 
6.8.
Translational Research
Blood and/or tumor tissue specimens will be collected at various times throughout the 
study in order to support research aimed at identifying indicators of sensitivity/resistance 
to GSK525762, understanding the biological effect of GSK525762 and BET inhibition, 
and also to support diagnostic assay development for NMC. 
Toward that end the successful collection of quality tumor specimens will be critical to 
furthering our understanding of BET biology and identifying the best way to treat 
patients with a BET inhibitor. Specifically, the evaluation of responders, responders at 
relapse, and non-responders for gene mutation status and/or pathway activation may lead 
to the discovery of potential new diagnostic markers or novel combinations. Similarly, 
pre- and post-dose tumor specimens will be evaluated for markers of target engagement, 
tumor response, and/or evaluated for changes in gene expression; thus supporting 
identification of a biologically effective dose and furthering our mechanistic 
understanding of BET inhibition in these settings. 
The biopsies will be assessed for transcripts or proteins that reflect BET target 
engagement and/or tumor biology (For NMC, markers of cell proliferation and/or cell 
differentiation (e.g., Ki67 and cytokeratin [Schwartz, 2011]) will be analyzed.  Biopsies 
may also be assessed for Deoxyribonucleic acid (DNA), Ribonucleic acid (RNA) or 
proteins which may be potential predictors of sensitivity or resistance to BET inhibition 
based on emerging data.
6.8.1.
Tumor Tissue Collection
NMC patients in Part 1 will be required to submit a fresh or archival tumor specimen for 
retrospective diagnostic confirmation. NMC patients in Part 2 will be required to submit 
a fresh or archival tumor specimen to the central laboratory for diagnosis. Due to the 
timely need to determine NMC status by NUT IHC testing, a pre-screen informed 


2011N118599_09
CONFIDENTIAL
BET115521
91
consent may be offered to expedite obtaining the tissue in Part 2. These specimens may 
also be evaluated retrospectively for exploratory research as described above. 
All non-NMC patients will also be asked to submit an archival tumor specimen for 
retrospective testing for potential markers of sensitivity and/or resistance, e.g., N-Myc 
amplification; however, this will not be an eligibility requirement.
During the accelerated dose escalation phase (Part 1), fresh pre- and post-dose biopsy 
collections will be optional until the standard 3+3 design is implemented.  During the 3+3 
dose escalation phase in Part 1, and during Part 2, pre- and post-treatment biopsies are 
collected as outlined in the Time and Events Tables and are mandatory. Archival tissue 
may be accepted as a pre-treatment specimen if the subject is treatment naïve. For 
subjects in Part 1 and 2, if tumor tissue is not accessible, discussion with the GSK 
medical monitor is required. 
Subjects must have a platelet count of ≥75,000/mm3 and a PT, INR and aPTT that are 
WNL within 48 hours prior to the post-dose biopsy. If study medication is held prior to 
the post-dose biopsy, dosing must be re-started and subjects should receive 4 consecutive 
days of dosing prior to collection of the biopsy. Specific timing of post-dose sample 
collection is defined in the T&E table. See Study Procedures Manual (SPM) and central 
lab manual for additional details.
6.8.2.
Whole blood LPS-induced IL-6, Plasma Cytokines, and Plasma 
Protein Biomarkers
6.8.2.1.
LPS-induced (Stimulated) Whole Blood Ex Vivo
GSK525762 has consistently shown inhibition of LPS induced IL-6 across different 
human cell populations and in different species. The action of the compound is through 
inhibition of the assembly of transcriptional complexes required to express the protein. 
Pre-clinical studies demonstrate that blood concentration of drug correlates to the degree 
of inhibition of LPS induced IL-6 in ex vivo whole blood samples. Therefore, this 
biomarker will be used as an indication of pharmacology and will be aligned with PK 
sampling. Since inhibition of BET family proteins is known to inhibit a range of pro-
inflammatory mediators and acute phase proteins, a number of additional proteins (46) 
will also be measured from these ex vivo samples.
6.8.2.2.
Systemic (Unstimulated) Plasma for Cytokines, Chemokines, and Acute 
Phase Proteins
The set of analytes identical to that used in the whole blood ex vivo assay (including for 
example, MCP-1, MIP1-β IL-8) will also be measured in plasma samples taken during 
PK sampling. This will assess systemic inflammatory response in the subject using 
biomarkers such as pro-inflammatory cytokines and acute phase proteins and correlate 
the systemic response to drug with that in stimulated and unstimulated blood. These 
biomarkers are expected to change over days rather than hours, based on the plasma half 
lives and pre-clinical data, such that sampling will also be performed after repeat dosing.


2011N118599_09
CONFIDENTIAL
BET115521
92
6.8.2.3.
Whole Blood mRNA
GSK525762 has been shown to modulate the expression of a number of different genes in 
unstimulated whole blood between 1 h and 6 h. The mRNA levels of 31 such genes form 
a ‘signature’ panel which will also be used as a biomarker of engagement of 
pharmacology and will be measured using mRNA isolated from whole blood. The 
modulation of a number of these genes will also be measured as changes in systemic 
proteins as well as in the analysis of the ex vivo assay blood samples (e.g. CCL2 and IL-
8) thus relating mRNA and protein expression with drug concentration.  Other 
translational research studies, such as transcriptomics profiling, will also be performed 
using whole blood mRNA from selected patients.
Until preliminary subject data are generated for these biomarkers, it will be necessary to 
monitor frequently. Please refer to the Time and Events Tables for specific details on 
timing of samples. Further details regarding the sampling procedure and how to process 
the blood samples will be provided in the SPM.
6.8.3.
Biomarker Blood Sample Timing and Schedule
A change in frequency of blood biomarker sampling times may be implemented based on 
emerging data. This would be determined during dose escalation decision meetings and 
communicated to the sites in the meeting minutes for implementation.
6.8.4.
Exploratory Safety Biomarker Blood Samples
Unscheduled biomarker sample(s) may be collected based on emerging safety. One to 
three samples may be collected in a day to address specific safety concerns. Each sample 
would be up to 10mL of whole blood to look at cytokines, gene signature (mRNA) or 
other plasma proteins. The timing of the samples will be based on emerging safety data 
and would be discussed and determined by GSK medical monitor and study team review.
6.9.
Adverse Events (AE) and Serious Adverse Events (SAE)
The investigator or site staff will be responsible for detecting, documenting and reporting 
events that meet the definition of an AE or SAE as outlined in Section 6.9.1 and Section 
6.9.2.
6.9.1.
Definition of an AE
Any untoward medical occurrence in a subject or clinical investigation subject, 
temporally associated with the use of a medicinal product, whether or not considered 
related to the medicinal product.
Note: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a medicinal product. For marketed medicinal products, this 
also includes failure to produce expected benefits, abuse, or misuse. Examples of events 
meeting the definition of an AE include:


2011N118599_09
CONFIDENTIAL
BET115521
93

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. 
6.9.2.
Definition of a SAE
A serious adverse event is any untoward medical occurrence that, at any dose:
a.
Results in death
b.
Is life-threatening
NOTE: The term 'life-threatening' in the definition of 'serious' refers to an event in which 
the subject was at risk of death at the time of the event. It does not refer to an event, 
which hypothetically might have caused death, if it were more severe.
c.
Requires hospitalization or prolongation of existing hospitalization
NOTE: In general, hospitalization signifies that the subject has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for observation 
and/or treatment that would not have been appropriate in the physician’s office or out 
subject setting. Complications that occur during hospitalization are AEs. If a 
complication prolongs hospitalization or fulfills any other serious criteria, the event is 
serious. When in doubt as to whether “hospitalization” occurred or was necessary, the AE 
should be considered serious.


2011N118599_09
CONFIDENTIAL
BET115521
94
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 are as follows:

All events of possible drug-induced liver injury with hyperbilirubinaemia defined as 
ALT 3xULN and bilirubin 2xULN (>35% direct) (or ALT 3xULN and 
INR>1.5, if INR measured) or termed ‘Hy’s Law’ events (INR measurement is not 
required and the threshold value stated will not apply to subjects receiving 
anticoagulants).
NOTE: bilirubin fractionation is performed if testing is available. If testing is unavailable, 
record presence of detectable urinary bilirubin on dipstick indicating direct bilirubin 
elevations and suggesting liver injury. If testing is unavailable and a subject meets the 
criterion of total bilirubin 2xULN, then the event is still reported as an SAE. If INR is 
obtained, include values on the SAE form. INR elevations >1.5 suggest severe liver 
injury 

Any new primary cancers

Significant Cardiac dysfunction 

Grade 4 laboratory abnormalities (not disease related)

Drug related hepatobiliary event leading to permanent discontinuation of study 
treatment
6.9.3.
Laboratory and Other Safety Assessment Abnormalities 
Reported as AEs and SAEs
Any abnormal laboratory findings (e.g., hematology, clinical chemistry, or urinalysis), or 
other safety assessments (e.g., ECGs, radiological scans, vital signs measurements) 
including those that worsen from baseline, that are judged by the investigator to be 


2011N118599_09
CONFIDENTIAL
BET115521
95
clinically significant are to be recorded as an AE or SAE, in accordance with the 
definitions provided. The investigator will exercise his or her medical and scientific 
judgment in deciding whether an abnormal laboratory finding or other abnormal 
assessment is clinically significant.
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. 
However, any clinically significant safety assessments that are associated with the 
underlying disease, unless judged by the investigator to be more severe than expected for 
the subject's condition, are not to be reported as AEs or SAEs. 
6.9.4.
Time Period and Frequency of Detecting AEs and SAEs
The investigator or site staff is responsible for detecting, documenting and reporting 
events that meet the definition of an AE or SAE. 
AEs will be collected from the time the first dose of study treatment is administered until 
28 days following discontinuation of study treatment regardless of initiation of a new 
cancer therapy or transfer to hospice. 
SAEs will be collected over the same time period as stated above for AEs. In addition, 
any SAE assessed as related to study participation (e.g., protocol-mandated procedures, 
invasive tests, or change in existing therapy), study treatment or GSK concomitant 
medication must be recorded from the time a subject consents to participate in the study 
up to and including any follow-up contact. All SAEs will be reported to GSK within 24 
hours, as indicated in Section 6.9.5.
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 28 days the investigator may report any adverse event that 
they believe possibly related to study treatment.  
6.9.5.
Prompt Reporting of SAEs and Other Events to GSK
SAEs, pregnancies, and liver function abnormalities and any other events meeting pre-
defined criteria will be reported promptly by the investigator to GSK as described in 
Table 20 once the investigator determines the event meets the protocol definition for that 
event.


2011N118599_09
CONFIDENTIAL
BET115521
96
Table 20
Reporting of SAEs and Other Events to GSK
Initial Reports
Follow-up Information on a 
Previous Report
Type of Event
Time Frame
Documents
Time Frame
Documents
All SAEs
24 hours
SAE data 
collection tool
24 hours
Updated SAE data 
collection tool 
Pregnancy
24 hours
Pregnancy 
Notification Form
24 hours
Pregnancy Follow 
up Form
Liver chemistry abnormalities:
ALT3xULN and 
bilirubin2xULN 
(>35% direct) (or 
ALT3xULN and 
INR>1.5, if INR 
measured)3
24 hours1
SAE data 
collection tool.
Liver Event Case 
Report Form 
(CRF) and liver 
imaging and/or 
biopsy CRFs if 
applicable2
24 hours
Updated SAE data 
collection tool. 
Updated Liver 
Event CRF2
ALT5xULN; 
ALT3xULN with 
symptoms of liver 
injury or 
hypersensitivity or 
3xULN 4 weeks
24 hours1
Liver Event CRF2
24 hours
Updated Liver 
Event CRF2
ALT3xULN and 
<5xULN and biliribin 
<2xULN
24 hours1
Liver Event CRF 
does not need 
completing unless 
elevations persist 
for 4 weeks or 
subject cannot be 
monitored weekly 
for 4 weeks2
1.
GSK to be notified at onset of liver chemistry elevations to discuss subject safety.
2.
Liver event documents should be completed as soon as possible
3.
INR measurement is not required; if measured, the threshold value stated will not apply to subjects receiving 
anticoagulants.
Methods for detecting, recording, evaluating, and following up on AEs and SAEs are 
provided in the SPM.
6.9.6.
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 


2011N118599_09
CONFIDENTIAL
BET115521
97
regulatory authority, Institutional Review Board (IRB)/Independent Ethics Committee 
(IEC) and investigators.
Investigator safety reports are prepared for suspected unexpected serious adverse 
reactions according to local regulatory requirements and GSK policy and are forwarded 
to investigators as necessary.
An investigator who receives an investigator safety report describing a SAE(s) or other 
specific safety information (e.g., summary or listing of SAEs) from GSK will file it with 
the IB and will notify the IRB/IEC, if appropriate according to local requirements.
6.10.
Pregnancy
6.10.1.
Time period for collecting pregnancy information
Reporting of any pregnancies in female subjects and/or female partners of male subjects 
will be collected after the start of dosing and until 7 months after the last dose of study 
drug.
6.10.2.
Action to be taken if pregnancy occurs
The investigator will collect pregnancy information on any female subject, who becomes 
pregnant while participating in this study. The investigator will record pregnancy 
information on the appropriate form and submit it to GSK within 24 hours of learning of 
a subject's pregnancy. The subject will also be followed to determine the outcome of the 
pregnancy. Information on the status of the mother and child will be forwarded to GSK. 
Generally, follow-up will be no longer than 6 to 8 weeks following the estimated delivery 
date. Any premature termination of the pregnancy will be reported.
While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy for medical reasons will be recorded 
as an AE or SAE.
A spontaneous abortion is always considered to be an SAE and will be reported as such. 
Furthermore, any SAE occurring as a result of a post-study pregnancy and is considered 
reasonably related to the study treatment by the investigator, will be reported to GSK as 
described in Section 6.9.5. While the investigator is not obligated to actively seek this 
information in former study participants, he or she may learn of an SAE through 
spontaneous reporting.
Any female subject who becomes pregnant while participating will be withdrawn from 
the study.
6.10.3.
Action to be taken if pregnancy occurs in a female partner of a 
male study subject
The investigator will attempt to collect pregnancy information on any female partner of a 
male study subject who becomes pregnant while participating in this study. The 
investigator will record pregnancy information on the appropriate form and submit it to 
GSK within 24 hours of learning of the partner’s pregnancy. The partner will also be 
followed to determine the outcome of the pregnancy. Information on the status of the 


2011N118599_09
CONFIDENTIAL
BET115521
98
mother and child will be forwarded to GSK. Generally, follow-up will be no longer than 
6 to 8 weeks following the estimated delivery date. Any premature termination of the 
pregnancy will be reported.
Procedures for pregnancy report will be located in the SPM.
6.11.
Pharmacogenetics
An important objective of the clinical study is PGx research. Participation in PGx is 
optional but all subjects who are eligible for the clinical study will be given the 
opportunity to participate. Subjects may decline participation without effect on their 
medical care or care during the clinical study. A separate consent signature is required for 
PGx research.
Subjects who provide consent will have a blood sample taken for analysis. The 
presence/absence of genetic variations in host DNA from blood will be analysed to 
determine their relationship with response (safety, tolerability, pharmacokinetics, and 
efficacy) to treatment with GSK525762. 
Information regarding pharmacogenetic research is included in Appendix 1. In approving 
the clinical protocol the IEC/IRB and, where required, the applicable regulatory agency 
also approve the PGx assessments (i.e., approval of Appendix 1), unless otherwise 
indicated. Where permitted by regulatory authorities, approval of the PGx assessments 
can occur after approval is obtained for the rest of the study. If so, then the written 
approval will clearly indicate approval of the PGx assessments is being deferred and the 
study, except for PGx assessments, can be initiated. When PGx assessments are not 
approved, then the approval for the rest of the study will clearly indicate this and 
therefore, PGx assessments will not be conducted.
7.
STUDY TREATMENTS
The term ‘study treatment’ is used throughout the protocol to describe any combination 
of products received by the subject as per the protocol design. Study treatment may 
therefore refer to the individual study treatments or the combination of those study 
treatments.
7.1.
GSK525762 Investigational Product Dosage/Administration
GSK525762 Tablets will be provided to sites by GSK. The contents of the label will be in 
accordance with all applicable regulatory requirements. An amorphous, free-base 
formulation of GSK525762 will be used in Part 1 (Table 21) and a crystalline, besylate 
formulation (Table 22) will be introduced in the besylate sub-study in Part 1 (US sites 
only) and the Part 2 expansion cohorts. After completion of the besylate sub-study and 
introduction of besylate material for Part 2, remaining subjects ongoing in Part 1 were
required to change from the amorphous free-base formulation to the besylate formulation 
(at the equivalent dose) based on the amorphous supply availability.
Under normal conditions of handling and administration, investigational product is not 
expected to pose significant safety risks to site staff. A Material Safety Data Sheet 
(MSDS) describing the occupational hazards and recommended handling precautions will 
be provided to site staff if required by local laws or will otherwise be available from GSK 
upon request.


2011N118599_09
CONFIDENTIAL
BET115521
99
Table 21
GSK525762 Amorphous Free-base Investigational Product 
Dosage/Administration
Investigational Product
Product name:
GSK525762 Amorphous Free Base Tablets1
Unit dose strength(s)/Dosage level(s):
1mg
10mg
30mg
Dosage form
Tablet
Tablet
Tablet
Manufacturer
GSK
GSK
GSK
Physical description:
white to off-white, round, biconvex tablets with no markings, 
uncoated tablet
Route/
Administration/ Duration:
Oral; see Time and Event Tables for schedule and 
administration timings
Dosing instructions:
Dose with 240mL water. No food or antacids for at least 1h 
before and 2h after dosing. (If a subject vomits after taking 
study drug, the subject should be instructed not to retake 
the dose and should take the next scheduled dose.)
1. Amorphous formulation is no longer available as of Amendment 9


2011N118599_09
CONFIDENTIAL
BET115521
100
Table 22
GSK525762 Besylate Investigational Product Dosage/Administration
Investigational Product
Product name:
GSK525762 Besylate Tablets
13C-GSK525762 Stable isotope powder for 
oral solution1
Unit dose 
strength(s)/Dosage 
level(s):
5mg
25mg
50mg1
Low dose
Dosage form
Tablet
Tablet
Tablet
Powder for oral solution
Manufacturer
GSK
GSK
GSK
GSK
Physical 
description:
White to slightly 
colored round, 
biconvex tablets 
with no markings, 
film-coated tablet
White to 
slightly 
colored , 
oval, 
biconvex 
tablets with 
no markings, 
film-coated 
tablet
White to slightly colored powder
Route/
Administration/ 
Duration:
Oral; see Time and Event Tables 
for schedule and administration 
timings
Administer orally as a single dose with 
GSK525762 Tablets (besylate Sub-Study for 
Treatment A2, B and C)
Dosing 
instructions:
Dose with 240mL water and should 
be taken at approximately the same 
time each day. May be taken with 
or without food.. (If a subject vomits 
after taking study drug, the subject 
should be instructed not to retake 
the dose and should take the next 
scheduled dose.)
Dissolve powder in 20 mL of water with 
bicarbonate buffer and administered with 
GSK525762 tablets (Besylate Sub-Study, 
Treatment A2, B and C)
1. Formulation is no longer available as of Amendment 9
7.2.
Handling and Storage of Study Treatment
GSK525762 Tablets must be stored in a secure area under the appropriate physical 
conditions for the product. Access to and administration of the GSK525762 Tablets will 
be limited to the investigator and authorized site staff. GSK525762 must be dispensed or 
administered only to subjects enrolled in the study and in accordance with the protocol.
Limited exposure and precautionary action (example: wearing gloves, washing hands 
post exposure, etc.) should be taken by site staff dispensing GSK525762 tablets.


2011N118599_09
CONFIDENTIAL
BET115521
101
GSK525762 Amorphous Free-base Tablets are to be stored at up to 30°C (86°F) and 
protected from light and moisture.
GSK525762 Besylate Tablets are to be stored at up to 30°C (86°F) and protected from 
moisture.
Sample accountability, return or destruction per institutions’ guidelines will be address in 
the SPM. 
7.3.
Meals and Dietary Restrictions
During Part 1, subjects will fast for at least one hour prior to each dose of study drug. 
After dosing, subjects will be asked to fast for an additional two hours. On serial PK 
sampling days (Week 1, Day 1 and Week 3, Day 4), subjects should fast overnight (i.e., 
at least 8 hours). These fasting requirements have been implemented in the protocol and 
informed consents to minimize pharmacokinetic variability. 
During Besylate Sub-Study, subjects will be asked to fast overnight (at least 8 hours) and 
continue fasting for 4 hours post-dose administration except for the fed administration 
where subject will be requested to ingest a high-fat high-calorie meal within 30 minutes 
prior to administration (FDA, 2002).
If a subject vomits after taking study drug, the subject should be instructed not to retake 
the dose and should take the next scheduled dose. Should a twice daily regimen be 
required, additional consideration will be paid to fasting requirements once the escalation 
period is past.
In Part 2, based on the results of the besylate sub-study showing a lack of effect of a 
high-fat high-calorie breakfast on the overall exposure (i.e. AUC) to GSK525762 
administered as besylate coated tablets, the fasting requirement is being lifted, except on 
Serial PK sampling days in Part 2 (Week 1 and Week 4). On these days, subjects should 
fast overnight (i.e., at least 8 hours). After dosing, subjects will be asked to fast for an 
additional two hours. These fasting requirements have been implemented in the protocol 
and informed consents to minimize PK variability.
Fasting will consist of avoiding the oral ingestion of calorie – containing products; 
however, ingestion of water is permitted. 
Subjects should abstain from consumption of Seville oranges, grapefruit, grapefruit 
hybrids or grapefruit juice and/or pomelos, exotic citrus fruits, from one day prior to the 
first dose of study treatment until the last dose of study drug.
7.4.
Treatment Assignment
This is an open-labeled study.
Subjects will be identified by a unique subject number that will remain consistent for the 
duration of the study. Subjects in Besylate Sub-Study will be assigned to a treatment 


2011N118599_09
CONFIDENTIAL
BET115521
102
sequence (see Table 4) in accordance with the randomization schedule generated by 
Discovery Biometrics, using a validated software.
Upon completion of all the required screening assessments, eligible subjects will be 
registered into RAMOS (Registration and Medication Ordering System), the GSK 
interactive voice response system (IVRS) RAMOS, by the investigator or authorized site 
staff. 
7.5.
Product Accountability
In accordance with local regulatory requirements, the investigator, designated site staff, 
or head of the medical institution (where applicable) must document the amount of 
investigational product dispensed and/or administered to study subjects, the amount 
returned by study subjects, and the amount received from and returned to GSK, when 
applicable. Product accountability records must be maintained throughout the course of 
the study. Refer to the SPM for further detailed instructions on product accountability.
7.6.
Treatment Compliance
At each visit, an evaluation of subject compliance with taken medication will be 
performed. The investigator will make every effort to bring non-compliant subjects into 
compliance. 
Compliance with GSK525762 will be assessed through querying the subject during the 
site visits and documented in the source documents and CRF. 
A record of the number of GSK525762 tablets dispensed to and taken by each subject 
must be maintained and reconciled with study treatment and compliance records. 
Treatment start and stop dates, including dates for treatment delays and/or dose 
reductions will also be recorded in the CRF.
7.7.
Dose Modifications
7.7.1.
Dose and Safety Management Guidelines
The following dose modification criteria should provide guidance for, but not act as a 
replacement for sound clinical judgment. The investigator should use clinical judgment to 
determine which drug may be contributing to the toxicity necessitating dose adjustment, 
and make the appropriate change for that drug. Further details are provided in the 
Appendix 3.
Dose reductions for individual subjects may be required, based on toxicity observed 
during the study. Table 24 describes the guidance for dose level reductions. All dose 
reductions should be discussed with the GSK Medical Monitor. 
Table 23
Guidance for GSK525762 Dose Reduction Levels
Current GSK525762 Dose (Total daily dose)
If subject requires a dose level reduction; new 
dose:


2011N118599_09
CONFIDENTIAL
BET115521
103
40 mg
No further dose reduction allowed
50 mg
40 mg
60 mg
50 mg
75 mg or 80 mg
60 mg
Table 24
Dose Adjustment/Stopping Safety Criteria
Toxicity
Dose Adjustment/Stopping 
Criteria
Management Guidelines
Thrombocytopenia
Grade 1 (platelets <LLN to 
≥75,000/mm3) & Grade 2 
(platelets <75,000 to 
≥50,000/mm3)
Continue dosing at same dose level with weekly or 
more frequent monitoring as necessary.
Grade 3 (platelets <50,000 to 
≥25,000/mm3)
Withhold GSK525762 and check aPTT, PT, and 
INR.  Monitor CBC twice a week and coagulation 
studies twice a week until normal, or increase 
monitoring frequency if clinically indicated. 
Hold GSK525762 until thrombocytopenia has 
resolved to ≤ Grade 2 AND aPTT, PT, and INR are 
all ≤ ULN. Drug may then be restarted at a lower 
dose level, after discussion with the medical 
monitor.
If safety lab abnormalities recur following 
rechallenge, drug may be discontinued or restarted 
at another lower dose level, after discussion with the 
medical monitor. If safety lab abnormalities recur to 
the same level following a second rechallange, drug 
will be discontinued.
Grade 4 (platelets  
<25,000/mm3), or any 
moderate to severe bleeding 
accompanied by  drug related 
thrombocytopenia
Withhold GSK525762 and check aPTT, PT, and 
INR.  Monitor CBC twice a week and coagulation 
studies twice a week until normal, or increase 
monitoring frequency if clinically indicated. 
Hold GSK525762 until thrombocytopenia has 
resolved to ≤Grade 2 AND aPTT, PT, and INR are 
all ≤ ULN. Drug may then be restarted at a lower 
dose level, after discussion with the medical 
monitor.
If safety lab abnormalities recur following 
rechallenge, drug may be held until platelet count 
recovers to Grade 2 (≥50,000/mm3). 
For subjects with moderate to severe bleeding 
requiring transfusion support, GSK525762 should 


2011N118599_09
CONFIDENTIAL
BET115521
104
Toxicity
Dose Adjustment/Stopping 
Criteria
Management Guidelines
be permanently discontinued.
If platelet count does not recover to ≥50,000/mm3
(Grade 2) within 14 days, GSK525762 should be 
permanently discontinued.
If platelet count recovers to ≥50,000/mm3 (Grade 2) 
within 14 days, GSK525762 may be continued at the 
current/reduced dose after discussion with the 
medical monitor.  
If platelet count does not recover to ≥25,000/mm3
(Grade 3) within 7 days, GSK525762 should be 
permanently discontinued.
QTcF
If >30 msec and < 60 msec 
change from baseline  AND 
manual QTcF <500 (average 
of three ECGs over at least 15 
minutes)
(1) Continue current dose of GSK525762
(2) Supplement electrolytes, particularly 
potassium and magnesium, to recommended 
levels:
a. Maintain serum potassium > 4mol/L
b. Maintain serum magnesium levels >0.85 
mmol/L
(3) Discontinue any concomitant medications 
with potential for QTcF prolongation.
(4) Consider 24 hour or longer telemetry 
monitoring if clinically indicated.
If 60 msec change from 
baseline occurs
OR
QTcF 500 
(average of three ECGs over 
at least 15 minutes)
Discontinue GSK525762 and notify the Medical 
Monitor. 
(1) Supplement electrolytes to recommended 
levels:
a. Maintain serum potassium > 4mol/L
b. Maintain serum magnesium levels >0.85 
mmol/L
(2) Rule out other potential etiologies for 
prolonged QTcF such as cardiac ischemia
(3) Discontinue any concomitant medications with 
potential for QTcF prolongation.
(4) Consider telemetry monitoring if clinically 
indicated.
This subject may consider restarting study treatment 
at one dose level reduced if all of the following 
criteria for QTcF re-challenge are met. If approval 
for re-challenge is granted, the subject must be re-
consented (with a separate informed consent 
specific to QTc prolongation)
(1) QTcF reduced to <450 msec,
(2) Potassium and magnesium levels are within 
institutional normal range,
(3) A favorable risk/benefit profile (in the medical 
judgement of the Investigator and the Medical 


2011N118599_09
CONFIDENTIAL
BET115521
105
Toxicity
Dose Adjustment/Stopping 
Criteria
Management Guidelines
Monitor),
(4) Approval within GSK medical governance:
a. agreement with SERM MD and PPL,
b. review with Chair or co-Chair of the GSK 
QT panel,
c. SERM VP and Clinical VP approval
d. Head Unit Physician approval
(5) Institutional IRB (or equivalent) approval, and
(6) The subject is re-consented regarding the 
possible increased risk of QTc prolongation. 
Discontinuation procedures:
If the subject is withdrawn due to QTcF event, the 
subject should complete the following activities post-
dose:
(1) Evaluation by cardiologist.
(2) Weekly assessments for QTcF should be 
performed for two weeks, and then next 
assessment at 4 weeks post-dose. 
a. If QTcF results have not resolved to 
baseline by 4 weeks post-dose, then 
continue every 4-5 weeks until resolution
Troponin
Troponin level >ULN
Contact the subject immediately for evaluation of 
symptoms and to obtain ECG. Repeat troponin 
within 24-48 hours or as soon as possible. 
For asymptomatic subjects with repeat troponin 
values >ULN, hold study medication(s), refer to a 
cardiologist and contact the GSK Medical Monitor. If 
the repeat value is within the normal range, the 
subject may continue study medication with close 
follow-up for symptoms, ECG monitoring and further 
troponin measurements as clinically indicated.
If the subject is symptomatic or the troponin level 
approaches the threshold for MI according to local 
lab parameters, the study medication must be 
withdrawn and the subject will be referred 
immediately to a cardiologist for appropriate medical 
care.
LVEF
Asymptomatic, absolute 
decrease of >10% in LVEF 
compared to baseline and the 
ejection fraction is below the 
institution’s lower limit of 
normal (LLN)
Temporarily discontinue investigational drugs(s) and 
repeat evaluation of LVEF within 2 weeks.
If LVEF recovers (defined as LLN and absolute 
decrease 10% compared to baseline) at any time 
during the next 4 weeks, after consultation and 
approval of the GSK medical monitor, the subject 
may be restarted on investigational drug(s) at a 
reduced dose. Monitoring to be performed at 2 and 
4 weeks after restarting investigational drug(s) and 


2011N118599_09
CONFIDENTIAL
BET115521
106
Toxicity
Dose Adjustment/Stopping 
Criteria
Management Guidelines
then per protocol specifications.
If LVEF does not recover within 4 weeks, 
permanently discontinue investigational drug(s). 
Evaluation by a cardiologist will be conducted. 
Ejection fraction should continue to be monitored at 
2 weeks, 4 weeks and every 4 weeks until 16 weeks 
or resolution, whichever is longer.
Grade 3 or 4
Permanently discontinue investigational drug(s). 
Evaluation by a cardiologist will be conducted. 
Ejection fraction should be monitored at 2 weeks, 4 
weeks and then every 4 weeks until 16 weeks or 
resolution.
Liver 

ALT 5X ULN, OR

ALT 3X ULN plus either 
bilirubin ≥2X ULN (>35% 
direct bilirubin, bilirubin 
fractionation required) or 
INR >1.5 without 
evidence of biliary 
obstruction or progressive 
disease, OR

ALT 3X ULN with 
symptoms of liver injury or 
hypersensitivitya
Refer to Section 14.3 (Appendix 3) for liver 
chemistry stopping criteria, treatment algorithms, 
reporting and follow-up of suspected liver events. 
Discontinue study medication(s) and notify the GSK 
Medical Monitor.
Hypo- and 
Hyperglycemia
(for management 
purposes, refer to 
mild, moderate 
and severe 
intensity criteria; 
however for CRF 
reporting use NCI-
CTCAE version 
4.0 Grade 1-5) 
Fasting blood glucose >150 
mg/dL to 250 mg/dL (Mild 
hyperglycemia)
Monitor fasting and preprandial glucose.
If persistent over 2 repeats over 3-4 weeks, consult 
Diabetologist and consider starting metformin.
Any blood glucose >250 
mg/dL (Moderate to Severe 
hyperglycemia)
Hold investigational product(s) and instruct subject 
to notify investigator immediately. 
Monitor for ketoacidosis as clinically indicated.
If subject has evidence of ketoacidosis, initiate 
prompt therapy. Antihyperglycemic therapy with 
insulin is preferred. Consult 
Diabetologist/Endocrinologist. Careful monitoring 
should be performed to control for rebound 
hypoglycemia as effect of investigational product(s) 
resolve 
May consider restarting study treatment at a 
reduced dose or dose level pre-event based on 
discussion with GSK Medical monitor.


2011N118599_09
CONFIDENTIAL
BET115521
107
Toxicity
Dose Adjustment/Stopping 
Criteria
Management Guidelines
Fasting blood glucose 
<70 mg/dL (Moderate to 
Severe hypoglycemia)
Hold investigational product(s).
Provide sugar containing liquids and monitor monitor 
blood sugar closely. Check for insulin and c-peptide 
levels. After blood sugar normalizes, may restart 
study treatment one dose level lower if the 
hypoglycemia cannot be attributed to any other 
cause, and fasting blood sugar will be monitored on 
a daily basis until the blood glucose level is 
stabilized.
Diarrhea
Grade 1
Initiate supportive care including loperamide. 
Grade 2
Initiate supportive care including loperamide. 
Consider temporary discontinuation of study 
medications and discuss with GSK Medical Monitor.
Grade 3 or 4
Above plus consider IV hydration, hospital 
admission and prophylactic antibiotics as 
appropriate. Withhold study drug until diarrhea has 
resolved to ≤Grade 1, continue diarrheal prophylaxis
May restart study treatment one dose level lower.
Mucositis
Grade 1-2
Encourage oral hygiene. Offer topical supportive 
anesthetics. Encourage adequate hydration.
Grade 3-4
Above, plus systemic opiate administration as 
needed. Consider IV hydration and hospital 
admission as appropriate. 
For mucositis >Grade 3, hold GSK525762 until 
mucositis is <Grade 1 and resume the same dose of 
GSK525762. If mucositis >Grade 3 recurs, hold 
GSK525762 until mucositis is <Grade 1, then reduce 
GSK525762 one dose level. If mucositis >Grade 3 
recurs a third time at reduced dose, hold 
GSK525762 until mucositis resolved to <Grade 1, 
then reduce GSK525762 one dose level (if possible) 
or discontinue permanently.
Pneumonitis
Grade 1
For all grades obtain high resolution chest CT if 
possible.
Consider evaluation by pulmonologist. 
Consider room air O2 saturation at rest via pulse 
oximetry reading ( X 2, 5 mins apart). 
If any decline is observed in O2 saturation, hold 
study drug, repeat chest x-ray to determine if 
progression of pneumonitis has occurred and 
consult pulmonologist.


2011N118599_09
CONFIDENTIAL
BET115521
108
Toxicity
Dose Adjustment/Stopping 
Criteria
Management Guidelines
Grade 2
Must be evaluated by pulmonologist. 
Consider pulmonary function tests including: 
spirometry, Diffusing Capacity of the Lung for 
Carbon Monoxide (DLCO), and weekly room air O2 
saturation at rest via pulse oximetry reading ( X 2, 5 
mins apart). Repeat evaluations every 8-12 weeks 
until return to wnl. Consider a bronchoscopy with 
biopsy and/or bronchoalveolar lavage. (BAL).
Treat only if symptomatic. Consider corticosteroids if 
symptoms are troublesome and infective origin is 
ruled out. Taper as medically indicated.
Hold investigational drug(s) until recovery to ≤Grade 
1, then reduce dose by at least 25%.  Discontinue 
investigational drug(s) if no recovery to ≤Grade 1 
within 4 weeks. 
Grade 3 and 4
Discontinue investigational drug(s).
Evaluation by pulmonologist. 
Required pulmonary function tests including: 
spirometry, DLCO, and room air O2 saturation at 
rest via pulse oximetry reading (X 2, 5 mins apart). 
Repeat evaluations at least every 8 weeks until 
return to wnl. Bronchoscopy with biopsy and/or BAL 
is recommended.
Consider treatment with corticosteroids in the 
appropriate clinical setting and in consultation with 
the pulmonologist (1-2 mg/kg of prednisone [or 
equivalent] IV once daily) if infectious origin is ruled 
out. Taper over 4-6 weeks
*Note: Baseline results are defined by the nearest timepoint prior to first dose. For this trial the Baseline QTcF value is 
determined by the mean of the triplicate W1D1 pre-dose QTcF results (when triplicate ECGs are indicated). If 
these results are not available, then the mean QTcF of the screening triplicate ECG results are considered 
baseline.
a. New or worsening symptoms believed to be related to liver injury (such as fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, or jaundice) or believed to be related to hypersensitivity (such as fever, rash or 
eosinophilia.
7.7.2.
Dose Adjustments for Toxicity
Table 25
Guidance for Dose Adjustment for Toxicity [Except those listed in 
Table 24]
Worst Grade
GSK525762
1
No change in dose.
2
For drug-related Grade 2 toxicities, continue dosing with no change or may consider holding 
for up to 1 week for toxicity to be < Grade 2. Continue at the same dose (dose reduction is 
required if the Grade 2 toxicity is considered a DLT).


2011N118599_09
CONFIDENTIAL
BET115521
109
Worst Grade
GSK525762
3
Hold dose until toxicity is Grade 1*, then restart with no change for 1st episode. Reduce by 
one dose level with 2nd episode if recovery to ≤Grade 1 within 21 days. If no recovery to 
≤Grade 1 after a 21 day delay in the 2nd episode, subject should be permanently 
discontinued.
4
Off protocol therapy.
In rare situations, based on discussion and written agreement between GSK medical 
monitor and investigator, if the patient is receiving benefit then the following criteria should 
be implemented: hold until toxicity is ≤Grade 1*, then restart with one dose level lower. If 
the same Grade 4 toxicity recurs, study drug will be permanently discontinued. 
*Note: Exceptions to drug-related Grade 1 requirement may be made for rash, alopecia, etc.  Exceptions to drug-
related Grade 1, 2, 3 requirements would be quickly reversible (<48 hours) laboratory abnormality (example: electrolyte 
changes).
Dose escalation decisions will take into account all available data, including 
pharmacokinetics data and the safety profile of prior cohorts, and will occur following 
review of these data by the investigator(s), GSK medical monitor, pharmacokineticist, 
and statistician. The decision and rationale will be documented in written format and 
distributed to the investigator(s), GSK medical monitor, pharmacokineticist, and 
statistician. 
The dosing schedule may also be adjusted to expand a dosing cohort to further evaluate 
[safety, pharmacokinetic and/or pharmacodynamic] findings at a given dose level, or to 
add cohorts to evaluate additional dose levels. The study procedures for these additional 
subject(s) or cohort(s) will be the same as that described for other study subjects.
8.
CONCOMITANT MEDICATIONS AND NON-DRUG 
THERAPIES
Subjects will be instructed to inform the investigator prior to starting any new 
medications from the Screening Visit until the end of the study (Final Study Visit). Any 
concomitant medication(s), including herbal preparations during the study will be 
recorded in the eCRF. The minimum requirement is that drug name, route of 
administration, dose and frequency of dosing, along with start and stop dates of 
administration should be recorded. Additionally, a complete list of all prior cancer 
therapies will be recorded in the eCRF.
If future changes are made to the list of permitted/prohibited medications, formal 
documentation will be provided by GSK and stored in the study file. Any such changes 
will be communicated to the investigative sites in the form of a letter. 
8.1.
Permitted Medications and Non-Drug Therapies
Subjects should receive full supportive care during the study, including transfusions of 
blood and blood products, and treatment with antibiotics, antiemetics, antidiarrheals, and 
analgesics, and other care as deemed appropriate, and in accordance with their 


2011N118599_09
CONFIDENTIAL
BET115521
110
institutional guidelines. The only caveat is that subjects should not receive those 
medications listed as prohibited in Section 8.2. 
Bisphosphonates will be allowed if subjects have been on a stable dose for at least three 
months.
Supportive measures including erythropoietin, blood transfusions, and hematopoietic 
colony stimulating factors for treatment of cytopenias are permitted. Erythropoiesis-
stimulating agents and colony-stimulating factors like filgrastim and pegfilgrastim may 
be used as clinically indicated.
Drugs with a low risk of causing QTc prolongation (e.g., aprepitant) may be used without 
restriction.
8.2.
Prohibited Medications and Non-Drug Therapies
8.2.1.
Prohibited Medications
Subjects should not receive other anti-cancer therapy [including chemotherapy, radiation 
therapy, immunotherapy, biologic therapy, investigational therapy, hormonal therapy 
(other than leuprolide or other GnRH agonists), surgery or tumor embolization] while on 
treatment in this study. Other anti-cancer therapy should not be administered unless one 
of the following occurs: documented disease progression; unacceptable or unmanageable 
toxicity; subject is withdrawn from the study at the investigator’s discretion or consent is 
withdrawn; or no further clinical benefit is anticipated which requires permanent 
discontinuation of study drug. Note, palliative radiation and/or surgical intervention may 
be permitted (for example to address pain management) and should be discussed with the 
GSK medical monitor prior to invention to determine appropriate dosing and schedule. 
Subjects may continue to use aspirin, but doses are not allowed to be greater than 100 mg 
per day. The use of non-steroidal anti-inflammatory drugs (NSAIDs) will be excluded, 
except for when NSAIDs will provide benefit over other analgesics and then to be used 
with caution, including concomitant use of proton pump inhibitors.Subjects taking 
enzyme-inducing antiepileptic agents or other potent inhibitors or inducers of CYP3A4 
enzymes should be transitioned to another agent at least 14 days (or 5 half-lives, 
whichever is longer) prior to the first dose of study agents.
Anticoagulants at therapeutic doses (e.g., warfarin, direct thrombin inhibitors, etc) are 
PROHIBITED from seven days prior to the first dose of study drug through completion 
of the Final Study Visit. Low dose (prophylactic) anticoagulants are permitted provided 
that subject’s PT/PTT meet entry criteria.  
If a subject requires medication for hyperemesis, due to the potential of serotonin 5-HT3 
receptor antagonists to increase QTcF, palonosetron (administered per the prescribing 
information) and ondansetron (at a maximum oral dose of 8 mg TID) are the only 
allowed drugs in this class (i.e. dolasetron and granisetron are not permitted).
Co-administration of the medications listed in Table 26 are prohibited for 5 half-lives (or 
at least 14 days, whichever is longer) prior to the first dose of study drug until 


2011N118599_09
CONFIDENTIAL
BET115521
111
discontinuation from the study drug due to unacceptable risk of Torsades de Pointes (with 
the exception of amiodarone, which is prohibited beginning 6 months prior to screening 
through discontinuation from the study; however, there may be situations when the 
subject is on study and Advanced Cardiac Life Support (ACLS) requires the use of 
amiodarone, which should be used as per local clinical guidelines). If a prohibited 
medication is required for single use (such as for a procedure) while study treatment(s) is 
held, the GSK Medical Monitor can approve such use.
Table 26
Drugs with a Risk of Torsades de Pointes that are Prohibited1
Amiodarone
Dronedarone
Moxifloxacin
Anagrelide
Droperidol
Papaverine
Azithromycin
Erythromycin
Pentamidine
Chloroquine
Escitalopram
Pimozide
Chlorpromazine
Flecainide
Procainamide
Cilostazol
Fluconazole
Propofol
Ciprofloxacin
Halofantrine
Quinidine
Citalopram
Haloperidol
Roxithromycin
Clarithromycin
Ibogaine
Sevoflurane
Cocaine
Ibutilide
Sotalol
Disopyramide
Levofloxacin
Sulpiride
Dofetilide
Levomepromazine
Sultopride
Domperidone
Levosulpiride
Terlipressin
Donepezil
Methadone
Thioridazine
Data Source: crediblemeds.org revision date 09 January 2017.
1. The above table is not exhaustive and prohibited drugs are defined by the online version at the time of screening of 
the subject
8.2.2.
Cautionary Medications
Subjects should minimize the use of medications which contain acetaminophen. Subjects 
should be informed of alternative medications. 
Co-administration of medications that are known to prolong the QT interval and have a 
risk of causing Torsades de Pointes are to be used with EXTREME CAUTION
beginning 14 days prior to the first dose of study drug until discontinuation from the 
study. These medications include (but are not limited to):


2011N118599_09
CONFIDENTIAL
BET115521
112
Table 27
Drugs with a Risk of Torsades de Pointes which are permitted for 
co-administration with Extreme Caution1
Alfuzosin
Foscarnet
Perphenazine
Apomorphine
Gemifloxacin
Pipamperone
Aripiprazole
Hydrocodone ER
Promethazine
Artenimole+piperaquine
Iloperidone
Rilpivirine
Asenapine
Imipramine
Risperidone
Atomoxetine
Isradipine
Saquinavir
Bedaquiline
Leuprolide
Sertindole
Buprenorphine
Lithium
Solifenacin
Clomipramine
Melperone
Tacrolimus
Clozapine
Mifepristone
Telavancin
Cyamemazine
Mirabegron
Telithromycin
Degarelix
Mirtazapine
Tetrabenazine
Delamanid
Moexipril/ hydrochlorothiazide
Tiapride
Desipramine
Nicardipine
Tizanidine
Dexmedetomidine
Norfloxacin
Tolterodine
Efavirenz
Nortriptyline
Trimipramine
Ezogabine
Ofloxacin
Tropisetron
Famotidine
Oxytocin
Vardenafil
Felbamate
Paliperidone
Venlafaxine
Fingolimod
Pasireotide
Zotepine
Flupentixol
Perflutren lipid microspheres
Data Source: crediblemeds.org revision date 09 January 2017
1. The above table is not exhaustive and these drugs are defined by the online version at the time of screening of 
the subject
After starting cautionary medications such as in Table 27, it is recommended that ECGs 
are implemented daily until the steady state. If there are abnormalities, implement 
additional cardiotoxicity monitoring as addressed in Table 24, Section 7.7.
GSK525762 is a moderate CYP3A4 inducer. Medications that have a narrow therapeutic 
index and that are substrates of CYP3A4 should be administered with caution, as their 
metabolism may be affected by co-administration with GSK525762 and result in 
decreased exposure. These include alfentanil, cyclosporine, dihydroergotamine, 
ergotamine, fentanyl, pimozide, quinidine, sirolimus, tacrolimus, and theophylline. 
GSK525762 is a substrate for breast cancer resistance protein (BCRP) and P-glycoprotein 
(Pgp) transporters. Therefore, potent inhibitors of these transporters, such as 
cyclosporine, tacrolimus, or ketoconazole, should be avoided.
GSK525762 in as inhibitor of organic anion transporter 1A1 (OAT1) and organic anion 
transporter 3 (OAT3) in vitro. Substrates of these transporters include agents such as 
methotrexate, penicillin G, and indomethacin. While co-administration of these agents 
with GSK525762 is not prohibited, they should be used with caution and additional 
monitoring for adverse effects should be utilized.


2011N118599_09
CONFIDENTIAL
BET115521
113
Higher doses of oral steroids can cause enzyme induction.  As such, oral steroids should 
be used with caution (and discussed with the GSK Medical Monitor).  NOTE:  Topical or 
inhaled steroids are permitted. 
Questions regarding concomitant medications should be directed to the GSK Medical 
Monitor for clarification.
8.3.
Treatment after Discontinuation of Study Treatment or 
Withdrawal from/Completion of 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.
Refer to Section 4.2.4.1 and Section 5 for follow-up assessment of subjects who are to be 
followed up for disease progression and/or survival after permanently discontinue from 
study treatment.
8.4.
Treatment of Study Treatment Overdose
In the event of a study drug overdose (defined as administration of more than the 
protocol-specified dose), the investigator should contact the GSK Medical Monitor 
immediately and closely monitor the subject for AEs/SAEs and laboratory abnormalities. 
Decisions regarding dose interruptions or modifications will be made by the investigator 
in consultation with the GSK Medical Monitor based on the clinical evaluation of the 
subject.
A plasma or urine sample for PK analysis may be requested by the GSK Medical Monitor 
on a case-by-case basis. This plasma or urine sample should be collected as soon as 
possible, but within 3 days from the date of the last dose of on-study dosing. 
Information regarding the quantity of the excess dose as well as the duration of the 
overdosing should be documented in the CRF.
9.
LIFESTYLE REQUIREMENTS (CONTRACEPTION)
9.1.
Female Subjects
Female subjects of childbearing potential must not become pregnant during the trial and 
for 7 months after stopping study medication and so must be sexually inactive by 
abstinence or use contraceptive methods with a failure rate of ≤1%.
Abstinence
Sexual inactivity by abstinence must be consistent with the preferred and usual lifestyle 
of the subject. Periodic abstinence (e.g. calendar, ovulation, symptothermal, post-
ovulation methods) and withdrawal are NOT acceptable methods of contraception. 


2011N118599_09
CONFIDENTIAL
BET115521
114
Contraceptive Methods with a Failure Rate of 1%

Non-hormonal intrauterine device (IUD) or intrauterine system (IUS) that meets the 
≤1% failure rate as stated in the product label

Male partner sterilization (vasectomy with documentation of azoospermia) prior to 
the female subject's entry into the study, and this male is the sole partner for that 
subject. For this definition, “documented” refers to the outcome of the 
investigator's/designee’s medical examination of the subject or review of the
subject's medical history for study eligibility, as obtained via a verbal interview with 
the subject or from the subject’s medical records.
These allowed methods of contraception are only effective when used consistently, 
correctly and in accordance with the product label. The investigator is responsible for 
ensuring subjects understand how to properly use these methods of contraception.
All hormonal means of birth control such as oral, injectable, dermal, subdermal or topical
contraceptives are NOT acceptable forms of birth control given that their efficacy has not 
been evaluated when given in combination with the investigational drugs.
9.2.
Male Subjects
This list does not apply to male subjects with a female partner of child bearing potential 
who are and will continue to be abstinent from penile-vaginal intercourse on a long term 
and persistent basis, when this is their preferred and usual lifestyle. Periodic abstinence 
(e.g. calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are 
NOT acceptable methods of contraception.
Male subjects with female partners of child-bearing potential must use one of the 
following contraceptive methods after the first dose of study treatment and until 16 weeks 
after the last dose of study drug(s).

Vasectomy with documentation of azoospermia. The documentation on male sterility 
can come from the site personnel’s: review of subject’s medical records, medical 
examination and/or semen analysis, or medical history interview, OR

Condom use PLUS partner use of a highly effective contraceptive (≤1% rate of 
failure per year) such as  intrauterine device or system, or hormonal birth control 
such as contraceptive subdermal implant, combined estrogen and progestogen oral 
contraceptive, injectable progestogen, contraceptive vaginal ring, or percutaneous 
contraceptive patches.
Male subjects whose partners are or become pregnant must continue to use condoms for 
16 weeks after after the last dose of study medication. Male subjects should be advised 
not to donate sperm while on study and for 16 weeks after the last dose of study 
medication.


2011N118599_09
CONFIDENTIAL
BET115521
115
10.
DATA MANAGEMENT
Subject data will be collected using defined electronic case report forms (eCRFs), 
transmitted electronically to GSK and combined with data provided from other sources in 
a validated data system. 
In all cases, subject initials will not be collected or transmitted to GSK according to GSK 
policy.
11.
DATA ANALYSIS AND STATISTICAL CONSIDERATIONS
11.1.
Sample Size Assumptions
11.1.1.
Part 1
The total number of subjects to be enrolled into Part 1will depend on the number of dose 
escalations required to establish the maximum tolerated dose of GSK525762; they are not 
driven by statistical considerations. To complete Part 1, it is estimated that 90 to 110
evaluable subjects will be enrolled. 
Doses to be studied in Part 1 will be guided by calculating the posterior probability that  
the DLT rate falls within an acceptable range for each subsequent dose after each dose 
cohort observation period.  The N-CRM method will be used to calculate posterior 
probabilities utilizing a pre-specified prior distribution.
11.1.2.
Besylate Sub-Study
At least 8 and up to 12 US subjects will participate in Besylate Sub-Study.  
Approximately 12 subjects will participate in the assessment to get at least 8 evaluable 
patients completing.  A subject is considered a completer if they have PK assessments 
from all treatment periods.
Based on a within-subject coefficient of variance for AUC of 50%, a correlation of 0.95 
between the enriched (liquid dose of GSK525762 added) and non-enriched PK, and 8 
subjects completing in Besylate Sub-Study, it is estimated that the half-width of the 90% 
CI for the ratio of the geometric means (besylate salt tablet compared to the amorphous 
free-base tablet) will be approximately 0.20.  Hence, if the ratio estimate is equal to 1, the 
90% CI will be 0.80 to 1.25.
11.1.3.
Part 2
The primary goal of Part 2 is to evaluate disease-specific efficacy in subjects with NMC, 
SCLC, CRPC, TNBC, ER+BC and GIST.

For NMC, efficacy is defined as a clinically meaningful response rate (defined as 
the percentage of subjects that have achieved a CR or PR) of 20% relative to a 5% 
response rate suggesting no activity


2011N118599_09
CONFIDENTIAL
BET115521
116

For CRPC and SCLC, efficacy is defined as a clinically meaningful response rate 
(defined as a percentage of subjects that have achieved as CR or PR; for CRPC 
subjects, defined as a percentage of subjects have PSA50 response) of 30% 
relative to a 10% response rate suggesting no activity.

For TNBC, efficacy is defined as a clinically meaningful response rate (defined as 
a percentage of subjects that have achieved as CR or PR) of 25% relative to a 
10% response rate suggesting no activity.

For ER+BC, efficacy is defined as a clinically meaningful response rate (defined 
as a percentage of subjects that have achieved as CR or PR) of 30% relative to a 
15% response rate suggesting no activity.

For GIST, efficacy is defined as a disease control rate (defined as a percentage of 
subjects that have achieved a CR or PR or SD that has lasted at least 16 weeks) of 
40% relative to a 15% disease control rate suggesting no activity.
Bayesian statistics will be employed to calculate the predictive probability that the 
response rate is greater than the historic response rate at interim analyses using a 
weak/non-informative prior. A Bayesian analysis expresses uncertainty about a parameter 
in terms of probability.  A prior distribution is defined to characterize the level of 
knowledge about a parameter before the data are collected.  Once the data are collected, a 
posterior distribution is formed using the prior distribution and the observed data.  A very 
weak prior Beta distribution with a mean response rate equal to the target response rate is 
assumed.  Thus, the posterior distribution for the response rate will be primarily driven by 
the data and can be derived as follows:
Let p denote the response rate, the number of responses in the current n subjects, x, 
follows a binomial distribution, Binomial (n, p).  Taking the Bayesian method and 
combining the prior distribution and the observed data x, the posterior distribution of the
response rate follows a beta distribution, i.e.
In the following case, 30% is the target response rate.
p Beta (0.03 + x, 0.07 + n-x) with the posterior mean (0.03+ x)/(0.07 + n).
Futility analysis for each disease cohort will begin when response data is available for at 
least 10 subjects. Each disease cohort may be stopped early for futility if the predictive 
probability of success (response rate ≥ historical response rate) is less than 1%.  Futility 
stopping rules are defined for each cohort in Section 3.2.7.
The following table describes for each disease cohort the null and alternative hypotheses 
that will be tested, maximum sample size and design characteristics.  Each maximum 
sample size was calculated to ensure that at least 80% power and a maximum type 1 error 
rate of 10% is maintained.


2011N118599_09
CONFIDENTIAL
BET115521
117
Null 
Hypothesis 
(H0) RR
Alternative 
Hypothesis 
(Target) (Ha) 
RR
Maximum 
Sample 
Size
Probability of 
stopping early 
for futility if H0 
is true
Average 
Sample Size 
if H0 is true
Actual 
Type I Error 
Rate (%)
Actual 
Power (%)
NMC 
5%
20%
25
0.891
14
8.8
80.2
CRPC 
10%
30%
22
0.860
16
6.0
82.5
TNBC 
10%
25%
37
0.876
23
6.4
81.7
ER+BC 
15%
30%
37
0.855
25
8.7
80.3
SCLC 
10%
30%
22
0.860
16
6.0
82.5
GIST
15%
40%
25
0.895
14
5.9
88
11.1.4.
Sensitivity Analysis
No sample size sensitivity analysis was performed.
11.1.5.
Sample Size Re-estimation
No sample size re-estimation will be performed.
11.1.6.
Subset Analysis for NMC Population
An exploratory review for NMC molecular subtype (e.g. NUT-BRD3, NUT-BRD4, and 
NUT-NSD3) will be conducted.
11.2.
Analysis Populations
All Treated Subjects (Safety and Clinical Activity) Population: This will consist of all 
subjects that received at least one dose of study treatment. Safety and clinical activity 
data will be evaluated based on this population.
The PK Population: This will consist of those subjects in All Subjects Population and 
for whom a PK sample is obtained and analyzed.
Pharmacodynamic Population: The PD Population is defined as subjects in the All 
Treated Subjects Population for whom a tumor biopsy or tissue was obtained and 
analysed for biomarkers.
More details of the analysis populations will be specified in RAP.


2011N118599_09
CONFIDENTIAL
BET115521
118
11.3.
Data Analysis Considerations
Data will be listed and summarized according to the GSK reporting standards, where 
applicable. Complete details will be documented in the RAP. Any deviations from, or 
additions to, the original analysis plan described in this protocol will be documented in 
the RAP and final study report.
As it is anticipated that accrual will be spread thinly across centers and summaries of data 
by center would be unlikely to be informative, data from all participating centers will be 
pooled prior to analysis. 
All data up to the time of study completion/withdrawal from study will be included in the 
analysis, regardless of duration of treatment. 
As the duration of treatment for a given subject will depend on efficacy and tolerability, 
the duration of follow-up will vary between subjects. Consequently there will be no 
imputation for missing data. 
Demographic and baseline characteristics will be summarized.
11.3.1.
Interim Analysis
An interim analysis of the key parameters may be carried-out before the conclusion of the 
study. Full details of procedures and of the analyses planned at the interim analysis will 
be provided in the Reporting and Analysis Plan (RAP).
The study will not utilize an Independent Data Monitoring Committee (IDMC).
11.3.2.
Final Analyses
Final analysis on Part 1 may be conducted when 

Part 1 is completed 

or at least 70% of subjects enrolled in every dose group at Part 1 are completed or 
progressed or died.
Final analyses will be carried-out following the DBF (data base frozen) after all the data 
queries has been resolved .
11.3.3.
Analysis Datasets
The construction of analysis data sets will be performed in accordance with all applicable 
GlaxoSmithKline standards and procedures.
11.3.4.
Withdrawal
Reason for subject withdrawal will be listed.


2011N118599_09
CONFIDENTIAL
BET115521
119
11.3.5.
Missing Data
Missing data will not be imputed. Where appropriate, available data will be summarized 
over specified intervals (e.g., from start of treatment until withdrawal from study) using 
suitable summary statistics.
11.3.6.
Derived and Transformed Data
The PK parameters, AUC, Cmax, and terminal half-life will be log-transformed prior to 
analysis.
11.3.7.
Assessment Windows
Safety assessments that occur prior to the administration of study drug will be considered 
screening assessments. Safety assessments that occur after dosing has begun will be 
considered as having occurred while on treatment.
Disease assessments will be distinguished as belonging to either screening, continued 
therapy or post-study phases of the study.
11.3.8.
Other Issues
Data from participating centers will be pooled by tumor cohort prior to analysis. It is 
anticipated that subject accrual may be limited across centers and summaries of data by 
center would likely not be informative. Therefore, these summaries will not be provided.
Demographic and baseline characteristics will be summarized.
For PK analyses, assay values below the quantitative limit (BQL) will be handled as 
described in the GSK Creatine phosphokinase (CPK)/M&S PK Methods.
There will be no adjustments for multiplicity.
11.4.
Efficacy Analyses
11.4.1.
Primary Analysis
For Part 1, anti-tumor activities will be evaluated based on clinical evidence and response 
criteria. If the data warrant, the response data will be summarized by dose level.
The primary aim of Part 2 is to demonstrate clinically meaningful response rates in each 
of the disease cohorts separately. 
Overall response rate is defined as the percentage of subjects who achieved CR or PR 
among subjects who received at least one dose of treatment. Overall response rate and the 
associated 2-sided 95% exact confidence limits will be provided separately for each 
disease cohort.
PSA 50 Response rate (RR) is defined as the response rate that a PSA reduction from 
baseline ≥50% is observed at 12 weeks and beyond (must be confirmed by a second 
value). RR will be reported for CRPC cohort along with the exact 95% confidence 


2011N118599_09
CONFIDENTIAL
BET115521
120
interval. Waterfall plots will be presented that show the maximum percentage of change 
in PSA reduction from baseline.
Disease Control Rate (DCR) is defined as the percentage of subjects who achieved CR, 
PR or SD (defined as ≥16 weeks in duration) among subjects who received at least one 
dose of treatment. Disease control rate and the associated 2-sided 95% exact confidence 
limits will be provided separately for GIST cohort.
11.4.2.
Secondary Analyses
For the analysis of PFS, if the subject received subsequent anti-cancer therapy prior to the 
date of documented events, PFS will be censored at the last adequate assessment (e.g. 
assessment where visit level response is CR, PR, or SD) prior to the initiation of therapy. 
Otherwise, if the subject does not have a documented date of events, PFS will be 
censored at the date of the last adequate assessment. For the analysis of overall survival 
(OS), the last date of known contact will be used for those subjects who have not died at 
the time of analysis; such subjects will be considered censored. Further details on rules 
for censoring will be provided in the RAP. Sensitivity analyses of PFS and further details 
on censoring rules will be provided in the RAP.  Progression free survival (PFS) and 
overall survival (OS) will be summarized using Kaplan-Meier method.
The duration of response is defined for the subject or subjects with a confirmed CR or 
PR, as the time from the first documented evidence of a CR or PR until the first 
documented disease progression or death due to any cause. Censoring rules for duration 
of response will be outlined in detail in the RAP.
Time to Response is defined, for subjects with a confirmed CR or PR, as the time from 
first dose to the first documented evidence of CR or PR.
If sample size permits, duration of response and time to response will be summarized 
descriptively using Kaplan-Meier medians and quartiles. Only the subset of subjects who 
show a confirmed complete or partial tumor response will be included. Censoring rules 
for duration of response will follow the rules for PFS outlined in detail in the RAP.
11.5.
Safety Analyses
Safety endpoints are described in Section 2. 
The All Subject population will consist of all subjects receiving at least one dose of study 
drug and will be used for the analysis of safety data. Complete details of the safety 
analyses will be provided in the RAP.
A listing by subject including treatment administered, and compliance, will be generated 
with dates and times of treatment administered. The number of subjects exposed to study 
drug will be tabulated for Part 1 (for each dose cohort) and Part 2.
Adverse events will be coded and grouped by system organ class (SOC) and preferred 
(coded) term (PT) using the Medical Dictionary for Regulatory Activities (MedDRA) 
system for adverse event coding. AEs will be graded according to the National Cancer 


2011N118599_09
CONFIDENTIAL
BET115521
121
Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 4. 
All AEs will be listed. A summary of the number and percent of subjects reporting each 
AE at least once will be produced for all AEs, for drug-related AEs and for SAEs for Part 
1 (for each dose cohort) and Part 2. A listing of those AEs identified as dose-limiting 
toxicities will also be produced for each dose cohort. A listing showing the relationship 
of AE verbatim text to group terms and body systems will also be produced. A listing of 
withdrawals due to AEs will be provided. Deaths and SAEs will be listed should they 
occur.
Clinical laboratory evaluations will be performed on the days specified in the Time and 
Events Tables. Clinical chemistry, coagulation, hematology and urinalysis values and 
change from baseline values will be listed for each subject and flagged high or low 
relative to their normal ranges, where applicable. The toxicity grade for laboratory data 
will be calculated using NCI CTCAE Version 4. The lab data will then be summarized 
according to the subject’s baseline grade and maximum grade for each cycle of therapy. 
A listing of subjects with potentially clinically important lab abnormalities will also be 
produced. A summary of lab values and change from (baseline) may be done for Part 1 
(for each dose cohort) and Part 2.
Vital signs and ECG data will be listed and summarized for Part 1(for each dose cohort) 
and Part 2. Changes from baseline will be included in the listings and summary.
ECOG Performance Status assessments will be listed and summarized for Part 1 (for each 
dose cohort) and Part 2.
All other relevant safety data will be listed and summarized according to the GSK IDSL 
standards as well.
All data will be listed. Further details will be provided in the RAP.
11.5.1.
Extent of Exposure
Extent of exposure of GSK525762 will depend on tolerability of the subjects to the doses 
administered and the course of their disease. The number of subjects exposed to 
GSK525762 will be summarized for each dose level administered.
11.5.2.
Adverse Events
Adverse events (AEs) will be coded using the standard GlaxoSmithKline Medical 
Dictionary for Regulatory Activities (MedDRA) and grouped by system organ class. AEs 
will be graded by the investigator according to the NCI-CTCAE (version 4.0). 
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, drug-
related AEs, serious AEs and AEs leading to discontinuation of study treatment.
If the AE is listed in the NCI CTCAE (version 4.0) table, the maximum grade will be 
summarized.


2011N118599_09
CONFIDENTIAL
BET115521
122
AEs of special interest will be outlined in the RAP.
The incidence of deaths and the primary cause of death will be summarized.
11.5.3.
Clinical Laboratory Evaluations
Hematology and clinical chemistry data will be summarized at each scheduled 
assessment according to NCI CTCAE grade (version 4.0). 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 NCI CTCAE 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). Unscheduled data 
will be included in “overall” and “any post-screening” summaries which will capture a 
worst case across all scheduled and unscheduled visits post first dose of study treatment. 
Further details will be provided in the RAP.
11.6.
Pharmacokinetic Analyses
11.6.1.
Pharmacokinetic Parameters
PK analyses will be the responsibility of Clinical Pharmacokinetics/Modelling & 
Simulation, GSK. Plasma GSK525762 and relevant metabolites, as appropriate, 
concentration-time data from dose escalation (Part 1) will be analyzed by non-
compartmental methods with WinNonlin.
From the plasma concentration-time data, the following pharmacokinetic parameters will 
be determined, as data permit: maximum observed plasma concentration (Cmax), time to 
Cmax (tmax), area under the plasma concentration-time curve (AUC(0-t) and AUC(0-∞) 
Week1 Day1 only) and apparent terminal phase half-life (t½). Trough concentration (C) 
samples collected on the specified days will be used to assess attainment of steady state. 
To estimate the extent of accumulation after repeat dosing, the observed accumulation 
ratio (Ro) may be determined. The ratio of AUC(0-) on Week 3 / AUC(0-∞) on Week 1 
will be calculated to assess time invariance. GSK525762 concentrations will be 
determined in urine samples to determine urinary recovery of unchanged drug and renal 
clearance.
11.6.2.
Statistical analysis of pharmacokinetic parameters
Statistical analyses of the PK parameters data will be conducted by Discovery 
Biometrics, GSK. Plasma concentration-time data will be listed by dose, age group, and 
summarized using descriptive statistics (n, mean, SD, median, minimum and maximum) 
by planned relative assessment time. Mean and/ or median values will be plotted over 
time. Individual plasma and urinary (if available) pharmacokinetic parameters values as 
well as a descriptive summary (mean, standard deviation, median, minimum, maximum, 
geometric mean, and the standard deviation, CV% and 95% confidence interval of log-
transformed parameters (if applicable)) by dose cohort and age group will be reported. 


2011N118599_09
CONFIDENTIAL
BET115521
123
Dose proportionality 
Cmax and AUC (AUC(0-∞), single dose, and AUC(0-), steady state) from Part 1 will be 
plotted as a function of the dose administered. If more than 2 dose cohorts are required to 
reach MTD (or the recommended dose based on available safety, PK and response data), 
dose proportionality of AUC and Cmax for GSK525762 following single dose 
administration and AUC(0-) and Cmax following repeat dose administration will be 
assessed graphically and using the power model as described below:
log (pharmacokinetic parameter) = a + b * log(dose)
where a is the intercept and b is the slope.
The power model will be fitted by restricted maximum likelihood (REML) using SAS 
Proc Mixed.  Both the intercept and slope will be fitted as fixed effects.  If there is 
sufficient data, the model may also be fit with the intercept and/or slope as random 
effects depending on the ability of the model to converge and on estimation of variance-
covariance matrix.  The mean slope and corresponding 90% confidence interval will be 
estimated from the power model.  
Separate models will be evaluated for amorphous tablet and besylate salt.
Relative bioavailability of the besylate salt tablet to the amorphous tablet ( Besylate 
Sub-Study)
Based on the US FDA guidance on relative bioavailability studies, two formulations will 
be considered bioequivalent if the 90% CI of the ratio for Cmax and AUC, based on log-
transformed data, is within the 80 to 125% equivalence limit. Recommendation on the 
dose amount impact of a deviation from bioequivalence with the besylate salt will be 
based on the magnitude of the change.
Food effect with besylate salt tablet (Besylate Sub-Study)
Pharmacokinetic (PK) parameters AUC(0-∞), and Cmax will be loge-transformed and 
analyzed using a mixed-effects model with and without food will be analyzed separately 
with fixed-effect terms for fed status (fed or fasted), and subject as a random effect. Point 
estimates and their associated 90% CIs will be constructed for the differences between 
fed and in fasted state. The point estimates and their associated 90% CIs were then 
backtransformed to provide point estimates and 90% CIs for the ratios of fed/fasted.
Non-parametric methods such as the Hodges and Lehmann estimator will be used to
estimate the median differences between the fed treatments and the fasted state
treatments for tmax. An associated 90% CI for the median differences will be 
constructed.
Based on the US FDA guidance on food-effect bioavailability studies, the absence of a
food-effect will be established if the 90% CI of the ratio for Cmax and AUC, based on
log-transformed data, is within the 80 to 125% equivalence limit. Recommendation on
the clinical significance of the effect of food will be based on the magnitude of the 
change and our understanding of the exposure-clinical response relationship.


2011N118599_09
CONFIDENTIAL
BET115521
124
For the evaluation of food effect, tmax at fed and fasted status will be presented by 
subject and dose cohort in tabular and graphical form.
11.6.3.
Population Pharmacokinetic Analysis
Plasma concentration-time data from parts 1 and 2 will be combined and may be 
combined with data from other studies and further analyzed using a population approach. 
A nonlinear mixed effects model will be used to determine population pharmacokinetic 
parameters (absorption rate, Ka, apparent clearance, CL/F and volume of distribution, 
V/F) and summary exposure measures (Cmax, AUC and Cav = AUC/) and identify 
important covariates (e.g., age, weight, or disease related covariates).
11.7.
Pharmacokinetic/Pharmacodynamic Analyses
Observed (Part 1) or predicted concentrations (Part 2) will be combined with safety and 
efficacy pharmacodynamic measures of interest to examine potential exposure response 
relationships.
The relationship between QTcF and concentration expressed as Cmax, Cav, and/or 
instantaneous time-matched concentration will be evaluated. A linear or non-linear mixed 
effects analysis of the relationship between  QTcF adjusted for baseline and –
concentration with a possible incorporation of time will be evaluated as a means of 
estimating QTcF effect in lieu of a thorough QT study.
Other quantitative safety parameters and biomarkers of interest will be plotted 
graphically against summary exposure measures (eg; Cmax, Ctrough, and Cav). Where 
evidence of a signal is seen, linear and non-linear mixed effect models will be fitted to 
the data to estimate PKPD parameters of interest; slope, baseline (E0), concentration for 
50% of maximum effect (EC50) and maximum effect (Emax).
Overall efficacy data, as assessed by conventional RECIST 1.1 criteria (best confirmed 
response) and overall tumor burden, may be described using ordered categorical model 
and continuous models with summary exposure parameters (eg; Cmax, Ctrough, and 
Cav) as covariates derived from the population PK analysis. Further model details will be 
provided in the Reporting and Analysis Plan [RAP].
11.8.
Translational Research Analyses
Exploratory analysis may be performed to examine potential relationships between 
anticancer activity and changes in markers of BET target inhibition or tumor biology (e.g. 
cytokines, acute phase proteins, relevant transcripts and/or proteins) or between 
anticancer activity and potential markers of sensitivity.
The results of translational research investigations may be reported separately from the 
main clinical study report or as an amendment. All endpoints of interest from all 
comparisons will be descriptively and/or graphically summarized as appropriate to the 
data. Further details on the translational research analyses will be addressed in the RAP.


2011N118599_09
CONFIDENTIAL
BET115521
125
11.9.
Pharmacogenetic Analyses
The results of pharmacogenetic research investigations will be reported separately from 
the main clinical study report or as an amendment. All endpoints of interest from all 
comparisons will be descriptively and/or graphically summarized as appropriate to the 
data. Further details on the pharmacogenetic research and analyses are found in 
Appendix 1 and will be addressed in the RAP.
12.
STUDY CONDUCT CONSIDERATIONS
12.1.
Posting of Information on Clinicaltrials.gov
Study information from this protocol will be posted on clinicaltrials.gov before enrolment 
of subjects begins.
12.2.
Regulatory and Ethical Considerations, Including the 
Informed Consent Process
Prior to initiation of a study site, GSK will obtain approval from the appropriate 
regulatory agency to conduct the study in accordance with ICH Good Clinical Practice 
(GCP) and applicable country-specific regulatory requirements.
The study will be conducted in accordance with all applicable regulatory requirements.
The study will be conducted in accordance with ICH Good Clinical Practice (GCP), all 
applicable subject privacy requirements, and the ethical principles that are outlined in the 
Declaration of Helsinki 2008, including, but not limited to:

Institutional Review Board (IRB)/Independent Ethics Committee (IEC) review and 
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, or from a guardian if the 
subject is less than 18 years of age, prior to participation in the study.
12.3.
Urgent Safety Measures
If an event occurs that is related to the conduct of the study or the development of the 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 IEC/IRB is notified.


2011N118599_09
CONFIDENTIAL
BET115521
126
12.4.
Quality Control (Study Monitoring)
In accordance with applicable regulations, GCP, and GSK procedures, the site will be 
contacted prior to the start of the study to review with the site staff the protocol, study 
requirements, and their responsibilities to satisfy regulatory, ethical, and GSK 
requirements. When reviewing data collection procedures, the discussion will include 
identification, agreement and documentation of data items for which the CRF will serve 
as the source document.
The investigator and the head of the medical institution (where applicable) agrees to 
allow the monitor direct access to all relevant documents and to allocate their time and 
the time to their staff to monitor to discuss findings and any issues.
Monitoring visits will be conducted in a manner to ensure that the:

Data are authentic, accurate, and complete.

Safety and rights of subjects are being protected.

Study is conducted in accordance with the currently approved protocol and any other 
study agreements, ICH GCP, and all applicable regulatory requirements.
12.5.
Quality Assurance
To ensure compliance with ICH GCP and all applicable regulatory requirements, GSK 
may conduct quality assurance audits of the site. Regulatory agencies may conduct a 
regulatory inspection at any time during or after completion of the study. In the event of 
an audit or inspection, the investigator (and institution) must agree to grant the auditor(s) 
and inspector(s) direct access to all relevant documents and to allocate their time and the 
time of their staff to discuss any findings/relevant issues.
12.6.
Study and Site Closure
The end of the study date is defined as last subject last visit (contact). 
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.


2011N118599_09
CONFIDENTIAL
BET115521
127
GSK may close sites which fail to recruit within a predefined timeframe, as defined 
within the Study Procedures Manual.
12.7.
Records Retention
Following closure of the study, the investigator or head of the medical institution (where 
applicable) must maintain all site study records (except for those required by local 
regulations to be maintained elsewhere) in a safe and secure location. The records must 
be easily accessible when needed (e.g., for a GSK audit or regulatory inspection) and 
must be available for review in conjunction with assessment of the facility, supporting 
systems, and relevant site staff.
Where permitted by local laws/regulations or institutional policy, some or all of the 
records may be maintained in a format other than hard copy (e.g., microfiche, scanned, 
electronic); however, caution must be exercised before such action is taken. The 
investigator must ensure that all reproductions are legible and are a true and accurate 
copy of the original. In addition, they must meet accessibility and retrieval standards, 
including regeneration of a hard copy, if required. The investigator must also ensure that 
an acceptable back-up of the reproductions exists and that there is an acceptable quality 
control procedure in place for creating the reproductions.
GSK will inform the investigator of the time period for retaining the site records in order 
to comply with all applicable regulatory requirements. The minimum retention time will 
meet the strictest standard applicable to a particular site, as dictated by local 
laws/regulations, GSK standard operating procedures, and/or institutional requirements.
The investigator must notify GSK of any changes in the archival arrangements, including, 
but not limited to archival of records at an off-site facility or transfer of ownership of the 
records in the event that the investigator is no longer associated with the site.
12.8.
Provision of Study Results to Investigators, Posting to the 
Clinical Trials Register and Publication
Where required by applicable regulatory requirements, an investigator signatory will be 
identified for the approval of the clinical study report. The investigator will be provided 
reasonable access to statistical tables, figures, and relevant reports and will have the 
opportunity to review the complete study results at a GSK site or other mutually-
agreeable location.
GSK will also provide the investigator with the full summary of the study results. The 
investigator is encouraged to share the summary results with the study subjects, as 
appropriate.
12.9.
Safety Review
12.9.1.
Dose Escalation Decisions
Dose escalation decisions will take into account all available data, including 
pharmacokinetics data and the safety profile of prior cohorts, and will occur following 
review of these data by the investigator(s), GSK medical monitor, clinical development 
scientist(s), pharmacokineticist, safety review team, and statistician. The decision and 


2011N118599_09
CONFIDENTIAL
BET115521
128
rationale will be documented in written format and distributed to the investigator(s), GSK 
medical monitor, pharmacokineticist, safety review team and statistician.


2011N118599_09
CONFIDENTIAL
BET115521
129
13.
REFERENCES
Adhikary S and Eilers M. Transcriptional regulation and transformation by Myc proteins. 
Nature Reviews Molecular Cell Biology, 2005;6:635-45.
Bauer DE, Mitchell CM, Strait KM, Lathan CS, Stelow EB, Lüer SC et al. 
Clinicopathologic features and long-term outcomes of NUT midline carcinoma. Clin 
Cancer Res. 2012;18(20):5773-9
C-H Gu, H Li, J Levons, K Lentz, R Gandhi, K Raghavan, and R Smith. Predicting effect 
of food on extent of drug absorption based on physicochemical properties. Pharm Res 
2007; 24:1118 – 1130)
Chung WH, Hung SL, Chen YT. Genetic predisposition of life-threatening antiepileptic-
induced skin reactions. Expert Opin. Drug Saf. 2010; 9: 15-21.
Delmore JE, Issa GC, Lemieux ME, et al. BET bromodomain inhibition as a therapeutic 
strategy to target c-Myc. Cell 2011;146:904-917.
Devine BJ.  Case Number 25 Gentamycin Therapy: Clinical Pharmacy 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 tumors: Revised 
RECIST guidelines (version 1.1). Europena Journal of Cancer. 2009; 45: 228-247.
FDA Guidance for industry: Food-effect bioavailability and fed bioequivalence studies. 
CDER 2002
Feng Q, Zhang Z, Shea MJ, Creighton CJ, Coarfa C, Hilsenbeck SG, et al. An 
epigenomic approach to therapy for tamoxifen-resistant breast cancer. Cell Res 
2014;24:809-19.
Ferrell PB, McLeod HL. Carbamazepine, HLA-B*1502 and risk of Stevens-Johnson 
syndrome and toxic epidermal necrolysis: US FDA recommendations. 
Pharmacogenomics. 2008; 9: 1543-46.
Filippakopoulos, P. et al. Selective inhibition of BET bromodomains. Nature 2010; 
468:1067-1073.
French C, Ramirez C, et al. BRD-NUT oncoproteins: a family of closely related nuclear 
proteins that block epithelial differentiation and maintain the growth of carcinoma cells. 
Oncogene, 2008;27:2237-42.
French, C.A., et al., Midline carcinoma of children and young adults with NUT 
rearrangement. J Clin Oncol, 2004. 22(20): p. 4135-9.


2011N118599_09
CONFIDENTIAL
BET115521
130
GlaxoSmithKline Document Number 2011N113741_05. GSK525762 Investigator’s 
Brochure, Version 05. 28 March 2016.
GlaxoSmithKline Report 2010N108204_00. The prediction of human pharmacokinetics 
and efficacious clinical dose of GSK525762 from pre-clinical data. June 2011.
Haack H, Johnson LA, Fry CJ, Crosby K, Polakiewicz RD, Stelow EB, Seung-Mo Hong, 
Schwartz BE, Cameron MJ, Rubin MA, Chang MC, Aster JC, French CA. Diagnosis of 
NUT Midline Carcinoma Using a NUT-Specific Monoclonal Antibody. Am J Surg 
Pathol 2009 33, 984-91.
Hetherington S, Hughes AR, Mosteller M, Shortino D, Baker KL, Spreen W, Lai E, 
Davies K, Handley A, Dow DJ, Fling ME, Stocum M, Bowman C, Thurmond LM, Roses 
AD. Genetic variations in HLA-B region and hypersensitivity reactions to abacavir. 
Lancet. 2002; 359:1121-2.
Hunt CM. Mitochondrial and immunoallergic injury increase risk of positive drug 
rechallenge after drug-induced liver injury: a systematic review. Hepatology. 2010; 2: 
2216–22.
Innocenti F, Undevia SD, Iyer L, Chen PX, Das S, Kocherginsky M, Karrison T, Janisch 
L, Ramirez J, Rudin CM, Vokes EE, Ratain MJ. Genetic variants in the UDP-
glucuronosyltransferase 1A1 gene predict the risk of severe neutropenia of irinotecan. J 
Clin Oncol 2004; 22: 1382-1388.
James LP. 2009. Pharmacokinetics of Acetaminophen - Protein Adducts ... Liver Failure. 
Drug Metab Disp, 37:1779-1784.
Lee JJ, Liu DD. A predictive probability design for Phase II cancer clinical trials.  Clin 
Trials. 2008; 5(2); 93-106.
Liu CY, Chen PM, Chiou TJ, Liu JH, Lin JK, Lin TC, Chen WS, Jiang JK, Wang HS, 
Wang WS. UGT1A1*28 polymorphism predicts irinotecan-induced severe toxicities 
without affecting treatment outcome and survival in patients with metastatic colorectal 
carcinoma. Cancer. 2008; 112: 1932-40.
Mallal S, Nolan D, Witt C, Masel G, Martin AM, Moore C, Sayer D, Castley A, Mamotte 
C, Maxwell D, James I. Association between presence of HLA-B*5701, HLA-DR7, and 
HLA-DQ3 and hypersensitivity to HIV-1 reverse-transcriptase inhibitor abacavir. Lancet. 
2002; 359:727-32.
Mertz JA Proc Natl Acad Sci 2011;108:16669-16674.
Nagarajan, S, Hossan, T, Alawi, M, et al. Bromodomain Protein BRD4 Is Required for 
Estrogen Receptor-Dependent Enhancer Activation and Gene Transcription. Cell Reports 
8, 460–469, July 24, 2014
NCI-CTCAE (NCI Common Terminology Criteria for Adverse Events), Version 4, 
DCTD, NCI, NIH, DHHS, May 28, 2009.


2011N118599_09
CONFIDENTIAL
BET115521
131
Neuenschwander, B, Branson, M, and Gsponer, T, Critical aspects of the Bayesian 
approach to phase I cancer trials. Stat Med. 2009; 27: 2420–39.
Nicodeme E, Jeffrey K, et al.  Suppression of inflammation by a synthetic histone mimic.  
Nature 2010; 478: 1119-1123.
NYHA, 1994; 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.
Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, Carbone PP. 
Toxicity and Response Criteria of the Eastern Cooperative Oncology Group, 1982.
Papay JI, Clines D, Rafi R, et al., Drug-induced liver injury following positive 
drugrechallenge. Regul Toxicol Pharmacol. 2009; 54: 84–90.
Parr, A., Gupta, M., Montague, T., and Hoke, F. Re-introduction of a Novel Approach to 
the Use of Stable Isotopes in Pharmacokinetic studies. The AAPS Journal 2012, 14:639-
645.
Puissant A, Frumm SM, Alexe G, Bassilet al. Targeting MYCN in Neuroblastoma by 
BET Bromodomain Inhibition. Cancer Discov 2013, 3: 308-23.
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
Schwartz BE, Hofer MD, Lemieux ME, Bauer DE, Cameron MJ, et al. 2011. 
Differentiation of NUT midline carcinoma by epigenomic reprogramming. Cancer 
Research, 2011 71:2686-2696.
Stelow, E.B., Bellizzi, A.M., Taneja, K., Mills, S.E., Legallo, R.D., Kutok, J.L., Aster, 
J.C., and French, C.A. NUT rearrangement in undifferentiated carcinomas of the upper 
aerodigestive tract. American Journal Surgical Pathology, 2008; 32:828-834.
Wyce A, Ganji G, Smitheman KN, et al. BET inhibition silences expression of MYCN 
and BCL2 and induces cytotoxicity in neuroblastoma tumor models. PLoS One 
2013;8:e72967.


2011N118599_09
CONFIDENTIAL
BET115521
132
14.
APPENDICES
14.1.
Appendix 1 : Pharmacogenetic Research
Pharmacogenetics – Background
Pharmacogenetics (PGx) is the study of variability in drug response due to hereditary 
factors in populations. There is increasing evidence that an individual's genetic 
background (i.e., genotype) may impact the pharmacokinetics (absorption, distribution, 
metabolism, elimination), pharmacodynamics (relationship between concentrations and 
pharmacologic effects or the time course of pharmacologic effects) and/or clinical 
outcome (in terms of efficacy and/or safety and tolerability). Some reported examples of 
PGx associations with safety/adverse events include:
PGx Associations with Safety Events
Drug
Disease
Gene
Outcome
Abacavir
HIV 
[Hetherington, 2002; 
Mallal, 2002]
HLA-B 
(Human 
Leukocyte 
Antigen B)
Carriage of the HLA-B*5701 variant has 
been shown to increase a patient's risk for 
experiencing hypersensitivity to abacavir. 
Prospective HLA-B*5701 screening and 
exclusion of HLA-B*5701 positive patients 
from abacavir treatment significantly 
decreased the incidence of abacavir 
hypersensitivity. Treatment guidelines and 
abacavir product labeling in the United 
States and Europe now recommend (US) 
or require (EU) prospective HLA-B*5701 
screening prior to initiation of abacavir to 
reduce the incidence of abacavir 
hypersensitivity. HLA-B*5701 screening 
should supplement but must never replace 
clinical risk management strategies for 
abacavir hypersensitivity.
Carbamazepine
Seizure, Bipolar 
disorders & 
Analgesia
[Chung, 2010]
HLA-
B*1502
Independent studies indicated that patients 
carrying HLA-B*1502 are at higher risk of 
Stevens-Johnson Syndrome and toxic 
epidermal necrolysis and that this marker is 
prevalent in some populations, particularly 
with Asian ancestry. Regulators, including 
the US FDA and the Taiwanese TFDA, 
have updated the carbamazepine drug 
label to indicate that screening is justified in 
patients with ancestry in populations in 
which HLA-B*1502 may be present.


2011N118599_09
CONFIDENTIAL
BET115521
133
Drug
Disease
Gene
Outcome
Irinotecan
Cancer [Innocenti, 
2004; Liu, 2008]
UGT1A1
Variations in the UGT1A1 gene can 
influence a patient’s ability to break down 
irinotecan, which can lead to increased 
blood levels of the drug and a higher risk of 
side effects. A dose of irinotecan that is 
safe for one patient with a particular 
UGT1A1 gene variation might be too high 
for another patient without this variation, 
raising the risk of certain side-effects, that 
include neutropenia following initiation of 
Irinotecan treatment. The irinotecan drug 
label indicates that individuals who are 
homozygous for UGT1A1*28 allele are at 
increased risk of neutropenia A genetic 
blood test (Invader UGT1A1 molecular 
assay) is available that can detect 
variations in the gene.  
A key component to successful PGx research is the collection of samples during the 
conduct of clinical studies.
Collection of whole blood samples, even when no a priori hypothesis has been identified, 
may enable PGx analysis to be conducted if at any time it appears that there is a potential 
unexpected or unexplained variation in handling or response to GSK525762.
Pharmacogenetic Research Objectives
The objective of the PGx research (if there is a potential unexpected or unexplained 
variation) is to investigate a possible genetic relationship to handling or response to 
GSK525762.  If at any time it appears there is potential variability in response in this 
clinical study or in a series of clinical studies with GSK525762 that may be attributable 
to genetic variations of subjects, the following objectives may be investigated – the 
relationship between genetic variants and study treatment with respect to:

Pharmacokinetics and/or pharmacodynamics of study treatment,

Safety and/or tolerability, and

Efficacy.
Study Population
Any subject who is enrolled in the clinical study can participate in the PGx research. Any 
subject who has received an allogeneic bone marrow transplant must be excluded from 
the PGx research.
Subject participation in the PGx research is voluntary and refusal to participate will not 
indicate withdrawal from the clinical study. Refusal to participate will involve no penalty 
or loss of benefits to which the subject would otherwise be entitled.


2011N118599_09
CONFIDENTIAL
BET115521
134
Study Assessments and Procedures
In addition to any blood samples taken for the clinical study, a whole blood sample 
(~10mL) will be collected for the PGx research using a tube containing EDTA. It is 
recommended that the blood sample be taken at the first opportunity after a subject has 
been randomized and provided informed consent for PGx research, but may be taken at 
any time while the subject is participating in the clinical study.
The PGx sample is labelled (or “coded”) with a study specific number that can be traced 
or linked back to the subject by the investigator or site staff. Coded samples do not carry 
personal identifiers (such as name or social security number). The blood sample is taken 
on a single occasion unless a duplicate sample is required due to inability to utilize the 
original sample. 
The DNA extracted from the blood sample may be subjected to sample quality control 
analysis. This analysis will involve the genotyping of several genetic markers to confirm 
the integrity of individual samples. If inconsistencies are noted in the analysis, then those 
samples may be destroyed. 
The need to conduct PGx analysis may be identified after a study (or set of studies) of 
GSK525762 has been completed and the study data reviewed. In some cases, the samples 
may not be studied. e.g., no questions are raised about how people respond to 
GSK525762. 
Samples will be stored securely and may be kept for up to 15 years after the last subject 
completes the study or GSK may destroy the samples sooner. GSK or those working with 
GSK (for example, other researchers) will use samples collected from the study for the 
purpose stated in this protocol and in the informed consent form. 
Subjects can request their sample to be destroyed at any time.
Subject Withdrawal from Study
If a subject who has consented to participate in PGx research and has a sample taken for 
PGx research withdraws from the clinical study for any reason other than lost to follow-
up, the subject will be given the following options:

The sample is retained for PGx research.

Any PGx sample is destroyed.
If a subject withdraws consent from the PGx research or requests sample destruction for 
any reason, the investigator must complete the appropriate documentation to request 
sample destruction within the timeframe specified by GSK and maintain the 
documentation in the site study records. In either case, GSK will only keep study 
information collected/generated up to that point.


2011N118599_09
CONFIDENTIAL
BET115521
135
Screen and Baseline Failures
If a blood sample for PGx research has been collected and it is determined that the 
subject does not meet the entry criteria for participation in the clinical study, then the 
investigator should instruct the participant that their PGx sample will be discarded. 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.
Pharmacogenetics Analyses
1.
Specific genes may be studied that encode the drug targets, or mechanism pathways, 
drug metabolizing enzymes, or which may underpin adverse events, disease risk or 
drug response. These candidate genes may include a common set of ADME 
(Absorption, Distribution, Metabolism and Excretion) genes that are studied to 
determine the relationship between gene variants and treatment response and/or 
tolerance. 
In addition, continuing research may identify other enzymes, transporters, proteins or 
receptors that may be involved in response to GSK525762. The genes that may code for 
these proteins may also be studied.
2.
Genome-wide scans involving a large number of polymorphic markers (e.g., single 
nucleotide polymorphisms) at defined locations in the genome, often correlated with 
a candidate gene, may be studied to determine the relationship between genetic 
variants and treatment response or tolerance. This approach is often employed when 
a definitive candidate gene(s) does not exist and/or the potential genetic effects are 
not well understood. 
If applicable and PGx research is conducted, appropriate statistical analysis methods will 
be used to evaluate pharmacogenetic data in the context of the other clinical data. Results 
of PGx investigations will be reported either as part of the main clinical study report or as 
a separate report. Endpoints of interest from all comparisons will be descriptively and/or 
graphically summarized as appropriate to the data. A detailed description of the analysis 
to be performed will be documented in the study reporting and analysis plan (RAP) or in 
a separate pharmacogenetics RAP, as appropriate. 
Informed Consent
Subjects who do not wish to participate in the PGx research may still participate in the 
clinical study. PGx informed consent must be obtained prior to any blood being taken for 
PGx research.


2011N118599_09
CONFIDENTIAL
BET115521
136
Provision of Study Results and Confidentiality of Subject’s PGx Data
GSK may summarize the cumulative the PGx research results in the clinical study report 
or may publish the results in scientific journals.
GSK does not inform the investigator, subject or anyone else (e.g., family members, 
study investigators, primary care physicians, insurers, or employers) of the PGx research 
results 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 
PGx studies is generally preliminary in nature, and therefore the significance and 
scientific validity of the results are undetermined. In general, GSK does not inform the 
investigator, subject or anyone else (e.g., family members, study investigators, primary 
care physicians, insurers, or employers) of the PGx research results unless required by 
law. The information generated from PGx research is preliminary in nature, and the 
significance and scientific validity of the results are undetermined at such an early stage 
of research.


2011N118599_09
CONFIDENTIAL
BET115521
137
14.2.
Appendix 2 : Cockcroft-Gault Formula
The Cockcroft-Gault formula is a commonly-used surrogate marker for actual creatinine 
clearance (CrCl) and employs creatinine measurements and a subject's weight (kg) to 
predict the clearance. 
If the subject is obese (>30% over ideal body weight), use ideal body weight in 
calculation of estimate CrCl.
If the subject is below ideal body weight, use actual body weight in calculation of 
estimate CrCl.
Cockcroft-Gault Formula for serum creatinine in mmol/L
CrCl (mL/min)=
Q X (140-age [years]) X actual body weight (kg)a
48816 X serum creatinine (mmol/L)
Q=0.85 for females
Q=1.0 for males
OR
a. Calculation of Ideal Body Weight Using the Devine Formula [Devine, 1974]
Male subjects:
50.0 kg + (2.3 kg X each inch over 5 feet)
or
50.0 kg + (0.906 kg X each cm over 152.4 cm)
Female subjects:
45.5 kg + (2.3 kg X each inch over 5 feet)
or
45.5 kg + (0.906 kg X each cm over 152.4 cm) 4 cm)
Cockcroft-Gault Formula for serum creatinine in mg/dL
For example:
For a male subject with actual body weight = 90.0 kg and height = 68 inches, the 
calculation would be as follows:
Ideal body weight= 50.0 + (2.3) (68-60) = 68.4 kg
This subject’s actual body weight is >30% over ideal body weight. In this case, the 
subject’s ideal body weight of 68.4 kg should be used in calculating estimated creatinine 
clearance.


2011N118599_09
CONFIDENTIAL
BET115521
138
14.3.
Appendix 3: Liver Events
14.3.1.
Liver Safety Stopping Criteria and Required Actions and Follow 
Up Assessments
Phase I/II liver chemistry stopping and increased monitoring criteria have been 
designed to assure subject safety and evaluate liver event etiology (in alignment with the 
FDA premarketing clinical liver safety guidance). 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM174090.pdf.
Table 28
Phase I/II liver chemistry stopping criteria and required follow up 
assessments 
Liver Chemistry Stopping Criteria – Liver Stopping Event
ALT-absolute
ALT 5xULN
ALT Increase
ALT 3xULN persists for 4 weeks
Bilirubin1, 2
ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin) 
INR2
ALT 3xULN and INR>1.5, if INR measured
Cannot Monitor
ALT 3xULN and cannot be monitored weekly for 4 weeks
Symptomatic3
ALT 3xULN associated with symptoms (new or worsening) believed to be related 
to liver injury or hypersensitivity
Required Actions and Follow up Assessments following ANY Liver Stopping Event
Actions
Follow Up Assessments

Immediately discontinue study treatment

Report the event to GSK within 24 hours

Complete the liver event eCRF and complete 
an SAE data collection tool if the event also 
meets the criteria for an SAE2

Perform liver event follow up assessments 

Monitor the subject until liver chemistries
resolve, stabilize, or return to within baseline 
(see MONITORING below)

Do not restart/rechallenge subject with 
study treatment unless allowed per protocol 
and GSK Medical Governance approval is 
granted (refer to Section 14.3.2)

If restart/rechallenge is not granted, 
permanently discontinue study treatment and 

Viral hepatitis serology4

Blood sample for pharmacokinetic (PK) analysis, 
obtained approximately 48h after last dose5

Serum creatine phosphokinase (CPK) and lactate 
dehydrogenase (LDH).

Fractionate bilirubin, if total bilirubin2xULN

Obtain complete blood count with differential to 
assess eosinophilia

Record the appearance or worsening of clinical 
symptoms of liver injury, or hypersensitivity, on the 
AE report form

Record use of concomitant medications on the 
concomitant medications report form including 
acetaminophen, herbal remedies, other over the 


2011N118599_09
CONFIDENTIAL
BET115521
139
may continue subject in the study for any 
protocol specified follow up assessments
MONITORING:
For bilirubin or INR criteria: 

Repeat liver chemistries(include ALT, AST, 
alkaline phosphatase, bilirubin) and perform 
liver event follow up assessments within 24 
hrs

Monitor subjects twice weekly until liver 
chemistries resolve, stabilize or return to 
within baseline

A specialist or hepatology consultation is 
recommended
For All other criteria: 

Repeat liver chemistries(include ALT, AST, 
alkaline phosphatase, bilirubin) and perform 
liver event follow up assessments within 24-
72 hrs 

Monitor subjects weekly until liver chemistries 
resolve, stabilize or return to within baseline
counter medications

Record alcohol use on the liver event alcohol 
intake case report form
For bilirubin or INR criteria:

Anti-nuclear antibody, anti-smooth muscle 
antibody, Type 1 anti-liver kidney microsomal 
antibodies, and quantitative total immunoglobulin 
G (IgG or gamma globulins).

Serum acetaminophen adduct high pressure liquid 
chromatography (HPLC) assay (quantifies 
potential acetaminophen contribution to liver injury 
in subjects with definite or likely acetaminophen 
use in the preceding week [James, 2009]).

Liver imaging (ultrasound, magnetic resonance, or 
computerised tomography) and /or liver biopsy to 
evaluate liver disease; complete Liver Imaging 
and/or Liver Biopsy eCRF forms.
1.
Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin fractionation is not 
immediately available, discontinue study treatment for that subject if ALT 3xULN and bilirubin 2xULN. 
Additionally, if serum bilirubin fractionation testing is unavailable, record presence of detectable urinary 
bilirubin on dipstick, indicating direct bilirubin elevations and suggesting liver injury. 
2.
All events of ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin) or ALT 3xULN and INR>1.5, if INR 
measured which may indicate severe liver injury (possible ‘Hy’s Law’), must be reported as an SAE (excluding 
studies of hepatic impairment or cirrhosis); INR measurement is not required and the threshold value stated 
will not apply to subjects receiving anticoagulants
3.
New or worsening symptoms believed to be related to liver injury (such as fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, or jaundice) or believed to be related to hypersensitivity (such as fever, rash or 
eosinophilia)
4.
Includes: Hepatitis A IgM antibody; Hepatitis B surface antigen and Hepatitis B Core Antibody (IgM); Hepatitis C 
RNA; Cytomegalovirus IgM antibody; Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, obtain 
heterophile antibody or monospot testing); Hepatitis E IgM antibody 
5.
Record the date/time of the PK blood sample draw and the date/time of the last dose of study treatment prior to 
blood sample draw on the eCRF. If the date or time of the last dose is unclear, provide the subject’s best 
approximation. If the date/time of the last dose cannot be approximated OR a PK sample cannot be collected in 
the time period indicated above, do not obtain a PK sample. Instructions for sample handling and shipping are in 
the SPM.


2011N118599_09
CONFIDENTIAL
BET115521
140
Table 29
Phase I/II Oncology liver chemistry increased monitoring criteria 
with continued therapy
Liver Chemistry Increased Monitoring Criteria – Liver Monitoring Event
Criteria
Actions

ALT 3xULN but <5xULN and

bilirubin <2xULN, without symptoms
believed to be related to liver injury or 
hypersensitivity and who can be 
monitored weekly for 4 weeks

Notify the GSK medical monitor within 24 hours of 
learning of the abnormality to discuss subject 
safety. 

Subject can continue study treatment

Subject must return weekly for repeat liver 
chemistries (ALT, AST, alkaline phosphatase, 
bilirubin) until they resolve, stabilise or return to 
within baseline1

If at any time subject meets the liver chemistry 
stopping criteria, proceed as described above

If, after 4 weeks of monitoring, ALT <3xULN and 
bilirubin <2xULN, monitor subjects twice monthly 
until liver chemistries normalize or return to within 
baseline.
1.
For the purpose of these guidelines “baseline” refers to laboratory assessments performed closest and prior to 
first dose of study treatment
References
James LP, Letzig L, Simpson PM, Capparelli E, Roberts DW, Hinson JA, Davern TJ, Lee 
WM. Pharmacokinetics of Acetaminophen-Adduct in Adults with Acetaminophen 
Overdose and Acute Liver Failure. Drug Metab Dispos 2009; 37:1779-1784.
14.3.2.
Liver Safety Drug Restart Guidelines
If subject meets liver chemistry stopping criteria do not restart/rechallenge subject with 
study treatment unless:

GSK Medical Governance approval is granted (as described below),

Ethics and/or IRB approval is obtained, if required, and

Separate consent for treatment restart/rechallenge is signed by the subject
If GSK Medical Governance approval to restart/rechallenge subject with study treatment 
is not granted, then subject must permanently discontinue study treatment and may 
continue in the study for protocol-specified follow up assessments


2011N118599_09
CONFIDENTIAL
BET115521
141
14.3.2.1.
Rechallenge Following Liver Stopping Events that are Possibly Related 
to Study Treatment
Following drug-induced liver injury, drug rechallenge is associated with a 13% 
mortality across all drugs in prospective studies [Andrade, 2009]. Clinical outcomes 
vary by drug, with nearly 50% fatality with halothane readministered within one month 
of initial injury. However, some drugs seldom result in recurrent liver injury or fatality. 
Risk factors for a fatal drug rechallenge outcome include:

hypersensitivity with initial liver injury (e.g. fever, rash, eosinophilia) 
[Andrade, 2009] 

jaundice or bilirubin >2xULN with initial liver injury (direct bilirubin >35% of 
total)

subject currently exhibits severe liver injury defined by: ALT 3xULN, 
bilirubin 2xULN (direct bilirubin >35% of total), or INR1.5

serious adverse event or fatality has earlier been observed with drug 
rechallenges [Papay, 2009]

evidence of drug-related preclinical liability (e.g. reactive metabolites; 
mitochondrial impairment [Hunt, 2010])
Rechallenge refers to resuming study treatment following drug induced liver injury 
(DILI). Because of the risks associated with rechallenge after DILI this should only be 
considered for a subject for whom there is compelling evidence of benefit from a critical 
or life-saving medicine, there is no alternative approved medicine available, and a 
benefit:risk assessment of rechallenge is considered to be favourable.
Approval by GSK for rechallenge with study treatment can be considered where:

Investigator requests consideration of rechallenge with study treatment for a subject 
who is receiving compelling benefit with study treatment that exceeds risk, and no 
effective alternative therapy is available. 

Ethics Committee or Institutional Review Board approval for rechallenge with study 
treatment must be obtained, as required.  

If the rechallenge is approved by GSK Medical Governance in writing, the subject 
must be provided with a clear description of the possible benefits and risks of study 
treatment administration, including the possibility of recurrent, more severe liver 
injury or death. 

The subject must also provide signed informed consent specifically for the 
rechallenge with study treatment. Documentation of informed consent must be 
recorded in the study chart. 

Study treatment must be administered at the dose specified by GSK.

Subjects approved by GSK Medical Governance for rechallenge with study 
treatment must return to the clinic twice a week for liver chemistry tests until stable 


2011N118599_09
CONFIDENTIAL
BET115521
142
liver chemistries have been demonstrated and then standard laboratory monitoring 
may resume as per protocol.

If after study treatment rechallenge, subject meets protocol-defined liver chemistry 
stopping criteria, study treatment should be permanently discontinued. 

Medical Monitor, and the Ethics Committee or Institutional Review Board as 
required, must be informed of the subject’s outcome following study treatment 
rechallenge. 

GSK to be notified of any adverse events, as per Section 6.9.
14.3.2.2.
Restart Following Transient Resolving Liver Stopping Events NOT 
Related to Study Treatment
Restart refers to resuming study treatment following liver stopping events in which there 
is a clear underlying cause (other than DILI) of the liver event (e.g. biliary obstruction, 
pancreatic events, hypotension, acute viral hepatitis). Furthermore, there should be no 
evidence of alcoholic hepatitis or hypersensitivity, and the study treatment should not be 
associated with HLA markers of liver injury.
Approval by GSK for study treatment restart can be considered where:

Investigator requests consideration for study treatment restart if liver chemistries 
have a clear underlying cause (e.g., biliary obstruction, hypotension and liver 
chemistries have improved to normal or are within 1.5 x baseline and ALT 
<3xULN).

Restart risk factors (e.g. fever, rash, eosinophilia, or hypersensitivity, alcoholic 
hepatitis, possible study treatment-induced liver injury or study treatment has an 
HLA genetic marker associated with liver injury (e.g. lapatinib, abacavir, 
amoxicillin/clavulanate) are reviewed and excluded

Ethics Committee or Institutional Review Board approval of study treatment restart 
must be obtained, as required.

If restart of study treatment is approved by GSK Medical Governance in writing, the 
subject must be provided with a clear description of the possible benefits and risks of 
study treatment administration, including the possibility of recurrent, more severe 
liver injury or death. 

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. 


2011N118599_09
CONFIDENTIAL
BET115521
143

If after study treatment re-start, subject meets protocol-defined liver chemistry 
stopping criteria, follow usual stopping criteria instructions.

Medical Monitor, and the Ethics Committee or Institutional Review Board as 
required, must be informed of the subject’s outcome following study treatment 
restart. 

GSK, or designee, to be notified of any adverse events, as per Section 6.9.
References:
Andrade RJ, Robles M, Lucena MI. Rechallenge in drug-induced liver injury: the 
attractive hazard. Expert Opin Drug Saf. 2009;8:709-714.
Hunt, CM. Mitochondrial and immunoallergic injury increase risk of positive drug 
rechallenge after drug-induced liver injury: A systematic review. Hepatol. 2010;52:2216-
2222.
Papay JI, Clines D, Rafi R, Yuen N, Britt SD, Walsh JS, et al. Drug-induced liver injury 
following positive drug rechallenge. Regul Tox Pharm. 2009;54:84-90. 


2 0 1 1 N 1 1 8 5 9 9 _ 0 9
C O N FI D E N TI A L
B E T 1 1 5 5 2 1
1 4 4
1 4. 4.
A p p e n di x 4: P ai n A s s e s s m e nt
C CI - T hi s s e cti o n c o nt ai n e d Cli ni c al O ut c o m e A s s e s s m e nt d at a c oll e cti o n q u e sti o n n air e s or i n di c e s, w hi c h 
ar e pr ot e ct e d b y t hir d p art y c o p yri g ht l a w s a n d t h er ef or e h a v e b e e n e x cl u d e d.


2011N118599_09
CONFIDENTIAL
BET115521
145
14.5.
Appendix 5: RECIST 1.1
I. Efficacy Assessment
Disease progression and response evaluations will be determined according to the 
definitions established in the Response Evaluation Criteria in Solid Tumors (RECIST 
1.1) [Chung, 2010; Eisenhauer, 2009].
See the Time and Events Tables for the schedule of efficacy assessments. Assessments 
must be performed on a calendar schedule and should not be affected by dose 
interruptions/delays. For post baseline assessments, a window of 14 days is permitted to 
allow for flexible scheduling.

The following are required at baseline: CT for Chest/Abdomen/Pelvis or MRI for 
Abdomen/Pelvis and clinical disease assessment for palpable lesions, brain scan and 
bone scan. At each post baseline assessment, evaluations of the sites of disease 
identified by these scans are required except for brain scan and bone scans. Brain and 
Bone scans should be performed as clinically indicated.
Confirmation of CR and PR are required per protocol. Confirmation assessments must be 
performed no less than 4 weeks after the criteria for response have initially been met and 
may be performed at the next protocol scheduled assessment. If a confirmation 
assessment is performed prior to the next protocol schedule assessment, the next protocol 
scheduled evaluation is still required (e.g. evaluations must occur at each protocol 
scheduled timepoint regardless of unscheduled assessments).
A baseline 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 as clinically indicated. In addition, in order to assign a response of CR in a 
subject with bone disease at baseline, a bone scan must be performed within the 
timeframe of 1 week prior to the first of images showing CR to 4 weeks after the next 
protocol specified assessment.
A baseline brain scan is required for all subjects. For subjects without CNS disease at 
baseline, subsequent brain scans should only be performed as clinically indicated (e.g. 
symptoms suggestive of CNS progression). For subjects with CNS disease at baseline, a 
brain scan is required as clinically indicated. In addition, in order to confirm a CR in a 
subject with brain disease at baseline, a brain scan must be performed 1 week prior to the 
1st set of images showing CR to 4 weeks after the next protocol specified assessment.
Ia. Baseline documentation of target and non-target lesions

All baseline lesion assessments must be performed within 28 days of 
randomizations. 

