Clinical trial NCT02082977
Conditions: Cancer Neoplasms
Keywords: Refractory Phase I study, dose escalation study diffuse large B cell lymphoma Relapsed Solid tumors transformed follicular lymphoma Multiple myeloma GSK2816126 Non-Hodgkin's lymphoma
Sponsor: GlaxoSmithKline
Start date: 2014-04-24; Completion date: 2017-06-20
Enrollment: 41 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
This is an open-label, multicenter, 2-part study to determine the recommended Phase 2 dose (RP2D) for GSK2816126 given twice weekly by intravenous (IV) infusion. Part 1 will be conducted in adult subjects with relapsed/refractory diffuse large B cell lymphoma (DLBCL), transformed follicular lymphoma (tFL), other Non-Hodgkin's lymphomas (NHL), solid tumors (including castrate resistant prostate cancer) and multiple myeloma (MM) to determine the safety and tolerability of GSK2816126. Expansion cohorts (Part 2) are planned to further explore clinical activity of GSK2816126 at the RP2D in subjects with Enhancer of Zeste 2 (EZH2) wild type and EZH2 mutant positive germinal center B-cell like diffuse large B cell lymphoma (GCB-DLBCL), tFL and MM.

Detailed description:

Arms: arm 1: Eligible subjects will receive GSK2816126 with a starting dose of 50 milligrams (mg) twice-weekly, as an intravenous solution for 28 days (3 weeks on/1 week off). arm 2: Eligible subjects will receive GSK2816126 with a dose of 100 mg twice-weekly, as an intravenous solution for 28 days (3 weeks on/1 week off). arm 3: Eligible subjects will receive GSK2816126 with a dose of 200 mg twice-weekly, as an intravenous solution for 28 days (3 weeks on/1 week off). arm 4: Eligible subjects will receive GSK2816126 with a dose of 400 mg twice-weekly, as an intravenous solution for 28 days (3 weeks on/1 week off). arm 5: Eligible subjects will receive GSK2816126 with a dose of 800 mg twice-weekly, as an intravenous solution for 28 days (3 weeks on/1 week off). arm 6: Eligible subjects will receive GSK2816126 with a dose of 1200 mg twice-weekly, as an intravenous solution for 28 days (3 weeks on/1 week off). arm 7: Eligible subjects will receive GSK2816126 with a dose of 1800 mg twice-weekly, as an intravenous solution for 28 days (3 weeks on/1 week off). arm 8: Eligible subjects will receive GSK2816126 with a dose of 2400 mg twice-weekly, as an intravenous solution for 28 days (3 weeks on/1 week off). arm 9: Eligible subjects will receive GSK2816126 with a dose of 3000 mg twice-weekly, as an intravenous solution for 28 days (3 weeks on/1 week off). arm 10: Subjects with Germinal Center B-cell-like Diffuse Large B-cell Lymphoma (GCB-DLBCL)-mutant and wild type, Transformed Follicular Lymphoma (TFL)-mutant and wild type as well as with multiple myeloma (MM) will be enrolled in Part 2 of the study. Subjects enrolled in Part 2 will receive recommended Phase II dose (RP2D).
Interventions: intervention 1: GSK2816126
Intervention descriptions: intervention 1: GSK2816126 will be supplied as a solution containing 15 milligram per milliliter (mg/mL) GSK2816126 in water for injection.

Protocol documents:
Prot_001.pdf: 
2012N149024_05
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TITLE PAGE
Division: Worldwide Development
Information Type: Protocol Amendment
Title:
A phase I open-label, dose escalation study to investigate the 
safety, pharmacokinetics, pharmacodynamics and clinical 
activity of GSK2816126 in subjects with relapsed/refractory 
diffuse large B cell lymphoma, transformed follicular 
lymphoma, other Non-Hodgkin’s lymphomas, solid tumors and 
multiple myeloma
Compound Number:
GSK2816126
Development Phase:
I
Effective Date:
20-MAR-2017
Protocol Amendment Number:  5 
Author (s):
Global Clinical Operations Sciences, USA
Drug Metabolism and Pharmacokinetics, USA
Cancer Epigenetics, USA
Non--Clinical Safety, USA
Cancer Research Epigenetics Management, USA
Non-Clinical Safety, USA 
Statistics, Oncology TA Group, USA
Global Clinical Operations Sciences, USA
Clinical Oncology, USA
Clinical Oncology, USA
Cancer Epigenetics DPU, USA
Clinical Pharmacology Modeling & Simulation, USA
        Statistics, Oncology TA Group, USA
Copyright 2017 the GlaxoSmithKline group of companies.  All rights reserved.  
Unauthorised copying or use of this information is prohibited.
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Revision Chronology
GlaxoSmithKline 
Document Number
Date
Version
2012N149024_00
2013-JUL-11
Original
2012N149024_01
2013-OCT-23
Amendment No. 1 
applies only to sites in the UK. Following review of the protocol by the MHRA, the 
following changes were  made:
1.
Removed wording from the protocol stating that GSK2816126 treatment will 
continue until commercial availability. 
2.
The stopping criterion based on QTc will be changed to ≥500 msec. 
3.
Added a QTc stopping criterion that patients will be withdrawn if they experience 
an increase in QTc >60msec from baseline following dose reduction and re-challenge.  
2012N149024_02
2013-OCT-30
Amendment No.: 02
applies to all study sites. Following review of the protocol by the FDA, the following 
changes were  made:
1.
The starting dose of GSK2816126 is reduced from 125 mg/dose to 50 mg/dose
2.
Updated Dose Limiting Tox language
3.
Revised 100% dose escalation wording
4.
Decreased QTc baseline exclusion criterion
5.
Added regular ECG monitoring timings
6.
Added blood glucose testing to our list of clinical lab tests
7.
Removed any wording pertaining to the use of central labs
8.
Removed wording from the protocol stating that GSK2816126 treatment will 
continue until commercial availability 
9.
Clarify that PET scans are optional
10.
Elaborated on CT scan timings
11.
The stopping criterion based on QTc will be changed to ≥500 msec
12.
Added a QTc stopping criterion that subjects will be withdrawn if they experience 


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an increase in QTc >60 msec from baseline following dose reduction and re-challenge 
13.
Added explanatory language to T&E Table around coagulation, CT and 
standalone PET assessments 
14.
Changed corticosteroid exclusion criteria
2012N149024_03
2015-APR-03
Amendment No. 03
03 applies to all study sites and includes the addition of solid tumor malignancies and 
other NHLs to Part 1 of the study, transformed follicular lymphoma subjects to Part 2 and 
multiple myeloma subjects to both Part 1 and 2.  The protocol title, study rationale, 
objectives, endpoints, hypotheses, inclusion/exclusion criteria, background, preclinical 
pharmacology and safety, risk/benefits, investigational plan, population rationale, T&E 
table, tumor biomarker analysis have all been updated to reflect these changes. RECIST 
criteria and multiple myeloma response criteria have also been added.  A description of 
genetic research has been added to the appendix.  To accommodate these changes we 
have also augmented the number of subjects, evaluation of futility, organ function table, 
data management and statistical analysis.  Other additions include dose adjustment for 
hematologic and non hematologic toxicity, description of the investigational product and 
time windows for the PK sample collection table. Additions were also made to the 
Pharmacodynamics and Translational Research sections to cover potential studies in a 
surrogate tissue.  Updated the Prohibited Meds Table 13 and Table 14.  Removed PD 
analysis from Part 2.
2012N149024_04
2016-MAR-17
Amendment No. 4
Amendment 04 applies to all study sites and includes the following updates:
1. Updated primary and secondary medical monitor contact information
2. Extend the period of post treatment contraception for women to 2 weeks (14 days) 
(previously 1 week).
3. Updated requirement for pregnancy test to within 7 days of first dose (previously 
within 14 days of first dose) and added  requirements for repeat testing every 4 
weeks.
4. Added requirement that any female subject who becomes pregnant while on study 
be withdrawn from the study.
5. Added that subjects be instructed to avoid excess exposure to sunlight and UV 
and to use protective measures if outdoors. 
6. Modified the storage period for diluted investigational product prior to infusion to 
12 hours (previously 48 hours).
7. Updated prohibited medications to clarify exclusion of IV ondansetron and 
palonosetron (oral doses up to 8mg TID are permitted).


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2012N149024_05
2017-MAR-20
Amendment No. 5
Amendment 5 applies to all global sites. Updates were made throughout the protocol to 
correct minor inconsistencies, spelling errors and provide further clarification.  The 
following updates have been made to the this amendment to align with updated GSK 
SOPs and Guidance documents, as well as, to include expansion cohorst in Part 1 of the 
study to explore further efficacy and safety data:

Updates made to the Part 1 and Part 2 Objectives, Endpoints and study hypothesis 
to align with the added Part 1 expansion cohorts of GCB DLBCL and solid 
tumors containing EZH2 inhibitor sensitizing mutations or prostate cancer to 
support MTD/RP2D and initiation of planned part 2 analysis

Study design and number of subjects updated to include the added Part 1 
expansion cohorts and update Part 2 expansion cohort

Inclusion and exclusion criteria updated to define eligibility of GCB DLBCL and
solid tumor subjects in Part 1 expansion cohort.  Exclusion for Central nervous 
system metastases, invasive malignancy other than disease under study and prior 
allogeneic transplant added.

Male and female contraception use and pregnancy information updated in 
inclusion criteria and Section 10 to align with GSK written standards

Statistical methods/Section 12 updated to include Part 1 interim analysis of 
futility and efficacy for GCB DLBCL subjects. Part 2 updated to further clarify 
that expansion design is planned based on predictive probability methodology. 
Rather than early stop for either futility or efficacy, Part 2 allows early stop for 
futility only.  Number of subjects to be enrolled into the Part 2 expansion cohorts 
updated accordingly

Risk Assessment updated to include: updated list of medications with risk and 
possible risk of tpd that are prohibited or to be used with caution;  drugs that are 
to be used with caution will require additional ECG monitoring; clarify
instructions for the treatment of infusion reactions; new drug interaction data; 
additional data and instructions for phototoxicity; and data and mitigation strategy 
for increased ALT levels seen in higher doses. 

PK/PD cohort moved from Part 1 to Part 2

Study rationale updated to include supporting rationale for inclusion of GCB-
DLBCL and solid tumor subjects (to include prostate cancer)

Safety management guidelines updated to clarify QTcF to be used for eligibility 


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and stopping criteria

Time and Events tables updated to clarify required assessments. Added 
clarification that brain scans are required for all subjects at screening and bone 
scans should be completed as clinically indicated.  Collection of Blood for PD 
biomarkers removed and collection of whole blood for biomarkers added

Response criteria added for subjects with prostate cancer in Appendix 7 of the 
protocol

Adverse event and serious adverse event Section 8 updated to align with latest 
GSK written standards, to include: further definition of events which would meet 
liver stopping and monitoring criteria, as well as, definition and process for study 
treatment restart and rechallenge after a liver event and removal of Section 8.4 
addressing disease related event

Section 9 updated with latest list of prohibited medications and those to be used 
with caution


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SPONSOR/MEDICAL MONITOR INFORMATION PAGE
Medical Monitor and Sponsor Contact Information:
Role
Name
Day Time Phone 
Number
After-hours 
Phone/Cell/
Pager Number
GSK Address
Primary 
Medical 
Monitor
 
 MD, 
PhD 
1250 South Collegeville Road,
Mailstop UP 4410
Collegeville, PA 19426, USA
 
Secondary 
Medical 
Monitors
MD
Office: 
Cell: 
1250 South Collegeville Road,
Mailstop UP 4410
Collegeville, PA 19426, USA
Office: 
1250 South Collegeville Road,
Mailstop UP 4410
Collegeville, PA 19426, USA
Sponsor Registered Address:
GlaxoSmithKline
Iron Bridge Road 
Stockley Park West, Uxbridge, Middlesex, UB11 1BU, UK
Telephone:  
 
GlaxoSmithKline
Five Moore Drive 
P.O. 13398
Research Triangle Park, NC 27709-3398, USA
Telephone: 
GlaxoSmithKline
1250 South Collegeville Road
Collegeville, PA 19426, USA
Telephone Number: 
In some countries, the clinical trial sponsor may be the local GlaxoSmithKline affiliate 
company (or designee).  Where applicable, the details of the Sponsor and contact person 
will be provided to the relevant regulatory authority as part of the clinical trial 
submission.
Regulatory Agency Identifying Number(s):
Compound Number
IND Number
EudraCT Number
GSK2816126
118286
2013-001585-42
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INVESTIGATOR PROTOCOL AGREEMENT PAGE
For protocol EZH117208
I confirm agreement to conduct the study in compliance with the protocol, as amended by 
this protocol amendment.
I acknowledge that I am responsible for overall study conduct. I agree to personally 
conduct or supervise the described study.
I agree to ensure that all associates, colleagues and employees assisting in the conduct of 
the study are informed about their obligations. Mechanisms are in place to ensure that site 
staff receives the appropriate information throughout the study. 
Investigator Name:
Investigator Address:
Investigator Phone Number:
Investigator Signature
Date


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TABLE OF CONTENTS
PAGE
LIST OF ABBREVIATIONS...........................................................................................14
PROTOCOL SYNOPSIS...............................................................................................18
1.
INTRODUCTION....................................................................................................31
1.1.
Background ................................................................................................31
1.2.
GSK2816126..............................................................................................31
1.2.1.
Pharmacokinetics of GSK2816126 in Humans ............................32
1.2.2.
Pre-Clinical Pharmacology & Safety of GSK2816126 ..................32
1.3.
Benefit/Risk Assessment ............................................................................35
1.3.1.
Risk Assessment .........................................................................36
1.3.2.
Benefit Assessment.....................................................................41
1.3.3.
Overall Benefit: Risk Conclusion..................................................41
1.4.
Communication Plan for Safety Evaluation .................................................41
1.4.1.
Contraindications, Warnings and Precautions..............................41
2.
OBJECTIVES, ENDPOINTS AND HYPOTHESES.................................................42
2.1.
Part 1: Phase I Dose Escalation .................................................................42
2.2.
Part 2: Expansion .......................................................................................45
3.
INVESTIGATIONAL PLAN.....................................................................................47
3.1.
Study Schematic.........................................................................................47
3.2.
Discussion of Study Design ........................................................................47
3.3.
Part 1: Dose-Escalation Phase ...................................................................48
3.3.1.
Accelerated Dose Escalation .......................................................48
3.3.2.
3+3 Dose Escalation Phase.........................................................49
3.3.2.1.
Toxicity Leading to Termination of Accelerated 
Titration ......................................................................50
3.3.3.
Dose Limiting Toxicity..................................................................51
3.3.4.
Maximum Tolerated Dose............................................................51
3.3.5.
Intra-subject Dose Escalation ......................................................51
3.3.6.
Alternative Dosing Schedules ......................................................52
3.3.7.
Part 1: Futility and Efficacy Analysis for GCB-DLBCL 
Subjects.......................................................................................52
3.4.
Part 2: Expansion Cohorts..........................................................................53
3.4.1.
Part 2  PK/PD cohort:...................................................................53
3.5.
Rationale ....................................................................................................54
3.5.1.
Rationale for Study ......................................................................54
3.5.2.
Rationale for Population...............................................................54
3.5.3.
Rationale for Dose and Schedule ................................................57
3.6.
Study Treatment .........................................................................................59
3.6.1.
Treatment Assignment.................................................................59
3.7.
Dosage and Administration of Study Treatment..........................................59
3.8.
Safety Management Guidelines..................................................................60
3.8.1.
QTcF Stopping Criteria ................................................................60
3.8.2.
Infusion Reaction Stopping Criteria and Management .................60
3.8.2.1.
Management of Infusion Reactions ............................61
3.8.3.
Dose Adjustment for Non-Hematologic Toxicity ...........................61


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3.8.4.
Dose Adjustment for Hematologic Toxicity...................................62
3.8.4.1.
For subjects with lymphoma and multiple 
myeloma:....................................................................62
3.8.4.2.
For subjects with solid tumors: ...................................63
3.9.
Guidelines for Events of Special Interest and Dose Modifications...............63
3.9.1.
Dose Modifications ......................................................................63
4.
INVESTIGATIONAL PRODUCT.............................................................................64
4.1.
Description of Investigational Product.........................................................64
4.2.
Preparation/Handling/Storage of GSK2816126 GSK Investigational 
Product.......................................................................................................64
4.3.
Product Accountability ................................................................................65
4.4.
Treatment Compliance................................................................................65
4.5.
Treatment of Investigational Product Overdose ..........................................65
5.
STUDY POPULATION...........................................................................................66
5.1.
Number of Subjects ....................................................................................66
5.2.
Subject Selection Criteria............................................................................66
5.2.1.
Part 1 Inclusion Criteria................................................................66
5.2.2.
Part 2 Inclusion Criteria................................................................69
5.2.3.
Part 1 and 2 Exclusion Criteria.....................................................70
6.
COMPLETION OR WITHDRAWAL OF SUBJECTS...............................................72
6.1.
Screen and Baseline Failures .....................................................................72
6.2.
Subject Completion Criteria ........................................................................72
6.3.
Permanent Discontinuation from Study Treatment......................................72
6.4.
Study Completion .......................................................................................73
6.5.
Treatment after the End of the Study ..........................................................73
7.
STUDY ASSESSMENTS AND PROCEDURES .....................................................73
7.1.
Time and Events Table(s)...........................................................................74
7.2.
Demographic/Medical History and Baseline Assessments..........................91
7.2.1.
Critical Baseline Assessments.....................................................92
7.3.
Safety Evaluations......................................................................................92
7.3.1.
Physical Examinations.................................................................93
7.3.2.
ECOG Performance Status..........................................................93
7.3.3.
Vital Signs....................................................................................93
7.3.4.
Safety Electrocardiogram.............................................................93
7.3.5.
Holter Monitoring .........................................................................94
7.3.6.
Laboratory Assessments .............................................................94
7.3.7.
Pregnancy Testing and Reporting................................................95
7.4.
Pharmacokinetics .......................................................................................96
7.4.1.
Blood Sample Collection for Pharmacokinetics............................96
7.4.2.
Bile Sample Collection for Pharmacokinetics...............................96
7.4.3.
Urine Sample Collection for Pharmacokinetics ............................96
7.4.4.
Plasma Sample for CYP3A4 Enzyme Activity ..............................96
7.4.5.
Pharmacokinetic Sample Analysis ...............................................97
7.5.
Pharmacodynamics ....................................................................................97
7.6.
Translational Research...............................................................................97
7.6.1.
Tumor Biomarker Analysis...........................................................98
7.6.1.1.
GCB-DLBCL Subtyping (DLBCL subjects only)..........99


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7.6.1.2.
EZH2 Mutation Analysis (required for study 
entry in Part 2 for GCB-DLBCL and tFL 
subjects only) .............................................................99
7.6.2.
Circulating cell free DNA/RNA Analysis .......................................99
7.6.3.
Circulating biomarker analysis .....................................................99
7.6.4.
RNA Expression Research ........................................................100
7.6.5.
Tumor Tissue collection.............................................................100
7.6.6.
Blood collection..........................................................................101
7.7.
Evaluation of Anti-Cancer Activity .............................................................101
7.8.
Genetic Research.....................................................................................102
8.
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS...................................102
8.1.
Definition of an AE....................................................................................102
8.2.
Definition of a SAE....................................................................................103
8.3.
Laboratory and Other Safety Assessment Abnormalities Reported 
as AEs and SAEs .....................................................................................105
8.3.1.
Liver Chemistry Stopping Criteria ..............................................105
8.3.1.1.
Study Treatment Restart or Rechallenge..................107
Refer to Appendix 3 for full guidance .........................................107
8.3.2.
Cardiovascular Events...............................................................108
8.4.
Time Period and Frequency of Detecting AEs and SAEs..........................108
8.4.1.
Method of Detecting AEs and SAEs...........................................108
8.4.2.
Prompt Reporting of SAEs and Other Events to GSK ................109
8.4.3.
Regulatory reporting requirements for SAEs..............................111
9.
CONCOMITANT MEDICATIONS AND NON-DRUG THERAPIES .......................111
9.1.
Permitted Medications ..............................................................................111
9.2.
Prohibited and Cautionary Medications.....................................................112
9.2.1.
Drugs that may alter the Pharmacokinetics of 
GSK2816126.............................................................................112
9.3.
Drugs that may have their Pharmacokinetics altered by 
GSK2816126............................................................................................113
9.4.
Drugs and QT prolongation.......................................................................116
9.5.
Non-Drug Therapies .................................................................................119
10. LIFESTYLE AND/OR DIETARY RESTRICTIONS................................................120
10.1.
Contraception ...........................................................................................120
10.1.1.
Female Subjects........................................................................120
10.1.2.
Male Subjects............................................................................121
10.2.
Lactation Restrictions................................................................................122
10.3.
Caffeine, Alcohol and Tobacco Restrictions..............................................122
10.4.
Sun and UV Exposure Restrictions...........................................................122
11. DATA MANAGEMENT .........................................................................................122
12. DATA ANALYSIS AND STATISTICAL CONSIDERATIONS.................................123
12.1.
Hypotheses...............................................................................................123
12.1.1.
Part 1: Dose-Escalation Phase ..................................................123
12.1.2.
Part 2: Expansion Cohorts.........................................................123
12.2.
Sample Size Determination ......................................................................124
12.2.1.
Part 1: Dose-Escalation Phase ..................................................124
12.2.1.1.
Dose Escalation in Part 1 .........................................124


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12.2.1.2.
Cohort Expansion in Part 1.......................................124
12.2.2.
Part 2: Expansion Cohort...........................................................127
12.3.
Data Analysis Considerations ...................................................................131
12.3.1.
Analysis Populations..................................................................131
12.3.2.
Analysis Data Sets.....................................................................131
12.3.3.
Treatment Comparisons ............................................................131
12.3.3.1.
Primary Comparisons of Interest ..............................131
12.3.3.2.
Other Comparisons of Interest..................................131
12.3.4.
Interim Analysis .........................................................................132
12.3.4.1.
Part 1 .......................................................................132
12.3.4.2.
Part 2 .......................................................................132
12.3.5.
Final Analyses ...........................................................................132
12.3.5.1.
Safety Analyses........................................................132
12.3.5.2.
Clinical Laboratory Evaluations ................................133
12.3.5.3.
Pharmacokinetic Analyses........................................133
12.3.5.3.1.
Non-compartmental 
Pharmacokinetic Analyses....................133
12.3.5.3.2.
Metabolic Profiling ................................134
12.3.5.3.3.
Population Pharmacokinetics................134
12.3.5.3.4.
Statistical Analyses of 
Pharmacokinetic Data...........................134
12.3.5.4.
Efficacy Analyses .....................................................135
12.3.6.
PK/PD Relationship ...................................................................135
12.3.7.
Pharmacodynamic Biomarkers and Exploratory Response 
Prediction Biomarkers................................................................135
13. STUDY CONDUCT CONSIDERATIONS .............................................................136
13.1.
Posting of Information on Clinicaltrials.gov................................................136
13.2.
Regulatory and Ethical Considerations, Including the Informed 
Consent Process ......................................................................................136
13.3.
Urgent Safety Measures ...........................................................................136
13.4.
Quality Control (Study Monitoring) ............................................................137
13.5.
Quality Assurance.....................................................................................137
13.6.
Study and Site Closure .............................................................................137
13.7.
Records Retention....................................................................................138
13.8.
Provision of Study Results to Investigators, Posting of Information 
on Publicly Available Clinical Trials Registers and Publication..................138
14. REFERENCES.....................................................................................................140
15. APPENDICES......................................................................................................142
15.1.
Appendix 1: COCKCROFT-GAULT FORMULA ........................................142
15.2.
Appendix 2: ECOG Performance Status1..................................................143
15.3.
Appendix 3: Liver Chemistry Monitoring, Interruption Stopping and 
Follow-up Criteria......................................................................................144
15.3.1.
Liver Safety Stopping Criteria and Required Action and 
Follow up Assessments .............................................................144
15.3.2.
Liver Safety – Study Treatment Restart or Rechallenge 
GuidelinesIf subject meets liver chemistry stopping criteria 
do not restart/rechallenge subject with study treatment 
unless:.......................................................................................147
15.4.
Appendix 4: Response Criteria .................................................................150


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15.5.
Appendix 5: RECIST 1.1...........................................................................153
15.6.
Appendix 6: Response Criteria for Multiple Myeloma................................160
15.7.
Appendix 7: Criteria for Response/Progression: Prostate Cancer .............164
15.7.1.
Disease Progression Endpoint...................................................164
15.7.2.
DiseaseResponse Endpoints.....................................................164
15.8.
Appendix 8: Genetic Research .................................................................166
15.9.
Appendix 9: Protocol Amendment Changes..............................................169
15.10. Appendix 10: Country Specific Requirements...........................................402


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LIST OF ABBREVIATIONS
AE(s)
Adverse Event(s)
ALT
Alanine aminotransferase
ALP
Alkaline phosphatase 
ANC
Absolute Neutrophil Count
AST
Aspartate aminotransferase
AUC
Area under the concentration-time curve
AUC0-24h
Area under the concentration-time curve from time zero (pre-dose) up 
to 24 hours
AUC(0-)
Area under the concentration-time curve from time zero (pre-dose) 
extrapolated to infinite time
AUC(0-t)
Area under the concentration-time curve from time zero (pre-dose) to 
last time of quantifiable concentration within a subject across all 
treatments
AUC(0-)
Area under the concentration-time curve over the dosing interval
-HCG
Beta-Human Chorionic Gonadotropin
BP
Blood pressure
BUN
Blood urea nitrogen
Cav
Averaged observed concentration
cfDNA
Circulating cell free DNA
CI
Confidence Interval
CL
Systemic clearance of parent drug
Cmax
Maximum observed concentration 
CR
Complete response
CRPC
Castration resistant prostate cancer
CRU
Clinical Research Unit
CT
Computed Tomography
CV
Coefficient of variance
CYP
Cytochrome P450
DLBCL
Diffuse Large B Cell Lymphoma
DLT
Dose-limiting toxicity
DMPK
Drug Metabolism and Pharmacokinetics
DNA
Deoxyribonucleic acid
DoR
Duration of Response
EC
Ethics committee
EC50
Exposure producing 50% of the maximum effect
ECG(s)
Electrocardiogram(s)
ECHO
Echocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
Electronic case report form
EZH2
Enhancer of Zeste Homolog 2
FACTS
Fixed and Adaptive Clinical Trial Simulator
FDG
[18F]fluorodeoxyglucose
FL
Follicular Lymphoma
FSH
Follicle Stimulating Hormone
GC
Germinal Center


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GCB
Germinal Center B-cell like 
GCB-DLBCL
Germinal Center B-cell-like Diffuse Large B-cell Lymphoma
GCP
Good Clinical Practice
GEP
Gene Expression Profile
GLP
Good Laboratory Practices
GSK
GlaxoSmithKline
H3K27me3
Tri-methylated Histone H3 lysine 27
HIV
Human Immunodeficiency Virus
h/hr
Hour(s)
HNSTD
Highest non-severely toxic dose
HR
Heart rate
HRT
Hormone replacement therapy
IB
Investigator’s Brochure
IC50
Half maximal inhibitory concentration
ICH
International Council on Harmonization
IgA
Immunoglobulin A
IgG
Immunoglobulin G
IgM
Immunoglobulin M
IHC
Immunohistochemistry
IND
Investigational New Drug
INR
International normalization ratio
IP
Investigational Product
IRB
Institutional Review Board
IV
Intravenous
IVRS
Interactive voice response system
kg
Kilogram
L
Liter
LDH
Lactate dehydrogenase
LFTs
Liver function tests
LHRH
luteinizing hormone releasing hormone
LSLV
Last subject’s last visit
LVEF 
Left Ventricular Ejection Fraction
µg
Microgram
µM
Micromolar
MCH
Mean corpuscular hemoglobin
MCHC
Mean corpuscular hemoglobin concentration
MCV
Mean corpuscular volume
mg
Milligrams
MFD
Maximum Feasible Dose
min
Minute
mL
Milliliter
MM
Multiple Myeloma
MRI
Magnetic Resonance Imaging
mRNA
Messenger RNA
MSDS
Material Safety Data Sheet
msec
Milliseconds


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MTD
Maximum Tolerated Dose
MUGA
Multigated  (radionuclide) angiogram
N-CRM
Neuenschwander-Continuous Reassessment Method
NCI-CTCAE
National Cancer Institute - Common Terminology Criteria for Adverse 
Events
NHL
Non-Hodgkin’s Lymphoma
NOAEL
No-observed-adverse-effect-level
NYHA
New York Heart Association
ORR
Overall Response Rate
PBMC
Peripheral blood mononuclear cell
PD
Progressive disease or pharmacodynamic
PET
Probability of early termination or positron emission tomography
PFS
Progression-free survival
PICC
Peripherally Inserted Central Catheter
PK
Pharmacokinetic
PO4
Phosphate
PPD
Product of the perpendicular diameters
PR
Partial response
PRC2
Polycomb Repressive Complex 2
PT
Prothrombin time
PTT
Partial Prothromboplastin time
QTc
Corrected QT interval duration
QTcB
QT interval corrected for heart rate by Bazett’s formula
QTcF
QT interval corrected for heart rate by Fridericia’s formula
R-CHOP
Rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone
RAP
Reporting and Analysis Plan
RBC
Red blood cells
RNA
Ribonucleic acid
RP2D
Recommended Phase 2 Dose
RT-PCR
Reverse transcription-polymerase chain reaction
SAE
Serious adverse event(s)
SAS
Statistical Analysis Software
SCID
Severe Combined Immodeficiency
SD
Stable disease
SPD
Sum of the products of the diameters
SPM
Study Procedures Manual
STD10
Severely toxic dose 10%
t
Time of last observed quantifiable concentration
t1/2
Terminal phase half-life
TdP
Torsades de Pointe
tFL
Transformed Follicular Lymphoma
τ
Dosing interval
tmax
Time of occurrence of Cmax
ULN
Upper limit of normal
UK
United Kingdom
US/USA
United States/United States of America


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Vd
Volume of distribution after IV administration
WBC
White blood cells
WT
Wild-type
Trademark Information
Trademarks of the GlaxoSmithKline 
group of companies
Trademarks not owned by the 
GlaxoSmithKline group of companies
NONE
Captisol
FACTS
SAS


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PROTOCOL SYNOPSIS

PROTOCOL TITLE: A phase I open-label, dose escalation study to investigate the 
safety, pharmacokinetics, pharmacodynamics and clinical activity of GSK2816126 
in subjects with relapsed/refractory diffuse large B cell lymphoma, transformed 
follicular lymphoma, other Non-Hodgkin’s lymphomas, solid tumors and multiple 
myeloma 

PROTOCOL NO.: EZH117208

U.S. Investigational New Drug (IND) NO.:  118286

CLINICAL PHASE:  I

COMPOUND: GSK2816126
STUDY RATIONALE:  Enhancer of zeste homolog 2 (EZH2), a component of the 
Polycomb Repressive Complex 2 (PRC2), mediates transcriptional repression of 
target genes through tri-methylation of histone H3 on lysine 27 (H3K27me3). EZH2 
and H3K27me3 are dysregulated in many cancers through diverse pathways. While 
EZH2 mutation plays a significant role in progression of certain lymphomas, data 
from prostate, breast, and several other tumors have demonstrated that increased 
EZH2 expression correlates with increased aggressiveness of tumors and poor 
prognosis. 
GSK2816126 is a selective and potent inhibitor of wild-type and mutant EZH2 
capable of decreasing H3K27me3 levels in all cell types examined. EZH2 inhibition 
has been shown to decrease the growth of several cell lines derived from EZH2 wild 
type (WT) and mutant lymphomas, SNF5-mutant malignant rhabdoid tumors, 
multiple myeloma, AML, neuroblastoma, prostate, breast, skin and colon cancers. 
Most of these cancers have an overall poor outlook either because of lack of any 
effective therapy or standard therapies do not result in a durable remission. This first 
study of this agent will be conducted in subjects with non-Hodgkin lymphomas, 
especially germinal center B-cell diffuse large B-cell lymphoma (GCB-DLBCL) and 
transformed follicular lymphoma (t-FL), and subjects with solid tumors (including 
castrate resistant prostate cancer) and multiple myeloma (MM) who have relapsed or 
are refractory to prior therapies and have a high degree of unmet medical need in 
terms of available treatment options.  


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
STUDY OBJECTIVES, ENDPOINTS AND HYPOTHESES:
Part 1 Objectives
Part 1 Endpoints
Primary

To determine the safety and 
tolerability and establish the 
recommended Phase 2 dose (RP2D)
of IV administered GSK2816126 

Adverse Events (AEs), Serious Adverse 
Events (SAEs), Dose Limiting Toxicity 
(DLT), withdrawals due to AEs, dose 
interruptions and reductions,  and changes 
in safety assessments (e.g., clinical 
laboratory parameters, vital signs, and 
cardiac parameters)
Secondary

To describe the pharmacokinetics of 
GSK2816126 after single- and 
repeated administration

To evaluate the relationship between 
GSK2816126 exposure and 
safety/efficacy/PD parameters

To determine clinical activity of 
GSK2816126 in GCB DLBCL and 
solid tumors containing EZH2 
inhibitor sensitizing mutations or
prostate cancer

GSK2816126 PK parameters following 
single- (Day 1) and repeat-dose  
administration of GSK2816126, including 
area under the concentration-time curve 
(AUC), pre-dose (trough) concentration at 
the end of the dosing interval (C), 
maximum observed concentration (Cmax), 
time of occurrence of Cmax (tmax), 
terminal phase half-life (t1/2), time 
invariance and accumulation ratio

GSK2816126 exposure markers (dose, 
concentration, Cmax or AUC) and 
safety/efficacy/PD responses. PD
response assessed by change from 
baseline in tri-methylation of Histone 
H3K27 (H3K27me3)

Best Overall Response rate (complete 
response [CR]  + partial response [PR])


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Part 1 Objectives
Part 1 Endpoints
Exploratory

To confirm tumor EZH2 and GCB-
DLBCL status

To investigate the mechanism of 
action of GSK2816126

To identify biomarkers predictive of 
response or resistance to 
GSK2816126

Immunohistochemistry (IHC) for 
confirmation of GCB-DLBCL status

PCR or NGS to determine EZH2 mutation 
status

Evaluate transcriptional and/or protein 
changes upon GSK2816126 treatment

Correlate baseline tumor genomic
[deoxyribonucleic acid (DNA)], protein 
and/or transcription [ribonucleic acid
(RNA)]  profiles with response
Hypothesis
No formal statistical hypotheses are being tested for the dose escalation in Part 1. Analysis of 
the data obtained from dose escalation in Part 1 will utilize descriptive methods only. 
The cohort expansion of GCB-DLBCL subjects in Part 1 will assess the overall response rate 
(p) of GCB-DLBCL patients. The null and alternative hypotheses for the overall response rate 
are detailed below:
The null hypothesis is:
H0: p≤20%
The alternative hypothesis is:
HA: p≥40%
For cohort expansion of solid tumor subjects in Part 1, there is no formal statistical 
hypothesis being tested. Analysis of the data obtained from solid tumor expansion cohort will 
utilize descriptive methods only.


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Part 2 Objectives
Part 2 Endpoints
Primary

To determine clinical activity of 
GSK2816126 in cohorts of subjects 
with EZH2 mutant and wild type 
GCB-DLBCL and  tFL and subjects 
with MM

Overall response rate (% of subjects 
achieving CR and PR per response 
criteria)
Secondary

To determine the safety, tolerability 
of the selected IV dose of 
GSK2816126

To characterize the population PK of 
GSK2816126

To evaluate the relationship between 
GSK2816126 exposure and PD 
parameters

To generate samples (data reported 
separately) with which to 
characterize the metabolic profile of 
GSK2816126 after repeat-dosing (In 
the PK/PD expansion cohort only)

To determine the amount of 
GSK2816126 excreted in urine after 
dosing at steady state

To evaluate the relationship between 
exposure and safety/efficacy 
parameters 

To begin to characterize the 
durability of response and 
progression free survival with
GSK2816126

To generate samples (data reported 
separately) with which to investigate 
the potential for GSK2816126 to 
affect cytochrome P450 (CYP) 3A4 
enzyme activity

AEs, SAEs, DLTs, withdrawals due to 
AEs, dose interruptions and reductions,  
and changes in safety assessments (e.g., 
clinical laboratory parameters, vital signs, 
and cardiac parameters)

Population PK parameters for 
GSK2816126 including clearance (CL), 
and volume of distribution (Vd) and 
relevant covariates which may influence 
exposure (e.g. age, weight, or disease 
related covariates).

GSK2816126 exposure markers (dose, 
concentration, Cmax or AUC) and PD 
responses. PD response assessed by 
change from baseline in tri-methylation of 
Histone H3K27 (H3K27me3)

Samples to characterize the metabolites in 
blood, bile and/or urine

Concentration of GSK2816126 in urine 
measured with an investigational bio-
analytical method and extrapolated to total 
amount excreted in urine over time using 
urine volume

GSK2816126 exposure markers (e.g. 
dose, concentration, Cmax, or AUC) and 
safety/efficacy responses. 

Duration of response (DoR)

Progression-free survival (PFS) 

Samples to assess a potential change in 
4b-OH cholesterol to cholesterol ratio in 
plasma following repeat dosing of 
GSK2816126 (data reported separately)
Exploratory

To identify biomarkers predictive of 
response or resistance to 

Evaluation of wild-type (WT) subject 


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Part 1 Objectives
Part 1 Endpoints
GSK2816126.

To investigate the mechanism of 
action of GSK2816126 

To investigate the relationship 
between genetic variants in 
candidate genes and the 
pharmacokinetics (PK) and safety 
profile of GSK2816126 based on 
Part 1 and 2 data combined
tumors for the presence of additional, 
undefined, mutations in the EZH2 gene

Correlate baseline tumor genomic
(DNA), protein and/or transcription 
(RNA)  profiles with response

Evaluate transcriptional and/or protein 
changes upon GSK2816126 treatment

Pharmacogenomic (PGx) analysis of 
whole blood
Hypothesis
In Part 2, the overall response rate (p) of GCB-DLBCL and tFL patients will be assessed for
each EZH2 mutation status cohort (wild type and mutant), and also for MM patients. 

For each of the GCB-DLBCL and tFL cohort, the null and alternative hypotheses of the 
overall response rate are as following:
The null hypothesis is:
H0: p≤20%
The alternative hypothesis is:
HA: p≥40%

For MM cohort:
The null hypothesis is:
H0: p≤10%
The alternative hypothesis is:
HA: p≥25%

STUDY DESIGN:  This study is divided into 2 parts; Part 1 of the study is a dose 
escalation phase to identify MTD and select the recommended Phase 2 dose (RP2D) 
based on the safety, PK, and PD profiles observed after IV administration of 
GSK2816126.  Eligible subjects with relapsed/refractory DLBCL, transformed FL
malignancies, other non-Hodgkin lymphomas (NHL), Multiple Myeloma (MM) and 
solid tumors will be enrolled in the dosing cohorts until a RP2D is established.  One 
or more dose level/s during Part 1 escalation may be expanded up to 12 subjects to 
explore safety and preliminary efficacy. At the identified MTD,  approximately 27
GCB-DLBCL subjects and approximately 15 subjects with solid tumors containing 
EZH2-inhibitor sensitizing mutations or metastatic castrate resistant prostate cancer 
(mCRPC, regardless of mutation status), may be enrolled to explore safety and 
preliminary efficacy.  Subjects may continue treatment in the study until disease 
progression, unacceptable toxicity, or withdrawal of consent.  Expansion cohorts 


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(Part 2) are planned in subjects with MM, and in subjects with both EZH2 mutant 
positive and EZH2 WT GCB-DLBCL and tFL to further explore clinical activity at 
the RP2D.

STUDY DURATION:  Duration of study will depend on recruitment rates, and 
timing of subjects’ duration on study (withdrawal rates due to toxicity or 
progression).

NUMBER OF SUBJECTS:  Up to approximately 250 subjects worldwide 
(inclusive both Parts 1 and 2).

INCLUSION/EXCLUSION CRITERIA:
Part I: 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.
Subjects eligible for enrollment in the study must meet all of the following criteria:
1. Provided signed written informed consent.
2. Males and females ≥18 years of age (at the time consent is obtained).
3. Tumor type criteria:  

Relapsed/refractory NHL that meets the following criteria:
o
Germinal Center B cell Diffuse large B cell lymphoma (GCB-
DLBCL) relapsed, or refractory to at least one prior regimen (e.g., 
rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone 
[R-CHOP]) AND not a candidate for standard salvage regimens or 
autologous or allogeneic stem cell transplant. Local confirmation of 
lymphoma subtype GCB-DLBCL is allowed for enrollment but must 
be confirmed through central laboratory testing.

Solid tumors that meet the following criteria:
o
Measurable disease by RECIST 1.1 in at least 1 site

For Castrate Resistant Prostate Cancer (CRPC) measurable 
disease can also include PSA level (see below)
o
Disease progression with the last line of therapy and at least one prior 
standard of care regimens, or tumor for which there is no approved 
therapy, or for which standard therapy is unsuitable or refused.
o
Mutation Status:

Solid tumor types, other than prostate, must have one of the 
following EZH2 inhibitor sensitizing mutations as determined 
via local testing:


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
An activating mutation in EZH2 (Y641F/C/S/H/N, 
A677V/G, and/or A687V 

Loss of a component of the SWI/SNF complex, 
including, but not limited to, ARID1A, SMARCB1 
(aka SNF5/INI1/BAF47), SMARCA4 (aka BRG1), or 
PBRM1 (aka PB1) as determined by molecular testing 
(bi-allelic loss or mutation) or immunohistochemistry

Loss of BAP1 (ubiquitin carboxy-terminal hydrolase) 
as determined by molecular testing (bi-allelic loss or 
mutation) or immunohistochemistry
o
CRPC subjects:

Must have measurable disease by either:

RECIST1.1 (Appendix 5), or

a minimum PSA of 5 ng/mL

Disease progression on last line of therapy and must have 
progressed on abiraterone, enzalutamide, or taxane 
chemotherapy

Subjects may continue GnRH agonists

Small cell prostate cancer is eligible
4. For all subjects: Availability of archival tissue, or willingness to undergo fresh 
biopsy if archival tissue is not available, as described in Section 7.6.1.1, Section
7.6.1.2, and Section 7.6.5.
5. Must have a pre-existing central venous access such as a port, Hickmann catheter,
or a peripherally inserted central catheter (PICC line) or be willing and able to 
have one inserted.
6. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1 (see 
Appendix 2).
7. Men with a female partner of childbearing potential must have either had a prior 
bilateral vasectomy with resultant azoospermia, bilateral orchiectomy, or must 
agree to use one of the contraception methods listed in Section 10.1 from the time 
of the first dose of study medication until at least 2 weeks (14 days) after the last 
dose of study treatment due to the long elimination phase of study drug.
8. A female subject is eligible to participate if she is of:

Non-child bearing potential as defined in Section 10.1.1.

Child bearing potential as defined in Section 10.1.1 and agrees to use 
effective contraception, as defined in Section 10.1, for an appropriate 
period of time (as determined by the product label) prior to the start of 
dosing to sufficiently minimize the risk of pregnancy and for at least 
2 weeks (14 days) following the last dose of study treatment. Women of 


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childbearing potential must have a negative serum pregnancy test within 
7 days of first dose of study treatment followed by negative urine or serum 
pregnancy test once every 4 weeks (prior to next dose cycle) thereafter.  
9.
Adequate organ system function as defined below:
System
LABORATORY VALUES
Hematologic
  ANC
1.2 x 10 9/L  
  Hemoglobin
9 g/dL 
  Platelets
75x 109/L  
 PT/INR and PTT
≤1.5 x ULN
Hepatic
  Albumin
2.5 g/dL
  Total bilirubin
1.5 times ULN
 AST and ALT
2.5  times ULN without liver metastases
5 times ULN if documented liver metastases
Renal
Calculate Creatinine Clearancea, b                50 mL/min                                                              
Reproductive/Endocrine for CRPC only
Testosterone 
<50 ng/dL (only for subjects with CRPC)
Cardiac
Left Ventricular Ejection Fraction (LVEF)
≥LLN (minimum of 50% LVEF) by ECHO  or MUGAc
Abbreviation(s): ANC, absolute neutrophil count; ALT, alanine aminotransferase; AST, aspartate aminotransferase; 
ECHO, echocardiogram; INR, international normalization ratio, MUGA, multigated (radionuclide) angiogram; PT, 
prothrombin time, PTT, partial thromboplastin time, ULN, upper limit of normal , LLN, lower limit of normal.
a.
Calculated by Cockcroft-Gault formula
b.
For MM subjects, adequate renal function is defined as calculated creatinine clearance ≥30 mL/min.
c.
ECHO is the preferred method and should always be used if available.
NOTE:  Laboratory results obtained during Screening should be used to determine 
eligibility criteria.  In situations where laboratory results are outside the permitted range, 
the investigator may opt to retest the subject and the subsequent within range screening 
result may be used to confirm eligibility.  
Part 2: Inclusion Criteria
1. In addition to inclusion criteria listed for Part 1, Part 2 will enroll GCB-DLBCL, tFL 
and MM subjects only. 
a.
Relapsed and/or refractory MM or tFL that have failed prior standard therapy 
and for which there is no standard salvage regimen
2. Lymphoma subjects will be required to undergo EZH2 mutation testing. This will 
require availability of archival tissue, or willingness to undergo fresh biopsy, for 
central testing of EZH2 mutation status.


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3. Based on the results of the mutation test, lymphoma subjects may be enrolled in one 
of four cohorts:

GCB-DLBCL EZH2 mutant cohort: 
o
Tumors must contain one, or more, of the following EZH2 activating 
mutations: Y641F; Y641N; Y641S; Y641H; Y641C; A677G; and/or 
A687V

GCB-DLBCL EZH2 wild type cohort:
o
Tumors that do not contain one of the above mutations
o
Subjects with tumors harboring EZH2 mutations other than the seven 
outlined above will be enrolled in the EZH2 wild type cohort

tFL EZH2 mutant cohort: 
o
Tumors must contain one, or more, of the following EZH2 activating 
mutations: Y641F; Y641N; Y641S; Y641H; Y641C; A677G; and/or 
A687V

tFL EZH2 wild type cohort:
o
Tumors that do not contain one of the above mutations
o
Subjects with tumors harboring EZH2 mutations other than the seven 
outlined above will be enrolled in the EZH2 wild type cohort
Part 1 and 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.
Subjects meeting any of the following criteria must not be enrolled in the study:
1. Receiving any cancer therapy within 2 weeks of first dose (including surgery and/or 
tumor embolization) 
Note: the following are allowed:

Corticosteroids to control systemic or local symptoms, up to a dose of 
10 mg prednisone or equivalent daily and stable for at least 7 days prior to 
enrollment.

Subjects with prostate cancer may remain on GnRH agonists. Other 
hormonal therapies (e.g., bicalutamide, abiraterone and enzlutimide) for 
prostate cancer must be stopped 4 weeks prior to enrolment  
Note: the following are NOT allowed:

Chemotherapy regimens with delayed toxicity within the last 3 weeks


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
Nitrogen mustards, Melphalan,  Monoclonal antibody or Nitrosourea 
within the last 6 weeks
2. Any major surgery, radiotherapy or immunotherapy within the 4 weeks prior to first 
dose of study drug, or palliative radiotherapy to a single symptomatic lesion within 
the 2 weeks prior to first dose of study drugs.
3. Subjects with prior allogeneic transplant are excluded: however, subjects who have 
previously received an autologous stem cell transplant are allowed if a minimum of 
100 days has elapsed from the time of transplant and the subject has recovered from 
transplant-associated toxicities prior to the first dose of GSK2816126
4. Received an investigational anti-cancer drug within 6 weeks, or within 5 half-lives 
(whichever is shorter) of the first dose of study drug. A minimum of 14 days must 
have passed between the last dose of prior investigational agent and the first dose of 
study drug. 
5. Current use of a prohibited medication or expected to require any of these 
medications during treatment with study drugs ( Section 9).
6. Known human immunodeficiency virus (HIV), or serological evidence for Hepatitis 
B (positive HBsAg), or chronic Hepatitis C infection.

For subjects who are negative for HBsAg, but HBcAb positive, a HBV DNA
(viral load) test will be performed and if negative are eligible.

Subjects with positive Hepatitis C antibody serology with a negative HCV 
RNA test results are eligible.
7. Concurrent use of therapeutic warfarin is allowed. However, anticoagulants that do 
not have reversal agents available are prohibited (see Section 9.2).
8. Unresolved toxicity greater than Grade 1 National Cancer Institute – Common 
Terminology Criteria for Adverse Events (NCI-CTCAE) version 4 from previous 
anti-cancer therapy, with the exception of alopecia and peripheral neuropathy [NCI-
CTCAE, 2009]. 

Lymphoma subjects with ≤Grade 3 lymphopenia can be enrolled at the 
discretion of the investigator
9. Packed red blood cell or platelet transfusion within 7 days of screening laboratory 
tests.
10. Psychological, familial, sociological or geographical conditions that do not permit 
compliance with the protocol.
11. Cardiac exclusion criteria:

History of acute coronary syndromes (including myocardial infarction and 
unstable angina), coronary angioplasty, or stenting within the past 6 months 
prior to first dose of study drug.

QT interval corrected for heart rate by Fridericia’s formula (QTcF) interval 
>450msec.


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
Uncontrolled arrhythmias.  Subjects with rate controlled atrial fibrillation for 
>1 month prior to first dose of study drugs may be eligible.

Class II, III or IV heart failure as defined by the New York Heart Association 
(NYHA) functional classification system.  
12. Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs 
chemically related to the study drug or their excipients.
13. Pregnant or lactating female.
14. Unwillingness or inability to follow the procedures outlined in the protocol.
15. Uncontrolled diabetes or other medical condition that may interfere with assessment 
of toxicity.
16. Central nervous system (CNS) metastases, with the following exception:

Subjects who have  previously treated CNS metastases, are asymptomatic, and 
have no requirement for steroids at least 14 days prior to first dose of study 
drug.

Subjects with carcinomatous meningitis are excluded regardless of clinical 
stability.
17. Invasive malignancy or history of invasive malignancy other than disease under 
study, except as noted below:

Any other invasive malignancy from which the subject has been disease-free 
for more than 2 years and, in the opinion of the principal investigator and 
GSK Medical Monitor, will not affect the evaluation of the effects of this 
clinical trial treatment on currently targeted malignancy, can be included in 
this clinical trial.

Curatively treated non-melanoma skin cancer and any carcinoma-in-situ.

STUDY TREATMENT DOSAGE/DOSAGE FORM, ROUTE, AND DOSE 
REGIMEN: Starting dose will be 50 mg, IV, twice weekly, with one 28 day cycle 
being defined as twice weekly dosing for three consecutive weeks and one week off. 
Dose escalations will be performed in Part 1 and dose adjustments are allowed to 
address tolerability and safety issues.  Alternative schedules may be evaluated if 
emerging data suggest that twice weekly administration with 2 hour infusions will 
result in excessive toxicity.  In addition, alternative dosing schedules may be 
considered if the safety, pharmacokinetic (PK), and pharmacodynamic (PD) data 
suggest that a sufficient therapeutic exposure cannot be achieved using the initial 
schedule and after a protocol amendment.

SAFETY ASSESSMENTS:  Routine physical examinations, vital sign 
measurements, echocardiograms, and monitoring of adverse events.  Cardiac safety 
monitoring will be required, consisting of triplicate 12-lead electrocardiograms 
(ECGs) pre-infusion of drug, at the end of infusion of drug, one at night prior to 
going to sleep (e.g., 10 pm) and one prior to discharge from the unit for Day 1, dose 
one only.  The subject will not be discharged from the unit unless the QTcF is 
<500 msec.  In addition, 24 hours of high fidelity 12-lead Holter monitoring will be 
performed for dose one.  Tracings from this will be used for concentration QT 
analysis as well.  Pre-infusion and end of infusion ECGs will be recorded for all 


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other ECG timepoints.  Laboratory testing includes at least hematology and clinical 
chemistry.  Additional safety assessments may be necessary based on emerging data.

PHARMACOKINETIC/PHARMACODYNAMIC MEASUREMENTS: There 
will be extensive serial blood sampling for PK and PD measurements in Part 1 of this 
study with limited blood sampling performed on all subjects in Part 2.  Urine and 
bile may be collected in some subjects in the Part 2 PK/PD expansion cohort. Single 
safety PK blood draws may be collected for subjects with severe adverse events or 
adverse events of concern.  Mandatory collection of pre-treatment and post-treatment 
biopsies will be implemented in Part 2 PK/PD cohorts.

CLINICAL ACTIVITY ASSESSMENTS:  CR, PR, PFS, DoR.

TRANSLATIONAL RESEARCH:  Translational or biomarker research may be 
performed on archival tissue, tumor biopsies and blood samples collected on study, 
to better understand DLBCL, transformed FL, and the mechanism of action  and 
response to GSK2816126. Performance of these investigations may be conditional 
on the results of the clinical trial principally, but not exclusively, on the primary 
measures of the clinical trial outcome and samples may be selected for analysis on 
the basis of the clinical outcome. Unless stated otherwise, these investigations may 
be performed irrespective of whether a response to GSK2816126 is observed and 
will be categorized as exploratory. Findings may be reported independently of any 
final clinical study report.  

STATISTICAL METHODS: 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 1 in GCB-DLBCL subjects is designed to evaluate preliminary efficacy at 
the MTD/RP2D or other dose level.  Futility and efficacy assessments will be 
conducted after 13 GCB-DLBCL subjects are enrolled, using overall response 
rate (ORR) as the efficacy endpoint, until up to 27 subjects are enrolled. The 
design allows interim analysis (IA) of futility and efficacy to be performed at 
any point in between. The futility and efficacy stopping rules are defined based 
on pre-specified type I error rate and power of the hypothesis testing of ORR. If 
the thresholds for futility are met, enrollment to Part 1 cohort/s may be stopped 
based upon the evaluation of the totality of the data. If the efficacy thresholds 
are reached, and the totality of the data support opening Part 2, then Part 2 will 
start. If neither futility nor efficacy thresholds are met at an interim analysis, and 
the totality of the data does not support continuation of the trial, then Part 1 may 
be stopped.
For the cohort expansion of solid tumor subjects in Part 1, there is no formal 
statistical hypothesis testing. Analysis of the data obtained from the solid tumor 
expansion cohort will only utilize descriptive methods.

Part 2 expansion phase of the study is designed to investigate clinical activity of 
GCB-DLBCL and tFL patients with EZH2 mutant and wild type, and MM patients, 
using ORR as the primary endpoint. Secondary endpoints such as PFS, TTR, TTP, 
DOR and OS will be evaluated.  In Part 2, for patients with GCB-DLBCL and tFL, 
futility assessment will be conducted on an ongoing basis after data are available 


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from the first 10 subjects and until up to 32 patients. For patients with MM, futility 
assessment will be conducted on an ongoing basis after data are available from the 
first 14 subjects and until up to 40 subjects.


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1.
INTRODUCTION
1.1.
Background
Enhancer of zeste homolog 2 (EZH2) is the catalytic subunit of the Polycomb Repressive 
Complex 2 (PRC2) responsible for maintaining transcriptional repression of target genes 
through tri-methylation of histone H3 on lysine 27 (H3K27me3). PRC2 activity is 
essential for maintaining the self-renewal capacity of embryonic and adult stem cells, and 
the dynamic regulation of this activity is critical for proper development and 
differentiation. 
EZH2 and H3K27me3 are dysregulated in nearly all cancers through numerous pathways 
including 1) recurrent gain-of-function heterozygous mutations in germinal center B-cell 
(GCB) diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), melanoma, 
and parathyroid adenoma, 2) EZH2 over-expression in numerous other aggressive tumors 
including those from prostate, breast, lung, liver, bladder, head and neck, skin, and 
kidney, and 3) inactivating mutations in UTX, an H3K27 demethylase that acts in 
opposition to EZH2, described in numerous tumor types including transitional cell 
bladder carcinoma, esophageal squamous cell carcinoma, renal cell carcinoma, multiple 
myeloma, and subgroup 4 medulloblastoma (McCabe, 2014). Furthermore, data from 
prostate, breast, and several other tumor types have demonstrated that increased EZH2 
expression correlates with increased aggressiveness of tumors and poor prognosis.
In the B-cell lineage, EZH2 is required by germinal center B-cells, which are the cells of
origin of the most common forms of Non-Hodgkin’s Lymphomas (NHL). GC derived 
DLBCLs are mostly addicted to EZH2 and require its histone methyltransferase activity 
for their survival. Recently, somatic activating mutations in EZH2 have been identified in 
follicular lymphoma (FL) and GCB-DLBCL [Morin, 2010; Morin, 2011; Pasqualucci, 
2011; Ernst, 2010].   The frequency of the most prevalent mutation, Y641, is 7-27% in 
FL and 22% in DLBCL [Bodor, 2013].  Biochemical studies have demonstrated that 
Y641, A677 and A687 mutants exhibit an altered substrate preference and catalytic 
efficiency to enhance the generation of H3K27me3.  Consistent with these biochemical 
data, primary lymphomas and lymphoma cell lines harboring EZH2 mutations have 
elevated levels of H3K27me3.  Mutant EZH2 maintains the proliferation, survival and 
blocks terminal differentiation of DLBCL cells.
1.2.
GSK2816126
GSK2816126 is a potent and highly selective inhibitor of both wild type (WT) and 
mutant (Y641N/F/C/H/S, A677G and A687V) EZH2 methyltransferase activity.  
Inhibition of H3K27 methylation by GSK2816126 is competitive with S-adenosyl-
methionine and non-competitive with peptide substrates [McCabe, 2012]. GSK2816126 
is highly selective against other methyltransferases and protein classes.  In particular, 
GSK2816126 is more than 1,000-fold selective for EZH2 versus 20 other human 
methyltransferases, including both SET-domain-containing and non-SET-domain-
containing methyltransferases.  EZH1, which is 96% identical to EZH2 within the SET 
domain, and 76% identical, overall, is inhibited more than 150-fold less potently 
[McCabe, 2012].


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1.2.1.
Pharmacokinetics of GSK2816126 in Humans
GSK2816126 pharmacokinetics (PK) have not yet been completely evaluated in humans. 
Whole blood human clearance for GSK2816126 was predicted from three species 
(mouse, rat and dog) using maximum life span power-law allometry to be around 
8.2 mL/min/kg. Volume of distribution was predicted from simple power-law allometry 
to be 4.8 L/kg and half-life around 6.5 hours. A 70 kg adult therefore has a predicted total 
blood clearance of 35 L/hr and a total blood volume of distribution of 336 L.
1.2.2.
Pre-Clinical Pharmacology & Safety of GSK2816126
In Vitro Testing
In cell culture, GSK2816126 induces loss of H3K27me3 in both EZH2 WT and mutant 
cell lines from diverse tumor types with the half maximal inhibitory concentration (IC50) 
values ranging from 10 - 252 nM independent of EZH2 mutation status [McCabe, 2012].  
In proliferation assays using a panel of B-cell lymphoma cell lines, those of DLBCL 
origin with EZH2 activating mutations are the most sensitive to GSK2816126.  The 
second most sensitive tumor type evaluated was multiple myeloma where a majority of 
cell lines exhibited growth inhibition when exposed to GSK2816126. However, the 
growth of a subset of several other tumor types including NHL, SNF5-mutant malignant 
rhabdoid tumors, AML, neuroblastoma, prostate, breast, skin, and colon cancers is also
sensitive to EZH2 inhibition.  
Time course studies demonstrate that inhibition of H3K27me3 is maximal after 2 days. 
Inhibition of cell proliferation begins as early as 2 days of EZH2 exposure but in some 
cases takes up to 2 weeks to reach maximal growth inhibition.  Both cytostatic and 
cytotoxic responses are observed among sensitive cell lines.  Together, these data indicate 
that global H3K27me3 can be used to assess on-target activity of an EZH2 inhibitor in 
both responsive and unresponsive tumors, and that  EZH2 activating mutations may 
provide a strong marker for subject selection in clinical studies.
In Vivo Testing
Pharmacokinetics:  The nonclinical pharmacokinetics of GSK2816126 were similar 
across species. GSK2816126 had moderate blood clearance in the mouse and rat and 
high blood clearance in the dog. Steady state volume of distribution was moderate to 
high in all species, indicating good distribution into tissues. GSK2816126 half life was 
2.8 hours in mice and rats and 7 hours in dogs. Systemic exposure to GSK2816126 
generally increased dose-proportionally in rats and increased greater than or dose 
proportionally in dogs. In vitro, GSK2816126 was highly bound to plasma proteins 
(³95.7%) in mouse, rat, dog and human.
Nonclinical Pharmacology:  In severe combined immunodeficiency (SCID) mice 
bearing subcutaneous xenografts derived from human DLCBL, multiple myeloma, or 
prostate cancer cell lines, GSK2816126 inhibits H3K27me3 after repeated daily or twice 
weekly dosing over 10-11 days.  The PD response is durable as H3K27me3 levels did not 
return to pre-dose levels by 7 days after the last dose. In mice bearing subcutaneous 
xenografts of EZH2 mutant lymphomas, 90-100% tumor growth inhibition is observed 


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with daily or twice weekly dosing over a five week period with or without a one week 
drug holiday in the third week. In some models, tumor stasis or complete tumor 
eradication is observed upon cessation of dosing. Together, these pre-clinical PD and 
efficacy data indicate a treatment cycle of twice weekly dosing of GSK2816126 for 2 or 
3 weeks followed by a 1 week drug holiday should effectively reduce H3K27me3 levels 
in the tumor.
The dose-limiting toxicity seen in rat and dog IV infusion toxicology studies conducted 
with GSK2816126 was vascular damage at the local infusion and/or indwelling catheter 
sites.  On the 4-week toxicity studies in rats (≥30 mg/kg) and dogs (≥100 mg/kg) twice 
weekly intravenous (IV) infusions (rats: 6 hours; dogs 8 to 16 hours) of GSK2816126 in 
vehicle containing 5% Captisol, there was vascular necrosis, inflammation, and edema.  
In these animals, there were secondary histopathologic changes in multiple tissues and 
clinical pathology findings consistent with an inflammatory response to the vascular 
damage.  Infusion site and secondary histopathologic findings were partially reversible 
and secondary clinical pathology effects were reversible.  Morbidity and mortality in rats 
given ≥300 mg/kg (maximum observed concentration [Cmax] ≥40.3 g/mL; area under the 
concentration-time curve from time zero (pre-dose) up to 24 hours (AUC0-24h)
≥285 g.h/mL) or dogs given ≥100 mg/kg (Cmax=10 g/mL; AUC0-24h=80 g.h/mL) were 
attributable to vascular or extravascular irritant effects of GSK2816126 and prolonged 
intravenous catheterization.  Infusion site reactions are likely related to the hemolytic 
and/or irritant (vesicant) potential of GSK2816126.  While some rats given 300 mg/kg on 
the 4 week twice weekly dose IV infusion study were terminated early (beginning 
following 4 doses) due to adverse clinical observations at the local infusion site (Day 1 
AUC0-24h of 285 g.h/mL; Cmax of 40.3 g/mL), IV infusions at 300 mg/kg on the 2 week, 
twice weekly IV infusion study (total number of 4 doses; AUC0-24h of 235 g.h/mL; Cmax
of 33.2 g/mL) did not result in similar GSK2816126-related infusion site reactions or 
early termination.  Increased concentrations of Captisol in the vehicle reduced the 
hemolytic potential in a concentration dependent manner.  Inclusion of 10% Captisol in 
GSK2816126 clinical formulation and administration through a central line (e.g. 
peripherally inserted central catheter [PICC]) should alleviate the infusion site reactions 
observed on the non-clinical toxicology studies.
Infusion rate and/or concentration-dependent, histamine reactions, which began within 
minutes of dose initiation, were observed at ≥300 mg/kg in dogs (Cmax 66.5 to 
130 µg/mL) and 300 mg/kg (Cmax 33.9 to 54.2µg/mL) in rats.  In dogs, histamine 
reactions resulted in discontinuation of dosing.  Histamine-related decreased body 
temperature, along with increased heart rate (HR) and decreased blood pressure (BP) 
likely led to mortality in restrained, but not in unrestrained, rats given an IV infusion of 
300 mg/kg (5 mL/kg/hr for 4 hours).  These effects could be ameliorated by 
discontinuation of dosing, administration of diphenhydramine hydrochloride, 
degranulation of mast cells prior to GSK2816126 dosing, and/or lengthening of the 
infusion time to reduce Cmax. These observations tended to occur only during the first 
exposure to the drug and not on subsequent administrations.  Human subjects will be 
monitored during the infusion for evidence of histamine release related 
symptoms/infusion reactions and treated as needed with supportive care per local 
standard of care.  (e.g., corticosteroids, oxygen, epinephrine, diuretics, IV fluid). The 
infusion duration can be lengthened with restart of the infusion or at the next infusion.  