Lymph nodes that have a short axis of <10mm are considered non-pathological and 
should not be recorded or followed.


2011N118599_09
CONFIDENTIAL
BET115521
146

Pathological lymph nodes with <15mm and but 10mm short axis are considered 
non measurable.

Pathological lymph nodes with 15mm short axis are considered measurable and can 
be selected as target lesions, however lymph nodes should not be selected as target 
lesions when other suitable target lesions are available. 

Measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in total, 
representative of all involved organs, should be identified as target lesions, and 
recorded and measured at baseline. These lesions should be selected on the basis of 
their size (lesions with the longest diameter) and their suitability for accurate 
repeated measurements (either by imaging techniques or clinically). 
Note: Cystic lesions thought to represent cystic metastases should not be selected as 
target lesions when other suitable target lesions are available.
Note: Measurable lesions that have been previously irradiated and have not been shown 
to be progressing following irradiation should not be considered as target lesions. 

Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue 
components, that can be evaluated by CT or MRI can be considered measurable.  
Bone scans, FDG-PET scans or X-rays are not considered adequate imaging 
techniques to measure bone lesions.

All other lesions (or sites of disease) should be identified as non-target and should 
also be recorded at baseline. Non-target lesions will be group by organ. 
Measurements of these lesions are not required, but the presence or absence of each 
should be noted throughout follow-up. 
Ib. Assessment Guidelines
Please note the following:

The same diagnostic method, including use of contrast when applicable, must be 
used throughout the study to evaluate a lesion.

All measurements should be taken and recorded in millimeters (mm), using a ruler or 
calipers.

Ultrasound is not a suitable modality of disease assessment. If new lesions are 
identified by ultrasound, confirmation by CT or MRI is required.

Fluorodeoxyglucose (FDG)-PET is generally not suitable for ongoing assessments of 
disease. However FDG-PET can be useful in confirming new sites of disease where 
a positive FDG-PET scans correlates with the new site of disease present on CT/MRI 
or when a baseline FDG-PET was previously negative for the site of the new lesion. 
FDG-PET may also be used in lieu of a standard bone scan providing coverage 
allows interrogation of all likely sites of bone disease and FDG-PET is performed at 
all assessments.

If PET/CT is performed then the CT component can only be used for standard 
response assessments if performed to diagnostic quality, which includes the required 


2011N118599_09
CONFIDENTIAL
BET115521
147
anatomical coverage and prescribed use of contrast. The method of assessment 
should be noted as CT on the CRF.
Clinical Examination: Clinically detected lesions will only be considered measurable 
when they are superficial (e.g., skin nodules). In the case of skin lesions, documentation 
by color photography, including a ruler/callipers to measure the size of the lesion, is 
required. [Chung, 2010; Eisenhauer, 2009]. 
CT and MRI: Contrast enhanced CT with 5mm contiguous slices is recommended.
Minimum size of a measurable baseline lesion should be twice the slice thickness, with a 
minimum lesion size of 10 mm when the slice thickness is 5 mm. MRI is acceptable, but 
when used, the technical specification of the scanning sequences should be optimised for 
the evaluation of the type and site of disease and lesions must be measured in the same 
anatomic plane by use of the same imaging examinations. Whenever possible the same 
scanner should be used. [Chung, 2010; Eisenhauer, 2009].
X-ray: In general, X-ray should not be used for target lesion measurements owing to 
poor lesion definition. Lesions on chest X-ray may be considered measurable if they are 
clearly defined and surrounded by aerated lung; however chest CT is preferred over chest 
X-ray [Chung, 2010; Eisenhauer, 2009].
Brain Scan: Baseline brain scans are required, then contrast enhanced MRI is preferable 
to contrast enhanced CT.
Bone Scan (typically bone scintigraphy): If a bone scan is performed and a new 
lesion(s) is equivocal, then correlative imaging (i.e.X-ray, CT, or MRI) is required to 
demonstrate malignant characteristics of the lesion(s). 
Note: PET [FDG or fluoride] may be used in lieu of a standard bone scan providing 
coverage allows interrogation of all likely sites of bone disease and PET is performed at 
all assessments.
Ic. Follow-up Assessments for Subjects Permanently Discontinued from 
Study Treatment
Refer to Section 4.2.4.1 and the Time and Events Tables found in the protocol for follow-
up assessment of subjects who are to be followed up for disease progression and/or
survival after permanently discontinue from study treatment
Id. Assessment of Subject Completion
If the last radiographic assessment was more than 8 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. 


2011N118599_09
CONFIDENTIAL
BET115521
148
II. Guidelines for Evaluation of Disease
IIa. Measurable and Non-measurable Definitions
Measurable lesion:
A non nodal lesion that can be accurately measured in at least one dimension (longest 
dimension) of

10 mm with MRI or CT when the scan slice thickness is no greater than 5mm. If 
the slice thickness is greater than 5mm, the minimum size of a measurable lesion 
must be at least double the slice thickness (e.g., if the slice thickness is 10 mm, a 
measurable lesion must be 20 mm).

10 mm calliper/ruler measurement by clinical exam or medical photography. 

20 mm by chest x-ray.
Additionally lymph nodes can be considered pathologically enlarged and measurable if

15mm in the short axis when assessed by CT or MRI (slice thickness recommended 
to be no more than 5mm). At baseline and follow-up, only the short axis will be 
measured [Chung, 2010; Eisenhauer, 2009].
Non-measurable lesion:
All other lesions including lesions too small to be considered measurable (longest 
diameter <10 mm or pathological lymph nodes with ≥ 10 mm and <15 mm short axis) as 
well as truly non-measurable lesions, which include: leptomeningeal disease, ascites, 
pleural or pericardial effusions, inflammatory breast disease, lymphangitic involvement 
of the skin or lung, abdominal masses/abdominal organomegaly identified by physical 
exam that is not measurable by reproducible imaging techniques [Eisenhauer, 2009].
Measurable disease: The presence of at least one measurable lesion. Palpable lesions 
that are not measurable by radiologic or photographic evaluations may not be utilized as 
the only measurable lesion.
Non-Measurable only disease: The presence of only non-measurable lesions. 
III. Response Criteria
IIIa. 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).


2011N118599_09
CONFIDENTIAL
BET115521
149

Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for progressive disease.

Progressive Disease (PD): At least a 20% increase in the sum of the diameters of 
target lesions, taking as a reference, the smallest sum of diameters recorded since the 
treatment started (e.g. percent change from nadir, where nadir is defined as the 
smallest sum of diameters recorded since treatment start). In addition, the sum must 
have an absolute increase from nadir of 5mm.

Not Applicable (NA): No target lesions at baseline.

Not Evaluable (NE): Cannot be classified by one of the five preceding definitions.
Note:

If lymph nodes are documented as target lesions the short axis is added into the sum 
of the diameters (e.g. sum of diameters is the sum of the longest diameters for non-
nodal lesions and the short axis for nodal lesions). When lymph nodes decrease to 
non-pathological size (short axis <10mm) they should still have a measurement 
reported in order not to overstate progression.

If at a given assessment time point all target lesions identified at baseline are not 
assessed, sum of the diameters cannot be calculated for purposes of assessing CR, 
PR, or SD, or for use as the nadir for future assessments. However, the sum of the 
diameters of the assessed lesions and the percent change from nadir should be 
calculated to ensure that progression has not been documented. If an assessment of 
PD cannot be made, the response assessment should be NE.

All lesions (nodal and non-nodal) should have their measurements recorded even 
when very small (e.g 2 mm). If lesions are present but too small to measure, 5 mm 
should be recorded and should contribute to the sum of the diameters, unless it is 
likely that the lesion has disappeared in which case 0 mm should be reported.

If a lesion disappears and reappears at a subsequent time point it should continue to 
be measured. The response at the time when the lesion reappears will depend upon 
the status of the other lesions. For example, if the disease had reached a CR status 
then PD would be documented at the time of reappearance. However, if the response 
status was PR or SD, the diameter of the reappearing lesion should be added to the 
remaining diameters and response determined based on percent change from baseline 
and percent change from nadir.
IIIb. 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. 


2011N118599_09
CONFIDENTIAL
BET115521
150

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 timepoint based on 
the assessment schedule, should be excluded from the response determination (e.g. 
non-target response does not have to be "Not Evaluable"). 
IIIc. 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.
IIId. 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
CR=complete response, PR = partial response, SD=stable disease, PD=progressive disease, NA= Not applicable, and 
NE=Not Evaluable


2011N118599_09
CONFIDENTIAL
BET115521
151
Note:

Subjects with a global deterioration of health status requiring discontinuation of 
treatment without objective evidence of disease progression at that time should be 
classified as having "symptomatic deterioration." Objective response status is 
determined by evaluations of disease burden. Every effort should be made to 
document the objective progression even after discontinuation of treatment. 

In some circumstances, it may be difficult to distinguish residual disease from 
normal tissue. When the evaluation of CR depends on this determination, it is 
recommended that the residual lesion be investigated (fine needle aspirate/biopsy) to 
confirm the CR.

The dosing schedule, dosing interruptions and design (see Time and Events Tables) 
should be considered when assessing tumor response. Thus, subjects with PD before 
the Week 9 visit, but without rapid clinical deterioration, may continue planned 
dosing schedule to allow detection of antitumor response. It is recommended that 
subjects who experience investigator-determined PD at the Week 9 visit, at the 
discretion of the investigator, may receive additional tumor assessment before the 
initiation of alternative anticancer therapy. 

During Part 1 or Part 2, is recommended that subjects who experience investigator-
determined PD at any time, at the discretion of the investigator, may receive 
additional tumor assessment before the initiation of alternative anticancer therapy.
IIIe. 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 4 weeks.

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. 
Alternative subjects lost to follow-up after an SD assessment not meeting the 
minimum time criteria will be considered not evaluable.
IIIf. Confirmation Criteria (recommended):

To be assigned a status of PR or CR, a confirmatory disease assessment should be 
performed no less than 4 weeks (28 days) after the criteria for response are first met.
IIIg. Independent Review
Disease progression and response evaluations will be collected centrally during the study 
and may be reviewed or analyzed by an independent central reviewer. Details will be 
provided in the SPM.


2011N118599_09
CONFIDENTIAL
BET115521
152
14.6.
Appendix 6: Response Criteria for Neuroblastoma
Response Criteria for Neuroblastoma Patients with Measurable Disease (using CT 
or MRI as per RECIST)
Follow standard RECIST criteria.
Response Criteria for Neuroblastoma Patients with MIBG Positive Lesions
MIBG Positive Lesions
Patients who have a positive MIBG scan at the start of therapy will be evaluable for 
MIBG response. The use of 123I for MIBG imaging is recommended for all scans. If the 
patient has only one MIBG positive lesion and that lesion was radiated, a biopsy must be 
done at least 28 days after radiation was completed and must show viable neuroblastoma.
The following criteria will be used to report MIBG response:
Complete response: 
Complete resolution of all MIBG positive lesions
Partial Response: 
Resolution of at least one MIBG positive lesion, with persistence 
of other MIBG positive lesions
Stable disease: 
No change in MIBG scan in number of positive lesions
Progressive disease:
Development of new MIBG positive lesions
The response of MIBG lesions will be assessed o using the Curie scale as outlined below. 
The body is divided into 9 anatomic sectors for osteomedullary lesions, with a 10th 
general sector allocated for any extra-osseous lesion visible on MIBG scan. In each 
region, the lesions are scored as follows. The absolute extension score is graded as: 
0 = no site per segment, 
1 = 1 site per segment, 
2 = more than one site per segment, 
3 = massive involvement (>50% of the segment). 
The absolute score is obtained by adding the score of all the segments. See diagram of 
sectors below:


2011N118599_09
CONFIDENTIAL
BET115521
153
The relative score is calculated by dividing the absolute score at each time point by the 
corresponding pre-treatment absolute score. The relative score of each patient is 
calculated at each response assessment compared to baseline and classified as below:
1.
Complete response: all areas of uptake on MIBG scan completely resolved. If 
morphological evidence of tumor cells in bone marrow biopsy or aspiration is 
present at enrollment, no tumor cells can be detected by routine morphology on two 
subsequent bilateral bone marrow aspirates and biopsies done at least 21 days apart 
to be considered a Complete Response.
2.
Partial response: Relative score ≤ 0.2 (lesions almost disappeared) to ≤ 0.5 (lesions 
strongly reduced).
3.
Stable disease: Relative score > 0.5 (lesions weakly but significantly reduced) to 1.0 
(lesions not reduced).
4.
Progressive disease: New lesions on MIBG scan.
Response Criteria for Neuroblastoma Patients with Bone Marrow Involvement
Bone Marrow Involvement 
Bone marrow obtained within 28 days prior to study enrollment with tumor cells seen on 
routine morphology (not by immunohistochemical staining only) of bilateral aspirate or 
biopsy on one bone marrow sample.
Bone Marrow responses are determined by H&E Staining of bilateral bone marrow 
biopsies and aspirates.
Complete Response: No tumor cells detectable by routine morphology on 2 consecutive 
bilateral bone marrow aspirates and biopsies performed at least 21 days apart. 
Normalization of urinary catecholamines or other tumor markers if elevated at study 
enrollment.


2011N118599_09
CONFIDENTIAL
BET115521
154
Progressive Disease: In patients who enroll with neuroblastoma in bone marrow by 
morphology have progressive disease if there is a doubling in the amount of tumor in the 
marrow AND a minimum of 25% tumor in bone marrow by morphology. (For example, a 
patient entering with 5% tumor in marrow by morphology must increase to ≥ 25% tumor 
to have progressive disease; a patient entering with 30% tumor must increase to > 60%).
In patients who enroll without evidence of neuroblastoma in bone marrow will be defined 
as progressive disease if tumor is detected in 2 consecutive bone marrow biopsies or 
aspirations done at least 21 days apart.
Stable Disease: Persistence of tumor in bone marrow that does not meet the criteria for 
either complete response or progressive disease.


2011N118599_09
CONFIDENTIAL
BET115521
155
14.7.
Appendix 7: NYHA Functional Classification System for 
Heart Failure
The New York Heart Association (NYHA) Functional Classification [NYHA, 1994]
provides a simple way of classifying the extent of heart failure. It places subjects in one 
of four categories based on the level of limitation experienced during physical activity:
Class
Symptoms
Class I
(Mild)
No limitation of physical activity. Ordinary physical activity does not cause 
undue fatigue, palpitation or dyspnea (shortness of breath).
Class II
(Mild)
Slight limitation of physical activity. Comfortable at rest, but ordinary physical 
activity results in fatigue, palpitation or dyspnea.
Class III
(Moderate)
Marked limitation of physical activity. Comfortable at rest, but less than 
ordinary physical activity results in fatigue, palpitation or dyspnea.
Class IV
(Severe)
Unable to carry out any physical activity without discomfort. Symptoms of 
cardiac insufficiency at rest. If any physical activity is undertaken, discomfort is 
increased.


2011N118599_09
CONFIDENTIAL
BET115521
156
14.8.
Appendix 8: Country Specific Requirements
14.8.1.
Investigational Product Label


2011N118599_09
CONFIDENTIAL
BET115521
157
14.8.2.
Medical Devices Used in the Study


2011N118599_09
CONFIDENTIAL
BET115521
158
14.9.
Appendix 9: Protocol Amendment Changes
AMENDMENT 1
Protocol Amendment 1 applies to all site(s) participating in the conduct of the study
Amendment 1 summary:
Amendment No.1: Amendment 1 applies to all study sites.  Modifications include 
updated medical monitoring information due to a personnel change on the GSK team. In 
addition, the following review of the protocol by the FDA, the following changes are 
made: For Part 1, the starting dose of GSK525762 is reduced from 5 mg/day to 2 mg/day. 
Cardiac troponin T level assessments are required as a part of the inclusion criteria and 
thereafter.   An observation of CTCAE Grade 2 drug related toxicity, including grade 2 
troponin T elevation, in one subject will end accelerated dose titration in Part 1.  Subjects 
with a history of gastrointestinal bleeding or active bleeding (positive guaiac fecal occult 
blood monitoring) will be excluded.  In addition, wording for dose escalation decisions 
has been modified to state that no more than a 2-fold increase in dose will occur between 
successive cohorts.  A staggered dosing approach will be implemented in the 3+3 dosing 
design to minimize potential for toxicity in multiple subjects. Alternative dosing 
regimens will not be implemented without consultation with FDA and a protocol 
amendment.  For Part 2 of the trial, stopping rules based on lack of efficacy and the 
futility rule have been modified. Additionally the disease assessment scans may be 
reviewed retrospectively by an independent radiologist.  Finally, multiple Time and 
Event Tables have been revised for consistency across Part 1 and Part 2 of the protocol.
List of Specific Changes
Rationale Change 1:
The sponsor and medical monitoring information has been updated based on internal 
GSK team personnel changes.
PREVIOUS TEXT, Section Sponsor/Medical Monitor Information 
SPONSOR SIGNATORY:
Jamie Freeman, MD, PhD 
VP, Cancer Research, Early Development 
GlaxoSmithKline Oncology
Date


2 0 1 1 N 1 1 8 5 9 9 _ 0 9
C O N FI D E N TI A L
B E T 1 1 5 5 2 1
1 5 9
Me dic al M o nit or a n d S p o ns or C o nt act I nf or m ati o n:
R ol e
N a m e
D ay Ti m e 
P h o n e 
N u m b er
Aft er -h o urs 
P h o n e/ C ell/ 
P a g er 
N u m b er
F ax N u m b er G S K A d dr ess
Pri m ary M e dic al 
M o nit or
 M D
Gl ax o S mit h Kli n e
1 2 5 0 S o ut h C oll e g evill e R o a d, 
M ailst o p U P 4 3 4 0
C oll e g evill e, P A 1 9 4 2 6, U S A
S ec o n d ary M e dic al 
M o nit or
 
M D, P h D
7 0 9 S w e d el a n d R o a d U W 2 2 3 0,
Ki n g of Pr ussi a, P A 1 9 4 0 6 -2 7 1 1 
U S A
R E VI S E D T E X T, Secti o n S p o ns or/ Me dic al M o nit or I nf or m ati o n
S P O N S O R SI G N A T O R Y:
Vija y  G Pe d dare ddi gari, M D
Ja mie Free ma n, M D, P h D 
Ass ociate Me dical Direct or, V P,
Ca ncer E pi ge netics, O nc ol o g y  Researc h & De vel o p me nt
Researc h, Earl y De vel o p me nt
Gla x o S mit h Kli ne O nc ol o g y
D ate
P P D
P P D
P P D
P P D
P P D
P P D


2 0 1 1 N 1 1 8 5 9 9 _ 0 9
C O N FI D E N TI A L
B E T 1 1 5 5 2 1
1 6 0
Me dic al M o nit or a n d S p o ns or C o nt act I nf or m ati o n:
R ol e
N a m e
D ay Ti m e 
P h o n e 
N u m b er
Aft er -h o urs 
P h o n e/ C ell/ 
P a g er 
N u m b er
F ax N u m b er G S K A d dr ess
Pri m ary M e dic al 
M o nit or
, M D
Gl ax o S mit h Kli n e
1 2 5 0 S o ut h C oll e g evill e R o a d, 
M ailst o p U P 4 3 4 0
C oll e g evill e, P A 1 9 4 2 6, U S A
S ec o n d ary M e dic al 
M o nit or
, 
M D, P h D
, 
M D, P h D
 
7 0 9 S w e d el a n d R o a d U W 2 2 3 0,
Ki n g of Pr ussi a, P A 1 9 4 0 6 -2 7 1 1 
U S A
Gl ax o S mit h Kli n e
1 2 5 0 S o ut h C oll e g evill e R o a d, 
M ailst o p U P 1 -1 4 5 0
C oll e g evill e, P A 1 9 4 2 6, U S A
R ati o n al e C h a n g e 2:
Base d o n F D A rec o m me n dati o n, t he starti n g d ose of G S K 5 2 5 7 6 2 will b e l o were d fr o m 5 
m g t o 2 m g o nce dail y . T his c ha n ge reflects use of 0. 3 m g/ k g as t he hi g hest n o n-se vere 
t o xic d ose ( H N S T D) i n t he d o g base d o n t he effect o n Q T pr ol o n gati o n. IC H S 9 
g ui deli nes n o w pre dict t he d o g as t he m ost se nsiti ve s pecies a n d 1/ 6 H N S T D tra nslates t o 
a 1. 7 m g starti n g d ose i n h u ma ns (ass u mi n g a 7 0 k g a d ult a n d a d ult s urface area of 1. 7 
m 2).  T his calc ulate d starti n g d ose has bee n r o u n de d t o 2 m g. 
P R E VI O U S T E X T, Secti o n Pr ot oc ol S y n o psis
D O S A G E/ D O S A G E F O R M, R O U T E, A N D D O S E R E GI M E N : Startin g d ose will be 
5 m g, orall y (ta blets), o nce a da y . 
R E VI S E D T E X T, Secti o n Pr ot oc ol S y n o psis
D O S A G E/ D O S A G E F O R M, R O U T E, A N D D O S E R E GI M E N : Starti n g d ose will be 
5 2
P P D
m g, orall y  (ta blets), o nce a da y. 
P P D
P P D
P P D
P P D
P P D
P P D
P P D


2011N118599_09
CONFIDENTIAL
BET115521
161
PREVIOUS TEXT, Section 1.2.2.2 Starting dose 
Based on tolerability, the HNSTD was defined as 1mg/kg in the dog. 1/6 dog HNSTD is 
3.33 mg/m2 which translates to a starting dose in man of 5.7 mg, assuming a 70 kg adult 
and adult surface area of 1.7 m2.
REVISED TEXT, Section 1.2.2.2 Starting dose 
Based on tolerability and QT prolongation tolerability, the HNSTD was defined as 
0.31mg/kg in the dog. 1/6 dog HNSTD is 13.33 mg/m2 which translates to a starting dose 
in man of 1.75.7 mg (rounded to a starting dose of 2 mg based on tablet strength), 
assuming a 70 kg adult and adult surface area of 1.7 m2. 
PREVIOUS TEXT. Section 1.2.2.2 Starting dose 
Taking all four approaches into consideration, a starting dose of 5 mg is proposed. This 
dose will provide a suitable safety margin to the QTc prolongation observed on repeat 
dosing in the dog (given that a 10 mg clinical dose is equivalent to 6 mg/m2, and has been 
shown to be equivalent to the QTc NOEL in the dog 4 week study).
REVISED TEXT, Section 1.2.2.2 Starting dose 
Taking all four approaches into consideration, a starting dose of 52 mg is proposed. This 
dose will provide a suitable5-fold safety margin to the QTc prolongation observed on 
repeat dosing in the dog (given that a 10 mg clinical dose is equivalent to 6 mg/m2, and 
has been shown to be equivalent to the HNSTD and QTc NOEL in the dog 4 week 
study).
PREVIOUS TEXT, Section 1.2.2.2 Starting Dose, Table 1 
Table 1
Predicted Safety Cover for proposed 5mg starting dose (data 
from most sensitive NOAEL/NOEL from 4 week toxicology 
studies)
Clinical starting dose
Dose (5 mg)
AUC (ng.hr/ml)
424
Free AUC 
(ng.hr/ml)
93
Cmax (ng/ml) 
21
Free Cmax 
(ng/ml)
4.6
Cardiotoxicity
QTc from single dose*
43.6x (NOEL)
51.6x (NOEL)
156.2x (NOEL)
184.6x (NOEL)
QTc on repeat dosing
1.8x (NOEL)
5.0x (LOEL)
2.2x (NOEL)
5.9x (LOEL)
5.1x (NOEL)
15.2x (LOEL)
6.0x (NOEL)
18.0x (LOEL)
Troponin
No cover
No cover


2011N118599_09
CONFIDENTIAL
BET115521
162
Clinical starting dose
Dose (5 mg)
AUC (ng.hr/ml)
424
Free AUC 
(ng.hr/ml)
93
Cmax (ng/ml) 
21
Free Cmax 
(ng/ml)
4.6
Gastrointestinal toxicity
In life changes
0.4x (NOAEL) 
4.4x (LOAEL)
3.8x (NOAEL) 
56.3x (LOAEL)
Microscopic changes
5.0x (NOAEL) 
21.0x (LOAEL)
15.2x (NOAEL) 
62.4x (LOAEL)
Haematopoietic toxicity
0.8x (NOAEL) 
4.4x (LOAEL)
6.8x (NOAEL) 
56.3x (LOAEL)
Lymphoid toxicity
4.4x (NOAEL) 
29.0x (LOAEL)
56.3x (NOAEL) 
156.7x (LOAEL)
Testicular toxicity
No cover
No cover
NO(A)EL = No observed (adverse) effect level
LO(A)EL = Lowest observed (adverse) effect level
*Calculated from single dose GLP dog CV study
REVISED TEXT, Section 1.2.2.2 Starting Dose, Table 1
Table 1
Predicted Safety Cover for proposed 25mg starting dose (data 
from most sensitive NOAEL/NOEL from 4 week toxicology 
studies)
Clinical starting dose
Dose (25 mg)
AUC 
(ng.hr/ml)
170424
Free AUC 
(ng.hr/ml)
3793
Cmax (ng/ml) 
8.421
Free Cmax 
(ng/ml)
1.854.6
Cardiotoxicity
QTc from single dose*
109.143.6x 
(NOEL)
128.951.6x 
(NOEL)
390.5156.2x 
(NOEL)
461.5184.6x 
(NOEL)
QTc on repeat dosing
4.61.8x 
(NOEL)
12.45.0x 
(LOEL)
5.42.2x
(NOEL)
14.745.9x 
(LOEL)
12.75.1x 
(NOEL)
38.015.2x 
(LOEL)
15.06.0x 
(NOEL)
45.018.0x 
(LOEL)
Troponin
No cover
No cover


2011N118599_09
CONFIDENTIAL
BET115521
163
Clinical starting dose
Dose (25 mg)
AUC 
(ng.hr/ml)
170424
Free AUC 
(ng.hr/ml)
3793
Cmax (ng/ml) 
8.421
Free Cmax 
(ng/ml)
1.854.6
Gastrointestinal toxicity
In life changes
1.00.4x 
(NOAEL) 
11.04.4x 
(LOAEL)
9.63.8x 
(NOAEL) 
140.756.3x 
(LOAEL)
Microscopic changes
12.45.0x 
(NOAEL) 
52.521.0x 
(LOAEL)
38.015.2x 
(NOAEL) 
156.062.4x 
(LOAEL)
Hepatic toxicity (single rat)
11.0x 
(NOAEL)
72.5x 
(LOAEL)
140.7x 
(NOAEL)
391.7x 
(LOAEL)
Hematopoietic toxicity
1.90.8x 
(NOAEL) 
11.04.4x 
(LOAEL)
17.1 6.8x
(NOAEL) 
140.756.3x 
(LOAEL)
Lymphoid toxicity
11.04.4x 
(NOAEL) 
72.529.0x 
(LOAEL)
140.756.3x 
(NOAEL) 
391.7156.7x 
(LOAEL)
Hemolysis (rat specific)
11.0x 
(NOAEL)
72.5x 
(LOAEL)
140.7x 
(NOAEL)
391.7x 
(LOAEL)
Clotting effects
12.4x 
(NOAEL)
52.5x 
(LOAEL)
38.0x (NOAEL)
156.0x 
(LOAEL)
Pancreatic toxicity (male rat 
specific)
74.4x 
(NOAEL)
391.7x 
(LOAEL)
8.6x (NOAEL)
72.5x (LOAEL)


2011N118599_09
CONFIDENTIAL
BET115521
164
Clinical starting dose
Dose (25 mg)
AUC 
(ng.hr/ml)
170424
Free AUC 
(ng.hr/ml)
3793
Cmax (ng/ml) 
8.421
Free Cmax 
(ng/ml)
1.854.6
Pulmonary effects (rat specific)
1.9x (NOEL)
11.0x (LOEL)
17.1x (NOEL)
140.7x (LOEL)
Testicular toxicity
No cover
No cover
NO(A)EL = No observed (adverse) effect level
LO(A)EL = Lowest observed (adverse) effect level
*Calculated from single dose GLP dog CV study
PREVIOUS TEXT, Section 1.3 Risk Assessment
Cardiovascular. Although there were minimal effects of GSK525762 on hERG current 
density or trafficking in HEK-293 cells or on ECG rhythms or arrhythmias in the ex vivo 
rabbit wedge assay, QT and QTc prolongation (maximum 41 milliseconds at 3 mg/kg for 
12 days) was seen in dogs after a single oral dose of 30 mg/kg or repeat dosing at t 1 
mg/kg/day in 4 week toxicology studies. Some evidence of adaptation was observed in 
the 4 week dog study. QTc prolongation observed at the early timepoints (Day 5-13) in 
dogs given 1 mg/kg had returned to baseline by the end of the study. No effect was seen 
in the dog at 0.3 mg/kg (6 mg/m2) where exposure is estimated to be approximately 
equivalent to that achieved by a 10 mg dose in humans if 100% bioavailability is 
assumed. However, the proposed starting dose in this FTIH BET115521 study is 5 mg.
Reproductive:  
Exposures associated with reproductive toxicity in male dogs overlap with the proposed 5 
mg starting dose in this FTIH study. 
REVISED TEXT, Section 1.3 Risk Assessment
Cardiovascular. Although there were minimal effects of GSK525762 on hERG current 
density or trafficking in HEK-293 cells or on ECG rhythms or arrhythmias in the ex vivo 
rabbit wedge assay, QT and QTc prolongation (maximum 41 milliseconds at 3 mg/kg for 
12 days) was were seen in dogs after a single oral dose of 30 mg/kg or repeat dosing at ≥t
1 mg/kg/day (maximum increase was 41 milliseconds following 12 doses of 3 
mg/kg/day) in 4 week toxicology studies. Some evidence of adaptation was observed in 
the 4 week dog study. QTc prolongation observed at the early timepoints (Day 5-13) in 
dogs given 1 mg/kg had returned to baseline by the end of the study. No effect was seen 
in the dog at 0.3 mg/kg (6 mg/m2) where exposure is estimated to be approximately 
equivalent to that achieved by a 10 mg dose in humans if 100% bioavailability is 
assumed. HoweverThis represents a 5-fold safety margin over the proposed starting dose 
of 2 mg in this First Time in Human (FTIH) BET115521 study is 5 mg.
Reproductive: 
Exposures associated with reproductive toxicity in male dogs overlap with the proposed 
25 mg starting dose in this FTIH study. 


2011N118599_09
CONFIDENTIAL
BET115521
165
PREVIOUS TEXT, Section 3.2.1.1, Accelerated Dose Titration 
An accelerated dose titration schema with one subject per dose level will be used initially 
to minimize suboptimal drug exposures. Sequential subjects will follow an accelerated 
dose escalation as described in below (see Table 3). Accelerated dose titration will 
continue until DLT has occurred. This may occur with a doubling of dose until one of the 
subjects experiences a DLT or the second subject experiences a ≥ Grade 2 drug-related 
adverse event as determined by CTCAE v. 4.0 (Table 3). See Alternative dosing Section 
3.2.1.4.
Table 3
Dose Escalation Procedures
Dose Level
Change in Dose
Dose Level -1
Lower doses may be used if Dose Level 1 is not tolerated. This 
may be achieved by reducing the dose or by alternate dosing (e.g. 
every other day)
Dose Level 1
Starting Dose at 5 mg once daily 
Subsequent dose levels Increase by 2-fold 
(one or fewer subjects with Grade 2 drug related toxicity AND 
no subjects with any DLTs in first 6 weeks of treatment)
End of Accelerated 
Titration Phase
Begin 3+3 Dose Escalation Phase
(2 or more subjects with Grade 2 drug related toxicity or one or 
more subjects with DLT in first 6 weeks of treatment)
REVISED TEXT, Section 3.2.1.1, Accelerated Dose Titration
An accelerated dose titration schema with one subject per dose level will be used initially 
to minimize suboptimal drug exposures. Sequential subjects will follow an accelerated 
dose escalation as described in below. Accelerated dose titration will continue until a ≥ 
Grade 2 drug-related adverse event or a DLT is observed in one subject (see Table 3).
This would end the accelerated dose escalation and would lead to the enrollment of a 
total of 3 subjects initially at this dose level. This may occur with a doubling of dose until 
one of the subjects experiences a DLT or the second subject experiences a ≥ Grade 2 
drug-related adverse event as determined by CTCAE v. 4.0 (Table 3). See Alternative 
dosing Section 3.2.1.6. Subsequent subjects will follow a 3+3 dose escalation schema as 
described below (see Table 4). If no more than one DLT is observed in these 3 subjects 
then an additional 3 subjects will be added as described in Table 4 (3+3 Dose Escalation 
Decision Process).  If two or more DLTs are observed at any dose level, the MTD will 
have been exceeded. 


2011N118599_09
CONFIDENTIAL
BET115521
166
Table3. Accelerated Dose Escalation Procedures
Table 3
Dose Escalation Procedures
Dose Level
Change in Dose
Dose Level -1
Lower doses may be used if Dose Level 1 is not tolerated. This 
may be achieved by reducing the dose or by alternate dosing (e.g. 
every other day)
Dose Level 1
Starting Dose at 25 mg once daily 
Subsequent dose 
levels
Increase by 2-fold 
(one or fewer subjects with No subjects with Grade 2 drug 
related toxicity AND no subjects with any DLTs in first 6 weeks of 
treatment)
End of Accelerated 
Titration Phase
Begin 3+3 Dose Escalation Phase
(2 or more subjects with 1 subject with any Grade 2 drug related 
toxicity or one or more subjects with DLT in the first 6 weeks of 
treatment)
Rationale Change 3
Eligibility for the BET115521 study will be restricted to subjects with NMC. Additional 
tumor types may be added in future protocol amendments based on scientific rationale 
and emerging preclinical data coupled with the emerging safety profile developed within 
the NMC population in the BET115521 study.
PREVIOUS TEXT, Section 3.2.1, Part 1 Single Dose and Repeat Dose Escalation in 
NMC
Additional tumor types may be added to Part 1 cohort based on emerging and compelling 
preclinical efficacy data and acceptable clinical safety data from the ongoing study 
(approval is required by Sponsor and subject to approval by GSK Global Safety Board). 
REVISED TEXT, Section 3.2.1, Part 1 Single Dose and Repeat Dose Escalation in 
NMC
Additional tumor types may be added to Part 1 cohort based on emerging and compelling 
preclinical efficacy data and acceptable clinical safety data from the ongoing study 
(approval is required by Sponsor and subject to approval by GSK Global Safety Board).


2011N118599_09
CONFIDENTIAL
BET115521
167
PREVIOUS TEXT, Section 3.2.4, Part 2 Expansion Cohort(s)
Additional tumor types may be added to Part 2 cohort expansion based on emerging and 
compelling preclinical efficacy data and acceptable clinical safety data from the ongoing 
study (approval is required by Sponsor and subject to approval by GSK Global Safety 
Board).
REVISED TEXT, Section 3.2.4, Part 2 Expansion Cohort(s)
Additional tumor types may be added to Part 2 cohort expansion based on emerging and 
compelling preclinical efficacy data and acceptable clinical safety data from the ongoing 
study (approval is required by Sponsor and subject to approval by GSK Global Safety 
Board).
PREVIOUS TEXT, Section 4.2.1 Inclusion Criteria
3. Diagnosis of NUT Midline Carcinoma (based on IHC or FISH) for NUT fusion protein 
or transcript (irrespective of the NUT fusion partner). Subjects may be treatment naïve or 
have had prior therapy. 
Additional tumor types may be added to the dose escalation Part 1 and tested in Part 2 
cohort expansion based on emerging and compelling preclinical efficacy data and 
acceptable clinical safety data from the ongoing study (approval is required by Sponsor 
and subject to approval by GSK Global Safety Board).
REVISED TEXT, Section 4.2.1 Inclusion Criteria
3. Diagnosis of NUT Midline Carcinoma based on IHC or FISH) for NUT fusion protein 
or transcript (irrespective of the NUT fusion partner). Subjects may be treatment naïve or 
have had prior therapy. 
Additional tumor types may be added to the dose escalation Part 1 and tested in Part 2 
cohort expansion based on emerging and compelling preclinical efficacy data and 
acceptable clinical safety data from the ongoing study (approval is required by Sponsor 
and subject to approval by GSK Global Safety Board).
Rationale Change 4
A dose escalation schema has been included to describe Accelerated Dose escalation 
transition to a traditional 3+3 design.  In addition, a staggered dosing approach will be 
implemented to minimize the risk of exceeding the maximum tolerated dose in multiple 
subjects.  New wording has been added that any alternative dosing regimens will not be 
implemented without consultation with FDA and a protocol amendment.  Finally, the 
timing of intra-subject dose escalation has been modified to lengthen the time period 
before a subject can dose escalate.  


2011N118599_09
CONFIDENTIAL
BET115521
168
PREVIOUS TEXT, Section 3.2.1.1 Accelerated Dose Titration
3+3 Dose Escalation Decision Process
Number of subjects at given 
dose level with DLT
Action
0 out of 3 subjects
Escalate to next dose level 
1 out of 3 subjects
Accrue 3 additional evaluable subjects at current dose 
level for a total of 6 evaluable subjects
1 out of 6 subjects
Escalate to the next dose level (Increase by 2-fold)
2 or more subjects in a dosing 
cohort (up to 6 subjects)
Maximum tolerated dose has been exceeded. Either 
evaluate an intermediate dose lower than current dose 
or expand a prior cohort. This will be the start of Part 
2 where Cohorts may dose up to 20 subjects. 
NEW TEXT, Section 3.2.1.1 Accelerated Dose Titration
Figure 2 Dose Escalation Schema
Dose Level 1 
Starting Dose = 
2mg
Single Subject
Dose Level 2 
Dose Increase 
2-fold
Single Subject
Dose Level 3 
Dose Increase  
2-fold
Single Subject
Dose Level X 
Single Patient 
≥ 2 grade toxicity
Dose level X
Add 2 additional 
subjects
Dose level X+1
Treat  3 Subjects  
Dose level X+2
Treat  3 Subjects  
No DLTs
No DLTs
End accelerated dose escalation/  
Start 3+3 Dosing Phase/ 
Dose increase ≤2 fold at each escalation 
Dose level X+1
Add  3 Subjects
(total =6 subjects)  
One DLT
(1DLT in 3 subjects)
Dose level X+2
Treat  3 Subjects  
One Additional DLT
(≥2 DLTs in 6 subjects)
MTD 
exceeded
No Additional DLT
(Total1 DLTs in 6 subjects)
Declare MTD at 
previous dose level or 
test intermediate dose
No DLTs
DOSE ESCALATION SCHEMA
If DLT/Toxicity at dose 
level 1 then de-escalate to 
dose level -1 (dose 1mg)
Accelerated Dose Escalation  
Recommended Phase II Dose (RP2D) will be MTD or a lower dose 
PREVIOUS TEXT, Section 3.2.1.2 Dose Escalation Rules (3+3 Design)
A standard 3+3 design will be implemented when one of the subject experiences a DLT 
or two or more of the subjects in the Accelerated Dose Escalation experience a ≥ Grade 2 
drug related adverse event as determined by CTCAE v. 4.0 as illustrated in Table 3. At 
this point, two additional subjects will be added to this dosing level for a total of at least 3 


2011N118599_09
CONFIDENTIAL
BET115521
169
subjects at this dosing level. If no more than one subject experiences a DLT from among 
these 3 subjects, then this dosing level cohort will expand to a total of 6 subjects. If two 
subjects experience a DLT while the cohort is expanding (recruiting), then no additional 
subjects would enter the cohort. Dose escalation decisions as shown in Dose Escalation 
Decision Process
Once a standard 3+3 dose escalation design is implemented the subjects will be entered in 
a staggered approach with at least 3 days between each subject to minimize the risk of 
inadvertently exceeding the maximum tolerated dose in multiple subjects.
As noted in Table 4, the escalation to the next dose level will not increase greater than 2 
fold from the previous dose level.
Table 4. Once MTD or biologically active dose (example: clinical response) is reached, 
additional cohorts may be explored with a lower dose or alternative dosing schedules to 
optimize the pharmacokinetic, safety and tolerability profile (see Section 3.2.1.5).
REVISION TEXT, Section 3.2.1.2 Dose Escalation Rules (3+3 Design)
A standard 3+3 design will be implemented when one of the subject experiences a DLT 
or two or more of the subjects in the Accelerated Dose Escalation experience a ≥ Grade 2 
drug related adverse event in the Accelerated Dose Escalation as determined by CTCAE 
v. 4.0 as illustrated in Table 3 or a DLT as illustrated in Table 3.  At this point, two 
additional subjects will be added to this dosing level for a total of at least 3 subjects at 
this dosing level. If no more than one subject experiences a DLT from among these 3 
subjects, then this dosing level cohort will expand to a total of 6 subjects. If two subjects 
experience a DLT while the cohort is expanding (recruiting), then no additional subjects 
would enter the cohort. Dose escalation decisions as shown in Dose Escalation Decision 
Process
Once a standard 3+3 dose escalation design is implemented the subjects will be entered in 
a staggered approach with at least 3 days between each subject to minimize the risk of 
inadvertently exceeding the maximum tolerated dose in multiple subjects.
As noted in Table 4, the escalation to the next dose level will not increase greater than 2 
fold from the previous dose level.
Table 4. Once MTD or biologically active dose (example: clinical response) is reached, 
additional cohorts may be explored with a lower dose or alternative dosing schedules to 
optimize the pharmacokinetic, safety and tolerability profile (see Section 3.2.1.5).At this 
point, two additional subjects will be added to this dosing level for a total of at least 3 
subjects at this dosing level, if no DLT are observed in any of the 3 patients then the 
dosing will proceed to the next higher dose level ( ≤ 2 fold increase in dose). If no more 
than one subject experiences a DLT from among these 3 subjects, then this dosing level 
cohort will expand to a total of 6 subjects. If two subjects experience a DLT while the 
cohort is expanding (recruiting), then no additional subjects would enter the cohort. Dose 
escalation decisions as shown in Table 4. Once MTD or biologically active dose 
(example: clinical response) is reached, additional cohorts may be explored with a lower 
dose or alternative dosing schedules to optimize the pharmacokinetic, safety and 
tolerability profile (see Section 3.2.1.5).


2011N118599_09
CONFIDENTIAL
BET115521
170
NEW TEXT, Section 3.2.1.4 Dose Escalation Decision Process 
Once a standard 3+3 dose escalation design is implemented the subjects will be entered in 
a staggered approach with at least 3 days between each subject to minimize the risk of 
inadvertently exceeding the maximum tolerated dose in multiple subjects.
As noted in Table 4, the escalation to the next dose level will not increase greater than 2 
fold from the previous dose level.
Table 4.
3+3 Dose Escalation Decision Process
Number of subjects at given 
dose level with DLT
Action
0 out of 3 subjects
Escalate to next dose level 
1 out of 3 subjects
Accrue 3 additional evaluable subjects at current dose 
level for a total of 6 evaluable subjects
1 out of 6 subjects
Escalate to the next dose level (Increase by 2-fold)
2 or more subjects in a dosing 
cohort (up to 6 subjects)
Maximum tolerated dose has been exceeded. Either 
evaluate an intermediate dose lower than current dose 
or expand a prior cohort.  This will be the start of Part 
2 where Cohorts may dose up to 20 subjects. 
NEW TEXT, 3.2.1.5 Alteration of Schedule
Alternative dosing regimens may be implemented after a protocol amendment.  
PREVIOUS TEXT, 3.2.1.6 Intra-Subject Dose Escalation
Intra-subject dose escalations may be considered on a case-by-case basis, provided that: 

The subject has not experienced any Grade 2 or higher drug related toxicity during 
the first 5 weeks of investigational therapy. 
REVISED TEXT, 3.2.1.6 Intra-Subject Dose Escalation
Intra-subject dose escalations may be considered on a case-by-case basis, provided that: 

The subject has not experienced any Grade 2 or higher drug related toxicity during 
the first 6 5 weeks of investigational therapy. 
Rationale Change 5
CTCAE grade 2 drug related toxicity including grade 2 cardiac troponin T elevation in 
one subject would end the Accelerated Dose Escalation phase. 


2011N118599_09
CONFIDENTIAL
BET115521
171
PREVIOUS TEXT, Section 3.1, Study Design/Schematic

An accelerated dose titration will be employed with one subject per dose level 
until the first instance of a dose limiting toxicity (DLT) or a second instance of 
Grade 2 toxicity occurs. Thereafter, subjects will be enrolled in a standard 3+3 
design. The frequency and schedule of dosing may be adjusted based on 
emerging safety and PK data. 
REVISED TEXT, Section 3.1, Study Design/Schematic

An accelerated dose titration will be employed with one subject per dose level 
until the first instance of a dose limiting toxicity (DLT) or a second instance of
Grade 2 drug related toxicity occurs. Thereafter, subjects will be enrolled in a 
standard 3+3 design. . The frequency and schedule of dosing may be adjusted 
based on emerging safety and PK data.
Rationale Change 6
Troponin T assessment will be required in the inclusion criteria and for dose limiting 
toxicity (DLT) determination. At some sites, troponin T is not available and a central 
laboratory has been established.  Therefore, troponin (I or T) checked locally and 
troponin T levels will be analyzed centrally to provide consistent monitoring of troponin 
T across the study.  This will allow the sites a real-time monitoring for cardiac toxicity 
and provide consistent monitoring of troponin T across the study.  In addition, the dose 
limiting toxicity definition has been clarified to exclude fatigue and mucosis which are 
common non-drug related events associated with disease.
PREVIOUS TEXT, Section 3.2.2. Dose Limiting Toxicity (DLT) 

Drug related Grade 3 or 4 non-hematologic toxicity (including QTc) as described in 
the Common Terminology Criteria for Adverse Events v 4.0 (excluding 
abnormalities of alanine aminotransferase (ALT) or aspartate aminotransferase 
(AST) (see criteria below). In addition, the DLT exceptions include: rash, diarrhea, 
nausea, and vomiting that do respond to standard medical care within 72 hours or for 
electrolyte disturbances within 24 hours). 

Troponin (I or T) > institutional ULN and > 10% coefficient of variance (CV) for the 
assay, measured on two separate occasion within 24 hours in order to confirm 
elevation, and with other clinical signs, symptoms, laboratory tests consistent with 
cardiac toxicity.
REVISED TEXT, Section 3.2.2. Dose Limiting Toxicity (DLT) 

Drug related Grade 3 or 4 non-hematologic toxicity (including QTc) as described in 
the Common Terminology Criteria for Adverse Events v 4.0 (excluding 
abnormalities of alanine aminotransferase (ALT) or aspartate aminotransferase 
(AST) (see criteria below). In addition, the DLT exceptions include: rash, fatigue, 
mucosis, diarrhea, nausea, and vomiting that do respond to standard medical care 
within 72 hours or for electrolyte disturbances within 24 hours).


2011N118599_09
CONFIDENTIAL
BET115521
172

Troponin (I or T) > institutional ULN and > 10% coefficient of variance (CV) for the 
assay, measured on two separate occasion within 24 hours in order to confirm 
elevation, and with other clinical signs, symptoms, laboratory tests consistent with 
cardiac toxicity.  Grade 2 Troponin T elevation ( central laboratory >ULN), 
measured on two separate occasions within 48 hours in order to confirm elevation 
and with other clinical signs, symptoms, laboratory tests consistent with cardiac
toxicity. (In the event a troponin T (central laboratory assessment) is not performed 
or a laboratory error occurs, considerations for a DLT criteria will involve review of 
two separate local troponin (I or T) assays done with in 48 hours at a local 
investigator site. Troponin I or T elevations greater than the upper limit of normal, 
and > 10% coefficient of variance (CV) for that assay will be considered as a grade 2 
elevation).
Rationale Change 7
The inclusion and exclusion criteria have been clarified to address Troponin assessments 
for Troponin T only.  In addition, additional clarifications regarding bleeding criteria 
have been modified.  The HbA1C has been clarified to apply to Part 1and Part 2. Subjects 
with a history of or active gastrointestinal bleeding will be excluded from the study. 

NEW TEXT, Abbreviations
EIAC
Enzyme-inducing anticonvulsant
HbA1C
hemoglobin A1C
PREVIOUS TEXT, Section 4.2.1, Inclusion Criteria 
5. All prior treatment- related toxicities must be CTCAE (Version 4.0) ≤ Grade 1 (except 
alopecia) at the time of treatment allocation [NCI-CTCAE, 2009], and stable for 4 weeks 
or longer at the time of screening evaluation. 
7. Adequate organ function as defined in Table 5.
Table 5
Definitions for Adequate Organ Function
System
Laboratory Values
Metabolic
Fasting Serum Glucose
<126 mg/dL
Cardiac
Ejection fraction
≥ LLN by ECHO (minimum of 50%)
Troponin (I or T)
Potassium
Magnesium
ULN 
≥LLN and ≤ULN 
≥LLN


2011N118599_09
CONFIDENTIAL
BET115521
173
REVISED TEXT, Section 4.2.1, Inclusion Criteria 
5. All prior treatment- related toxicities must be CTCAE (Version 4.0) ≤ Grade 1 (except 
alopecia) at the time of treatment allocation [NCI-CTCAE, 2009], and stable for 4 weeks 
or longer at the time of screening evaluation. 
7. Adequate organ function as defined in Table 5.
Table 5
Definitions for Adequate Organ Function
System
Laboratory Values
Metabolic
Fasting Serum Glucose
<126 mg/dL
HbA1C
normal
Cardiac
Ejection fraction
≥ LLN by ECHO (minimum of 50%)
Troponin (I or T)
Potassium
Magnesium
ULN 
≥LLN and ≤ULN 
≥LLN
Gastrointestinal
Guaiac fecal occult blood test
Negative 
PREVIOUS TEXT, Section 4.2.2. Exclusion Criteria
6. Symptomatic or untreated leptomeningeal or brain metastases or spinal cord 
compression.
NOTE: Subjects previously treated for these conditions that have had stable CNS disease 
(verified with consecutive imaging studies) for >1months months, are asymptomatic and 
off corticosteroids, or are on stable dose of corticosteroids for at least 1 month prior to 
study Day 1 are permitted. Stability of brain metastases must be confirmed with imaging. 
If patient treated with gamma knife the can be enrolled 2 weeks post-procedure as long as 
there are no post-procedure complications/stable. In addition, subjects treated or currently 
taken EIAC are allowed on study.
7. Part 1: Based on normal HbA1C subjects would be allowed study entry.
9. Any of the following ECG findings:

Baseline QTcF interval ≥450 msec

Any clinically significant ECG assessments should be reviewed prior to study 
entry.
11. Pulmonary hemoptysis > 1 teaspoon in 24 hours within the last 14 days. 


2011N118599_09
CONFIDENTIAL
BET115521
174
REVISED and NEW TEXT, Section 4.2.2. Exclusion Criteria
6. Symptomatic or untreated leptomeningeal or brain metastases or spinal cord 
compression.
NOTE: Subjects previously treated for these conditions that have had stable CNS disease 
(verified with consecutive imaging studies) for >1months months, are asymptomatic and 
off corticosteroids, or are on stable dose of corticosteroids for at least 1 month prior to 
study Day 1 are permitted. Stability of brain metastases must be confirmed with imaging. 
If patient treated with gamma knife the can be enrolled 2 weeks post-procedure as long as 
there are no post-procedure complications/stable. In addition, subjects treated or currently 
takening enzyme-inducing anticonvulsant (EIAC) are allowed on study.
7. Part 1: Based on normal HbA1C subjects would be allowed study entry.
9. Any of the following EKG findings:

Baseline QTcF interval ≥450 msec

Any clinically significant ECG assessments should be reviewed by the site 
cardiologist prior to study entry.
10 11. Pulmonary hemoptysis > 1 teaspoon in 24 hours within the last 28 14 days. 
11. History of major gastrointestinal bleeding within the last 6 months. Any evidence of 
active gastrointestinal bleeding. (positive guaiac fecal occult blood test) excludes the 
subject.
Rationale Change 8
The Time and Events tables are modified to ensure consistency of timings and to correct 
errors that occurred during publishing. In addition, guaiac fecal occult blood testing has 
been added to the assessments to check for any evidence of gastrointestinal bleeding.
Section 5.0, Time and Events


2011N118599_09
CONFIDENTIAL
BET115521
175
PREVIOUS TEXT, Table 6: Part 1 – Baseline through Week 6
Time and Events: Table 6
Part 1 – Baseline through Week 6
Assessments for 
Baseline to Week 7
Screen1
W
1, 
D1
W
1, 
D2
W2, D1
W
2,
D2
W2, 
D3
W2, D4 
and D5
W
3, 
D
1
W
3, 
D2
W
3, 
D3
W
3, 
D4
W
3
, 
D
5
W
3, 
D6
an
d 
D7
W
4, 
D1
W
4
, 
D
2
W
4, 
D3
W
4
, 
D
4
W4, 
D5
W
4
, 
D
6
W
4, 
D
7
W
5
, 
D
1
W
6
, 
D
1
Females: Pregnancy Test 2
Males: Testosterone 2
X
X
X
X
Vital Signs (BP, T, Heart Rate, Resp)
X
X
X
X
X
X
X
X
X
X
X
Height and Weight 4
X
X
X
X
X
X
X
Hematology, Clinical Chemistry, 
Pancreatic, Coagulation
X
X
X
X
X
X
X
X
X
X
X
Creatine phosphokinase
X
X
X
X
X
X
X
X
Fasting Blood Glucose;c-peptide; Insulin; 
and 1,5AG 5
X
X
X
X
X
X
X
X
X
X
X
Fasting Lipid Panel, hA1C 
X
X
X
X
X
X
X
X
X
X
X
Urinalysis
X
X
X
X
X
X
X
Thyroid monitoring 6
X
X
X
X
X
X
X


2011N118599_09
CONFIDENTIAL
BET115521
176
Time and Events: Table 6
Part 1 – Baseline through Week 6
Assessments for 
Baseline to Week 7
Screen1
W
1, 
D1
W
1, 
D2
W2, D1
W
2,
D2
W2, 
D3
W2, D4 
and D5
W
3, 
D
1
W
3, 
D2
W
3, 
D3
W
3, 
D4
W
3
, 
D
5
W
3, 
D6
an
d 
D7
W
4, 
D1
W
4
, 
D
2
W
4, 
D3
W
4
, 
D
4
W4, 
D5
W
4
, 
D
6
W
4, 
D
7
W
5
, 
D
1
W
6
, 
D
1
HBsAg and hepatitis C antibody7
X
X
X
ECHO
X
X
Troponin and NT-proBNP 9
X
X8
X8
X
X
X
X
X
CK and CK-MB (12-18 hrs post dose and 
as clinically indicated)
X
12-lead ECG 10,11
X
X
X
X
X10
X
X
X
X1
0
X
X1
0
X
X
X
X
1
0
X
X
1
0
X10
X
X
X
X
Telemetry 10
(starts at least 60mins pre-dose and 
capture at least 48hrs post-dose)
X
48 hrs 9
Response 16
X
PK Blood Sampling (See Table 9)
X
X
X
X
X
X


2011N118599_09
CONFIDENTIAL
BET115521
177
Time and Events: Table 6
Part 1 – Baseline through Week 6
Assessments for 
Baseline to Week 7
Screen1
W
1, 
D1
W
1, 
D2
W2, D1
W
2,
D2
W2, 
D3
W2, D4 
and D5
W
3, 
D
1
W
3, 
D2
W
3, 
D3
W
3, 
D4
W
3
, 
D
5
W
3, 
D6
an
d 
D7
W
4, 
D1
W
4
, 
D
2
W
4, 
D3
W
4
, 
D
4
W4, 
D5
W
4
, 
D
6
W
4, 
D
7
W
5
, 
D
1
W
6
, 
D
1
PK Urine Sampling (See Table 11)
X
X
X
X
X
X
LPS Blood sample (See Table 10)
X
Plasma Sample for Protein Biomarkers 
(See Table 10)
X
X
X
X
X
X
X
X
X
PD Whole Blood sampling 
(mRNA sampling) (See Table 10)
X
X
Footnote 9: Troponin will be performed at the local (troponin I or T) and central lab (troponin I). Note, on Day 1 and Day 2 only the local 
lab assessments for troponin will be collected three times in 24 hours. Central lab assessments for troponin will only collected once on 
Day 1 and Day 2. Any unscheduled troponin assessments will be collected in duplicate for central and local assessments.
Footnote 11. W2 D2, W3 D2, W3 D4, W4 D2, W4 D4, W4 D5 are optional but if there is >30msec increase in QTcF the optional ECG 
days going forward become mandatory. On days when timing of ECGs are not specified in the Table 9 (Example: W2 D3, W3 D5, W4 
D7) these assessments should be taken prior to dosing.
Footnote 12. Drug dispensing: From Day 1 to Wk 6, subjects may be dispensed drug at the clinic or provided drug for home dosing. The 
drug should be ingested in the morning at 8am 2 hours.


2011N118599_09
CONFIDENTIAL
BET115521
178
REVISED TEXT, Table 6 Time and Events: Part 1 – Baseline to Week 6
Table 6
Time and Events: Part 1 – Baseline to Week 6 7(Continued)
Time and Events: Table 6
Part 1 – Baseline through Week 6
Assessments for 
Baseline to Week 7
Screen1
W1, 
D1
W1, 
D2
W1, D3
W2, 
D1
W2,
D2
W2, 
D3
W2, 
D4 
and 
D5
W
3
, 
D
1
W
3
,
D
2
W
3
,
D
3
W
3
,
D
4
W
3
,
D
5
W
3, 
D
6
a
n
d 
D
7
W
4
,
D
1
W
4
,
D
2
W
4, 
D
3
W
4
,
D
4
W4
, 
D5
W
4, 
D6
W4, 
D7
W5, 
D1
W6, 
D1
Females: Pregnancy Test 2
Males: Testosterone 2
X
X
X
X
Vital Signs (BP, T, Heart Rate, 
Resp) and Pain Assessment
X
X
X
X
X
X
X
X
X
X
X
X
Height and Weight 4
X
X
X
X
X
X
X
X
Hematology, Clinical 
Chemistry, Pancreatic, 
Coagulation
X
X
X
X
X
X
X
X
X
X
X
X
Creatine phosphokinase
X
X
X
X
X
X
X
X
X
Fasting Blood Glucose;c-
peptide; Insulin; and 1,5AG 5
X
X
X
X
X
X
X
X
X
X
X
X


2011N118599_09
CONFIDENTIAL
BET115521
179
Time and Events: Table 6
Part 1 – Baseline through Week 6
Assessments for 
Baseline to Week 7
Screen1
W1, 
D1
W1, 
D2
W1, D3
W2, 
D1
W2,
D2
W2, 
D3
W2, 
D4 
and 
D5
W
3
, 
D
1
W
3
,
D
2
W
3
,
D
3
W
3
,
D
4
W
3
,
D
5
W
3, 
D
6
a
n
d 
D
7
W
4
,
D
1
W
4
,
D
2
W
4, 
D
3
W
4
,
D
4
W4
, 
D5
W
4, 
D6
W4, 
D7
W5, 
D1
W6, 
D1
Fasting Lipid Panel, hA1C 
X
X
X
X
X
X
X
X
X
X
X
X
hA1C
X
X
Guaiac fecal occult blood test
X
X
Urinalysis
X
X
X
X
X
X
X
Thyroid monitoring 6
X
X
X
X
X
X
X
HBsAg and hepatitis C 
antibody7
X
X
X
ECHO
X
X
X
Troponin and NT-proBNP 9
X
X89
X89
X
X
X
X
X
X
X
CK and CK-MB (12-18 hrs post 
dose and as clinically 
indicated)
X


2011N118599_09
CONFIDENTIAL
BET115521
180
Time and Events: Table 6
Part 1 – Baseline through Week 6
Assessments for 
Baseline to Week 7
Screen1
W1, 
D1
W1, 
D2
W1, D3
W2, 
D1
W2,
D2
W2, 
D3
W2, 
D4 
and 
D5
W
3
, 
D
1
W
3
,
D
2
W
3
,
D
3
W
3
,
D
4
W
3
,
D
5
W
3, 
D
6
a
n
d 
D
7
W
4
,
D
1
W
4
,
D
2
W
4, 
D
3
W
4
,
D
4
W4
, 
D5
W
4, 
D6
W4, 
D7
W5, 
D1
W6, 
D1
12-lead ECG 10,11
X
X
X
X
X10
X
X
X
X
1
0
X X
1
0
X X
X
X
1
0
X
X
1
0
X10
X
X
X
X
Triplet ECGs at pre-treatment10
X10
X10
X
X
X11
X
X
X
X
X
1
1
X X X
X
X
1
1
X
X
1
1
X11
X
X
X
X
Primary PK day Triplet ECGs 
(see Table 9 for more details, 
ECG timings pre-treatment, 
0.5hr, 1hr, 2hr, 4hr, 8hr) 11
X
Telemetry 10
(starts at least 60mins pre-dose 
and capture at least 48hrs 
post-dose)
X
48 hr9 10
Response 16
X


2011N118599_09
CONFIDENTIAL
BET115521
181
Time and Events: Table 6
Part 1 – Baseline through Week 6
Assessments for 
Baseline to Week 7
Screen1
W1, 
D1
W1, 
D2
W1, D3
W2, 
D1
W2,
D2
W2, 
D3
W2, 
D4 
and 
D5
W
3
, 
D
1
W
3
,
D
2
W
3
,
D
3
W
3
,
D
4
W
3
,
D
5
W
3, 
D
6
a
n
d 
D
7
W
4
,
D
1
W
4
,
D
2
W
4, 
D
3
W
4
,
D
4
W4
, 
D5
W
4, 
D6
W4, 
D7
W5, 
D1
W6, 
D1
PK Blood Sampling (See Table 
8 9)
X
X
X
X
X
X
X
PK Urine Sampling (See Table 
10 11)
X
X
X
X
X
X
LPS Blood sample (See Table 
10 9)
X
X
X
X
X
Plasma Sample for Protein 
Biomarkers (See Table 10 9)
X
X
X
X
X
X
X
X
X
X
X
X
PD Whole Blood sampling 
(mRNA sampling) (See Table 
10 9)
X
X
X
X
Footnote 9. Troponin will be performed at the local (troponin I or T) and central lab (troponin IT). Note, on Day 1 and Day 2 only the 
local lab assessments for troponin will be collected three times in 24 hours. Central lab assessments for troponin will only collected once 
on Day 1 and Day 2. Any unscheduled troponin assessments will be collected in duplicate for central and local assessments.


2011N118599_09
CONFIDENTIAL
BET115521
182
Footnote 11. W2 D2, W3 D2, W3 D4, W4 D2, W4 D4, W4 D5 are optional but if unless there is a >30msec increase in QTcF in which 
case the optional ECG days going forward become mandatory. On days when timing of ECGs are not specified in the See Table 9 for 
more specific details on timing of ECGs on PK sampling days. (Example: W2 D3, W3 D5, W4 D7) these assessments should be taken 
prior to dosing.
Footnote 12. Drug dispensing: From Day 1 to Wk 6, subjects may be dispensed drug at the clinic or provided drug for home dosing. The 
drug should be ingested in the morning at approximately the same time everyday. 8am 2 hours. Subjects will fast for at least one hour 
prior to each dose of study drug. After dosing, subjects should fast for an additional two hours.


2011N118599_09
CONFIDENTIAL
BET115521
183
PREVIOUS TEXT, Time and Events: Table 7 Part 1 – Week 8 until End-of-Study
Time and Events: Table 
7
Week 10 to Week 48
Monthly 
Visit
Every 
other 
month
Every 
three 
months 1
Discharge 
/ 
progressio
n2
Part 1:
Assessments for 
Week 8 until End of 
study
W8, 
D1
W12
, D1
W16
, 
D1
W20
,
D1
W24, 
D1
W28
, 
D1
W32
,
D1
W36,D
1
W40,D
1
W
44
,D
1
Wk 48 
onward 
Every 4 
weeks Until
Discharge/ 
progression 
1
Wk 48 
onward 
Every 
8weeks
Until
Dischar
ge/ 
progres
sion 1
Wk 48 
onward 
Every 
12weeks 
Until
Discharge/ 
progressio
n 1
Follow-up 14
End
SAFETY
Females: Pregnancy Test 
(serum or urine)
X
X
X
X
X
X
X
X
X
X
X
X
Males: Testosterone 
(free)
X
X
X
X
X
X
X
X
X
X
X
X
Physical Examination 3
X
X
X
X
X
X
X
X
X
X
X
X
ECOG Performance 
Status
X
X
X
X
X
X
X
X
X
X
X
X


2011N118599_09
CONFIDENTIAL
BET115521
184
Time and Events: Table 
7
Week 10 to Week 48
Monthly 
Visit
Every 
other 
month
Every 
three 
months 1
Discharge 
/ 
progressio
n2
Part 1:
Assessments for 
Week 8 until End of 
study
W8, 
D1
W12
, D1
W16
, 
D1
W20
,
D1
W24, 
D1
W28
, 
D1
W32
,
D1
W36,D
1
W40,D
1
W
44
,D
1
Wk 48 
onward 
Every 4 
weeks Until
Discharge/ 
progression 
1
Wk 48 
onward 
Every 
8weeks
Until
Dischar
ge/ 
progres
sion 1
Wk 48 
onward 
Every 
12weeks 
Until
Discharge/ 
progressio
n 1
Follow-up 14
End
Vital Signs (BP, HR, T) 
X
X
X
X
X
X
X
X
X
X
X
X
Weight
X
X
X
X
X
X
X
X
X
X
X
X
Hematology/Clinical 
Chemistry, 
Pancreatic
X
X
X
X
X
X
X
X
X
X
X
X
Cytokine Samples
As clinically appropriate
Coagulation
X
X
X
X
X
X
X
X
X
X
X
X
Fasting Blood Glucose 4
X
X
X
X
X
X
X
X
X
X
X
X
Insulin and 1,5 AG 5
X
X
X
X
X
X
X
X
X
X
X
X


2011N118599_09
CONFIDENTIAL
BET115521
185
Time and Events: Table 
7
Week 10 to Week 48
Monthly 
Visit
Every 
other 
month
Every 
three 
months 1
Discharge 
/ 
progressio
n2
Part 1:
Assessments for 
Week 8 until End of 
study
W8, 
D1
W12
, D1
W16
, 
D1
W20
,
D1
W24, 
D1
W28
, 
D1
W32
,
D1
W36,D
1
W40,D
1
W
44
,D
1
Wk 48 
onward 
Every 4 
weeks Until
Discharge/ 
progression 
1
Wk 48 
onward 
Every 
8weeks
Until
Dischar
ge/ 
progres
sion 1
Wk 48 
onward 
Every 
12weeks 
Until
Discharge/ 
progressio
n 1
Follow-up 14
End
Fasting Lipid Panel, 
hA1C
X
X
X
X
X
X
X
X
X
X
X
X
Thyroid monitoring 6
X
X
X
X
X
X
Urinalysis
X
X
X
X
X
X
CARDIOTOXICITY MONITORING
ECHO
X
X
X
X
X
X
X
Troponin and NT-proBNP
8
X
X
X
X
X
X
X
12-lead ECG
X
X
X
X
X
X
X


2011N118599_09
CONFIDENTIAL
BET115521
186
Time and Events: Table 
7
Week 10 to Week 48
Monthly 
Visit
Every 
other 
month
Every 
three 
months 1
Discharge 
/ 
progressio
n2
Part 1:
Assessments for 
Week 8 until End of 
study
W8, 
D1
W12
, D1
W16
, 
D1
W20
,
D1
W24, 
D1
W28
, 
D1
W32
,
D1
W36,D
1
W40,D
1
W
44
,D
1
Wk 48 
onward 
Every 4 
weeks Until
Discharge/ 
progression 
1
Wk 48 
onward 
Every 
8weeks
Until
Dischar
ge/ 
progres
sion 1
Wk 48 
onward 
Every 
12weeks 
Until
Discharge/ 
progressio
n 1
Follow-up 14
End
Holter Monitoring and 
telemetry
As clinically indicated
STUDY DRUGS
Dispense study drugs, 
assess compliance
X
X
X
X
X
X
X
X
X
X
X
PK SAMPLING
PK Blood Sampling (See 
Table 9)
X
PK Urine Sampling (See 
Table 11)
X


2011N118599_09
CONFIDENTIAL
BET115521
187
Time and Events: Table 
7
Week 10 to Week 48
Monthly 
Visit
Every 
other 
month
Every 
three 
months 1
Discharge 
/ 
progressio
n2
Part 1:
Assessments for 
Week 8 until End of 
study
W8, 
D1
W12
, D1
W16
, 
D1
W20
,
D1
W24, 
D1
W28
, 
D1
W32
,
D1
W36,D
1
W40,D
1
W
44
,D
1
Wk 48 
onward 
Every 4 
weeks Until
Discharge/ 
progression 
1
Wk 48 
onward 
Every 
8weeks
Until
Dischar
ge/ 
progres
sion 1
Wk 48 
onward 
Every 
12weeks 
Until
Discharge/ 
progressio
n 1
Follow-up 14
End
PD BLOOD SAMPLING
LPS Blood sample 
Plasma Sample for 
Protein Biomarkers
X
X
X
X
X
X
X
PD Whole Blood 
sampling 
(mRNA sampling) 
X


2011N118599_09
CONFIDENTIAL
BET115521
188
REVISED TEXT, Time and Events: Table 7 Part 1 – Week 710 until End-of-Study
Time and Events: 
Table 7
Part 1 - Week 7 10 to Week 48
Month
ly 
Visit
Every 
other 
month
Ever
y 
three
mont
hs 1
Discharge/ progression2
Part 1:
Assessments for 
Week 7 8 until End of 
study
W7, 
D1
W8, 
D1
W1
2, 
D1
W1
6, 
D1
W2
0,
D1
W24, 
D1
W2
8, 
D1
W3
2,
D1
W36,
D1
W40,
D1
W44,
D1
Wk 48 
onwar
d 
Every 
4 
weeks 
Until
Discha
rge/ 
progre
ssion 1
Wk 48 
onward 
Every 
8weeks
Until
Discha
rge/ 
progre
ssion 1
Wk 
48 
onwa
rd 
Every 
12we
eks 
Until
Disch
arge/ 
progr
essio
n 1
Follow-up 14
End
Females: Pregnancy 
Test (serum or urine)
X
X
X
X
X
X
X
X
X
X
X
X
X
Males: Testosterone 
(free)
X
X
X
X
X
X
X
X
X
X
X
X
X
Physical Examination 3
X
X
X
X
X
X
X
X
X
X
X
X
X


2011N118599_09
CONFIDENTIAL
BET115521
189
Time and Events: 
Table 7
Part 1 - Week 7 10 to Week 48
Month
ly 
Visit
Every 
other 
month
Ever
y 
three
mont
hs 1
Discharge/ progression2
Part 1:
Assessments for 
Week 7 8 until End of 
study
W7, 
D1
W8, 
D1
W1
2, 
D1
W1
6, 
D1
W2
0,
D1
W24, 
D1
W2
8, 
D1
W3
2,
D1
W36,
D1
W40,
D1
W44,
D1
Wk 48 
onwar
d 
Every 
4 
weeks 
Until
Discha
rge/ 
progre
ssion 1
Wk 48 
onward 
Every 
8weeks
Until
Discha
rge/ 
progre
ssion 1
Wk 
48 
onwa
rd 
Every 
12we
eks 
Until
Disch
arge/ 
progr
essio
n 1
Follow-up 14
End
ECOG Performance 
Status
X
X
X
X
X
X
X
X
X
X
X
X
X
Vital Signs (BP, HR, T,
Resp) 
and Pain Assessment
X
X
X
X
X
X
X
X
X
X
X
X
X
Weight
X
X
X
X
X
X
X
X
X
X
X
X
X


2011N118599_09
CONFIDENTIAL
BET115521
190
Time and Events: 
Table 7
Part 1 - Week 7 10 to Week 48
Month
ly 
Visit
Every 
other 
month
Ever
y 
three
mont
hs 1
Discharge/ progression2
Part 1:
Assessments for 
Week 7 8 until End of 
study
W7, 
D1
W8, 
D1
W1
2, 
D1
W1
6, 
D1
W2
0,
D1
W24, 
D1
W2
8, 
D1
W3
2,
D1
W36,
D1
W40,
D1
W44,
D1
Wk 48 
onwar
d 
Every 
4 
weeks 
Until
Discha
rge/ 
progre
ssion 1
Wk 48 
onward 
Every 
8weeks
Until
Discha
rge/ 
progre
ssion 1
Wk 
48 
onwa
rd 
Every 
12we
eks 
Until
Disch
arge/ 
progr
essio
n 1
Follow-up 14
End
Hematology/Clinical 
Chemistry, Pancreatic
X
X
X
X
X
X
X
X
X
X
X
X
X
Cytokine Samples
X
As clinically appropriate
Guaiac fecal occult 
blood test
X
X
X
As clinically appropriate


2011N118599_09
CONFIDENTIAL
BET115521
191
Time and Events: 
Table 7
Part 1 - Week 7 10 to Week 48
Month
ly 
Visit
Every 
other 
month
Ever
y 
three
mont
hs 1
Discharge/ progression2
Part 1:
Assessments for 
Week 7 8 until End of 
study
W7, 
D1
W8, 
D1
W1
2, 
D1
W1
6, 
D1
W2
0,
D1
W24, 
D1
W2
8, 
D1
W3
2,
D1
W36,
D1
W40,
D1
W44,
D1
Wk 48 
onwar
d 
Every 
4 
weeks 
Until
Discha
rge/ 
progre
ssion 1
Wk 48 
onward 
Every 
8weeks
Until
Discha
rge/ 
progre
ssion 1
Wk 
48 
onwa
rd 
Every 
12we
eks 
Until
Disch
arge/ 
progr
essio
n 1
Follow-up 14
End
Coagulation and 
Creatine phosphokinase
X
X
X
X
X
X
X
X
X
X
X
X
X
Fasting Blood Glucose 4
X
X
X
X
X
X
X
X
X
X
X
X
X
C-peptide, Insulin and 
1,5 AG 5
X
X
X
X
X
X
X
X
X
X
X
X
X


2011N118599_09
CONFIDENTIAL
BET115521
192
Time and Events: 
Table 7
Part 1 - Week 7 10 to Week 48
Month
ly 
Visit
Every 
other 
month
Ever
y 
three
mont
hs 1
Discharge/ progression2
Part 1:
Assessments for 
Week 7 8 until End of 
study
W7, 
D1
W8, 
D1
W1
2, 
D1
W1
6, 
D1
W2
0,
D1
W24, 
D1
W2
8, 
D1
W3
2,
D1
W36,
D1
W40,
D1
W44,
D1
Wk 48 
onwar
d 
Every 
4 
weeks 
Until
Discha
rge/ 
progre
ssion 1
Wk 48 
onward 
Every 
8weeks
Until
Discha
rge/ 
progre
ssion 1
Wk 
48 
onwa
rd 
Every 
12we
eks 
Until
Disch
arge/ 
progr
essio
n 1
Follow-up 14
End
Fasting Lipid Panel, 
hA1C
X
X
X
X
X
X
X
X
X
X
X
X
X
hA1C
X
X
X
X
X
X
X
X
Thyroid monitoring 6
X
X
X
X
X
X
X
X
X
Urinalysis
X
X
X
X
X
X
X


2011N118599_09
CONFIDENTIAL
BET115521
193
Time and Events: 
Table 7
Part 1 - Week 7 10 to Week 48
Month
ly 
Visit
Every 
other 
month
Ever
y 
three
mont
hs 1
Discharge/ progression2
Part 1:
Assessments for 
Week 7 8 until End of 
study
W7, 
D1
W8, 
D1
W1
2, 
D1
W1
6, 
D1
W2
0,
D1
W24, 
D1
W2
8, 
D1
W3
2,
D1
W36,
D1
W40,
D1
W44,
D1
Wk 48 
onwar
d 
Every 
4 
weeks 
Until
Discha
rge/ 
progre
ssion 1
Wk 48 
onward 
Every 
8weeks
Until
Discha
rge/ 
progre
ssion 1
Wk 
48 
onwa
rd 
Every 
12we
eks 
Until
Disch
arge/ 
progr
essio
n 1
Follow-up 14
End
CARDIOTOXICITY MONITORING
ECHO
X
X
X
X
X
X
X
X
X
Troponin and NT-
proBNP 8
X
X
X
X
X
X
X
X
X
Triplet ECGs at pre-
treatment
X
X
X
X
X
X
X
X
X
X
X
X


2011N118599_09
CONFIDENTIAL
BET115521
194
Time and Events: 
Table 7
Part 1 - Week 7 10 to Week 48
Month
ly 
Visit
Every 
other 
month
Ever
y 
three
mont
hs 1
Discharge/ progression2
Part 1:
Assessments for 
Week 7 8 until End of 
study
W7, 
D1
W8, 
D1
W1
2, 
D1
W1
6, 
D1
W2
0,
D1
W24, 
D1
W2
8, 
D1
W3
2,
D1
W36,
D1
W40,
D1
W44,
D1
Wk 48 
onwar
d 
Every 
4 
weeks 
Until
Discha
rge/ 
progre
ssion 1
Wk 48 
onward 
Every 
8weeks
Until
Discha
rge/ 
progre
ssion 1
Wk 
48 
onwa
rd 
Every 
12we
eks 
Until
Disch
arge/ 
progr
essio
n 1
Follow-up 14
End
Primary PK day Triplet 
ECGs 
(see Table 9 for more 
details, 
ECG timing pre-
treatment, 0.5hr, 
1hr, 2hr, 4hr, 8hr)
X


2011N118599_09
CONFIDENTIAL
BET115521
195
Time and Events: 
Table 7
Part 1 - Week 7 10 to Week 48
Month
ly 
Visit
Every 
other 
month
Ever
y 
three
mont
hs 1
Discharge/ progression2
Part 1:
Assessments for 
Week 7 8 until End of 
study
W7, 
D1
W8, 
D1
W1
2, 
D1
W1
6, 
D1
W2
0,
D1
W24, 
D1
W2
8, 
D1
W3
2,
D1
W36,
D1
W40,
D1
W44,
D1
Wk 48 
onwar
d 
Every 
4 
weeks 
Until
Discha
rge/ 
progre
ssion 1
Wk 48 
onward 
Every 
8weeks
Until
Discha
rge/ 
progre
ssion 1
Wk 
48 
onwa
rd 
Every 
12we
eks 
Until
Disch
arge/ 
progr
essio
n 1
Follow-up 14
End
12-lead ECG
X
X
X
X
X
X
X
X
Holter Monitoring and 
telemetry
X
As clinically appropriate
Telemetry
As clinically appropriate


2011N118599_09
CONFIDENTIAL
BET115521
196
Time and Events: 
Table 7
Part 1 - Week 7 10 to Week 48
Month
ly 
Visit
Every 
other 
month
Ever
y 
three
mont
hs 1
Discharge/ progression2
Part 1:
Assessments for 
Week 7 8 until End of 
study
W7, 
D1
W8, 
D1
W1
2, 
D1
W1
6, 
D1
W2
0,
D1
W24, 
D1
W2
8, 
D1
W3
2,
D1
W36,
D1
W40,
D1
W44,
D1
Wk 48 
onwar
d 
Every 
4 
weeks 
Until
Discha
rge/ 
progre
ssion 1
Wk 48 
onward 
Every 
8weeks
Until
Discha
rge/ 
progre
ssion 1
Wk 
48 
onwa
rd 
Every 
12we
eks 
Until
Disch
arge/ 
progr
essio
n 1
Follow-up 14
End
STUDY DRUGS
Dispense study drugs, 
assess compliance
X
X
X
X
X
X
X
X
X
X
X
X
PK SAMPLING
PK Blood Sampling (See 
Table 9)
X


2011N118599_09
CONFIDENTIAL
BET115521
197
Time and Events: 
Table 7
Part 1 - Week 7 10 to Week 48
Month
ly 
Visit
Every 
other 
month
Ever
y 
three
mont
hs 1
Discharge/ progression2
Part 1:
Assessments for 
Week 7 8 until End of 
study
W7, 
D1
W8, 
D1
W1
2, 
D1
W1
6, 
D1
W2
0,
D1
W24, 
D1
W2
8, 
D1
W3
2,
D1
W36,
D1
W40,
D1
W44,
D1
Wk 48 
onwar
d 
Every 
4 
weeks 
Until
Discha
rge/ 
progre
ssion 1
Wk 48 
onward 
Every 
8weeks
Until
Discha
rge/ 
progre
ssion 1
Wk 
48 
onwa
rd 
Every 
12we
eks 
Until
Disch
arge/ 
progr
essio
n 1
Follow-up 14
End
PK Urine Sampling (See 
Table 11)
X
PD BLOOD SAMPLING
LPS Blood sample 


2011N118599_09
CONFIDENTIAL
BET115521
198
Time and Events: 
Table 7
Part 1 - Week 7 10 to Week 48
Month
ly 
Visit
Every 
other 
month
Ever
y 
three
mont
hs 1
Discharge/ progression2
Part 1:
Assessments for 
Week 7 8 until End of 
study
W7, 
D1
W8, 
D1
W1
2, 
D1
W1
6, 
D1
W2
0,
D1
W24, 
D1
W2
8, 
D1
W3
2,
D1
W36,
D1
W40,
D1
W44,
D1
Wk 48 
onwar
d 
Every 
4 
weeks 
Until
Discha
rge/ 
progre
ssion 1
Wk 48 
onward 
Every 
8weeks
Until
Discha
rge/ 
progre
ssion 1
Wk 
48 
onwa
rd 
Every 
12we
eks 
Until
Disch
arge/ 
progr
essio
n 1
Follow-up 14
End
Plasma Sample for 
Protein Biomarkers (Pre-
dose)
X
X
X
X
X
X
X
PD Whole Blood 
sampling 
(mRNA sampling) 
X


2011N118599_09
CONFIDENTIAL
BET115521
199
Footnote 8. Troponin will be performed at the local (troponin I or T) and central lab (troponin T I).
Footnote 15. The drug should be ingested in the morning at approximately the same time every day. 8am 2 hours. Subjects will fast for 
at least one hour prior to each dose of study drug. After dosing, subjects should fast for an additional two hours.


2011N118599_09
CONFIDENTIAL
BET115521
200
Time and 
Events: Table 7
Part 1 - Week 7 10 to Week 48
Monthl
y Visit
Every 
other 
month
Every 
three
months 
1
Discharge/ progression2
Part 1:
Assessments 
for 
Week 7 8 until 
End of study
W7, 
D1
W8, 
D1
W12, 
D1
W16, 
D1
W2
0,
D1
W24, 
D1
W2
8, 
D1
W32,
D1
W36,
D1
W40,
D1
W44,
D1
Wk 48 
onward 
Every 4 
weeks 
Until
Dischar
ge/ 
progre
ssion 1
Wk 48 
onward 
Every 
8weeks
Until
Discharg
e/ 
progress
ion 1
Wk 48 
onward 
Every 
12weeks 
Until
Discharg
e/ 
progress
ion 1
Follow-up 14
End
Females: 
Pregnancy Test 
(serum or urine)
X
X
X
X
X
X
X
X
X
X
X
X
X
Males: 
Testosterone 
(free)
X
X
X
X
X
X
X
X
X
X
X
X
X
Physical 
Examination 3
X
X
X
X
X
X
X
X
X
X
X
X
X
ECOG 
Performance 
Status
X
X
X
X
X
X
X
X
X
X
X
X
X


2011N118599_09
CONFIDENTIAL
BET115521
201
Time and 
Events: Table 7
Part 1 - Week 7 10 to Week 48
Monthl
y Visit
Every 
other 
month
Every 
three
months 
1
Discharge/ progression2
Part 1:
Assessments 
for 
Week 7 8 until 
End of study
W7, 
D1
W8, 
D1
W12, 
D1
W16, 
D1
W2
0,
D1
W24, 
D1
W2
8, 
D1
W32,
D1
W36,
D1
W40,
D1
W44,
D1
Wk 48 
onward 
Every 4 
weeks 
Until
Dischar
ge/ 
progre
ssion 1
Wk 48 
onward 
Every 
8weeks
Until
Discharg
e/ 
progress
ion 1
Wk 48 
onward 
Every 
12weeks 
Until
Discharg
e/ 
progress
ion 1
Follow-up 14
End
Vital Signs (BP, 
HR, T, Resp) 
and Pain 
Assessment
X
X
X
X
X
X
X
X
X
X
X
X
X
Weight
X
X
X
X
X
X
X
X
X
X
X
X
X
Hematology/Clini
cal Chemistry, 
Pancreatic
X
X
X
X
X
X
X
X
X
X
X
X
X
Cytokine 
Samples
X
As clinically appropriate


2011N118599_09
CONFIDENTIAL
BET115521
202
Time and 
Events: Table 7
Part 1 - Week 7 10 to Week 48
Monthl
y Visit
Every 
other 
month
Every 
three
months 
1
Discharge/ progression2
Part 1:
Assessments 
for 
Week 7 8 until 
End of study
W7, 
D1
W8, 
D1
W12, 
D1
W16, 
D1
W2
0,
D1
W24, 
D1
W2
8, 
D1
W32,
D1
W36,
D1
W40,
D1
W44,
D1
Wk 48 
onward 
Every 4 
weeks 
Until
Dischar
ge/ 
progre
ssion 1
Wk 48 
onward 
Every 
8weeks
Until
Discharg
e/ 
progress
ion 1
Wk 48 
onward 
Every 
12weeks 
Until
Discharg
e/ 
progress
ion 1
Follow-up 14
End
Guaiac fecal 
occult blood test
X
X
X
As clinically appropriate
Coagulation and 
Creatine 
phosphokinase
X
X
X
X
X
X
X
X
X
X
X
X
X
Fasting Blood 
Glucose 4
X
X
X
X
X
X
X
X
X
X
X
X
X
C-peptide, Insulin 
and 1,5 AG 5
X
X
X
X
X
X
X
X
X
X
X
X
X


2011N118599_09
CONFIDENTIAL
BET115521
203
Time and 
Events: Table 7
Part 1 - Week 7 10 to Week 48
Monthl
y Visit
Every 
other 
month
Every 
three
months 
1
Discharge/ progression2
Part 1:
Assessments 
for 
Week 7 8 until 
End of study
W7, 
D1
W8, 
D1
W12, 
D1
W16, 
D1
W2
0,
D1
W24, 
D1
W2
8, 
D1
W32,
D1
W36,
D1
W40,
D1
W44,
D1
Wk 48 
onward 
Every 4 
weeks 
Until
Dischar
ge/ 
progre
ssion 1
Wk 48 
onward 
Every 
8weeks
Until
Discharg
e/ 
progress
ion 1
Wk 48 
onward 
Every 
12weeks 
Until
Discharg
e/ 
progress
ion 1
Follow-up 14
End
Fasting Lipid 
Panel, hA1C
X
X
X
X
X
X
X
X
X
X
X
X
X
hA1C
X
X
X
X
X
X
X
X
Thyroid 
monitoring 6
X
X
X
X
X
X
X
X
X
Urinalysis
X
X
X
X
X
X
X
CARDIOTOXICITY MONITORING
ECHO
X
X
X
X
X
X
X
X
X


2011N118599_09
CONFIDENTIAL
BET115521
204
Time and 
Events: Table 7
Part 1 - Week 7 10 to Week 48
Monthl
y Visit
Every 
other 
month
Every 
three
months 
1
Discharge/ progression2
Part 1:
Assessments 
for 
Week 7 8 until 
End of study
W7, 
D1
W8, 
D1
W12, 
D1
W16, 
D1
W2
0,
D1
W24, 
D1
W2
8, 
D1
W32,
D1
W36,
D1
W40,
D1
W44,
D1
Wk 48 
onward 
Every 4 
weeks 
Until
Dischar
ge/ 
progre
ssion 1
Wk 48 
onward 
Every 
8weeks
Until
Discharg
e/ 
progress
ion 1
Wk 48 
onward 
Every 
12weeks 
Until
Discharg
e/ 
progress
ion 1
Follow-up 14
End
Troponin and NT-
proBNP 8
X
X
X
X
X
X
X
X
X
Triplet ECGs at 
pre-treatment
X
X
X
X
X
X
X
X
X
X
X
X


2011N118599_09
CONFIDENTIAL
BET115521
205
Time and 
Events: Table 7
Part 1 - Week 7 10 to Week 48
Monthl
y Visit
Every 
other 
month
Every 
three
months 
1
Discharge/ progression2
Part 1:
Assessments 
for 
Week 7 8 until 
End of study
W7, 
D1
W8, 
D1
W12, 
D1
W16, 
D1
W2
0,
D1
W24, 
D1
W2
8, 
D1
W32,
D1
W36,
D1
W40,
D1
W44,
D1
Wk 48 
onward 
Every 4 
weeks 
Until
Dischar
ge/ 
progre
ssion 1
Wk 48 
onward 
Every 
8weeks
Until
Discharg
e/ 
progress
ion 1
Wk 48 
onward 
Every 
12weeks 
Until
Discharg
e/ 
progress
ion 1
Follow-up 14
End
Primary PK day 
Triplet ECGs 
(see Table 9 for 
more details, 
ECG timing pre-
treatment, 0.5hr, 
1hr, 2hr, 4hr, 8hr)
X
12-lead ECG
X
X
X
X
X
X
X
X


2011N118599_09
CONFIDENTIAL
BET115521
206
Time and 
Events: Table 7
Part 1 - Week 7 10 to Week 48
Monthl
y Visit
Every 
other 
month
Every 
three
months 
1
Discharge/ progression2
Part 1:
Assessments 
for 
Week 7 8 until 
End of study
W7, 
D1
W8, 
D1
W12, 
D1
W16, 
D1
W2
0,
D1
W24, 
D1
W2
8, 
D1
W32,
D1
W36,
D1
W40,
D1
W44,
D1
Wk 48 
onward 
Every 4 
weeks 
Until
Dischar
ge/ 
progre
ssion 1
Wk 48 
onward 
Every 
8weeks
Until
Discharg
e/ 
progress
ion 1
Wk 48 
onward 
Every 
12weeks 
Until
Discharg
e/ 
progress
ion 1
Follow-up 14
End
Holter Monitoring 
and telemetry
X
As clinically appropriate
Telemetry
As clinically appropriate
STUDY DRUGS
Dispense study 
drugs, assess 
compliance
X
X
X
X
X
X
X
X
X
X
X
X
PK SAMPLING


2011N118599_09
CONFIDENTIAL
BET115521
207
Time and 
Events: Table 7
Part 1 - Week 7 10 to Week 48
Monthl
y Visit
Every 
other 
month
Every 
three
months 
1
Discharge/ progression2
Part 1:
Assessments 
for 
Week 7 8 until 
End of study
W7, 
D1
W8, 
D1
W12, 
D1
W16, 
D1
W2
0,
D1
W24, 
D1
W2
8, 
D1
W32,
D1
W36,
D1
W40,
D1
W44,
D1
Wk 48 
onward 
Every 4 
weeks 
Until
Dischar
ge/ 
progre
ssion 1
Wk 48 
onward 
Every 
8weeks
Until
Discharg
e/ 
progress
ion 1
Wk 48 
onward 
Every 
12weeks 
Until
Discharg
e/ 
progress
ion 1
Follow-up 14
End
PK Blood 
Sampling (See 
Table 9)
X
PK Urine 
Sampling (See 
Table 11)
X
PD BLOOD 
SAMPLING
LPS Blood 
sample 


2011N118599_09
CONFIDENTIAL
BET115521
208
Time and 
Events: Table 7
Part 1 - Week 7 10 to Week 48
Monthl
y Visit
Every 
other 
month
Every 
three
months 
1
Discharge/ progression2
Part 1:
Assessments 
for 
Week 7 8 until 
End of study
W7, 
D1
W8, 
D1
W12, 
D1
W16, 
D1
W2
0,
D1
W24, 
D1
W2
8, 
D1
W32,
D1
W36,
D1
W40,
D1
W44,
D1
Wk 48 
onward 
Every 4 
weeks 
Until
Dischar
ge/ 
progre
ssion 1
Wk 48 
onward 
Every 
8weeks
Until
Discharg
e/ 
progress
ion 1
Wk 48 
onward 
Every 
12weeks 
Until
Discharg
e/ 
progress
ion 1
Follow-up 14
End
Plasma Sample 
for 
Protein 
Biomarkers (Pre-
dose)
X
X
X
X
X
X
X
PD Whole Blood 
sampling 
(mRNA sampling) 
X


2011N118599_09
CONFIDENTIAL
BET115521
209
PREVIOUS TEXT, Time and Events Table 8 Part 2
Time and Events: Table 8
Month 1 1
Month 
2
Month 
3
Month 
4
Monthly 
Visit
Every other 
month
Every three 
months
Discharge
/ progression1
Part 2:
Assessments 
Screening
W1 
D1
W1
D3 
or 
D4 
or 
D5
W2
D1
W2
D3 
or 
D4 
or 
D5
W3
D1
W4 D1
W8,
D1
W12,
D1
W16, 
D1
Wk 20 
onward
Every
4 weeks 
until
Discharge/ 
progression1
Wk 20 
onward
Every 
8weeks until
Discharge/ 
progression1
Wk 20 
onward
Every 
12weeks 
until
Discharge/ 
progression1
Follow-up 2
End
Fasting Lipid Panel, hA1C
X
X
X
X
X
X
X
Urinalysis
X
X
X
X
X
X
X
X
ECHO
X
X
X
X
X
X
X
Troponin and NT-proBNP 11
X
X
X
X
X
X
X
X
X
X
X
12-lead ECG
X
X
X
X
X
X
X
X
X
X
Holter Monitoring
X
PK Urine Sampling 
(See Table 11)
X
X
Disease characteristics
X
Footnote 11. Troponin will be performed at the local (troponin I or T) and central lab (troponin TI).


2011N118599_09
CONFIDENTIAL
BET115521
210
REVISED TEXT, Time and Events Table 8 - Part 2
Time and Events: Table 8 – Part 2
Time and Events: Table 8
Month 1 1
Month 
2
Month 
3
Month 
4
Monthly 
Visit
Every other 
month
Every three 
months
Discharge/ progression1
Part 2:
Assessments 
Screening
W1 
D1
W1
D3 
or 
D4 
or 
D5
W2
D1
W2
D3 
or 
D4 
or 
D5
W3
D1
W4 D1
W8,
D1
W12,
D1
W16, 
D1
Wk 20 
onward
Every
4 weeks 
until
Discharge/ 
progression1
Wk 20 
onward
Every 
8weeks until
Discharge/ 
progression1
Wk 20 
onward
Every 
12weeks 
until
Discharge/ 
progression1
Follow-up 2
End
Fasting Lipid Panel, hA1C
X
X
X
X
X
X
X
hA1C
X
X
X
X
X
X
X
Urinalysis
X
X
X
X
X
X
X
X
ECHO
X
X
X
X
X
X
X
X
Troponin and NT-proBNP 11
X
X
X
X
X
X
X
X
X
X
X
12-lead ECG
X
X
X
X
X
X
X
X
X
X
Holter Monitoring
X
X
As clinically indiciated
Telemetry (24hr monitoring)
X
As clinically indicated


2011N118599_09
CONFIDENTIAL
BET115521
211
Time and Events: Table 8 – Part 2
Time and Events: Table 8
Month 1 1
Month 
2
Month 
3
Month 
4
Monthly 
Visit
Every other 
month
Every three 
months
Discharge/ progression1
Part 2:
Assessments 
Screening
W1 
D1
W1
D3 
or 
D4 
or 
D5
W2
D1
W2
D3 
or 
D4 
or 
D5
W3
D1
W4 D1
W8,
D1
W12,
D1
W16, 
D1
Wk 20 
onward
Every
4 weeks 
until
Discharge/ 
progression1
Wk 20 
onward
Every 
8weeks until
Discharge/ 
progression1
Wk 20 
onward
Every 
12weeks 
until
Discharge/ 
progression1
Follow-up 2
End
PK Urine Sampling 
(See Table 11)
X
X
Disease characteristics
X
Footnote 11. Troponin will be performed at the local (troponin I or T) and central lab (troponin TI).
Footnote 18. The drug should be ingested in the morning at approximately the same time every day. 8am 2 hours. Subjects will fast for 
at least one hour prior to each dose of study drug. After dosing, subjects should fast for an additional two hours.


2011N118599_09
CONFIDENTIAL
BET115521
212
PREVIOUS TEXT, Table 9 Time and Events for Pharmacokinetics Part 1
Table 9: Time and Events Table for Pharmacokinetics Part 1
Plasma Pharmacokinetics (PK)
Within 60 
minutes 
prior to 
dose
Baseline
Timings Post Dose
0hr
PK
0.5 hr
5 mins
PK
1hr
5 mins
PK
2hr
10 mins
PK
4hr
15 mins
PK
8hr
15 mins
Week 1 Day 1 PK Sample
X
X
X
X
X
X
Week 1 Day 1 Urine Sample (see Table 10)
Urine sample 0-2hrs
Urine sample 2-24hrs
Week 1 Day 1 Safety Labs (see Table 8)
X
Week 1 Day 1 LPS blood samples (whole blood transcriptional panel)1
X
X
X
X
Week 1 Day 1 PD Whole Blood sampling (mRNA sampling)
X
X
X
X
Week 1 Day 1 ECG (triplicate readings 5 mins apart +/10 mins of PK 
sample) 1
X
X
X
X
Week 1 Day 1 Investigational Product dose
X
Week 1 Day 2 PK Sample
(this sample is 24hr 1hr after Wk1 D1 dose)
X
Week 1 Day 2 LPS blood samples 
(this sample is 24hr 1hr after Wk1 D1 dose)
X
Week 1 Day 2 PD Whole Blood sampling (mRNA sampling)
(this sample is 24hr 1hr after Wk1 D1 dose)
X
Week 1 Day 3 PK Sample
(this sample is 48hr 1hr after Wk1 D1 dose)
X
Week 1 Day 3 PD Whole Blood sampling (mRNA sampling)
(this sample is 48hr - 1hr after Wk1 D1 dose)
X
Week 4 Day 6 PK sample
X
X
X
X
X
X
Week 4 Day 6 LPS blood samples (whole blood transcriptional panel)1
X
X
X
Week 4 Day 7 PK Sample 
(this sample is 24hr 1hr after Wk4 D6 dose)
X
Week 4 Day 7 LPS blood samples (whole blood transcriptional panel)1
X
X
X
Week 5, Day 1 PK Sample
(this sample is 48hr - 1hr after Wk4 D6 dose)
X


2011N118599_09
CONFIDENTIAL
BET115521
213
Table 9: Time and Events Table for Pharmacokinetics Part 1
Plasma Pharmacokinetics (PK)
Within 60 
minutes 
prior to 
dose
Baseline
Timings Post Dose
0hr
PK
0.5 hr
5 mins
PK
1hr
5 mins
PK
2hr
10 mins
PK
4hr
15 mins
PK
8hr
15 mins
Safety Labs 
X
ECG (triplicate readings 5 mins apart +/10 of PK sample)
X
X
X
X
X
X
Investigational Product dose
X
Week 8 Day 1 
X
Single draw between 
0.5-2 hr
Single draw between 
4-8 hr
Safety Labs 
X
ECG (triplicate readings 5 mins apart +/10 of PK sample)
X
between 0.5-2 hr
between 4-8 hr
Investigational Product dose
X
Footnote 1: LPS and PD whole blood timing may be adjusted based on pharmacokinetic profile observed in the patient cohorts. The 
timing adjustment may shift to be closer to Tmax. For example, LPS samples could be 1hr 5 mins, 2hr -10mins and 4 hrs 15 mins. 
The shift in timing would be determined during a dose escalation meeting or safety review meeting and circulated in the minutes to the 
investigators to address the new timings.


2011N118599_09
CONFIDENTIAL
BET115521
214
REVISED TEXT, Table 9 Time and Events: Pharmacokinetics and Biomarker Sampling for Part 1
Table 9: Time and Events Table for Pharmacokinetics and Biomarker Sampling for Part 1
Plasma Pharmacokinetics (PK) and Biomarker Sampling
Within 60 minutes 
prior to dose
Baseline
Timings Post Dose
0hr
PK
0.5 hr
5 mins
PK
1hr
5 mins
PK
2hr
10 mins
PK
4hr
15 mins
PK
8hr
15 mins
Screening visit: Plasma Sample for Protein Biomarkers
(collect at anytime at screening visit as no dose is given)
X (collect at anytime 
during screening 
visit)
Screening visit: PD Whole Blood sampling (mRNA sampling)
(collect at anytime at screening visit as no dose is given)
X (collect at anytime 
during screening 
visit)
Week 1 Day 1 ECG (triplicate readings 5 mins apart +/10 mins of PK 
sample) 1, 3
X
X
X
X
X
X
Week 1 Day 1 PK Urine Sample (see Table 11 10)
Urine sample 0-2hrs
Urine sample 2-24hrs
Week 1 Day 1 Safety Labs (see Table 8)
X
Week 1 Day 1 Plasma Sample for Protein Biomarkers
X
Week 1 Day 1 LPS blood samples (whole blood transcriptional panel)1
X
X
X
X
Week 1 Day 1 PD Whole Blood sampling (mRNA sampling)
X
X
X
X
Week 1 Day 1 PK Sample
X
X
X
X
X
X
Week 1 Day 1 Investigational Product dose
X
Week 1 Day 2 PK Sample (this sample is 24hr 1hr after Wk1 D1 dose)
X
Week 1 Day 2 Plasma Sample for Protein Biomarkers
X
Week 1 Day 2 LPS blood samples 
(this sample is 24hr 1hr after Wk1 D1 dose)
X
Week 1 Day 2 PD Whole Blood sampling (mRNA sampling)
(this sample is 24hr 1hr after Wk1 D1 dose)
X
Week 1 Day 3 Plasma Sample for Protein Biomarkers
(this sample is 48hr 1hr after Wk1 D1 dose)
X
Week 1 Day 3 PK Sample
(this sample is 48hr 1hr after Wk1 D1 dose)
X


2011N118599_09
CONFIDENTIAL
BET115521
215
Table 9: Time and Events Table for Pharmacokinetics and Biomarker Sampling for Part 1
Plasma Pharmacokinetics (PK) and Biomarker Sampling
Within 60 minutes 
prior to dose
Baseline
Timings Post Dose
0hr
PK
0.5 hr
5 mins
PK
1hr
5 mins
PK
2hr
10 mins
PK
4hr
15 mins
PK
8hr
15 mins
Week 1 Day 3 PD Whole Blood sampling (mRNA sampling)
(this sample is 48hr - 1hr after Wk1 D1 dose)
X
Week 2 Days 1, 4, and 5 Plasma Sample for Protein Biomarkers
Week 3 Days 1, 6 and 7 Plasma Sample for Protein Biomarkers
Week 4 Day 1 Plasma Sample for Protein Biomarkers
X
Week 4 Day 6 ECG (triplicate readings 5 mins apart +/10 of PK sample) 3
X
X
X
X
X
X
Week 4 Day 6 PK sample
X
X
X
X
X
X
Week 4 Day 6 Safety Labs (see Table 8)
X
Week 4 Day 6 Plasma Sample for Protein Biomarkers
X
Week 4 Day 6 LPS blood samples (whole blood transcriptional panel)3
X
X
X
Week 4 Day 6 Investigational Product dose
X
Week 4 Day 7 PK Sample 
(this sample is 24hr 1hr after Wk4 D6 dose)
X
Week 4 Day 7 Plasma Sample for Protein Biomarkers
X
Week 4 Day 7 LPS blood samples (whole blood transcriptional panel)1
X
X
X
X
Week 5, Day 1 PK Sample
(this sample is 48hr - 1hr after Wk4 D6 dose)
X
Week 5 Day 1 Plasma Sample for Protein Biomarkers
(this sample is 48hr - 1hr after Wk4 D6 dose)
X
Week 8 Day 1 PK Blood Sample
X
Single draw between 
0.5-2 hr
Single draw between 
4-8 hr


2011N118599_09
CONFIDENTIAL
BET115521
216
Table 9: Time and Events Table for Pharmacokinetics and Biomarker Sampling for Part 1
Plasma Pharmacokinetics (PK) and Biomarker Sampling
Within 60 minutes 
prior to dose
Baseline
Timings Post Dose
0hr
PK
0.5 hr
5 mins
PK
1hr
5 mins
PK
2hr
10 mins
PK
4hr
15 mins
PK
8hr
15 mins
Week 1 Day 1 PK Urine Sample (see Table 11 10)
X
Urine sample 0-2hrs
Urine sample 2-24hrs
Safety Labs (see Table 8)
X
Week 8 Day 1 ECG (triplicate readings 5 mins apart +/10 of PK sample) 3
X
between 0.5-2 hr
between 4-8 hr
Week 8 Day 1 Investigational Product dose
X
Footnote 1: LPS and PD whole blood timing may be adjusted based on pharmacokinetic profile observed in the patient cohorts. The 
timing adjustment may shift to be closer to Tmax. For example, LPS samples could be 1hr 5 mins, 2hr -10mins and 4 hrs 15 mins. 
The shift in timing would be determined during a dose escalation meeting or safety review meeting and circulated in the minutes to the 
investigators to address the new timings.
Footnote 2: PK sampling should be completed within 10mins following ECGs in a consistent manner from visit to visit.


2011N118599_09
CONFIDENTIAL
BET115521
217
PREVIOUS TEXT, Table 10 Time and Events: Pharmacokinetics and Biomarker Sampling for Part 2
Time and Events Table 10, Part 2
Baseline
Timings Post Dose
Within 60 minutes 
prior to dose
0hr
PK
0.5 Hr
PK
1hr
PK
2hr
PK
4hr
PK
8hr
Week 2, Day 1 PK Sample
X
Single draw
Between
0.5-2hr
Single draw
Between
4-8hr
Week 2 Day 1 LPS blood samples (whole blood transcriptional panel)1
X
Single draw
Between
0.5-2hr
Single draw
Between
4-8hr
Week 2 Day 1 Plasma Sample for Protein Biomarkers
X
Week 2 Day 1 PD Whole Blood sampling (mRNA sampling)
X
Single draw
Between
0.5-2hr
Single draw
Between
4-8hr
Safety Labs (see Table 6.)
X
Investigational Product dose
X
Week 8, Day 1 PK Sample
X
Single draw
Between
0.5-2hr
Single draw
Between
4-8hr
Safety Labs (see Table 6.)
X
Investigational Product dose
X


2011N118599_09
CONFIDENTIAL
BET115521
218
PREVIOUS TEXT, Table 10
PREVIOUS TEXT, Table 10 Time and Events: Pharmacokinetics for Part 2
Tiem and Events Table 10, Part 2
Baseline
Timings Post Dose
Within 60 minutes 
prior to dose
0hr
PK
0.5 Hr
PK
1hr
PK
2hr
PK
4hr
PK
8hr
Week 2, Day 1 PK Sample
X
Single draw
Between
0.5-2hr
Single draw
Between
4-8hr
Week 2 Day 1 LPS blood samples (whole blood transcriptional panel)1
X
Single draw
Between
0.5-2hr
Single draw
Between
4-8hr
Week 2 Day 1 Plasma Sample for Protein Biomarkers
X
Week 2 Day 1 PD Whole Blood sampling (mRNA sampling)
X
Single draw
Between
0.5-2hr
Single draw
Between
4-8hr
Safety Labs (See Table 6)
X
Investigational Product dose
X
Week 8, Day 1 PK Sample
X
Single draw
Between
0.5-2hr
Single draw
Between
4-8hr
Safety Labs (See Table 6)
X
Investigational Product dose
X


2011N118599_09
CONFIDENTIAL
BET115521
219
REVISED TEXT, Table 10 Time and Events: Pharmacokinetics and Biomarkers Sampling for Part 2
Table 10 Time and Events: Pharmacokinetics and Biomarker Sampling for Part 2
Tiem and Events Table 10, Part 2
Baseline
Timings Post Dose
Time and Events
Within 60 minutes 
prior to dose
0hr
PK
0.5 Hr
PK
1hr
PK
2hr
PK
4hr
PK
8hr
Week 2, Day 1 PK Sample
X
Single draw
Between
0.5-2hr
Single draw
Between
4-8hr
Week 2 Day 1 LPS blood samples (whole blood transcriptional panel)1
X
Single draw
Between
0.5-2hr
Single draw
Between
4-8hr
Week 2 Day 1 Plasma Sample for Protein Biomarkers
X
Week 2 Day 1 PD Whole Blood sampling (mRNA sampling)
X
Single draw
Between
0.5-2hr
Single draw
Between
4-8hr
Safety blood sampling1 Safety Labs (see Table 6)
X
Investigational Product dose
X
Week 8, Day 1 PK Sample
X
Single draw
Between
0.5-2hr
Single draw
Between
4-8hr
Safety blood sampling1 Safety Labs (see Table 6)
X
Investigational Product dose
X
Footnote 1: The term “safety blood sampling” references any non-PK or non-biomarker sampling.  Example of “safety blood sampling” 
includes blood sampling for haematology, clinical chemistry, pancreatic, coagulation, etc.