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Premedications (antihistamines or similar) may be provided at the next infusion or prior 
to treatment of new subjects.
In dogs, a mild, reversible dose dependent decrease in minute (up to 128 mL/min/kg; 
49%) and tidal volume (8 mL/kg; 56%) at 100 mg/kg and an elevation in Corrected QT 
interval duration (QTc) interval at 30 (maximum increase of 12 msec or 5%) and 100 
(maximum increase of 18 msec or 8%) mg/kg were observed following the end of a 
single 8 hour infusion.  These effects did not directly correlate with peak GSK2816126 
blood levels as the onset was 4-7 hours following the end of the infusion.  QTc interval 
elevations were not observed following repeat dosing.  
A direct effect on human ether à go-go-related gene (hERG) channel repolarization is 
unlikely (IC25 of 54.2 µM; 28.61 µg/mL), however, GSK2816126 did block hERG 
current density in vitro consistent with an effect on hERG channel trafficking.  The 
mechanism for this change is unclear.  Evaluation of the QTc interval has been 
incorporated into this clinical study protocol. 
GSK2816126 has evidence of absorbance within the 290-700 nm wavelength range of 
concern for photosafety.  While GSK2816126A has no absorbance peaks (λmax) > than 
290 nm, there is an absorbance peak at 285 nm with a small tail of absorbance that 
extends to ~380 nm and therefore, has a potential risk for phototoxicity.  To date, no in 
vivo phototoxicity or Bio-distribution studies of the product in the skin or the eyes have 
been completed.  No photosafety concerns have been observed in humans at doses up to 
3000 mg/day, however, only a limited number of patients have received GSK2816126.  
To minimize the risk for potential phototoxicity, human subjects will be instructed to 
minimize or avoid prolonged exposure to natural or artificial sunlight (e.g., tanning beds,
sunlamps, UVA or UVB treatments) and wear loose fitting clothing with long sleeves, 
sunglasses, and broad rim hat that protect the skin from sun exposure AND use a broad 
spectrum sunscreen (e.g., UVA and UVB protective with minimum SPF 30) on any 
uncovered areas of the body if outdoors from the time of first dose of study medication 
until at least 2 weeks (14 days) following last dose of study medication due to long 
elimination phase.
Based on the infusion site reactions in dogs following twice weekly dosing for 4 weeks, 
the no-observed-adverse-effect-level (NOAEL) is 30 mg/kg (AUC0-24h of 14.9 g.h/mL; 
Cmax of 1.96 g/mL) and the highest non-severely toxic dose (HNSTD) is 100 mg/kg 
(AUC0-24h of 80.1g.h/mL; Cmax of 9.88 g/mL).  In rats following twice weekly dosing 
for 4 weeks, a NOAEL was not established at the lowest dose tested of 30 mg/kg (AUC0-
24h of 23.5 g.h/mL and Cmax of 2.97 g/mL).   Due to similar exposure in rats at 
300 mg/kg on Day 1 of the 2 and 4 week studies, the severely toxic dose 10% (STD10) in 
rats is estimated to be between 100 and 300 mg/kg (AUC0-24h between 54 and
235 g.h/mL; Cmax between 8 and 33 g/mL; exposures based on twice weekly dosing 
for 2 weeks).  For the purpose of the starting dose justification in this protocol, we will 
use the lower estimate of 100 mg/kg as the STD10.  However, because the smaller calibre 
of rodent vessels used for the drug infusion are more sensitive to injury and irritant 
effects, the dog findings are more appropriate to use for the local tolerability.


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1.3.
Benefit/Risk Assessment
Summaries of findings from nonclinical studies conducted with GSK2816126 can be 
found in Section 1.2.2 of the protocol and the Investigator’s Brochure (IB) 
[GlaxoSmithKline Document Number 2013N169204_04, 2017]. Toxicology studies 
performed in dogs and rats suggest that the primary toxicities of GSK2816126 are 
cardiovascular, hemolytic and allergic (see Section 4 of GSK2816126 IB 
[GlaxoSmithKline Document Number 2013N169204_04, 2017 ]).
This section outlines the risk assessment and mitigation strategy for this protocol based 
on nonclinical and clinical findings. Additional information on clinical findings can be 
found in Section 1.3.1 of the protocol and Section 5 and Section 6 of the Investigator’s 
Brochure [GlaxoSmithKline Document Number 2013N169204_04, 2017].


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1.3.1.
Risk Assessment
Potential Risk of Clinical 
Significance
Data/Rationale for Risk
Mitigation Strategy
Cardiovascular – QT 
prolongation
QTc prolongation was observed (up to 
8%; 18 msec in dog) following the end of 
a single 8 hour infusion
Effect did not directly correlate with peak 
GSK2816126 blood levels; onset was 4-
7 hours following the end of the infusion; 
reversed within 3-8 hours following 
onset
Effects not observed following repeat 
dosing in dogs
No arrhythmias were detected in 
preclinical studies 
The mechanism for the QTc 
prolongation is unlikely due to a direct 
effect on hERG repolarization as 
GSK2816126 weekly inhibited hERG tail 
current (IC25 of 54.2 µM; 28.61 µg/mL).  
However, GSK2816126 was shown to 
block hERG current density in vitro 
consistent with an effect on hERG 
channel traffickin
Protocol includes cardiovascular 
eligibility criteria, laboratory 
assessments (potassium and 
magnesium), cardiac monitoring 
(electrocardiograms [ECGs], 
Holter monitoring during the 
study, and dose 
stopping/modification criteria for 
the management of QT 
prolongation)
Co-administration of medications 
that are known to prolong the QT 
interval and have a risk of 
causing Torsades de Pointes 
(TdP) are prohibited. Drugs that 
have a possible risk of TdP will 
be used with caution and
additional ECG monitoring
required.
All subjects will remain in the 
clinical research unit (CRU) after 
receiving their first dose of study 
medication (Week 1, Day 1) with 
periodic ECGs and Holter 
monitoring for 24 hours.  
Subjects will not be discharged 
from the unit unless their last 
measured QTc on an ECG 
performed immediately prior to 
discharge after the first dose is 
<500 msec.
Timings for in-house on-drug 
ECGs are pre-infusion, at the 
end of infusion, before bed, and 
before discharge the next 
morning for Day 1 of cycle 1 only.  
Refer to Section 7.1 (T&E) for 
other ECG timings
Local Infusion Site 
Reaction
Vascular/perivascular inflammation 
and necrosis (in rats at all dose levels, 
including controls, and in dogs given 
100 mg/kg)
Dose-limiting vascular damage 
(necrosis, inflammation, edema and/or 
hemorrhage) at the local infusion and/or 
Subjects will be dosed via a 
central venous access device 
with a formulation including 10% 
Captisol
Subjects will be monitored 
closely for infusion site reactions 
(during infusion and for one hour 


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Potential Risk of Clinical 
Significance
Data/Rationale for Risk
Mitigation Strategy
indwelling catheter sites was observed 
in rats and dogs following twice weekly 
IV infusions of GSK2816126 (vehicle 
containing 5% Captisol) (6 to 16 hours) 
for 2 to 4 weeks
Inflammation at the infusion site led to 
secondary histopathologic changes in 
multiple peritoneal and retroperitoneal 
tissues/organs and clinical pathology 
findings; morbidity/mortality observed in 
rats (30 mg/kg; Cmax 2.97 g/mL; 
AUC0-24h 23.5 g.h/mL) and dogs 
(100 mg/kg; Cmax=9.88 g/mL and 
AUC0-24h=80.1 g.h/mL) was 
attributable to vascular or extravascular 
irritant (vesicant) effects of GSK2816126 
and prolonged intravenous 
catheterization
Infusion site and secondary 
histopathologic findings were partially 
reversible and secondary clinical 
pathology effects were reversible
post infusion) and if reaction 
occurs, infusion will be 
interrupted and the appropriate 
clinical intervention commenced.  
See Management of Infusion Site 
Reaction (Section 3.8.2)
Laboratories will be monitored as 
well, including liver function tests 
(LFTs), other chemistries, and 
hematology
Histamine 
Reaction/InfusionReaction
Acute histamine-like reactions seen 
in rats and dogs which began within 
minutes of dosing were observed at 
≥300 mg/kg in dogs (Cmax 66.5 to 
130 µg/mL) and 300 mg/kg (Cmax 33.9 to 
54.2 µg/mL) in rats.
In dogs, histamine reactions resulted in 
discontinuation of dosing.  In rats, 
histamine-related decreased body 
temperature, along with increased HR 
and decreased BP likely led to mortality 
in restrained, but not in unrestrained 
animals
Subjects will be monitored during 
the infusion for evidence of 
histamine release related 
symptoms/infusion reactions and 
treated as needed with 
supportive care per local 
standard of care (e.g., 
corticosteroids, oxygen, 
epinephrine, diuretics, IV fluid).    
The infusion duration can be 
lengthened with restart of the 
infusion or at the next infusion.  
Premedications (antihistamines 
or similar) may be provided at the 
next infusion or prior to treatment 
of new subjects.
Drug Interactions
No in vivo drug-drug interaction (DDI) 
studies have been performed.
GSK2816126 is metabolized by CYP3A 
enzymes in vitro. GSK2816126 has also 
been shown to be a substrate of P-gp 
and BCRP transporters. Therefore, 
The potential for drug-drug 
interactions will be monitored in 
clinical trials and some 
concomitant medications are 
prohibited or to be used with 
caution (see Section 9).


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Potential Risk of Clinical 
Significance
Data/Rationale for Risk
Mitigation Strategy
substances that potently inhibit or 
induce CYP3A, P-gp or BCRP could 
lead to higher/lower exposure in 
subjects, potentially leading to 
alterations of the pharmacologic effects 
of GSK2816126. 
On the other hand, GSK2816126 was 
shown to inhibit CYP2C8, CYP2C9, 
CYP2C19 and CYP3A4 with IC50 values 
<5 M. GSK2816126 activate human 
PXR [(exposure producing 50% of 
the maximum effect (EC50 = 
10 M)] and, therefore, may have the 
potential to induce CYP enzymes.  A 
further in vitro study in cultured human 
hepatocytes (n=3 donors) showed 
induction of CYP3A4 messenger RNA 
(mRNA) with a calculated EC50 of 4.22-
5.43 M and Emax of 3.22-16.5-fold.
In vitro studies demonstrated that 
GSK2816126 (up to 100 M) has the 
potential to inhibit human transporters 
BCRP, OATP1B1, OATP1B3, OCT2, 
MATE1 and MATE2-K (IC50 values of 
21, 13, 34, 2.88, 0.025 and 0.95 M, 
respectively), however, GSK2816126 
did not inhibit P-gp (up to 100 M) or 
OAT1 and OAT3 (up to 25 M).  
Based upon the current average clinical 
Cmax of 58 M (30.6 g/mL) at 3000 mg 
dose, mathematical model simulations 
suggest that GSK2816126 has the 
potential to perpetrate a clinical DDI 
when co-administered with sensitive 
substrates of transporters OATP1B1, 
BCRP, OCT2, MATE1 and MATE2-K 
upon inhibition, and CYP2C8, 2C9, 
2C19 upon inhibition, and CYP3A4 upon 
inhibition or induction.
Phototoxicity
GSK2816126 has recently been 
demonstrated to be phototoxic in an in 
vitro assay for phototoxicity (3T3 Neutral 
Red Uptake Phototoxicity Test).   To 
date, no photosafety concerns have 
been observed in humans at doses up 
Subjects will be instructed to 
minimize or avoid prolonged 
exposure to natural or artificial 
sunlight (e.g., tanning beds, 
sunlamps, UVA or UVB 
treatments) and wear loose fitting 


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Potential Risk of Clinical 
Significance
Data/Rationale for Risk
Mitigation Strategy
to 3000 mg/day, however, only a limited 
number of subjects have received 
GSK2816126.
clothing with long sleeves, 
sunglasses, and broad rim hat 
that protect the skin from sun 
exposure AND use a broad 
spectrum sunscreen (e.g., UVA 
and UVB protective with 
minimum SPF 30) on any 
uncovered areas of the body if 
outdoors from the time of first 
dose of study medication until at 
least 2 weeks (14 days) following 
last dose of study medication
due to long elimination phase.
Hepatic Toxicity
In first in human study EZH117208 
(present study), an increase in level of 
ALT has been noted in the group of 
subjects receiving doses of 1800 mg to 
3000 mg (single infusion dose). None of 
these ALT increases have been 
associated with increase in total bilirubin 
or INR and all have shown improvement 
following either withholding or 
discontinuing GSK2816126. The 
3000 mg dose has been declared to 
exceed the MTD. The highest dose 
being explored in this study is 2400 mg .
In nonclinical species  given 
GSK2816126, twice weekly for 2 and/or 
4 weeks, changes in liver pathology 
(inflammation, hyperplasia) in dogs and 
clinical chemistry parameters (i.e. 
increases in ALT, AST, alkaline 
phosphatase (ALP), bilirubin and 
decreases in albumin) in rats and dogs 
were observed and were consistent with 
systemic inflammation.  These effects 
were considered secondary to vascular 
damage at the infusion and/or surgical 
site and attributable to vascular or 
extravascular irritant (vesicant) 
effects of GSK2816126 and 
prolonged intravenous 
catheterization.
No current evidence suggests the 
presence of reactive metabolites. No 
glutathione conjugates were identified in 
the in vitro, ex vivo studies that were 
Dosing at 3000 mg has been 
discontinued, with the highest 
dose being explored is at 
2400 mg. Continued laboratory 
and clinical monitoring for liver 
dysfunction (LFT, coagulation 
parameters INR/PTT, other blood 
chemistry, clinical observation for 
jaundice). Dose management 
and stopping criteria as per 
guidelines for non-hematologic 
toxicity (Section 3.8.3 and Table 
4) and hepatic safety monitoring 
(Section 8.3.1)


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Potential Risk of Clinical 
Significance
Data/Rationale for Risk
Mitigation Strategy
conducted. GSK2816126 is not a CYP 
metabolism-dependent inhibitor. 
Based on in vivo dosing to rats twice 
weekly for 2 weeks at doses up to 
300 mg/kg, no evidence of induction of 
PXR panel genes was noted. This is in 
agreement with the observation that 
GSK2816126 is not a rat PXR activator. 
It is however a human PXR activator, 
and an in vitro inducer of CYP3A4 in 
human hepatocytes, suggesting species 
differences between rat and human.
GSK2816126 is an in vitro inhibitor 
against hepatic transporters OATP1B1, 
OATP1B3 and BCRP with a moderate in 
vitro potency (IC50: 13-34 µM). With the 
high clinic concentration, a potential risk 
for inhibiting hepatobiliary excretion of 
substrates of these transporters cannot 
be excluded.


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1.3.2.
Benefit Assessment
Study EZH117208 is an open-label, dose escalation study and the first study of this agent 
to be conducted in humans.  GSK2816126 has promising growth inhibitory activity in 
cell lines derived from multiple tumor types; however, it is unknown whether 
GSK2816126 will have efficacy in patients with these tumors.  Thus, any potential 
beneficial effect for an individual subject attributable to GSK2816126 is unknown.  Data 
obtained in Study EZH117208 may assist in progressing the knowledge base on 
lymphoma and other tumor types and their treatment(s), or help identify individuals more 
likely to benefit or have side-effects from GSK2816126.  Study participants may benefit 
from the medical tests and screening performed during the study.
1.3.3.
Overall Benefit: Risk Conclusion
Current data from GSK2816126 clinical study and nonclinical development indicate a 
potential for clinical utility in the treatment of subjects with relapsed and/or refractory 
DLBCL and/or transformed FL, NHL, multiple myeloma, and other solid tumors. 
Considering the overall poor outlook of these subjects on failing prior therapy and 
recognizing the measures taken to minimise risk to subjects participating in the Phase I 
clinical trials, the potential risks identified in association with GSK2816126 are justified 
by the anticipated benefits that may be afforded to subjects with the previously 
mentioned tumor types that have been shown in nonclinical models to respond to 
GSK2816126.  
1.4.
Communication Plan for Safety Evaluation
This phase I study is intended to enroll subjects at two or more sites.  Safety evaluations 
will be closely monitored by a GlaxoSmithKline (GSK) Safety Review Team that 
includes the GSK medical monitor and GSK safety physician.  There will be a 2 way 
communication between the local participating sites and the GSK team via email, fax and 
phone.  The GSK team will review all safety data throughout the study, and safety 
findings with GSK2816126 will be discussed with investigators from all participating 
sites on a monthly basis and appropriate action will be taken.  Urgent safety information 
will be shared with all the participating sites at the earliest possible time after the data 
becomes available, or sooner if necessary.
1.4.1.
Contraindications, Warnings and Precautions
The following Contraindications, Warnings and Precautions apply:
Contraindications: Animal reproductive studies have not been conducted with 
GSK2816126.  Therefore, the compound must not be administered to pregnant women or 
nursing mothers.
Safety and efficacy in the paediatric populations has not been investigated, therefore, 
GSK2816126 should not be administered to children.
Any known hypersensitivity to agents structurally similar to GSK2816126 or the 
constituents of the vehicle would contraindicate GSK2816126 use.


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Warnings:  GSK2816126 is intended for investigational use only by selected 
investigators familiar with the information in this Protocol and experienced in conducting 
clinical studies.
GSK2816126 may only be administered to human subjects participating in clinical 
studies sponsored/approved by GSK and who have provided formal written consent.
Precautions:  ECG monitoring for evidence of QTc prolongation must be conducted.   
Co-administration of medications that are known to prolong the QT interval and have a 
risk of causing TdP are to be avoided beginning 14 days prior to the first dose of study 
drug or longer if necessary, as determined by the primary investigator or medical monitor 
until discontinuation from the study. Co-administration of medications that are known to 
prolong the QT interval and have a possible risk of causing TdP are to be used with 
caution. Subjects will be instructed to minimize or avoid prolonged exposure to natural 
or artificial sunlight (e.g., tanning beds, sunlamps, UVA or UVB treatments) and wear 
loose fitting clothing with long sleeves, sunglasses, and broad rim hat that protect the skin 
from sun exposure AND use a broad spectrum sunscreen (e.g., UVA and UVB protective 
with minimum SPF 30) on any uncovered areas of the body if outdoors from the time of 
first dose of study medication until at least 2 weeks (14 days) following last dose of study 
medication due to long elimination phase.
Potential for Abuse and Dependence: Not Known
Overdosage:  There is no specific antidote for overdose with GSK2816126.  In the event 
of a suspected overdose, it is recommended that the appropriate supportive clinical care 
should be instituted, as dictated by the subjects’ clinical status.
2.
OBJECTIVES, ENDPOINTS AND HYPOTHESES
2.1.
Part 1: Phase I Dose Escalation
Part 1 Objectives
Part 1 Endpoints
Primary

To determine the safety and 
tolerability, and establish the 
recommended Phase 2 dose (RP2D)
of IV administered GSK2816126 

Adverse Events (AEs), Serious Adverse 
Events (SAEs), Dose Limiting Toxicity 
(DLT), withdrawals due to AEs, dose 
interruptions and reductions,  and changes 
in safety assessments (e.g., clinical 
laboratory parameters, vital signs, and 
cardiac parameters)
Secondary

To describe the pharmacokinetics of 
GSK2816126 after single- and 
repeated administration

GSK2816126 PK parameters following 
single- (Day 1) and repeat-dose  
administration of GSK2816126, including 
area under the concentration-time curve 
(AUC), pre-dose (trough) concentration at 
the end of the dosing interval (C), 
maximum observed concentration (Cmax), 
time of occurrence of Cmax (tmax), 
terminal phase half-life (t1/2), time 


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Part 1 Objectives
Part 1 Endpoints

To evaluate the relationship between 
GSK2816126 exposure and 
safety/efficacy/PD parameters

To determine clinical activity of 
GSK2816126 in GCB DLBCL and 
solid tumors containing EZH2 
inhibitor sensitizing mutations or
prostate cancer
invariance and accumulation ratio

GSK2816126 exposure markers (dose, 
concentration, Cmax or AUC) and 
safety/efficacy/PD responses. PD
response assessed by change from 
baseline in tri-methylation of Histone 
H3K27 (H3K27me3)

Best Overall Response rate (complete 
response [CR]  + partial response [PR])
Exploratory

To confirm tumor EZH2 and GCB-
DLBCL status

To investigate the mechanism of 
action of GSK2816126

To identify biomarkers predictive of 
response or resistance to 
GSK2816126

Immunohistochemistry (IHC) for 
confirmation of GCB-DLBCL status

PCR or NGS to determine EZH2 mutation 
status

Evaluate transcriptional and/or protein 
changes upon GSK2816126 treatment

Correlate baseline tumor genomic
[deoxyribonucleic acid (DNA)], 
protein and/or transcription 
[ribonucleic acid (RNA)]  profiles 
with response
Hypothesis
No formal statistical hypotheses are being tested for the dose escalation in Part 1. Analysis of 
the data obtained from dose escalation of Part 1 will utilize descriptive methods only. 
The cohort expansion of GCB-DLBCL patients in Part 1 will assess the overall response rate 
(p) of GCB-DLBCL patients. The null and alternative hypotheses for the overall response rate 
are detailed below:
The null hypothesis is:
H0: p≤20%


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Part 1 Objectives
Part 1 Endpoints
The alternative hypothesis is:
HA: p≥40%
For cohort expansion of solid tumor subjects in Part 1, there is no formal statistical 
hypothesis being tested. Analysis of the data obtained from solid tumor expansion cohort will 
utilize descriptive methods only.


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2.2.
Part 2: Expansion
Part 2 Objectives
Part 2 Endpoints
Primary

To determine clinical activity of 
GSK2816126 in cohorts of subjects 
with EZH2 mutant and wild type 
GCB-DLBCL and tFL and subjects 
with MM

Overall response rate (% of subjects 
achieving CR and PR per response 
criteria)
Secondary

To determine the safety, tolerability 
of the selected IV dose of 
GSK2816126

To characterize the population PK of 
GSK2816126

To evaluate the relationship between 
GSK2816126 exposure and PD 
parameters

To generate samples (data reported 
separately) with which to 
characterize the metabolic profile of 
GSK2816126 after repeat-dosing (In 
the PK/PD expansion cohort only)

To determine the amount of 
GSK2816126 excreted in urine after 
dosing at steady state

To generate samples (data reported 
separately) with which to investigate 
the potential for GSK2816126 to 
affect cytochrome P450 (CYP) 3A4 
enzyme activity

AEs, SAEs, DLTs, withdrawals due to 
AEs, dose interruptions and reductions,  
and changes in safety assessments (e.g., 
clinical laboratory parameters, vital signs, 
and cardiac parameters)

Population PK parameters for 
GSK2816126 including clearance (CL), 
and volume of distribution (Vd) and 
relevant covariates which may influence 
exposure (e.g. age, weight, or disease 
related covariates)

GSK2816126 exposure markers (dose, 
concentration, Cmax or AUC) and PD 
responses. PD response assessed by 
change from baseline in tri-methylation of 
Histone H3K27 (H3K27me3)

Samples to characterize the metabolites in 
blood, bile and/or urine

Concentration of GSK2816126 in urine 
measured with an investigational bio-
analytical method and extrapolated to total 
amount excreted in urine over time using 
urine volume

Samples to assess a potential change in
4b-OH cholesterol to cholesterol ratio in 
plasma following repeat dosing of 
GSK2816126 (data reported separately)

GSK2816126 exposure markers (e.g. 
dose, concentration, Cmax, or AUC) and 
safety/efficacy/ responses


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Part 2 Objectives
Part 2 Endpoints

To evaluate the relationship between 
exposure and safety/efficacy 
parameters 

To begin to characterize the 
durability of response and 
progression free survival with 
GSK2816126

Duration of response (DoR)

Progression-free survival (PFS) 
Exploratory

To identify biomarkers predictive of 
response or resistance to 
GSK2816126

To investigate the mechanism of 
action of GSK2816126 

To investigate the relationship 
between genetic variants in 
candidate genes and the 
pharmacokinetics (PK) and safety 
profile of GSK2816126 based on 
Part 1 and 2 data combined

Evaluation of wild-type (WT) subject 
tumors for the presence of additional, 
undefined, mutations in the EZH2 gene

Correlate baseline tumor genomic (DNA), 
protein and/or transcription (RNA)  profiles 
with response

Evaluate transcriptional and/or protein 
changes upon GSK2816126 treatment

Pharmacogenomic (PGx) analysis of 
whole blood
Hypothesis
In Part 2, the overall response rate (p) of GCB-DLBCL and tFL patients will be assessed for
each EZH2 mutation status cohort (wild type and mutant), and also for MM patients. 

For each of the GCB-DLBCL and tFL cohort, the null and alternative hypotheses of the 
overall response rate are as following:
The null hypothesis is:
H0: p≤20%
The alternative hypothesis is:
HA: p≥40%

For MM cohort:
The null hypothesis is:
H0: p≤10%
The alternative hypothesis is:
HA: p≥25%


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3.
INVESTIGATIONAL PLAN
3.1.
Study Schematic
Part 1
Accelerated Dose Titration followed by 3+3 Dose Escalation
To determine the safety and tolerability of GSK2816126 in subjects with relapsed/refractory 
DLBCL, transformed FL, other NHLs, solid tumors and MM 
Part 1 will include a cohort expansion at MTD or any dose level to enroll subjects with GCB-DLBCL 
and solid tumors with EZH2 inhibitor sensitizing mutations or prostate cancer

Part 2
Cohort Expansion in both WT and EZH2 mutation-positive subjects
To determine clinical activity of GSK2816126 in relapsed/refractory GCB-DLBCL and tFL subjects 
with WT and EZH2 mutation-positive tumors and MM subjects
3.2.
Discussion of Study Design
Protocol waivers or exemptions are not allowed.  Therefore, adherence to the study 
design requirements, including those specified in the Time and Events Table 
(Section 7.1), are essential.
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.
This is a Phase I, open-label, multiple-dose, multicenter, dose-escalation, first-time-in-
human study conducted in two parts.  In Part 1, an accelerated dose titration will be 
employed with one subject per dose level until the first instance of a ≥Grade 2 drug 
related non-hematological toxicity or dose limiting toxicity (DLT) (Section 3.3.3) occurs. 
Exceptions for pre-specified Grade 3 non-serious non-hematological drug related adverse 
events that would allow continuation of accelerated dose escalation are listed in 
Section 3.3.1.
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, the safety information 
from prior cohorts, as well as the recommended dose from a Continuous Reassessment 
Method [Neuenschwander-Continuous Reassessment Method (N-CRM)] analysis
[Neuenschwander, 2008].  The N-CRM is a type of Bayesian adaptive dose-escalation 
scheme.  The method is fully adaptive and makes use of all the DLT information 
available at the time of each dose assignment.  The Fixed and Adaptive Clinical Trial 
Simulator (FACTS) will be used to conduct the N-CRM analysis.  The DLT information 


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on all subjects enrolled in the trial is used to update the estimated dose-toxicity 
relationship and to provide supportive information in addition to the 3+3 design in the 
next escalation/de-escalation decision.
After the accelerated dose titration, subjects will be enrolled in a standard 3+3 dose 
escalation design. Dose escalation will continue until a recommended Phase 2 dose
(RP2D) is determined or until a maximum tolerated dose (MTD) or a dose of 3000 mg 
twice-weekly is reached. Any dose level during Part 1 dose escalation may be expanded 
up to 12 subjects to explore safety and preliminary efficacy.  At MTD/RP2D the cohort 
may be expanded to enroll approximately 27 GCB-DLBCL subjects and approximately 
15 subjects with solid tumors containing EZH2-sensitive mutations or prostate cancer to 
explore additional safety and preliminary efficacy.   Based on results of the Part 1 
analysis in totality, Part 2 expansion cohorts may be opened.and subjectswill be assigned 
to cohorts based on disease and EZH2 mutation status.
Safety assessments will be performed weekly for the first 4 weeks and then at regular 
intervals as outlined in the Time and Events Table (Section 7.1). 
Disease response in lymphoma and solid tumor subjects will be assessed as described in 
the T&E table (Section 7.1).  
Futility and Efficacy analysis will be performed on GCB-DLBCL subjects enrolled at the 
MTD/RP2D in cohort expansion of Part 1 as listed in Section 12.2.1.2.
3.3.
Part 1: Dose-Escalation Phase
3.3.1.
Accelerated Dose Escalation
Initially, an accelerated dose titration scheme will be used starting with a dose of 50 mg 
[Simon, 1997]. Evaluation of at least one subject who has completed one cycle of 
treatment is required prior to determining the dose for the next cohort, with one cycle 
being defined as twice weekly dosing for three weeks and one week off. In the absence 
of Grade 2 or higher non-hematologic toxicity (described in Section 3.3.2.1) or a Dose 
Limiting Toxicity (DLT) (described in Section 3.3.3), subsequent cohorts will allow up to 
100% dose escalations up to 500 mg (approximately 1/6th of the dog HNSTD).
Subsequent dose escalation steps would be up to a maximum of 50% at each step (Table 
1).  Following the initial occurrence of a Grade 2 toxicity or DLT in a subject during the 
first cycle (within 28 days of dose 1), accelerated titration will transition to a standard 
3+3 dose escalation.


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Table 1
Dose Titration Procedures
Dose Level
Toxicity in Study
Increase in Dose
Accelerated Dose Titration Phase
Dose Level -1 
Lower doses may be used if Dose Level 1 exposure 
is significantly higher than predicted or if there is 
excessive toxicity. This may be achieved by 
reducing the dose or by alternate dosing schedules
Dose Level 1 
Starting Dose:  50 mg
Subsequent Dose 
Levels 
No subjects with a Grade 2 
toxicity (exceptions below in 
Section 3.3.2.1) or DLT 
(Section 3.3.3) 
Increase by ≤100% increase in dose up to 500 mg, 
≤50% increase in dose thereafter
(No subjects with Grade 2 drug related toxicity 
AND no subjects with any DLTs in first 28 days of 
treatment)
End of 
Accelerated Dose 
Titration Phase
One subject Grade 2 drug 
related non-hematological 
toxicity in the first 28 days of 
treatment) or Grade 3 drug 
related specific toxicity (See 
Section 3.3.2.1)
Begin 3+3 dose escalation phase
(note that once 3+3 phase is initiated, the procedure 
may revert to the accelerated dose titration phase –
see criteria below in Reverting to Accelerated Dose 
Titration)
3.3.2.
3+3 Dose Escalation Phase
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 subjects, then dosing will proceed to the next higher dose level (≤100% 
increase in dose up to 500 mg, ≤50% increase in dose thereafter). An additional three 
subjects will be enrolled at this dose level if 1 of 3 subjects experiences a DLT.  Subjects 
will be entered in a staggered approach with at least 7 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 1. Escalation to the 
next dose level will not increase greater than 2 fold from the previous dose level up to a 
dose of 500 mg. Subsequent dose escalation steps would be up to a maximum of 50% at 
each step. If 2 or more DLTs are observed at any dose level, the MTD will have been 
exceeded.
An evaluable subject in Table 2 is defined as a subject who has been on study for at least 
28 days (one cycle).  Evaluation of safety data from at least 1 subject during the 
accelerated dose titration or at least 3 subjects in the standard dose titration who have 
completed 28 days of dosing on study (one cycle) is required prior to defining a new dose 
and starting the next cohort. Once a higher dose has been cleared, subjects at lower dose 
levels who remain on study drug and have not experienced dose limiting toxicity will be 
allowed to escalate up to that level.
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 N-CRM analysis described in 
Section 12.


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Table 2
3 + 3 Dose Escalation Design
Number of Subjects with 
DLT in a Cohort
Action
0 out of 3 subjects
Escalate to the next dose level with increase 100% up to 500 mg, 
≤50% thereafter if none of the subjects have Grade 2 toxicity (in the 
first 4 weeks of treatment)
Escalate to next dose level with an increase of 50% if (in the first 
4 weeks of treatment) there has been:
- One or more subjects with Grade 2 toxicity
1 out of 3 subjects
Accrue 3 additional evaluable subjects at current dose level for a total 
of 6 evaluable subjects
1 out of 6 subjects
Escalate to the next dose level with an increase of 50%
2 or more subjects in a dosing 
cohort (up to 6 subjects)
MTD has been exceeded.  Either evaluate an intermediate dose lower 
than current dose or expand a prior cohort up to 12 subjects
Reverting from 3+3 Dose Escalation to Accelerated Dose Titration: Once Grade 2 
toxicity is seen in one subject, there are 2 scenarios where the accelerated dose escalation 
may be resumed.
1) If two additional subjects are added at the dose where Grade 2 toxicity was seen 
in the initial subject and if no Grade 2 or higher toxicity is seen in either of the 2 
new subjects, the accelerated dose escalation may be resumed, or
2) If the 3+3 method is used and, at the next higher dose, the 3 subjects do not have 
a grade 2 or higher toxicity, the accelerated dose escalation may be resumed.  
(Before any decision is made to reinitiate accelerated dose titration a discussion 
between the investigators and  the GSK medical monitor is required)
3.3.2.1.
Toxicity Leading to Termination of Accelerated Titration
The following events will result in an end to accelerated dose escalation:

Any Grade 2 or higher adverse event that is considered related to the study 
medication except for alopecia, drug-related Grade 3 fatigue, or asthenia; diarrhea, 
nausea, and/or vomiting that respond to standard medical care within 48hrs; or
Grade 3 or higher electrolyte abnormalities unrelated to underlying malignancy and 
corrected within  48 hrs

Grade 2 QT interval corrected for heart rate prolongation (confirmed on triplicate 
ECGs by manual reading) 

Grade 2 alanine aminotransferase (ALT) increase (unless clearly attributed to the 
underlying disease)

Any grade adverse events that are considered in the judgment of the investigator and 
GSK Medical Monitor to be serious and related to the drug and requiring additional 
subjects to better understand the toxicity


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3.3.3.
Dose Limiting Toxicity
Dose-limiting toxicity (DLT): An event will be considered a DLT if it occurs within the 
first 4 weeks (28 days) of treatment and meets one of the following criteria (Table 3
[NCI-CTCAE, 2009]) unless it can be clearly established that the event is unrelated to 
treatment.
Table 3
Dose-Limiting Toxicity Criteria
Toxicity
DLT Definition
Hematologic

Grade 4 absolute neutrophil count (ANC) for >7 days

Febrile neutropenia ( according to CTCAE v.4.0 criteria) 

Grade 4 thrombocytopenia or anemia for >7 days
Non-hematologic

Grade 3 or greater nausea, vomiting, or diarrhea that does not respond 
to standard medical care within 48 hours

Grade 3 or greater clinically significant non-hematologic toxicity per 
national cancer institute - common terminology criteria for adverse 
events (NCI-CTCAE), v 4.0  
Infusion reactions

Infusion reactions will not be considered a DLT unless a ≥grade 3 
reaction recurs after administration of optimal prophylaxis
Other

Inability to receive >75% of scheduled doses in treatment period due to 
toxicity

Grade 2 or higher toxicity that does not meet the above definitions but, 
in the judgment of the investigator and GSK medical monitor, is dose 
limiting

Grade 2 or higher toxicity which occurs beyond 28 days which in the 
judgment of the investigator and GSK Medical Monitor is considered to 
be a DLT
3.3.4.
Maximum Tolerated Dose
The MTD will be exceeded if 2 or more subjects in a cohort of up to 6 subjects 
experience a DLT.
The RP2D will be determined based on the MTD or biologically active dose (example: 
clinical response), the safety profile, and available PD data generated from all subjects in 
Part 1.  If necessary, alternate schedules can be explored to determine additional 
biologically active doses even after a RP2D is defined.
3.3.5.
Intra-subject Dose Escalation
Intra-subject dose escalations may be considered on a case-by-case basis, provided that 
the subject has not experienced a ≥Grade 2 drug related non-hematological toxicity or 
DLT in the accelerated dose escalation phase (Section 3.3.1 and Section 3.3.3), or a DLT 
in the 3+3 dose escalation, and contingent upon one of the following:

A higher dose level cohort has been cleared in either the accelerated dose titration 
phase or the 3+3 phase.


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
If a dose level has been cleared and no subjects have been identified for 
enrollment at the next dose level, and after the subject has completed a minimum 
of 8 weeks of dosing on that regimen without a DLT, that subject may be 
escalated to the next higher dose level after review of all safety data, and 
approval by a GSK Medical Monitor.  In this case, the subject must follow the 
dosing schedule outlined in the Time and Events Table (Section 7.1) (starting at 
Day 1) as he/she will be the first subject exposed to the higher dose level. 
Decision on intra-subject dose escalation will be made after review of all safety data and 
approval by a GSK Medical Monitor and discussion with the investigator.  In this case, 
the subject may begin dosing at the higher dose level as it will have already been 
demonstrated to be tolerable and monitoring will be performed as described in the 
protocol. Subjects approved for intra-subject dose escalation may require additional 
limited PK and/or PD sampling as determined by GSK Clinical Pharmacology.  
Additional safety assessments may be specified at the time of the dose escalation or 
schedule modification based on the safety profile in previous subjects at the higher dose 
level.
3.3.6.
Alternative Dosing Schedules
Alternative schedules may be evaluated based on emerging data.  Less frequent dosing 
schedules (e.g., once weekly) may be implemented without an amendment if emerging 
data suggest that twice weekly administration will result in excessive toxicity or if PD 
data suggest less frequent administration may be warranted.  In this case, the starting dose 
would be one dose level above the highest dose which has been determined to be 
tolerable when administered twice weekly. In addition, alternative dosing schedules 
which result in increased frequency of administration may be considered if the safety,
PK, and PD data suggest that a sufficient therapeutic exposure cannot be achieved using 
the initial dosing schedule; this would require a protocol amendment.  Dose escalation 
will continue using the guidelines outlined in Table 2.
3.3.7.
Part 1: Futility and Efficacy Analysis for GCB-DLBCL Subjects
There will be a GCB-DLBCL expansion cohort enrolled after the completion of dose 
escalation in Part 1. For the GCB-DLBCL expansion cohort in Part 1, futility and 
efficacy evaluation of overall response data will be performed in order to support the 
early decision regarding opening Part 2 dose expansion. The methodology is based on the 
Bayesian predictive probability of success if enrollment continues until all planned 
subjects are recruited [Lee, 2008]. Details of the predictive probability methodology, 
futility and efficacy evaluation are explained in Section 12.2.1.2. In summary, a 
minimum of 13 and maximum of 27 GCB-DLBCL patients will be enrolled. Once 13
GCB-DLBCL patients at MTD/RP2D have been enrolled (including patients in dose 
escalation phase) and have completed response assessments of safety and efficacy, 
response data will be reviewed on an ongoing basis for evidence of futility or efficacy. 
For futility/efficacy analysis, subjects evaluable for response assessment will be defined 
by any or all of the following criteria:


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
Subjects who have at least two post-baseline radiological disease assessments and 
have been on study for at least 28 days (one cycle)

Subjects who have progressed or have died or have withdrawn from study treatment 
due to any reason.
Interim analysis (IA) of futility and efficacy can be conducted at any time after 13 GCB-
DLBCL subjects have enrolled and are evaluable for response assessment. If the 
thresholds for futility are met, the Part 1 expansion cohort may be stopped based upon the
evaluation of the totality of the data. If the efficacy thresholds are reached, then Part 2 
expansion may be opened. If neither futility nor efficacy thresholds are met at any interim 
analysis, and the totality of the data does not support continuation of the trial, then the 
trial may be terminated. All available data will be considered in making decision of 
termination or continuation of the trial.
3.4.
Part 2: Expansion Cohorts
Part 2:  Expansion Cohorts in both wild type and EZH2 mutation-positive GCB-
DLBCL and tFL subjects, and subjects with MM 
The primary objective of Part 2 is to investigate whether administration of GSK2816126 
at the RP2D has a potentially clinically meaningful activity for more tumor types, if 
notable response rate is observed in Part 1 expansion cohort of GCB-DLBCL patients. 
Expansion cohorts will be enrolled in Part 2, including GCB-DLBCL and tFL patients 
with mutant and wild type EZH2 and patients with MM. Similar to Part 1 expansion
design, Part 2 expansion design is planned based on predictive probability methodology.
Rather than early stop for either futility or efficacy, Part 2 allows early stop for futility 
only. For each expansion cohort of GCB-DLBCL and tFL patients, a minimum of 10 and 
maximum of 32 patients will be enrolled at the RP2D. For MM cohort, a minimum of 14 
and maximum of 40 patients will be enrolled at the RP2D. Interim analysis of response 
data will start from minimum number of patients enrolled and at any time thereafter. 
Details of Part 2 designs and stopping criteria are elaborated in Section 12.2. All 
available data will be considered in making decision of termination or continuation of the 
trial.
It is noted that patients with GCB-DLBCL, tFL and MM enrolled at MTD/RP2D in the 
previous stages of the trial (dose escalation and cohort expansion in Part 1) will be 
included for the Part 2 analysis.
3.4.1.
Part 2 PK/PD cohort:  
In Part 2 a cohort of up to 12 subjects may be enrolled at RP2D to collect adequate data 
on safety, pharmacokinetics, or pharmacodynamics. Urine, bile, and additional blood 
samples may be collected following repeated administration for drug metabolite profiling 
and to obtain information on renal excretion of GSK2816126.  Mandatory collection of 
pre- and post-treatment tumor biopsies will be required for enrollment in a PK/PD cohort


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3.5.
Rationale
3.5.1.
Rationale for Study
Enhancer of zeste homolog 2 (EZH2), a component of the Polycomb Repressor Complex 
2 (PRC2), mediates transcriptional repression of target genes through tri-methylation of 
histone H3 on lysine 27 (H3K27me3). EZH2 and H3K27me3 are dysregulated in many 
cancers through diverse pathways. While EZH2 mutation plays a significant role in 
progression of certain lymphomas, data from prostate, breast, and several other solid 
tumors have demonstrated that increased EZH2 expression correlates with increased 
aggressiveness of tumors and poor prognosis. 
GSK2816126 is a selective and potent inhibitor of wild-type and mutant EZH2 capable of 
decreasing H3K27me3 levels in all cell types examined. EZH2 inhibition has been shown 
to decrease the growth of several cell lines derived from EZH2 wild type (WT) and 
mutant lymphomas, SNF5-mutant malignant rhabdoid tumors, multiple myeloma, AML, 
neuroblastoma, prostate, breast, skin and colon cancers. 
Most of these cancers have an overall poor outlook either because of lack of any effective 
therapy or standard therapies do not result in a durable remission. This first study of this 
agent will be conducted in subjects with non-Hodgkin lymphomas, especially germinal 
center B-cell diffuse large B-cell lymphoma (GCB-DLBCL) and transformed follicular 
lymphoma (t-FL), and subjects with multiple myeloma or solid tumors who have relapsed 
or are refractory to prior therapies and have a high degree of unmet medical need in terms 
of available treatment options.  
3.5.2.
Rationale for Population
Preclinical studies demonstrate that B-cell lymphomas of DLBCL origin with EZH2 
activating mutations are the most sensitive to GSK2816126; however, the growth of a 
subset of EZH2 wild-type lymphomas, SNF5-mutant malignant rhabdoid tumors, 
multiple myeloma, AML, neuroblastoma, prostate, breast, skin, and colon cancers are 
also sensitive to EZH2 inhibition. There is increasing evidence that a large number of 
solid tumors or subtypes may be driven by EZH2 mutation or over expression. Often, 
these tumors have poor prognosis. Therefore, the study includes subjects with non-
Hodgkin Lymphoma and enriched for subsets (GCB-DLBCL, tFL) as well as multiple 
myeloma and solid tumors that have relapsed or are refractory to prior treatment with 
standard of care or do not have standard of care available or refuse standard of care 
therapy. 
Part 1 will be comprised of 2 phases: 

Part 1 dose escalation which will include subjects with MM, 
relapsed/refractory tFL and DLBCL, other NHLs and solid tumors , and

Part 1 cohort expansion at the highest tolerated dose/MTD which will include
a cohort of subjects with relapsed/refractory GCB-DLBCL and a cohort of 
subjects with prostate cancer or solid tumors containing EZH2 inhibitior 
sensitizing mutations.


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Part 2 will be comprised of cohort expansions in subjects with GCB-DLBCL,
transformed follicular lymphoma and multiple myeloma. 
EZH2 and H3K27me3 are dysregulated in nearly all cancers through numerous pathways 
including 1) recurrent gain-of-function heterozygous mutations in germinal center B-cell 
(GCB) DLBCL, FL, melanoma, and parathyroid adenoma, 2) EZH2 over-expression in 
numerous other aggressive tumors including those from prostate, breast, lung, liver, 
bladder, head and neck, skin, and kidney, and 3) inactivating mutations in UTX.  H3K27
demethylase that acts in opposition to EZH2, described in numerous tumor types 
including transitional cell bladder carcinoma, esophageal squamous cell carcinoma, renal 
cell carcinoma, multiple myeloma, and subgroup 4 medulloblastoma [McCabe, 2014]. 
Furthermore, data from prostate, breast, and several other tumor types have demonstrated 
that increased EZH2 expression correlates with increased aggressiveness of tumors and 
poor prognosis [GlaxoSmithKline Document Number 2013N169204_04, 2017]
McCabe, 2014


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With regard to haematological indications for GSK2816126, preclinical studies 
demonstrate that B-cell lymphomas of DLBCL with EZH2 activating mutations are the 
most sensitive to GSK2816126. Approximately 22% of GCB-DLBCL tumors have an 
EZH2-activating mutation, whereas ABC DLBCL does not contain EZH2- activating 
mutations (McCabe, 2014). Early follicular lymphoma lesions have been shown to have 
EZH2 mutations, as well as mutations in other genes that disrupt chromatin structure 
[Friedberg, 2015]. 
Of particular interest is that there is some data to suggest that certain tumor types may 
respond to EZH2 inhibitors regardless of EZH2 inhibitor sensitizing status.  Data 
presented at ASH Lymphoma Biology 2016 [Morschhauser, 2016] suggests that patients 
who have DLBCL (both GCB or nonGCB) and EZH2 mutated FL who are treated with 
the EZH2 targeted agent tazemetostat can achieve responses, providing proof of concept 
in DLBCL.  Patients with GCB-DLBCL were analysed by EZH2-mutation status. Of 
patients with EZH2 mutation 1/5 had a PR [Overall Response Rate (ORR)=20%]. Of 
those without a mutation, 3/19 had PR or CR (ORR=15.7%; 2 with CR). Therefore, Part 
1 cohort expansion in GCB-DLBCL will enroll patients regardless of EZH2 related 
mutation status.
Neuroendocrine prostate cancer (NEPC) is a subtype of castration-resistant prostate 
cancer associated with aggressive clinical features and poor overall survival (Wang, 
2014). Mounting evidence suggests that NEPC evolves from prostate adenocarcinoma as 
one mechanism of resistance to androgen. Data from metastatic biopsies obtained from 
patients progressing on abiraterone or enzalutamide suggests that at least 10% of patients 
with late-stage castration-resistant prostate adenocarcinoma (CRPC) eventually develop 
small-cell NEPC. NEPC cancer is driven by N-Myc. N-Myc in turn drives EZH2, making 
neuroendocrine prostate cancer sensitive to inhibition [Dardenne, 2016]. Additionally, 


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EZH2 has been described as an epigenetic driver of aggressive prostate cancer. EZH2 
dysregulation may be involved in the progression from early prostate cancer to late
[Yang, 2013].  One of the most prevalent genetic modifications observed in prostate 
cancer is the fusion between the TMPRSS2 and ERG genes, resulted from an abnormal 
translocation on chromosome 21. Detected in more than half of all prostate tumors, this 
fusion gene consisting of the androgen-responsive TMPRSS2 promoter and the ERG 
coding region is able to substantially upregulate ERG expression, which has been proven 
to induce cell proliferation and invasion [Kumar-Sinha, 2008]. Notably, it has been 
demonstrated that ERG can directly activate EZH2, which synergistically result in cancer 
progression through histone methylation linked de-differentiation [Yu, 2010]. Several 
studies have also confirmed that expression of EZH2 shows a correlated pattern with the 
stage of prostate cancer development [Berezovska, 2006; Saramaki, 2006; Hoffmann, 
2007].Therefore, subjects with prostate cancer will be enrolled regardless of EZH2 
related mutation status.
This study of GSK2816126 will focus primarily on the GCB-DLBCL NHL in order to 
ascertain a clinical benefit in a defined tumor type, for which there is high probability of 
potential benefit. However, solid tumors with changes to EZH2 inhibitor sensitizing 
mutations will be evaluated. These will be targeted as it is felt that they are most likely to 
show benefit. The exception in the solid tumor cohort will be prostate cancer, for which 
no mutation status will be required.
3.5.3.
Rationale for Dose and Schedule
The doses of GSK2816126 for evaluation in this study were selected based on available 
preclinical biology, toxicology, and pharmacokinetic data as well as predicted 
pharmacokinetic and response information for humans.  Refer to the IB for more 
information [GlaxoSmithKline Document Number 2013N169204_04, 2017].
Human Pharmacokinetic Extrapolation
Whole blood human clearance was predicted from three species (mouse, rat and dog) 
using maximum life span power-law allometry to be around 8.2 ml/min/kg. Volume of 
distribution was predicted from simple power-law allometry to be 4.8 L/kg and half-life 
around 6.5 hours. A 70 kg adult therefore has a predicted total clearance of 35 L/hr and a 
total volume of distribution of 336 L.
Starting Dose and Infusion Duration
Three approaches have been considered to establish the starting dose for GSK2816126 in 
hematological malignancies assuming a 70 kg adult with a surface area of 1.7 m2. 

One tenth of the rat STD10 as per ICH S9 guidance
The STD10 in the rat was defined as 100 mg/kg administered over 6-hour infusion 
twice-weekly for 2 to 4 weeks. One-tenth (1/10) of the rat STD10 is 60 mg/m2. 
These doses were well tolerated in dogs. A starting dose based on 1/10 of the rat 
STD10 would be 110 mg using the human equivalent dose calculation. 


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
One sixth of the dog HNSTD as per ICH S9 guidance
Based on tolerability, the HNSTD in the dog was defined as 100 mg/kg administered 
as an 8–hour infusion twice-weekly for 4 weeks. A starting dose based on 1/6 of the 
dog HNSTD would be 610 mg using the human equivalent dose calculation. 

The minimum anticipated biologically effective dose 
A daily dose of 15 mg/kg or twice-weekly dose of 50 mg/kg in the Pfeiffer xenograft 
mouse model resulted in minimum target engagement as measured by a 15% 
reduction in H3K27 tri-methylation and 35% to 38% tumor growth inhibition. The 
minimum anticipated biologically effective dose is 287 mg twice-weekly based on 
providing similar free exposure while the dose would be 800 mg based on providing 
similar total blood exposure.
An infusion duration of 2-hours is proposed for this clinical study. This infusion duration 
is shorter than the infusion duration used in animals but can be justified based on the 
following points:

With infusion of a volume of 250 mL over 2 hours, GSK2816126 doses up to 
1250 mg will provide infusion concentration up to the infusion concentration of 
5 mg/mL used in dogs while doses up to 2500 mg will provide infusion 
concentration up to the concentration of 10 mg/mL used in rats. A 3000 mg dose 
would provide an infusion concentration of 12 mg/mL.

The infusion will be performed into a larger (central) vein in humans than in 
animals. A shorter infusion duration and higher local blood flow would lead to a 
shorter exposure of the local area of the vein to high concentrations of 
GSK2816126.

The main factor for the long infusion duration in animals was the histamine-
release like reaction. Subjects will be monitored during the infusion for evidence 
of  histamine release related symptoms/infusion reactions and treated as needed 
with supportive care per local standard of care (e.g., corticosteroids, oxygen, 
epinephrine, diuretics, IV fluid). The infusion duration can be lengthened with 
restart of the infusion or at the next infusion.  Premedications (antihistamines or 
similar) may be provided at the next infusion or prior to treatment of new 
subjects.
Taking all three approaches into consideration and the shorter infusion duration of 2-
hours, a starting dose of 50 mg twice-weekly as a 2-hour infusion is proposed. This dose 
provides a predicted total blood AUC of 1.43g.h/mL and a total blood Cmax of 
0.428 g/mL. The AUC is 38-fold lower than the AUC (0-24hr) for the rat STD10 of
100 mg/kg, 18-fold lower than the AUC at the lowest tested dose in rat (30 mg/kg), and 
56-fold lower than the AUC for the dog HNSTD of 100 mg/kg. The Cmax is 18-fold 
lower than the Cmax for the rat STD10 of 100mg/kg, 6.9-fold lower than the Cmax at the 
lowest tested dose in rat (30 mg/kg), and 23-fold lower than the Cmax for the dog 
HNSTD of 100 mg/kg. The starting dose of 50 mg will provide a suitable safety margin 
for the anticipated toxicities, while minimizing the number of subjects with aggressive 
lymphomas exposed to sub-therapeutic doses.


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Predicted Effective Dose and Dosing Frequency
The potential therapeutic dose for GSK2816126 in human was derived using available 
preclinical, PK and efficacy data from Karpas-422 and Pfeiffer tumor xenograft studies. 
Based on PK/PD modeling of Karpas-422 and Pfeiffer xenograft data, tumor eradication 
with GSK2816126 could be achieved in mice with an average total blood concentration 
target over the dosing interval of 1 ug/mL or an average free concentration of 16ng/mL. 
This free concentration is similar to the in vitro exposure producing 50% of the maximum 
effect (EC50) obtained in Karpas-422 or Pfeiffer cell lines and to the average free 
concentration obtained with 50 mg/kg dosed daily in Karpas-422 xenograft model where 
more than 90% tumor growth inhibition was observed. This average free concentration 
could be achieved on average with twice-weekly administration of 950 mg in humans. 
Due to species differences in protein binding and blood to plasma partitioning, a dose of 
up to 2700 mg could be needed to achieve the average total blood concentration target of 
1 ug/mL.
The rationale for the proposed schedule of twice weekly, 3 weeks on / 1 week off for 
each 28-day cycle is based on preclinical in vivo observations.  Briefly, mice with Pfeiffer 
tumor xenograft were treated daily with 50 mg/kg for 10 days. Tumor H3K27 tri-
methylation levels were measured and tri-methylation inhibition was observed up to 
5 days after the last administration.  Using in vivo murine tumor xenograft models, 
schedules with progressively longer dosing intervals (i.e., from daily to once or twice-
weekly to intermittent twice-weekly dosing with 2 weeks on/ 1 week off) were evaluated.  
Similar tumor growth inhibition were observed for the same total weekly dose, regardless 
of dosing frequency, except for lower tumor growth inhibition being observed with once 
weekly dosing.  
Taken together, these data support a schedule of twice weekly, 3 weeks on / 1 week off. 
3.6.
Study Treatment
3.6.1.
Treatment Assignment

This is an open-label study

Subjects will be identified by a unique subject number that will 
remain consistent for the duration of the study
3.7.
Dosage and Administration of Study Treatment
Due to the risk of infusion site reaction and/or infusion rate/concentration dependent 
histamine reactions, central venous access such as a port, Hickmann catheter or PICC line 
will be required.
GSK2816126 will be administered initially twice-weekly 3 weeks on / 1 week off of each 
28-day cycle.  The dose of the study treatment is discussed in Section 3.3 and Section 3.4.  
Investigational product (IP) details are provided in Table 5. It will be diluted in saline or 
D5W to a fixed 250 mL volume. This volume will be infused over a minimum of 2 hours 
(up to 4 hours). Additional details are provided in the SPM. 


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3.8.
Safety Management Guidelines
3.8.1.
QTcF Stopping Criteria
The QTcF is the QT interval corrected for heart rate according Fridericia’s formula 
(QTcF). 

For eligibility and withdrawal, subjects QTcF value will be used. 

For purposes of data analysis, QTcF values will  be used.
If a subject that meets the corrected QTcF1 interval duration criteria below, study 
treatment(s) will be withheld.  

QTcF interval ≥500 msec; GSK2816126 will be permanently discontinued.

QTcF interval increase from baseline ≥60 msec and maximum QTcF <500 msec; 
GSK2816126 may be restarted one dose level lower once the QTcF returns to 
baseline.  If QTcF prolongation meeting stopping criteria recurs after re-challenge, 
GSK2816126 must be permanently discontinued.
1Based on average QTcF value of triplicate electrocardiograms (ECGs) to include manual 
over-read.  For example, if an ECG demonstrates a prolonged QTcF 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 QTcF values of the 3 ECGs to determine whether the subjects 
should have study treatment discontinued.
3.8.2.
Infusion Reaction Stopping Criteria and Management
A subject may be withdrawn from treatment with GSK2816126 for safety-related reasons
if the following criteria are met:

Occurrence of a ≥Grade 3 infusion-related reaction that does not resolve to 
≤Grade 1despite adequate clinical intervention and prevents re-initiation of the 
infusion on any given treatment day


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3.8.2.1.
Management of Infusion Reactions
Infusion Related Reaction
Infusion Related Reaction
Grade 1: 
Continue infusion and closely monitor the subject 
Grade 2/3:
Temporarily interrupt study medication and:
-
Administer diphenhydramine or similar anti-
histamine 
-
Provide supportive care per local standard of 
care (e.g., corticosteroids, oxygen, 
epinephrine, diuretics, IV fluid)
-
May resume infusion once resolved to 
≤grade 1*
-
For grade 3 reactions, corticosteroids may be 
considered 
Grade 4:
-
Discontinue infusion.  Administer 
diphenhydramine, corticosteroids and 
supportive care per local standard of care
-
May consider restarting study treatment at a 
reduced dose or dose level pre-event based 
on discussion with GSK Medical Monitor
*Recommend following institutional guidelines for re-starting after infusion reactions 
seen with cytotoxic therapy. A general guideline would be as follows:
- Restart under observation at an infusion rate of 25% of the original rate for the 
first 30 minutes
- If no reaction, increase infusion rate by 25% of the original rate every half hour 
until full dose administered
- If Grade 1 reaction, continue at the rate at which the reaction occurs
-If Grade 2 or 3 infusion related reaction consider premedication for all 
subsequent infusions per local standard of care.
3.8.3.
Dose Adjustment for Non-Hematologic Toxicity
See Table 4 Dose Adjustment Guideline for drug related non-hematologic toxicities 
based on worst grade.


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Table 4
Dose Adjustment Guideline for Drug Related Non-Hematologic 
Toxicity
Worst Grade
Dose Adjustment
G1
No change in dose
G2
Continue dosing with no change OR
Consider holding for up to 2  weeks for toxicity to resolve to baseline or ≤ Grade 1, then 
continue at the same dose OR dose reduce to  1 dose level lower per dose escalation 
scheme if the toxicity is considered a DLT.
G3 and 4
Hold for up to 2 weeks for toxicity to resolve to baseline or ≤Grade 1, then dose reduce to 1 
dose level lower per dose escalation scheme
If no recovery to ≤Grade 1* or baseline after 14 days, patient should be withdrawn.
If the non-hematologic toxicity or event resolves to baseline or Grade 1 within 14 days 
of stopping therapy, treatment with GSK2816126 may be restarted at 1 dose level lower 
than the current dose. For a non-DLT, the treatment with GSK2816126 could restart at a 
full dose, if deemed appropriate.
If the non-hematologic toxicity does not resolve to Grade 1 or baseline within 14 days, 
the subject should be withdrawn from the treatment permanently (Section 6.3).  However, 
if the investigator and GSK Medical Monitor agree that further treatment will benefit the 
subject, treatment can restart  at 1 dose level lower and under weekly clinical 
monitoring.  If the toxicity resolves to Grade 1 or baseline, the dose may be resumed to 
the initial dose level. 
3.8.4.
Dose Adjustment for Hematologic Toxicity
3.8.4.1.
For subjects with lymphoma and multiple myeloma:
The treatment may be held for 2 weeks if:

neutrophil and platelet count did not recover to neutrophils ≥0.5 x 109/L and platelets 
≥25 x 109/L
The treatment may resume as soon as count recovery has occurred (i.e., neutrophils ≥0.5 
and platelets ≥25 x 109/L).
When the treatment resumes, the dose may be adjusted based on platelet count, i.e., dose 
can be reduced by 1 or 2 dose levels when the platelet count ≤25 x 109/L (G4 
thrombocytopenia) and it is not attributed to the disease. If a subject has persistent G4 
thrombocytopenia for 4 weeks not attributed to disease or requires platelet transfusions 
for bleeding in the absence of the disease, the subject will be withdrawn from the study.
For non drug-related hematologic toxicity institutional guidelines for re-starting may be 
followed.  


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3.8.4.2.
For subjects with solid tumors:
Thrombocytopenia: 
- Grade 1 & 2 (platelet count ≥50,000): Continue dosing at same dose level with weekly 
or more frequent monitoring as necessary.
- Grade 3 (platelet count between 25,000 to <50,000): After discussion with medical 
monitor and using sound clinical judgement, continue at same dose or consider dose 
interruption until count recovery to Grade 2 or less. Monitor platelet count at a minimum 
of twice weekly.
- Grade 4 (platelet count below 25,000): Interrupt study medication and monitor platelet 
count every 2-3 days. If platelet counts recover to Grade 2, discuss with medical monitor 
resuming treatment at the same or adjusted dose based on sound clinical judgement. 
Platelet transfusion is allowed based on institutional guidelines. In case of platelet 
transfusion, hold drug for at least 7 days from day of transfusion, and if platelet counts 
recover to Grade 2 consider initiating treatment at a lower dose using sound clinical 
judgement and after consulting with the GSK medical monitor. Discontinue treatment if 
drug has to be held for >14 days or greater than 2 dose reductions required.
3.9.
Guidelines for Events of Special Interest and Dose 
Modifications
3.9.1.
Dose Modifications
Dose reductions for GSK2816126 will depend on their starting dose.  If a subject has a 
dose reduction for toxicity the dose will be reduced by one dose level .  Approval from 
the GSK Medical Monitor is required to restart a dose after 14 days of dose interruption.  
Following a dose reduction subjects may be re-escalated to a higher dose level with the 
approval of the GSK Medical Monitor if the toxicity has resolved.


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4.
INVESTIGATIONAL PRODUCT
The term ‘study treatment’ is used throughout the protocol to describe the investigational 
product received by the subject as per the protocol design.  
4.1.
Description of Investigational Product
Table 5
Investigational Product
Product name:
GSK2816126 Injection,15 mg/mL, 30 mL vial with 25 mL fill volume
Formulation 
description:
Solution containing 15 mg/mL GSK2816126 in water for Injection, 
methanesulfonic  acid, Captisol and acetic acid  
Dosage form:
A solution stored at 2-8°C, protected from light
Unit dose 
strength(s)
15 mg/mL
Route/
Regimen
Delivered as an intravenous solution over 2 - 4 hours Study drug can be diluted 
into saline or dextrose for a final volume of 250ml at ambient temperature and 
normal room lighting up to 12 hours prior to infusion.  PVH, PE and PA bags 
and tubing are all acceptable
Physical 
description:
A clear, pale yellow coloured solution, essentially free from visible particles of 
foreign matter
GSK2816126 will be provided to sites by GSK. The contents of the label will be in 
accordance with all applicable regulatory requirements.
4.2.
Preparation/Handling/Storage of GSK2816126 GSK 
Investigational Product
Preparation
Under normal conditions of handling and administration, IP 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.
In the case of unintentional occupational exposure notify the study monitor, the GSK 
Medical Monitor and/or the study manager.
Take adequate precautions to avoid direct eye or skin contact and the generation of 
aerosols or mists.
Refer to the Study Procedures Manual (SPM) for detailed procedures for the disposal 
and/or return of unused study treatment(s).


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Storage
GSK2816126 must be stored in a secure area under the appropriate physical conditions 
for the product. Access to and administration of the GSK2816126 will be limited to the 
investigator and authorized site staff. GSK2816126 must be dispensed or administered 
only to subjects enrolled in the study and in accordance with the protocol.
GSK2816126 is to be stored protected from light in 30 mL Type 1glass vials, at a 
temperature range of [2C/36F to 8C/46F]. Maintenance of a temperature log (manual 
or automated) is required.
4.3.
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 IP 
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.
4.4.
Treatment Compliance
When subjects are dosed at the study site, they will receive study treatment directly from 
the investigator or designee, under medical supervision.  The date and time of each dose 
administered in the clinic will be recorded in the source documents.  The dose of study 
treatment and study participant identification will be confirmed at the time of dosing by a 
member of the study site staff other than the person administering the study treatment.  
GSK2816126 will be intravenously administered to subjects at the study site.  
Administration will be documented in the source documents and reported in the electric 
case report form (eCRF).  Treatment start and stop dates, including dates for treatment 
delays and/or dose reductions will also be recorded in the eCRF.
4.5.
Treatment of Investigational Product Overdose
In the event of an overdose (defined as administration of more than the protocol-specified 
dose) of GSK2816126 the investigator should:

Contact the GSK Medical Monitor immediately

Closely monitor the subject for AEs/SAEs and laboratory abnormalities until 
GSK2816126 can no longer be detected systemically 

Obtain a plasma sample for PK analysis within 24 hours from the date of the last 
dose of study treatment if requested by the GSK Medical Monitor (determined on 
a case-by-case basis)

Document the quantity of the excess dose as well as the duration of the 
overdosing in the eCRF


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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.
5.
STUDY POPULATION
5.1.
Number of Subjects
A maximum of approximately 250 subjects will be enrolled.   See Section 12.2 for 
sample size assumptions.
The number of dose levels and the level at which the RP2D [or maximum tolerated dose
(MTD) or maximum feasible dose (MFD)] is reached cannot be determined in advance.  
An adequate number of subjects will be enrolled into the study to establish the 
recommended dose(s) for further study.  It is estimated that approximately 40 subjects 
will be enrolled into Part 1 dose-escalation of the study.  Additionally in Part 1 cohort 
expansion, approximately 27 GCB-DLBCL subjects and approximately 15 solid tumor 
subjects containing EZH2 inhibitor sensitizing mutations or subjects with prostate cancer
will be enrolled. 
Approximately up to 168 subjects will be enrolled in Part 2 in five expansion cohorts: 
two GCB-DLBCL cohorts with up to 32 subjects from the EZH2 wild-type population, 
and up to 32 subjects from the EZH2 mutation positive population, and two tFL cohorts 
with up to 32 subjects from the EZH2 wild-type population and up to 32 subjects from 
the EZH2 mutation positive population and up to 40 subjects in the MM cohort.  
Additional subjects/cohorts may be enrolled to allow for evaluation of additional dose 
levels. 
In Part 1 (dose-escalation) of the study, if subjects prematurely discontinue, additional 
subjects may be enrolled and assigned to the same treatment sequence at the discretion of 
the Sponsor in consultation with the investigator.  Subjects will not be replaced in Part 2 
(expansion cohort) of the study.
5.2.
Subject Selection Criteria
5.2.1.
Part 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.
Subjects eligible for enrollment in the study must meet all of the following criteria:
1. Provided signed written informed consent.
2. Males and females ≥18 years of age (at the time consent is obtained).
3. Tumor type criteria


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
Relapsed/refractory non-Hodgkin’s lymphoma (NHL) that meets the 
following criteria:
o
Germinal Center B cell Diffuse large B cell lymphoma (GCB-
DLBCL) relapsed or refractory to at least one prior regimen (e.g., 
rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone 
[R-CHOP]) AND  not a candidate for standard salvage regimens or 
autologous or allogeneic stem cell transplant. Local confirmation of 
lymphoma subtype GCB-DLBCL is allowed for enrollment but must 
be confirmed through central laboratory testing.

Solid tumors that meet the following criteria:
o
Measurable disease by RECIST 1.1 in at least 1 site

For Castrate Resistant Prostate Cancer (CRPC) measurable 
disease can also include PSA level (see below)
o
Disease progression with the last line of therapy and at least one prior
standard of care regimens, or tumor for which there is no approved 
therapy, or for which standard therapy is unsuitable or refused.
o
Mutation  Status:

Solid tumor types, other than prostate, must have one of the 
following EZH2 inhibitor sensitizing mutations as determined 
via local testing:

An activating mutation in EZH2 (Y641F/C/S/H/N, 
A677V/G, and/or A687V 

Loss of a component of the SWI/SNF complex, 
including, but not limited to, ARID1A, SMARCB1 
(aka SNF5/INI1/BAF47), SMARCA4 (aka BRG1), or 
PBRM1 (aka PB1) as determined by molecular testing 
(bi-allelic loss or mutation) or immunohistochemistry

Loss of BAP1 (ubiquitin carboxy-terminal hydrolase) 
as determined by molecular testing (bi-allelic loss or 
mutation) or immunohistochemistry
o
CRPC subjects:

Must have measurable disease by either:

RECIST1.1 (see Appendix 5) or,

A minimum PSA of 5 ng/mL

Disease progression on last line of therapy and must have 
progressed on abiraterone, enzalutamide, or taxane 
chemotherapy

Subjects may continue GnRH agonists

Small cell prostate cancer is eligible


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4. For all subjects: Availability of archival tissue, or willingness to undergo fresh 
biopsy if archival tissue is not available as described in Section 7.6.1.1,Section
7.6.1.2 and Section 7.6.5.
5. Must have a pre-existing central venous access such as a port, Hickmann catheter,
or a peripherally inserted central catheter (PICC line) or be willing and able to 
have one inserted.
6. ECOG Performance Status of 0 or 1 (see Appendix 2).
7. Men with a female partner of childbearing potential must have either had a prior 
bilateral vasectomy with resultant azoospermia, bilateral orchiectomy, or must 
agree to use one of the contraception methods listed in Section 10.1 from the time 
of the first dose of study medication until at least 2 weeks (14 days) after the last 
dose of study treatment due to long elimination phase.
8. A female subject is eligible to participate if she is of:

Non-childbearing potential as defined in Section 10.1.1

Child bearing potential as defined in Section 10.1.1 and agree to use 
effective contraception, as defined in Section 10.1, for an appropriate 
period of time (as determined by the product label) prior to the start of 
dosing to sufficiently minimize the risk of pregnancy and for at least 
2 weeks (14 days) following the last dose of study treatment. Women of 
childbearing potential must have a negative serum pregnancy test within 
7 days of first dose of study treatment followed by negative urine or serum 
pregneancy test once every 4 weeks (prior to next dose cycle) thereafter.
9.
Adequate organ system function as defined below:
System
LABORATORY VALUES
Hematologic
  ANC
1.2 x 109/L  
  Hemoglobin
9 g/dL 
  Platelets
75x 109/L  
 PT/INR and PTT
≤1.5 x ULN
Hepatic
  Albumin
2.5 g/dL
  Total bilirubin
1.5 times ULN
 AST and ALT
2.5  times ULN without liver metastases
5 times ULN if documented liver metastases
Renal
Calculate Creatinine Clearancea, b  
50 mL/min                                                              
Reproductive/Endocrine for CRPC only
Testosterone 
<50 ng/dL (only for subjects with CRPC)
Cardiac
Left Ventricular Ejection Fraction (LVEF)
≥LLN (minimum of 50% LVEF) by ECHO  or MUGAc


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Abbreviation(s): ANC, absolute neutrophil count; ALT, alanine aminotransferase; AST, aspartate aminotransferase; 
ECHO, echocardiogram; INR, international normalization ratio, MUGA, multigated (radionuclide) angiogram; PT, 
prothrombin time, PTT, partial thromboplastin time, ULN, upper limit of normal , LLN, lower limit of normal.
a.
Calculated by Cockcroft-Gault formula
b.
For MM subjects, adequate renal function is defined as calculated creatinine clearance ≥30 mL/min.
c.
ECHO is the preferred method and should always be used if available
NOTE:  Laboratory results obtained during Screening should be used to determine 
eligibility criteria.  In situations where laboratory results are outside the permitted range, 
the investigator may opt to retest the subject and the subsequent within range screening 
result may be used to confirm eligibility.  
5.2.2.
Part 2 Inclusion Criteria
1. In addition to inclusion criteria listed for Part 1, Part 2 will enroll GCB-DLBCL, 
tFL and MM subjects only.

Relapsed and/or refractory MM or tFL that have failed prior standard therapy 
and for which there is no standard salvage regimen
2.
Lymphoma subjects will be required to undergo EZH2 mutation testing. This will 
require availability of archival tissue, or willingness to undergo fresh biopsy, for
central testing of EZH2 mutation status.
3. Based on the results of the mutation test, lymphoma subjects may be enrolled in one 
of four cohorts:

GCB-DLBCL EZH2 mutant cohort: 
o
Tumors must contain one, or more, of the following EZH2 activating 
mutations: Y641F; Y641N; Y641S; Y641H; Y641C; A677G; and/or 
A687V

GCB-DLBCL EZH2 wild type cohort:
o
Tumors that do not contain one of the above mutations
o
Subjects with tumors harboring EZH2 mutations other than the seven 
outlined above will be enrolled in the EZH2 wild type cohort

tFL EZH2 mutant cohort: 
o
Tumors must contain one, or more, of the following EZH2 activating 
mutations: Y641F; Y641N; Y641S; Y641H; Y641C; A677G; and/or 
A687V

tFL EZH2 wild type cohort:
o
Tumors that do not contain one of the above mutations
o
Subjects with tumors harboring EZH2 mutations other than the seven 
outlined above will be enrolled in the EZH2 wild type cohort


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5.2.3.
Part 1 and 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.
Subjects meeting any of the following criteria must not be enrolled in the study:
1. Receiving any cancer therapy within 2 weeks of first dose  (including surgery and/or 
tumor embolization)
Note: the following are allowed:

Corticosteroids to control systemic or local symptoms, up to a dose of 
10 mg prednisone or equivalent daily and stable for at least 7 days prior to 
enrollment.

Subjects with prostate cancer may remain on GnRH agonists. Other 
hormonal therapies (e.g., bicalutamide, abiraterone and enzlutimide) for 
prostate cancer must be stopped 4 weeks prior to enrolment.
Note: the following are NOT allowed:

Chemotherapy regimens with delayed toxicity within the last 3 weeks.

Nitrogen mustards, Melphalan,  Monoclonal antibody or Nitrosourea 
within the last 6 weeks.
2. Any major surgery, radiotherapy or immunotherapy within the 4 weeks prior to first 
dose of study drug, or palliative radiotherapy to a single symptomatic lesion within 
the 2 weeks prior to first dose of study drugs.
3. Subjects with prior allogeneic transplant are excluded: however, subjects who have 
previously received an autologous stem cell transplant are allowed if a minimum of 
100 days has elapsed from the time of transplant and the subject has recovered from 
transplant-associated toxicities prior to the first dose of GSK2816126
4. Received an investigational anti-cancer drug within 6 weeks, or within 5 half-lives 
(whichever is shorter) of the first dose of study drug. A minimum of14 days must 
have passed between the last dose of prior investigational agent and the first dose of 
study drug. 
5. Current use of a prohibited medication or expected to require any of these 
medications during treatment with study drugs (see Section 9).
6. Known human immunodeficiency virus (HIV), or serological evidence for Hepatitis 
B (positive HBsAg) or chronic Hepatitis C infection.

Subjects who are negative for HBsAg, but HBcAb positive, a HBV DNA 
(viral load) test will be performed and if negative are eligible.  


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
Subjects with positive Hepatitis C antibody serology with a negative HCV 
RNA test results are eligible.  
7. Concurrent use of therapeutic warfin is allowed. However, anticoagulants that do not 
have reversal agents available are prohibited (see Section 9.2). .  
8. Unresolved toxicity greater than Grade 1 National Cancer Institute – Common 
Terminology Criteria for Adverse Events (NCI-CTCAE) version 4 from previous 
anti-cancer therapy, with the exception of alopecia and peripheral neuropathy [NCI-
CTCAE, 2009]. 

Lymphoma subjects with ≤Grade 3 lymphopenia can be enrolled at the 
discretion of the investigator
9. Packed red blood cell or platelet transfusion within 7 days of screening laboratory 
tests.
10.
Psychological, familial, sociological or geographical conditions that do not permit 
compliance with the protocol.
11.
Cardiac exclusion criteria:

History of acute coronary syndromes (including myocardial infarction and 
unstable angina), coronary angioplasty, or stenting within the past 6 months 
prior to first dose of study drug.

QTcF interval >450 msec 

Uncontrolled arrhythmias.  Subjects with rate controlled atrial fibrillation for 
>1 month prior to first dose of study drugs may be eligible.

Class II, III or IV heart failure as defined by the New York Heart Association 
(NYHA) functional classification system. 
12.
Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs 
chemically related to the study drug or their excipients.
13.
Pregnant or lactating female.
14.
Unwillingness or inability to follow the procedures outlined in the protocol.
15.
Uncontrolled diabetes or other medical condition that may interfere with 
assessment of toxicity.
16.
Central nervous system (CNS) metastases, with the following exception:

Subjects who have previously treated CNS metastases, are asymptomatic, 
and have no requirement for steroids at least 14 days prior to first dose of 
study drug.

Subjects with carcinomatous meningitis are excluded regardless of clinical 
stability.
17.
Invasive malignancy or history of invasive malignancy other than disease under 
study, except as noted below:

Any other invasive malignancy from which the subject has been disease-
free for more than 2 years and, in the opinion of the principal investigator 
and GSK Medical Monitor, will not affect the evaluation of the effects of 


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this clinical trial treatment on currently targeted malignancy, can be 
included in this clinical trial.

Curatively treated non-melanoma skin cancer and any carcinoma-in-situ.
6.
COMPLETION OR WITHDRAWAL OF SUBJECTS
6.1.
Screen and Baseline Failures
Data for screen and baseline failures will be collected in source documentation at the site 
but will not be transmitted to GSK.
Retention of screen-failure tumor tissue: all or a portion of archival or fresh biopsy tissue 
from screen-failure subjects, used for central testing of GCB-DLBCL or EZH2 mutation 
status, will be retained.  This tissue may be used in the validation of potential diagnostic 
assays to detect EZH2 mutations and/or for GCB-DLBCL subtyping.
6.2.
Subject Completion Criteria
For Part 1 (dose-escalation phase), a completed subject is one who has completed the 
DLT observation period, has discontinued study treatment for reasons listed in 
Section 6.3 and completed a post-treatment follow-up visit or has died while receiving 
study treatment or are receiving ongoing study treatment at the time of the Sponsor’s 
decision to close the study.  
For Part 2 (expansion cohort), a completed subject is one who has discontinued study 
treatment for reasons listed in Section 6.3 and completed a post-treatment follow-up visit 
or has died while receiving study treatment.
6.3.
Permanent Discontinuation from Study Treatment
Subjects will receive study treatment until disease progression, death or unacceptable 
toxicity, including meeting stopping criteria for liver chemistry defined in Section 8.3.1.  
In addition, study treatment will be permanently discontinued for any of the following 
reasons:

Substantial deviation(s) from the protocol

Request of the subject or proxy (withdrawal of consent by subject or proxy)

Investigator’s discretion

A dose delay of >21days unless the investigator and GSK Medical Monitor agree that 
further treatment may benefit the subject

Intercurrent illness that prevents further administration of study treatment(s)

Subject is lost to follow-up

Study is closed or terminated

Female subject who becomes pregnant while on study treatment


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The primary reason study treatment was permanently discontinued must be documented 
in the subject’s medical records and eCRF. 
If the subject voluntarily discontinues from treatment due to toxicity, ‘adverse event’ will 
be recorded as the primary reason for permanently discontinuation on the eCRF.
Once a subject has permanently discontinued from study treatment, the subject will not 
be allowed to be retreated.  
All subjects who discontinue from study treatment will have safety/disease assessments 
at the post study treatment Follow Up Visit as specified in the Time and Events Tables.
6.4.
Study Completion
A subject will be considered to have completed the study after they have completed their 
post treatment follow up visit 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.
Per the EU Clinical Trial Directive, the end of the study is defined as the last subject’s 
last visit.
6.5.
Treatment after the End of the Study
The investigator is responsible for ensuring that consideration has been given for the 
post-study care of the subject’s medical condition whether or not GSK is providing 
specific post-study treatment.
7.
STUDY ASSESSMENTS AND PROCEDURES
A signed, written informed consent form must be obtained from the subject prior to any 
study-specific procedures or assessments being performed.
The timing of each assessment is listed in the Time and Events Table (Section 7.1).  The 
timing and number of the planned study assessments may be altered during the course of 
the study based on newly available data (e.g. to obtain data closer to the time of peak 
plasma concentrations) to ensure appropriate monitoring for the following assessments: 
safety, PK, PD/biomarker.  The change in timing or addition of time points for any of the 
planned study assessments listed above must be approved and documented by GSK, but 
this will not constitute a protocol amendment.  The institutional review board (IRB) or 
ethics committee (EC) will be informed of any safety issues that require alteration of the 
safety monitoring scheme.  
Whenever vital signs, 12-lead ECGs and blood draws are scheduled for the same nominal 
time, the assessments should occur in the following order: 12-lead ECG, vital signs, 
blood draws.  Detailed procedures for obtaining each assessment are provided in the 
SPM.


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7.1.
Time and Events Table(s)
This section consists of the Time and Events Table(s) and supplemental footnotes to 
describe assessment windows and sequencing of study-specific assessments and 
procedures. 


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Table 6
Time and Events(See also PK sampling table for PK sampling schedule on Day 1 and Day 15)
STUDY PHASE
SCREEN
First Treatment Period
Cycle 1
Continuation Phase
Cycle 2 and beyond
Follow-Upj
VISIT
Screen
Day 1 
and 4a
Day 8 
and 11 a
Day 15 
and 18 a
Day 21
VISIT WINDOW 
(days)
-14
7l
7l
Assessments (notes)
Informed consent
X
Demographic data
X
Record subject using 
interactive voice 
response system
(IVRS) system
X
X
Height/Weight (Refer to 
Section 7.3.1)
Measurements in 
metric scale.  
Height measured 
only at screening
X
X
Every 4weeks
(Cycle Day 1)
X
Pregnancy test
In females of child 
bearing potential, 
a serumi B-HCG 
pregnancy test is 
required within 7
days of first dose 
of study drug;
urine or serumi B-
HCG test 
thereafter.
X
Every 4 weeks
(Cycle Day 1)
X


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STUDY PHASE
SCREEN
First Treatment Period
Cycle 1
Continuation Phase
Cycle 2 and beyond
Follow-Upj
VISIT
Screen
Day 1 
and 4a
Day 8 
and 11 a
Day 15 
and 18 a
Day 21
VISIT WINDOW 
(days)
-14
7l
7l
Disease characteristics 
(Refer to Section 7.2)
Record date of 
diagnosis, primary 
tumor type, 
histology, stage, 
etc.
X
Prior anti-cancer 
therapy & radiation
Record date of 
therapies
X
Prior surgical 
procedures
X
Past and current 
medical conditions
X
Alcohol consumption
X
Past and current 
tobacco use
X
Physical examination
X
Day 1
Day 8
Day 15
X
Every 4 weeks
Cycle Day 1
ECOG PS
See Appendix 2
X
X
X
X
X
X
X
Vital signs
BP, body 
temperature, 
pulse rate, 
respirations
Cycle 1 Day 1 
vitals should be 
taken at same 
time points as PK 
draws on PK 
Table 7
X
X (Day
1 
follow 
PK 
Table 
7)
X
X
X
Prior to each infusion
X


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STUDY PHASE
SCREEN
First Treatment Period
Cycle 1
Continuation Phase
Cycle 2 and beyond
Follow-Upj
VISIT
Screen
Day 1 
and 4a
Day 8 
and 11 a
Day 15 
and 18 a
Day 21
VISIT WINDOW 
(days)
-14
7l
7l
ECGb
Pre-infusion and 
at the end of 
infusion except 
on Day 1 (Section 
7.3.4). Two 
copies of the 
ECG tracing 
should be 
obtained at the 
time of the ECG, 
one to be kept in 
the study file for 
retrospective 
collection by the 
sponsor if 
necessary.  ECG 
data should be 
reviewed by 
qualified 
personnel with 
experience in this 
study population
X
Xb
X
X
On Day 4 of each cycle
X


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STUDY PHASE
SCREEN
First Treatment Period
Cycle 1
Continuation Phase
Cycle 2 and beyond
Follow-Upj
VISIT
Screen
Day 1 
and 4a
Day 8 
and 11 a
Day 15 
and 18 a
Day 21
VISIT WINDOW 
(days)
-14
7l
7l
Holter Monitoring
Continuous 12-
lead Holter 
ECGs (obtained 
via a Holter 
monitor) will be 
acquired for a 
total of 
approximately 
24 hours 
beginning an 
hour before 
infusion on Day 
1 only  
X
(Day 1)


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STUDY PHASE
SCREEN
First Treatment Period
Cycle 1
Continuation Phase
Cycle 2 and beyond
Follow-Upj
VISIT
Screen
Day 1 
and 4a
Day 8 
and 11 a
Day 15 
and 18 a
Day 21
VISIT WINDOW 
(days)
-14
7l
7l
ECHO /MUGA
At Screening 
X
Concomitant 
medications
See Section 9.2
for list of 
prohibited and 
cautionary 
medications
X
X
X
X
X
continuous
X
Adverse events (Refer 
to Section 8) 
Adverse event 
assessment 
should be 
continuous
X
X
X
X
X
continuous
X
Blood Sampling: on dosing days, collect blood samples prior to dosing unless otherwise noted
Chemistry
No need to 
repeat at pre-
dose Day 1 if 
screening 
assessments 
were performed 
within 72 hours
of first dose  (- 1 
day visit window 
after screening)
X
X
X
X
X
Prior to every infusion
X


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STUDY PHASE
SCREEN
First Treatment Period
Cycle 1
Continuation Phase
Cycle 2 and beyond
Follow-Upj
VISIT
Screen
Day 1 
and 4a
Day 8 
and 11 a
Day 15 
and 18 a
Day 21
VISIT WINDOW 
(days)
-14
7l
7l
Hematology
No need to 
repeat at pre-
dose Day 1 if 
screening 
assessments 
were performed 
within 72 hours
of first dose (- 1 
day visit window 
after screening)
X
X
X
X
X
Prior to every infusion
X
Coagulation
PT/PTT/INR.
No need to 
repeat at pre-
dose Day 1 if 
screening 
assessments 
were performed 
within 72 hours   
of first dose (- 1 
day visit window 
after screening)
X


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STUDY PHASE
SCREEN
First Treatment Period
Cycle 1
Continuation Phase
Cycle 2 and beyond
Follow-Upj
VISIT
Screen
Day 1 
and 4a
Day 8 
and 11 a
Day 15 
and 18 a
Day 21
VISIT WINDOW 
(days)
-14
7l
7l
Blood sample for 
circulating biomarkers
A blood sample 
for circulating 
biomarkers 
should be 
obtained on Day 
1 (prior to 
treatment), Day 
21and at the time 
of disease 
progression
X
X
X (at 
progression
)
Blood sample for 
Genetic research
A 6mL blood 
sample 
should be 
collected 
after 
screening 
(preferably 
on day 1) if 
informed 
consent has 
been 
obtained for 
Genetic 
research
X


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STUDY PHASE
SCREEN
First Treatment Period
Cycle 1
Continuation Phase
Cycle 2 and beyond
Follow-Upj
VISIT
Screen
Day 1 
and 4a
Day 8 
and 11 a
Day 15 
and 18 a
Day 21
VISIT WINDOW 
(days)
-14
7l
7l
Whole Blood for 
Biomarkersg
Whole blood 
should be 
obtained prior to 
dosing on day 
1,day 18  and 
C2D1 (sample 
taken prior to 
dosing)
X (Day 
1)
X (Day 
18)
X (C2W1D1 pre dose 
only)
PK sampling for Part 1
For details, see 
Table 7
Day 1 
(Table
7)
Day 
4pre-
dose 
and 
end of 
infusion
Soon 
after 
ECG 
collecti
on
Day 15 
(Table 7)
At the time of 
circulating 
biomarker 
collection
Cycle 2, 4, 6 and 12 –
pre-dose and within 5 
min prior to end of 
infusion on Day 4 


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STUDY PHASE
SCREEN
First Treatment Period
Cycle 1
Continuation Phase
Cycle 2 and beyond
Follow-Upj
VISIT
Screen
Day 1 
and 4a
Day 8 
and 11 a
Day 15 
and 18 a
Day 21
VISIT WINDOW 
(days)
-14
7l
7l
PK sampling for Part 2
Three samples 
to be collected 
on Day 1 and 
Day 11: 
Predose within 
60 minutes prior 
to start of 
infusion, single 
draw between 
0.5 and 1.9 h 
from start of 
infusion, single 
draw between 
3-6h following 
end of infusion.
Day 1 
and 
pre-
dose 
on Day 
4
X (after 
4th
dose, 
Day 
11)
pre-dose 
on Day 
15
Cycle 2, 4, 6 and 12 –
pre-dose and within 5 
min prior to end of 
infusion on Day 4 
Translational Research
Tumor Tissue for EZH2 
mutation and GCB 
confirmation testing 
(required: for all GCB 
DLBCL and tFL  
subjects)c
Availability of 
archival tissue 
(or fresh biopsy) 
is required for 
central testing of 
GCB-subtype  
and EZH2 
mutation status
X


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STUDY PHASE
SCREEN
First Treatment Period
Cycle 1
Continuation Phase
Cycle 2 and beyond
Follow-Upj
VISIT
Screen
Day 1 
and 4a
Day 8 
and 11 a
Day 15 
and 18 a
Day 21
VISIT WINDOW 
(days)
-14
7l
7l
Tumor tissue for solid 
tumors (including 
prostate subjects)c
Availability of 
archival tissue 
(or fresh biopsy)
X
Tumor biopsy for PD 
optional for Part 1 and 
Part 2. Required for  
PK/PD cohort 
A tumor biopsy 
should be 
obtained at D1 
(up to -14 days)
and after 6th dose 
Day 18(+3 day 
window)
X
X (After 
6th dose, 
Day 18)h
Tumor biopsy for 
biomarker research
Recommended  
for all subjects 
X (at pro-
gression)
Additional Assessments for PD/PK Cohortm
Blood for metabolite 
evaluation (Part 2
PK/PD expansion cohort 
only
Day 1 
(Table 
7) 
Day 15 
(Table 7)
Urine for Metabolite 
(Part 2 PK/PD 
expansion cohort only) 
On Day 15, urine 
samples should 
be collected 
while subject is in 
the office
Day 1 
prior to 
first 
dose 
and 
from 0 
to 24h
Day 15 
from 0 to
8 h


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STUDY PHASE
SCREEN
First Treatment Period
Cycle 1
Continuation Phase
Cycle 2 and beyond
Follow-Upj
VISIT
Screen
Day 1 
and 4a
Day 8 
and 11 a
Day 15 
and 18 a
Day 21
VISIT WINDOW 
(days)
-14
7l
7l
Bile for metabolite (Part 
2 PK/PD expansion 
cohort only) – at least 4 
subjects)
Day 15
Plasma for 4-
hydroxycholesterol and 
cholesterol assay (Part 
2 PK/PD expansion 
cohort only)
X (Day 
1 prior 
to First 
Dose)
X
Disease Assessments for Lymphoma Subjects: Baseline disease assessments at screening and repeated 8 weeks after dosing is initiated and every 12 
weeks thereafter
Computed 
Tomography (CT)k
Must be 
completed within 
4 weeks of first 
dose of 
GSK2816126 
and repeated 8 
weeks after 
dosing is 
initiated.  Every 
12 weeks 
thereafter
X
X
Xd


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STUDY PHASE
SCREEN
First Treatment Period
Cycle 1
Continuation Phase
Cycle 2 and beyond
Follow-Upj
VISIT
Screen
Day 1 
and 4a
Day 8 
and 11 a
Day 15 
and 18 a
Day 21
VISIT WINDOW 
(days)
-14
7l
7l
Positron emission 
tomography (PET)
The use of 
standalone PET 
or PET in 
combination with 
CT scan is 
optional. 
Standalone PET 
does not replace 
CT
Xe
Xe
Xd,e
Bone Marrow biopsy
See Section 7.7
X
Xf
Xf
B symptoms
See Section 7.7
X
X
X
X
X
X
Disease Assessments for Multiple Myeloma (MM) subjects: Baseline disease assessments at screening, week 4 and then every 6 weeks there after unless 
otherwise noted
Disease Characteristics
Every 6 weeks 
after Wk4, 
Including 
cytogenetics as 
appropriate
X
X
Total Protein, CRP, 2 
microglobulin
Every 6 weeks 
after Wk4
X
X
Response Assessment
Every 6 weeks 
after Wk4; 
Response criteria 
in Appendix 6
X


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STUDY PHASE
SCREEN
First Treatment Period
Cycle 1
Continuation Phase
Cycle 2 and beyond
Follow-Upj
VISIT
Screen
Day 1 
and 4a
Day 8 
and 11 a
Day 15 
and 18 a
Day 21
VISIT WINDOW 
(days)
-14
7l
7l
SPEP, FLC assay, 
quantitative 
immunoglobulins ( IgG, 
IgA, IgM)
Not required for 
subjects with 
non-secretory 
MM
X
X
UPEP
Only required if 
paraprotein is 
present in urine
X
Extramedullary Disease 
Assessment
Only required for 
MM with 
extramedullary 
disease
X
BM aspirate and biopsy
Required for non-
secretory MM, or 
as appropriate 
for other subjects
X
Day 18
Week 10, Day 1
Disease Assessments for Solid Tumors: Baseline disease assessments at screening and repeated every 8 weeks after dosing is initiated
CT/ Magnetic 
Resonance Imaging
(MRI)k
Must be 
completed within 
4 weeks of first 
dose of 
GSK2816126 
and repeated 
every 8 weeks
X
Xd
Xd


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STUDY PHASE
SCREEN
First Treatment Period
Cycle 1
Continuation Phase
Cycle 2 and beyond
Follow-Upj
VISIT
Screen
Day 1 
and 4a
Day 8 
and 11 a
Day 15 
and 18 a
Day 21
VISIT WINDOW 
(days)
-14
7l
7l
Positron emission 
tomography (PET)
The use of 
standalone PET 
or PET in 
combination with 
CT scan is 
optional. 
Standalone PET 
does not replace 
CT
Xe
Xd,e
Xd,e
Disease Assessments for Prostate Cancer: (in addition to those assessments for all solid tumor subjects): Baseline disease assessments at 
screening and repeated as noted below after dosing is initiated
PSA
Wk 9 and every 4
weeks thereafter
X
X
X
Study Medication
GSK2816126 Dosinga
Dosed 2x weekly with at least 2-3 non-dosing days in between dosing days (3 weeks on/1 week off)
a.
A subject is to receive two doses per week which should be given with at least 2 non-dosing days in between on the same day of the week during Cycle 1.- If there is a 
need to change scheduling after Cycle 1, the scheduled days of the week can change as long as there are 2-3non-dosing days between dosing days.  
b.
Timings for triplicate in-house on-drug ECGs are pre-infusion, at the end of infusion, before bed, and before discharge the next morning for Day 1 of cycle 1 only.  
Other protocol-mandated ECGs should be performed in triplicate pre-infusion and at the end of infusion (Section 7.3.4). Two copies of the ECG tracing should be 
obtained at the time of the ECG, one to be kept in the study file for retrospective collection by the sponsor if necessary.  ECG data should be reviewed 
by qualified personnel with experience in this study population
c.
Retention of screen-failure tumor tissue: all or a portion of archival or fresh biopsy tissue from screen-failure subjects, used for central testing of GCB-DLBCL or EZH2 
mutation status, will be retained. This tissue may be used in the validation of potential diagnostic assays to detect EZH2 mutations and/or for GCB-DLBCL subtyping.
d.
If the Follow-up visit ≥ 8weeks from the previous response scan time point, scans should be obtained to confirm/ evaluate response.  
e.
Standalone PET dose not replace CT.  Diagnostic CT is the preferred method of disease assessment.  PET/CT may be used as an alternative at the investigator’s 
discretion.  


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f.
Only if initially and/or previously positive & required for CR or as clinically indicated.
g.
Whole Blood for Biomarker sample at Cycle 2 day 1 must  be taken prior to start of dosing.
h.
If tissue sample not able to be taken at C1D18, site should discuss with GSK regarding having the sample taken at the next possible Cycle visit
i.
Serum beta-human chorionic gonadotropin (B-HCG) pregnancy test
j.
Follow up visit should be performed 30 days from last dose of study medication
k.
Baseline brain scans are required for all subjects.  Thereafter brain scans should be conducted as clinically indicated.  Bone scans are to be conducted as clinically 
indicated at baseline and subsequent follow up timepoints.  Subjects undergoing baseline full body CT/PET will not require this additional scans, unless clinically 
indicated. 
l.
After Cycle 1, assessments that are conducted at less frequent intervals (i.e., every 8 weeks) will have a visit window of 7 days after Cycle 1
m.
Part 2 subjects enrolled into the PK/PD cohort will have these assessments performed in addition to all other study assessments included in the Time and Events table


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Table 7
Time and Events, PK Sampling Table for Part 1, Day 1 and Day 15
Duration of Infusion in hours
2
3
4
From start of infusion - 60 mins
Predose
Predose
Predose
5 mins
0.5 hr
0.5 hr
0.5 hr
5 mins
1 hr
1 hr
1 hr
- 5 mins
2 hr (prior to end of infusion)
2 hr
2 hr
- 5 mins
3 hr (prior to end of infusion)
4 hr (prior to end of infusion)
From end of infusion 5 mins
0.5 h
0.5 h
0.5 h
5 mins
1 hr
1 hr
1 hr
5 mins
2 hr
2 hr
2 hr
15 mins
4 hr
4 hr
4 hr
15 mins
6 hr
6 hr
6 hr
From start of infusion 1hour
12 hr (Day 1 only)
12 hr (Day 1 only)
12 hr (Day 1 only)
1 hour
18 hr (Day 1 only)
18 hr (Day 1 only)
18 hr (Day 1 only)
1 hour
24 hr
24 hr
24 hr
2 hour
**72 or 96 hr
72 or 96 hr
72 or 96 hr
**72 hour sample corresponds to Cycle 1 Day 4 pre infusion sample.  EOI sample should also be taken at C1D4.


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7.2.
Demographic/Medical History and Baseline Assessments
The following demographic parameters will be captured during Screening: date of birth 
(in accordance with local data protection legislation), gender, race and ethnicity.
Baseline (Screening) assessments obtained will include:

Complete physical examination, including height (in cm) and weight (in kg)

Vital signs (BP, temperature, respiratory rate, pulse rate)

Past and current medical conditions, alcohol and tobacco use

ECOG performance status

Lactate dehydrogenase (LDH) level

Disease characteristics for all subjects including: 

Date of initial diagnosis 

Initial diagnosis tumor histology

ECOG performance status at initial diagnosis

Tumor location involvement at initial diagnosis 

Previous cancer treatments (e.g., cytotoxics, radiotherapy, maintenance, surgery)

Ongoing toxicities related to previous treatment

Best response to previous treatment(s)

Date of relapse/refractory diagnosis

Tumor histology (if relapse/refractory tumor biopsy completed). For Part 2
subjects, tumor biopsy is mandatory for inclusion. See Section 7.6.5. 

ECOG performance score at time of first relapse/refractory diagnosis (as 
applicable)

Diagnostic quality CT imaging with contrast within 28 days of first dose of study 
treatment identifying nodes, nodal masses, spleen/liver nodules and, if applicable 
measurable extra nodal disease. Diagnostic quality CT imaging is the preferred 
method of disease assessment. If PET/CT has been performed within this window, 
diagnostic CT will not be required.  See Section 7.7 for further information.

If completed and will be utilized for assessment of disease, PET imaging within 28 
days of first dose of study treatment. Images may be obtained from standalone PET 
scanners or via combination PET/CT scanners. Standalone PET does not replace 
diagnostic CT. See Section 15.4 for further information.

For NHL, unilateral or bilateral bone marrow biopsy within 35 days prior to 
commencing study therapy. 

Clinical laboratory tests:  hematology, clinical chemistry, coagulation parameters 


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
Serum beta-human chorionic gonadotropin (-HCG) pregnancy test for female 
subjects of childbearing potential only 

12-lead ECG

ECHO or MUGA

Review of concomitant medications

Baseline assessments for subjects with GCB-DLBCL

Ann Arbor stage of initial diagnosis for NHL

Ann Arbor stage of relapse/refractory diagnosis for NHL

GCB testing confirming status

LDH level at initial diagnosis

LDH level at time of first relapse/refractory diagnosis (as applicable)

Baseline assessment for Subjects with multiple myeloma

International staging system (ISS) stage at initial diagnosis and 
screening

Type (active or smoldering)

Presence of plasmacytoma

Cytogenetics

Presence of extramedullary disease

Laboratory assessment: Total protein, paraprotein, CRP and β2-
microglobulin; for secretory MM: SPEP, UPEP, IgG, IgA, IgM, FLC 
assay
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.
7.2.1.
Critical Baseline Assessments
Cardiovascular medical history/risk factors will be assessed at baseline.
7.3.
Safety Evaluations
Planned time points for all safety assessments are provided in the Time and Events Table 
(Section 7.1).


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7.3.1.
Physical Examinations
A complete physical examination will include assessments of the head, eyes, ears, nose, 
throat, skin, thyroid, neurological, lungs, cardiovascular, abdomen (liver and spleen), 
lymph nodes and extremities.  Height and weight will also be measured and recorded.
A brief physical examination will include assessments of the skin, lungs, cardiovascular 
system, and abdomen (liver and spleen).
7.3.2.
ECOG Performance Status
The performance status will be assessed using the ECOG scale (Section 15.2) as specified 
in the Time and Events Table (Section 7.1).
7.3.3.
Vital Signs
Vital sign measurements will include systolic and diastolic BP, temperature, respiration 
rate and pulse rate.  Vital signs should be measured after resting for at least 5 minutes in a 
semi-supine position.  Vital signs will be measured more frequently if warranted by 
clinical condition of the subject.  On days where vital signs are measured multiple times
(Cycle 1 Day 1), temperature does not need to be repeated unless clinically indicated.  
Refer to the SPM for details regarding measurement of vital signs.
7.3.4.
Safety Electrocardiogram
Safety twelve-lead ECGs will be obtained in triplicate over a brief (e.g., 5-10 minute) 
recording period at designated time points during the study using an ECG machine that 
automatically calculates the HR and measures PR, QRS, QT, and QTc intervals.  At each 
assessment, a 12-lead ECG will be performed by qualified personnel at the site after the 
subject has at least a 5 minute rest and is in a semi-[recumbent or supine] position. Refer 
to the SPM for details regarding ECG procedures.
Standard 12-lead ECGs (safety ECGs) will be performed as part of the real-time 
assessment of subjects. 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
The QTc is the QT interval corrected for heart rate according to Fredericia’s formula 
(QTcF).

For eligibility and withdrawal, QTcF will be used for all subjects

For purposes of data analysis, QTcF values 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 C1D1 predose QTcF 
results.  If these results are not available, then the mean of QTcF of the screening 
triplicate ECG results would be used.


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Timings for in-house on-drug ECGs on Day 1 only are pre-infusion, post-infusion, before 
bed (between 9-10 pm) and before discharge the next morning. These ECGs are in 
addition to the Holter monitoring.  Subjects will not be discharged from their overnight 
stay in the Phase I unit after dose 1 until the QTcF is <500 msec.
For all doses after the first dose, ECGs will be recorded pre-infusion and at the end of 
infusion.  See Time & Events Table (Section 7.1) for exact timings.Refer to Section 3.8.1
for QTc withdrawal/stopping criteria.  Additional QTc readings may be necessary.
7.3.5.
Holter Monitoring
In addition to the 12-lead safety ECGs performed during the study, continuous 12-lead 
Holter ECGs (obtained via a Holter monitor) will be acquired for a total of approximately 
24 hours beginning an hour before the first infusion.  Subjects will be monitored 
overnight in the CRU.  The Holter monitor-derived ECGs will not provide real-time 
assessment of cardiac rhythm and morphology but will be analyzed retrospectively and 
included in the DLT and concentration QT analysis. 
Refer to Section 3.8.1 for QTc interval withdrawal criteria and additional readings that 
may be necessary.  Refer to the SPM for details regarding Holter monitoring procedures.
7.3.6.
Laboratory Assessments
All protocol required laboratory assessmentsshould be performed according to the Time 
and Events Table (Section 7.1).  Details for the preparation and shipment of samples will 
be provided in the SPM.
Prior to administration of the first dose of study treatment, results of laboratory 
assessments should be reviewed.  Any laboratory test with a value outside the normal 
range may be repeated (prior to the first dose) at the discretion of the investigator.
If additional non-protocol specified laboratory assessments are performed at the 
institution’s local laboratory and result in a change in patient management or are 
considered clinically significant by the Investigator (for example SAE or AE or dose 
modification) the results must be recorded in the subject’s CRF. Refer to the SPM for 
appropriate processing and handling of samples to avoid duplicate and/or additional 
blood draws. 
Abnormal laboratory results that are considered by the investigator to be clinically 
significant should be recorded on the eCRF as AEs.   All laboratory tests with values that 
are significantly abnormal during participation in the study or within 30 days after the last 
dose of study treatment should be repeated until the values return to normal or baseline.  
If such values do not return to normal within a period judged reasonable by the 
investigator, the etiology should be identified and the sponsor notified.
Hematology, clinical chemistry, urinalysis and additional parameters to be tested are 
listed below and are to be performed at the institutions local laboratory:


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Table 8
List of Clinical Laboratory Tests
Hematology
Platelet Count
RBC Indices:
Automated WBC Differential:
RBC Count
MCV
Neutrophils
WBC Count (absolute) 
MCH
Lymphocytes
Reticulocyte Count
MCHC
Monocytes
Hemoglobin
Eosinophils
Hematocrit
Basophils
Clinical Chemistry
BUN
Potassium
AST
Total and direct bilirubin
Creatinine
Chloride
ALT
Uric Acid
Sodium
Calcium
Alkaline phosphatase
Total Protein
Magnesium
Glucose
LDH
FSH and estradiol (as needed in women of non-child bearing potential and all peri menopausal women)
Pregnancy test for females (serum B-HCG at screening, Urine or serum B-HCG during Continuation Phase)
Abbreviation(s): ALT, alanine aminotransferase; AST, aspartate aminotransferase; BUN, blood urea nitrogen; FSH, 
follicle stimulating hormone; LDH, lactate dehydrogenase; MCH, mean corpuscular hemoglobin;  MCHC, mean 
corpuscular hemoglobin concentration; MCV, mean corpuscular volume; RBC, red blood cell;  WBC, white blood cell.
7.3.7.
Pregnancy Testing and Reporting
The need for a screening pregnancy test depends on whether a female subject is of 
childbearing potential or non-childbearing potential.
If a female subject is of childbearing potential, she must have a serum -HCG pregnancy 
test performed within 7 days prior to the first dose of study treatment.  Subjects with 
positive pregnancy test result must be excluded from the study.  Subjects with negative 
pregnancy test result must agree to use an effective contraception method as described in 
Section 10.1 during the study until at least 2 weeks (14 days) after permanent 
discontinuation of study treatment.
Any pregnancy that occurs during study participation must be reported using a clinical 
trial pregnancy notification and follow –up form.  To ensure subject safety, each 
pregnancy must be reported to GSK within 2 weeks of learning of its occurrence.  The 
pregnancy must be followed up to determine outcome (including premature termination) 
and status of mother and child.  While pregnancy itself is not considered to be an AE or 
SAE, pregnancy complications and elective terminations for medical reasons must be 
reported as an AE or SAE.  Spontaneous abortions must be reported as an SAE.
Any SAE occurring in association with a pregnancy brought to the investigator’s 
attention after the subject has completed the study and considered by the investigator as 
possibly related to the study treatments, must be promptly reported to GSK.
Any female subject who becomes pregnant while participating in the study will be 
withdrawn from the study. Study treatment should be immediately withdrawn from a 
subject who becomes pregnant during the study in order to eliminate further exposure of 
the embryo to the study treatment.


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In addition, the investigator must attempt to collect pregnancy information on any female 
partners of male study subjects who become pregnant while the subject is enrolled in the 
study.  Pregnancy information must be reported to GSK as described above.
7.4.
Pharmacokinetics
7.4.1.
Blood Sample Collection for Pharmacokinetics
Blood samples for PK analysis of GSK2816126 will be collected at the time points 
indicated in the Time and Events Schedule (Section 7.1). Some of the blood drawn may 
be used to produce dry blood matrix samples at the same time points. Each PK sample 
should be collected as close as possible to the planned time relative to the dose (i.e., time 
zero) administered to the subject on PK days. The actual date and time of each blood 
sample collection will be recorded. The timing of PK samples may be altered and/or PK 
samples may be obtained at additional time points to ensure thorough PK monitoring. 
This would not require a protocol amendment.
Subjects participating in the Part 2 PK/PD expansion cohort, additional blood samples 
will be collected for metabolite profiling.
Details on PK blood sample and dry blood matrix sample collection, processing, storage 
and shipping procedures are provided in the SPM.
7.4.2.
Bile Sample Collection for Pharmacokinetics
Subjects participating in the Part2 PK/PD expansion cohort, bile samples for analysis of 
GSK2816126 and its metabolites may be collected via the Entero-Test [Guiney, 2011] 
over the time period specified in the Time and Events Table (see Section 7.1).  
Full details of the Entero-Test sample collection, processing, storage and shipping 
procedures are provided in the SPM.
7.4.3.
Urine Sample Collection for Pharmacokinetics
Urine may be collected for metabolic profiling in subjects in the PK/PD expansion cohort 
of Part 2 at the time points indicated in the Time and Events Schedule (Section 7.1).
7.4.4.
Plasma Sample for CYP3A4 Enzyme Activity
Plasma collected in the Part 2 PK/PD expansion cohort may be analyzed for 4β-
hydroxycholesterol (as well as cholesterol) as a potential in vivo marker of CYP3A4 
enzyme activity and the results will be reported under a separate Mechanistic Safety and 
Disposition protocol. Samples collected pre-treatment and at steady-state will be 
compared to evaluate this potential biomarker. 
Details on CYP3A4 enzyme activity marker plasma sample collection, processing, 
storage and shipping procedures are provided in the SPM.


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7.4.5.
Pharmacokinetic Sample Analysis
Blood sample analysis will be performed under the management of Bioanalysis 
Immunogenicity and Biomarker, In Vitro In Vivo Translation , Platform Technology and 
Science, GSK.  Concentrations of GSK2816126 will be determined in blood samples 
using the most current approved and validated analytical methodology. Blood raw data 
will be stored in the Good Laboratory Practices (GLP) Archives, GSK. Once the blood 
has been analyzed for GSK2816126, any remaining blood may be analyzed qualitatively 
for circulating metabolites and the results reported under a separate drug metabolism and 
pharmacokinetics (DMPK) protocol.
If dry blood matrix samples are collected, they will be analyzed under the management of 
Bioanalysis Immunogenicity and Biomarker, In Vitro In Vivo Translation , Platform 
Technology and Science, GSK. Concentrations of GSK2816126 will be determined in 
dry blood matrix samples using a validated analytical methodology. Dried blood matrix 
raw data will be stored in the Good Laboratory Practices (GLP) Archives, GSK.
Urine sample analysis may be performed under the management of  Bioanalysis, 
Immunogenicity and Biomarker, In Vitro In Vivo Translation , Platform Technology and 
Science, GSK.  Concentrations of GSK2816126 may be determined in urine samples 
using an investigative analytical methodology.  Urine raw data will be stored in the GLP 
Archives, GSK.
The urine and bile samples may be analyzed for compound-related metabolites and the 
results will be reported under a separate  protocol.
Plasma analysis for 4β-hydroxycholesterol and cholesterol may be conducted and the 
results reported under a separate protocol.
7.5.
Pharmacodynamics
Changes from baseline H3K27me3 will be assessed in pre- and post-treatment samples
for tumor or surrogate tissue/body fluid [e.g. Peripheral blood mononuclear cell
(PBMCs), blood, skin or hair].
7.6.
Translational Research
Translational or biomarker research may be performed on archival tissue, tumor biopsies, 
blood samples or other surrogate tissue (e.g. skin or hair) collected at various times 
throughtout the study, to better understand the mechanism of action and response to 
GSK2816126. The successful collection of quality tissue specimens will be critical to 
furthering our understanding of EZH2 biology and identifying the best way to treat 
patients with an EZH2 inhibitor.
Comparative examination of pre-dosing profiles of participants may uncover known or 
novel candidate biomarkers/profiles which could be used to predict response to treatment 
with GSK2816126 or provide new insights into lymphoma, other cancers, and medically 


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related conditions.  Comparative examination of post-dosing profiles in conjunction with 
pre-dosing profiles may yield known and novel candidate biomarkers/profiles and new 
insights which relate to the action of GSK2816126.
Performance of these investigations may be conditional on the results of the clinical trial 
principally, but not exclusively, on the primary measures of the clinical trial outcome and 
samples may be selected for analysis on the basis of the clinical outcome.
Unless stated otherwise, these investigations may be performed irrespective of whether a 
response to GSK2816126 is observed.
All samples may be retained for a maximum of 15 years after the last subject completes 
the trial.
Novel candidate biomarkers and subsequently discovered biomarkers of the biological 
response associated with lymphoma, or other cancers,and/or the action of GSK2816126
may be identified by application of. DNA/gene, RNA and protein analysis of blood and 
tumor tissue including but not limited to the following analyses:

Confirmation of GCB-subtype DLBCL status by IHC analysis using the standard 
methods or tumor Gene Expression Profile (GEP) signature

Confirmation of EZH2 WT status by targeted sequencing of EZH2 gene

Subject tumors determined to be wild-type for the seven pre-defined EZH2 
mutations assessed in the screening assay may be evaluated for the presence 
of additional, undefined, mutations in the EZH2 gene

DNA analyses may be performed for somatic mutations in genes of interest 
(including, but not limited to, EZH2,UTX, BAP1, ARID1A, SMARCB1, 
SMARCA4, and PBRM1).  Translocations including, but not limited to, BCL-2, 
BCL-6 and c-MYC, which have been observed in DLBCL, may also be assessed

Circulating cell free-DNA (cfDNA) analysis of blood/plasma

Circulating biomarker (DNA, RNA and/or protein) analysis of plasma

RNA transcriptome analysis of blood and/or tissue samples.

Measurement of the levels of a subset of RNA species in blood and/or tissue 
samples

Analysis of protein expression by IHC or an alternative method may also be 
performed for proteins of interest.
7.6.1.
Tumor Biomarker Analysis
To evaluate candidate biomarkers and identify novel predictors of sensitivity and/or 
resistance to GSK2816126, DNA, RNA or protein measurements will be assessed in 
archival tumor tissue or fresh biopsies.  Specific tests, exploratory analyses and tissue 
requirements for each tumor type are indicated below and/or Table 6.   


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7.6.1.1.
GCB-DLBCL Subtyping (DLBCL subjects only)
Central confirmation of GCB DLBCL status will be confirmed by an IHC test utilizing 
the Choi algorithm [Choi, 2009] in Part 1 and 2.
Local testing, in advance of central confirmation may be performed to determine GCB 
status for enrollment using the Choi algorithm or a suitable alternative algorithm.  
7.6.1.2.
EZH2 Mutation Analysis (required for study entry in Part 2 for GCB-
DLBCL and tFL subjects only)
Screening for eligibilityfor Part 2 of the study will be conducted using either an NGS-
based gene panel  or a custom quantitative real time polymerase chain reaction (RT-PCR) 
test based on TaqMan PCR chemistry.  Both tests detect 7 known activating mutations in 
the EZH2 gene: Y641F (c.1937A>T); Y641N (c.1936T>A); Y641S (c.1937A>C); 
Y641H (c.1936T>C); Y641C (c.1937A>G); A677G (c.2045C>G); and A687V 
(c.2075C>T) .
EZH2 mutation analysis on archival tumor samples or fresh biopsies from subjects 
enrolled in Part 1 may also be performed, though the presence of an EZH2 mutation is 
not required for study entry in Part 1. 
7.6.2.
Circulating cell free DNA/RNA Analysis
Plasma samples may be analyzed to investigate mutations, including but not limited to 
EZH2, in cfDNA.
Tumor-specific circulating cell-free deoxyribonucleic acid (cfDNA) levels detected in 
plasma or serum have been found to correlate with increasing tumor burden and decline 
following therapy.  Furthermore, cfDNA in cancer participants can harbor many genetic 
alterations (mutations, microsatellite alterations, aberrant methylation), which are 
generally consistent with the tumor. Additionally exosomes, released from tumors cells 
into circulation, which contain both DNA and RNA are increasingly being recognized as 
important source of cancer biomarkers. Thus, tumor-specific circulating cfDNA and 
exosomes have the potential to be a useful source of biomarkers of therapeutic response 
as well as offering a less invasive blood based technique for identifying and selecting 
participants for certain treatment.  Methylation status of cfDNA may also be investigated.
7.6.3.
Circulating biomarker analysis
Levels of circulating biomarkers may be assessed to determine relationships between 
biomarker expression and response to GSK2816126, as well as to better understand the 
expression of circulating biomarkers in lymphoma and other tumor types.
Biomarkers circulating in the plasma have been found to correlate with tumor pathway 
activation.  Blood-based markers have the important advantage that specimens are readily 
available, simple to prepare and store, and can be taken prior to and during treatment.  
This allows for the assessment of predictive markers based on the baseline evaluation as 


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well as markers of activity and resistance based on changes that occur during treatment.  
Therefore, a broad panel of biomarkers may be evaluated in plasma and correlated with 
clinical outcome to treatment with GSK2816126.
7.6.4.
RNA Expression Research 
Transcriptional (RNA) analyses may be performed to better understand changes in gene 
expression profile upon treatment with GSK2816126 in tumor tissue and/or blood.  
.
RNA expression studies may be conducted using RNA-seq, quantitative RT-PCR, and/or 
alternative equivalent technologies, which can facilitate the simultaneous measurement of 
the relative abundances of RNA species resulting in a RNA expression profile for each 
blood and tumor tissue sample. The RNAs assayed may be those involved in tumor 
pathogenesis, the absorption, distribution, metabolism, or excretion of GSK2816126, or 
in the subject’s response to GSK2816126. In addition, continuing research may identify
other proteins or regulatory RNAs that may be involved in response to GSK2816126 or 
tumor pathogenesis. The RNAs that code for these proteins and/or regulatory RNAs may 
also be studied. This will enable the evaluation of changes in RNA expression profiles
that may correlate with biological response relating to specific cancers, and medically 
related conditions or the action of GSK2816126.
7.6.5.
Tumor Tissue collection
Part 1:

DLBCL subjects:  the availability of archived tissue (or willingness to undergo 
fresh biopsy) is required for determination of EZH2 mutation status, and/or GCB-
subtype.

All other subjects:  an archival tumor specimen (or willingness to undergo fresh 
biopsy) for retrospective DNA, RNA or protein testing of potential markers of 
sensitivity and/or resistance. Subjects for whom archived tissue is not available 
and biopsies are not feasible will be eligible for enrollment and participation in 
the study at the discretion of the GSK medical monitor. Contact GSK medical 
monitor for confirmation of enrollement and sudy entry if biopsies are not 
feasible.

Pre and post treatment biopsies for PD and translational research activities are 
optional for all subjects.
Part 2:

DLBCL cohorts:  a fresh tumor biopsy is required for all screened subjects to 
determine EZH2 mutation status and GCB-subtype.  

tFL cohorts:  a fresh tumor biopsy is required for all screened subjects to 
determine EZH2 mutation status. 


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
MM cohort:  an archival tumor specimen or fresh tumor biopsy is required.

PK/PD cohorts: Pre treatment and post treatment biopsies are required

Pre and post treatment biopsies for PD and translational research activities are 
optional for all other subjects.
Retention of screen-failure tumor tissue: all or a portion of archival or fresh biopsy tissue 
from screen-failure subjects, used for central testing of GCB-DLBCL or EZH2 mutation 
status, will be retained.  This tissue may be used in the validation of potential diagnostic 
assays to detect EZH2 mutations and/or for GCB-DLBCL subtyping.
A tumor biopsy at progression for biomarker research is recommended for all subjects.
Further details on sample requirements and collection will be provided in the SPM.
7.6.6.
Blood collection
Blood samples will be collected at multiple time points from all subjects on study (Parts 1 
and 2) for pharmacodynamic and exploratory biomarker testing (Section 7.1).
A change in frequency of blood biomarker sampling times may be implemented based on 
emerging data.  This would be determined by GSK and documented in formal 
communication to sites for implementation but would not require a protocol amendment..
Further details on sample requirements and collection will be provided in the SPM.
7.7.
Evaluation of Anti-Cancer Activity
Disease assessment may include imaging and physical examination (as indicated for 
palpable/superficial lesions). Refer to Appendix 4 for more details on response 
assessment criteria. 

Disease assessment for lymphomas will be completed within 4 weeks of first dose 
of GSK2816126 and repeated 8 weeks after dosing is initiated, every 12 weeks 
thereafter, and at the final study visit. 

Disease assessment for solid tumors will be completed within 4 weeks of first 
dose of GSK2816126 and repeated every 8 weeks after dosing is initiated, and at 
the final study visit. 

Disease assessment for MM will be completed within 4 weeks of first dose of 
GSK2816126, week 4 and repeated every 6 weeks thereafter.  
See the Time and Events Table (Section 7.1) for the schedule of assessments of anti-
cancer activity.  Assessments must be performed on a calendar schedule and should not 
be affected by dose interruptions/delays.  For post-baseline assessments, a window of 
7 days is permitted to allow for flexible scheduling.  If the last radiographic assessment 
was more than 8 weeks prior to the subject’s withdrawal from study and progressive 


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disease has not been documented, a disease assessment should be obtained at the time of 
withdrawal from study.
For subjects with NHL, the following B symptoms should be assessed at the time points 
in the Time and Events Table (Section 7.1): 

night sweats without signs of infection

unintentional weight loss of ≥10% within the previous 6 months

recurrent, unexplained fever of greater than 38oC for 2 weeks without signs of 
infection
If a lymphoma subject had involvement of bone marrow at baseline, and a CR is 
suspected, a bone marrow biopsy must be obtained. A repeat bone marrow biopsy will be 
performed within 8 weeks of the imaging confirmed CR in accordance with the response 
guidelines. See Appendix 4: Section 15.4 for additional details.
Tumor response will be assessed as outlined above and in the Time and Events Schedule 
by the investigator using:

Lymphoma Subjects: Revised Response Criteria for Malignant Lymphoma 
(RRCLM)(Appendix 4)

Solid Tumor RECIST 1.1 (Appendix 5)

Multiple Myeloma: International Myeloma Working Group (IMWG) 
(Appendix 6)

Prostate: RECIST 1.1 and PSA ( Appendix 7)
7.8.
Genetic Research
The information regarding genetic research is included in Appendix 8.
8.
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS
The investigator or site staff will be responsible for detecting, documenting and reporting 
events that meet the definition of an AE or SAE as outlined in Section 8.1 and 
Section 8.2, respectively.
8.1.
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 


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also includes failure to produce expected benefits, abuse, or misuse. Examples of events 
meeting the definition of an AE include:

Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or grade of the condition

New conditions detected or diagnosed after study treatment administration even 
though it may have been present prior to the start of the study

Signs, symptoms, or the clinical sequelae of a suspected interaction

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
treatment or a concomitant medication (overdose per se will not be reported as an 
AE/SAE). 
“Lack of efficacy” or “failure of expected pharmacological action” per se is not to be 
reported as an AE or SAE.  However, any signs and symptoms and/or clinical sequelae 
resulting from “lack of efficacy” will be reported as an AE or SAE, if they fulfill the 
definition of an AE or SAE. 
Events that do not meet the definition of an AE include:

Medical or surgical procedure (e.g., endoscopy, appendectomy); the condition that 
leads to the procedure is an AE.

Situations where an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).

Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present 
or detected at the start of the study that do not worsen.