2011N118599_09
CONFIDENTIAL
BET115521
220
Rationale Change 9
This section was modified for consistency with the Time and Event tables in Section 5.
PREVIOUS TEXT, Section 6.2.3 Vitals
Vital sign measurements will include systolic and diastolic blood pressure, pulse rate, 
temperature and pain using a numerical rating scale from 0 to 10 [De Conno, 1994]. The 
vital signs will be measured after resting for at least 5 minutes in a supine or semi-
recumbent position. On days where vital signs are measured multiple times, temperature 
does not need to be repeated, unless clinically indicated.
REVISED TEXT, Section 6.2.3 Vitals
Vital sign measurements will include systolic and diastolic blood pressure, pulse rate, 
respiration, temperature and pain using a numerical rating scale from 0 to 10 [De Conno, 
1994]. The vital signs will be measured after resting for at least 5 minutes in a supine or 
semi-recumbent position. On days where vital signs are measured multiple times, 
temperature does not need to be repeated, unless clinically indicated.
PREVIOUS TEXT, Section 6.2.8 Clinical Laboratory Assessments:
Other Tests
Coagulation tests (prothrombin time, partial thromboplastin time, international normalized ratio, and fibrinogen)
Pancreatic markers (amylase and lipase)
Fasting Lipid panel (triglycerides and total cholesterol, LDL, HDL)
C-Peptide
Troponin (I or T at local laboratory, Troponin I at central laboratory]
Insulin 
Hemoglobin A1C
1,5 –Anhydroglucitol (1,5 AG)
NT-proBNP
Thyroid-stimulating hormone (TSH)
Free Thyroxine 3 (Free T3)
Free Thyroxine 4 (Free T4)
Creatine kinase (CK)
Creatine Kinase-MB (CK-MB)
Testosterone for males (free and complete testosterone at prior to first dose, free testosterone after first dose)
Pregnancy test for females (serum at screening, Urine or serum post dose)
Cytokine samples (TNF-alpha,IL-1,IL-6, IL-10)


2011N118599_09
CONFIDENTIAL
BET115521
221
REVISED TEXT. Section 6.2.8 Clinical Laboratory Assessments:
Other Tests
Coagulation tests (prothrombin time, partial thromboplastin time, international normalized ratio, and fibrinogen)
Pancreatic markers (amylase and lipase)
Fasting Lipid panel (triglycerides and total cholesterol, LDL, HDL)
C-Peptide
Troponin (I or T at local laboratory, Troponin T I at central laboratory)
Insulin 
Hemoglobin A1C
1,5 –Anhydroglucitol (1,5 AG)
NT-proBNP
Thyroid-stimulating hormone (TSH)
Free Thyroxine 3 (Free T3)
Free Thyroxine 4 (Free T4)
Creatine kinase (CK)
Creatine Kinase-MB (CK-MB)
Testosterone for males (free and complete testosterone at prior to first dose, free testosterone after first dose)
Pregnancy test for females (serum at screening, Urine or serum post dose)
Cytokine samples (TNF-alpha,IL-1,IL-6, IL-10)
Guaiac fecal occult blood


2011N118599_09
CONFIDENTIAL
BET115521
222
PREVIOUS TEXT, Section 6.2.9:
Troponin I will be assessed at a central laboratory as a means of consistent evaluation 
across all subjects. A second sample will be assessed at a local laboratory for purposes of 
subject management (e.g., enrolment criteria). Whenever possible, troponin I will be 
assayed by the local laboratory. However, either troponin I or troponin T may be assessed 
at a local laboratory.
REVISED TEXT, Section 6.2.9:
Troponin IT will be assessed at a central laboratory as a means of consistent evaluation 
across all subjects. A second sample will be assessed at a local laboratory for purposes of 
subject management (e.g., enrolment criteria). Whenever possible, troponin IT will be 
assayed by the local laboratory. However, either troponin I or troponin T may be assessed 
at a local laboratory.
NEW TEXT, Section 7.3:
These fasting requirements have been implemented in the protocol and informed consents 
to minimize pharmacokinetic variability.
Rationale Change 10
The BET115512 study data may potentially be utilized for registration purposes. 
Therefore, the disease assessment imaging will be gathered for potential central review.
NEW TEXT, Section 6.3, Efficacy
6.3 Efficacy
6.3.1 Disease Assessment
Tumor response will be assessed as outlined in Time and Event Schedule by the 
investigator using RECIST 1.1 and documented in the eCRF as: progressive disease 
(PD), stable disease (SD), partial response (PR), and complete response (CR) (See 
Appendix 4). See the SPM for additional instructions.
GSK requires sites to provide electronic copies (upload digital images or images on CD) 
of scans for all subjects for central storage which may be transferred to a central 
independent imaging center. This includes baseline scans and all scans performed during 
the course of the study. GSK may request an independent review of scans. See SPM for 
additional details.
PREVIOUS TEXT, Section 14.4 Appendix 4: RECIST 1.1:
Disease progression and response evaluations may be reviewed and analyzed by an 
independent reviewer or central review. Details will be provided in the SPM.


2011N118599_09
CONFIDENTIAL
BET115521
223
REVISED TEXT, Section 14.4 Appendix 4: RECIST 1.1:
Disease progression and response evaluations will be collected centrally during the study 
and may be reviewed and or analyzed by an independent reviewer or central reviewer. 
Details will be provided in the SPM.
Rationale Change 11
The Material Safety Data Sheet (MSDS) classifies GSK525762 as an oral toxicity 
Category 4, Reproductive Hazard. Additional instructions have been provided to the site 
staff regarding handling and exposure to GSK525762.
NEW TEXT, Section 7.2 Handling and Storage of Study Treatment, new second 
paragraph
Limited exposure and precautionary action (example: wearing gloves, washing hands 
post exposure, etc.) should be taken by site staff dispensing GSK525762 tablets.
Rationale Change 12
Dose adjustments table has been clarified for drug related toxicity. Clinically 
manageable laboratory abnormalities activities would not implement a dosing delay or 
adjustment.
PREVIOUS TEXT, Section 7.7.1. Dose Adjustments for Toxicity- Table 17
Worst Grade
GSK525762
1
No change in dose
2
Decrease by one dose level for LFT changes. For other Grade 2 toxicities, continue dosing 
with no change
3
Hold dose for one week intervals until Grade 2 then restart with no change for 1st episode. 
Utilize an alternative, less frequent schedule or reduce by one dose level with 2nd episode. 
If no recovery to ≤Grade 1* after a 21 day delay, patient should go off protocol therapy.
4
Off protocol therapy
In rare situations, based on discussion and written agreement between GSK medical 
monitor and investigator, if the patient is receiving benefit then the following criteria should 
be implemented: hold dose for one week intervals until <Grade 2 then restart with no 
change for 1st episode. Utilize an alternative, less frequent schedule or reduce by one dose 
level with 2nd episode. If no recovery to ≤Grade 1* after a 21 day delay, patient should go 
off protocol therapy
*Note: Exceptions to Grade 1 requirement may be made for Rash, alopecia, etc.


2011N118599_09
CONFIDENTIAL
BET115521
224
REVISED TEXT, Section 7.7.1. Dose Adjustments for Toxicity- Table 17
Toxicity
Worst Grade
GSK525762
1
No change in dose
2
Decrease by one dose level for LFT changes. For other drug – related Grade 2 toxicities, 
continue dosing with no change
3
Hold dose for one week intervals until drug – related Grade 2 then restart with no change 
for 1st episode. Utilize an alternative, less frequent schedule or reduce by one dose level 
with 2nd episode. If no recovery to ≤Grade 1* after a 21 day delay, patient should go off 
protocol therapy.
4
Off protocol therapy
In rare situations, based on discussion and written agreement between GSK medical 
monitor and investigator, if the patient is receiving benefit then the following criteria should 
be implemented: hold dose for one week intervals until < drug – related Grade 2 then restart 
with no change for 1st episode. Utilize an alternative, less frequent schedule or reduce by 
one dose level with 2nd episode. If no recovery to ≤Grade 1* after a 21 day delay, patient 
should go off protocol therapy
*Note: Exceptions to ≤drug – related Grade 1 requirement may be made for Rash, alopecia, etc. Exceptions to ≤drug 
– related Grade 1, 2, 3 requirements would be quickly reversible (48 hours) laboratory abnormality (example: 
electrolyte changes).
Rationale Change 13
Additional clarification has been provided regarding the analysis populations.  FDA 
recommended including an exploratory analysis to assess safety and activity in the NUT-
variant subset.  In addition, clarification regarding the stopping rule for futility has been 
provided.
NEW TEXT, Section 11.1.5 Subset Analysis for NMC Population
An exploratory review for NMC molecular subtype (e.g. NUT-BRD3, NUT-BRD4 and 
NUT-variant) will be conducted.
Section 11.2, Stopping Rule for Futility (Interim Analysis) 
PREVIOUS TEXT, Section 11.2, Stopping Rule for Futility (Interim Analysis) 
An interim analysis will be conducted by a GSK statistician for this study in order to 
assess futility.  Assessing for futility will involve: (1) safety review and (2) efficacy. 
Safety Review: If a dose limiting toxicity has been observed in 4/20 subjects within the 
first 6 weeks then further analysis and data review may occur. Additional discussions 
between investigator(s) and GSK Medical Monitor will occur to determine if subjects 
receiving benefit and if potential alterations in schedule or regimen may need to be 
implemented to address the observed toxicity being observed in the specific cohort or 
tumor type.


2011N118599_09
CONFIDENTIAL
BET115521
225
Efficacy: If zero responses are observed among the 20 subjects at interim, then in 
conjunction with a thorough review of additional data, that cohort may be closed for 
further enrollment. If one or more subjects respond, then an additional 20 subjects may be 
enrolled to more accurately define the true response rate.
REVISED TEXT, Section 11.2, Stopping Rule for Futility (Interim Analysis) 
An interim analysis will be conducted for Part 2 of this study in order by a GSK 
statistician for this study in order to assess futility after response data are available for the 
first 20 subjects based on the overall best response rate.  Assessing for futility will 
involve: (1) safety review and (2) efficacy. If 0 responses are observed, then Part 2 of 
trial will be terminated with no further enrollment.  
Safety Review: If a dose limiting toxicity has been observed in 4/20 subjects within the 
first 6 weeks then further analysis and data review may occur. Additional discussions 
between investigator(s) and GSK Medical Monitor will occur to determine if subjects 
receiving benefit and if potential alterations in schedule or regimen may need to be 
implemented to address the observed toxicity being observed in the specific cohort or 
tumor type.
Efficacy: If zero responses are observed among the 20 subjects at interim, then in 
conjunction with a thorough review of additional data, that cohort may be closed for 
further enrollment. If one or more subjects respond, then an additional 20 subjects may be 
enrolled to more accurately define the true response rate.
If at least 1 response occurs then an additional 20 subjects with NMC may be enrolled.   
Emerging safety data will also be reviewed.  Safety data will be reviewed on an ongoing 
basis and after the first 20 patients to ensure the safety profile supports continued 
enrolment.  If there is sufficient sample size an exploratory analysis will be undertaken to 
evaluate whether response rates differ between between molecular subtypes (e.g. NUT-
BRD3, NUT-BRD4, NUT-variant).
NEW TEXT
Efficacy Review: 
If there is sufficient sample size an exploratory analysis will be undertaken to evaluate 
whether response rates differ between molecular subtypes (e.g. NUT BRD3, NUT BRD4, 
variant).
PREVIOUS TEXT, Section 11.3 Analysis Populations
All Subjects (Safety and Clinical Activity) Population: This will consist of all subjects 
that received at least one dose of study treatment. Safety and clinical activity data will be 
evaluated based on this population.
Evaluable population: Any subject who received 75% of planned drug dosing by the first 
planned disease assessment. All subjects should have appropriate confirmatory scans at 
least 4 weeks subsequently. 


2011N118599_09
CONFIDENTIAL
BET115521
226
The PK Population: This will consist of those subjects in All Subjects Population and for 
whom a PK sample is obtained and analyzed.
REVISED TEXT, Section 11.3 Analysis Populations
All Subjects (Safety and Clinical Activity) Population: This will consist of all subjects 
that received at least one dose of study treatment. Safety and clinical activity data will be 
evaluated based on this population.
Evaluable population: Any subject who received 75% of planned drug dosing by the first 
planned disease assessment. All subjects should have appropriate confirmatory scans at 
least 4 weeks subsequently. 
The PK Population: This will consist of those subjects in All Subjects Population and 
for whom a PK sample is obtained and analyzed.
Assay Validation Population: Due to the rarity of NMC disease, the Assay Validation 
population is defined as all subjects who were consented, screened for the study 
(regardless if the subject met eligibility requirements for study enrollment) and whose 
tissue was assayed by IHC and/or FISH.  Data from this population may be used for 
future validation of the assay.
PREVIOUS TEXT, Section 11.5.1 Primary Analysis
The primary analysis will be based on the ‘All Subject Population’. A secondary analysis 
wil be based on the ‘Evaluable Population’ which consists of all subjects who received at 
least 75% of planned dosing of drug by the first planned disease assessment.
REVISED TEXT, Section 11.5.1 Primary Analysis
The primary analysis will be based on the ‘All Subject Population’. A secondary analysis 
wil be based on the ‘Evaluable Population’ which consists of all subjects who received at 
least 75% of planned dosing of drug by the first planned disease assessment.
Rationale Change 14
The clinical benefit rate has been revised from disease assessment at week 4 to week 8 to 
be consistent with the Time and Event Tables in Section 5.
PREVIOUS TEXT, 11.5.2. Secondary Analyses
The Clinical Benefit rate is defined as the percentage of subjects with a confirmed 
complete response (CR), partial response (PR) or stable disease lasting at least 4 weeks. 
Exact methods for calculated confidence intervals will be in the RAP. 
REVISED TEXT, 11.5.2. Secondary Analyses
The Clinical Benefit rate is defined as the percentage of subjects with a confirmed 
complete response (CR), partial response (PR) or stable disease lasting at least 8 4 weeks. 
Exact methods for calculated confidence intervals will be in the RAP. 


2011N118599_09
CONFIDENTIAL
BET115521
227
AMENDMENT 02
Protocol Amendment 02 applies to all site(s) participating in the 
conduct of the study
Amendment 02 Summary of Substantial Changes:
Section 1, Introduction
Streamlined / reorganized text (Section 1.1, Background)
Added data on additional tumor cell lines (Section 1.2, Study Population Rationale)
Updated table on predicted safety cover for proposed 2 mg starting dose (Section 1.3, 
Dose Rationale)
Updated Risk Assessment (Section 1.5) in line with current asset language
Section 2, Objectives & Endpoints
Revised Text (strikethrough=deleted text; bold=new text):
Primary
Objective

To determine the safety, tolerability and maximum tolerated dose (MTD) of 
GSK525762 in subjects 16 years or older

To determine the safety, tolerability and maximum tolerated dose (MTD) 
of GSK525762 in subjects 12 to ≤15 years old

To evaluate the clinical activity of GSK525762 in subjects with NUT Midline 
Carcinoma (NMC). 
Endpoints

AEs, SAEs, dose reductions or delays, withdrawals due to toxicities and 
changes in safety assessments (e.g., laboratory parameters, vital signs, ECG, 
cardiotoxicity, gastrointestinal, etc) to determine the MTD in subjects 16 years 
or older

AEs, SAEs, dose reductions or delays, withdrawals due to toxicities and 
changes in safety assessments (e.g., laboratory parameters, vital signs, 
ECG, cardiotoxicity, gastrointestinal, etc) to determine the MTD in 
subjects 12 to ≤15 years old.

Assess overall response rate (RR) by RECIST 1.1 in NMC
Hypothesis

No formal statistical hypotheses will be tested in Part 1. Analysis will be 
descriptive and exploratory. 

The primary goal of Part 2 is to demonstrate a clinically meaningful response 
rate of 20% in NMC relative to a 5% response rate suggesting no activity. This 
will be conducted by testing the null hypothesis that P0≤0.050 versus the 
alternative that P1≥0.200, assuming the maximum response rate for an 
ineffective drug is 0.05 and the minimum response rate for an effective drug is 
0.20. 


2011N118599_09
CONFIDENTIAL
BET115521
228
Secondary (Objectives and Endpoints only)
Objectives

To characterize the pharmacokinetics (PK) of GSK525762 in subjects 16 
years or older. 

To characterize the pharmacokinetics (PK) of GSK525762 in subjects 12 
to ≤15 years old

To evaluate cardiac safety, including the potential for QTcQTcF, of GSK525762 
in subjects with NUT Midline Carcinoma (NMC) and to assess PK/QTcQTcF
relationship.

To evaluate the exposure response (pharmacokinetic/pharmacodynamic 
[PK/PD]) relationship between GSK525762 and safety and efficacy parameters.

To evaluate the effect of treatment with GSK525762 on tumor growth and 
survivalof subjects with NUT Midline Carcinoma (NMC).

To evaluate systemic and ex-vivo on-target BET inhibitory effects
Endpoints

PK parameter values for GSK525762 following single and repeat-dose oral 
administration in subjects 16 years or older

Changes in cardiac safety including QTc PK parameter values for 
GSK525762 following single and repeat-dose oral administration GSK525762.
in subjects 12 to ≤15 years old

Changes from baseline and PK / biomarker response relationship in markers of 
BET pharmacology LPS induced IL-6 in whole blood.

Changes in cardiac safety including QTcF following single and repeat-
dose oral administration GSK525762.

Progression free survival (PFS), clinical benefit rate (CBR), time to response, 
duration of response, overall survival (OS), and exploratory analysis for 
antitumor response by various imaging modalities.
Exploratory (Objectives and Endpoints only)
Objectives

To evaluate the PD effect of GSK525762 on NMC biopsies tumor biology

Correlation of GSK525762 exposure to changes in PD markers in tumor 
and/or surrogate tissue

To identify potential indicators of sensitivity or response to GSK525762

To evaluate exploratory markers of BET inhibition.

To evaluate the exposure response (PK/PD) relationship between GSK525762 
PK and exploratory markers of BET inhibition and PD effects on NMC tumor 
biopsies.


2011N118599_09
CONFIDENTIAL
BET115521
229
Exploratory (Objectives and Endpoints only)
Endpoints

Tumor Biopsy: The samples will be evaluated for alterations in BRD-NUT by 
IHC and FISH for BRD4- NUT and changes in morphology and 
immunophenotype consistent with differentiation. Additionally, protein and
mRNA expression of Keratin and other differentiation markers will be analyzed.

If sufficient tumor sample is remaining, gene expression of Brd4-NUT, Brd3-
NUT and other “signature” markers of pathway inhibition may be evaluated in 
pre and postdose treated samples.

Changes from baseline and PK / biomarker response relationship in markers of 
BET pharmacology (serum amyloid A (SAA), haptoglobin, PK/PD parameter 
values for exposure response (by RECIST and 18FDG-PET [if data allows]) 
relationship between GSK525762 and QTc, troponin and tumor response 
following single and repeat-dose oral administration.

Dose related changes in markers of cell proliferation and/or cell 
differentiation in tumor and/or surrogate tissue

Dose related changes in transcription of genes and/or changes in 
expression of proteins regulated by BRD proteins in tumor and/or 
surrogate tissue

PK/PD parameter values for exposure response (by RECIST and 18FDG-
PET [if data allows]) relationship between GSK525762 and QTcF, troponin 
and tumor response following single and repeat-dose oral administration.

Changes from baseline and dose/response relationship in ex vivo LPS 
induced cytokines including IL-6 in whole blood and in systemic 
cytokines including IL-6

Section 3, Investigational Plan
Added language for MM, SCLC, CRC, NB and MYCN driving solid tumors (including 
NSCLC with MYCN amplification) (Section 3.1, Study Design/Schematic; Section 3.2.5, 
Part 2 Expansion Cohorts)
Added inclusion of pediatric subjects 12 - ≤15 years old to Part 1B, pediatric dose 
expansion and to Part 2
Changed text throughout to reflect proposed modified dosing regimen (Week 1 - dose on 
Day 1, off drug on Day 2, dose on Days 3, 4 and 5, off drug on Days 6 and 7;  Week 2 –
dose on Days 1 through 5, off drug Days 6 and 7; Week 3 – start daily doing).
Added language (for subjects who agree) regarding mandatory collection of tumor tissue 
in Part 1 if, after reaching the MTD and dosing at least 12 subjects, adequate tumor tissue 
(N=10 subjects) has not been collected.


2011N118599_09
CONFIDENTIAL
BET115521
230
Added language in the Intra-Subject Dose Escalation (Section 3.2.2.5) to allow for dose 
escalation in a subjects in Part 1, if after 8 weeks of dosing, no additional subjects have 
been identified.
Section 4, Study Population
Modified inclusion criteria to allow for enrolment of subjects with SCLC, CRC, NB, MM 
and other solid tumors with MYCN amplification (e.g., NSCLC)
Modified inclusion criteria to allow subjects 16 and older into adult cohort and subjects 
12 to ≤15 years old to pediatric cohort
Removed metabolic criteria for inclusion in study
Allowed for treatment after disease progression (under specific circumstances where 
subject will benefit from treatment) (Section 4.2.4.1)
Section 5, Time and Events Table
Tables reformatted and changes made in line with proposed changes to protocol 
execution/study population(s)
Section 6, Study Procedures
Added language (for subjects who agree) regarding mandatory collection of tumor tissue 
in Part 1 if, after reaching the MTD and dosing at least 12 subjects, adequate tumor tissue 
(N=10 subjects) has not been collected.
Plasma protein biomarker language changed to include IL-6, haptoglobin and CRP (after 
single and repeat dosing)
Section 7, Study Treatments
Added text to describe/allow for administration of study medication via enteral feeding 
tube
Section 8, Concomitant Medications and Non-Drug Therapies
Text added to restrict antacids for at least one hour before and 2 hours after dosing.
Specified high-dose steroids as a cautionary medication.


2 0 1 1 N 1 1 8 5 9 9 _ 0 9
C O N FI D E N TI A L
B E T 1 1 5 5 2 1
2 3 1
A M E N D M E N T 0 3
Pr ot o c ol C h a n g e s f or A m e n d m e nt 3 ( 0 4 -F E B -2 0 1 4) fr o m t h e Pr ot o c ol 
A m e n d m e nt 2 ( 2 9 -A U G- 2 0 1 2)
W here t he A me n d me nt A p plies
Pr ot oc ol A me n d me nt 0 3 a p plies t o all site(s) partici pati n g i n t he c o n d uct of t he st u d y .
Ge ner al Pr ot oc ol C h a n ges
T he N M C P D E x pa nsi o n C o h ort was a d de d t o t he pr ot oc ol t o e val uate t he 
p har mac o d y n a mic effects of G S K 5 2 5 7 6 2 acr oss t he pre dicte d efficaci o us d ose ra n ge at 
d oses t hat ha ve bee n pre vi o usl y  cleare d d uri n g 3 + 3 d ose escalati o n.  T he c ollecti o n of 
E C Gs, P K sa m ples a n d li ver c he mistr y  were clarifie d or c orrecte d.  C ha n ges are n ote d 
bel o w wit h stri ket hr o u g h t o i de ntif y delete d te xt a n d b ol d u n derli ni n g t o i de ntif y ne w or 
re place me nt te xt. 
List of C h a n ges
Pre vi o us Te xt:
A ut h or:
P P D
Gl o bal Cli nical O perati o nal Scie nces, U S A
Gl o bal Cli nical Safet y  & P har mac o vi gila nce, U S A
O nc ol o g y  Bi o mar kers, U S A
Cli nical P har mac ol o g y  M o deli n g & Si m ulati o n, U K
Gl o bal Cli nical O pera ti o nal Scie nces, U S A
E x pl orat or y  De vel o p me nt Scie nce, P T S, U K
Bi otra nsf or mati o n a n d Dr u g Dis p ositi o n, P T S, U K
Cli nical P har mac ol o g y  M o deli n g & Si m ulati o n, U S A
Q ua ntitati ve Scie nces -Ge netics, U S A
O nc ol o g y  Bi o mar kers, U S A
S A Pat h ol o g y , P T S, U K
Gl o bal Cli nical Safet y  & P har mac o vi gila nce, U S A
E pi N o va D P U, U K
Ca ncer Researc h, E pi ge netics Ma na ge me nt, U S A
Disc o ver y  Bi o metrics, I m m u n o Infla m mati o n, U K
Bi ol o g y , E pi ge netics Ma na ge me nt, U S A
Statistics, O nc ol o g y  T A Gr o u p, U S A


2 0 1 1 N 1 1 8 5 9 9 _ 0 9
C O N FI D E N TI A L
B E T 1 1 5 5 2 1
2 3 2
Re vise d Te xt:
A ut h or:
Gl o bal Cli nical O perati o nal Scie nces, U S A
Gl o bal Cli nical Safet y  & P har mac o vi gila nce, U S A
O nc ol o g y Bi o m ar kers, U S A
Cli nical P har mac ol o g y  M o deli n g & Si m ulati o n, U K
Gl o bal Cli nical O perati o nal Scie nces, U S A
E x pl orat or y  De vel o p me nt Scie nce, P T S, U K
Bi otra nsf or mati o n a n d Dr u g Dis p ositi o n, P T S, U K
C a ncer Rese arc h E pi ge netics M a n a ge me nt, U S A
Cli nical P har mac ol o g y  M o deli n g & Si m ulati o n, U S A
Gl o b al Cli nic al O per ati o n al Scie nces, U S A
Gl o b al Cli nic al O per ati o n al Scie nces, U S A
Q ua ntitati ve Scie nces -Ge netics, U S A
O nc ol o g y  Bi o mar kers, U S A
S A Pat h ol o g y , P T S, U K
Gl o b al Cli nic al S afet y & P h ar m ac o vi gil a nce, U S A
Gl o bal Cli nical Safet y  & P har mac o vi gila nce, U S A
E pi N o va D P U, U K
Ca ncer Researc h, E pi ge netics Ma na ge me nt, U S A
Gl o b al Cli nic al S afet y & P h ar m ac o vi gil a nce, U S A
Disc o ver y  Bi o metrics, I m m u n o Infla m mati o n, U K
Bi ol o g y , E pi ge netics Ma na ge me nt, U S A
Statistics, O nc ol o g y  T A Gr o u p, U S A
Pre vi o us Te xt:
S p o ns or Si g n at or y:
Si g n at ure:
D ate:
Kla us E d var dse n, M D
V P, Ca ncer Researc h
Re vise d Te xt:
S P O N S O R SI G N A T O R Y:
C hrist o p her C ar pe nter, M D, P h D
V P, D P U -He a d C a ncer E pi ge netics
D ate
Kla us E d var dse n, M D
V P, Ca ncer Researc h
P P D
Pre vi o us Te xt:


2 0 1 1 N 1 1 8 5 9 9 _ 0 9
C O N FI D E N TI A L
B E T 1 1 5 5 2 1
2 3 3
R ol e
N a m e
D a y Ti m e 
P h o n e 
N u m b er
Aft er -h o ur s 
P h o n e/ C ell/
P a g er 
N u m b er
F a x 
N u m b er
G S K A d dr e s s
Pri m ary 
M e dic al 
M o nit or
 
, 
M D
Gl ax o S mit h Kli n e
1 2 5 0 S o ut h C oll e g evill e R o a d, 
M ailst o p U P 4 3 4 0
C oll e g evill e, P A 1 9 4 2 6, U S A
S ec o n d ary 
M e dic al 
M o nit or
, 
M D
 
Gl ax o S mit h Kli n e
1 2 5 0 S o ut h C oll e g evill e R o a d, 
M ailst o p U P 1 4 5 0
C oll e g evill e, P A 1 9 4 2 6, U S A
Re vise d Te xt:
R ol e
N a m e
D a y Ti m e 
P h o n e 
N u m b er
Aft er -h o ur s 
P h o n e/ C el l/
P a g er 
N u m b er
F a x 
N u m b er
G S K A d dr e s s
Pri m ar y 
M e di c al 
M o nit or
, 
M D, P h D
 
 
Gl a x o S mit h Kli n e
1 2 5 0 S o ut h C oll e g e vill e R o a d, 
U P 4 2 1 0
C oll e g e vill e, P A 1 9 4 2 6, U S A
S e c o n d ar y 
M e di c al 
M o nit or
 
M D, P h D
Gl a x o S mit h Kli n e
1 2 5 0 S o ut h C oll e g e vill e R o a d
M ail st o p U P 4 4 1 0
C oll e g e vill e, P A 1 9 4 2 6, U S A
Pri m ary 
M e dic al 
M o nit or
 
, 
M D
Gl ax o S mit h Kli n e
1 2 5 0 S o ut h C oll e g evill e R o a d, 
M ailst o p U P 4 3 4 0
C oll e g evill e, P A 1 9 4 2 6, U S A
S ec o n d ary 
M e dic al 
M o nit or
, 
M D
 
Gl ax o S mit h Kli n e
1 2 5 0 S o ut h C oll e g evill e R o a d, 
M ailst o p U P 1 4 5 0
C oll e g evill e, P A 1 9 4 2 6, U S A
P P D
Rati o nale f or C ha n ge:
T he a ut h ors, s p o ns or si g nat ure, a n d me dical m o nit ori n g i nf or mati o n were u p date d base d 
o n i nter nal pers o n nel c ha n ges t o t he G S K tea m. 
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P
P
D
P P D
P P D


2011N118599_09
CONFIDENTIAL
BET115521
234
Previous Text:

STUDY DESIGN AND DURATION: This study is divided into 2 parts; Part 1 
of the study is a dose escalation phase to select the recommended dose for Part 2 
based on the safety, pharmacokinetic, and pharmacodynamic profiles observed 
after oral administration of GSK525762. Eligible subjects with NUT midline 
carcinoma, small cell lung cancer, colorectal cancer, neuroblastomaand any 
other MYCN-amplified solid tumor will be enrolled in the dosing cohorts until a 
maximum tolerated dose (MTD) is established.  Subjects may continue 
treatment in the study until disease progression, unacceptable toxicity, 
withdrawal of consent, or commercial supply of GSK525762 becomes available 
to the subject. An expansion cohort is planned to further explore clinical activity 
at the MTD in NMC (Part 2). Duration of study will depend on recruitment 
rates, and timing of subjects’ duration on study (withdrawal rates due to toxicity 
or progression).

PHARMACOKINETIC/PHARMACODYNAMIC MEASUREMENTS: 
There is serial pharmacokinetic (PK) sampling for this study. Single safety PK 
blood draws may be collected for subjects with severe adverse events or adverse 
events of concern.  Blood samples will be collected for analysis of protein 
biomarkers (cytokines and acute phase proteins) and mRNA. LPS induction of 
cytokines in whole blood will be assessed. In addition, pre-treatment and post-
treatment tumor samples will be collected from selected subjects to be evaluated 
for target engagement and effects of GSK525762 on tumor biology.
Revised Text:

STUDY DESIGN AND DURATION: This study is divided into 2 parts; Part 
1A of the study is a dose escalation phase to select the recommended dose for 
Part 2 based on the safety, pharmacokinetic, and pharmacodynamic profiles 
observed after oral administration of GSK525762. Eligible subjects with NUT 
midline carcinoma, small cell lung cancer, colorectal cancer, neuroblastoma and 
any other MYCN-amplified solid tumor will be enrolled in the dosing cohorts 
until a maximum tolerated dose (MTD) is established.  Subjects with NMC will 
also be enrolled in a pharmacodynamic dose expansion cohort during Part 
1A.  Subjects may continue treatment in the study until disease progression, 
unacceptable toxicity, or withdrawal of consent. or commercial supply of 
GSK525762 becomes available to the subject.  Once the MTD is determined 
in adult subjects, Part 1B will be opened to enroll pediatric subjects 12 to 
≤15 years of age with solid tumors to determine the MTD in pediatric 
subjects.  Dose escalation in Part 1B will begin at 25% of the adult MTD 
and dose escalation will follow a 3+3 design.  Pediatric subjects 12 to ≤15 
years old may be enrolled in Part 2 once the MTD has been determined in 
Part 1B. An expansion cohort is planned to further explore clinical activity at 
the MTD in NMC (Part 2). Duration of study will depend on recruitment rates, 
and timing of subjects’ duration on study (withdrawal rates due to toxicity or 
progression).


2011N118599_09
CONFIDENTIAL
BET115521
235

PHARMACOKINETIC/PHARMACODYNAMIC MEASUREMENTS: 
There is extensive serial pharmacokinetic (PK) sampling in Part 1 and limited 
PK sampling in Part 2 for this study. Single safety PK blood draws may be 
collected for subjects with severe adverse events or adverse events of concern.  
Blood samples will be collected for analysis of protein biomarkers (cytokines 
and acute phase proteins) and mRNA. LPS induction of cytokines in whole 
blood will be assessed. In addition, pre-treatment and post-treatment tumor 
samples will be collected from selected subjects to be evaluated for target 
engagement and effects of GSK525762 on tumor biology.
Rationale for Change:
The study design was updated with the addition of the NMC PD Expansion Cohort to 
evaluate the pharmacodynamic effects of GSK525762 at doses that have been cleared 
during 3+3 dose escalation during Part 1A.  The study design was also clarified in this 
section to reference the pediatric cohort in Part1B.  The duration of exposure on the study 
was updated in accordance with the Commission Directive 2005/28/EC such that 
availability of commercial drug supply was not included in duration of treatment on 
study.  The collection of PK during Part 1 and Part were clarified.
Previous Text in Section 1.5 Risk Assessment:
Reproductive: In 4-week toxicology studies, bilateral sperm retention, germ cell 
degeneration and tubular vacuolization, and depletion of testicular germinal epithelium 
occurred in male dogs receiving ≥ 0.3 mg/kg and male rats receiving ≥ 10mg/kg doses of 
GSK525762.  Exposures associated with reproductive toxicity in male dogs overlap with 
the proposed 5 mg starting dose in this FTIH study. In the BET11521 study, specific 
contraceptive guidelines and precautions for males and females are provided in the 
protocol.  In addition, subjects will be informed of potential reproductive risks and 
precautions in the informed consent.
Potential drug-drug interactions based on nonclinical studies: There is low potential 
for GSK525762 to induce or inhibit cytochrome P450 (CYP) enzymes or to inhibit Pgp 
or BCRP.  Use of concurrent drugs with potential to prolonged QTcF will be used with 
extreme caution or prohibited (as outlined in Section 7.1 of the protocol).  Regarding 
drugs for hyperemesis, palonosetron and ondansetron at a maximum dose of 8 mg TID 
will be the only allowed serotonin 5-HT3 receptor antagonist drugs. 


2011N118599_09
CONFIDENTIAL
BET115521
236
Revised Text in Section 1.5 Risk Assessment:
Reproductive: In 4-week toxicology studies, bilateral sperm retention, germ cell 
degeneration and tubular vacuolization, and depletion of testicular germinal epithelium 
occurred in male dogs receiving ≥ 0.3 mg/kg and male rats receiving ≥ 10mg/kg doses of 
GSK525762.  Exposures associated with reproductive toxicity in male dogs overlap with 
the proposed 5 mg starting dose in this FTIH study. In the BET11521 study, specific 
contraceptive guidelines and precautions for males and females are provided in the 
protocol.  In addition, the informed consent will include potential reproductive risks 
and precautions in addition to recommendations for the preservation of 
reproductive capacity. In addition, subjects will be informed of potential reproductive 
risks and precautions in the informed consent.
Potential drug-drug interactions based on nonclinical studies: There is low potential 
for GSK525762 to induce or inhibit cytochrome P450 (CYP) enzymes or to inhibit Pgp 
or BCRP.  Use of concurrent drugs with potential to prolonged QTcF will be used with 
extreme caution or prohibited (as outlined in Section 7.1 of the protocol).  Regarding
drugs for hyperemesis, palonosetron (administered per the prescribing information)
and ondansetron (at a maximum oral dose of 8 mg TID) will be the only allowed 
serotonin 5-HT3 receptor antagonist drugs. 
Rational for change:
Additional text was added to emphasize the recommendations for the preservation of 
reproductive capacity included in the informed consent.  The guidance of potential drug-
drug interactions and allowance of serotonin 5-HT3 receptor antagonist drugs were 
clarified.
Previous Text:
3.1 Study Design/Schematic
Protocol waivers or exemptions are not allowed. Therefore, adherence to the study design 
requirements, including those specified in the Time and Events Tables, are essential.
This is an open-label, single and repeat dose, 2-part study to determine the maximum 
tolerated dose (MTD) and the recommended Phase 2 dose (RP2D) for GSK525762 given 
once-daily orally. (Part 1A) will be conducted in adult subjects with NMC, small cell 
lung cancer (SCLC), colorectal cancer (CRC), neuroblastoma (NB), MYCN  driven solid 
tumors [including non-small cell lung cancer (NSCLC) with MYCN amplification].  
Once the MTD is determined in adult subjects, a pediatric cohort of subjects 12 to ≤15 
years of age with solid tumors will be opened (Part 1B) to evaluate MTD in this age 
group. An expansion cohort (Part 2) is planned to further explore clinical activity of 
GSK525762 in subjects with NMC as shown in Figure 1. The expansion cohort will 
enroll both adult (16 years old and above) and pediatric (12 to ≤15 years) subjects at their 
appropriate R2PD doses.


2011N118599_09
CONFIDENTIAL
BET115521
237
In Part 1A, an accelerated dose titration will be employed with one subject per dose level 
until the first instance of a Grade 2 drug related toxicity occurs. Thereafter, subjects will 
be enrolled in a standard 3+3 design. 
After the MTD has been determined in Part 1A, Part 1B and Part 2 will be opened. Dose 
titration in the pediatric subjects in Part 1B will start at 25% of the MTD determined in 
Part 1A and will follow a standard 3+3 design. Pediatric subjects will be entered to Part 2 
upon completion of Part 1B.
In both Parts 1 and 2, all subjects will be evaluated for systemic and ex-vivo on-target 
BET inhibitory effects in blood. In addition, pre-treatment and post-treatment tumor 
samples will be collected from selected subjects to be evaluated for target engagement 
and effects of GSK525762 on tumor biology. 
Revised Text:
3.1 Study Design/Schematic
Protocol waivers or exemptions are not allowed. Therefore, adherence to the study design 
requirements, including those specified in the Time and Events Tables, are essential.
This is an open-label, single and repeat dose, 2-part study to determine the maximum 
tolerated dose (MTD) and the recommended Phase 2 dose (RP2D) for GSK525762 given 
once-daily orally. (Part 1A) will be conducted in adult subjects with NMC small cell lung 
cancer (SCLC), colorectal cancer (CRC), neuroblastoma (NB), MYCN  driven solid 
tumors [including non-small cell lung cancer (NSCLC) with MYCN amplification].
During the dose escalation of Part 1A, additional subjects with NMC will be 
enrolled in a Pharmacodynamic (PD) Expansion Cohort to evaluate the 
pharmacodynamic effects of GSK525762 at lower doses that have been previously 
cleared during dose escalation. This will enable collection of pharmacodynamic 
data across the predicted efficacious dose range and contribute to the evaluation of 
a biologically efficacious dose. Once the MTD RP2D is determined in adult subjects, a
Part 1B will be opened to enroll pediatric cohort of subjects 12 to ≤15 years of age with 
solid tumors will be opened (Part 1B) to determine the MTD RP2D in this age group. 
Dose escalation in Part 1B will begin at 25% of the adult MTD and dose escalation 
will follow a 3+3 design.  An expansion cohort (Part 2) is planned to further explore 
clinical activity of GSK525762 in subjects with NMC as shown in Figure 1. The 
expansion cohort will enroll both adult (16 years old and above) and pediatric (12 to ≤15 
years) subjects at their appropriate R2PD doses.
Rationale for Change:
The study design was updated with the addition of the NMC PD Expansion Cohort to 
evaluate the pharmacodynamic effects of GSK525762 at doses that have been cleared 
during 3+3 dose escalation during Part 1A.  


2011N118599_09
CONFIDENTIAL
BET115521
238
Previous Text:
Figure 1.
Study Schema
Part 1A: 
Single and Repeat Dose 
Finding Cohorts  
in age ≥16yrs
(n~18-32 subjects)
Part 2: 
Expansion Cohort 
NMC Expansion Cohort
(n~40 subjects)
Part 1B: 
Single and Repeat Dose 
Finding Cohorts
in age group 12 to ≤15 yrs
(n~12-18 subjects)
Revised Text:
Figure 1.
Study Schema
Rationale for Change:
Figure 1 was updated to include the NMC PD Expansion Cohort.


2011N118599_09
CONFIDENTIAL
BET115521
239
Previous Text:
3.2.1 Part 1 Dose Escalation
Part 1A will start with an accelerated dose escalation schema in subjects ≥16 years old 
with one subject per dose level.  Accelerated dose titration will stop once a single Grade 
2 or higher drug-related adverse event is observed in one subject, at which point a 
standard 3+3 dose escalation design will be implemented to define the MTD.  The details 
of these 2 dose escalation strategies are in Figure 2.
Part 1B will be initiated after the MTD is reached in Part 1A and will start at 25% of the 
MTD determined in Part 1A. Part 1B will follow a standard 3+3 design.
Revised Text:
3.2.1 Part 1 Dose Escalation
Part 1A will start with an accelerated dose escalation schema in subjects ≥16 years old 
with one subject per dose level.  Accelerated dose titration will stop once a single Grade 
2 or higher drug-related adverse event is observed in one subject, at which point a 
standard 3+3 dose escalation design will be implemented to define the MTD.  The details 
of these 2 dose escalation strategies are in Figure 2.
Part 1B will be initiated after the MTD is reached in Part 1A and will start at 25% of the 
MTD determined in Part 1A. Part 1B will follow a standard 3+3 design.
In the accelerated dose escalation cohorts and the 3+3 dose escalation cohorts, the 
dose will be escalated based on all available data, including PK data and the safety 
profile of prior cohorts, as well as the predicted dose from the Neuenschwander-
Continuous Reassessment Method (N-CRM) design 
[NeuenschwanderNeuenschwander, 2009].  N-CRM design is a type of Bayesian 
adaptive dose escalation scheme.  The method is fully adaptive and makes use of all 
the Dose Limiting Toxicity (DLT) information available at the time of each dose 
assignment.  The DLT information of all subjects enrolled in the trial are used to 
update the dose-toxicity relationship and provide supportive information in addition 
to 3+3 design in the next escalation/de-escalation decision.
Rationale for Change:
Dose escalation follows the 3+3 design and the protocol was updated to clarify that dose 
escalation decisions includes evaluation of all safety data from prior dose cohorts, PK/PD 
data, and supportive information that results from the CRM. 


2011N118599_09
CONFIDENTIAL
BET115521
240
Previous Text:
Dose 
Day 1
Day 2
Day 3
Day 4
Day 5
Day 6
Day 7
Week 1
Dose
Dose
Dose
Dose
ECG,Tele,Holter
ECG,Tele
ECG
ECG,Holter
ECG
ECG
Week 2
Dose
Dose
Dose
Dose
Dose
ECG
ECG,Holter
ECG
ECG
Week 3
Dose
Dose
Dose
Dose
Dose
Dose
Dose
ECG
ECG
Week 4
Dose
Dose
Dose
Dose
Dose
Dose
Dose
ECG,Holter
ECG
Revised Text:
Table 2.
Dosing Schedule and Cardiac Monitoring for Part 1A and Part 1B
Dose 
Day 1
Day 2
Day 3
Day 4
Day 5
Day 6
Day 7
Week 1
Dose
Dose
Dose
Dose
ECG,Tele,Holter
ECG,Tele
ECG
ECG,Holter
ECG
ECG
Week 2
Dose
Dose
Dose
Dose
Dose
ECG
ECG
ECG Holter
ECG
ECG
Week 3
Dose
Dose
Dose
Dose
Dose
Dose
Dose
ECG
ECG
Week 4
Dose
Dose
Dose
Dose
Dose
Dose
Dose
ECG,Holter
ECG
Rationale: 
Corrections were made to clarify that ECGs are to be collected on Week 2 Day 4 and not 
Week 2 Day 5.  
Previous Text:
3.2.2.6 Intra-Subject Dose Escalation
Intra-subject dose escalations may be considered on a case-by-case basis, provided that 
the subject has not experienced any Grade 2 or higher drug related toxicity during the 
first 4 weeks of investigational therapy in the accelerated dose escalation phase or a DLT 
in the 3+3 dose escalation phase and contingent upon one of the following:

If additional subject(s) have been enrolled at a higher dose in the dose escalation 
phase and at least one subject has completed 4 weeks of dosing on that regimen 
without a DLT, and after review of all safety data and approval by a GSK Medical 
Monitor, a subject on a lower dose level may be increased up to the highest dose 


2011N118599_09
CONFIDENTIAL
BET115521
241
level tested.  In this case the subject may begin daily dosing at the higher dose level 
as it will have already been demonstrated to be tolerable.

If no further subjects have been identified for a subsequent higher dose level and 
after a subject has completed 4 weeks of dosing on that regimen without a DLT, that 
subject may be escalated to the next higher dose level after an additional 4 weeks of 
dosing (total of 8 weeks of dosing), review of all safety data and approval by a GSK 
Medical Monitor. In this case the subject must follow the staggered dosing schedule 
outlined in Table 2, as he/she will be the first subject exposed to the higher dose. 
Additional safety assessments such as insulin/glucose or cardiac monitoring may be 
specified at the time of dose escalation or schedule modification based on the safety 
profile in previous subjects at the higher dose level. Intra-subject dose escalations or 
schedule modification will be discussed with investigators and approved by the GSK 
Medical Monitor and safety monitoring required will be specified in writing.
Revised Text:
3.2.2.6 Intra-Subject Dose Escalation
Intra-subject dose escalations may be considered on a case-by-case basis, provided that 
the subject has not experienced any Grade 2 or higher drug related toxicity during the 
first 4 weeks of investigational therapy in the accelerated dose escalation phase or a DLT 
in the 3+3 dose escalation phase and contingent upon one of the following:

If additional subject(s) have been enrolled at a higher dose in the dose escalation 
phase and at least one subject has completed 4 weeks of dosing on that regimen 
without a DLT, and after review of all safety data and approval by a GSK Medical 
Monitor, a subject on a lower dose level may be increased up to the highest dose 
level tested.  In this case the subject may begin daily dosing at the higher dose level 
as it will have already been demonstrated to be tolerable.

If no further subjects have been identified for a subsequent higher dose level and 
after a subject has completed 4 weeks of dosing on that regimen without a DLT, that 
subject may be escalated to the next higher dose level after an additional 4 weeks of 
dosing (total of 8 weeks of dosing), review of all safety data and approval by a GSK 
Medical Monitor. In this case the subject must follow the staggered dosing schedule 
outlined in Table 2, as he/she will be the first subject exposed to the higher dose. 
Subjects approved for intra-subject dose escalation will require additional limited 
PK sampling at the higher dose (pre-dose, 0.5, 3 and 6-8 hours), as determined by 
GSK Clinical Pharmacology.  Additional safety assessments such as insulin/glucose or 
cardiac monitoring may be specified at the time of dose escalation or schedule 
modification based on the safety profile in previous subjects at the higher dose level. 
Intra-subject dose escalations or schedule modification will be discussed with 
investigators and approved by the GSK Medical Monitor and safety monitoring required 
will be specified in writing.
Rationale for Change:


2011N118599_09
CONFIDENTIAL
BET115521
242
Subjects who are approved for intra-subject dose escalation will require PK sampling at 
the higher approved dose in order to evaluate PK parameters at the higher dose level.
Additional Text:
3.2.5 Part 1 NMC Pharmacodynamic Expansion Cohort
In the event there are no available enrollment slots during 3+3 dose escalation, 
eligible subjects with NMC (Section 6.2) may be enrolled in a Pharmacodynamic 
(PD) Expansion Cohort to evaluate the pharmacodynamics of GSK525762 at doses 
that have previously been cleared during 3+3 dose escalation.  Three subjects with 
NMC will be allowed to enroll at the last cleared dose level only if subjects with 
NMC or other solid tumor types (Section 4.2.1 Inclusion Criteria) have already 
enrolled in 3+3 dose escalation. Enrollment in the PD Expansion Cohort will 
continue until either 12 subjects with NMC are enrolled in the PD Expansion 
Cohort, or until the RP2D is determined in Part 1A, whichever occurs first.  
Eligibility criteria for subjects diagnosed with NMC to enroll in this cohort are 
described in Section 4.2 (Part 1A).   Biopsy collection will be mandatory as 
described in Section 3.2.2.4, unless a waiver is granted by the GSK medical monitor.  
18FDG-PET will be required for all subjects in this cohort.
Subjects in the PD Dose Expansion Cohort will start with same staggered dosing 
during the first two weeks as described in Section 3.2.2 (Table 2); subjects will begin 
continuous dosing in Week 3.  Extensive monitoring for cardiac safety signals will 
be performed as required in Part 1A, with triplicate 12-lead ECGs, 48-hour 
telemetry, and 24-hour Holter monitoring to be performed on the days indicated in 
Table 2.  All safety and PK evaluations will be performed as outlined in the Time 
and Events Tables for Part 1A (Section 5).  Safety data from subjects in the NMC 
PD Expansion Cohort will be reviewed on an ongoing basis by the GSK medical 
monitor, GSK Safety Review Team, and investigators for consideration during 3+3 
dose escalation decisions.  
Subjects will be eligible for intra-subject dose escalation to a higher approved dose 
as described in Section 3.2.2.6, upon completion of the 4 week observation period, 
tumor biopsy collection, and approval by the investigator and GSK medical monitor 
in consultation with the GSK study team.  Subjects approved for intra-subject dose 
escalation will require additional limited PK sampling (pre-dose, 0.5, 3 and 6-8 
hours) at the higher dose, as determined by GSK Clinical Pharmacology. Subjects 
may continue on daily administration of GSK525762 until permanent 
discontinuation or completion of the study as described in Section 4.2.3.


2011N118599_09
CONFIDENTIAL
BET115521
243
Rationale for additional text:
The study design was updated with the addition of the NMC PD Expansion Cohort to 
evaluate the pharmacodynamics of GSK525762 at doses that have been cleared during 
3+3 dose escalation during Part 1A.
Previous Text:
4.2 Inclusion Criteria
Deviations from inclusion criteria are not allowed because they can potentially jeopardize 
the scientific integrity of the study, regulatory acceptability or subject safety. Therefore, 
adherence to the criteria as specified in the protocol is essential.
A subject will be eligible for inclusion in this study only if all of the following criteria 
apply:
1. Part 1A: Male or female 16 years or older, at the time of signing the informed 
consent.
Part 1B: Male or female 12 years to ≤15 years, at the time of signing the informed 
consent
Part 2: Male or female 16 years or older, at the time of signing the informed 
consent. After completion of Part 1B, male or female 12 years to ≤15 years, at the 
time of signing the informed consent.
2. Capable of giving written informed consent, which includes compliance with the 
requirements and restrictions listed in the consent form. If the subject is less than 
18 years old, an Assent form and Consent form (replacing “you will” with “your 
child will” will be required).  
Revised Text:
4.2 Inclusion Criteria
Deviations from inclusion criteria are not allowed because they can potentially jeopardize 
the scientific integrity of the study, regulatory acceptability or subject safety. Therefore, 
adherence to the criteria as specified in the protocol is essential.
A subject will be eligible for inclusion in this study only if all of the following criteria 
apply:
1. Part 1A: Male or female 16 years or older, at the time of signing the informed 
consent.
Part 1B: Male or female 12 years to ≤15 years, at the time of signing the informed 
consent


2011N118599_09
CONFIDENTIAL
BET115521
244
Part 2: Male or female 16 years or older, at the time of signing the informed 
consent. After completion of Part 1B, male or female 12 years to ≤15 years, at the 
time of signing the informed consent.
2. Capable of giving written informed consent, which includes compliance with the 
requirements and restrictions listed in the consent form. If the subject is less than 
18 years old, an Assent form and parental/guardian Consent form (replacing 
“you will” with “your child will” will be required).
Rationale for Change:
A clarification was made to the age requirement in Part 2 and emphasis was added for the 
parental/guardian Consent Form. 


2011N118599_09
CONFIDENTIAL
BET115521
245
Previous Text: Table 8  Time and Events: Part 1
Part 1 
Assessments
Notes
S
C
R
E
O
T
Week 1
Week 2
W3
W4
W5
W7
W9
q4W
q8W
D
1
D
2
D
3
D
4
D
5
D
6
D
7
D
1
D
2
D
3
D
4
D
5
D
6
D
7
D
1
D
4
D
1
D
4
D
1
D
1
D
1
D
1
D
1
Informed 
consent
Unless otherwise noted, screening 
assessments to be completed within 
14 days of first dose.
X
Demography
X
Medical history
X
Disease 
characteristics
X
Cardiology 
evaluation
X
Prior therapy
X
Register subject
X
TREATMENT PHASE
Study Drug
Administer study 
drug
Administer about same time of day. No 
food or antacids 1h before and 2h 
after.
X
X
X
X
X
X
X
X
X
Daily
Review subject 
diary
Diary not required when dosed in 
clinic.
X
X
X
X
X
X
X
Safety
Pregnancy test/  
testosterone
Females: serum pregnancy test within 
7 days of first dose; urine or serum 
test thereafter. Males: complete and 
free testosterone at SCR; free 
testosterone thereafter.
X
X
X
X
X
X
Physical exam
X
X
X
X
X
X
X
X
X
X
ECOG PS
X
X
X
X
X
X
X
X
X
X
Vital Signs
SBP, DBP, heart rate, respiratory rate, 
temp
X
X
X
X
X
X
X
X
X
X
X
X
X


2011N118599_09
CONFIDENTIAL
BET115521
246
Part 1 
Assessments
Notes
S
C
R
E
O
T
Week 1
Week 2
W3
W4
W5
W7
W9
q4W
q8W
D
1
D
2
D
3
D
4
D
5
D
6
D
7
D
1
D
2
D
3
D
4
D
5
D
6
D
7
D
1
D
4
D
1
D
4
D
1
D
1
D
1
D
1
D
1
Pain
X
X
X
X
X
X
X
X
X
X
X
X
X
Weight and 
height
Height at SCR only
X
X
X
X
X
X
X
X
X
X
Chest x-ray
X
Pulmonary 
function test
X
Adverse events
continuous from signing of informed consent
Concomitant 
medications
continuous from signing of informed consent
Laboratory assessments: For details please see following tables
Tests
X
X
X
X
X
X
X
X
X
X
X
X
X
Cardiac Monitoring
Echocardiogram
Within 35 days of first dose
X
X
X
X
X
X
12-lead ECGs
SCR ECGs within 35 days of first 
dose. For timing of ECGs on O days, 
see Table 10 and Table 11. 
Otherwise, triplicate ECGs at 
approximately same time of day, and 
prior to dose on dosing days. If QTcF 
increase >30msec, ECGs daily 
through W2.
X
O
O
X
O
X
X
X
O
X
X
X
O
X
X
X
X
O
X
X
Holter monitoring
At least 24 h, on dosing days start at 
least 60 min pre-dose.
X
X
X
X
X
X
Telemetry
Start at least 60 min predose and for 
at least 48 h.
X
X
Efficacy
CT/MRI Scans
SCR assessment within 35 days of 
first dose. Target lesions to be 
identified at SCR and followed.
X
X
X
X
Tumor sample
Optional during rapid dose escalation; 
X
One postdose sample between W1D4 and W9D1, timing optimized based on 
X


2011N118599_09
CONFIDENTIAL
BET115521
247
Part 1 
Assessments
Notes
S
C
R
E
O
T
Week 1
Week 2
W3
W4
W5
W7
W9
q4W
q8W
D
1
D
2
D
3
D
4
D
5
D
6
D
7
D
1
D
2
D
3
D
4
D
5
D
6
D
7
D
1
D
4
D
1
D
4
D
1
D
1
D
1
D
1
D
1
required during 3+3 dose escalation
tumor type and emerging data
PET scan
Optional during rapid dose escalation; 
required during 3+3 dose escalation
X
X
Neuroblastoma Assessments
CT/MRI
One or more tests should be used as 
appropriate for disease. The same 
modalities utilized at screening should 
be used throughout study. Screening 
assessment within 35 days of first 
dose
X
X
X
MIBG scan 
X
X
X
FDG-PET
X
X
X
99Tc scintigraphy 
for bone scan
X
X
X
Bilateral bone 
marrow aspirates 
and biopsy
X
X
X
Urine HVA, VMA, 
dopamine
X
X
X
X
X
Pharmacokinetics (PK) and Pharmacodynamics (PD): For details please see following tables
PK and 
biomarker 
X
X
X
X
X
X


2011N118599_09
CONFIDENTIAL
BET115521
248
Part 1 
Assessments
Notes
S
C
R
E
O
T
Week 1
Week 2
W3
W4
W5
W7
W9
q4W
q8W
D
1
D
2
D
3
D
4
D
5
D
6
D
7
D
1
D
2
D
3
D
4
D
5
D
6
D
7
D
1
D
4
D
1
D
4
D
1
D
1
D
1
D
1
D
1
samples
Samples for 
mRNA
X
X
X
X
X
LPS blood 
sample
X
PK Urine 
samples 
X
X
Pharmacogenomics (PGx)
PGx sample
X
FOLLOW-UP PHASE
Follow-up contact by clinic visit or other means (telephone contact, email, etc) for survival status and anticancer therapy every 6 months. Disease assessment will be collected for 
subjects who discontinue study medication due to any reason other than progression or death. Individual subjects will be considered to have completed the study 2 years after their last 
treatment or upon death, whichever is sooner. Document the cause of death. For the study, the Follow-up Phase ends after a minimum of 70% of subjects have died or 5 years after 
the last subject is enrolled in Phase 2.
Abbreviations: CK=creatine kinase; CRP=c-reactive protein; D=day; DBP=diastolic blood pressure; ECG=electrocardiogram; ECOG PS=Eastern Cooperative Oncology Group 
Performance Status; EOT=End-of-Treatment; FLC=free light chain; HVA=homovanillic acid; LPS=lipopolysaccharide; MIBG=meta-iodo-benzyl-guanidine; q4W=every 4 weeks; 
q8W=every 8weeks; SBP=systolic blood pressure; SCR=Screening; SPEP=serum protein electrophoresis; UPEP=urine protein electrophoresis; VMA= vanillylmandelic acid; W=week
Revised Text: Table 8  Time and Events: Part 1
Part 1 
Assessments
Notes
S
C
R
E
O
T
Week 1
Week 2
W3
W4
W5
W7
W9
q4W
q8W
D
1
D
2
D
3
D
4
D
5
D
6
D
7
D
1
D
2
D
3
D
4
D
5
D
6
D
7
D
1
D
4
D
1
D
4
D
1
D
1
D
1
D
1
D
1
Informed consent
Unless otherwise noted, screening 
assessments to be completed within 
14 days of first dose.
X
Demography
X
Medical history
X


2011N118599_09
CONFIDENTIAL
BET115521
249
Part 1 
Assessments
Notes
S
C
R
E
O
T
Week 1
Week 2
W3
W4
W5
W7
W9
q4W
q8W
D
1
D
2
D
3
D
4
D
5
D
6
D
7
D
1
D
2
D
3
D
4
D
5
D
6
D
7
D
1
D
4
D
1
D
4
D
1
D
1
D
1
D
1
D
1
Disease 
characteristics
X
Cardiology 
evaluation
X
Prior therapy
X
Register subject
X
TREATMENT PHASE
Study Drug
Administer study 
drug
Administer about same time of day. No 
food or antacids 1h before and 2h 
after.
X
X
X
X
X
X
X
X
X
Daily
Review subject 
diary
Diary not required when dosed in 
clinic.
X
X
X
X
X
X
X
Safety
Pregnancy test/  
testosterone
Females: serum pregnancy test within 
7 days of first dose; urine or serum 
test thereafter. Males: complete and 
free testosterone at SCR; free 
testosterone thereafter.
X
X
X
X
X
X
Physical exam
X
X
X
X
X
X
X
X
X
X
ECOG PS
X
X
X
X
X
X
X
X
X
X
Vital Signs
SBP, DBP, heart rate, respiratory rate, 
temp
X
X
X
X
X
X
X
X
X
X
X
X
X
Pain
X
X
X
X
X
X
X
X
X
X
X
X
X
Weight and height
Height at SCR only
X
X
X
X
X
X
X
X
X
X
Chest x-ray
X
Pulmonary function 
test
X
Adverse events
continuous from signing of informed consent
Concomitant 
continuous from signing of informed consent


2011N118599_09
CONFIDENTIAL
BET115521
250
Part 1 
Assessments
Notes
S
C
R
E
O
T
Week 1
Week 2
W3
W4
W5
W7
W9
q4W
q8W
D
1
D
2
D
3
D
4
D
5
D
6
D
7
D
1
D
2
D
3
D
4
D
5
D
6
D
7
D
1
D
4
D
1
D
4
D
1
D
1
D
1
D
1
D
1
medications
Laboratory assessments: For details please see following tables
Tests
X
X
X
X
X
X
X
X
X
X
X
X
X
Cardiac Monitoring
Echocardiogram
Within 35 days of first dose
X
X
X
X
X
X
12-lead ECGs 
(Triplicate)
Triplicate SCR ECGs within 35 days 
of first dose. For timing of triplicate
ECGs on O days, see Table 10 and 
Table 11. Otherwise, triplicate ECGs 
at approximately same time of day, 
and prior to dose on dosing days. If 
QTcF increase >30msec, ECGs daily 
through W2.
X
O
O
X
O
X
X
X
O
X
X
X
O
X
X
X
X
O
X
X
Holter monitoring
At least 24 h, on dosing days start at 
least 60 min predose.
X
X
X
X
X
X
Telemetry
Start at least 60 min predose and for 
at least 48 h.
X
X
Efficacy
CT/MRI Scans
SCR assessment within 35 days of 
first dose. Target lesions to be 
identified at SCR and followed.
X
X
X
X
Tumor sample
Optional during rapid dose escalation; 
required during 3+3 dose escalation
X
One postdose sample between W1D4 and W9D1, timing optimized based on 
tumor type and emerging data
X
PET scan
Optional during rapid dose escalation; 
required during 3+3 dose escalation
X
X


2011N118599_09
CONFIDENTIAL
BET115521
251
Part 1 
Assessments
Notes
S
C
R
E
O
T
Week 1
Week 2
W3
W4
W5
W7
W9
q4W
q8W
D
1
D
2
D
3
D
4
D
5
D
6
D
7
D
1
D
2
D
3
D
4
D
5
D
6
D
7
D
1
D
4
D
1
D
4
D
1
D
1
D
1
D
1
D
1
Neuroblastoma Assessments
CT/MRI
One or more tests should be used as 
appropriate for disease. The same 
modalities utilized at screening should 
be used throughout study. Screening 
assessment within 35 days of first 
dose
X
X
X
MIBG scana
X
X
X
FDG-PET
X
X
X
99Tc scintigraphy 
for bone scan
X
X
X
Bilateral bone 
marrow aspirates 
and biopsy
X
X
X
Urine HVA, VMA, 
dopamine
X
X
X
X
X
Pharmacokinetics (PK) and Pharmacodynamics (PD): For details please see following tables
PK and biomarker 
samples
X
X
X
X
X
X
Samples for mRNA
X
X
X
X
X
LPS blood sample
X
PK Urine samples 
X
X
Pharmacogenomics (PGx)
PGx sample
X


2011N118599_09
CONFIDENTIAL
BET115521
252
Part 1 
Assessments
Notes
S
C
R
E
O
T
Week 1
Week 2
W3
W4
W5
W7
W9
q4W
q8W
D
1
D
2
D
3
D
4
D
5
D
6
D
7
D
1
D
2
D
3
D
4
D
5
D
6
D
7
D
1
D
4
D
1
D
4
D
1
D
1
D
1
D
1
D
1
FOLLOW-UP PHASE
Follow-up contact by clinic visit or other means (telephone contact, email, etc) for survival status and anticancer therapy every 6 months. Disease assessment will be collected for subjects who discontinue 
study medication due to any reason other than progression or death. Individual subjects will be considered to have completed the study 2 years after their last treatment or upon death, whichever is 
sooner. Document the cause of death. For the study, the Follow-up Phase ends after a minimum of 70% of subjects have died or 5 years after the last subject is enrolled in Phase 2.
Abbreviations: CK=creatine kinase; CRP=c-reactive protein; D=day; DBP=diastolic blood pressure; ECG=electrocardiogram; ECOG PS=Eastern Cooperative Oncology Group Performance Status; 
EOT=End-of-Treatment; FLC=free light chain; HVA=homovanillic acid; LPS=lipopolysaccharide; MIBG=meta-iodo-benzyl-guanidine; q4W=every 4 weeks; q8W=every 8weeks; SBP=systolic blood 
pressure; SCR=Screening; SPEP=serum protein electrophoresis; UPEP=urine protein electrophoresis; VMA= vanillylmandelic acid; W=week
a.
Subjects with neuroblastoma will have MIBG and bone marrow biopsies after week 24 as clinical indicated to confirm complete remission.
Rationale for Change:
Corrections were made to the Table 8 to clarify that triplicate ECGs are collected during Part 1 and MIBG scan for subjects with 
neuroblastoma.
Previous Text: Table 9
Time and Events: Part 1 Laboratory Assessments
NB: On dosing days, collect blood 
samples prior to dosing. W1D1 samples 
not needed if SCR sample collected 
within 72h of first dose.
Notes
SCR
EOT
W1
W2
W3
W5
W7
W9
q4W
q8W
D1
D2
D6
D1
D6
D1
D1
D1
D1
D1
D1
Troponin, NT-proBNP-9
W1D1, W1D2: local lab sample 3X/24h; 
central lab sample 1X/24h. Unscheduled 
collect 2 samples: 1 for local, 1 for 
central lab
X
X
X
X
X
X
X
X
X
X
X
Hematology
X
X
X
X
X
X
X
X
X
Clinical chemistry
X
X
X
X
X
X
X
X
X
Pancreatic
X
X
X
X
X
X
X
X
X
Coagulation
X
X
X
X
X
X
X
X
X
Creatine phosphokinase
X
X
X
X
X
X
X
X
X


2011N118599_09
CONFIDENTIAL
BET115521
253
NB: On dosing days, collect blood 
samples prior to dosing. W1D1 samples 
not needed if SCR sample collected 
within 72h of first dose.
Notes
SCR
EOT
W1
W2
W3
W5
W7
W9
q4W
q8W
D1
D2
D6
D1
D6
D1
D1
D1
D1
D1
D1
Liver chemistry
X
X
X
X
X
X
X
X
Fasting blood glucose and insulin 
Will be performed at central lab if not 
available at local lab
X
X
X
X
X
X
X
X
X
c-peptide and 1,5 AG
Will be performed at central lab if not 
available at local lab
X
X
X
X
X
HbA1c
X
X
X
X
X
X
Fasting lipids
X
X
X
X
X
X
Thyroid monitoring
TSH, free T3, free T4. If TSH is 
abnormal W1D1, monitor TSH, free T3 
and free T4 going forward
X
X
X
X
X
X
Urinalysis
X
X
X
X
X
X
Guaiac fecal occult blood
X
X
X
X
Pregnancy test, females
Serum pregnancy test within 7 days of 
first dose; urine or serum test thereafter
X
X
X
X
X
X
Testosterone, males
Complete and free testosterone at SCR; 
free testosterone thereafter
X
X
X
X
X
X
CK, CK-MB
Predose and 12-18 h post dose
X
as clinically appropriate
Safety Cytokines
X
as clinically appropriate following fever
HBsAg, HepC antibody
If hepatits C antibody positive, perform 
third generation immunoassay on  same 
sample to confirm results
X
C=cycle; D=day; EOT=End of Treatment Visit; q4W=Every 4 weeks; q8W=every 8 weeks; SCR=Screening; W=week


2011N118599_09
CONFIDENTIAL
BET115521
254
Revised Text:
Table 9
Time and Events: Part 1 Laboratory Assessments
NB: On dosing days, collect blood 
samples prior to dosing. W1D1 samples 
not needed if SCR sample collected 
within 72h of first dose.
Notes
SCR
EOT
W1
W2
W3
W5
W7
W9
q4W
q8W
D1
D2
D6
D1
D6
D1
D1
D1
D1
D1
D1
Troponin, NT-proBNP-9
W1D1, W1D2: local lab sample 3X/24h; 
central lab sample 1X/24h. Unscheduled 
collect 2 samples: 1 for local, 1 for 
central lab
X
X
X
X
X
X
X
X
X
X
X
Hematology
X
X
X
X
X
X
X
X
X
Clinical chemistry
X
X
X
X
X
X
X
X
X
Pancreatic
X
X
X
X
X
X
X
X
X
Coagulation
X
X
X
X
X
X
X
X
X
Creatine phosphokinase
X
X
X
X
X
X
X
X
X
Liver chemistry
X
X
X
X
X
X
X
X
X
Fasting blood glucose and insulin 
Will be performed at central lab if not 
available at local lab
X
X
X
X
X
X
X
X
X
c-peptide and 1,5 AG
Will be performed at central lab if not 
available at local lab
X
X
X
X
X
HbA1c
X
X
X
X
X
X
Fasting lipids
X
X
X
X
X
X
Thyroid monitoring
TSH, free T3, free T4. If TSH is 
abnormal W1D1, monitor TSH, free T3 
and free T4 going forward
X
X
X
X
X
X
Urinalysis
X
X
X
X
X
X
Guaiac fecal occult blood
X
X
X
X
Pregnancy test, females
Serum pregnancy test within 7 days of 
first dose; urine or serum test thereafter
X
X
X
X
X
X
Testosterone, males
Complete and free testosterone at SCR; 
free testosterone thereafter
X
X
X
X
X
X


2011N118599_09
CONFIDENTIAL
BET115521
255
NB: On dosing days, collect blood 
samples prior to dosing. W1D1 samples 
not needed if SCR sample collected 
within 72h of first dose.
Notes
SCR
EOT
W1
W2
W3
W5
W7
W9
q4W
q8W
D1
D2
D6
D1
D6
D1
D1
D1
D1
D1
D1
CK, CK-MB
Predose and 12-18 h post dose
X
as clinically appropriate
Safety Cytokines
This is collected as part of the 
Predose PK sample and is sent to 
GSK DMPK.
X
as clinically appropriate following fever
HBsAg, HepC antibody
If hepatits C antibody positive, perform 
third generation immunoassay on  same 
sample to confirm results
X
C=cycle; D=day; EOT=End of Treatment Visit; q4W=Every 4 weeks; q8W=every 8 weeks; SCR=Screening; W=week
Rationale for Change:
A correction was added to clarify that liver chemistry is collected at Week 7 Day 1.
Previous Text:  
Table 10
Time and Events: Part 1 Pharmacokinetics and Biomarker Sampling, Week 1 and Week 2
W1D1
W1D5
W2D4 + 1 day
pre 
dose
15 min 
± 5m 
30 
min 
±5m
1h 
±5m
2h 
±10m
4h 
±15m
8h 
±1h
16h 
±2h
24h 
±2h
33h 
±3h
30 
min 
±5m
3h 
±15m
pre 
dose
30 
min 
±5m
3h 
±15m
8h 
±1h
12-lead ECG, in 
triplicate, 5 minutes 
apart and within 10 
min of PK draw
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
PK and protein 
biomarker sample
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Urine PK sampling 
(Part 1A only)
X
0-2h
2-24h


2011N118599_09
CONFIDENTIAL
BET115521
256
W1D1
W1D5
W2D4 + 1 day
pre 
dose
15 min 
± 5m 
30 
min 
±5m
1h 
±5m
2h 
±10m
4h 
±15m
8h 
±1h
16h 
±2h
24h 
±2h
33h 
±3h
30 
min 
±5m
3h 
±15m
pre 
dose
30 
min 
±5m
3h 
±15m
8h 
±1h
mRNA whole blood 
sample
X
X
X
X
X
X
LPS whole blood 
sample
X
X
X
X
X
X
Plasma samples will be divided at the GSK DMPK facility where bioanalysis of PK is performed and shipped to a vendor for systemic cytokine assessment (pre-dose and at 15 min, 30 
min, 1 hr, 2 hr, and 4hr) and acute phase protein assessment at pre-dose and at 2,4, 8 and 24 hr post-dose.  The frequency of sampling may be changed (likely reduced) based on 
data from the first few subjects assessed.
Revised Text:
Table 10
Time and Events: Part 1 Pharmacokinetics and Biomarker Sampling, Week 1 and Week 2
W1D1
W1D5
W2D4 + 1 day
pre 
dose
15 min 
± 5m 
30 
min 
±5m
1h 
±5m
2h 
±10m
4h 
±15m
8h 
±1h
16h 
±2h
24h 
±2h
33h 
±3h
30 
min 
±5m
3h 
±15m
pre 
dose
30 
min 
±5m
3h 
±15m
8h 
±1h
12-lead ECG, in 
triplicate, 5 minutes 
apart and within 10 
minutes prior to 
the 15 min and 30 
min PK draws and 
within 15 minutes 
prior to the other 
PK draws.min of PK 
draw
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
PK and protein 
biomarker sample
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X


2011N118599_09
CONFIDENTIAL
BET115521
257
W1D1
W1D5
W2D4 + 1 day
pre 
dose
15 min 
± 5m 
30 
min 
±5m
1h 
±5m
2h 
±10m
4h 
±15m
8h 
±1h
16h 
±2h
24h 
±2h
33h 
±3h
30 
min 
±5m
3h 
±15m
pre 
dose
30 
min 
±5m
3h 
±15m
8h 
±1h
Urine PK sampling 
(Part 1A only)a
X
0-2h
2-24h
mRNA whole blood 
sample
X
X
X
X
X
X
LPS whole blood 
sample
X
X
X
X
X
X
Plasma samples will be divided at the GSK DMPK facility where bioanalysis of PK is performed and shipped to a vendor for systemic cytokine assessment (pre-dose and at 15 min, 30 min, 1 hr, 2 hr, and 
4hr) and acute phase protein assessment at pre-dose and at 2,4, 8 and 24 hr post-dose.  The frequency of sampling may be changed (likely reduced) based on data from the first few subjects assessed.
a.
Urine samples for quantitative analysis of GSK525762 are not required in the NMC PD Expansion Cohort.
Rationale for Change:
Flexibility was added to allow for the collection of blood samples for PK analysis at the earlier time points indicated.  Urine samples are 
not required from the NMC PD Expansion Cohort for quantitative metabolite analysis of GSK525762 since samples will be collected in 
the 3+3 dose escalation.


2011N118599_09
CONFIDENTIAL
BET115521
258
Previous Text: 
Table 11
Time and Events: Part 1 Pharmacokinetics and Biomarker Sampling, Week 3 and Week 9
W3D4 + 2 days
W9D1 ±4 days
(if dose has been escalated, +4 to 
+7 days)
EOT
pre 
dose
15 min 
± 5m 
30 min 
±5m
1h 
±5m
2h 
±10m
4h 
±15m
8h 
±1h
16h 
±2h
24h 
±1h
48h 
±1h
pre 
dose
0.5-2h
4 - 8h
12-lead ECG, in 
triplicate, 5 minutes 
apart and within 10 
min of PK draw
X
X
X
X
X
X
X
X
X
X
X
X
X
PK and protein 
biomarker sample
X
X
X
X
X
X
X
X
X
X
X
X
X
Urine PK sampling 
(Part 1A only)
0-2h
2-24h
mRNA whole blood 
sample
X
X
LPS whole blood 
sample
Plasma samples will be divided at the GSK DMPK facility where bioanalysis of PK is performed and shipped to a vendor for acute phase protein assessment at pre-dose and at 2, 4, 8 
and 24 hr post-dose.  The frequency of sampling may be changed (likely reduced) based on data from the first few subjects assessed.


2011N118599_09
CONFIDENTIAL
BET115521
259
Revised Text: Table 11
Time and Events: Part 1 Pharmacokinetics and Biomarker Sampling, Week 3 and Week 9
W3D4 + 2 days
W9D1 ±4 days
(if dose has been escalated, +4 to 
+7 days)
EOT
pre 
dose
15 min 
± 5m
30 min 
±5m
1h 
±5m
2h 
±10m
4h 
±15m
8h 
±1h
16h 
±4h
24h 
±1h
48h 
±1h
pre 
dose
0.5-2h
4 - 8h
12-lead ECG, in 
triplicate, 5 minutes 
apart and within 10 
min prior of to the 
15 min and 30 min 
of PK draws and 
within 15 minutes 
prior to the other
PK draws
X
X
X
X
X
X
X
X
X
X
X
X
X
PK and protein 
biomarker sample
X
X
X
X
X
X
X
X
X
X
X
X
X
Urine PK sampling 
(Part 1A only)a
0-2h
2-24h
mRNA whole blood 
sample
X
X
LPS whole blood 
sample
Plasma samples will be divided at the GSK DMPK facility where bioanalysis of PK is performed and shipped to a vendor for acute phase protein assessment at pre-dose and at 2, 4, 8 
and 24 hr post-dose.  The frequency of sampling may be changed (likely reduced) based on data from the first few subjects assessed.
a.
Urine samples for quantitative analysis of GSK525762 are not required in the NMC PD Expansion Cohort.
Rationale for Change:
The window for collecting blood for PK and performing ECGs at the 16 hour time point was extended from 16h 2h to 16 4h to allow 
for more flexibility in collecting samples at this timepoint. Urine samples are not required from the NMC PD Expansion Cohort for 
quantitative metabolite analysis of GSK525762 since samples will be collected in the 3+3 dose escalation.


2011N118599_09
CONFIDENTIAL
BET115521
260
Previous Text: Table 12
Time and Events: Part 2
Part 2 Assessments
Notes
SCR
EOT
W1
W2
W3
W4
W5
W9
W13
q4W
q8W
D1
D1
D1
D1
D1
D1
D1
D1
D1
Informed consent
Unless otherwise noted, screening 
assessments to be completed within 14 
days of first dose.
X
Demography
X
Medical history
X
Disease characteristics
X
Cardiology evaluation
X
Prior therapy
X
Register subject
X
TREATMENT PHASE
Study Drug
Dispense study drug
Administer about same time of day. No 
food or antacids 1h before and 2h after.
X
X
X
X
X
X
X
X
Review compliance
Not required when dosed in clinic.
X
X
X
X
Safety
Pregnancy test/testosterone
Females: serum pregnancy test within 7 
days of first dose; urine or serum test 
thereafter. Males: complete and free 
testosterone at SCR; free testosterone 
thereafter.
X
X
X
X
X
X
Physical exam
X
X
X
X
X
X
X
X
X
X
ECOG 
X
X
X
X
X
X
X
X
X
X
Vital Signs
X
X
X
X
X
X
X
X
X
X
Weight and height
Height at SCR only
X
X
X
X
X
X
X
Chest x-ray
X
Pulmonary function test
X
Adverse events
continuous from signing of informed consent
Concomitant medications
continuous from signing of informed consent
Laboratory assessments: For details please see following tables
Tests
X
X
X
X
X
X
X
X
Cardiac Monitoring
ECHO
Within 35 days of first dose
X
X
X
X
X
X
X
X


2011N118599_09
CONFIDENTIAL
BET115521
261
Part 2 Assessments
Notes
SCR
EOT
W1
W2
W3
W4
W5
W9
W13
q4W
q8W
D1
D1
D1
D1
D1
D1
D1
D1
D1
12-lead ECGs (triplicate)
Screening ECGs within 35 days of first 
dose. Triplicate ECGs prior to dosing. If 
QTcF increase >30msec, ECGs daily 
through W2.
X
X
X
X
X
X
X
X
X
X
Holter monitoring
At least 24 h, on dosing days start predose.
X
X
X
Telemetry
Starting predose and for at least 48 h.
X
Efficacy
Lesion  assessments
X
X
X
X
Tumor sample
X
One postdose sample, between W1D4 and 
W9D1, timing optimized based on emerging data
PET scan
X
PK and PD
PK and protein biomarker 
samples
Three samples to be collected each
sampling day for each type of analysis: 
Predose within 60 minutes prior to dose, 
single draw between 0.5-2h postdose, 
single draw between 4-8h postdose. 
Plasma samples will be divided at the GSK 
DMPK facility where bioanalysis of PK is 
performed and shipped to a vendor for 
acute phase protein assessment.
X
X
Blood samples for mRNA
X
X
X
LPS blood sample
X
X
        PGx 
PGx sample
X
FOLLOW-UP PHASE
Follow-up contact by clinic visit or other means (telephone contact, email, etc) for survival status and anticancer therapy every 6 months. Disease assessment will be collected for subjects who discontinue 
study medication due to any reason other than progression or death. Individual subjects will be considered to have completed the study 2 years after their last treatment or upon death, whichever is 
sooner. Document the cause of death. For the study, the Follow-up Phase ends after a minimum of 70% of subjects have died or 5 years after the last subject is enrolled in Phase 2.
Abbreviations: CK=creatine kinase; D=day; ECG=electrocardiogram; ECOG PS=Eastern Cooperative Oncology Group Performance Status; EOT=End-of-Treatment; q4W=every 4 weeks; q8W=every 
8weeks; SCR=Screening; Wk=week


2011N118599_09
CONFIDENTIAL
BET115521
262
Revised Text: Table 12
Time and Events: Part 2
Part 2 Assessments
Notes
SCR
EOT
W1
W2
W3
W4
W5
W9
W13
q4W
q8W
D1
D1
D1
D1
D1
D1
D1
D1
D1
Informed consent
Unless otherwise noted, screening 
assessments to be completed within 14 
days of first dose.
X
Demography
X
Medical history
X
Disease characteristics
X
Cardiology evaluation
X
Prior therapy
X
Register subject
X
TREATMENT PHASE
Study Drug
Dispense study drug
Administer about same time of day. No 
food or antacids 1h before and 2h after.
X
X
X
X
X
X
X
X
Review compliance
Not required when dosed in clinic.
X
X
X
X
Safety
Pregnancy test/testosterone
Females: serum pregnancy test within 7 
days of first dose; urine or serum test 
thereafter. Males: complete and free 
testosterone at SCR; free testosterone 
thereafter.
X
X
X
X
X
X
Physical exam
X
X
X
X
X
X
X
X
X
X
ECOG 
X
X
X
X
X
X
X
X
X
X
Vital Signs
X
X
X
X
X
X
X
X
X
X
Weight and height
Height at SCR only
X
X
X
X
X
X
X
Chest x-ray
X
Pulmonary function test
X
Adverse events
continuous from signing of informed consent
Concomitant medications
continuous from signing of informed consent
Laboratory assessments: For details please see following tables
Tests
X
X
X
X
X
X
X
X
Cardiac Monitoring
ECHO
Within 35 days of first dose
X
X
X
X
X
X
X
X


2011N118599_09
CONFIDENTIAL
BET115521
263
Part 2 Assessments
Notes
SCR
EOT
W1
W2
W3
W4
W5
W9
W13
q4W
q8W
D1
D1
D1
D1
D1
D1
D1
D1
D1
12-lead ECGs (triplicate 
Single)
Screening ECGs within 35 days of first 
dose. TriplicateECGs prior to dosing. If 
QTcF increase >30msec, ECGs daily 
through W2.
X
X
X
X
X
X
X
X
X
X
Holter monitoring
At least 24 h, on dosing days start predose.
X
X
X
Telemetry
Starting predose and for at least 48 h.
X
Efficacy
Lesion  assessments
X
X
X
X
Tumor sample
X
One postdose sample, between W1D4 and 
W9D1, timing optimized based on emerging data
PET scan
X
PK and PD
PK and protein biomarker 
samples
Three samples to be collected each 
sampling day for each type of analysis: 
Predose within 60 minutes prior to dose, 
single draw between 0.5-2h postdose, 
single draw between 4-8h postdose. 
Plasma samples will be divided at the GSK 
DMPK facility where bioanalysis of PK is 
performed and shipped to a vendor for 
acute phase protein assessment.
X
X
X
Blood samples for mRNA
X
X
X
LPS blood sample
X
X
        PGx 
PGx sample
X
FOLLOW-UP PHASE
Follow-up contact by clinic visit or other means (telephone contact, email, etc) for survival status and anticancer therapy every 6 months. Disease assessment will be collected for subjects who discontinue 
study medication due to any reason other than progression or death. Individual subjects will be considered to have completed the study 2 years after their last treatment or upon death, whichever is 
sooner. Document the cause of death. For the study, the Follow-up Phase ends after a minimum of 70% of subjects have died or 5 years after the last subject is enrolled in Phase 2.
Abbreviations: CK=creatine kinase; D=day; ECG=electrocardiogram; ECOG PS=Eastern Cooperative Oncology Group Performance Status; EOT=End-of-Treatment; q4W=every 4 weeks; q8W=every 
8weeks; SCR=Screening; Wk=week


2011N118599_09
CONFIDENTIAL
BET115521
264
Rationale for Change:
Corrections were made to clarify that single ECGs are collected in Part 2 and PK 
collection on Week 4 Day 1 to coincide with Holter monitoring.


2011N118599_09
CONFIDENTIAL
BET115521
265
Previous Text:
6.6.3 Urine Collection
Urine samples for quantitative analysis of GSK525762 will be collected over 24 hours in 
two samples (sample collected 0-2hr and second sample collected 2-24hr) immediately 
following dosing on Week 1 Day 1 and in Week 3. Urine samples will be collected in 
subjects in Part 1A once the 3+3 dose escalation has been reached. Additional sampling 
may be instituted based on emerging data.  
Revised Text:
6.6.3 Urine Collection
Urine samples for quantitative analysis of GSK525762 will be collected over 24 hours in 
two samples (sample collected 0-2hr and second sample collected 2-24hr) immediately 
following dosing on Week 1 Day 1 and in Week 3. Urine samples will be collected in 
subjects in Part 1A once the 3+3 dose escalation has been reached. Additional sampling 
may be instituted based on emerging data.  Urine collection will not be required in the 
PD Expansion Cohort.
Rationale for Change:
Urine samples are not required from the NMC PD Expansion Cohort for quantitative 
metabolite analysis of GSK525762 since samples will be collected in the 3+3 dose 
escalation.
Previous Text:
6.4.5 Safety Electrocardiograms
Safety ECGs will be performed at the time points specified in Time and Events using a 
standard 12-lead ECG machine that automatically calculates the HR and measures PR, 
QRS, QT and QTcF intervals. Details will be provided in the SPM. In Part 1, the 
investigator will review the ECG data manually, and should not rely solely on the 
automatic readings of the equipment, when making decisions regarding dosing of 
subjects.

During Part 1, a single 12-lead ECG should be performed at Screening and at all 
other time points that are not associated with a Serial Pharmacokinetic sampling day. 
Triplicate ECGs should be done for all time points on Serial Pharmacokinetic 
sampling days. 
Standard 12-lead ECGs (Safety ECGs) will be performed as part of the real-time
assessment of subjects and may not be included in the primary QT analysis. Safety ECGs 
should be reviewed by the investigator on an ongoing basis for safety purposes. The 
dosing for each new week in the first cycle should not begin until the safety ECG has 
been reviewed and no significant abnormalities have been detected


2011N118599_09
CONFIDENTIAL
BET115521
266
In addition to the Safety ECGs performed during the study, continuous 12-lead Holter 
ECGs (obtained via a Holter monitor) will be acquired while subjects are at the site. Dual 
snap electrodes will be utilized to enable simultaneous collection of Holter and safety 
ECG data.
All ECGs must include QTcF measurements. Those values greater than 480 msec as 
calculated by the machine must be confirmed manually using Fridericia’s formula given 
below:

The Fridericia’s formula is: QTcF=QT x (1/[RR/1000])1/3

If there are any clinically significant abnormalities including but not limited to a 
QTcF >480 msec, confirm with two additional ECGs taken at least 5 minutes apart.

During Part 1, a single 12-lead ECG should be performed at screening and at all 
other time points that are not associated with a serial pharmacokinetic sampling day. 
Triplicate ECGs should be done for all time points on serial pharmacokinetic 
sampling days. During Part 2, single 12-lead ECGs should be performed at the time 
points indicated in the Time and Events Tables.
Revised Text:
6.4.5 Safety Electrocardiograms
Safety ECGs will be performed at the time points specified in Time and Events using a 
standard 12-lead ECG machine that automatically calculates the HR and measures PR, 
QRS, QT and QTcF intervals. Details will be provided in the SPM. In Part 1, the 
investigator will review the ECG data manually, and should not rely solely on the 
automatic readings of the equipment, when making decisions regarding dosing of 
subjects.

During Part 1, a single triplicate 12-lead ECG should be performed at Screening and 
at all other time points. that are not associated with a Serial Pharmacokinetic 
sampling day. Triplicate ECGs should be done for all time points on Serial 
Pharmacokinetic sampling days. During Part 2, single 12-lead ECGs should be 
performed at the time points indicated in the Time and Events Tables.
Standard 12-lead ECGs (Safety ECGs) will be performed as part of the real-time 
assessment of subjects and may not be included in the primary QT analysis. Safety ECGs 
should be reviewed by the investigator on an ongoing basis for safety purposes. The 
dosing for each new week in the first cycle should not begin until the safety ECG has 
been reviewed and no significant abnormalities have been detected
In addition to the Safety ECGs performed during the study, continuous 12-lead Holter 
ECGs (obtained via a Holter monitor) will be acquired while subjects are at the site. Dual 
snap electrodes will be utilized to enable simultaneous collection of Holter and safety 
ECG data.


2011N118599_09
CONFIDENTIAL
BET115521
267
All ECGs must include QTcF measurements. Those values greater than 480 msec as 
calculated by the machine must be confirmed manually using Fridericia’s formula given 
below:

The Fridericia’s formula is: QTcF=QT x (1/[RR/1000])1/3

If there are any clinically significant abnormalities including but not limited to a 
QTcF >480 msec, confirm with two additional ECGs taken at least 5 minutes apart.

During Part 1, a single 12-lead ECG should be performed at screening and at all 
other time points that are not associated with a serial pharmacokinetic sampling day. 
Triplicate ECGs should be done for all time points on serial pharmacokinetic 
sampling days. During Part 2, single 12-lead ECGs should be performed at the time 
points indicated in the Time and Events Tables.
Rationale for changes:
Corrections were made to clarify that triplicate ECGs are collected in Part 1 and single 
ECGs are collected in Part 2.
Previous Text:
If a subject vomits within four hours after taking study medication, the subject should be 
instructed not to retake the dose and should take the next scheduled dose.
Revised Text:
If a subject vomits after taking study drug, the subject should be instructed not to 
retake the dose and should take the next scheduled dose. If a subject vomits within 
four hours after taking study medication, the subject should be instructed not to retake the 
dose and should take the next scheduled dose.
Rationale for Change:
The instructions for subjects who vomit after taking study drug was corrected to reflect 
the dosing instructions in Table 17.
Other Changes:
The protocol was updated to change EKG to ECG for consistency.  


2011N118599_09
CONFIDENTIAL
BET115521
268
AMENDMENT 04
Protocol Changes for Amendment 4 (06-OCT-2014) from the Protocol Amendment 
3 (04-FEB-2014)
Protocol Amendment 4 applies to all site(s) participating in the conduct of the study
Amendment 04 summary: Amendment 04 includes the addition of subjects with the 
following solid tumor types: castration-resistant prostate cancer (CRPC), triple negative 
breast cancer (TNBC) estrogen receptor positive breast cancer (ER positive), and non-
small cell lung cancer (NSCLC). Multiple myeloma (MM), a haematological malignancy 
previously included in the trial, is now removed from this trial as it is included in a 
separate trial open for hematologic malignancies with dose escalation to better define the 
benefit/risk balance. Additional details of twice daily (BID) dosing during dose escalation 
have been included. A Besylate Sub-Study has been added to determine the relative 
bioavailability (BA), food effect, and dose proportionality of the besylate formulation of 
GSK525762 at or near the MTD. An update to inclusion criteria has been made to allow 
subjects with evaluable disease to be enrolled in the NMC PD cohort. An updated 
imaging schedule for NMC subjects has been included.
Changes are noted below with strikethrough to identify deleted text and underlining to 
identify new or replacement text.
List of Specific Changes
Title Page
Added Text:
Description
This is an open-label, single and repeat dose, multicenter, 2 part study to determine the 
MTD and the recommended Phase 2 dose (RP2D) for GSK525762 given orally once or 
twice daily. Part 1 will be conducted in subjects with NMC and other solid tumors in 
adult subjects (Part 1A) and pediatric subjects (Part 1B). Expansion cohorts (Part 2) are 
planned to further explore the clinical activity of GSK525762 in subjects with NMC and 
other specific solid tumors based on emerging data.
Subject
Revised Text:
Oncology, GSK525762, BET inhibitorInhibitor, NUT Midline Carcinoma, NMC, 
Bromodomain Inhibitor, BRD3, BRD4.


2 0 1 1 N 1 1 8 5 9 9 _ 0 9
C O N FI D E N TI A L
B E T 1 1 5 5 2 1
2 6 9
A ut h ors
Re vise d Te xt:
O nc ol o g y  Bi o mar kers, U S A
Bi ol o g y , E pi ge netics Ma na ge me nt, U S A
Gl o bal F or m ulati o n De vel o p me nt, P T S, U S A
Bi otra nsf or mati o n a n d Dr u g Dis p ositi o n, P T S, U K
M olec ular Me dici ne U nit, U S A
Ca ncer Researc h E pi ge netics Ma na ge me nt, U S A
Cli nical P har mac ol o g y  M o deli ng & Si m ulati o n, U S A
Gl o bal Cli nical O perati o nal Scie nces, U S A
Gl o bal Cli nical O perati o nal Scie nces, U S A
Ca ncer Researc h E pi ge netics, U S A
S A Pat h ol o g y, P T S, U K
Gl o bal Cli nical Sa fet y & P har mac o vi gila nce, U S A
E pi N o va D P U, U K
Gl o bal Cli nical Safet y  & P har mac o vi gila nce, U S A
Bi ol o g y , E pi ge netics Ma na ge me nt, U S A
Statistics, O nc ol o g y  T A Gr o u p, U S A
S p o n s or/ m e d i c al m o nit or I nf or m ati o n P a g e
R ati o n ale f or C h a n ge: T he s p o ns or a n d me dical m o nit ori n g i nf or mati o n has bee n 
u p date d base d o n i nter nal G S K tea m pers o n nel c ha n ges.
Me dic al M o nit or a n d S p o ns or C o nt act I nf or m ati o n
Re vise d Te xt:
R ol e
N a m e
D a y 
Ti m e 
P h o n e 
N u m b er
Aft er -h o ur s 
P h o n e/ C ell/
P a g er 
N u m b er
F a x 
N u m b er
G S K A d dr e s s
Pri m ary 
M e dic al 
M o nit or
, 
M D, P h D
 
Gl ax o S mit h Kli n e
1 2 5 0 S o ut h C oll e g evill e R o a d, 
U P 4 2 1 0 U P 4 4 1 0
C oll e g evill e, P A 1 9 4 2 6, U S A
S ec o n d ary 
M e dic al 
M o nit or
M D, P h D
Gl ax o S mit h Kli n e
1 2 5 0 S o ut h C oll e g evill e R o a d
M ailst o p U P 4 4 1 0
C oll e g evill e, P A 1 9 4 2 6, U S A
P P D
P P D
P P D
P P D
P P D
P P D
P P D
P P D


2011N118599_09
CONFIDENTIAL
BET115521
270
Section PROTOCOL SYNOPSIS
Objectives and Endpoints
Rationale for Change: Primary Objectives and Endpoints were updated to include goals 
of the besylate sub-study and reference to BID dosing.
Revised Text: 
Primary
Objective

To determine the safety, tolerability and maximum tolerated dose (MTD) of 
GSK525762 in subjects 16 years or older following QD and/or BID dosing 
schedules.

To determine the safety, tolerability and maximum tolerated dose (MTD) of 
GSK525762 in subjects 12 to ≤15 years old

To evaluate the clinical activity of GSK525762 in NMC

To evaluate, after single dose administration, the relative bioavailability of the 
GSK525762 besylate tablet compared to the amorphous free-base tablet, the 
effect of high-fat high-calorie meal on the bioavailability of the besylate tablet 
and the dose proportionality of two doses of GSK525762 administered as the 
besylate tablets.
Endpoints

AEs, SAEs, dose reductions or delays, withdrawals due to toxicities and 
changes in safety assessments (e.g., laboratory parameters, vital signs, ECG, 
cardiotoxicity, gastrointestinal, etc) to determine the MTD in subjects 16 years 
or older

AEs, SAEs, dose reductions or delays, withdrawals due to toxicities and 
changes in safety assessments (e.g., laboratory parameters, vital signs, ECG, 
cardiotoxicity, gastrointestinal, etc) to determine the MTD in subjects 12 to ≤15 
years old.

Assess overall response rate (RR) by RECIST 1.1 in NMC

PK parameter values for GSK525762 following single oral administration as 
amorphous free-base or besylate tablet.


2011N118599_09
CONFIDENTIAL
BET115521
271
Secondary (Objectives and Endpoints only)
Objectives

To characterize the pharmacokinetics (PK) of GSK525762 in subjects 16 years 
or older following QD and/or BID dosing schedules. 

To characterize the pharmacokinetics (PK) of GSK525762 in subjects 12 to 
≤15 years old

To evaluate cardiac safety, including the potential for QTcF, of GSK525762 and 
to assess PK/QTcF relationship following QD and/or BID dosing schedules.

To evaluate the exposure response (pharmacokinetic/pharmacodynamic 
[PK/PD]) relationship between GSK525762 and safety and efficacy parameters 
following QD and/or BID dosing schedules.

To evaluate the effect of treatment with GSK525762 on tumor growth and 
survival

To evaluate systemic and ex vivo on-target BET inhibitory effects
Study Design And Duration
Rationale for Change: The study design was updated to include“recommended phase 2 
dose (RP2D)” in addition to recommended dose for Part 2” to better summarize the long-
term goal of determining the MTD which will aim to expand beyond Part 2 of the trial. 
The study design was also updated to include the additional tumor types allowed with this 
amendment and multiple myeloma subjects were removed. The rationale for including 
additional solid tumors is included as part of the overall Study Population Rationale 
(Section 1.2). Multiple myeloma subjects will now be excluded from further enrolment in 
this solid tumor trial, as there is now a separate phase 1 dose escalation trial open in for 
hematologic malignancies to better define the benefit/risk balance. It has been difficult to 
enrol MM patients to this trial (1 out of 18 subjects over 2 years) and the higher doses 
already reached with solid tumors pose additional risk to MM patients.
Revised Text:
This study is divided into 2 parts: 

Part 1A of the study is a dose escalation phase to determine the maximum 
tolerated dose (MTD) and select the a recommended dose for Part 2 or a 
recommended Phase 2 dose (RP2D) based on the safety, pharmacokinetic, 
and pharmacodynamic profiles observed after oral administration of 
GSK525762. Eligible subjects with NUT midline carcinoma (NMC), small 
cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), colorectal 
cancer (CRC), neuroblastoma (NB), castration resistant prostate cancer 
(CRPC), triple negative breast cancer (TNBC), estrogen receptor positive 
(ER positive) breast cancer, multiple myeloma and any other MYCN-
amplified solid tumor will be enrolled in the dosing cohorts until a maximum 
tolerated dose (MTD) is established.  Subjects with NMC will also be 
enrolled in a pharmacodynamic dose expansion cohort during Part 1A.  


2011N118599_09
CONFIDENTIAL
BET115521
272
Subjects may continue treatment in the study until disease progression, 
unacceptable toxicity, or withdrawal of consent. Once the MTD is 
determined in adult subjects,  

Part 1A  besylate sub-study  will explore the relative bioavailability, food 
effect and dose proportionality of besylate formulation. The sub-study will be 
conducted in subjects eligible for Part 1A at the MTD or a dose near the 
MTD or RP2D. This will be an open-label, randomized, single dose, four 
period, cross over sub-study to investigate the relative bioavailability of the 
besylate tablet compared to the amorphous free-base tablet, the effect of 
high-fat high-calorie meal on the bioavailability of the besylate tablet and the 
dose proportionality of two doses of GSK525762 administered as besylate 
tablets.

Part 1B will be opened to enroll pediatric subjects 12 to ≤15 years of age with 
solid tumors to determine the MTD in pediatric subjects.  Dose escalation in 
Part 1B will begin at 25% of the adult MTD and dose escalation will follow a 
3+3 design.  Pediatric subjects 12 to ≤15 years old may be enrolled in Part 2 
once the MTD has been determined in Part 1B. An

Part 2 is an expansion cohort is planned to further explore clinical activity at 
the MTD in NMC (Part 2) subjects.   

Duration of study will depend on recruitment rates, and timing of subjects’ 
duration on study (withdrawal rates due to toxicity or progression).
Subject Sample
Rationale for Change: Overall subject numbers were increased to account for the 
subjects in the besylate sub-study.
Revised Text:
Approximately 70-90100 subjects worldwide.
Section 1.2. Study Population Rationale
Rationale for Change:Updated various references and resources to reflect most current 
publication. Updated study population rationale section to include recent preclinical and 
other emerging data for inclusion of select solid tumor types. Multiple myeloma was 
removed from this section.


2 0 1 1 N 1 1 8 5 9 9 _ 0 9
C O N FI D E N TI A L
B E T 1 1 5 5 2 1
2 7 3
Re vise d Te xt, Secti o n 1. 2. 1. N U T mi dli ne c arci n o m a
P ar a gr a p h 1 :
N M Cs are i n varia bl y  let hal a n d des pite a g gressi ve c he m ot hera pe utic re gi me ns, s u bjects 
ha ve a me dia n life e x pecta nc y  of o nly 6. 7 m o nt hs ( N = 6 3 patie nts) [ Ba uer, 2 0 1 2 ,
 
pers o nal c o m m u nicati o n ].
Re vise d Te xt, Secti o n 1. 2. 2
1. 2. 2.
Ot her s oli d t u m ors t u m or t y pes
Rece ntl y  p u blis he d data as well as data ge nerate d i nter nall y at G S K a n d b y c olla b orat ors
ha ve de m o nstrate d t he p ote ntial a p plicati o n of B R D e xtra -ter mi nal ( B E T) i n hi bit ors i n 
t u m or t ypes ot her t ha n N M C, i ncl u di n g m ulti ple m y el o ma ( M M), s mall cell l u n g ca ncer 
( S C LC), c ol orectal ca ncer ( C R C)n o n -s mall cell l u n g ca ncer ( N S C L C), c ol orectal ca ncer 
( C R C), castrati o n resista nt pr ostate ca ncer ( C R P C), tri ple ne gati ve breast ca ncer ( T N B C);  
estr o ge n rece pt or p ositi ve ( E R p ositi ve) breast ca ncer ,  ne ur o blast o ma ( N B), ac ute 
le u ke mias, a n d ot her N-M y c dri ve n t u m ors. St u dies i n le u ke mia a n d M M ha ve s h o w n 
t hat s mall m olec ule i n hi biti o n of B E T pr otei n bi n di n g t o c hr o mati n ca n directl y bl oc k 
b ot h c -M y c e x pressi o n a n d its d o w nstrea m tra nscri pti o nal f u ncti o ns, res ulti n g i n 
si g nifica nt a nti-t u m or effects [ Del m ore, 2 0 1 1; Mertz, 2 0 1 1]. M yc fa mil y pr otei ns pla y  a 
ce ntral r ole i n t he re g ulati o n of ge ne e x pressi o n a n d cell c y cle c o ntr ol. T heir e n ha nce d 
e x pressi o n has bee n i m plicate d i n all as pects of t u m or cell bi ol o g y  [ A d hi kar y, 2 0 0 5].
Base d o n t he precli nical fi n di n gs wit hi n G S K, s u bjects wit h t he multi ple m yel o ma, s mall 
cell l u n g ca ncer, c ol orectaln o n -s mall cell l u n g ca ncer ( N S C LC), c ol orectal ca ncer, 
castrati o n resista nt pr ostate ca ncer ( C R P C), tri ple ne gati ve breast ca ncer ( T N B C), 
estr o ge n rece pt or p ositi ve ( E R p ositi ve) breast ca ncer, ne ur o blast o ma, a n d N -M y c 
a m plifie d s oli d t u m ors will be e nr olle d t o t he d ose fi n di n g part of t he st u d y .
M ulti pl e M y el o m a
Rece nt p u blicati o ns de m o nstrate d sile nci n g of c -M y c e x pressi o n b y B E T i n hi bit ors i n 
M M [ Del m ore, 2 0 1 1], B ur kitt’s l y m p h o ma, a n d ac ute m y el oi d le u ke mia [ Mertz, 2 0 1 1].
A hi g h perce nta ge of M M li nes ( 6 2 %, 1 3/ 2 1) are se nsiti ve t o G S K 5 2 5 7 6 2, m ost of w hic h 
are M yc dri ve n. Rela pse d refract or y m yel o ma patie nts will be eli gi ble f or t he d ose 
escalati o n part of t he st u d y . Gi ve n t he se nsiti vit y of a maj ority of M M li nes teste d a n d 
t hat m ost were Myc dri ve n, a selecti o n mar ker will n ot be use d f or e ntr y i nt o t he d ose 
escalati o n part of t he st u d y . H o we ver, data will be c ollecte d retr os pecti vel y fr o m 
a vaila ble tiss ues i n or der t o i de ntif y  p ote ntial pre dicti ve bi o mar kers.
S m all C ell L u n g C a n c er
G S K 5 2 5 7 6 2 was f o u n d t o i n hi bit gr o wt h of t he great maj orit y  of all S C LC li nes teste d, 
wit h 3 3 of 3 7 li nes p ossessi n g gI C 5 0 < 1 0 µ M. I n or der t o i de ntif y  t he m ore se nsiti ve cell 
li nes, t he criteri o n f or G S K 5 2 5 7 6 2 se nsiti vit y was defi ne d as gI C1 0 0 (c o nce ntrati o n 
res ulti n g i n net cell deat h) < 1 0 µ M. B y t his defi niti o n, 3 8 % ( 1 4/ 3 7) of S C L C li nes are 
P P D


2011N118599_09
CONFIDENTIAL
BET115521
274
more sensitive in a subset of SCLC cell lines, with 46% (18 of 39) of cell lines possessing 
a gIC50 < 1 µM. It was confirmed in several of the cell lines that apoptosis (assessed by 
caspase cleavage) is induced at concentrations above the gIC100.  In the 14 most sensitive 
cell lines, the median gIC50 = 0.53 µM and the median gIC100 = 2.2 µM. For comparison, 
GSK525762 has been tested in two cultured lines from NUT-midline carcinoma with an 
average gIC50 = 0.12 µM and average gIC100 = 0.32 µM Additionally, significant tumor 
growth inhibition was observed in a subset of cell line and patient-derived subcutaneous 
xenograft models of SCLC. 
No correlation between status of c-Myc or L-Myc and sensitivity was found. N-Myc 
amplified cell lines were found to be sensitive, though the low number (N=2) of lines 
tested with this amplification does not allow for a firm conclusion to be drawn. Although 
no predictive marker of GSK525762 sensitivity in SCLC has been identified and 
considering the high percentage of cell lines that are sensitive, we would enroll all 
relapsed refractory SCLC patients in the dose escalation part of the study while collecting 
data retrospectively on potential predictive biomarkers from the available tissues.
Non-Small Cell Lung Cancer
GSK525762 inhibited cell growth in a high percentage of NSCLC cell lines, with 73% 
(19/26) of cell lines tested exhibiting a gIC50 <1µM. Median gIC50 across the NSCLC cell 
line panel was 0.61µM. MYCN amplified cell lines were among the most sensitive 
NSCLC cell lines to GSK525762, with a median gIC50 of 0.17µM and gIC100 of 3.6µM 
(n=4). A subset of NSCLC cell lines, including the MYCN-amplified lines, exhibited a 
cytotoxic response to GSK525762. Given the broad sensitivity of NSCLC cell lines to 
GSK525762, a selection marker will not be used for entry into the dose escalation part of 
the study.
Colorectal Cancer 
In colorectal cell lines, initial data using the same criterion of sensitivity indicates that 
GSK525762 is cytotoxic inhibits growth in a high percentage of lines tested (54%, 
7/1358%, 25/43 with gIC100 < 10 µM). In the 7 sensitive cell lines, the median gIC50 = 
0.18 µM and the median gIC100 = 2.2 µM. Also, GSK525762 was found to be sensitive in 
KRAS-mutant colorectal lines, as 5/7 sensitive lines possess this mutation < 1 µM). No 
markers of sensitivity in these lines has been identified yet and, as with SCLC, we 
recommend dosing of all relapsed refractory CRC without a selection marker in an initial 
clinical trial.
Neuroblastoma
All NB cell lines are sensitive to GSK525762, with 83% of cell lines tested to date (n = 
6) were found to be sensitive to GSK525762, with an average (15/18) exhibiting a gIC50
= 0.43 µM (n=6) and average gIC100 = 2.3 µM (n=4). The agent is sensitive in MYCN-
amplified lines, as 3 of the 4 lines < 1µM. Median gIC50 across the NB cell line panel was 
0.48µM, with a subset of cell lines exhibiting a cytotoxic response to GSK525762. The 
agent is sensitive in MYCN amplified cell lines, as 10 of the 15 sensitive cell lines possess 
the copy number increase. As with MM, CRC, and SCLC, subjects with NB may be 
eligible without regard to N-myc status .


2011N118599_09
CONFIDENTIAL
BET115521
275
N-Myc amplified solid tumors
N-Myc driven solid tumors from different sources have shown to be sensitive to 
GSK525762. GSK525762 was tested in a panel of NSCLC lines, and N-Myc 
amplification was found to be CRC, a selection marker of sensitivity.  One hundred 
percent (5/5) of N-Myc amplified lines were highly sensitive while only 8.3% (1/12) of 
non N-Myc amplified lines were highly sensitive.  GSK525762 possesses a median 
gIC50 = 0.37 µM (n=5), gIC100 = 4.7 µM (n=4), in N-Myc amplified cell lines will not 
be used in NB patients for entry into the dose escalation part of the study.
Castration-Resistant Prostate Cancer
A subset of protate cancer cell lines were found to be sensitive to GSK525762, with 57% 
(4/7) of cell lines exhibiting a gIC50 <1µM. Apoptosis was observed in a subset of 
prostate cancer cell lines as measured by poly ADP ribose polymerase (PARP) cleavage 
and accumulation of cells in sub-G1 phase of cell cycle. Prostate cancer lines cell lines, 
including models of CRPC, with high androgen receptor (AR) and high c-Myc protein 
expression were found to be the most sensitive (lowest gIC50) to GSK525762A. 
Consistent with in vitro observations, significant tumor growth inhibition was observed in 
a subcutaneous patient-derived xenograft model of CRPC expressing high levels of AR 
and MYC. In contrast, no significant inhibition of tumor growth was observed in a 
second model expressing low levels of AR and MYC. Given the limited availability of 
pre-clinical prostate models and the broad sensitivity of prostate cancer cell lines to 
GSK525762, we recommend that no selection marker be used for entry into the dose 
escalation part of the study.
Triple Negative and ER-positive Breast Cancer
A subset of breast cancer cell lines representing the ER-positive and triple negative sub-
types were found to be sensitive to GSK525762, with 55% (17/31) cell lines tested 
exhibiting a gIC50 < 1µM. Median gIC50 across the breast cancer cell line panel was 
980nM, with a subset of cell lines exhibiting a cytotoxic response to GSK525762. 
The activity observed with GSK525762 in ER+ breast cancer cell lines is consistent with 
data reported in two recent publications using the tool BET inhibitor JQ1 [Feng Q, 2014; 
Nagarajan, 2014]. Given the broad activity of BET inhibitors across the ER+ and triple 
negative subtypes, we recommend that no selection marker be used for entry into the 
dose escalation part of the study for ER-positive and TNBC patients.
N-Myc amplified solid tumors
A large majority of N-Myc amplified cell lines from various tumor types, including 
SCLC, NSCLC, and neuroblastoma, are highly sensitive to GSK525762. Across the three 
tumor types, 16 of 19 (84%) MYCN-amplified cell lines possess a gIC50 < 1µM, and 11 of 
19 (58%) exhibit a cytotoxic response to GSK525762. Expression of MYCN was 
suppressed by GSK525762 in SCLC and NB cell lines, which is consistent with 
published reports [Puissant 2013; Wyce 2013].


2011N118599_09
CONFIDENTIAL
BET115521
276
Given the high percentage of responsive cell lines in multiple myeloma, small cell lung 
cancer, non-small cell lung cancer, colorectal, castration-resistant prostate cancer, triple-
negative breast cancer, ER-positive breast cancer, and neuroblastoma it is appropriate to 
include refractory patients who have failed prior treatments regimens into the dose 
escalation phase of this study where this medicine may prolong survival. In addition 
subjects with any solid tumor that demonstrates N-myc amplification (e.g., NSCLC with 
N-Myc amplification) will be eligible for the dose escalation phase of the study.
Section 1.3 Dose Rationale
Rationale for Change: Updated with clinical pharmaocokinetic data from subjects 
enrolled to date on ongoing trial to support continuation of dose escalation in effort to 
determine MTD. Also included rationale for BID dosing supported by preclinical and 
clinical pharmaocokinetic and pharmacodynamic data.
Revised Text, Section 1.3.1
1.3.1
Human Pharmacokinetic extrapolation Pharmacokinetics
Whole blood human clearance was predicted from three species (mouse, rat and dog) 
using simple power-law allometry (in the absence of detectable in vitro metabolism) to be 
2.8 ml/min/kg. Volume of distribution was predicted from Gastroplus to be 2.6 L/kg and 
half-life 10 hours (GlaxoSmithKline Document Number 2010N108204_00, 2011). As the 
in vitro blood to plasma ration was 0.86, a 70 kg adult therefore has predicted total 
clearance of 10.1 L/hr and a total plasma volume of distribution of 157 L. Bioavailability 
is predicted to be high given GSK525762 is a Bio-pharmaceutics Classification System 
(BCS) Class 1 molecule, and assumed to fall in the range 50-100%.
As of 23-July-2014, the pharmacokinetics of GSK525762 has been evaluated in 19 
subjects following single and repeated daily administration of 2 mg to 60 mg of 
GSK525762. The summary statistics of the preliminary PK parameters are summarized in 
Table 1 and Table 2 after single and repeat daily oral administration, respectively. 
GSK525762 pharmacokinetics are characterized by a rapid absorption with maximum 
concentration occurring mostly within the first hour after dosing. GSK525762 is 
eliminated rapidly with an average terminal phase half-life of 3 to 7 hours, leading to a 
lack of accumulation following once daily oral administration. Following single oral 
administration and repeated once daily administration of 2 mg to 60 mg of GSK525762, 
Cmax and AUC tended to increase in a dose proportional fashion. 


2011N118599_09
CONFIDENTIAL
BET115521
277
Table 1
Summary Statistics of GSK525762 Preliminary PK Parameters 
Following a Single Oral Administration of GSK525762 in Study 
BET115521
2 mg
4 mg
8 mg
16 mg
30 mg
60 mg
Parameters
Unit
N=3
N=4
N=1
N=3
N=4
N=4
Cmax
ng/mL
51.0 
(41%)
70.4 
(29%)
120
176 
(37%)
604 (30%)
940 (31%)
tmax
h
0.5 (0.5 -
0.6)
1.2 (0.5 
- 2.0)
1.1
2.0
2.0 (0.97 -
2.0)
1.0 (0.5 - 2.0)
AUC
ng.h/m
L
172 (42%)
361 
(35%)
434
884 
(40%)
4420 (63%)
3720 (57%)
t1/2z
h
3.3 
(103%)
5.1 
(36%)
2.95
6.9 
(46%)
6.4 (37%)
6.1 (49%)
Note: Data are presented as geometric mean (CV%) for all parameters except for tmax where the median (min-max) 
are presented. If N=1, individual data are presented. Cmax is the maximum concentration observed at time tmax. AUC 
is the area under the concentration-time curve from 0 to infinity. T1/2 is the terminal phase half-life.
Table 2
Summary Statistics of GSK525762 Preliminary PK Parameters 
Following Repeat Daily Oral Administration of GSK525762 in Study 
BET115521
2 mg
4 mg
8 mg
16 mg
30 mg
60 mg
Parameters
Unit
N=1
N=2
N=1
N=3
N=4
N=2
Cmax
ng/mL
52
47.6 ; 
59.9
103
138 
(25%)
603 (17%)
602; 736
tmax
h
1.0
1.0 ; 
4.0
0.5
1.5
0.9 (0.32 -
4.0)
1.0 ; 1.0
AUC
ng.h/mL
160
225 ; 
497
330
674 
(21%)
3150 
(55%)
2010; 
5290
t1/2z
h
4.27
3.69 ; 
4.46
4.92
3.6 
(7.8%)
5.2 (26%)
2.5; 4.9
Cmax Week 3 / 
Cmax Week 1
--
1.42
0.968 ; 
0.609
0.857
0.780 
(12%)
0.998 
(24%)
1.01; 
1.23
AUCWeek 3 / AUC 
Week 1
--
1.38
0.900 ; 
1.64
0.759
0.774 
(20%)
0.724 
(12%)
0.898; 
0.712
AUCweek 3 / AUCt 
Week 1
--
1.39
0.904 ; 
1.67
0.763
0.792 
(20%)
0.799 
(11%)
0.902; 
0.778
Note: Data are presented as geometric mean (CV%) for all parameters except for tmax where the median (min-max) 
are presented. If N=1 or 2, individual data are presented. Cmax is the maximum concentration observed at time tmax. 
AUCis the area under the concentration-time curve from 0 to 24 hours, the end of the dosing interval. T1/2 is the 
terminal phase half-life.


2011N118599_09
CONFIDENTIAL
BET115521
278
Added Text:
1.3.5. BID Dose Cohort 
1.3.5.1.  Preclinical Rationale
Pre-clinical pharmacokinetic and pharmacodynamic data suggests a potential benefit of a 
BID dosing regimen compared to QD dosing. In mice, GSK525762 has a short half-life 
of about 1.5 hours. Single dose pharmacodynamic experiments were performed in three 
SCLC and one CRC mouse xenograft model. Dose-dependent changes in gene expression 
were observed in all models at early time points post-dose; however, expression returned 
to pre-treatment levels within 8-12 hours. Additionally, in a subcutaneous multiple 
myeloma cell line xenograft study, c-Myc protein levels were significantly reduced 2 and 
5 hours post-dose, and returned to baseline by 8 hours.The transient effects on gene 
expression observed in these studies with QD dosing highlights the potential benefit of 
BID dosing by extending the duration of gene silencing within a 24 hour period.
QD and BID dosing have been further explored in efficacy studies in the above-
mentioned SCLC and CRC xenograft models. In a subcutaneous, patient-derived model 
of SCLC, BID dosing at 12.5mg/kg resulted in improved tumor growth inhibition 
compared to 25 mg/kg QD (74% versus 60%, respectively).  Improved efficacy with BID 
dosing was also observed in the cell line xenograft model of CRC. BID dosing at 
12.5mg/kg resulted in 48% tumor growth inhibition, whereas 25mg/kg QD dosing 
resulted in 34% inhibition.  In a third model, a cell line xenograft of SCLC, there was no 
significant difference in tumor growth inhibition resulting from 12.5mg/kg BID versus 
25mg/kg QD dosing. Thus, we observed equivalent or improved efficacy with BID 
dosing in all xenograft models tested.
1.3.5.2.  Clinical Rationale
Based on the pharmacokinetics of GSK525762 observed to date, with  the short half-life 
of about 5 hours, it is predicted that even 100 mg QD doses would result in the trough 
concentrations falling below the average in vitro IC50 (0.08 uM to 1.3 uM) for the tumor 
types selected for this study. Dividing the daily dose into two doses administered about 
12 hours apart would maintain the concentrations above the lower in vitro IC50 for doses 
around 30 mg BID.  
1.3.6. Doses for Besylate Bioavailability/Food Effect/Dose Proportionality Sub-
Study
A dose at or near the maximum tolerated dose or the recommended Phase 2 dose will be 
used to evaluate the relative bioavailability of the besylate salt tablet compared to the 
amorphous free-base tablet, as this dose would be the dose level used in Part 2. 
As GSK525762 is a compound with high solubility but low permeability, it is expected 
that administration with food will have no effect or possibly a negative effect on its 
absorption [Gu, 2007] Pharm Res 2007, and a dose at or near the MTD or RP2D will be 
used to evaluate the effect of food on the relative BA of GSK525762 administered as the 
besylate salt tablet.  


2011N118599_09
CONFIDENTIAL
BET115521
279
In addition, to evaluate the dose proportionality of the PK of GSK525762 after fasted 
administration as besylate salt tablet, a lower dose of half to one-third of the MTD or 
RP2D will be evaluated.
Section 1.4 Rationale for Study and Endpoints
Rationale for Change: Updated this section to include additional solid tumors and the 
besylate sub-study and to removemultiple myeloma.
Study schema was replaced to provide additional clarification and to include the Besylate 
sub-study. A separate schema was included to illustrate the besylate sub-study.
Revised Text:
Safety and efficacy (RR) are being assessed to address the primary objectives of the 
study. The safety assessments along with the PK will be important for determining the 
MTD of once daily and/or twice daily dosing. The pharmacodynamic assessments will 
further support the recommended Phase II doses (RP2D) and expand the understanding 
regarding mechanism of action. The response rate hurdle of 20% in NMC was 
determined based on 3 parameters: NMC is a rare population, there is currently no 
standard of care therapy for NMC, and NMC carries a poor prognosis (median survival of 
9.56.7 months [French, 2010] [Bauer, 2012]).
Given the poor prognosis and high unmet medical need of NMC, as well as in other 
tumor types such as relapsed/refractory SCLC, NSCLC, CRC, MM, NBCRPC, TN and 
ER+ BC, NB and N-Myc amplified tumors and the exceptional drug-to-target alignment 
of GSK525762, a combined Phase I/II study (BET115521) is proposed. The BET115521 
study comprises an accelerated dose titration (Part 1), which will include subjects with 
NMC and other tumor types that are predicted to be responsive to GSK525762, to 
determine a maximum tolerated dose (MTD). The besylate sub-study will be an open-
label, randomized, single dose, four period, crossover sub-study to investigate the relative 
bioavailability of the besylate salt tablet compared to the amorphous free-base tablet at a 
dose at or near the MTD or RP2D, the effect of high-fat high-calorie meal on the 
bioavailability of the besylate salt tablet at or near the MTD or RP2D and the dose 
proportionality of two doses of GSK525762 administered as besylate salt tablets. Results 
of the besylate sub-study will enable the use of the besylate salt tablet formulation later in 
this study and provide recommendation around the need for fasting status when 
administering GSK525762.
The recommended phase II dose (RP2D) of GSK525762 with possible adjustment based 
on the relative bioavailability of the besylate salt formulation, will be studied in the 
cohort expansion (Part 2) to determine efficacy, safety and tolerability in NMC patients.


2011N118599_09
CONFIDENTIAL
BET115521
280
Section 1.5. Risk Assessment
Rationale for Change: Minor updates for clarification are included in this section. The 
risk assessment was also updated to include reproductive risks based on emerging 
preclinical data. 
Revised Text:
Paragraph 1:
However, toxicologyToxicology studies performed in dogs, rats and mice suggest that the 
primary toxicities of GSK525762 are gastrointestinal, cardiovascular, pancreatic, 
hematologic and reproductive (see Clinical Investigational Brochure, Section 3.4).
Paragraph  7 (Telemetry):
Continuous telemetric in-patient monitoring for potential adverse arrhythmias will be 
performed for at least 48 hours from the startadministration of each the first dose.
Paragraph  8 Heading:
Holter Monitoring and Serum Markers
Paragraph  11 (Cytokines):
In vitro incubation of human whole blood for 24 hours with GSK525762 resulted in a 
time and concentration-dependent induction of IL-1β. The maximum effect was variable 
between donors (34 to 3986 pg/mL, mean 1238 pg/mL from 16 donors); however, the 
concentration required to drive this effect was consistent across the donors (pEC50 6.0, 
0.42ug/mL). This effect was not observed in whole blood from other species (rat and 
dog) or in preparations of human PBMCs or neutrophils.  A human Cmax of 0.42 ug/mL 
would only be anticipated above the preclinical MTD (human doses 75-100 mg).  Parity 
at Cmax for the EC20 from the most sensitive donor in these studies (pEC20 6.16, 0.29 
ug/mL) is predicted to correspond to ~50 mg of a dose in humans. Special note is made 
for the occurrence of fever which could be symptomatic of cytokine level elevation 
during dosing of the compound (see protocol Section 7.7,  Table 28 “Fever”), and close 
monitoring of cytokine levels will be instigated at this point.
Added Text:
Preliminary rat embryo fetal development 
GSK525762 at 0, 1, 3, 10, or 30 mg/kg/day (total dose; doses expressed as parent 
compound) was given orally by gavage BID (doses given 6 hours apart) to pregnant rats 
on Days 0 through 17 post-coitus. Dose-dependent maternal toxicity (reduced body 
weight gain and reduced food consumption) was evident at ≥10 mg/kg/day. Embryo-fetal 
toxicity was evident as both pre-implantation loss and increased fetal resorptions leading 
to complete loss of litters at 30 mg/kg/day, and dose-dependent increased fetal 
resorptions at doses ≥1 mg/kg/day. Developmental toxicity was evident as decreased fetal 
weights at 10 mg/kg/day and fetal malformations and/or variations at all doses 


2011N118599_09
CONFIDENTIAL
BET115521
281
(membranous ventricular septal defects in the heart ≥1 mg/kg/day; great vessel, heart, 
kidney, ovary, uterus, and ureter malformations and/or variations at 10 mg/kg/day). The 
AUC0-t and Cmax at 1 mg/kg/day (the lowest dose tested) in non-mated female rats after 
5 doses were 54 ng.h/mL and 18 ng/mL, respectively.
Section 2.
Objectives, Endpoints, Hypotheses
Rationale for Change: Primary Objectives and Endpoints were updated to include goals 
of the besylate sub-study and reference to BID dosing.
Revised Text:
2.
OBJECTIVES, ENDPOINTS, HYPOTHESES FOLLOWING QD AND/OR 
BID DOSING SCHEDULES
Primary
Objective

To determine the safety, tolerability and maximum tolerated dose (MTD) of 
GSK525762 in subjects 16 years or older following QD and/or BID dosing 
schedules.

To determine the safety, tolerability and maximum tolerated dose (MTD) of 
GSK525762 in subjects 12 to ≤15 years old

To evaluate the clinical activity of GSK525762 in NMC

To evaluate, after single dose administration, the relative bioavailability of the 
GSK525762 besylate tablet compared to the amorphous free-base tablet, the 
effect of high-fat high-calorie meal on the bioavailability of the besylate tablet 
and the dose proportionality of two doses of GSK525762 administered as the 
besylate tablets.
Endpoints

AEs, SAEs, dose reductions or delays, withdrawals due to toxicities and 
changes in safety assessments (e.g., laboratory parameters, vital signs, ECG, 
cardiotoxicity, gastrointestinal, etc) to determine the MTD in subjects 16 years 
or older

AEs, SAEs, dose reductions or delays, withdrawals due to toxicities and 
changes in safety assessments (e.g., laboratory parameters, vital signs, ECG, 
cardiotoxicity, gastrointestinal, etc) to determine the MTD in subjects 12 to ≤15 
years old.

Assess overall response rate (RR) by RECIST 1.1 in NMC

PK parameter values for GSK525762 following single oral administration as 
amorphous free-base or besylate tablet.


2011N118599_09
CONFIDENTIAL
BET115521
282
Secondary (Objectives and Endpoints only)
Objectives

To characterize the pharmacokinetics (PK) of GSK525762 in subjects 16 years 
or older following QD and/or BID dosing schedules. 

To characterize the pharmacokinetics (PK) of GSK525762 in subjects 12 to 
≤15 years old

To evaluate cardiac safety, including the potential for QTcF, of GSK525762 and 
to assess PK/QTcF relationship following QD and/or BID dosing schedules.

To evaluate the exposure response (pharmacokinetic/pharmacodynamic 
[PK/PD]) relationship between GSK525762 and safety and efficacy parameters 
following QD and/or BID dosing schedules.

To evaluate the effect of treatment with GSK525762 on tumor growth and 
survival

To evaluate systemic and ex vivo on-target BET inhibitory effects
Section 3.1. Study Design/Schematic
Rationale for Change: Updated this section to include additional solid tumors and the 
besylate sub-study and to removemultiple myeloma.
Revised Text:
Paragraph 2:
This is an open-label, single and repeat dose, 2-part study to determine the maximum 
tolerated dose (MTD) and the recommended Phase 2 dose (RP2D) for GSK525762 given 
once-daily orally. Twice daily dosing may also be explored upon evaluation of safety, 
PK, and PD data from once-daily dosing. (Part 1A) will be conducted in adult subjects 
with NMC, multiple myeloma (MM), small cell lung cancer (SCLC), non-small cell lung 
cancer (NSCLC), colorectal cancer (CRC), neuroblastoma (NB), castration resistant 
prostate cancer (CRPC), triple negative breast cancer (TNBC), estrogen receptor positive 
(ER positive) breast cancer, and MYCN  driven solid tumors [including non-small cell 
lung cancer (NSCLC) with MYCN amplification].  During the dose escalation of Part 
1A, additional subjects with NMC will be enrolled in a Pharmacodynamic (PD) 
Expansion Cohort to evaluate the pharmacodynamic effects of GSK525762 at lower 
doses that have been previously cleared during dose escalation.  This will enable 
collection of pharmacodynamic data across the predicted efficacious dose range and 
contribute to the evaluation of a biologically efficacious dose.  Once the RP2D is 
determined in adult subjects, Part 1B will be opened to enroll pediatric subjects 12 to ≤15 
years of age with solid tumors to determine the RP2D in this age group. Once the RP2D 
is determined in Part 1A, a besylate sub-study will be opened to approximately 10 
subjects to investigate the relative bioavailability of the besylate tablet compared to the 
amorphous free-base tablet at the MTD or RP2D, the effect of high-fat high-calorie meal 
on the bioavailability of the besylate tablet at the MTD or RP2D and the dose 
proportionality of two doses of GSK525762 administered as besylate tablet. This sub-


2011N118599_09
CONFIDENTIAL
BET115521
283
study will also use a stable isotope of GSK525762 in order to reduce the variability in the 
measurement of drug exposure caused by day-to-day biologic variations. After Part 1A is 
complete and the relative BA of the formulation for Part 2 is confirmed, an Dose 
escalation in Part 1B will begin at 25% of the adult MTD and dose escalation will follow 
a 3+3 design.  An expansion cohort (Part 2) is planned to further explore clinical activity 
of GSK525762 in subjects with NMC as shown in Figure 1. The expansion cohort will 
enroll both adult (16 years old and above) and pediatric (12 to ≤15 years) subjects at their 
appropriate R2PD doses. After the MTD is determined in adult subjects, Part 1B is 
planned for enrollment of pediatric subjects 12 to ≤15 years of age with solid tumors to 
determine the RP2D in this age group. Dose escalation in Part 1B will begin at 25% of 
the adult MTD and dose escalation will follow a 3+3 design.
Paragraph 4:
After the MTD has been determined in Part 1A, and the besylate sub-study has 
completed, Part 1B and Part 2 will be opened. Dose titration in the pediatric subjects in 
Part 1B will start at 25% of the MTD determined in Part 1A and will follow a standard 
3+3 design. Pediatric subjects 12 to 15 years of age will be entered allowed to enroll in
Part 2 upon completion of once the MTD has been determined in Part 1B.
Figure 1 Study Schema (Deleted)


2011N118599_09
CONFIDENTIAL
BET115521
284
Figure 1 Study Schema (Replaced)
Part 1 and 2
B. Besylate Sub-Study (N=8 to 10 subjects)
After completion of either sequence all subjects enrolled in the sub-study will be allowed to continue in the 
study with a continuous once daily schedule. 
Section 3.2.1.  Part 1 Dose Escalation
Rationale for Change: An upper dosing limit of 200mg per day was included for 
consistency. The trial exploring GSK525762 in hematologic malignancies has an upper 
limit for daily dose administration. 
Added Text:
Dose escalation will continue until an MTD is determined or until a dose of 200mg per 
day is reached. 
Section 3.2.2.  Dose Escalation and Schedule
Rationale for Change: This section was updated to include details for twice daily 
dosing.


2011N118599_09
CONFIDENTIAL
BET115521
285
Added footnote (Section 3.2.2.1, Table 5 Accelerated Dose Escalation Procedures in 
Part 1A):
NOTE: Route/Administration/Duration: Oral QD or BID (specific dosing instructions 
will be provided to each subject).
Revised Text:
3.2.2.6.
BID Dosing Cohort
BID dosing, may also be explored. This approach will be considered ifexplored, based on 
the safety and PK data suggest that a sufficient therapeutic exposure cannot be achieved 
using the initial schedule. If a shorter recovery period is used, the short half life.  The 
initial dose level will be 50% of the highest completed dose level (at or below MTD) 
with the initial schedulefor BID will be 20mg BID or “x”mg BID (where 2x is equivalent 
to the last once daily dose cleared for dose escalation in Part 1A) – whichever is lower. 
Dosing will be separated by approximately 12 hours (± 1 hr). Escalation can then proceed 
as described using the 3 + 3 dose escalation. Alternative schedules with intense 
supportive careAdditional blood samples will be collected for PK, PD, and safety as 
described in Table 11.
Subjects may need to undergo dose modification(s) to manage toxicities.  A dose 
adjustment (e.g., BID dose level with a minimum 25% reduction in total daily dosing or 
QD at the same or lower dose level) may also be explored after consultation with GSK 
Medical Monitor. The investigator should use clinical judgment to determine whether the 
dosing scheduling may be contributing to any potential toxicity necessitating dose 
adjustment, and make the appropriate change after consultation with the GSK Medical 
Monitor.
Section 3.2.5
Rationale for Change: This section was updated with language to clarify that NMC 
subjects with non-measurable disease per RECIST 1.1 may still be considered for 
enrolment.
Revised Text:
3.2.5. Part 1A
3.2.5.1.  NMC Pharmacodynamic Expansion Cohort (Paragraph 1)
In the event there are no available enrollment slots during 3+3 dose escalation, eligible 
subjects with NMC (Section 6.2) may be enrolled in a Pharmacodynamic (PD) Expansion 
Cohort to evaluate the pharmacodynamics of GSK525762 at doses that have previously 
been cleared during 3+3 dose escalation.  Three subjects with NMC will be allowed to 
enroll at the last cleared dose level only if subjects with NMC or other solid tumor types 
(Section 4.2.1 Inclusion Criteria) have already enrolled in 3+3 dose escalation. 
Enrollment in the PD Expansion Cohort will continue until either 12 subjects with NMC 
are enrolled in the PD Expansion Cohort, or until the RP2D is determined in Part 1A, 


2011N118599_09
CONFIDENTIAL
BET115521
286
whichever occurs first.  Eligibility criteria for subjects diagnosed with NMC to enroll in 
this cohort are described in Section 4.2 (Part 1A). NMC subjects with non-measurable 
disease by RECIST 1.1 but clinically evaluable for progression or response may be 
considered for enrollment after discussion with the GSK Medical Monitor.  Biopsy 
collection will be mandatory as described in Section 3.2.2.4, unless a waiver is granted by 
the GSK medical monitor.  18FDG-PET will be required for all subjects in this cohort
New Section added (Section 3.2.6)
Rationale for Change: This section was included to provide details for the besylate sub-
study.
Added Text:
3.2.6. Bioavailability, Food Effect, and Dose Proportionality Besylate Sub-Study
Part 1A will include a besylate sub-study that will be an open-label, randomized, single 
dose, four period, cross over study to investigate the relative bioavailability of the 
besylate salt tablet compared to the amorphous free-base tablet at or near the MTD or 
RP2D, the effect of high-fat high-calorie meal on the bioavailability of the besylate salt 
tablet at or near the MTD or RP2D and the dose proportionality of two doses of 
GSK525762 administered as besylate salt tablets. GSK525762 dosing will be separated 
by at least 48 hours.  Up to 12 subjects may be enrolled in besylate sub-study. A subject 
requiring dose reduction or discontinuation from study before completion of the Besylate 
Sub-Study will be replaced by a new enrollment. All subjects enrolled to the Besylate 
Sub-Study, on completion of their participation in this segment of the study, will continue 
on a daily dosing schedule till disease progression or discontinuation due to 
investigational agent related toxicity or withdrawal of informed consent.
The high-fat (approximately 50% of the total caloric content of the meal), high-calorie 
meal (approximately 800 to 1000 calories) will be the representative example given by 
the 2002 US FDA guidance [FDA,2002]. It includes the following: two eggs fried in 
butter, two strips of bacon, two slices of toast with butter, four ounces of hash brown 
potatoes and eight ounces of whole milk.
In order to reduce variability in measurement of drug exposure caused by day-to-day 
biologic variation, a small (<10% of total dose) liquid dose of GSK525762, a stable, non-
radioactive 13C isotope labeled version of GSK525762 besylate salt, will be 
coadministered orally with each fasted treatment in besylate sub-study to serve as an 
internal standard for quantitation purposes (Refer to Section 7.1 for additional 
information). Use of this stable isotope approach will allow better characterization of the 
impact of the besylate salt and dose on GSK525762 bioavailability, if any (Parr, 2012).


2011N118599_09
CONFIDENTIAL
BET115521
287
Table 9
Besylate Sub-Study Study Design: BA, Food Effect and Dose 
Proportionality Evaluation
Besylate Sub-Study: Single Dose PK Evaluation
Sample 
Size
Sequence
Period 1
(Week 1 Day 1)
Period 2
(Week 1 Day 3)
Period 1
(Week 2 Day 1)
Period 4
(Week 2 Day 3)
6
1
Treatment A
Treatment B
Treatment C
Treatment D
6
2
Treatment B
Treatment A
Treatment C
Treatment D
Treatment A: RP2D (or MTD) amorphous free-base tablet + low dose stable isotope in solution, fasted 
administration
Treatment B: RP2D (or MTD) besylate tablet + low dose stable isotope in solution, fasted administration
Treatment C: half to one-third of RP2D (or MTD) besylate tablet + low dose stable isotope in solution, fasted 
administration 
Treatment D: RP2D (or MTD) besylate tablet, fed administration with FDA recommended high fat breakfast
Section 4.1. Number of Subjects
Rationale for change: The overall subject numberswere increased to include subjects 
enrolled in besylate sub-study.
Added Text:
Paragraph 1:
The besylate sub-study will enroll approximately 12 evaluable subjects. 
Section 4.2.1.  Inclusion Criteria
Rationale for change: Additional solid tumors were added to inclusion criteria and 
multiple myeloma was removed. Language was included to allow enrolment of NMC 
patients with non-measurable disease at a previously cleared dose level. And Table 10 
was updated to reflect adequate organ function values appropriate for CRPC subjects.
Revised Text: 
Paragraph 1:
Deviations from inclusion criteria are not allowed because they can potentially jeopardize 
the scientific integrity of the study, regulatory acceptability or subject safety. Therefore, 
adherence to the criteria as specified in the protocol is essential. Additional details 
regarding the enrollment and registration process for this study can be found in the Study 
Procedures Manual.


2011N118599_09
CONFIDENTIAL
BET115521
288
Paragraph 2:
A subject will be eligible for inclusion in this study only if all of the following criteria 
apply and after consultation with GSK:
Inclusion Criteria No. 3 Bullet Point “2”:

SCLC, CRC, NB, TNBC, ER positive BC, CRPC, NSCLC, MM (subjects with 
history of allotransplant are excluded) and any other solid tumor (e.g., NSCLC) 
which has been confirmed by clinical testing to be MYCN amplified (amplified 
is defined as a MYCN gene copy number gain of ≥5).  Subjects should have 
tumor progression after receiving at least one prior standard/approved 
chemotherapy, or where there is no approved therapy, or where standard therapy 
is refused.
Inclusion Criteria No. 4:
Subjects with solid tumors, with the exception of CRPC, must demonstrate measurable 
disease, per RECIST v1.1. NOTE: Subjects with NMC that do not meet the RECIST v1.1 
criteria for measurable disease, but have evaluable disease may be considered for 
enrollment in the NMC PD Cohort at the previously cleared dose level.
Inclusion Criteria No. 7 : 
Adequate organ function added for Reproductive/Endocrine System in Table 10.
Table 10
Definitions for Adequate Organ Function
Added Rows:
Reproductive/Endocrine
Testosterone 
<50ng/dL (only for subjects with CRPC)
Deleted footnote:
For MM subjects, calculated creatinine clearance criteria is <2.5mg/dL or 14-hour urine 
creatinine clearance of ≥ 30 mL/min
Section 4.2.2.
Exclusion Criteria
Rationale for change: Exclusion criteria updated to define acceptable prior treatment 
usage for CRPC subjects, and also a new exclusion criteria was added for subjects 
enrolling in besylate sub-study.
Added Text, bullet point “e” for Exclusion Criteria no. 2:
e.
Anti-androgen (e.g., bicalutamide) therapies for prostate cancer must be stopped 4 
weeks prior to enrollment. Second line hormone therapies such as enzalutamide, 
abiraterone, or orteronel should be stopped 2 weeks prior to enrollement.  Subjects with 
prostate cancer should remain on luteinizing hormone releasing hormone (LHRH) 
agonists or antagonists. Subjects with prostate cancer may also remain on low-dose 
prednisone or prednisolone (up to 10 mg/day) and still be eligible for this study.


2011N118599_09
CONFIDENTIAL
BET115521
289
Added Text, Exclusion Criteria no. 12:
12.
Besylate Sub-Study only: unable or unwilling to eat the FDA recommended high-
fat high-calorie breakfast (two eggs fried in butter, two strips of bacon, 4 oz. of hash 
brown potatoes and 8 oz of whole milk) within the recommended 30 minutes.
Section 5.
TIME AND EVENTS TABLES
Rationale for change: The time and events tables were modified to ensure consistency 
of timings, correct previous errors, to include new assessments for CRPC and to remove 
assessments specific for multiple myeloma subjects. New tables were added for the BID 
dosing and the besylate sub-study. A summary of assessments added and removed are 
included below.
Table 11  Time and Events: Part 1
Assessments added:
Laboratory assessments Tests at visit W4D1
CT/MRI Scans and PET Scan at visit W5D1
Castrate-Resistant Prostate Cancer Assessments (Vitamin D3 and PTH; Urinalysis,Urine 
microscopy and UPC; Urine electrolytes; PSA) at Screening visit
PK and biomarker samples at visit q8WD1
Blood samples for circulating exploratory biomarkers (cfDNA, etc) at Screening, W4D1 
and EOT visits.
Assessments removed:
Multiple Myeloma (MM) Assessments
Revised Text under the Notes column of Neuroblastoma Assessments:
One or more tests should be used as appropriate for disease. The same modalities utilized 
at screening should be used throughout study. Screening aAssessment within 35 days of 
first dose can be used as screening assessment.
Table 12
Time and Events: Part 1 Laboratory Assessments
W4D1 Visit added to the table.
Assessments added: Troponin, NT-proBNP-9 at W4D1 visit, Hematology at W2D1 and 
W4D1 visits, HbA1c at W4D1 visit


2011N118599_09
CONFIDENTIAL
BET115521
290
Revised Tables:
Table 13
QD Dosing Time and Events: Part 1 Pharmacokinetics and Biomarker Sampling, Week 1 and Week 2
W1D1
W1D5
W2D4 + 1 day
pre 
dose
15 min 
± 5m 
30 
min 
±5m
1h 
±5m
2h 
±10m
4h 
±15m
8h 
±1h
16h
±2h
12h 
±1h
24h 
±2h1h
33h48h
±3h1h
30 min 
±5m
3h ±15m
pre 
dose
30 min 
±5m
3h ±15m
8h 
±1h
mRNA whole blood 
sample
X
X
X
X
X
X
X
Table 14
QD Dosing Time and Events: Part 1 Pharmacokinetics and Biomarker Sampling, Week 3 and Week 9
W3D4 + 2 days
W9D1 ±4 days
(if dose has been escalated, +4 to 
+7 days)
EOT
EOT
pre 
dose
15 min 
± 5m 
30 min 
±5m
1h ±5m
2h 
±10m
4h 
±15m
8h 
±1h
16h ±4h
12h ±1h
24h ±1h
48h ±1h
pre dose
0.5-2h
4 - 8h
mRNA whole blood 
sample
X
X
X
X
LPS whole blood 
sample


2011N118599_09
CONFIDENTIAL
BET115521
291
New Tables Added:
Table 15
BID Dosing Time and Events: Part 1 Pharmacokinetics and Biomarker Sampling, Week 1
W1D1
W1D2  and 
W1D3
(relative to 
W1D1 Morning 
Dose)
W1D5
ECG and PK 
samples after 
Morning Dose only
Morning Dose 
Evening Dose
pre 
dose
0H
15 
min 
±5m
30 
min 
±5m
1h 
±5m
2h 
±10m
4h 
±15m
8h 
±1h
pre 
dose  
(12h-
15m)
12h
15 
min(12.25h) 
± 5m
30 min 
(12.5h) 
±5m
1h 
(13h) 
±5m
2h 
(14h) 
±10m
4h 
(16h) 
±15m
8h 
(20h) 
±1h
12 h 
(24h) 
±1h
36 h 
(48h) 
(pre-
dose) 
±1h
30 min 
±5m
3h 
±15m
Dose
X
X
X
12-lead 
ECG, in 
triplicate, 5 
minutes 
apart and 
within 10 
minutes 
prior to the 
15 min and 
30 min PK 
draws and 
within 15 
minutes 
prior to the 
other PK 
draws.
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
PK and 
protein 
biomarker 
sample
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Urine PK 
sampling 
(Part 1A 
only)a
X
0-2h
2-12h


2011N118599_09
CONFIDENTIAL
BET115521
292
W1D1
W1D2  and 
W1D3
(relative to 
W1D1 Morning 
Dose)
W1D5
ECG and PK 
samples after 
Morning Dose only
Morning Dose 
Evening Dose
pre 
dose
0H
15 
min 
±5m
30 
min 
±5m
1h 
±5m
2h 
±10m
4h 
±15m
8h 
±1h
pre 
dose  
(12h-
15m)
12h
15 
min(12.25h) 
± 5m
30 min 
(12.5h) 
±5m
1h 
(13h) 
±5m
2h 
(14h) 
±10m
4h 
(16h) 
±15m
8h 
(20h) 
±1h
12 h 
(24h) 
±1h
36 h 
(48h) 
(pre-
dose) 
±1h
30 min 
±5m
3h 
±15m
mRNA 
whole blood 
sample
X
X
X
X
X
X
X
X
X
X
Plasma samples will be divided at the GSK DMPK facility where bioanalysis of PK is performed and shipped to a vendor for systemic cytokine assessment (pre-dose and at 15 min, 30 min, 1 hr, 2 hr, and 
4hr) and acute phase protein assessment at pre-dose and at 2,4, 8 and 24 hr post-dose.  The frequency of sampling may be changed (likely reduced) based on data from the first few subjects assessed. 
a.
Urine samples for quantitative analysis of GSK525762 are not required in the NMC PD Expansion Cohort.


2011N118599_09
CONFIDENTIAL
BET115521
293
Table 16
BID Dosing Time and Events: Part 1 Pharmacokinetics and Biomarker Sampling, Week 2 and Week 3
W2D4 + 1 day ECG and PK 
samples after Morning Dose 
only
W3D4 ±2 days
W3D5 and 
W3D6 
(relative to 
W3D4 
Morning 
Dose)
Morning Dose
Evening Dose
(For W3D4 subjects that are not staying overnight after the 
evening dose, the 15min – 8h PK/ECG timepoints are optional)
pre 
dose 
(Prior 
to 
Dosing)
30m 
± 
5m 
3h 
± 
15m
8 h 
±5m
pre 
dose 
0h
15m 
±5m
30m
±5m
1h 
±10m
2h 
±15m
4h 
±15m
8h 
±1h
pre 
dose
12h
15m 
±5m 
(12.25m)
30m 
±5m
1h 
(13h)
±10m
2h 
(14h)
±15m
4h 
(16h)
±15m
8h 
(20h)
±1h
12h 
(24h) 
±1h
(pre 
dose)
36h 
(48h) 
±1h
(pre 
dose)
Dose
X
X
X
X
X
12-lead 
ECG, in 
triplicate, 
5 minutes 
apart and 
within 10 
min prior 
to the 15 
min and 
30 min 
PK draws 
and 
within 15 
minutes 
prior to 
the other
PK draws
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
PK and 
protein 
biomarker 
sample
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Urine PK 
sampling 
X
0-2h
2-12h


2011N118599_09
CONFIDENTIAL
BET115521
294
W2D4 + 1 day ECG and PK 
samples after Morning Dose 
only
W3D4 ±2 days
W3D5 and 
W3D6 
(relative to 
W3D4 
Morning 
Dose)
Morning Dose
Evening Dose
(For W3D4 subjects that are not staying overnight after the 
evening dose, the 15min – 8h PK/ECG timepoints are optional)
pre 
dose 
(Prior 
to 
Dosing)
30m 
± 
5m 
3h 
± 
15m
8 h 
±5m
pre 
dose 
0h
15m 
±5m
30m
±5m
1h 
±10m
2h 
±15m
4h 
±15m
8h 
±1h
pre 
dose
12h
15m 
±5m 
(12.25m)
30m 
±5m
1h 
(13h)
±10m
2h 
(14h)
±15m
4h 
(16h)
±15m
8h 
(20h)
±1h
12h 
(24h) 
±1h
(pre 
dose)
36h 
(48h) 
±1h
(pre 
dose)
(Part 1A 
only)a
mRNA 
whole 
blood 
sample
X
X
X
Plasma samples will be divided at the GSK DMPK facility where bioanalysis of PK is performed and shipped to a vendor for acute phase protein assessment at pre-dose and at 2, 4, 8 and 24 hr post-dose.  
The frequency of sampling may be changed (likely reduced) based on data from the first few subjects assessed.
a.
Urine samples for quantitative analysis of GSK525762 are not required in the NMC PD Expansion Cohort


2011N118599_09
CONFIDENTIAL
BET115521
295
Table 17
BID Dosing Time and Events: Part 1 Pharmacokinetics and Biomarker Sampling, Week 9
W9D1 ±4 days
ECG and PK samples after Morning Dose only
EOT
pre dose
0.5-2h
4 - 8h
12-lead ECG, in triplicate, 5 minutes apart and within 10 min prior to the 15 min and 30 
min PK draws and within 15 minutes prior to the other PK draws
X
X
X
PK and protein biomarker sample
X
X
X
mRNA whole blood sample
X
X
Table 18  Time and Events: Part 2
Assessments added:
Blood samples for circulating exploratory biomarkers (cfDNA, etc) at Screening, W4D1 and EOT visits.
Revised Text under the Notes column of 12-lead ECGs (Single) Assessments:
Screening ECGs within 35 days of first dose. ECGs prior to dosing. If QTcF increase >30msec, ECGs daily through W2.


2011N118599_09
CONFIDENTIAL
BET115521
296
New Tables Added: 
Table 20
Time and Events: Besylate Sub-Study
Besylate Sub-
Study 
Assessments
Notes
S
C
R
E
O
T
Week 1
Week 2
W3
W4
W5
W7
W9
q4W
q8W
D
1
D
2
D
3
D
4
D
5
D
6
D
7
D
1
D
2
D
3
D
4
D
5
D
6
D
7
D
1
D
4
D
1
D
4
D
1
D
1
D
1
D
1
D
1
Informed consent
Unless otherwise noted, screening 
assessments to be completed within 
14 days of first dose.
X
Demography
X
Medical history
X
Disease 
characteristics
X
Cardiology 
evaluation
X
Prior therapy
X
Register subject
X
TREATMENT PHASE
Study Drug
Administer study 
drug
Administer about same time of day. No 
food or antacids 1h before and 2h 
after.
X
X
X
X
Continuous dosing starting W2D5
Review subject 
diary
Diary not required when dosed in 
clinic.
X
X
X
X
X
X
X
X
X
Safety
Pregnancy test/  
testosterone
Females: serum pregnancy test within 
7 days of first dose; urine or serum test 
thereafter. Males: complete and free 
testosterone at SCR; free testosterone 
thereafter.
X
X
X
X
X
X
Physical exam
X
X
X
X
X
X
X
X
X
X
ECOG PS
X
X
X
X
X
X
X
X
X
X
Vital Signs
SBP, DBP, heart rate, respiratory rate, 
temp
X
X
X
X
X
X
X
X
X
X


2011N118599_09
CONFIDENTIAL
BET115521
297
Besylate Sub-
Study 
Assessments
Notes
S
C
R
E
O
T
Week 1
Week 2
W3
W4
W5
W7
W9
q4W
q8W
D
1
D
2
D
3
D
4
D
5
D
6
D
7
D
1
D
2
D
3
D
4
D
5
D
6
D
7
D
1
D
4
D
1
D
4
D
1
D
1
D
1
D
1
D
1
Pain
X
X
X
X
X
X
X
X
X
X
Weight and height
Height at SCR only
X
X
X
X
X
X
X
X
X
X
Chest x-ray
X
Pulmonary function 
test
X
Adverse events
SAEs collected continuously from signing of informed consent. AEs collected continuously from first dose.
Concomitant 
medications
continuous from signing of informed consent
Laboratory assessments: For details please see following tables
Tests
X
X
X
X
X
X
X
X
X
X
Cardiac Monitoring
Echocardiogram
Within 35 days of first dose
X
X
X
X
X
12-lead ECGs 
(Triplicate)
Triplicate SCR ECGs within 35 days of 
first dose. For timing of triplicate ECGs 
on O days, see Table 11 and Table 12. 
Otherwise, triplicate ECGs at 
approximately same time of day, and 
prior to dose on dosing days. If QTcF 
increase >30msec, ECGs daily 
through W2.
X
O
X
X
X
X
X
X
X
X
O
X
X
Holter monitoring
At least 24 h, on dosing days start at
least 60 min predose.
X
X
X
X
Telemetry 
(Potentially will be 
removed for 
Besylate Sub-
Study based on 
emerging data 
from Part 1)
Start at least 60 min predose and for at 
least 48 h. 
X
X
Efficacy
CT/MRI Scans
SCR assessment within 35 days of 
X
X
X
X


2011N118599_09
CONFIDENTIAL
BET115521
298
Besylate Sub-
Study 
Assessments
Notes
S
C
R
E
O
T
Week 1
Week 2
W3
W4
W5
W7
W9
q4W
q8W
D
1
D
2
D
3
D
4
D
5
D
6
D
7
D
1
D
2
D
3
D
4
D
5
D
6
D
7
D
1
D
4
D
1
D
4
D
1
D
1
D
1
D
1
D
1
first dose. Target lesions to be 
identified at SCR and followed.
PET scan
X
X
Neuroblastoma Assessments
CT/MRI
One or more tests should be used as 
appropriate for disease. The same 
modalities utilized at screening should 
be used throughout study. Screening 
assessment within 35 days of first 
dose
X
X
X
MIBG scana
X
X
X
FDG-PET
X
X
X
99Tc scintigraphy
for bone scan
X
X
X
Bilateral bone 
marrow aspirates 
and biopsy
X
X
X
Urine HVA, VMA, 
dopamine
X
X
X
X
X
Pharmacokinetics (PK) and Pharmacodynamics (PD): For details please see following tables
PK samples
X
X
X
X
X
X
X
X
X
X
Pharmacogenomics (PGx)
PGx sample
X
FOLLOW-UP PHASE
Follow-up contact by clinic visit or other means (telephone contact, email, etc) for survival status and anticancer therapy every 6 months. Disease assessment will be collected for subjects who discontinue 
study medication due to any reason other than progression or death. Individual subjects will be considered to have completed the study 2 years after their last treatment or upon death, whichever is 
sooner. Document the cause of death. For the study, the Follow-up Phase ends after a minimum of 70% of subjects have died or 5 years after the last subject is enrolled in Phase 2.
Abbreviations: CK=creatine kinase; CRP=c-reactive protein; D=day; DBP=diastolic blood pressure; ECG=electrocardiogram; ECOG PS=Eastern Cooperative Oncology Group Performance Status; 
EOT=End-of-Treatment; FLC=free light chain; HVA=homovanillic acid; LPS=lipopolysaccharide; MIBG=meta-iodo-benzyl-guanidine; q4W=every 4 weeks; q8W=every 8weeks; SBP=systolic blood 
pressure; SCR=Screening; SPEP=serum protein electrophoresis; UPEP=urine protein electrophoresis; VMA= vanillylmandelic acid; W=week
a.
Subjects with neuroblastoma will have MIBG and bone marrow biopsies after week 24 as clinical indicated to confirm complete remission.


2011N118599_09
CONFIDENTIAL
BET115521
299
Table 21
Time and Events: Besylate Sub-Study Pharmacokinetics Sampling, Week 1 and Week 2
W1D1, W1D3, W2D1 and W2D3
pre 
dose
15 min ± 
5m 
30 min 
±5m
1h ±5m
1.5h ± 
5m
2h ±10m
3h ±15m
4h ±15m
6h 
±15mn
8h ±30 
mn
24h ±2h
48h ±2h a
12-lead ECG, in triplicate, 5 
minutes apart and within 10 
minutes prior to the 30 min PK 
draws and within 15 minutes 
prior to the other PK draws
serial ECGs only W1D1
X
X
X
X
X
X
X
X
X
X
PK sample
X
X
X
X
X
X
X
X
X
X
X
X
a.
On W1D3 and W2D3, the 48 hour sample has to be taken prior to GSK525762 dosing. 
Table 22
Time and Events: Besylate Sub-StudyPharmacokinetics Sampling, Week 5 and Week 9
W5
W9D1 ±4 days
(if dose has been escalated, +4 to +7 days)
Pre dose
30 min ±5m
3h ±15m
8h
±30m
pre dose
0.5-2h
4 - 8h
12-lead ECG, in triplicate, 5 minutes apart and within 10 min prior 
to the 15 min and 30 min PK draws and within 15 minutes prior to 
the other PK draws
X
X
X
X
X
X
X
PK sample
X
X
X
X
X
X
X


2011N118599_09
CONFIDENTIAL
BET115521
300
Section 6.1.2.  Visit Windows
Rationale for change: A window for visits in the besylate sub-study was included.
Added Text, Paragraph 9:
Besylate Sub-Study - +1 day window is allowed as long as there are at least 48 hours 
between the single doses.
Section 6.2. Baseline Assessment for NMC Subjects
Rationale for change: Clarification was included for baseline assessments for NMC 
subjects.
Revised Text, Paragraph 2:
Further retrospective FISH testing will be undertaken for all enrolled NMC subjects in 
order to identify characterize the BRD3 or BRD 4NUT gene fusion partner and to support 
exploratory analysis of differential outcomes based on the NUT fusion partner. The cut-
off for FISH positivity has not been robustly established but will be assessed during 
development. The IHC and FISH analyses will be performed at a central laboratory.
Section 6.3. Baseline Assessment for Non-NMC Subjects
Rationale for change(s): Additional tumor types were added and MM removed from this 
section.
Revised Text, Paragraph 1:
Subjects diagnosed with SCLC, CRC, NB, CRPC, TNBC, ER+BC or NSCLC or MM
[based on standard diagnostic criteria, such as histology, cytology (including bone 
marrow evaluation)] or serological criteria (such as serum M-protein) will be considered 
eligible for Part 1 of the study.  In instances where a solid tumor subject’s MYCN 
amplification status is known, then that subject will be considered eligible.  N-Myc copy 
number gain of ≥5 will be considered positive for MYCN amplification. N-Myc testing 
may be performed using any method.
Table 23   QT Withdrawal Criteria
Rationale for change: Lowered QTcF withdrawal upper limit from 500 to 480 to be 
consistent with GSK QT withdrawal criteria.Removed reference to subjects with 
underlying bundle branch block, as these subjects are exluded from trial. Baseline QT 
results was defined.


2011N118599_09
CONFIDENTIAL
BET115521
301
Revised Text:
If QTcF > 500480 msec, or uncorrected QT > 600 msec (Grade 3 or 4), or any change from 
*baseline of ≥60 msec even if not exceeding 500480 msec, (all measurements based on an 
averaged manual overread of three ECGs over at least 15 minutes) permanently discontinue study 
medications and notify the GSK Medical Monitor.
For subjects with underlying bundle branch block, follow the criteria below:* Baseline results are 
defined by the nearest timepoint prior to first dose. For this trial the Baseline QTcF value is 
determined by the mean of the triplicate W1D1 predose QTcF results. If these results are not 
available, then the mean QTcF of the screening triplicate ECG results would be used.
Baseline QTcF value with bundle branch 
block
Discontinuation QTcF with bundle branch 
block
<450 msec
>500 msec
450-480 msec
530 msec
Section 6.4.7.
Telemetry
Rationale for change: Flexible language to allow removal of telemetry requirement after 
all data is collected up to MTD and analyzed for QT safety and reviewed by our safety 
board was included.
Revised Text:
ToIn Part 1 to complement real-time ECG assessements assessments, monitoring for 
potential adverse arrhythmias will be conducted utilizing continuous telemetry will be 
performedmonitoring as outlined in the Time and Events Tables for at least 48 hours 
from the start of dose. If clinically indicated, telemetry may be extended past 48 hours. 
Participating sites will have trained staff capable of monitoring and responding in real 
time to any potential cardiac adverse event detected by telemetry. In addition, emergency 
resuscitation equipment including appropriate pharmacological agents will also be 
immediately accessible.
At the end of Part 1, an analysis of data collected on the QT interval up to, and including, 
the MTD expansion will be carried out. If the analysis by the GSK Cardiac Safety Panel 
of internal and external experts indicates that telemetry is no longer required for 
monitoring the QT interval, then the study can progress to the next stage without 
telemetry. 
Removal of the telemetry requirement will be conveyed to the sites in the first instance 
through a separate document (or “note to file”) that will note - i) a summary of the 
analysis, and ii) the decision to proceed without telemetry monitoring in the next stage of 
this study. This will allow the sites to submit the necessary documentation to the 
IECs/IRBs for approval and to start the next stage of this study without telemetry. 
However, this process will be permitted only if there are no other cardiac monitoring 
changes to be implemented. If additional cardiac monitoring changes are required, a 
protocol amendment will be necessary before the next stage of the study can start.


2011N118599_09
CONFIDENTIAL
BET115521
302
Table 24
Clinical Laboratory Tests
Rationale for change: Clarification was provided for safety cytokine sample collection 
at screening.
Revised Text:
Pregnancy test for females (serum at screening, Urine or serum post dose)Cytokine samples 
(collected as part of Predose PK sample for plasma cytokines; may also be performed as clinically 
appropriate following fever)
Guaiac fecal occult blood
Section 6.5.1.  Disease Assessment
Rationale for change: Disease assessment updated to include PCWG2 guidelines for 
CRPC subjects.
Revised Text, Paragraph 1:
Tumor response will be assessed as outlined in Time and Event Schedule by the 
investigator using RECIST 1.1 (Appendix 4) or the Prostate Cancer Working Group 2 
(PCWG2) guidelines and documented in the eCRF as: progressive disease (PD), stable 
disease (SD), partial response (PR), and complete response (CR).  For subjects with MM 
or NB the appropriate tests and criteria will be followed (See Time and Events Schedule, 
Appendix 5 and Appendix 6). See the SPM for additional instructions.
Section 6.6.3.  Urine Collection
Rationale for change: Pooled urine sample collection timepoints was adjusted to reflect 
sample collections for both QD and BID dosing cohorts.
Revised Text, Paragraph 1:
Urine samples for quantitative analysis of GSK525762 will be collected over 24a dosing 
interval hours in two samples (sample collected 0-2hr and second sample collected 2-
24hrend of dosing interval hr) immediately following dosing on Week 1 Day 1 and in 
Week 3. Urine samples will be collected in subjects in Part 1A (with the exclusion of 
besylate sub-study) once the 3+3 dose escalation has been reached. Additional sampling 
may be instituted based on emerging data.  
Section 6.8. Translational Research
Rationale for change: Minor updates were made to this section to clarify that pre- and 
post-treatment biopsy collections are mandated during the 3+3 design (when there is 
accessible tumor tissue).
Revised Text, Paragraph 2 and 3:
NMC patients will be required to submit a fresh or archival tumor specimen for diagnosis 
or diagnostic confirmation. These archival specimens may also be evaluated 
retrospectively for exploratory research. Selected During the 3+3 design NMC patients 


2011N118599_09
CONFIDENTIAL
BET115521
303
will also be required to supply fresh pre and post-treatment biopsies to test for relevant 
markers of tumor PD and/or biological effect and to support identification of a 
biologically effective dose.
Non-NMC patients will also be asked to submit an archival tumor specimen for 
retrospective testing for potential markers of sensitivity and/or resistance, eg. N-Myc 
amplification; however this will not be an eligibility requirement. Furthermore, as for 
NMC patients, selectedduring the 3+3 design non-NMC patients will be required to 
supply fresh pre and post-treatment biopsies for tumor PD. 
Section 6.8.1.  Tumor Tissue Collection
Rationale for change: This section was updated to reflect exploratory analysis planned 
and to remove reference to multiple myeloma.
Revised Text, Paragraph 5:
The biopsies will be assessed for transcripts or proteins that reflect BET target 
engagement and/or tumor biology (e.g., c-Myc protein level changes in multiple 
myeloma; changes in expression of genes important in SCLC tumorigenesis such as 
CCND1, SRC, NMYC and MLKL; changes in NMYC expression and protein in 
neuroblastoma).  For NMC, markers of cell proliferation and/or cell differentiation (e.g., 
Ki67 and cytokeratin [Schwartz, 2011]) will be analyzed.  Biopsies may also be assessed 
for DNA, RNA or proteins which may be potential predictors of sensitivity or resistance 
to BET inhibition based on emerging data.
Section 6.8.2.3.  Whole Blood mRNA
Rationale for change: This section was updated to reflect current exploratory analysis 
planned for mRNA samples.
Revised Text, Paragraph 1:
GSK525762 has been shown to modulate the expression of a number of different genes in 
unstimulated whole blood between 1 h and 6 h. The mRNA levels of 31 such genes form 
a ‘signature’ panel which will also be used as a biomarker of engagement of 
pharmacology. A and will be measured using mRNA isolated from whole blood. The 
modulation of a number of these genes will also be measured as changes in systemic 
proteins as well as in the analytes from analysis of the ex vivo assay blood samples (e.g. 
CCL2 and IL-8) thus relating mRNA and protein expression with drug concentration.  
Other translational research studies, such as transcriptomics profiling, will also be 
performed using whole blood mRNA from selected patients.


2011N118599_09
CONFIDENTIAL
BET115521
304
Section 7.1. GSK525762 Investigational Product Dosage/Administration
Rationale for change: This section was updated to include the besylate formulation
Revised Text:
Paragraph 1:
GSK525762 Tablets will be provided to sites by GSK. The contents of the label will be in 
accordance with all applicable regulatory requirements.  Two investigational drug 
formulations will be introduced in Part 1.  An amorphous, free-base formulation of 
GSK525762 will be used in Part 1 (Table 26) and a crystalline, besylate formulation 
(Table 27) will be introduced in the besylate sub-study in Part 1A and the Part 2 NMC 
expansion cohort.
Table 26:
Table 26
GSK525762 Amorphous Free-base Investigational Product 
Dosage/Administration
Investigational Product
Product name:
GSK525762 AmorphousFree Base Tablets
Unit dose strength(s)/Dosage level(s):
1mg
10mg
30mg
*100mg
Dosage form
Tablet
Tablet
Tablet
Tablet
Manufacturer
GSK
GSK
GSK
GSK
Physical description:
white to off-white, round, biconvex 
tablets with no markings, 
uncoated tablet
white to off-white, 
capsule shaped, 
biconvex tablets with 
no markings, 
uncoated tablet
Route/
Administration/ Duration:
Oral; OD; see Time and Event Tables for schedule and 
administration timings
Dosing instructions:
Dose with 240mL water and should be taken between 7 am 
and 10 am. No food or antacids for at least 1h before and 
2h after dosing. (If a subject vomits after taking study drug, 
the subject should be instructed not to retake the dose and 
should take the next scheduled dose.)
*100 mg tablets were never supplied to the sites/clinics.


2011N118599_09
CONFIDENTIAL
BET115521
305
Added Text:
Table 27
GSK525762 Besylate Investigational Product Dosage/Administration
Investigational Product
Product name:
GSK525762 Besylate Tablets
13C-GSK525762 Stable isotope powder for 
oral solution
Unit dose 
strength(s)/Dosage 
level(s):
5mg
25mg
50mg
Low dose
Dosage form
Tablet
Tablet
Tablet
Powder for oral solution
Manufacturer
GSK
GSK
GSK
GSK
Physical 
description:
White to off-
white, round, 
biconvex tablets 
with no 
markings, film-
coated tablet
White to off-
white, oval, 
biconvex 
tablets with no 
markings, film-
coated tablet
White to off-white powder
Route/
Administration/ 
Duration:
Oral; see Time and Event Tables 
for schedule and administration 
timings
Administer orally as a single dose with 
GSK525762 Tablets (besylate Sub-Study for 
Treatment A, B and C)
Dosing 
instructions:
Dose with 240mL water and should 
be taken between 7 am and 10 am. 
No food or antacids for at least 1h 
before and 2h after dosing. (If a 
subject vomits after taking study 
drug, the subject should be 
instructed not to retake the dose 
and should take the next scheduled 
dose.)
Dissolve powder in 10 mL of water with 
bicarbonate buffer and administered with 
GSK525762 tablets (Besylate Sub-Study, 
Treatment A, B and C)
Section 7.1.1.  Preparation of GSK525762 Tablets for Administration via 
Enteral Feeding Tube
Rationale for change: Minor updates were included to provide clarification on 
GSK525762 as a dosing solution.
Revised Text, Paragraph 2:
The dose compounding should be performed only by pharmacy or appropriately trained 
personnel (please refer to Pharmacy Manual). A GSK525762 dosing solution is to be 
prepared by allowing GSK525762 tablets to disintegrate in 50 mL sterile water. 
GSK525762 tablets contain inert insoluble excipients that will remain in suspension. The 
contents will be mixed to ensure that complete dispersion is achieved. All contents will 
be transferred into a syringe for administration via feeding tube. The compounding vessel 


2011N118599_09
CONFIDENTIAL
BET115521
306
should be rinsed and the syringe and feeding tube flushed with further additions of sterile 
water. Total water volume will be 255 mL.
Section 7.2. Handling and Storage of Study Treatment
Rationale for change: Additional storage instructions for study treatment were included.
Revised Text, Paragraph 3:
GSK525762 Tablets are to be stored at up to 30°C (86°F).) and protected from light and 
moisture.
Section 7.3. Meals and Dietary Restrictions
Rationale for change: Instructions for meals and dietary restrictions were updated with 
information for besylate sub-study.
Revised Text, Paragraph 1:
Subjects will fast for at least one hour prior to each dose of study drug. After dosing, 
subjects will be asked to fast for an additional two hours.  These fasting requirements 
have been implemented in the protocol and informed consents to minimize 
pharmacokinetic variability. During Besyalte Sub-Study, subjects will be asked to fast 
overnight (at least 8 hours) and continue fasting for 4 hours post dose administration 
except for the fed administration where subject will be requested to ingest a high-fat 
high-calorie meal within 30 minutes prior to administration (FDA 2002).
Section 7.4. Treatment Assignment
Rationale for change: Updates to this section were included to clarify the randomization 
schedule for the besylate sub-study.
Revised Text, Paragraph 2:
Subjects will be identified by a unique subject number that will remain consistent for the 
duration of the study. Subjects in Besylate Sub-Study will be assigned to a treatment 
sequence (see Table 9) in accordance with the randomization schedule generated by 
Discovery Biometrics, using a validated software.
Section 7.7.1.   Dose and Safety Management Guidelines, 
Rationale for change: Updates were included in the Dose Adjustment/Stopping Criteria 
for QTc (to clarify “baseline”) and to provide additional guidance for thrombocytopenia 
(previouslynot includedin this section).


2011N118599_09
CONFIDENTIAL
BET115521
307
Revised Text:
Table 28
Dose Adjustment/Stopping Safety Criteria
Toxicity
Dose Adjustment/Stopping 
Criteria
Management Guidelines
Thrombocytopenia
Grade 1 & 2 (platelet count 
above 50,000) 
Continue dosing at same dose level with weekly or 
more frequent monitoring as necessary
Grade 3 (platelet count between 
25,000-50,000)
After discussion with medical monitor and using 
sound clinical judgement, continue at same dose 
or adjust dose (e.g. consider reduced daily dosing 
or dosing on alternate days). Monitor CBC at least 
twice a week, more frequently if necessary 
Grade 4 (platelet count below 
25,000) 
Temporarily interrupt study medication and 
monitor CBC every 2-3 days. If platelet counts 
recover to Grade 3 and is steady for at least 2 
CBC reads at least 3days apart, or rising, discuss 
with medical monitor resuming treatment at the 
same or adjusted dose (see Grade 3) based on 
sound clinical judgement.
QTcF
QT monitoring:
If >30msec and ≤60 msec 
change from baseline* occurs.
Management Guidelines for QTcF: 
Continue dosing and follow activities.
Manually calculate QTcF to reconfirm clinically 
significant prolongation.
Supplement electrolytes, particularly potassium 
and magnesium, to recommended levels:
(1) Maintain serum potassium > 4mol/L
(2) Maintain serum magnesium levels 0.85 mmol/L
Discontinue any concomitant medications with 
potential for QTcF prolongation.
Consider 24 hour or longer telemetry monitoring if 
clinically indicated.
QTcF
QT monitoring:
If >30msec and ≤60 msec 
change from baseline occurs.
Management Guidelines for QTcF: 
Continue dosing and follow activities.
Manually calculate QTcF to reconfirm clinically 
significant prolongation.
Supplement electrolytes, particularly potassium 
and magnesium, to recommended levels:
(1) Maintain serum potassium > 4mol/L
(2) Maintain serum magnesium levels 0.85 mmol/L
Discontinue any concomitant medications with 
potential for QTcF prolongation.
Consider 24 hour or longer telemetry monitoring if 
clinically indicated.
Grade 1 or 2 Temporarily discontinue study 
medications and review the following activities:


2011N118599_09
CONFIDENTIAL
BET115521
308
Toxicity
Dose Adjustment/Stopping 
Criteria
Management Guidelines
Grade 1 or 2 
During telemetry monitoring if a 
Grade 1-2: If >60msec change 
from baseline* and not 
exceeding 480 msec for QTcF 
(Averaged manual overread of 
three ECGs over at least 15 
minutes)
QTcF>480 msec (Averaged 
manual overread of three ECGs 
over at least 15 minutes)
If QTcF > 60 msec over 
baseline* value AND QTcF>480 
msec (Averaged manual 
overread of three ECGs over at 
least 15 minutes)
Manual calculate QTcF to reconfirm clinically 
significant prolongation.
Supplement electrolytes, particularly potassium 
and magnesium, to recommended levels:
(1) Maintain serum potassium > 4mol/L
(2) Maintain serum magnesium levels 0.85 mmol/L
Rule out other potential etiologies for prolonged 
QTcF such as cardiac ischemia
Discontinue any concomitant medications with 
potential for QTcF prolongation.
Consider telemetry monitoring if clinically 
indicated.
May consider restarting study treatment at a 
reduced dose or dose level pre-event based on 
discussion with GSK Medical Monitor.
Permanently discontinue study medications and 
notify the GSK Medical Monitor. 
If the subject is variable around 480 msec 
assessments may be repeated. This subject may
consider restarting study treatment at a reduced 
dose or dose level pre-event based on discussions 
with GSK Medical Monitor, Investigator and 
cardiologist.

QTcF Rechallenge Procedures:
Do not rechallenge with study treatment unless 
under the following conditions: 
(1) QTcF event reduced to Grade ≤1,
(2) potassium and magnesium levels are within 


2011N118599_09
CONFIDENTIAL
BET115521
309
Toxicity
Dose Adjustment/Stopping 
Criteria
Management Guidelines
institutional normal range,
(3) a favorable risk/benefit profile,
(4) approval by the internal GSK Medical Monitor,
(5) IRB approval, and
(6) the subject is re-consented regarding the 
possible increase risk of QTcF prolongation. If 
approval for re-treatment is granted, the subject 
must be re-consented (with a separate informed 
consent specific to QTcF prolongation). 

Discontinuation procedures:
If the subject is withdrawn due to QTcF 
event, the subject should complete the 
following activities post-dose:

Evaluation by cardiologist.

Weekly assessments for QTcF should 
be monitored weekly for two weeks, 
and then next assessment at 4 weeks 
post-dose. If QTcF results have not 
resolved to baseline then continue 
every 4-5 weeks until resolution.
* Baseline results are defined by the nearest timepoint prior to first dose. For this trial the Baseline QTcF 
value is determined by the mean of the triplicate W1D1 predose QTcF results. If these results are not 
available, then the mean QTcF of the screening triplicate ECG results are considered baseline.
Section 7.7.2.  Dose Adjustments for Toxicity, Table 29
Rationale for change: Revised Dose Adjustment for Toxicity to include specific 
guidance for thrombocytopenia.
Revised Title:
Table 29
Guidance for Dose Adjustment for Toxicity
Revised Footnote: 
*Note: Exceptions to drug-related Grade 1 requirement may be made for Rash, 
alopecia, etc.  Exceptions to drug-related Grade 1, 2, 3 requirements would be quickly 
reversible (<48 hours) laboratory abnormality (example: electrolyte changes).In the case 
of thrombocytopenia, a subject may be considered for restarting study treatment if a 
resolution from Grade 4 to Grade 3 is experienced and after discussion with GSK medical 
monitor. See guidance in Table 28 above.


2011N118599_09
CONFIDENTIAL
BET115521
310
Table 31
Drugs with a Risk of Torsades de Pointes that are Prohibited
Rationale for change: Updated source for drugs with a risk of Torsades de Pointes that 
are prohibited.
Added row:
Levofloxacin
Levaquin
Table Footnote revised:
Data Source: www.QTdrugscrediblemeds.org (revised 25-Mar-2008)
Section 11.1.  Sample Size Assumptions
Rationale for change:
Revised Text: Updates were made to sample size assumptions to include rationale for 
sample size for besylate sub-study.
Section 11.1.1.   Part 1
The total number of subjects to be enrolled into Part 11A and Part 1B will depend on the 
number of dose escalations required to establish the maximum tolerated dose of 
GSK525762; they are not driven by statistical considerations. To complete Part 1, it is 
estimated that 3050 to 5070 evaluable subjects will be enrolled. 
Section 11.1.2.   Part 1A Besylate Sub-Study
At least 8 and up to 12 subjects will participate in Besylate Sub-Study.  
Approximately 12 subjects will participate in the assessment to get at least 8 evaluable 
patients completing.  A subject is considered a completer if they have PK assessments 
from all treatment periods.
Based on a within-subject coefficient of variance for AUC of 50%, a correlation of 0.95 
between the enriched (liquid dose of GSK525762 added) and non-enriched PK, and 8 
subjects completing in Besylate Sub-Study, it is estimated that the half-width of the 90% 
CI for the ratio of the geometric means (besylate salt tablet compared to the amorphous 
free-base tablet) will be approximately 0.20.  Hence, if the ratio estimate is equal to 1, the 
90% CI will be 0.80 to 1.25.
Section 11.1.6.
Subset Analysis for NMC Population
An exploratory review for NMC molecular subtype (e.g. NUT-BRD3, NUT-BRD4, and 
NUT-otherNSD3) will be conducted.


2011N118599_09
CONFIDENTIAL
BET115521
311
Section 11.3.
Analysis Populations
Rationale for change: This section was updated to further define subjects included in the 
PD population.
Revised Text:
Paragraph 1
All Treated Subjects (Safety and Clinical Activity) Population: This will consist of all 
subjects that received at least one dose of study treatment. Safety and clinical activity 
data will be evaluated based on this population.
Paragraph 3
Assay Validation Pharmacodynamic Population: Due to the rarity of NMC disease, 
the Assay Validation population The PD Population is defined as all subjects who were 
consented, screened in the All Treated Subjects Population for the study (regardless if the 
subject met eligibility requirements for study enrollment) and whose whom a tumor 
biopsy or tissue was assayed by IHC and/or FISH. Data from this population may be used 
for future validation of the assay obtained and analysed for biomarkers
Section 11.7.
Pharmacokinetic Analyses
Rationale for change: This section was updated to further define subjects included in the 
PK population and to include plans for analyses for the besylate sub-study.
Revised Text:
11.7.1. Pharmacokinetic Parameters
PK analyses will be the responsibility of Clinical Pharmacokinetics/Modelling & 
Simulation, GSK. Plasma GSK525762 concentration-time data from dose escalation (Part 
1) will be analyzed by non-compartmental methods with WinNonlin.
From the plasma concentration-time data, the following pharmacokinetic parameters will 
be determined, as data permit: maximum observed plasma concentration (Cmax), time to 
Cmax (tmax), area under the plasma concentration-time curve (AUC(0-t) and AUC(0-∞) 
Week1 Day1 only) and apparent terminal phase half-life (t½). Trough concentration (C)
samples collected on the specified days will be used to assess attainment of steady state. 
To estimate the extent of accumulation after repeat dosing, the observed accumulation 
ratio (Ro) may be determined. The ratio of AUC(0-) on Week 3 AUC(0-) / Week 1 
AUC(0-) will be calculated to assess time invariance. GSK525762 concentrations will 
be determined in urine samples to determine urinary recovery of unchanged drug and 
renal clearance.


2011N118599_09
CONFIDENTIAL
BET115521
312
11.7.2. Statistical analysis of pharmacokinetic parameters
Statistical analyses of the PK parameters data will be conducted by Discovery 
Biometrics, GSK. Plasma concentration-time data will be listed by dose, age group, and 
summarized using descriptive statistics (n, mean, SD, median, minimum and maximum) 
by planned relative assessment time. Mean and/ or median values will be plotted over 
time. Individual plasma and urinary (if available) pharmacokinetic parameters values as 
well as a descriptive summary (mean, standard deviation, median, minimum, maximum, 
geometric mean, and the standard deviation, CV% and 95% confidence interval of log-
transformed parameters (if applicable)) by dose cohort and age group will be reported. 
Dose proportionality 
Cmax and AUC (AUC(0-∞), single dose, and AUC(0-), steady state) from Part 1 will be 
plotted as a function of the dose administered. If more than 2 dose cohorts are required to 
reach MTD (or the recommended dose based on available safety, PK and response data), 
dose proportionality of AUC and Cmax for GSK525762 following single dose 
administration and AUC(0-) and Cmax following repeat dose administration will be 
assessed graphically and using the power model (details will be provided in the Reporting 
and Analysis Plan [RAP]). as described below:
log (pharmacokinetic parameter) = a + b * log(dose)
where a is the intercept and b is the slope.
The power model will be fitted by restricted maximum likelihood (REML) using SAS 
Proc Mixed.  Both the intercept and slope will be fitted as fixed effects.  If there is 
sufficient data, the model may also be fit with the intercept and/or slope as random 
effects depending on the ability of the model to converge and on estimation of variance-
covariance matrix.  The mean slope and corresponding 90% confidence interval will be 
estimated from the power model.  
Separate models will be evaluated for amorphous tablet and besylate salt. 
Relative bioavailability of the besylate salt tablet to the amorphous tablet ( Besylate 
Sub-Study)
Based on the US FDA guidance on relative bioavailability studies, two formulations will 
be considered bioequivalent if the 90% CI of the ratio for Cmax and AUC, based on
log-transformed data, is within the 80 to 125% equivalence limit. Recommendation on
the dose amount impact of a deviation from bioequivalence with the besylate salt will be 
based on the magnitude of the change.


2011N118599_09
CONFIDENTIAL
BET115521
313
Food effect with besylate salt tablet (Besylate Sub-Study)
Pharmacokinetic (PK) parameters AUC(0-∞), and Cmax will be loge-transformed and 
analyzed using a mixed-effects model with and without food will be analyzed separately 
with fixed-effect terms for fed status (fed or fasted), and subject as a random effect. Point 
estimates and their associated 90% CIs will be constructed for the differences between 
fed and in fasted state. The point estimates and their associated 90% CIs were then 
backtransformed to provide point estimates and 90% CIs for the ratios of fed/fasted. Non-
parametric methods such as the Hodges and Lehmann estimator will be used to estimate 
the median differences between the fed treatments and the fasted state treatments for 
tmax. An associated 90% CI for the median differences will be constructed.
Based on the US FDA guidance on food-effect bioavailability studies, the absence of a 
food-effect will be established if the 90% CI of the ratio for Cmax and AUC, based on 
log-transformed data, is within the 80 to 125% equivalence limit. Recommendation on 
the clinical significance of the effect of food will be based on the magnitude of the 
change and our understanding of the exposure-clinical response relationship.
For the evaluation of food effect, tmax at fed and fasted status will be presented by 
subject and dose cohort in tabular and graphical form.
Section 11.7.3.
Population Pharmacokinetic Analysis
Section 11.8.
Pharmacokinetic/Pharmacodynamic Analyses
Rationale for change: Minor updates were included to further clarify plans for PK/PD 
analyses.
Revised Text, Paragraph 2, 3 and 4:
The relationship between QTcF and concentration expressed as Cmax, Cav, and/or
instantaneous time-matched concentration will be plotted graphically.evaluated. A linear 
or non-linear mixed effects analysis of the slope of the relationship between QTcF
adjusted for baseline and –concentration responses adjusting for baseline with a possible 
incorporation of time will be evaluated as a means of estimating QTcF effect in lieu of a 
thorough QT study.
Other quantitative safety parameters and biomarkers of interest including changes in 
tropinin, insulin and blood glucose levels will be plotted graphically against summary 
exposure measures (eg; Cmax, Ctrough, and Cav). Where evidence of a signal is seen, 
linear and non-linear mixed effect models will be fitted to the data to estimate PKPD 
parameters of interest; slope, baseline (E0), locationconcentration for 50% of maximum 
effect (EC50) and maximum effect (Emax).
Overall efficacy data, as assessed by conventional RECIST 1.1 criteria (best confirmed 
response) and overall tumor burden, will may be described using ordered categorical 
model and continuous models with summary exposure parameters (eg; Cmax, Ctrough, 
and Cav) as covariates derived from the population PK analysis. Further model details 
will be provided in the Reporting and Analysis Plan [RAP].


2011N118599_09
CONFIDENTIAL
BET115521
314
Section 12.9.1.
Dose Escalation Decisions
Rationale for change: Minor updates made to this section to further define the internal 
GSK team involved in dose escalation decisions.
Revised Text:
Dose escalation decisions will take into account all available data, including 
pharmacokinetics data and the safety profile of prior cohorts, and will occur following 
review of these data by the investigator(s), GSK medical monitor, clinical development 
scientist(s), pharmacokineticist, safety review team, and statistician. The decision and 
rationale will be documented in written format and distributed to the investigator(s), GSK 
medical monitor, pharmacokineticist, safety review team and statistician.
Section 13. REFERENCES
Rationale for change(s): The reference section was updated to reflect new/revised 
references used throughout the protocol amendment.
Added references:
Bauer DE, Mitchell CM, Strait KM, Lathan CS, Stelow EB, Lüer SC et al. 
Clinicopathologic features and long-term outcomes of NUT midline carcinoma. Clin 
Cancer Res. 2012;18(20):5773-9
FDA Guidance for industry: Food-effect bioavailability and fed bioequivalence studies. 
CDER 2002
Feng Q, Zhang Z, Shea MJ, Creighton CJ, Coarfa C, Hilsenbeck SG, et al. An 
epigenomic approach to therapy for tamoxifen-resistant breast cancer. Cell Res 
2014;24:809-19.
Parr A., Gupta, M., Montague, T., and Hoke, F. Re-introduction of a Novel Approach to 
the Use of Stable Isotopes in Pharmacokinetic studies. The AAPS Journal 2012, 14:639-
645.
C-H Gu, H Li, J Levons, K Lentz, R Gandhi, K Raghavan, and R Smith. Predicting effect 
of food on extent of drug absorption based on physicochemical properties. Pharm Res 
2007 24:1118 – 1130)
Nagarajan, S, Hossan, T, Alawi, M, et al. Bromodomain Protein BRD4 Is Required for 
Estrogen Receptor-Dependent Enhancer Activation and Gene Transcription. Cell Reports 
8, 460–469, July 24, 2014
Puissant A, Frumm SM, Alexe G, Bassil CF, Qi J, Chanthery YH, et al. Targeting 
MYCN in Neuroblastoma by BET Bromodomain Inhibition. Cancer Discov 2013.
Wyce A, Ganji G, Smitheman KN, Chung CW, Korenchuk S, Bai Y, et al. BET 
inhibition silences expression of MYCN and BCL2 and induces cytotoxicity in 
neuroblastoma tumor models. PLoS One 2013;8:e72967.


2011N118599_09
CONFIDENTIAL
BET115521
315
Section 14.6  Appendix 6: Response Criteria for Multiple Myeloma
Rationale for change: The response criteria for MM subjects was removed due to 
removal of MM subjects for enrolment in the trial.
Deleted Text:
Section 14.6  Appendix 6: Response Criteria for Multiple Myeloma
Consensus Recommendations for the Uniform Reporting of Clinical Trials:  Report 
of the International Myeloma Workshop Consensus Panel
Response Criteria
sCR (stringent complete response): 
Complete response as defined below plus: 

normal free light chain (FLC) ratio and

absence of clonal cells in bone marrow by immunohistochemistry or 2-4 color 
flow cytometry 
CR (complete response):

Negative serum and urine immunofixation, and

Disappearance of any soft tissue plasmacytomas, and

5% plasma cells in bone marrow 
VGPR (very good partial response):

Serum and urine M-component detectable by immunofixation but not on 
electrophoresis  OR

90% or greater reduction in serum M-component plus urine M-component < 
100mg/24h
PR (partial response):

50% reduction of serum M-protein and reduction in 24 hour urinary M-protein 
by 90% or to < 200mg/24h, and 

If the serum and urine M-protein are not measurable, a 50% decrease in the 
difference between involved and uninvolved free light chain levels is required in 
place of the M-protein criteria.  If serum and urine M-protein are not 
measurable, and serum free light chain assay is also not measurable, 50% 
reduction in bone marrow plasma cells is required in place of M-protein, 
provided baseline bone marrow plasma cell percentage was 30%, and

In addition to the above listed criteria, if present at baseline, a 50% reduction 
in the size of the soft tissue plasmacytomas is also required.


2011N118599_09
CONFIDENTIAL
BET115521
316
MR (minimal response):

25% but 49% reduction of serum M-protein and reduction in 24 hour urinary 
M-protein by 50% to 89%, AND

If present at baseline, 25% to 49% reduction in the size of soft tissue 
plasmacytomas is also required.

No increase in size or number of lytic bone lesions (development of 
compression fracture does not exclude response).
SD (stable disease):

Not meeting criteria for CR, VGPR, PR, MR or PD
PD (progressive disease): 
Requires any one or more of the following

Increase of 25% from lowest response value in any one or more of the following: 

serum M-component (absolute increase must be 0.5 g/dl), or 

urine M-component (absolute increase must be 200 mg/24h), or

the difference between involved and uninvolved free light chain levels (absolute 
increase must be > 10mg/dl): only for patients without measurable serum and 
urine M-protein levels,  or 

bone marrow plasma cell percentage (the absolute % must be 10%) – only for 
patients without measurable serum and urine M-protein levels and without 
measurable disease by FLC level

definite development of new bone lesions or soft tissue plasmacytomas or 
definite increase in the size of existing bone lesions or soft tissue plasmacytomas

development of hypercalcemia (corrected calcium > 11.5 mg/dl or 2.65 mmol/l) 
that can be attributed solely to the plasma cell proliferative disorder
a. All response categories (CR, sCR, VGPR, PR,MR and PD) require two consecutive 
assessments made at any time before the institution of any new therapy; CR, sCR, 
VGPR, PR, MR, and SD categories also require no known evidence of progressive or 
new bone lesions if radiographic studies were performed. VGPR and CR categories 
require serum and urine studies regardless of whether disease at baseline was 
measurable on serum, urine, both, or neither. Radiographic studies are not required to 
satisfy these response requirements. Bone marrow assessments need not be confirmed. 
For PD, serum M-component increases of more than or equal to 1 g/dL are sufficient 
to define relapse if starting M-component is ≥ 5 g/dL.
b. Clarifications to IMWG criteria for coding CR and VGPR in patients in whom the 
only measurable disease is by serum FLC levels: CR in such patients indicates a 
normal FLC ratio of 0.26 to 1.65 in addition to CR criteria listed above. VGPR in such 
patients requires a > 90% decrease in the difference between involved and uninvolved 
FLC levels. 
c. Clarifications to IMWG criteria for coding PD: Bone marrow criteria for PD are to be 
used only in patients without measurable disease by M protein and by FLC levels; 


2011N118599_09
CONFIDENTIAL
BET115521
317
“25% increase” refers to M protein, FLC, and bone marrow results, and does not refer 
to bone lesions, soft tissue plasmacytomas, or hypercalcemia and the “lowest response 
value” does not need to be a confirmed value. 
References
Durie BGM, Harousseau J-L, Miguel JS, et. al. International uniform response criteria for 
multiple myeloma. Leukemia, 2006:20: 1467-73.
Rajkumar SV, Harousseau JL, Durie B, et al.  Consensus recommendations for the 
uniform reporting of clinical trials: Report of the International Myeloma Workshop 
Consensus Panel 1.  Blood.  2011;117:4691-4695.


2011N118599_09
CONFIDENTIAL
BET115521
318
AMENDMENT 05
Protocol Changes for Amendment 5 (DD-MMM-YYYY) from the Protocol 
Amendment 4 (06-OCT-2014)
Protocol Amendment 5 applies to all site(s) participating in the conduct of the study
Amendment 05 summary: Amendment 05 includes the following additional expansion 
cohorts for Part 2 of the trial: castration-resistant prostate cancer (CRPC), triple negative 
breast cancer (TNBC), estrogen receptor positive breast cancer (ER positive) and small 
cell lung cancer (SCLC). An update was included regarding the Besylate Sub-Study to 
clarify that this sub-study would only be conducted at centers in the United States. The 
pediatric cohort in Part 1B was removed for further evaluation in a separate study. An 
update to the QTc management guidelines has been included.  
General Protocol Changes
Part 1B has been removed. Reference to Part1A and/or Part1B has been changed to Part 1 
wherever applicable throughout the protocol.
Changes are noted below with strikethrough to identify deleted text and underlining to 
identify new or replacement text.
List of Specific Changes
TITLE PAGE
Rationale for Change: Part 1B has been removed. Reference to Part1A and/or Part1B 
has been changed to Part 1.
Revised Text: 
Description: This is an open-label, single and repeat dose, multicenter, 2 part study to 
determine the MTD and the recommended Phase 2 dose (RP2D) for GSK525762 given 
orally once or twice daily. Part 1 will be conducted in subjects with NMC and other solid 
tumors in adult subjects (Part 1A) and pediatric subjects (Part 1B).1). Expansion cohorts 
(Part 2) are planned to further explore the clinical activity of GSK525762 in subjects with 
NMC and other specific solid tumors based on emerging data.
Section ABBREVIATIONS
Abbreviations added
LCNEC
Large cell neuroendocrine carcinoma tumor
PSA
Prostate-Specific Antigen


2011N118599_09
CONFIDENTIAL
BET115521
319
Section PROTOCOL SYNOPSIS 
Objectives, Endpoints, Hypotheses
Rationale for Change: This section was updated to remove objectives, endpoints or 
hypotheses related to the pediatric subjects and the hypothesis section was updated to 
include or the additional tumor types in Part 2 included with this amendment.  
Revised Text: 
Primary
Objective

To determine the safety, tolerability and maximum tolerated dose (MTD) of 
GSK525762 in subjects 16 years or older following QD and/or BID dosing 
schedules.

To determine the safety, tolerability and maximum tolerated dose (MTD) of 
GSK525762 in subjects 12 to ≤15 years old

To evaluate the clinical activity of GSK525762 in NMC and other solid tumors.

To evaluate, after single dose administration, the relative bioavailability of the 
GSK525762 besylate tablet compared to the amorphous free-base tablet, the
effect of high-fat high-calorie meal on the bioavailability of the besylate tablet 
and the dose proportionality of two doses of GSK525762 administered as the 
besylate tablets.
Endpoints

AEs, SAEs, dose reductions or delays, withdrawals due to toxicities and 
changes in safety assessments (e.g., laboratory parameters, vital signs, ECG, 
cardiotoxicity, gastrointestinal, etc) to determine the MTD in subjects 16 years 
or older

AEs, SAEs, dose reductions or delays, withdrawals due to toxicities and 
changes in safety assessments (e.g., laboratory parameters, vital signs, ECG, 
cardiotoxicity, gastrointestinal, etc) to determine the MTD in subjects 12 to ≤15 
years old.

Assess overall response rate (RR) by RECIST 1.1 in NMC and other solid 
tumors.

PK parameter values for GSK525762 following single oral administration as 
amorphous free-base or besylate tablet
Hypothesis

No formal statistical hypotheses will be tested in Part 1. Analysis will be 
descriptive and exploratory. 

The primary goal of Part 2 is to demonstrate a clinically meaningful response 
rate of 20% in , defined as follows: 
NMC relative to a 5% response rate suggesting no activity. This: this will be 
conducteddetermined by testing the null hypothesis that P0≤0.050 versus
the alternative that P1≥0.200, assumingresponse rate is ≤5%, with about 
80% power when the maximumtrue response rate is 20%.


2011N118599_09
CONFIDENTIAL
BET115521
320
Primary
SCLC and CRPC: this will be determined by testing the null hypothesis that 
the response rate for an ineffective drug is 0.05 and≤10%, with about 80%  
power when the minimumtrue response rate for an effective drug is 0.20.
is 30%.
ER+BC: this will be determined by testing the null hypothesis that the 
response rate is ≤15%, with about 80% power when the true response 
rate is 30%.
TNBC:this will be determined by testing the null hypothesis that the 
response rate is ≤10%, with about 80%  power when the true response 
rate is 25%.
Secondary (Objectives and Endpoints only)
Objectives

To characterize the pharmacokinetics (PK) of GSK525762 in subjects 16 years 
or older following QD and/or BID dosing schedules. 

To characterize the pharmacokinetics (PK) of GSK525762 in subjects 12 to 
≤15 years old

To evaluate cardiac safety, including the potential for QTcF, of changes with
GSK525762 and to assess PK/QTcF relationship following QD and/or BID 
dosing schedules.

To evaluate the exposure response (pharmacokinetic/pharmacodynamic 
[PK/PD]) relationship between GSK525762 and safety and efficacy parameters 
following QD and/or BID dosing schedules.

To evaluate the effect of treatment with GSK525762 on tumor growth and 
survival.

To evaluate systemic and ex vivo on-target BET inhibitory effects.
Endpoints

PK parameter values for GSK525762 following single and repeat-dose oral 
administration in subjects 16 years or older

PK parameter values for GSK525762 following single and repeat-dose oral 
administration in subjects 12 to ≤15 years old

Changes in cardiac safety including QTcF following single and repeat-dose oral 
administration GSK525762.

Progression free survival (PFS), time to response, duration of response, overall 
survival (OS), and exploratory analysis for antitumor response by various 
imaging modalities.


2011N118599_09
CONFIDENTIAL
BET115521
321
Exploratory (Objectives and Endpoints only)
Objectives

To evaluate the effect of GSK525762 on tumor biology

Correlation of GSK525762 exposure to changes in PD markers in tumor and/or 
surrogate tissue 

To identify potential indicators of sensitivity or response to GSK525762.

To evaluate systemic and ex vivo on-target BET inhibitory effects.
Endpoints

Dose related changes in markers of cell proliferation and/or cell differentiation 
in tumor and/or surrogate tissue

Dose related changes in transcription of genes and/or changes in expression of 
proteins regulated by BRD proteins in tumor and/or surrogate tissue

PK/PD parameter values for exposure response (by RECIST and 18FDG-PET
[if data allows]) relationship between GSK525762 exposure and QTcF, troponin 
and tumor response following single and repeat-dose oral administration.

Changes from baseline and dose/response relationship in ex vivo LPS induced 
cytokines including IL-6 in whole blood and systemic cytokines including IL-6.
Study Design And Duration: 
Rationale for Change: This section was updated to include the additional expansion 
cohorts for Part 2 (CRPC, TNBC, ER positive and SCLC), to clarify that the sub-study 
would be conducted in the US only and remove reference of the pediatric cohort (Part 
1B).
Revised Text:
This study is divided into 2 parts: 

Part 1A1 of the study is a dose escalation phase to determine the maximum 
tolerated dose (MTD) and select a recommended dose for Part 2 or a 
recommended Phase 2 dose (RP2D) based on the safety, pharmacokinetic, 
and pharmacodynamic profiles observed after oral administration of 
GSK525762. Eligible subjects with NUT midline carcinoma (NMC), small 
cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), colorectal 
cancer (CRC), neuroblastoma (NB), castration resistant prostate cancer 
(CRPC), triple negative breast cancer (TNBC), estrogen receptor positive 
(ER positive) breast cancer, and any other MYCN-amplified solid tumor will 
be enrolled in the dosing cohorts until a maximum tolerated dose (MTD) is 
established.  Subjects with NMC will also be enrolled in a pharmacodynamic 
dose expansion cohort during Part 1A1.  Subjects may continue treatment in 
the study until disease progression, unacceptable toxicity, or withdrawal of 
consent.   

Part 1A 1 besylate sub-study will explore the relative bioavailability, food 
effect and dose proportionality of besylate formulation. The sub-study will be 
conducted at active centers in the United States in subjects eligible for Part 


2011N118599_09
CONFIDENTIAL
BET115521
322
1A1 at the MTD or a dose near the MTD or RP2D. This will be an open-
label, randomized, single dose, four period, cross over sub-study to 
investigate the relative bioavailability of the besylate tablet compared to the 
amorphous free-base tablet, the effect of high-fat high-calorie meal on the 
bioavailability of the besylate tablet and the dose proportionality of two doses 
of GSK525762 administered as besylate tablets.

Part 1B will be opened to enroll pediatric subjects 12 to ≤15 years of age with 
solid tumors to determine the MTD in pediatric subjects.  Dose escalation in 
Part 1B will begin at 25% of the adult MTD and dose escalation will follow a 
3+3 design.  Pediatric subjects 12 to ≤15 years old may be enrolled in Part 2 
once the MTD has been determined in Part 1B.

Part 2 is an expansion cohort planned to further explore clinical activity at the 
MTD in NMC, SCLC, CRPC, and TN and ER positive BC subjects  

Duration of study will depend on recruitment rates, and timing of subjects’ 
duration on study (withdrawal rates due to toxicity or progression).
Subject Sample
Rationale for Change: The overall subject numbers were increased to accommodate 
enrolment into additional expansion cohorts added to Part 2 (CRPC, TNBC, ER+BC and 
SCLC).
Revised Text:
Approximately 70-100 subjects worldwide.Worldwide approximately 60 subjects will be 
enrolled in Part 1, and approximately 150 subjects will be enrolled in Part 2.
Pharmacokinetic/Pharmacodynamic Measurements: 
Rationale for Change: Minor updates were made to this section to provide further 
clarification on planned cytokine testing.
Revised Text:
There is extensive pharmacokinetic (PK) sampling in Part 1 and limited PK sampling in 
Part 2 for this study. Single safety PK blood draws may be collected for subjects with 
severe adverse events or adverse events of concern.  Blood samples will be collected for 
analysis of protein biomarkers (cytokines and acute phase proteins) and mRNA. Ex-vivo
LPS induction of cytokines in whole blood will be assessed. In addition, pre-treatment 
and post-treatment tumor samples will also be collected from selected subjects to be 
evaluated for target engagement and effects of GSK525762 on tumor biology. 
Data Analysis
Rationale for Change: Minor updates were made to this section to clarify and reflect 
that futility assessments would be conducted for each expansion cohort, now that 
additional cohorts have been added to Part 2.


2011N118599_09
CONFIDENTIAL
BET115521
323
Revised Text: 
Subject demographic and safety data will be collected on electronic case report forms 
(eCRFs). All data will be pooled and descriptive safety analyses summarized and listed 
by cohort at study conclusion. Part 2 of the study is powered to test overall Response 
Rate (RR). A futility assessment will be conducted after data are available from the first 
2010 subjects in each expansion cohort in Part 2.
Section 1.2.1.
NUT midline carcinoma
Rationale for Change: Updates were made to this section based on emerging data.


2011N118599_09
CONFIDENTIAL
BET115521
324
Revised Text
Paragraph 5:
NMC is extremely rare (fewer than 100 cases have been identified globally to date), 
andwith approximately 20 cases being reported in the United States annually, however 
due to misdiagnosis or underdiagnosis, the exact incidence and frequency of NMC are 
not well established (http://www.nmcregistry.org/). NMC may affect subjects of all ages 
(age range 0-78 yrs). The only known long-term survivor had a complete tumor resection. 
Therefore, patients with this rare tumor have a significant unmet medical need for more 
effective therapy.
Section 1.2.2 Other tumor types
Rationale for Change: Updates were made to this section based on emerging data.
Revised Text
Non-Small Cell Lung Cancer
GSK525762 inhibited cell growth in a high percentagesubset of NSCLC cell lines, with 
73% (19/2646% (33/72) of cell lines tested exhibiting a gIC50 <1µM. Median gIC50 across 
the NSCLC cell line panel was 0.61µM1.1µM. MYCN amplified cell lines and large cell 
neuroendocrine carcinoma (LCNEC) cell lines were among the most sensitive NSCLC 
cell lines to GSK525762, with a median gIC50 of 0.17µM and gIC100 of 3.6µM 0.24µM
(n=4). for each sub-type). A subset of NSCLC cell lines, including the MYCN-amplified 
and LCNEC lines, exhibited a cytotoxic response to GSK525762. Given the broad 
sensitivity of NSCLC cell lines to GSK525762, a selection marker will not be used for 
entry into the dose escalation part of the study.
Section 1.3.1 Human Pharmacokinetics
Rationale for Change: Updates were made to this section based on emerging data.
Revised Text
Whole blood human clearance was predicted from three species (mouse, rat and dog) 
using simple power-law allometry (in the absence of detectable in vitro metabolism) to be 
2.8 ml/min/kg. Volume of distribution was predicted from Gastroplus to be 2.6 L/kg and 
half-life 10 hours (GlaxoSmithKline Document Number 2010N108204_00, 2011). As the 
in vitro blood to plasma ration was 0.86, a 70 kg adult therefore hashad a predicted total 
clearance of 10.1 L/hr and a total plasma volume of distribution of 157 L. Bioavailability 
is predicted to be high given GSK525762 is a Bio-pharmaceutics Classification System 
(BCS) Class 1 molecule, and assumed to fall in the range 50-100%.
As of 23-July-2014of 06-February-2015, the pharmacokinetics of GSK525762 has been 
evaluated in 1923 subjects following single and repeated daily administration of 2 mg to 
60 mg of GSK525762 in the BET115521 trial. The summary statistics of the preliminary 
PK parameters are summarized in Table 1 and Table 2 after single and repeat daily oral 


2011N118599_09
CONFIDENTIAL
BET115521
325
administration, respectively. GSK525762 pharmacokinetics are characterized by a rapid 
absorption with maximum concentration occurring mostly within the first hour after 
dosing. GSK525762 is eliminated rapidly with an average terminal phase half-life of 3 to 
7 hours, leading to a lack of accumulation following once daily oral administration. 
Following single oral administration and repeated once daily administration of 2 mg to 60 
mg of GSK525762, Cmax and AUC tended to increase in a dose proportional fashion with 
a full overlap for individual AUC between 30 and 60 mg cohorts. 
Table 1
Summary Statistics of GSK525762 Preliminary PK Parameters Following 
a Single Oral Administration of GSK525762 in Study BET115521
2 mg
4 mg
8 mg
16 mg
30 mg
60 mg
Parameters
Unit
N=3
N=4
N=1
N=3
N=4
N=48
Cmax
ng/mL
51.0 
(41%)
70.4 
(29%)
120
176 
(37%)
604 (30%)
940 (31871 
(25%)
tmax
h
0.5 (0.5 -
0.6)
1.2 (0.5 
- 2.0)
1.1
2.0
2.0 (0.97 -
2.0)
1.0 (0.5 - 24.0)
AUC
ng.h/mL
172 (42%)
361 
(35%)
434
884 
(40%)
4420 
(63%)
3720 (574330 
(46%)
t1/2z
h
3.3 
(103%)
5.1 
(36%)
2.95
6.9 
(46%)
6.4 (37%)
6.1 (495.7 
(36%)
Table 2
Summary Statistics of GSK525762 Preliminary PK Parameters Following 
Repeat Daily Oral Administration of GSK525762 in Study BET115521
2 mg
4 mg
8 mg
16 mg
30 mg
60 mg
Parameters
Unit
N=1
N=2
N=1
N=3
N=4
N=26
Cmax
ng/mL
52
47.6 ; 
59.9
103
138 
(25%)
603 (17%)
602; 
736634 
(53%)
tmax
h
1.0
1.0 ; 4.0
0.5
1.5
0.9 (0.32 -
4.0)
1.0 ; 
1.(0.50 -
2.0)
AUC
ng.h/m
L
160
225 ; 497
330
674 
(21%)
3150 (55%)
2010; 
52901.0 
(0.50 -
2.0)
t1/2z
h
4.27
3.69 ; 
4.46
4.92
3.6 
(7.8%)
5.2 (26%)
2.5; 
4.93.48 
(32%)
Cmax Week 3 / Cmax 
Week 1
--
1.42
0.968 ; 
0.609
0.857
0.780 
(12%)
0.998 
(24%)
1.01; 
1.2300 
(21%)
AUCWeek 3 / AUC 
Week 1
--
1.38
0.900 ; 
1.64
0.759
0.774 
(20%)
0.724 
(12%)
0.898; 
0.712


2011N118599_09
CONFIDENTIAL
BET115521
326
2 mg
4 mg
8 mg
16 mg
30 mg
60 mg
Parameters
Unit
N=1
N=2
N=1
N=3
N=4
N=26
AUCweek 3 / AUCt 
Week 1
--
1.39
0.904 ; 
1.67
0.763
0.792 
(20%)
0.799 
(11%)
0.902; 
0.778758 
(12%)
Section 1.3.6. Doses for Besylate Bioavailability/Food Effect/Dose 
Proportionality Sub-Study
Revised Text
A dose at or near the maximum tolerated dose or the recommended Phase 2 dose will be 
used to evaluate the relative bioavailability of the besylate salt tablet compared to the 
amorphous free-base tablet, as this dose would be the dose level used in Part 2. 
Section 1.4. Rationale for Study and Endpoints
Rationale for Change: This section was updated to clarify that the besylate sub-study 
will only be conducted in the US.
Revised Text
Paragraph 2:
Given the poor prognosis and high unmet medical need of NMC, as well as in other 
tumor types such as relapsed/refractory SCLC, NSCLC,CRC, MM, CRPC, TN and ER+ 
BC, NB and N-Myc amplified tumors and the exceptional drug-to-target alignment of 
GSK525762, a combined Phase I/II study (BET115521) is proposed. The BET115521 
study comprises an accelerated dose titration (Part 1), which will include subjects with 
NMC and other tumor types that are predicted to be responsive to GSK525762, to 
determine a maximum tolerated dose (MTD). The besylate sub-study will be an open-
label, randomized, single dose, four period, crossover sub-study to investigate the relative 
bioavailability of the besylate salt tablet compared to the amorphous free-base tablet at a 
dose at or near the MTD or RP2D, the effect of high-fat high-calorie meal on the 
bioavailability of the besylate salt tablet at or near the MTD or RP2D and the dose 
proportionality of two doses of GSK525762 administered as besylate salt tablets. Results 
of the besylate sub-study will enable the use of the besylate salt tablet formulation later in 
this study and provide recommendation around the need for fasting status when 
administering GSK525762. The besylate sub-study will be conducted at centers in the 
United States.  


2011N118599_09
CONFIDENTIAL
BET115521
327
Section 2
Objectives, Endpoints, Hypotheses following QD and/or BID 
dosing schedules
Rationale for Change: This section was updated to remove objectives, endpoints or 
hypotheses related to the pediatric subjects and the hypothesis section was updated to 
include or the additional tumor types in Part 2 included with this amendment.
Revised Text
Primary
Objective

To determine the safety, tolerability and maximum tolerated dose (MTD) of 
GSK525762 in subjects 16 years or older following QD and/or BID dosing 
schedules.

To determine the safety, tolerability and maximum tolerated dose (MTD) of 
GSK525762 in subjects 12 to ≤15 years old

To evaluate the clinical activity of GSK525762 in NMC and other solid tumors.

To evaluate, after single dose administration, the relative bioavailability of the 
GSK525762 besylate tablet compared to the amorphous free-base tablet, the 
effect of high-fat high-calorie meal on the bioavailability of the besylate tablet 
and the dose proportionality of two doses of GSK525762 administered as the 
besylate tablets.
Endpoints

AEs, SAEs, dose reductions or delays, withdrawals due to toxicities and 
changes in safety assessments (e.g., laboratory parameters, vital signs, ECG, 
cardiotoxicity, gastrointestinal, etc) to determine the MTD in subjects 16 years 
or older

AEs, SAEs, dose reductions or delays, withdrawals due to toxicities and 
changes in safety assessments (e.g., laboratory parameters, vital signs, ECG, 
cardiotoxicity, gastrointestinal, etc) to determine the MTD in subjects 12 to ≤15 
years old.

Assess overall response rate (RR) by RECIST 1.1 in NMC and other solid 
tumors.

PK parameter values for GSK525762 following single oral administration as 
amorphous free-base or besylate tablet
Hypothesis

No formal statistical hypotheses will be tested in Part 1. Analysis will be 
descriptive and exploratory. 

The primary goal of Part 2 is to demonstrate a clinically meaningful response 
rate of 20% in , defined as follows: 
NMC relative to a 5% response rate suggesting no activity. This: this will be 
conducteddetermined by testing the null hypothesis that P0≤0.050 versus
the alternative that P1≥0.200, assumingresponse rate is ≤5%, with about 
80% power when the maximumtrue response rate is 20%.
SCLC and CRPC: this will be determined by testing the null hypothesis that 


2011N118599_09
CONFIDENTIAL
BET115521
328
Primary
the response rate for an ineffective drug is 0.05 and≤10%, with about 80%  
power when the minimumtrue response rate for an effective drug is 0.20.
is 30%.
ER+BC: this will be determined by testing the null hypothesis that the 
response rate is ≤15%, with about 80% power when the true response 
rate is 30%.
TNBC:this will be determined by testing the null hypothesis that the 
response rate is ≤10%, with about 80%  power when the true response 
rate is 25%.
Secondary (Objectives and Endpoints only)
Objectives

To characterize the pharmacokinetics (PK) of GSK525762 in subjects 16 years 
or older following QD and/or BID dosing schedules. 

To characterize the pharmacokinetics (PK) of GSK525762 in subjects 12 to 
≤15 years old

To evaluate cardiac safety, including the potential for QTcF, of changes with
GSK525762 and to assess PK/QTcF relationship following QD and/or BID 
dosing schedules.

To evaluate the exposure response (pharmacokinetic/pharmacodynamic 
[PK/PD]) relationship between GSK525762 and safety and efficacy parameters 
following QD and/or BID dosing schedules.

To evaluate the effect of treatment with GSK525762 on tumor growth and 
survival.

To evaluate systemic and ex vivo on-target BET inhibitory effects.
Endpoints

PK parameter values for GSK525762 following single and repeat-dose oral 
administration in subjects 16 years or older

PK parameter values for GSK525762 following single and repeat-dose oral 
administration in subjects 12 to ≤15 years old

Changes in cardiac safety including QTcF following single and repeat-dose oral 
administration GSK525762.

Progression free survival (PFS), time to response, duration of response, overall 
survival (OS), and exploratory analysis for antitumor response by various 
imaging modalities.


2011N118599_09
CONFIDENTIAL
BET115521
329
Exploratory (Objectives and Endpoints only)
Objectives

To evaluate the effect of GSK525762 on tumor biology

Correlation of GSK525762 exposure to changes in PD markers in tumor and/or 
surrogate tissue 

To identify potential indicators of sensitivity or response to GSK525762.

To evaluate systemic and ex vivo on-target BET inhibitory effects.
Endpoints

Dose related changes in markers of cell proliferation and/or cell differentiation 
in tumor and/or surrogate tissue

Dose related changes in transcription of genes and/or changes in expression of 
proteins regulated by BRD proteins in tumor and/or surrogate tissue

PK/PD parameter values for exposure response (by RECIST and 18FDG-PET
[if data allows]) relationship between GSK525762 exposure and QTcF, troponin 
and tumor response following single and repeat-dose oral administration.