The disease/disorder being studied, or expected progression, signs, or symptoms of 
the disease/disorder being studied, unless more severe than expected for the subject’s 
condition. 
8.2.
Definition of a SAE
A SAE is any untoward medical occurrence that, at any dose:
a.
Results in death
b.
Is life-threatening
NOTE:  The term 'life-threatening' in the definition of 'serious' refers to an event in 
which the subject was at risk of death at the time of the event.  It does not refer to an 
event, which hypothetically might have caused death, if it were more severe.
c.
Requires hospitalization or prolongation of existing hospitalization
NOTE:  In general, hospitalization signifies that the subject has been detained 
(usually involving at least an overnight stay) at the hospital or emergency ward for 
observation and/or treatment that would not have been appropriate in the physician’s 
office or out-subject setting. Complications that occur during hospitalization are 


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AEs. If a complication prolongs hospitalization or fulfills any other serious criteria, 
the event is serious.  When in doubt as to whether “hospitalization” occurred or was 
necessary, the AE should be considered serious.
Hospitalization for elective treatment of a pre-existing condition that did not worsen 
from baseline is not considered an AE.
d.
Results in disability/incapacity, or
NOTE:  The term disability means a substantial disruption of a person’s ability to 
conduct normal life functions.  This definition is not intended to include experiences 
of relatively minor medical significance such as uncomplicated headache, nausea, 
vomiting, diarrhea, influenza, and accidental trauma (e.g. sprained ankle) which may 
interfere or prevent everyday life functions but do not constitute a substantial 
disruption.
e.
Is a congenital anomaly/birth defect. 
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.
All events of possible study treatment-induced liver injury with hyperbilirubinemia 
defined as ALT 3 times ULN and bilirubin ≥2 times ULN (>35% direct) (or 
ALT ≥3 times ULN and INR >1.5, if INR is measured) or termed ‘Hy’s Law’ events 
(INR measurement is not required and the threshold value stated will not apply to 
subjects receiving anticoagulants).

NOTE:  Bilirubin fractionation is performed if testing is available.  
If testing is not available, record presence of detectable urinary 
bilirubin on dipstick indicating direct bilirubin elevations and 
suggesting liver injury.  If testing is unavailable and a subject meets 
the criterion of total bilirubin ≥2 times ULN, then the event is still
reported as a SAE.  If INR is obtained, include values on the SAE 
form.  INR elevations >1.5 suggest severe liver injury.


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8.3.
Laboratory and Other Safety Assessment Abnormalities 
Reported as AEs and SAEs
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis), or 
other safety assessments (e.g., ECGs, radiological scans, vital signs measurements) 
including those that worsen from baseline, and events felt to be clinically significant in 
the medical and scientific judgment of the investigator are to be recorded as an AE or 
SAE, in accordance with the definitions provided.
In addition, an associated AE or SAE is to be recorded for any laboratory test result or 
other safety assessment that led to an intervention, including permanent discontinuation 
of study treatment, dose reduction, and/or dose interruption/delay.
Any new primary cancer must be reported as a SAE. 
However, any clinically significant safety assessments that are associated with the 
underlying disease, unless judged by the investigator to be more severe than expected for 
the subject's condition, are not to be reported as AEs or SAEs.
8.3.1.
Liver Chemistry Stopping Criteria
Liver chemistry threshold stopping criteria have been designed to assure subject safety 
and to evaluate liver event etiology during administration of study treatment(s) and the 
follow-up period (in alignment with the FDA premarketing clinical liver safety 
guidance).  
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM174090.pdf
See Figure 1 and Figure 2 for liver stopping criteria for subjects without and with liver 
metastases, respectively. The algorithms are best read from left to right.


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Figure 1
Phase I/II Liver Chemistry Stopping and Increased Monitoring 
Algorithm for Subjects WITH entry criteria ALT ≤2.5xULN
Liver Safety Required Actions and Follow up Assessments Section can be found in 
Appendix 3


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Figure 2
Phase I/II Liver Chemistry Stopping and Increased Monitoring 
Algorithm including Subjects WITH documented liver 
metastases/tumor infiltration at baseline AND entry criteria 
ALT>2.5xULN but ≤5xULN
Liver Safety Required Actions and Follow up Assessments Section can be found in 
Appendix 3
8.3.1.1.
Study Treatment Restart or Rechallenge
If subject meets liver chemistry stopping criteria do not restart/rechallenge subject with 
study treatment unless:

GSK Medical Governance approval is granted

Ethics and/or Institutional Review Board (IRB) approval is obtained, if 
required, and

Separate consent for treatment restart/rechallenge is signed by the subject
Refer to Appendix 3 for full guidance


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8.3.2.
Cardiovascular Events
Investigators will be required to fill out event specific data collection tools for the 
following AEs and SAEs:  

Myocardial infarction/unstable angina

Congestive heart failure

Arrhythmias

Valvulopathy

Pulmonary hypertension

Cerebrovascular events/stroke and transient ischemic attack

Peripheral arterial thromboembolism

Deep venous thrombosis/pulmonary embolism

Revascularisation
This information should be recorded in the specific cardiovascular eCRF within one week 
of when the AE/SAE(s) are first reported.
8.4.
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 
30 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 8.4.
After discontinuation of study treatment, the investigator will monitor all AEs/SAEs that 
are ongoing until resolution or stabilization of the event or until the subject is lost to 
follow-up.  At any time after 30 days the investigator may report any AE that they 
believe possibly related to study treatment.   
8.4.1.
Method of Detecting AEs and SAEs
Care must be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended 
and non-leading verbal questioning of the subject is the preferred method to inquire about 
AE occurrence. Appropriate questions include:


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“How are you feeling?” or for pediatric studies, “How does your child seem to feel?”
“Have you had any (other) medical problems since your last visit/contact?” or for 
pediatric studies, “Has your child had any (other) medical problems or seem to act 
differently in any way since his/her last visit/contact?”
“Have you taken any new medicines, other than those provided in this study, since your 
last visit/contact?” or for pediatric studies, ”Has your child needed to take any medicines, 
other than those provided in this study, since his/her last visit/contact?”
8.4.2.
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 the 
following table once the investigator determines the event meets the protocol definition 
for that event.


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Initial Reports
Follow-up Information on a Previous 
Report
Type of Event
Time Frame
Documents
Time Frame
Documents
All SAEs
24 hours
SAE data collection 
tool
24 hours
Updated SAE data 
collection tool 
“CV events” and/or 
“death”
Initial and 
follow up 
reports to be 
completed 
within one 
week of when 
the 
cardiovascular 
event or death 
is reported
“CV events” 
and/or “death” 
data collection 
tool(s) if 
applicable
Initial and follow 
up reports to be 
completed within 
one week of when 
the cardiovascular 
event or death is 
reported
Updated “CV 
events” and/or 
“death” data 
collection tool(s) if 
applicable
Pregnancy
2 Weeks
Pregnancy 
Notification Form
2 Weeks
Pregnancy 
Follow-up Form
Liver chemistry abnormalities (Section 8.3.1):
ALT 3 times ULN and 
bilirubin 2 times ULN 
(>35% direct) (or ALT 
3 times ULN and INR 
>1.5, if INR is 
measured)c
24 hoursa
SAE data collection 
tool;
Liver Event eCRF 
and liver imaging 
and/or biopsy 
eCRFs if 
applicableb
24 hours
Updated SAE data 
collection tool. 
Updated Liver Event 
eCRFb
ALT 5 times ULN; ALT 
3 times ULN with 
hepatitis or rash or 3 
times ULN 4 weeks
24 hoursa
Liver Event eCRFb
24 hours
Updated Liver Event 
eCRFb
ALT 3 times ULN and 
<5 times ULN and 
bilirubin <2 times ULN
24 hoursa
Liver Event eCRF 
does not need to be 
completed unless 
elevations persist 
for 4 weeks or 
subject cannot be 
monitored weekly 
for 4 weeksb
a.
GSK to be notified at onset of liver chemistry elevations to discuss subject safety.
b.
Liver event documents should be completed as soon as possible
c.
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.


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8.4.3.
Regulatory reporting requirements for SAEs
Prompt notification of SAEs by the investigator to GSK is essential so that legal 
obligations and ethical responsibilities towards the safety of subjects are met.
GSK has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a product under clinical investigation.  GSK will 
comply with country specific regulatory requirements relating to safety reporting to the 
regulatory authority, IRB/EC and investigators.
Investigator safety reports are prepared for suspected unexpected serious adverse 
reactions according to local regulatory requirements and GSK policy and are forwarded 
to investigators as necessary.
An investigator who receives an investigator safety report describing a SAE(s) or other 
specific safety information (e.g., summary or listing of SAEs) from GSK will file it with 
the IB and will notify the IRB/EC, if appropriate according to local requirements.
9.
CONCOMITANT MEDICATIONS AND NON-DRUG 
THERAPIES
Subjects will be instructed to inform the investigator prior to starting any new 
medications from the time of first dose of study treatment until the end of the study (Final 
Study Visit).  Any concomitant medication(s), including non-prescription medication(s) 
and herbal product(s), taken during the study will be recorded in the eCRF.  Additionally, 
a complete list of all prior anti-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.
9.1.
Permitted Medications
Subjects should receive full supportive care during the study, including transfusions of 
blood and blood products, and treatment with antibiotics, antiemetics, antidiarrheals, and 
analgesics, and other care as deemed appropriate and in accordance with their 
institutional guidelines and considering the list of contra-indicated medicines included in 
Section 9 of the protocol.
Palliative radation and/or surgical intervention is permitted after discussion with the GSK 
medical monitor and documenting the treatment in the eCRF. 
Questions regarding concomitant medications should be directed to the GSK Medical 
Monitor for clarification.


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9.2.
Prohibited and Cautionary Medications
Subjects should not receive those medications listed as prohibited in Section 9.2
Subjects should not receive other anti-cancer therapy including chemotherapy, radiation 
therapy, immunotherapy, biologic therapy, investigational therapy, hormone therapy 
(other than leuprolide or other GnRH angonists for mCRPC), surgery or tumour 
embolizationwhile 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. .
Concurrent use of therapeutic warfarin may be allowed. However, increased monitoring 
of INR and bleeding with dose titration for warfarin is recommended due to potential 
increase in warfarin concentration when administered with study treatment GSK2816126.
Anticoagulants that do not have reversal agents available are prohibited from 14 days 
prior to the first dose of study drug through completion of the Final Study Visit.  
9.2.1.
Drugs that may alter the Pharmacokinetics of GSK2816126
It has been demonstrated in vitro that GSK2816126 is metabolized by CYP3A enzymes.
However, turnover in human liver microsomes and hepatocytes was low and the relative 
contribution of this pathway to the elimination of GSK2816126 is presently unknown. 
GSK2816126 has also been shown to be a substrate of P-gp and BCRP transporters. .
Therefore, substances that potently inhibit or induce CYP3A, P-gp or BCRP (Table 9) 
should be avoided during the course of the study where possible as these drugs could lead 
to higher/lower exposure in subjects, potentially leading to alterations of the 
pharmacologic effects of GSK2816126.  
The impact of inhibition of P-gp or BCRP on GSK2816126 pharmacokinetics has not 
been assessed in humans. Drugs that are mild to moderate inhibitors of P-gp and BCRP 
should be administered with caution because they may alter GSK2816126 levels (Table 
10).


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Table 9
Prohibited Drugs Potentially Affecting GSK2816126 
Pharmacokinetics Resulting in Increased or Decreased GSK2816126 
Exposure
PROHIBITED – strong inducers/inhibitors of CYP3A, , Pgp, Bcrp, since levels of GSK2816126 may be 
decreased/increased
Strong CYP3A/Pgp/Bcrp Inhibitor/Inducer
Therapeutic Area
clarithromycin, telithromycin, rifamycin class agents 
(e.g.  rifampin, rifabutin, rifapentine) troleandomycin
Antibiotics
itraconazole, ketoconazole
Antifungals
Nefazodone
Antidepressants
Amprenavir, atazanivir delaviridine, fosamprenavir 
indinavir, lopinavir,nelfinavir, ritonavir, saquinavir, 
tipranivir
Antiretrovirals, Protease Inhibitors
carbamazepine, cyclosporine, phenobarbital, 
amiodarone
Miscellaneous
Table 10
Use with Caution Drugs Potentially Affecting GSK2816126 
Pharmacokinetics Resulting in Increased or Decreased GSK2816126 
Exposure
USE WITH CAUTION – Potential for Inducers/inhibitors of CYP3A, Pgp and BCRP since levels of 
GSK2816126 may be decreased/increased
Mild/Moderate CYP3A or Pgp Inhibitor/Inducer
Therapeutic Area
voriconazole
Antifungal
diltiazem, verapamil
Antiarrhythmics
Cortisone (>50 mg), hydrocortisone (>40 mg), 
prednisone or prednisolone (>10 mg), 
methylprednisolone or triamcinolone (>8 mg), 
betamethasone or dexamethasone (>1.5 mg)
Glucocorticoids (oral)
aprepitant, cimetidine, montelukast, 
Miscellaneous
1.
NOTE:  Topical or inhaled steroids are permitted.
9.3.
Drugs that may have their Pharmacokinetics altered by 
GSK2816126
The potential for pharmacokinetic interactions with drugs likely to be co-administered 
with GSK2816126 in vivo has not been assessed. In vitro data suggests that GSK2816126 
has the potential to inhibit CYP2C8, CYP2C9, CYP2C19, and CYP3A (IC50’s <9 µM). 
GSK2816126 does not appear to be an inhibitor of CYP1A2 or CYP2D6. GSK2816126 
is also an in vitro inhibitor of human transporters BCRP, OATP1B1, OATP1B3, OCT2, 
MATE1 and MATE2-K (IC50 values of 21, 13, 34, 2.88, 0.025 and 0.95 M, 
respectively) In addition, GSK2816126 was shown to activate human PXR (EC50 = 
6.3 M) and, therefore, may have the potential to induce CYP enzymes.  A further in 


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vitro study showed induction of CYP3A4 mRNA with a calculated EC50 of 4.22-5.43 M 
and Emax of 3.22-16.5-fold.  
These results suggest that narrow therapeutic index medications that are substrates of 
CYP2C8, CYP2C9, CYP2C19 and CYP3A4, and/or transporters BCRP, OATP, OCT2, 
MATE1 and MATE2-K should be prohibited as their levels may be increased, and could
lead to adverse effect (Table 11). Co-administration of sensitive substrates of these CYPs 
and/or transporters  should be used with caution as their levels may be increased or 
decreased (Table 11). Discussion by the PI/staff with the GSK medical monitor(s) must 
occur before use of these drugs.
Table 11
Prohibited Drugs Potentially Affected by GSK2816126
PROHIBITED – highly sensitive and/or low therapeutic index 
CYP3A/CYP2C8/CYP2C9/CYP2C19/OCT2/MATE substrates since levels of these drugs may be 
increased
CYP3A Substrate
Therapeutic Area
alprazolam, diazepam, midazolam, triazolam
Hypnotics and Sedatives
diergotamine, ergotamine, eletriptan
Antimigraine agents
pimozide, 
Antidepressant, Antipsychotics, Antianxiety agents
cyclosporine, sirolimus, tacrolimus
Immunosuppressive agents
astemizole
Antihistamine
sildenafil, tadalafil, vardenafil
Erectile Dysfunction agents
eplerenone
Selective Aldosterone Blockers
tizanidine
Muscle Relaxant
quinidine
Antiarrhythmics
CYP2C8, CYP2C9 and CYP2C19 Substrate
Amiodarone
Antiarrhythmics
Paclitaxel
Anticancer
tolbutamide, nateglinide
Antidiabetic
phenytoin, s-mephenytoin
Anticonvulsants
acenocoumarol 
Anticoagulant
Cyclophosphamide
Immunosuppressant
OCT2, MATE1, MATE2-K Substrate
Cisplatin
Anticancer
Dofetilide, pilsicainide, procainamide
Antiarrhythmics


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Table 12
Use with Caution - Drugs Potentially Affected by GSK2816126
USE WITH CAUTION – Monitor for side effects since levels of these drugs may be increased. 
Consider dose reduction.
CYP2C8/9/19/3A/OATP1B1/OATP1B3 Substrate
Therapeutic Area
felodipine
Calcium Channel Blockers
lovastatin, rosuvastatin, atorvastatin, fluvastatin
HMG-CoA Reductase Inhibitors
oral budesonide
Corticosteroids
fentanyl, alfentanil
Analgesics
Warfarin*, cilostazole
Anticoagulants and Antiplatelets
Rosiglitazone, repaglinide
Antidiabetics
OCT2, MATE1, MATE2-K Substrate
captopril
Anti-Hypertensive
ganciclovir, tenofovir
Antiviral
gabapentin,
Anticonvulsants
certirizine, ranitidine
H2 Blocker
metformin
Antidiabetics
atecegatran metoxil
Anticoagulants
glycopyrronium
Respiratory, COPD
pindolol, triamterene
Antihypertension
varenicline
Others
USE WITH CAUTION – Monitor for loss of efficacy or substitute another medication
Substrates of CYP3A4/CYP2B6 that are affected 
by induction 
Therapeutic Area
doxycycline, chloramphenicol, 
Antibiotics
caspofungin,  terbinafine
Antifungals
enalapril, diltiazem, amlodipine, nifedipine, 
nisoldipine
Antihypertensives
amitriptyline, nortriptyline, desipramine, imipramine, 
protriptyline, clomipramine, doxepin
Antidepressants
glipizide, glyburide,  tolazamide, chlorpropamide
Antidiabetics
zonisamide, valproate, divalproex
Anticonvulsants
buspirone
Antidepressant, Antipsychotics, Antianxiety agents
buprenorphine, naloxone, naltrexone, nalmefene
Opioid agonist/antagonists
aprepitant, clofibrate,, tramadol, methohexital, 
estazolam, galantamine, leflunomide, solifenacin, 
sulfasalazine, 
Miscellaneous
*Concurrent use of therapeutic warfarin may be allowed. Increased monitoring of INR and bleeding with 
dose titration of warfarin is recommended due to potential increase in warfarin concentration when co-
administered with GSK2816126. However, anticoagulants that do not have reversal agents available are 
prohibited


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9.4.
Drugs and QT prolongation
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 with 
a minimum of 14 days 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 requires the 
use of amiodarone, which should be used as per local clinical guidelines). The 
medications with a risk of torsade de pointes are provided in Table 13.
Co-administration of medication that are known to prolong the QT interval and have a 
possible risk of causing Torsades de Pointes “possible-torsadogenic medication”are to be 
used with Extreme Caution beginning 14 days prior the first dose of study drug until 
discontinuation from the study. On starting cautionary medications such as in Table 14, 
additional ECG monitoring should be implemented after cycle 1.  Additional ECGs 
should be taken at the next scheduled study visit following the initiation of the “possible-
torsadogenic medication”.  If there are no abnormalities, regular cardiac safety 
monitoring can be resumed per Table 6. If there are abnormalities, implement additional 
cardiotoxcity monitoring as addressed in Section 3.8.1. and contact GSK Medical 
Monitor.
Neither list is all inclusive and subject to change based on evolving data. Both tables are 
taken from the www.crediblemeds.org website available as of 09-Jan-2017.  Latest list of 
medications is available on www. crediblemeds.org website.
Questions regarding concomitant medications whould be directed to the GSK Medical 
Monitor.
Table 13
Drugs  Known to prolong the QT interval and have a Risk of 
Torsades de Pointes that are PROHIBITED for Co-Administration 
with GSK2816126
Generic Name
Drug Class
Generic Name
Drug Class
Amiodarone
Anti-arrhythmic
Haloperidol
Anti-psychotic
Anagrelide
Phosphodiesterase 3 
inhibitor
Ibogaine(only on non 
US Market)
Psychedelic
Arsenic trioxide
Anti-cancer
Ibutilide
Anti-arrhythmic
Astemizole 
(Removed from  
Market)
Antihistamine
Levofloxacin
Antibiotic
Azithromycin
Antibiotic
Levomepromazine(Only 
on Non  US Market)
Antipsychotic
Bepridil (Removed 
from  Market)
Anti-anginal
Levomethadyl acetate 
(Removed from Market)
Opiate
Chloroquine
Anti-malarial
Levosulpiride (only on 
non US Market)
Antipsychotic
Chlorpromazine
Anti-psychotic / Anti-
Mesoridazine 
Anti-psychotic


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Generic Name
Drug Class
Generic Name
Drug Class
emetic
(Removed from  
Market)
Cilostazol
Phosphodiesterase 3 
inhibitor
Methadone
Opiate
Ciprofloxacin
Antibiotic
Moxifloxacin
Antibiotic
Cisapride 
(Removed from  
Market)
GI stimulant
Ondansetron
Anti-emetic
Citalopram
Anti-depressant, SSRI
Oxaliplatin
Antineoplastic Agent
Clarithromycin
Antibiotic
Papaverine HCL (Intra-
coronary)
Vasodilator, Coronary
Cocaine
Local anesthetic
Pentamidine
Antibiotic
Disopyramide
Anti-arrhythmic
Pimozide
Anti-psychotic
Dofetilide
Anti-arrhythmic
Probucol (Removed 
from  Market)
Antilipemic
Domperidone 
(Only on non US 
Market)
Anti-nausea
Procainamide 
Anti-arrhythmic
Donepezil
Cholinesterase inhibitor
Propofol
Anaesthetic, general
Dronedarone
Anti-arrhythmic
Quinidine
Anti-arrhythmic
Droperidol
Anti-psychotic / Anti-
emetic
Roxithromycin (Only on 
Non US Market)
Antibiotic
Erythromycin
Antibiotic
Sevoflurane
Anesthetic, general
Escitalopram
Anti-depressant, SSRI
Sotalol
Anti-arrhythmic
Flecainide
Anti-arrhythmic
Sparfloxacin (Removed 
from  Market)
Antibiotic
Fluconazole
Antifungal
Sulpiride (Only non US 
Market)
Anti-psychotic, 
atypical
Gatifloxacin 
(Removed from 
Market)
Antibiotic
Sulyopride (Only on 
Non US Market)
Anti-psychotic, 
atypical
Grepafloxacin (Off 
market worldwide)
Antibiotic
Terlipressin (Only on 
non US Market)
Vasoconstrictor
Halofantrine
Anti-malarial
Terfenadine (Removed 
from US Market)
Antihistamine
Thioridazine
Anti-psychotic
Vandetanib
Anti-cancer
Data Source: www.crediblemeds.org (9 January 2017)


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Table 14
Drugs Known to prolong the QT interval with a Possible Risk of 
Torsades de Pointes that are Permitted for co-administration with 
Extreme Caution
Generic Name
Drug Class
Generic Name
Drug Class
Alfuzosin
Alpha1-blocker
Mirabegron
Beta3 adrenergic 
antagonist
Apomorphine
Dopamine agonist
Mirtazapine
Anti-depressant, Tetracyclic
Aripiprazole
Anti-psychotic, atypical
Moexipril/HCTZ
Anti-hypertensive
Nicardipine
Anti-hypertensive
Artenimol+piperaqui
ne
Antimalarial
Nilotinib
Kinase inhibitor
Asenapine
Anti-psychotic, atypical
Norfloxacin
Antibiotic
Atomoxetine
Norepinephrine reuptake 
inhibitor
Nortriptyline
Antibiotic
Bedaquiline
Antibiotic
Ofloxacin
Antibiotic
Bendamustine
Alkylating agent
Bortezomib
Proteasome inhibitor
Osimertinib
Tyrsine kinase inhibitor
Bosutinib
Tyrosine kinase inhibitor
Oxytocin
Oxytocic
Buprenorphine
Opioid receptor modulator
Paliperidone
Anti-psychotic, atypical
Capecitabine
Anticancer
Panobinostat
Histone deacetylase 
inhibitor
Ceritinib
Kinase inhibitor
Pasireotide
Somatostatin analog
Clomipreamine
Antidepressant, Tricyclic
Pazopanib
Tyrosine kinase inhibitor
Clozapine
Anti-psychotic, atypical
Perflutren lipid 
microspheres
Imaging contrast agent
Crizotinib
Kinase inhibitor
Perphenazine
Antipsychotic
Cyamemazine 
(cyamepromazine)(
Only on Non US 
Market)
Antipsychotic
Pipamperone (On 
non US Market)
Antipsychotic
Dabrafenib
Anti-cancer
Promethazine
Anti-psychotic / Anti-emetic
Dasatinib
Tyrosine kinase inhibitor
Degarelix
Gonadotropin Releasing 
Hormone
Delamanid (Only on 
Non US Market)
Antibiotic
Rilpivirine
Anti-viral
Desipramine
Antidepressant, Tricyclic
Risperidone
Anti-psychotic, atypical
Dexmedetomidine
Sedative
Romidepsin
Histone deacetylase 
inhibitor
Dolasetron
Anti-emetic
Saquinavir
Anti-viral
Efavirenz
Antiretroviral
Sertindole (On non 
US Market)
Anti-psychotic, atypical
Eribulin mesylate
Anti-cancer
Solifenacin
Muscle Relaxant
Ezogabine 
(Retigabine)
Anticonvulsant
Sorafenib
Tyrosine kinase inhibitor
Famotidine
H2-receptor antagonist
Sunitinib
Anti-cancer
Felbamate
Anti-convulsant
Fingolimod
Sphingosine phospate 
receptor modulator
Tamoxifen
Anti-cancer


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Generic Name
Drug Class
Generic Name
Drug Class
Flupentixol (Only on 
Non US Market)
Dopamine 2 and 5HT2a 
antagonist
Telavancin
Antibiotic
Foscarnet
Anti-viral
Telithromycin
Antibiotic
Tetrabenazine 
Monoamine Transporter 
Inhibitor
Tiapride (Only on 
Non US Market)
Selective D2, D3 dopamine 
antogonist
Gemifloxacin
Antibiotic
Tizanidine
Muscle relaxant
Granisetron
Anti-emetic
Tolterodine
Muscle relaxant
Hydrocodone-ER
Analgesic
Toremifene
Estrogen 
agonist/antagonist
Iloperidone
Anti-psychotic, atypical
Trimipramine
Antidepressant, Tricyclic
Imipramine 
(melipramine)
Antidepressant, Tricyclic
Tropisetron (only on 
Non US Market)
Antiemetic
Isradipine
Anti-hypertensive
Vardenafil
Phosphodiesterase inhibitor
Lapatinib
Anti-cancer
Vemurafenib
Kinase Inhibitor
Lenvatinib
Anticancer
Venlafaxine
Anti-depressant, SNRI
Leuprolide
Gonadotropin Receptor 
Anonist
Vorinostat
Histone deacetylase 
inhibitor
Lithium
Anti-mania
Melperone (Only on 
Non US Market)
Antipsychotic, atypical
Zotepine (Only on 
Non US Market)
Anti-psychotic, atypical
Mifepristone
Progesterone antagonist
Data Source: www.crediblemeds.org (9 January 2017)
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. Intravenous administration of 
these drugs are not permitted. 
9.5.
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 within 14 days prior to 
the first dose of GSK2816126 throughout the study until the final study visit. Herbal 
products include, but are not limited to:

St. John’s Wort, kava, ephedra (ma huang), gingko biloba, dehydroepiandrosterone, 
yohimbe, saw palmetto, and ginseng
The investigator should contact a GSK Medical Monitor before initiating treatment with 
any herbal preparation including marijuana. 


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10.
LIFESTYLE AND/OR DIETARY RESTRICTIONS
10.1.
Contraception
10.1.1.
Female Subjects
A female of non-childbearing potential is defined as:

Post menopausal women (including all women 60 years of age or older) with 1 
year without menses with an appropriate clinical profile (e.g. age appropriate, 
>45 years) in the absence of hormone replacement therapy (HRT) or medical 
suppression of the menstral cycle (e.g. leuprolide treatment). In questionable 
cases for women <60 years of age, a blood sample with simultaneous follicle 
stimulating hormone (FSH) and estradiol falling into the central laboratory’s 
post-menopausal reference range is confirmatory [Kronenberg, 2008; Strauss and 
Barbieri, 2004].  Females under 60 years of age, who are on hormone 
replacement therapy (HRT) and whose menopausal status is in doubt, will be 
required to use one of the contraceptive methods listed below 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 2-4 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.  If laboratory 
values for FSH and estradiol are drawn and the results do not confirm menopause 
on a potential subject that otherwise met the specifications for being post 
menopausal as defined below without question, the subject may still enroll in the 
study as a female of non-childbearing potential if approved by the medical 
monitor and the safety physician.

Females under 60 year of age with a documented bilateral tubal ligation or 
salpingectomy, hysteroscopic tubal occlusion procedure with follow up 
confirmation of bilateral tubal occlusion, hysterectomy or bilateral oophorectomy 
(surgical menopause) and no plans to utilize assisted reproductive techiniques 
(e.g., in vitro fertilization or donor embryo transfer).
A female of childbearing potential is defined as any female who does not meet the 
criteria of non-childbearing potential as described in the previous paragraph and to also 
include:

Females with functioning ovaries (i.e. post menarche, premenopausal women with 
no documented impairment of oviduct or uterine function that would cause 
sterility).

Females with oligomenorrhea, females who are peri-menopausal and young 
females who have begun to menstrusate.
Female subjects of childbearing potential must not become pregnant during the study and 
so must be sexually inactive by abstinence or use non-hormonal contraceptive methods 


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with a failure rate of <1% per year  when used consistently and correctly and , when 
applicable, in accordance with the product label.  These are defined below.
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. 
Complete abstinence from sexual intercourse for 14 days prior to first dose of study 
treatment, through the dosing period, and for at least two weeks (14 days) after the last 
dose of study treatment.
Requirements for Female Subjects of Reproductive Potential:  Contraceptive 
Methods with a Failure Rate of <1% per year:

GSK2816126 is a potential CYP3A enzyme inducer which may decrease the 
efficacy of hormonal contraceptives.  Therefore the use of 
hormonalcontraceptives is excluded.

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 and/or semen analysis of the subject or 
review of the subject's medical history or medical history interview provided by the 
subject or her partner. ,
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.
10.1.2.
Male Subjects
To prevent pregnancy in a female partner or to prevent exposure of any partner to the 
study treatment from a male subject’s semen, male subjects must use one of the following 
contraceptive methods from the time of first dose of study medication until at least 2 
weeks (14 days) following last dose of study medication:

Vasecetomy with documentation of azoospermia or bilateral orchiectomy.  The 
documentation on male sterility can come from the site personnel’s; review of 
subjects medical records, medical examination and/or semen analysis, or medical 
history interview provided by the subject or his partner.

Abstinence from penile-vaginal intercourse, 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.


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
Male condom plus partner use of a highly effective contraceptive (< 1% rate of 
failure per year as stated in the product label) 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. 
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.
10.2.
Lactation Restrictions
Female subjects who are lactating must discontinue nursing prior to the first dose of study 
treatment and must refrain from nursing throughout the treatment period and for at least 
two weeks (14 days) after last dose of study treatment.
10.3.
Caffeine, Alcohol and Tobacco Restrictions
Subjects will abstain from ingesting alcohol, tobacco products, caffeine- or xanthine-
containing products (e.g., coffee, tea, cola drinks, chocolate) for 24 hours prior to the start 
of dosing until collection of the final PK and or PD sample during each session.
10.4.
Sun and UV Exposure Restrictions
Prior to starting study drug, subjects should be instructed to follow the below procedures 
from the time of first dose of study medication until at least 2 weeks (14 days) following 
last dose of study medication due to long elimination phase of GSK2816126:

Minimize or avoid prolonged exposure to natural or artificial sunlight
(e.g., tanning beds, sunlamps, UVA or UVB treatments)

Wear loose fitting clothing with long sleeves, sunglasses, and broad rim hat that
protect the skin from sun exposure AND use a broad spectrum sunscreen (e.g.,
UVA and UVB protective with minimum SPF 30) on any uncovered areas of the
body if outdoors
11.
DATA MANAGEMENT
For this study, data will be collected using defined eCRFs in the validated data system, 
InForm. Some data (i.e. Biomarker, PK, Holter, ECG) will be transmitted electronically 
to GSK from an external vendor via a validated data system.
In all cases, subject initials will not be collected or transmitted to GSK according to GSK 
policy.
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 


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the course of the study. GSK may request an independent review of scans. See SPM for 
additional details.  
12.
DATA ANALYSIS AND STATISTICAL CONSIDERATIONS
12.1.
Hypotheses
12.1.1.
Part 1: Dose-Escalation Phase
No formal statistical hypotheses are being tested for the dose escalation in Part 1. 
Analysis of the data obtained from dose escalation of Part 1 will utilize descriptive 
methods only. 
The cohort expansion of GCB-DLBCL subjects in Part 1 will assess the overall response 
rate (p) of GCB-DLBCL patients. The null and alternative hypotheses for the overall 
response rate are detailed below:
The null hypothesis is:
H0: p≤20%
The alternative hypothesis is:
HA: p≥40%
For cohort expansion of solid tumor subjects in Part 1, there is no formal statistical 
hypothesis are being tested. Analysis of the data obtained from solid tumor expansion
will utilize descriptive methods only. 
12.1.2.
Part 2: Expansion Cohorts
The null hypothesis and alternative hypothesis for the four expansion cohorts of GCB-
DLBCL and tFL patients in Part 2 are same as those in Part 1. That is, for each cohort:
The null hypothesis is:
H0: p≤20%
The alternative hypothesis is:
HA: p≥40%
For MM cohort, the null hypothesis is:
H0: p≤10%
The alternative hypothesis is:
HA: p≥25%


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12.2.
Sample Size Determination
The sample size planned for Part 1 arises from the predefined criteria for dose selection 
and is not driven by statistical considerations. 
In addition, Part 1 expansion may include up to 27 GCB-DLBCL subjects at MTD/RP2D
twice-weekly for 3 out of 4 weeks followed by 1 week off. This will allow 
futility/success analysis with type I error rate no more than 0.1and at least 80% of power. 
Additionally, 15 subjects with solid tumors or prostate cancer may be enrolled for the 
evaluation of safety, futility and efficacy. 
The additional 168 subjects in Part 2 of the study (which includes up to 32 subjects each 
for the EZH2 mutant and EZH2 WT GCB-DLBCL populations, and up to 32 subjects 
each for EZH2 mutant and EZH2 WT tFL populationsas well as up to 40 MM subjects) 
will provide additional safety and tolerability information about the treatment and a better 
precision around the response rate estimate.
Approximately 168 subjects will be enrolled in Part 2 in five expansion cohorts: two 
GCB-DLBCL cohorts with up to 32 subjects from the EZH2 wild-type population, and 
up to 32 subjects from the EZH2 mutation positive population, and two tFL cohorts with 
up to 32 subjects from the EZH2 wild-type population and up to 32 subjects from the 
EZH2 mutation positive population and up to 40 subjects in the MM cohort.  Additional 
subjects/cohorts may be enrolled to allow for evaluation of additional dose levels. 
12.2.1.
Part 1: Dose-Escalation Phase
12.2.1.1.
Dose Escalation in Part 1
The total number of subjects to be enrolled for dose escalation in Part 1 will depend on 
the number of subjects needed to characterize individual dose cohorts. The sample size is 
not driven by statistical considerations. However, it is anticipated that approximately 40 
subjects will be enrolled.  Given true incidence rates of DLTs, the associated probabilities
of escalating to the next dose in a 3+3 scheme are provided for reference below in Table 
15.
Table 15
Statistical Basis for Phase I Dose Escalation in a 3+3 Scheme
True incidence of dose-limiting toxicity
10%
20%
30%
40%
50%
60%
Probability of escalating the dose
0.91
0.71
0.49
0.31
0.17
0.08
12.2.1.2.
Cohort Expansion in Part 1
For GCB-DLBCL expansion cohort in Part 1, futility and efficacy evaluation of response 
data will be performed in order to support the early decision of Part 2 expansion. The 
sample size and stopping rules are based on the predictive probability methodology of 
Lee & Liu [Lee, 2008]. The predictive probability design is similar to a two-stage design 
in that it allows for early termination of the trial due to either futility or efficacy.  The 


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differences are that the predictive probability design allows for evaluation of stopping 
rules on an on-going basis, once a minimum number of subjects are evaluable, rather than 
at only two stages. While the two designs have comparable type I error rates and power,
the probability of early termination is greater with the predictive probability design
compared with two-stage design.
The detailed decision rules of the design for Part 1 expansion cohort are listed in Table 
16. The decision rules to stop the trial for either futility or efficacy were constructed as 
follows:

If Predictive probability of response greater than the null hypothesis<θL, then stop the 
trial and reject the alternative hypothesis (i.e., claim futility); and 

If Predictive probability of response greater than the null hypothesis >θU, then stop 
the trial and reject the null hypothesis (i.e., declare efficacy);

Otherwise continue enrollment,
Where θL and θU are prespecified lower and upper limit of probabilities for establishing 
stopping criteria in terms of futility and efficacy, respectively.
The hypothesis of overall response rate (p) of GCB-DLBCL subjects for the cohort 
expansion design are detailed below. 
The null hypothesis is:
H0: p≤20%
The alternative hypothesis is:
HA:p≥40%
As listed in Table 16, the futility/efficacy evaluation will start with 13 subjects and allow 
for maximum of 27 subjects (including GCB-DLBCL subjects enrolled at the RP2D in 
the dose escalation phase.) This design will have a type I error rate () of 0.087 and a 
power of 0.803.  In this particular expansion part, the trial is designed to allow stopping
for both futility and efficacy.  The trial may be stopped early for futility if the predictive 
probability of the overall response rate greater than the null hypothesis of 20% is very 
low, i.e.below 5.0% for this design, and may be stopped early for efficacy if the 
predictive probability of the overall response rate greater than 20%  is very high, i.e.
90.0% or above.  The type I error rate, power, and predictive probability of success were 
derived by explicitly stating null and alternative hypothesis of response rate, the 
minimum and maximum sample size, futility and efficacy stopping boundaries and the 
selection of the optimizing criterion as the maximization of power under the alternative 
hypothesis.  The Bayesian prior used in determining the design was Beta (0.15, 0.85), a 
distribution with a mean response rate of 15%.  Under the null hypothesis, that is, if the 
true response rate is 20%, the expected sample size of the design is 16.48 subjects and 
probability of early termination (PET) is 96.3%.  Under the alternative hypothesis, that is,


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if the true response rate is at least 40%, the expected sample size of the design is 16.98
subjects and PET is 94.7%.
The input parameters for finding the design shown in Table 16 are:
Nmin
13
Cohort
1
Nmax
27
theta_Lbegin
0.05
theta_Lend
0.05
theta_Lstep
0.001
theta_Upper
0.9
theta_Tbegin
0.9
theta_Tend
0.9
theta_Tstep
0.001
p_0
0.2
p_1
0.4
Prior a0
0.15
Prior b0
0.85
Type I Error
0.1
Power
0.8
Table 16
Stopping Rules for GSK2816126 Part 1 GCB-DLBCL Cohort 
Expansion
No. of Subjects Evaluated 
for Response
Stopping  Criteria [1]
Stop for Futility if No. of 
Responders (CR+PR) Less 
Than or Equal To This Number
Declaration of Efficacy if No. of 
Responders (CR+PR) Greater 
Than or Equal To This Number
13
2
6
14
2
7
15
2
7
16
3
7
17
3
7
18
3
8
19
4
8
20
4
8
21
5
8
22
5
9
23
5
9
24
6
9


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No. of Subjects Evaluated 
for Response
Stopping  Criteria [1]
Stop for Futility if No. of 
Responders (CR+PR) Less 
Than or Equal To This Number
Declaration of Efficacy if No. of 
Responders (CR+PR) Greater 
Than or Equal To This Number
25
6
9
26
7
9
27
8
9
[1]:  The specific criteria for stopping the GCB-DLBCL expansion cohort for futility or efficacy.  For instance, if there are 
20 subjects, then the trial may be stopped for futility if No. of Responders ≤4, or Part 2 opened for efficacy if No. of 
Responders ≥8.
12.2.2.
Part 2: Expansion Cohort
Upon completion of cohort expansion in Part 1 and the totality of data supports opening 
Part 2, GCB-DLBCL and tFL patients in both mutation status, as well as patients with 
MM will be enrolled at RP2D for Part 2 study. There are 5 cohorts in Part 2, i.e. 2 cohorts 
for GCB-DLBCL patients (mutant and wild type), 2 cohorts for tFL petients (mutant and 
wild type), and 1 cohort for MM patients.
For each of GCB-DLBCL and tFL cohorts, at least 10 subjects and up to 32 subjects will 
be enrolled at the RP2D (including subjects enrolled in the previous stage), using 
decision rules defined in Table 17. The sample size and stopping rules are based on the 
methodology of Lee & Liu [Lee, 2008]. 
The assumptions underlying the design are detailed below for GCB-DLBCL and tFL 
cohorts. The null hypothesis is:
H0: p≤20%
The alternative hypothesis is:
HA:p≥40%
As listed in Table 17, the futility/efficacy evaluation will start with 10 subjects and until
maximum of 32 subjects. This design allows to stop early for futility only. The design 
will have a type I error rate () of 0.066 and a power of 0.801.  The trial may be stopped 
early for futility if the predictive probability of the overall response rate greater than the 
null hypothesis of 20%  is below 10% for this design. The type I error rate, power, and 
predictive probability of success were derived by explicitly stating null and alternative 
hypothesis of response rate, the minimum and maximum sample size, futility and efficacy 
stopping boundaries and the selection of the optimizing criterion as the maximization of 
power under the alternative hypothesis.  The Bayesian prior used in determining the 
design was Beta (0.15, 0.85), a distribution with a mean response rate of 15%.  Under the 
null hypothesis, that is, if the true response rate is 20%, the expected sample size of the 
design is 16.06 subjects and probability of early termination (PET) is 90.8%.  Under the 


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alternative hypothesis, that is, if the true response rate is at least 40%, the expected 
sample size of the design is 29.16 subjects and PET is 18.1%.
The input parameters for the design shown in Table 17 are:
Nmin
10
Cohort
1
Nmax
32
theta_Lbegin
0.1
theta_Lend
0.1
theta_Lstep
0.001
theta_Upper
1
theta_Tbegin
0.9
theta_Tend
0.9
theta_Tstep
0.001
p_0
0.2
p_1
0.4
Prior a0
0.15
Prior b0
0.85
Type I Error
0.1
Power
0.8
Table 17
Stopping Rules for GSK2816126 GCB-DLBCL and tFL Cohort
Expansion in Part 2
Number of evaluable 
subjects
Stop for Futility if No. of Responders 
(CR+PR) Less Than or Equal To This Number
10
1
11
1
12
2
13
2
14
2
15
3
16
3
17
3
18
3
19
4
20
4
21
4
22
5


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Number of evaluable 
subjects
Stop for Futility if No. of Responders 
(CR+PR) Less Than or Equal To This Number
23
5
24
5
25
6
26
6
27
6
28
7
29
7
30
8
31
8
32
9
For MM cohort, at least 14 subjects and up to 40 subjects will be enrolled at the RP2D, 
using decision rules defined in Table 18. The sample size and stopping rules are based on 
the methodology of Lee & Liu [Lee, 2008]. The null hypothesis underlying the design is:
H0: p≤10%
The alternative hypothesis is:
HA; p25%
The input parameters for the design shown in Table 18 are:
Nmin
14
Cohort
1
Nmax
40
theta_Lbegin
0.1
theta_Lend
0.1
theta_Lstep
0.001
theta_Upper
1
theta_Tbegin
0.9
theta_Tend
0.9
theta_Tstep
0.001
p_0
0.1
p_1
0.25
Prior a0
0.1
Prior b0
0.9
Type I Error
0.1
Power
0.8


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Table 18
Stopping Rules for GSK2816126 Cohort Expansion of MM Subjects 
in Part 2
Number of evaluable subjects
Stop for Futility if No. of Responders 
(CR+PR) Less Than or Equal To This 
Number
14
1
15
1
16
1
17
1
18
1
19
1
20
1
21
2
22
2
23
2
24
2
25
2
26
2
27
3
28
3
29
3
30
3
31
3
32
4
33
4
34
4
35
4
36
4
37
5
38
5
39
5
40
6
As listed in Table 18, the futility/efficacy evaluation will start with 14 subjects until
maximum of 40 subjects (including MM subjects enrolled at the RP2D in the dose 
escalation phase, if any). This design allows to stop early for futility only. The design will 
have a type I error rate () of 0.072 and a power of 0.814.  The trial may be stopped early 
for futility if the predictive probability of the overall response rate greater than the null 
hypothesis of 10%  is below 10% for this design. The type I error rate, power, and 
predictive probability of success were derived by explicitly stating null and alternative 
hypothesis of response rate, the minimum and maximum sample size, futility and efficacy 


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stopping boundaries and the selection of the optimizing criterion as the maximization of 
power under the alternative hypothesis.  The Bayesian prior used in determining the 
design was Beta (0.10, 0.90), a distribution with a mean response rate of 10%.  Under the 
null hypothesis, that is, if the true response rate is 10%, the expected sample size of the 
design is 20.82 subjects and probability of early termination (PET) is 89.0%.  Under the 
alternative hypothesis, that is, if the true response rate is at least 25%, the expected 
sample size of the design is 36.56 subjects and PET is 16.7%.
12.3.
Data Analysis Considerations
Data will be listed and summarized according to the GSK reporting standards, where
applicable.  Complete details will be documented in the Reporting and Analysis Plan 
(RAP).  Any deviations from, or additions to, the original analysis plan described in this 
protocol will be documented in the RAP and final study report.
12.3.1.
Analysis Populations
All Subjects Population: This will consist of all subjects who received at least one dose 
of study treatment.  Safety and clinical activity analyses will be evaluated based on this 
population.
The PK Concentration Population: This will consist of those subjects in All Subjects 
Population for whom a PK sample is obtained and analyzed.
12.3.2.
Analysis Data Sets
The construction of analysis data sets will be performed in accordance with all applicable 
GSK standards and procedures.
12.3.3.
Treatment Comparisons
No formal hypothesis testing will be performed between dose cohorts. Safety, PK, PD 
marker, and efficacy summaries will be provided by dose cohort and planned time of 
assessment in Part 1 and by expansion cohort and planned time of assessment in Part 2.
12.3.3.1.
Primary Comparisons of Interest
All available data, including adverse events, changes in laboratory values and other safety 
parameters will be evaluated for each dose cohort in Part 1, in addition to futility and 
success analyses, and for each expansion cohort in Part 2.
12.3.3.2.
Other Comparisons of Interest

PK: PK parameters will be evaluated and summarized for each dose cohort in Part 1. 

PD marker: Changes from baseline in PD markers will be evaluated and summarized 
for each dose cohort in Part 1 and for each cohort in Part 2.


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
Clinical anti-cancer activity: The number of subjects with complete responses, partial 
responses, stable disease, and progressive disease for each dose cohort in Part 1 and 
for each expansion cohort in Part 2 will be listed and summarized if data warrant. 
12.3.4.
Interim Analysis
12.3.4.1.
Part 1
Futility and efficacy interim analysis of overall response rate will be performed 
continuously for GCB-DLBCL expansion cohort in Part 1 of the study, after 13 subjects 
have been enrolled.  In addition, safety, PK, and PD marker data will be examined during 
Part 1. Prior to determining the GSK2816126 dose for the next cohort, exploratory 
analyses will be conducted to assess the relationship of GSK2816126 dose levels with 
safety, PK and PD parameters using all data from available cohorts. If success criteria are 
reached at an interim analysis for GCB-DLBCL at MTD/RP2D twice-weekly every 3 out 
of 4 weeks followed by 1 week off, and the totality of data support opening Part 2, then 
Part 2 will begin and Part 1 expansion will close. 
Full details of procedures and of the analyses planned at the interim analysis will be 
provided in the Reporting and Analysis Plan (RAP).
12.3.4.2.
Part 2
For each expansion cohort, after the initial 10 subjects have enrolled at the RP2D dose, 
response data will be reviewed on an ongoing basis and the number of responses 
observed will be compared with the stopping rules provided in Section 12.2.2. In 
addition, safety, PK, and PD marker data will be analyzed. Full details of procedures and 
of the analyses planned at the interim analysis will be provided in the Reporting and 
Analysis Plan (RAP).
12.3.5.
Final Analyses
12.3.5.1.
Safety Analyses
Safety endpoints are described in Section 2.  The All Subjects population will be used for 
the analysis of safety data.  All serially collected safety endpoints (e.g., laboratory tests, 
vital signs, ECGs) will be summarized according to the scheduled, nominal visit at which 
they were collected and across all on-treatment time points using a “worst-case” analysis.  
Complete details of the safety analyses will be provided in the RAP.
A listing by subject including treatment administered and compliance will be generated 
with dates and times of treatment administered. 
All relevant safety data will be listed and summarized according to current standards. 
The RAP will list the templates for the displays.  All AEs will be listed.  A summary of 
the number and percent of subjects reporting each AE at least once will be produced for 


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all AEs, for drug-related AEs and for SAEs for Part 1 (for each dose cohort) and Part 2.  
A listing of those AEs identified as dose-limiting toxicities will also be produced for each 
dose cohort for Part 1.  A listing showing the relationship of AE verbatim text to group 
terms and body systems will also be produced.  A listing of withdrawals due to AEs will 
be provided.  Deaths and SAEs will be listed should they occur.
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.
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.
12.3.5.2.
Clinical Laboratory Evaluations
Hematology and clinical chemistry data will be summarized using frequencies and 
proportions according to NCI-CTCAE v4.0 grade [NCI-CTCAE, 2009].  Laboratory test 
results outside the reference ranges that do not have associated NCI-CTCAE criteria will 
be summarized using proportions.  Summaries will include data from scheduled 
assessments only, and all data will be reported according to the nominal visit date for 
which it was recorded (i.e., no visit windows will be applied).  Unscheduled data will be 
included in “overall” and “any post-screening” summaries which will capture a worst 
case across all scheduled and unscheduled visits post first dose of study treatment.  
Further details will be provided in the RAP.
12.3.5.3.
Pharmacokinetic Analyses
Pharmacokinetic analyses will be the responsibility of the Clinical Pharmacology, 
Modeling and Simulation Department, GSK.
12.3.5.3.1. Non-compartmental Pharmacokinetic Analyses
Pharmacokinetic analysis of GSK2816126 in Part 1 will be conducted by non-
compartmental methods. The following pharmacokinetic parameters will be determined if 
data permit:

maximum observed plasma concentration (Cmax)

time to Cmax (tmax)

area under the plasma concentration-time curve [AUC from time zero (pre-dose) 
to last time of quantifiable concentration, AUC(0-t) and/or AUC from time zero 
(pre-dose) extrapolated to infinite time AUC(0-∞)] after single dose and AUC(0-
t) and AUC over the dosing interval [AUC(0-tau)] after repeated administration

apparent terminal phase elimination rate constant (λz)

apparent terminal phase half-life (t½)

clearance (CL)

volume (V)


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To estimate the extent of accumulation after repeat dosing, the observed accumulation 
ratio (Ro) may be determined from the ratio of AUC(0-) in Day 15 / AUC(0-) in Day 1.  
The ratio of AUC(0-) on Day 15 / Day 1 AUC(0-∞) will be calculated to assess time 
invariance. 
GSK2816126 concentrations will be determined in urine samples to determine urinary 
recovery of unchanged drug and renal clearance.
12.3.5.3.2. Metabolic Profiling
In a subset of subjects, blood samples will be pooled and analyzed qualitatively for 
circulating metabolites; 0-24 hour urine samples will also be analyzed for GSK2816126 
and compound related metabolites. These results will be performed under a separate 
DMPK protocol and reported separately.
12.3.5.3.3. Population Pharmacokinetics
Blood concentration-time data from Part 2 (Expansion Cohorts) will be combined with 
data from Part 1 and analyzed using a population approach. A nonlinear mixed effects 
model will be used to determine population pharmacokinetic parameters and identify 
relevant covariates (e.g., age, weight, or disease related covariates).
12.3.5.3.4. Statistical Analyses of Pharmacokinetic Data
Statistical analyses of the PK parameter data will be the responsibility of Discovery 
Biometrics, Oncology, GSK.
GSK2816126 concentration-time data will be listed for each subject and summarized by 
planned time point and dose cohort in Part 1 and by planned time point and expansion 
cohort in Part 2.
Pharmacokinetic parameters will be listed and summarized descriptively (mean, standard 
deviation, median, minimum, maximum, geometric mean (excluding tmax), and the 
standard deviation, CV% and 95% confidence interval (CI) of log-transformed 
parameters) by dose cohort in Part 1.
Dose Proportionality: If more than 2 dose cohorts are required to reach RP2D, dose 
proportionality of GSK2816126 AUC(0-∞) and Cmax following single dose 
administration and AUC(0-tau) and Cmax following repeat dose administration will be 
evaluated graphically and using the power model as described below:
Where a is the intercept and b is the slope.


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The power model will be fitted by restricted maximum likelihood using statistical 
analysis software (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% CI will be estimated 
from the power model.
12.3.5.4.
Efficacy Analyses
Anti-tumor activity for lymphoma subjects will be assessed based on the Response 
Criteria listed in Section 15.4.  Anti-tumor activity for subjects with solid tumors will be 
assessed based on the Response Criteria listed in 15.5. Anti-tumor activity for subjects 
with MM will be assessed based on the Response Criteria listed in 15.6.  Anti-tumor 
activity for subjects with prostate cancer will be assessed based on the Response Criteria 
listed in 15.7. The response data will be summarized by study part, and cohort within Part
2.  Full details will be specified in the RAP.
If the data warrant, PFS and DoR will be calculated and listed for each subject in Part 1 
and Part 2. PFS is defined as time from the date of first dose to the date of disease 
progression according to clinical or radiological assessment or death due to any causes, 
whichever occurs earliest.  DoR is defined as the interval of time from first documented 
evidence of CR or PR until disease progression or death due to any cause.If the subject 
does not have a documented date of event, PFS will be censored at the date of the last
adequate assessment.  Further details on rules of censoring will be provided in the RAP.  
PFS will be summarized using the Kaplan-Meier method if the data warrant.
12.3.6.
PK/PD Relationship
Observed or predicted concentrations or exposure measures (Cmax, C, AUC, or 
averaged observed concentration [Cav]) will be combined with safety, efficacy, 
exploratory markers and/or PD measures of interest to examine potential exposure 
response relationships.
The relationships will first be explored graphically. Where evidence of a signal is seen, 
linear and non-linear models may be fitted to the data to estimate PK/PD parameters of 
interest; slope, baseline (E0), EC50, and maximum effect (Emax).
12.3.7.
Pharmacodynamic Biomarkers and Exploratory Response 
Prediction Biomarkers
As data warrant, analyses may be performed to explore the relationship between 
biomarkers (i.e., somatic mutations), subject baseline characteristics, and other clinical 
outcomes. All endpoints of interest will be descriptively and/or graphically summarized 
as appropriate to the data. 
As data warrant, analyses may be performed to determine relationships between 
circulating and tumor biomarkers, expression and clinical response, activity, or resistance 
to GSK2816126.


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The results of exploratory biomarker research investigations will be reported separately 
from the main clinical study report. Full details will be provided in a RAP.
13.
STUDY CONDUCT CONSIDERATIONS
13.1.
Posting of Information on Clinicaltrials.gov
Study information from this protocol will be posted on clinicaltrials.gov before 
enrollment of subjects begins.
13.2.
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 International Council on 
Harmonization/Good Clinical Practice (ICH/GCP) and applicable country-specific 
regulatory requirements.
The study will be conducted in accordance with all applicable regulatory requirements.
The study will be conducted in accordance with ICH GCP, all applicable subject privacy 
requirements, and the ethical principles that are outlined in the Declaration of Helsinki 
2008, including, but not limited to:

IRB/EC review and approval of study protocol and any subsequent amendments

Subject informed consent

Investigator reporting requirements
GSK will provide full details of the above procedures, either verbally, in writing, or both.
Written informed consent must be obtained from each subject prior to participation in the 
study.
In approving the clinical protocol the IEC/IRB and, where required, the applicable 
regulatory agency are also approving the optional assessments, e.g. genetic research
described in Appendix 5, unless otherwise indicated.  Where permitted by regulatory 
authorities, approval of the optional assessments can occur after approval is obtained for 
the rest of the study.  If so, then the written approval will clearly indicate approval of the 
optional assessments is being deferred and the study, except for the optional assessments, 
can be initiated.  When the optional assessments are not approved, then the approval for 
the rest of the study will clearly indicate this and therefore, the optional assessments will 
not be conducted.
13.3.
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 


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investigator will take appropriate urgent safety measures to protect subjects against any 
immediate hazard.
The Sponsor will work with the investigator to ensure the IRB/EC is notified.
13.4.
Quality Control (Study Monitoring)
In accordance with applicable regulations, GCP and GSK procedures, the site will be 
contacted prior to the start of the study to review with the site staff the protocol, study 
requirements, and their responsibilities to satisfy regulatory, ethical, and GSK 
requirements.  When reviewing data collection procedures, the discussion will include 
identification, agreement and documentation of data items for which the eCRF will serve 
as the source document.
The investigator and the head of the medical institution (where applicable) agrees to 
allow the monitor direct access to all relevant documents and to allocate their time and 
the time to their staff to monitor to discuss findings and any issues.
Monitoring visits will be conducted in a manner to ensure that the:

Data are authentic, accurate, and complete.

Safety and rights of subjects are being protected.

Study is conducted in accordance with the currently approved protocol and any other 
study agreements, ICH GCP, and all applicable regulatory requirements.
13.5.
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.
13.6.
Study and Site Closure
The end of the study will be defined as the date of the last visit of the last subject 
enrolled.
Upon completion or termination of the study, the monitor will conduct site closure 
activities with the investigator or site staff (as appropriate), in accordance with applicable 
regulations, ICH/ GCP, and GSK Standard Operating Procedures.
GSK reserves the right to temporarily suspend or terminate the study at any time for 
reasons including (but not limited to) safety issues, ethical issues, or severe 
noncompliance.  If GSK determines that such action is required, GSK will discuss the 
reasons for taking such action with the investigator or head of the medical institution 
(where applicable).  When feasible, GSK will provide advance notice to the investigator 
or head of the medical institution of the impending action.


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If a study is suspended or terminated for safety reasons, GSK will promptly inform all 
investigators, heads of the medical institutions (where applicable),and/or institutions 
conducting the study.  GSK will also promptly inform the relevant regulatory authorities 
of the suspension/termination along with the reasons for such action.  Where required by 
applicable regulations, the investigator or head of the medical institution must inform the 
IRB/EC promptly and provide the reason(s) for the suspension/termination.
GSK may also close study sites which fail to recruit subjects within a predefined 
timeframe, as defined within the Study Procedures Manual (SPM).
13.7.
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.
13.8.
Provision of Study Results to Investigators, Posting of 
Information on Publicly Available Clinical Trials Registers 
and Publication
Where required by applicable regulatory requirements, an investigator signatory will be 
identified for the approval of the clinical study report.  The investigator will be provided 
reasonable access to statistical tables, figures, and relevant reports and will have the 
opportunity to review the complete study results at a GSK site or other mutually-
agreeable location.


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GSK will also provide the investigator with the full summary of the study results.  The 
investigator is encouraged to share the summary results with the study subjects, as 
appropriate.
The results summary will be posted to the GSK Clinical Study Register no later than 8 
months after the final primary completion date, the date that the final subject was 
examined or received an intervention for the purposes of final collection of data for the 
primary outcome.  In addition, a manuscript will be submitted to a peer reviewed journal 
for publication no later than 18 months after the last subject’s last visit (LSLV).  When 
manuscript publication in a peer-reviewed journal is not feasible, a statement will be 
added to the register to explain the reason for not publishing.


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14.
REFERENCES
Berezovska, O.P., Glinskii, A.B., Yang, Z., Li, X.M., Hoffman, R.M., and Glinsky, G.V. 
(2006). Essential role for activation of the Polycombgroup (PcG) protein chromatin 
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Bodor C, Grossmann V, Popov N et al. EZH2 mutations are frequent and represent an 
early event in follicular lymphoma. Blood 2013; 122:3165-8.
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.
Dardenne E, Beltran H, Benelli M, Gayvert K, Berger A, Puca L, et al., 2016, Cancer 
Cell 30, 563–577
Ernst T, Chase AJ, Score J, et al. Inactivating mutations of the histone methyltransferase 
gene EZH2 in myeloid disorders. Nat Genet 2010; 42:722-6.
Friedberg JW, Taylor MD, Cerhan JR, et al. ... Transformed follicular non-Hodgkin
lymphoma. Blood. 2015;125(1):40–47
GlaxoSmithKline Document Number 2013N169204_04. Version 04. GSK2816126 
Investigator’s Brouchure. Report Date: 25-Jan-2017
Guiney WJ, Beaumont C, Thomas SR, et al. Use of Entero-Test, a simple approach for 
non-invasive clinical evaluation of the biliary disposition of drugs. Br J Clin Pharmacol. 
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Hoffmann, M.J., Engers, R., Florl, A.R., Otte, A.P., Muller, M., and Schulz, W.A. 
(2007). Expression changes in EZH2, but not in BMI- 1, SIRT1, DNMT1 or DNMT3B 
are associated with DNA methylation changes in prostate cancer. Cancer Biolo Ther 6, 
1403–1412.
Kronenberg HM, Melmed S, Polonsky KS, Larsen PR, editors. Williams Textbook of
Endocrinology, 11th edition. Philadelphia: Saunders, 2008.
Kumar-Sinha, C., Tomlins, S.A., & Chinnaiyan, A.M. (2008) Recurrent gene fusions in 
prostate cancer. Nat Rev Cancer, Vol. 8 No.7, (Jul), pp. 497-551
Lee JJ, Liu DD (2008).  A predictive probability design for Phase II cancer clinical trials.  
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McCabe MT & Creasy CL. EZH2 as a potential target in cancer therapy. Epigenomics 
2014; 6:341-51.
McCabe, MT, Ott, HM, Ganji, G, et al. EZH2 inhibition as a therapeutic strategy for 
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Morin RD, Johnson NA, Severson TM, et al. Somatic mutations altering EZH2 (Tyr641) 
in follicular and diffuse large B-cell lymphomas of germinal-center origin. Nat Genet 
2010; 42:181-5.
Morin RD, Mendez-Lago M, Mungall AJ, et al. Frequent mutation of histone-modifying 
genes in non-Hodgkin lymphoma. Nature 2011; 476:298-303.
Morschhauser, F, Sallas G, et al. Initial Safety and Efficacy Report from Phase 2 Global, 
Multicenter Study of Tazemetostat in Patients with Relapsed or Refractory (R/R)
NonHodgkin Lymphoma (NHL).  American Society for Hematology 2016 Meeting on 
Lymphoma Biology. June 19-21, 2016
NCI-CTCAE (NCI Common Terminology Criteria for Adverse Events), Version 4.0, 
DCTD, NCI, NIH, DHHS, 28 May 2009.
Neuenschwander B, Branson M, Gsponer T (2008).  Critical aspects of the Bayesian 
approach to phase I cancer trials.  Statist Med. 27:2420-2439.
Pasqualucci L, Trifonov V, Fabbri G, et al. Analysis of the coding genome of diffuse 
large B-cell lymphoma. Nat Genet 2011; 43:830-7.
Saramaki, O.R., Tammela, T.L., Martikainen, P.M., Vessella, R.L., and Visakorpi, T. 
(2006). The gene for polycomb group protein enhancer of zeste homolog 2 (EZH2) is 
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15.
APPENDICES
15.1.
Appendix 1: COCKCROFT-GAULT FORMULA
ClCr (mL/min) =  
Q x (140 - age[yr]) x ideal body weight [kg]*
72 x serum creatinine [mg/dL]
Q = 0.85 for females
Q = 1.0 for males
OR
ClCr (mL/min) =  
K x (140 - age[yr]) x ideal body weight [kg]*
Serum creatinine [umol/L]
K = 1.0 for females  
K = 1.23 for males
*Calculation of Ideal Body Weight Using the Devine Formula [Devine, 1974]
Ideal body weight:
Males = 
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)
Females = 
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)
Example:
Male, actual body weight = 90.0 kg, height = 68 inches
Ideal body weight = 50.0 + (2.3) (68-60) = 68.4 kg.
This subject’s actual body weight is >30% over ideal body weight.  Therefore, in this case, the 
subject’s ideal body weight of 68.4 kg should be used in calculating estimated CrCl.
Reference
Devine, BJ.  Case Number 25 Gentamicin Therapy: Clinical Pharmacology Case Studies.  
Drug Intelligence and Clinical Pharmacy. 1974; 8:650-655.