Changes from baseline and dose/response relationship in ex vivo LPS induced 
cytokines including IL-6 in whole blood and systemic cytokines including IL-6.
Section 3.1. Study Design/Schematic
Rationale for Change: This section was updated to include the additional expansion 
cohorts for Part 2 (CRPC, TNBC, ER positive and SCLC), to clarify that the sub-study 
would be conducted in the US only and remove reference of the pediatric cohort (Part 
1B).
Revised Text
Paragraph 2 
This is an open-label, single and repeat dose, 2-part study to determine the maximum 
tolerated dose (MTD) and the recommended Phase 2 dose (RP2D) for GSK525762 given 
once-daily orally.  Twice daily dosing may also be explored upon evaluation of safety, 
PK, and PD data from once-daily dosing.  Part 1A1 will be conducted in adult subjects 
with NMC, small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC), 
colorectal cancer (CRC), neuroblastoma (NB), castration resistant prostate cancer 
(CRPC), triple negative breast cancer (TNBC), estrogen receptor positive (ER positive) 
breast cancer, and MYCN  driven solid tumors.  During the dose escalation of Part 1A1, 
additional subjects with NMC will be enrolled in a Pharmacodynamic (PD) Expansion 
Cohort to evaluate the pharmacodynamic effects of GSK525762 at lower doses that have 
been previously cleared during dose escalation.  This will enable collection of 
pharmacodynamic data across the predicted efficacious dose range and contribute to the 
evaluation of a biologically efficacious dose.  Once the RP2D is determined in Part 1A, a
besylate A sub-study will be opened to approximately 10 subjects in the United States to 
investigate the relative bioavailability of the besylate tablet compared to the amorphous 
free-base tablet at the MTD or RP2D, the effect of high-fat high-calorie meal on the 


2011N118599_09
CONFIDENTIAL
BET115521
330
bioavailability of the besylate tablet at the MTD or RP2D and the dose proportionality of 
two doses of GSK525762 administered as besylate tablet. This sub-study will also use a 
stable isotope of GSK525762 in order to reduce the variability in the measurement of 
drug exposure caused by day-to-day biologic variations. After Part 1A is complete and 
the relative BA of the formulation for Part 2 is confirmed, an eExpansion cohorts (Part 2) 
is are planned to further explore clinical activity of GSK525762 in subjects with NMC, 
SCLC, CRPC, TNBC and ER+BC as shown in Figure 1. The expansion cohorts will 
enroll both adult (16 years old and above) and pediatric (12 to ≤15 years) subjects at 
theirthe appropriate R2PD doses. After the MTD is determined in adult subjects, Part 1B 
is planned for enrollment of pediatric subjects 12 to ≤15 years of age with solid tumors to 
determine the RP2D in this age group. Dose escalation in Part 1B will begin at 25% of 
the adult MTD and dose escalation will follow a 3+3 design. . 
Paragraph 4 and 5
After the MTD has been determined in Part 1A, and the besylate sub-study has 
completed1, Part 1B and Part 2 will be opened. Dose titration in the pediatric subjects in 
Part 1B will start at 25% of the MTD determined in Part 1A and will follow a standard 
3+3 design. Pediatric subjects 12 to 15 years of age for the SCLC, TNBC, ER+BC and 
CRPC expansion cohorts. The NMC expansion cohort will be allowed to enroll in Part 2 
once the MTD has been determined inPart 1B.opened with the pivotal besylate tablet 
after results from the besylate study are available.
In both Parts 1 and 2, all subjects will be evaluated for systemic and ex-vivo on-target 
BET inhibitory effects in blood. In addition, pre-treatment and post-treatment tumor 
samples will be collected from selected subjects to be evaluated for target engagement 
and effects of GSK525762 on tumor biology.
Figure 1 Study Schema
A. Part 1 and 2
Revised figure to reflect removal of Part 1B (pediatric cohort), to clarify that the sub-
study would be conducted in the US only and to update number of subjects planned to be 
enrolled
B. Besylate Sub-Study (N=8up to 1012 subjects in the United States)
After completion of either sequence all subjects enrolled in the sub-study will be allowed 
to continue in the study with a continuous once daily schedule.


2011N118599_09
CONFIDENTIAL
BET115521
331
Section 3.2.1
Part 1 Dose Escalation
Rationale for Change: This section was updated to remove reference of the pediatric 
cohort (Part 1B).
Revised Text
Paragraph 2 and 3
Part 1B will be initiated after the MTD is reached in Part 1A and will start at 25% of the 
MTD determined in Part 1A. Part 1B will follow a standard 3+3 design.
In the accelerated dose escalation cohorts and the 3+3 dose escalation cohorts, the dose 
will be escalated based on all available data, including PK data and the safety profile of 
prior cohorts, as well as the predictedrecommended dose from the Neuenschwander-
Continuous Reassessment Method (N-CRM) design [Neuenschwander, 2009].
Figure 2  Dose Escalation Schema
Revised figure to reflect removal of Part 1B (pediatric cohort)
Section 3.2.2.2
3+3 Dose Escalation in Part 1A1
Rationale for Change: Minor updates were made to this section to provide additional 
clarification on the NMC PD cohort.
Revised Text
Paragraph 2
Once the MTD is reached, up to 12 additional subjects may be enrolled at the MTD to 
further evaluate safety and obtain tumor tissue for PD biomarkers. Up to an additional 6 
subjects may be enrolled at any dose level below the MTD to order to obtain additional 
tumor tissue (tumor biopsies would be required; see additional details in Section 
6.8.1).dose/response information related to tumor PD.  Additional cohorts (with daily 
exposure not exceeding QD MTD exposure) may also be initiated to explore alternative 
dosing schedules to optimize the PK, safety and tolerability profile (see Section3.2.2.4).  
The enrolment of additional subjects as described could be in parallel with Part 2 
enrolment.
Deleted Section 3.2.2.3
3+3 Dose Escalation in Part 1B
Rationale for Change: This section was updated to remove reference of the pediatric 
cohort (Part 1B).
Deleted Text
Section 3.2.2.3
3+3 Dose Escalation in Part 1B
Once MTD in declared in adult patients (age ≥16yrs), a pediatric cohort of subjects 12 to 
≤15 yrs old will be opened. The starting dose for this cohort will be 25% of the adult 
MTD and dose escalation will follow a 3+3 design (Table 7 and Table 8). Each dose 
escalation will ≤2-fold increase over the dose of the prior cohort. Once MTD is reached, 
up to 6 additional patients may be enrolled at the MTD dose and each of 2 dose levels 
below the MTD to obtain additional safety and PK data and tissue for PD analysis if 
necessary.


2011N118599_09
CONFIDENTIAL
BET115521
332
Table 7
Dose escalation procedures in Part 1B
Dose Level
Change in Dose
Dose Level -1
Lower doses may be used if Dose Level 1 is not tolerated. This 
may be achieved by reducing the dose or by alternate dosing 
(e.g. every other day)
Dose Level 1 (25% of adult MTD)
Begin 3+3 Dose Escalation Phase
Dose Level 2
Increase by 2-fold 
(No subjects with any DLTs in first 4 weeks of treatment)
Subsequent dose levels
Continue  3+3 Dose Escalation 
Table 8
Dose Escalation Decision Process in Part 1B
Number of subjects at given dose 
level with DLT
Action
0 out of 3 subjects
Escalate to next dose level 
1 out of 3 subjects
Accrue 3 additional evaluable subjects at current dose level for a 
total of 6 evaluable subjects
1 out of 6 subjects
Escalate to the next dose level (Increase by 2-fold)
2 or more subjects in a dosing cohort 
(up to 6 subjects)
Maximum tolerated dose has been exceeded. Either evaluate an 
intermediate dose lower than current dose or expand a prior 
cohort. 


2011N118599_09
CONFIDENTIAL
BET115521
333
Section 3.2.3
Dose Limiting Toxicity (DLT)
Rationale for Change: This section was updated for consistency with CTCAE 
guidelines.
Revised Text
1st Bullet Point:

Neutropenia:
- Grade 4 neutropenia lasting 5days7days.
- Febrile neutropenia: ANC<500/mm3 and fever 38.5C which persists > 48as 
defined by CTCAE version 4.0 lasting for >24 hours despite adequate treatment with 
antibiotics and/or antifungal/antiviral agents.
7th  Bullet Point:

ALT ≥>3x ULN + bilirubin 2xULN (>35% direct) or ALT between 3-5 X ULN 
with bilirubin < 2xULN but with hepatitis symptoms or rash or ALT ≥>5xULN.
Section 3.2.6
Bioavailability, Food Effect, and Dose Proportionality 
Besylate Sub-Study
Rationale for Change: This section was updated to clarify that the sub-study would be 
conducted in the US only.
Revised Text
Paragraph 1
Part 1A1 will include a besylate sub-study that will be an open-label, randomized, single 
dose, four period, cross over study to investigate the relative bioavailability of the 
besylate salt tablet compared to the amorphous free-base tablet at or near the MTD or 
RP2D, the effect of high-fat high-calorie meal on the bioavailability of the besylate salt 
tablet at or near the MTD or RP2D and the dose proportionality of two doses of 
GSK525762 administered as besylate salt tablets. GSK525762 dosing will be separated 
by at least 48 hours.  Up to 12 subjects in the United States may be enrolled in besylate 
sub-study. 
Table 7 (Besylate Sub-Study Design: BA, Food Effect and Dose Proportionality 
Evaluation)
Sample 
Size
Sequence
Period 1
(Week 1 Day 1)
Period 2
(Week 1 Day 3)
Period 13
(Week 2 Day 1)
Period 4
(Week 2 Day 3)


2011N118599_09
CONFIDENTIAL
BET115521
334
Section 3.2.7
Part 2 Expansion Cohort
Rationale for Change: The overall enrolment numbers were updated to accommodate 
enrolment of additional subjects into the supplementary expansion cohorts now included 
with this amendment. This section also includes information on the predictive probability 
design and the futility assessments planned for each cohort in Part 2.
Revised Text
Up to 40Approximately 150 subjects with NMC may, SCLC, CRPC, TNBC and ER+BC 
will be enrolled in an expansion cohort at the RP2D (appropriate to each age group) to 
gather more safety data and to further assess anti-tumor activity.  Pediatric subjects 12 to 
≤15 years old may be enrolled in Part 2 once the MTD has been determined in Part 1B.
Subjects in Part 2 will start with a continuous daily dosing schedule unless safety, PK or 
PD data necessitate a different dosing schedule. The final dose and regimen for Part 2 
will be decided upon completion of dose escalation in Part 1A and Part 1B for the 
respective age groups1.
For purposes of assessing activity, it will be assumed that the maximum response rate for 
an ineffective drug is 0.05 and the minimum response rate for an effective drug is 0.20. 
Futility assessment will be conducted after data are available from the first 20 subjects. 
Safety from all prior subjects, will be reviewed along with this response data (and PK/PD 
and biomarker data when available) for consideration regarding expansion cohorts.
The statistical design and number of subjects to be enrolled in a cohort is based on the 
predictive probability of success if enrollment continues until all planned subjects are 
recruited [Lee, 2008]. The predictive probability design allows for evaluation of stopping 
rules after each subject once a minimum number of subjects are evaluable.   In this 
particular study, we will stop only for futility. Final decisions on stopping enrollment will 
depend on the totality of the data collected.
For NMC, once 10 subjects have been enrolled into the expansion cohort to examine 
safety and efficacy, if 0 responses are observed, further enrolment into this cohort may be 
terminated. The number of observed confirmed responses will guide further enrolment 
according to the rules summarized in Figure 3. A maximum of 40 subjects in this cohort 
will be enrolled at the RP2D.  All available data will be considered in making enrollment 
decisions.
Figure 3
Diagram of Stopping Rules for NMC Cohort Expansion
Number of Responses
Number of 
Subjects
0
1
2
3
10
11
12


2011N118599_09
CONFIDENTIAL
BET115521
335
Number of Responses
Number of 
Subjects
0
1
2
3
13
14
15
16
17
18
19
20
21
22
23
24
25
Figure 3: The shaded regions are the specific regions for stopping the study for futility. For instance, if there is no 
response in 10 subjects, then the predictive probability for success will be 10% or less (the futility criterion) and the 
study will be stopped.
For SCLC and CRPC, once 10 subjects have been enrolled in the cohort to examine 
safety and efficacy, if 0 responses are observed in either cohort, further enrolment into 
this cohort may be terminated. The number of observed confirmed responses will guide 
further enrolment according to the rules summarized in Figure 4. A maximum of 22 
subjects will be enrolled at the RP2D.  All available data will be considered in making 
enrollment decisions.
Figure 4
Diagram of Stopping Rules for SCLC and CRPC Cohort Expansion
Number of Responses
Number of Subjects
0
1
2
3
4
10
11
12
13
14
15
16


2011N118599_09
CONFIDENTIAL
BET115521
336
Number of Responses
17
18
19
20
21
22
Figure 4 Legend:  The shaded regions are the specific regions for stopping the study for futility.  For instance, if there is 
no response in 10 subjects, then the predictive probability for success will be 1% or less (the futility criterion) and the 
study will be stopped. 
For TNBC, once 10 subjects have been enrolled in the cohort to examine safety and 
efficacy, if 0 responses are observed in the cohort, Part 2 of the trial may be terminated 
with no further enrolment in this cohort. The number of observed confirmed responses 
will guide further enrolment according to the rules summarized in Figure 5. A maximum 
of 37 subjects will be enrolled at the RP2D.  All available data will be considered in 
making enrollment decisions.
Figure 5
Diagram of Stopping Rules for TNBC Cohort Expansion
Number of Responses
Number of Subjects
0
1
2
3
4
5
6
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25


2011N118599_09
CONFIDENTIAL
BET115521
337
Number of Responses
26
27
28
29
30
31
32
33
34
35
36
37
Figure 5 Legend:  The shaded regions are the specific regions for stopping the study for futility.  For instance, if there is
no response in 10 subjects, then the predictive probability for success will be 1% or less (the futility criterion) and the 
study will be stopped.
For ER+BC, once 10 subjects have been enrolled in each cohort to examine safety and 
efficacy, if 0 responses are observed, further enrolment into this cohort may be 
terminated. The number of observed confirmed responses will guide further enrolment 
according to the rules summarized in Figure 6. A maximum of 37 subjects per cohort will 
be enrolled at the RP2D.  All available data will be considered in making enrollment 
decisions.
Figure 6
Diagram of Stopping Rules for ER+BC Cohort Expansion
Number of Responses
Number of 
Subjects
0
1
2
3
4
5
6
7
8
10
11
12
13
14
15
16
17
18
19


2011N118599_09
CONFIDENTIAL
BET115521
338
Number of Responses
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
Figure 6 Legend:  The shaded regions are the specific regions for stopping the study for futility.  For instance, if there is 
no response in 10 subjects, then the predictive probability for success will be 1% or less (the futility criterion) and the 
study will be stopped.
Additional safety assessments such as insulin/glucose or cardiac monitoring may be 
specified. Plasma samples for pharmacokinetic evaluation will be collected in all 
subjects. Plasma samples and tumor biopsies will be collected pre- and post-treatment for 
the pharmacodynamic evaluation. 
Section 4.1 Number of Subjects
Rationale for Change: Overall enrolment numbers were updated in this section.
Revised Text
Paragraph 1:
The number of dose levels and the level at which the MTD will be reached cannot be 
determined in advance. An adequate number of subjects will be enrolled into the study to 
establish a recommended dose(s) and schedule(s) of GSK525762 for further study. To 
complete Part 1A and Part 1B1, it is estimated 30 to 50 60 evaluable subjects will be 
enrolled. The besylate sub-study will enroll approximately 10 to 12 evaluable subjects in 
the United States only.  Part 2 will enroll approximately 40 NMC150 subjects.


2011N118599_09
CONFIDENTIAL
BET115521
339
Section 4.2.1 Inclusion Criteria
Rationale for Change: This section was updated to clarify tumor types eligible for 
enrolment in Part 1 and Part 2 and remove reference of the pediatric cohort (Part 1B). 
Part 2 specific exclusion criteria were added for CRPC subjects.
Revised Text: 
Bullet Point 1: 
Part 1A: Male or female 16 years or older, at the time of signing the informed 
consent.
Part 1B: Male or female 12 years to ≤15 years, at the time of signing the informed 
consent
Part 2: Male or female 16 years or older, at the time of signing the informed consent. 
After completion of Part 1B, male or female 12 years, at the time of signing the 
informed consent.
Bullet Point 3: 
Diagnosis of one of the following:

Part 1 Only:

NUT Midline Carcinoma based on ectopic expression of NUT protein as 
determined by IHC and/or detection of NUT gene translocation as 
determined by FISH. Subjects may be treatment naïve or have had prior 
therapy.

SCLC, CRC, NB, TNBC, ER positive BC, CRPC, NSCLC, and any other 
solid tumor which has been confirmed by clinical testing to be MYCN 
amplified (defined as a MYCN gene copy number gain of ≥5).  Subjects 
should have tumor progression after receiving at least one prior 
standard/approved chemotherapy, or where there is no approved therapy, or 
where standard therapy is refused.

Pediatric solid tumors in Part 1B must have progressed after receiving at least 
one prior standard/approved chemotherapy, or where there is no approved 
therapy, or where standard therapy is refused, may be enrolled.

Part 2 Only: 

NUT Midline Carcinoma as diagnosed by the Central Laboratory. Subjects 
may be treatment naïve or have had prior therapy.

SCLC, CRPC, TNBC and ER+BC
Bullet Point 4: 
Subjects with solid tumors, with the exception of CRPC, must demonstrate 
measurable disease, per RECIST v1.1. NOTE: Subjects with NMC that do not meet 
the RECIST v1.1 criteria for measurable disease, but have evaluable disease may be 
considered for enrollment in the NMC PD Cohort at the previously cleared dose 
level. after discussion with the GSK medical monitor.


2011N118599_09
CONFIDENTIAL
BET115521
340
Bullet Point 7 (Table 8):
Rationale for Change: The requirement for stool guaiac testing (fecal occult blood 
testing) was eliminated after discussion with the clinical and safety teams to achieve 
alignment across all GSK BET inhibitor protocols. Any recent evidence of overt 
gastrointestinal bleeding will remain exclusionary.
Revised Text:
System
Laboratory Values
Gastrointestinal
Guaiac fecal occult blood test
Negative 
Footnote no. 3 added for TSH: If TSH is abnormal, but free T3 and/or free T4 are normal, 
then the subject may still be considered eligible for enrolment.
Added Text 
4.2.1.1.1
Specific Eligibility Criteria for Part 2 CRPC Expansion Cohort
Subjects must meet all of the following additional inclusion criteria in order to be 
considered eligible for this cohort:
11. Histologically or cytologically confirmed diagnosis of prostate adenocarcinoma, 
surgically castrated or continuously medically castrated (for 8 weeks prior to 
pre-screening)
12. Persistent disease with evidence of disease progression following standard 
therapy(ies) including prior treatment with androgen/androgen receptor directed 
therapy, including enzalutamide and/or abiraterone
13. Ongoing androgen deprivation therapy with a serum testosterone level 
<1.7 nmol/L or <50 ng/dL [Scher, 2008]
14. PSA levels 2.0 ng/mL [Scher, 2008]
NOTE:  If PSA level has been obtained within 14 days of Screening, this test 
does not need to be repeated and the result previously obtained may be used 
for the Screening value.


2011N118599_09
CONFIDENTIAL
BET115521
341
Section 4.2.2
Exclusion Criteria
Rationale for Change: Minor change made for clarification. The requirement for stool 
guaiac testing (fecal occult blood testing) was eliminated after discussion with the clinical 
and safety teams to achieve alignment across all GSK BET inhibitor protocols. Any 
recent evidence of overt gastrointestinal bleeding will remain exclusionary.
Revised Text:
Bullet Point 10: 
Pulmonary hemoptysis Hemoptysis > 1 teaspoon in 24 hours within the last 28 days
Bullet Point 11: 
History of major gastrointestinal bleeding within the last 6 months.  Any evidence of 
active gastrointestinal bleeding (positive guaiac fecal occult blood test) excludes the 
subject. 


2011N118599_09
CONFIDENTIAL
BET115521
342
Section 5.  TIME AND EVENTS TABLES
Rationale for changes: The time and events tables were modified to ensure consistency of timings, correct previous errors, and to include 
new assessments for CRPC in Part 2.
The requirement for stool guaiac testing (fecal occult blood testing) was eliminated after discussion with the clinical and safety teams to 
achieve alignment across all GSK BET inhibitor protocols. Any recent evidence of overt gastrointestinal bleeding will remain 
exclusionary.
Table 9   Time and Events: Part 1
Assessments Removed

Pharmacogenomics (PGx): Blood samples for circulating exploratory biomarkers (cfDNA, etc)

Castrate-Resistant Prostate Cancer Assessments: Vitamin D3 and PTH, Urinalysis Urine microscopy 
UPC, Urine electrolytes

Pharmacokinetics (PK) and Pharmacodynamics (PD): Samples for mRNA at Screening Visit
Footnote added to CT/MRI Scans (Efficacy): Per RECIST 1.1 baseline (within 35 days of first dose) bone scans and brain scans are to be 
conducted for all subjects. Thereafter scans should be conducted as clinically indicated. Subjects undergoing baseline full body PET/CT 
and/or brain MRI will not require these additional scans, unless clinically appropriate.


2011N118599_09
CONFIDENTIAL
BET115521
343
Revised Text
Part 1 
Assessments
Notes
S
C
R
E
O
T
Week 1
Week 2
W3
W4
W5
W7
W9
q4W
q8W
D
1
D
2
D
3
D
4
D
5
D
6
D
7
D
1
D
2
D
3
D
4
D
5
D
6
D
7
D
1
D
4
D
1
D
4
D
1
D
1
D
1
D
1
D
1
Safety
Adverse events
SAEs collected continuouslycontinuous from signing of informed consent; AEs collected continuously from time of first dose
Efficacy
CT/MRI Scansa
SCR assessment within 35 28 days 
of first dose. Target lesions to be 
identified at SCR and followed.
X
X
X
X
X
Tumor sample
Optional during rapid dose 
escalation; required during 3+3 dose 
escalation. EOT sample should be 
collected at time of progression 
where feasible.
X
All Tumor Types: One postdose sample between W1D4 and W9D1, timingcollected 
anytime betweenW2D1-D5 or W3D1 (2-4h post-dose). Timing may be further optimized 
based on tumor type and emerging data.
X
Castrate-Resistant Prostate Cancer Assessments
PSA
PSA to be collected in line with 
PCWG2 guidelines. Levels may be 
checked more frequently if 
appropriate.
X
X
X
Part 1 Assessments
Notes
S
C
R
E
O
T
Week 1
Week 2
W3
W4
W
5
W7
W9
q4W
q8W
D
1
D
2
D
3
D
4
D
5
D
6
D
7
D
1
D
2
D
3
D
4
D
5
D
6
D
7
D
1
D
4
D
1
D
4
D
1
D
1
D
1
D
1
D
1
Pharmacokinetics (PK) and Pharmacodynamics (PD)
Optional Saliva 
and/or Sweat Sample
A saliva and/or sweat sample may be 
requested on serial PK sampling days. 
Additional collection details will be provided 
in the SPM.
X
X


2011N118599_09
CONFIDENTIAL
BET115521
344
Part 1 Assessments
Notes
S
C
R
E
O
T
Week 1
Week 2
W3
W4
W
5
W7
W9
q4W
q8W
D
1
D
2
D
3
D
4
D
5
D
6
D
7
D
1
D
2
D
3
D
4
D
5
D
6
D
7
D
1
D
4
D
1
D
4
D
1
D
1
D
1
D
1
D
1
Blood samples for 
circulating 
exploratory 
biomarkers (cfDNA, 
etc)
X
X
X
Table 10
Time and Events: Part 1 Laboratory Assessments
Revised Notes for Troponin, NT-proBNP-9:
For Troponin: W1D1, W1D2: local lab sample 3X/24h; central lab sample 1X/24h. All other timepoints, including unscheduled
Unscheduled collect 2 samples: 1 for local, 1 for central lab
Assessment Removed:
Guaiac fecal occult blood.
Hematology at q8W D1 Visit.
Table 11
QD Dosing Time and Events: Part 1 Pharmacokinetics and Biomarker Sampling, Week 1 and Week 2
Revised Text
W1D1
W1D5
W2D4 + 1 day
pre 
dose
15 min 
± 5m 
30 
min 
±5m
1h 
±5m
2h 
±10m
4h 
±15m
8h 
±1h
12h 
±1h2h
24h 
±1h2h
48h
±1h2h a
30 
min 
±5m
3h ±15m
pre 
dose
30 min 
±5m
3h ±15m
8h 
±1h
Urine PK sampling 
(Part 1A1 only)ab
X
0-2h
2-24h
Footnote added to W1D1 48h ±2h Time point: 48h PK sample to be collected prior to dosing on W1D3


2011N118599_09
CONFIDENTIAL
BET115521
345
Table 12
QD Dosing Time and Events: Part 1 Pharmacokinetics and Biomarker Sampling, Week 3 and Week 9
Revised Text
W3D4 + 2 days
W9D1 ±4 days
(if dose has been escalated, +4 to +7 
days)
EOT
EOT
pre 
dose
15 min 
± 5m 
30 min 
±5m
1h ±5m
2h 
±10m
4h 
±15m
8h 
±1h
12h 
±1h2h
24h 
±1h2h a
48h 
±1h2h a
pre dose
0.5-2h
4 - 8h
Urine PK sampling (Part 
1A1 only) ab
0-2h
2-24h
Footnote added to W3D4 + 2 days 24h ±2h and 48h ±2h Time points: 24h and 48h PK samples to be collected prior to dosing on those 
days


2011N118599_09
CONFIDENTIAL
BET115521
346
Table 13
BID Dosing Time and Events: Part 1 Pharmacokinetics and Biomarker Sampling, Week 1
Revised Text
W1D1
W1D2  and 
W1D3
(relative to 
W1D1 
Morning 
Dose)
W1D5
ECG and PK 
samples after 
Morning Dose only
Morning Dose 
Evening Dose
pre 
dose
0H
15 
min 
±5m
30 
min 
±5m
1h 
±5m
2h 
±10m
4h 
±15m
8h 
±1h
pre 
dose  
(12h-
15m)
12h
15 
min(12.25h) 
± 5m
30 min 
(12.5h) 
±5m
1h 
(13h) 
±5m
2h 
(14h) 
±10m
4h 
(16h) 
±15m
8h 
(20h) 
±1h
12 h 
(24h) 
±1h
36 h 
(48h) 
(pre-
dose) 
±1h
30 min 
±5m
3h 
±15m
12-lead ECG, 
in triplicate, 5 
minutes apart 
and within 10 
minutes prior 
to the 15 min 
and 30 min 
PK draws 
and within 15 
minutes prior 
to the other 
PK draws.12-
lead ECG, in 
triplicatea
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
PK and 
protein 
biomarker 
sample b
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Urine PK 
sampling(Part 
1A only)ac
X
0-2h
2-12h
Plasma samples will be divided at the GSK DMPK facility where bioanalysis of PK is performed and shipped to a vendor for systemic cytokine assessment (pre-dose and at 15 min, 30 min, 1 hr, 2 hr, and 
4hr) and acute phase protein assessment at pre-dose and at 2,4, 8 and 24 hr post-dose.  The frequency of sampling may be changed (likely reduced) based on data from the first few subjects assessed. 


2011N118599_09
CONFIDENTIAL
BET115521
347
W1D1
W1D2  and 
W1D3
(relative to 
W1D1 
Morning 
Dose)
W1D5
ECG and PK 
samples after 
Morning Dose only
Morning Dose 
Evening Dose
pre 
dose
0H
15 
min 
±5m
30 
min 
±5m
1h 
±5m
2h 
±10m
4h 
±15m
8h 
±1h
pre 
dose  
(12h-
15m)
12h
15 
min(12.25h) 
± 5m
30 min 
(12.5h) 
±5m
1h 
(13h) 
±5m
2h 
(14h) 
±10m
4h 
(16h) 
±15m
8h 
(20h) 
±1h
12 h 
(24h) 
±1h
36 h 
(48h) 
(pre-
dose) 
±1h
30 min 
±5m
3h 
±15m
a.
Triplicate ECGs should be collected 5 minutes apart and within 10 minutes prior to the 15 min and 30 min PK draws and within 15 minutes prior to the other PK draws.
b.
PK blood samples collected overnight may be kept refrigerated at 4ºC in the event the PK lab is closed overnight (stable up to 12H)
c.
Urine samples for quantitative analysis of GSK525762 are not required in the NMC PD Expansion Cohort.


2011N118599_09
CONFIDENTIAL
BET115521
348
Table 14
BID Dosing Time and Events: Part 1 Pharmacokinetics and Biomarker Sampling, Week 2 and Week 3
Revised Text
W2D4 + 1 day ECG and PK 
samples after Morning Dose 
only
W3D4±+2 days
W3D5 and 
W3D6 
(relative to 
W3D4 
Morning 
Dose)
Morning Dose
Evening Dose
(For W3D4 subjects that are not staying overnight after the 
evening dose, the 15min – 8h PK/ECG timepoints are optional)
pre 
dose 
(Prior 
to 
Dosing)
30m 
± 
5m 
3h 
± 
15m
8 h 
±5m
pre 
dose 
0h
15m 
±5m
30m
±5m
1h 
±5m 
10m
2h 
±10m
15m
4h 
±15m
8h 
±1h
pre 
dose
12h
15m 
±5m 
(12.25m)
30m 
±5m
1h 
(13h)
±5m
10m
2h 
(14h)
±10m
15m
4h 
(16h)
±15m
8h 
(20h)
±1h
12h 
(24h) 
±1h
(pre 
dose)
36h 
(48h) 
±1h
(pre 
dose)
12-lead 
ECG, in 
triplicate, 5 
minutes 
apart and 
within 10 
min prior 
to the 15 
min and 
30 min  PK 
draws and 
within 15 
minutes 
prior to the 
other PK 
draws a
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
PK and 
protein 
biomarker 
sample b
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Urine PK 
sampling 
X
0-2h
2-12h


2011N118599_09
CONFIDENTIAL
BET115521
349
W2D4 + 1 day ECG and PK 
samples after Morning Dose 
only
W3D4±+2 days
W3D5 and 
W3D6 
(relative to 
W3D4 
Morning 
Dose)
Morning Dose
Evening Dose
(For W3D4 subjects that are not staying overnight after the 
evening dose, the 15min – 8h PK/ECG timepoints are optional)
pre 
dose 
(Prior 
to 
Dosing)
30m 
± 
5m 
3h 
± 
15m
8 h 
±5m
pre 
dose 
0h
15m 
±5m
30m
±5m
1h 
±5m 
10m
2h 
±10m
15m
4h 
±15m
8h 
±1h
pre 
dose
12h
15m 
±5m 
(12.25m)
30m 
±5m
1h 
(13h)
±5m
10m
2h 
(14h)
±10m
15m
4h 
(16h)
±15m
8h 
(20h)
±1h
12h 
(24h) 
±1h
(pre 
dose)
36h 
(48h) 
±1h
(pre 
dose)
(Part 1A 
only)ac
mRNA 
whole 
blood 
sample
X
X
X
X
X
Plasma samples will be divided at the GSK DMPK facility where bioanalysis of PK is performed and shipped to a vendor for acute phase protein assessment at pre-dose and at 2, 4, 8 and 24 hr post-dose.  
The frequency of sampling may be changed (likely reduced) based on data from the first few subjects assessed.
a.
Triplicate ECGs should be collected 5 minutes apart and within 10 minutes prior to the 15 min and 30 min PK draws and within 15 minutes prior to the other PK draws.
b.
PK blood samples collected overnight may be kept refrigerated at 4ºC in the event the PK lab is closed overnight (stable up to 12H)
c.
Urine samples for quantitative analysis of GSK525762 are not required in the NMC PD Expansion Cohort.


2011N118599_09
CONFIDENTIAL
BET115521
350
Table 16
Time and Events: Part 2
Assessments Added: Castrate-Resistant Prostate Cancer Assessments (PSA and Serum testosterone) at SCR W1 D1, W2 D1, W3 D1, W4 
D1, W5 D1, W9 D1, W13 D1, q4W D1 and EOT Visits
Assessments Removed: LPS blood sample, Blood samples for mRNA
Revised Text
Part 2 Assessments
Notes
SCR
EOT
W1
W2
W3
W4
W5
W9
W13
q4W
q8W
D1
D1
D1
D1
D1
D1
D1
D1
D1
Safety
Adverse events
SAEs collected continuouslycontinuous from signing of informed consent; AEs collected continuously from time of first 
dose
Efficacy
Tumor sample
X
One postdose sample between W1D4 and 
W9D1, timing optimized based on emerging data
PETCT scan or MRI
Scans within 28 days of first dose may be 
used as screening assessment. Additional 
bone scans and brain scans not required
unless clinically indicated.
X
X
X
X
PK and PD
PK and protein biomarker 
samples
Three samples to be collected each 
sampling day for each type of analysis: 
Predose within 60 minutes prior to dose, 
single draw between 0.5-2h postdose, 
single draw between 4-8h postdose. 
Plasma samples will be divided at the GSK 
DMPK facility where bioanalysis of PK is 
performed and shipped to a vendor for 
acute phase protein assessment.
X
X
X
Blood samples for circulating 
exploratory biomarkers 
(cfDNA, etc)
X
X
X


2011N118599_09
CONFIDENTIAL
BET115521
351
Part 2 Assessments
Notes
SCR
EOT
W1
W2
W3
W4
W5
W9
W13
q4W
q8W
D1
D1
D1
D1
D1
D1
D1
D1
D1
Safety
Adverse events
SAEs collected continuouslycontinuous from signing of informed consent; AEs collected continuously from time of first 
dose
PGx Translational Research
PGx sample
X
Tumor Sample
EOT biopsy should be collected at time of 
disease progression where feasible
X
All Tumor Types: One postdose 
sample collected anytime 
betweenW2D1-D5 or W3D1 (2-4h 
post-dose). Timing may be further 
optimized based on tumor type and 
emerging data
X


2 0 1 1 N 1 1 8 5 9 9 _ 0 9
C O N FI D E N TI A L
B E T 1 1 5 5 2 1
3 5 2
T a bl e 1 8   Ti m e a n d E v e nt s: B e s y l at e S u b-St u d y
Assess me nt A d de d: P K sa m ples at q 8 W D 1 Visit, C T/ M RI  Sca ns a n d P E T Sca n 
( Efficac y) at W 5 D 1 Visit
S e cti o n 6. 1. 2.  Vi sit Wi n d o w s
Re vise d Te xt
P ar a gr a p h 1
Scree ni n g ( b aseli ne t o pre -d ose ): All assess me nts s h o ul d be c o m plete d wit hi n 3 5 1 4 
da y s pri or t o scree ni n gfirst d ose, e xce pt f or t h ose s pecifie d i n T & E ta ble (e. g. C T, M RI, 
E C H O) . N ote f or fe males, pre g na nc y testi n g s h o ul d be perf or me d wit hi n 7 da ys pri or t o 
first d ose. Als o, cli nical la bs perf or me d d uri n g scree ni n g wit hi n 7 2 h o urs of first d ose d o 
n ot nee d t o be re peate d o n Da y  1.
S e cti o n 6. 2
B a s eli n e A s s e s s m e nt f or N M C S u bj e ct s
R ati o n ale f or C h a n ge: Mi n or u p dates were ma de t o t his secti o n t o i ncl u de me nti o n of 
N G S f or p ote ntial N M C dia g n osis.
Re vise d Te xt
F or N M C s u bjects, a dia g n osis of N M C base d o n a p ositi ve I H C test at scree ni n g will be 
re q uire d. A ≥2 0 % n uclei stai ni n g c ut off will be a p plie d f or a p ositi ve dia g n osis as a 
s u bset of ger m cell t u m ors (fr o m testis a n d o var y) wea kly stai n f or t he N U T pr otei n ( 5 % 
ma xi mal n uclei stai ni n g, 
, pers o nal c o m m u nicati o n). Fl u oresce nce i n -sit u 
h y bri dizati o n ( FI S H) testi n g or ne xt ge nerati o n se q ue nci n g ( N G S) will be u n derta ke n 
pr os pecti vel y t o pr o vi de c o nfir mati o n of b or derli ne I H C stai ni n g ( n uclear stai ni n g ≥1 % 
a n d < 2 0 %) a n d retr os pecti vel y  t o c o nfir m N U T ge ne tra nsl ocati o n i n all p ositi ve IH C 
cases .
F urt her retr os pecti ve testi n g will be u n derta ke n f or all e nr olle d N M C s u bjects i n or der t o
c haracterize t he N U T ge ne f usi o n part ner a n d t o s u p p ort e x pl orat or y  a nalysis of 
differe ntial o utc o mes base d o n t he N U T f usi o n part ner. T he I H C a n d FIS H or N G S
a nal ys es will be perf or me d at a ce ntral la b orat or y .
S e cti o n 6. 3
B a s eli n e A s s e s s m e nt f or N o n -N M C S u bj e ct s
R ati o n ale f or C h a n ge: 
P P D
Mi n or u p dates ma de t o t his secti o n t o c orrect pre vi o us err ors a n d 
t o re m o ve a ny refere nce t o pe diatric c o h ort.


2011N118599_09
CONFIDENTIAL
BET115521
353
Revised Text
Subjects diagnosed with SCLC, CRC, NB, CRPC, TNBC, ER+BC or NSCLC [based on 
standard diagnostic criteria, such as histology, cytology (including bone marrow 
evaluation)] or serological criteria (such as serum M-proteinPSA) will be considered 
eligible for Part 1 of the study.  In instances where a solid tumor subject’s MYCN 
amplification status is known, then that subject will be considered eligible.  N-Myc copy 
number gain of ≥5 will be considered positive for MYCN amplification. N-Myc testing 
may be performed using any method.
Subjects with pediatric solid tumors enrolled in Part 1B must have diagnosis confirmed 
by standard criteria as appropriate for their tumor.
Section 6.4.5
Safety Electrocardiograms
Rationale for Change: This section was updated to ensure consistency with new QTc 
management guidelines.
Revised Text
Paragraph 2 onwards:
In addition to the Safety ECGs performed during the study, continuous 12-lead Holter 
ECGs (obtained via a Holter monitor) will be acquired while subjects are at the site. Dual 
snap electrodes will be utilized to enable simultaneous collection of Holter and safety 
ECG data.
All ECGs must include QTcF measurements. Those values greater than 480 msec as 
calculated by the machine must be confirmed manually using Fridericia’s formula given 
below:

The Fridericia’s formula is: QTcF=QT x (1/[RR/1000])1/3

If there are any clinically significant abnormalities including but not limited to a 
QTcF >480 msec, confirm with two additional ECGs taken at least 5 minutes apart.
Table 23
QT Withdrawal Criteria
If QTcF > 480 msec, or uncorrected QT > 600 msec (Grade 3 or 4), or any change from *baseline 
of ≥60 msec even if not exceeding 480 msec, (all measurements based on an averaged manual 
overread of three ECGs over at least 15 minutes) permanently discontinue study medications and 
notify the GSK Medical Monitor.
* Baseline results are defined by the nearest timepoint prior to first dose. For this trial the Baseline 
QTcF value is determined by the mean of the triplicate W1D1 predose QTcF results. If these 
results are not available, then the mean QTcF of the screening triplicate ECG results would be 
used.
If a subject meets the corrected QT (QTc) interval duration criteria below, study 
treatment(s) will be withheld.

QTc interval ≥ 500 msec OR interval increase from baseline 60 msec: IP 
will be discontinued unless the benefits of therapy outweigh the risk of 


2011N118599_09
CONFIDENTIAL
BET115521
354
rechallenge in the opinion of the Investigator, the GSK Medical Monitor, as 
well as the GSK medical governance. In this situation, rechallenge may be 
permitted (see Table 25 for rechallenge guidelines).
NOTE: QT interval duration criteria should be based on the average QTc value of 
triplicate electrocardiograms (ECGs) to include manual over-read. For example, if an 
ECG demonstrates a prolonged QT interval, obtain 2 additional ECGs over a brief period 
(e.g., within approximately 10 minutes of the abnormal ECG, if possible, and 
approximately 10 minutes apart from each other), and then use the averaged QTc values 
of the 3 ECGs to determine whether the subjects should have study treatment 
discontinued.
The QTc is the QT interval corrected for heart rate according to Fridericia’s formula 
(QTcF). 

For eligibility and withdrawal, QTcF will be used for all subjects. 

For purposes of data analysis, QTcF will be used.
Baseline results are defined by the nearest timepoint prior to first dose. For this trial the 
Baseline QTcF value is determined by the mean of the triplicate W1D1 predose QTcF 
results. If these results are not available, then the mean QTcF of the screening triplicate 
ECG results would be used.
Abnormal ECGs should be evaluated manually prior to final decision making. ECG data 
may be transferred and reviewed by an independent central reviewer. Instructions for 
submission of qualifying ECHOs scans are provided in the SPM. 
Table 21  Clinical Laboratory Tests
Rationale for Change: The requirement for stool guaiac testing (fecal occult blood 
testing) was eliminated after discussion with the clinical and safety teams to achieve 
alignment across all GSK BET inhibitor protocols. Any recent evidence of overt 
gastrointestinal bleeding will remain exclusionary.
Deleted Text
Guaiac fecal occult blood


2011N118599_09
CONFIDENTIAL
BET115521
355
Section 6.6.3.  Urine Collection
Revised Text
Paragraph 1
Urine samples for quantitative analysis of GSK525762 will be collected at pre-dose and 
over a dosing interval hours in two samples (sample collected 0-2hr and second sample 
collected 2-end of dosing intervalhr) immediately following dosing on Week 1 Day 1 and 
in Week 3. Urine samples will be collected in subjects in Part 1A1 (with the exclusion of 
besylate sub-study) once the 3+3 dose escalation has been reached. Additional sampling 
may be instituted based on emerging data.  
Section 6.8 Translational Research
Rationale for Change: This section was revised and reworded to provide additional 
rationale, details and clarification on the translational research strategy for this study.
Revised Text
Blood and/or tumor tissue specimens will be collected at various times throughout the 
study in order to support research aimed at identifying indicators of sensitivity/resistance 
to GSK525762 and, understanding the biological effect of GSK525762 and BET 
inhibition, and also to support diagnostic assay development for NMC. 
Toward that end the successful collection of quality tumor specimens will be critical to 
furthering our understanding of BET biology and indentifying the best way to treat 
patients with a BET inhibitor. Specifically, the evaluation of responders, responders at 
relapse, and non-responders for gene mutation status and/or pathway activation may lead 
to the discovery of potential new diagnostic markers or novel combinations. Similarly, 
pre- and post-dose tumor specimens will be evaluated for markers of target engagement, 
tumor response, and/or evaluated for changes in gene expression; thus supporting 
identification of a biologically effective dose and furthering our mechanistic 
understanding of BET inhibition in these settings. 
The biopsies will be assessed for transcripts or proteins that reflect BET target 
engagement and/or tumor biology (For NMC, markers of cell proliferation and/or cell 
differentiation (e.g., Ki67 and cytokeratin [Schwartz, 2011]) will be analyzed. Biopsies 
may also be assessed for DNA, RNA or proteins which may be potential predictors of 
sensitivity or resistance to BET inhibition based on emerging data.
6.8.1
Tumor Tissue Collection
NMC patients will be required to submit a fresh or archival tumor specimen for diagnosis 
or diagnostic confirmation. These archival specimens may also be evaluated 
retrospectively for exploratory research. During the 3+3 design NMC patients will also 
be required to supply fresh pre and post-treatment biopsies to test for relevant markers of 
tumor PD and/or biological effect and to support identification of a biologically effective 
dose. as described above. 


2011N118599_09
CONFIDENTIAL
BET115521
356
NonAll non-NMC patients will also be asked to submit an archival tumor specimen for 
retrospective testing for potential markers of sensitivity and/or resistance, eg. N-Myc 
amplification; however this will not be an eligibility requirement. Furthermore, as for 
NMC patients, during the 3+3 design non-NMC patients will be required to supply fresh 
pre and post-treatment biopsies for tumor PD. 
During the accelerated dose escalation phase (Part 1), fresh pre- and post-dose biopsy 
collections will be optional until the standard 3+3 design is implemented.  During the 3+3 
dose escalation phase in Part 1, and during Part 2, pre- and post-treatment biopsies are 
mandatory. For subjects in Part 1 and 2, if tumor tissue is not accessible, discussion with 
the GSK medical monitor is required. 
Archival tissue may be accepted as a pre-treatment specimen if the subject is treatment 
naïve. Specific timing of post-treatment sample collection is defined in the T&E table. 
See Study Procedures Manual (SPM) and central lab manual for additional details.
Blood samples collected at time points described in the Time and Events tables for PK 
and PD testing will be required for all subjects.
6.8.1
Tumor Tissue Collection
During the accelerated dose escalation phase (Part 1A), biopsy assessments will be 
optional until the standard 3+3 design is implemented.  Once the 3+3 design is 
implemented in Part 1A, sites will be required to obtain pre- and post-treatment biopsies 
(when tumor tissue is accessible). 
Up to 6 additional subjects per dose level may be enrolled and required to consent to pre 
and post treatment biopsies during the 3+3 dose escalation, for a maximum of 9 subjects 
per cohort until MTD is reached. Up to12 additional subjects may be enrolled and 
required to consent to pre and post treatment biopsies at the MTD for a maximum of 18 
subjects (tumor tissue may be collected from one or more histological subtypes). 
Additional biopsy patients will help determine biologically effective dose(s) and provide 
additional safety data. The goal is to obtain evaluable tissue biopsies from approximately 
8-10 subjects at MTD and 4-6 subjects at lower dose levels. This may occur in-stream 
before reaching MTD based upon adverse events or response profile. The tumor types 
appropriate for biopsy and pharmacodynamic evaluation may be restricted to a few 
specific tumor types/subtypes based on emerging pre-clinical data. Depending upon the 
emerging safety profile, Part 2 of the study may begin after enrollment of 6 subjects at 
the MTD or after determination of a biologically effective dose. Tumor biopsies will be 
optional for subjects below age 16 in either Part 1B or Part 2.
Archival tissue may be accepted as a pre-treatment specimen if the subject is treatment 
naïve.  Specific timing of post-treatment sample collection will be based upon tumor type 
and emergent data.  See Study Procedures Manual (SPM) for details.
For subjects with accessible tumor and who have signed the appropriate consent form the 
procedure will consist of approximately 3 core needle biopsies of the same accessible 
target tumor at the designated pre and post treatment time points.  Where feasible, 


2011N118599_09
CONFIDENTIAL
BET115521
357
biopsies are requested at time of progression. Further details regarding the biopsy 
procedure and how to process the tumor samples will be provided in the SPM.
The biopsies will be assessed for transcripts or proteins that reflect BET target 
engagement and/or tumor biology (For NMC, markers of cell proliferation and/or cell 
differentiation (e.g., Ki67 and cytokeratin [Schwartz, 2011]) will be analyzed.  Biopsies 
may also be assessed for DNA, RNA or proteins which may be potential predictors of 
sensitivity or resistance to BET inhibition based on emerging data.
Section 6.9.3
Laboratory and Other Safety Assessment Abnormalities 
Reported as AEs and SAEs
Rationale for Change: This section was updated to provide additional clarification 
regarding reporting of AEs for lab abnormalities.


2011N118599_09
CONFIDENTIAL
BET115521
358
Revised Text
Paragraph 1
Any abnormal laboratory test results (findings (e.g., hematology, clinical chemistry, or 
urinalysis), or other safety assessments (e.g., ECGs, radiological scans, vital signs 
measurements) including those that worsen from baseline, and events felt that are judged 
by the investigator 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. The investigator will exercise his or her medical and scientific judgment in 
deciding whether an abnormal laboratory finding or other abnormal assessment is 
clinically significant.
Section 7.1 GSK525762 Investigational Product Dosage/Administration
Rationale for Change: This section was updated to provide clarity on which 
formulations were being used for which part of the trial.
Revised Text
Paragraph 1:
GSK525762 Tablets will be provided to sites by GSK. The contents of the label will be in 
accordance with all applicable regulatory requirements.  Two investigational drug 
formulations will be introduced in Part 1.  An amorphous, free-base formulation of 
GSK525762 will be used in Part 1 (Table 23) and a crystalline, besylate formulation 
(Table 2724) will be introduced in the besylate sub-study in Part 1A1 (US sites only) and 
the Part 2 NMC expansion cohortcohorts.
Table 23 (GSK525762 Amorphous Free-base Investigational Product 
Dosage/Administration):
Removed details of 100 mg tablet 
Table 24 (GSK525762 Besylate Investigational Product Dosage/Administration)
Investigational Product
Product name:
GSK525762 Besylate Tablets
13C-GSK525762 Stable isotope powder 
for oral solution
Physical 
description:
White to off-
white,slightly 
colored round, 
biconvex tablets 
with no 
markings, film-
coated tablet
White to off-
whiteslightly 
colored , oval, 
biconvex tablets 
with no markings, 
film-coated tablet
White to off-whiteslightly colored powder


2011N118599_09
CONFIDENTIAL
BET115521
359
Investigational Product
Dosing 
instructions:
Dose with 240mL water and should be 
taken between 7 am and 10 am. No 
food or antacids for at least 1h before 
and 2h after dosing. (If a subject 
vomits after taking study drug, the 
subject should be instructed not to 
retake the dose and should take the 
next scheduled dose.)
Dissolve powder in 1020 mL of water with 
bicarbonate buffer and administered with 
GSK525762 tablets (Besylate Sub-Study, 
Treatment A, B and C)
Section 7.7.1
Dose and Safety Management Guidelines
Rationale for Change: The QTc management guidelines were updated to reflect new 
guidelines.
Revised Text
Table 25
Dose Adjustment/Stopping Safety Criteria
Toxicity
Dose Adjustment/Stopping 
Criteria
Management Guidelines
QTcF

QT monitoring:

If >30msec and 
≤60 msec 
change from 
baseline* occurs.
Grade 1 or 2 
During telemetry 
monitoring if a Grade 1-2: 
If >60msec change from 
baseline* and not 
exceeding 480 msec for 
QTcF (Averaged  AND
manual overreadQTcF 
<500 (average of three 
ECGs over at least 15 
minutes)
Management Guidelines for QTcF: 

Continue dosing and follow activities.
current dose of GSK525762
Manually calculate QTcF to reconfirm clinically significant 
prolongation.

Supplement electrolytes, particularly potassium and 
magnesium, to recommended levels:
(1) Maintain serum potassium > 4mol/L
(2) Maintain serum magnesium levels 0.85 mmol/L

Discontinue any concomitant medications with 
potential for QTcF prolongation.
Consider 24 hour or longer telemetry monitoring if clinically 
indicated.
Grade 1 or 2 Temporarily discontinue study medications and 
review the following activities:
Manual calculate QTcF to reconfirm clinically significant 
prolongation.
Supplement electrolytes, particularly potassium and 
magnesium, to recommended levels:
(1) Maintain serum potassium > 4mol/L
(2) Maintain serum magnesium levels 0.85 mmol/L
(1) Rule out other potential etiologies for prolonged QTcF 
such as cardiac ischemia
(2) Discontinue any concomitant medications with 
potential for QTcF prolongation.
(3) Consider telemetry monitoring if clinically indicated.
May consider restarting study treatment at a reduced dose or 
dose level pre-event based on discussion with GSK Medical 


2011N118599_09
CONFIDENTIAL
BET115521
360
Toxicity
Dose Adjustment/Stopping 
Criteria
Management Guidelines
Monitor.
Permanently discontinue study medications and notify the 
GSK Medical Monitor. 
If the subject is variable around 480 msec assessments may 
be repeated. This subject may consider restarting study 
treatment at a reduced dose or dose level pre-event based on 
discussions with GSK Medical Monitor, Investigator and 
cardiologist.
If 60 msec change from 
baseline occurs
OR
QTcF>480 msec 
(Averaged manual 
overread 500 
(average of three ECGs 
over at least 15 minutes)
If QTcF > 60 msec over 
baseline* value AND 
QTcF>480 msec 
(Averaged manual 
overread of three ECGs 
over at least 15 minutes)

Discontinue GSK525762 and notify the GSK Medical 
Monitor. 
(4) Supplement electrolytes to recommended levels:
a.
Maintain serum potassium > 4mol/L
b.
Maintain serum magnesium levels >0.85 mmol/L
(5) Rule out other potential etiologies for prolonged 
QTcF such as cardiac ischemia
(6) Discontinue any concomitant medications with 
potential for QTcF prolongation.
(7) Consider telemetry monitoring if clinically 
indicated.

This subject may consider restarting study treatment at a 
previous dose level if the following criteria for QTcF 
rechallenge are met :

QTcF Rechallenge Procedures:
Do not rechallenge with study treatment unless under the 
following conditions: 
(1) QTcF event reduced to Grade ≤1<450 msec,
(2)
potassium and magnesium levels are within 
institutional normal range,
(3) a favorable risk/benefit profile
(3)
(4) approval by (in the internal medical judgement of 
the Investigator and the GSK Medical Monitor),
(4)
(5) IRB approval within GSK medical governance:
a.
agreement with SERM MD and PPL,
b.
review with Chair or co-Chair of the GSK QT 
panel,
c.
SERM VP and Clinical VP approval, and
d.
(6) the Head Unit Physician approval
(5)
Institutional IRB (or equivalent) approval, and
(6)
The subject is re-consented regarding the possible 
increaseincreased risk of QTcFQTc prolongation. 

If approval for re-treatmentchallenge is granted, the 
subject must be re-consented (with a separate 
informed consent specific to QTcFQTc prolongation)

Discontinuation procedures:
If the subject is withdrawn due to QTcF event, the subject 
should complete the following activities post-dose:
(1) Evaluation by cardiologist.
(2) Weekly assessments for QTcF should be monitored 


2011N118599_09
CONFIDENTIAL
BET115521
361
Toxicity
Dose Adjustment/Stopping 
Criteria
Management Guidelines
weekly for two weeks, and then next assessment at 4 weeks 
post-dose.
(3) If QTcF results have not resolved to baseline by 4 weeks 
post-dose, then continue every 4-5 weeks until resolution
Liver 
ALT ≥>5X ULN
ALT≥>3X ULN and 
bilirubin >/= 2X ULN 
(>35% direct bilirubin, 
bilirubin fractionation 
required) or INR >1.5 
without evidence of biliary 
obstruction or progressive 
disease
ALT ≥>3X ULN with the 
appearance hepatitis 
symptoms or rash
In the absence of known hepatic metastases, discontinue 
study medications, notify the GSK Medical Monitor, and refer 
to follow-up procedures outlined in Appendix 3, Section IIIa, 
Liver chemistry follow-up procedures. In the presence of 
known hepatic metastases, if there is evidence to suggest a 
drug induced effect, discontinue study medications, notify the 
GSK Medical Monitor, and refer to follow-up procedures 
outlined in Appendix 3, Section IIIa, Liver Chemistry Follow-
Up Procedures.
Section 8.2.1
Cautionary Medications
Rationale for Change: The data source for Table 27 was updated in this section.
Revised Text
Table 27
Drugs with a Risk of Torsades de Pointes which are permitted for 
co-administration with Extreme Caution
Generic Name
Brand Name
Amiodarone
Cordarone, Pacerone, Nexterone
Astemizole
Hismanal
Chlorpromazine
Thorazine, Largactil, Megaphen
Clarithromycin
Biaxin, Prevpac
Haloperidol
Haldol
*There may be situations when the subject is on study that Advanced Cardiac Life Support (ACLS) requires the use of 
amiodarone, which should be used as per local clinical guidelines
Data Source: www.QTdrugscrediblemeds.org (revised 2502-Mar-20082015)
Section 11.1 Sample Size Assumptions
Rationale for Change: Analysis and sample size updated for new tumor types included 
in Part 2 and additional information provided on rationale for sample size, futility and 
probability predictions. 


2011N118599_09
CONFIDENTIAL
BET115521
362
Revised Text
11.1.1 Part 1
The total number of subjects to be enrolled into Part 1A and Part 1B will1will depend on 
the number of dose escalations required to establish the maximum tolerated dose of 
GSK525762; they are not driven by statistical considerations. To complete Part 1, it is 
estimated that 50 to 70 evaluable subjects will be enrolled.
11.1.2 Part 1A Besylate Sub-Study
Doses to be studied in Part 1 will be guided by calculating the posterior probability that  
the DLT rate falls within an acceptable range for each subsequent dose after each dose 
cohort observation period.  The N-CRM method will be used to calculate posterior 
probabilities utilizing a pre-specified prior distribution.
11.1.2 Besylate Sub-Study
Paragraph 1:
At least 8 and up to 12 US subjects will participate in Besylate Sub-Study.  
11.1.3 Part 2
UpThe primary goal of Part 2 is to 40 evaluate disease-specific efficacy in subjects in 
with NMC, SCLC, CRPC, TNBC and ER+BC. .

For NMC, efficacy is defined as a clinically meaningful response rate (defined as 
the NMC expansionpercentage of subjects that have achieved a CR or PR) of 20% 
relative to a 5% response rate suggesting no activity

For CRPC and SCLC, efficacy is defined as a clinically meaningful response rate 
(defined as a percentage of subjects that have achieved as CR or PR) of 30% 
relative to a 10% response rate suggesting no activity.

For TNBC, efficacy is defined as a clinically meaningful response rate (defined as 
a percentage of subjects that have achieved as CR or PR) of 25% relative to a 
10% response rate suggesting no activity.

For ER+BC, efficacy is defined as a clinically meaningful response rate (defined 
as a percentage of subjects that have achieved as CR or PR) of 30% relative to a 
15% response rate suggesting no activity.
Bayesian statistics will be employed to calculate the predictive probability that the 
response rate is greater than the historic response rate at interim analyses using a 
weak/non-informative prior. A Bayesian analysis expresses uncertainty about a parameter 
in terms of probability.  A prior distribution is defined to characterize the level of 
knowledge about a parameter before the data are collected.  Once the data are collected, a 
posterior distribution is formed using the prior distribution and the observed data.  A very 
weak prior Beta distribution with a mean response rate equal to the target response rate is 


2011N118599_09
CONFIDENTIAL
BET115521
363
assumed.  Thus, the posterior distribution for the response rate will be primarily driven by 
the data and can be derived as follows:
Let p denote the response rate, the number of responses in the current n subjects, x, 
follows a binomial distribution, Binomial (n, p).  Taking the Bayesian method and 
combining the prior distribution and the observed data x, the posterior distribution of the 
response rate follows a beta distribution, i.e.
In the following case, 30% is the target response rate.
p Beta (0.03 + x, 0.07 + n-x) with the posterior mean (0.03+ x)/(0.07 + n).
Futility analysis for each disease cohort will begin when response data is available for at 
least 10 subjects. Each disease cohort may be enrolled. With a sample size of 
approximately 40 subjects, the study will have 90% statistical power to teststopped early 
for futility if the predictive probability of success (response rate ≥ historical response 
rate) is less than 1%.  Futility stopping rules are defined for each cohort in Section 3.2.7.
The following table describes for each disease cohort the null hypothesis that overall 
Response Rate (RR) P0≤0.05 versus the and alternative that P1≥0.20 at actual alpha=0.05 
(using a two-stagehypotheses that will be tested, maximum sample size and design, 
verified using Green Dahlberg two-stage design [, 1992]. characteristics.  Each maximum 
sample size was calculated to ensure that at least 80% power and a maximum type 1 error 
rate of 10% is maintained.
Null 
Hypothesis 
(H0) ORR
Alternative 
Hypothesis 
(Target) (Ha) 
ORR
Maximum 
Sample 
Size
Probability of 
stopping early 
for futility if H0 
is true
Average 
Sample Size 
if H0 is true
Actual 
Type I Error 
Rate (%)
Actual 
Power (%)
NMC 
5%
20%
25
0.891
14
8.8
80.2
CRPC 
10%
30%
22
0.860
16
6.0
82.5
TNBC 
10%
25%
37
0.876
23
6.4
81.7
ER+BC 
15%
30%
37
0.855
25
8.7
80.3
SCLC 
10%
30%
22
0.860
16
6.0
82.5
11.1.4 Sensitivity Analysis
ANo sample size sensitivity analysis was performed to assess the effect on power if the 
true response rate varies from the anticipated 20%..


2011N118599_09
CONFIDENTIAL
BET115521
364
Table 32
Sample Size Sensitivity Analysis
True Response Rate
N1
N2
Overall Power
15%
20
20
69%
20%
20
20
90%
25%
20
20
98%
30%
20
20
99%
N1=Sample size at interim. N1+N2=Total sample size
Deleted Section 11.2 Stopping Rule for Futility (Interim Analysis)
Rationale for Change: This section was deleted as the stopping rule for futility is 
described in the previous sections and elsewhere in the protocol.
Deleted Text:
11.2
Stopping Rule for Futility (Interim Analysis)
An interim analysis will be conducted for Part 2 of this study in order to assess futility 
after response data are available for the first 20 subjects based on the overall best 
response rate.  If 0 responses are observed, then Part 2 of trial will be terminated with no 
further enrolment.  
If at least 1 response occurs then an additional 20 subjects with NMC may be enrolled.   
Emerging safety data will also be reviewed.  Safety data will be reviewed on an ongoing 
basis and after the first 20 patients to ensure the safety profile supports continued 
enrolment.  If there is sufficient sample size an exploratory analysis will be undertaken to 
evaluate whether response rates differ between molecular subtypes (e.g. NUT-BRD3, 
NUT-BRD4, NUT-variant).
There is a 1% probability of stopping for futility under the alternative hypothesis (i.e 
incorrectly stopping at the interim when in drug is efficacious) and a 36% probability of 
stopping for futility under the null hypothesis (i.e. correctly stopping at the interim when 
the drug is not efficacious).
At final analysis, if >=5 responses are observed then we reject the null hypothesis and 
accept the alternative hypothesis that there is at least a 20% response rate in NMC 
following dosing with GSK525762.
Section 11.4.1
Primary Analysis
Rationale for Change: The analysis section was updated to include additional tumor 
types in Part 2 now included with this protocol amendment.


2011N118599_09
CONFIDENTIAL
BET115521
365
Revised Text
For Part 1, anti-tumor activities will be evaluated based on clinical evidence and response 
criteria. If the data warrant, the response data will be summarized by dose level.
The primary aim of Part 2 is to demonstrate a clinically meaningful response raterates in 
each of 20% relative to a 5% response rate suggesting no activitythe disease cohorts 
separately. 
The overallOverall response rate is defined as the percentage of subjects with a 
confirmed complete response (who achieved CR) or a partial response (PR) at any time 
as per RECIST 1.1 criteria. Subjects with unknown or missing response will be treated as 
non responders, i.e., these among subjects will be included in the denominator when 
calculating the percentage. Exact methods for calculatedwho received at least one dose of 
treatment. Overall response rate and the associated 2-sided 95% exact confidence 
intervalslimits will be in the RAP. 
The number and types of responses, as outlined in RECIST 1.1, will be listed and 
summarized, as appropriate, for the NMCprovided separately for each disease cohort in 
Part 2.
NMC is an extremely rare cancer and there is no known response to chemotherapy. This 
cancer has an extremely poor survival rate of 6.7 months (median). Based on dialog 
between investigators and GSK, it is estimated that a RR of 20% would be the lowest 
threshold which is of clinical relevance. The study is based on the assumption that the 
maximum response rate for an ineffective drug is 0.05 and the minimum response rate for 
an effective drug is 0.20. A futility assessment will be conducted after data is available 
from the first 20 subjects. If 0 responses are observed among the 20 subjects at interim, 
then in conjunction with a thorough review of additional data, that cohort may be closed 
for further enrollment. If one or more subjects respond, then an additional 20 subjects 
may be enrolled to more accurately define the true response rate.
At final analysis, if 5 responses are observed then the null hypothesis will be rejected 
and the alternative hypothesis that there is at least a 20% response rate in NMC following 
dosing with GSK525762 will be accepted.
Section 13
References
Rationale for Change: References were updated based on updates made throughout the 
protocol amendment.
Reference Deleted
Alderton G. Anticancer drugs: Targeting MYC? You BET. Nature Reviews Cancer, 
2011;11:693.
Carroll K. Back to Basics: Explaining Sample Size in Outcome Trials, Are Statisticians 
Doing a Thorough Job. Pharmaceutical Statistic., 2009, 8(3): 333-45.


2011N118599_09
CONFIDENTIAL
BET115521
366
French CA, Kutok JL, Faquin WC, et al. Midline carcinoma of children and young adults 
with NUT rearrangement. Journal of Clinical Oncology. 2004;22:4135-4139.
French, C.A., Molecular pathology of NUT midline carcinomas. Journal of Clinical 
Pathology, 2010; 63:492-496.
Green SJ and Dahlberg S (1992). Planned Versus Attained Design in Phase II Clinical 
Trials. Statistics and Medicine 11:853-862.
Mallal S, Phillips E, Carosi G, Molina JM, Workman C, Tomazic J, Jägel-Guedes E, 
Rugina S, Kozyrev O, Cid JF, Hay P, Nolan D, Hughes S, Hughes A, Ryan S, Fitch N, 
Schulz C, Heinemann V, Schalhorn A, Moosmann N, Zwingers T, Boeck S, Giessen C, 
Nicodeme E, Jeffrey K, et al. Suppression of inflammation by a synthetic histone mimic. 
Nature 2010; 478: 1119-1123.
Stemmler HJ. UGT1A1 gene polymorphism: Impact on toxicity and efficacy of 
irinotecan-based regimens in metastatic colorectal cancer. World J. Gastroenterol. 2009; 
15: 5058-66.
Thorborn D, Benbow A; PREDICT-1 Study Team. HLA-B*5701 screening for 
hypersensitivity to abacavir. N Engl J Med. 2008; 358; 568-78
Yan J, Diaz J, Jiao J, Wang R and You J. Perturbation of BRD4 function by BRD4-NUT 
abrogates cellular differentiation in NUT midline carcinoma. Journal of Biological 
Chemistry, 2011.
Yang Z, He, N. & Zhou, Q. Brd4 recruits P-TEFb to chromosomes at late mitosis to 
promote G1 gene expression and cell cycle progression. Mol. Cell. Biol. 28, 967–976 
(2008).
Yang Z. et al. Recruitment of P-TEFb for stimulation of transcriptional elongationby the 
bromodomain protein Brd4. Mol. Cell 19, 535–545 (2005).
Reference Added
Lee JJ, Liu DD. A predictive probability design for Phase II cancer clinical trials.  Clin 
Trials. 2008; 5(2); 93-106.
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


2011N118599_09
CONFIDENTIAL
BET115521
367
AMENDMENT 06
Protocol Changes for Amendment 6 (DD-MMM-YYYY) from the Protocol 
Amendment 5 (24-MAR-2015)
Protocol Amendment 6 applies to all site(s) participating in the conduct of the study
Amendment 06 summary: Amendment 6 includes updated guidance on contraception 
use based on emerging data from preclinical studies. Section 6.4.6 was updated to clarify 
how the Holter Monitoring data will be reviewed and analyzed. Additionally, updates 
were made throughout to correct minor inconsistencies and provide further clarification, 
specifically with the Time and Events Tables. Furthermore, the dosing schedule was 
updated from a staggered (1,3,5,7) dosing schedule in the first two weeks to a continuous 
daily dosing schedule. Finally, after an internal QTc analysis and evaluation of cardiac 
safety data collected  from all subjects up to the 100 mg QD cohort available by May 15 
2015, the 48-hour telemetry requirement has been removed for all parts of the study and 
the frequency of Holter Monitoring has been decreased in Part 1.  
Changes are noted below with strikethrough to identify deleted text and underlining to 
identify new or replacement text.
List of Specific Changes
SPONSOR/MEDICAL MONITOR INFORMATION PAGE
Rationale for Change: Updated to include back-up medical monitor’s cell phone 
number.
Added Text: 
After-hours contact number added for Secondary Medical Monitor
PROTOCOL SYNOPSIS
Rationale for Change: After an internal QTc analysis and evaluation of cardiac safety 
data collected from all subjects up to the 100 mg QD cohort available by May 15 2015, 
the 48-hour telemetry requirement was removed for all parts of the study and the 
frequency of Holter Monitoring was decreased in Part 1. There was no GSK525762 
related QTc prolongation observed within the first 48 hours of treatment.Therefore the 
inpatient telemetry on W1D1 and W1D2 was discontinued. Although the presence of a 
slight delayed QT prolonging effect was noted, this did not lead to any marked 
prolongation (no individual subjects with delta >60ms or QTc >500ms). The frequency 
of Holter monitoring in Part 1 was also reduced from 6 timepoints to 4 timepoints, as the 
ECG time-points currently included in the required assessments provide adequate cardiac 
safety assessments of any potential QT-prolonging effect (including potential delayed 
effects). All Holter monitoring will continue to be reviewed at a central lab for 
arrhythmia assessment. The overnight stays previously mandated as part of the 48-hour 
in-patient telemetry will only be required on serial ECG/PK days at sites that are unable 
to collect after-hours PK timepoints as outpatient.


2011N118599_09
CONFIDENTIAL
BET115521
368
Revised Text:
SAFETY MEASUREMENTS: Routine physical examinations, vital sign 
measurements, echocardiograms, and monitoring of adverse events. Stringent Ccardiac 
safety monitoring will be required, consisting of at least 48 hours of telemetry following 
the first dose (overnight stays in research facility necessary), 24 hours of Holter 
monitoring at Screening and in Week 1, Week 2, and Week 4, and Week 9, and triplicate
12-lead ECGs prior to dosing on selected days and prior to drawing PK samples on serial 
PK sampling days (overnight stays in research facility may be necessary in Part 1).). 
Extensive laboratory testing includes, in addition to standard hematology, clinical 
chemistry, pancreatic, coagulation, and liver chemistry panels, testing for troponin, c-
peptide, 1,5 AG, HBA1c, and thyroid monitoring. Additional safety assessments may be 
necessary if a combination treatment regimen is administered to address specific safety 
concerns with the other agent(s) being administered.
Section 1.5 Risk Assessment
Rationale for Change: The Telemetry was removed from the Risk Assessment section 
after an internal QTc analysis and evaluation of cardiac safety data collected from all 
subjects up to the 100 mg QD cohort available by May 15 2015, the 48-hour telemetry 
requirement was removed for all parts of the study and the frequency of Holter 
Monitoring was decreased in Part 1. There was no GSK525762 related QTc prolongation 
observed within the first 48 hours of treatment. Therefore the inpatient telemetry on 
W1D1 and W1D2 was discontinued. Although the presence of a slight delayed QT 
prolonging effect was noted, this did not lead to any marked prolongation (no individual 
subjects with delta >60ms or QTc >500ms). The frequency of Holter monitoring in Part 
1 was also reduced from 6 timepoints to 4 timepoints, as the ECG time-points currently 
included in the required assessments provide adequate cardiac safety assessments of any 
potential QT-prolonging effect (including potential delayed effects). All Holter 
monitoring will continue to be reviewed at a central lab for arrhythmia assessment. 
The Reproductive Risk section was also updated after new findings related to 
GSK525762 in a rat female fertility study in which adverse reproductive findings in 
pregnant rats (maternal and embryo-fetal) were observed. This section was updated with 
a summary of those findings.
Revised Text:
Cardio-vascular: (Paragraph 2)  
Given the risks of long QTc associated arrhythmias, and of compound associated 
cardiomyopathy, subjects will be monitored closely for changes in QTc with triplicate 
12-lead ECG, Holter monitoring, telemetry, and for elevations in plasma Troponin. 
Inpatient 48-hour telemetry was originally required for all subjects following the first 
dose of study drug, as part of the cardiac monitoring. Evaluation of cardiac safety data 
from subjects treated up to the 100 mg QD cohort by the cut-off date of May 15, 2015 
demonstrated no significant QTc prolongation after single and repeat dose administration. 
Therefore, the 48-hour telemetry requirement was removed and the frequency of Holter 
monitoring was reduced with Protocol Amendment 6.


2011N118599_09
CONFIDENTIAL
BET115521
369
Specific stopping criteria and management guidelines are provided for cardiac toxicities.
Deleted Text:
Telemetry 
Continuous telemetric in-patient monitoring for potential adverse arrhythmias will be 
performed for at least 48 hours from the administration of the first dose.  Thereafter, 
hospitalization and monitoring will be instituted if significant QTcF prolongation is 
detected for the immediate detection of any detected dysrhythmia.  Participating sites will 
have trained staff capable of monitoring and responding in real time any potential cardiac 
adverse event detected by telemetry.  In addition, trained personnel and emergency 
resuscitation equipment, including appropriate pharmacological agents, will also be 
immediately accessible.  
Revised Text:
Reproductive and Developmental: In 4-week toxicology studies, bilateral sperm 
retention, germ cell degeneration and tubular vacuolization, and depletion of testicular 
germinal epithelium occurred in male dogs receiving ≥ 0.3 mg/kg and male rats receiving 
≥ 10 mg/kg doses of GSK525762.  Exposures associated with reproductive toxicity in 
male dogs overlap with the proposed 5 mg starting dose in this FTIH study.
Preliminary rat embryo fetal development 
GSK525762 at 0, 1, 3, 10, or 30 mg/kg/day (total dose; doses expressed as parent 
compound) was given orally by gavage BID (doses given 6 hours apart) to pregnant rats 
on Days 0 through 17 post-coitus. Dose-dependent maternal toxicity (reduced body 
weight gain and reduced food consumption) was evident at ≥10 mg/kg/day. Embryo-fetal 
toxicity was evident as both pre-implantation loss and increased fetal resorptions leading 
to complete loss of litters at 30 mg/kg/day, and dose-dependent increased fetal 
resorptions at doses ≥1 mg/kg/day. Developmental toxicity was evident as decreased fetal 
weights at 10 mg/kg/day and fetal malformations and/or variations at all doses 
(membranous ventricular septal defects in the heart ≥1 mg/kg/day; great vessel, heart, 
kidney, ovary, uterus, and ureter malformations and/or variations at 10 mg/kg/day). The 
AUC0-t and Cmax at 1 mg/kg/day (the lowest dose tested) in non-mated female rats after 
5 doses were 54 ng.h/mL and 18 ng/mL, respectively.
No ovarian histologic changes were observed in the 4 week toxicology studies, however 
female fertility (disrupted estrous cyclicity, delays to mating and/or reduced fertility 
index) was affected in rats given 30 mg/kg/day GSK525762 for 15 days prior to mating 
and 15 days prior to mating through to Day 6 post coitus (pc). Systemic exposure in rats 
was approximately 2-fold higher than current exposure in late stage cancer patients (at 60 
mg/day). No fertility effects were observed when 30 mg/kg/day was given for 6 weeks 
followed by 6 weeks off-dose prior to mating.
Reproductive and developmental toxicity ( decreased fetal body weight, fetal 
malformations or variations and / or pre- and post-implantation loss) occurred in rats 
given GSK525762 ≥1mg/kg/day from conception through gestation day 17 (of 21 days) 


2011N118599_09
CONFIDENTIAL
BET115521
370
and when dosed at ≥10 mg/kg/day for 14 days and dosing stopped prior to mating or 
continued until Day 6 pc. Systemic exposure in rats was approximately 80-fold lower 
than current exposure in late stage cancer patients (at 60 mg/day). These results are 
consistent with observations that BRD2, BRD3, BRD4 and BRDT have crucial roles in 
reproduction and development [see the GSK 525762 IB [GlaxoSmithKline Document 
Number 2011N113741_03] for references.
Based on the findings in these reproductive and developmental toxicity studies in rats 
with GSK525762, there is a substantiated risk for adverse effects on embryofetal 
development and impacts on female fertility.
In the BET11521 study, specific contraceptive guidelines and precautions for males and 
females are provided in the protocol.  In addition, the informed consent will include 
potential reproductive risks and precautions in addition to recommendations for the 
preservation of reproductive capacity.
Section 3.2.2.
Dose Escalation and Schedule
Rationale for Change: The original staggered dosing schedule (1,3,5,7) was designed to 
include dosing breaks over the course of the first two weeks to monitor for any potential 
immediate toxicities before moving into continuous daily dosing in the third week. As 
included in the rationale for removal of 48-hour telemetry and reduction of holter 
monitoring frequency, after an internal QTc analysis and evaluation of cardiac safety data 
collected from all subjects up to the 100 mg QD cohort available by May 15 2015, 
evidence of a slight delayed QT prolonging effect was noted, however this did not lead to 
any marked prolongation and there were no individual subjects with delta >60ms or QTc 
>500ms. 
In an effort to achieve an optimal dosing schedule and further explore alternate dosing 
schedules (i.e.; two weeks of dosing, followed by one week off study drug), the 
intermittent dosing was modified to allow subjects to begin continuous daily dosing on 
Day 1. 
Revised Text:
A unique, staggered dosing schedule will be implemented to monitor for safety (Table 4). 
This approach allows repeat dosing in a step-wise fashion to detect changes in safety, 
such as cardiotoxicity. Alternative dosing regimens and/or schedule may be implemented 
based on emerging PK and safety data.
In Part 1, subjects will follow the dose schedule outlined in Table 4. Alternative dosing 
regimens and/or schedule may be implemented based on emerging PK and safety 
data.Specifically, in Week 1 subjects will receive a single dose of study drug on Day 1, 
rest on Day 2, receive study drug on Day 3, Day 4, and Day 5, and rest again on Day 6 
and Day 7. In Week 2, subjects will receive study drug on Day 1 through Day 5, and rest 
Day 6 and Day 7. From Week 3 the subject will start daily dosing which will continue 
until study completion. 


2011N118599_09
CONFIDENTIAL
BET115521
371
Extensive monitoring for cardiac safety signals will be performed, with triplicate 12-lead 
ECGs, 48-hour telemetry, and 24-hour Holter monitoring to be performed on the days 
indicated in Table 4. 
Subjects will be evaluated for dose limiting toxicities (DLTs) during the first 4 weeks of 
treatment (Section 3.2.3).
Table 4
Dosing Schedule and Cardiac Monitoring for Part 1
Section 3.2.2.4.
Alteration of Schedule
Rationale for Change: This section was updated to include a statement that PK 
sampling and other assessments may be modified if alternate dosing schedules are 
explored to reflect the new dosing schedule. This was to allow PK and/or other safety 
assessments to be collected during dosing days, and also to exempt subjects from having 
these assessments if they fell on a non-dosing day under a revised altered schedule.
Revised Text:
Alterations may be made to the schedule of administration and/or PK/PD sampling 
schedule based on the results of emerging PK and safety data.
Schedules that incorporate a recovery period may be explored (e.g. every other day or 
two weeks on treatment followed by one week off). This approach will be considered if 
the safety and PK data suggest that a therapeutic exposure cannot be achieved using the 
initial schedule without excessive toxicity. The starting dose for the alternate schedule 
will be the highest completed dose level (at or below MTD) with the initial schedule. 
Escalation can then proceed as described using 3 + 3 dose escalation.  If alternative 
dosing schedules are explored, PK sampling times and other safety assessments may be 
modified to reflect the new dosing schedule. 


2011N118599_09
CONFIDENTIAL
BET115521
372
Section 3.2.2.6.
Intra-Subject Dose Escalation
Revised Text
Paragraph 1, Bullet point no 2:
If no further subjects have been identified for a subsequent higher dose level and after a 
subject has completed 4 weeks of dosing on that regimen without a DLT, that subject 
may be escalated to the next higher dose level after an additional 4 weeks of dosing (total 
of 8 weeks of dosing), review of all safety data and approval by a GSK Medical Monitor. 
In this case the subject must follow the staggered dosing/monitoring schedule for the first 
4-weeks as outlined in Table 4, as he/she will be the first subject exposed to the higher 
dose. 
Section 3.2.5.1.
NMC Pharmacodynamic Expansion Cohort
Rationale for Change: The rationale for moving from a staggered dosing schedule to a 
continuous daily dosing schedule is explained above and all reference to staggered dosing 
was removed throughout the protocol.
Revised Text
Paragraph 2:
Subjects in the NMC PD Expansion Cohort will start with same staggered dosing 
schedule during the first two weeks as described in Section 3.2.2 (Table 4); subjects will 
begin continuous dosing in Week 3.  Extensive monitoring for cardiac safety signals will 
be performed as required in Part 1, with triplicate 12-lead ECGs, 48-hour telemetry, and 
24-hour Holter monitoring to be performed on the days indicated in Table 4.  All safety 
and PK evaluations will be performed as outlined in the Time and Events Tables for Part 
1 (Section 5).  Safety data from subjects in the NMC PD Expansion Cohort will be 
reviewed on an ongoing basis by the GSK medical monitor, GSK Safety Review Team, 
and investigators for consideration during 3+3 dose escalation decisions.
Section 3.2.6.
Bioavailability, Food Effect, and Dose Proportionality 
Besylate Sub-Study
Table 7
Besylate Sub-Study Design: BA, Food Effect and Dose Proportionality 
Evaluation:
Rationale for Change: Minor updates were made to this section to clarify treatment arm 
A as A2 to be consistent with the naming convention of this treatment arm in GSK’s 
internal interactive voice response system for registration of subjects.
Revised Text: ‘Treatment A’ changed to ‘Treatment A2’ throughout the Table.


2011N118599_09
CONFIDENTIAL
BET115521
373
Section 3.2.7.
Part 2 Expansion Cohort
Rationale for Change:
Revised Text This section was updated to clarify that during the futility assessment for 
individual cohorts in Part 2, if stopping criteria were met, further enrolment into that 
specific cohort would cease, but would not require stopping enrolment in other cohorts.
Paragraph 1:
Approximately 150 subjects with NMC, SCLC, CRPC, TNBC and ER+BC will be 
enrolled in expansion cohort at the RP2D (appropriate to each age group) to gather more 
safety data and to further assess anti-tumor activity.
Footnote for Figure 3, Figure 4, Figure 5 and Figure 6:
The shaded regions are the specific regions for stopping the studyenrollment for futility.
For instance, if there is no response in 10 subjects, then the predictive probability for 
success will be 10% or less (the futility criterion) and further enrollment the studyinto 
this cohort will be stopped.
Section 4.2.1.
Inclusion Criteria
Rationale for Change: Based on emerging data from pre-clinical fetal and embryo 
toxicity studies, the inclusion criteria specifying contraception requirements were updated 
to extend the length of time for contraception use for subjects. A summary of the findings 
from these preclinical studies may be found in the body of the protocol under 
Reproductive Risks in Section 1.5.
Revised Text
Inclusion criteria no 9, Bullet point no 2:
Child-bearing potential and agrees to use one of the contraception methods (described in 
Section 9.1) for an appropriate period of time (as determined by the product label or 
investigator) prior to the start of dosing to sufficiently minimize the risk of pregnancy at 
that point. Female subjects must agree to use contraception until at least 7 months4 weeks 
after the last dose of study medication.
Inclusion criteria no 10:
Male subjects must agree to use one of the methods of contraception specified. This 
method must be used from the time of the first dose of study medication until least 16 
weeks after the last dose of study medication. In addition, male subjects whose partners 
are or become pregnant while on study medication must continue to use condoms for 7 
days after stopping study medications.


2011N118599_09
CONFIDENTIAL
BET115521
374
Section 4.2.3.1.
Permanent Discontinuation from Study Treatment
Rationale for Change: Minor updates were made to this section to further clarify the 
follow up phase and requirements.
Revised Text
Paragraphs 7 and 8:
All subjects who permanently discontinue study treatment without disease progression 
will be followed for progression according to the protocol schedule until:
New anti-cancer therapy is initiated
progression
death, or
subject has been followed for 2 years after stopping treatment. 
All subjects who permanently discontinue study treatment will be followed for survival 
and new anti-cancer therapy [including radiotherapy] every 6 months until death or until 
the subject has been followed for 2 years. Reporting of any pregnancies in female 
subjects and/or female partners of male subjects will also be collected until 7 months 
after the last dose of study drug. If subjects are unable or unwilling to attend clinic visits 
during follow-up, contact to assess survival may be made via another form of 
communication (e.g., telephone, email, etc.).


2011N118599_09
CONFIDENTIAL
BET115521
375
Section 5.
TIME AND EVENTS TABLES
Rationale for Change: The time and events tables were modified to ensure consistency of timings, correct previous errors, provide 
additional clarifications and to include new updates based on removal of telemetry and revised holter monitoring schedule.
Table 9
Time and Events: Part 1 
Revised Text:
Part 1 
Assessments
Notes
S
C
R
Q4 and Q8W 
Initiated from 
Week 9
E
O
T
Week 1
Week 2
W3
W4
W5
W7
W9
q4W
q8W
D
1
D
2
D
3
D
4
D
5
D
6
D
7
D
1
D
2
D
3
D
4
D
5
D
6
D
7
D
1
D
4
D
1
D
4
D
1
D
1
D
1
D
1
D
1
TREATMENT PHASE
Study Drug
Administer study 
drug
Administer about same time of day. 
No food or antacids 1h before and 2h 
after.
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Daily
Cardiac Monitoring
12-lead ECGs 
(Triplicate)
Triplicate SCR ECGs within 35 days 
of first dose. For timing of triplicate 
ECGs on O days, see Table 11 and 
Table 12. Otherwise, triplicate ECGs 
at approximately same time of day, 
and prior to dose on dosing days. If 
QTcF increase >30msec, ECGs daily 
through W2.
X
O
O
O
X
O
X
X
X
O
X
X
X
O
X
X
X
X
O
X
X
Holter monitoring
At least 24 h, on dosing days start at 
least 60 min predose.
X
X
X
X
X
X
Telemetry
Start at least 60 min predose and for 
at least 48 h.
X
X
Efficacy
CT/MRI Scansa
SCR assessment within 2835 days of 
first dose. Target lesions to be 
identified at SCR and followed.
X
X
X
X
X


2011N118599_09
CONFIDENTIAL
BET115521
376
Part 1 
Assessments
Notes
S
C
R
Q4 and Q8W 
Initiated from 
Week 9
E
O
T
Week 1
Week 2
W3
W4
W5
W7
W9
q4W
q8W
D
1
D
2
D
3
D
4
D
5
D
6
D
7
D
1
D
2
D
3
D
4
D
5
D
6
D
7
D
1
D
4
D
1
D
4
D
1
D
1
D
1
D
1
D
1
Tumor sample
Optional during rapid dose escalation; 
required during 3+3 dose escalation. 
EOT sample should be collected at 
time of progression where feasible.
X
All Tumor Types: One postdose sample collected anytime betweenW2D1-D5 or W3D1 
(2-4h post-dose). Timing may be further optimized based on tumor type and emerging 
data.
X
PET scan
Optional during rapid dose escalation; 
required during 3+3 dose escalation.
SCR assessment within 35 days of 
first dose.
X
X
X
Table 10
Time and Events: Part 1 Laboratory Assessments
Revised Text:
NB: On dosing days, collect blood 
samples prior to dosing. W1D1 
samples not needed if SCR 
sample collected within 72h of first 
dose.
Notes
SCR
Q4 and Q8W 
Initiated from 
Week 9
EOT
W1
W2
W3
W4
W5
W7
W9
q4W
q8W
D1
D2
D6
D1
D6
D1
D1
D1
D1
D1
D1
D1
Troponin, NT-proBNP-9
For Troponin: W1D1 &, W1D2: 
local lab sample collect 3X/24h; 
central lab sample collect 1X/24h. 
All other timepoints, including 
unscheduled collect 2 samples: 1 
for local, 1 for central lab
X
X
X
X
X
X
X
X
X
X
X
X


2011N118599_09
CONFIDENTIAL
BET115521
377
Table 11
QD Dosing Time and Events: Part 1 Pharmacokinetics and Biomarker Sampling, Week 1 and Week 2
Revised Footnote:
Plasma samples will be divided at the GSK DMPK facility where bioanalysis of PK is performed and shipped to a vendor for systemic 
cytokine assessment (pre-dose and at 15 min, 30 min, 1 hr, 2 hr, and 4hr) and acute phase protein assessment at pre-dose, and at 2, 4, 8, 12
and 24 hr post-dose.  The frequency of sampling may be changed (likely reduced) based on data from the first few subjects assessed. 
Footnote added for W1D1 12h ±2h Time point:
PK blood samples collected after-hours may be kept refrigerated at 4ºC in the event the PK lab is closed overnight (stable up to 12H)
Table 12
QD Dosing Time and Events: Part 1 Pharmacokinetics and Biomarker Sampling, Week 3 and Week 9
Revised Footnote:
Plasma samples will be divided at the GSK DMPK facility where bioanalysis of PK is performed and shipped to a vendor for systemic 
cytokine assessment and acute phase protein assessment at pre-dose and at 2, 4, 8, 12 and 24 hr post-dose.  The frequency of sampling 
may be changed (likely reduced) based on data from the first few subjects assessed. 
Footnote added for W3D4 + 2 days 12h ±2h Time point:
PK blood samples collected after-hours may be kept refrigerated at 4ºC in the event the PK lab is closed overnight (stable up to 12H).


2011N118599_09
CONFIDENTIAL
BET115521
378
Table 13
BID Dosing Time and Events: Part 1 Pharmacokinetics and Biomarker Sampling, Week 1
Revised Footnote:
Plasma samples will be divided at the GSK DMPK facility where bioanalysis of PK is performed and shipped to a vendor for systemic 
cytokine assessment (pre-dose and at 15 min, 30 min, 1 hr, 2 hr, and 4hr) and acute phase protein assessment for morning and evening 
dosing at pre-dose and at 2, 4, 8, 12 and 24 hr post-dose.  The frequency of sampling may be changed (likely reduced) based on data from 
the first few subjects assessed. 
Table 14
BID Dosing Time and Events: Part 1 Pharmacokinetics and Biomarker Sampling, Week 2 and Week 3
Assessments Removed:
Urine PK sampling at pre dose (Morning Dose) on W3D4 +2 days Visit
Revised Footnote:
Plasma samples will be divided at the GSK DMPK facility where bioanalysis of PK is performed and shipped to a vendor for systemic 
cytokine assessment and acute phase protein assessment at pre-dose and at 2, 4, 8, 12 and 24 hr post-dose.  The frequency of sampling 
may be changed (likely reduced) based on data from the first few subjects assessed.
Table 15
BID Dosing Time and Events: Part 1 Pharmacokinetics and Biomarker Sampling, Week 9
Assessments Removed:
mRNA whole blood sample at pre dose on W9D1 ±4 days Visit 


2011N118599_09
CONFIDENTIAL
BET115521
379
Table 16
Time and Events: Part 2
Part 2 Assessments
Notes
SCR
Q4, Q8 and Q12 Initiated from 
Week 13
EOT
W1
W2
W3
W4
W5
W9
W13
q4W
q8W
q12W
D1
D1
D1
D1
D1
D1
D1
D1
D1
D1
Laboratory assessments: For details please see Table 17
Tests
X
X
X
X
X
X
X
X
X
X
X
X
Cardiac Monitoring
Telemetry
Start predose and for at least 48 h.
X
Efficacy
CT scan or MRI
Scans within 28 35 days of first dose may 
be used as screening assessment. 
Additional bone scans and brain scans not 
required unless clinically indicated.
X
X
X
X
PET scan
Scans within 35 days of first dose may be 
used as screening assessment.
X
PK
PK 
Three samples to be collected each 
sampling day for each type of analysis: 
Predose within 60 minutes prior to dose, 
single draw between 0.5-2h postdose, 
single draw between 4-8h postdose. 
Plasma samples will be divided at the 
GSK DMPK facility where bioanalysis of 
PK is performed and shipped to a vendor 
for acute phase protein assessment.
X
X
X
Translational Research
Tumor Sample
EOT biopsy should be collected at time 
of disease progression where feasible
X
All Tumor Types: One postdose 
sample collected anytime 
betweenW2D1-D5 or W3D1 (2-4h 
post-dose). Timing may be further 
optimized based on tumor type 
and emerging data
X


2011N118599_09
CONFIDENTIAL
BET115521
380
Table 17
Time and Events: Part 2 Laboratory Assessments
Revised Text:
NB: On dosing days, 
collect blood samples prior 
to dosing. W1D1 samples 
not needed if SCR sample 
is within 72h of first dose
Notes
SCR
Q4, Q8 and Q12W Initiated 
from Week 13
EOT
W1
W2
W3
W4
W5
W9
W13
q4W
q8W
qQ12w
D1
D4
D1
D4
D1
D1
D1
D1
D1
D1
D1
D1
Table 18
Time and Events: Besylate Sub-Study
Revised Text:
Besylate Sub-
Study 
Assessments
Notes
S
C
R
Q4 and Q8W 
Initiated from 
Week 9
E
O
T
Week 1
Week 2
W3
W4
W5
W7
W9
q4W
q8W
D
1
D
2
D
3
D
4
D
5
D
6
D
7
D
1
D
2
D
3
D
4
D
5
D
6
D
7
D
1
D
4
D
1
D
4
D
1
D
1
D
1
D
1
D
1
Cardiac Monitoring
12-lead ECGs 
(Triplicate)
Triplicate SCR ECGs within 35 days of 
first dose. For timing of triplicate ECGs 
on O days, see Table 11 and Table 
12. Otherwise, triplicate ECGs at 
approximately same time of day, and 
prior to dose on dosing days. If QTcF 
increase >30msec, ECGs daily 
through W2.
X
O
X
X
X
X
X
X
X
X
O
X
X
Holter monitoring
At least 24 h, on dosing days start at 
least 60 min predose.
X
X
X
X
Telemetry 
(Potentially will be 
removed for 
Besylate Sub-
Study based on 
Start at least 60 min predose and for 
at least 48 h. 
X
X


2011N118599_09
CONFIDENTIAL
BET115521
381
Besylate Sub-
Study 
Assessments
Notes
S
C
R
Q4 and Q8W 
Initiated from 
Week 9
E
O
T
Week 1
Week 2
W3
W4
W5
W7
W9
q4W
q8W
D
1
D
2
D
3
D
4
D
5
D
6
D
7
D
1
D
2
D
3
D
4
D
5
D
6
D
7
D
1
D
4
D
1
D
4
D
1
D
1
D
1
D
1
D
1
emerging data from 
Part 1)
Efficacy
PET scan
SCR assessment within 35 days of 
first dose.
X
X
X


2011N118599_09
CONFIDENTIAL
BET115521
382
Section 6.4.4.
Echocardiogram (ECHO)
Rationale for Change: This section was updated to clarify that GSK is receiving all
ECHOs, not just those with a >10% LVEF decrease from baseline. 
Revised Text:
For all subjects, ECHOs will be performed at screening and at assessment times as 
outlined in Section 5. ECHOs should be evaluated and compared to baseline by the same 
reader. Copies of all ECHO scans performed on subjects who experience an absolute 
decrease >10% in LVEF compared to baseline concurrent with LVEF < LLN will be 
required by GSK for review. 
ECHO data may will be transferred and reviewed by an independent cardiologist. 
Instructions for submission of qualifying ECHO scans are provided in the SPM.
Section 6.4.6.
Holter Monitoring
Rationale for Change: This section was updated to reflect the actual analysis of the
Holter Monitoring at the central cardiac monitoring lab and clarify that ECGs are not 
being extracted from the 24-hour holter; however arrhythmia assessments will continue at 
the central cardiac monitoring lab for the holter monitoring.
Revised Text
Paragraph 3, 4 and 5:
Analysis of intervals and morphology from the continuous digital ECG data will be 
acquired and stored electronically and manually over-read by an external central 
validated ECG laboratory. Around each of the designated time points, 3 ECGs will be 
selected approximately 2 minutes apart. In order to increase consistency of ECG 
interpretation, a limited number of central ECG over-readers will be used throughout the 
study. All ECGs for a given subject will be over-read by the same reader from the central 
validated ECG laboratory. The central reader will be blinded to subject identifiers (e.g., 
subject number, age, and sex), treatment assignment, and study day when Holter ECGs 
data were was collected. The final intervals and morphology analyses entered into the 
database will be those generated by the central ECG laboratory.
Baseline QT/QTcF values will be determined on Study Day -1 using time matched ECGs 
obtained from the Holter monitor at approximately the same time points as planned for: 
Week 1 Day 1 to 2; Week 2 Day 3 to 4, Week 3 Day 5 to 6 and Week 4 Day 7 to Week 5 
Day 1. The mean from triplicate ECGs will be evaluated at each time point. For a given 
time point, the mean QTcF from 3 separate beats should be analyzed on each ECG. 
Analysis of Lead II will be conducted with V5 as back-up and one of the remaining 
precordial leads as an alternative when T waves are not well defined in Leads II or V5. 
QTcF for an individual beat will be calculated from the preceding RR interval since using 
the average heart rate (RR) intervals from the ECG could result in inaccurate QTcF 
calculations due to beat to beat variations in the RR intervals. 


2011N118599_09
CONFIDENTIAL
BET115521
383
QT values should not be reported when the rhythm is other than sinus rhythm (sinus 
rhythm with normal respiratory variation is acceptable), and in intraventricular 
conduction delays (IVCD, QRS >120 msec). The other ECG information (including the 
rhythm and presence of IVCD) should be reported. The choice of the 3 consecutive beats 
to be measured should avoid ectopic beats and the first beat after an ectopic beat. If 
IVCD occur, these should be reported. 
Section 6.4.7.
Telemetry
Rationale for Change: The rationale for removing the 48-hour telemetry is explained 
above and all sections containing language around the original telemetry requirements 
were updated throughout the protocol.
Revised Text
In Part 1As part of the original cardiac monitoring plan, and to complement real-time 
ECG assessments, monitoring for potential adverse arrhythmias will bewas conducted 
utilizing continuous telemetry monitoring. as outlined in the Time and Events Tables for 
at least 48 hours from the start of dose. If clinically indicated, telemetry may be extended 
past 48 hours. Participating sites will have trained staff capable of monitoring and 
responding in real time to any potential cardiac adverse event detected by telemetry. In 
addition, emergency resuscitation equipment including appropriate pharmacological 
agents will also be immediately accessible throughout the study. 
At the end of Part 1, an analysis of data collected on the QT interval up to, and including, 
the MTD expansion will be carried out. If the analysis by the GSK Cardiac Safety Panel 
of internal and external experts indicates that telemetry is no longer required for 
monitoring the QT interval, then the study can progress to the next stage without 
telemetry. After internal QTc analysis and evaluation of cardiac safety data collected 
from subjects up to the 100 mg QD cohort by the cut-off date of May 15, 2015, The GSK 
Cardiac Safety Panel approved the removal of the 48-hour telemetry requirement was 
removed from all parts of the study in Protocol Amendment 6.

Removal of the telemetry requirement will be conveyed to the sites in the first 
instance through a separate document (or “note to file”) that will note - i) a summary of 
the analysis, and ii) the decision to proceed without telemetry monitoring in the next 
stage of this study. This will allow the sites to submit the necessary documentation to the 
IECs/IRBs for approval and to start the next stage of this study without telemetry. 
However, this process will be permitted only if there are no other cardiac monitoring 
changes to be implemented. If additional cardiac monitoring changes are required, a 
protocol amendment will be necessary before the next stage of the study can start.
Section 6.6.2.
Plasma Sample Analysis
Rationale for Change: A statement was added in this section to further clarify planned 
analysis for plasma samples from subjects.
Revised Text


2011N118599_09
CONFIDENTIAL
BET115521
384
Paragraph 1:
Plasma analysis will be performed under the management of Worldwide Bioanalysis, 
Drug Metabolism and Pharmacokinetics (DMPK), GlaxoSmithKline. Concentrations of 
GSK525762 will be determined in plasma samples using the currently approved 
analytical methodology. In addition, selected metabolites of GSK525762 may also be 
quantified using approved analytical methodology. Raw data will be stored in the GLP 
Archives, GlaxoSmithKline.
Section 6.6.3.
Urine Collection
Rationale for Change: A statement was added in this section to further clarify planned 
analysis for plasma samples from subjects.
Revised Text
Paragraph 2:
Selected urine samples may be analyzed qualitatively and/or quantitatively for 
GSK525762 metabolites and the results will be reported under a separate DMPK 
protocol.
Section 6.10.1.
Time period for collecting pregnancy information
Rationale for Change: The length of time for collecting information on any possible 
pregnancies after stopping study drug was extended to 7 months based on emerging data 
from the preclinical female fertility studies in rats. The summary of findings from these 
studies may be found in the Reproductive Risks section under Risk Assessment Section 
1.5 of the protocol.
Revised Text
All pregnanciesReporting of any pregnancies in female subjects and/or female partners of 
male subjects will be collected after the start of dosing and until for 16 weeks7 months
after the last dose of study drug.
Section 7.1. GSK525762 Investigational Product Dosage/Administration
Rationale for Change: The morning dose of study medication (for subjects dosing once 
daily and twice daily) should be taken in the morning around the same time each dosing 
day. The time window was removed to allow additional flexibility. Further instructions 
on timing for dosing are included in the subject dosing diaries. 


2011N118599_09
CONFIDENTIAL
BET115521
385
Revised Text
Table 23 GSK525762 Amorphous Free-base Investigational Product 
Dosage/Administration
Dosing instructions: Dose with 240mL water and should be taken between 7 am and 10 
am. No food or antacids for at least 1h before and 2h after dosing. (If a subject vomits 
after taking study drug, the subject should be instructed not to retake the dose and should 
take the next scheduled dose)
Table 24 GSK525762 Besylate Investigational Product Dosage/Administration
‘Treatment A’ changed to ‘Treatment A2’ throughout the Table.
Section 7.7.1.
Dose and Safety Management Guidelines
Rationale for Change: A minor change was made to the Management Guidelines for 
subjects with Pneumonitis to clarify that Medical Monitor approval is required prior to a 
subject restarting study treatment.


2011N118599_09
CONFIDENTIAL
BET115521
386
Revised Text
Table 25
Dose Adjustment/Stopping Safety Criteria:
Toxicity
Dose 
Adjustment/Stopping 
Criteria
Management Guidelines
Pneumonitis
Grade 3 and 4
(Grade 3 and 4) Evaluation by 
pulmonologist. Required pulmonary 
function tests including: spirometry, 
DLCO, and room air O2 saturation at rest 
via pulse oximetry reading (X 2, 5 mins 
apart). Repeat evaluations at least every 8 
weeks until return to wnl. Bronchoscopy 
with biopsy and/or BAL is recommended.
Consider corticosteroids if infective origin 
is ruled out. Taper as medically indicated.
(Grade 3) Hold investigational drug(s) until 
recovery to < Grade 1. Discontinue 
investigational drug(s) if no recovery to 
<Grade 1 within 4 weeks. May consider 
restarting study treatment at a reduced dose 
after discussion with GSK Medical Monitor 
if there is clinical benefit.
Grades 1-3: May consider restarting study 
treatment at a reduced dose or dose level 
pre-event based onafter discussion with 
GSK Medical Monitor.
(Grade 4) Discontinue investigational 
drug(s)
Section 8.2.1.
Cautionary Medications
Rationale for Change: This table was updated with the most recent list of drugs with a 
Risk of Torsades de Pointes which are permitted with extreme caution during the study.


2011N118599_09
CONFIDENTIAL
BET115521
387
Revised Text:
Table 27
Drugs with a Risk of Torsades de Pointes which are permitted for co-
administration with Extreme Caution
Generic Name
Brand Name
Amiodarone
Cordarone, Pacerone, Nexterone
Astemizole
Hismanal
Chlorpromazine
Thorazine, Largactil, Megaphen
Clarithromycin
Biaxin, Prevpac
Degarelix
Firmagon
HaloperidolLeuprolide
Haldol Lupron
Tropisetron
Navoban and Setrovel
*There may be situations when the subject is on study that Advanced Cardiac Life 
Support (ACLS) requires the use of amiodarone, which should be used as per local 
clinical guidelines
Data Source: www.crediblemeds.org (revised 0227-Mayr-2015)
Section 8.2.2.
Potential Drug Interactions with GSK525762
Rationale for Change: This section was updated with emerging metabolite data from the 
ongoing clinical studies with GSK525762.
Revised Text
Paragraph 1:
The precise in vivo metabolic liability for GSK525762 has yet to be assessed. In vitro 
data suggests that GSK525762 is only metabolized by CYP3A4 and thus 
coadministration of inducers and inhibitors of CYP3A4 should be avoided during the 
course of the study where possible as they may respectively decrease or increase 
exposure to GSK525762. has a negligible turnover and GSK525762 has low potential to 
inhibit the major human CYP isoforms (IC50’s ≥ 33 µM) or major transporters. There is
with no evidence for time dependent inhibition of CYP2D6 or CYP3A4. These results 
suggest a low risk for therapeutic drug interactions although inducers and inhibitors of 
both CYP2D6 and CYP3A4 should be avoided during the course of the study where 
possible. Potential interactions with other Cytochrome P450 metabolized drugs or effects 
on transporters have not been assessed.
Section 8.3. Prohibited Medications
Rationale for Change: This section was updated to include additional drugs that may 
impact the exposure of GSK525762 based on emerging metabolite data from the ongoing 
clinical studies with GSK525762.


2011N118599_09
CONFIDENTIAL
BET115521
388
Revised Text
Table 28
Drugs with a Risk of Torsades de Pointes that are Prohibited
Added a drug:
Generic Name
Brand Name
Clarithromycin
Biaxin, Prevpac
Section 9.1. Female Subjects
Rationale for Change: Based on emerging data from pre-clinical fetal and embryo 
toxicity studies, the inclusion criteria specifying contraception requirements were updated 
to extend the length of time for contraception use for subjects. A summary of the findings 
from these preclinical studies may be found in the body of the protocol under 
Reproductive Risks in Section 1.5. Double Barrier methods was also removed from 
Contraceptive Methods with a Failure Rate of 1% to align with the Clinical Trial 
Facilitation Group (CTFG)’s guidance related to contraception use in clinical trials which 
lists a combination of male condom with either cap, diaphragm or sponge with 
spermicide (double barrier methods) as an acceptable, but not a highly effective, birth 
control method.
Revised Text
Paragraph 1:
Female subjects of childbearing potential must not become pregnant during the trial and 
for 7 months after stopping study medication and so must be sexually inactive by 
abstinence or use contraceptive methods with a failure rate of < 1%.
Paragraph 3:
Contraceptive Methods with a Failure Rate of 1%

Intrauterine device (IUD) or intrauterine system (IUS) that meets the <1% failure 
rate as stated in the product label

Male partner sterilization (vasectomy with documentation of azoospermia) prior to 
the female subject's entry into the study, and this male is the sole partner for that 
subject. For this definition, “documented” refers to the outcome of the 
investigator's/designee’s medical examination of the subject or review of the 
subject's medical history for study eligibility, as obtained via a verbal interview with 
the subject or from the subject’s medical records.

Double barrier method: condom and occlusive cap (diaphragm or cervical/vault 
caps) plus spermicidal agent (foam/gel/film/cream/suppository) 


2011N118599_09
CONFIDENTIAL
BET115521
389
Section 9.2. Male Subjects
Rationale for Change: The additional guidance for condom use specific to males with a 
pregnant partner were included as there is not yet sufficient evidence to rule out the 
potential of 762 being transferred to a developing embryo or fetus via the semen.
Added Text:
In addition, male subjects whose partners are or become pregnant while on study 
medication must continue to use condoms for 7 days after stopping study medications.
Section 11.6.1.
Pharmacokinetic Parameters
Rationale for Change: A minor change was made to this section to correct a previous 
error.
Revised Text
Paragraph 2:
From the plasma concentration-time data, the following pharmacokinetic parameters will 
be determined, as data permit: maximum observed plasma concentration (Cmax), time to 
Cmax (tmax), area under the plasma concentration-time curve (AUC(0-t) and AUC(0-∞) 
Week1 Day1 only) and apparent terminal phase half-life (t½). Trough concentration (C) 
samples collected on the specified days will be used to assess attainment of steady state. 
To estimate the extent of accumulation after repeat dosing, the observed accumulation 
ratio (Ro) may be determined. The ratio of AUC(0-) on Week 3 / AUC(0-∞) on Week 1
AUC(0-) / Week 1 AUC(0-) will be calculated to assess time invariance. GSK525762 
concentrations will be determined in urine samples to determine urinary recovery of 
unchanged drug and renal clearance.


2011N118599_09
CONFIDENTIAL
BET115521
390
AMENDMENT 07
Protocol Changes for Amendment 7 (10-MAR-2016) from the Protocol Amendment 
6 (19-JUN-2015)
Protocol Amendment 7 applies to all site(s) participating in the conduct of the study.
Amendment 07 summary: 
Amendment 07 updates were made, to include the final dose and regimen for Part 2,
which was determined to be 75 mg once daily based on emerging data from Part 1 and 
Besylate Sub-Study; to clarify that the besylate salt tablets will be the formulation used 
for subjects enrolled in Part 2 (and potentially for ongoing or newly enrolled subjects in 
Part 1); to update required number of subjects to be enrolled in the Part 1; to update the 
subject and study completion details; to update the Visit window for Discontinuation and 
End of Treatment; to update diagnosis criteria of NMC for Part 1 and 2 for NMC 
subjects; to update dosing, handling and storage instruction for GSK525762 Besylate 
tablet; to modify the meals and dietary restrictions based on the results of the besylate 
sub-study, the fasting requirement is being lifted, except on Serial PK sampling days in 
Part 2 (Week 1 and Week 4); to include the details about interim and final analysis. 
Additionally, following updates were in the time and event table, 12-lead ECGs 
monitoring for prolonged QTcF for Part 1 and 2 was updated, tumor sampling time point 
was updated for Part 1 and 2; optional Sweat PK sampling for Part1 was removed; 
optional saliva sampling for time points for part 1 was updated; pain assessments was 
included for Part 2; W1D1, ECHO was made optional for Part 2; and CT Scan, MRI and 
PET scan detail were updated for Part 2.
Changes are noted below with strikethrough to identify deleted text and underlining to 
identify new or replacement text.
List of Specific Changes
PROTOCOL SYNOPSIS
Rationale for Change: This section was updated to increase the total number of subjects 
to be enrolled in the Part 1 based on actual recruitment.
Revised Text:

SUBJECT SAMPLE: Worldwide approximately 6090 subjects will be enrolled 
in Part 1, and approximately 150 subjects will be enrolled in Part 2.
Rationale for Change: The analyses sections were updated throughout the protocol to 
allow for the flexibility to conduct an interim analysis at some point during the study, 
prior to end of Part 2.


2011N118599_09
CONFIDENTIAL
BET115521
391
Revised Text:
DATA ANALYSIS: Subject demographic and safety data will be collected on electronic 
case report forms (eCRFs). All data will be pooled and descriptive safety analyses 
summarized and listed by cohort at study conclusion of Part 2 expansion cohorts. 
Additional analyses may occur between Part 1 and Part 2 and details will be included in 
the Reporting Analysis Plan (RAP). Part 2 of the study is powered to test overall 
Response Rate (RR). A futility assessment will be conducted after data are available from 
the first 10 subjects in each expansion cohort in Part 2.
Section 1.3.1.
Human Pharmacokinetics
Rationale for Change: This section was updated to include reference to the latest 
Investigator Brochure, rather than include a summary of the pharmacokinetic data 
collected to date in this section, as study is ongoing and data is continuously emerging.
Revised Text:
Second paragraph
As of 06-February-2015, the pharmacokinetics of GSK525762 has been evaluated in 23 
subjects following single and repeated daily administration of 2 mg to 60 mg of 
GSK525762 in the BET115521 trial. The summary statistics of the preliminary PK 
parameters are summarized in Table 1 and Table 2 after single and repeat daily oral 
administration, respectively. Information on the pharmacokinetics of GSK525762 in 
humans can be found in the Investigator’s Brochure (2011N113741_04). In summary,
GSK525762 pharmacokinetics are characterized by a rapid absorption with maximum 
concentration occurring mostly within the first hour after dosing. GSK525762 is 
eliminated rapidly with an average terminal phase half-life of 3 to 7 hours, leading to a 
lack of accumulation following once daily oral administration. Following single oral 
administration and repeated once daily administration of 2 mg to 60100 mg of 
GSK525762, Maximum observed concentrations (Cmax) and Area under concentration-
time curve (AUC) tended to increase in a dose proportional fashion with a largefull
overlap for individual AUC between 30, 60, 80 and 100 and 60 mg cohorts. 
Table 27
Summary Statistics of GSK525762 Preliminary PK Parameters 
Following a Single Oral Administration of GSK525762 in Study 
BET115521
2 mg
4 mg
8 
mg
16 mg
30 mg
60 mg
Parameter
s
Unit
N=3
N=4
N=1
N=3
N=4
N=8
Cmax
ng/mL
51.0 (41%)
70.4 (29%)
120
176 
(37%)
604 (30%)
871 (25%)
tmax
h
0.5 (0.5 -
0.6)
1.2 (0.5 -
2.0)
1.1
2.0
2.0 (0.97 -
2.0)
1.0 (0.5 -
4.0)
AUC
ng.h/
mL
172 (42%)
361 (35%)
434
884 
(40%)
4420 (63%)
4330 (46%)
t1/2z
h
3.3 (103%)
5.1 (36%)
2.95
6.9 
(46%)
6.4 (37%)
5.7 (36%)


2011N118599_09
CONFIDENTIAL
BET115521
392
Note: Data are presented as geometric mean (CV%) for all parameters except for tmax where the median (min-max) 
are presented. If N=1, individual data are presented. Cmax is the maximum concentration observed at time tmax. AUC 
is the area under the concentration-time curve from 0 to infinity. T1/2 is the terminal phase half-life.
Table 28
Summary Statistics of GSK525762 Preliminary PK Parameters 
Following Repeat Daily Oral Administration of GSK525762 in 
Study BET115521
2 mg
4 mg
8 mg
16 mg
30 mg
60 mg
Parameters
Unit
N=1
N=2
N=1
N=3
N=4
N=6
Cmax
ng/mL
52
47.6 ; 
59.9
103
138 
(25%)
603 (17%)
634 
(53%)
tmax
h
1.0
1.0 ; 4.0
0.5
1.5
0.9 (0.32 -
4.0)
1.0 (0.50 
- 2.0)
AUC
ng.h/m
L
160
225 ; 497
330
674 
(21%)
3150 (55%)
1.0 (0.50 
- 2.0)
t1/2z
h
4.27
3.69 ; 
4.46
4.92
3.6 
(7.8%)
5.2 (26%)
3.48 
(32%)
Cmax Week 3 / Cmax 
Week 1
--
1.42
0.968 ; 
0.609
0.857
0.780 
(12%)
0.998 
(24%)
1.00 
(21%)
AUCweek 3 / AUCt 
Week 1
--
1.39
0.904 ; 
1.67
0.763
0.792 
(20%)
0.799 
(11%)
0.758 
(12%)
Note: Data are presented as geometric mean (CV%) for all parameters except for tmax where the median (min-max) 
are presented. If N=1 or 2, individual data are presented. Cmax is the maximum concentration observed at time tmax. 
AUCis the area under the concentration-time curve from 0 to 24 hours, the end of the dosing interval. T1/2 is the 
terminal phase half-life.
Section 3.2.2.2.
3+3 Dose Escalation in Part 1
Rationale for Change: Minor grammatical error corrected in this section.
Revised Text:
Second paragraph
Once the MTD is reached, up to 12 additional subjects may be enrolled at the MTD to 
further evaluate safety and tumor PD. Up to an additional 6 subjects may be enrolled at 
any dose level below the MTD into order to obtain additional dose/response information 
related to tumor PD.  Additional cohorts (with daily exposure not exceeding QD MTD 
exposure) may also be initiated to explore alternative dosing schedules to optimize the 
PK, safety and tolerability profile (see Section 3.2.2.4).  The enrolment of additional 
subjects as described could be in parallel with Part 2 enrolment.


2011N118599_09
CONFIDENTIAL
BET115521
393
Section 3.2.2.4.
Alteration of Schedule
Rationale for Change: This section was updated to include the final dose and regimen 
for Part 2 and to allow for the introduction of the besylate tablets to Part 1 subjects based 
on emerging data from Part 1 and Besylate Sub-Study.
Revised Text:
New text added after second paragraph:
On completion of the besylate sub-study for relative bioavailabilty of besylate 
formulation in tablet form, and having determined a dose for Part 2, all subjects in Part 1 
daily dosing cohorts and in Part 2 will be administered the besylate tablets at the 
recommended Part 2 dose of 75 mg once daily. Those subjects in Part 1 daily dosing 
cohort who were on amorphous tablet dosing before availability of besylate tablets, they 
will be switched to the equivalent besylate tablet dose and will have limited PK samples 
drawn after start on besylate tablets.
In Part 2, subjects approved to alter their current dose level with either a dose reduction 
or dose escalation may require additional limited PK sampling (pre-dose, 0.5, and 3 
hours) at the new dose level, after 4-7 days at the adjusted dose level.
Section 3.2.2.6.
Intra-Subject Dose Escalation
Rationale for Change: Minor clarification made in this section to clarify intra-subject 
dose escalation was relevant to Part 1 subjects only.
Revised Text:
Second paragraph
In Part 1, Subjects approved for intra-subject dose escalation will require additional 
limited PK sampling (pre-dose, 0.5, 3 and 6-8 hours) at the higher dose, as determined by 
GSK Clinical Pharmacology.  Additional safety assessments such as insulin/glucose or 
cardiac monitoring may be specified at the time of dose escalation or schedule 
modification based on the safety profile in previous subjects at the higher dose level. 
Intra-subject dose escalations or schedule modification will be discussed with 
investigators and approved by the GSK Medical Monitor and safety monitoring required 
will be specified in writing.


2011N118599_09
CONFIDENTIAL
BET115521
394
Section 3.2.7.
Part 2 Expansion Cohort
Rationale for Change: This section was updated to include the final dose and regimen 
for Part 2 based on emerging data from Part 1 and Besylate Sub-Study.
Additional text added to further clarify statistical design and observed response data that 
will guide futility assessments and further enrolment decisions for each expansion cohort 
in Part 2.
Revised Text:
First and second paragraph
Based on the analysis and evaluation of the safety profile and available 
pharmacodynamic, pharmacokinetic and efficacy data generated from all subjects 
enrolled in Part 1 as of January 28, 2016, including the analysis of subjects enrolled in the 
Besylate Sub-Study, the final dose and regimen for Part 2 is determined to be 75 mg once 
daily. The besylate salt tablets will be the formulation used for subjects enrolled in Part 2 
(and potentially for ongoing or newly enrolled subjects in Part 1). Additional details and 
supporting information are provided under separate cover in a companion document and 
dose decision memo. Approximately 150 subjects with NMC, SCLC, CRPC, TNBC and 
ER+BC will be enrolled in expansion cohort at the RP2D to gather more safety data and 
to further assess anti-tumor activity. 
Subjects in Part 2 will start with a continuous daily dosing schedule unless safety, PK or 
PD data necessitate a different dosing schedule. The final dose and regimen for Part 2 
will be decided upon completion of dose escalation in Part 1.
Third paragraph
For NMC, to test for 20% ORR relative to a 5% ORR suggesting no activity with 0.1 
type I error and 80% power, first interim look may be conducted once 10 evaluable 
subjects have been enrolled into the expansion cohort or treated at the same dose level to 
examine safety and efficacy; if 0 responses are observed, further enrolment into this 
cohort may be terminated. The number of observed confirmed responses will guide 
further enrolment according to the rules summarized in Figure 3. A maximum of 2540 
subjects in this cohort will be enrolled at the RP2D.  All available data will be considered 
in making enrollment decisions.
Fourth paragraph
For SCLC and CRPC, to test for 30% ORR relative to a 10% ORR suggesting no activity 
with 0.1 type I error and 80% power, first interim look maybe conducted once 10 
evaluable subjects have been enrolled in the either cohort or treated at the same dose 
level to examine safety and efficacy, if 0 responses are observed in either cohort, further 
enrolment into this cohort may be terminated. The number of observed confirmed 
responses will guide further enrolment according to the rules summarized in Figure 4. A 
maximum of 22 subjects will be enrolled at the RP2D.  All available data will be 
considered in making enrollment decisions.
Fifth paragraph


2011N118599_09
CONFIDENTIAL
BET115521
395
For TNBC, to test for 25% ORR relative to a 10% ORR suggesting no activity with 0.1 
type I error and 80% power, first interim look maybe conduced once 10 evaluable TNBC
subjects have been enrolled in the cohort or treated at the same dose level to examine 
safety and efficacy, if 0 responses are observed in the cohort, Part 2 of the trial may be 
terminated with no further enrolment in this cohort. The number of observed confirmed 
responses will guide further enrolment according to the rules summarized in Figure 5. A 
maximum of 37 subjects will be enrolled at the RP2D.  All available data will be 
considered in making enrollment decisions.
Sixth paragraph
For ER+BC, to test for 25% ORR relative to a 10% ORR suggesting no activity with 0.1 
type I error and 80% power, first interim look maybe conduced once 10 evaluable 
ER+BC subjects have been enrolled in this each cohort or treated at the same dose level
to examine safety and efficacy, if 0 responses are observed, further enrolment into this 
cohort may be terminated. The number of observed confirmed responses will guide 
further enrolment according to the rules summarized in Figure 6. A maximum of 37 
subjects per cohort will be enrolled at the RP2D.  All available data will be considered in 
making enrollment decisions
Section 4.1. Number of Subjects
Rationale for Change: This section was updated to increase the total number of subjects 
to be enrolled in the Part 1 based on actual recruitment.
Revised Text:
First paragraph:
The number of dose levels and the level at which the MTD will be reached cannot be 
determined in advance. An adequate number of subjects will be enrolled into the study to 
establish a recommended dose(s) and schedule(s) of GSK525762 for further study. To 
complete Part 1, it is estimated 3060 to 6090 evaluable subjects will be enrolled. The 
besylate sub-study will enroll approximately 10 to 12 evaluable subjects in the United 
States only.  Part 2 will enroll approximately 150 subjects.
Section 4.2.3.2.
Subject and Study Completion
Rationale for Change: This section was updated to clarify the definition of a completed 
subject in the study.


2011N118599_09
CONFIDENTIAL
BET115521
396
Revised Text:
4.2.3.2.
Subject and Study Completion
A subject will be considered to have completed the study 2 years after the last treatment 
or if the subject dies or is still in follow-up at the time the study is closed or terminated, 
whichever is sooner. Document the cause of death in the CRF. A subject will be 
considered to have withdrawn from the study if the subject has not died and is lost to 
follow-up, has withdrawn consent, or at the investigator’s discretion is no longer being 
followed.
In Part 1, a subject will be considered to have completed the study if:

they complete screening assessments, the 28-day DLT observation period, and the 
end-of-treatment follow-up visit,

they progress or die while receiving study treatment, or

are receiving ongoing study treatment at the time of the Sponsor’s decision to 
close the study.
In Part 2, a subject will be considered to have completed the study if:

they progressed or die while receiving study treatment, or

are receiving ongoing study treatment at the time of the Sponsor’s decision to 
close the study.
Subjects who have not died, and are no longer being followed for survival are considered 
to have discontinued the study.  The End of Study eCRF should only be completed when 
a subject is no longer being followed.  The study may be considered completed for 
purposes of a final analysis when 70% of subjects enrolled at part 2 have progressed or 
died.  If available, subjects continuing on treatment at the time of final analysis may be 
offered the option to continue in a rollover trial.


2011N118599_09
CONFIDENTIAL
BET115521
397
Section 5.
TIME AND EVENTS TABLES
Rationale for Change: The time and events tables were modified to correct previous errors and provide additional clarifications around 
timings and procedures as appropriate. No new procedures were added.
Revised Text:
Table 9
Time and Events: Part 1
Part 1 
Assessments
Notes
S
C
R
Q4 and Q8W 
Initiated from 
Week 9
E
O
T
Week 1
Week 2
W3
W4
W5
W7
W9
q4W
q8W
D
1
D
2
D
3
D
4
D
5
D
6
D
7
D
1
D
2
D
3
D
4
D
5
D
6
D
7
D
1
D
4
D
1
D
4
D
1
D
1
D
1
D
1
D
1
Cardiac Monitoring
12-lead ECGs 
(Triplicate)
For timing of triplicate ECGs on O 
days, see Table 11 and Table 12. 
Otherwise, triplicate ECGs at 
approximately same time of day, and 
prior to dose on dosing days. If QTcF 
increase >30msec, ECGs daily 
through W2.should be repeated Q2-3 
days until QTcF is within 30msec from 
baseline.
X
O
O
O
O
X
X
X
O
X
X
X
O
X
X
X
X
O
X
X
Efficacy
Tumor sample
Optional during rapid dose escalation; 
required during 3+3 dose escalation. 
EOT sample should be collected at 
time of progression where feasible.
X
All Tumor Types: One postdose sample collected anytime betweenW2D1-W3D1 (4-6h2-
4h post-dose). Timing may be further optimized based on tumor type and emerging 
data.
X


2011N118599_09
CONFIDENTIAL
BET115521
398
Part 1 
Assessments
Notes
S
C
R
Q4 and 
Q8W 
Initiated 
from Week 
9
E
O
T
Week 1
Week 2
W3
W4
W5
W7
W9
q4W
q8W
D
1
D
2
D
3
D
4
D
5
D
6
D
7
D
1
D
2
D
3
D
4
D
5
D
6
D
7
D
1
D
4
D
1
D
4
D
1
D
1
D
1
D
1
D
1
Pharmacokinetics (PK) and Pharmacodynamics (PD): For details please see following tables
LPS blood sample
Not required with BID dosing 
schedule.
X
Optional Saliva 
and/or Sweat Sample 
A saliva and/or sweat sample may 
be requested on serial PK sampling 
days. Additional collection details 
will be provided in the SPM.
X
X
Blood samples for 
circulating 
exploratory 
biomarkers (cfDNA, 
etc)
EOT circulating biomarker blood 
samples to be collected with lab 
assessments.
X
X
X
Table 10
Time and Events: Part 1 Laboratory Assessments
NB: On dosing days, collect blood 
samples prior to dosing. W1D1 
samples not needed if SCR 
sample collected within 72h of first 
dose.
Notes
SCR
Q4 and Q8W 
Initiated from 
Week 9
EOTa
W1
W2
W3
W4
W5
W7
W9
q4W
q8W
D1
D2
D6
D1
D6
D1
D1
D1
D1
D1
D1
D1
Footnote added to EOT time point:
a.
EOT circulating biomarker blood samples to be collected with lab assessments.


2011N118599_09
CONFIDENTIAL
BET115521
399
Table 11
QD Dosing Time and Events: Part 1 Pharmacokinetics and Biomarker Sampling, Week 1 and Week 2
W1D1
W1D5
W2D4 + 1 day
pre 
dose
15 min 
± 5m 
30 
min 
±5m
1h 
±5m
2h 
±10m
4h 
±15m
8h 
±1h
12h 
±2h a
24h 
±2h
48h ±2h
b, d
30 
min 
±5m
3h 
±15m
pre 
dose
30 min 
±5m
3h 
±15m
8h 
±1h
Optional Saliva 
Sample
X
X
X
X
X
Footnote added to W1D1, 48h ±2h time point:
d.
W1D1 48h assessments (ECG, PK and mRNA) are optional
Table 12
QD Dosing Time and Events: Part 1 Pharmacokinetics and Biomarker Sampling, Week 3 and Week 9
W3D4 + 2 days (if dose has been altered (including held and resumed) serial PK sampling should occur 4 
to 7 days after dosing resumed)
W9D1 ±4 days
(if dose has been reduced or
escalated, +4 to +7 days)
EOT
pre 
dose
15 min 
± 5m 
30 min 
±5m
1h 
±5m
2h 
±10m
4h 
±15m
8h 
±1h
12h 
±2h a
24h ±2h
b
48h ±2h
b, d
pre dose
0.5-2h
4 - 8h
Footnote added to W3D4 + 2 days, 48h ±2h time point:
d) W3D4 48h assessments (ECG, PK and mRNA) are optional.


2011N118599_09
CONFIDENTIAL
BET115521
400
Table 13
BID Dosing Time and Events: Part 1 Pharmacokinetics and Biomarker Sampling, Week 1
W1D1
W1D2  and 
W1D3
(relative to 
W1D1 
Morning 
Dose)
W1D5
ECG and PK 
samples after 
Morning Dose 
only
Morning Dose 
Evening Dose
pre 
dose
0H
15 
min 
±5m
30 
min 
±5m
1h 
±5m
2h 
±10m
4h 
±15m
8h 
±1h
pre 
dose  
(12h-
15m)
12h
15 
min(12.25h) 
± 5m
30 min 
(12.5h) 
±5m
1h 
(13h) 
±5m
2h 
(14h) 
±10m
4h 
(16h) 
±15m
8h 
(20h) 
±1h
12 h 
(24h) 
±1h
36 h 
(48h) 
(pre-
dose) 
±1hd
30 min 
±5m
3h 
±15m
Footnote added to W1D2  and W1D3, 36 h (48h) (pre-dose) ±1h time point: 
d) W1D1 48h assessments (ECG, PK and mRNA) are optional.


2011N118599_09
CONFIDENTIAL
BET115521
401
Table 14
BID Dosing Time and Events: Part 1 Pharmacokinetics and Biomarker Sampling, Week 2 and Week 3
W2D4 + 1 day ECG and PK 
samples after Morning Dose only
W3D4 +2 days
W3D5 and 
W3D6 
(relative to 
W3D4 
Morning 
Dose)
Morning Dose
Evening Dose
(For W3D4 subjects that are not staying overnight after the 
evening dose, the 15min – 8h PK/ECG timepoints are optional)
pre 
dose 
(Prior 
to 
Dosing)
30m 
± 
5m 
3h 
± 
15m
8 h 
±1h5m
pre 
dose 
0h
15m 
±5m
30m
±5m
1h 
±5m
2h 
±10m
4h 
±15m
8h 
±1h
pre 
dose
12h
15m 
±5m 
(12.25m)
30m 
±5m
1h 
(13h)
±5m
2h 
(14h)
±10m
4h 
(16h)
±15m
8h 
(20h)
±1h
12h 
(24h) 
±1h
(pre 
dose)
36h 
(48h) 
±1h
(pre 
dose)
d
Footnote added to W3D5 and W3D6 (relative to W3D4 Morning Dose), 36h (48h) ±1h (pre dose)time point: 
d.
W3D4 48h assessments (ECG, PK and mRNA) are optional.


2011N118599_09
CONFIDENTIAL
BET115521
402
Table 16
Time and Events: Part 2
Part 2 Assessments
Notes
SCR
Q4, Q8 and Q12 Initiated from 
Week 13
EOT
W1
W2
W3
W4
W5
W9
W13
q4W
q8W
q12W
D1
D1
D1
D1
D1
D1
D1
D1
D1
D1
TREATMENT PHASE
Study Drug
Dispense study drug
Administer about same time of day. No 
food or antacids 1h before and 2h after.
X
X
X
X
X
X
X
X
Review compliance
Not required when dosed in clinic.
X
X
X
X
X
X
X
X
X
X
Safety
Vital Signs and Pain 
Assessments
X
X
X
X
X
X
X
X
X
X
Cardiac Monitoring
ECHO
If Baseline ECHO Wwithin 35 days of first 
dose, the Week 1 Day 1 ECHO is only 
required if clinically appropriate.
X
X
optional
X
X
X
X
X
X
12-lead ECGs (Single)
ECGs prior to dosing. If QTcF increase 
>30msec, ECGs should be repeated Q2-
3 days until QTcF is within 30msec from 
baseline.daily through W2.
X
X
X
X
X
X
X
X
X
X
Efficacy
CT scan or MRI a, b
Scans within 35 days of first dose may be 
used as screening assessment. 
Additional bone scans and brain scans 
not required unless clinically indicated.
X
X
X
X
PET scan (FDG or fluoride)
b, c
Scans within 35 days of first dose may be 
used as screening assessment. Follow 
up scans conducted as clinically 
appropriate.
X
PK
PK 
Three samples to be collected each 
sampling day for each type of analysis: 
Predose During first 4 weeks collect a 
predose within 60 minutes prior to dose, 
X
X
X
X


2011N118599_09
CONFIDENTIAL
BET115521
403
Part 2 Assessments
Notes
SCR
Q4, Q8 and Q12 Initiated from 
Week 13
EOT
W1
W2
W3
W4
W5
W9
W13
q4W
q8W
q12W
D1
D1
D1
D1
D1
D1
D1
D1
D1
D1
a single draw between 0.5-2h postdose,
and a single draw between 4-8h 
postdose (fasting requirements 
apply).Thereafter only a Predose and 
0.5hour post-dose sample are collected. 
NOTE: If dose level is adjusted, 
additional PK sampling may be 
requested.
Blood samples for 
circulating exploratory 
biomarkers (cfDNA, etc)
Baseline sample collected pre-dose on 
W1D1. EOT circulating biomarker blood 
samples to be collected with lab 
assessments.
X
X
X
X
Translational Research
PGx sample
X
Tumor Sample
PK samples should be collected within 
1hour of on-treatment biopsy. EOT 
biopsy should be collected at time of 
disease progression where feasible
X
All Tumor Types: One postdose 
sample collected anytime between
W2D1- W3D1 (2-4h 4-6h post-
dose). Timing may be further 
optimized based on tumor type and 
emerging data
X
FOLLOW-UP PHASE
Footnote added to CT scan/MRI and PET scan efficacy assessments:
a.
Per RECIST 1.1 baseline (within 35 days of first dose) bone scans and brain scans are to be conducted for all subjects. Thereafter scans should 
be conducted as clinically indicated. Subjects undergoing baseline full body PET/CT and/or brain MRI will not require these additional scans, unless 
clinically appropriate.
b.
PET scan (FDG or fluoride) required at baseline and follow up scans should be collected when clinically appropriate.
c.
Disease assessments should be performed no less than 4 weeks (28 days) after first dose and  after previous on-treatment scan.  


2011N118599_09
CONFIDENTIAL
BET115521
404
Table 29
Time and Events: Part 2 Laboratory Assessments
NB: On dosing days, 
collect blood samples prior 
to dosing. W1D1 samples 
not needed if SCR sample 
is within 72h of first dose
Notes
SCR
Q4, Q8 and Q12W Initiated 
from Week 13
EOTb
W1
W2
W3
W4
W5
W9
W13
q4W
q8W
q12w
D1
D4 a
D1
D4 a
D1
D1
D1
D1
D1
D1
D1
D1
Footnote added to W1D4, W2D4 and EOT Time point: 
a.
Optional Visits, should be conducted when additional monitoring of laboratory values is clinically appropriate
b.
EOT circulating biomarker blood samples to be collected with lab assessments.


2011N118599_09
CONFIDENTIAL
BET115521
405
Table 30
Time and Events: Besylate Sub-Study
Besylate Sub-
Study 
Assessments
Notes
S
C
R
Q4 and Q8W 
Initiated from 
Week 9
E
O
T
Week 1
Week 2
W3
W4
W5
W7
W9
q4W
q8W
D
1
D
2
D
3
D
4
D
5
D
6
D
7
D
1
D
2
D
3
D
4
D
5
D
6
D
7
D
1
D
4
D
1
D
4
D
1
D
1
D
1
D
1
D
1
Laboratory assessments: For details please see corresponding days in Table 10
Tests
X
X
X
X
X
X
X
X
X
X
X
Cardiac Monitoring
12-lead ECGs 
(Triplicate)
For timing of triplicate ECGs on O 
days, see Table 19Table 11 and Table 
20Table 12. Otherwise, triplicate 
ECGs at approximately same time of 
day, and prior to dose on dosing days. 
If QTcF increase >30msec, ECGs 
should be repeated Q2-3 days until  
QTcF is within 30msec from baseline.
ECGs daily through W2.
X
O
X
X
X
X
X
X
X
X
O
X
X


2 0 1 1 N 1 1 8 5 9 9 _ 0 9
C O N FI D E N TI A L
B E T 1 1 5 5 2 1
4 0 6
S e cti o n 6. 1. 2.
Vi sit Wi n d o w s
R ati o n ale f or C h a n ge: T he E O T a n d St u d y Disc o nti n uati o n secti o n was u p date d t o 
clarif y ti mi n g of t his visit.
Re vise d Te xt:
Ei g ht h p ar a gr a p h :
Disc o nti n u ati o n / E n d of Tre at me nt visit : s h o ul d be wit hi n 1 4 t o 2 8 da y s fr o m last d ose 
of st u d y  dr u gs. If a s u bject is u na ble t o ret ur n t o t he cli nic d ue t o h os pitalizati o n, site 
staffs are e nc o ura ge d t o tele p h o ne t he s u bject f or assess me nt of a d verse e ve nts .
S e cti o n 6 . 2. B a s eli n e A s s e s s m e nt f or N M C S u bj e ct s
R ati o n ale f or C h a n ge: T his secti o n was u p date d t o clarif y  acce pta ble a n d re q uire d 
dia g n ostic met h o ds f or N M C s u bjects.
Re vise d Te xt:
F or N M C s u bjects, i n Part 1 a dia g n osis of N M C base d o n a p ositi ve I H C test a n d/ or 
detecti o n of N U T ge ne tra nsl ocati o n as deter mi ne d b y FI S H at scree ni n g will be re q uire d. 
I n Part 2, a dia g n osis of N M C base d o n a p ositi ve I H C test will be re q uire d. A ≥2 0 % 
n uclei stai ni n g c ut off will be a p plie d f or a p ositi ve dia g n osis as a s u bset of ger m cell 
t u m ors (fr o m testis a n d o var y) wea kly stai n f or t he N U T pr otei n ( 5 % ma xi mal n uclei 
stai ni n g,  
, pers o nal c o m m u nicati o n). Fl u oresce nce i n -sit u h ybri dizati o n ( FI S H) 
testi n g or ne xt ge nerati o n se q ue nci n g ( N G S) will be u n derta ke n pr os pecti vel y t o pr o vi de 
c o nfir mati o n of b or derli ne I HC stai ni n g ( n uclear stai ni n g ≥1 % a n d < 2 0 %) a n d 
retr os pecti vely c haracterize t he N U T ge ne f usi o n part ner a n d t o s u p p ort e x pl orat or y  
a nal ys is of differe ntial o utc o mes base d o n t he N U T f usi o n part ner. T he I H C a n d FI S H or 
N G S a nal ys es will be perf or me d at a ce ntral la b orat or y .
S e cti o n 6 . 7. 2.
A s s e s s m e nt s f or P E T
6. 7. 2.
A s s e s s m e nt s f or 1 8 F D G -P E T
R ati o n ale f or C h a n ge: 
P P D
T his secti o n was u p date d t o pr o vi de a d diti o nal g ui da nce a n d 
clarificati o n ar o u n d t he P E T assess me nts f or s u bjects i n Part 1 a n d Part 2.


2011N118599_09
CONFIDENTIAL
BET115521
407
Revised Text:
First and second paragraph:
During the dose escalation phase in Part 1 18F-FDG PET assessments will be optional 
until the standard 3+3 design is implemented. At this point, the sites will be required to 
perform 18F-FDG PET assessments for all NMC subjects and other solid tumors as 
appropriate.
At selected sites, subjects 18F-FDG PET avid tumors are eligible for pre-dose and post-
dose (baseline and on treatment) 18F-FDG PET assessments. The initial assessment 
should be performed as close to Tmax as possible and pharmacokinetics sampling will be 
performed as outlined in Time and Events Table to pair with 18F-FDG PET assessments. 
Additional scans may be performed at different timepoints based on emerging data during 
the study. 
During Part 2 PET (FDG or fluoride) scans should be performed at baseline, with follow 
up scans conducted as clinically appropriate (as outlined in the T&E Table 16).
Section 6.8.1.
Tumor Tissue Collection
Rationale for Change: Further clarification added to this section to the requirements for 
tumor tissue collection in Part 1 and Part 2.
Language was also included to allow for the introduction of a pre-screen consent to 
subjects in order to facilitate collection of tumor tissue. 
Revised Text:
First paragraph:
NMC patients in Part 1 will be required to submit a fresh or archival tumor specimen for 
diagnosis or retrospective diagnostic confirmation.  NMC patients in Part 2 will be 
required to submit a fresh or archival tumor specimen to the central laboratory during the 
14 day screening period for diagnosis. Due to the timely need to determine NMC status 
by NUT IHC testing, a pre-screen informed consent may be offered to expedite obtaining 
the archival tissue in Part 2. These specimens may also be evaluated retrospectively for 
exploratory research as described above. 
Third Paragraph:
During the accelerated dose escalation phase (Part 1), fresh pre- and post-dose biopsy 
collections will be optional until the standard 3+3 design is implemented.  During the 3+3 
dose escalation phase in Part 1, and during Part 2, pre- and post-treatment biopsies 
collected between W2D1 – W3D1 (4-6 hrs post-dose) are mandatory. For subjects in Part 
1 and 2, if tumor tissue is not accessible, discussion with the GSK medical monitor is 
required. 


2011N118599_09
CONFIDENTIAL
BET115521
408
Section 6.8.2.2.
Systemic (Unstimulated) Plasma for Cytokines, 
Chemokines, and Acute Phase Proteins
Rationale for Change: A minor correction was made to the list of possible analytes 
being measured in plasma samples to change MIP1-α to MIP1-β.
Revised Text:
The set of analytes identical to that used in the whole blood ex vivo assay (including for 
example, MCP-1, MIP1-βα, IL-8) will also be measured in plasma samples taken during 
PK sampling and at the time of any Grade 2 fever or symptoms of a cytokine storm. This 
will assess systemic inflammatory response in the subject using biomarkers such as pro-
inflammatory cytokines and acute phase proteins and correlate the systemic response to 
drug with that in stimulated and unstimulated blood. These biomarkers are expected to 
change over days rather than hours, based on the plasma half lives and pre-clinical data, 
such that sampling will also be performed after repeat dosing.
Section 7.1. GSK525762 Investigational Product Dosage/Administration
Rationale for Change: This section was updated following results from the besylate sub-
study, showing the besylate salt coated tablet is bioequivalent to the amorphous free-base 
uncoated tablet. In addition there is a lack of effect of a high-fat high-calorie breakfast on 
the overall exposure (i.e. AUC) to GSK525762 administered as besylate coated tablets 
while administration with food tended to slightly decrease Cmax. The fasting requirement 
is thus no longer necessary in subjects taking the besylate formulation in Part 2.
Therefore, language was added to allow for the introduction of the besylate tablets to Part 
1 subjects. The dose administration section was also updated to allow study drug to be 
taken any time of day as long as taken at the same time each day (Part 1 and Part 2) and 
to be taken with or without food (Part 2 subjects only).
Revised Text:
First paragraph:
GSK525762 Tablets will be provided to sites by GSK. The contents of the label will be in 
accordance with all applicable regulatory requirements. An amorphous, free-base 
formulation of GSK525762 will be used in Part 1 (Table 23) and a crystalline, besylate 
formulation (Table 24) will be introduced in the besylate sub-study in Part 1 (US sites 
only) and the Part 2 expansion cohorts. After completion of the besylate sub-study and 
introduction of besylate material for Part 2, remaining subjects ongoing in Part 1 may be 
required to change from the amorphous free-base formulation to the besylate formulation 
(at the equivalent dose) based on the amorphous supply availability.


2011N118599_09
CONFIDENTIAL
BET115521
409
Table 24:
Table 24
GSK525762 Besylate Investigational Product 
Dosage/Administration
Dosing 
instructions:
Dose with 240mL water and 
should be taken between 7 am 
and 10 am at approximately the 
same time each day. May be 
taken with or without food. No 
food or antacids for at least 1h 
before and 2h after dosing. (If a 
subject vomits after taking study 
drug, the subject should be 
instructed not to retake the dose 
and should take the next 
scheduled dose.)
Dissolve powder in 20 mL of water with 
bicarbonate buffer and administered with 
GSK525762 tablets (Besylate Sub-Study, 
Treatment A2, B and C)
Section 7.2. Handling and Storage of Study Treatment
Rationale for Change: Updated storage requirements were included in this section for 
the besylate tablets.
Revised Text:
Third and fourth paragraph:
GSK525762 Amorphous Free-base Tablets are to be stored at up to 30°C (86°F) and 
protected from light and moisture.
GSK525762 Besylate Tablets are to be stored at up to 30°C (86°F) and protected from 
moisture.
Section 7.3. Meals and Dietary Restrictions
Rationale for Change:  This section was updated based on the results of the besylate 
sub-study showing a lack of effect of a high-fat high-calorie breakfast on the overall 
exposure (i.e. AUC) to GSK525762 administered as besylate coated tablets, to clarify 
that the fasting requirement is being lifted in Part 2; however, on Serial PK sampling days
in Part 2 (Week 1 and Week 4) subjects will still be required to fast overnight (i.e., at 
least 8 hours). 


2011N118599_09
CONFIDENTIAL
BET115521
410
Revised Text:
First three paragraph:
Subjects During Part 1 subjects will fast for at least one hour prior to each dose of study 
drug. After dosing, subjects will be asked to fast for an additional two hours.  These 
fasting requirements have been implemented in the protocol and informed consents to 
minimize pharmacokinetic variability. During BesylteBesylate Sub-Study, subjects will 
be asked to fast overnight (at least 8 hours) and continue fasting for 4 hours post dose 
administration except for the fed administration where subject will be requested to ingest 
a high-fat high-calorie meal within 30 minutes prior to administration (FDA, 2002). 
If a subject vomits after taking study drug, the subject should be instructed not to retake 
the dose and should take the next scheduled dose. Requirements for fasting before and 
after dosing may be modified based on emerging pharmacokinetic, pharmacodynamic, 
and safety data. Any change in fasting requirements will be communicated to each 
investigator and site staff in future protocol amendment. Should a twice daily regimen be 
required, additional consideration will be paid to this requirement fasting requirements
once the escalation period is past.
In Part 2 based on the results of the besylate sub-study showing a lack of effect of a high-
fat high-calorie breakfast on the overall exposure (i.e. AUC) to GSK525762 administered 
as besylate coated tablets, the fasting requirement is being lifted , except on Serial PK 
sampling days in Part 2 (Week 1 and Week 4). On these days, subjects should fast 
overnight (i.e., at least 8 hours). After dosing, subjects will be asked to fast for an 
additional two hours. These fasting requirements have been implemented in the protocol 
and informed consents to minimize PK variability.
Section 8.2.1.
Cautionary Medications
Rationale for Change: The data source for Table 27 was updated with latest revision 
date.
Revised Text:
Table 27
Drugs with a Risk of Torsades de Pointes which are permitted 
for co-administration with Extreme Caution
Table Footnote revised:
Data Source: www.crediblemeds.org (revised 1727-DecMay-2015)


2011N118599_09
CONFIDENTIAL
BET115521
411
Section 8.2.2.
Potential Drug Interactions with GSK525762
Rationale for Change: This DDI section was updated based on emerging metabolite 
data.
Revised Text:
The precise in vivo metabolic liability for GSK525762 has yet to be assessed. In vitro 
data suggests that GSK525762 is only metabolized by CYP3A4 and thus 
coadministration of inducers and inhibitors of CYP3A4 should be avoided during the 
course of the study where possible as they may respectively decrease or increase 
exposure to GSK525762. GSK525762 has low potential to inhibit the major human CYP 
isoforms (IC50’s ≥ 33 µM) or major transporters. There is no evidence for time 
dependent inhibition of CYP2D6 or CYP3A4. GSK525762 is considered to have a low 
risk of causing clinically relevant perpetrator drug interactions with CYP3A4, CYP2B6 
and CYP2C8 enzymes and/or PgP, BCRP, OATP1B3, OAT1, OCT2, MATE1, MATE2-
K, BSEP or MRP2 transporters either via direct or metabolism-dependent inhibition.
GSK525762 was shown to be an inhibitor of OATP1B1 and OAT3 in vitro, however, the 
clinical impact of this inhibition is only deemed a concern for sensitive substrates of 
OATP1B1 or OAT3 (e.g. methotrexate).
Potential interactions with other Cytochrome P450 metabolized drugs have not been 
assessed.
Section 8.3. Prohibited Medications 
Rationale for Change: This section was updated to clarify that only ORAL 
administration of palonosetron and ondansetron are allowed at 8 mg TID.
Revised Text:
Table 28
Drugs with a Risk of Torsades de Pointes that are Prohibited
Generic Name
Brand Name
Arsenic trioxide
Trisenox
Asenapine
Saphris,Sycrest
Bepridil
Vascor
Chloroquine
Aralen
Cisapride
Propulsid
Clarithromycin
Biaxin, Prevpac
Disopyramide
Norpace
Dofetilide
Tikosyn
Domperidone
Motilium
Droperidol
Inapsine
Erythromycin
Erythrocin, E.E.S.
Halofantrine
Halfan
Hydrocodone
Hysingla ER and Zohydro ER


2011N118599_09
CONFIDENTIAL
BET115521
412
Generic Name
Brand Name
Ibutilide
Corvert
Levofloxacin
Levaquin
Levomethadyl
Orlaam
Mesoridazine
Serentil
Methadone
Dolophine, Methadose
Pentamidine
Pentam, NebuPent
Pimozide
Orap
Probucol
Lorelco
Procainamide
Pronestyl, Procan
Quinidine
Quinaglute, Cardioquin
Sotalol
Betapace
Sparfloxacin
Zagam
Terfenadine
Seldane
Thioridazine
Mellaril
Data Source: crediblemeds.org
Last paragraph:
If a subject requires medication for hyperemesis, due to the potential of serotonin 5-HT3 
receptor antagonists to increase QTcF, palonosetron and ondansetron at a maximum oral
dose of 8 mg TID are the only allowed drugs in this class.
Section 8.4. Non-Drug Therapies
Rationale for Change: A minor error was corrected in this section.
Revised Text:
Non-drug anti-cancer therapies (e.g., radiation therapy, surgery, and/or tumor 
embolization) will not be permitted from the transition screening visit through the post-
study follow-up visit. 
NOTE: Subjects may receive palliative radiation treatment during this study. 
Subjects will abstain from using herbal preparations/medications throughout the study 
until the final study visit.  Decaffeinated tea and coffee are permissible. 
Section 11.1.
Sample Size Assumptions
Rationale for Change: This section was updated to increase the total number of subjects 
to be enrolled in the Part 1 based on actual recruitment.


2011N118599_09
CONFIDENTIAL
BET115521
413
Revised Text:
First paragraph: 
The total number of subjects to be enrolled into Part 1will depend on the number of dose 
escalations required to establish the maximum tolerated dose of GSK525762; they are not 
driven by statistical considerations. To complete Part 1, it is estimated that 650 to 970 
evaluable subjects will be enrolled.
Section 11.2.
Analysis Populations
Rationale for Change: The analyses sections were updated throughout the protocol to 
allow for the flexibility to conduct an interim analysis at some point during the study,
prior to end of Part 2. This section was included to note that full details of the analysis 
populations will be included in the reporting and analysis plan (RAP).
Revised Text:
Last paragraph: 
More details of the analysis populations will be specified in RAP.
Section 11.3.
Data Analysis Considerations
Rationale for Change: The analyses sections were updated throughout the protocol to 
allow for the flexibility to conduct an interim analysis at some point during the study, 
prior to end of Part 2.
Revised Text:
New sub section added:
11.3.1.
Interim Analysis
An interim analysis of the key parameters may be carried-out before the conclusion of the 
study. Full details of procedures and of the analyses planned at the interim analysis will 
be provided in the Reporting and Analysis Plan (RAP).
The study will not utilize an Independent Data Monitoring Committee (IDMC).
11.3.2.
Final Analyses
Final analysis on Part 1 may be conducted when 

Part 1 is completed 

or at least 70% of subjects enrolled in every dose group at Part 1 are completed or 
progressed or died.
Final analyses will be carried-out following the DBF (data base frozen) after all the data 


2011N118599_09
CONFIDENTIAL
BET115521
414
queries has been resolved .
Section 11.6.1.
Pharmacokinetic Parameters
Rationale for Change: This section was updated to clarify that parent and metabolite 
data would both be analyzed as part of PK analysis. 
Revised Text:
PK analyses will be the responsibility of Clinical Pharmacokinetics/Modelling & 
Simulation, GSK. Plasma GSK525762 and relevant metabolites, as appropriate,
concentration-time data from dose escalation (Part 1) will be analyzed by non-
compartmental methods with WinNonlin.
Section 11.6.3.
Population Pharmacokinetic Analysis
Rationale for Change: This section was updated to clarify that PK data from other 
ongoing studies using GSK525762 may be taken into consideration when analyzing PK 
data from this study.
Revised Text:
Plasma concentration-time data from parts 1 and 2 will be combined and may be 
combined with data from other studies and further analyzed using a population approach. 
A nonlinear mixed effects model will be used to determine population pharmacokinetic 
parameters (absorption rate, Ka, apparent clearance, CL/F and volume of distribution, 
V/F) and summary exposure measures (Cmax, AUC and Cav = AUC/) and identify 
important covariates (e.g., age, weight, or disease related covariates).
Section 13
References
Rationale for Change: Reference was added based on updates made in the protocol 
amendment.
Reference added:
GlaxoSmithKline Document Number 2011N113741_04. GSK525762 Investigator's 
Brochure, Version 20. March 2015.


2 0 1 1 N 1 1 8 5 9 9 _ 0 9
C O N FI D E N TI A L
B E T 1 1 5 5 2 1
4 1 5
A M E N D M E N T 0 8
Pr ot oc ol C h a n ges f or A me n d me nt 8 ( 0 2- D E C -2 0 1 6 ) fr o m t he Pr ot oc ol A me n d me nt 
7 ( 1 0-M A R -2 0 1 6 )
Pr ot oc ol A me n d me nt 8 a p plies t o all site(s) p artici p ati n g i n t he c o n d uct of t he st u d y .
A m e n d me nt 0 8 s u m m ar y: 
A me n d me nt 8 i ncl u des c ha n ges as t he res ult of t he Dear I n vesti gat or Letter, date d 1 6 
N o ve m ber 2 0 1 6 w hic h o utli nes t he u p date d t hr o m b oc yt o pe nia ma na ge me nt g ui deli nes, 
as o utli ne d i n t he Dear I nvesti gat or Letter, date d 1 6 N o ve m ber 2 0 1 6. T his a me n d me nt 
als o i ncl u des i n crease d c oa g ulati o n m o nit ori n g f or Part 2 (a d de d at W 2 D 1, W 3 D 1 a n d 
c ha n ge d fr o m q 8 W t o q 4 W after Wee k 1 3), a d diti o n of Fact or VII m o nit ori n g i n Part 2 
(at Scree ni n g, W 3 D 1 a n d refle x testi n g if P T or I N R are ≥1. 5 X U L N) a n d a d diti o n of 
la b orat or y val ues re q uire d pri or t o perf or mi n g t he p ost-d ose bi o ps y .
C ha n ges are n ote d bel o w wit h stri ket hr o u g h t o i de ntif y delete d te xt a n d u n derli ni n g t o 
i de ntif y ne w or re place me nt te xt. Re visi o ns wit hi n ta bles will be dis pla ye d as te xt
List of S pecific C h a n ges
S P O N S O R/ M E DI C A L M O NI T O R I N F O R M A TI O N P A G E
Me dic al M o nit or a n d S p o ns or C o nt act I nf or m ati o n:
R ati o n ale f or c h a n ge: T he bac k - u p me dical m o nit or i nf or mati o n has bee n u p date d base d
o n G S K pers o n nel c ha n ges. 
Re vise d te xt:
R ol e
N a m e
D a y 
Ti m e 
P h o n e 
N u m b er
Aft er -h o ur s 
P h o n e/ C ell /
P a g er 
N u m b er
F a x 
N u m b er
G S K A d dr e s s
Pri m ary 
M e dic al 
M o nit or
 
 M D, 
P h D
Gl ax o S mit h Kli n e
1 2 5 0 S o ut h C oll e g evill e R o a d, 
U P 4 4 1 0
C oll e g evill e, P A 1 9 4 2 6, U S A
S ec o n d ary 
M e dic al 
M o nit or
 M D, 
P h D
Gl ax o S mit h Kli n e
1 2 5 0 S o ut h C oll e g evill e R o a d
M ailst o p U P 4 4 1 0
C oll e g evill e, P A 1 9 4 2 6, U S A
P P D
P P D
P P D
P P D
P P D


2011N118599_09
CONFIDENTIAL
BET115521
416
NEW text added, ABBREVIATIONS
INR
International Normalized Ratio
Rationale for change: Addition of laboratory values required prior to performing the post-dose biopsy added to reduce the risk for 
bleeding after biopsy.
Section 5. Time and Events Tables
Table 7: Time and Events: Part 1
Revised text:
Part 1 
Assessments
Notes
S
C
R
Q4 and Q8W 
Initiated 
from Week 9
E
O
T
Week 1
Week 2
W3
W4
W5
W7
W9
q4W
q8W
D
1
D
2
D
3
D
4
D
5
D
6
D
7
D
1
D
2
D
3
D
4
D
5
D
6
D
7
D
1
D
4
D
1
D
4
D
1
D
1
D
1
D
1
D
1
Informed 
consent
Unless otherwise noted, screening 
assessments to be completed 
within 14 days of first dose.
X
Demography
X
Medical history
X
Disease 
characteristics
X
Cardiology 
evaluation
X
Prior therapy
X
Register subject
X
TREATMENT PHASE
Study Drug


2011N118599_09
CONFIDENTIAL
BET115521
417
Part 1 
Assessments
Notes
S
C
R
Q4 and Q8W 
Initiated 
from Week 9
E
O
T
Week 1
Week 2
W3
W4
W5
W7
W9
q4W
q8W
D
1
D
2
D
3
D
4
D
5
D
6
D
7
D
1
D
2
D
3
D
4
D
5
D
6
D
7
D
1
D
4
D
1
D
4
D
1
D
1
D
1
D
1
D
1
Administer study 
drug
Administer about same time of 
day. No food or antacids 1h before 
and 2h after.
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Daily
Review subject 
diary
Diary not required when dosed in 
clinic.
X
X
X
X
X
X
X
Safety
Pregnancy test/  
testosterone
Females: serum pregnancy test 
within 7 days of first dose; urine or 
serum test thereafter. Males: 
complete and free testosterone at 
SCR; free testosterone thereafter.
X
X
X
X
X
X
Physical exam
X
X
X
X
X
X
X
X
X
ECOG PS
X
X
X
X
X
X
X
X
X
X
Vital Signs
SBP, DBP, heart rate, respiratory 
rate, temp
X
X
X
X
X
X
X
X
X
X
X
X
X
Pain
X
X
X
X
X
X
X
X
X
X
X
X
X
Weight and 
height
Height at SCR only
X
X
X
X
X
X
X
X
X
X
Chest x-ray
X
Pulmonary 
function test
X
Adverse events
SAEs collected continuously from signing of informed consent; AEs collected continuously from time of first dose
Concomitant 
medications
continuous from signing of informed consent
Laboratory assessments: For details please see following tables
Tests
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Cardiac Monitoring


2011N118599_09
CONFIDENTIAL
BET115521
418
Part 1 
Assessments
Notes
S
C
R
Q4 and Q8W 
Initiated 
from Week 9
E
O
T
Week 1
Week 2
W3
W4
W5
W7
W9
q4W
q8W
D
1
D
2
D
3
D
4
D
5
D
6
D
7
D
1
D
2
D
3
D
4
D
5
D
6
D
7
D
1
D
4
D
1
D
4
D
1
D
1
D
1
D
1
D
1
Echocardiogram
Within 35 days of first dose
X
X
X
X
X
X
12-lead ECGs 
(Triplicate)
For timing of triplicate ECGs on O 
days, see Table 9 and Table 10. 
Otherwise, triplicate ECGs at 
approximately same time of day, 
and prior to dose on dosing days. 
If QTcF increase >30msec, ECGs 
should be repeated Q2-3 days 
until QTcF is within 30msec from 
baseline.
X
O
O
O
O
X
X
X
O
X
X
X
O
X
X
X
X
O
X
X
Holter monitoring
At least 24 h, on dosing days start 
at least 60 min predose.
X
X
X
Efficacy
CT/MRI Scansa
SCR assessment within 35 days 
of first dose. Target lesions to be 
identified at SCR and followed.
X
X
X
X
X
Tumor sample
Optional during rapid dose 
escalation; required during 3+3 
dose escalation. EOT sample 
should be collected at time of 
progression where feasible.
Subjects must have a platelet 
count of ≥75,000/mm3 and a PT, 
INR and aPTT that are WNL within 
48 hours prior to the post-dose 
biopsy.
X
All Tumor Types: One post-dose
sample collected anytime 
between W2D1-W3D1 (4-6h 
post-dose). Timing may be 
further optimized based on tumor 
type and emerging data.
X
PET scan
Optional during rapid dose 
escalation; required during 3+3 
dose escalation.
X
X
X


2011N118599_09
CONFIDENTIAL
BET115521
419
Part 1 
Assessments
Notes
S
C
R
Q4 and Q8W 
Initiated 
from Week 9
E
O
T
Week 1
Week 2
W3
W4
W5
W7
W9
q4W
q8W
D
1
D
2
D
3
D
4
D
5
D
6
D
7
D
1
D
2
D
3
D
4
D
5
D
6
D
7
D
1
D
4
D
1
D
4
D
1
D
1
D
1
D
1
D
1
SCR assessment within 35 days 
of first dose.
Castrate-Resistant Prostate Cancer Assessments
PSA
PSA to be collected in line with 
PCWG2 guidelines. Levels may 
be checked more frequently if 
appropriate.
X
X
X
Table 14: Time and Events: Part 2
Revised text:
Part 2 Assessments
Notes
SCR
Q4, Q8 and Q12 Initiated 
from Week 13
EOT
W1
W2
W3
W4
W5
W9
W13
q4W
q8W
q12W
D1
D1
D1
D1
D1
D1
D1
D1
D1
D1
Informed consent
Unless otherwise noted, screening 
assessments to be completed within 
14 days of first dose.
X
Demography
X
Medical history
X
Disease characteristics
X
Cardiology evaluation
X
Prior therapy
X
Register subject
X
TREATMENT PHASE
Study Drug
Dispense study drug
Administer about same time of day. 
X
X
X
X
X
X
X
X


2011N118599_09
CONFIDENTIAL
BET115521
420
Part 2 Assessments
Notes
SCR
Q4, Q8 and Q12 Initiated 
from Week 13
EOT
W1
W2
W3
W4
W5
W9
W13
q4W
q8W
q12W
D1
D1
D1
D1
D1
D1
D1
D1
D1
D1
Review compliance
Not required when dosed in clinic.
X
X
X
X
X
X
X
X
X
X
Safety
Pregnancy 
test/testosterone
Females: serum pregnancy test 
within 7 days of first dose; urine or 
serum test thereafter. Males: 
complete and free testosterone at 
SCR; free testosterone thereafter.
X
X
X
X
X
X
Physical exam
X
X
X
X
X
X
X
X
X
X
ECOG 
X
X
X
X
X
X
X
X
X
X
Vital Signs and Pain 
Assessments
X
X
X
X
X
X
X
X
X
X
Weight and height
Height at SCR only
X
X
X
X
X
X
X
Chest x-ray
X
Pulmonary function test
X
Adverse events
SAEs collected continuously from signing of informed consent; AEs collected continuously from time of first 
dose
Concomitant 
medications
continuous from signing of informed consent
Laboratory assessments: For details please see Table 15
Tests
X
X
X
X
X
X
X
X
X
X
X
X
Castrate-Resistant Prostate Cancer Assessments
PSA
X
X
X
X
X
X
X
X
X
X
Serum testosterone
X
X
X
X
X
X
X
X
X
X
Cardiac Monitoring
ECHO
If Baseline ECHO within 35 days of 
first dose, the Week 1 Day 1 ECHO 
is only required if clinically 
appropriate.
X
X
optional
X
X
X
X
X
X
12-lead ECGs (Single)
ECGs prior to dosing. If QTcF 
X
X
X
X
X
X
X
X
X
X


2011N118599_09
CONFIDENTIAL
BET115521
421
Part 2 Assessments
Notes
SCR
Q4, Q8 and Q12 Initiated 
from Week 13
EOT
W1
W2
W3
W4
W5
W9
W13
q4W
q8W
q12W
D1
D1
D1
D1
D1
D1
D1
D1
D1
D1
increase >30msec, ECGs should be 
repeated Q2-3 days until QTcF is 
within 30msec from baseline.
Holter monitoring
At least 24 h, on dosing days start 
predose.
X
X
X
Efficacy
Lesion  assessments
X
X
X
X
CT scan or MRI a, b
Scans within 35 days of first dose 
may be used as screening 
assessment. Additional bone scans 
and brain scans not required unless 
clinically indicated.
X
X
X
X
PET scan (FDG or 
fluoride) b, c
Scans within 35 days of first dose 
may be used as screening 
assessment. Follow up scans 
conducted as clinically appropriate.
X
PK
PK 
Three samples to be collected each 
sampling day: During first 4 weeks 
collect a predose within 60 minutes 
prior to dose, a single draw between 
0.5-2h postdose, and a single draw 
between 4-8h postdose (fasting 
requirements apply).Thereafter only 
a Predose and 0.5hour post-dose 
sample are collected. 
NOTE: If dose level is adjusted, 
additional PK sampling may be 
requested.
X
X
X
X
Blood samples for 
circulating exploratory 
Baseline sample collected pre-dose 
on W1D1 EOT circulating biomarker 
X
X
X


2011N118599_09
CONFIDENTIAL
BET115521
422
Part 2 Assessments
Notes
SCR
Q4, Q8 and Q12 Initiated 
from Week 13
EOT
W1
W2
W3
W4
W5
W9
W13
q4W
q8W
q12W
D1
D1
D1
D1
D1
D1
D1
D1
D1
D1
biomarkers (cfDNA, etc)
blood samples to be collected with 
lab assessments.
Translational Research
PGx sample
X
Tumor Sample
PK samples should be collected 
within 1 hour of on-treatment biopsy. 
EOT biopsy should be collected at 
time of disease progression where 
feasible. Subjects must have a 
platelet count of ≥75,000/mm3 and a 
PT, INR and aPTT that are WNL 
within 48 hours prior to the post-dose 
biopsy.
X
All Tumor Types: One 
post-dose sample 
collected anytime 
between W2D1- W3D1 
(4-6h post-dose). Timing 
may be further optimized 
based on tumor type and 
emerging data.
X
FOLLOW-UP PHASE
Follow-up contact by clinic visit or other means (telephone contact, email, etc) for survival status and anticancer therapy every 6 months. Disease assessment will be collected 
for subjects who discontinue study medication due to any reason other than progression or death. Individual subjects will be considered to have completed the study 2 years 
after their last treatment or upon death, whichever is sooner. Document the cause of death. For the study, the Follow-up Phase ends after a minimum of 70% of subjects have 
died or 5 years after the last subject is enrolled in Phase 2.
Abbreviations: CK=creatine kinase; D=day; ECG=electrocardiogram; ECOG PS=Eastern Cooperative Oncology Group Performance Status; EOT=End-of-Treatment; 
q4W=every 4 weeks; q8W=every 8 weeks; SCR=Screening; Wk=week; PT=Prothrombin Time; INR=International Normalized Ratio; aPTT=Activated partial thromboplastin 
time; WNL=Within normal limits
a.
Per RECIST 1.1 baseline (within 35 days of first dose) bone scans and brain scans are to be conducted for all subjects. Thereafter scans should be conducted as 
clinically indicated. Subjects undergoing baseline full body PET/CT and/or brain MRI will not require these additional scans, unless clinically appropriate.
b.
PET scan (FDG or fluoride) required at baseline and follow up scans should be collected when clinically appropriate.
c.
Disease assessments should be performed no less than 4 weeks (28 days) after first dose and from previous on-treatment scan. 


2011N118599_09
CONFIDENTIAL
BET115521
423
Table 15: Time and Events: Part 2 Laboratory Assessments
Rationale for change: Increased frequency of coagulation monitoring and addition of Factor VII testing due to higher than expected 
number of haemorrhagic events observed with the use of GSK525762 in the BET115521 study. GSK is investigating the potential effects 
of GSK525762 on coagulation, including possible decrease in Factor VII activity.
Revised text:
NB: On dosing days, 
collect blood samples 
prior to dosing. W1D1 
samples not needed if 
SCR sample is within 
72h of first dose
Notes
SCR
Q4, Q8 and Q12W 
Initiated from Week 13
EOT b
W1
W2
W3
W4
W5
W9
W13
q4W
q8W
q12W
D1
D4 a
D1
D4 a
D1
D1
D1
D1
D1
D1
D1
D1
Troponin, NT-proBNP-9
1 sample for local 
lab (troponin I or 
T), 1 sample for 
central lab 
(troponin T) 
X
X
X
X
X
X
X
X
X
Hematology
X
X
X
X
X
X
X
X
X
X
Clinical chemistry
X
X
X
X
X
X
X
X
X
X
Pancreatic
X
X
X
X
X
X
X
X
X
X
Coagulation
X
X
X
X
X
X
X
X
X
X
X
Factor VII Assay
Also perform if PT 
or INR are 
≥1.5XULN
X
X
Liver chemistry
X
X
X
X
X
X
X
X
X
X
X
X
Creatine phosphokinase
X
X
X
X
X
X
X
X
Fasting blood glucose 
and insulin
Will be performed 
at central lab if not 
available at local 
lab
X
X
X
X
X
X
X
X
X
X
c-peptide and 1,5 AG
Will be performed 
at central lab if not 
available at local 
X
X
X
X
X


2011N118599_09
CONFIDENTIAL
BET115521
424
NB: On dosing days, 
collect blood samples 
prior to dosing. W1D1 
samples not needed if 
SCR sample is within 
72h of first dose
Notes
SCR
Q4, Q8 and Q12W 
Initiated from Week 13
EOT b
W1
W2
W3
W4
W5
W9
W13
q4W
q8W
q12W
D1
D4 a
D1
D4 a
D1
D1
D1
D1
D1
D1
D1
D1
lab
HbA1c
X
X
X
X
Fasting lipids
X
X
X
X
X
X
X
X
Urinalysis
X
X
X
X
X
X
X
Thyroid monitoring
TSH, free T3, free 
T4. If TSH is 
abnormal W1D1, 
monitor TSH, free 
T3 and free T4 
going forward
X
X
X
X
X
X
X
Cytokines
X
as clinically appropriate
HBsAg, HepC antibody
If hepatits C 
antibody positive, 
perform third 
generation 
immunoassay on  
same sample to 
confirm results
X
a.
Optional Visits, should be conducted when additional monitoring of laboratory values is clinically appropriate.
b.
EOT circulating biomarker blood samples to be collected with lab assessments.
Abbreviations: D=day; EOT=End of Treatment Visit; q4W=Every 4 weeks; q8W=every 8 weeks; q12W=every 12 weeks; SCR=Screening Visit; W=week; ULN=Upper limit of normal


2011N118599_09
CONFIDENTIAL
BET115521
425
Section 6.4.8 Clinical Laboratory Assessments
Table 19: Clinical Laboratory Tests
Rationale for change: Addition of Factor VII Assay testing, per updated Table 15: Time 
and Events: Part 2 Labortatory Assessments.
Revised Text
Other Tests
Coagulation tests (prothrombin time, partial thromboplastin time, international normalized ratio, and fibrinogen)
Factor VII Assay
Pancreatic markers (amylase and lipase)
Fasting Lipid panel (triglycerides and total cholesterol, LDL, HDL)
C-Peptide
Troponin (I or T at local laboratory, Troponin T at central laboratory]
Insulin
Hemoglobin A1C
1,5 –Anhydroglucitol (1,5 AG)
NT-proBNP
Thyroid-stimulating hormone (TSH)
Free Thyroxine 3 (Free T3)
Free Thyroxine 4 (Free T4)
Creatine kinase (CK)
Creatine Kinase-MB (CK-MB)
Testosterone for males (free and complete testosterone at prior to first dose, free testosterone after first dose)
Pregnancy test for females (serum at screening, Urine or serum post dose)Cytokine samples (collected as part of 
Predose PK sample for plasma cytokines; may also be performed as clinically appropriate following fever)
Section 7.7.1 Dose and Safety Management Guidelines
Table 23 Dose Adjustment/Stopping Safety Criteria
Rationale for change: Due to the higher than expected number of haemorrhagic events 
observed with the use of GSK525762 in BET115521, many of which have occurred in 
the presence of moderate to severe thrombocytopenia, this section is being updated with 
more stringent guidelines for thrombocytopenia management
Toxicity
Dose Adjustment/Stopping 
Criteria
Management Guidelines
Thrombocytopenia
Grade 1 (platelets <LLN to 
≥75,000/mm3) & Grade 2 
(platelets <75,000 to 
≥50,000/mm3) Grade 1 & 2
(platelet count above 50,000) 
Continue dosing at same dose level with weekly or 
more frequent monitoring as necessary
Grade 3 (platelets <50,000 to 
≥25,000/mm3) Grade 3 
(platelet count between 25,000 
50,000)
Withhold GSK525762 and check aPTT, PT, and 
INR.  Monitor CBC twice a week and coagulation 
studies twice a week until normal, or increase 
monitoring frequency if clinically indicated.
Hold GSK525762 until thrombocytopenia has 
resolved to ≤ Grade 2 AND aPTT, PT, and INR are 
all ≤ ULN. Drug may then be restarted at the same 


2011N118599_09
CONFIDENTIAL
BET115521
426
Toxicity
Dose Adjustment/Stopping 
Criteria
Management Guidelines
dose or at lower dose level, after discussion with the 
medical monitor.
If safety lab abnormalities recur following 
rechallenge, drug may be discontinued or restarted 
at a lower dose level, after discussion with the 
medical monitor. After discussion with medical 
monitor and using sound clinical judgement, 
continue at same dose or adjust dose (e.g. consider 
reduced daily dosing or dosing on alternate days). 
Monitor CBC at least twice a week, more frequently 
if necessary 
Grade 4 (platelets  
<25,000/mm3), or any 
moderate to severe bleeding 
accompanied by  drug related 
thrombocytopenia Grade 4 
(platelet count below 25,000
Withhold GSK525762 and check aPTT, PT, and 
INR.  Monitor CBC twice a week and 
coagulation studies twice a week until normal, or 
increase monitoring frequency if clinically 
indicated. Hold GSK525762 until 
thrombocytopenia has resolved to ≤Grade 2 
AND aPTT, PT, and INR are all ≤ ULN. Drug 
may then be restarted at a lower dose level, 
after discussion with the medical monitor.
For subjects with moderate to severe bleeding 
requiring transfusion support, GSK525762 should 
be permanently discontinued.
If platelet count does not recover to ≥50,000/mm3
(Grade 2) within 14 days, GSK525762 should be 
permanently discontinued.
If platelet count recovers to ≥50,000/mm3 (Grade 2) 
within 14 days, GSK525762 may be continued at the 
current/reduced dose after discussion with the
medical monitor.  
Temporarily interrupt study medication and monitor 
CBC every 2-3 days. If platelet counts recover to 
Grade 3 and is steady for at least 2 CBC reads at 
least 3days apart, or rising, discuss with medical 
monitor resuming treatment at the same or adjusted 
dose (see Grade 3) based on sound clinical 
judgement


2011N118599_09
CONFIDENTIAL
BET115521
427
AMENDMENT 09
Protocol Changes for Amendment 9 (24-FEB-2017) from the Protocol Amendment 8
(02-DEC-2016)
Protocol Amendment 9 applies to all site(s) participating in the conduct of the study.
Amendment 09 summary:
Amendment 9 applies to all global sites. Updates were made throughout the protocol to 
correct minor inconsistencies, spelling and typographical errors and provide further 
clarification. The following changes have been made based on comments from regulatory 
agencies during review of this protocol and other GSK525762 protocols: addition of 
exclusion criteria for exclusionary medications; updated exclusion of bleeding to include 
all history of bleeding and added known bleeding disorders; addition of laboratory 
monitoring required prior to surgeries, as described in Section 6.4.6.2 and Section 6.8.1; 
addition of guidance for dose reduction levels, as described in Section 7.7.1; updated 
dose adjustment/stopping safety criteria, as described in Table 24 and Table 25; updated 
prohibited medications in Section 8.2.1. In addition, other changes include: addition of a 
GIST cohort in Part 2, including background information, updated endpoints, overall Part 
2 sample size, futility information, eligibility criteria and Section 11, Data Analysis and 
Statistical Considerations; updated Section 1.5 Risk Assessment to include current 
available data; removal of cytokines throughout protocol; updated sample size for MTD 
dose level in Part 1; update to contraception use in Inclusion 9 and 10 and clarifications 
in Section 9 Lifestyle Requirements; removal of Holter monitoring; changes to Part 1 
time and events tables which includes removal of certain ECG time points, change from 
required to optional for urine PK samples and certain PK/ECG/biomarker tests (see 
Tables 12 to 14), addition of Factor VII assay testing, additional lab samples at Week 7 
and Week 11, change in timing of on-treatment biopsy; changes to Part 2 time and events 
tables which includes additional lab samples at Week 7 and 11 and increase in Factor VII 
testing, addition of pregnancy/testosterone test at W1D1; change in timing of on-
treatment biopsy and removal of an ECHO time point; change to the pregnancy reporting 
guidelines to 24 hours; addition of wording that subjects are to abstain from consuming 
certain fruits in Section 7.3; updates to Section 8, Concomitant Medications and Non-
Drug Therapies to reorganize and update the prohibited, cautionary medication tables and 
drug interaction information; removal of fever and diarrhea information from Appendix 
3. Additionally, Appendix 3 was updated with the current GSK Liver Event and follow-
up information, but the liver event criteria did not change.
Version and document number changed for Investigator’s Brochure, GlaxoSmithKline 
Document Number, 2011N113741_04, Version 4 to GlaxoSmithKline Document 
Number 2011N113741_05 Version 5 throughout the document.


2011N118599_09
CONFIDENTIAL
BET115521
428
NEW TEXT, Abbreviations
GIST
Gastrointestinal Stromal Tumor
NSAIDs
Non-Steroidal Anti-Inflammatory Drugs
List of Specific Changes
PROTOCOL SYNOPSIS
Objective & Endpoint
Primary endpoint, Point 2
Rationale for Change: Include PSA50 criteria and GIST endpoints with addition of 
GIST cohort.
Revised Text:

Assess overall response rate (RR) usingby RECIST 1.1 in NMC and other solid tumors or 
PSA50 response rate using PCWG2 guidelines in CRPC or DCR (CR+PR+ SD ≥16 weeks 
in duration) in GIST.
Primary Hypothesis
Rationale for Change: Include GIST information with addition of GIST cohort.
Revised Text:
Gastrointestinal stromal tumor (GIST): this will be determined by testing the null hypothesis that the 
disease control rate is ≤15%, with about 80%  power when the true disease control rate is 40%.
SUBJECT SAMPLE:
Rationale for Change: Update number of subjects to allow for additional subjects to be 
enrolled in Part 1 at the MTD and the addition of the GIST cohort in Part 2. 
Revised Text:
Worldwide approximately 90 110 subjects will be enrolled in Part 1, and approximately 
1750 subjects will be enrolled in Part 2. 
EFFICACY MEASUREMENTS: 


2011N118599_09
CONFIDENTIAL
BET115521
429
Rationale for Change: Include PSA50 criteria and GIST endpoints with addition of 
GIST cohort.
Revised Text:
Response Rate (RR), Disease Control Rate (DCR), PSA50 response rate, Progression 
Free Survival (PFS) and Overall Survival (OS), time to response and duration of 
response. 
SAFETY MEASUREMENTS: 
Rationale for Change: After an internal evaluation of cardiac safety data collected from 
all subjects available by 20Dec2016, the Holter Monitoring was removed, as the ECG 
time-points currently included in the required assessments provide adequate cardiac 
safety assessments of any potential QT-prolonging effect (including potential delayed 
effects).
Revised Text:
Routine physical examinations, vital sign measurements, echocardiograms, and 
monitoring of adverse events. Cardiac safety monitoring will be required, consisting of 
24 hours of Holter monitoring at Screening and in Week 1 and Week 4, and triplicate 12-
lead ECGs in Part 1 prior to dosing on selected days and prior to drawing PK samples on 
serial PK sampling days (overnight stays in research facility may be necessary in Part 1).


2011N118599_09
CONFIDENTIAL
BET115521
430
Section 1. INTRODUCTION
Section 1.2.2 
Other tumor types
Rationale for Change: Addition of GIST cohort and rational to support using a BET 
inhibitor in this tumor type. 
Revised Text:
First paragraph first sentence:
acute leukemias, gastrointestinal stromal tumors (GIST), and other N-Myc driven tumors.
Second paragraph
Based on the preclinical findings within GSK and with collaborators, subjects with small 
cell lung cancer, non-small cell lung cancer (NSCLC), colorectal cancer, castration 
resistant prostate cancer (CRPC), triple negative breast cancer (TNBC), estrogen receptor 
positive (ER positive) breast cancer, neuroblastoma, and N-Myc amplified solid tumors 
will be enrolled to the dose finding part of the study. In addition, Part 2 expansion cohorts 
will enrol subjects with NMC, SCLC, CRPC, TNBC, ER+BC and GIST.
Last Paragraph, GIST (Gastrointestinal Stromal Tumor) point added
GIST (Gastrointestinal Stromal Tumor)
The super-enhancer profiling of sarcoma tumor samples and cell lines identified 
conserved super-enhancer program in GIST tumors. Some of the genes associated with 
super-enhancers in GIST tumors include well-established drivers, such as KIT and 
PDGFRA, but also potential novel targets, such as ETV1 and HAND1. GIST-specific KIT
super-enhancer regulating KIT gene activity is remarkably sensitive to bromodomain 
inhibition. KIT-dependent GIST cell lines have an IC50 to the prototypical bromodomain 
inhibitor, JQ1, ranging from 150 – 470nM (Matthew Hemming, personal communication, 
December 2016). Other bromodomain inhibitors, including GSK525762, demonstrate 
similar selective toxicity in KIT-dependent GIST cell lines. At the gene and protein 
expression levels, BET bromodomain inhibitors attenuate the expression of genes, 
associated with superenhancers, such as KIT, ETV1 and HAND1, suggesting that BET 
proteins are required for the maintenance of GIST super-enhancer associated
transcriptional program and are critical regulators of GIST growth and survival. In 
support of this mechanism, uncoupling KIT expression from its native super-enhancer 
leads to resistance to bromodomain inhibition. In KIT-dependent GIST cells, 
bromodomain inhibition shows synergistic toxicity with KIT-inhibition, further 
suggesting an independent and complimentary mechanism of action in GIST (Matthew 
Hemming, personal communication, December 2016). These evolving data have driven 
strong enthusiasm in developing bromodomain inhibitors in GIST. 
Section 1.4. Rationale for Study and Endpoints
Rationale for Change: Addition of GIST cohort (second paragraph) and clarification of 
the tumor types included in Part 2 (third paragraph).
Revised Text:


2011N118599_09
CONFIDENTIAL
BET115521
431
Second paragraph first sentence
Given the poor prognosis and high unmet medical need of NMC, as well as in other 
tumor types such as relapsed/refractory SCLC, NSCLC, CRC, CRPC, TN and ER+ BC, 
GIST, NB and N-Myc amplified tumors and the exceptional drug-to-target alignment of 
GSK525762, a combined Phase I/II study (BET115521) is proposed.
Third paragraph first sentence 
The recommended phase II dose (RP2D) of GSK525762 with possible adjustment based 
on the relative bioavailability of the besylate salt formulation, will be studied in the 
cohort expansion (Part 2) to determine efficacy, safety and tolerability in NMC 
patientsand other tumor types including SCLC, CRPC, TNBC, ER+BC and GIST.
Section 1.5. Risk Assessment
Rationale for Change: Risk assessment section changed to be in line with changes 
throughout the protocol (e.g. removal of Holter monitoring, will no longer collect 
cytokines in event of fever) and updated section with most current pre-clinical data.
Revised Text:
Gastrointestinal: Second and Third Sentence
Microscopic examination included degenerative changes in the esophagus, stomach, 
small and large intestine, including erosion or ulceration, mucosal congestion, 
hemorrhage and edema, crypt dilatation and focal inflammatory cell infiltration in the 28
daytoxicology studies of up to 3 month durationy in the dog and rat. Recovery was 
evident after a minimum of 3 weeks off dose. 
Cardio-vascular:  
First Paragraph first sentence
Although there were minimal effects of GSK525762 on current density and no effects on
trafficking in HEK-293 cells or on ECG rhythms or arrhythmias in the ex vivo rabbit 
wedge assay, QT and QTc prolongation (maximum 41 milliseconds at 3 mg/kg for 12 
days) was seen in dogs after a single oral dose of 30 mg/kg or repeat dosing at 
1 mg/kg/day in 4 week toxicology studies of up to 3 month duration.  
First Paragraph fourth sentence
Increases in biomarkers of cardiac damage (cardiac troponin I and T, myosin light chain
and NT-proANP) were also seen in the rat and cardiac troponin I in the dog. 
Second Paragraph first sentence
Given the risks of long QTc associated arrhythmias, and of compound associated 
cardiomyopathy, subjects will be monitored closely for changes in QTc with triplicate 
12-lead ECG, Holter monitoring, and for elevations in plasma Troponin.
Second Paragraph fourth sentence


2011N118599_09
CONFIDENTIAL
BET115521
432
Therefore, the 48-hour telemetry requirement was removed and the frequency of Holter 
monitoring was reduced with Protocol Amendment 6 and upon further review of the 
totality of data, Holter monitoring was removed in Amendment 9.
Safety ECGs
First Paragraph second sentence
The mean from triplicate ECGs (when indicated) will be evaluated at each time point.
Subpoint  Serum Markers 
Holter Monitoring and Serum Markers 
Heading of subsection and first sentence
In addition to the Safety ECGs performed during the study, continuous 12-lead Digital 
Holter ECGs will be acquired at baseline and at selected time points during therapy for 
accurate retrospective analysis of QTcF variation.  Laboratorylaboratory evaluations for 
cardiac troponins and electrolytes will be performed and NT-pro-brain natriuretic peptide 
(BNP) will be checked at baseline, regular intervals (as specified in the Time and Events
tables of the protocol), and when clinically warranted during the study treatment.  
Hematologic and lymphoid:  
First Two Sentence
Lymphoid toxicity was observed in rats and dogs manifested by bone marrow hypo-
cellularity and variable and inconsistent changes in decreased total white cell lymphocyte 
and decreased platelet counts.  There were variable and inconsistent changes in multiple
red blood cell parameterss and reticulocytes in the periphery, and decreased organ 
weight, thymus, spleen, and lymph node hypocellularity.  
Deleted text 
Cytokines: In vitro incubation of human whole blood for 24 hours with GSK525762 
resulted in a time and concentration-dependent induction of IL-1β.  The maximum effect 
was variable between donors (34 to 3986 pg/mL, mean 1238 pg/mL from 16 donors); 
however, the concentration required to drive this effect was consistent across the donors 
(pEC50 6.0, 0.42ug/mL).  This effect was not observed in whole blood from other species 
(rat and dog) or in preparations of human PBMCs or neutrophils.  Special note is made 
for the occurrence of fever which could be symptomatic of cytokine level elevation 
during dosing of the compound (see protocol Section 7.7, Table 23“Fever”), and close 
monitoring of cytokine levels will be instigated at this point.
Pulmonary: 
First paragraph first sentence


2011N118599_09
CONFIDENTIAL
BET115521
433
Aggregates of foamy macrophages in peri-bronchiolar areas were evident in rats given 
≥10 mg/kg/day for 28 days.
First paragraph fourth sentence
This finding is unlikely to affect pulmonary function; no effects were observed in the 3 
month studies in rats and dogs.however the effect of dosing beyond 4 weeks is unknown. 
Hepatic Toxicity: 
Non-adverse liver changes were observed in rats and dogs including increases in bilirubin 
levels and transient increases in AST in rats. Necrosis was observed in one rat at 30 
mg/kg/day in the 4 week study. GSK525762 has been demonstrated to undergo 
bioactivation in vitro which indicates potential for idiosyncratic heptotoxicity. The 
precursor metabolite has been observed in clinical plasma samples.
The BET115521 protocol includes frequent monitoring of liver biochemistry along with 
stopping criteria for dose limiting toxicity (DLT), liver monitoring guidelines and 
management (see Section 3.2.3, Section 7.7.2, and Appendix 3).
Reproductive and Developmental:
First Paragraph first sentence
In 4-week toxicology studies of up to 3 month duration, bilateral sperm retention, germ 
cell degeneration and tubular vacuolization, and depletion of testicular germinal 
epithelium occurred in male dogs receiving ≥ 0.301 mg/kg and male rats receiving ≥ 10 
mg/kg doses of GSK525762.  Exposures associated with reproductive toxicity in male 
dogs overlap with the proposed 5 mg starting dose in this FTIH study.
First Paragraph third sentence
These changes were accompanied in rats and dogs by changes in sperm morphology, 
motility and number and hormonal changes (decreased testosterone and Inhibin B in rats 
and increased FSH in rats and dogs).  Reduced prostate weight and secretory content was 
also evident in the rat.  An effect on spermatogenesis is anticipated. Full or partial 
reversibility of the testicular effects was observed in the 3 month rat and dogs studies 
following a 17 week off dose period.
Section 2.
OBJECTIVES, ENDPOINTS, HYPOTHESES FOLLOWING QD 
AND/OR BID DOSING SCHEDULES
Objective & Endpoint
Primary Endpoint Point 2
Rationale for Change: Include PSA50 criteria and GIST endpoints with addition of 
GIST cohort.
Revised Text:


2011N118599_09
CONFIDENTIAL
BET115521
434

Assess overall response rate (RR) using RECIST 1.1 in NMC and other solid tumors 
or PSA50 response rate using PCWG2 guidelines in CRPC or DCR (CR+PR+ SD ≥ 
16 weeks in duration) in GIST.
Primary Hypothesis
Rationale for Change: Include GIST information with addition of GIST cohort.
Revised Text:
GIST: this will be determined by testing the null hypothesis that the disease control rate 
is ≤15%, with about 80% power when the true disease control rate is 40%.
Section 3.1. Study Design/Schematic
Rationale for Change: Include GIST information and rationale.
Revised Text:
Second Paragraph Last sentence
Expansion cohorts (Part 2) are planned to further explore clinical activity of GSK525762 
in subjects with NMC, SCLC, CRPC, TNBC, and ER+BC and GIST as shown in Figure 
1.
Fouth Paragraph Third sentence
The GIST expansion cohort is being added in Amendment 9 due to pre-clinical evidence 
for bromodomain inhibition in GIST.
Section 3.2.2.
Dose Escalation and Schedule
Rationale for Change: Simplification of section due to removal of Holter monitoring. 
Revised Text:
First Paragraph Onwards
In Part 1, subjects will follow the dose schedule outlined in Table 2dose once or twice 
daily, depending on the cohort. Alternative dosing regimens and/or schedule may be 
implemented based on emerging PK and safety data.
Extensive mMonitoring for cardiac safety signals will be performed, with triplicate 12-
lead ECGs, and 24-hour Holter monitoring to be performed on the days indicated in 
Table 2the Time and Events Table. 
Subjects will be evaluated for dose limiting toxicities (DLTs) during the first 4 weeks of 
treatment (Section 3.2.3).


2011N118599_09
CONFIDENTIAL
BET115521
435
Table 2
Dosing Schedule and Cardiac Monitoring for Part 1
Section 3.2.2.2.
3+3 Dose Escalation in Part 1
Rationale for Change: Increase the number of subjects that may be treated at the MTD 
to gather additional data at the MTD for Part 1.
Revised Text:
Second Paragraph First sentence
Once the MTD is reached, up to 12 20 additional subjects may be enrolled at the MTD to 
further evaluate safety and tumor PD.
Section 3.2.2.4.
Alteration of Schedule
Rationale for Change: Additional PK samples may not be required in all cases and 
timing will be on a case-by-case basis, depending on the subject’s current dose level and 
time on treatment.
Revised Text:
Fourth Paragraph 
In Part 2, subjects approved to alter their current dose level with either a dose reduction 
or dose escalation may require additional limited PK sampling, after discussion with the 
GSK Medical Monitor. (pre-dose, 0.5, and 3 hours) at the new dose level, after 4-7 days 
at the adjusted dose level.
Section 3.2.2.6.
Intra-Subject Dose Escalation
Rationale for Change: Update to account for removal of Table 2.
Revised Text:
Bullet point 2 Second Sentence
In this case the subject must follow the dosing/monitoring schedule for the first 4-weeks 
as outlined in Table2the Time and Events Tables, as he/she will be the first subject 
exposed to the higher dose.
Dose 
Day 1
Day 2
Day 3
Day 4
Day 5
Day 6
Day 7
Week 1
Dose
Dose
Dose
Dose
ECG
ECG
ECG
ECG,Holter
ECG
ECG
Week 2
Dose
Dose
Dose
Dose
Dose
ECG
ECG
ECG
ECG
Week 3
Dose
Dose
Dose
Dose
Dose
Dose
Dose
ECG
ECG
Week 4
Dose
Dose
Dose
Dose
Dose
Dose
Dose
ECG,Holter
ECG
Dose
Dose
Dose
Dose
Dose


2011N118599_09
CONFIDENTIAL
BET115521
436
Section 3.2.5.1.
NMC Pharmacodynamic Expansion Cohort
Rationale for Change: Update to account for removal of Table 2 and Holter monitoring.
Revised Text:
Second Paragraph First sentence
Subjects in the NMC PD Expansion Cohort will start with same dosing schedule 
described in Section 3.2.2 (Table 2); Extensive mMonitoring for cardiac safety signals 
will be performed as required in Part 1, with triplicate 12-lead ECGs , and 24-hour Holter 
monitoring to be performed on the days indicated in Table 2the Time and Events Table.  
Section 3.2.7.
Part 2 Expansion Cohort
Rationale for Change: Addition of GIST cohort and related futility information. 
Revised Text:
First Paragraph Last sentence
Approximately 1570 subjects with NMC, SCLC, CRPC, TNBC, and ER+BC and GIST 
will be enrolled in expansion cohort at the RP2D to gather more safety data and to further 
assess anti-tumor activity. 
Below Figure 6 Table 6 
For GIST, to test for 40% DCR relative to a 15% DCR suggesting no activity with 0.1
type I error and 80% power, first interim look maybe conducted once 8 evaluable GIST 
subjects have been enrolled in this cohort or treated at the same dose level to examine 
safety and efficacy, if 0 confirmed response or SD with at least 16 weeks is observed, 
further enrolment into this cohort may be terminated. The number of observed confirmed 
responses will guide further enrolment according to the rules summarized in Table 5. A 
maximum of 25 subjects will be enrolled at the RP2D.  All available data will be 
considered in making enrollment decisions.


2011N118599_09
CONFIDENTIAL
BET115521
437
Table 5
Decision Making Criteria for Futility of GIST
Number of Evaluable 
Subjects 
This Number of Confirmed 
Responses/SD to Stop Early 
for Futility
Probability of continuing 
enrolling when DCR=0.4
Probability of continuing 
enrolling when DCR=0.15 
  8
0
0.0000
0.7275
  9
0
0.0000
0.7275
10
1
0.0000
0.4496
11
1
0.0000
0.4496
12
1
0.0000
0.4496
13
1
0.0000
0.4496
14
2
0.0000
0.3087
15
2
0.0000
0.3087
16
2
0.0000
0.3087
17
2
0.0000
0.3087
18
3
0.0000
0.2215
19
3
0.0000
0.2215
20
3
0.0000
0.2215
21
4
0.0000
0.1532
22
4
0.0000
0.1532
23
4
0.0000
0.1532
24
5
0.0000
0.1047
25
6
0.0585
0.0000
Section 4.1. Number of Subjects
Rationale for Change: Update number of subjects to allow for additional subjects to be 
enrolled in Part 1 at the MTD and the addition of the GIST cohort in Part 2 (first 
paragraph) and clarification to include all tumor types in Part 2 (third paragraph).
Revised Text:
First Paragraph Third and Fourth sentence
To complete Part 1, it is estimated 60 90 to 90110 evaluable subjects will be enrolled. 
The besylate sub-study will enroll approximately 10 to 12 subjects in the United States 
only. Part 2 will enroll approximately 1750 subjects.
Third Paragraph 
If subjects discontinue the study before completing Week 8 during Part 2, additional 
subjects may be enrolled at the discretion of the Sponsor in consultation with the 
investigator to ensure adequate population for determination of response within NMC
and other expansion cohorts.
Section 4.2.1.
Inclusion Criteria


2011N118599_09
CONFIDENTIAL
BET115521
438
Rationale for Change: Include GIST as tumor type for Part 2. Update the adequate 
organ function table (Table 6) to clarify the footnotes. Update the contraception language 
based on GSK guidelines.
Revised Text:
Inclusion Criteria No. 3, Part 2 Only: Bullet Point “2”:
SCLC, CRPC, TNBC, and ER+BC and GIST
Inclusion Criteria No. 7, 
Table 6
Definitions for Adequate Organ Function


2011N118599_09
CONFIDENTIAL
BET115521
439
System
Laboratory Values
Hematologic
Absolute neutrophil count (ANC)
1.5 X 109/L
Hemoglobin
9.5 g/dL (patients that required transfusion or 
growth factor need to demonstrate stable 
haemoglobin for 7 days of 9.5 g/dL)
Platelets
100 X 109/L 
PT/INR and PTT 3
≤ 1.5 X ULN
Hepatic
Total bilirubin
≤1.5 x X ULN (isolated bilirubin >1.5 X ULN is 
acceptable if bilirubin is fractionated and direct 
bilirubin <35% or subject has a diagnosis of Gilbert’s 
syndrome)
ALT and AST
2.5 ULN 
Renal
Creatinine
OR
Calculated creatinine clearance [calculated by 
Cockcroft Gault formula1, 2]
OR
24-hour urine creatinine clearance 2
≤1.5 X ULN
≥ 50 mL/min
≥ 50 mL/min
Cardiac
Ejection fraction
≥ Lower limit of normal (LLN) by Echocardiogram
(ECHO) (minimum of 50%)
Troponin (T)
Potassium
Magnesium
ULN 
≥LLN and ≤ULN
≥LLN
Thyroid
Thyroid stimulating hormone (TSH)2
≥LLN and ≤ULN
Reproductive/Endocrine
Testosterone 
<50ng/dL (only for subjects with CRPC)
1. See Appendix 2 for Cockcroft Gault formula
2. If bleeding risk discharged in Part 1, coagulation criteria may be adjusted for Part 2
23. If TSH is abnormal, but free T3 and/or free T4 are normal, then the subject may still be considered eligible for 
enrolment.
Inclusion Criteria No. 9, Bullet Point “2”:
Child-bearing potential and agrees to use one of the contraception methods (described in 
Section 9.1) for an appropriate period of time (as determined by the product label or 
investigator)from the time of the screening pregnancy test prior to the start of dosing to 
sufficiently minimize the risk of pregnancy at that point. Female subjects must agree to 
use contraception until 7 months after the last dose of study medication.
Inclusion Criteria No. 9, Bullet Point “3”:
Negative serum pregnancy test ≤ 7 days prior to first study drug dose, for women of 
childbearing potential.


2011N118599_09
CONFIDENTIAL
BET115521
440
Inclusion Criteria No. 10 modified and splitted to add criteria No.11
10. Male subjects with a female partner of childbearing potential must agree to use one of 
the methods of contraception specified in Section 9.2. This method must be used from the 
time of the first dose of study medication until 16 weeks after the last dose of study 
medication. In addition, m
11. Male subjects whose partners are or become pregnant while on study medication must 
continue to use condoms for 7 days16 weeks following the last dose ofafter stopping
study medications.
Section  4.2.1.
Inclusion Criteria
Rationale for Change: Include GIST-specific criteria for eligibility. 
Revised Text:
New sub section added
4.2.1.2.
Specific Eligibility Criteria for Part 2 GIST Cohort
16.
Histopathologically confirmed diagnosis of advanced (metastatic and/or 
unresectable) GIST.
17.
Subjects must have had failure of at least imatinib as therapy for advanced disease 
due to progression.  There is no limit on the number of prior TKI therapies.
4.2.2. Exclusion Criteria
Rationale for Change: Simplificaiton of criterion 2. Futher clarification in criteria 4 and 
8. Addition of criterion 5 and expand criterion 12 to further minimize the risk of 
bleeding.
Revised Text:
Exclusion Criteria No. 2
2.
Prior treatments usage as defined:
a.
Use of an investigational anti-cancer drug within 14 days or 5 half-lives, 
whichever is longer, prior to the first dose of the investigational products study 
medication. Note that an investigational drug is defined as a drug without an approved 
oncologic indication.
b.
A minimum of 14 days between termination of the investigational drug and 
administration of GSK525762.
c.b.
Any therapy related toxicities must also have resolved to Grade 1 or less. 
Note that an investigational drug is defined as a drug without an approved oncologic 
indication. 


2011N118599_09
CONFIDENTIAL
BET115521
441
d.c.
Chemotherapy, radiotherapy, anti-neoplastic antibody or targeted therapy or 
immunotherapy within 14 days, major surgery within 28 days (or 42 days for prior 
nitrosoureas or mitomycin C) prior to the first dose of the investigational productstudy 
medication.
Exclusion Criteria No. 4
Current use of a prohibited medication or requires any of these medications during 
treatment with the investigational drugs (details will be available in Section 8.38.2). This 
includes excluding current medications known or suspected to be associated QT 
prolongation and strong inducers or inhibitors of CYP3A4. In addition, any subject who 
may require a QT prolonging medication while on trial should not be enrolled.
Exclusion Criteria No. 5
Concurrent use of non-steroidal anti-inflammatory drugs (NSAIDs) except for cases 
where NSAIDs provide benefit over other analgesics or high dose aspirin (allowed up to 
100 mg PO daily). Details are available in Section 8.2.
Exclusion Criteria No. 8 Bullet point 2
Clinically significant conduction abnormalities or arrhythmias or, subjects with Bundle 
Branch Block.
Exclusion Criteria No.12
History of major gastrointestinal bleeding within the last 6 months.  Any evidence of 
active gastrointestinal bleeding excludes the subject. Subjects with a history of known 
bleeding disorder(s) or history of clinically significant hemorrhage (e.g., GI, neurologic) 
within the past 6 months.
Section 4.2. Eligibility Criteria
Rationale for Change: Addition of definition of a screen failure.
Revised Text:
New sub section added:
Section 4.2.3.
Screen Failures
Screen failures are defined as subjects who consent to participate in the clinical trial but 
are never subsequently dosed with study treatment.
Section 4.2.4.1.
Permanent Discontinuation from Study Treatment
Rationale for Change: Clarify that assessments occur at the End of Treatment visit for 
subjects who discontinue to clarify that all subjects should be followed for survival and 
new anti-cancer therapy.


2011N118599_09
CONFIDENTIAL
BET115521
442
Revised Text:
Sixth Paragraph
All subjects who discontinue from study treatment will have safety assessments at the 
time of discontinuation and during post study treatment follow-up (End of Treatment) as 
specified in Time and Events Tables. 
Eight Paragraph first sentence
All subjects who permanently discontinue study treatment for any reason will be 
followed for survival and new anti-cancer therapy [including radiotherapy] every 6 
months until death or until the subject has been followed for 2 years.


2011N118599_09
CONFIDENTIAL
BET115521
443
5.
TIME AND EVENTS TABLES
Rationale for Change: Table 7: Clarification to dispensing of study medication, reduction of ECGs and removal Holter monitoring. 
Scans should be completed within 28 days of first dose to align with other sections of the protocol. Addition of labs at W11D1 to increase 
frequency of monitoring. Urine PK samples are now optional. Saliva samples should not be collected for subjects in BID cohorts. Post-
dose biopsy moved out to W3-W4 and language added so that subjects who require a dose interruption due to laboratory requirements 
may still undergo a biopsy at a later point. Additional minor clarifications throughout. Table 8: Removal of triplicate troponin collection, 
additional safety labs added at W11D1, addition of Factor VII testing, removal of cytokine collection and other minor clarifications. Table 
9 and 10: Clarification when fasting requirements apply. Table 11 and 12: Many samples are now optional. Table 14: Additional lab 
monitoring at W7D1 and W11D1, clarification to dispensing of study medication, removal of Holter monitoring, update to timeframe for 
scans prior to first dose, additional pregnancy test for woman of childbearing potential at W1D1, change in timing of post-dose tumor 
biopsy and other minor clarifications throughout. Table 15: Additional safety labs at W7D1 and W11D1, additional Factor VII testing at 
W5D1 and reflex if aPTT is abnormal or with a bleeding event, removal of cytokine collection and other minor clarifications. 
Revised Text:
Table 7 Time and Events: Part 1
Part 1 
Assessments
Notes
S
C
R
Refer to Section 6.1.2 for visit windows.
Q4 and 
Q8W 
Initiated 
from 
Week 9
E
O
T
Week 1
Week 2
W3
W4
W5
W7
W9
W11
q4
W
q8
W
D
1
D
2
D
3
D
4
D
5
D
6
D
7
D
1
D
2
D
3
D
4
D
5
D
6
D
7
D
1
D
4
D
1
D
4
D
1
D
1
D
1
D1
D
1
D
1
Informed consent
Unless otherwise noted, 
screening assessments to be 
completed within 14 days of 
first dose.
X
Demography
X
Medical history
X
Disease 
characteristics
X


2011N118599_09
CONFIDENTIAL
BET115521
444
Part 1 
Assessments
Notes
S
C
R
Refer to Section 6.1.2 for visit windows.
Q4 and 
Q8W 
Initiated 
from 
Week 9
E
O
T
Week 1
Week 2
W3
W4
W5
W7
W9
W11
q4
W
q8
W
D
1
D
2
D
3
D
4
D
5
D
6
D
7
D
1
D
2
D
3
D
4
D
5
D
6
D
7
D
1
D
4
D
1
D
4
D
1
D
1
D
1
D1
D
1
D
1
Cardiology 
evaluation
X
Prior therapy
X
Register subject
X
TREATMENT PHASE
Study Drug
Dispense study 
druga
Refer to SPM for further 
details 
Administer about same time 
of day. No food or antacids 
1h before and 2h after.
X
X
X
X
X
X
X
Review subject 
diary compliance
Diary not required when 
dosed in clinic.
X
X
X
X
X
X
X
Safety
Pregnancy test b/  
testosterone
Females: serum pregnancy 
test within 7 days of first 
dose; urine or serum test 
thereafter. Males: complete 
and free testosterone at SCR; 
free testosterone thereafter.
X
X
X
X
X
X
Physical Exam
X
X
X
X
X
X
X
X
X
ECOG PS
X
X
X
X
X
X
X
X
X
X


2011N118599_09
CONFIDENTIAL
BET115521
445
Part 1 
Assessments
Notes
S
C
R
Refer to Section 6.1.2 for visit windows.
Q4 and 
Q8W 
Initiated 
from 
Week 9
E
O
T
Week 1
Week 2
W3
W4
W5
W7
W9
W11
q4
W
q8
W
D
1
D
2
D
3
D
4
D
5
D
6
D
7
D
1
D
2
D
3
D
4
D
5
D
6
D
7
D
1
D
4
D
1
D
4
D
1
D
1
D
1
D1
D
1
D
1
Vital Signs
SBP, DBP, heart rate, 
respiratory rate, temp
X
X
X
X
X
X
X
X
X
X
X
X
X
Pain
X
X
X
X
X
X
X
X
X
X
X
X
X
Weight and height
Height at SCR only
X
X
X
X
X
X
X
X
X
X
Chest x-ray
X
Pulmonary 
function test
X
Adverse events
SAEs collected continuously from signing of informed consent; AEs collected continuously from time of first dose
Concomitant 
medications
Continuous from signing of informed consent
Laboratory assessments: For details please see following tables
Tests
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Cardiac Monitoring
Echocardiogram
Within 35 days of first dose
X
X
X
X
X
X
12-lead ECGs 
(Triplicate)
For timing of triplicate ECGs 
on Oc days, see Table 10 and 
Table 11 Tables 9 through 
13. Otherwise, triplicate 
ECGs at approximately same 
time of day, and prior to dose 
on dosing days. If QTcF 
increase >30msec, ECGs 
should be repeated Q2-3 
days until QTcF is within 
X
O
O
O
O
X
X
X
O
X
X
X
O
X
X
X
X
O
X
X


2011N118599_09
CONFIDENTIAL
BET115521
446
Part 1 
Assessments
Notes
S
C
R
Refer to Section 6.1.2 for visit windows.
Q4 and 
Q8W 
Initiated 
from 
Week 9
E
O
T
Week 1
Week 2
W3
W4
W5
W7
W9
W11
q4
W
q8
W
D
1
D
2
D
3
D
4
D
5
D
6
D
7
D
1
D
2
D
3
D
4
D
5
D
6
D
7
D
1
D
4
D
1
D
4
D
1
D
1
D
1
D1
D
1
D
1
30msec from baseline.
Holter monitoring
At least 24 h, on dosing days 
start at least 60 min predose.
X
X
X
Efficacy
CT/MRI Scansd a
SCR assessment within 2835
days of first dose. Target 
lesions to be identified at 
SCR and followed.
X
X
X
X
X
Tumor sample
Optional during rapid dose
escalation; required during 
3+3 dose escalation. EOT 
sample should be collected at 
time of progression where 
feasible. Subjects must have 
a platelet count of
≥75,000/mm3 and a PT, INR 
and aPTT that are WNL 
within 48 hours prior to the 
post-dose biopsye.
X
One post-
dose 
sample 
collected 
anytime 
between 
W3D1-
W4D1 (4-
6h post-
dose). 
X
PET scand
Optional during rapid dose 
escalation; required during 
3+3 dose escalation.
SCR assessment within 2835
days of first dose.
X
X
X
Castrate-Resistant Prostate Cancer Assessments
PSA
PSA to be collected in line 
with PCWG2 guidelines. 
X
X
X


2011N118599_09
CONFIDENTIAL
BET115521
447
Part 1 
Assessments
Notes
S
C
R
Refer to Section 6.1.2 for visit windows.
Q4 and 
Q8W 
Initiated 
from 
Week 9
E
O
T
Week 1
Week 2
W3
W4
W5
W7
W9
W11
q4
W
q8
W
D
1
D
2
D
3
D
4
D
5
D
6
D
7
D
1
D
2
D
3
D
4
D
5
D
6
D
7
D
1
D
4
D
1
D
4
D
1
D
1
D
1
D1
D
1
D
1
Levels may be checked more 
frequently if appropriate.
Neuroblastoma Assessments
CT/MRI
One or more tests should be 
used as appropriate for 
disease. The same modalities 
utilized at screening should 
be used throughout study. 
Screening Assessment within 
28 35 days of first dose can 
be used as screening 
assessment.
X
X
X
MIBG scanf b
X
X
X
FDG-PET
X
X
X
99Tc scintigraphy 
for bone scan
X
X
X
Bilateral bone 
marrow aspirates 
and biopsy
X
X
X
Urine HVA, VMA, 
dopamine
X
X
X
X
X
Pharmacokinetics (PK) and Pharmacodynamics (PD): For details please see following tables
PK and biomarker 
samplesc
Fasting requirements apply 
for PK samples on W1D1 and 
W3D4.
X
X
X
X
X
X
X
Samples for 
mRNAc
X
X
X
X
LPS blood sample
Not required with BID dosing 
schedule.
X
PK Urine samples 
These are optional as of 
Amendment 9.
X
X
Optional Saliva 
and Sample
A saliva sample may be 
requested on serial PK 
X
X


2011N118599_09
CONFIDENTIAL
BET115521
448
Part 1 
Assessments
Notes
S
C
R
Refer to Section 6.1.2 for visit windows.
Q4 and 
Q8W 
Initiated 
from 
Week 9
E
O
T
Week 1
Week 2
W3
W4
W5
W7
W9
W11
q4
W
q8
W
D
1
D
2
D
3
D
4
D
5
D
6
D
7
D
1
D
2
D
3
D
4
D
5
D
6
D
7
D
1
D
4
D
1
D
4
D
1
D
1
D
1
D1
D
1
D
1
sampling days. Additional 
collection details will be 
provided in the SPM . Not 
collected with BID dosing 
schedule.
Blood samples for 
circulating 
exploratory 
biomarkers 
(cfDNA, etc)
EOT circulating biomarker 
blood samples to be collected 
with lab assessments.
X
X
X
Pharmacogenomics (PGx)
PGx sample
Blood sample should be 
collected after screening 
(preferably on D1) if informed 
consent has been obtained 
for Genetic research.
X
FOLLOW-UP PHASE
Follow-up contact by clinic visit or other means (telephone contact, email, etc) for survival status and anticancer therapy every 6 months. Disease assessment will be collected for 
subjects who discontinue study medication due to any reason other than progression or death. Individual subjects will be considered to have completed the study 2 years after their last 
treatment or upon death, whichever is sooner. Document the cause of death. For the study, the Follow-up Phase ends after a minimum of 70% of subjects have died or 5 years after 
the last subject is enrolled in Phase 2.


2011N118599_09
CONFIDENTIAL
BET115521
449
Part 1 
Assessments
Notes
S
C
R
Refer to Section 6.1.2 for visit windows.
Q4 and 
Q8W 
Initiated 
from 
Week 9
E
O
T
Week 1
Week 2
W3
W4
W5
W7
W9
W11
q4
W
q8
W
D
1
D
2
D
3
D
4
D
5
D
6
D
7
D
1
D
2
D
3
D
4
D
5
D
6
D
7
D
1
D
4
D
1
D
4
D
1
D
1
D
1
D1
D
1
D
1
Abbreviations: CK=creatine kinase; CRP=c-reactive protein; D=day; DBP=diastolic blood pressure; ECG=electrocardiogram; ECOG PS=Eastern Cooperative Oncology Group 
Performance Status; EOT=End-of-Treatment; FLC=free light chain; HVA=homovanillic acid; LPS=lipopolysaccharide; MIBG=meta-iodo-benzyl-guanidine; q4W=every 4 weeks; 
q8W=every 8weeks; SBP=systolic blood pressure; SCR=Screening; SPEP=serum protein electrophoresis; UPEP=urine protein electrophoresis; VMA= vanillylmandelic acid; W=week; 
PT=Prothrombin Time; INR=International Normalized Ratio; aPTT=Activated partial thromboplastin time; WNL=Within normal limits
a.
Suggested timing of study medication dispensing; may be altered at the discretion of the Investigator or designee, based on availability and visit schedule.  
b.
Not required for women of non-childbearing potential, as defined in Section 4.2, Inclusion Criterion 9.
c.
Some of these samples will be optional as of Amendment 9; please see Tables 12-14 for further details.
d.
Per RECIST 1.1 baseline (within 28 35 days of first dose) bone scans and brain scans are to be conducted for all subjects. Thereafter, scans should be conducted as 
clinically indicated. Subjects undergoing baseline full body PET/CT and/or brain MRI will not require these additional scans, unless clinically appropriate. Disease assessments should 
be performed no less than 4 weeks (28 days) after first dose and from previous on-treatment scan.
e.
If the post-dose biopsy is not performed during this timeframe due to lab abnormalities or subject status, it should be performed at the next agreed upon visit with the GSK 
Medical Monitor after subject recovery.
f.
Subjects with neuroblastoma will have MIBG and bone marrow biopsies after week 24 as clinical indicated to confirm complete remission.
Table 8 Time and Events: Part 1 Laboratory Assessments
NB: On dosing days, collect 
blood samples prior to dosing. 
W1D1 samples not needed if 
SCR sample collected within 
72h of first dose.
Notes
SCR
Refer to Section 6.1.2 for visit windows.
Q4 and Q8W 
Initiated from 
Week 9
EOTa
W1
W2
W3
W4
W5
W7
W9
W11
q4W
q8W
D1
D2
D6
D1
D6
D1
D1
D1
D1
D1
D1
D1
D1
Troponin, NT-proBNP 9
For Troponin. : W1D1 & W1D2: 
local lab sample collect 3X/24h; 
central lab sample collect 
1X/24h. All other timepoints, 
including unscheduled, collect 2 
samples: 1 for local, 1 for central 
lab
X
X
X
X
X
X
X
X
X
X
X
X


2011N118599_09
CONFIDENTIAL
BET115521
450
NB: On dosing days, collect 
blood samples prior to dosing. 
W1D1 samples not needed if 
SCR sample collected within 
72h of first dose.
Notes
SCR
Refer to Section 6.1.2 for visit windows.
Q4 and Q8W 
Initiated from 
Week 9
EOTa
W1
W2
W3
W4
W5
W7
W9
W11
q4W
q8W
D1
D2
D6
D1
D6
D1
D1
D1
D1
D1
D1
D1
D1
Hematology
X
X
X
X
X
X
X
X
X
X
X
X
X
Clinical chemistry
X
X
X
X
X
X
X
X
X
Pancreatic
X
X
X
X
X
X
X
X
X
Coagulation
X
X
X
X
X
X
X
X
X
X
Factor VII Assay
Also perform if PT, INR or aPTT 
are ≥1.5XULN, or in case of 
bleeding event
X
X
X
Creatine phosphokinase
X
X
X
X
X
X
X
X
X
Liver chemistry
X
X
X
X
X
X
X
X
X
X
Fasting blood glucose and 
insulin 
Will be performed at central lab if
not available at local lab
X
X
X
X
X
X
X
X
X
c-peptide and 1,5 AG
Will be performed at central lab if 
not available at local lab
X
X
X
X
X
HbA1c
X
X
X
X
X
X
X
Fasting lipids
X
X
X
X
X
X
Thyroid monitoring
TSH, free T3, free T4 at SCR 
and W1. If TSH is abnormal at
W1D1, continue monitoring TSH, 
free T3 and free T4 going 
forward at time points indicated 
in this Table and at any time 
when clinically appropriate.
X
X
X
X
X
X
Urinalysis
X
X
X
X
X
X
Pregnancy testb, females
Serum pregnancy test within 7 
days of first dose; urine or serum 
test thereafter
X
X
X
X
X
X
Testosterone, males
Complete and free testosterone 
X
X
X
X
X
X


2011N118599_09
CONFIDENTIAL
BET115521
451
NB: On dosing days, collect 
blood samples prior to dosing. 
W1D1 samples not needed if 
SCR sample collected within 
72h of first dose.
Notes
SCR
Refer to Section 6.1.2 for visit windows.
Q4 and Q8W 
Initiated from 
Week 9
EOTa
W1
W2
W3
W4
W5
W7
W9
W11
q4W
q8W
D1
D2
D6
D1
D6
D1
D1
D1
D1
D1
D1
D1
D1
at SCR; free testosterone 
thereafter
CK, CK-MB
Predose and 12-18 h post dose
X
as clinically appropriate
Safety Cytokines
This is collected as part of the 
Predose PK sample and is sent 
to GSK DMPK.
X
as clinically appropriate following fever
HBsAg, HepC antibody
If hepatits C antibody positive, 
perform third generation 
immunoassay on  same sample 
to confirm results
X
C=cycle; D=day; EOT=End of Treatment Visit; q4W=Every 4 weeks; q8W=every 8 weeks; SCR=Screening; W=week
a.
EOT circulating biomarker blood samples to be collected with lab assessments.
b.
Not required for women of non-childbearing potential, as defined in Section 4.2, Inclusion Criterion 9.
Table 9
QD Dosing Time and Events: Part 1 Pharmacokinetics and Biomarker Sampling, Week 1 and Week 2
W1D1 (fasting requirements apply)
W1D5
W2D4 + 1 day
pre 
dose
15 min 
± 5m 
30 
min 
±5m
1h 
±5m
2h 
±10m
4h 
±15m
8h 
±1h
12h 
±2h a
24h 
±2h
48h ±2h
b, d
30 
min 
±5m
3h 
±15m
pre 
dose
30 min 
±5m
3h 
±15m
8h 
±1h
Table 10
QD Dosing Time and Events: Part 1 Pharmacokinetics and Biomarker Sampling, Week 3 and Week 9
W3D4 + 2 days (if dose has been altered (including held and resumed) serial PK sampling should occur 4 
to 7 days after dosing resumed) (fasting requirements apply)
W9D1 ±4 days
(if dose has been reduced or 
escalated, +4 to +7 days)
EOT
pre
dose
15 min 
± 5m 
30 min 
±5m
1h 
±5m
2h 
±10m
4h 
±15m
8h 
±1h
12h 
±2h a
24h ±2h
b
48h ±2h
b, d
pre dose
0.5-2h
4 - 8h


2011N118599_09
CONFIDENTIAL
BET115521
452
Table 11
BID Dosing Time and Events: Part 1 Pharmacokinetics and Biomarker Sampling, Week 1
W1D1
W1D2  and 
W1D3
(relative to 
W1D1 
Morning 
Dose)
W1D5
ECG and 
PK 
samples 
after 
Morning 
Dose only
Morning Dose (fasting requirements apply)
Evening Dose (relative to W1D1 Morning Dose)
pre 
dos
e
0
H
15 
min 
±5
m
30 
min 
±5
m
1h 
±5
m
2h 
±10
m
4h 
±15
m
8h 
±1
h
pre 
dose  
(12h-
15m)
d
12
h d
15 
min(12.25
h) ± 5m d
30 
min 
(12.5h
) ±5m
d
1h 
(13h
) 
±5m
d
2h 
(14h) 
±10
m d 
4h 
(16h) 
±15
m d
8h 
(20h
) 
±1h
d
12 h 
(24h
) 
±1h
d
36 h 
(48h) 
(pre-
dose
) 
±1h
d
30 
min 
±5
m
3h 
±15
m
DoseAdminister/do
se Study 
Medication
X
X
X
12-lead ECG, in 
triplicatea
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
PK and protein 
biomarker sample b
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Urine PK sampling
c
X
0-2h
2-12h
mRNA whole blood 
sample
X
X
X
Xd
X
X
X
X
X
X
Plasma samples will be divided at the GSK DMPK facility where bioanalysis of PK is performed and shipped to a vendor for systemic cytokine assessment and acute phase protein
assessment for morning and evening dosing at pre-dose and at 2, 4, 8, 12 and 24 hr post-dose.  The frequency of sampling may be changed based on data from the first few subjects 
assessed. 
a.
Triplicate ECGs should be collected 5 minutes apart and within 10 minutes prior to the 15 min and 30 min PK draws and within 15 minutes prior to the other PK draws.