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15.2.
Appendix 2: ECOG Performance Status1
CCI - This section contained Clinical Outcome Assessment data collection questionnaires or indices, which are protected by third 
party copyright laws and therefore have been excluded.


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15.3.
Appendix 3: Liver Chemistry Monitoring, Interruption 
Stopping and Follow-up Criteria
15.3.1.
Liver Safety Stopping Criteria and Required Action and Follow up 
Assessments
Phase I/II liver chemistry stopping and increased monitoring criteria have been 
designed to assure subject safety and evaluate liver event etiology (in alignment with the 
FDA premarketing clinical liver safety guidance). 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM174090.pdf.
Phase I/II liver chemistry stopping criteria and required follow up assessments 
Liver Chemistry Stopping Criteria – Liver Stopping Event
Subject with entry criteria ALT≤ 2.5 x ULN
ALT-absolute
ALT 5xULN
ALT Increase
ALT 3xULN persists for 4 weeks
Bilirubin1, 2
ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin) 
INR2
ALT 3xULN and INR>1.5, if INR measured
Cannot Monitor
ALT 3xULN and cannot be monitored weekly for 4 weeks
Symptomatic3
ALT 3xULN associated with symptoms (new or worsening) believed to be related 
to liver injury or hypersensitivity
Liver Chemistry Stopping Criteria – Liver Stopping Event
Including subjects with documented liver metastases/tumor infiltration at baseline AND 
entry criteria ALT>2.5 x ULN but ≤5 x ULN
ALT-absolute
Both ALT 5xULN and 2x baseline value
ALT Increase
Both ALT 3xULN and ≥ 1.5x baseline value that persists for 4 weeks
Bilirubin1, 2
ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin) 
INR2
ALT 3xULN and INR>1.5, if INR measured
Cannot Monitor
Both ALT 3xULN and ≥1.5x baseline value that cannot be monitored for 4 weeks
Symptomatic3
Both ALT 3xULN and ≥1.5x baseline value associated with symptoms (new or 
worsening) believed to be related to liver injury or hypersensitivity
Required Actions and Follow up Assessments following ANY Liver Stopping Event


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


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will not apply to subjects receiving anticoagulants
3.
New or worsening symptoms believed to be related to liver injury (such as fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, or jaundice) or believed to be related to hypersensitivity (such as fever, rash or 
eosinophilia)
4.
Includes: Hepatitis A IgM antibody; Hepatitis B surface antigen and Hepatitis B Core Antibody (IgM); Hepatitis C 
RNA; Cytomegalovirus IgM antibody; Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, obtain 
heterophile antibody or monospot testing); Hepatitis E IgM antibody 
5.
Record the date/time of the PK blood sample draw and the date/time of the last dose of study treatment prior to 
blood sample draw on the eCRF. If the date or time of the last dose is unclear, provide the subject’s best 
approximation. If the date/time of the last dose cannot be approximated OR a PK sample cannot be collected in 
the time period indicated above, do not obtain a PK sample. Instructions for sample handling and shipping are in 
the SRM.
Phase I/II Oncology liver chemistry increased monitoring criteria with continued 
therapy
Liver Chemistry Increased Monitoring Criteria – Liver Monitoring Event
Criteria
Actions
Subject with entry criteria ALT≤2.5x ULN
ALT 3xULN but <5xULN and
bilirubin <2xULN, without symptoms believed 
to be related to liver injury or hypersensitivity 
and who can be monitored weekly for 4 weeks
Subject with documented liver 
metastases/tumor infiltration at baseline 
AND entry criteria ALT>2.5 x ULN but ≤5 x 
ULN
ALT ≥3x ULN and 1.5x baseline value but ALT 
<5x ULN and 2x baseline value and bilirubin 
<2xULN, without symptoms believed to be 
related to liver injury, or hypersensitivity and
who can be monitored weekly for 4 weeks

Notify the GSK medical monitor within 24 hours of 
learning of the abnormality to discuss subject 
safety. 

Subject can continue study treatment

Subject must return weekly for repeat liver 
chemistries (ALT, AST, alkaline phosphatase, 
bilirubin) until they resolve, stabilise or return to 
within baseline1

If at any time subject meets the liver chemistry 
stopping criteria, proceed as described above
For subjects with entry criteria ALT≤2.5 x ULN

If, after 4 weeks of monitoring, ALT <3xULN and 
bilirubin <2xULN, monitor subjects twice monthly 
until liver chemistries normalize or return to within 
baseline.
For subjects with documented liver 
metastases/tumor infiltration at baseline AND entry 
criteria ALT>2.5 x ULN but ≤5 x ULN

If, after 4 weeks of monitoring, ALT <3xULN and 
<1.5x baseline value, and bilirubin <2xULN, monitor 
subjects twice monthly until liver chemistries 
normalize or return to within baseline
1.
For the purpose of these guidelines “baseline” refers to laboratory assessments performed closest and prior to 
first dose of study treatment


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References
James LP, , Letzig L, Simpson PM, Capparelli E, Roberts DW, Hinson JA, Davern TJ, 
Lee WM. Pharmacokinetics of Acetaminophen-Adduct in Adults with Acetaminophen 
Overdose and Acute Liver Failure. Drug Metab Dispos 2009; 37:1779-1784.
15.3.2.
Liver Safety – Study Treatment Restart or Rechallenge 
GuidelinesIf subject meets liver chemistry stopping criteria do 
not restart/rechallenge subject with study treatment unless:

GSK Medical Governance approval is granted (as described below),

Ethics and/or IRB approval is obtained, if required, and

Separate consent for treatment restart/rechallenge is signed by the subject
If GSK Medical Governance approval to restart/rechallenge subject with study treatment 
is not granted, then subject must permanently discontinue study treatment and may 
continue in the study for protocol-specified follow up assessments
1. Rechallenge Following Liver Stopping Events that are Possibly Related to 
Study Treatment
Following drug-induced liver injury, drug rechallenge is associated with a 13% 
mortality across all drugs in prospective studies [Andrade, 2009]. Clinical outcomes 
vary by drug, with nearly 50% fatality with halothane readministered within one month 
of initial injury. However, some drugs seldom result in recurrent liver injury or fatality. 
Risk factors for a fatal drug rechallenge outcome include:

hypersensitivity with initial liver injury (e.g. fever, rash, eosinophilia) 
[Andrade, 2009] 

jaundice or bilirubin >2xULN with initial liver injury (direct bilirubin >35% of 
total)

subject currently exhibits severe liver injury defined by: ALT 3xULN, 
bilirubin 2xULN (direct bilirubin >35% of total), or INR1.5

serious adverse event or fatality has earlier been observed with drug 
rechallenges [Papay, 2009]

evidence of drug-related preclinical liability (e.g. reactive metabolites; 
mitochondrial impairment [Hunt, 2010])
Rechallenge refers to resuming study treatment following drug induced liver injury 
(DILI). Because of the risks associated with rechallenge after DILI this should only be 
considered for a subject for whom there is compelling evidence of benefit from a critical 
or life-saving medicine, there is no alternative approved medicine available, and a 
benefit:risk assessment of rechallenge is considered to be favourable.


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Approval by GSK for rechallenge with study treatment can be considered where:

Investigator requests consideration of rechallenge with study treatment for a subject 
who is receiving compelling benefit with study treatment that exceeds risk, and no 
effective alternative therapy is available. 

Ethics Committee or Institutional Review Board approval for rechallenge with study 
treatment must be obtained, as required.  

If the rechallenge is approved by GSK Medical Governance in writing, the subject 
must be provided with a clear description of the possible benefits and risks of study 
treatment administration, including the possibility of recurrent, more severe liver 
injury or death. 

The subject must also provide signed informed consent specifically for the 
rechallenge with study treatment. Documentation of informed consent must be 
recorded in the study chart. 

Study treatment must be administered at the dose specified by GSK.

Subjects approved by GSK Medical Governance for rechallenge with study 
treatment must return to the clinic twice a week for liver chemistry tests until stable 
liver chemistries have been demonstrated and then standard laboratory monitoring 
may resume as per protocol.

If after study treatment rechallenge, subject meets protocol-defined liver chemistry 
stopping criteria, study treatment should be permanently discontinued. 

Medical Monitor, and the Ethics Committee or Institutional Review Board as 
required, must be informed of the subject’s outcome following study treatment 
rechallenge. 

GSK to be notified of any adverse events, as per Section 8 of the protocol.
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 


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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. 

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 8.
References:
Andrade RJ, Robles M, Lucena MI. Rechallenge in drug-induced liver injury: the 
attractive hazard. Expert Opin Drug Saf. 2009;8:709-714.
Hunt, CM. Mitochondrial and immunoallergic injury increase risk of positive drug 
rechallenge after drug-induced liver injury: A systematic review. Hepatol. 2010;52:2216-
2222.
Papay JI, Clines D, Rafi R, Yuen N, Britt SD, Walsh JS, et al. Drug-induced liver injury 
following positive drug rechallenge. Regul Tox Pharm. 2009;54:84-90.


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15.4.
Appendix 4: Response Criteria
Non-Hodgkin’s Lymphoma Response Criteria
This study employs response criteria from the Revised Response Criteria for Malignant 
Lymphoma (RRCML), [Cheson, 2007].  These criteria use the following categories of 
response: CR, PR, Stable Disease (SD), Relapse and Progression.  Because the criteria 
for PR requires a decrease by 50% in sum of products of the diameters (SPD) in the six
largest dominant nodes or nodal masses, six dominant nodes and/or nodal masses must be 
identified if > six involved nodes/nodal masses are present.
Complete Response
To be assigned a status of complete response, all changes must be confirmed by 
repeat assessments performed no less than four weeks after the criteria for CR were 
met.
1. Complete disappearance of all detectable clinical evidence of disease and disease 
related B-symptoms, if present prior to therapy. 
2. All lymph nodes and nodal masses must have regressed on CT to normal size.  
Nodes that were 1.1 to 1.5 cm in their longest diameter and more than 1.0 cm in 
their shortest diameter prior to treatment must have decreased to ≤ 1.0 cm in their 
shortest diameter.  Nodes that were > 1.5 cm in their longest diameter prior to 
therapy must have decreased to ≤ 1.5 cm in the longest diameter.
3. The spleen and/or liver, if considered to be enlarged due to lymphoma before 
therapy on the basis of a CT scan, should be considered normal size by imaging 
studies, and nodules related to lymphoma should disappear.  However, 
determination of splenic involvement is not always reliable because spleen 
considered normal in size may still contain lymphoma, whereas an enlarged 
spleen may reflect variations in anatomy, blood volume, the use of hematopoietic 
growth factors, or causes other than lymphoma.
4. If the bone marrow was involved by lymphoma prior to treatment, the biopsy 
must be cleared. The biopsy sample on which this determination is made must be 
adequate (with a goal of > 20 mm unilateral core). If the sample is indeterminate 
by morphology, it should be negative by immunohistochemistry. A sample that is 
negative by immunohistochemistry but that demonstrates a small population of 
clonal lymphocytes by flow cytometry will be considered a CR until data become 
available demonstrating a clear difference in subject outcome.  
Partial Response 
To be assigned a status of partial response, all changes must be confirmed by repeat 
assessments performed no less than four weeks after the criteria for PR were met.
1. At least a 50% decrease from baseline in the SPD of up six of the largest 
dominant nodes or nodal masses. 


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2. No increase in the size of the liver or the spleen.  No unequivocal progression in 
any nonmeasurable or nondominant site.
3. Splenic and hepatic nodules must regress by ≥50% in SPD compared to baseline. 
If only a single nodule/lesion, it must regress by ≥50% in the greatest transverse 
diameter compared to baseline. 
4. With the exception of splenic and hepatic nodules, involvement of other organs is 
accessible and no measureable disease should be present. 
5. Bone marrow assessment is not relevant for determination of a PR if the sample 
was positive prior to treatment.  However, if positive, the cell type should be 
specified. Subjects who achieve CR criteria above, except for persistent 
morphologic bone marrow involvement will be considered partial responders. 
When the bone marrow was involved before therapy and a clinical CR was 
achieved, but no bone marrow assessment after therapy, subjects must be 
considered partial responders. 
6. No new sites of disease must be observed.
7. When performed, positron emission tomography (PET) must be positive in at 
least one previously involved site. 
Stable Disease 
Neither sufficient shrinkage to qualify for a CR or PR nor sufficient increase to qualify 
for progressive disease taking as reference the smallest SPD since the treatment started.
When performed, PET should be positive at prior sites of disease with no new areas of 
involvement on the CT or PET.
Relapsed Disease (after CR)/Progressive Disease (after PR, SD)
Criteria for determining PD for new lesions and target lesions are shown in Table 19:
Table 19
Criteria for determining PD for new lesions and target lesions
Nodes
Extranodal (‘liver/spleen’ & ‘other’ 
categories)
New node/lesionc
A node that was normal (1.5 x 
1.0cm, including nodes that were 
not previously visible) and PET 
negative at baseline, must increase to 
>2.0 x 1.5 cm. The new lesion must 
not be attributable to non-lymphoma-
related causes.
If PET is performed, the lesion 
must be PET positive.
An unequivocal new lesion at a site 
where there was no disease at baseline 
(including being PET negative), 
provided the lesion cannot be attributed 
to non-lymphoma-related causes. 
If PET is not performed the new 
lesion must be >1.5cm in the long 
axisa.  
If PET is performed, the lesion must 
be PET positive.
Single target node/lesion
Increase in product of the 
perpendicular diameters (PPD)
50% increase from nadir in the PPD 
of any baseline dominant node. The 
long axis must increase by at least 
5mm and to >2.0cm.
50% increase from nadir in the PPD of 
any baseline dominant target lesion, 
and at least a 5mm increase in either of 
the axes, and the lesion must be 


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Nodes
Extranodal (‘liver/spleen’ & ‘other’ 
categories)
If PET is performed, the lesion 
must be PET positive.
>1.5cm x 1.5 cm.
If PET is performed, the lesion must 
be PET positive.
Increase in long axis
50% increase from nadir in the long 
axis of any baseline dominant node. 
The long axis must increase by at 
least 5mm and to >2.0 cm.
If PET is performed, the lesion 
must be PET positive.
50% increase from nadir in the long 
axis of any baseline dominant lesion, 
and at least a 5mm increase in the long 
axis, and the lesion must be >1.5cm x 
1.5cm.
If PET is performed, the lesion must 
be PET positive.
Multiple target nodes/lesions
Increase in SPD
50% increase from nadir in the SPD 
of baseline dominant nodes and at 
least one node should have a long 
axis >1.5cmb.
If PET is performed, nodes >1.5cm 
must be PET positive.
50% increase from nadir in the SPD of 
baseline dominant lesions and at least 
one lesion should have a long axis 
>1.5cmb.
If PET is performed, lesions >1.5cm 
must be PET positive.
a.
Due to the resolution of PET imaging, requiring a lesion to be PET positive will normally mean it will be at least 
1.5cm. To ensure consistency when PET is not performed a minimum lesion size of >1.5cm is required.
b.
Requiring that at least one lesion is >1.5cm minimises the risk of declaring PD based on small artefactual 
changes and allows for the introduction of PET positivity for declaring PD (when PET is performed).
c.
Abnormal nodes/extranodal lesions present at baseline that normalise/resolve and then subsequently 
enlarge/relapse are not to be classified as new lesions. 
Response Assessment
CT scans remain the standard for evaluation of nodal disease.  Chest, abdominal, and 
pelvic CT scans should be done even if those areas were not initially involved because of 
the unpredictable pattern of relapse in NHL.  Neck can be evaluated if present at baseline.
References: 
Cheson B, Pfister B, Juweid M, Gascoyne RD, Specht L, Horning SJ, et al. Revised 
response criteria for malignant lymphoma. J Clin Oncol 2007; 25:579-586.


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15.5.
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 Table 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 7 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 (bone scan as clinically indicated). 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 should be performed as clinically indicated. 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 1 week 
prior to 4 weeks after.
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.


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
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, [18F]fluorodeoxyglucose (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 


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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 optimized for 
the evaluation of the type and site of disease and lesions must be measured in the same 
anatomic plane by use of the same imaging examinations. Whenever possible the same 
scanner should be used. [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 8.3.1.1 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. 


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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. Note: non-
measurable only disease is not allowed per protocol.
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).


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
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for progressive disease.

Progressive Disease (PD): At least a 20% increase in the sum of the diameters of 
target lesions, taking as a reference, the smallest sum of diameters recorded since the 
treatment started (e.g. percent change from nadir, where nadir is defined as the 
smallest sum of diameters recorded since treatment start). In addition, the sum must 
have an absolute increase from nadir of 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. 


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
Not Applicable (NA): No non-target lesions at baseline.

Not Evaluable (NE): Cannot be classified by one of the four preceding definitions.
Note:

In the presence of measurable disease, progression on the basis of solely non-target 
disease requires substantial worsening such that even in the presence of SD or PR in 
target disease, the overall tumor burden has increased sufficiently to merit 
discontinuation of therapy.

Sites of non-target lesions, which are not assessed at a particular 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
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. 


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
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 unique design (see Table 2 of the 
protocol) should be considered when assessing tumor response. Thus, subjects with 
PD before Week 8, 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 8, 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 may be collected centrally during the study 
and may be reviewed or analyzed by an independent central reviewer. Details will be 
provided in the SPM.
References:
Chung WH, Hung SL, Chen YT. Genetic predisposition of life-threatening antiepileptic-
induced skin reactions. Expert Opin. Drug Saf. 2010; 9: 15-21.
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).  European Journal of Cancer. 2009; 45: 228-247.


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15.6.
Appendix 6: Response Criteria for Multiple Myeloma
Consensus Recommendations [Rajkumar, 2011] for the Uniform Reporting of 
Clinical Trials:  Report of the International Myeloma Working Group (IMWG) 
Consensus Panel
Response Criteria [Durie, 2006]
sCR (stringent complete response):
Complete response as defined below plus:

normal free light chain (FLC) ratio and

absence of clonal cells in bone marrow by immunohistochemistry or 
2-4 color flow cytometry.
CR (complete response):

Negative serum and urine immunofixation, and

Disappearance of any soft tissue plasmacytomas, and

5% plasma cells in bone marrow.
VGPR (very good partial response):

Serum and urine M-component detectable by immunofixation but 
not on electrophoresis  OR

90% or greater reduction in serum M-component plus urine M-
component < 100mg/24h.
PR (partial response):

50% reduction of serum M-protein and reduction in 24 hour 
urinary M-protein by 90% or to < 200mg/24h, and

If the serum and urine M-protein are not measurable, a 50% 
decrease in the difference between involved and uninvolved free 
light chain levels is required in place of the M-protein criteria.  If 
serum and urine M-protein are not measurable, and serum free light 
chain assay is also not measurable, 50% reduction in bone marrow 
plasma cells is required in place of M-protein, provided baseline 
bone marrow plasma cell percentage was 30%, and

In addition to the above listed criteria, if present at baseline, a 50% 
reduction in the size of the soft tissue plasmacytomas is also 
required.


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


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such subjects requires a > 90% decrease in the difference between involved and 
uninvolved FLC levels.


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c.
Clarifications to IMWG criteria for coding Progressive Disease: Bone marrow criteria 
for Progressive Disease are to be used only in subjects without measurable disease by 
M protein and by FLC levels; “25% increase” refers to M protein, FLC, and bone 
marrow results, and does not refer to bone lesions, soft tissue plasmacytomas, or 
hypercalcemia and the “lowest response value” does not need to be a confirmed 
value.
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.


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15.7.
Appendix 7: Criteria for Response/Progression: Prostate 
Cancer 
15.7.1.
Disease Progression Endpoint
The disease progression endpoint is defined by 1 or more of the following criteria:

PSA progression according to the PCWG3 criteria 
o
Subjects are not required to discontinue treatment on the basis of meeting 
PSA progression alone.
o
PSA progression [Scher, 2016] is defined as:

If there has been a decline from baseline: time from start of 
therapy to first PSA increase that is 25% and 2 ng/mL in 
absolute value from the nadir, and which is confirmed by a second 
value 3 or more weeks later (i.e., a confirmed rising trend) at least 
9 weeks after the start of treatment

If there has NOT been a decline from baseline: time from start of 
therapy to first PSA increase that is 25% and 2 ng/mL in 
absolute value from the baseline value, determined at least 9 weeks 
after start of treatment

Radiographic progression  by RECIST 1.1 for subjects with measurable 
disease.(Appendix 5)

Bone progression on bone scan according to the PCWG3 criteria 
o
Bone progression [Scher, 2016] will be determined as the appearance of 
2 new lesions on bone scan and at least an additional 2 bone lesions at 
the next scan (every 8 weeks). The date of progression is the date of the 
first scan that indicates the change. Subjects should not be discontinued 
from study treatment(s) due to the occurrence of bone scan changes in the 
first 12 weeks that do not meet PCWG3 guidelines for progression.
15.7.2.
DiseaseResponse Endpoints 

PSA response according to the PCWG3 criteria:
o
Only subjects who have a baseline PSA value and at least one post-
baseline assessment will be included in the analysis of PSA response.
o
PSA Response Rate is defined as proportion of subjects with a decrease of 
50% in the PSA concentration from the baseline PSA value determined 
at least 9 weeks after start of treatment and confirmed after ≥4 weeks by 
an additional PSA evaluation.

Radiographic response By Recist 1.1 for subjects with measurable disease 
(Appendix 5)


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References
Scher HI, Morris MJ, Stadler WM, Higano C, Basch E, Fizazi K, et al. Trial design and 
objectives for castration-resistant prostate cancer: updated recommendations from the 
Prostate Cancer Clinical Trials Working Group 3. Journal of Clinical Oncology. 2016; 
doi: 10.1200/JCO.2015.64.2702.


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15.8.
Appendix 8: Genetic Research
Genetic Research Objectives and Analyses
The objectives of the genetic research are to investigate the relationship between genetic 
variants and:

Response to medicine, including GSK2816126] or any concomitant medicines;

Disease susceptibility, severity, and progression and related conditions
Genetic data may be generated while the clinical study is underway or following 
completion of the study.  Genetic evaluations may include focused candidate gene 
approaches and/or examination of a large number of genetic variants throughout the 
genome (whole genome analyses). Genetic analyses will utilize data collected in the 
clinical study and will be limited to understanding the objectives highlighted above.  
Analyses may be performed using data from multiple clinical studies to investigate these 
research objectives.
Appropriate descriptive and/or statistical analysis methods will be used. A detailed 
description of any planned analyses will be documented in a Reporting and Analysis Plan 
(RAP) prior to initiation of the analysis. Planned analyses and results of genetic
investigations will be reported either as part of the clinical RAP and study report, or in a 
separate genetics RAP and report, as appropriate.
Study Population
Any subject who is enrolled in the clinical study can participate in genetic research.  Any 
subject who has received an allogeneic bone marrow transplant must be excluded from 
the genetic research.
Study Assessments and Procedures
A key component of successful genetic research is the collection of samples during 
clinical studies. Collection of samples, even when no a priori hypothesis has been 
identified, may enable future genetic analyses to be conducted to help understand 
variability in disease and medicine response.

A 6 ml blood sample will be taken for Deoxyribonucleic acid (DNA) extraction. 
Blood sample is collected at the baseline visit, after the subject has been 
randomized and provided informed consent for genetic research. If a subject 
initially declines to participate in genetic research and then changes their mind, a 
sample should be obtained at the earliest opportunity. Instructions for collection 
and shipping of the genetic sample are described in the laboratory manual. The 
DNA from the blood sample may undergo quality control analyses to confirm the 
integrity of the sample. If there are concerns regarding the quality of the sample,
then the sample may be destroyed. The blood sample is taken on a single occasion 
unless a duplicate sample is required due to inability to utilize the original sample.  


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The genetic sample is labelled (or “coded”) with the same study specific number as used 
to label other samples and data in the study.   This number can be traced or linked back to 
the subject by the investigator or site staff. Coded samples do not carry personal 
identifiers (such as name or social security number). 
Samples will be stored securely and may be kept for up to 15 years after the last subject 
completes the study or GSK may destroy the samples sooner.  GSK or those working 
with GSK (for example, other researchers) will only use samples collected from the study 
for the purpose stated in this protocol and in the informed consent form.  Samples may be 
used as part of the development of a companion diagnostic to support the GSK medicinal 
product.
Subjects can request their sample to be destroyed at any time.
Informed Consent
Subjects who do not wish to participate in the genetic research may still participate in the 
clinical study.  Genetic informed consent must be obtained prior to any blood being taken
for genetic analysis.
Subject Withdrawal from Study
If a subject who has consented to participate in genetic research withdraws from the 
clinical study for any reason other than being lost to follow-up, the subject will be given a 
choice of one of the following options concerning the genetic sample, if already 
collected:

Continue to participate in the genetic research in which case the genetic DNA sample 
is retained

Discontinue participation in the genetic research and destroy the genetic DNA 
sample 
If a subject withdraws consent for genetic research or requests sample destruction for any 
reason, the investigator must complete the appropriate documentation to request sample 
destruction within the timeframe specified by GSK and maintain the documentation in 
the site study records. 
Genotype data may be generated during the clinical study or after completion of the 
clinical study and may be analyzed during the clinical study or stored for future analysis. 

If a subject withdraws consent for genetic research and genotype data has not 
been analyzed, it will not be analyzed or used for future research.  

Genetic data that has been analyzed at the time of withdrawn consent will 
continue to be stored and used, as appropriate. 


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Screen and Baseline Failures
If a sample for genetic research has been collected and it is determined that the subject 
does not meet the entry criteria for participation in the clinical study, then the investigator 
should instruct the participant that their genetic sample will be destroyed. No forms are 
required to complete this process as it will be completed as part of the consent and 
sample reconciliation process.  In this instance a sample destruction form will not be 
available to include in the site files.
Provision of Study Results and Confidentiality of Subject’s Data
GSK may summarize the genetic research results in the clinical study report, or 
separately and may publish the results in scientific journals. 
GSK may share genetic research data ‘with other scientists to further scientific 
understanding in alignment with the informed consent. GSK does not inform the subject, 
family members, insurers, or employers of individual genotyping results that are not 
known to be relevant to the subject’s medical care at the time of the study, unless 
required by law. This is due to the fact that the information generated from genetic
studies is generally preliminary in nature, and therefore the significance and scientific 
validity of the results are undetermined.  Further, data generated in a research laboratory 
may not meet regulatory requirements for inclusion in clinical care.


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15.9.
Appendix 9: Protocol Amendment Changes
AMENDMENT 1
Where the Amendment Applies
This amendment applies only to sites in the UK.
Summary of Amendment Changes with Rationale
Following the guidance from the MHRA following the submission of our CTA, GSK 
agrees to remove wording from the protocol stating that GSK2816126 treatment will 
continue until commercial availability.  
In accord with MHRA’s guidance, the stopping criterion based on QTc in Section 3.8.1 
of the protocol will be changed to ≥500 msec.
In further accordance with the MHRA, a QTc stopping criterion was added where 
patients will be withdrawn from study if they experience an increase in QTc > 60msec 
from baseline following dose reduction and re-challenge.
List of Specific Changes
PROTOCOL SYNOPSIS
PREVIOUS TEXT

STUDY DESIGN:  This study is divided into 2 parts; Part 1 of the study is a dose 
escalation phase to select the recommended Part 2 dose (RP2D) based on the safety, 
PK, and PD profiles observed after IV administration of GSK2816126.  Eligible 
subjects with relapsed/refractory DLBCL and transformed FL malignancies will be 
enrolled in the dosing cohorts until a RP2D is established.  Subjects may continue 
treatment in the study until disease progression, unacceptable toxicity, withdrawal of 
consent, or commercial supply of GSK2816126 becomes available to the subject.  
Expansion cohorts are planned in subjects with both EZH2 mutant positive and 
EZH2 WT tumors to further explore clinical activity at the RP2D (Part 2).
REVISED TEXT

STUDY DESIGN:  This study is divided into 2 parts; Part 1 of the study is a dose 
escalation phase to select the recommended Part 2 dose (RP2D) based on the safety, 
PK, and PD profiles observed after IV administration of GSK2816126.  Eligible 
subjects with relapsed/refractory DLBCL and transformed FL malignancies will be 
enrolled in the dosing cohorts until a RP2D is established.  Subjects may continue 
treatment in the study until disease progression, unacceptable toxicity, or withdrawal 
of consent, or commercial supply of GSK2816126 becomes available to the subject.  
Expansion cohorts are planned in subjects with both EZH2 mutant positive and 
EZH2 WT tumors to further explore clinical activity at the RP2D (Part 2).


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Section 3.8.1 QTc Stopping Criteria
PREVIOUS TEXT
QTc Stopping Criteria
If a subject that meets the corrected QT (QTc)1 interval duration criteria below, study 
treatment(s) will be withheld.  

QT interval (corrected for HR) ≥530 msec
REVISED TEXT
QTc Stopping Criteria
If a subject that meets the corrected QT (QTc)1 interval duration criteria below, study 
treatment(s) will be withheld.  

QT interval (corrected for HR) ≥530 500 msec; IP will be permanently 
discontinued.

QTc interval increase from baseline ≥ 60 msec and maximum QTc  < 500 msec; 
IP may be restarted at a 33% reduction in dose once the QTc returns to 
baseline.  If QTc prolongation meeting stopping criteria recurs after re-
challenge, IP must be permanently discontinued.


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AMENDMENT [2]
Where the Amendment Applies
This amendment applies to all investigator sites participating in this study and includes 
changes made in country specific amendment 1.  
Summary of Amendment Changes with Rationale
Following the guidance from the FDA after submission of our IND, we have lowered our 
starting dose of GSK2816126 from 125 mg to 50 mg. 
Addressing the FDA’s comment “All adverse events, whether believed related or 
unrelated to study drug, must be included when dose limiting toxicity and stopping rules 
are invoked,” we have updated our Dose Limiting toxicities language.
Based on comments from the FDA, we have revised 100% dose escalation wording
In accordance with FDA comments, we have decreased our baseline QTc Exclusion 
criterion from >480msec to >450msec and added an increase from baseline QTc stopping 
criterion of ≥ 60 msec
To better define our ECG testing, we added regular ECG monitoring timings to the Time 
& Events table
To correct an earlier oversight, blood glucose testing was added to our list of clinical lab 
tests
In accordance with our laboratory specifications, we have removed any wording 
pertaining to the use of central labs
Following the guidance from the MHRA following the submission of our CTA, GSK 
agrees to remove wording from the protocol stating that GSK2816126 treatment will 
continue until commercial availability.  
In accord with MHRA’s guidance, the stopping criterion based on QTc in Section 3.8.1 
of the protocol will be changed to ≥500 msec.
In further accordance with the MHRA, a QTc stopping criterion was added where 
subjects will be withdrawn from study if they experience an increase in QTc > 60msec 
from baseline following dose reduction and re-challenge.
At the request of our investigators, to clarify that PET scans are optional in this study, 
additional wording was added to the T&E Table Section 7.1.
At the request of our investigators, additional wording was added to the T&E Table and 
Section 7.2 to clarify CT scan timings.
Added explanatory language to T&E Table around coagulation, CT and standalone PET 
assessments


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Changed the corticosteroid exclusion criteria to 7 days in the synopsis and Section 5.2.3
List of Specific Changes
Protocol Synopsis
PREVIOUS TEXT
1. Cardiac exclusion criteria:

History of acute coronary syndromes (including myocardial infarction and 
unstable angina), coronary angioplasty, or stenting within the past 6 months 
prior to first dose of study drug.

QTc interval >480msec 

Uncontrolled arrhythmias.  Subjects with rate controlled atrial fibrillation for 
> 1 month prior to first dose of study drugs may be eligible.

Class II, III or IV heart failure as defined by the New York Heart Association 
(NYHA) functional classification system.  
2. Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs 
chemically related to the study drug or their excipients.
3. Pregnant or lactating female.
4. Unwillingness or inability to follow the procedures outlined in the protocol.
5. Uncontrolled diabetes or other medical condition that may interfere with 
assessment of toxicity.

STUDY TREATMENT DOSAGE/DOSAGE FORM, ROUTE, 
AND DOSE REGIMEN: Starting dose will be 125 mg, IV, twice 
weekly.  Dose escalations will be performed in Part 1 and dose 
adjustments are allowed to address tolerability and safety issues.  
Alternative schedules may be evaluated if emerging data suggest that 
twice weekly administration with 2 hour infusions will result in 
excessive toxicity.  In addition, alternative dosing schedules may be 
considered if the safety, pharmacokinetic (PK), and 
pharmacodynamic (PD) data suggest that a sufficient therapeutic 
exposure cannot be achieved using the initial schedule and after a 
protocol amendment.

SAFETY ASSESSMENTS:  Routine physical examinations, vital 
sign measurements, echocardiograms, and monitoring of adverse 
events.  Cardiac safety monitoring will be required, consisting of 
triplicate 12-lead electrocardiograms (ECGs) pre-infusion of drug, 
immediately post-infusion of drug, one at night prior to going to 
sleep (e.g., 10 pm), and one prior to discharge from the unit.  The 
subject will not be discharged from the unit unless the QTc is <500 
msec.  In addition, 24 hours of high fidelity 12-lead Holter 
monitoring will be performed.    Tracings from this will be used for 


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concentration QT analysis as well.  Laboratory testing includes at 
least hematology and clinical chemistry.  Additional safety 
assessments may be necessary based on emerging data.
REVISED TEXT
1.
Cardiac exclusion criteria:

History of acute coronary syndromes (including myocardial infarction and 
unstable angina), coronary angioplasty, or stenting within the past 6 months 
prior to first dose of study drug(s).

QTc interval >480msec >450msec

Uncontrolled arrhythmias.  Subjects with rate controlled atrial fibrillation for 
> 1 month prior to first dose of study drugs may be eligible.

Class II, III or IV heart failure as defined by the New York Heart Association 
(NYHA) functional classification system.  
2. Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs 
chemically related to the study drug or their excipients.
3.
Pregnant or lactating female.
4.
Unwillingness or inability to follow the procedures outlined in the protocol.
5.
Uncontrolled diabetes or other medical condition that may interfere with 
assessment of toxicity.

STUDY TREATMENT DOSAGE/DOSAGE FORM, ROUTE, 
AND DOSE REGIMEN: Starting dose will be 125 mg 50 mg, IV, 
twice weekly.  Dose escalations will be performed in Part 1 and dose 
adjustments are allowed to address tolerability and safety issues.  
Alternative schedules may be evaluated if emerging data suggest that 
twice weekly administration with 2 hour infusions will result in 
excessive toxicity.  In addition, alternative dosing schedules may be 
considered if the safety, pharmacokinetic (PK), and 
pharmacodynamic (PD) data suggest that a sufficient therapeutic 
exposure cannot be achieved using the initial schedule and after a 
protocol amendment.
SAFETY ASSESSMENTS: 
Routine physical examinations, vital sign measurements, echocardiograms, and 
monitoring of adverse events.  Cardiac safety monitoring will be required, consisting of 
triplicate 12-lead electrocardiograms (ECGs) pre-infusion of drug, immediately post-at 
the end of infusion of drug, one at night prior to going to sleep (e.g., 10 pm), and one 
prior to discharge from the unit for Day 1, dose one only.  The subject will not be 
discharged from the unit unless the QTc is <500 msec.  In addition, 24 hours of high 
fidelity 12-lead Holter monitoring will be performed for Dose one.  Tracings from this 
will be used for concentration QT analysis as well.  Pre-infusion and end of infusion 
ECGs will be recorded for all other ECG timepoints. Laboratory testing includes at least 


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hematology and clinical chemistry.  Additional safety assessments may be necessary 
based on emerging data.
Section 1.2.2 Nonclinical Pharmacology
PREVIOUS TEXT
Based on the infusion site reactions, in dogs following twice weekly dosing for 4 weeks, 
the no-observed-adverse-effect-level (NOAEL) is 30 mg/kg (AUC0-24h of 14.9 g.h/mL; 
Cmax of 1.96 g/mL) and the highest non-severely toxic dose (HNSTD) is 100 mg/kg 
(AUC0-24h of 80.1g.h/mL; Cmax of 9.88 g/mL).  In rats following twice weekly dosing 
for 4 weeks, a NOAEL was not established at the lowest dose tested of 30 mg/kg (AUC0-
24h of 23.5 g.h/mL and Cmax of 2.97 g/mL).   Due to similar exposure in rats at 300 
mg/kg on Day 1 of the 2 and 4 week studies, the severely toxic dose 10% (STD10) in rats 
is estimated to be between 100 and 300 mg/kg (AUC0-24h between 54 and 235 g.h/mL; 
Cmax between 8 and 33 g/mL; exposures based on twice weekly dosing for 2 weeks).  
However, because the smaller calibre of rodent vessels used for the drug infusion are 
more sensitive to injury and irritant effects, the dog findings are more appropriate to use 
for the local tolerability.
REVISED TEXT
Based on the infusion site reactions, in dogs following twice weekly dosing for 4 weeks, 
the no-observed-adverse-effect-level (NOAEL) is 30 mg/kg (AUC0-24h of 14.9 g.h/mL; 
Cmax of 1.96 g/mL) and the highest non-severely toxic dose (HNSTD) is 100 mg/kg 
(AUC0-24h of 80.1g.h/mL; Cmax of 9.88 g/mL).  In rats following twice weekly dosing 
for 4 weeks, a NOAEL was not established at the lowest dose tested of 30 mg/kg (AUC0-
24h of 23.5 g.h/mL and Cmax of 2.97 g/mL).   Due to similar exposure in rats at 300 
mg/kg on Day 1 of the 2 and 4 week studies, the severely toxic dose 10% (STD10) in rats 
is estimated to be between 100 and 300 mg/kg (AUC0-24h between 54 and 235 g.h/mL; 
Cmax between 8 and 33 g/mL; exposures based on twice weekly dosing for 2 weeks).  
For the purpose of the starting dose justification in this protocol, we will use the 
lower estimate of 100 mg/kg as the STD10.  However, because the smaller calibre of 
rodent vessels used for the drug infusion are more sensitive to injury and irritant effects, 
the dog findings are more appropriate to use for the local tolerability.
Section 1.3.1 Risk Assessment
PREVIOUS TEXT
Potential Risk of 
Clinical Significance
Data/Rationale for Risk
Mitigation Strategy
Cardiovascular – QT 
prolongation
QTc prolongation was observed (up to 
8%; 18 msec in dog) following the end of 
a single 8 hour infusion
Effect did not directly correlate with peak 
GSK2816126 blood levels; onset was 4-7 
hours following the end of the infusion; 
Protocol includes cardiovascular 
eligibility criteria, laboratory 
assessments (potassium and 
magnesium, cardiac monitoring 
(electrocardiograms [ECGs], 
Holter monitoring during the study, 


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Potential Risk of 
Clinical Significance
Data/Rationale for Risk
Mitigation Strategy
reversed within 3-8 hours following onset
Effects not observed following repeat 
dosing in dogs
No arrhythmias were detected in 
preclinical studies. 
The mechanism for the QTc prolongation 
is unlikely due to a direct effect on hERG 
repolarization as GSK2816126 weekly 
inhibited hERG tail current (IC25 of 
54.2 µM; 28.61 µg/mL).  However, 
GSK2816126 was shown to block hERG 
current density in vitro consistent with an 
effect on hERG channel trafficking.
and dose stopping/modifications 
criteria for the management of QT 
prolongation)
Co-administration of medications 
that are known to prolong the QT 
interval and have a risk of causing 
Torsades de Pointes and drugs 
that have a possible risk of 
Torsades de Pointes are 
prohibited 
All subjects will remain in the 
clinical research unit (CRU) after 
receiving their first dose of study 
medication (Week 1, Day 1) with 
periodic ECGs and Holter 
monitoring for 24 hours.  Subjects 
will not be discharged from the unit 
unless their last measured QTc on 
an ECG performed immediately 
prior to discharge is <500 msec.
REVISED TEXT
Potential Risk of 
Clinical Significance
Data/Rationale for Risk
Mitigation Strategy
Cardiovascular – QT 
prolongation
QTc prolongation was observed (up to 
8%; 18 msec in dog) following the end of 
a single 8 hour infusion
Effect did not directly correlate with peak 
GSK2816126 blood levels; onset was 4-7 
hours following the end of the infusion; 
reversed within 3-8 hours following onset
Effects not observed following repeat 
dosing in dogs
No arrhythmias were detected in 
preclinical studies. 
The mechanism for the QTc prolongation 
is unlikely due to a direct effect on hERG 
repolarization as GSK2816126 weekly 
inhibited hERG tail current (IC25 of 
54.2 µM; 28.61 µg/mL).  However, 
GSK2816126 was shown to block hERG 
current density in vitro consistent with an 
effect on hERG channel trafficking.
Protocol includes cardiovascular 
eligibility criteria, laboratory 
assessments (potassium and 
magnesium, cardiac monitoring 
(electrocardiograms [ECGs], 
Holter monitoring during the study, 
and dose stopping/modifications 
criteria for the management of QT 
prolongation)
Co-administration of medications 
that are known to prolong the QT 
interval and have a risk of causing 
Torsades de Pointes and drugs 
that have a possible risk of 
Torsades de Pointes are 
prohibited
All subjects will remain in the 
clinical research unit (CRU) after 
receiving their first dose of study 
medication (Week 1, Day 1) with 
periodic ECGs and Holter 


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Potential Risk of 
Clinical Significance
Data/Rationale for Risk
Mitigation Strategy
monitoring for 24 hours.  Subjects 
will not be discharged from the unit 
unless their last measured QTc on 
an ECG performed immediately 
prior to discharge after the first 
dose is <500 msec.
After Day 1 during the first 3 
weeks of treatment and on Day
4 of subsequent cycles, ECGs 
will be performed pre-infusion 
and at the end of infusion.
Section 3.3.1 Accelerated Dose Escalation
PREVIOUS TEXT
Initially, an accelerated dose titration scheme will be used starting with a dose of 125 mg 
[Simon, 1997]. Evaluation of at least one subject who has completed one cycle of 
treatment is required prior to determining the dose for the next cohort with one cycle 
being defined as twice weekly dosing for three weeks and one week off. In the absence 
of Grade 2 or higher non-hematologic toxicity (described in Section 3.3.2.1) or a Dose 
Limiting Toxicity (DLT) (described in Section 3.3.3), subsequent cohorts will be dose 
escalated by up to 100% (Table 1).  Following the initial occurrence of a Grade 2 toxicity 
or DLT in a subject during the first cycle (within 28 days of dose 1), accelerated titration 
will transition to a standard 3+3 dose escalation.
Table 1
Dose Titration Procedures
Dose Level
Toxicity in Study
Increase in Dose
Accelerated Dose Titration Phase
Dose Level -1 
Lower doses may be used if Dose Level 1 exposure 
is significantly higher than predicted or if there is 
excessive toxicity. This may be achieved by 
reducing the dose or by alternate dosing schedules.
Dose Level 1 
Starting Dose:  125 mg
Subsequent Dose 
Levels 
No subjects with a Grade 2 
toxicity (exceptions below in 
Section 3.3.2.1) or DLT 
(Section 3.3.3) 
Increase by ≤100% increase in dose
(No subjects with Grade 2 drug related toxicity 
AND no subjects with any DLTs in first 28 days of 
treatment)
End of 
Accelerated Dose 
Titration Phase
One subject Grade 2 drug 
related non-hematological 
toxicity in the first 28 days of 
treatment) or Grade 3 drug 
related specific toxicity (See 
Section 3.3.2.1)
Begin 3+3 dose escalation phase
(note that once 3+3 phase is initiated, the procedure 
may revert to the accelerated dose titration phase –
see criteria below in Reverting to Accelerated Dose 
Titration)


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REVISED TEXT
Initially, an accelerated dose titration scheme will be used starting with a dose of 125 mg
50 mg [Simon, 1997]. Evaluation of at least one subject who has completed one cycle of 
treatment is required prior to determining the dose for the next cohort with one cycle 
being defined as twice weekly dosing for three weeks and one week off. In the absence 
of Grade 2 or higher non-hematologic toxicity (described in Section 3.3.2.1) or a Dose 
Limiting Toxicity (DLT) (described in Section 3.3.3), subsequent cohorts will be dose 
escalated by up to 100% allow up to 100% dose escalations up to 500 mg 
(approximately 1/6 th of the dog HNSTD). Subsequent dose escalation steps would 
be up to a maximum of 50% at each step (Table 1).  Following the initial occurrence of 
a Grade 2 toxicity or DLT in a subject during the first cycle (within 28 days of dose 1), 
accelerated titration will transition to a standard 3+3 dose escalation.
Table 1
Dose Titration Procedures
Dose Level
Toxicity in Study
Increase in Dose
Accelerated Dose Titration Phase
Dose Level -1 
Lower doses may be used if Dose Level 1 exposure 
is significantly higher than predicted or if there is 
excessive toxicity. This may be achieved by 
reducing the dose or by alternate dosing schedules.
Dose Level 1 
Starting Dose:  125 mg 50 mg
Subsequent Dose 
Levels 
No subjects with a Grade 2 
toxicity (exceptions below in 
Section 3.3.2.1) or DLT 
(Section 3.3.3) 
Increase by ≤100% increase in dose up to 500 mg, 
≤50% increase in dose thereafter.
(No subjects with Grade 2 drug related toxicity 
AND no subjects with any DLTs in first 28 days of 
treatment)
End of 
Accelerated Dose 
Titration Phase
One subject Grade 2 drug 
related non-hematological 
toxicity in the first 28 days of 
treatment) or Grade 3 drug 
related specific toxicity (See 
Section 3.3.2.1)
Begin 3+3 dose escalation phase
(note that once 3+3 phase is initiated, the procedure 
may revert to the accelerated dose titration phase –
see criteria below in Reverting to Accelerated Dose 
Titration)
Section 3.3.2 Dose Escalation Phase
PREVIOUS TEXT
3+3 Dose Escalation Phase
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 subjects, then dosing will proceed to the next higher dose level (≤100% 
increase in dose). An additional three subjects will be enrolled at this dose level if 1 of 3 
subjects experiences a DLT.  Subjects will be entered in a staggered approach with at 
least 7 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 


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outlined in Table 1. 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.
Evaluation of safety data from at least 1 subject during the accelerated dose titration and 
at least 3 subjects in the standard dose titration who have completed 28 days of dosing on 
study (one cycle) is required prior to defining a new dose and starting the next cohort. 
Once a higher dose has been cleared, subjects at lower dose levels who remain on study 
drug and have not experienced dose limiting toxicity will be allowed to escalate up to that 
level.
In the accelerated dose escalation cohorts and the 3+3 dose escalation cohorts, the dose 
will be escalated based on all available data, including PK data and the safety profile of 
prior cohorts, as well as the predicted dose from N-CRM design [Neuenschwander, 2008] 
described in Section 12.
Table 2
3 + 3 Dose Escalation Design
Number of Subjects with 
DLT in a Cohort
Action
0 out of 3 subjects
Escalate to the next dose level with increase 100% if none of the 
subjects have Grade 2 toxicity (in the first 4 weeks of treatment)
Escalate to next dose level with an increase of 50% if (in the first 
4 weeks of treatment) there has been:
- One or more subjects with Grade 2 toxicity
1 out of 3 subjects
Accrue 3 additional evaluable subjects at current dose level for a total 
of 6 evaluable subjects
1 out of 6 subjects
Escalate to the next dose level with an increase of 50%
2 or more subjects in a dosing 
cohort (up to 6 subjects)
MTD has been exceeded.  Either evaluate an intermediate dose lower 
than current dose or expand a prior cohort up to 12 subjects
REVISED TEXT
3+3 Dose Escalation Phase
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 subjects, then dosing will proceed to the next higher dose level (≤100% 
increase in dose up to 500 mg, ≤50% increase in dose thereafter). An additional three 
subjects will be enrolled at this dose level if 1 of 3 subjects experiences a DLT.  Subjects 
will be entered in a staggered approach with at least 7 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 1. Escalation to the 
next dose level will not increase greater than 2 fold from the previous dose level up to a 
dose of 500mg. Subsequent dose escalation steps would be up to a maximum of 50% 
at each step. If 2 or more DLTs are observed at any dose level, the MTD will have been 
exceeded.


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Evaluation of safety data from at least 1 subject during the accelerated dose titration and 
at least 3 subjects in the standard dose titration who have completed 28 days of dosing on 
study (one cycle) is required prior to defining a new dose and starting the next cohort. 
Once a higher dose has been cleared, subjects at lower dose levels who remain on study
drug and have not experienced dose limiting toxicity will be allowed to escalate up to that 
level.
In the accelerated dose escalation cohorts and the 3+3 dose escalation cohorts, the dose 
will be escalated based on all available data, including PK data and the safety profile of 
prior cohorts, as well as the predicted dose from N-CRM design [Neuenschwander, 2008] 
described in Section 12.
Table 2
3 + 3 Dose Escalation Design
Number of Subjects with 
DLT in a Cohort
Action
0 out of 3 subjects
Escalate to the next dose level with increase 100% up to 500 mg, 
≤50% thereafter if none of the subjects have Grade 2 toxicity (in the 
first 4 weeks of treatment)
Escalate to next dose level with an increase of 50% if (in the first 
4 weeks of treatment) there has been:
- One or more subjects with Grade 2 toxicity
1 out of 3 subjects
Accrue 3 additional evaluable subjects at current dose level for a total 
of 6 evaluable subjects
1 out of 6 subjects
Escalate to the next dose level with an increase of 50%
2 or more subjects in a dosing 
cohort (up to 6 subjects)
MTD has been exceeded.  Either evaluate an intermediate dose lower 
than current dose or expand a prior cohort up to 12 subjects
Section 3.3.3 Dose Limiting Toxicity
PREVIOUS TEXT
Dose Limiting Toxicity
Dose-limiting toxicity (DLT) is defined as any adverse event which is related 
(definitely, probably or possibly) to study drug (using the National Cancer Institute –
Common Terminology Criteria for Adverse Events [NCI-CTCAE], v4.0) during the first 
28 days of treatment and meets the criteria listed in Table 3 [NCI-CTCAE, 2009].
REVISED TEXT
Dose Limiting Toxicity
Dose-limiting toxicity (DLT):  An event will be considered a DLT if it occurs within 
the first 4 weeks (28 days) of treatment, and meets one of the following criteria 
(Table 3 [NCI-CTCAE v.4.0, 2009]) unless it can be clearly established that the 
event is unrelated to treatment. is defined as any adverse event which is related 
(definitely, probably or possibly) to study drug (using the National Cancer Institute –


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Common Terminology Criteria for Adverse Events [NCI-CTCAE], v4.0) during the first 
28 days of treatment and meets the criteria listed in Table 3 [NCI-CTCAE, 2009].
Section 3.5.3 Rationale for Dose and Schedule
PREVIOUS TEXT

One tenth of the rat STD10 as per ICH S9 guidance
The STD10 in the rat was defined as between100 and 300 mg/kg administered over 
6-hour infusion twice-weekly for 2 to 4 weeks. One-tenth (1/10) of the rat STD10 is 
between 60 and 180 mg/m2. These doses were well tolerated in dogs. A starting dose 
based on 1/10 of the rat STD10 would be between 110 and 330 mg using the human 
equivalent dose calculation. 
Taking all three approaches into consideration and the rationale for a 2-hour infusion 
duration, a starting dose of 125 mg twice-weekly as a 2-hour infusion is proposed. This 
dose provides a predicted total blood AUC of 3.58 g.h/mL and a total blood Cmax of 
1.07 g/mL. The AUC is 15 to 66-fold lower than the AUC (0-24hr) for the rat STD10 
between 100 and 300 mg/kg, 7-fold lower than the AUC at the lowest tested dose in rat 
(30 mg/kg), and 22-fold lower than the AUC for the dog HNSTD of 100 mg/kg. The 
Cmax is 7 to 31-fold lower than the Cmax for the rat STD10 between 100 and 300 
mg/kg, 2.8-fold lower than the Cmax at the lowest tested dose in rat (30 mg/kg), and 9.2-
fold lower than the Cmax for the dog HNSTD of 100 mg/kg. The starting dose of 125 mg 
will provide a suitable safety margin for the anticipated toxicities, while minimizing the 
number of subjects with aggressive lymphomas exposed to sub-therapeutic doses.
REVISED TEXT

One tenth of the rat STD10 as per ICH S9 guidance
The STD10 in the rat was defined as between100 and 300 mg/kg administered over 
6-hour infusion twice-weekly for 2 to 4 weeks. One-tenth (1/10) of the rat STD10 is 
between 60 and 180 mg/m2. These doses were well tolerated in dogs. A starting dose 
based on 1/10 of the rat STD10 would be between 110 and 330 mg using the human 
equivalent dose calculation. 
Taking all three approaches into consideration and the shorter infusion duration of
rationale for a 2-hours infusion duration, a starting dose of 125 mg 50 mg twice-weekly 
as a 2-hour infusion is proposed. This dose provides a predicted total blood AUC of 3.58
43 g.h/mL and a total blood Cmax of 1.07 428 g/mL. The AUC is 15 to 66 38-fold 
lower than the AUC (0-24hr) for the rat STD10 between of 100 and 300 mg/kg, 7 18-fold 
lower than the AUC at the lowest tested dose in rat (30 mg/kg), and 22 56-fold lower than 
the AUC for the dog HNSTD of 100 mg/kg. The Cmax is 7 to 31 18-fold lower than the 
Cmax for the rat STD10 between of 100 and 300 mg/kg, 2.8 6.9-fold lower than the 
Cmax at the lowest tested dose in rat (30 mg/kg), and 9.2 23-fold lower than the Cmax 
for the dog HNSTD of 100 mg/kg. The starting dose of 125 mg 50 mg will provide a 
suitable safety margin for the anticipated toxicities, while minimizing the number of 
subjects with aggressive lymphomas exposed to sub-therapeutic doses.


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Section 3.8.1 QTc Stopping Criteria
PREVIOUS TEXT
QTc Stopping Criteria
If a subject that meets the corrected QT (QTc)1 interval duration criteria below, study 
treatment(s) will be withheld.  

QT interval (corrected for HR) ≥530 msec
REVISED TEXT
QTc Stopping Criteria
If a subject that meets the corrected QT (QTc)1 interval duration criteria below, study 
treatment(s) will be withheld.  

QT interval (corrected for HR) ≥530 msec; IP will be permanently discontinued.

QTc interval increase from baseline ≥ 60 msec; IP may be restarted at a 33% 
reduction in dose once the QTc returns to baseline.  If QTc prolongation 
meeting stopping criteria recurs after re-challenge, IP must be permanently 
discontinued.
Section 5.2.3 Exclusion Criteria # 10 
PREVIOUS TEXT
10. Cardiac exclusion criteria:

History of acute coronary syndromes (including myocardial infarction and 
unstable angina), coronary angioplasty, or stenting within the past 6 months 
prior to first dose of study drug(s).

QTc interval >480msec 

Uncontrolled arrhythmias.  Subjects with rate controlled atrial fibrillation for 
> 1 month prior to first dose of study drugs may be eligible.

Class II, III or IV heart failure as defined by the New York Heart Association 
(NYHA) functional classification system.  
REVISED TEXT
10. Cardiac exclusion criteria:

History of acute coronary syndromes (including myocardial infarction and 
unstable angina), coronary angioplasty, or stenting within the past 6 months 
prior to first dose of study drug(s).


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
QTc interval >480msec >450msec

Uncontrolled arrhythmias.  Subjects with rate controlled atrial fibrillation for 
> 1 month prior to first dose of study drugs may be eligible.

Class II, III or IV heart failure as defined by the New York Heart Association 
(NYHA) functional classification system.  


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Section 7.1 Time & Events Table
PREVIOUS TEXT
ECG
Two copies of the 
ECG tracing 
should be 
obtained at the 
time of the ECG, 
one to be kept in 
the study file for 
retrospective 
collection by the 
sponsor if 
necessary.  ECG 
data should be 
reviewed by 
qualified 
personnel with 
experience in this 
study population
X
Xb
X
X
Every 4 weeks
X
REVISED TEXT
ECG
Pre-infusion and 
at the end of 
infusion except 
on Day 1 
(Section 7.3.4).
Two copies of the 
ECG tracing 
should be 
obtained at the 
time of the ECG, 
one to be kept in 
the study file for 
retrospective 
collection by the 
sponsor if 
necessary.  ECG 
data should be 
reviewed by 
qualified 
personnel with 
experience in this 
study population
X
Xb
X
X
Every 4 weeks On 
Day 4 of each 
cycle
X


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Section 7.1 Time & Events Table
PREVIOUS TEXT
Chemistry
Evaluations 
performed by a 
central laboratory.  
No need to repeat 
at pre-dose Day 1 
if screening 
assessments were 
performed within 
14 days of first
dose.
X
X
X
X
X
Prior to every 
infusion
Hematology
Evaluations 
performed by a 
central laboratory.  
No need to repeat 
at pre-dose Day 1 
if screening 
assessments were 
performed within 
14 days of first 
dose.
X
X
X
X
X
Every 4 weeks
Coagulation
PT/PTT/INR
X
Blood sample 
for circulating 
biomarkers
A blood sample for 
circulating 
biomarkers should 
be obtained on 
Day 1 (prior to 
treatment), Day 21 
(and at the time of 
disease 
progression.
X
X
PK sampling 
for Part 1
For details, see 
Table 7
Day 1 
(Table 
7)
Soon 
after 
ECG 
and 
PD 
bioma
rker 
collect
ion
Day 
15 
(Table 
7)
At 
time 
of PD 
bioma
rker 
collect
ion
Cycle 2, 4, 6 and 
12 – pre-dose and 
within 5 min prior 
to end of infusion 
on one treatment 
day between Day 
4 and Day 24


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PK sampling 
for Part 2
Three samples to 
be collected on 
Day 1 and Day 
11: Predose 
within 60 minutes 
prior to start of 
infusion, single 
draw between 
0.5 and 1.9 h 
from start of 
infusion, single 
draw between 3-
6h following end 
of infusion
Day 
1 
and 
pre-
dose 
on 
Day 
4
X 
(after 
4th
dose, 
Day 
11)
pre-
dose 
on 
Day 
15
Cycle 2, 4, 6 and 
12 – pre-dose and 
within 5 min prior 
to end of infusion 
on one treatment 
day between Day 
4 and Day 24
REVISED TEXT
Chemistry
Evaluations 
performed by a 
central 
laboratory.  No 
need to repeat 
at pre-dose Day 
1 if screening 
assessments 
were performed 
within 14 days 
of first dose.
X
X
X
X
X
Prior to every 
infusion
Hematology
Evaluations 
performed by a 
central 
laboratory. No 
need to repeat 
at pre-dose Day 
1 if screening 
assessments 
were performed 
within 14 days 
of first dose.
X
X
X
X
X
Every 4 weeks
Coagulation
PT/PTT/INR
X
Blood 
sample for 
circulating 
biomarkers
A blood sample 
for circulating 
biomarkers 
should be 
obtained on Day 
1 (prior to 
treatment), Day 
21 (and at the 
time of disease 
progression.
X
X


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PK sampling 
for Part 1
For details, see 
Table 7
Day 1 
(Table 
7)
Soon after 
ECG and 
PD 
biomarker 
collection
Day 15 
(Table 
7)
At time of 
PD 
biomarker 
collection
Cycle 2, 4, 6 
and 12 – pre-
dose and 
within 5 min 
prior to end 
of infusion on 
one 
treatment 
day between
Day 4 and 
Day 24
PK sampling 
for Part 2
Three samples 
to be collected 
on Day 1 and 
Day 11: 
Predose within 
60 minutes 
prior to start of 
infusion, single
draw between 
0.5 and 1.9 h 
from start of 
infusion, single 
draw between 
3-6h following 
end of infusion
Day 1 
and 
pre-
dose 
on Day 
4
X (after 4th
dose, Day 
11)
pre-
dose 
on Day 
15
Cycle 2, 4, 6 
and 12 – pre-
dose and 
within 5 min 
prior to end 
of infusion on 
one 
treatment 
day between
Day 4 and 
Day 24
Section 11.Data Management
PREVIOUS TEXT
DATA MANAGEMENT
For this study, data will be collected using defined eCRFs, transmitted electronically to 
GSK and combined with data provided from other sources in a validated data system.
When laboratory samples (i.e., hematology and clinical chemistry) are analyzed by a 
central laboratory the results will be stored in a database maintained by the central 
laboratory and transferred to GSK at agreed times.
In all cases, subject initials will not be collected or transmitted to GSK according to GSK 
policy.