2011N118599_09
CONFIDENTIAL
BET115521
453
b.
PK blood samples collected overnight may be kept refrigerated at 4ºC in the event the PK lab is closed overnight (stable up to 12H)
c.
Urine samples for quantitative analysis of GSK525762 are not required in the NMC PD Expansion Cohortoptional as of Amendment 9.
d.
W1D1 48h assessments (ECG, PK and mRNA)These assessments (ECG, PK and mRNA) are optional as of Amendment 9.
Table 12
BID Dosing Time and Events: Part 1 Pharmacokinetics and Biomarker Sampling, Week 2 and Week 3
W2D4 + 1 day ECG and PK 
samples after Morning Dose 
only
W3D4 +2 days
W3D5 and 
W3D6 
(relative to 
W3D4 
Morning 
Dose)
Morning Dose (fasting requirements apply)
Evening Dose (relative to W3D4 Morning Dose)
(For W3D4 subjects that are not staying overnight after the evening 
dose, the 15min – 8h PK/ECG timepoints are optional)
pre 
dose 
(Prior 
to 
Dosing)
30m 
± 
5m 
3h 
± 
15m
8 h 
±1
h
pre 
dos
e 
0h
15m 
±5
m
30m
±5
m
1h 
±5
m
2h 
±10m
4h 
±15m
8h 
±1h
pre 
dos
e
12h
15m 
±5m 
(12.25m)
d
30m 
±5
m d
1h 
(13h
)
±5m
d
2h 
(14h)
±10m
d
4h 
(16h)
±15m
d
8h 
(20h)
±1h d
12h 
(24h) 
±1h
(pre 
dose
) d
36h 
(48h) 
±1h
(pre 
dose)
d
Dose
Administer 
Study 
Medication
X
X
X
X
X
12-lead 
ECG, in 
triplicate a
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
PK and 
protein 
biomarker 
sample b
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Urine PK
sampling c
0-2h
2-12h
mRNA 
whole 
blood 
X
X
X
X


2011N118599_09
CONFIDENTIAL
BET115521
454
W2D4 + 1 day ECG and PK 
samples after Morning Dose 
only
W3D4 +2 days
W3D5 and 
W3D6 
(relative to 
W3D4 
Morning 
Dose)
Morning Dose (fasting requirements apply)
Evening Dose (relative to W3D4 Morning Dose)
(For W3D4 subjects that are not staying overnight after the evening 
dose, the 15min – 8h PK/ECG timepoints are optional)
pre 
dose 
(Prior 
to 
Dosing)
30m 
± 
5m 
3h 
± 
15m
8 h 
±1
h
pre 
dos
e 
0h
15m 
±5
m
30m
±5
m
1h 
±5
m
2h 
±10m
4h 
±15m
8h 
±1h
pre 
dos
e
12h
15m 
±5m 
(12.25m)
d
30m 
±5
m d
1h 
(13h
)
±5m
d
2h 
(14h)
±10m
d
4h 
(16h)
±15m
d
8h 
(20h)
±1h d
12h 
(24h) 
±1h
(pre 
dose
) d
36h 
(48h) 
±1h
(pre 
dose)
d
sample
Plasma samples will be divided at the GSK DMPK facility where bioanalysis of PK is performed and shipped to a vendor for systemic cytokine assessment and acute phase protein 
assessment at pre-dose and at 2, 4, 8, 12 and 24 hr post-dose.  The frequency of sampling may be changed based on data from the first few subjects assessed.
a.
Triplicate ECGs should be collected 5 minutes apart and within 10 minutes prior to the 15 min and 30 min PK draws and within 15 minutes prior to the other PK draws.
b.
PK blood samples collected overnight may be kept refrigerated at 4ºC in the event the PK lab is closed overnight (stable up to 12H)
c.
Urine samples for quantitative analysis of GSK525762 are optional as of Amendment 9not required in the NMC PD Expansion Cohort.
d.
W3D4 48hThese assessments (ECG, PK and mRNA) are optional as of Amendment 9.


2011N118599_09
CONFIDENTIAL
BET115521
455
Table 14
Time and Events: Part 2
Part 2 
Assessments
Notes
SCR
Refer to Section 6.1.2 for visit windows.
Q4, Q8 and Q12 Initiated 
from Week 13
EOT
W1
W2
W3
W4
W5
W7
W9
W11
W13
q4W
q8W
q12W
D1
D1
D1
D1
D1
D1
D1
D1
D1
D1
D1
D1
Informed consent
Unless otherwise noted, 
screening assessments to be 
completed within 14 days of first 
dose.
X
Demography
X
Medical history
X
Disease 
characteristics
X
Cardiology 
evaluation
X
Prior therapy
X
Register subject
X
TREATMENT PHASE
Study Drug
Dispense study 
druga
Refer to SPM for further details.
Administer about same time of 
day.
X
X
X
X
X
X
X
X
Review compliance
Not required when dosed in 
clinic. 
X
X
X
X
X
X
X
X
X
X
Safety
Pregnancy 
testb/testosterone
Females: serum pregnancy test 
within 7 days of first dose; urine 
or serum test thereafter. Males: 
complete and free testosterone 
at SCR; free testosterone 
thereafter.
X
X
X
X
X
X
X
Physical exam
X
X
X
X
X
X
X
X
X
X
ECOG 
X
X
X
X
X
X
X
X
X
X
Vital Signs and Pain 
Assessments
X
X
X
X
X
X
X
X
X
X
Weight and height
Height at SCR only
X
X
X
X
X
X
X
Chest x-ray
X


2011N118599_09
CONFIDENTIAL
BET115521
456
Part 2 
Assessments
Notes
SCR
Refer to Section 6.1.2 for visit windows.
Q4, Q8 and Q12 Initiated 
from Week 13
EOT
W1
W2
W3
W4
W5
W7
W9
W11
W13
q4W
q8W
q12W
D1
D1
D1
D1
D1
D1
D1
D1
D1
D1
D1
D1
Pulmonary function 
test
X
Adverse events
SAEs collected continuously from signing of informed consent; AEs collected continuously from time of first dose
Concomitant 
medications
continuous from signing of informed consent
Laboratory assessments: For details please see Table 15
Tests
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Castrate-Resistant Prostate Cancer Assessments
PSA
X
X
X
X
X
X
X
X
X
X
Serum 
Complete 
testosterone
X
X
X
X
X
X
X
X
X
X
Cardiac Monitoring
ECHO
If Baseline ECHO within 35 
days of first dose, the Week 1 
Day 1 ECHO is only required if 
clinically appropriate.
X
X
optional
X
X
X
X
X
12-lead ECGs 
(Single)
ECGs prior to dosing. If QTcF 
increase >30msec, ECGs 
should be repeated Q2-3 days 
until QTcF is within 30 msec 
from baseline.
X
X
X
X
X
X
X
X
X
X
Holter monitoring
At least 24 h; on dosing days 
start predose
X
X
X
Efficacy
Lesion  
assessments
X
X
X
X
CT scan or MRI c a,b
Scans within 2835 days of first 
dose may be used as screening 
assessment. Additional bone 
scans and brain scans not 
X
X
X
X


2011N118599_09
CONFIDENTIAL
BET115521
457
Part 2 
Assessments
Notes
SCR
Refer to Section 6.1.2 for visit windows.
Q4, Q8 and Q12 Initiated 
from Week 13
EOT
W1
W2
W3
W4
W5
W7
W9
W11
W13
q4W
q8W
q12W
D1
D1
D1
D1
D1
D1
D1
D1
D1
D1
D1
D1
required unless clinically 
indicated.
PET scan (FDG or 
fluoride) cb, c
Scans within 2835 days of first 
dose may be used as screening 
assessment. Follow up scans 
conducted as clinically 
appropriate.
X
PK
PK 
Three samples to be collected 
each sampling day: During first 
4 weeks collect a predose within 
60 minutes prior to dose, a 
single draw between 0.5-2h 
postdose, and a single draw 
between 4-8h postdose (fasting 
requirements apply).Thereafter 
only a Predose and 0.5 hour 
post-dose sample are collected. 
NOTE: If dose level is adjusted, 
additional PK sampling may be 
requested.
X
X
X
X
Blood samples for 
circulating 
exploratory 
biomarkers (cfDNA, 
etc)
Baseline sample collected pre-
dose on W1D1 EOT circulating 
biomarker blood samples to be 
collected with lab assessments.
X
X
X
Translational Research
PGx sample
Blood sample should be 
collected after screening 
(preferably on W1D1) if 
informed consent has been 
X


2011N118599_09
CONFIDENTIAL
BET115521
458
Part 2 
Assessments
Notes
SCR
Refer to Section 6.1.2 for visit windows.
Q4, Q8 and Q12 Initiated 
from Week 13
EOT
W1
W2
W3
W4
W5
W7
W9
W11
W13
q4W
q8W
q12W
D1
D1
D1
D1
D1
D1
D1
D1
D1
D1
D1
D1
obtained for Genetic research.
Tumor Sample
PK samples should be collected 
within 1 hour of on-treatment 
biopsy. EOT biopsy should be 
collected at time of disease 
progression where feasible. 
Subjects must have a platelet 
count of ≥75,000/mm3 and a 
PT, INR and aPTT that are 
WNL within 48 hours prior to the 
post-dose biopsye.
X
One post-
dose 
sample 
collected 
anytime 
between 
W3D1-
W4D1 (4-6h 
post-dose)f
X
FOLLOW-UP PHASE
Follow-up contact by clinic visit or other means (telephone contact, email, etc) for survival status and anticancer therapy every 6 months. Disease assessment will be collected 
for subjects who discontinue study medication due to any reason other than progression or death. Individual subjects will be considered to have completed the study 2 years 
after their last treatment or upon death, whichever is sooner. Document the cause of death. For the study, the Follow-up Phase ends after a minimum of 70% of subjects have 
died or 5 years after the last subject is enrolled in Phase 2.
Abbreviations: CK=creatine kinase; D=day; ECG=electrocardiogram; ECOG PS=Eastern Cooperative Oncology Group Performance Status; EOT=End-of-Treatment; q4W=every 
4 weeks; q8W=every 8weeks; SCR=Screening; Wk=week; PT=Prothrombin Time; INR=International Normalized Ratio; aPTT=Activated partial thromboplastin time; WNL=Within 
normal limits
a.
Suggested timing of study medication dispensing; may be altered at the discretion of the Investigator or designee, based on availability and visit schedule.
b.
Not required for women of non-childbearing potential, as defined in Section 4.2, Inclusion Criterion 9.
a .c. Per RECIST 1.1 baseline (within 2835 days of first dose) bone scans and brain scans are to be conducted for all subjects. Thereafter, scans should be conducted as
clinically indicated. Subjects undergoing baseline full body PET/CT and/or brain MRI will not require these additional scans, unless clinically appropriate. Disease 
assessments should be performed no less than 4 weeks (28 days) after first dose and from previous on-treatment scan.
b.
PET scan (FDG or fluoride) required at baseline and follow up scans should be collected when clinically appropriate.
d.
Disease assessments should be performed no less than 4 weeks (28 days) after first dose and from previous on-treatment scan. 
e.
If the post-dose biopsy is not performed during this timeframe due to lab abnormalities or subject status, it should be performed at the next agreed upon visit with the GSK 
Medical Monitor after subject recovery.
c.f. Timing may be further optimized based on tumor type and emerging data.


2011N118599_09
CONFIDENTIAL
BET115521
459
Part 2 
Assessments
Notes
SCR
Refer to Section 6.1.2 for visit windows.
Q4, Q8 and Q12 Initiated 
from Week 13
EOT
W1
W2
W3
W4
W5
W7
W9
W11
W13
q4W
q8W
q12W
D1
D1
D1
D1
D1
D1
D1
D1
D1
D1
D1
D1
Table 15
Time and Events: Part 2 Laboratory Assessments
NB: On dosing days, 
collect blood samples 
prior to dosing. 
W1D1 samples not 
needed if SCR 
sample is within 72h 
of first dose
Notes
SCR
Q4, Q8 and Q12W 
Initiated from Week 13
EOT
b
W1
W2
W3
W4
W5
W7
W9
W11
W13
q4W
q8W
q12W
D1
D4 a
D1
D4 a
D1
D1
D1
D1
D1
D1
D1
D1
D1
D1
Troponin, NT-
proBNP-9
1 sample for 
local lab 
(troponin I or T), 
1 sample for 
central lab 
(troponin T) 
X
X
X
X
X
X
X
X
X
Hematology
X
X
X
X
X
X
X
X
X
X
X
X
Clinical chemistry
X
X
X
X
X
X
X
X
X
X
Pancreatic
X
X
X
X
X
X
X
X
X
X
Coagulation
X
X
X
X
X
X
X
X
X
X
X
X
Factor VII Assay
Also perform if 
PT, or INR or 
aPTT are 
≥1.5XULN, or in 
case of bleeding 
event
X
X
X
Liver chemistry
X
X
X
X
X
X
X
X
X
X
X
X
X
X


2011N118599_09
CONFIDENTIAL
BET115521
460
NB: On dosing days, 
collect blood samples 
prior to dosing. 
W1D1 samples not 
needed if SCR 
sample is within 72h 
of first dose
Notes
SCR
Q4, Q8 and Q12W 
Initiated from Week 13
EOT
b
W1
W2
W3
W4
W5
W7
W9
W11
W13
q4W
q8W
q12W
D1
D4 a
D1
D4 a
D1
D1
D1
D1
D1
D1
D1
D1
D1
D1
Creatine 
phosphokinase
X
X
X
X
X
X
X
X
Fasting blood 
glucose and insulin
Will be 
performed at 
central lab if not 
available at local 
lab
X
X
X
X
X
X
X
X
X
X
c-peptide and 1,5 AG
Will be 
performed at 
central lab if not 
available at local 
lab
X
X
X
X
X
HbA1c
X
X
X
X
Fasting lipids
X
X
X
X
X
X
X
X
Urinalysis
X
X
X
X
X
X
X
Thyroid monitoring
TSH, free T3, 
free T4 at SCR 
and W1. If TSH 
is abnormal 
W1D1, continue
monitoring TSH, 
free T3 and free 
T4 going forward
at time points 
indicated in this 
Table and at any 
time when 
clinically 
appropriate. 
X
X
X
X
X
X
X


2011N118599_09
CONFIDENTIAL
BET115521
461
NB: On dosing days, 
collect blood samples 
prior to dosing. 
W1D1 samples not 
needed if SCR 
sample is within 72h 
of first dose
Notes
SCR
Q4, Q8 and Q12W 
Initiated from Week 13
EOT
b
W1
W2
W3
W4
W5
W7
W9
W11
W13
q4W
q8W
q12W
D1
D4 a
D1
D4 a
D1
D1
D1
D1
D1
D1
D1
D1
D1
D1
Cytokines
X
as clinically appropriate
HBsAg, HepC 
antibody
If hepatits C 
antibody 
positive, perform 
third generation 
immunoassay on  
same sample to 
confirm results
X
Abbreviations: D=day; EOT=End of Treatment Visit; q4W=Every 4 weeks; q8W=every 8 weeks; q12W=every 12 weeks; SCR=Screening Visit; W=week; ULN=Upper 
limit of normal
a. Optional Visits, should be conducted when additional monitoring of laboratory values is clinically appropriate.
b.  EOT circulating biomarker blood samples to be collected with lab assessments.


2 0 1 1 N 1 1 8 5 9 9 _ 0 9
C O N FI D E N TI A L
B E T 1 1 5 5 2 1
4 6 2
S e cti o n 6. 1. 2.
Vi sit Wi n d o w s
R ati o n ale f or C h a n ge: A d diti o nal g ui da nce f or wi n d o w f or N M C dia g n ostic testi n g a n d 
Part 2 visits. Clarificati o n t o wi n d o ws f or visits fr o m Wee k 4 o n.
Re vise d Te xt:
Ne w te xt a d de d
Scree ni n g ( b aseli ne t o pre- d ose ):
First p ar a gr a p h, L ast se nte nce
I n Part 2, testi n g by t he ce ntral la b orat or y  f or N M C dia g n osis m ust be c o m plete d wit hi n 3 
m o nt hs pri or t o si g ni n g t he mai n c o nse nt ( n o ot her treat me nts ma y  ha ve bee n recei ve d 
after t he ce ntral dia g n osis t hr o u g h st u d y  e nr oll me nt).
Fift h, Sixt h , Seve nt h a n d Ei g ht h p ar a gr a p h s
Part 2 o nl y  –
Wee k 1 t hr o u g h Wee k 3: assess me nts ca n be +/- 2 da y s, wit h t he e xce pti o n 
of W 1 D 1 assess me nts, w hic h m ust occ ur o n W 1 D 1.
P art 1 a n d P art 2 – Visits bet wee n Wee k 4 t o Wee k 9 (i ncl usi ve): Cli nic V isits ca n be 
sc he d ule d 3 da y s
P art 1 a n d P art 2 - M o nt hl y V isits after Wee k 9 u ntil Wee k 5 2: After t he first disease 
assess me nt has bee n c o m plete d t he n t he m o nt hl y  cli nic visits ca n be sc he d ule d 5 da y s.
P art 1 a n d P art 2 - M o nt hl y V isits after Wee k 5 2: cli nic V isits ca n be sc he d ule d 7 
da y s.
S e cti o n 6. 2.
B a s eli n e A s s e s s m e nt f or N M C S u bj e ct s
R ati o n ale f or C h a n ge: A d diti o nal g ui da nce f or N M C dia g n ostic testi n g i n case of 
p ote ntial f or false ne gati ve b y  ce ntral la b orat or y testi n g a n d a d diti o n of FI S H testi n g
w hic h ma y  ta ke place retr os pecti vely o n N M C sa m ples. 
Re vise d Te xt:
F or N M C s u bjects i n Part 1, a dia g n osis of N M C base d o n a p ositi ve I H C test a n d/ or 
detecti o n of N U T ge ne tra nsl ocati o n as deter mi ne d b y  FI S H at scree ni n g will be re q uire d. 
I n Part 2, a dia g n osis of N M C base d o n a p ositi ve I H C test perf or me d at a ce ntral 
la b orat or y will be re q uire d. A ≥2 0 % n uclei stai ni n g c ut off will be a p plie d f or a p ositi ve 
dia g n osis as a s u bset of ger m cell t u m ors (fr o m testis a n d o var y ) wea kly stai n f or t h e 
N U T pr otei n ( 5 % ma xi mal n uclei stai ni n g, 
, pers o nal c o m m u nicati o n). I n 
rare i nsta nces, w here a s u bject’s t u m or pre vi o usl y teste d p ositi ve f or N M C b y ot her 
met h o ds, a n d a false ne gati ve b y  ce ntral la b orat or y is s us pecte d d ue t o p o or q ualit y 
a nd/ or heter o ge neit y of t he tiss ue, retesti n g ma y  be c o nsi dere d o n a case-b y -case basis i n 
P P D


2011N118599_09
CONFIDENTIAL
BET115521
463
consultation with GSK Medical Monitor. If the retest by the central laboratory is positive 
for NMC, the subject may be considered eligible for enrollment.
In Part 2, fluorescence in situ hybridization (FISH) or next generation sequencing (NGS) 
may be undertaken retrospectively to characterize the NUT gene fusion partner and to 
support exploratory analysis of differential outcomes based on the NUT fusion partner.
Section 6.3. Baseline Assessment for Non-NMC Subjects
Rationale for Change: Clarification of tumor types included in Part 2.
Revised Text:
Last sentence 
Subjects diagnosed with SCLC, CRPC, TNBC, ER+BC or GIST will be eligible for Part 
2 of the study.
Deleted Section 6.4.6. Holter Monitoring and 6.4.7. Telemetry
Rationale for Change: Holter monitoring is being removed in Amendment 9 and 
telemetry was removed in Amendment 6; text being removed from body of protocol to 
avoid confusion of required tests.
Deleted Text:
Section 6.4.6. Holter Monitoring
Digital Holter ECG data will be obtained from 12-lead continuous Holter monitoring 
device supplied by the Sponsor. ECG acquisition via the Holter monitoring device will be 
performed at planned time points indicated in the Time and Events and should be 
obtained prior to phlebotomy and vital sign time points. Collection of critical ECG data 
shortly after meals or during sleep should be avoided since QT prolongation occurs at 
these times and a change in the QT-RR relationship occurs during sleep. Meals should be 
administered according to the guidelines provided in Section 7.3 and in the SPM as meal 
and snack times will need to be adjusted accordingly on dosing and ECG sampling days. 
Analysis of intervals and morphology from the continuous digital ECG data will be 
acquired and stored electronically and manually over-read by an external central 
validated ECG laboratory. In order to increase consistency of ECG interpretation, a 
limited number of central ECG over-readers will be used throughout the study. All ECGs 
for a given subject will be over-read by the same reader from the central validated ECG 
laboratory. The central reader will be blinded to subject identifiers (e.g., subject number, 
age, and sex), treatment assignment, and study day when Holter data was collected. The 
final intervals and morphology analyses entered into the database will be those generated 
by the central ECG laboratory. 
6.4.7. Telemetry
As part of the original cardiac monitoring plan, and to complement real-time ECG 
assessments, monitoring for potential adverse arrhythmias was conducted utilizing 
continuous telemetry monitoring. In addition, emergency resuscitation equipment 
including appropriate pharmacological agents will also be immediately accessible 
throughout the study. 


2011N118599_09
CONFIDENTIAL
BET115521
464
After internal QTc analysis and evaluation of cardiac safety data collected from subjects 
up to the 100 mg QD cohort by the cut-off date of May 15, 2015, the 48-hour telemetry 
requirement was removed from all parts of the study in Protocol Amendment 6.
Section 6.4.6.
Clinical Laboratory Assessments
Rationale for Change: Clarification to testosterone testing and removal of cytokines 
being collected with fever.
Revised Text:
Table 19 Clinical Laboratory Tests
Other Tests
Testosterone for males (free and complete testosterone at prior to first dose, free testosterone after first dose and as 
indicated in the Time and Events tables for CRPC subjects)
Pregnancy test for females (serum at screening, Urine or serum post dose)
Cytokine samples (collected as part of Predose PK sample for plasma cytokines); may also be performed as clinically 
appropriate following fever)
Section 6.4.6.2 Added
Rationale for Change: Addition of laboratory testing prior to scheduled surgeries to 
minimize the risk of bleeding during or after surgery.
Revised Text:
6.4.6.2.
Clinical Laboratory Assessments Required Prior to Scheduled 
Surgeries
Subjects must have a platelet count of ≥75,000/mm3 and a PT, INR and aPTT that are 
within normal limits within 48 hours prior to the post-dose biopsy and any scheduled 
surgical procedures.
Section 6.5.1.
Disease Assessment
Rationale for Change: Addition of reference to Prostate Working Group 2 guidelines.
Revised Text:
First Sentence
Tumor response will be assessed as outlined in Time and Event Schedule by the 
investigator using RECIST 1.1 (Appendix 6) or the Prostate Cancer Working Group 2 
(PCWG2) guidelines [Scher, 2008] and documented in the eCRF as: progressive disease 
(PD), stable disease (SD), partial response (PR), and complete response (CR).  
6.6.3. Urine Collection
Rationale for Change: Urine PK will no longer be required to be collected in this study.


2011N118599_09
CONFIDENTIAL
BET115521
465
Revised Text:
First paragraph
Urine samples for quantitative analysis of GSK525762 will may be collected at pre-dose 
and over a dosing interval immediately following dosing on Week 1 Day 1 and in Week 
3at the time points noted in the Time and Events Tables for Part 1 of the study (these 
samples are optional as of Amendment 9). Urine samples will be collected in subjects in
Part 1 (with the exclusion of besylate sub-study) once the 3+3 dose escalation has been 
reached. Additional sampling may be instituted based on emerging data.  
Section 6.8.1.
Tumor Tissue Collection
Rationale for Change: Removal of 14 day window for collection of tissue for NMC 
subjects in Part 2 for the diagnostic testing. Pre-screen consents will be allowed for 
archival or fresh tissue biopsy in Part 2 NMC subjects. Addition of language regarding 
the required laboratory values prior to post-dose biopsy.
Revised Text:
First paragraph second and third sentence
NMC patients in Part 2 will be required to submit a fresh or archival tumor specimen to 
the central laboratory during the 14 day screening period for diagnosis. Due to the timely 
need to determine NMC status by NUT IHC testing, a pre-screen informed consent may 
be offered to expedite obtaining the archival tissue in Part 2.
Third paragraph onwards
During the accelerated dose escalation phase (Part 1), fresh pre- and post-dose biopsy 
collections will be optional until the standard 3+3 design is implemented.  During the 3+3 
dose escalation phase in Part 1, and during Part 2, pre- and post-treatment biopsies are 
collected as outlined incollected between W2D1 – W3D1 (4-6 hrs post-dose) the Time 
and Events Tables and are mandatory. Archival tissue may be accepted as a pre-treatment 
specimen if the subject is treatment naïve. For subjects in Part 1 and 2, if tumor tissue is 
not accessible, discussion with the GSK medical monitor is required.
Archival tissue may be accepted as a pre-treatment specimen if the subject is treatment 
naïve. Subjects must have a platelet count of ≥75,000/mm3 and a PT, INR and aPTT that 
are WNL within 48 hours prior to the post-dose biopsy. If study medication is held prior 
to the post-dose biopsy, dosing must be re-started and subjects should receive 4 
consecutive days of dosing prior to collection of the biopsy. Specific timing of post-
treatmentdose sample collection is defined in the T&E table. See Study Procedures 
Manual (SPM) and central lab manual for additional details.
Section 6.8.2.2.
Systemic (Unstimulated) Plasma for Cytokines, 
Chemokines, and Acute Phase Proteins
Rationale for Change: Removal of collection of cytokines in case of fever. 


2011N118599_09
CONFIDENTIAL
BET115521
466
Revised Text:
First sentence
The set of analytes identical to that used in the whole blood ex vivo assay (including for 
example, MCP-1, MIP1-β IL-8) will also be measured in plasma samples taken during 
PK samplingand at the time of any Grade 2 fever or symptoms of a cytokine storm.
Deleted section 6.9.4. 
Disease-Related Events and/or Disease-Related 
Outcomes Not Qualifying as SAEs
Rationale for Change: Removal of section as there have been no pre-defined disease-
related events.
Deleted Text:
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 CRF 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 medication(s) or protocol 
design/procedures and the disease progression, then this must be reported as an SAE. 
6.9.6. 6.9.5.
Prompt Reporting of SAEs and Other Events to GSK
Rationale for Change: Updated pregnancy reporting timeframe to 24 hours, per GSK 
policy.
Revised Text:
Table 2020
Reporting of SAEs and Other Events to GSK
Initial Reports
Follow-up Information on a 
Previous Report
Type of Event
Time Frame
Documents
Time Frame
Documents
All SAEs
24 hours
SAE data 
collection tool
24 hours
Updated SAE data 
collection tool 
Pregnancy
2 Weeks24 
hours
Pregnancy 
Notification Form
2 Weeks24 hours
Pregnancy Follow 
up Form
Liver chemistry abnormalities:
ALT3xULN and 
bilirubin2xULN 
(>35% direct) (or 
ALT3xULN and 
INR>1.5, if INR 
measured)3
24 hours1
SAE data 
collection tool.
Liver Event Case 
Report Form 
(CRF) and liver 
imaging and/or 
biopsy CRFs if 
applicable2
24 hours
Updated SAE data 
collection tool. 
Updated Liver 
Event CRF2


2011N118599_09
CONFIDENTIAL
BET115521
467
Initial Reports
Follow-up Information on a 
Previous Report
Type of Event
Time Frame
Documents
Time Frame
Documents
ALT5xULN; 
ALT3xULN with 
hepatitis or 
rashsymptoms of liver 
injury or 
hypersensitivity or 
3xULN 4 weeks
24 hours1
Liver Event CRF2
24 hours
Updated Liver 
Event CRF2
ALT3xULN and 
<5xULN and biliribin 
<2xULN
24 hours1
Liver Event CRF 
does not need 
completing unless 
elevations persist 
for 4 weeks or 
subject cannot be 
monitored weekly 
for 4 weeks2
4.
GSK to be notified at onset of liver chemistry elevations to discuss subject safety.
5.
Liver event documents should be completed as soon as possible
6.
INR measurement is not required; if measured, the threshold value stated will not apply to subjects receiving 
anticoagulants.
6.10.2.
Action to be taken if pregnancy occurs
Revised Text:
First paragraph second sentence 
The investigator will record pregnancy information on the appropriate form and submit it 
to GSK within 2 weeks24 hours of learning of a subject's pregnancy.
Third paragraph second sentence
Furthermore, any SAE occurring as a result of a post-study pregnancy and is considered 
reasonably related to the study treatment by the investigator, will be reported to GSK as 
described in Section 6.9.56.9.6.
6.10.3.
Action to be taken if pregnancy occurs in a female partner of a 
male study subject
Revised Text:
First paragraph second sentence 
The investigator will record pregnancy information on the appropriate form and submit it 
to GSK within 2 weeks24 hours of learning of the partner’s pregnancy.
Section 7.1. GSK525762 Investigational Product Dosage/Administration


2011N118599_09
CONFIDENTIAL
BET115521
468
Footnote updated for Table 21 and 21
Rationale for Change: Clarify that amorphous product is no longer available and all 
study medication must be taken by mouth, as of Amendment 9. 
Revised Text:
Table 22 footnote
1. Amorphous formulation is no longer available as of Amendment 9
Table 23 Footnote
1. Formulation is no longer available as of Amendment 9
Third paragraph onwards: Deleted text
Preparation of GSK525762 Tablets for Administration via Enteral Feeding Tube
Administration via enteral feeding tube is intended only for subjects who are unable to 
swallow and retain orally administered GSK525762 tablets as directed in Section 7.1. 
The dose compounding should be performed only by pharmacy or appropriately trained 
personnel (please refer to Pharmacy Manual). A GSK525762 dosing solution is to be 
prepared by allowing GSK525762 tablets to disintegrate in 50 mL sterile water. All 
contents will be transferred into a syringe for administration via feeding tube. The 
compounding vessel should be rinsed and the syringe and feeding tube flushed with 
further additions of sterile water. Total water volume will be 255 mL.
GSK525762 dosing solutions may be stored in the syringe at up to 30°C (86°F) prior to 
administration.  Dosing must be completed on the day of solution preparation.
Section 7.3. Meals and Dietary Restrictions
Rationale for Change: Clarification that subjects must fast prior to serial PK days. 
Addition of restriction from certain fruits and juices due to the potential for drug 
interactions with study medication.
Revised Text:
First paragraph 
During Part 1, subjects will fast for at least one hour prior to each dose of study drug. 
After dosing, subjects will be asked to fast for an additional two hours. On serial PK 
sampling days (Week 1, Day 1 and Week 3, Day 4), subjects should fast overnight (i.e., 
at least 8 hours). These fasting requirements have been implemented in the protocol and 
informed consents to minimize pharmacokinetic variability. 
Last paragraph 


2011N118599_09
CONFIDENTIAL
BET115521
469
Subjects should abstain from consumption of Seville oranges, grapefruit, grapefruit 
hybrids or grapefruit juice and/or pomelos, exotic citrus fruits, from one day prior to the 
first dose of study treatment until the last dose of study drug.
7.7.1. Dose and Safety Management Guidelines
Rationale for Change: Added guidance for dose adjustment dose levels. Updated the 
management guidelines based on recent regulatory feedback and removed fever 
guidelines as there have been no occurrences clinically which warrant the need for such 
guidance. 
New text added & Table 23 added
Revised Text:
Dose reductions for individual subjects may be required, based on toxicity observed 
during the study. Table 23 describes the guidance for dose level reductions. All dose 
reductions should be discussed with the GSK Medical Monitor. 
Table 23
Guidance for GSK525762 Dose Reduction Levels
Current GSK525762 Dose (Total daily dose)
If subject requires a dose level reduction; new 
dose:
40 mg
No further dose reduction allowed
50 mg
40 mg
60 mg
50 mg
75 mg or 80 mg
60 mg
Table 2423
Dose Adjustment/Stopping Safety Criteria
Toxicity
Dose Adjustment/Stopping 
Criteria
Management Guidelines
Thrombocytopenia
Grade 1 (platelets <LLN to 
≥75,000/mm3) & Grade 2 
(platelets <75,000 to 
≥50,000/mm3)
Continue dosing at same dose level with weekly or 
more frequent monitoring as necessary.
Grade 3 (platelets <50,000 to 
≥25,000/mm3)
Withhold GSK525762 and check aPTT, PT, and 
INR.  Monitor CBC twice a week and coagulation 
studies twice a week until normal, or increase 
monitoring frequency if clinically indicated. 
Hold GSK525762 until thrombocytopenia has 
resolved to ≤ Grade 2 AND aPTT, PT, and INR are 
all ≤ ULN. Drug may then be restarted at the same 
dose or at a lower dose level, after discussion with 
the medical monitor.


2011N118599_09
CONFIDENTIAL
BET115521
470
Toxicity
Dose Adjustment/Stopping 
Criteria
Management Guidelines
If safety lab abnormalities recur following 
rechallenge, drug may be discontinued or restarted 
at another lower dose level, after discussion with the 
medical monitor. If safety lab abnormalities recur to 
the same level following a second rechallenge, drug 
will be discontinued.
Grade 4 (platelets  
<25,000/mm3), or any 
moderate to severe bleeding 
accompanied by  drug related 
thrombocytopenia
Withhold GSK525762 and check aPTT, PT, and 
INR.  Monitor CBC twice a week and coagulation
studies twice a week until normal, or increase 
monitoring frequency if clinically indicated. 
Hold GSK525762 until thrombocytopenia has 
resolved to ≤Grade 2 AND aPTT, PT, and INR are 
all ≤ ULN. Drug may then be restarted at a lower 
dose level, after discussion with the medical 
monitor.
If safety lab abnormalities recur following 
rechallenge, drug may be held until platelet count 
recovers to Grade 2 (≥50,000/mm3). 
For subjects with moderate to severe bleeding 
requiring transfusion support, GSK525762 should 
be permanently discontinued.
If platelet count does not recover to ≥50,000/mm3
(Grade 2) within 14 days, GSK525762 should be 
permanently discontinued.
If platelet count recovers to ≥50,000/mm3 (Grade 2) 
within 14 days, GSK525762 may be continued at the 
current/reduced dose after discussion with the 
medical monitor.  
If platelet count does not recover to ≥25,000/mm3
(Grade 3) within 7 days, GSK525762 should be 
permanently discontinued.
QTcF
If >30 msec and < 60 msec 
change from baseline  AND
manual QTcF <500 (average
of three ECGs over at least 15 
minutes)
(5) Continue current dose of GSK525762
(6) Supplement electrolytes, particularly 
potassium and magnesium, to recommended 
levels:
a. Maintain serum potassium > 4mol/L
b. Maintain serum magnesium levels >0.85 
mmol/L
(7) Discontinue any concomitant medications 
with potential for QTcF prolongation.
(8) Consider 24 hour or longer telemetry 
monitoring if clinically indicated.


2011N118599_09
CONFIDENTIAL
BET115521
471
Toxicity
Dose Adjustment/Stopping 
Criteria
Management Guidelines
If 60 msec change from 
baseline occurs
OR
QTcF 500 
(average of three ECGs over 
at least 15 minutes)
Discontinue GSK525762 and notify the Medical 
Monitor. 
(5) Supplement electrolytes to recommended 
levels:
c. Maintain serum potassium > 4mol/L
d. Maintain serum magnesium levels >0.85 
mmol/L
(6) Rule out other potential etiologies for 
prolonged QTcF such as cardiac ischemia
(7) Discontinue any concomitant medications with 
potential for QTcF prolongation.
(8) Consider telemetry monitoring if clinically 
indicated.
This subject may consider restarting study treatment 
at one dose level reduced if all of the following 
criteria for QTcF re-challenge are met. If approval 
for re-challenge is granted, the subject must be re-
consented (with a separate informed consent 
specific to QTc prolongation)
(7) QTcF reduced to <450 msec,
(8) Potassium and magnesium levels are within 
institutional normal range,
(9) A favorable risk/benefit profile (in the medical 
judgement of the Investigator and the Medical 
Monitor),
(10) Approval within GSK medical governance:
a. agreement with SERM MD and PPL,
b. review with Chair or co-Chair of the GSK 
QT panel,
c. SERM VP and Clinical VP approval
d. Head Unit Physician approval
(11) Institutional IRB (or equivalent) approval, and
(12) The subject is re-consented regarding the 
possible increased risk of QTc prolongation. 
Discontinuation procedures:
If the subject is withdrawn due to QTcF event, the 
subject should complete the following activities post-
dose:
(3) Evaluation by cardiologist.
(4) Weekly assessments for QTcF should be 
performed for two weeks, and then next 
assessment at 4 weeks post-dose.
a. If QTcF results have not resolved to 
baseline by 4 weeks post-dose, then 
continue every 4-5 weeks until resolution
Troponin
Troponin level >ULNand 
>10% CV level.
Contact the subject immediately for evaluation of 
symptoms and to obtain ECG. Repeat troponin 
within 24-48 hours or as soon as possible. 


2011N118599_09
CONFIDENTIAL
BET115521
472
Toxicity
Dose Adjustment/Stopping 
Criteria
Management Guidelines
For asymptomatic subjects with repeat troponin 
values >ULNand >10% CV, hold study 
medication(s), refer to a cardiologist and contact the 
GSK Medical Monitor. If the repeat value is within 
the normal range, the subject may continue study 
medication with close follow-up for symptoms, ECG 
monitoring and further troponin measurements as 
clinically indicated.
If the subject is symptomatic or the troponin level 
approaches the threshold for MI according to local 
lab parameters, the study medication must be 
withdrawn and the subject will be referred 
immediately to a cardiologist for appropriate medical 
care.May consider restarting study treatment at a 
reduced dose or dose level pre-event based on 
discussion with GSK Medical Monitor.
LVEF
Asymptomatic, absolute 
decrease of >10% in LVEF 
compared to baseline and the 
ejection fraction is below the 
institution’s lower limit of 
normal (LLN)
Temporarily discontinue investigational drugs(s) and 
repeat evaluation of LVEF within 2 weeks
If LVEF recovers (defined as LLN and absolute 
decrease 10% compared to baseline) at any time 
during the next 4 weeks, after consultation and 
approval of the GSK medical monitor, the subject 
may be restarted on investigational drug(s) at a 
reduced dose. Monitoring to be performed at 2 and 
4 weeks after restarting investigational drug(s) and 
then per protocol specifications.
If LVEF does not recover within 4 weeks, 
permanently discontinue investigational drug(s). 
Evaluation by a cardiologist will be conducted. 
Ejection fraction should continue to be monitored at 
2 weeks, 4 weeks and every 4 weeks until 16 weeks 
or resolution, whichever is longer.
May consider restarting study treatment at a 
reduced dose or dose level pre-event based on 
discussion with GSK Medical.
Grade 3 or 4
Permanently discontinue investigational drug(s). 
Evaluation by a cardiologist will be conducted. 
Ejection fraction should be monitored at 2 weeks, 4 
weeks and then every 4 weeks until 16 weeks or 
resolution.
Liver 

ALT 5X ULN, OR

ALT 3X ULN andplus 
either bilirubin ≥>/= 2X 
ULN (>35% direct 
bilirubin, bilirubin 
fractionation required) or 
Refer to Section14.3 (Appendix 3) for liver chemistry 
stopping criteria, treatment algorithms, reporting and 
follow-up of suspected liver events. In the absence 
of known hepatic metastases, d Discontinue study 
medication(s) and notify the GSK Medical Monitor,
and refer to follow-up procedures outlined in 


2011N118599_09
CONFIDENTIAL
BET115521
473
Toxicity
Dose Adjustment/Stopping 
Criteria
Management Guidelines
INR >1.5 without 
evidence of biliary 
obstruction or progressive 
disease, OR

ALT 3X ULN with the 
appearance hepatitis 
symptoms or 
rashsymptoms of liver 
injury or hypersensitivitya
Appendix 3, , Section IIIa, Liver chemistry follow-up 
procedures. In the presence of known hepatic 
metastases, if there is evidence to suggest a drug 
induced effect, discontinue study medications, notify 
the GSK Medical Monitor, and refer to follow-up 
procedures outlined in Appendix 3, Section IIIa, 
Liver Chemistry Follow-Up Procedures.
Hypo- and 
Hyperglycemia
(for management 
purposes, refer to 
mild, moderate 
and severe 
intensity criteria; 
however for CRF 
reporting use NCI-
CTCAE version 
4.0 Grade 1-5) 
Fasting blood glucose >150 
mg/dL to 250 mg/dL (Mild 
hyperglycemia)(Mild) Fasting 
blood glucose >150 mg/dL
Monitor fasting and preprandial glucose.
If persistent over 2 repeats over 3-4 weeks, consult 
Diabetologist and consider starting metformin.
Fasting blood glucose 
<70 mg/dL OR aAny blood 
glucose >250 mg/dL
(Moderate to Severe 
hyperglycemia)
Hold investigational product(s) and instruct subject 
to notify investigator immediately. 
If a blood glucose >250 mg/dL is observed the 
subject should be mMonitored for ketoacidosis as 
clinically indicated.
If subject has evidence of ketoacidosis, initiate 
prompt therapy. Antihyperglycemic therapy with 
insulin is preferred. Consult 
Diabetologist/Endocrinologist .Careful monitoring 
should be performed to control for rebound 
hypoglycemia as effect of investigational product(s) 
resolve Treatment should be undertaken with 
awareness that the action of insulin or other 
antihyperglycemic agents (e.g. sulfonylureas, 
biguanides, etc.) may be substantially blocked by 
the action of the study medication. The action of 
insulin or other antihyperglycemic agents should be 
restored as study medication is cleared. If an 
antihyperglycemic agent is administered, then the 
subject should be observed closely for rebound 
hypoglycemia as the study medication is cleared. 
Intravenous insulin treatment is recommended.
May consider restarting study treatment at a 
reduced dose or dose level pre-event based on 
discussion with GSK Medical monitor.


2011N118599_09
CONFIDENTIAL
BET115521
474
Toxicity
Dose Adjustment/Stopping 
Criteria
Management Guidelines
Fasting blood glucose 
<70 mg/dL (Moderate to 
Severe hypoglycemia)
Hold investigational product(s).
Provide sugar containing liquids and monitor monitor 
blood sugar closely. Check for insulin and c-peptide 
levels. After blood sugar normalizes, may restart 
study treatment one dose level lower if the 
hypoglycemia cannot be attributed to any other 
cause, and fasting blood sugar will be monitored on 
a daily basis until the blood glucose level is 
stabilized.
Diarrhea
Grade 1
Initiate supportive care including loperamide. 
Grade 2
Initiate supportive care including loperamide. 
Consider temporary discontinuation of study 
medications and discuss with GSK Medical Monitor.
Grade 3 or 4
Above plus consider IV hydration, hospital 
admission and prophylactic antibiotics as 
appropriate. Withhold study drug until diarrhea has 
resolved to ≤Grade 1, continue diarrheal 
prophylaxisConsider temporary discontinuation of 
study medications and discuss with GSK Medical 
Monitor.
Additional guidance is located inAppendix 3May 
restart study treatment at a reduced dose or dose 
level pre-event based on discussion with GSK 
Medical monitor.one dose level lower.
Mucositis
Grade 1-2
Encourage oral hygiene. Offer topical supportive 
anesthetics. Encourage adequate hydration.
Grade 3-4
Above, plus systemic opiate administration as 
needed. Consider IV hydration and hospital 
admission as appropriate. 
For mucositis >Grade 3, hold GSK525762 until 
mucositis is <Grade 1 and resume the same dose of 
GSK525762. If mucositis >Grade 3 recurs, hold 
GSK525762 until mucositis is <Grade 1, then reduce 
GSK525762 one dose level. If mucositis >Grade 3 
recurs a third time at reduced dose, hold 
GSK525762 until mucositis resolved to <Grade 1, 
then reduce GSK525762 one dose level (if possible) 
or discontinue permanently.May restart study 
treatment at a reduced dose or dose level pre-event 
based on discussion with GSK Medical monitor.
Pneumonitis
Grade 1
For all grades obtain high resolution chest CT if 
possible.
Consider evaluation by pulmonologist. 
Consider room air O2 saturation at rest via pulse 
oximetry reading ( X 2, 5 mins apart). Repeat 
evaluations every 8-12 weeks until return to within 
normal limits. Continue investigational drug(s) at 
current dose(s).


2011N118599_09
CONFIDENTIAL
BET115521
475
Toxicity
Dose Adjustment/Stopping 
Criteria
Management Guidelines
If any decline is observed in O2 saturation, hold 
study drug, repeat chest x-ray to determine if 
progression of pneumonitis has occurred and 
consult pulmonologist.
Grade 2
ConsiderMust be evaluatedion by pulmonologist. 
Consider pulmonary function tests including: 
spirometry, Diffusing Capacity of the Lung for 
Carbon Monoxide (DLCO), and weekly room air O2 
saturation at rest via pulse oximetry reading ( X 2, 5 
mins apart). Repeat evaluations every 8-12 weeks 
until return to wnl. Consider a bronchoscopy with 
biopsy and/or bronchoalveolar lavage. (BAL).
Treat only if symptomatic. Consider corticosteroids if 
symptoms are troublesome and infective origin is 
ruled out. Taper as medically indicated.
Hold investigational drug(s) until recovery to 
≤<Grade 1, then reduce dose by at least 25%.  
Discontinue investigational drug(s) if no recovery to 
≤<Grade 1 within 4 weeks. May consider escalation 
to pre-event dose after discussion with GSK Medical 
Monitor
Grade 3 and 4
Discontinue investigational drug(s).
Evaluation by pulmonologist. 
Required pulmonary function tests including: 
spirometry, DLCO, and room air O2 saturation at 
rest via pulse oximetry reading (X 2, 5 mins apart). 
Repeat evaluations at least every 8 weeks until 
return to wnl. Bronchoscopy with biopsy and/or BAL 
is recommended.
Consider treatment with corticosteroids in the 
appropriate clinical setting and in consultation with 
the pulmonologist (1-2 mg/kg of prednisone [or 
equivalent] IV once daily) if infectious origin is ruled 
out. Taper over 4-6 weeks (Grade 3) Hold 
investigational drug(s) until recovery to < Grade 1. 
Discontinue investigational drug(s) if no recovery to 
<Grade 1 within 4 weeks. May consider restarting 
study treatment at a reduced dose after discussion 
with GSK Medical Monitor if there is clinical benefit.
Grades 1-3: May consider restarting study treatment 
at a reduced dose or dose level pre-event after 
discussion with GSK Medical Monitor.
(Grade 4) Discontinue investigational drug(s)
Fever
Grade 1 
(Grade 1) 
(1) Continue current dose(s) of study treatment(s) 


2011N118599_09
CONFIDENTIAL
BET115521
476
Toxicity
Dose Adjustment/Stopping 
Criteria
Management Guidelines
and monitor for change in severity. 
Grade 2
(Grade 2) 
(1) Consider temporary discontinuation of study 
medication and monitor for change in severity. 
(2) Assess or inquire if the subject is experiencing in 
combination with fever: swelling, redness, extreme 
fatigue or nausea. Assess vital signs.
(3) Collect  Cytokine blood samples as outlined in 
the SPM.  Collect blood culture and investigate viral 
infections as applicable.
(4) May consider restarting study treatment at a 
reduced dose or dose level pre-event based on 
discussion with GSK Medical monitor.
Grade 3-4
Grade 3-4
(1) Temporary discontinuation of study medication 
and monitor for change in severity. 
2) Assess or inquire if the subject is experiencing in 
combination with fever: swelling, redness, extreme 
fatigue or nausea. 
(3) Collect Cytokine blood samples  as outlined in 
the SPM.  Collect blood culture and investigate viral 
infections as applicable.
(4) May consider restarting study treatment at a 
reduced dose or dose level pre-event based on 
discussion with GSK Medical Monitor
*Note: Baseline results are defined by the nearest timepoint prior to first dose. For this trial the Baseline QTcF value is 
determined by the mean of the triplicate W1D1 predose QTcF results (when triplicate ECGs are indicated). If 
these results are not available, then the mean QTcF of the screening triplicate ECG results are considered 
baseline.
a. New or worsening symptoms believed to be related to liver injury (such as fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, or jaundice) or believed to be related to hypersensitivity (such as fever, rash or 
eosinophilia.
Section 7.7.2 Dose Adjustments for ToxicityDose Adjustments for Toxicity
Rationale for Change: Updated based on regulatory feedback.
Revised Text:
Table 2524Guidance for Dose Adjustment for Toxicity [Except those listed in Table 
24]
Worst Grade
GSK525762
1
No change in dose.


2011N118599_09
CONFIDENTIAL
BET115521
477
2
For drug-related Grade 2 toxicities, continue dosing with no change or may consider holding 
for up to 1 week for toxicity to be < Grade 2. Continue at the same dose (dose reduction is 
required if the Grade 2 toxicity is considered a DLT).
3
Hold dose for one week intervals until toxicity is Grade 1*, then restart with no change for 
1st episode. . Reduce by one dose level with 2nd episode if recovery to ≤Grade 1 within 21 
days. If no recovery to ≤Grade 1 after a 21 day delay in the 2nd episode, subject should be 
permanently discontinued.
drug-related Grade 2 then restart with no change for 1st episode. Utilize an alternative, less 
frequent schedule or reduce by one dose level with 2nd episode. If no recovery to ≤Grade 
1* after a 21 day delay, patient should go off protocol therapy.
4
Off protocol therapy
In rare situations, based on discussion and written agreement between GSK medical 
monitor and investigator, if the patient is receiving benefit then the following criteria should 
be implemented: hold dose for one week intervals until toxicity is ≤Grade 1*, then restart 
with one dose level lower. If the same Grade 4 toxicity recurs, study drug will be 
permanently discontinued. < drug-related Grade 2 then restart with no change for 1st 
episode. Utilize an alternative, less frequent schedule or reduce by one dose level with 2nd 
episode. If no recovery to ≤Grade 1* after a 21 day delay, patient should go off protocol 
therapy.
*Note: Exceptions to drug-related Grade 1 requirement may be made for rash, alopecia, etc.  Exceptions to drug-
related Grade 1, 2, 3 requirements would be quickly reversible (<48 hours) laboratory abnormality (example: electrolyte 
changes). In the case of thrombocytopenia, a subject may be considered for restarting study treatment if a resolution 
from Grade 4 to Grade 3 is experienced and after discussion with GSK medical monitor. See guidance in Table 23 
above.
Section 7.8 deleted
Rationale for Change: Events of Special Interest are defined in the RAP and may 
change during the study based on clinical data. 
7.8 Guidelines for Events of Special Interest and Dose Modifications
The severity of adverse events will be graded utilizing the CTCAE v4. Additional details 
regarding fever, diarrhea, rash and liver toxicity are outlined in Appendix 3.
Section 8 CONCOMITANT MEDICATIONS AND NON-DRUG THERAPIES
Rationale for Change: Section was updated and reorganized for clarity and ease of 
reading. The sections were also updated with most recent drug interaction data, including 
updating the prohibited and cautionary medication tables. The restriction for antacids 
around dosing was removed. Restriction of NSAIDs and aspirin use and guidance to 
minimize the use of acetaminophen were added to minimize the risk of bleeding. 
Heading of Section 8.1 changed 
Section 8.1. Permitted Medications and Non-Drug Therapies
Revised Text:


2011N118599_09
CONFIDENTIAL
BET115521
478
Fourth Paragraph
Drugs with a low risk of causing QTc prolongation (e.g., aprepitant) may be used without 
restriction.
Heading of Section 8.2. changed
8.2.
Prohibited Medications and Cautionary MedicationsNon-Drug 
Therapies
Inserted new subsection Section 8.2.1.
Prohibited Medications
Section 8.2.1.Prohibited Medications
Subjects should not receive other anti-cancer therapy [including chemotherapy, radiation 
therapy, immunotherapy, biologic therapy, investigational therapy, hormonal therapy 
(other than leuprolide or other GnRH agonists), surgery or tumor embolization] while on 
treatment in this study. Other anti-cancer therapy should not be administered unless one 
of the following occurs: documented disease progression; unacceptable or unmanageable 
toxicity; subject is withdrawn from the study at the investigator’s discretion or consent is 
withdrawn; or no further clinical benefit is anticipated which requires permanent 
discontinuation of study drug. Note, palliative radiation and/or surgical intervention may 
be permitted (for example to address pain management) and should be discussed with the 
GSK medical monitor prior to invention to determine appropriate dosing and schedule. 
The use of certain medications and illicit drugs within 5 half-lives or 28 days (if the drug 
is a potential enzyme inducer) prior to the first dose of study medication (and for the 
duration of the study) will not be allowed. If a prohibited medication is required for 
single use (such as for a procedure) while study treatment(s) is held, the GSK Medical 
Monitor can approve such use.
Subjects may continue to use aspirin, but doses are not allowed to be greater than 100 mg 
per day. The use of non-steroidal anti-inflammatory drugs (NSAIDs) will be excluded, 
except for when NSAIDs will provide benefit over other analgesics and then to be used 
with caution, including concomitant use of proton pump inhibitors.
Subjects taking enzyme-inducing antiepileptic agents or other potent inhibitors or 
inducers of CYP3A4 enzymes should be transitioned to another agent at least 14 days (or 
5 half-lives, whichever is longer) prior to the first dose of study agents.
Anticoagulants at therapeutic doses (e.g., warfarin, direct thrombin inhibitors, etc) are 
PROHIBITED from seven days prior to the first dose of study drug through completion 
of the Final Study Visit. Low dose (prophylactic) anticoagulants are permitted provided 
that subject’s PT/PTT meet entry criteria.  
Antacids should not be consumed for at least 1h before and 2h after administration of 
GSK525762.


2011N118599_09
CONFIDENTIAL
BET115521
479
If a subject requires medication for hyperemesis, due to the potential of serotonin 5-HT3 
receptor antagonists to increase QTcF, palonosetron (administered per the prescribing 
information) and ondansetron at a maximum oral dose of 8 mg TID are the only allowed 
drugs in this class (i.e. dolasetron and granisetron are not permitted).
Co-administration of the medications listed in Table 26 are prohibited for 5 half-lives (or 
at least 14 days, whichever is longer) prior to the first dose of study drug until 
discontinuation from the study drug due to unacceptable risk of Torsades de Pointes (with 
the exception of amiodarone, which is prohibited beginning 6 months prior to screening 
through discontinuation from the study; however, there may be situations when the 
subject is on study and Advanced Cardiac Life Support (ACLS) requires the use of 
amiodarone, which should be used as per local clinical guidelines). If a prohibited 
medication is required for single use (such as for a procedure) while study treatment(s) is 
held, the GSK Medical Monitor can approve such use.
Table 26 Drugs with a Risk of Torsades de Pointes that are Prohibited1
Amiodarone
Dronedarone
Moxifloxacin
Anagrelide
Droperidol
Papaverine
Azithromycin
Erythromycin
Pentamidine 
Chloroquine
Escitalopram
Pimozide
Chlorpromazine
Flecainide
Procainamide
Cilostazol
Fluconazole
Propofol
Ciprofloxacin
Halofantrine
Quinidine
Citalopram
Haloperidol
Roxithromycin
Clarithromycin
Ibogaine
Sevoflurane
Cocaine
Ibutilide
Sotalol
Disopyramide
Levofloxacin
Sulpiride
Dofetilide
Levomepromazine
Sultopride
Domperidone
Levosulpiride
Terlipressin
Donepezil
Methadone
Thioridazine
Data Source: crediblemeds.org revision date 09 January 2017.
1. The above table is not exhaustive and prohibited drugs are defined by the online version at the time of screening of 
the subject
8.2.1.8.2.2.
Cautionary Medications
Revised Text:
Subjects should minimize the use of medications which contain acetaminophen. Subjects 
should be informed of alternative medications. 
If a subject requires medication for hyperemesis, due to the potential of serotonin 5-HT3
receptor antagonists to increase QTcF, palonosetron and ondansetron at a maximum oral
dose of 8 mg TID are the only allowed drugs in this class.


2011N118599_09
CONFIDENTIAL
BET115521
480
Co-administration of medications that are known to prolong the QT interval and have a 
risk of causing Torsades de Pointes are to be used with EXTREME CAUTION
beginning 14 days prior to the first dose of study drug until discontinuation from the 
study. These medications include (but are not limited to):


2011N118599_09
CONFIDENTIAL
BET115521
481
Table 2725Drugs with a Risk of Torsades de Pointes which are permitted for co-
administration with Extreme Caution1
Generic Name
Brand Name
Amiodarone
Cordarone, Pacerone, Nexterone
Astemizole
Hismanal
Chlorpromazine
Thorazine, Largactil, Megaphen
Degarelix
Firmagon
Leuprolide
Lupron
Tropisetron
Navoban and Setrovel
*There may be situations when the subject is on study that Advanced Cardiac Life 
Support (ACLS) requires the use of amiodarone, which should be used as per local 
clinical guidelines
Data Source: www.crediblemeds.org (revised 17-Dec-2015)
Alfuzosin
Foscarnet
Perphenazine
Apomorphine
Gemifloxacin
Pipamperone
Aripiprazole
Hydrocodone ER
Promethazine
Artenimole+piperaquine
Iloperidone
Rilpivirine
Asenapine
Imipramine
Risperidone
Atomoxetine
Isradipine
Saquinavir
Bedaquiline
Leuprolide
Sertindole
Buprenorphine
Lithium
Solifenacin
Clomipramine
Melperone
Tacrolimus
Clozapine
Mifepristone
Telavancin
Cyamemazine
Mirabegron
Telithromycin
Degarelix
Mirtazapine
Tetrabenazine
Delamanid
Moexipril/
hydrochlorothiazide
Tiapride
Desipramine
Nicardipine
Tizanidine
Dexmedetomidine
Norfloxacin
Tolterodine
Efavirenz
Nortriptyline
Trimipramine
Ezogabine
Ofloxacin
Tropisetron
Famotidine
Oxytocin
Vardenafil
Felbamate
Paliperidone
Venlafaxine
Fingolimod
Pasireotide
Zotepine
Flupentixol
Perflutren lipid 
microspheres
Data Source: crediblemeds.org revision date 09 January 2017
1. The above table is not exhaustive and these drugs are defined by the online version 
at the time of screening of the subject
After starting cautionary medications such as in Table 27Table 25, it is recommended 
that ECGs are implemented daily until the steady state. If there are abnormalities, 


2011N118599_09
CONFIDENTIAL
BET115521
482
implement additional cardiotoxicity monitoring as addressed in Table 24Table 23, 
Section7.7.
GSK525762 is a moderate CYP3A4 inducer. Medications that have a narrow therapeutic 
index and that are substrates of CYP3A4 should be administered with caution, as their 
metabolism may be affected by co-administration with GSK525762 and result in 
decreased exposure. These include alfentanil, cyclosporine, dihydroergotamine, 
ergotamine, fentanyl, pimozide, quinidine, sirolimus, tacrolimus, and theophylline. 
GSK525762 is a substrate for breast cancer resistance protein (BCRP) and P-glycoprotein 
(Pgp) transporters. Therefore, potent inhibitors of these transporters, such as 
cyclosporine, tacrolimus, or ketoconazole, should be avoided.
GSK525762 in as inhibitor of organic anion transporter 1A1 (OAT1) and organic anion 
transporter 3 (OAT3) in vitro. Substrates of these transporters include agents such as 
methotrexate, penicillin G, and indomethacin. While co-administration of these agents 
with GSK525762 is not prohibited, they should be used with caution and additional 
monitoring for adverse effects should be utilized.
Higher doses of oral steroids can cause enzyme induction.  As such, oral steroids should 
be used with caution (and discussed with the GSK Medical Monitor).  NOTE:  Topical or 
inhaled steroids are permitted. 
Questions regarding concomitant medications should be directed to the GSK Medical 
Monitor for clarification.
Section 8.2.2. Potential Drug Interactions with GSK525762
The precise in vivo metabolic liability for GSK525762 has yet to be assessed. In vitro 
data suggests that GSK525762 is only metabolized by CYP3A4 and thus 
coadministration of inducers and inhibitors of CYP3A4 should be avoided during the 
course of the study where possible as they may respectively decrease or increase 
exposure to GSK525762.GSK525762 is considered to have a low risk of causing 
clinically relevant perpetrator drug interactions with CYP3A4, CYP2B6 and CYP2C8 
enzymes and/or PgP, BCRP, OATP1B3, OAT1, OCT2, MATE1, MATE2-K, BSEP or 
MRP2 transporters either via direct or metabolism-dependent inhibition.
GSK525762 was shown to be an inhibitor of OATP1B1 and OAT3 in vitro, however, the 
clinical impact of this inhibition is only deemed a concern for sensitive substrates of 
OATP1B1 or OAT3 (e.g. methotrexate).
Potential interactions with other Cytochrome P450 metabolized drugs have not been 
assessed.
Higher doses of oral steroids can cause enzyme induction.  As such, oral steroids should 
be used with caution (and discussed with the GSK Medical Monitor).  NOTE:  Topical or 
inhaled steroids are permitted. 


2011N118599_09
CONFIDENTIAL
BET115521
483
8.3.
Prohibited MedicationsSubjects should not receive other anti-cancer therapy 
[including chemotherapy, radiation therapy, immunotherapy, biologic therapy, 
investigational therapy, hormonal therapy (other than leuprolide or other GnRH agonists), 
surgery or tumor embolization] while on treatment in this study. Other anti-cancer 
therapy should not be administered unless one of the following occurs: documented 
disease progression; unacceptable or unmanageable toxicity; subject is withdrawn from 
the study at the investigator’s discretion or consent is withdrawn; or no further clinical 
benefit is anticipated which requires permanent discontinuation of study drug. Note, 
palliative radiation and/or surgical intervention may be permitted (for example to address 
pain management) and should be discussed with the GSK medical monitor prior to 
invention to determine appropriate dosing and schedule. 
Co-administration of medications that are known to prolong the QT interval and have a 
risk of causing Torsades de Pointes are PROHIBITED for 5 half-lives of the drug prior 
to the first dose of study drug until discontinuation from the study drug with the 
exception of amiodarone which is prohibited beginning 6 months prior to Screening 
through discontinuation from the study. (However, there may be situations when the 
subject is on study and Advanced Cardiac Life Support (ACLS) requires the use of 
amiodarone, which should be used as per local clinical guidelines). These medications 
include (but are not limited to):
Table 26
Drugs with a Risk of 
Torsades de Pointes that are 
ProhibitedGeneric Name
Brand Name
Arsenic trioxide
Trisenox
Asenapine
Saphris,Sycrest
Bepridil
Vascor
Chloroquine
Aralen
Cisapride
Propulsid
Clarithromycin
Biaxin, Prevpac
Disopyramide
Norpace
Dofetilide
Tikosyn
Domperidone
Motilium
Droperidol
Inapsine
Erythromycin
Erythrocin, E.E.S.
Halofantrine
Halfan
Hydrocodone
Hysingla ER and Zohydro ER
Ibutilide
Corvert
Levofloxacin
Levaquin
Levomethadyl
Orlaam
Mesoridazine
Serentil
Methadone
Dolophine, Methadose
Pentamidine
Pentam, NebuPent
Pimozide
Orap
Probucol
Lorelco
Procainamide
Pronestyl, Procan
Quinidine
Quinaglute, Cardioquin


2011N118599_09
CONFIDENTIAL
BET115521
484
Table 26
Drugs with a Risk of 
Torsades de Pointes that are 
ProhibitedGeneric Name
Brand Name
Sotalol
Betapace
Sparfloxacin
Zagam
Terfenadine
Seldane
Thioridazine
Mellaril
Data Source: crediblemeds.org
At time of screening, if a subject is currently receiving any of the listed prohibited 
medications/substances, the medication or substance must be discontinued for a period of 
at least 14 days prior to the administration of the first dose of study drug in order for the 
subject to meet study eligibility.
If a subject requires medication for hyperemesis, due to the potential of serotonin 5-HT3 
receptor antagonists to increase QTcF, palonosetron and ondansetron at a maximum oral 
dose of 8 mg TID are the only allowed drugs in this class.
8.4.  Non-Drug Therapies
Non-drug anti-cancer therapies (e.g., radiation therapy, surgery, and/or tumor 
embolization) will not be permitted from the screening visit through the post-study 
follow-up visit. 
NOTE: Subjects may receive palliative radiation treatment during this study. 
Subjects will abstain from using herbal preparations/medications throughout the study 
until the final study visit.  Decaffeinated tea and coffee are permissible. 
Herbal products include, but are not limited to:

St. John’s Wort, kava, ephedra (ma huang), gingko biloba, dehydroepiandrosterone 
(DHEA), yohimbe, saw palmetto , ginseng
The investigator should contact a GSK Medical Monitor before initiating treatment with 
any herbal preparation including marijuana. 
9.1.
Female Subjects
Rationale for Change: Clarification to section. 
Revised Text:
First paragraph first sentence 
Female subjects of childbearing potential must not become pregnant during the trial and 
for 7 months after stopping study medication and so must be sexually inactive by 
abstinence or use contraceptive methods with a failure rate of ≤< 1%.


2011N118599_09
CONFIDENTIAL
BET115521
485
Contraceptive Methods with a Failure Rate of 1%
First bullet point
Non-hormonal Iintrauterine device (IUD) or intrauterine system (IUS) that meets the 
≤<1% failure rate as stated in the product label
Last paragraph
All Hhormonal means of birth control such as oral, injectable, dermal, subdermal or 
topical contraceptives are NOT acceptable forms of birth control given that their efficacy 
has not been evaluated when given in combination with the investigational drugs.
Section 9.2. Male Subjects
Rationale for Change: Update to reflect current GSK guidance and to align with 
Inclusion criteria. 
Revised Text:
First paragraph first sentence onwards
This list does not apply to male subjects with a female partner of child bearing potential 
who are and will continue to be abstinent from penile-vaginal intercourse on a long term 
and persistent basis, when this is their preferred and usual lifestyle. Periodic abstinence 
(e.g. calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are 
NOT acceptable methods of contraception.
Male subjects with female partners of child-bearing potential must use one of the 
following contraceptive methods after the first dose of study treatment and until 16 weeks 
after the last dose of study drug(s).
Vasectomy with documentation of azoospermia. The documentation on male sterility can 
come from the site personnel’s: review of subject’s medical records, medical 
examination and/or semen analysis, or medical history interview, OR
Condom use plusPLUS partner use of a highly effective contraceptive (≤1% rate of 
failure per year) such as occlusive cap (diaphragm or cervical/vault cap) intrauterine 
device or system, or hormonal birth control such as contraceptive subdermal implant, 
combined estrogen and progestogen oral contraceptive, injectable progestogen, 
contraceptive vaginal ring, or percutaneous contraceptive patches. plus spermicidal 
agent (foam/gel/film/cream/suppository), or intrauterine device. OR
Abstinence, defined as sexual inactivity consistent with the preferred and usual lifestyle 
of the subject. Periodic abstinence (e.g. calendar, ovulation, symptothermal, post-
ovulation methods) and withdrawal are not acceptable methods of contraception
In addition, mMale subjects whose partners are or become pregnantwhile on study 
medication must continue to use condoms for 7 days16 weeks after stopping after the last 
dose of study medications. Male subjects should be advised not to donate sperm while on 
study and for 16 weeks after the last dose of study medication.


2011N118599_09
CONFIDENTIAL
BET115521
486
Section 11.1.1.
Part 1
Rationale for Change: Update number of subjects to allow for additional subjects to be 
enrolled in Part 1 at the MTD and the addition of the GIST cohort in Part 2.
Revised Text:
First paragraph second sentence 
To complete Part 1, it is estimated that 60 90 to 90 110 evaluable subjects will be 
enrolled.
Section 11.1.3.
Part 2
Rationale for Change: Addition of GIST cohort information and inclusion of PSA50 
response for CRPC. 
Revised Text:
First paragraph first sentence onwards
The primary goal of Part 2 is to evaluate disease-specific efficacy in subjects with NMC, 
SCLC, CRPC, TNBC,  and ER+BC and GIST.

For NMC, efficacy is defined as a clinically meaningful response rate (defined as 
the percentage of subjects that have achieved a CR or PR) of 20% relative to a 5% 
response rate suggesting no activity

For CRPC and SCLC, efficacy is defined as a clinically meaningful response rate 
(defined as a percentage of subjects that have achieved as CR or PR; for CRPC 
subjects, defined as a percentage of subjects have PSA50 response) of 30% 
relative to a 10% response rate suggesting no activity.

For TNBC, efficacy is defined as a clinically meaningful response rate (defined as 
a percentage of subjects that have achieved as CR or PR) of 25% relative to a 
10% response rate suggesting no activity.

For ER+BC, efficacy is defined as a clinically meaningful response rate (defined 
as a percentage of subjects that have achieved as CR or PR) of 30% relative to a 
15% response rate suggesting no activity.

For GIST, efficacy is defined as a disease control rate (defined as a percentage of 
subjects that have achieved a CR or PR or SD that has lasted at least 16 weeks) of 
40% relative to a 15% disease control rate suggesting no activity.
In text Table 


2011N118599_09
CONFIDENTIAL
BET115521
487
Null 
Hypothesis 
(H0) ORR
Alternative 
Hypothesis 
(Target) (Ha) 
ORR
Maximum 
Sample 
Size
Probability of 
stopping early 
for futility if H0 
is true
Average 
Sample Size 
if H0 is true
Actual 
Type I Error 
Rate (%)
Actual 
Power (%)
NMC 
5%
20%
25
0.891
14
8.8
80.2
CRPC 
10%
30%
22
0.860
16
6.0
82.5
TNBC 
10%
25%
37
0.876
23
6.4
81.7
ER+BC 
15%
30%
37
0.855
25
8.7
80.3
SCLC 
10%
30%
22
0.860
16
6.0
82.5
GIST
15%
40%
25
0.895
14
5.9
88
Section 11.4.1.
Primary Analysis
Rationale for Change: Addition of PSA50 response information for CRPC and GIST 
analysis information.
Revised Text:
Fourth paragraph onwards
PSA 50 Response rate (RR) is defined as the response rate that a PSA reduction from 
baseline ≥50% is observed at 12 weeks and beyond (must be confirmed by a second 
value). RR will be reported for CRPC cohort along with the exact 95% confidence 
interval. Waterfall plots will be presented that show the maximum percentage of change 
in PSA reduction from baseline.
Disease Control Rate (DCR) is defined as the percentage of subjects who achieved CR, 
PR or SD (defined as ≥16 weeks in duration) among subjects who received at least one 
dose of treatment. Disease control rate and the associated 2-sided 95% exact confidence 
limits will be provided separately for GIST cohort.
Section 14 APPENDICES
Heading of subsection 14.3 is modified Section 
Rationale for Change: Fever and diarrhea guidelines were removed. Fever was removed 
as this has not been seen clinically and diarrhea was removed because guidance is 
presented in Table 24. The Liver Events section was then reorganized with updated tables 
and figures, though the stopping criteria have not changed.


2011N118599_09
CONFIDENTIAL
BET115521
488
Revised Text:
Section 14.3. Appendix 3: Dose Adjustment/Stopping Criteria/Supportive 
CareLiver Events
Section 14.3.
Revised Text:
Subpoints I and II under section 14.3 is deleted
I.Fever
Safety monitoring cytokine blood samples may be collected (based on Table 23 of the 
protocol). These samples include (but not limited to) assessments for TNF-alpha, IL-1,IL-
6, IL-10 as outlined in the SPM. 
Assess or inquire if the subject is experiencing in combination with fever: swelling, 
redness, extreme fatigue or nausea. 
II.Diarrhea
General considerations for diarrhea management
Rule out other or concomitant causes. These include medications (e.g., stool softeners, 
laxatives, antacids, etc), infection by C. difficile or Candida species, partial bowel 
obstruction, malabsorption/lactose intolerance, fecal impaction, diets high in fiber or 
lactose.
For uncomplicated Grade 1 to 2 diarrhea (i.e., mild to moderate and defined as 
CTCAE Grade 1-2 with no complicating signs or symptoms):

Dietary modifications: stop all lactose containing products and eat small meals. A 
BRAT (banana, rice, apples, toast) diet can be helpful.

Hydration: drink 8-10 large glasses of clear liquids per day (e.g., Gatorade or broth)

Consider administration of standard dose of loperamide (subjects should have 
loperamide available in order to start at the first signs of diarrhea):

Initial dose of 4 mg followed by 2 mg every four hours or after every unformed 
stool; maximum 16 mg/day.

Continuation of loperamide is suggested until diarrhea free for 12 hours

Consider a temporary investigational drug dose interruption until symptoms have 
resolved to baseline or Grade 1. Re-treatment with GSK525762 may then be 
resumed at 100%. Please refer to for additional guidance.

If mild to moderate diarrhea persists for more than 24 hours, administer loperamide 2 
mg every two hours; maximum 16 mg/day. Consider adding oral antibiotics.


2011N118599_09
CONFIDENTIAL
BET115521
489

If mild to moderate diarrhea persists after 48 hours total treatment with loperamide, 
start second-line agents (otreotide, budesonide or tincture of opium). Consider 
adding oral antibiotics.
For Grade 3 to 4 diarrhea or complicated Grade 1 to 2 diarrhea (i.e., cramping,
nausea/vomiting ≥ Grade 2, decreased performance status, fever, sepsis, Grade 3 or 4 
neutropenia, frank bleeding, dehydration):

The subject must call the investigator immediately for any complicated severe 
diarrhea event.

Discontinue GSK1120212 treatment and hold until symptoms resolve to Grade 1 or 
baseline. Consider re-starting therapy at a reduced dose.

If loperamide has not been initiated, initiate loperamide immediately. Initial dose 4 
mg followed by 2 mg every two hours or after every unformed stool; maximum 16 
mg/day.

For dehydration, use intravenous fluids as appropriate; if severe dehydration, 
administer octreotide.

Administer antibiotics as needed (e.g., fluoroquinolones), especially if diarrhea is 
persistent beyond 24 hours or there is fever or Grade 3 to 4 neutropenia.

Intervention should be continued until the subject is diarrhea free for at least 24 
hours.

Intervention may require hospitalization for subjects most at risk for life-threatening 
complications.
III.Hepatobiliary Events
Monitoring, Interruption, and Stopping Criteria for Hepatobiliary Events
Liver chemistry stopping criteria are defined as follows: 
ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin) (or ALT3xULN and 
INR>1.5, if INR measured)
*serum bilirubin fractionation should be performed if testing is available; if unavailable, 
withdraw subject (if ALT 3xULN and total bilirubin 2xULN) and measure urinary 
bilirubin via dipstick
** INR testing not required per protocol and the threshold value does not apply to 
subjects receiving anticoagulants
ALT 5xULN.
ALT 3xULN if associated with symptoms (new or worsening) believed to be related to 
hepatitis (such as fatigue, nausea, vomiting, right upper quadrant pain or tenderness or 
jaundice) or hypersensitivity (such as fever, rash or eosinophilia)
ALT 3xULN persists for 4 weeks.


2011N118599_09
CONFIDENTIAL
BET115521
490
ALT 3xULN and cannot be monitored weekly for 4 weeks.
Subjects with ALT 3xULN and < 5xULN and bilirubin < 2xULN, who do not exhibit 
hepatitis symptoms or rash, can continue study treatment as long as they can be 
monitored weekly for 4 weeks. 
Refer to the diagram in Figure 7 for a visual presentation of the procedures listed 
below. When any of the liver chemistry stopping criteria is met, do the following:

Immediately discontinue subject from study treatment 

Notify the GSK Medical Monitor within 24 hours of learning of the abnormality to 
confirm the subject’s study treatment cessation and follow-up

Complete the liver event case report forms. If the event also meets the criteria of an 
SAE (see Section 6.9.2 of the protocol), the SAE data collection tool will be 
completed separately with the relevant details

All events of ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin) (or 
ALT3xULN and INR>1.5, if INR measured; INR measurement is not required 
and the threshold value stated will not apply to subjects receiving 
anticoagulants), termed ‘Hy’s Law’, must be reported as an SAE (excluding 
studies of hepatic impairment or cirrhosis).

NOTE: if serum bilirubin fractionation is not immediately available, and if 
ALT≥ 3xULN and bilirubin ≥ 2xULN, discontinue subject from study treatment. 
Serum bilirubin fractionation should be performed if testing is available. If 
testing is unavailable, record presence of detectable urinary bilirubin on 
dipstick, indicating direct bilirubin elevations and suggesting liver injury

Complete the liver imaging and/or liver biopsy CRFs if these tests are performed

Perform liver event follow up assessments as outlined below, and monitor the subject 
until liver chemistries resolve, stabilize, or return to baseline values as described 
below

For studies where survival or progression is an endpoint, follow-up for overall 
survival or progression is required following discontinuation from study treatment. 

Do not restart investigational product unless written approval is granted by GSK 
Medical Governance, whereupon the subject continues in the study after completion 
of the liver chemistry monitoring. See Section IIIc of Appendix 3 for drug 
restart/rechallenge process.
In addition, for subjects meeting liver stopping criterion 1: 

Make every reasonable attempt to have subjects return to clinic within 24 hours for 
repeat liver chemistries, liver event follow up assessments (refer to Section IIIa of 
Appendix 3), and close monitoring

A specialist or hepatology consultation is recommended

Monitor subjects twice weekly until liver chemistries (ALT, AST, alkaline 
phosphatase, bilirubin) resolve, stabilize or return to within baseline values.


2011N118599_09
CONFIDENTIAL
BET115521
491
For subjects meeting criteria 2-5:

Make every reasonable attempt to have subjects return to clinic within 24-72 hours
for repeat liver chemistries and liver event follow up assessments (refer to Section 
IIIa).

Monitor subjects weekly until liver chemistries (ALT, AST, alkaline phosphatase, 
bilirubin) resolve, stabilize or return to within baseline values; 

Subjects meeting criterion 5 should be monitored as frequently as possible.
Section 14.3.1
Section 14.3.1.IIIa.Liver Event Follow Up AssessmentsSafety Stopping Criteria and 
Required Actions and Follow Up Assessments
Phase I/II liver chemistry stopping and increased monitoring criteria have been 
designed to assure subject safety and evaluate liver event etiology (in alignment with the 
FDA premarketing clinical liver safety guidance). 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM174090.pdf.
Table 28
Phase I/II liver chemistry stopping criteria and required follow up 
assessments 
Liver Chemistry Stopping Criteria – Liver Stopping Event
ALT-absolute
ALT 5xULN
ALT Increase
ALT 3xULN persists for 4 weeks
Bilirubin1, 2
ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin) 
INR2
ALT 3xULN and INR>1.5, if INR measured
Cannot Monitor
ALT 3xULN and cannot be monitored weekly for 4 weeks
Symptomatic3
ALT 3xULN associated with symptoms (new or worsening) believed to be related 
to liver injury or hypersensitivity
Required Actions and Follow up Assessments following ANY Liver Stopping Event
Actions
Follow Up Assessments

Immediately discontinue study treatment

Report the event to GSK within 24 hours

Complete the liver event eCRF and complete 
an SAE data collection tool if the event also 
meets the criteria for an SAE2

Perform liver event follow up assessments 

Viral hepatitis serology4

Blood sample for pharmacokinetic (PK) analysis, 
obtained approximately 48h after last dose5

Serum creatine phosphokinase (CPK) and lactate 
dehydrogenase (LDH).

Fractionate bilirubin, if total bilirubin2xULN


2011N118599_09
CONFIDENTIAL
BET115521
492

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 Appendix7)

If restart/rechallenge is not granted, 
permanently discontinue study treatment and 
may continue subject in the study for any 
protocol specified follow up assessments
MONITORING:
For bilirubin or INR criteria: 

Repeat liver chemistries(include ALT, AST, 
alkaline phosphatase, bilirubin) and perform 
liver event follow up assessments within 24 
hrs

Monitor subjects twice weekly until liver 
chemistries resolve, stabilize or return to 
within baseline

A specialist or hepatology consultation is 
recommended
For All other criteria: 

Repeat liver chemistries(include ALT, AST, 
alkaline phosphatase, bilirubin) and perform 
liver event follow up assessments within 24-
72 hrs 

Monitor subjects weekly until liver chemistries 
resolve, stabilize or return to within baseline

Obtain complete blood count with differential to 
assess eosinophilia

Record the appearance or worsening of clinical 
symptoms of liver injury, or hypersensitivity, on the 
AE report form

Record use of concomitant medications on the 
concomitant medications report form including 
acetaminophen, herbal remedies, other over the 
counter medications

Record alcohol use on the liver event alcohol 
intake case report form
For bilirubin or INR criteria:

Anti-nuclear antibody, anti-smooth muscle 
antibody, Type 1 anti-liver kidney microsomal 
antibodies, and quantitative total immunoglobulin 
G (IgG or gamma globulins).

Serum acetaminophen adduct high pressure liquid 
chromatography (HPLC) assay (quantifies 
potential acetaminophen contribution to liver injury 
in subjects with definite or likely acetaminophen 
use in the preceding week [James, 2009]).

Liver imaging (ultrasound, magnetic resonance, or 
computerised tomography) and /or liver biopsy to 
evaluate liver disease; complete Liver Imaging 
and/or Liver Biopsy eCRF forms.
1.
Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin 
fractionation is not immediately available, discontinue study treatment for that subject if ALT 
3xULN and bilirubin 2xULN. Additionally, if serum bilirubin fractionation testing is 
unavailable, record presence of detectable urinary bilirubin on dipstick, indicating direct 
bilirubin elevations and suggesting liver injury. 
2.
All events of ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin) or ALT 3xULN and 
INR>1.5, if INR measured which may indicate severe liver injury (possible ‘Hy’s Law’), must 
be reported as an SAE (excluding studies of hepatic impairment or cirrhosis); INR 
measurement is not required and the threshold value stated will not apply to subjects 
receiving anticoagulants
3.
New or worsening symptoms believed to be related to liver injury (such as fatigue, nausea, 
vomiting, right upper quadrant pain or tenderness, or jaundice) or believed to be related to 
hypersensitivity (such as fever, rash or eosinophilia)
4.
Includes: Hepatitis A IgM antibody; Hepatitis B surface antigen and Hepatitis B Core Antibody 
(IgM); Hepatitis C RNA; Cytomegalovirus IgM antibody; Epstein-Barr viral capsid antigen IgM 
antibody (or if unavailable, obtain heterophile antibody or monospot testing); Hepatitis E IgM 
antibody 
5.
Record the date/time of the PK blood sample draw and the date/time of the last dose of study 


2011N118599_09
CONFIDENTIAL
BET115521
493
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.
Table 29
Phase I/II Oncology liver chemistry increased monitoring criteria 
with continued therapy
Liver Chemistry Increased Monitoring Criteria – Liver Monitoring Event
Criteria
Actions
ALT 3xULN but <5xULN and
bilirubin <2xULN, without symptoms believed to 
be related to liver injury or hypersensitivity and
who can be monitored weekly for 4 weeks

Notify the GSK medical monitor within 24 hours of 
learning of the abnormality to discuss subject 
safety. 

Subject can continue study treatment

Subject must return weekly for repeat liver 
chemistries (ALT, AST, alkaline phosphatase, 
bilirubin) until they resolve, stabilise or return to 
within baseline1

If at any time subject meets the liver chemistry 
stopping criteria, proceed as described above

If, after 4 weeks of monitoring, ALT <3xULN and 
bilirubin <2xULN, monitor subjects twice monthly 
until liver chemistries normalize or return to within 
baseline.
1.
For the purpose of these guidelines “baseline” refers to laboratory assessments performed closest and prior 
to first dose of study treatment
References
James LP, Letzig L, Simpson PM, Capparelli E, Roberts DW, Hinson JA, Davern TJ, Lee 
WM. Pharmacokinetics of Acetaminophen-Adduct in Adults with Acetaminophen 
Overdose and Acute Liver Failure. Drug Metab Dispos 2009; 37:1779-1784.
For subjects meeting any of the liver chemistry stopping criteria, make every attempt to 
carry out the liver event follow up assessments described below:

Viral hepatitis serology including:

Hepatitis A Immunoglobulin M (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) 


2011N118599_09
CONFIDENTIAL
BET115521
494

Hepatitis E IgM antibody.

Blood sample for pharmacokinetic (PK) analysis, obtained within 2 days of last dose. 
Record the date/time of the PK blood sample draw and the date/time of the last dose 
of study treatment prior to blood sample draw on the CRF. If the date or time of the 
last dose is unclear, provide the subject’s best approximation. If the date/time of the 
last dose cannot be approximated OR a PK sample cannot be collected in the time 
period indicated above, do not obtain a PK sample. Instructions for sample handling 
and shipping are in the SPM. 

Serum creatine phosphokinase (CPK) and lactate dehydrogenase (LDH).

Fractionate bilirubin, if total bilirubin 2xULN.

Obtain complete blood count with differential to assess eosinophilia.

Record the appearance or worsening of clinical symptoms of hepatitis, or 
hypersensitivity, such as fatigue, nausea, vomiting, right upper quadrant pain or 
tenderness, fever, rash or eosinophilia as relevant on the AE form.

Record use of concomitant medications such as acetaminophen, herbal remedies, 
other over the counter medications, or putative hepatotoxins, on the Concomitant 
Medications CRF page.J

Record alcohol use on the Liver Event CRF page.
The following assessments are required for subjects with ALT 3xULN and bilirubin 
2xULN (>35% direct) but are optional for other abnormal liver chemistries:

Anti-nuclear antibody, anti-smooth muscle antibody, and Type 1 anti-liver kidney 
microsomal antibodies, and quantitative total immunoglobulin G (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]).

Only in those with underlying chronic hepatitis B at study entry (identified by 
positive hepatitis B surface antigen): quantitative hepatitis B DNA and hepatitis delta 
antibody

Liver imaging (ultrasound, magnetic resonance, or computerized tomography) to 
evaluate liver disease. The Liver Imaging and/or Liver Biopsy CRF pages are also to 
be completed if these tests are performed.
IIIb.Liver Chemistry Monitoring Criteria
For subjects with ALT 3xULN but <5xULN and bilirubin <2xULN, without hepatitis 
symptoms or rash, and who can be monitored weekly for 4 weeks, the following actions 
should be taken:

Notify the GSK Medical Monitor within 24 hours of learning of the abnormality to 
discuss subject safety


2011N118599_09
CONFIDENTIAL
BET115521
495

Subject can continue study treatment if liver chemistries (ALT, AST, alkaline 
phosphatase, bilirubin) can be monitored weekly for up to 4 weeks

If at any point these subjects meet the liver chemistry stopping criteria, immediately 
withdraw study treatment, perform additional testing and continue safety follow-up 
until liver chemistries resolve, stabilize or return to baseline values

If, after 4 weeks of monitoring, ALT <3xULN and bilirubin <2xULN, monitor 
subjects twice monthly until liver chemistries normalize or return to within baseline 
values. 
Refer to Figure 7 for the algorithm of liver chemistry monitoring, stopping and follow up 
criteria.
Figure 7 Liver Safety Algorithms
Phase II Liver Safety Algorithms
ALT>3xULN
plus Bilirubin>2xULN 
(>35% direct) (or plus
INR>1.5, if measured)*
No
Yes
Yes
•Instruct subject to stop investigational product (IP)
•Notify GSK + arrange clinical followup within 24-72h
•Perform liver chemistries and liver event follow up 
assessments (serology, PK sample etc as in protocol) 
•Complete liver event CRF, SAE data collection tool if 
appropriate, + liver imaging +/or biopsy CRFs if these 
tests performed.
•Obtain weekly liver chemistries [**as far as possible] 
until resolved, stabilised or returned to baseline 
•Withdraw subject from study after liver chemistry 
monitoring complete + do not re-challenge with IP
•Instruct subject to stop investigational product (IP)
•Notify GSK + arrange clinical followup within 24h
•Perform liver chemistries and liver event follow up 
assessments (serology, PK sample etc as in protocol) 
•Report as an SAE (excl. hepatic impairment or cirrhosis 
studies)+ and complete liver event CRF, SAE data 
collection tool, + liver imaging +/or biopsy CRFs if tests 
performed.
•Obtain twice weekly liver chemistries until resolved, 
stabilised or returned to baseline values
•Consultation with hepatologist/specialist recommended
•Withdraw subject from study after liver chemistry 
monitoring complete + do not re-challenge with IP
ALT>5xULN
Hepatitis 
symptoms
or rash?
No
Able to 
monitor weekly                       
for 4 wks?
No
Notify GSK within 24h to 
discuss subject safety
Continue IP
Check liver chemistry 
weekly for 4 weeks
No
No**
Yes
Yes
Continue IP
Obtain twice monthly liver 
chemistries until normalised
or back to baseline values
Yes
Yes
ALT>3xULN or bilrubin >2xULN?
Yes
*INR value not applicable to patients on anticoagulants
14.3.2 IIIc.Liver Safety Drug Restart Guidelines
If subject meets liver chemistry stopping criteria do not restart/rechallenge subject with 
study treatment unless:

GSK Medical Governance approval is granted (as described below),

Ethics and/or IRB approval is obtained, if required, and

Separate consent for treatment restart/rechallenge is signed by the subject


2011N118599_09
CONFIDENTIAL
BET115521
496
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
14.3.2.1 Rechallenge Following Liver Stopping Events that are Possibly Related to 
Study Treatment
Following drug-induced liver injury, drug rechallenge is associated with a 13% 
mortality across all drugs in prospective studies [Andarde, 2009]. Clinical outcomes 
vary by drug, with nearly 50% fatality with halothane readministered within one month 
of initial injury. However, some drugs seldom result in recurrent liver injury or fatality. 
Risk factors for a fatal drug rechallenge outcome include:

hypersensitivity with initial liver injury (e.g. fever, rash, eosinophilia) 
[Andarde, 2009] 

jaundice or bilirubin >2xULN with initial liver injury (direct bilirubin >35% of 
total)

subject currently exhibits severe liver injury defined by: ALT 3xULN, 
bilirubin 2xULN (direct bilirubin >35% of total), or INR1.5

serious adverse event or fatality has earlier been observed with drug 
rechallenges [Papay, 2009]

evidence of drug-related preclinical liability (e.g. reactive metabolites; 
mitochondrial impairment [Hunt, 2010])
Rechallenge refers to resuming study treatment following drug induced liver injury 
(DILI). Because of the risks associated with rechallenge after DILI this should only be 
considered for a subject for whom there is compelling evidence of benefit from a critical 
or life-saving medicine, there is no alternative approved medicine available, and a 
benefit:risk assessment of rechallenge is considered to be favourable.
Approval by GSK for rechallenge with study treatment can be considered where:

Investigator requests consideration of rechallenge with study treatment for a subject 
who is receiving compelling benefit with study treatment that exceeds risk, and no 
effective alternative therapy is available. 

Ethics Committee or Institutional Review Board approval for rechallenge with study 
treatment must be obtained, as required.  

If the rechallenge is approved by GSK Medical Governance in writing, the subject 
must be provided with a clear description of the possible benefits and risks of study 
treatment administration, including the possibility of recurrent, more severe liver 
injury or death. 

The subject must also provide signed informed consent specifically for the 
rechallenge with study treatment. Documentation of informed consent must be 
recorded in the study chart. 


2011N118599_09
CONFIDENTIAL
BET115521
497

Study treatment must be administered at the dose specified by GSK.

Subjects approved by GSK Medical Governance for rechallenge with study 
treatment must return to the clinic twice a week for liver chemistry tests until stable 
liver chemistries have been demonstrated and then standard laboratory monitoring 
may resume as per protocol.

If after study treatment rechallenge, subject meets protocol-defined liver chemistry 
stopping criteria, study treatment should be permanently discontinued. 

Medical Monitor, and the Ethics Committee or Institutional Review Board as 
required, must be informed of the subject’s outcome following study treatment 
rechallenge. 

GSK to be notified of any adverse events, as per Section 6.9..
14.3.2.2.
Restart Following Transient Resolving Liver Stopping Events 
NOT Related to Study Treatment
Restart refers to resuming study treatment following liver stopping events in which there 
is a clear underlying cause (other than DILI) of the liver event (e.g. biliary obstruction, 
pancreatic events, hypotension, acute viral hepatitis). Furthermore, there should be no 
evidence of alcoholic hepatitis or hypersensitivity, and the study treatment should not be 
associated with HLA markers of liver injury.
Approval by GSK for study treatment restart can be considered where:

Investigator requests consideration for study treatment restart if liver chemistries 
have a clear underlying cause (e.g., biliary obstruction, hypotension and liver 
chemistries have improved to normal or are within 1.5 x baseline and ALT 
<3xULN).

Restart risk factors (e.g. fever, rash, eosinophilia, or hypersensitivity, alcoholic 
hepatitis, possible study treatment-induced liver injury or study treatment has an 
HLA genetic marker associated with liver injury (e.g. lapatinib, abacavir, 
amoxicillin/clavulanate) are reviewed and excluded

Ethics Committee or Institutional Review Board approval of study treatment restart 
must be obtained, as required.

If restart of study treatment is approved by GSK Medical Governance in writing, the 
subject must be provided with a clear description of the possible benefits and risks of 
study treatment administration, including the possibility of recurrent, more severe 
liver injury or death. 

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.


2011N118599_09
CONFIDENTIAL
BET115521
498

Subjects approved by GSK Medical Governance for restarting study treatment must 
return to the clinic once a week for liver chemistry tests until stable liver chemistries 
have been demonstrated and then laboratory monitoring may resume as per protocol. 

If after study treatment re-start, subject meets protocol-defined liver chemistry 
stopping criteria, follow usual stopping criteria instructions.

Medical Monitor, and the Ethics Committee or Institutional Review Board as 
required, must be informed of the subject’s outcome following study treatment 
restart. 

GSK, or designee, to be notified of any adverse events, as per Section 6.9.
References:
Andrade RJ, Robles M, Lucena MI. Rechallenge in drug-induced liver injury: the 
attractive hazard. Expert Opin Drug Saf. 2009;8:709-714.
Hunt, CM. Mitochondrial and immunoallergic injury increase risk of positive drug 
rechallenge after drug-induced liver injury: A systematic review. Hepatol. 2010;52:2216-
2222.
Papay JI, Clines D, Rafi R, Yuen N, Britt SD, Walsh JS, et al. Drug-induced liver injury 
following positive drug rechallenge. Regul Tox Pharm. 2009;54:84-90. 
Drug restart may be considered for a subject exhibiting compelling benefit for a critical 
medicine following drug-induced liver injury, if there is favorable benefit: risk ratio and 
no alternative medicine available.
Background Information on Drug Restart/Rechallenge
Following drug-induced liver injury, drug restart or rechallenge is associated with a 
13% mortality across all drugs in prospective studies (Expert Opin Drug Saf 
2009;8:709-714). Clinical outcomes vary by drug, with nearly 50% fatality with 
halothane readministered in one month of initial injury. However, some drugs seldom 
result in recurrent liver injury or fatality. Risk factors for a fatal drug restart/rechallenge 
outcome include: hypersensitivity1 with initial liver injury (e.g. fever, rash, eosinophilia), 
jaundice or bilirubin>2xULN or INR>1.5 suggesting severe liver injury, prior IP-related 
severe or fatal drug restart/rechallenge (Papay, 2009; Hunt, 2010) or evidence of drug-
related preclinical liability / mitochondrial impairment (Hunt, 2010).


2011N118599_09
CONFIDENTIAL
BET115521
499
Drug Restart/Rechallenge Process (also see Figure8)
Principal Investigator (PI) requests consideration of drug restart for a subject receiving 
compelling benefit from a critical or life-saving drug, who exhibits liver chemistry 
elevation meeting subject stopping criteria, with no alternative treatment.
GSK Medical Monitor & Clinical Safety Physician to review the subject’s 
restart/rechallenge risk factors & complete checklist (See Table below).
Checklist for drug restart/rechallenge for critical medicine (Following drug-induced 
liver injury, drug rechallenge is associated with 13% mortality across all drugs in 
prospective studies)
Yes
No
Compelling benefit of the investigational product (IP) for this subject 
and no alternative therapy. Provide brief explanation:
Relative benefit-risk favorable for drug restart/rechallenge, after 
considering the following high risk factors:
Initial liver injury event included: 
fever, rash, eosinophilia, or hypersensitivity
or bilirubin2xULN (direct bilirubin >35% of total)
Subject currently exhibits ALT 3xULN, bilirubin 2xULN (direct 
bilirubin >35% of total, if available), or INR1.5
Severe or fatal restart/rechallenge has earlier been observed with IP If 
yes, please provide brief explanation:
IP associated with known preclinical hepatic liability/ injury  
If GSK provides written approval for restart/rechallenge following the above review, the 
Principal Investigator (PI) must ensure the following:

The PI is to obtain Ethics Committee or Institutional Review Board review of 
drug reinitiation, as required. 

PI must discuss the possible benefits and risks of drug reinitiation with the 
subject.

The subject must sign informed consent with a clear description of possible 
benefits and risks of drug administration, including recurrent liver injury or 
death. Consent specifically for the IP restart must be recorded in the study chart.


2011N118599_09
CONFIDENTIAL
BET115521
500

The drug must be reinitiated at GSK approved dose(s). 

Subjects approved by GSK for restart of IP must return to the clinic twice a 
week for liver chemistry tests until stable, liver chemistries have been 
demonstrated and then laboratory monitoring may resume as per protocol. If 
protocol defined stopping criteria for liver chemistry elevations are met, study 
drug must be stopped. 

The Ethics Committee or Institutional Review Board is to be informed of the 
subject’s outcome, as required.

GSK is to be notified of any adverse events, as per Section 6.9 of the protocol.
Figure 8
Process for Drug Restart After Possible Drug-induced Liver Injury
Section 14.4.1.
Appendix 5: RECIST 1.1
I. Efficacy Assessment
Rationale for Change: Text added to section that was previously missing for 
clarification. 
Revised Text:
Fourth paragraph third sentence 


2011N118599_09
CONFIDENTIAL
BET115521
501
In addition, in order to assign a response of CR in a subject with bone disease at baseline, 
a bone scan must be performed within the timeframe of 1 week prior to the first of 
images showing CR to 4 weeks after the next protocol specified assessment.
II. Guidelines for Evaluation of Disease
Non-Measurable only disease: The presence of only non-measurable lesions. Note: non-
measurable only disease is not allowed per protocol.
IIId. Evaluation of overall response
Note Bullet point 3

The dosing schedule, dosing interruptions and design (see Table 2of the protocol 
Time and Events Tables) should be considered when assessing tumor response. 
Thus, subjects with PD before the Week 9 visit8, but without rapid clinical 
deterioration, may continue planned dosing schedule to allow detection of antitumor 
response. It is recommended that subjects who experience investigator-determined 
PD at the wWeek 9 visit8, at the discretion of the investigator, may receive 
additional tumor assessment before the initiation of alternative anticancer therapy. 
Section 14.8 is added
Rationale for Change: Added in case of use for countries participating in study.
Added Text:
14.7. Appendix 8: Country Specific Requirements
14.7.1.
Investigational Product Label
14.7.2.
Medical Devices Used in the Study

SAP_001.pdf: 
CONFIDENTIAL
The GlaxoSmithKline group of companies
BET115521
1
Division
:
Worldwide Development
Information Type
:
Reporting and Analysis Plan (RAP)
Title
:
Reporting and Analysis Plan for A Phase I/II Open-Label, 
Dose Escalation Study to Investigate the Safety, 
Pharmacokinetics, Pharmacodynamics, and Clinical Activity 
of GSK525762 in Subjects with NUT Midline Carcinoma 
(NMC) and Other Cancers
Compound Number 
:
GSK525762
Effective Date 
:
20-SEP-2016
Description :

The purpose of this RAP is to describe the planned analyses and output to be 
included in the Clinical Study Report for Protocol BET115521.

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 
Part 1 Interim Analysis and Statistical Analysis Complete (SAC) deliverable.
Author’s Name and Functional Area: 
20-SEP-2016
Manager  (Clinical Statistics)
20-SEP-2016
Principle Statistician (Clinical Statistics)
20-SEP-2016
Director (Clinical Pharmacology, CPMS)
20-SEP-2016
Manager (Clinical Programming)
Approved by: 
20-SEP-2016
Senior Statistics Director (Clinical Statistics)
Copyright 2019 the GlaxoSmithKline group of companies. All rights reserved.  
Unauthorised copying or use of this information is prohibited.
PPD
PPD
PPD
PPD
PPD


CONFIDENTIAL
BET115521
2
TABLE OF CONTENTS
PAGE
1.
REPORTING & ANALYSIS PLAN SYNPOSIS.........................................................5
2.
SUMMARY OF KEY PROTOCOL INFORMATION ..................................................9
2.1.
Changes to the Protocol Defined Statistical Analysis Plan............................9
2.2.
Study Objective(s) and Endpoint(s)...............................................................9
2.3.
Study Design ..............................................................................................11
2.4.
Statistical Hypotheses.................................................................................13
3.
PLANNED ANALYSES ..........................................................................................13
3.1.
Interim Analyses .........................................................................................13
3.1.1.
Part 1: Dose Escalation Phase ....................................................14
3.1.1.1.
Description of the New Continual 
Reassessment Method...............................................14
3.1.1.2.
Prior Probability Distribution .......................................15
3.1.1.3.
Displays To Be Created For Dose Escalation 
Review .......................................................................15
3.1.2.
Part 2: Expansion Phase .............................................................16
3.1.2.1.
Stopping Rules for Futility...........................................16
3.1.2.2.
Operating Characteristics of the Stopping 
Rules for Futility..........................................................21
3.1.2.3.
Displays To Be Created For Expansion Cohort 
Review .......................................................................22
3.2.
Final Analyses ............................................................................................23
4.
ANALYSIS POPULATIONS ...................................................................................23
4.1.
Protocol Deviations.....................................................................................24
5.
CONSIDERATIONS FOR DATA ANALYSES AND DATA HANDLING 
CONVENTIONS.....................................................................................................25
6.
STUDY POPULATION ANALYSES .......................................................................26
6.1.
Overview of Planned Analyses ...................................................................26
6.1.1.
Disposition of Subjects.................................................................26
6.1.2.
Protocol Deviations......................................................................27
6.1.3.
Demographic and Baseline Characteristics..................................27
6.1.4.
Treatment Compliance.................................................................27
6.1.5.
Concomitant Medications.............................................................27
6.1.6.
Subsequent Anti-Cancer Therapies .............................................28
7.
EFFICACY ANALYSES..........................................................................................29
7.1.
Overview of Planned Efficacy Analyses ......................................................29
7.2.
Primary Efficacy Analyses ..........................................................................30
7.3.
Secondary Efficacy Analyses......................................................................30
8.
SAFETY ANALYSES .............................................................................................33
8.1.
Overview of Planned Analyses ...................................................................33
8.2.
Extent of Exposure .....................................................................................34
8.3.
Adverse Events...........................................................................................34
8.3.1.
Adverse Events of Special Interest ..............................................35


CONFIDENTIAL
BET115521
3
8.3.2.
Deaths and Serious Adverse Events............................................36
8.3.3.
Adverse Events Leading to Discontinuation of Study 
Treatment and/or Withdrawal from the Study and Other 
Significant Adverse Events ..........................................................37
8.4.
Pregnancies................................................................................................37
8.5.
Clinical Laboratory Evaluations...................................................................38
8.5.1.
Analyses of Liver Function Tests .................................................39
8.6.
Other Safety Measures...............................................................................40
8.6.1.
Vital Signs....................................................................................40
8.6.2.
Performance Status.....................................................................40
8.6.3.
ECG.............................................................................................40
8.6.4.
LVEF ...........................................................................................41
8.6.5.
Liver Events.................................................................................41
9.
PHARMACOKINETIC ANALYSES.........................................................................41
9.1.
Overview of Planned Pharmacokinetic Analyses ........................................41
9.2.
Drug Concentration Measures ....................................................................42
9.3.
Pharmacokinetic Parameters......................................................................42
9.3.1.
Deriving Pharmacokinetic Parameters.........................................42
9.3.2.
Statistical Analysis of Pharmacokinetic Parameters.....................43
9.3.2.1.
Dose proportionality....................................................43
9.3.2.2.
Relative bioavailability of the besylate salt 
tablet to the amorphous free base tablet 
(Besylate Sub-Study)..................................................45
9.3.2.3.
Food effect with besylate salt tablet (Besylate 
Sub-Study) .................................................................46
9.3.2.4.
Relative Bioavailability of Solution to Besylate 
Salt Tablet (Besylate Sub-Study)................................47
9.4.
Population Pharmacokinetic (PopPK) Analyses..........................................47
10. PHARMACODYNAMIC ANALYSES.......................................................................48
10.1.
Overview of Planned Pharmacodynamic Analyses .....................................48
11. PHARMACOKINETIC / PHARMACODYNAMIC ANALYSES .................................48
12. REFERENCES.......................................................................................................49
13. APPENDICES........................................................................................................50
13.1.
Appendix 1: Time & Events.........................................................................51
13.1.1.
Protocol Defined Time & Events ..................................................51
13.2.
Appendix 2: Assessment Windows .............................................................52
13.3.
Appendix 3: Treatment States and Phases.................................................53
13.3.1.
Treatment Phases .......................................................................53
13.3.2.
Treatment States .........................................................................53
13.3.2.1.
Treatment States for Disease Response Data............53
13.3.2.2.
Treatment States for AE Data.....................................53
13.4.
Appendix 4: Data Display Standards & Handling Conventions....................55
13.4.1.
Study Treatment & Sub-group Display Descriptors......................55
13.4.2.
Baseline Definition & Derivations .................................................56
13.4.2.1.
Baseline Definitions....................................................56
13.4.2.2.
Derivations and Handling of Missing Baseline 
Data ...........................................................................56


CONFIDENTIAL
BET115521
4
13.4.3.
Reporting Process & Standards...................................................57
13.5.
Appendix 5: Derived and Transformed Data ...............................................59
13.5.1.
General........................................................................................59
13.5.2.
Study Population..........................................................................59
13.5.3.
Safety ..........................................................................................60
13.6.
Appendix 6: Premature Withdrawals & Handling of Missing Data ...............62
13.6.1.
Premature Withdrawals................................................................62
13.6.2.
Handling of Missing Data.............................................................62
13.6.2.1.
Handling of Missing and Partial Dates ........................62
13.7.
Appendix 7: Values of Potential Clinical Importance ...................................66
13.7.1.
Laboratory Values........................................................................66
13.7.2.
ECG.............................................................................................67
13.7.3.
Vital Signs....................................................................................67
13.7.4.
Left Ventricular Ejection Fraction .................................................67
13.8.
Appendix 8: Multicenter Studies..................................................................68
13.8.1.
Methods for Handling Centres .....................................................68
13.9.
Appendix 9: Model Checking and Diagnostics for Statistical 
Analyses.....................................................................................................69
13.10. Appendix 10 – Abbreviations & Trade Marks ..............................................70
13.10.1. Abbreviations...............................................................................70
13.10.2. Trademarks .................................................................................71
13.11. Appendix 11: List of Data Displays..............................................................72
13.11.1. Data Display Numbering..............................................................72
13.11.2. Mock Example Shell Referencing ................................................72
13.11.3. Deliverable [Priority].....................................................................72
13.12. Appendix 12: Example Mock Shells for Data Displays ................................73


CONFIDENTIAL
BET115521
5
1.
REPORTING & ANALYSIS PLAN SYNPOSIS
Overview
Key Elements of the RAP
Purpose

The purpose of this reporting and analysis plan (RAP) is to describe the planned 
analyses and output to be included in the Study Report for Protocol BET115521.  
This RAP is intended to describe the safety and efficacy analyses required for 
the study. This document will be provided to the study team members to convey 
the content of interim analysis and the Statistical Analysis Complete (SAC) 
deliverables.
Protocol

This RAP is based on the protocol amendment 6 [(Dated: 19/JUN/2015) of 
study BET115521(GSK Document Number. : 2011N118599_06] and eCRF 
Version 14.0
Primary 
Objective 

To determine the safety, tolerability and maximum tolerated dose (MTD) of 
GSK525762 in subjects 16 years or older following Once Daily (QD) and/or BID 
dosing schedules.

To evaluate the clinical activity of GSK525762 in NMC and other solid tumors.

To evaluate, after single dose administration, the relative bioavailability of the 
GSK525762 besylate tablet compared to the amorphous free-base tablet, the 
effect of high-fat high-calorie meal on the bioavailability of the besylate tablet 
and the dose proportionality of two doses of GSK525762 administered as the 
besylate tablets.
Primary 
Endpoint

AEs, SAEs, dose reductions or delays, withdrawals due to toxicities and 
changes in safety assessments (e.g., laboratory parameters, vital signs, 
Electrocardiogram( ECG), cardiotoxicity, gastrointestinal, etc) to determine the 
MTD in subjects 16 years or older

Assess overall response rate (ORR) by RECIST 1.1 in NMC and other solid 
tumors.

Pharmacokinetic (PK) parameter values for GSK525762 following single oral 
administration as amorphous free-base or besylate tablet
Study 
Design

Part 1 of the study is a dose escalation phase to determine the maximum 
tolerated dose (MTD) and select a recommended dose for Part 2 or a 
recommended Phase 2 dose (RP2D) based on the safety, pharmacokinetic, and 
pharmacodynamic profiles observed after oral administration of GSK525762. 
Eligible subjects with NUT midline carcinoma (NMC), small cell lung cancer 
(SCLC), non-small cell lung cancer (NSCLC), colorectal cancer (CRC), 
neuroblastoma (NB), castration resistant prostate cancer (CRPC), triple negative 
breast cancer (TNBC), estrogen receptor positive (ER positive) breast cancer, 
and any other MYCN-amplified solid tumor will be enrolled in the dosing cohorts 
until a maximum tolerated dose (MTD) is established.  Subjects with NMC will 
also be enrolled in a pharmacodynamic dose expansion cohort during Part 1.  
Subjects may continue treatment in the study until disease progression, 
unacceptable toxicity, or withdrawal of consent.   

Part 1 besylate sub-study will explore the relative bioavailability, food effect and 


CONFIDENTIAL
BET115521
6
Overview
Key Elements of the RAP
dose proportionality of besylate formulation. The sub-study will be conducted at 
active centers in the United States in subjects eligible for Part 1 at the MTD or a 
dose near the MTD or RP2D. This will be an open-label, randomized, single 
dose, four period, cross over sub-study to investigate the relative bioavailability 
of the besylate tablet compared to the amorphous free-base tablet, the effect of 
high-fat high-calorie meal on the bioavailability of the besylate tablet and the 
dose proportionality of two doses of GSK525762 administered as besylate 
tablets.
Besylate Sub-Study: Single Dose PK Evaluation
Sample 
Size
Sequence
Period 1
(Week 1 Day 
1)
Period 2
(Week 1 Day 3)
Period 3
(Week 2 
Day 1)
Period 4
(Week 2 
Day 3)
6
1
Treatment A2
Treatment B
Treatment C
Treatment D
6
2
Treatment B
Treatment A2
Treatment C
Treatment D
Treatment A: 80mg QD amorphous free-base tablet + low dose (6mg) stable isotope in 
solution, fasted administration
Treatment B: 80mg QD besylate tablet + low dose (6mg) stable isotope in solution, fasted 
administration
Treatment C: 30mg QD besylate tablet + low dose (6mg) stable isotope in solution, fasted 
administration 
Treatment D: 80mg QD besylate tablet, fed administration with FDA recommended high 
fat breakfast
Planned 
Analyses
Two formal interim analyses will be performed for Part 1 of the study. The interim 
analysis on Part 1 will be conducted when 

All subjects enrolled in Part 1 QD dosing have had at least two post-baseline 
disease assessments or progressed or died or withdrawn from the study. 

All subjects enrolled in Part 1 BID dosing have had at least two post-
baseline disease assessments or progressed or died or withdrawn from the 
study
During Part 2 (Expansion Cohort), regular futility analyses of response data will be 
conducted in order to determine whether the futility criteria for stopping have been 
met. The study will not be stopped early for positive response based on success 
criteria. 

For each expansion cohort, after the initial evaluable10 subjects have enrolled at 
the RP2D dose, response data will be reviewed on an ongoing and the cohort 
may be stopped for lack of evidence of efficacy (i.e. futility). 
Final analyses will be carried-out at the time when 70% of all Part 2 subjects have 
progressed or died following the DBF (data base frozen) for Part 1 and DBF (data 


CONFIDENTIAL
BET115521
7
Overview
Key Elements of the RAP
base frozen) for Part 2 after all the data queries have been resolved.
Analysis 
Populations

All Evaluable Subjects : This population will consist of all subjects that who 
have at least two post-dose disease assessment and been exposed to study 
drug for at least 28 days or have progressed or have died or have withdrawn 
from the study due to any reason.

All Treated Subjects : This population will consist of all subjects that received at 
least one dose of study treatment

PK Concentration Population : This population will consist of all subjects in the 
All Treated Subject Population for whom a blood sample for pharmacokinetics 
is obtained and analyzed

PK Parameter Population: This population will consist of all subjects in the PK 
Concentration Population for whom a PK parameter has been obtained

Besylate Sub-Study PK Parameter Population: This population will consist of all 
subjects in the PK Parameter Population who participated in the besylate sub-
study. Any PK parameters obtained from a treatment that deviates from the 
assigned treatment won’t be included in the primary relative bioavailability, food 
effect, or dose proportionality analyses

PD Population : This population will consist of subjects in the All Treated 
Subjects Population for whom a sample was obtained and analyzed for 
biomarkers
Hypothesis
No formal statistical hypotheses will be tested in Part 1. Analysis will be descriptive 
and exploratory. 
The primary goal of Part 2 is to demonstrate a clinically meaningful response, 
defined as follows: 
NMC: this will be determined by testing the null hypothesis that the response 
rate is ≤5%, with about 80% power when the true response rate is 20%.
Small cell lung cancer (SCLC) and Castrate-Resistant Prostate Cancer 
(CRPC): this will be determined by testing the null hypothesis that the 
response rate is ≤10%, with about 80% power when the true response rate 
is 30%.
ER+BC: this will be determined by testing the null hypothesis that the 
response rate is ≤15%, with about 80% power when the true response rate 
is 30%.
Triple Negative Breast Cancer (TNBC): this will be determined by testing the 
null hypothesis that the response rate is ≤10%, with about 80% power when 
the true response rate is 25%.
Primary 
Analyses

Safety: The All-Treated Subjects population will be used for the reporting and 
analysis of safety data.  Some safety data may also be summarized separately 
by age, race, gender or other factors as needed. Summaries on extent of 
exposure, Adverse Events, clinical laboratory test results, vital signs, ECG , 


CONFIDENTIAL
BET115521
8
Overview
Key Elements of the RAP
LVEF and liver events will  be provided.

Efficacy: This study employs response criteria from RECIST version 1.1. The 
Overall Response Rate (ORR) is defined as the percentage of subjects 
achieving a confirmed Complete Response (CR) or Partial Response (PR) from 
the start of treatment until disease progression or the start of new anti-cancer 
therapy. Summaries of ORR by dose and tumor types will be provided.

PK analysis:  The pharmacokinetic (PK) analyses will be based on the PK 
Concentration, PK Parameter and Besylate Sub-Study PK Parameter 
populations, unless otherwise specified.
Secondary 
Analyses
The secondary efficacy analyses on PFS (Progression Free Survival), OS (Overall 
Survival), DOR (Duration of Response), and TTR (Time to Response) will be based 
on the All Treated Subjects population, unless otherwise specified.


CONFIDENTIAL
BET115521
9
2.
SUMMARY OF KEY PROTOCOL INFORMATION
2.1.
Changes to the Protocol Defined Statistical Analysis Plan
There were no changes or deviations to the originally planned statistical analysis 
specified in the protocol amendment 7 (Dated: 10/MAR/2016).
2.2.
Study Objective(s) and Endpoint(s)
Objectives
Endpoints
Primary Objectives
Primary Endpoints

To determine the safety, tolerability 
and maximum tolerated dose 
(MTD) of GSK525762 in subjects 
16 years or older following Once 
Daily (QD) and/or BID dosing
schedules.

AEs, SAEs, dose reductions or delays, withdrawals 
due to toxicities and changes in safety assessments 
(e.g., laboratory parameters, vital signs, 
Electrocardiogram( ECG), cardiotoxicity, 
gastrointestinal, etc) to determine the MTD in 
subjects 16 years or older

To evaluate the clinical activity of 
GSK525762 in NMC and other 
solid tumors.

Assess overall response rate (RR) by RECIST 1.1 in 
NMC and other solid tumors.

To evaluate, after single dose 
administration, the relative 
bioavailability of the GSK525762 
besylate tablet compared to the 
amorphous free-base tablet, the 
effect of high-fat high-calorie meal 
on the bioavailability of the besylate 
tablet and the dose proportionality 
of two doses of GSK525762 
administered as the besylate 
tablets.

Pharmacokinetic (PK) parameter values for 
GSK525762 following single oral administration as 
amorphous free-base or besylate tablet
Secondary Objectives
Secondary Endpoints

To characterize the 
pharmacokinetics (PK) of 
GSK525762 in subjects 16 years or 
older following QD and/or BID 
dosing schedules. 

PK parameter values for GSK525762 following single 
and repeat-dose oral administration in subjects 16 
years or older

To evaluate cardiac safety, 
including the potential for QT 
duration corrected for heart rate by 
Fridericia’s formula (QTcF)
changes with GSK525762 and to 
assess PK/QTcF relationship 
following QD and/or BID dosing 
schedules.

Changes in cardiac safety including QTcF following 
single and repeat-dose oral administration 
GSK525762.


CONFIDENTIAL
BET115521
10
Objectives
Endpoints

To evaluate the exposure response 
(pharmacokinetic/pharmacodynami
c [PK/PD]) relationship between 
GSK525762 and safety and 
efficacy parameters following QD 
and/or BID dosing schedules.

To evaluate the effect of treatment 
with GSK525762 on tumor growth 
and survival.

Progression free survival (PFS), time to response, 
duration of response, overall survival (OS), and 
exploratory analysis for antitumor response by 
various imaging modalities.
Exploratory Objectives
Exploratory Endpoints

To evaluate the effect of 
GSK525762 on tumor biology

Dose related changes in markers of cell proliferation 
and/or cell differentiation in tumor and/or surrogate 
tissue

Correlation of GSK525762 
exposure to changes in PD 
markers in tumor and/or surrogate 
tissue 

Dose related changes in transcription of genes 
and/or changes in expression of proteins regulated 
by BRD proteins in tumor and/or surrogate tissue

To identify potential indicators of 
sensitivity or response to 
GSK525762.

PK/PD parameter values for exposure response (by 
RECIST and 18FDG-PET [if data allows]) 
relationship between GSK525762 exposure and 
QTcF, troponin and tumor response following single 
and repeat-dose oral administration.

To evaluate systemic and ex vivo 
on-target BET inhibitory effects.

Changes from baseline and dose/response 
relationship in ex vivo Lipopolysaccharide (LPS) 
induced cytokines including Interleukin 6 (IL-6) in 
whole blood and systemic cytokines including IL-6.


CONFIDENTIAL
BET115521
11
2.3.
Study Design
Overview of Study Design and Key Features
Design
Features

Part 1 of the study is a dose escalation phase to determine the maximum 
tolerated dose (MTD) and select a recommended dose for Part 2 or a 
recommended Phase 2 dose (RP2D) based on the safety, pharmacokinetic, 
and pharmacodynamic profiles observed after oral administration of 
GSK525762. Eligible subjects with NUT midline carcinoma (NMC), small cell 
lung cancer (SCLC), non-small cell lung cancer (NSCLC), colorectal cancer 
(CRC), neuroblastoma (NB), castration resistant prostate cancer (CRPC), triple 
negative breast cancer (TNBC), estrogen receptor positive (ER positive) breast 
cancer, and any other MYCN-amplified solid tumor will be enrolled in the 
dosing cohorts until a maximum tolerated dose (MTD) is established.  Subjects 
with NMC will also be enrolled in a pharmacodynamic dose expansion cohort 
during Part 1.  Subjects may continue treatment in the study until disease 
progression, unacceptable toxicity, or withdrawal of consent.   

Part 1 besylate sub-study will explore the relative bioavailability, food effect and 
dose proportionality of besylate formulation. The sub-study will be conducted at 
active centers in the United States in subjects eligible for Part 1 at the MTD or a 
dose near the MTD or RP2D. This will be an open-label, randomized, single 
dose, four period, cross over sub-study to investigate the relative bioavailability 
of the besylate tablet compared to the amorphous free-base tablet, the effect of 
high-fat high-calorie meal on the bioavailability of the besylate tablet and the 
dose proportionality of two doses of GSK525762 administered as besylate 
tablets.
Besylate Sub-Study: Single Dose PK Evaluation
Sample 
Size
Sequence
Period 1
(Week 1 Day 
1)
Period 2
(Week 1 Day 3)
Period 3
(Week 2 
Day 1)
Period 4
(Week 2 
Day 3)
6
1
Treatment A2
Treatment B
Treatment C
Treatment D
6
2
Treatment B
Treatment A2
Treatment C
Treatment D
Treatment A: 80mg QD amorphous free-base tablet + low dose (6mg) stable isotope in 
solution, fasted administration
Treatment B: 80mg QD besylate tablet + low dose (6mg) stable isotope in solution, 
fasted administration
Treatment C: 30mg QD besylate tablet + low dose (6mg) stable isotope in solution, 
fasted administration 
Treatment D: 80mg QD besylate tablet, fed administration with FDA recommended high 
fat breakfast

Part 2 is an expansion cohort planned to further explore clinical activity at the 
MTD in NMC, SCLC, CRPC, and TNBC and ER positive BC subjects.


CONFIDENTIAL
BET115521
12
Overview of Study Design and Key Features
  
Dosing

Starting dose will be 2 mg, orally (tablets), once a day. Dose escalations will be 
performed in Part 1 and dose adjustments are allowed to address tolerability 
and safety issues. Alternate dosing schedules (BID or intermittent dosing) may 
be used based on PK and safety.

Subjects enrolled in the Part 1 dose escalation phase will be administered 
GSK525762 as an amorphous tablet.

Subjects enrolled in the Part 2 dose expansion phase will be administered 
GSK525762 as a besylate tablet.
Treatment 
Assignment

This is a non-randomized open-label study.  
Interim 
Analysis

An interim analysis of the key parameters may be carried-out before the 
conclusion of the study. Full details of procedures and of the analyses planned 
at the interim analysis will be provided in the Reporting and Analysis Plan 
(RAP).

Two formal interim analyses will be performed for Part 1 of the study. The 
interim analysis on Part 1 will be conducted when 

All subjects enrolled in Part 1 QD dosing, including subjects enrolled in the 
Besylate Sub-Study, have had at least two post-baseline disease 
assessments or progressed or died or withdrawn from the study. 

All subjects enrolled in Part 1 BID dosing have had at least two post-
baseline disease assessments or progressed or died or withdrawn from 
the study

An interim analysis of the Part 1 Besylate Sub-Study will be conducted 


CONFIDENTIAL
BET115521
13
Overview of Study Design and Key Features
once the last patient enrolled in the Besylate Sub-Study completes their final 
respective PK blood draw for analysis. This interim analysis will not be a 
formal analysis, but will be used to determine if the besylate 
formulation is viable for use in Part 2.

Interim analysis on futility will be conducted during Part 2 
2.4.
Statistical Hypotheses
No formal statistical hypotheses will be tested in Part 1. Analysis will be descriptive and 
exploratory. 
The primary goal of Part 2 is to demonstrate a clinically meaningful response, defined as 
follows: 
NMC: this will be determined by testing the null hypothesis that the response rate 
is ≤5%, with about 80% power when the true response rate is 20%.
Small cell lung cancer (SCLC) and Castrate-Resistant Prostate Cancer (CRPC): 
this will be determined by testing the null hypothesis that the response rate is 
≤10%, with about 80% power when the true response rate is 30%.
ER+BC: this will be determined by testing the null hypothesis that the response 
rate is ≤15%, with about 80% power when the true response rate is 30%.
Triple Negative Breast Cancer (TNBC): this will be determined by testing the null 
hypothesis that the response rate is ≤10%, with about 80% power when the true 
response rate is 25%.
3.
PLANNED ANALYSES
3.1.
Interim Analyses
An interim analysis of the key parameters may be carried-out before the conclusion of the 
study. Full details of procedures and of the analyses planned at the interim analysis are
provided in this document (the RAP).
The study will not utilize an Independent Data Monitoring Committee (IDMC).
Dose escalation and stopping rules are guidelines for decision-making and the totality of 
the data will be considered by the team when making a decision. Clinical trial data used 
in these decisions will be in-stream data only; that is, the data will not necessarily be 
cleaned in advance of the formal interim analyses.


CONFIDENTIAL
BET115521
14
3.1.1.
Part 1: Dose Escalation Phase
Two formal interim analyses will be performed for Part 1 of the study. The interim 
analysis on Part 1 will be conducted when 

All subjects enrolled in Part 1 QD dosing have had at least two post-baseline 
disease assessments or progressed or died or withdrawn from the study. 

All subjects enrolled in Part 1 BID dosing have had at least two post-baseline 
disease assessments or progressed or died or withdrawn from the study
An interim analysis of the Part 1 Besylate Sub-Study will be conducted once the last 
patient enrolled in the Besylate Sub-Study completes their final respective PK blood draw 
for analysis. This interim analysis will not be a formal analysis, but will be used to 
determine if the besylate formulation is viable for use in Part 2.
3.1.1.1.
Description of the New Continual Reassessment Method
The N-CRM is a type of Bayesian adaptive dose-escalation scheme that estimates the 
parameters of a statistical model relating dose and toxicity, and is expected to locate the 
MTD efficiently while minimizing the number of subjects exposed to pharmacologically 
inactive or unsafe dose levels. The method is fully adaptive and makes use of all the 
toxicity information available at the time of each dose assignment. N-CRM estimates 
may be provided at dose escalation meetings as supportive material to the primary 3+3 
dose escalation design.
The N-CRM estimates, for each potential dose, the (Bayesian) posterior probabilities that 
the DLT rate lies in each of four predefined toxicity ranges:

A dose falls in the Under-dosing range if the rate of a DLT at the dose is in the 
interval [0%, 16%).

A dose falls in the Target toxicity range if the rate of a DLT at the dose is in the 
interval [16%, 33%).

A dose falls in the Excessive toxicity range if the rate of a DLT at the dose is in the 
interval [33%, 60%).

A dose falls in the Unacceptable toxicity range if the rate of a DLT at the dose is in 
the interval [60%, 100%].
Additionally, the following over-dose constraints for the recommended dose will be 
maintained: 

The posterior probability of the DLT rate lying in the Excessive Toxicity or 
Unacceptable Toxicity range is 0.25 or less. 

The recommended dose is no more than 2 times that of the previous dose. 
Note that a de-escalation recommendation is possible using this method. At the time of 
each dose-escalation decision, the dose with the highest posterior probability of lying in 


CONFIDENTIAL
BET115521
15
the Target Toxicity range (subject to the given constraints) will be the model-
recommended dose for the next cohort.
3.1.1.2.
Prior Probability Distribution 
Elicited prior probabilities of a DLT at each dose were used to determine the prior 
distribution of the parameters of an explicit logistic dose-toxicity model, namely
,
where pd is the probability of a DLT at dose d, and dm is a reference dose. 
The prior distribution of (, ln()) will be assumed to be bivariate normal with means 
(standard deviations):  E[]=-1.4346 (1.829), E[ln()]=-0.0394 (0.4282), with 
correlation between and ln() set to ρ=-0.25 and dm=50mg.
3.1.1.3.
Displays To Be Created For Dose Escalation Review
Evaluation of at least three subjects who have completed one cycle (28 days) of 
continuous daily dosing is required prior to determining the dose for the next cohort.
Review of preliminary data will be performed after completion of each dosing cohort in 
Part 1. Preliminary safety and study population data may include a demographic 
summary, adverse event (AE) summary, AE summary by maximum toxicity category, 
SAE listing, listing of AEs that are reported to be DLT’s, and listing of AEs leading to 
dose modification. Spreadsheets containing relevant study data may also be supplied by 
the study data manager. Displays that may be created by the S&P team for these interim 
analyses are specified in the RAP spreadsheet
Further, after the first instance of a DLT and for each subsequent cohort, the 
recommended dose from the N-CRM method and updated posterior estimates of the 
probabilities of being in each dose-toxicity range may be provided. The Fixed and 
Adaptive Clinical Trial Simulator (FACTS) (Version 2.4 or higher) software from 
Tessella will be used to make N-CRM calculations. 
Prior to determining a dose for the next cohort, exploratory analyses will be conducted to 
assess the relationship of dose levels with safety, PK, and pharmacodynamic parameters 
using all data from available cohorts.
The GSK study team, in collaboration with study investigators, will review all relevant 
data to support:

whether the current dose had acceptable toxicity, and

the decision regarding the next dose level based on the totality of the data


CONFIDENTIAL
BET115521
16
3.1.2.
Part 2: Expansion Phase
3.1.2.1.
Stopping Rules for Futility
During Part 2 (Expansion Cohort), regular futility analyses of response data will be 
conducted in order to determine whether the futility criteria for stopping have been met. 
The study will not be stopped early for positive response based on success criteria. 
For each expansion cohort, after the initial 10 evaluable subjects have enrolled at the 
RP2D dose, response data will be reviewed on an ongoing and the cohort may be stopped 
for lack of evidence of efficacy (i.e. futility). 
For NMC, once 10 evaluable subjects have been enrolled into the expansion cohort to 
examine safety and efficacy, if 0 responses are observed, further enrolment into this 
cohort may be terminated. The number of observed confirmed responses will guide 
further enrolment according to the rules summarized in Figure 1. A maximum of 25
subjects in this cohort will be enrolled at the RP2D.  All available data will be considered 
in making enrollment decisions.
Figure 1
Diagram of Stopping Rules for NMC Cohort Expansion
Number of Responses
Number of 
Subjects
0
1
2
3
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25


CONFIDENTIAL
BET115521
17
Figure 1: The shaded regions are the specific regions for stopping the study for futility. For instance, if there is no 
response in 10 subjects, then the predictive probability for success will be 10% or less (the futility criterion) and the 
study will be stopped.
For SCLC and CRPC, once 10 evaluable subjects have been enrolled in the cohort to 
examine safety and efficacy, if 0 responses are observed in either cohort, further 
enrolment into this cohort may be terminated. The number of observed confirmed 
responses will guide further enrolment according to the rules summarized in Figure 2. A 
maximum of 22 subjects will be enrolled at the RP2D.  All available data will be 
considered in making enrollment decisions.
Figure 2
Diagram of Stopping Rules for SCLC and CRPC Cohort Expansion
Number of Responses
Number of Subjects
0
1
2
3
4
10
11
12
13
14
15
16
17
18
19
20
21
22
Figure 2 Legend:  The shaded regions are the specific regions for stopping the study for futility.  For instance, if there is 
no response in 10 subjects, then the predictive probability for success will be 1% or less (the futility criterion) and the 
study will be stopped.
For TNBC, once 10 evaluable subjects have been enrolled in the cohort to examine safety 
and efficacy, if 0 responses are observed in the cohort, Part 2 of the trial may be 
terminated with no further enrolment in this cohort. The number of observed confirmed 
responses will guide further enrolment according to the rules summarized in Figure 3. A 
maximum of 37 subjects will be enrolled at the RP2D.  All available data will be 
considered in making enrollment decisions.


CONFIDENTIAL
BET115521
18
Figure 3
Diagram of Stopping Rules for TNBC Cohort Expansion
Number of Responses
Number of Subjects
0
1
2
3
4
5
6
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
Figure 3 Legend:  The shaded regions are the specific regions for stopping the study for futility.  For instance, if there is 
no response in 10 subjects, then the predictive probability for success will be 1% or less (the futility criterion) and the 
study will be stopped.


CONFIDENTIAL
BET115521
19
For ER+BC, once 10 evaluable subjects have been enrolled in each cohort to examine 
safety and efficacy, if 0 responses are observed, further enrolment into this cohort may be 
terminated. The number of observed confirmed responses will guide further enrolment 
according to the rules summarized in Figure 4. A maximum of 37 subjects per cohort will 
be enrolled at the RP2D.  All available data will be considered in making enrollment 
decisions.


CONFIDENTIAL
BET115521
20
Figure 4
Diagram of Stopping Rules for ER+BC Cohort Expansion
Number of Responses
Number of 
Subjects
0
1
2
3
4
5
6
7
8
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
Figure 4 Legend:  The shaded regions are the specific regions for stopping the study for futility.  For instance, if there is 
no response in 10 subjects, then the predictive probability for success will be 1% or less (the futility criterion) and the 
study will be stopped.


CONFIDENTIAL
BET115521
21
Because subjects enroll at different times, not all subjects will have had the same number 
of disease assessments at the time of each futility analysis. Subjects will be analyzed 
against the stopping criteria according to their order of enrolment/treatment. For example, 
the first futility assessment will be conducted after the 10th treated subject has completed 
a sufficient number of disease assessments to determine a confirmed response. The first 
10 subjects treated will be included in the first futility assessment;.
Stopping boundaries are based on the number of confirmed responses out of the number 
of evaluated subjects; however, subjects who are ongoing in the trial at the time of a 
futility assessment with either a non-confirmed response or stable disease may eventually 
have a confirmed response. Therefore, the total number of subjects with confirmed or 
unconfirmed responses plus those who are ongoing with stable disease should be 
compared to the futility boundary to prevent stopping the trial for futility before all 
potential confirmed responses are fully realized. Because this represents the best-case 
scenario, if this count is still within the futility region, the study should be stopped.
3.1.2.2.
Operating Characteristics of the Stopping Rules for Futility
The stopping rules in Figure 1, Figure 2, Figure 3 and Figure 4 are based on the 
methodology of Lee & Liu [Lee, 2008]. 
The following table describes for each disease cohort the null and alternative hypotheses 
that will be tested, maximum sample size and design characteristics.  Each maximum 
sample size was calculated to ensure that at least 80% power and a maximum type 1 error 
rate of 10% is maintained.
Table 1
Diagram of Stopping Rules for Expansion Cohorts
Null 
Hypothesis 
(H0) ORR
Alternative 
Hypothesis 
(Target) (Ha) 
ORR
Maximum 
Sample 
Size
Probability of 
stopping early 
for futility if H0 
is true
Average 
Sample Size 
if H0 is true
Actual 
Type I Error 
Rate (%)
Actual 
Power (%)
NMC 
5%
20%
25
0.891
14
8.8
80.2
CRPC 
10%
30%
22
0.860
16
6.0
82.5
TNBC 
10%
25%
37
0.876
23
6.4
81.7
ER+BC 
15%
30%
37
0.855
25
8.7
80.3
SCLC 
10%
30%
22
0.860
16
6.0
82.5


CONFIDENTIAL
BET115521
22
3.1.2.3.
Displays To Be Created For Expansion Cohort Review
All Evaluable Subjects will be defined as the study population used for decision-making 
at the futility analysis. Because subjects treated at RP2D enrol at different times, not all 
subjects will have been on the study long enough to have single or multiple post-baseline 
disease assessments. Since disease assessments are to be completed every 4 weeks, for 
NMC, TNBC, ER+BC and SCLC cohorts, subjects who have at least two post-baseline 
radiological disease assessment and have been on study for at least 28 days or have 
progressed or have died or have permanently discontinued study treatment or withdrawn 
from the study treatment will be included in this population. For CRPC cohort, subjects 
who have at least two post-baseline radiological disease assessments or have had 13th
week visit PSA test results or have progressed or died or permanently withdraw from the 
study treatment will be included in this population. This will be the population for 
summaries of response data for expansion cohort futility analysis. 
All Treated will be defined as the population of all subjects that have been treated with 
at least one dose of the study drug at the time of the futility analysis. This will be the 
population for listings of data and for summaries of safety data and will include subjects 
from both Part1 and Part2.
A listing of subject responses over time will be produced. The listing will show the 
responses observed at each disease assessment for each subject along with the best 
confirmed and unconfirmed response. To be assigned a status of confirmed PR or 
confirmed CR, a confirmatory disease assessment should be performed no less than four 
weeks (28 days) after the criteria for response are first met. The definition of ongoing 
with stable disease is for subjects with Stable Disease as the best overall response and 
still on treatment at the time of futility analysis. The study population for this display 
will be All Treated population. A listing of Investigator-Assessed Target Lesion 
Assessments for ongoing with stable disease subjects will also be provided.
A listing of subject status and best overall response will be provided using the All 
Treated Subjects Population. This listing will be sorted by date of first dose and will 
show whether or not each subject is ongoing study treatment, whether the subject has had 
at least twopost-baseline radiological disease assessment, whether the subject is evaluable 
for the futility analysis, and best confirmed and unconfirmed response.
Summaries of confirmed best response will be provided so that the study team can 
compare the study data to the stopping rules for futility and to the success rules. 
Summaries of unconfirmed best response and will also be provided. The population for 
these displays will be All Evaluable Subjects.
If data allow, Summary of Kaplan-Meier Estimates of Progression Free Survival and the 
corresponding listings will be provided. 
The total number of subjects with confirmed or unconfirmed responses or who are 
ongoing with stable disease should be compared to the futility boundary to prevent 
stopping the trial for futility before confirmed responses are fully realized. If this count is 
within the futility region, the study may be stopped based on the totality of the data. The 
purpose of including ongoing subjects with stable disease in this count is to avoid 


CONFIDENTIAL
BET115521
23
incorrectly stopping the study early when responses of ongoing subjects have not been 
fully realized. 
As always, these rules are guidelines for decision-making and the totality of the data will 
be considered by the team when making a decision to stop the study.
Table 2
Examples of Documentation of Recommendation from Futility 
Analysis During Part 2 (Expansion Cohort)
Example 1:
Number of Subjects (All Treated Subjects): 
20
Number of Evaluable Subjects:
18
Futility Region: 
1 or less
Number With Confirmed Response:
1
Number With Unconfirmed Response:
1
Number Ongoing with Stable Disease:
1
Recommendation: 
Continue
Note:  Compare (Number With Confirmed Response + Number Ongoing with Unconfirmed Response & SD) to Futility 
Region.
Example 2:
Number of Subjects (All Treated Subjects): 
20
Number of Evaluable Subjects:
18
Futility Region: 
1 or less
Number With Confirmed Response:
0
Number With Unconfirmed Response:
0
Number Ongoing with Stable Disease:
1
Recommendation: 
Stop
Note:  Compare (Number With Confirmed Response + Number Ongoing with Unconfirmed Response & SD) to Futility 
Region.
3.2.
Final Analyses
Final analyses will be carried-out at the time when 70% of all Part 2 subjects have 
progressed or died following the DBF (data base frozen) for Part 1 and DBF (data base 
frozen) for Part 2 after all the data queries have been resolved.
4.
ANALYSIS POPULATIONS
Population
Definition / Criteria
Analyses Evaluated
All Evaluable 
Subjects 

This population will consist of all subjects that 
who have at least two post-dose disease 
assessment and been exposed to study drug 
for at least 28 days or have progressed or 
have died or have withdrawn from the study 
due to any reason.

Dose Expansion 
futility analyses


CONFIDENTIAL
BET115521
24
Population
Definition / Criteria
Analyses Evaluated
All Treated 
Subjects (Safety 
and Clinical 
Activity)

This population will consist of all subjects that 
received at least one dose of study treatment

Clinical Activity

Safety
PK Concentration 
Population

This population will consist of all subjects in 
the All Treated Subject Population for whom a 
blood sample for pharmacokinetics is obtained 
and analyzed

PK concentration
PK Parameter 
Population

This population will consist of all subjects in 
the PK Concentration Population for whom a 
PK parameter has been obtained

PK parameters
Besylate Sub-
Study PK 
Parameter 
Population

This population will consist of all subjects in 
the PK Parameter Population who participated 
in the besylate sub-study. Any PK parameters 
obtained from a treatment that deviates from 
the assigned treatment won’t be included in 
the primary relative bioavailability, food effect, 
or dose proportionality analyses

Besylate sub-study 
PK parameters
PD Population

This population will consist of subjects in the 
All Treated Subjects Population for whom a 
sample was obtained and analyzed for 
biomarkers

Plasma cytokines

LPS stimulated 
cytokines

Gene expression
NOTES : 

Please refer to Appendix 11: List of Data Displays which details the population to be used for each displays 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.
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 in 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.


CONFIDENTIAL
BET115521
25
5.
CONSIDERATIONS FOR DATA ANALYSES AND DATA 
HANDLING CONVENTIONS
Table 3 provides an overview of appendices within the RAP for outlining general 
considerations for data analyses and data handling conventions. 
Table 3
Overview of Appendices
Section
Component
13.4
Appendix 4: Data Display Standards & Handling Conventions
13.5
Appendix 5: Derived and Transformed Data
13.6
Appendix 6: Premature Withdrawals & Handling of Missing Data
13.7
Appendix 7: Values of Potential Clinical Importance


CONFIDENTIAL
BET115521
26
6.
STUDY POPULATION ANALYSES
6.1.
Overview of Planned Analyses
The study population analyses will be based on the All Treated Subjects population, 
unless otherwise specified.
Table 4 provides an overview of the planned study population analyses, with full details 
of data displays being presented in Appendix 11: List of Data Displays.
Table 4
Overview of Planned Study Population Analyses
Endpoint / Parameter
Data Displays Generated
Table
Figure
Listing
Disposition
Y
Y
Analysis Populations
Y
Y
Protocol Deviations
Y
Y
Demographics
Y
Y
Race
Y
Y
Disease Burden
Y
Y
Substance Use
Y
Y
Current/Past Medical Conditions
Y
Y
Disease Characteristics at Initial Diagnosis
Y
Y
Disease Characteristics at Screening 
Y
Y
Metastatic Disease at Screening
Y
Y
Prior Anti-Cancer Therapy
Y
Y
Prior Cancer-Related Surgical Procedures
Y
Y
Concomitant Medications
Y
Y
NOTES :

Y = Yes display generated.
6.1.1.
Disposition of Subjects
A summary of the number of subjects in each of the dosing groups/cohorts 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 ongoing or discontinued study treatment and a 
summary of the primary reasons for discontinuation of study treatment. Reasons for study 
treatment discontinuation will be presented in the order they are displayed in the eCRF. A
listing of study treatment discontinuation will be generated. The listing will include last 
dose date and reasons for study treatment discontinuation as well as study part of 
discontinuation.


CONFIDENTIAL
BET115521
27
6.1.2.
Protocol Deviations
All protocol deviations will be summarized and listed and will include inclusion and 
exclusion deviations as well as other deviations.
6.1.3.
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 <18, 18-64, 65-74, and >74. The count and percentage 
will be computed for sex and ethnicity.
Race and racial combinations will be summarized and listed.
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. Medical conditions present at screening will be listed and 
will be summarized by past and current categories.
Substance use, including smoking history and alcohol use, will be summarized and listed.
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 the best response to the most recent prior anti-cancer 
therapy will be provided. A summary of the number of prior anti-cancer therapy regimens 
will also be produced. 
Prior anti-cancer radiotherapy will be summarized and listed. Prior cancer-related 
surgeries will be summarized and listed.
Bromodomains (BRDs) are small protein domains, found in a variety of proteins, that 
recognize and bind to acetylated histone tails. The bromodomain extra-terminal (BET) 
family of bromodomain proteins includes the BRD3, BRD4 and BRDT [testes] proteins
will be summarized and listed.
6.1.4.
Treatment Compliance
A listing of planned and actual treatments will be produced.
In addition, summaries of study treatment exposure and dose modifications (e.g. number 
of dose reductions, number of dose interruptions) will further characterize compliance.
6.1.5.
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 


CONFIDENTIAL
BET115521
28
ingredients. ATC classification Level 1 (Body System) information will be included in 
the dataset created but will not appear on the listing or summary.
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.
Blood products or blood supportive care products will be summarized separately. The 
frequency and percentage of subjects using blood products and blood supportive care 
products after the start of study medication will be provided. Supporting listings will also 
be provided.
Note: In order to be considered a concomitant medication, the concomitant medication 
must have been taken at some point during the on-therapy window.
6.1.6.
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 anti-cancer therapy will 
be summarized. Time from study treatment discontinuation to the first post study 
treatment 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.


CONFIDENTIAL
BET115521
29
7.
EFFICACY ANALYSES
7.1.
Overview of Planned Efficacy Analyses
The primary efficacy analyses will be based on the All Treated Subjects population, 
unless otherwise specified, and all summaries and data listings will use treatment labels 
as specified in Section 13.4.1. All summaries will be presented by Cohort and Study Part 
and overall.
Table 5 provides an overview of the planned efficacy analyses, with full details of data 
displays being presented in Appendix 11: List of Data Displays.
Table 5
Overview of Planned Efficacy Analyses
Endpoint / Parameter
Absolute
Stats Analysis
Summary
Individual
T
F
L
T
F
F
L
Tumor Assessments (Investigator accessed and independent radiologist-assessed)
Target Lesions
Y
Y
Non-Target Lesions
Y
New Lesions
Y
Tumor Response
(confirmed and 
unconfirmed)
Y
Y
Y
Time to Event
Progression-Free 
Survival
Y
Y
Y
Y
Overall Survival
Y
Y
Y
Y
Time to Response
Y
Y
Y
Duration of Response
Y
Y
Y
NOTES :

T = Table, F = Figure, L = Listing, Y = Yes display generated.

Stats Analysis = Represents TFL related to any formal statistical analyses (i.e. modelling) conducted.

Summary = Represents TFL related to any summaries (i.e. descriptive statistics) of the observed raw data.

Individual = Represents FL related to any displays of individual subject observed raw data.
Endpoint / Parameter
Absolute
Change from Baseline
Stats Analysis
Summary
Individual
Stats Analysis
Summary
Individual
T
F
L
T
F
F
L
T
F
L
T
F
F
L
Tumor Assessments
Target Lesions
Y
Y
Y
NOTES :

T = Table, F = Figure, L = Listing, Y = Yes display generated.

Stats Analysis = Represents TFL related to any formal statistical analyses (i.e. modelling) conducted.

Summary = Represents TFL related to any summaries (i.e. descriptive statistics) of the observed raw data.

Individual = Represents FL related to any displays of individual subject observed raw data.


CONFIDENTIAL
BET115521
30
7.2.
Primary Efficacy Analyses
This study employs response criteria from RECIST version 1.1. The Overall Response 
Rate (ORR) is defined as the percentage of subjects achieving a confirmed Complete 
Response (CR) or Partial Response (PR) from the start of treatment until disease 
progression or the start of new anti-cancer therapy.
Subjects with Not Evaluable or missing response will be treated as non-responders; i.e. 
they will be included in the denominator when calculating the percentage.
For Part 1, anti-tumor activities will be evaluated based on clinical evidence and response 
criteria. If the data warrant, the response data will be summarized by dose level and 
tumor type. 
The primary aim of Part 2 is to demonstrate clinically meaningful response rates in each 
of the disease cohorts separately. 
Overall response rate is defined as the percentage of subjects who achieved CR or PR 
among subjects who received at least one dose of treatment. Overall response rate and the 
associated 2-sided 95% exact confidence limits will be provided separately for each 
disease cohort.  Confirmed and unconfirmed response summaries will be provided.
7.3.
Secondary Efficacy Analyses
The secondary efficacy analyses will be based on the All Treated Subjects population, 
unless otherwise specified.
Secondary Efficacy Parameters
Progression-
Free 
Survival 
(PFS)

PFS is defined as the interval of time (in months) between the date of first dose
and the earlier of the date of disease progression and the date of death due to 
any cause. 
Overall 
Survival 
(OS)

OS is defined as the interval of time (in months) between the date of first dose
and the date of death due to any cause.
Duration of 
Response 
(DOR)

DOR is defined as the time from first documented evidence of CR or PR until 
disease progression or death due to any cause among subjects who achieve a 
response (i.e. unconfirmed or confirmed CR or PR).
Time to 
Response 
(TTR)

TTR is defined, for subjects with a confirmed CR or PR, as the time from first 
dose to the first documented evidence of CR or PR.
The date of documented disease progression will be defined as the first date of disease 
progression according to clinical or radiological assessment. 


CONFIDENTIAL
BET115521
31
If there is no adequate baseline assessment, the subjects will be censored at their date of
first dose day. Subjects without any adequate post-baseline tumor assessments will be 
censored at the date of first dose day.
Subjects who progressed or died after an extended period without adequate assessment 
will be censored at their date of last adequate assessment prior to progression or death 
even if subsequent information is available regarding progression or death. An adequate 
assessment is defined as an assessment where the response is CR, PR, or SD. The date of 
response at that assessment will be used for censoring. Censoring rules are defined in 
table below.
Subjects should not start subsequent anti-cancer therapy while on study. For subjects who 
receive subsequent anti-cancer therapy the following rules will apply:

If the start date of the anti-cancer therapy is partial (i.e. either missing the day but 
has the month and year available or missing both day and month), the imputation 
rules described in Section 13.6.2.1. will be applied. No imputation will be made for 
completely missing dates.

If anti-cancer therapy is started without documented disease progression or is started 
prior to documented disease progression, PFS will be censored at the date of the last 
adequate assessment that is no later than the date of initiation of anti-cancer therapy 
(i.e. if an assessment occurs on the same day as the start of new anti-cancer therapy 
the assessment will be used, as it will be assumed the assessment occurred prior to 
the administration of new anti-cancer therapy). The date of response at the last 
adequate assessment will be used as the censoring value.

If a subject has only a baseline visit or does not have an adequate assessment that is 
no later than the date of initiation of anti-cancer therapy, PFS will be censored at the 
date of randomization.
If a subject has neither progressed nor died nor started new anti-cancer therapy, then PFS 
will be censored at the date of the last adequate assessment defined as an assessment 
where the Independent Reviewer/response is CR, PR, SD. The date of response will be 
used as the censoring date.
A summary of the assignments for progression and censoring dates for PFS are specified 
in the table below.
Censoring Rules
Situation
Date of Event 
(Progression/Death) 
or Censoring
Outcome: Event 
(Progression/Death) 
or Censoring
No (or inadequate) baseline tumor 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


CONFIDENTIAL
BET115521
32
Censoring Rules
Situation
Date of Event 
(Progression/Death) 
or Censoring
Outcome: Event 
(Progression/Death) 
or Censoring
No post-baseline 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
No progression (or death)
Date of last ‘adequate’ 
assessment of 
response2
Censored
New anticancer treatment started (prior to documented 
disease progression).3
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)
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 [Independent Reviewer/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.
PFS, OS, DOR and TTR will be graphically presented by dose and disease cohort using 
Kaplan-Meier plots if the data warrant.
If data permits, PFS, OS, DOR and TTR will be summarized descriptively by dose and 
disease cohort using Kaplan-Meier medians and quartiles. Only the subset of subjects 
who show a confirmed complete or partial tumor response will be included.
A sensitivity analysis will be performed using RECIST 1.1 alone for determining disease 
progression and RECIST 1.1 and clinical progression for determining disease 
progression.  Additionally, separate analyses will be completed based on the investigator 
assessment of response and the independent radiological assessment of response. 
Subjects that were enrolled with multiple myeloma and neuroblastoma will not have an 
independent radiological assessment of response.


CONFIDENTIAL
BET115521
33
Secondary Statistical Analyses
Endpoint(s)

PFS

OS

TTR

DOR
Method of Analysis

Kaplan-Meier (if data warrant)
Sensitivity and Supportive Statistical Analyses

Performed using RECIST 1.1 alone and RECIST 1.1 with clinical progression for assessment 
of response

Performed using investigator assessment of response and independent radiological 
assessment of response
8.
SAFETY ANALYSES
8.1.
Overview of Planned Analyses
The safety analyses will be based on the All Treated Subjects population, unless 
otherwise specified, and all summaries and data listings will use treatment labels as 
specified in Section 13.4.1. All summaries will be presented by Cohort and Study Part 
and overall.
Table 6 provides an overview of the planned analyses, with further details of data 
displays being presented in Appendix 11: List of Data Displays.
Table 6
Overview of Planned Safety Analyses
Endpoint / Parameter
Absolute
Change from Baseline
Summary
Individual
Summary
Individual
T
F
F
L
T
F
F
L
Exposure
Y
Y
Y
Adverse Events
Y
Y
Lab Chemistry
Y
Y
Y
Y
Y
Y
Lab Hematology
Y
Y
Y
Y
Urinalysis
Y
Y
Vital Signs
Y
Y
Y
Y
Y
ECG
Y
Y
Y
Y
Y
Y
ECOG Performance 
Status
Y
Y
Y
Y
LVEF
Y
Y
Y
Y
Liver Events
Y
Y
Constitutional 
Symptoms
Y
Y


CONFIDENTIAL
BET115521
34
NOTES :

T = Table, F = Figure, L = Listing, Y = Yes display generated.

Stats Analysis = Represents TFL related to any formal statistical analyses (i.e. modelling) conducted.

Summary = Represents TFL related to any summaries (i.e. descriptive statistics) of the observed raw data.

Individual = Represents FL related to any displays of individual subject observed raw data.    
8.2.
Extent of Exposure
The number of doses administered of study treatment will be summarised with mean, 
median, standard deviation, minimum, and maximum. The duration of exposure to study 
treatment in weeks (from first day to last day of treatment plus) will also be summarised. 
Dose intensity will be summarized using mean, median, standard deviation, minimum, 
and maximum.
Dose delays, reductions, escalations, and interruptions will be summarised by number of 
modifications and reasons for modifications. The summaries of dose modifications will 
be provided only if the data warrant. All the dose reductions, dose escalations, dose 
interruptions and missed doses and dose delays will be listed separately.
A horizontal bar graph of duration of treatment in days (from first day to last day of 
treatment plus 1 day) will be produced. This graph will display duration of treatment in 
days for each subject along with the treatment that the subject received and the subject’s 
best response.
8.3.
Adverse Events
An overview summary of AEs, including counts and percentages of subjects with any 
AE, AEs related to study treatment, AEs leading to permanent discontinuation of study 
treatment, AE leading to dose reductions, AEs leading to dose delays OR interruptions,
SAEs, SAEs related to study treatment, fatal SAEs, and fatal SAEs related to study 
treatment will be produced. A summary of non-serious AEs that occurred in strictly 5% 
of the subjects or above will be provided (no rounding for the percentage will be used in 
terms of 5% threshold, e.g. events with 4.9% incidence rate should not be included in this 
table). The summary will be displayed by System Organ Class (SOC) and Preferred Term 
(PT).
The relationship between Medical Dictionary for Regulatory Affairs (MedDRA) SOC, 
PT, and Verbatim Text will be displayed.
Adverse events will be graded according to the CTCAE, Version 4.0. Adverse events will 
be coded to the PT level using the MedDRA dictionary. 
A summary of number and percentage of subjects with any adverse events by maximum 
grade will be produced. AEs will be sorted by PT in descending order of total incidence.
The summary will use the following algorithms for counting the subject:

Preferred term row: Subjects experiencing the same AE preferred term several 
times with different grades will only be counted once with the maximum grade.


CONFIDENTIAL
BET115521
35

Any event row: Each subject with at least one adverse event will be counted only 
once at the maximum grade no matter how many events they have.
In addition, the frequency and percentage of AEs (all grades) will be summarized and 
displayed in two ways: 1) in descending order of total incidence by PT only and 2) in 
descending order of total incidence by SOC and PT. In the SOC row, the number of 
subjects with multiple events under the same system organ class will be counted once. 
A separate summary will be provided for study treatment-related AEs. A study treatment-
related AE is defined as an AE for which the investigator classifies the relationship to 
study treatment as “Yes”. A worst case scenario approach will be taken to handle missing 
relatedness data, i.e. the summary table will include events with the relationship to study 
treatment as ‘Yes’ or missing. The summary table will be displayed in descending order 
of total incidence by PT only.
All AEs will be listed. Additionally, a listing of subject IDs for each individual AE will 
be produced. 
A listing of adverse events recorded as dose-limiting toxicities will be provided. 
Additionally, a summary of the number of patients experiencing DLT’s in each cohort 
will be provided.
8.3.1.
Adverse Events of Special Interest
A comprehensive list of MedDRA terms based on clinical review will be used to identify 
each type of events. 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 agreements in place at the time of reporting. 
The adverse events of special interest include but not limit to the following categories:

Haematopoietic thrombocytopenia [NARROW] SMQ

Haemorrhages [NARROW] SMQ

Anaemias nonhaemolytic and marrow depression HLGT

Torsade de pointes/QT prolongation [NARROW] SMQ,

Drug related hepatic disorders - comprehensive search [NARROW] SMQ,

Noninfectious diarrhoea [NARROW] SMQ

Constipation PT

Nausea and vomiting HLT

Rash Preferred Terms
The events of special interest are listed in Section 13.5.3.


CONFIDENTIAL
BET115521
36
Summaries of the number and percentage of subjects with these events will be 
summarized by categories of AE of SI,  preferred term and maximum toxicity grade in 
one table. The summary of event characteristics for each category of AE of SI will also 
be provided, including number of subjects with any event, number of events, number of 
subjects with any event that is serious, number of subjects with any event that is related 
to study treatment, the outcome of the event, maximum grade and the action taken for the 
event. The percentage will be calculated in two ways, one with number of subjects with 
event as the denominator and the other with total number of subjects as the denominator. 
The worst case approach will be applied at subject level for the event outcome and 
maximum grade, i.e. a subject will only be counted once as the worst case from all the 
events experienced by the subject. For action taken to a event, subject will be counted 
once under each action, e.g. if a subject has a event leading to both study treatment 
discontinuation and dose reduction, the subject will be counted once under both actions.
For each category of AE of SI, the summary of onset and duration will also be provided. 
Time to onset (days) and duration of first occurrence (days) will be summarized. In 
addition to descriptive statistics (mean, median, min, max), time to onset will be 
summarized in categories of  1-14 days, 15-28 days and >28 days, and duration of first 
occurrence will be summarized in categories of 1-5 days, 6-10days, >10 days.   
In addition, AEs of special interest will be listed separately.
8.3.2.
Deaths and Serious Adverse Events 
In the event that a subject has withdrawn consent, no data after the withdrawal of consent 
date from this subject including death is supposed to appear in the database, which should 
be part of the data cleaning process. All deaths will be summarised based on the number 
and percentage of subjects. This summary will classify subjects by time of death relative 
to the last dose of medication (>30 days or 30 days) and 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 PT only.
A study treatment-related SAE is defined as an SAE for which the investigator classifies 
the relationship to study treatment as “Yes”. A worst case scenario approach will be
taken to handle missing data, i.e. the summary table will include events with the 
relationship to study treatment as ‘Yes’ or missing. 
SAEs are included in the listing of all adverse events. Separate supportive listings with 
subject-level details will be generated for

Fatal SAEs 

Non-Fatal SAEs.


CONFIDENTIAL
BET115521
37
8.3.3.
Adverse Events Leading to Discontinuation of Study Treatment 
and/or Withdrawal from the Study and Other Significant Adverse 
Events
The following categories of AEs will be summarized separately in descending order of 
total incidence by PT only and separate supportive listings will be generated with subject 
level details for those subjects:

AEs Leading to Discontinuation of Study Treatment

AEs Leading to Withdrawal from the Study

AEs Leading to Dose Interruptions

AEs Leadings to Dose Reductions

AEs Leading to Dose Increases
An AE leading to dose modification is an AE for which the action with respect to dosing 
is recorded as reduction or interruption of dose. Given the worst action is available; this 
AE will only be included in the summary table corresponding to the worst action. For 
example, AEs that lead to both a dose modification and a discontinuation of study 
treatment will only appear in the AEs leading to discontinuation of study treatment 
summary. All dose modifications due to AE will be listed in the listing.
8.4.
Pregnancies
Any pregnancy complication or elective termination of a pregnancy for medical reasons 
will be recorded as an AE or SAE as described in the protocol. If subjects or subjects’ 
partner become pregnant while on the study, the information will be included in the 
narratives and no separate table or listing will be produced.


CONFIDENTIAL
BET115521
38
8.5.
Clinical Laboratory Evaluations
The assessment of laboratory toxicities will examine the following laboratory tests: 
Serum Chemistry
Blood urea nitrogen
Sodium
Magnesium 
Potassium
aspartate aminotransferase
Total and direct bilirubin
Uric acid
Creatinine
Chloride
alanine aminotransferase
Albumin
Fasting Glucose
Total carbon dioxide
alkaline phosphatase
Total protein
Creatine phosphokinase
Ionized calcium
gamma-glutamyltransferase
Total calcium
Hematology
Platelet count
Automated White Blood Cell 
Red blood cell count
Differential:
White blood cell count (absolute)
Neutrophils (absolute)
Hemoglobin
Lymphocytes (absolute)
Monocytes (absolute)
Eosinophils (absolute)
Basophils (absolute)
Routine Urinalysis
Specific gravity
pH, glucose, protein, blood, and ketones by dipstick
Microscopic examination (if blood or protein is abnormal)
Other Tests
Coagulation tests (prothrombin time, partial thromboplastin time, international normalized ratio, and fibrinogen)
Pancreatic markers (amylase and lipase)
Fasting Lipid panel (triglycerides and total cholesterol, LDL, HDL)
C-Peptide
Troponin (I or T at local laboratory, Troponin T at central laboratory]
Insulin
Hemoglobin A1C
1,5 –Anhydroglucitol (1,5 AG)
NT-proBNP
Thyroid-stimulating hormone (TSH)
Free Thyroxine 3 (Free T3)
Free Thyroxine 4 (Free T4)
Creatine kinase (CK)
Creatine Kinase-MB (CK-MB)
Testosterone for males (free and complete testosterone at prior to first dose, free testosterone after first dose)
Pregnancy test for females (serum at screening, Urine or serum post dose)Cytokine samples (collected as part of 
Predose PK sample for plasma cytokines; may also be performed as clinically appropriate following fever)
Laboratory grades will be reported using the Common Terminology Criteria for Adverse 
Events (CTCAE v4.0).
Summary of lab values and change from baseline by scheduled visits using mean, 
median, standard deviation, minimum, and maximum will be provided.
Summaries of lab data by maximum toxicity grade will be provided.
Summaries of worst case grade increase from baseline grade will be provided for all the 
lab tests that are gradable by CTCAE v4.0. These summaries will display the number and 
percentage of subjects with a maximum post-baseline grade increasing from their 


CONFIDENTIAL
BET115521
39
baseline grade. Any increase in grade from baseline will be summarized along with any 
increase to a maximum grade of 3 and any increase to a maximum grade of 4. Missing 
baseline grade will be assumed as grade 0. In addition, the summary will include grade 
increase from baseline by scheduled visits. For laboratory tests that are graded for both 
low and high values, summaries will be done separately and labeled by direction, e.g.
sodium will be summarized as hyponatremia and hypernatremia.
For lab tests that are not gradable by CTCAE v4.0, summaries of worst case changes 
from baseline with respect to normal range will be generated. Decreases to low, changes 
to normal or no changes from baseline, and increases to high will be summarized at each 
scheduled visit as well as for the worst case post-baseline. If a subject has a decrease to 
low and an increase to high during the same time interval, then the subject is counted in 
both the “Decrease to Low” categories and the “Increase to High” categories. In addition, 
the summary will include worst case changes from baseline with respect to normal range 
by scheduled visits.
Separate summary tables for hematology and chemistry laboratory tests will be produced.
A supporting listing of laboratory data for subjects with abnormalities of potential clinical 
concern will be provided. A separate listing of laboratory data with character values will 
also be provided.
Detailed derivation of baseline assessment is specified in Section 13.4.2.
Unless otherwise specified, the denominator in percentage calculation at each scheduled 
visit will be based on the number of subjects with non-missing value at each particular 
visit.
8.5.1.
Analyses of Liver Function Tests
Summaries of hepatobiliary laboratory events including possible Hy’s law cases will be 
provided in addition to what has been described above. 
Possible Hy’s law cases are defined as any elevated (ALT≥3×ULN and total 
bilirubin≥2×ULN (with direct bilirubin 35% of total bilirubin, if direct bilirubin is 
measured)) OR (ALT ≥3×ULN and INR >1.5, if INR is measured). Note that INR 
measurement is not required and the threshold value stated will not apply to patients 
receiving anticoagulants.
LFT patient profiles plots for subjects experiencing an ALT, AST or total bilirubin of 
toxicity grade 2 or above will be produced. 
A plot of maximum total bilirubin versus maximum ALT will be generated. A trellis 
display of LFT shifts from baseline to maximum values will be provided. A matrix 
display of LFT results will also be produced.
A summary of liver re-challenges, adaptations and recovery will be provided. The re-
challenge is defined as an ALT elevation, followed by treatment interruption and 
subsequently an ALT value of Grade 1 or below on or prior to re-starting study treatment, 


CONFIDENTIAL
BET115521
40
where the ALT elevation means ALT is >3xULN and ≤3xULN at baseline. The 
adaptation is defined as an ALT elevation followed by an ALT assessment returning to 
baseline grade or below without any dose interruption between the ALT elevation and 
normalization. Recovery is defined as ALT Grade 1 or below for 2 consecutive visits or 
Grade 1 or below for one visit if subject discontinued and no data available.
8.6.
Other Safety Measures
Unless otherwise specified, the denominator in the percentage calculation at each 
scheduled visit will be based on the number of subjects with non-missing value at each 
particular visit.
8.6.1.
Vital Signs
Values of vital signs as well as the change from baseline will be summarized by 
scheduled visit using mean, median, standard deviation, minimum and maximum. 
Summaries of values of potential clinical concern with respect to the categories defined 
in Section 13.7.3. will be performed. These summaries will display the number and 
percentage of subjects with any PCI at each scheduled assessment time and for the worst 
case post-baseline.
8.6.2.
Performance Status
ECOG performance status will be summarized at baseline and each post-baseline
scheduled visit. Summaries will use frequency and percentage of subjects at each planned 
assessment time. A summary of change from baseline by scheduled visits will be 
performed, as well as the worst case post-baseline and the best case post-baseline changes 
during the study (improved, no change, deteriorated). 
A supporting listing will also be provided. 
8.6.3.
ECG
A summary of the number and percentage of subjects who had normal and abnormal 
(clinically significant and not clinically significant) ECG findings will be displayed by 
scheduled visits as well as for the worst case post-baseline. 
Summaries of values of potential clinical concern with respect to the categories defined 
in Section 13.7.2. will be performed. These summaries will display the number and 
percentage of subjects with any PCI at each scheduled assessment time and for the worst 
case post-baseline. 
In addition, ECG interval values will be also be summarized. 
QTcF prolongation will be monitored throughout the study.  Descriptive statistics and  
categorical analyses of QTcF and QTcF mean and individual profile plots will be 
generated periodically.
Listings of abnormal ECG findings and a listing of ECG values will be provided.


CONFIDENTIAL
BET115521
41
8.6.4.
LVEF
Absolute change and relative percent change from baseline in LVEF will be summarized 
at each scheduled assessment time and for the worst case post-baseline. Only the post-
baseline assessments that used the same method (i.e. ECHO) as the baseline assessments 
will be used to derive the change from baseline. 
Summaries of values of potential clinical concern with respect to the categories defined 
in Section 13.7.4. will be performed. These summaries will display the number and 
percentage of subjects with any PCI at each scheduled assessment time and for the worst 
case post-baseline. 
LVEF results will also be listed with subject level details including absolute change from 
baseline.
8.6.5.
Liver Events 
For any liver events that occur during the study, the liver event information for RUCUM 
score will be summarized, including whether the subject was age 55 or over, whether the 
subject became pregnant, liver imaging normal or not, a biopsy was taken or not, whether 
there was fasting or significant dietary change, whether the subject took any 
unconventional medications, timing when the event occurs (while on treatment or after 
stopping treatment) and summary statistics for time from first dose to start of liver event 
and time from last dose to start of liver event. If the number of events does not support a 
summary, then only listings will be produced.
For subjects with multiple events, the first event will be used for the summary tables. All 
events with subject level details will be displayed in a supporting listing.
9.
PHARMACOKINETIC ANALYSES
9.1.
Overview of Planned Pharmacokinetic Analyses
The pharmacokinetic (PK) analyses will be based on the PK Concentration, PK 
Parameter and Besylate Sub-Study PK Parameter populations, unless otherwise specified.
Table 7 provides an overview of the planned analyses, with full details being presented in 
Appendix 11: List of Data Displays. 
Table 7
Overview of Planned Pharmacokinetic Analyses
Endpoint / Paramete/ 
Display Type]
Untransformed
Log-Transformed
Stats Analysis
Summary
Individual
Stats Analysis
Summary
Individual
T
F
L
T
F
F
L
T
F
L
T
F
F
L
GSK525762 PK 
Parameters (Part 1 
only)
Y
Y
Y
Y
Y
Y
Y
Y
Y
Y
GSK525762 PK 
Concentrations
Y
Y
Y
Y
Y
Y
Y
13C GSK525762 PK 
Y
Y
Y
Y
Y
Y
Y
Y
Y


CONFIDENTIAL
BET115521
42
Endpoint / Paramete/ 
Display Type]
Untransformed
Log-Transformed
Stats Analysis
Summary
Individual
Stats Analysis
Summary
Individual
T
F
L
T
F
F
L
T
F
L
T
F
F
L
Parameters (Besylate 
Sub-Study only)
13C GSK525762 PK 
Concentrations
(Besylate Sub-Study 
only)
Y
Y
Y
Y
Y
Y
Y
NOTES :

T = Table, F = Figure, L = Listings, Y = Display generated.

Stats Analysis = Represents TFL related to any formal statistical analyses (i.e. modelling) conducted.

Summary = Represents TFL related to any summaries (i.e. descriptive statistics) of the observed raw data.

Individual = Represents FL related to any displays of individual subject observed raw data.    
9.2.
Drug Concentration Measures
Refer to Appendix 4: Data Display Standards & Handling Conventions (Section 13.4.3
Reporting Process & Standards).
9.3.
Pharmacokinetic Parameters
9.3.1.
Deriving Pharmacokinetic Parameters

Refer to Appendix 4: Data Display Standards & Handling Conventions
(Section 13.4.3 Reporting Process & Standards).

The pharmacokinetic parameters will be calculated by standard non-compartmental 
analysis according to current working practices and using Phoenix WinNonlin 
software (versions 6.3).

All calculations of non-compartmental parameters will be based on actual sampling 
times.

Pharmacokinetic parameters described in Table 8 will be determined from the plasma
concentration-time data, as data permits.
Table 8
Derived Pharmacokinetic Parameters
Parameter
Parameter Description
AUC(0-t)
Area under the concentration-time curve from time zero to the time of the last quantifiable 
concentration (C(t)) will be calculated using the linear trapezoidal rule for each incremental 
trapezoid and the log trapezoidal rule for each decremental trapezoid.  
AUC(0-∞)
Area under the concentration-time curve extrapolated to infinity will be calculated as: 
AUC = AUC(0-t) + C(t) / lambda_z
This will be calculated for Week 1/Day 1 only
AUC(0-τ)
Area under the concentration-time curve from time zero to the predose of the next dose. For 
BID administration, AUC(0-24) will also be computed, as data permits.
Cmax
Maximum observed plasma concentration, determined directly from the concentration-time 
data. For BID administration, Cmax will be obtained after each administration, i.e. morning 
and evening administration, as data permits.


CONFIDENTIAL
BET115521
43
Parameter
Parameter Description
tmax
Time to reach Cmax, determined directly from the concentration-time data.
t½
Apparent terminal half-life will be calculated as: 
t½ = ln2 / λz
λz
Apparent terminal phase elimination rate constant
Cτ
Trough concentration
CL/F
Apparent Clearance
V/F
Apparent Volume
NOTES:

Additional parameters may be included as required.
To estimate the extent of accumulation after repeat dosing, the observed accumulation 
ratio (Ro) may be determined as the ratio of AUC(0-) on Week 3 AUC(0-) / Week 1 
AUC(0-). Rs, the ratio of AUC(0-) on Week 3 AUC(0-) / Week 1 AUC(0-) may be 
calculated to assess time invariance.
GSK525762 concentrations will be determined in urine samples to determine urinary 
recovery of unchanged drug and renal clearance.
9.3.2.
Statistical Analysis of Pharmacokinetic Parameters
Statistical analyses of the PK parameters data will be conducted by Oncology Statistics 
and Programming, GSK. Plasma concentration-time data will be listed by dose, age 
group, and summarized using descriptive statistics (n, mean, SD, median, minimum and 
maximum) by planned relative assessment time. Mean and/ or median values will be 
plotted over time. Individual plasma and urinary (if available) pharmacokinetic 
parameters values as well as a descriptive summary (mean, standard deviation, median, 
minimum, maximum, geometric mean, and the standard deviation, CV% and 95% 
confidence interval of log-transformed parameters (if applicable)) by dose cohort and age 
group will be reported.
The following pharmacokinetic statistical analyses will only be performed, if sufficient 
data is available (i.e. if subjects have well defined plasma profiles). 
9.3.2.1.
Dose proportionality 
Cmax and AUC (AUC(0-∞), single dose, and AUC(0-) or AUC(0-24), steady state),
from Part 1 will be plotted as a function of the dose administered. Dose proportionality of 
AUC and Cmax for GSK525762 following single dose administration and AUC(0-) or 
AUC(0-24) and Cmax following repeat dose administration will be assessed graphically 
and using the power model as described below:
log (pharmacokinetic parameter) = a + b * log(dose)
where a is the intercept and b is the slope.
The power model will be fitted by restricted maximum likelihood (REML) using SAS 
Proc Mixed.  Both the intercept and slope will be fitted as fixed effects.  If there is 


CONFIDENTIAL
BET115521
44
sufficient data, the model may also be fit with the intercept and/or slope as random 
effects depending on the ability of the model to converge and on estimation of variance-
covariance matrix.  The mean slope and corresponding 90% confidence interval will be 
estimated from the power model.  
If data permit, a separate power model will be fit for PK parameters calculated from 
samples obtained following administration of BID dosing.  For this dose proportionality 
analysis, Cmax for the morning dose and AUC(0-24) will be evaluated.
Part 1 Dose Proportionality Analysis
Endpoint(s)

Cmax and AUC (AUC(0-∞), single dose, and AUC(0-) or AUC(0-24), steady state
Model Specification

Proc Mixed code for dose proportionality analysis:
PROC MIXED data=pkpar;
BY paramcd;
CLASS subjid;
MODEL logpk = logdose / ddfm=kr;
RANDOM subjid;
RUN;
Model Checking & Diagnostics

Refer to Appendix 9: Model Checking and Diagnostics for Statistical Analyses.
For Besylate  Sub-Study analysis, the following power model will be fitted:
log (pharmacokinetic parameter) = a + b * log(dose) + c * log(C13PKparameter)
where a is the intercept and b is the slope.
The power model will be fitted by restricted maximum likelihood (REML) using SAS 
Proc Mixed.  Both the intercept and slope and C13PKparameter will be fitted as fixed 
effects.    The mean slope and corresponding 90% confidence interval will be estimated 
from the power model.  
The besylate sub-study primary analysis will exclude data for a given period for a subject 
if the subject did not receive the correct dose during that period or the protocol-defined 
diet was not adhered to.  A sensitivity analysis including data from all subjects based on 
actual treatment will also conducted.The analysis without C13PKparameters in the power 
model will also be provided as the sensitivity analysis.
Besylate Sub-Study Dose Proportionality Analysis
Endpoint(s)

Cmax and (AUC(0-∞)
Model Specification

Proc Mixed code for dose proportionality analysis in besylate sub-study:
PROC MIXED data=pkpar;
BY paramcd;


CONFIDENTIAL
BET115521
45
Besylate Sub-Study Dose Proportionality Analysis
CLASS subjid;
MODEL logpk = logdose logc13pkpar / ddfm=kr;
RANDOM subjid;
RUN;
Model Checking & Diagnostics

Refer to Appendix 9: Model Checking and Diagnostics for Statistical Analyses.
9.3.2.2.
Relative bioavailability of the besylate salt tablet to the amorphous free 
base tablet (Besylate Sub-Study)
Pharmacokinetic (PK) parameters AUC(0-∞), AUC(0-t) and Cmax derived from 
treatments A2, B and C only will be loge-transformed and separately analyzed using a 
mixed-effects model with a fixed-effect term for treatments , and subject as a random 
effect. C13 PK parameter will be included in the model as a covariate.  Point estimates 
and associated 90% CIs will be constructed for the differences between besylate salt 
(treatment B) and amorphous tables (treatment A2). The point estimates and their 
associated 90% CIs will then be back-transformed to provide point estimates and 90% 
CIs for the ratio of besylate salt/amorphous. Non-parametric methods such as the Hodges 
and Lehmann estimator will be used to estimate the median differences between the 
besylate salt tables and the amorphous tablets for tmax. An associated 90% CI for the 
median differences will be constructed.  The besylate sub-study primary analysis will 
exclude data for a given period for a subject if the subject did not receive the correct dose 
or formulation during that period or the protocol-defined diet was not adhered to.  A 
sensitivity analysis including data from all subjects based on actual treatment will also 
conducted with the exclusion of data collected after administration of the incorrect 
formulation in period 3 or 4.
Based on the US FDA guidance on relative bioavailability studies, two formulations will 
be considered bioequivalent if the 90% CI of the ratio for Cmax and AUC, based on log-
transformed data, is within the 80 to 125% equivalence limit. Recommendation on the 
dose amount impact of a deviation from bioequivalence with the besylate salt will be 
based on the magnitude of the change.
The analysis without C13PKparameters in the mixed effects model will also be provided 
as the sensitivity analysis. 
Relative Bioavailability of the Besylate Salt Tablet to the Amorphous Free Base Tablet 
Analysis (Besylate Sub-Study)
Endpoint(s)

AUC(0-∞), AUC(0-t) and Cmax
Model Specification

Only include treatments A2, B and C in the model.
Proc Mixed code for relative bioavailability assessment:
PROC MIXED data=pkpar;
BY paramcd;
CLASS subjid patrtcd;


CONFIDENTIAL
BET115521
46
Relative Bioavailability of the Besylate Salt Tablet to the Amorphous Free Base Tablet 
Analysis (Besylate Sub-Study)
MODEL logpk = patrtcd  logc13pkpar / ddfm=kr;
RANDOM subjid;
ESTIMATE ‘Besylate Salt – Amorphous’ patrtcd -1 1 0 / alpha=0.1;
LSMEANS patrtcd;
RUN;
Model Checking & Diagnostics

Refer to Appendix 9: Model Checking and Diagnostics for Statistical Analyses.
9.3.2.3.
Food effect with besylate salt tablet (Besylate Sub-Study)
Pharmacokinetic (PK) parameters AUC(0-∞), AUC(0-t) and Cmax will be loge-
transformed and separately analyzed using a mixed-effects model with a fixed-effect term
for treatments, and subject as a random effect. Point estimates and associated 90% CIs 
will be constructed for the differences between fed (treatment D) and fasted state
(treatment B). The point estimates and associated 90% CIs will then be back-transformed 
to provide point estimates and 90% CIs for the ratios of fed/fasted. Non-parametric 
methods such as the Hodges and Lehmann estimator will be used to estimate the median 
differences between the fed and fasted state for tmax. An associated 90% CI for the 
median differences will be constructed. The besylate sub-study primary analysis will 
exclude data for a given period for a subject if the subject did not receive the correct dose 
or formulation during that period or the protocol-defined diet was not adhered to.  A 
sensitivity analysis including data from all subjects based on actual treatment will also 
conducted with the exclusion of data collected after administration of the incorrect 
formulation in period 3 or 4.
Food Effect with Besylate Salt Tablet Analysis (Besylate Sub-Study)
Endpoint(s)

AUC(0-∞), AUC(0-t) and Cmax
Model Specification

Proc Mixed code for food effect assessment:
PROC MIXED data=pkpar;
BY paramcd;
CLASS subjid patrtcd;
MODEL logpk = patrtcd / ddfm=kr;
RANDOM subjid;
ESTIMATE ‘Fed – Fasted’ patrtcd 0 -1 0 1 / alpha=0.1;
LSMEANS patrtcd;
RUN;
Model Checking & Diagnostics

Refer to Appendix 9: Model Checking and Diagnostics for Statistical Analyses.


CONFIDENTIAL
BET115521
47
9.3.2.4.
Relative Bioavailability of Solution to Besylate Salt Tablet (Besylate 
Sub-Study)
Dose normalized pharmacokinetic (PK) parameters AUC(0-∞), and Cmax will be loge-
transformed and separately analyzed using a mixed-effects model with a fixed-effect term
for PK type (C13 solution or besylate tablet), and subject as a random effect. Point 
estimates and associated 90% CIs will be constructed for the differences between solution 
and besylate tablet. The point estimates and associated 90% CIs will then be back-
transformed to provide point estimates and 90% CIs for the ratios of solution to besylate 
tablet. Non-parametric methods such as the Hodges and Lehmann estimator will be used 
to estimate the median differences between solution and besylate tablet for tmax. An 
associated 90% CI for the median differences will be constructed.
The PK parameters for the C13 solution (6 mg administered) and the besylate tablet (80 
mg administered fasted) will be  dose normalized to 10 mg. 
Relative Bioavailability of Solution to Besylate Salt Tablet Analysis (Besylate Sub-Study)
Endpoint(s)

AUC(0-∞), and Cmax
Model Specification

Proc Mixed code for relative bioavailability assessment:
PROC MIXED data=pkpar;
BY paramcd;
CLASS subjid pktype;
MODEL dnlogpk = pktype / ddfm=kr;
RANDOM subjid;
ESTIMATE ‘Solution - Tablet ’ pktype -1 1 / alpha=0.1;
LSMEANS pktype;
RUN;
Model Checking & Diagnostics

Refer to Appendix 9: Model Checking and Diagnostics for Statistical Analyses.
9.4.
Population Pharmacokinetic (PopPK) Analyses

The primary goal of this analysis is to characterize the population pharmacokinetics 
of GSK525762 administered in subjects with solid tumors.

A summary of the planned population pharmacokinetic analyses are outlined below:
o
Plasma concentration-time data from parts 1 and 2 will be combined and further 
analyzed using a population approach. 
o
A nonlinear mixed effects model will be used to determine population 
pharmacokinetic parameters (absorption rate, Ka, apparent clearance, CL/F and 
volume of distribution, V/F) and summary exposure measures (Cmax, AUC and 
Cav = AUC/) and identify important covariates (e.g., age, weight, or disease 
related covariates).


CONFIDENTIAL
BET115521
48
10.
PHARMACODYNAMIC ANALYSES
10.1.
Overview of Planned Pharmacodynamic Analyses
The pharmacodynamic analyses will be detailed in a Pharmacodynamic RAP supplement 
and will not be discussed as part of this RAP.
11.
PHARMACOKINETIC / PHARMACODYNAMIC
ANALYSES

Observed (Part 1) or predicted concentrations (Part 2) will be combined with safety 
and efficacy pharmacodynamic measures of interest to examine potential exposure 
response relationships.

The relationship between QTcF and concentration expressed as Cmax, Cav, and/or 
instantaneous time-matched concentration will be evaluated. A linear or non-linear 
mixed effects analysis of the relationship between  QTcF adjusted for baseline and –
concentration with a possible incorporation of time  will be evaluated as a means of 
estimating QTcF effect in lieu of a thorough QT study.

Other quantitative safety parameters, including platelet count, and biomarkers of 
interest will be plotted graphically against summary exposure measures (eg; Cmax, 
Ctrough, and Cav). Where evidence of a signal is seen, linear and non-linear mixed 
effect models will be fitted to the data to estimate PKPD parameters of interest; slope, 
baseline (E0), concentration for 50% of maximum effect (EC50) and maximum effect 
(Emax).


CONFIDENTIAL
BET115521
49
12.
REFERENCES
Cheson B, Pfister B, Juweid M, et al. Revised response criteria for malignant lymphoma. 
Journal of Clinical Oncology, 2007; 25:579-586.
Choi WL, Weisenburger, DD, Greiner TC, et al. A new immunostain algorithm classifies 
diffuse large B-cell lymphoma into molecular subtypes with high accuracy. Clin Cancer 
Res 2009;15:5494-5502.
Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid 
tumors:  Revised RECIST guidelines (version 1.1). European Journal of Cancer, 2009; 
45:228-247.
GSK Document Number. : 2011N118599_06: BET115521 A phase I/II open-label, dose 
escalation study to investigate the safety, pharmacokinetics, pharmacodynamics and 
clinical activity of GSK525762 in subjects with NUT midline carcinoma (NMC) and 
other cancers. March 24, 2015
GUI_137354: Information for Authors: Reporting and Analysis Plans
Jennison C, Turnbull BW. Confidence intervals for a binomial parameter following a 
multistage test with applications to MIL-STD 105D and medical trials. Technometrics, 
1983; 25:49-58.
Lee JJ, Liu DD. A predictive probability design for Phase II cancer clinical trials. Clinical
Trials, 2008; 5:93-106.
Neuenschwander B, Branson M, Gsponer T. Critical aspects of the Bayesian approach to 
phase I cancer trials. Statistics in Medicine, 2008; 27:2420-2439.
SOP_54838: Development, Review and Approval of Reporting and Analysis Plans


CONFIDENTIAL
BET115521
50
13.
APPENDICES
Section
Appendix
RAP Section 5 : General Considerations for Data Analyses & Data Handling Conventions
Section 13.1
Appendix 1: Time and Events
Section 13.2
Appendix 2: Assessment Windows
Section 13.3
Appendix 3: Treatment States & Phases
Section 13.4
Appendix 4: Data Display Standards & Handling Conventions

Study Treatment & Sub-group Display Descriptors

Baseline Definitions & Derivations

Reporting Process & Standards
Section 13.5
Appendix 5: Derived and Transformed Data

General, Study Population & Safety

Pharmacokinetic

Pharmacodynamic and or Biomarkers
Section 13.6
Appendix 6: Premature Withdrawals & Handling of Missing Data

Premature Withdrawals

Handling of Missing Data
Section 13.7
Appendix 7: Values of Potential Clinical Importance
Section 13.8
Appendix 8: Multicentre Studies

Laboratory Values

ECG

Vital Signs
Section 13.9
Appendix 9: Model Checking and Diagnostics for Statistical Analyses
Other RAP Appendices
Section 13.10
Appendix 10: Abbreviations & Trade Marks
Section 13.11
Appendix 11: List of Data Displays
Section 13.12
Appendix 12: Example Mock Shells for Data Displays


CONFIDENTIAL
BET115521
51
13.1.
Appendix 1: Time & Events
13.1.1.
Protocol Defined Time & Events
See Protocol Section 5.


CONFIDENTIAL
BET115521
52
13.2.
Appendix 2: Assessment Windows
No assessment windows will be applied.


CONFIDENTIAL
BET115521
53
13.3.
Appendix 3: Treatment States and Phases
13.3.1.
Treatment Phases
Adverse events, serious adverse events, death, laboratory data, vitals, ECG, 
echocardiogram (ECHO), Eastern Cooperative Oncology Group (ECOG) result, and and 
other safety domains will be assigned to the treatment phases defined below. Partial dates 
will be imputed into full dates, if applicable, for slotting data to the appropriate categories 
below (see Section 13.6.2). Flag variables (time in relation to study treatment) indicating 
the study time periods will be added to these datasets.
Assessments and events will be classified according to the time of occurrence relative to 
Study Treatment Start Date.
Treatment Phase
Definition
Pre-Therapy
Date ≤ Study Treatment Start Date
On-Therapy
Study Treatment Start Date < Date ≤ Study Treatment Stop Date
Some datasets include the first dose day as On-therapy and some exclude the first dose 
date as On-Therapy. The first dose day (Day 1) is considered pre-therapy for ECOG, 
ECG, vital signs, liver events, lab tests, cardiac scan, and other safety domains. The first 
dose day (Day 1) is considered to be On-therapy for adverse events and concomitant 
medications.
13.3.2.
Treatment States
Assessments and events will be classified according to time of occurrence relative to the 
start and/or stop date of the study treatment.
13.3.2.1.
Treatment States for Disease Response Data
Treatment State
Definition
Time to 
Progression
Date of Progression or Date of Last Disease Assessment - Study Treatment Start Date
+ 1
Time to Response
Date of First Partial or Complete Response of a Confirmed Partial or Complete 
Response – Study Treatment Start Date + 1
Duration of 
Response
Date of Progression – Date of First Partial or Complete Response of a Confirmed 
Partial or Complete Response + 1
13.3.2.2.
Treatment States for AE Data
Treatment State
Definition
Pre-Treatment
AE Start Date < Study Treatment Start Date
On-Treatment
If AE onset date is on or after treatment start date & on or before treatment stop date.
Study Treatment Start Date  ≤ AE Start Date ≤ Study Treatment Stop Date 
Onset Time  

If Treatment Start Date ˃AE Onset Date = AE Onset Date - Treatment Start Date


CONFIDENTIAL
BET115521
54
Treatment State
Definition
Since 1st Dose
(Days)

If Treatment Start Date ≤ AE Onset Date = AE Onset Date - Treatment Start Date 
+1

Missing otherwise.
Duration (Days) 
AE Resolution Date – AE Onset Date + 1
Drug-related
If relationship is marked ‘YES’ on [Inform/CRF OR value is missing].
NOTES: 

If the study treatment stop date is missing then the AE will be considered to be On-Treatment.


CONFIDENTIAL
BET115521
55
13.4.
Appendix 4: Data Display Standards & Handling 
Conventions
13.4.1.
Study Treatment & Sub-group Display Descriptors
Treatment Group Descriptions
RandAll NG 
Data Displays for Reporting 
Code
Description
Data Display
Order [1]
A
GSK525762 Active Dose
GSK525762 X mg (QD or BID)
5
A2
RP2D (or MTD) amorphous free-base 
tablet, fasted
A2
1
B
RP2D (or MTD) besylate tablet, fasted
B
2
C
half to one-third of RP2D (or MTD) 
besylate tablet, fasted
C
3
D
RP2D (or MTD) besylate tablet, fed
D
4
NOTES:
1.
Order represents treatments being presented in TFL, as appropriate.
Treatment Group Descriptions
Treatment
Data Display
Description
Order [1]
Part 1 QD 
dosing
2-16 mg QD
Combine lower dose cohorts 2mg, 
4mg, 8mg, 16mg
1
30 mg QD
2
60 mg QD
3
80 mg QD
4
100 mg QD
5
Total QD
6
Part 1 BID 
dosing
20 mg BID
8
30 mg BID
9
Total BID
10
Besylate 
Sub-Study
Besylate
Besylate Sub-Study subjects only
11
Part 2 
Dose
75 mg QD
Besylate formula
12
Total
Total 
All subjects combined
13
NOTES:
1.
Order represents treatments being presented in TFL, as appropriate.


CONFIDENTIAL
BET115521
56
Cohort Descriptions
Group Description
Data Display
Order [1]
NMC Cohort
NMC 
1
CRPC Cohort
CRPC 
2
TNBC Cohort
TNBC 
3
ER+BC Cohort
ER+BC
4
SCLC Cohort
SCLC
5
Combined Cohorts
All Subjects
6
Study Part Descriptions
Group Description
Data Display
Order [1]
Part 1: Dose Escalation Phase
Part 1: Dose Escalation Phase
1
Part 1: Besylate Sub-Study
Part 1: Besylate Sub-Study
2
Part 2: Expansion Phase
Part 2
3
Combined Study Parts
All Study Parts
4
13.4.2.
Baseline Definition & Derivations
13.4.2.1.
Baseline Definitions
Baseline will be defined as the most recent, non-missing value prior to or on the first 
study treatment dose date. For laboratory data, baseline will be defined as the most 
recent, non-missing value from a central laboratory prior to or on the first study treatment 
dose date. If there are no central labs collected for a subject and lab test prior to or on the 
first dose of study treatment, the most recent, non-missing value from a local laboratory 
prior to or on the first dose of study treatment will be defined as the baseline value.
For subjects who did not receive study treatment during the study, baseline will be 
defined as the latest, non-missing collected value.
For ECG analyses, subject level baseline is defined as the mean of triplicate baseline 
assessments.
13.4.2.2.
Derivations and Handling of Missing Baseline Data
Definition
Reporting Details
Change from Baseline
= Post-Dose Visit Value – Baseline
% Change from Baseline
= 100 x [(Post-Dose Visit Value – Baseline) / Baseline]
NOTES :

Unless otherwise stated, if baseline data is missing no derivation will be performed and will be set to missing.

The baseline definition will be footnoted on all change from baseline displays.


CONFIDENTIAL
BET115521
57
13.4.3.
Reporting Process & Standards
Reporting Process
Software

The currently supported versions of SAS software be used.
Reporting Area
HARP Server
US1SALX00259
HARP Area
: Compound:GSK525762, Study:BET115521
QC Spreadsheet
: arprod\gsk525762\bet115521\.\documents
Analysis Datasets 

Analysis datasets for Part 1 IAs will be created under IDSL standard

Analysis datasets will be created according to CDISC standards (SDTM IG Version X.X & 
AdaM IG Version X.X].

For creation of ADaM datasets (ADCM/ADAE), the same version of dictionary datasets will be 
implemented for conversion from SI to SDTM.
Generation of RTF Files

RTF files will be generated for SAC and IA upon request.
Reporting Standards
General

The current GSK Integrated Data Standards Library (IDSL) will be applied for reporting, unless 
otherwise stated:
o
4.03 to 4.23: General Principles
o
5.01 to 5.08: Principles Related to Data Listings
o
6.01 to 6.11: Principles Related to Summary Tables
o
7.01 to 7.13: Principles Related to Graphics 
Formats

All data will be reported according to the actual treatment the subject received unless 
otherwise stated.

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.

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).


CONFIDENTIAL
BET115521
58
Reporting Standards

Unscheduled or unplanned readings will be presented within the subject’s listings. 

Visits outside the protocol defined time-windows (i.e. recorded as protocol deviations) will 
be included in listings but omitted from figures, summaries and statistical analyses.
Unscheduled Visits

Unscheduled visits will not be included in summary tables.

Unscheduled visits will be included in figures.

All unscheduled visits will be included in listings.
Descriptive Summary Statistics
Continuous Data
Refer to IDSL Statistical Principle 6.06.1
Categorical Data
N, n, frequency, %
Reporting of Pharmacokinetic Concentration Data
Descriptive 
Summary Statistics
Refer to IDSL Statistical Principle 6.06.1
Assign zero to NQ values (Refer to GUI_51487 for further details)
Reporting of Pharmacokinetic Parameters
Descriptive 
Summary Statistics
(Log Transformed)
N, n, geometric mean, 95% CI of geometric mean, standard deviation (SD)
of logged data and [between and or within] geometric coefficient of variation
(CVb/w (%)) will be reported.
[1] CVb (%) = √(exp(SD2) - 1) * 100
(SD = SD of log transformed data)
[2] CVw (%) = √ (exp(MSE) - 1) * 100
(MSE = mean square error from mixed effect model of loge-transformed data).
Parameters Not 
Being Log 
Transformed
Tmax
Summary Tables
[The following PK parameters will not be summarised: “Insert PK 
parameters”.]
Listings
[Additionally, include the first point, last point and number of points used in 
the determination of lambda_z for listings.]
Graphical Displays

Refer to IDSL Statistical Principals 7.01 to 7.13.


CONFIDENTIAL
BET115521
59
13.5.
Appendix 5: Derived and Transformed Data
13.5.1.
General
Multiple Measurements at One 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 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.

Subjects having both High and Low values for Normal Ranges at any post-baseline visits for 
safety parameters will be counted in both the High and Low categories of “Any visit post-
baseline” row of related summary tables. This will also be applicable to relevant Potential 
Clinical Importance summary tables.
Study Day

Calculated as the number of days from study treatment start date:

Ref Date = Missing, then Study Day = Missing 

Ref Date < Study Treatment Start Date, then Study Day = Ref Date – Study Treatment Start 
Date

Ref Data ≥ Study Treatment Start Date, then Study Day = Ref Date – (Study Treatment Start 
Date) + 1    
13.5.2.
Study Population
Demographics
Age

GSK standard IDSL algorithms will be used for calculating age where birth date will be imputed 
as follows:
o
Any subject with a missing day will have this imputed as day ‘15’. 
o
Any subject with a missing date and month will have this imputed as ‘30th June’.

Birth date will be presented in listings as ‘YYYY’.
Body Mass Index (BMI)

Calculated as Weight (kg) / [Height (m)2
Extent of Exposure

Number of days of exposure to study drug will be calculated based on the formula:  
Duration of Exposure in Days = Treatment Stop Date – (Treatment Start Date) + 1

Subjects who were randomized but did not report a treatment start date will be categorised as 
having zero days of exposure. 

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.


CONFIDENTIAL
BET115521
60
13.5.3.
Safety
Adverse Events
AE’S OF Special Interest

Drug eruption

Fixed drug eruption

Dermatitis allergic

Exfoliative rash

Eyelid rash

Genital rash

Mucocutaneous rash

Nodular rash

Paraneoplastic rash

Perineal rash

Rash

Rash erytematous

Rash follicular

Rash generalised

Rash macular

Rash macula-papular

Rash maculovesicular

Rash morbilliform

Toxic skin eruption

Red man syndrome

Dermatitis exfoliative

Dermatitis exfoliative 
generalised

Urticaria popular

Urticaria physical

Urticaria pigmentosa

Urticaria vesiculosa

Urticaria

Urticaria vasculitis

Rash popular

Rash papulosquamous

Rash pruritic

Rash pustular

Rash vesicular

Vasculitic rash

Vuvovaginal rash

Parakeratosis

Epidermal necrosis

Acantholysis

Transient acantholytic 
dermatosis

Skin disorder

Pain of skin

Cutaneous contour 
deformity

Peau d’orange

Skin plaque

Skin degenerative disorder

Stevens-Johnson 
syndrome

Skin reaction

Dermatitis allergic

Panniculitis

Erythema induration

Chronic actinic dermatitis

Pruritus allergic

Allergic respiratory 
symptom

Drug hypersensitivity

Erythma dyschromicum 
perstans

Skin induration

Excessive skin

Skin discolouration

Sca

Dilated pores

Skin fibrosis

Sticky skin

Scar pain

Dermatosis

Koebner phenomenom

Skin fragility

Skin discomfort

Skin texture abnormal

Fingerprint loss

Skin odour abnormal

Skin lesion

Skin fissures 

Papule

Dry skin

Skin maceration

Tubuculid

Cutaneous calcification

Skin swelling

Skin tightness

Skin warm

Skin necrosis

Macule

Eosinophilic pustular 


CONFIDENTIAL
BET115521
61
Adverse Events
AE’S OF Special Interest

Dermatitis atopic

Eczema herpeticum

Skin sensitisation

Erythema multiforme

Toxic epidermal necrolysis

Drug reaction with 
eosinophilia and 
systematic symptoms
folliculitis

Pathergy reaction
Laboratory Parameters

If a laboratory value which is expected to have a numeric value for summary purposes, has a 
non-detectable level reported in the database, where the numeric value is missing, but typically 
a character value starting with ‘<x’ or ‘>x’ (or indicated as less than x or greater than x in the 
comment field) is present, the number of significant digits in the observed values will be used to 
determine how much to add or subtract in order to impute the corresponding numeric value. 
o
Example 1: 2 Significant Digits =  ‘< x ‘ becomes x – 0.01
o
Example 2: 1 Significant Digit   =  ‘> x’ becomes x + 0.1
o
Example 3: 0 Significant Digits = ‘< x’ becomes x – 1    


CONFIDENTIAL
BET115521
62
13.6.
Appendix 6: Premature Withdrawals & Handling of Missing 
Data
13.6.1.
Premature Withdrawals
Element
Reporting Detail
General

In Part 1, a subject will be considered to have completed the study if
o
they complete screening assessments, the 28-day DLT observation period, 
and the end-of-treatment follow-up visit,
o
they progress or die while receiving study treatment, or
o
are receiving ongoing study treatment at the time of the Sponsor’s decision 
to close the study.

In Part 2, a subject will be considered to have completed the study if:
o
they progressed or die while receiving study treatment, or
o
are receiving ongoing study treatment at the time of the Sponsor’s decision 
to close the study.

Withdrawn subjects may be replaced in the study.

All available data from subjects who were withdrawn from the study will be listed 
and all available planned data will be included in summary tables and figures, 
unless otherwise specified.
13.6.2.
Handling of Missing Data
Element
Reporting Detail
General

Missing data occurs when any requested data is not provided, leading to blank 
fields on the collection instrument :
o These data will be indicated by the use of a “blank” in subject listing displays. 
Unless all data for a specific visit are missing in which case the data is 
excluded from the table. 
o Answers such as “Not applicable” and “Not evaluable” are not considered to 
be missing data and should be displayed as such.
Outliers

Any subjects excluded from the summaries and/or statistical analyses will be 
documented along with the reason for exclusion in the clinical study report.
13.6.2.1.
Handling of Missing and Partial Dates
Imputed partial dates will not be used to derive study day, duration (e.g. duration of 
adverse events), or elapsed time variables. In addition, imputed dates are not used for 
deriving the last contact date in the overall survival analysis dataset.
With the exception of new anti-cancer start date on the Oncology time to event analysis 
dataset and exposure end date on the Exposure analysis dataset, imputed dates will also 
not be stored on datasets. 


CONFIDENTIAL
BET115521
63
Imputed dates will not be displayed in listings. However, where necessary, display 
macros may impute dates as temporary variables for the purpose of sorting data in listings 
only. In addition partial dates may be imputed for ‘slotting’ data to study time periods or 
for specific analysis purposes as outlined below. 
The partial date imputation will follow ADaM conventions. The ADaM approach is to 
populate the numeric date variables with the imputed date and add a flag variable to the 
dataset that indicates the level of imputation. 
The flag variable can contain the values: blank, 'D', 'M', 'Y'. 
blank: indicates that no imputation was done
D='Day': indicates that the day portion of the date is imputed
M='Month': indicates that the month and day portions of the date are imputed
Y='Year': indicates that the entire date (year, month, and day) is imputed
Example of date variables: 
XYZD_ - character date variable
XYZDT - numeric date variable
XYZDTFL - flag variable
Details on imputing partial dates for specific datasets are outlined below.
Element
Reporting Detail
General
Partial dates will be displayed as captured in subject listing displays.
Adverse 
Events

The eCRF allows for the possibility of partial dates (i.e., only month and year) to be 
recorded for AE start and end dates; that is, the day of the month may be missing. In 
such a case, the following conventions will be applied for calculating the time to onset 
and the duration of the event:
o
Missing Start Day: First of the month will be used unless this is before the start 
date of study treatment; in this case the study treatment start date will be used and 
hence the event is considered On-treatment as per Appendix 3: Treatment States 
and Phases.
o
Missing Stop Day: Last day of the month will be used, unless this is after the stop 
date of study treatment; in this case the study treatment stop date will be used.

Completely missing start or end dates will remain missing, with no imputation applied. 
Consequently, time to onset and duration of such events will be missing.

Start or end dates which are completely missing (i.e. no year specified) will remain 
missing, with no imputation applied.
Anti-Cancer 
Therapy and 
Radiotherapy

Completely missing start or end dates will remain missing, with no imputation applied.

If partial start date contains a year only set to January 1st.

If partial start date contains a month and year set to the 1st of the month.

No imputation for partial end dates will be performed.
Surgical 
Procedures

No Imputation for completely missing dates

If partial date contains a year only set to January 1st.

If partial date contains a month and year set to the 1st of the month


CONFIDENTIAL
BET115521
64
Element
Reporting Detail
Concomitant 
Medication 
and Blood 
and Blood 
Supportive 
Products

No Imputation for completely missing start or end dates

If study treatment start date is missing (i.e. subject 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.

If study treatment start date is missing (i.e. subject 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.

If partial end date contains year only, set end date = earliest of December 31 or date of 
last contact.

If partial end date contains month and year, set end date = earliest of last day of the 
month or date of last contact.
Time to Event 
and 
Response for 
Anti-Cancer 
Therapy 
Where 
applicable: 
Radiotherapy,
Surgical 
Procedures

Start dates for follow-up anti-cancer therapy, radiotherapy (where applicable), and 
surgical procedures (where applicable) will be temporarily imputed in order to define 
event and censoring rules for progression-free survival, response rate, or duration of 
response (i.e. start date for new anti-cancer therapy). Dates will only be imputed when 
a month and year are available but the day is missing. The imputed dates will not be 
stored on the anti-cancer therapy, radiotherapy, or surgical procedure datasets. The 
following rules will be used to impute the date when partial start dates are present on 
anti-cancer therapy radiotherapy, and/or surgical procedures datasets.

No Imputation for completely missing start dates

No imputation for missing start day and month (note the eCRF should only allow for 
missing day)

If partial start date falls in the same month as the last dose of study treatment, then 
assign to earlier of (date of last dose of study treatment+1, last day of month). 

If partial start date falls in the same month as the subject’s last assessment and the 
subject’s last assessment is progressive disease (PD), then assign to earlier of (date of 
PD+1, last day of month). 

If both rules above apply, then assign to latest of the 2 dates 

Otherwise, impute missing day to the first of the month.

No imputation for partial end dates will be performed
Exposure 
End Dates for 
Subjects Who 
Are Still on 
Study at the 
Time of 
Analysis

If exposure end date is missing, then assign exposure end date as the earliest of: the 
date of the data cutoff, the date of withdrawal from the study, or the death date.

The imputed exposure end date will be used to calculate cumulative dose and 
exposure duration.

The imputed exposure end date will be stored in the exposure analysis dataset and an 
exposure end date imputation flag variable will be derived indicating which exposure 
end date records are imputed. 


CONFIDENTIAL
BET115521
65
Element
Reporting Detail

Imputed exposure end dates will also be stored on the study treatment end date 
variable.

For subjects who have missing end dates in their last exposure record because they 
are still on study treatment, the on-therapy indicator variables (time in relation to study 
treatment) are assigned to on-therapy for all records where the 'dataset'.'date' is after 
or on the study treatment start date.


CONFIDENTIAL
BET115521
66
13.7.
Appendix 7: Values of Potential Clinical Importance
13.7.1.
Laboratory Values
Reference ranges for all laboratory parameters collected throughout the study are 
provided by the laboratory. A laboratory value that is outside the reference range is 
considered either high abnormal (value above the upper limit of the reference range) or 
low abnormal (value below the lower limit of the reference range). Note: a high abnormal 
or low abnormal laboratory value is not necessarily of clinical concern. The laboratory 
reference ranges will be provided on the listings of laboratory data. Clinical laboratory 
test results outside of the reference range will be flagged in the listings.
To identify laboratory values of potential clinical importance, National Cancer Institute 
Common Terminology Criteria for Adverse Events (NCI-CTCAE v4.0) will be used to 
assign grades to the relevant laboratory parameters. NCI-CTCAE v4.0 can be found at
http://ctep.cancer.gov/reporting/ctc.html.
For laboratory data that are not listed in the NCI CTCAE v4.0, a summary of values 
outside the normal range will be provided.


CONFIDENTIAL
BET115521
67
13.7.2.
ECG
ECG Parameter
Units
Clinical Concern Range
Lower
Upper
Absolute
Absolute QTcF Interval
msec
≥ 450
< 481 
≥ 481 
< 501
≥ 501 
Absolute PR Interval
msec
< 110
> 220
Absolute QRS Interval
msec
< 75 
> 110 
Change from Baseline
Increase from Baseline QTc
msec
> 30  
≤ 60
msec
> 60  
13.7.3.
Vital Signs
Vital Sign Parameter
(Absolute)
Units
Clinical Concern Range
Lower
Upper
Systolic Blood Pressure
mmHg
>120 to <140 (Grade 1)
mmHg
≥140 to <160 (Grade 2)
mmHg
≥160 (Grade 3)
Diastolic Blood Pressure
mmHg
> 80 to < 90 (Grade 1)
mmHg
≥ 90 to < 100 (Grade 2)
mmHg
≥ 100 (Grade 3)
Heart Rate
bpm
< 60
> 100
Temperature
Degrees C
≤ 35
≥ 38
13.7.4.
Left Ventricular Ejection Fraction
LVEF
Units
Clinical Concern Range
Absolute Change from Baseline
%
0 < Decrease < 10
%
10 ≤ Decrease < 20
%
Decrease ≥ 20
%
Decrease ≥ 0 and ≥ LLN
%
Decrease ≥ 10 and < LLN
%
Decrease ≥ 20 and ≥LLN
%
Decrease ≥ 20 and < LLN
Relative Percent Change from Baseline
%
Decrease ≥ 20 and ≥ LLN
%
Decrease ≥ 20 and < LLN
To identify LVEF values of potential clinical importance, NCI-CTCAE v4.0 will be used 
to assign categories that align with the grades for ‘Ejection fraction decreased’.


CONFIDENTIAL
BET115521
68
13.8.
Appendix 8: Multicenter Studies
13.8.1.
Methods for Handling Centres

Data from all participating centers will be pooled prior to analysis. 

It is anticipated that subject accrual will be spread thinly across centers and 
summaries of data by center would be unlikely to be informative and will not, 
therefore, be provided.


CONFIDENTIAL
BET115521
69
13.9.
Appendix 9: Model Checking and Diagnostics for Statistical 
Analyses
Not applicable for this study.


CONFIDENTIAL
BET115521
70
13.10.
Appendix 10 – Abbreviations & Trade Marks
13.10.1.
Abbreviations
Abbreviation
Description
ADaM
Analysis Data Model
AE
Adverse Event
AIC
Akaike's Information Criteria
A&R
Analysis and Reporting 
CDISC
Clinical Data Interchange Standards Consortium
CI
Confidence Interval
CPMS
Clinical Pharmacology Modelling & Simulation
CS
Clinical Statistics
CSR
Clinical Study Report
CTR
Clinical Trial Register
CVb / CVw
Coefficient of Variation (Between) / Coefficient of Variation (Within)
DOB
Date of Birth
DP
Decimal Places
eCRF
Electronic Case Record Form
IA
Interim Analysis
ICH
International Conference on Harmonisation
IDMC
Independent Data Monitoring Committee 
IDSL
Integrated Data Standards Library
IMMS
International Modules Management System
IP
Investigational Product
ITT
Intent-To-Treat
GUI
Guidance
LOC
Last Observation Carries Forward
MMRM
Mixed Model Repeated Measures
PCI
Potential Clinical Importance 
PD
Pharmacodynamic
PDMP
Protocol Deviation Management Plan
PK
Pharmacokinetic
PP
Per Protocol
QC
Quality Control
QTcF
Frederica’s QT Interval Corrected for Heart Rate
QTcB
Bazett’s QT Interval Corrected for Heart Rate
RAP
Reporting & Analysis Plan
RAMOS
Randomization & Medication Ordering System 
SAC
Statistical Analysis Complete
SDTM
Study Data Tabulation Model
SOP
Standard Operation Procedure
TA
Therapeutic Area
TFL
Tables, Figures & Listings 
GSK
GlaxoSmithKline


CONFIDENTIAL
BET115521
71
13.10.2.
Trademarks
Trademarks of the GlaxoSmithKline 
Group of Companies
Trademarks not owned by the 
GlaxoSmithKline Group of Companies
None
FACTs
SAS
WinNonlin


CONFIDENTIAL
BET115521
72
13.11.
Appendix 11: List of Data Displays
13.11.1.
Data Display Numbering
The following numbering will be applied for RAP generated displays:
Section
Tables
Figures
Study Population
1.0010 to 1.1200
Efficacy
2.0010 to 2.0540
12.0010 to 12.0140
Safety
3.0010 to 3.3050
13.0010 to 13.0550
Pharmacokinetic
5.001041 to 5.0210
15.0010to 15.0090
Section
Listings
ICH Listings
21.0010 to 25.0050
Other Listings
21.0010 to 25.0050
13.11.2.
Mock Example Shell Referencing
Non IDSL specifications will be referenced as indicated and if required an example 
mock-up displays provided in Appendix 12: Example Mock Shells for Data Displays.
Section
Figure
Table
Listing
Study Population
POP_Fn
POP_Tn
POP_Ln
Efficacy
EFF_Fn
EFF_Tn
EFF_Ln
Safety
SAFE_Fn
SAFE_Tn
SAFE_Ln
Pharmacokinetic
PK_Fn
PK_Tn
PK_Ln
Pharmacodynamic and / or Biomarker
PD_Fn
PD_Tn
PD_Ln
Pharmacokinetic / Pharmacodynamic
PKPD_Fn
PKPD_Tn
PK/PD_Ln
NOTES: 

Non-Standard displays are indicated in the ‘IDSL / TST ID / Example Shell’ or ‘Programming Notes’ column as 
‘[Non-Standard] + Reference.’
13.11.3.
Deliverable [Priority]
Delivery [Priority] [1]
Description
IA QD [X]
Interim Analysis Statistical Analysis Complete for QD dosing
IA BID [X]
Interim Analysis Statistical Analysis Complete for BID dosing
IA Exp [X]
Interim Analysis for expansion cohort futility analysis
SAC [X]
Final Statistical Analysis Complete
NOTES: 
1.
Indicates priority (i.e. order) in which displays will be generated for the reporting effort.


CONFIDENTIAL
BET115521
73
13.12.
Appendix 12: Example Mock Shells for Data Displays
Example Non-Standard                                  
Protocol: BET115521                                                                       Page 1 of 1
Population: All Treated Subjects                                                  (Data as of: 30MAY2013)
Table 1
Table of PSA response
Treatment: GSK525762
xxmg 
(N=xx)
PSA Changes 
  Decline>=50% from baseline (>=12week)
  xx (xx%)
  Decline>=30% from baseline (>=12week)
xx (xx%)
  No significant PSA change1
xx (xx%)
  PSA Progression
  xx (xx%) 
  Not Evaluable2
  xx (xx%) 
Response Rate 
  PSA >=50% reduction 
  xx (xx%) 
  95% Confidence Interval 
(xx%, xx%) 
1 Subjects who do not have decline>=30% from baseline (>=12week) or PSA progression
2 Subjects who do not have baseline PSA value or still on treatment but do not have ≥12 week visit PSA test 
results are treated as not evaluable  


CONFIDENTIAL
BET115521
74
Example Non-Standard                                  
Protocol: BET115521                                                                            Page 1 of 1
Population: All Treated Subjects                                                    (Data as of: 30MAY2013)
Listing 1
Listing of Subject Best Response for Interim Review by First Dose Date (Tumor type)
Treatment: GSK525762
Date 
of 
First 
Dose
Subject
Ongoing?
Measurable 
disease at 
baseline
At 
Least 
One 
Post-
Baseline 
Assessment?
Evaluable 
for 
Interim 
Analysis?
Best 
Response   
(Confirmed)
Best Response 
(Unconfirmed)
01Apr2012
xxx
Yes
Yes
Yes
Yes
SD
CR
05May2012
xxx
Yes
Yes
Yes
Yes
SD
SD
06May2012
xxx
No
Yes
Yes
Yes
PR
PR
08Jan2013
xxx
No
Yes
Yes
Yes
SD
SD
08Mar2013
xxx
Yes
Yes
No
No
08Apr2013
xxx
Yes
No
No
No
NE
NE
Response: CR = Complete Response, PR = Partial Response, SD = Stable Disease, PD = Progressive Disease, NE= 
Not Evaluable.
Note to programmer: This display should be sorted by Date of First Dose


CONFIDENTIAL
BET115521
75
Example Non-Standard                                  
Protocol: BET115521                                                                            Page 1 of 1
Population: All Treated Subjects                                                    (Data as of: 30MAY2013)
Listing 2
Listing of CRPC Subject PSA Response for Interim Review by First Dose Date 
Treatment: GSK525762
Date 
of 
First 
Dose
Subject
Ongoing?
Had ≥12 
week PSA 
Assessment?
Evaluable 
for 
Interim 
Analysis?
Maximum PSA 
Decline %
PSA Response 
01Apr2012
xxx
Yes
Yes
Yes
85
Decline>=50% from baseline (>=12week)
05May2012
xxx
Yes
Yes
Yes
41
Decline>=30% from baseline (>=12week)
06May2012
xxx
No
Yes
Yes
No decline
PSA progression
09Jun2012
xxx
No
Yes
Yes
5
PSA progression
08Jan2013
xxx
No
Yes
Yes
10
No significant PSA change
08Mar2013
xxx
Yes
No
No
20
Not Evaluable
08Apr2013
xxx
Yes
No
No
No decline
Not Evaluable
Note to programmer: This display should be sorted by Date of First Dose