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REVISED TEXT
DATA MANAGEMENT
For this study, data will be collected using defined eCRFs, transmitted electronically to 
GSK and combined with data provided from other sources in a validated data system.
When laboratory samples (i.e., hematology and clinical chemistry) are analyzed by a 
central laboratory the results will be stored in a database maintained by the central 
laboratory and transferred to GSK at agreed times.
For this study, data will be collected using defined eCRFs in the validated data 
system, InForm. Some data (i.e. Biomarker, PK, Holter ECG) will be transmitted 
electronically to GSK from an external vendor via a validated data system, the 
External Alliance Portal.
In all cases, subject initials will not be collected or transmitted to GSK according to GSK 
policy.
Section 7.1 Time & Events Table reference
PREVIOUS TEXT
a.
A subject is to receive two doses per week which should be given 3 days apart. If there is a need to change 
scheduling, the scheduled days of the week can change as long as there are 3-4 days between doses.  Up to 
5 days between doses is permitted for  exceptional circumstances
b.
Timings for in-house on-drug ECGs are pre-infusion, immediately post-infusion, before bed, and before 
discharge the next morning for Day 1 of cycle 1 only.  Other ECGs should be performed as instructed 
elsewhere within this protocol.
c.
Retention of screen-failure tumor tissue: all or a portion of archival or fresh biopsy tissue from screen-failure 
subjects, used for central testing of GCB-DLBCL or EZH2 mutation status, will be retained.  This tissue may 
be used in the validation of potential diagnostic assays to detect EZH2 mutations and/or for GCB-DLBCL 
subtyping.
d.
If the Follow-up visit ≥ 8weeks from the previous response scan time point, scans should be obtained to 
confirm/ evaluate response.  
e.
If utilized for subject evaluation at baseline, PET must continue to be used in subsequent assessment 
timepoints. 
f.
Only if initially and/or previously positive & required for CR or as clinically indicated.
REVISED TEXT
a.
A subject is to receive two doses per week which should be given 3 days apart. If there is a need to change 
scheduling, the scheduled days of the week can change as long as there are 3-4 days between doses.  Up to 
5 days between doses is permitted for  exceptional circumstances
b.
Timings for in-house on-drug ECGs are pre-infusion, immediately post-infusion at the end of infusion, 
before bed, and before discharge the next morning for Day 1 of cycle 1 only.  Other protocol-mandated
ECGs should be performed as instructed elsewhere within this protocol pre-infusion and at the end of 
infusion (Section 7.3.4).
c.
Retention of screen-failure tumor tissue: all or a portion of archival or fresh biopsy tissue from screen-failure 
subjects, used for central testing of GCB-DLBCL or EZH2 mutation status, will be retained.  This tissue may 


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be used in the validation of potential diagnostic assays to detect EZH2 mutations and/or for GCB-DLBCL 
subtyping.
d.
If the Follow-up visit ≥ 8weeks from the previous response scan time point, scans should be obtained to 
confirm/ evaluate response.  
e.
If utilized for subject evaluation at baseline, PET must continue to be used in subsequent assessment 
timepoints. 
f.
Only if initially and/or previously positive & required for CR or as clinically indicated.
Section 7.3.4 Electrocardiogram
PREVIOUS TEXT
Electrocardiogram
Twelve -lead ECGs will be obtained in triplicate at designated time points during the 
study using an ECG machine that automatically calculates the HR and measures PR, 
QRS, QT, and QTc intervals.  At each assessment a 12-lead ECG will be performed by 
qualified personnel at the site after the subject has at least a 5 minute rest and is in a 
semi-[recumbent or supine] position. 
Timings for in-house on-drug ECGs on Day 1 are pre-infusion, post-infusion, before bed 
(between 9-10pm) and before discharge the next morning. Subjects will not be 
discharged until ECG has normalized (QTc < 500 msec).
Refer to Section 3.8.1 for QTc withdrawal criteria.  Additional QTc readings may be 
necessary.
Refer to the SPM for details regarding ECG procedures.
REVISED TEXT
Electrocardiogram
Twelve -lead ECGs will be obtained in triplicate at designated time points during the 
study using an ECG machine that automatically calculates the HR and measures PR, 
QRS, QT, and QTc intervals.  At each assessment, a 12-lead ECG will be performed by 
qualified personnel at the site after the subject has at least a 5 minute rest and is in a 
semi-[recumbent or supine] position.  Refer to the SPM for details regarding ECG 
procedures.
Timings for in-house on-drug ECGs on Day 1 only are pre-infusion, post-infusion, before 
bed (between 9-10pm) and before discharge the next morning. These ECGs are in 
addition to the Holter monitoring.  Subjects will not be discharged from their 
overnight stay in the Phase I unit after dose 1 until ECG has normalized (the QTc is < 
500 msec.)
For all doses after the first dose, ECGs will be recorded pre-infusion and at the end 
of infusion.  See Time & Events Table (Section 7.1) for exact timings.
Refer to Section 3.8.1 for QTc withdrawal/stopping criteria.  Additional QTc readings 
may be necessary.


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Table 7 List of Clinical Laboratory Tests
REVISED TEXT
List of Clinical Laboratory Tests
Hematology
Platelet Count
RBC Indices:
Automated WBC Differential:
RBC Count
MCV
Neutrophils
WBC Count (absolute) 
MCH
Lymphocytes
Reticulocyte Count
MCHC
Monocytes
Hemoglobin
Eosinophils
Hematocrit
Basophils
Clinical Chemistry
BUN
Potassium
AST
Total and direct bilirubin
Creatinine
Chloride
ALT
Uric Acid
Sodium
Calcium
Alkaline phosphatase
Total Protein
Magnesium
Glucose
LDH
PO4
FSH and estradiol (as needed in women of non-child bearing potential only)
Abbreviation(s): ALT, alanine aminotransferase; AST, aspartate aminotransferase; BUN, blood urea nitrogen; FSH, 
follicle stimulating hormone; LDH, lactate dehydrogenase; MCH, mean corpuscular hemoglobin;  MCHC, mean 
corpuscular hemoglobin concentration; MCV, mean corpuscular volume; PO4, phosphate; RBC, red blood cell;  WBC, 
white blood cell.
PROTOCOL SYNOPSIS
PREVIOUS TEXT

STUDY DESIGN:  This study is divided into 2 parts; Part 1 of the study is a dose 
escalation phase to select the recommended Part 2 dose (RP2D) based on the safety, 
PK, and PD profiles observed after IV administration of GSK2816126.  Eligible 
subjects with relapsed/refractory DLBCL and transformed FL malignancies will be 
enrolled in the dosing cohorts until a RP2D is established.  Subjects may continue 
treatment in the study until disease progression, unacceptable toxicity, withdrawal of 
consent, or commercial supply of GSK2816126 becomes available to the subject.  
Expansion cohorts are planned in subjects with both EZH2 mutant positive and 
EZH2 WT tumors to further explore clinical activity at the RP2D (Part 2).
REVISED TEXT

STUDY DESIGN:  This study is divided into 2 parts; Part 1 of the study is a dose 
escalation phase to select the recommended Part 2 dose (RP2D) based on the safety, 
PK, and PD profiles observed after IV administration of GSK2816126.  Eligible 
subjects with relapsed/refractory DLBCL and transformed FL malignancies will be 
enrolled in the dosing cohorts until a RP2D is established.  Subjects may continue 
treatment in the study until disease progression, unacceptable toxicity, or withdrawal 
of consent, or commercial supply of GSK2816126 becomes available to the subject.  


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Expansion cohorts are planned in subjects with both EZH2 mutant positive and 
EZH2 WT tumors to further explore clinical activity at the RP2D (Part 2).
Section 3.8.1 QTc Stopping Criteria
PREVIOUS TEXT
QTc Stopping Criteria
If a subject that meets the corrected QT (QTc)1 interval duration criteria below, study 
treatment(s) will be withheld.  

QT interval (corrected for HR) ≥530 msec
REVISED TEXT
QTc Stopping Criteria
If a subject that meets the corrected QT (QTc)1 interval duration criteria below, study 
treatment(s) will be withheld.  

QT interval (corrected for HR) ≥530 500 msec; IP will be permanently 
discontinued.

QTc interval increase from baseline ≥ 60 msec and maximum QTc  < 500 msec; 
IP may be restarted at a 33% reduction in dose once the QTc returns to 
baseline.  If QTc prolongation meeting stopping criteria recurs after re-
challenge, IP must be permanently discontinued.


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Section 7.1 Time & Events Table
PREVIOUS TEXT
CT
Must be 
completed within 
4 weeks of first 
dose of 
GSK2816126 and 
repeated every 8 
weeks.  
X
X
Xd
a.
A subject is to receive two doses per week which should be given 3 days apart. If there is a need to change 
scheduling, the scheduled days of the week can change as long as there are 3-4 days between doses.  Up to 
5 days between doses is permitted for  exceptional circumstances.
b.
Timings for in-house on-drug ECGs are pre-infusion, at the end of infusion, before bed, and before discharge 
the next morning for Day 1 of cycle 1 only.  Other protocol-mandated ECGs should be performed pre-infusion 
and at the end of infusion (Section 7.3.4).
c.
Retention of screen-failure tumor tissue: all or a portion of archival or fresh biopsy tissue from screen-failure 
subjects, used for central testing of GCB-DLBCL or EZH2 mutation status, will be retained.  This tissue may 
be used in the validation of potential diagnostic assays to detect EZH2 mutations and/or for GCB-DLBCL 
subtyping.
d.
If the Follow-up visit ≥ 12weeks from the previous response scan time point, scans should be obtained to 
confirm/ evaluate response.  
e.
If utilized for subject evaluation at baseline, PET must continue to be used in subsequent assessment 
timepoints. 
f.
Only if initially and/or previously positive & required for CR or as clinically indicated.
REVISED TEXT
CT
Must be 
completed within 
4 weeks of first 
dose of 
GSK2816126 and 
repeated everyin
8 weeks.  Every 
12 weeks 
thereafter.
X
X
Xd
a.
A subject is to receive two doses per week which should be given 3 days apart. If there is a need to change 
scheduling, the scheduled days of the week can change as long as there are 3-4 days between doses.  Up to 
5 days between doses is permitted for  exceptional circumstances.
b.
Timings for in-house on-drug ECGs are pre-infusion, at the end of infusion, before bed, and before discharge 
the next morning for Day 1 of cycle 1 only.  Other protocol-,mandated ECGs should be performed pre-
infusion and at the end of infusion (Section 7.3.4).
c.
Retention of screen-failure tumor tissue: all or a portion of archival or fresh biopsy tissue from screen-failure 
subjects, used for central testing of GCB-DLBCL or EZH2 mutation status, will be retained.  This tissue may 
be used in the validation of potential diagnostic assays to detect EZH2 mutations and/or for GCB-DLBCL 
subtyping.
d.
If the Follow-up visit ≥ 12weeks from the previous response scan time point, scans should be obtained to 
confirm/ evaluate response.  
e.
If utilized for subject evaluation at baseline, PET must continue to be used in subsequent assessment 
timepoints. Diagnostic CT is the preferred method of disease assessment.  PET/CT may be used as an 
alternative at the investigator’s discretion.  
f.
Only if initially and/or previously positive & required for CR or as clinically indicated.


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Section 7.1 Time & Events Table
PREVIOUS TEXT
Positron 
emission 
tomography 
(PET)
The use of 
standalone PET or 
PET in combination 
with CT scan is 
optional at the 
discretion of the 
investigator. 
Xe
Xe
Xd,e
REVISED TEXT
Positron 
emission 
tomography 
(PET)
The use of 
standalone PET or 
PET in combination 
with CT scan is 
optional at the 
descreation of the 
investigator.
Xe
Xe
Xd,e
Section 7.2  Demographic/Medical History and Baseline Assessments
PREVIOUS TEXT

Diagnostic quality CT imaging with contrast within 28 days of first dose of study 
treatment identifying nodes, nodal masses, splenic/liver nodules and, if applicable 
measurable extranodal disease. See Section 7.7 for further information.
REVISED TEXT

Diagnostic quality CT imaging with contrast within 28 days of first dose of study 
treatment identifying nodes, nodal masses, splenic/liver nodules and, if applicable 
measurable extranodal disease is the preferred method of disease assessment. If 
PET/CT has been performed within this window, diagnostic CT will not be 
required.  See Section 7.7 for further information.


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Section 7.1 Time & Events Table
REVISED TEXT
Coagulation
PT/PTT/INR.
No need to 
repeat at pre-
dose Day 1 if 
screening 
assessments 
were performed 
within 14 days 
of first dose.
X
CT
Must be 
completed within 
4 weeks of first 
dose of 
GSK2816126 
and repeated 8 
weeks after 
dosing is 
initiated.  Every 
12 weeks 
thereafter.
X
X
Xd
Positron 
emission 
tomography 
(PET)
The use of 
standalone PET or 
PET in combination 
with CT scan is 
optional. 
Standalone PET 
dose not replace 
CT.
Xe
Xe
Xd,e
Bone Marrow 
biopsy
See Section 7.7
X
Xf
Xf
B symptoms
See Section 7.7
X
X
X
X
X
X
Disease 
assessment
Baseline disease 
identified at 
screening and 
repeated every 8 
weeks 
X
X
X d
ECOG 
Performance 
status 
See Appendix 2
X
X
X
X
X
Study Medication
GSK2816126 
Dosing
Dosed 2x weekly at least 3 days apart (3 weeks on/1 
week off)


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a.
A subject is to receive two doses per week which should be given 3 days apart. If there is a need to change 
scheduling, the scheduled days of the week can change as long as there are 3-4 days between doses.  Up 
to 5 days between doses is permitted for exceptional circumstances.
b.
Timings for in-house on-drug ECGs are pre-infusion, at the end of infusion, before bed, and before 
discharge the next morning for Day 1 of cycle 1 only.  Other protocol-mandated ECGs should be performed 
pre-infusion and at the end of infusion (Section 7.3.4).
c.
Retention of screen-failure tumor tissue: all or a portion of archival or fresh biopsy tissue from screen-failure 
subjects, used for central testing of GCB-DLBCL or EZH2 mutation status, will be retained.  This tissue may 
be used in the validation of potential diagnostic assays to detect EZH2 mutations and/or for GCB-DLBCL 
subtyping.
d.
If the Follow-up visit ≥ 12weeks from the previous response scan time point, scans should be obtained to 
confirm/ evaluate response.  
e.
Standalone PET dose not replace CT.  Diagnostic CT is the preferred method of disease assessment.  
PET/CT may be used as an alternative at the investigator’s discretion.  
f.
Only if initially and/or previously positive & required for CR or as clinically indicated.
Synopsis and Section 5.2.3
PREVIOUS TEXT
Exclusion Criteria
Deviations from exclusion criteria are not allowed because they can potentially 
jeopardize the scientific integrity of the study, regulatory acceptability or subject safety.  
Therefore, adherence to the criteria as specified in the protocol is essential.
Subjects meeting any of the following criteria must not be enrolled in the study:
1
Currently receiving cancer therapy  (chemotherapy, radiation therapy, 
immunotherapy or biologic therapy) (permitting corticosteroids to control 
systemic or local symptoms, up to a dose of 10 mg prednisolone or equivalent 
daily and stable for at least 2 weeks prior to enrollment).
REVISED TEXT
Exclusion Criteria
Deviations from exclusion criteria are not allowed because they can potentially 
jeopardize the scientific integrity of the study, regulatory acceptability or subject safety.  
Therefore, adherence to the criteria as specified in the protocol is essential.
Subjects meeting any of the following criteria must not be enrolled in the study:
1
Currently receiving cancer therapy  (chemotherapy, radiation therapy, 
immunotherapy or biologic therapy) (permitting corticosteroids to control 
systemic or local symptoms, up to a dose of 10 mg prednisolone or equivalent 
daily and stable for at least 2 weeks 7 days prior to enrollment).


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AMENDMENT [3]
Where the Amendment Applies
This amendment applies to all investigator sites participating in this study.  
Summary of Amendment Changes with Rationale
Based on emerging data, addition of solid tumor malignancies and other NHLs to Part 1 
of the study and transformed follicular lymphoma subjects to Part 2.  Multiple myeloma 
subjects have been added to both Part 1 and Part 2.  The protocol title, study rationale, 
objectives, endpoints, hypotheses, inclusion/exclusion criteria, background, preclinical 
pharmacology and safety, risk/benefits, investigational plan, population rationale, T&E 
table, tumor biomarker analysis have all been updated to reflect these changes. 
RECIST criteria and multiple myeloma response criteria have also been added. A 
description of genetic research has been added to the Appendix 8.  To accommodate 
these changes we have also augmented the number of subjects, evaluation of futility, data 
management and statistical analysis.  
Other additions include dose adjustment for hematologic and non hematologic toxicity, 
description of the investigational product and time windows for the PK sample collection 
table.  We also updated the Prohibited Meds table 13 and table 14 and removed the PD 
analysis from Part 2 of the study.  
List of Specific Changes
Title page
REVISED TEXT
Title:
A phase I open-label, dose escalation study to investigate the 
safety, pharmacokinetics, pharmacodynamics and clinical 
activity of GSK2816126 in subjects with relapsed/refractory 
diffuse large B cell lymphoma, transformed follicular 
lymphoma, other Non-Hodgkin’s lymphomas, solid tumors and 
multiple myeloma
REVISED TEXT
Description: This is an open-label, multicenter, 2-part study to determine the 
recommended Phase 2 dose (RP2D) for GSK2816126 given twice weekly by IV infusion.  
Part 1 will be conducted in adult subjects with relapsed/refractory diffuse large B cell 
lymphoma (DLBCL), transformed follicular lymphoma (tFL), other Non-Hodgkin’s 
lymphomas (NHL), solid tumors and multiple myeloma (MM).  Expansion cohorts 
(Part 2) are planned to further explore clinical activity of GSK2816126 in subjects with


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EZH2 wild type and EZH2 mutant positive germinal centre B-cell like diffuse large B
cell lymphoma (GCB-DLBCL), tFL and MM.
Subject: Relapsed, refractory, Phase I study, dose escalation study, GSK2816126, 
diffuse large B cell lymphoma, transformed follicular lymphoma, NonHodgkin’s 
lymphoma, solid tumors, multiple myeloma. 
Author (s):
Statistics, Oncology TA Group, USA
Cancer Research Epigenetics Management, USA
Clinical Statistics, USA
Molecular Medicine Management, USA
Pre-Clinical Safety Assessment, USA
Cancer Research Epigenetics Management, USA 
Clinical Pharmacology Modeling & Simulation, USA
Non-Clinical Safety Assessment, USA
Global Clinical Operational Sciences, USA
Global Clinical Operational Sciences, USA
Precision Medicine and Diagnostics, USA
Cancer Research Epigenetics Management, USAWhite,
Global Regulatory Affairs, USA
Sponsor Signatory:
REVISED TEXT
Vicki Goodman, MD Chris Carpenter, MD, PhD
Director, Clinical Development VP, DPU Head Cancer 
Epigenetics
Date
PPD


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Sponsor/Medical Monitor Information Page
REVISED TEXT
Medical Monitor and Sponsor Contact Information:
Role
Name
Day Time 
Phone 
Number
After-hours 
Phone/Cell/
Pager 
Number
Fax Number
GSK Address
Primary 
Medical 
Monitor
MD
MD, PhD
1250 South Collegeville Rd
Mailstop UP 4410
Collegeville, PA 19426, USA
Secondary 
Medical 
Monitor
MD
MD, 
PhD 
1250 South Collegeville Road,
Mailstop UP4400UP4410
Collegeville, PA 19426, USA
 
Investigator PROTOCOL Agreement Page
REVISED TEXT
For protocol number EZH117208
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.
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


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LIST OF ABBREVIATIONS
Added the abbreviations tFL (Transformed Follicular Lymphoma), CRPC (Castrate 
resistant prostate cancer) and MM (Multiple Myeloma). 
PROTOCOL SYNOPSIS
REVISED TEXT
PROTOCOL TITLE: A phase I open-label, dose escalation study to investigate the 
safety, pharmacokinetics, pharmacodynamics and clinical activity of GSK2816126 in 
subjects with relapsed/refractory diffuse large B cell lymphoma and, transformed 
follicular lymphoma, other Non-Hodgkin’s lLymphomas, other solid tumors and multiple 
myeloma. types
STUDY RATIONALE: Current data from GSK2816126 preclinical development 
indicate a potential to inhibit the Enhancer of Zeste 2 (EZH2) enzyme component ofthe 
Polycomb Repressive Complex 2 and that this inhibition may have clinical utility in the 
treatment of certain lymphomas, including DLBCL and transformed FL. Relapsed and/or 
refractory DLBCL and transformed FL have an overall poor outlook. This is the first 
study of this agent to be conducted in subjects with these relapsed and/or refractory 
lymphoma malignancies for which no standard therapies are anticipated to result in a 
durable remission.
STUDY RATIONALE:  Enhancer of zeste homolog 2 (EZH2), a component of the 
Polycomb Repressive Complex 2 (PRC2), mediates transcriptional repression of 
target genes through tri-methylation of histone H3 on lysine 27 (H3K27me3). EZH2 
and H3K27me3 are dysregulated in many cancers through diverse pathways. While 
EZH2 mutation plays a significant role in progression of certain lymphomas, data 
from prostate, breast, and several other tumors have demonstrated that increased 
EZH2 expression correlates with increased aggressiveness of tumors and poor 
prognosis. 
GSK2816126 is a selective and potent inhibitor of wild-type and mutant EZH2 
capable of decreasing H3K27me3 levels in all cell types examined. EZH2 inhibition 
has been shown to decrease the growth of several cell lines derived from EZH2 wild 
type (WT) and mutant lymphomas, SNF5-mutant malignant rhabdoid tumors, 
multiple myeloma, AML, neuroblastoma, prostate, breast, skin and colon cancers. 
Most of these cancers have an overall poor outlook either because of lack of any 
effective therapy or standard therapies do not result in a durable remission. This first 
study of this agent will be conducted in subjects with non-Hodgkin lymphomas, 
especially germinal center B-cell diffuse large B-cell lymphoma (GCB-DLBCL) and 
transformed follicular lymphoma (t-FL), and subjects with solid tumors and multiple 
myeloma (MM) who have relapsed or are refractory to prior therapies and have a 
high degree of unmet medical need in terms of available treatment options.   


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
STUDY OBJECTIVES, ENDPOINTS AND HYPOTHESES:
Part 1 Objectives
Part 1 Endpoint

To confirm tumor EZH2 and GCB-DLBCL 
status

To investigate the mechanism of action and 
additional indicators of sensitivity and 
resistance to GSK2816126

To generate samples (data reported 
separately) with which to investigate the 
potential for GSK2816126 to affect 
cytochrome P450 (CYP) 3A4 enzyme 
activity

Tumor gene expression profile (GEP) for 
confirmation of GCB-DLBCL status

Tumor baseline genetic profiles, response

Samples to assess a potential change in 4b-OH 
cholesterol to cholesterol ratio in plasma following 
repeat dosing of GSK2816126 (data reported 
separately)
No formal statistical hypotheses are being tested in Part 1: Phase I dose escalation.  Analysis of the data 
obtained from Part 1 will only utilize descriptive methods


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
STUDY OBJECTIVES, ENDPOINTS AND HYPOTHESES:
Part 2 Objectives
Part 2 Endpoints
Primary

To determine clinical activity of 
GSK2816126 ina cohorts of subjects 
with EZH2 mutant and wild type 
germinal center B-cell-like diffuse 
large B-cell lymphoma (GCB-DLBCL 
and in a cohort of subjects with 
GCB-DLBCL harboring mutations in 
the EZH2 genetFL and subjects with 
MM

Objective response rate (% of 
subjects achieving CR and PR per
response criteria)
Secondary

To determine the safety, tolerability 
of the selected IV dose of 
GSK2816126

To characterize the population PK of 
GSK2816126

To evaluate the relationship between 
exposure and safety/efficacy/PD
parameters 

To begin to characterize the 
durability of response and 
progression free survival with 
GSK2816126

AEs, SAEs, DLTs, withdrawals due to 
AEs, dose interruptions and reductions,  
and changes in safety assessments (e.g., 
clinical laboratory parameters, vital signs, 
and cardiac parameters)

Population PK parameters for 
GSK2816126 including clearance (CL), 
and volume of distribution (Vd) and 
relevant covariates which may influence 
exposure (e.g. age, weight, or disease 
related covariates).

GSK2816126 exposure markers (e.g. 
dose, concentration, Cmax, or AUC) and 
safety/efficacy/PD responses. 
Pharmacodynamic response assessed by 
change from baseline in tri-methylation of 
H3K27me3

Duration of response (DoR)

Progression-free survival (PFS) 
Exploratory

To confirm tumor EZH2 and GCB-
DLBCL status

To identify biomarkers predictive of 
response or resistance to 
GSK2816126.

To investigate the mechanism of 
action of GSK2816126 by evaluating 
changes in gene expression profiles

Tumor gene expression profile (GEP) for 
confirmation of GCB-DLBCL status

Evaluation of wild-type (WT) subject 
tumors for the presence of additional, 
undefined, mutations in the EZH2 gene

Deoxyribonucleic acid (DNA), ribonucleic 
acid (RNA) and protein markers in tumor 
and blood
Hypothesis
The primary goal of Part 2 is to detect whether administration of GSK2816126 could lead to a 
clinically meaningful response rate of at least 30% in subjects with GCB-DLBCL compared to 
a 10% or less response rate suggesting inadequate clinical activity in subjects with GCB-
DLBCL.  This will be conducted by testing the null hypothesis that P0≤10% versus the
alternative that P1≥30%, assuming the maximum response rate for an ineffective drug is 


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Part 2 Objectives
Part 2 Endpoints
10% and the minimum response rate for an effective drug is 30%.
The primary objective of Part 2 is to determine whether administration of GSK2816126 has a 
potentially clinically meaningful response rate. 

In subjects with GCB-DLBCL, this will be determined in each EZH2 mutation status 
cohort (wild type and mutant) by testing the null hypothesis that the response rate is 
≤10%, with about 90% power when the true response rate is 30%.  

In subjects with tFL, this will be determined in each EZH2 mutation status cohort by 
testing the null hypothesis that the response rate is ≤5%, with about 80% power when 
the true response rate is 25%. 
In subjects with MM, this will be determined by testing the null hypothesis that the response 
rate is ≤5%, with about 85% power when the true response rate is 20%.  

STUDY DESIGN:  This study is divided into 2 parts; Part 1 of the study is a dose 
escalation phase to select the recommended Part 2 dose (RP2D) based on the safety, 
PK, and PD profiles observed after IV administration of GSK2816126.  Eligible 
subjects with relapsed/refractory DLBCL and, transformed FL malignancies, other 
Non Hodgkin’s lymphomas (NHL) and solid tumor types will be enrolled in the 
dosing cohorts until a RP2D is established.  Subjects may continue treatment in the 
study until disease progression, unacceptable toxicity, or withdrawal of consent.  
Expansion cohorts (Part 2) are planned in subjects with MM, and in subjects with 
both EZH2 mutant positive and EZH2 WT GCB-DLBCL and tFL to further explore 
clinical activity at the RP2D.

NUMBER OF SUBJECTS:  Approximately 100 169 subjects worldwide (inclusive 
both Parts 1 and 2).

INCLUSION/EXCLUSION CRITERIA:
Part I: Inclusion Criteria 
3. Tumor type criteria:  

Relapsed/refractory NHL that meets one of the following criteria:
o
Diffuse large B cell lymphoma or transformed follicular lymphoma 
relapsed after, or refractory to at least one prior chemotherapy 
regimen (e.g., rituximab, cyclophosphamide, doxorubicin, vincristine, 
prednisone [R-CHOP]) AND  not a candidate for standard salvage 
regimens or autologous stem cell transplant (e.g., due to age, 
comorbid conditions or failure to respond to salvage chemotherapy).  
Local confirmation of lymphoma subtype (e.g. GCB-DLBCL) is 
allowed for enrollment but must be confirmed through central 
laboratory testing.
o
DLBCL or transformed FL relapsed after or refractory to at least two 
prior chemotherapy regimens.


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o
Other NHLs that have failed at least one prior line of therapy and for 
which there is no standard salvage regimen.

Relapsed and/or refractory MM that have failed prior standard therapy and 
for which there is no standard salvage regimen.

Solid tumors (RECIST evaluable, with the exception of castrate resistant 
prostate cancer (CRPC)) at least one and not more than three standard of care 
chemotherapeutic regimens, or tumor for which there is no approved therapy, 
or for which standard therapy is refused.  
4. DLBCL and tFL: Availability of archival tissue, or willingness to undergo fresh 
biopsy for: confirmation of GCB-DLBCL status (DLBCL subjects); retrospective 
central testing of EZH2 mutation status (DLBCL ,and tFL subjects).For all other 
tumor types: availability of either archival tissue or fresh biopsies. 
5. Must have a pre-existing central venous access such as a port, Hickmann catheter, 
or a peripherally inserted central catheter (PICC line) or be willing and able to 
have one inserted.
Inclusion criteria no. 9:
The laboratory value for Adequate organ system function of prothrombin 
time/international normalization ratio (PT/INR) and partial thromboplastin time 
(PTT), under hematology section was changed from 1.5 x upper limit of normal 
(ULN) to ≤1.5 x ULN  
System
LABORATORY VALUES
Hematologic
  ANC
1.2 x 109/L  
  Hemoglobin
9 g//dL 
  Platelets
75x 109/L  
 Platelets for Subjects with MM
≥ 50,000 (transfusion independent)
 PT/INR and PTT
≤1.5 x ULN
Hepatic
  Albumin
2.5 g/dL
  Total bilirubin
1.5 times ULN
 AST and ALT
2.5  times ULN without liver metastases
5 times ULN if documented liver metastases
Renal
Serum Creatinine
1.5 mg/dL 
or
Calculate Creatinine Clearancea, b  OR            
24 hr urine Creatinine Clearance
50 mL/min                                                              
≥50mL/min
Reproductive/Endocrine
Testosterone 
<50ng/dL (only for subjects with CRPC)
Cardiac
Left Ventricular Ejection Fraction (LVEF)
≥LLN (minimum of 50% LVEF) by ECHO  or MUGAc


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Abbreviation(s): ANC, absolute neutrophil count; ALT, alanine aminotransferase; AST, aspartate aminotransferase; 
ECHO, echocardiogram; INR, international normalization ratio, MUGA, multigated (radionuclide) angiogram; PT, 
prothrombin time, PTT, partial thromboplastin time, ULN, upper limit of normal , LLN, lower limit of normal.
4.
Calculated by Cockcroft-Gault formula
5.
For MM subjects, adequate renal function is defined as serum creatinine ≤ 2.5 mg/dL OR creatinine clearance 
(either calculated or obtained via 24 hr urine collection) ≥ 30 mL/minECHO is the preferred method
Part 2: Inclusion Criteria
1. In addition to inclusion criteria listed for Part 1, Part 2 will enroll GCB-DLBCL, tFL 
and MM subjects only. 
2. Lymphoma subjects will be required to undergo EZH2 mutation testing. This will 
require availability of archival tissue, or willingness to undergo fresh biopsy, for 
central testing of EZH2 mutation status.
3. Based on the results of the mutation test, lymphoma subjects may be enrolled in one 
of four cohorts:

GCB-DLBCL EZH2 mutant cohort: 
o
Tumors must contain one, or more, of the following EZH2 activating 
mutations: Y641F; Y641N; Y641S; Y641H; Y641C; A677G; and/or 
A687V

GCB-DLBCL EZH2 wild type cohort:
o
Tumors that do not contain one of the above mutations
o
Subjects with tumors harboring EZH2 mutations other than the seven 
outlined above will be enrolled in the EZH2 wild type cohort

tFL EZH2 mutant cohort: 
o
Tumors must contain one, or more, of the following EZH2 activating 
mutations: Y641F; Y641N; Y641S; Y641H; Y641C; A677G; and/or 
A687V

tFL EZH2 wild type cohort:
o
Tumors that do not contain one of the above mutations
o
Subjects with tumors harboring EZH2 mutations other than the seven 
outlined above will be enrolled in the EZH2 wild type cohort
4. Subjects should have accessible tumor and willingness to undergo two biopsies.  
Subjects for whom biopsies are not feasible will be eligible for enrollment at the 
discretion of the GSK medical monitor.  Contact GSK medical monitor for 
confirmation of enrollment and study entry if biopsies are not feasible.


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Exclusion Criteria
Exclusion criteria no.1
Currently receiving cancer therapy  (chemotherapy, radiation therapy, 
immunotherapy or biologic therapy) (permitting corticosteroids to control systemic 
or local symptoms, up to a dose of 10 mg prednisolone or equivalent daily and stable 
for at least 7 days prior to enrollment).

Hormonal (e.g., anti-androgen) therapies for prostate cancer must be 
stopped 4 to 6 weeks prior to enrolment.  Subjects with prostate cancer may 
remain on luteinizing hormone releasing hormone (LHRH) agonists.  
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.
Exclusion criteria no. 8:
Unresolved toxicity greater than Grade 1 National Cancer Institute – Common 
Terminology Criteria for Adverse Events (NCI-CTCAE) version 4 from previous 
anti-cancer therapy, with the exception of alopecia and peripheral neuropathy [NCI-
CTCAE, 2009]. 
Lymphoma subjects with ≤ Grade 3 lymphopenia can be enrolled at the 
discretion of the investigator

STATISTICAL METHODS: Subject demographic and safety data 
will be collected on electronic case report forms (eCRFs).  All data 
will be pooled and descriptive safety analyses summarized and listed 
by cohort at study conclusion.  Part 2 of the study is designed to 
evaluate preliminary efficacy.  A futility assessment will be 
conducted after data are available from the first 12 subjects in Part 2 
and after that until up to 30 GCB-DLBCL subjects and 16 tFL 
subjects have been enrolled in each of the EZH2 WT and EZH2 
mutant cohorts.  Also, in the MM cohort a futility assessment will be 
conducted after data are available from the first 13 subjects in Part 2 
and after that until up to 37 subjects.

PHARMACOKINETIC/PHARMACODYNAMIC 
MEASUREMENTS: There will be extensive serial blood sampling 
for PK and PD measurements in Part 1 of this study with limited 
blood sampling performed on all subjects in Part 2.  Urine and bile 
may be collected in some subjects in the Part 1 PK/PD expansion 
cohort. Single safety PK blood draws may be collected for subjects 
with severe adverse events or adverse events of concern.  In addition, 
pre-treatment and post-treatment tumor tissue samples will be 
optional for Part 1, but required for all subjects in Part 2 (unless
discussed with medical monitor) to evaluate target engagement and 


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effects of GSK2816126 on tumor biology.  Mandatory collection of 
pre-treatment and post-treatment biopsies will be implemented in 
Part 1 PK/PD cohorts based on outcome of preliminary PD data in 
surrogate tissue (e.g. PBMCs from blood).
Section 1:INTRODUCTION
REVISED TEXT
1.1. Background
Enhancer of Zeste 2 (EZH2) is the enzyme component of the Polycomb Repressive
Complex 2 (PRC2) that methylates histone H3 on lysine 27 (H3K27), resulting in
epigenetic silencing of target gene expression. PRC2 activity is essential for maintaining
the self-renewal capacity of embryonic and adult stem cells and the dynamic regulation
of this activity is critical for proper development and differentiation.
Enhancer of zeste homolog 2 (EZH2) is the catalytic subunit of the Polycomb Repressive 
Complex 2 (PRC2) responsible for maintaining transcriptional repression of target genes 
through tri-methylation of histone H3 on lysine 27 (H3K27me3). PRC2 activity is 
essential for maintaining the self-renewal capacity of embryonic and adult stem cells, and 
the dynamic regulation of this activity is critical for proper development and 
differentiation. 
EZH2 and H3K27me3 are dysregulated in nearly all cancers through numerous pathways 
including 1) recurrent gain-of-function heterozygous mutations in germinal center B-cell 
(GCB) diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), melanoma, 
and parathyroid adenoma, 2) EZH2 over-expression in numerous other aggressive tumors 
including those from prostate, breast, lung, liver, bladder, head and neck, skin, and 
kidney, and 3) inactivating mutations in UTX, an H3K27 demethylase that acts in 
opposition to EZH2, described in numerous tumor types including transitional cell
bladder carcinoma, esophageal squamous cell carcinoma, renal cell carcinoma, multiple 
myeloma, and subgroup 4 medulloblastoma (McCabe & Creasy 2014). Furthermore, data 
from prostate, breast, and several other tumor types have demonstrated that increased 
EZH2 expression correlates with increased aggressiveness of tumors and poor prognosis. 
In the B-cell lineage, EZH2 is required by germinal center B-cells, which are the cells of 
origin of the most common forms of Non-Hodgkin’s Lymphomas (NHL). GC derived 
DLBCLs are mostly addicted to EZH2 and require its histone methyltransferase activity 
for their survival. Recently, somatic activating mutations in EZH2 have been identified in 
follicular lymphoma (FL) and GCB-DLBCL [Morin, 2010; Morin, 2011; Pasqualucci, 
2011; Ernst, 2010].   The frequency of the most prevalent mutation, Y641, is 7-27% in 
FL and 22% in DLBCL [Bodor, 2013].  Biochemical studies have demonstrated that 
Y641, A677 and A687 mutants exhibit an altered substrate preference and catalytic 
efficiency to enhance the generation of H3K27me3.  Consistent with these biochemical 
data, primary lymphomas and lymphoma cell lines harboring EZH2 mutations have 
elevated levels of H3K27me3.  Mutant EZH2 maintains the proliferation, survival and 
blocks terminal differentiation of DLBCL cells.


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1.2.1. Pharmacokinetics of GSK2816126 in Humans
GSK2816126 pharmacokinetics (PK) havehas not yet been completely evaluated in 
humans. Whole blood human clearance for GSK2816126 was predicted from three 
species (mouse, rat and dog) using maximum life span power-law allometry to be around 
8.2 mL/min/kg. Volume of distribution was predicted from simple power-law allometry 
to be 4.8 L/kg and half-life around 6.5 hours. A 70 kg adult therefore has a predicted total 
blood clearance of 35 L/hr and a total blood volume of distribution of 336 L.
1.2.2. Pre-Clinical Pharmacology & Safety of GSK2816126
In Vitro Testing
In cell culture, GSK2816126 induces loss of H3K27me3 in both EZH2 WT and mutant 
cell lines from diverse tumor types with the half maximal inhibitory concentration (IC50) 
values ranging from 10 - 252 nM independent of EZH2 mutation status [McCabe, 2012].  
In proliferation assays using a panel of B-cell lymphoma cell lines, those of DLBCL 
origin with EZH2 activating mutations are the most sensitive to GSK2816126.  The 
second most sensitive tumor type evaluated was multiple myeloma where a majority of 
cell lines exhibited growth inhibition when exposed to GSK2816126. However, the 
growth of a subset of several other tumor types including NHL, SNF5-mutant malignant 
rhabdoid tumors, AML, neuroblastoma, prostate, breast, skin, and colon cancers is also 
sensitive to EZH2 inhibition.  
Time course studies demonstrate that inhibition of H3K27me3 is maximal after 2 days. 
Inhibition of cell proliferation begins as early as 2 days of EZH2 exposure but in some 
cases takes up to 2 weeks to reach maximal growth inhibition.  Both cytostatic and 
cytotoxic responses are observed among sensitive cell lines.  Together, these data indicate 
that global H3K27me3 can be used to assess on-target activity of an EZH2 inhibitor in 
both responsive and unresponsive tumors, and that  EZH2 activating mutations may 
provide a strong marker for subject selection in clinical studies.
Nonclinical Pharmacology  
Paragraph 1
In severe combined immunodeficiency (SCID) mice bearing subcutaneous xenografts 
derived from human DLCBL, multiple myeloma, or prostate cancer cell lines, 
GSK2816126 inhibits H3K27me3 after repeated daily or twice weekly dosing over 10-11 
days.  The PD response is durable as H3K27me3 levels did not return to pre-dose levels 
by 7 days after the last dose. In mice bearing subcutaneous xenografts of EZH2 mutant 
lymphomas, 90-100% tumor growth inhibition is observed with daily or twice weekly 
dosing over a five week period with or without a one week drug holiday in the third 
week. In some models, tumor stasis or complete tumor eradication is observed upon 
cessation of dosing. Together, these pre-clinical PD and efficacy data indicate a treatment 
cycle of twice weekly dosing of GSK2816126 for 2 or 3 weeks followed by a 1 week 
drug holiday should effectively reduce H3K27me3 levels in the tumor be efficacious.


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Paragraph 3
Infusion rate and/or concentration-dependent, histamine reactions, which began within 
minutes of dose initiation, were observed at ≥300 mg/kg in dogs (Cmax 66.5 to 
130 µg/mL) and 300 mg/kg (Cmax 33.9 to 54.2 µg/mL) in rats.  In dogs, histamine 
reactions resulted in discontinuation of dosing.  In rats, Histamine-related decreased 
body temperature, along with increased heart rate (HR) and decreased blood pressure 
(BP) likely led to mortality in restrained, but not in unrestrained, rats given an IV 
infusion of 300 mg/kg (5 mL/kg/hr for 4 hours).  These effects could be ameliorated by 
discontinuation of dosing, administration of diphenhydramine hydrochloride, 
degranulation of mast cells prior to GSK2816126 dosing, and/or lengthening of the 
infusion time to reduce Cmax. These observations tended to occur only during the first 
exposure to the drug and not on subsequent administrations.  Human subjects will be 
monitored during the infusion for evidence of histamine release related symptoms and 
treated as needed (e.g., with anti-histamines).  Subsequent subjects treated at that dose or 
treated as needed (e.g., with anti-histamines) may be treated prophylactically with 
antihistamine and/or by lengthening the infusion duration.
Paragraph 4
In dogs, a mild, reversible dose dependent decrease in minute (up to 128 mL/min/kg; 
49%) and tidal volume (8 mL/kg; 56%) at 100 mg/kg and an elevation in QTcR interval 
at 30 (maximum increase of 12 msec or 5%) and 100 (maximum increase of 18 msec or 
8%) mg/kg were observed following the end of a single 8 hour infusion.  These effects 
did not directly correlate with peak GSK2816126 blood levels as the onset was 4-7 hours 
following the end of the infusion.  QTcR interval elevations were not observed following 
repeat dosing.  
Paragraph 5
A direct effect on human ether à go-go-related gene (hERG) channel repolarization is 
unlikely (IC25 of 54.2 µM; 28.61 µg/mL), however, GSK2816126 did block hERG 
current density in vitro consistent with an effect on hERG channel trafficking.  The 
mechanism for this change is unclear.  Evaluation of the QTc interval has been 
incorporated into the initial this clinical study protocol.s including this one.


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Section 1.3: Benefit:Risk Assessment
REVISED TEXT
1.3.1. Risk Assessment
Potential Risk of 
Clinical Significance
Data/Rationale for Risk
Mitigation Strategy
Cardiovascular – QT 
prolongation
QTc prolongation was observed (up to 
8%; 18 msec in dog) following the end of 
a single 8 hour infusion
Effect did not directly correlate with peak 
GSK2816126 blood levels; onset was 4-7 
hours following the end of the infusion; 
reversed within 3-8 hours following onset
Effects not observed following repeat 
dosing in dogs
No arrhythmias were detected in 
preclinical studies. 
The mechanism for the QTc prolongation 
is unlikely due to a direct effect on hERG 
repolarization as GSK2816126 weekly 
inhibited hERG tail current (IC25 of 
54.2 µM; 28.61 µg/mL).  However, 
GSK2816126 was shown to block hERG 
current density in vitro consistent with an 
effect on hERG channel trafficking.
Protocol includes cardiovascular 
eligibility criteria, laboratory 
assessments (potassium and 
magnesium, cardiac monitoring 
(electrocardiograms [ECGs], 
Holter monitoring during the study, 
and dose stopping/modifications
criteria for the management of QT 
prolongation)
Co-administration of medications 
that are known to prolong the QT 
interval and have a risk of causing 
Torsades de Pointes and drugs 
that have a possible risk of 
Torsades de Pointes are 
prohibited 
All subjects will remain in the 
clinical research unit (CRU) after 
receiving their first dose of study 
medication (Week 1, Day 1) with 
periodic ECGs and Holter 
monitoring for 24 hours.  Subjects 
will not be discharged from the unit
unless their last measured QTc on 
an ECG performed immediately 
prior to discharge after the first 
dose is <500 msec.
Timings for in-house on-drug 
ECGs are pre-infusion, at the 
end of infusion, before bed, and 
before discharge the next 
morning for Day 1 of cycle 1 
only.  Refer to Section 7.1 
(T&E) for other ECG timings
After Day 1 during the first 3 
weeks of treatment and on Day 4 
of subsequent cycles, ECGs will 
be performed pre-infusion and at 
the end of infusion.


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1.3.2. Benefit Assessment
Study EZH117208 is an open-label, dose escalation study and the first study of this agent 
to be conducted in subjects with relapsed and/or refractory DLBCL or transformed FL in 
humans.  GSK2816126 has promising preclinicalgrowth inhibitory activity in DLBCLcell 
lines derived from multiple tumor types, however it is unknown whether GSK2816126 
will have efficacy in patients with these tumors DLBCL  tThus,, thus any potential 
beneficial effect for an individual subject attributable to GSK2816126 is unknown.  Data 
obtained in Study EZH117208 may assist in progressing the knowledge base on 
lymphoma and other tumor types DLBCLand their treatment(s), or help identify 
individuals more likely to benefit or have side-effects from GSK2816126.  Study 
participants may benefit from the medical tests and screening performed during the study.
1.3.3. Overall Benefit: Risk Conclusion
Current data from GSK2816126 preclinical development indicate a potential for clinical 
utility in the treatment of subjects with relapsed and/or refractory DLBCL and/or 
transformed FL, NHL, MM and other solid tumor types. Considering the overall poor 
outlook of these subjects and recognizing the measures taken to minimise risk to subjects 
participating in the Phase I clinical trials, the potential risks identified in association with 
GSK2816126 are justified by the anticipated benefits that may be afforded to subjects 
with the previously mentioned tumor types that have been shown in preclinical models to 
respond to GSK2816126.  
Section 2:OBJECTIVES, ENDPOINTS AND HYPOTHESES
REVISED TEXT  2.1
Part 1 Objectives
Part 1 Endpoint

To confirm tumor EZH2 and GCB-DLBCL 
status

To investigate the mechanism of action and 
additional indicators of sensitivity and 
resistance to GSK2816126

To generate samples (data reported 
separately) with which to investigate the 
potential for GSK2816126 to affect 
cytochrome P450 (CYP) 3A4 enzyme 
activity

Tumor gene expression profile (GEP) for 
confirmation of GCB-DLBCL status

Tumor baseline genetic profiles, response

Samples to assess a potential change in 4b-OH 
cholesterol to cholesterol ratio in plasma following 
repeat dosing of GSK2816126 (data reported 
separately)
No formal statistical hypotheses are being tested in Part 1: Phase I dose escalation.  Analysis of the data 
obtained from Part 1 will only utilize descriptive methods


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REVISED TEXT
2.2
Part 2: Expansion
Part 2 Objectives
Part 2 Endpoints
Primary

To determine clinical activity of 
GSK2816126 in cohorts of subjects 
with EZH2 mutant and wild type 
GCB-DLBCL and tFL and subjects 
with MM To determine clinical 
activity of GSK2816126 in a cohort 
of subjects with EZH2 wild type 
germinal center B-cell-like diffuse 
large B-cell lymphoma (GCB-
DLBCL) and in a cohort of subjects 
with GCB-DLBCL harboring 
mutations in the EZH2 gene

Objective response rate (% of 
subjects achieving CR and PR per
response criteria)
Secondary

To determine the safety, tolerability 
of the selected IV dose of 
GSK2816126

To characterize the population PK of 
GSK2816126

To evaluate the relationship between 
exposure and safety/efficacy/PD
parameters 

To begin to characterize the 
durability of response and 
progression free survival with 
GSK2816126

AEs, SAEs, DLTs, withdrawals due to 
AEs, dose interruptions and reductions,  
and changes in safety assessments (e.g., 
clinical laboratory parameters, vital signs, 
and cardiac parameters)

Population PK parameters for 
GSK2816126 including clearance (CL), 
and volume of distribution (Vd) and 
relevant covariates which may influence 
exposure (e.g. age, weight, or disease 
related covariates).

GSK2816126 exposure markers (e.g. 
dose, concentration, Cmax, or AUC) and 
safety/efficacy/PD responses. 
Pharmacodynamic response assessed by 
change from baseline in tri-methylation of 
H3K27me3

Duration of response (DoR)

Progression-free survival (PFS) 
Exploratory

To confirm tumor EZH2 and GCB-
DLBCL status

To identify biomarkers predictive of 
response or resistance to 
GSK2816126.

To investigate the mechanism of 
action of GSK2816126 by evaluating 
changes in gene expression profiles

Tumor gene expression profile (GEP) for 
confirmation of GCB-DLBCL status

Evaluation of wild-type (WT) subject 
tumors for the presence of additional, 
undefined, mutations in the EZH2 gene

Deoxyribonucleic acid (DNA), ribonucleic 
acid (RNA) and protein markers in tumor 
and blood
Hypothesis
The primary goal of Part 2 is to detect whether administration of GSK2816126 could lead to a 
clinically meaningful response rate of at least 30% in subjects with GCB-DLBCL compared to 
a 10% or less response rate suggesting inadequate clinical activity in subjects with GCB-


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Part 2 Objectives
Part 2 Endpoints
DLBCL.  This will be conducted by testing the null hypothesis that P0≤10% versus the 
alternative that P1≥30%, assuming the maximum response rate for an ineffective drug is 10% 
and the minimum response rate for an effective drug is 30%.
The primary objective of Part 2 is to determine whether administration of GSK2816126 has a 
potentially clinically meaningful response rate. 

In subjects with GCB-DLBCL, this will be determined in each EZH2 mutation status 
cohort (wild type and mutant) by testing the null hypothesis that the response rate is 
≤10%, with about 90% power when the true response rate is 30%.  

In subjects with tFL, this will be determined in each EZH2 mutation status cohort by 
testing the null hypothesis that the response rate is ≤5%, with about 80% power when 
the true response rate is 25%. 
In subjects with MM, this will be determined by testing the null hypothesis that the response 
rate is ≤5%, with about 85%  power when the true response rate is 20%.
Section 3: INVESTIGATIONAL PLAN
REVISED TEXT
3.1. Study Schematic
Part 1
Accelerated Dose Titration followed by 3+3 Dose Escalation
To determine the safety and tolerability of GSK2816126 in subjects with
relapsed/refractory DLBCL  and, transformed FL, other NHLs subjects, solid tumors and 
MM

Part 2
Cohort Expansion in both WT and EZH2 mutation-positive subjects
To determine clinical activity of GSK2816126 in relapsed/refractory GCB-DLBCL and
transformedtFL subjects with WT and EZH2 mutation-positive tumors and MM subjects
3.2. Discussion of Study Design
Paragraph 3
This is a Phase I, open-label, multiple-dose, multicenter, dose-escalation, first-time-in-
human study conducted in two parts.  In Part 1, an accelerated dose titration will be 
employed with one subject per dose level until the first instance of a ≥ Grade 2 drug 
related non-hematological toxicity or dose limiting toxicity (DLT) (Section 3.3.3) occurs. 
Exceptions for except for apre-specified Grade 3 non-serious non-hematological drug 
related adverse events that would allow continuation of accelerated dose escalation are 
listed in Section 3.3.2.1. or dose limiting toxicity (DLT) (Section 3.3.3).


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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
information fromof prior cohorts, as well as the recommended predicted dose from 
Neuenschwander B- a Continuous Reassessment Method (N-CRM) design analysis
[Neuenschwander, 2008].  The N-CRM is a type of Bayesian adaptive dose-escalation 
scheme.  The method is fully adaptive and makes use of all the DLT information 
available at the time of each dose assignment.  The Fixed and Adaptive Clinical Trial 
Simulator (FACTS) will be used to conduct the N-CRM analysis.  The DLT information 
on all subjects enrolled in the trial are is used to update the estimated dose-toxicity 
relationship and to provide supportive information in addition to the 3+3 design in the 
next escalation/de-escalation decision.
After the accelerated dose titration, subjects will be enrolled in a standard 3+3 dose 
escalation design. Dose escalation will continue until an RP2D is determined or until an 
MTD or a dose of 3000 mg twice-weekly is reached [Maximum Feasible Dose (MFD)]. 
After the RP2D (or MTD/MFD) has been determined in Part1, then Part 2 expansion 
cohorts will be opened. In Part 2, subjects with will be assigned to one of two four
cohorts based on disease and EZH2 mutation status.
Safety assessments will be performed weekly for the first 4 weeks and then at regular 
intervals as outlined in the Time and Events Table (Section 7.1). 
Disease response in lymphoma and solid tumor subjects will be assessed everyas 
described in the T&E table (Section 7.1).
3.3.2
3+3 Dose Escalation Phase
Paragraph 3
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 N-CRM analysis described in 
Section 12.
Part 1 PK/PD cohorts:  Any dose level may be expanded up to 12 subjects in order to 
collect adequate data on safety, pharmacokinetics, or pharmacodynamics. Urine, bile, and 
additional blood samples may be collected following repeated administration for drug 
metabolite profiling and to obtain information on renal excretion of GSK2816126.  
Initially, optional pre- and post-treatment tumor biopsies will be requested.  At MTDIf 
preliminary PD data warrant, mandatory collection of pre- and post-treatment tumor 
biopsies willmay be required for enrollment in a PK/PD a cohort.  Mandatory biopsies 
may be instituted:at lower dose levels once evidence of target engagement has been 
demonstrated in surrogate tissue (e.g. H3K27me3 from PBMCs in blood); or if sufficient


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3.3.2.1. Toxicity Leading to Termination of Accelerated Titration 
The following events will result in an end to accelerated dose escalation: 
REVISED POINT 
• Any Grade 2 or higher adverse event that is considered related to the study 
medication except for alopecia, drug-related Grade 3 fatigue, or asthenia; diarrhea, 
nausea, and/or vomiting that respond to standard medical care within 48hrs; or Grade 
3 or higher electrolyte abnormalities unrelated to underlying malignancy and 
corrected within in 48 hrs) that is considered related to the study medication.  
3.3.3. Dose Limiting Toxicity 
Table 3 
Dose-Limiting Toxicity Criteria 
REVISED ROW 
Toxicity 
DLT Definition 
Hematologic 
• 
Grade 4 absolute neutrophil count (ANC) for >7 days 
• 
Febrile neutropenia (defined as concurrent Grade 4 neutropenia and 
• 
fever >38.5C and lasting >24 hrs) ( according to CTCAE v.4.0 criteria)  
• 
Grade 4 thrombocytopenia or anemia for > 7 days 
Non-hematologic 
• 
Grade 3 or greater nausea, vomiting, or diarrhea that does not respond 
to standard medical care within 72 48 hours.  
• 
Grade 3 or greater clinically significant non-hematologic toxicity per 
NCI-CTCAE, v 4.0   
 
 
1.4. 
Part 2: Expansion Cohort 
Revised Text 
Part 2:  Expansion Cohorts in both wild type and EZH2 mutation-positive GCB-
DLBCL and tFL subjects and subjects with MM  
Lymphoma subjects will be enrolled based on EZH2 mutation status.  There will be up to 
30 subjects per group in both GCB-DLBCL cohorts, up to 16 subjects per group in both 
tFL cohort s, and up to 37 subjects with MM.  Multiple myeloma subjects will be selected 
independent of their EZH2 mutation status.   
 
Once preliminary PD data have been reviewed, the planned sample collection study 
day(s) may be revised based on newly available data to ensure appropriate monitoring. 
These changes must be approved and documented by GSK, but will not constitute a 
protocol amendment. 
 
 


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Further evaluation of futility:
The methodology is based on the predictive probability of success if enrollment continues 
until all planned subjects are recruited to 30 subjects[Lee, 2008]. The predictive 
probability design is similar to a Green-Dahlberg design in that it allows for early 
stopping for futility.  The differences are that the predictive probability design allows for 
evaluation of stopping rules after each subject, rather than at only two stages, once a 
minimum number of subjects are evaluable.  In this particular study, we will stop only for 
futility.  While the two designs have similar type I and type II error rates, the probability 
of early termination is greater with the predictive probability design.
In both EZH2 mutation status cohorts, after After 12 subjects have been enrolled in each 
cohort to examine safety and efficacy, the number of observed confirmed responses will 
guide further enrollment according to the rules summarized in Figure 1. A maximum of 
30 subjects per cohort will be enrolled at the RP2D. All available data will be considered 
in making enrollment decisions.
Figure 1
Diagram of Stopping Rules for EZH2 Cohort Expansion: 
GSK2816126
Number of Responses
Number of 
Subjects
0
1
2
3
4
5
≥6
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
Figure 1 Legend:  The shaded regions are the specific regions for stopping the study for futility.  For instance, if there is 
only one response in fourteen subjects, then the predictive probability for success will be 5.0% or less (the futility 
criterion) and the study will be stopped.


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In the tFL cohort, after 12 subjects have been enrolled to examine safety and efficacy, the 
number of observed confirmed responses will guide further enrolment according to the 
rules summarized in Figure 2. A maximum of 16 subjects will be enrolled at the RP2D. 
All available data will be considered in making enrollment decisions.
Figure 2
Diagram of Stopping Rules for tFL Cohort Expansion: GSK2816126
Number of Responses
Number of 
Subjects
0
1
2
>3
12
13
14
15
16
Figure 2 Legend:  The shaded regions are the specific regions for stopping the study for futility.  For instance, if there is 
no response in twelve subjects, then the predictive probability for success will be 1% or less (the futility criterion) and 
the study will be stopped.
For the MM cohort: After 13 subjects have been enrolled to examine safety and efficacy, 
the number of observed confirmed responses will guide further enrollment 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.
Figure 3
Diagram of Stopping Rules for MM Cohort Expansion
Number of 
Subjects
0
1
2
3
4
13
14
15
16
17
18
19
20
21
22
23
24
25


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Number of 
Subjects
0
1
2
3
4
26
27
28
29
30
31
32
33
34
35
36
37
The shaded regions are the specific regions for stopping the study for futility.  For instance, if there is no response in 
13 subjects, then the predictive probability for success will be 1% or less (the futility criterion) and the study may be 
stopped.
3.5. Rationale
3.5.1. Rationale for Study
Enhancer of zeste homolog 2 (EZH2)), a component of the Polycomb Repressor 
Complex 2 (PRC2), mediates transcriptional repression of target genes through tri-
methylation of histone H3 on lysine 27 (H3K27me3). EZH2 and H3K27me3 are 
dysregulated in many cancers through diverse pathways. While EZH2 mutation plays a 
significant role in progression of certain lymphomas, data from prostate, breast, and 
several other solid tumors have demonstrated that increased EZH2 expression correlates 
with increased aggressiveness of tumors and poor prognosis. 
GSK2816126 is a selective and potent inhibitor of wild-type and mutant EZH2 capable of 
decreasing H3K27me3 levels in all cell types examined. EZH2 inhibition has been shown 
to decrease the growth of several cell lines derived from EZH2 wild type (WT) and 
mutant lymphomas, SNF5-mutant malignant rhabdoid tumors, multiple myeloma, AML, 
neuroblastoma, prostate, breast, skin and colon cancers. 
Most of these cancers have an overall poor outlook either because of lack of any effective 
therapy or standard therapies do not result in a durable remission. This first study of this 
agent will be conducted in subjects with non-Hodgkin lymphomas, especially germinal 
center B-cell diffuse large B-cell lymphoma (GCB-DLBCL), and transformed follicular 
lymphoma (t-FL), tFL, and subjects with multiple myeloma and solid tumors who have 


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relapsed or are refractory to prior therapies and have a high degree of unmet medical 
need in terms of available treatment options.  
Relapsed and/or refractory DLBCL and transformed FL have an overall poor outlook. 
This is the first study of this agent to be conducted in subjects with these relapsed and/or 
refractory lymphoma malignancies for which no standard therapies are anticipated to 
result in a durable remission. Current data from GSK2816126 preclinical development 
indicate a potential to inhibit the EZH2 enzyme component of the PRC2 and that this 
inhibition may have clinical utility in the treatment of certain cancers including DLBCL, 
SNF5-mutant malignant rhabdoid tumors, multiple myeloma, AML, neuroblastoma, 
prostate, breast, skin, and colon cancerslymphomas, including DLBCL and transformed 
FL.
3.5.2. Rationale for Population
Preclinical studies demonstrate that B-cell lymphomas of DLBCL origin with EZH2 
activating mutations are the most sensitive to GSK2816126; however, the growth of a 
subset of EZH2 wild-typelymphomas, SNF5-mutant malignant rhabdoid tumors, multiple 
myeloma, AML, neuroblastoma, prostate, breast, skin, and colon cancers are also 
sensitive to EZH2 inhibition. There is increasing evidence that a large number of solid 
tumors or subtypes may be driven by EZH2 mutation or over expression. Often, these 
tumors have poor prognosis. Therefore, the study includes subjects with Non-Hodgkin’s 
Lymphoma and enriched for subsets (GCB-DLBCL, tFL) as well as multiple myeloma 
and solid tumors that have relapsed or are refractory to prior treatment with standard of 
care or do not have standard of care available or refuse standard of care therapy. 
Preclinical studies demonstrate that B-cell lymphomas of DLBCL origin with EZH2 
activating mutations are the most sensitive to GSK2816126; however, the growth of a 
subset of EZH2 wild-type lymphomas, SNF5-mutant malignant rhabdoid tumors, 
multiple myeloma, AML, neuroblastoma, prostate, breast, skin, and colon cancers EZH2 
WT DLBCL cell lines and primary DLBCL samples are sensitive to GSK2816126EZH2 
inhibition treatment.  Activating mutations in EZH2 occur in GCB-DLBCL and follicular 
lymphoma, but not lymphomas of ABC (Activated B cell phenotype) origin.  These are 
post-germinal center B cells which are not dependent on EZH2.  In addition, B-cell 
lymphoma cell lines of ABC origin are not sensitive to GSK2816126 [Beguelin, 2013].


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Section 3.8.2. Infusion Reaction Stopping Criteria and Management
REVISED TEXT
3.8.3. 3.8.2.1 Management of Infusion Site Reactions
Infusion Site Reaction
Infusion Site (Histamine) Reaction
Grade 1: 
Continue infusion and closely monitor the subject 
Grade 2/3:
Temporarily interrupt study medication and:
-
Administer diphenhydramine 50 mg or similar 
anti-histamine 
-
provide supportive care
-
may resume infusion once resolved to </= 
grade 1*
-
For grade 3 reactions, corticosteroids may be 
considered 
Grade 4:
-
Discontinue infusion.  Administer 
diphenhydramine, corticosteroids and 
supportive care as above.
-
May consider restarting study treatment at a 
reduced dose or dose level pre-event based on 
discussion with GSK Medical Monitor.
*Recommend following institutional guidelines for re-starting after infusion reactions 
seen with cytotoxic therapy. A general guideline would be as follows:
- Restart under observation at a rate of 25% the original rate for the first 30 mins
- If no reaction, increase infusion rate by 25% of original rate every half hour till full dose 
administered
- If Grade 1 reaction, continue at the rate at which the reaction occurs
ADDED SECTIONS
3.8.3. Dose Adjustment for Non-Hematologic Toxicity
See Table 4 Dose Adjustment Guideline for drug related non-hematologic toxicities 
based on worst grade.


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Table 4
Dose Adjustment Guideline for Drug Related Non-Hematologic Toxicity
Worst Grade
Dose Adjustment
G1
No change in dose
G2
Continue dosing with no change OR
Consider holding for up to 2  weeks for toxicity to resolve to baseline or ≤ Grade 1, then 
continue at the same dose OR dose reduce by at least 25% if the toxicity is considered a 
DLT.
G3 and 4
Hold for up to 2 weeks for toxicity to resolve to baseline or ≤ Grade 1, then dose reduce by 
at least 25%.
If no recovery to ≤Grade 1* or baseline after 14 days, patient should be withdrawn.
If the non-hematologic toxicity or event resolves to baseline or Grade 1 within 14 days 
of stopping therapy, treatment with GSK2816126 may be restarted with at least 25%
dose reduction. For a non-DLT, the treatment with GSK2816126 could restart at a full 
dose, if deemed appropriate.
If the non-hematologic toxicity does not resolve to Grade 1 or baseline within 14 days, 
the subject should be withdrawn from the treatment permanently (Section 6.3).  However, 
if the investigator and GSK Medical Monitor agree that further treatment will benefit the 
subject, treatment can restart with at least 25% dose reduction under weekly clinical 
monitoring.  If the toxicity resolves to Grade 1 or baseline, the dose may be resumed to 
the initial dose level. 
3.8.4. Dose Adjustment For Hematologic Toxicity
3.8.4.1.
For subjects with lymphoma and multiple myeloma:
The treatment may be held for 2 weeks if:

≤5% myeloblasts in bone marrow AND

neutrophil and platelet count did not recover to neutrophils ≥0.5 x 109/L and platelets 
≥25 x 109/L
The treatment may resume as soon as count recovery has occurred (i.e., neutrophils ≥0.5 
and platelets ≥25 x 109/L).
The treatment may be held for additional 1-2 weeks if the neutrophil and platelet count 
did not recover after 2 weeks. 
When the treatment resumes, the dose may be adjusted based on platelet count, i.e., dose 
can be reduced by at least 25% increments up to twice when the platelet count ≤25 x 
109/L (G4 thrombocytopenia) and it is not attributed to the disease. If a subject has 
persistent G4 thrombocytopenia for 4 weeks not attributed to disease or requires platelet 
transfusions for bleeding in the absence of the disease, the subject will be withdrawn 
from the study. 


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3.8.4.2.
For subjects with solid tumors:
- Grade 1 & 2 (platelet count ≥ 50,000): Continue dosing at same dose level with weekly 
or more frequent monitoring as necessary
- Grade 3 (platelet count between 25,000 to <50,000): After discussion with medical 
monitor and using sound clinical judgement, continue at same dose or adjust dose (e.g. 
consider missing one dose or till count recovery to Grade 2). Monitor CBC at least twice 
a week, more frequently if necessary
- Grade 4 (platelet count below 25,000): Interrupt study medication and monitor CBC 
every 2-3 days. If platelet counts recover to Grade 2, discuss with medical monitor 
resuming treatment at the same or adjusted dose based on sound clinical judgement. 
Platelet transfusion is allowed based on institutional guidelines. In case of platelet 
transfusion, hold drug for at least 7 days from day of transfusion, and if platelet counts 
recover to Grade 2 consider initiating treatment at a lower dose using sound clinical 
judgement and after consulting with the GSK medical monitor. Discontinue treatment if 
drug has to be held for >14 days or greater than 2 dose reductions required.
Section 4: INVESTIGATIONAL PRODUCT
4.1.
Description of Investigational Product
Table 5
Investigational Product
REVISED ROW
Route/
Regimen
Delivered as an intravenous solution over 2 - 4 hours Study drug can be diluted 
into saline or dextrose for a final volume of 250ml at ambient temperature and 
normal room lighting up to 48 hours prior to infusion.  PVH, PE and PA bags 
and tubing are all acceptable.  Requires protection from light during 
administration. 


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Section 5: STUDY POPULATION
REVISED TEXT
5.1. Number of Subjects
A maximum of approximately 169 Approximately 100 subjects will be enrolled.   See 
Section 12.4 for sample size assumptions.
The number of dose levels and the level at which the RP2D (or MTD or MFD) is reached 
cannot be determined in advance.  An adequate number of subjects will be enrolled into 
the study to establish the recommended dose(s) for further study.  It is estimated that 40 
subjects will be enrolled into Part 1 (dose-escalation) of the study.  Up to 60 129 subjects 
will be enrolled in Part 2 in five expansion cohorts: two GCB-DLBCL cohorts with up to 
30 subjects from the EZH2 wild-type population, and up to 30 subjects from the EZH2 
mutation positive population, and two tFL cohorts with up to 16 subjects from the EZH2 
wild-type population and up to 16 subjects from the EZH2 mutation positive population 
and up to 37 subjects in the MM cohort.  Additional subjects/cohorts may be enrolled to 
allow for evaluation of additional dose levels. 
Section 5.2. Subject Selection Criteria
REVISED TEXT
5.2.1. Part 1 Inclusion Criteria
Specific information regarding warnings, precautions, contraindications, AEs, and other
pertinent information on the GSK study treatment that may impact subject eligibility is
provided in the IB and SPM [GlaxoSmithKline Document Number 2013N169204_00,
2013].
Inclusion criteria no 3: 
Tumor type criteria:  

Relapsed/refractory NHL that meets one of the following criteria:
o
GCB-Diffuse large B cell lymphoma (DLBCL) or transformed 
follicular lymphoma relapsed after, or refractory to at least one prior 
chemotherapy regimen (e.g., rituximab, cyclophosphamide, 
doxorubicin, vincristine, prednisone [R-CHOP]) AND  not a 
candidate for standard salvage regimens or autologous stem cell 
transplant (e.g., due to age, comorbid conditions or failure to respond 
to salvage chemotherapy).  Local confirmation of lymphoma subtype 
(e.g. GCB-DLBCL) is allowed for enrollment but must be confirmed 
through central laboratory testing.
o
GCB/ -DLBCL or transformed FL relapsed after or refractory to at 
least two prior chemotherapy regimens


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o
Other NHLs that have failed at least one prior line of therapy.

Relapsed and/or refractory MM that have failed prior standard therapy and 
for which there is no standard salvage regimen.

Solid tumors (RECIST evaluable, with the exception of castrate resistant 
prostate cancer (CRPC)) at least one and not more than three standard of care 
chemotherapeutic regimens, or tumor for which there is no approved therapy, 
or for which standard therapy is refused.  
Inclusion criteria no.4:  
DLBCL and tFL: Availability of archival tissue, or willingness to undergo fresh 
biopsy for: confirmation of GCB-DLBCL status (DLBCL subjects); retrospective 
central testing of EZH2 mutation status (DLBCL ,and tFL subjects), 
For all other tumor types: availability of archival tissue or fresh biopsies as 
applicable. DLBCL and tFL: Availability of archival tissue, or willingness to undergo 
fresh biopsy for: confirmation of GCB-DLBCL status (DLBCL subjects); 
retrospective central testing of EZH2 mutation status (DLBCL, and tFL subjects), 
For all other tumor types: availability of either archival tissue or fresh biopsies
Part 1 Cohort Expansion Tumor Type
Inclusion Criteria no 9
Adequate organ system function as defined below:
System
LABORATORY VALUES
Hematologic
  ANC
1.2 x 109/L  
  Hemoglobin
9 g//dL 
  Platelets
75x 109/L  
 Platelets for Subjects with MM
≥ 50,000 (transfusion independent)
 PT/INR and PTT
≤1.5 x ULN
Hepatic
  Albumin
2.5 g/dL
  Total bilirubin
1.5 times ULN
 AST and ALT
2.5  times ULN without liver metastases
5 times ULN if documented liver metastases
Renal
Serum Creatinine
1.5 mg/dL 
or
Calculate Creatinine Clearance a, b   OR         
24 hr urine Creatinine Clearance
50 mL/min                                                              
≥50mL/min
Reproductive/Endocrine
Testosterone 
<50ng/dL (only for subjects with CRPC)


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Cardiac
Left Ventricular Ejection Fraction (LVEF)
≥LLN (minimum of 50% LVEF) by ECHO  or MUGAc
Abbreviation(s): ANC, absolute neutrophil count; ALT, alanine aminotransferase; AST, aspartate aminotransferase; 
ECHO, echocardiogram; INR, international normalization ratio, MUGA, multigated (radionuclide) angiogram; PT, 
prothrombin time, PTT, partial thromboplastin time, ULN, upper limit of normal , LLN, lower limit of normal.
Calculated by Cockcroft-Gault formula
6.
For MM subjects, adequate renal function is defined as serum creatinine ≤ 2.5 mg/dL OR creatinine clearance 
(either calculated or obtained via 24 hr urine collection) ≥ 30 mL/minECHO is the preferred method
7.
ECHO is the preferred method
5.2.2. Part 2 Inclusion Criteria
Inclusion criteria no. 1:
In addition to inclusion criteria listed for Part 1, Part 2 will enroll GCB-DLBCL tFL 
and MM subjects only and subjects will be required to undergo EZH2 mutation
testing. Local mutation testing is allowed for enrollment but must be confirmed 
through central laboratory testing.testing by a central laboratory prior to enrollment
This will require availability of archival tissue, or willingness to undergo fresh 
biopsy, for central testing of EZH2 mutation status.
Inclusion criteria no. 2:
Based on the results of the mutation test, lymphoma subjects may be enrolled in one 
of four cohorts:

GCB-DLBCL EZH2 mutantion cohort: 
o
Tumors must contain one, or more, of the following EZH2 activating 
mutations: Y641F; Y641N; Y641S; Y641H; Y641C; A677G; and/or 
A687V

GCB-DLBCL EZH2 wild type cohort:
o
Tumors that do not contain one of the above mutations
o
Subjects with tumors harboring EZH2 mutations other than the seven 
outlined above will be enrolled in the EZH2 wild type cohort

tFL EZH2 mutant cohort: 
o
Tumors must contain one, or more, of the following EZH2 activating 
mutations: Y641F; Y641N; Y641S; Y641H; Y641C; A677G; and/or 
A687V

tFL EZH2 wild type cohort:
o
Tumors that do not contain one of the above mutations
o
Subjects with tumors harboring EZH2 mutations other than the seven 
outlined above will be enrolled in the EZH2 wild type cohort


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
Subjects should have accessible tumor and willingness to undergo two 
biopsies. Subjects for whom biopsies are not feasible may be eligible for 
enrollment at the discretion of the GSK medical monitor; contact GSK 
medical monitor to discuss possible enrollment.
5.2.3. Exclusion Criteria
Exclusion criteria no.1
Currently receiving cancer therapy  (chemotherapy, radiation therapy, 
immunotherapy or biologic therapy) (permitting corticosteroids to control systemic 
or local symptoms, up to a dose of 10 mg prednisolone or equivalent daily and stable 
for at least 7 days prior to enrollment).

Hormonal (e.g., anti-androgen) therapies for prostate cancer must be 
stopped 4 to 6 weeks prior to enrolment.  Subjects with prostate cancer may 
remain on luteinizing hormone releasing hormone (LHRH) agonists.  
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.
Exclusion criteria no. 8:
Unresolved toxicity greater than Grade 1 National Cancer Institute – Common 
Terminology Criteria for Adverse Events (NCI-CTCAE) version 4 from previous 
anti-cancer therapy, with the exception of alopecia and peripheral neuropothy [NCI-
CTCAE, 2009]. 
Unresolved toxicity greater than NCI-CTCAE version 4 (Grade 1 if marrow is clear, 
Grad 2 if not) from previous anti-cancer therapy, with the exception of alopecia and 
lymphopenia [NCI-CTCAE, 2009].

Lymphoma subjects with ≤ Grade 3 lymphopenia can be enrolled at the 
discretion of the investigator
Section 6: COMPLETION OR WITHDRAWAL OF SUBJECTS
REVISED TEXT
6.3.
Permanent Discontinuation from Study Treatment 
Subjects will receive study treatment until disease progression, death or unacceptable 
toxicity, including meeting stopping criteria for liver chemistry defined in Section 8.3.1.  
In addition, study treatment willmay be permanently discontinued for any of the 
following reasons:

Substantial dDeviation(s) from the protocol

Request of the subject or proxy (withdrawal of consent by subject or proxy)

Investigator’s discretion


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
A dose delay of > 21days unless the investigator and GSK Medical Monitor agree 
that further treatment may benefit the subject

Intercurrent illness that prevents further administration of study treatment(s)

Subject is lost to follow-up or study is closed or terminated.
The primary reason study treatment was permanently discontinued must be documented 
in the subject’s medical records and eCRF. 
If the subject voluntarily discontinues from treatment due to toxicity, ‘adverse event’ will 
be recorded as the primary reason for permanently discontinuation on the eCRF.
Once a subject has permanently discontinued from study treatment, the subject will not 
be allowed to be retreated.
If the subject voluntarily discontinues from treatment due to toxicity, ‘AE’ will be 
recorded as the primary reason for permanently discontinuation on the eCRF.   
Section 7: STUDY ASSESSMENTS AND PROCEDURES
Table 6
Time and Events, Treatment Phase:  Screening through Day 28 (See 
also PK sampling table for PK sampling schedule on Day 1 and Day 15)
Details added:

Window period of ‘-1 Day’ was added to the Safety Assessments heading under 
Study Phase column

‘At Screening’ was added under Visit Window for ECHO assessment

The frequency of assessment was changed from ‘Every 4 weeks’ to Prior to every 
infusion’ for Hematology parameters in Continuation phase

Day 4 pre-dose and end of infusion was added for PK sampling for Part 1 at Day 
1 and 4 Visit.

Blood samples for Genetic research were added at screening and Day 1 and 4 
Visit.

The time points for blood samples obtained for assessing PD biomarkers were 
revised as prior to dosing on D1 (baseline), 2 hours after the end of the infusion 
on day 1, 4, 8, 11,15, and 18 and at day 21 and 28 visits (1-2 days).

Archival Tissue for mutation testing will be for All DLBCL and tFL subjects.

The time points for tumor biopsy was revised to be obtained at D1 (up to -14 
days) and after 6th dose Day 18 (+3 day window) 


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
Clinical Activity Assessments sub-heading was changed to Disease Assessments 
for Lymphoma Subjects

Footnote a. was changed as follows: A subject is to receive two doses per week 
which should be given 3 days apart. If there is a need to change scheduling after 
Cycle 1, the scheduled days of the week can change as long as there are 3-4 days 
between doses.  Up to 5 days between doses is permitted for exceptional 
circumstances.


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Table 6
Time and Events, Treatment Phase:  Screening through Day 28 (See also PK sampling table for PK sampling 
schedule on Day 1 and Day 15)

Added rows are as follows:
STUDY PHASE
SCREEN
First Treatment Period
Continuation 
Phase
Follow-
Up
VISIT
Screen
Day 1 
and 4a
Day 8 
and 11 a
Day 15 
and 18 a
Day 21 
VISIT WINDOW (days)
-14
7
Disease Assessments for Solid Tumors
CT/MRI
Must be repeated every 8 
weeks
X
X
Xd
Positron emission tomography (PET)
The use of standalone PET 
or PET in combination with 
CT scan is optional. 
Standalone PET dose not 
replace CT
Xe
Xe
Xd,e
Disease Assessments for Prostate Cancer
Vitamin D3 and PTH
X
X
Xd
Urinalysis
Urine microscopy
UPC
X
Xe
Xd,e
Urine electrolytes
X
PSA
X
Tumor biopsy for PD optional for Part 
1 and Part 2. Required for Part 1 
PK/PD cohort at MTD
A tumor biopsy should be 
obtained at D1 (up to -14 
days) and after 6th dose Day 
18(+3 day window)
X
X (After 
6th dose, 
Day 18)


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Disease Assessments for Multiple Myeloma (MM) 
Disease Characteristics
Every 6 weeks after Wk4, 
Including cytogenetics as 
appropriate
X
Total Protein, CRP, 2 
microglobulin
Every 6 weeks after Wk4
X
Response Assessment
Every 6 weeks after Wk4; 
Response criteria in 
Appendix 6
SPEP, FLC assay, quantitative 
immunoglobulins ( IgG, IgA, IgM)
Not required for subjects 
with non-secretory MM
X
UPEP
Only required if paraprotein 
is present in urine
X
Extramedullary Disease 
Assessment
Only required for MM with 
extramedullary disease
X
BM aspirate and biopsy
Required for non-secretory 
MM, or as appropriate for 
other subjects
X
Day 18
Week 10, Day 1


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Disease Assessments for Solid Tumors
CT/MRI
Must be repeated every 8 
weeks
X
X
Xd
Positron emission tomography 
(PET)
The use of standalone PET 
or PET in combination with 
CT scan is optional. 
Standalone PET does not 
replace CT
Xe
Xe
Xd,e
Disease Assessments for Prostate Cancer
Vitamin D3 and PTH
X
X
Xd
Urinalysis
Urine microscopy
UPC
X
Xe
Xd,e
Urine electrolytes
X
PSA
Wk 9 and every 8 weeks 
thereafter
X
ECOG Performance status 
See Appendix 2
X
X
X
X
X


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Table 7
Time and Events, PK Sampling Table for Part 1, Day 1 and Day 15
Duration of Infusion in hours
2
3
4
From start of infusion - 60 mins
Predose
Predose
Predose
5 mins
0.5 hr
0.5 hr
0.5 hr
5 mins
1 hr
1 hr
1 hr
- 5 mins
2 hr (prior to end of infusion)
2 hr
2 hr
- 5 mins
3 hr (prior to end of infusion)
4 hr (prior to end of infusion)
From end of infusion 5 mins
0.5 h
0.5 h
0.5 h
5 mins
1 hr
1 hr
1 hr
5 mins
2 hr
2 hr
2 hr
15 mins
4 hr
4 hr
4 hr
15 mins
6 hr
6 hr
6 hr
From start of infusion 1hour
12 hr (Day 1 only)
12 hr (Day 1 only)
12 hr (Day 1 only)
1 hour
18 hr (Day 1 only)
18 hr (Day 1 only)
18 hr (Day 1 only)
1 hour
24 hr
24 hr
24 hr
2 hour
72 or 96 hr
72 or 96 hr
72 or 96 hr
* Stability has been established for up to 9 hours on wet ice or at 4°C for GSK2816126 in whole blood.


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Section 7.2. Demographic/Medical History and Baseline Assessments
REVISED POINTS

Ann Arbor stage of initial diagnosis for NHL

Ann Arbor stage of relapse/refractory diagnosis for NHL

For NHL, Uunilateral or bilateral bone marrow biopsy within 35 days prior to 
commencing study therapy. 

Baseline assessment for Subjects with multiple myeloma

International staging system (ISS) stage at initial diagnosis and 
screening

Type (active or smoldering)

Presence of plasmacytoma

Cytogenetics

Presence of extramedullary disease

Laboratory assessment: Total protein, paraprotein, CRP and β2-
microglobulin; for secretory MM: SPEP, UPEP, IgG, IgA, IgM, FLC 
assay
Section 7.5. Pharmacodynamics
REVISED TEXT
Changes from baseline H3K27me3 will be assessed in pre- and post-treatment samples 
by immunohistochemistry (IHC) for tumor or surrogate tissue/body fluid (e.g. PBMCs, 
blood, skin or hair)., and Enzyme-linked immunosorbent assay for peripheral blood 
mononuclear cells (PBMCs [blood]), or other tissue or body fluid.
Section 7.6. Translational Research 
REVISED TEXT
Translational or biomarker research may be performed on archival tissue, tumor biopsies, 
blood samples or other surrogate tissue (e.g. skin or hair) collected on study, to better 
understand DLBCL, transformed FL, MM, mechanism of action of and response to 
GSK2816126.
Comparative examination of pre-dosing profiles of participants may uncover known or 
novel candidate biomarkers/profiles which could be used to predict response to treatment 
with GSK2816126 or provide new insights into lymphoma, other cancers,DLBCL and 
medically related conditions.  Comparative examination of post-dosing profiles in 
conjunction with pre-dosing profiles may yield known and novel candidate 
biomarkers/profiles and new insights which relate to the action of GSK2816126.


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Performance of these investigations may be conditional on the results of the clinical trial 
principally, but not exclusively, on the primary measures of the clinical trial outcome and 
samples may be selected for analysis on the basis of the clinical outcome.
Unless stated otherwise, these investigations may be performed irrespective of whether a 
response to GSK2816126 is observed.
All samples may be retained for a maximum of or 15 years after the last subject 
completes the trial.
Novel candidate biomarkers and subsequently discovered biomarkers of the biological 
response associated with lymphoma, other cancers, or medically related conditions and/or 
the action of GSK2816126 may be identified by application of the following. DNA/gene, 
RNA and protein analysis of blood and tumor tissue including but not limited to the 
following analyses:

Confirmation of GCB-subtype DLBCL status by analysis IHC analysis using the
Choi standard methods or of tumor GEP signature
7.6.1. Tumor Biomarker Analysis
DLBCL/tFL patients:  A requirement for inclusion in this study is availability of archival 
tissue, or willingness to undergo fresh biopsy for the following:

Confirmation of GCB-subtype DLBCL status by analysis of tumor by IHC using 
the standard methods (DLBCL subjects)

Confirmation of EZH2 WT status by targeted sequencing of EZH2 gene (DLBCL 
and tFL subjects)

DNA, RNA or protein measurements to identify predictors of sensitivity or 
resistance to GSK2816126

All other patients will be asked to submit an archival tumor specimen for 
retrospective DNA, RNA or protein testing of potential markers of sensitivity 
and/or resistance; however this will not be an eligibility requirement.
7.6.1.2. 
EZH2 Mutation Analysis (required for study entry Part 2 for GCB-
DLBCL and tFL subjects only)
Screening for eligibility for Part 2 of the study will be conducted using a custom 
quantitative real time polymerase chain reaction (RT-PCR) test based on TaqMan PCR 
chemistry.  The test detects 7 known activating mutations in the EZH2 gene: Y641F 
(c.1937A>T); Y641N (c.1936T>A); Y641S (c.1937A>C); Y641H (c.1936T>C); Y641C 
(c.1937A>G); A677G (c.2045C>G); and A687V (c.2075C>T) (AltheaDX 2014).
7.6.2. Circulating cell free DNA Analysis
Paragraph 1:


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Plasma samples collected will be analyzed to investigate mutations, including but not 
limited to EZH2, in cfDNA.
7.6.3. Circulating biomarker analysis 
Paragraph 1:
Levels of circulating biomarkers, may be assessed to determine relationships between 
biomarker expression and response to GSK2816126, as well as to better understand the 
expression of circulating biomarkers in DLBCL and transformed FL lymphoma and other 
tumor types.
7.6.4. RNA Expression Research of a Subset of RNA Species
Paragraph 3
RNA expression studies may be conducted using RNA-seq, quantitative RT-PCR, and/or 
alternative equivalent technologies, which can facilitate the simultaneous measurement of 
the relative abundances of RNA species resulting in a RNA expression profile for each 
blood and tumor tissue sample. The RNAs assayed may be those involved in tumor
pathogenesis, the absorption, distribution, metabolism, or excretion of GSK2816126, or 
in the subject’s response to GSK2816126. In addition, continuing research may identify 
other proteins or regulatory RNAs that may be involved in response to GSK2816126 or 
tumor the pathogenesis. The RNAs that code for these proteins and/or regulatory RNAs 
may also be studied. This will enable the evaluation of changes in RNA expression 
profiles that may correlate with biological response relating to DLBCL lymphoma, other 
cancers, and medically related conditions or the action of GSK2816126.
7.6.5. Tumor Tissue collection
Paragraphs 1, 2 and 3
The availability of archived tissue (or willingness to undergo fresh biopsy) is required for 
all screened lymphoma subjects for determination of EZH2 mutation status, and/or for 
GCB-subtypingsubtype of DLBCL subjects.
Pre-treatment (baseline), and Post-treatment (Day 18 11) tumor biopsies are required for 
all subjects in Part 2 (optional for Part 1).  Subjects for whom biopsies are not feasible 
will be eligible for enrollment and participation in study at the discretion of the GSK 
medical monitor.  Contact GSK medical monitor for confirmation of enrollment and 
study entry if biopsies are not feasible.
A tumor biopsy at progression for biomarker research is recommended for all subjects.
For Part 1 PK/PD cohorts, pre-treatment and post-treatment tumor biopsies will be 
initially optional.  At MTD, mandatory collection of pre- and post-treatment tumor 
biopsies will be required for further enrollment of subjects in a PK/PD cohort.  
Mandatory biopsies may be instituted: at lower dose levels once evidence of target 
engagement has been demonstrated in surrogate tissue (H3K27me3 from PBMCs in 


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blood); or if sufficient evidence of target engagement (e.g. dose dependence) is not 
observed in PD assay from surrogate tissue. Optional tumor biopsies may be requested 
for all or a portion of subjects in Part 2. Subjects for whom biopsies are not feasible will 
be eligible for enrollment and participation in study at the discretion of the GSK medical 
monitor.  Contact GSK medical monitor for confirmation of enrollment and study entry if 
biopsies are not feasible.
7.6.6. Blood collection 
Blood samples will be collected at multiple time points from all subjects on study (Parts 1 
and 2) for pharmacodynamic and exploratory biomarker testing (Section 7.1).
Further details on sample requirements and collection will be provided in the SPM.
Section 7.7. Evaluation of Anti-Cancer Activity
REVISED TEXT
Disease assessment may include imaging and physical examination (as indicated for 
palpable/superficial lesions). Refer to Appendix 4 (Section 15.4) for more details on 
response assessment criteria. Disease assessment for lymphomas will be completed 
within 4 weeks prior to the first dose of GSK2816126 then every 8 weeks thereafter, 
completed within 4 weeks of first dose of GSK2816126 and repeated 8 weeks after dosing is 
initiated, every 12 weeks thereafter, and at the final study visit. Disease assessment for solid 
tumors will be completed at 8 weeks of first dose of GSK2816126 and repeated every 8 weeks 
thereafter, and at the final study visit. . Disease assessment for MM will be completed 
within 4 weeks of first dose of GSK2816126 and repeated every 6weeks thereafter.  See the 
Time and Events Table (Section 7.1) for the schedule of assessments of anti-cancer 
activity.  Assessments must be performed on a calendar schedule and should not be 
affected by dose interruptions/delays.  For post-baseline assessments, a window of 7 
days is permitted to allow for flexible scheduling.  If the last radiographic assessment was 
more than 8 weeks prior to the subject’s withdrawal from study and progressive disease 
has not been documented, a disease assessment should be obtained at the time of 
withdrawal from study.
For subjects with NHL, Tthe following B symptoms should be assessed at the time points 
in the Time and Events Table (Section 7.1): 

night sweats without signs of infection

unintentional weight loss of ≥10% within the previous 6 months

recurrent, unexplained fever of great than 38oC for 2 weeks without signs of 
infection
If a subject had involvement of bone marrow at baseline, and a CR is suspected, a bBone 
marrow biopsy must be obtained as described in Section 7.2.1. If a subject had 
involvement of bone marrow at baseline, and a CR is suspected,A a repeat bone marrow 


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biopsy will be performed within 8 weeks of the imaging confirmed CR in accordance 
with the response guidelines (Appendix 4: Section 15.4).
ADDED SECTION
7.8 Genetic Research
The information regarding genetic research is included in Appendix 6.  
Section 8.2: Definition of an SAE
REVISED TEXT
g. Protocol-Specific SAEs:
Section 9.4  Drugs and QT Prolongation
Completely updated Table 13 and Table 14
Table 13  Drugs with a Risk of Torsades de Pointes that are not permitted for Co-
Administration with GSK2816126
Generic Name
Drug Class
Generic Name
Drug Class
Amiodarone
Anti-arrhythmic
Halofantrine
Anti-malarial
Anagrelide
Phosphodiesterase 3 
inhibitor
Haloperidol
Anti-psychotic
Arsenic trioxide
Anti-cancer
Ibutilide
Anti-arrhythmic
Astemizole 
(Removed from US 
Market)
Antihistamine
Levofloxacin
Antibiotic
Azithromycin
Antibiotic
Levomethadyl 
(Removed from US 
Market)
Opiate
Bepridil (Removed 
from US Market)
Anti-anginal
Mesoridazine 
(Removed from US 
Market)
Anti-psychotic
Chloroquine
Anti-malarial
Methadone
Opiate
Chlorpromazine
Anti-psychotic / Anti-
emetic
Moxifloxacin
Antibiotic
Cisapride (Removed 
from US Market)
GI stimulant
Ondansetron
Anti-emetic
Citalopram
Anti-depressant, SSRI
Pentamidine
Antibiotic
Clarithromycin
Antibiotic
Pimozide
Anti-psychotic
Cocaine
Local anesthetic
Probucol (Removed 
from US Market)
Antilipemic
Disopyramide
Anti-arrhythmic
Procainamide (Oral 
off US mkt)
Anti-arrhythmic


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Generic Name
Drug Class
Generic Name
Drug Class
Dofetilide
Anti-arrhythmic
Quinidine
Anti-arrhythmic
Domperidone (On 
non US Market)
Anti-nausea
Sevoflurane
Anesthetic, general
Dronedarone
Anti-arrhythmic
Sotalol
Anti-arrhythmic
Droperidol
Anti-psychotic / Anti-
emetic
Sparfloxacin 
(Removed from US 
Market)
Antibiotic
Erythromycin
Antibiotic
Sulpiride (On non 
US Market)
Anti-psychotic, atypical
Escitalopram
Anti-depressant, SSRI
Terfenadine 
(Removed from US 
Market)
Antihistamine
Flecainide
Anti-arrhythmic
Thioridazine
Anti-psychotic
Grepafloxacin (Off 
market worldwide)
Antibiotic
Vandetanib
Anti-cancer
Data Source: www.crediblemeds.org (27 February 2015)
Table 14  Drugs with a Possible Risk of Torsades de Pointes that are Prohibited
Generic Name
Drug Class
Generic Name
Drug Class
Alfuzosin
Alpha1-blocker
Norfloxacin
Antibiotic
Apomorphine
Dopamine agonist
Ofloxacin
Antibiotic
Aripiprazole
Anti-psychotic, atypical
Olanzapine
Anti-psychotic, atypical
Atazanavir
Anti-viral
Oxytocin
Oxytocic
Bedaquiline
Antibiotic
Paliperidone
Anti-psychotic, atypical
Bortezomib
Proteasome inhibitor
Pasireotide
Somatostatin analog
Bosutinib
Tyrosine kinase inhibitor
Pazopanib
Tyrosine kinase inhibitor
Clozapine
Anti-psychotic, atypical
Perflutren lipid 
microspheres
Imaging contrast agent
Crizotinib
Kinase inhibitor
Pipamperone (On 
non US Market)
Antipsychotic
Dabrafenib
Anti-cancer
Promethazine
Anti-psychotic / Anti-emetic
Dasatinib
Tyrosine kinase inhibitor
Quetiapine
Anti-psychotic, atypical
Dexmedetomidine
Sedative
Ranolazine
Anti-anginal
Dihydroartemisinin+
piperaquine
Anti-malarial
Rilpivirine
Anti-viral
Dolasetron
Anti-nausea
Risperidone
Anti-psychotic, atypical
Eribulin
Anti-cancer
Roxithromycin (On 
non US Market)
Antibiotic
Famotidine
H2-receptor antagonist
Saquinavir
Anti-viral
Felbamate
Anti-convulsant
Sertindole (On non 
US Market)
Anti-psychotic, atypical
Fingolimod
Sphingosine phospate 
receptor modulator
Sorafenib
Tyrosine kinase inhibitor
Foscarnet
Anti-viral
Sunitinib
Anti-cancer
Fosphenytoin
Anti-convulsant
Tacrolimus
Immunosuppressant
Gatifloxacin 
(Removed from US 
Antibiotic
Tamoxifen
Anti-cancer


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Generic Name
Drug Class
Generic Name
Drug Class
Market)
Gemifloxacin
Antibiotic
Telavancin
Antibiotic
Granisetron
Anti-nausea
Telithromycin
Antibiotic
Iloperidone
Anti-psychotic, atypical
Tetrabenazine 
(Orphan drug in US)
Monoamine Transporter 
Inhibitor
Isradipine
Anti-hypertensive
Tizanidine
Muscle relaxant
Lapatinib
Anti-cancer
Tolterodine
Muscle relaxant
Lithium
Anti-mania
Toremifene
Estrogen 
agonist/antagonist
Mifepristone
Progesterone antagonist
Vardenafil
Phosphodiesterase inhibitor
Mirabegron
Beta3 adrenergic antagonist
Vemurafenib
Kinase inhibitor
Mirtazapine
Anti-depressant, Tetracyclic
Venlafaxine
Anti-depressant, SNRI
Moexipril/HCTZ
Anti-hypertensive
Vorinostat
Anti-cancer
Nicardipine
Anti-hypertensive
Ziprasidone
Anti-psychotic, atypical
Nilotinib
Anti-cancer
Data Source: www.crediblemeds.org (27 February 2015)
Section 11  Data Management
REVISED TEXT
Paragraph 1
For this study, data will be collected using defined eCRFs in the validated data system, 
InForm. Some data (i.e. Biomarker, PK, Holter ECG) will be transmitted electronically 
to GSK from an external vendor via a validated data system, the External Alliance Portal.
Section 12.4. Sample Size Determination 
REVISED TEXT
The sample size planned for Part 1 arises from the predefined criteria for dose selection 
and is not driven by statistical considerations. 
The additional 129 subjects in Part 2 of the study (which includes approximately 30 
subjects each for the EZH2 mutant and EZH2 WT GCB-DLBCL populations and 16 
subjects each for the EZH2 mutant and EZH2 WT tFL populations, as well as up to 37 
MM subjects) will provide additional safety and tolerability information about the 
treatment and a better precision around the response rate estimate.
12.4.1. Part 1: Dose-Escalation Phase 
The total number of subjects to be enrolled in Part 1 will depend on the number of 
subjects needed to characterize individual dose cohorts. The sample size is not driven by 
statistical considerations. However, it is anticipated that approximately 40 subjects will 
be enrolled.  Given true incidence rates of DLTs, the associated probabilities of 


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escalating to the next dose in a 3+3 scheme are provided for reference below in Section 
12.4.1. Table 15.
12.4.2. Part 2: Expansion Cohort 
An initial dose escalation will be used to establish the RP2D for GSK2816126.  Once the 
final dose is confirmed, at least 12 and up to 30 subjects in both GCB-DLBCL mutation 
status cohorts, up to 16 subjects in both tFL mutation status cohorts and up to 37 subjects 
with MM will be enrolled at that dose, using decision rules defined in Figure 1, Figure 2 
and Figure 3. The sample size and stopping rules are based on the methodology of Lee & 
Liu [Lee, 2008]. 
The assumptions underlying the design are detailed below. 
The assumptions underlying the design are detailed below for both GCB-DLBCLEZH2 
cohorts. The null hypothesis is:
H0: p≤10%
The alternative hypothesis is:
HA:p>10 30%
For GCB-DLBCL cohorts, starting with 12 subjects and allowing for a maximum sample 
size of 30, this design will have a type I error rate () of 0.062 and 88.9% power when 
the true response rate is 30%.  The trial is not designed to stop early for efficacy, but is 
designed to stop early for futility if the predictive probability of success is 5.0% or less.  
The type I error rate, power, and predictive probability of success to stop early for futility 
were derived from explicitly stating the minimum and maximum sample size, futility 
stopping rate and selection of the optimizing criterion as the maximization of power 
under the alternative hypothesis.  The Bayesian prior used in determining the design was 
Beta (0.15, 0.85), a distribution with a mean response rate of 15%.  Under the null 
hypothesis, if the true response rate is 10%, the expected sample size of the design is 18.0
subjects per expansion cohort and probability of early termination (PET) is 88.7%.  
Under the alternative hypothesis, if the true response rate is 30%, the expected sample 
size of the design is 29.0 subjects per expansion cohort and PET is 8.8%.
The assumptions underlying the design are detailed below for both the tFL cohorts. The 
null hypothesis is:
H0: p≤5%
The alternative hypothesis is:
HA:p>5%
Starting with 12 subjects and allowing for a maximum sample size of 16, this design will 
have a type I error rate () of 0.043 and 80.1% power when the true response rate is 25%.  


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The trial is not designed to stop early for efficacy, but is designed to stop early for futility 
if the predictive probability of success is about 1.0% or less.  The type I error rate, power, 
and predictive probability of success to stop early for futility were derived from explicitly 
stating the minimum and maximum sample size, futility stopping rate and selection of the 
optimizing criterion as the minimization of the expected sample size under the null 
hypothesis.  The Bayesian prior used in determining the design was Beta (0.05, 0.95), a 
distribution with a mean response rate of 5%.  Under the null hypothesis, if the true 
response rate is 5%, the expected sample size of the design is 14 subjects per expansion 
cohort and probability of early termination (PET) is 83.3%.  Under the alternative 
hypothesis, if the true response rate is 30%, the expected sample size of the design is 16 
subjects per expansion cohort and PET is 8.5%.
The assumptions underlying the design are detailed below for MM subjects. The null 
hypothesis is:
H0: p≤5%
The alternative hypothesis is:
HA; p>5%
Starting with 13 subjects and allowing for a maximum sample size of 37, this design will 
have a type I error rate () of 0.032 and about 85% power when the true response rate is 
20%.  The trial is not designed to stop early for efficacy, but is designed to stop early for 
futility if the predictive probability of success is about 1.0% or less.  The type I error rate, 
power, and predictive probability of success to stop early for futility were derived from 
explicitly stating the minimum and maximum sample size, futility stopping rate and 
selection of the optimizing criterion as the minimization of the power under the 
alternative hypothesis.  The Bayesian prior used in determining the design was Beta 
(0.20, 0.80), a distribution with a mean response rate of 20%.  Under the null hypothesis, 
if the true response rate is 5%, the expected sample size of the design is 22 subjects and 
probability of early termination (PET) is 91%. Under the alternative hypothesis, if the 
true response rate is 20%, the expected sample size of the design is 36 subjects per 
expansion cohort and PET is 10%.
Section 12.5 Data Analysis Considerations
REVISED TEXT
12.5.3. Treatment Comparisons
No formal hypothesis testing will be performed between dose cohorts. Safety, PK, PD 
marker, and efficacy summaries will be provided by dose cohort and planned time of 
assessment in Part 1 and by expansion cohort and planned time of assessment in Part 2.


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12.5.3.2. Other Comparisons of Interest

PK: PK parameters will be evaluated and summarized for each dose cohort in Part 1. 

PD marker: Changes from baseline in PD markers will be evaluated and summarized 
for each dose cohort in Part 1 and for each cohort (EZH2 WT and EZH2-mutant) in 
Part 2.

Clinical anti-cancer activity: The number of subjects with a complete responses, 
partial responses, stable disease, and progressive disease for each dose cohort in Part 
1 and for each expansion cohort in Part 2 will be listed and summarized if data 
warrant. 
12.5.5.4. Efficacy Analyses
Paragraph 1
Anti-tumor activity for lymphoma subjects will be assessed based on the Response 
Criteria listed in 15.4.  Anti-tumor activity for subjects with solid tumors will be assessed 
based on the Response Criteria listed in 15.5. Anti-tumor activity for subjects with MM 
will be assessed based on the Response Criteria listed in 15.6. The response data will be 
summarized by study part, and cohort within Part 2.  Full details will be specified in the 
RAP.
Section 13: STUDY CONDUCT CONSIDERATIONS
REVISED TEXT
13.2. Regulatory and Ethical Considerations, Including the Informed Consent 
Process
ADDED TEXT
In approving the clinical protocol the IEC/IRB and, where required, the applicable 
regulatory agency are also approving the optional assessments, e.g. genetic research 
described in Appendix 5, unless otherwise indicated.  Where permitted by regulatory 
authorities, approval of the optional assessments can occur after approval is obtained for 
the rest of the study.  If so, then the written approval will clearly indicate approval of the 
optional assessments is being deferred and the study, except for the optional assessments, 
can be initiated.  When the optional assessments are not approved, then the approval for 
the rest of the study will clearly indicate this and therefore, the optional assessments will 
not be conducted.
Section 14: REFERENCES
ADDED REFERENCES
AltheaDX Design validation report for the EZH2 mutation detection assay panel for 
clinical testing. CO-121613-001. Report Date: 27-JAN-2014.


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Bodor C, Grossmann V, Popov N et al. EZH2 mutations are frequent and represent an 
early event in follicular lymphoma. Blood 2013;122:3165-8.
Chung WH, Hung SL, Chen YT. Genetic predisposition of life-threatening antiepileptic-
induced skin reactions. Expert Opin. Drug Saf. 2010; 9: 15-21.
McCabe MT & Creasy CL. EZH2 as a potential target in cancer therapy. Epigenomics 
2014;6:341-51.
RECIST guidelines (version 1.1). Europena Journal of Cancer. 2009; 45: 228-247.
www.crediblemeds.org (27 February 2015)
Section 15: APPENDICES 
REVISED TEXT
15.5. 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 Table 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 1 week prior to 4 
weeks after 


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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.

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.


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
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 
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.


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Ic. Follow-up Assessments for Subjects Permanently Discontinued from Study 
Treatment 
Refer to 8.3.1.1 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. 
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.


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Non-Measurable only disease: The presence of only non-measurable lesions. Note: non-
measurable only disease is not allowed per protocol.
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).

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 


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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. 

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.


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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
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 unique design (see Table 2 of the 
protocol) should be considered when assessing tumor response. Thus, subjects with 
PD before Week 8, 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 8, 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. 


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
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.
15.6. Appendix 6: Genetic Research
Genetic Research Objectives and Analyses
The objectives of the genetic research are to investigate the relationship between genetic 
variants and: 

Response to medicine, including [GSK2816126] or any concomitant medicines;

[Disease susceptibility, severity, and progression and related conditions
Genetic data may be generated while the clinical study is underway or following 
completion of the study.  Genetic evaluations may include focused candidate gene 
approaches and/or examination of a large number of genetic variants throughout the 
genome (whole genome analyses). Genetic analyses will utilize data collected in the 
clinical study and will be limited to understanding the objectives highlighted above.  
Analyses may be performed using data from multiple clinical studies to investigate these 
research objectives.
Appropriate descriptive and/or statistical analysis methods will be used. A detailed 
description of any planned analyses will be documented in a Reporting and Analysis Plan 
(RAP) prior to initiation of the analysis. Planned analyses and results of genetic 
investigations will be reported either as part of the clinical RAP and study report, or in a 
separate genetics RAP and report, as appropriate.
Study Population
Any subject who is enrolled in the clinical study, can participate in genetic research.  Any 
subject who has received an allogeneic bone marrow transplant must be excluded from 
the genetic research.


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


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
Discontinue participation in the genetic research and destroy the genetic DNA 
sample 
If a subject withdraws consent for genetic research or requests sample destruction for any 
reason, the investigator must complete the appropriate documentation to request sample 
destruction within the timeframe specified by GSK and maintain the documentation in 
the site study records. 
Genotype data may be generated during the clinical study or after completion of the 
clinical study and may be analyzed during the clinical study or stored for future analysis. 

If a subject withdraws consent for genetic research and genotype data has not 
been analyzed, it will not be analyzed or used for future research.  

Genetic data that has been analyzed at the time of withdrawn consent will 
continue to be stored and used, as appropriate. 
Screen and Baseline Failures
If a sample for  genetic research has been collected and it is determined that the subject 
does not meet the entry criteria for participation in the clinical study, then the investigator 
should instruct the participant that their genetic sample will be destroyed. No forms are 
required to complete this process as it will be completed as part of the consent and 
sample reconciliation process.  In this instance a sample destruction form will not be 
available to include in the site files.
Provision of Study Results and Confidentiality of Subject’s Data
GSK may summarize the genetic research results in the clinical study report, or 
separately and may publish the results in scientific journals. 
GSK may share genetic research data ‘with other scientists to further scientific 
understanding in alignment with the informed consent. GSK does not inform the subject, 
family members, insurers, or employers of individual genotyping results that are not 
known to be relevant to the subject’s medical care at the time of the study, unless 
required by law. This is due to the fact that the information generated from genetic 
studies is generally preliminary in nature, and therefore the significance and scientific 
validity of the results are undetermined.  Further, data generated in a research laboratory 
may not meet regulatory requirements for inclusion in clinical care.


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Section 15.6 Appendix 6: Response Criteria for Multiple Myeloma
Consensus Recommendations [Rajkumar, 2011] for the Uniform Reporting of 
Clinical Trials:  Report of the International Myeloma Working Group (IMWG) 
Consensus Panel
Response Criteria [Durie, 2006]
sCR (stringent complete response):
Complete response as defined below plus:

normal free light chain (FLC) ratio and

absence of clonal cells in bone marrow by immunohistochemistry or 
2-4 color flow cytometry.
CR (complete response):

Negative serum and urine immunofixation, and

Disappearance of any soft tissue plasmacytomas, and

5% plasma cells in bone marrow.
VGPR (very good partial response):

Serum and urine M-component detectable by immunofixation but 
not on electrophoresis  OR

90% or greater reduction in serum M-component plus urine M-
component < 100mg/24h.
PR (partial response):

50% reduction of serum M-protein and reduction in 24 hour 
urinary M-protein by 90% or to < 200mg/24h, and

If the serum and urine M-protein are not measurable, a 50% 
decrease in the difference between involved and uninvolved free 
light chain levels is required in place of the M-protein criteria.  If 
serum and urine M-protein are not measurable, and serum free light 
chain assay is also not measurable, 50% reduction in bone marrow 
plasma cells is required in place of M-protein, provided baseline 
bone marrow plasma cell percentage was 30%, and

In addition to the above listed criteria, if present at baseline, a 50% 
reduction in the size of the soft tissue plasmacytomas is also 
required.


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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 Progressive Disease.
Progressive Disease:
Requires any one or more of the following:

Increase of 25% from lowest response value in any one or more of the following: 

serum M-component (absolute increase must be 0.5 g/dl), or

urine M-component (absolute increase must be 200 mg/24h), or

the difference between involved and uninvolved free light chain 
levels (absolute increase must be > 10mg/dl): only for subjects 
without measurable serum and urine M-protein levels, or

bone marrow plasma cell percentage (the absolute % must be 10%) 
– only for subjects without measurable serum and urine M-protein 
levels and without measurable disease by FLC level.

definite development of new bone lesions or soft tissue 
plasmacytomas or definite increase in the size of existing bone 
lesions or soft tissue plasmacytomas.

development of hypercalcemia (corrected calcium > 11.5 mg/dl or 
2.65 mmol/l) that can be attributed solely to the plasma cell 
proliferative disorder.
a.
All response categories (CR, sCR, VGPR, PR, MR and Progressive Disease) require 
two consecutive assessments made at any time before the institution of any new 
therapy; CR, sCR, VGPR, PR, MR, and SD categories also require no known 
evidence of progressive or new bone lesions if radiographic studies were performed.  
VGPR and CR categories require serum and urine studies regardless of whether 
disease at baseline was measurable on serum, urine, both, or neither.  Radiographic 
studies are not required to satisfy these response requirements.  Bone marrow 
assessments need not be confirmed.  For Progressive Disease, serum M-component 
increases of more than or equal to 1 g/dL are sufficient to define relapse if starting M-
component is ≥5 g/dL.
b. Clarifications to IMWG criteria for coding CR and VGPR in subjects in whom the 
only measurable disease is by serum FLC levels:  CR in such subjects indicates a 


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normal FLC ratio of 0.26 to 1.65 in addition to CR criteria listed above.  VGPR in 
such subjects requires a > 90% decrease in the difference between involved and 
uninvolved FLC levels.
c.
Clarifications to IMWG criteria for coding Progressive Disease: Bone marrow criteria 
for Progressive Disease are to be used only in subjects without measurable disease by 
M protein and by FLC levels; “25% increase” refers to M protein, FLC, and bone 
marrow results, and does not refer to bone lesions, soft tissue plasmacytomas, or 
hypercalcemia and the “lowest response value” does not need to be a confirmed 
value.


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AMENDMENT [4]
Where the amendment applies
This amendment applies to all investigator sites participating in this study
Summary of Amendment Changes with Rationale
Based on emerging data and guidance from ANSM following the submission of our 
CTA, GSK agreed to update the protocol for the following:

Update the instructions for investigational product to  restrict the storage duration 
of the final diluted solution to not more than 12 hours at ambient temperature 
(Protocol previously noted storage up to 48 hours), 

Instruct the investigators to inform their patients that they should: minimize or 
avoid prolonged exposure to natural or artificial sunlight; to wear sunglasses and 
loose fitting clothing to protect the skin; and to use a broad spectrum sunscreen on 
any uncovered areas of the body if outdoors.  

Amend the protocol to extend the period of post treatment contraception for 
women to 2 weeks (14 days).  
In addition, updates to the timing and frequency of pregnancy testing were updated to 
align with current GSK SOP.  Text was added to protocol to clarify those females who 
become pregnant while on study should be immediately withdrawn from study treatment 
and withdrawn from the study.
Lastly, the administration of ondansetron and palonosetron was clarified to allow oral 
doses up to 8mg TID and exclude IV.
AUTHORS:
PPD


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Sponsor/medical monitor Information Page
Medical Monitor and Sponsor Contact Information:
Role
Name
Day 
Time 
Phone 
Number
After-
hours 
Phone/Ce
ll/
Pager 
Number
Fax 
Number
GSK Address
Primary 
Medical 
Monitor
MD, PhD
1250 South Collegeville 
Road,
Mailstop UP 4410
Collegeville, PA 19426, 
USA
Seconda
ry
Primary
Medical 
Monitor
 MD, 
PhD 
1250 South Collegeville 
Road,
Mailstop UP 4410
Collegeville, PA 19426, 
USA
Seconda
ry 
Medical 
Monitor
 MD
Office: 
Cell: 
1250 South Collegeville 
Road,
Mailstop UP 4410
Collegeville, PA 19426, 
USA
PROTOCOL SYNOPSIS
REVISED TEXT
INCLUSION/EXCLSUION CRITERIA:
Part 1: Inclusion Criteria
8. Women of childbearing potential must have a negative serum pregnancy test within 
147 days of first dose of study treatment and agree to use effective contraception, as 
defined in Section 10.1, during the study and for at least one two weeks (14 days)
following the last dose of study treatment.
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


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Section 4.
INVESTIGATIONAL PRODUCT
REVISED TEXT
4.1: Description of Investigational Product
Table 5
Investigational Product
Product 
name:
GSK2816126 Injection,15 mg/mL, 30 mL vial with 25 mL fill volume
Formulation 
description:
Solution containing 15 mg/mL GSK2816126 in water for Injection, 
methanesulfonic  acid, Captisol and acetic acid  
Dosage form:
A solution stored at 2-8°C, protected from light
Unit dose 
strength(s)
15 mg/mL
Route/
Regimen
Delivered as an intravenous solution over 2 - 4 hours Study drug can be 
diluted into saline or dextrose for a final volume of 250ml at ambient 
temperature and normal room lighting up to 4812 hours prior to 
infusion.  PVH, PE and PA bags and tubing are all acceptable
Physical 
description:
A clear, pale yellow coloured solution, essentially free from visible 
particles of foreign matter
Section 5
STUDY POPULATION
REVISED TEXT
Section 5.2
Subject Selection Criteria
5.2.1
Part 1 Inclusion Criteria
8.  Women of childbearing potential must have a negative serum pregnancy test 
within 14 7 days of first dose of study treatment and agree to use effective 
contraception, as defined in Section 10.1, during the study and for at least one two 
weeks (14 days) following the last dose of study treatment.
Section 6.3
PERMANENT DISCONTINUATOIN FROM STUDY 
TREATMENT
REVISED TEXT
Female subject who becomes pregnant while on study treatment


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Section 7
STUDY ASSESSMENTS AND PROCEDURES
REVISED TEXT
Table 6
Time and Events, Treatment Phase:  Screening through Day 28 (See also 
PK sampling table for PK sampling schedule on Day 1 and Day 15)
Details added:

In females of child bearing potential, a serum pregnancy test is required at 
screening if performed within 14 7 days of first dose of study drug; and repeat as 
clinically indicated urine or serum test thereafter.

Urine or serum pregnancy tests were added to Continuation Phase ‘Every 4 
Weeks’ and at time of Follow Up Visit

Section 7.3.6 Laboratory Assessments

Table 8
List of Clinical Laboratory Tests
Hematology
Platelet Count
RBC Indices:
Automated WBC Differential:
RBC Count
MCV
Neutrophils
WBC Count (absolute) 
MCH
Lymphocytes
Reticulocyte Count
MCHC
Monocytes
Hemoglobin
Eosinophils
Hematocrit
Basophils
Clinical Chemistry
BUN
Potassium
AST
Total and direct bilirubin
Creatinine
Chloride
ALT
Uric Acid
Sodium
Calcium
Alkaline phosphatase
Total Protein
Magnesium
Glucose
LDH
PO4
FSH and estradiol (as needed in women of non-child bearing potential only)
Pregnancy test for females (serum at screening, Urine or serum during Continuation Phase)
Abbreviation(s): ALT, alanine aminotransferase; AST, aspartate aminotransferase; BUN, blood urea nitrogen; FSH, 
follicle stimulating hormone; LDH, lactate dehydrogenase; MCH, mean corpuscular hemoglobin;  MCHC, mean 
corpuscular hemoglobin concentration; MCV, mean corpuscular volume; PO4, phosphate; RBC, red blood cell;  WBC, 
white blood cell.
Section 7.3.7 Pregnancy Testing and Reporting
The need for a screening pregnancy test depends on whether a female subject is of 
childbearing potential or non-childbearing potential.
If a female subject is of childbearing potential, she must have a serum -HCG pregnancy 
test performed within 14 7 days prior to the first dose of study treatment.  Subjects with 
positive pregnancy test result must be excluded from the study.  Subjects with negative 
pregnancy test result must agree to use an effective contraception method as described in 


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Section 10.1 during the study until at least 1 2 weeks (14 days) after permanent 
discontinuation of study treatment.
Any pregnancy that occurs during study participation must be reported using a clinical 
trial pregnancy form.  To ensure subject safety, each pregnancy must be reported to GSK 
within 2 weeks of learning of its occurrence.  The pregnancy must be followed up to 
determine outcome (including premature termination) and status of mother and child.  
While pregnancy itself is not considered to be an AE or SAE, pregnancy complications 
and elective terminations for medical reasons must be reported as an AE or SAE.  
Spontaneous abortions must be reported as an SAE.
Any SAE occurring in association with a pregnancy brought to the investigator’s 
attention after the subject has completed the study and considered by the investigator as 
possibly related to the study treatments, must be promptly reported to GSK.
Any female subject who becomes pregnant while participating in the study will be 
withdrawn from the study. Study treatment should be immediately withdrawn from a 
subject who becomes pregnant during the study in order to eliminate further exposure of 
the embryo to the study treatment.
Section 9
CONCOMITANT MEDICATIONS AND NON DRUG THERAPIES
REVISED TEXT
Section 9.4
Drugs and QT Prolongation
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. Intravenous administration of
these drugs are not permitted
Section 10
LIFESTYLE AND/OR DIETARY RESTRICTIONS
REVISED TEXT
Section 10.1.1 Female Subjects
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. 
Complete abstinence from sexual intercourse for 14 days prior to first dose of study 
treatment, through the dosing period, and for at least two one weeks (14 days) after the 
last dose of study treatment.


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Section 10.2
Lactation Restrictions
Female subjects who are lactating must discontinue nursing prior to the first dose of study 
treatment and must refrain from nursing throughout the treatment period and for at least 
one two weeks (14 days) after last dose of study treatment.
Section 10.4
Sun and UV Exposure Restrictions
Prior to starting study drug, subjects should be instructed to:

Minimize or avoid prolonged exposure to natural or artificial sunlight
(e.g., tanning beds, sunlamps, UVA or UVB treatments)

Wear loose fitting clothing with long sleeves, sunglasses, and broad rim hat that
protect the skin from sun exposure AND use a broad spectrum sunscreen (e.g.,
UVA and UVB protective with minimum SPF 30) on any uncovered areas of the
body if outdoors


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STUDY PHASE
SCREEN
First Treatment Period
Cycle 1
Continuation 
Phase
Cycle 2 and 
beyond
Follow-
Upj
VISIT
Screen
Day 1 
and 4a
Day 8 
and 11 a
Day 15 
and 18 a
Day 
21
VISIT WINDOW (days)
-14
7l
7l
Assessments (notes)
Informed consent
X
Demographic data
X
Record subject using IVRS system
X
X
Height/Weight (Refer to Section 7.3.1)
Measurements in metric 
scale.  Height measured 
only at screening
X
X
Every 4weeks
(Cycle Day 1)
X
Pregnancy test
In females of child 
bearing potential, a 
serumi B-HCG pregnancy 
test is required within 7
days of first dose of study 
drug; urine or serumn B-
HCGtest thereafter.
X
Every 4 
weeks
(Cycle Day 1)
X
Disease characteristics (Refer to Section 7.2)
Record date of diagnosis, 
primary tumor type, 
histology, stage, etc.
X
Prior anti-cancer therapy & radiation
Record date of therapies
X
Prior surgical procedures
X
Past and current medical conditions
X
Alcohol consumption
X
Past and current tobacco use
X
Physical examination
X
Day 1
Day 8
Day 15
X
Every 4 weeks
Cycle Day 1
ECOG PS
See Appendix 2
X
X
X
X
X
X
X


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STUDY PHASE
SCREEN
First Treatment Period
Cycle 1
Continuation 
Phase
Cycle 2 and 
beyond
Follow-
Upj
VISIT
Screen
Day 1 
and 4a
Day 8 
and 11 a
Day 15 
and 18 a
Day 
21
VISIT WINDOW (days)
-14
7l
7l
Vital signs
BP, body temperature, 
pulse rate, respirations
Cycle 1 Day 1 vitals 
should be taken at same 
time points as PK draws 
on PK Table 7
X
X (Day
1 follow 
PK 
Table 
7)
X
X
X
Prior to each 
infusion
X
ECGb
Pre-infusion and at the 
end of infusion except on 
Day 1 (Section 7.3.4). 
Two copies of the ECG 
tracing should be 
obtained at the time of 
the ECG, one to be kept 
in the study file for 
retrospective collection by 
the sponsor if necessary.  
ECG data should be 
reviewed by qualified 
personnel with 
experience in this study 
population
X
Xb
X
X
On Day 4 of 
each cycle
X


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STUDY PHASE
SCREEN
First Treatment Period
Cycle 1
Continuation 
Phase
Cycle 2 and 
beyond
Follow-
Upj
VISIT
Screen
Day 1 
and 4a
Day 8 
and 11 a
Day 15 
and 18 a
Day 
21
VISIT WINDOW (days)
-14
7l
7l
Holter Monitoring
Continuous 12-lead 
Holter ECGs (obtained 
via a Holter monitor) 
will be acquired for a 
total of approximately 
24 hours beginning an 
hour before infusion on 
Day 1 only  
X
(Day 1)
ECHO /MUGA
At Screening 
X
Concomitant medications
See Section 9.2 for list of 
prohibited and cautionary 
medications
X
X
X
X
X
continuous
X
Adverse events (Refer to Section 8) 
Adverse event 
assessment should be 
continuous
X
X
X
X
X
continuous
X
Blood Sampling: on dosing days, collect blood samples prior to dosing unless otherwise noted
Chemistry
No need to repeat at pre-
dose Day 1 if screening 
assessments were 
performed within 72 
hours of first dose  (- 1 
day visit window after 
screening)
X
X
X
X
X
Prior to every 
infusion
X


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STUDY PHASE
SCREEN
First Treatment Period
Cycle 1
Continuation 
Phase
Cycle 2 and 
beyond
Follow-
Upj
VISIT
Screen
Day 1 
and 4a
Day 8 
and 11 a
Day 15 
and 18 a
Day 
21
VISIT WINDOW (days)
-14
7l
7l
Hematology
No need to repeat at pre-
dose Day 1 if screening 
assessments were 
performed within 72 
hours of first dose (- 1 
day visit window after 
screening)
X
X
X
X
X
Prior to every 
infusion
X
Coagulation
PT/PTT/INR.
No need to repeat at pre-
dose Day 1 if screening 
assessments were 
performed within 72 
hours days of first dose(-
1 day visit window after 
screening)
X
Blood sample for circulating biomarkers
A blood sample for 
circulating biomarkers 
should be obtained on 
Day 1 (prior to treatment), 
Day 21and at the time of 
disease progression
X
X
X (at 
progression)


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STUDY PHASE
SCREEN
First Treatment Period
Cycle 1
Continuation 
Phase
Cycle 2 and 
beyond
Follow-
Upj
VISIT
Screen
Day 1 
and 4a
Day 8 
and 11 a
Day 15 
and 18 a
Day 
21
VISIT WINDOW (days)
-14
7l
7l
Blood sample for Genetic research
A 6mL blood sample 
should be collected 
after screening 
(preferably on day 1) 
if informed consent 
has been obtained 
for Genetic research
X
Whole Blood for Biomarkersg
Whole blood should be 
obtained prior to dosing 
on day 1,day 18  and 
C2D1 (sample taken prior 
to dosing)
X (Day 
1)
X (Day 18)
X (C2W1D1 
pre dose 
only)
PK sampling for Part 1
For details, see Table 7
Day 1 
(Table
7)
Day 
4pre-
dose 
and 
end of 
infusion
Soon 
after ECG 
collection
Day 15 
(Table 7)
At 
the 
time 
of 
circul
ating 
biom
arker 
collec
tion
Cycle 2, 4, 6 
and 12 – pre-
dose and 
within 5 min 
prior to end 
of infusion on 
Day 4 


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STUDY PHASE
SCREEN
First Treatment Period
Cycle 1
Continuation 
Phase
Cycle 2 and 
beyond
Follow-
Upj
VISIT
Screen
Day 1 
and 4a
Day 8 
and 11 a
Day 15 
and 18 a
Day 
21
VISIT WINDOW (days)
-14
7l
7l
PK sampling for Part 2
Three samples to be 
collected on Day 1 and 
Day 11: Predose within 
60 minutes prior to start 
of infusion, single draw 
between 0.5 and 1.9 h 
from start of infusion, 
single draw between 3-
6h following end of 
infusion.
Day 1 
and 
pre-
dose 
on Day 
4
X (after 
4th dose, 
Day 11)
pre-dose 
on Day 15
Cycle 2, 4, 6 
and 12 – pre-
dose and 
within 5 min 
prior to end 
of infusion on 
Day 4 
Translational Research
Tumor Tissue for EZH2 mutation and GCB 
confirmation testing (required: for all GCB 
DLBCL and tFL  subjects)c
Availability of archival 
tissue (or fresh biopsy) is 
required for central 
testing of GCB-subtype  
and EZH2 mutation 
status
X
Tumor tissue for solid tumors (including 
prostate subjects)c
Availability of archival 
tissue (or fresh biopsy)
X
Tumor biopsy for PD optional for Part 1 and 
Part 2Required for  PK/PD cohort 
A tumor biopsy should be 
obtained at D1 (up to -14 
days) and after 6th dose 
Day 18(+3 day window)
X
X (After 6th
dose, Day 
18)h


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STUDY PHASE
SCREEN
First Treatment Period
Cycle 1
Continuation 
Phase
Cycle 2 and 
beyond
Follow-
Upj
VISIT
Screen
Day 1 
and 4a
Day 8 
and 11 a
Day 15 
and 18 a
Day 
21
VISIT WINDOW (days)
-14
7l
7l
Tumor biopsy for biomarker research
Recommended  for all 
subjects 
X (at pro-
gression)
Additional Assessments for PD/PK Cohortm
Blood for metabolite evaluation (Part 2 PK/PD 
expansion cohort only
Day 1 
(Table 
7) 
Day 15 
(Table 7)
Urine for Metabolite (Part 2 PK/PD expansion 
cohort only) 
On Day 15, urine 
samples should be 
collected while subject is 
in the office
Day 1 
prior to 
first 
dose 
and 
from 0 
to 24h
Day 15 
from 0 to 8
h
Bile for metabolite (Part 2 PK/PD expansion 
cohort only) – at least 4 subjects)
Day 15
Plasma for 4-hydroxycholesterol and 
cholesterol assay (Part 2 PK/PD expansion 
cohort only)
X (Day 
1 prior 
to First 
Dose)
X


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STUDY PHASE
SCREEN
First Treatment Period
Cycle 1
Continuation 
Phase
Cycle 2 and 
beyond
Follow-
Upj
VISIT
Screen
Day 1 
and 4a
Day 8 
and 11 a
Day 15 
and 18 a
Day 
21
VISIT WINDOW (days)
-14
7l
7l
Disease Assessments for Lymphoma Subjects: Baseline disease assessments at screening and repeated 8 weeks after dosing is initiated and every 12 weeks 
thereafter
CTk
Must be completed within 
4 weeks of first dose of 
GSK2816126 and 
repeated 8 weeks after 
dosing is initiated.  Every 
12 weeks thereafter
X
X
Xd
Positron emission tomography (PET)
The use of standalone 
PET or PET in 
combination with CT 
scan is optional. 
Standalone PET does not 
replace CT
Xe
Xe
Xd,e
Bone Marrow biopsy)
See Section 7.7
X
Xf
Xf
B symptoms
See Section 7.7
X
X
X
X
X
X
Disease Assessments for Multiple Myeloma (MM) subjects: Baseline disease assessments at screening, week 4 and then every 6 weeks there after unless otherwise 
noted
Disease Characteristics
Every 6 weeks after Wk4, 
Including cytogenetics as 
appropriate
X
X
Total Protein, CRP, 2 microglobulin
Every 6 weeks after Wk4
X
X
Response Assessment
Every 6 weeks after Wk4; 
Response criteria in 
Appendix 6
X


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STUDY PHASE
SCREEN
First Treatment Period
Cycle 1
Continuation 
Phase
Cycle 2 and 
beyond
Follow-
Upj
VISIT
Screen
Day 1 
and 4a
Day 8 
and 11 a
Day 15 
and 18 a
Day 
21
VISIT WINDOW (days)
-14
7l
7l
SPEP, FLC assay, quantitative 
immunoglobulins ( IgG, IgA, IgM)
Not required for subjects 
with non-secretory MM
X
X
UPEP
Only required if 
paraprotein is present in 
urine
X
Extramedullary Disease Assessment
Only required for MM 
with extramedullary 
disease
X
BM aspirate and biopsy
Required for non-
secretory MM, or as 
appropriate for other 
subjects
X
Day 18
Week 10, Day 
1
Disease Assessments for Solid Tumors: Baseline disease assessments at screening and repeated every 8 weeks after dosing is initiated
CT/MRIk
Must be completed within 
4 weeks of first dose of 
GSK2816126 and
repeated every 8 weeks
X
Xd
Xd
Positron emission tomography (PET)
The use of standalone 
PET or PET in 
combination with CT 
scan is optional. 
Standalone PET does not 
replace CT
Xe
Xd,e
Xd,e


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STUDY PHASE
SCREEN
First Treatment Period
Cycle 1
Continuation 
Phase
Cycle 2 and 
beyond
Follow-
Upj
VISIT
Screen
Day 1 
and 4a
Day 8 
and 11 a
Day 15 
and 18 a
Day 
21
VISIT WINDOW (days)
-14
7l
7l
Disease Assessments for Prostate Cancer: (in addition to those assessments for all solid tumor subjects): Baseline disease assessments at screening and 
repeated as noted below after dosing is initiated
PSA
Wk 9 and every 4 weeks 
thereafter
X
Every 4 weeks
(Cycle Day 1)
X
Study Medication
GSK2816126 Dosing
Dosed 2x weekly with at least 2-3 non-dosing days in between dosing days (3 weeks on/1 week off)


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AMENDMENT [5]
Where the Amendment Applies
Amendment 5 applies to all global sites.
Summary of Amendment Changes with Rationale
Updates were made throughout the protocol to correct minor inconsistencies, spelling 
errors and provide further clarification.  The following updates have been made to the 
this amendment to align with updated GSK SOPs and Guidance documents, as well as, to 
include expansion cohorst in Part 1 of the study to explore further efficacy and safety 
data:

Updates made to the Part 1 and Part 2 Objectives, Endpoints and study hypothesis 
to align with the added Part 1 expansion cohorts of GCB DLBCL and solid 
tumors containing EZH2 inhibitor sensitizing mutations or prostate cancer to 
support MTD/RP2D and initiation of planned part 2 analysis

Study design and number of subjects updated to include the added Part 1 
expansion cohorts and update Part 2 expansion cohort

Inclusion and exclusion criteria updated to define eligibility of GCB DLBCL and 
solid tumor subjects in Part 1 expansion cohort.  Exclusion for Central nervous 
system metastases, invasive malignancy other than disease under study and prior 
allogeneic transplant added.

Male and female contraception use and pregnancy information updated in 
inclusion criteria and Section 10 to align with GSK written standards

Statistical methods/Section 12 updated to include Part 1 interim analysis of 
futility and efficacy for GCB DLBCL subjects. Part 2 updated to further clarify 
that expansion design is planned based on predictive probability methodology.
Rather than early stop for either futility or efficacy, Part 2 allows early stop for 
futility only.  Number of subjects to be enrolled into the Part 2 expansion cohorts 
updated accordingly

Risk Assessment updated to include: updated list of medications with risk and 
possible risk of tpd that are prohibited or to be used with caution;  drugs that are 
to be used with caution will require additional ECG monitoring; clarify 
instructions for the treatment of infusion reactions; new drug interaction data; 
additional data and instructions for phototoxicity; and data and mitigation strategy 
for increased ALT levels seen in higher doses. 

PK/PD cohort moved from Part 1 to Part 2

Study rationale updated to include supporting rationale for inclusion of GCB-
DLBCL and solid tumor subjects (to include prostate cancer)

Safety management guidelines updated to clarify QTcF to be used for eligibility 
and stopping criteria


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
Time and Events tables updated to clarify required assessments. Added 
clarification that brain scans are required for all subjects at screening and bone 
scans should be completed as clinically indicated.  Collection of Blood for PD 
biomarkers removed and collection of whole blood for biomarkers added

Response criteria added for subjects with prostate cancer in Appendix 7 of the 
protocol

Adverse event and serious adverse event Section 8 updated to align with latest 
GSK written standards, to include: further definition of events which would meet 
liver stopping and monitoring criteria, as well as, definition and process for study 
treatment restart and rechallenge after a liver event and removal of Section 8.4 
addressing disease related event

Section 9 updated with latest list of prohibited medications and those to be used 
with caution
List of Specific Changes

Author (s):


Global Clinical Operations Sciences, USA

Drug Metabolism and Pharmacokinetics, USA

Cancer Epigenetics, USA

Non--Clinical Safety, USA

Cancer Research Epigenetics Management, 

Non-Clinical Safety, USA 

Statistics, Oncology TA Group, USA

Global Clinical Operations Sciences, USA

Clinical Oncology, USA

Clinical Oncology, USA

Cancer Epigenetics DPU, USA

Clinical Pharmacology Modeling & Simulation, 

         Statistics, Oncology TA Group, USA
PPD


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Sponsor/Medical Monitor Information Page
REVISED TEXT
Medical Monitor and Sponsor Contact Information:
Role
Name
Day Time Phone 
Number
After-hours 
Phone/Cell/
Pager 
Number
GSK Address
Primary 
Medical 
Monitor
MD, 
PhD 
1250 South Collegeville 
Road,
Mailstop UP 4410
Collegeville, PA 19426, 
USA
 
Secondary 
Medical 
Monitors
MD
Office:
Cell: 
1250 South Collegeville 
Road,
Mailstop UP 4410
Collegeville, PA 19426, 
USA
Office
1250 South Collegeville 
Road,
Mailstop UP 4410
Collegeville, PA 19426, 
USA
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


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LIST OF ABBREVIATIONS
Added the abbreviations TdP (Torsades de Pointe)
Section
Protocol Synopsis: Study Rationale
Rationale for Change: 

Clarified that subjects with castrate resistant prostate cancer are included in the 
cohort of subjects with solid tumors.

Clarified the patient population to be enrolled under this amendment to include 
patients with  GCB DLBCL and solid tumors containing EZH2 inhibitor 
sensitizing mutations or prostate cancer
REVISED TEXT

Most of these cancers have an overall poor outlook either because of lack of any 
effective therapy or standard therapies do not result in a durable remission. This 
first study of this agent will be conducted in subjects with non-Hodgkin 
lymphomas, especially germinal center B-cell diffuse large B-cell lymphoma 
(GCB-DLBCL) and transformed follicular lymphoma (t-FL), and subjects with 
solid tumors ( including castrate resistant prostate cancer) and multiple myeloma 
(MM) who have relapsed or are refractory to prior therapies and have a high 
degree of unmet medical need in terms of available treatment options.   
Section
Protocol Synopsis: Study Objectives, Endpoints And 
Hypotheses
Rationale for Change:

Moved Part 1 objectives for the PD/PK cohort to Part 2 of the study

Included the hypothesis and statistical analysis plan for the Part 1 expansion of 
GCB DLBCL and solid tumor subjects. GCB-DLBCL cohort expansion was 
added into Part 1 dose escalation phase. The study design was based on predictive 
probability methodology (Liu, 2008) to allow interim futility/efficacy assessment 
by comparing the overall responses with the pre-specified futility and efficacy 
stopping criteria, in order to enabling early decision of opening Part 2 expansion 
phase or terminating the trial. 

Due to the improvement of response rates of cancer treatments over time, the 
study designs in Part 2 expansion phase based on predictive probability method 
were revised by updating the null and alternative hypothesis, to align with the 
current typical response rates. The sample size and futility stopping criteria for 
each cohort (GCB-DLBCL mutant and wild type, tFL mutant and wild type, and 
MM) are updated

Update Part 1 and Part 2 exploratory objectives and endpoints


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REVISED TEXT
Part 1 Objectives
Part 1 Endpoints
Secondary

To describe the 
pharmacokinetics of 
GSK2816126 after single-
and repeated administration

To evaluate the relationship 
between GSK2816126 
exposure and 
safety/efficacy/PD 
parameters

To determine clinical activity 
of GSK2816126 in GCB 
DLBCL and solid tumors 
containing EZH2 inhibitor 
sensitizing mutations or 
prostate cancer


Evaluate the relationship 
between GSK2816126 
exposure markers and 
safety/efficacy/PD responses

To generate samples (data 
reported separately) with 
which to characterize the 
metabolic profile of 
GSK2816126 after repeat-
dosing (In the PK/PD 

GSK2816126 PK parameters 
following single- (Day 1) and 
repeat-dose  administration of 
GSK2816126, including area 
under the concentration-time 
curve (AUC), pre-dose (trough) 
concentration at the end of the 
dosing interval (C), maximum 
observed concentration (Cmax), 
time of occurrence of Cmax 
(tmax), terminal phase half-life 
(t1/2), time invariance and 
accumulation ratio

GSK2816126 exposure markers 
(dose, concentration, Cmax or 
AUC) and safety/efficacy/PD 
responses. Pharmacodynamic PD
response assessed by change from 
baseline in tri-methylation of 
Histone H3K27 (H3K27me3)

Best Overall Response rate 
(complete response [CR]  + partial 
response [PR])

Samples to characterize the 
metabolites in blood, bile and/or 
urine

Concentration of GSK2816126 in 
urine measured with an 
investigational bio-analytical 


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Part 1 Objectives
Part 1 Endpoints
expansion cohort only)

To determine the amount 
of GSK2816126 excreted in 
urine after dosing at steady 
state
method and extrapolated to total 
amount excreted in urine over time 
using urine volume
Explorator
y

To confirm tumor EZH2 and 
GCB-DLBCL status

To investigate the 
mechanism of action and 
additional indicators of 
sensitivity and resistance to 
of GSK2816126

To identify biomarkers 
predictive of response or 
resistance to GSK2816126

To generate samples (data 
reported separately) with 
which to investigate the 
potential for GSK2816126 to 
affect cytochrome P450 
(CYP) 3A4 enzyme activity

IHCfor confirmation of GCB-
DLBCL status

PCR or NGS to determine EZH2 
mutation status 

Evaluate transcriptional and/or 
protein changes upon 
GSK2816126 treatment

Correlate baseline tumor genomic 
(DNA), protein and/or 
transcription (RNA)  profiles with 
response

Tumor baseline genetic profiles, 
response

Samples to assess a potential 
change in 4b-OH cholesterol to 
cholesterol ratio in plasma 
following repeat dosing of 
GSK2816126 (data reported 
separately)
Hypothesis
No formal statistical hypotheses are being tested in Part 1: Phase I dose 
escalation.  Analysis of the data obtained from Part 1 will only utilize 
descriptive methods


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Part 1 Objectives
Part 1 Endpoints
No formal statistical hypotheses are being tested for the dose escalation in 
Part 1. Analysis of the data obtained from dose escalation of Part 1 will 
utilize descriptive methods only. 
The cohort expansion of GCB-DLBCL patients in Part 1 will assess the 
overall response rate (p) of GCB-DLBCL patients. The null and alternative 
hypotheses for the overall response rate are detailed below:
The null hypothesis is:
H0: p≤20%
The alternative hypothesis is:
HA: p≥40%
For cohort expansion of solid tumor subjects in Part 1, there is no formal 
statistical hypothesis being tested. Analysis of the data obtained from solid 
tumor expansion cohort will utilize descriptive methods only.


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Part 2 Objectives
Part 2 Endpoints
Primary

To determine clinical 
activity of GSK2816126 in 
cohorts of subjects with 
EZH2 mutant and wild type 
GCB-DLBCL and tFL and 
subjects with MM

ObjectiveOverall response rate (% 
of subjects achieving CR and PR 
per response criteria)
Secondary

To determine the safety, 
tolerability of the selected 
IV dose of GSK2816126

To characterize the 
population PK of 
GSK2816126

To evaluate the relationship 
between GSK2816126 
exposure and PD 
parameters

To generate samples (data 
reported separately) with 
which to characterize the 
metabolic profile of 
GSK2816126 after repeat-
dosing (In the PK/PD 
expansion cohort only)

To determine the 
amount of GSK2816126 
excreted in urine after 
dosing at steady state

AEs, SAEs, DLTs, withdrawals 
due to AEs, dose interruptions and 
reductions,  and changes in safety 
assessments (e.g., clinical 
laboratory parameters, vital signs, 
and cardiac parameters)

Population PK parameters for 
GSK2816126 including clearance 
(CL), and volume of distribution 
(Vd) and relevant covariates 
which may influence exposure 
(e.g. age, weight, or disease 
related covariates)

GSK2816126 exposure markers 
(dose, concentration, Cmax or 
AUC) and PD responses. PD 
response assessed by change from 
baseline in tri-methylation of 
Histone H3K27 (H3K27me3)

Samples to characterize the 
metabolites in blood, bile and/or 
urine

Concentration of GSK2816126 in 
urine measured with an 
investigational bio-analytical 
method and extrapolated to total 
amount excreted in urine over time 


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Part 2 Objectives
Part 2 Endpoints


To evaluate the relationship 
between exposure and 
safety/efficacy parameters 

To begin to characterize the 
durability of response and 
progression free survival 
with GSK2816126

To generate samples 
(data reported separately) 
with which to investigate 
the potential for 
GSK2816126 to affect 
cytochrome P450 (CYP) 
3A4 enzyme activity
using urine volume

GSK2816126 exposure markers 
(e.g. dose, concentration, Cmax, 
or AUC) and safety/efficacy 
responses. 

Duration of response (DoR)

Progression-free survival (PFS) 


Samples to assess a potential 
change in 4b-OH cholesterol to 
cholesterol ratio in plasma 
following repeat dosing of 
GSK2816126 (data reported 
separately)
Exploratory

To identify biomarkers 
predictive of response or 
resistance to GSK2816126

To investigate the 
mechanism of action of 
GSK2816126 by evaluating 
changes in gene expression 
profiles

To investigate the 
relationship between 
genetic variants in 
candidate genes and the 
pharmacokinetics (PK) and 
safety profile of 
GSK2816126 based on Part 
1 and 2 data combined

Evaluation of wild-type (WT) 
subject tumors for the presence of 
additional, undefined, mutations 
in the EZH2 gene

Correlate baseline tumor genomic 
(DNA), protein and/or 
transcription (RNA)  profiles with 
response

Evaluate transcriptional and/or 
protein changes upon 
GSK2816126 treatment

Deoxyribonucleic acid (DNA), 
ribonucleic acid (RNA) and 
protein markers in tumor and 
blood

Pharmacogenomic (PGx) analysis 
of whole blood


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Part 2 Objectives
Part 2 Endpoints
Hypothesis
In Part 2, the overall response rate (p) of GCB-DLBCL and tFL patients 
will be assessed for each EZH2 mutation status cohort (wild type and 
mutant), and also for MM patients. 

For each of the GCB-DLBCL and tFL cohort, the null and alternative 
hypotheses of the overall response rate are as following:
The null hypothesis is:
H0: p≤20%
The alternative hypothesis is:
HA: p≥40%

For MM cohort:
The null hypothesis is:
H0: p≤10%
The alternative hypothesis is:
HA: p≥25%
The primary objective of Part 2 is to determine whether administration of 
GSK2816126 has a potentially clinically meaningful response rate. 

In subjects with GCB-DLBCL, this will be determined in each EZH2 
mutation status cohort (wild type and mutant) by testing the null 
hypothesis that the response rate is ≤10%, with about 90% power 
when the true response rate is 30%.  

In subjects with tFL, this will be determined in each EZH2 mutation 
status cohort by testing the null hypothesis that the response rate is 
≤5%, with about 80% power when the true response rate is 25%. 

In subjects with MM, this will be determined by testing the null 
hypothesis that the response rate is ≤5%, with about 85% power when 
the true response rate is 20%.


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Section
Protocol Synopsis
Rationale for Change: Included expansion cohort in Part 1 of the study to enroll at the 
MTD an additional 27 GCB-DLBCL and 15 solid tumor subjects to collect 
additional safety and efficacy data in these patient populations. Clarified that solid 
tumor cohort in Part 1expansion will include subjects with solid tumors containing 
EZH2-inhibitor sensitizing mutations or metastatic castrate resistant prostate cancer 
(mCRPC, regardless of mutation status).  Updated the total number of subjects 
expected to be enrolled based on addition of the Part 1 expansion cohort and updated 
Part 2 cohort subject numbers.
REVISED TEXT

Study Design:This study is divided into 2 parts; Part 1 of the study is a dose 
escalation phase to identify MTD and select the recommended Phase 2 dose (RP2D) 
based on the safety, PK, and PD profiles observed after IV administration of 
GSK2816126.  Eligible subjects with relapsed/refractory DLBCL, transformed FL
malignancies, other Non non-Hodgkin’s lymphomas (NHL), Multiple Myeloma 
(MM) and solid tumors will be enrolled in the dosing cohorts until a RP2D is 
established.  One or more dose level/s during Part 1 escalation may be expanded up to 
12 subjects to explore safety and preliminary efficacy. At the identified MTD,  
approximately 27 GCB-DLBCL subjects and approximately 15 subjects with solid 
tumors containing EZH2-inhibitor sensitizing mutations or metastatic castrate 
resistant prostate cancer (mCRPC, regardless of mutation status), may be enrolled to 
explore safety and preliminary efficacy.  Subjects may continue treatment in the study 
until disease progression, unacceptable toxicity, or withdrawal of consent.  Expansion 
cohorts (Part 2) are planned in subjects with MM, and in subjects with both EZH2 
mutant positive and EZH2 WT GCB-DLBCL and tFL to further explore clinical 
activity at the RP2D.

NUMBER OF SUBJECTS:  Approximately Up to approximately 250169 subjects 
worldwide (inclusive both Parts 1 and 2).
INCLUSION/EXCLUSION CRITERIA:
Rationale for Change: In line with the added Part 1 expansion cohort, updated  that the 
NHL tumor types to be enrolled under this amendment will include GCB-DLBCL 
subjects and the inclusion criteria for these subjects.  Removed criteria for tFL and 
other NHLs. Updated the tumor type criteria for solid tumor subjects including
subjects with CRPC. Updated the inclusion of women who are of child bearing 
potential and male and female contraception use per GSK document standards.
Updated the adequate organ funcation table to clarify renal parameters and clarify 
footnotes.
Part I: Inclusion Criteria 
Subjects eligible for enrollment in the study must meet all of the following criteria:


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3. Tumor type criteria:  

Relapsed/refractory NHL that meets one of the following criteria:
o
Germinal Ccenter B cell Diffuse large B cell lymphoma (GCB-
DLBCL) or transformed follicular lymphoma relapsed after, or 
refractory to at least one prior chemotherapy regimen (e.g., rituximab, 
cyclophosphamide, doxorubicin, vincristine, prednisone [R-CHOP]) 
AND not a candidate for standard salvage regimens or autologous or 
allogeneic stem cell transplant. (e.g., due to age, comorbid conditions 
or failure to respond to salvage chemotherapy).  Local confirmation of 
lymphoma subtype (e.g. GCB-DLBCL) is allowed for enrollment but 
must be confirmed through central laboratory testing.
o
DLBCL or transformed FL relapsed after or refractory to at least two 
prior chemotherapy regimens.
o
Other NHLs that have failed at least one prior line of therapy and for 
which there is no standard salvage regimen.

Relapsed and/or refractory MM that have failed prior standard therapy and 
for which there is no standard salvage regimen.

Solid tumors [RECIST evaluable, with the exception of castrate resistant 
prostate cancer (CRPC) at least one and not more than three standard of care 
chemotherapeutic regimens, or tumor for which there is no approved therapy, 
or for which standard therapy is refused.

Solid tumors that meet the following criteria:
o
Measurable disease  by RECIST 1.1 in at least 1 site

For Castrate Resistant Prostate Cancer (CRPC) measurable 
disease can also include PSA level (see below)
o
Disease progression with the last line of therapy and at least one  prior 
standard of care regimens, or tumor for which there is no approved 
therapy, or for which standard therapy is unsuitable or refused.
o
Mutation Status:

Solid tumor types, other than prostate, must havea one of the 
following EZH2 inhibitor sensitizing mutations as determined 
via local testing:

An activating mutation in EZH2 (Y641F/C/S/H/N, 
A677V/G, and/or A687V 

Loss of a component of the SWI/SNF complex, 
including, but not limited to, ARID1A, SMARCB1 
(aka SNF5/INI1/BAF47), SMARCA4 (aka BRG1), or 
PBRM1 (aka PB1) as determined by molecular testing 
(bi-allelic loss or mutation) or immunohistochemistry

Loss of BAP1 (ubiquitin carboxy-terminal hydrolase) 
as determined by molecular testing (bi-allelic loss or 
mutation) or immunohistochemistry


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o
CRPC subjects:

Must have measurable disease by either:

RECIST1.1 (Appendix 5), or

a minimum PSA of 5 ng/mL 

Disease progression on last line of therapy and must have 
progressed on abiraterone, enzalutamide, or taxane 
chemotherapy

Subjects may continue GnRH agonists

Small cell prostate cancer is eligible
DLBCL and tFL: Availability of archival tissue, or willingness to undergo fresh 
biopsy for: confirmation of GCB-DLBCL status (DLBCL subjects); retrospective 
central testing of EZH2 mutation status (DLBCL, and tFL subjects).  For all other 
tumor types: availability of either archival tissue or fresh biopsies. 
4. For all subjects: Availability of archival tissue, or willingness to undergo fresh 
biopsy if archival tissue is not available, as described in Section 7.6.1.1, Section
7.6.1.2 and Section 7.6.5.
5. Must have a pre-existing central venous access such as a port, Hickmann catheter,
or a peripherally inserted central catheter (PICC line) or be willing and able to 
have one inserted.
6. ECOG Performance Status of 0 or 1 (see Appendix 2).
7. Men with a female partner of childbearing potential must have either had a prior 
bilateral vasectomy with resultant azoospermia, bilateral orchiectomy, or must 
agree to use one of the contraception methods listed in Section 10.1 from the time 
of the first dose of study medication until at least 2 weeks (14 days) 3 months
after the last dose of study treatment due to the long elimination phase of study 
drug.for clearance of any altered sperm.
8. A female subject is eligible to participate ifs she is of:

Non-child bearing potential as defined in Section 10.1.1.
i.
Women of childbearing potential must have a negative serum 
pregnancy test within 7 days of first dose of study treatment and 
agree to use effective contraception, as defined in Section 10.1, 
during the study and for at least two weeks (14 days) following the 
last dose of study treatment.  

Child bearing potential as defined in Section 10.1.1 and agrees to use 
effective contraception, as defined in Section 10.1, for an appropriate 
period of time (as determined by the product label) prior to the start of 
dosing to sufficiently minimize the risk of pregnancy and for at least 
2 weeks (14 days) following the last dose of study treatment. Women of 
childbearing potential must have a negative serum pregnancy test within 
7 days of first dose of study treatment followed by negative urine or serum 
pregnancy test once every 4 weeks (prior to next dose cycle) thereafter.  


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9. Adequate organ system function as defined below:
System
LABORATORY VALUES
Hematologic
  ANC
1.2 x 10 9/L  
  Hemoglobin
9 g//dL 
  Platelets
75x 109/L  
  Platelets for Subjects with MM
≥ 50,000 (transfusion independent)
  PT/INR and PTT
≤1.5 x ULN
Hepatic
  Albumin
2.5 g/dL
  Total bilirubin
1.5 times ULN
  AST and ALT
2.5  times ULN without liver metastases
5 times ULN if documented liver metastases
Renal
Serum Creatinine
1.5 mg/dL 
or
Calculate Creatinine Clearancea, b  OR     
24 hr urine Creatinine Clearance
50 mL/min                                                           
≥50mL/min
Reproductive/Endocrine for CRPC 
only
Testosterone 
<50 ng/dL (only for subjects with CRPC)
Cardiac
Left Ventricular Ejection Fraction 
(LVEF)
≥LLN (minimum of 50% LVEF) by ECHO  or 
MUGAc
Abbreviation(s): ANC, absolute neutrophil count; ALT, alanine aminotransferase; AST, 
aspartate aminotransferase; ECHO, echocardiogram; INR, international normalization 
ratio, MUGA, multigated (radionuclide) angiogram; PT, prothrombin time, PTT, partial 
thromboplastin time, ULN, upper limit of normal , LLN, lower limit of normal.
a.
Calculated by Cockcroft-Gault formula
b. For MM subjects, adequate renal function is defined as serum creatinine ≤ 2.5 mg/dL 
OR calculated creatinine clearance (either calculated or obtained via 24 hr urine 
collection) ≥30 mL/minECHO is the preferred method
c.
ECHO is the preferred method and should always be used if available.
NOTE:  Laboratory results obtained during Screening should be used to determine 
eligibility criteria.  In situations where laboratory results are outside the permitted range, 
the investigator may opt to retest the subject and the subsequent within range screening 
result may be used to confirm eligibility.  Subjects requiring transfusions to meet 
eligibility criteria are not eligible.


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Rationale for Change: Included the tumor type inclusion criteria for tFL and MM patients 
to be enrolled into Part 2 of the study.
Part 2: Inclusion Criteria
1.
In addition to inclusion criteria listed for Part 1, Part 2 will enroll GCB-DLBCL, 
tFL and MM subjects only. 
a.
Relapsed and/or refractory MM or tFL that have failed prior standard therapy 
and for which there is no standard salvage regimen
Rationale for Change: 

Clarified the exclusion of cancer therapies received prior to first dose.  

Added the exclusion of subjects with prior allogeneic transplant. 

To manage exposure to another investigational product, clarified the time period 
between use of another investigational product and first dose of study treatment. 

Concurrent use of therapeutic warfarin is allowed. Added in Section 9.2 additional 
monitoring for INR and bleeding. Clarified that anticoagulants that do not have 
reversal agents available are prohibited .

Included exclusion for  use of packed red blood cell or  platelet transfusion within 
7 days of screening laboratory tests to ensure that the subject has relatively stable 
bone marrow function and does not have any serious condition that would lead to 
dependency on frequent transfusions.

To further clarify subject population, added criteria to exclude subjects with CNS 
involvement and other invasive malignancies.
Part 1 and 2: Exclusion Criteria
Subjects meeting any of the following criteria must not be enrolled in the study:
1.
Currently rReceiving any cancer therapy within 2 weeks of first dose  
(chemotherapy, radiation therapy, immunotherapy or biologic therapyincluding 
surgery, and/or tumor embolization) (permitting corticosteroids to control systemic or 
local symptoms, up to a dose of 10 mg prednisolone or equivalent daily and stable for 
at least 7 days prior to enrollment).
Note: the following are allowed:

Corticosteroids to control systemic or local symptoms, up to a dose of 
10 mg prednisone or equivalent daily and stable for at least 7 days prior to 
enrolment.

Subjects with prostate cancer may remain on GnRH agonists. Other 
hormonal therapies (e.g., bicalutamide, abiraterone and enzlutimide) for 
prostate cancer must be stopped 4 weeks prior to enrolment  


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Note: the following are NOT allowed:

Chemotherapy regimens with delayed toxicity within the last 3 weeks

Nitrogen mustards, Melphalan,  Monoclonal antibody or Nitrosourea 
within the last 6 weeks

Hormonal (e.g., anti-androgen) therapies for prostate cancer must be stopped 
4 to 6 weeks prior to enrolment. Subjects with prostate cancer may remain on 
luteinizing hormone releasing hormone (LHRH) agonists.  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.
2.
Any major surgery, radiotherapy or immunotherapy within the 4 weeks prior to first 
dose of study drug, or palliative radiotherapy to a single symptomatic lesion within 
the 2 weeks prior to first dose of study drugs.
3.
Subjects with prior allogeneic transplant are excluded: however, subjects who have 
previously received an autologous stem cell transplant are allowed if a minimum of 
100 days has elapsed from the time of transplant and the subject has recovered from 
transplant-associated toxicities prior to the first dose of GSK2816126

Subjects who have previously received an autologousstem cell transplant are 
allowed if a minimum of 100 days has elapsed from the time of transplant and the 
subject has recovered from transplant-associated toxicities prior to the first dose 
of GSK2816126
4.
Received an investigational anti-cancer drug within 4 6 weeks, or within 5 half-lives 
(whichever is shorter) of the first dose of study drug.  At least A minimum of 14 days 
must have passed between the last dose of prior investigational agent and the first 
dose of study drug. 
5.
Current use of a prohibited medication or expected to require any of these 
medications during treatment with study drugs ( Section 9).
6.
Known HIV, or serological evidence for Hepatitis B (positive HBsAg), or chronic
Hepatitis C infection.

For sSubjects who are negative for HBsAg, but HBcAb positive, a HBV
DNA (viral load) test will be performed and if negative are eligible.positive 
will be excluded.  

Subjects with positive Hepatitis C antibody serology with abut negative HCV 
RNA test results are eligible.  
7.
Concurrent use of therapeutic warfarin is allowed. However, anticoagulants that do 
not have reversal agents available are prohibited (see Section 9.2). Current use of 
therapeutic warfarin.  Therapeutic dosing of warfarin is defined as resulting in an 
International Normalization Ratio (INR) low molecular weight heparin is permitted.  
8.
Unresolved toxicity greater than Grade 1 National Cancer Institute – Common 
Terminology Criteria for Adverse Events (NCI-CTCAE) version 4 from previous 
anti-cancer therapy, with the exception of alopecia and peripheral neuropathy [NCI-
CTCAE, 2009]. 


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
Lymphoma subjects with ≤Grade 3 lymphopenia can be enrolled at the
discretion of the investigator
9.
Packed red blood cell or  platelet transfusion within 7 days of screening laboratory 
tests.
10.
Psychological, familial, sociological or geographical conditions that do not permit 
compliance with the protocol.
11.
Cardiac exclusion criteria:

History of acute coronary syndromes (including myocardial infarction and 
unstable angina), coronary angioplasty, or stenting within the past 6 months 
prior to first dose of study drug.

QTcF interval >450msec. 

Uncontrolled arrhythmias.  Subjects with rate controlled atrial fibrillation for 
>1 month prior to first dose of study drugs may be eligible.

Class II, III or IV heart failure as defined by the New York Heart Association 
(NYHA) functional classification system.  
12.
Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs 
chemically related to the study drug or their excipients.
13.
Pregnant or lactating female.
14.
Unwillingness or inability to follow the procedures outlined in the protocol.
15.
Uncontrolled diabetes or other medical condition that may interfere with 
assessment of toxicity.
16.
Central nervous system (CNS) metastases, with the following exception:

Subjects who have  previously treated CNS metastases, are asymptomatic, and 
have no requirement for steroids at least 14 days prior to first dose of study 
drug.

Subjects with carcinomatous meningitis are excluded regardless of clinical 
stability.
17.
Invasive malignancy or history of invasive malignancy other than disease under 
study, except as noted below:

Any other invasive malignancy from which the subject has been disease-free 
for more than 2 years and, in the opinion of the principal investigator and 
GSK Medical Monitor, will not affect the evaluation of the effects of this 
clinical trial treatment on currently targeted malignancy, can be included in 
this clinical trial.

Curatively treated non-melanoma skin cancer and any carcinoma-in-situ.
Rationale for Change: STATISTICAL METHODS - GCB-DLBCL cohort expansion 
was added into Part 1 dose escalation phase. The study design was based on predictive
probability methodology (Liu, 2008) to allow interim futility/efficacy assessment by 
comparing the overall responses with the pre-specified futility and efficacy stopping 
criteria, in order to enabling early decision of opening Part 2 expansion phase or 
terminating the trial. Due to the improvement of response rates of cancer treatments over 


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time, the study designs in Part 2 expansion phase based on predictive probability method 
were revised by updating the null and alternative hypothesis, to align with the current 
typical response rates. The sample size and futility stopping criteria for each cohort 
(GCB-DLBCL mutant and wild type, tFL mutant and wild type, and MM) are updated

STUDY TREATMENT DOSAGE/DOSAGE FORM, ROUTE, AND DOSE 
REGIMEN: Starting dose will be 50 mg, IV, twice weekly, with one 28 day cycle 
being defined as twice weekly dosing for three consecutive weeks and one week off.  
Dose escalations will be performed in Part 1 and dose adjustments are allowed to 
address tolerability and safety issues.  Alternative schedules may be evaluated if 
emerging data suggest that twice weekly administration with 2 hour infusions will 
result in excessive toxicity.  In addition, alternative dosing schedules may be 
considered if the safety, pharmacokinetic (PK), and pharmacodynamic (PD) data
suggest that a sufficient therapeutic exposure cannot be achieved using the initial 
schedule and after a protocol amendment.

SAFETY ASSESSMENTS:  Routine physical examinations, vital sign 
measurements, echocardiograms, and monitoring of adverse events.  Cardiac safety 
monitoring will be required, consisting of triplicate 12-lead electrocardiograms 
(ECGs) pre-infusion of drug, at the end of infusion of drug, one at night prior to 
going to sleep (e.g., 10 pm) and one prior to discharge from the unit for Day 1, dose 
one only.  The subject will not be discharged from the unit unless the QTcF is 
<500 msec.  In addition, 24 hours of high fidelity 12-lead Holter monitoring will be 
performed for dose one.  Tracings from this will be used for concentration QT 
analysis as well.  Pre-infusion and end of infusion ECGs will be recorded for all 
other ECG timepoints.  Laboratory testing includes at least hematology and clinical 
chemistry.  Additional safety assessments may be necessary based on emerging data.


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
PHARMACOKINETIC/PHARMACODYNAMIC MEASUREMENTS: There 
will be extensive serial blood sampling for PK and PD measurements in Part 1 of this 
study with limited blood sampling performed on all subjects in Part 2.  Urine and 
bile may be collected in some subjects in the Part 21 PK/PD expansion cohort. 
Single safety PK blood draws may be collected for subjects with severe adverse 
events or adverse events of concern.  Mandatory collection of pre-treatment and 
post-treatment biopsies will be implemented in Part 21 PK/PD cohorts. based on 
outcome of preliminary PD data in surrogate tissue (e.g. Peripheral blood 
mononuclear cells (PBMCs) from blood).

TRANSLATIONAL RESEARCH:  Translational or biomarker research may be 
performed on archival tissue, tumor biopsies and blood samples collected on study, 
to better understand DLBCL, transformed FL, and the mechanism of action of and 
response to GSK2816126. Performance of these investigations may be conditional 
on the results of the clinical trial principally, but not exclusively, on the primary 
measures of the clinical trial outcome and samples may be selected for analysis on 
the basis of the clinical outcome. Unless stated otherwise, these investigations may 
be performed irrespective of whether a response to GSK2816126 is observed and 
will be categorized as exploratory. Findings may be reported independently of any 
final clinical study report.  .

STATISTICAL METHODS: 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 1 in GCB-DLBCL subjects is designed to evaluate preliminary efficacy at 
the MTD/RP2D or other dose level.  Futility and efficacy assessments will be 
conducted after 13 GCB-DLBCL subjects are enrolled, using overall response 
rate (ORR) as the efficacy endpoint, until up to 27 subjects are enrolled. The 
design allows interim analysis (IA) of futility and efficacy to be performed at 
any point in between. The futility and efficacy stopping rules are defined based 
on pre-specified type I error rate and power of the hypothesis testing of ORR. If 
the thresholds for futility are met, enrollment to Part 1 cohort/s may be stopped 
based upon the evaluation of the totality of the data. If the efficacy thresholds 
are reached, and the totality of the data support opening Part 2, then Part 2 will 
start. If neither futility nor efficacy thresholds are met at an interim analysis, and 
the totality of the data does not support continuation of the trial, then Part 1 may 
be stopped.
For the cohort expansion of solid tumor subjects in Part 1, there is no formal 
statistical hypothesis testing. Analysis of the data obtained from the solid tumor 
expansion cohort will only utilize descriptive methods.

Part 2 expansion phase of the study is designed to investigate clinical activity of 
GCB-DLBCL and tFL patients with EZH2 mutant and wild type, and MM patients, 
using ORR as the primary endpoint. Secondary endpoints such as PFS, TTR, TTP, 
DOR and OS will be evaluated.  In Part 2, for patients with GCB-DLBCL and tFL, 
futility assessment will be conducted on an ongoing basis after data are available 
from the first 10 subjects and until up to 32 patients. For patients with MM, futility 
assessment will be conducted on an ongoing basis after data are available from the 
first 14 subjects and until up to 40 subjects.


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
A futilityassessment will be conducted after data are available from the first 12 
subjects in Part 2 and after that until up to 30 GCB-DLBCL subjects and 16 tFL 
subjects have been enrolled in each of the EZH2 WT and EZH2 mutant cohorts.  
Also, in the MM cohort a futility assessment will be conducted after data are 
available from the first 13 subjects in Part 2 and after that until up to 37 subjects.
Section 1.2.2 Pre-Clinical Pharmacology & Safety of GSK2816126
Rationale for Change: 
Nonclinical Pharmacology - Added clarification of  treatment options for possible 
infusion reactions.  Updated to be in line with changes throughtout the protocol. Included
updated data and guidance for human subjects based on preclinical data from ongoing 
phototoxicity testing. Updated to be in line with Risk Section of the protocol.
REVISED TEXT
Nonclinical Pharmacology:  Human subjects will be monitored during the infusion for 
evidence of histamine release related symptoms/infusion reactions and treated as needed 
with supportive care per local standard of care.  (e.g., corticosteroids, oxygen, 
epinephrine, diuretics, IV fluidwith anti-histamines).  . Subsequent subjects may be 
treated prophylactically with antihistamine and/or by lengthening the infusion duration. .  
The infusion duration can be lengthened with restart of the infusion or at the next 
infusion.  Premedications (antihistamines or similar) may be provided at the next infusion 
or prior to treatment of new subjects.
In dogs, a mild, reversible dose dependent decrease in minute (up to 128 mL/min/kg; 
49%) and tidal volume (8 mL/kg; 56%) at 100 mg/kg and an elevation in QTc interval at 
30 (maximum increase of 12 msec or 5%) and 100 (maximum increase of 18 msec or 
8%) mg/kg were observed following the end of a single 8 hour infusion.  These effects 
did not directly correlate with peak GSK2816126 blood levels as the onset was 4-7 hours 
following the end of the infusion.  QTc interval elevations were not observed following 
repeat dosing.  
A direct effect on human ether à go-go-related gene (hERG) channel repolarization is 
unlikely (IC25 of 54.2 µM; 28.61 µg/mL), however, GSK2816126 did block hERG 
current density in vitro consistent with an effect on hERG channel trafficking.  The 
mechanism for this change is unclear.  Evaluation of the QTc interval has been 
incorporated into this clinical study protocol. 
GSK2816126 has evidence of absorbance within the 290-700 nm wavelength range of 
concern for photosafety.  While GSK2816126A has no absorbance peaks (λmax) > than 
290 nm, there is an absorbance peak at 285 nm with a small tail of absorbance that 
extends to ~380 nm and therefore, has a potential risk for phototoxicity.  To date, no in 
vivo phototoxicity or Bio-distribution studies of the product in the skin or the eyes have 
been completed.  No photosafety concerns have been observed in humans at doses up to 
3000 mg/day, however, only a limited number of patients have received GSK2816126.  


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To minimize the risk for potential phototoxicity, human subjects will be instructed to 
minimize or avoid prolonged exposure to natural or artificial sunlight (e.g., tanning beds, 
sunlamps, UVA or UVB treatments) and wear loose fitting clothing with long sleeves, 
sunglasses, and broad rim hat that protect the skin from sun exposure AND use a broad 
spectrum sunscreen (e.g., UVA and UVB protective with minimum SPF 30) on any 
uncovered areas of the body if outdoors from the time of first dose of study medication 
until at least 2 weeks (14 days) following last dose of study medication due to long 
elimination phase.
Section 1.3
Benefit/Risk Assessment
Rationale for Change: Updated text based on new preclinical and human data, as well 
as, to to be in line with changes throughtout the protocol. 
REVISED TEXT
Summaries of findings from pre-nonclinical studies conducted with GSK2816126 can be 
found in Section 1.2.2 of the protocol and the Investigator’s Brochure (IB) 
[GlaxoSmithKline Document Number 2013N16904_04, 20172013N169204_00, 2013].  
GSK2816126 has not yet been administered to human subjects and Ttoxicology studies 
performed in dogs and rats suggest that the primary toxicities of GSK2816126 are 
cardiovascular, hemolytic and allergic (see Section 43, GSK2816126 IB 
[GlaxoSmithKline Document Number 2013N16904_04, 2017, 2013N169204_00, 2013)].  
This section outlines the risk assessment and mitigation strategy for this protocol based 
on nonclinical and clinical findings. Additional information on clinical findings can be 
found in Section 1.3.1 of the protocol and Section 5 and Section 6 of the Investigator’s 
Brochure [GlaxoSmithKline Document Number 2013N16904_04, 2017].
Section 1.3.1 Risk Assessment
Rationale for Change: 
Cardiovascular – QT prolongation- Based on review of QTc data from the study with the 
GSK co-chairs of the QT panel and Global Safety Board, it was agreed that the restriction 
on the administration of drugs possibly associated with Torsade de Pointes could be 
relaxed and will be included as medications to be used with caution (Table 14). 
Additional ECG assessments will be recommended when these medications are initiated 
after Cycle 1. Exclusion and withdrawal criteria for cardiac monitoring will remain as 
stated in the protocol (e.g., patients with a QTc > 450 msec are excluded from entry and 
patients > 500 msec will be withdrawn as dictated by the protocol).


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Histamine Reaction/InfusionReaction – Added that this risk/mitigation includes 
infusion reactions/histamine reactions and that mitgaton strategy that should be used per 
local standard of care.  Updates made in line with changes through the protocol.
Drug Interactions – Included most recent DDI data.
Phototoxicity – Included updated data and guidance for human subjects based on 
preclinical data from ongoing phototoxicity testing. Updated to be in line Section 1.2.2 of 
the protocol.
Hepatic Toxicity – Nonclinical and current clinical data, possible risks and mitigation 
strategy added for possible increased liver function tests/ALT.
REVISED TEXT
Potential Risk of Clinical 
Significance
Data/Rationale for Risk
Mitigation Strategy
Cardiovascular – QT 
prolongation
QTc prolongation was observed (up to 
8%; 18 msec in dog) following the end of 
a single 8 hour infusion
Effect did not directly correlate with peak 
GSK2816126 blood levels; onset was 4-
7 hours following the end of the infusion; 
reversed within 3-8 hours following 
onset
Effects not observed following repeat 
dosing in dogs
No arrhythmias were detected in 
preclinical studies 
The mechanism for the QTc 
prolongation is unlikely due to a direct 
effect on hERG repolarization as 
GSK2816126 weekly inhibited hERG tail 
current (IC25 of 54.2 µM; 28.61 µg/mL).  
However, GSK2816126 was shown to 
block hERG current density in vitro 
consistent with an effect on hERG 
channel traffickin
Protocol includes cardiovascular 
eligibility criteria, laboratory 
assessments (potassium and 
magnesium), cardiac monitoring 
(electrocardiograms [ECGs], 
Holter monitoring during the 
study, and dose 
stopping/modification criteria for 
the management of QT 
prolongation)
Co-administration of medications 
that are known to prolong the QT 
interval and have a risk of 
causing Torsades de Pointes 
(TdP) are prohibited. and dDrugs 
that have a possible risk of 
TdPTorsades de Pointes are 
prohibitedwill be used with 
caution and additional ECG 
monitoring required.
All subjects will remain in the 
clinical research unit (CRU) after 
receiving their first dose of study 
medication (Week 1, Day 1) with 
periodic ECGs and Holter 
monitoring for 24 hours.  
Subjects will not be discharged 
from the unit unless their last 


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measured QTc on an ECG 
performed immediately prior to 
discharge after the first dose is 
<500 msec.
Timings for in-house on-drug 
ECGs are pre-infusion, at the 
end of infusion, before bed, and 
before discharge the next 
morning for Day 1 of cycle 1 only.  
Refer to Section 7.1 (T&E) for 
other ECG timings
Local Infusion Site 
Reaction
Vascular/perivascular inflammation 
and necrosis (in rats at all dose levels, 
including controls, and in dogs given 
100 mg/kg)
Dose-limiting vascular damage 
(necrosis, inflammation, edema and/or 
hemorrhage) at the local infusion and/or 
indwelling catheter sites was observed 
in rats and dogs following twice weekly 
IV infusions of GSK2816126 (vehicle 
containing 5% Captisol) (6 to 16 hours) 
for 2 to 4 weeks
Inflammation at the infusion site led to 
secondary histopathologic changes in 
multiple peritoneal and retroperitoneal 
tissues/organs and clinical pathology 
findings; morbidity/mortality observed in 
rats (30 mg/kg; Cmax 2.97 g/mL; 
AUC0-24h 23.5 g.h/mL) and dogs 
(100 mg/kg; Cmax=9.88 g/mL and 
AUC0-24h=80.1 g.h/mL) was 
attributable to vascular or extravascular 
irritant (vesicant) effects of GSK2816126 
and prolonged intravenous 
catheterization
Infusion site and secondary 
histopathologic findings were partially 
reversible and secondary clinical 
pathology effects were reversible
Subjects will be dosed via a 
central venous access device 
with a formulation including 10% 
Captisol
Subjects will be monitored 
closely for infusion site reactions 
(during infusion and for one hour 
post infusion) and if reaction 
occurs, infusion will be 
interrupted and the appropriate 
clinical intervention commenced.  
See Management of Infusion Site 
Reaction (Section 3.8.2)
Laboratories will be monitored as 
well, including liver function tests 
(LFTs), other chemistries, and 
hematology


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Histamine 
Reaction/InfusionReaction
Acute histamine-like reactions seen 
in rats and dogs which began within 
minutes of dosing were observed at 
≥300 mg/kg in dogs (Cmax 66.5 to 
130 µg/mL) and 300 mg/kg (Cmax 33.9 to 
54.2 µg/mL) in rats.
In dogs, histamine reactions resulted in 
discontinuation of dosing.  In rats, 
histamine-related decreased body 
temperature, along with increased HR 
and decreased BP likely led to mortality 
in restrained, but not in unrestrained 
animals
Subjects will be monitored during 
the infusion for evidence of 
histamine release related 
symptoms histamine release 
related symptoms/infusion 
reactions and treated as needed 
with anti-histamines 
andsupportive care per local 
standard of care (e.g., 
corticosteroids, oxygen, 
epinephrine, diuretics, IV 
fluid).Severe cases will also be 
treated with corticosteroids.  .  
Subsequent subjects treated at 
that dose or higher doses will be 
treated prophylactically with anti-
histamines. If necessary based 
on emerging clinical data, tThe
infusion duration can be 
lengthened with restart of the 
infusion or at the next infusion.  
Premedications (antihistamines 
or similar) may be provided at the 
next infusion or prior to treatment 
of new subjects.
Drug Interactions
No in vivo drug-drug interaction studies 
have been performed. Based on in vitro 
data, GSK2816126 has a potential to 
inhibit cytochrome P450 (CYP) 2C8, 
2C9, 2C19 and 3A4 enzymes and to 
induce CYP3A enzymes.  In addition, in 
vitro data suggests that GSK2816126 is 
a substrate for CYP3A enzymes and for 
P-gp, BCRP, and may be a substrate for 
OAT transporters. No in vivo drug-drug 
interaction (DDI) studies have been 
performed.
GSK2816126 is metabolized by CYP3A 
enzymes in vitro. GSK2816126 has also 
been shown to be a substrate of P-gp 
and BCRP transporters. Therefore, 
substances that potently inhibit or 
The potential for drug-drug 
interactions will be monitored in 
clinical trials and some 
concomitant medications are 
prohibited or to be used with 
caution (see Section 9).


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induce CYP3A, P-gp or BCRP could 
lead to higher/lower exposure in 
subjects, potentially leading to 
alterations of the pharmacologic effects 
of GSK2816126. 
On the other hand, GSK2816126 was
shown to inhibit CYP2C8, CYP2C9, 
CYP2C19 and CYP3A4 with IC50 values 
<5 M. GSK2816126 activate human 
PXR (EC50 = 10 M) and, therefore, 
may have the potential to induce CYP 
enzymes.  A further in vitro study in 
cultured human hepatocytes (n=3 
donors) showed induction of CYP3A4 
mRNA with a calculated EC50 of 4.22-
5.43 M and Emax of 3.22-16.5-fold.
In vitro studies demonstrated that 
GSK2816126 (up to 100 M) has the 
potential to inhibit human transporters 
BCRP, OATP1B1, OATP1B3, OCT2, 
MATE1 and MATE2-K (IC50 values of 
21, 13, 34, 2.88, 0.025 and 0.95 M, 
respectively), however, GSK2816126 
did not inhibit P-gp (up to 100 M) or 
OAT1 and OAT3 (up to 25 M).  
Based upon the current average clinical 
Cmax of 58 M (30.6 g/mL) at 3000 mg 
dose, mathematical model simulations 
suggest that GSK2816126 has the 
potential to perpetrate a clinical DDI 
when co-administered with sensitive 
substrates of transporters OATP1B1, 
BCRP, OCT2, MATE1 and MATE2-K 
upon inhibition, and CYP2C8, 2C9, 
2C19 upon inhibition, and CYP3A4 upon 
inhibition or induction.


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Phototoxicity
GSK2816126 has recently been 
demonstrated to be phototoxic in an in 
vitro assay for phototoxicity (3T3 Neutral 
Red Uptake Phototoxicity Test).   To 
date, no photosafety concerns have 
been observed in humans at doses up 
to 3000 mg/day, however, only a limited 
number of patients have received 
GSK2816126.
Subjects will be instructed to 
minimize or avoid prolonged 
exposure to natural or artificial 
sunlight (e.g., tanning beds, 
sunlamps, UVA or UVB 
treatments) and wear loose fitting 
clothing with long sleeves, 
sunglasses, and broad rim hat 
that protect the skin from sun 
exposure AND use a broad 
spectrum sunscreen (e.g., UVA 
and UVB protective with 
minimum SPF 30) on any 
uncovered areas of the body if 
outdoors from the time of first 
dose of study medication until at 
least 2 weeks (14 days) following 
last dose of study medication
due to long elimination phase.
Hepatic Toxicity
In first in human study EZH117208 
(present study), an increase in level of 
ALT has been noted in the group of 
subjects receiving doses of 1800 mg to 
3000 mg (single infusion dose) None of 
these ALT increases have been 
associated with increase in total bilirubin 
or INR and all have shown improvement 
following either withholding or 
discontinuing GSK2816126. The 
3000 mg dose has been declared to 
exceed the MTD. The highest dose 
being explored in this study is 2400 mg . 
In nonclinical species  given 
GSK2816126, twice weekly for 2 and/or 
4 weeks, changes in liver pathology 
(inflammation, hyperplasia) in dogs and 
clinical chemistry parameters (i.e. 
increases in ALT, AST, ALP, bilirubin 
and decreases in albumin) in rats and 
dogs were observed and were 
Dosing at 3000 mg has been 
discontinued, with the highest 
dose being explored is at 
2400 mg. Continued laboratory 
and clinical moniotoring for liver 
dysfunction (LFT, coagulation 
parameters INR/PTT, other blood 
chemistry, clinical observation for 
jaundice). Dose management 
and stopping criteria as per 
guidelines for non-hematologic 
toxicity (Section 3.8.3 and Table 
4) and hepatic safety monitoring 
(Section 8.3.1)


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consistent with systemic inflammation.  
These effects were considered 
secondary to vascular damage at the 
infusion and/or surgical site and 
attributable to vascular or 
extravascular irritant (vesicant) 
effects of GSK2816126 and 
prolonged intravenous 
catheterization.
No current evidence suggests the 
presence of reactive metabolites. No 
glutathione conjugates were identified in 
the in vitro, ex vivo studies that were 
conducted. GSK2816126 is not a CYP 
metabolism-dependent inhibitor. 
Based on in vivo dosing to rats twice 
weekly for 2 weeks at doses up to 
300 mg/kg, no evidence of induction of 
PXR panel genes was noted. This is in 
agreement with the observation that 
GSK2816126 is not a rat PXR activator. 
It is however a human PXR activator, 
and an in vitro inducer of CYP3A4 in 
human hepatocytes, suggesting species 
differences between rat and human.
GSK2816126 is an in vitro inhibitor 
against hepatic transporters OATP1B1, 
OATP1B3 and BCRP with a moderate in 
vitro potency (IC50: 13-34 µM). With the 
high clinic concentration, a potential risk 
for inhibiting hepatobiliary excretion of 
substrates of these transporters cannot 
be excluded.
Section 1.3.3 Overall Benefit: Risk Conclusion
Rationale for Change: Included mention of clinical data generated from the 
GSK2816126 study.


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REVISED TEXT
Current data from GSK2816126 clinical study and prenonclinical development indicate a 
potential for clinical utility in the treatment of subjects with relapsed and/or refractory 
DLBCL and/or transformed FL, NHL, multiple myeloma, and other solid tumors.  
Considering the overall poor outlook of these subjects on failing prior therapy and 
recognizing the measures taken to minimise risk to subjects participating in the Phase I 
clinical trials, the potential risks identified in association with GSK2816126 are justified 
by the anticipated benefits that may be afforded to subjects with the previously 
mentioned tumor types that have been shown in nonpreclinical models to respond to 
GSK2816126.  
Section 1.4.1 Contraindications, Warnings and Precautions
Rationale for Change: Updated section in line with Section 1.2.2 and Section 1.3.1.
REVISED TEXT
Contraindications:
Any known hypersensitivity to agents structurally similar to GSK2816126 or the 
constituents of the vehicle would contraindicate GSK2816126 use.
Precautions:  Until clinical safety information for GSK2816126 is available, ECG 
monitoring for evidence of QTc prolongation must be conducted.   Co-administration of 
medications that are known to prolong the QT interval and have a risk of causing 
Torsades de Pointes(TdP) are to be avoided beginning 14 days prior to the first dose of 
study drug or longer if necessary, as determined by the primary investigator or medical 
monitor until discontinuation from the study. Co-administration of medications that are 
known to prolong the QT interval and have a possible risk of causing TdP are to be used 
with caution.  Subjects will be instructed to minimize or avoid prolonged exposure to 
natural or artificial sunlight (e.g., tanning beds, sunlamps, UVA or UVB treatments) and 
wear loose fitting clothing with long sleeves, sunglasses, and broad rim hat that protect 
the skin from sun exposure AND use a broad spectrum sunscreen (e.g., UVA and UVB 
protective with minimum SPF 30) on any uncovered areas of the body if outdoors from 
the time of first dose of study medication until at least 2 weeks (14 days) following last 
dose of study medication due to long elimination phase.
Section 2.1
Part 1: Phase I Dose Escalation
Rationale for Change – See rationale for change to Part 1 and Part 2 objectives and 
endpoints under Synopsis.


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Part 1 Objectives
Part 1 Endpoints
Secondary

To describe the pharmacokinetics of 
GSK2816126 after single- and 
repeated administration

To evaluate the relationship between 
GSK2816126 exposure and 
safety/efficacy/PD parameters

To determine clinical activity of 
GSK2816126 in GCB DLBCL and 
solid tumors containing EZH2 
inhibitor sensitizing mutations or 
prostate cancer


Evaluate the relationship between 
GSK2816126 exposure markers and 
safety/efficacy/PD responses

To generate samples (data reported 
separately) with which to 
characterize the metabolic profile of 
GSK2816126 after repeat-dosing (In 
the PK/PD expansion cohort only)

To determine the amount of 
GSK2816126 excreted in urine after 
dosing at steady state

GSK2816126 PK parameters following 
single- (Day 1) and repeat-dose  
administration of GSK2816126, including 
area under the concentration-time curve 
(AUC), pre-dose (trough) concentration at 
the end of the dosing interval (C), 
maximum observed concentration (Cmax), 
time of occurrence of Cmax (tmax), 
terminal phase half-life (t1/2), time 
invariance and accumulation ratio

GSK2816126 exposure markers (dose, 
concentration, Cmax or AUC) and 
safety/efficacy/PD responses. 
Pharmacodynamic PD response assessed 
by change from baseline in tri-methylation 
of Histone H3K27 (H3K27me3)

Best Overall Response rate (complete 
response [CR]  + partial response [PR])

Samples to characterize the metabolites in 
blood, bile and/or urine

Concentration of GSK2816126 in urine 
measured with an investigational bio-
analytical method and extrapolated to total 
amount excreted in urine over time using 
urine volume


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Part 1 Objectives
Part 1 Endpoints
Exploratory

To confirm tumor EZH2 and GCB-
DLBCL status

To investigate the mechanism of 
action and additional indicators of 
sensitivity and resistance to of 
GSK2816126

To identify biomarkers predictive 
of response or resistance to 
GSK2816126

To generate samples (data 
reported separately) with which to 
investigate the potential for 
GSK2816126 to affect cytochrome 
P450 (CYP) 3A4 enzyme activity

IHCfor confirmation of GCB-DLBCL status

PCR or NGS to determine EZH2 mutation 
status 

Evaluate transcriptional and/or protein 
changes upon GSK2816126 treatment

Correlate baseline tumor genomic (DNA), 
protein and/or transcription (RNA)  profiles 
with response

Tumor baseline genetic profiles, response

Samples to assess a potential change in 
4b-OH cholesterol to cholesterol ratio in 
plasma following repeat dosing of 
GSK2816126 (data reported separately)
Hypothesis
No formal statistical hypotheses are being tested in Part 1: Phase I dose escalation.  Analysis 
of the data obtained from Part 1 will only utilize descriptive methods
No formal statistical hypotheses are being tested for the dose escalation in Part 1. Analysis of 
the data obtained from dose escalation of Part 1 will utilize descriptive methods only. 
The cohort expansion of GCB-DLBCL patients in Part 1 will assess the overall response rate 
(p) of GCB-DLBCL patients. The null and alternative hypotheses for the overall response rate 
are detailed below:
The null hypothesis is:
H0: p≤20%
The alternative hypothesis is:
HA: p≥40%


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Part 1 Objectives
Part 1 Endpoints
For cohort expansion of solid tumor subjects in Part 1, there is no formal statistical 
hypothesis being tested. Analysis of the data obtained from solid tumor expansion cohort will 
utilize descriptive methods only.
Section 2.2
Part 2: Expansion
Part 2 Objectives
Part 2 Endpoints
Primary

To determine clinical activity of 
GSK2816126 in cohorts of subjects 
with EZH2 mutant and wild type 
GCB-DLBCL and tFL and subjects 
with MM

ObjectiveOverall response rate (% of 
subjects achieving CR and PR per
response criteria)
Secondary

To determine the safety, tolerability 
of the selected IV dose of 
GSK2816126

To characterize the population PK of 
GSK2816126

To evaluate the relationship between 
GSK2816126 exposure and PD 
parameters

To generate samples (data reported 
separately) with which to 
characterize the metabolic profile of 
GSK2816126 after repeat-dosing (In 
the PK/PD expansion cohort only)

To determine the amount of 
GSK2816126 excreted in urine after 
dosing at steady state

AEs, SAEs, DLTs, withdrawals due to 
AEs, dose interruptions and reductions,  
and changes in safety assessments (e.g., 
clinical laboratory parameters, vital signs, 
and cardiac parameters)

Population PK parameters for 
GSK2816126 including clearance (CL), 
and volume of distribution (Vd) and 
relevant covariates which may influence 
exposure (e.g. age, weight, or disease 
related covariates)

GSK2816126 exposure markers (dose, 
concentration, Cmax or AUC) and PD 
responses. PD response assessed by 
change from baseline in tri-methylation of 
Histone H3K27 (H3K27me3)

Samples to characterize the metabolites in 
blood, bile and/or urine

Concentration of GSK2816126 in urine 
measured with an investigational bio-
analytical method and extrapolated to total 
amount excreted in urine over time using 


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Part 2 Objectives
Part 2 Endpoints

To generate samples (data 
reported separately) with which to 
investigate the potential for 
GSK2816126 to affect cytochrome 
P450 (CYP) 3A4 enzyme activity

To evaluate the relationship between 
exposure and safety/efficacy 
parameters 

To begin to characterize the 
durability of response and 
progression free survival with 
GSK2816126
urine volume

Samples to assess a potential change in 
4b-OH cholesterol to cholesterol ratio in 
plasma following repeat dosing of 
GSK2816126 (data reported separately)

GSK2816126 exposure markers (e.g. 
dose, concentration, Cmax, or AUC) and 
safety/efficacy/ responses

Duration of response (DoR)

Progression-free survival (PFS) 
Exploratory

To identify biomarkers predictive of 
response or resistance to 
GSK2816126

To investigate the mechanism of 
action of GSK2816126 by evaluating 
changes in gene expression profiles

To investigate the relationship 
between genetic variants in 
candidate genes and the 
pharmacokinetics (PK) and safety 
profile of GSK2816126 based on 
Part 1 and 2 data combined

Evaluation of wild-type (WT) subject 
tumors for the presence of additional, 
undefined, mutations in the EZH2 gene

Correlate baseline tumor genomic (DNA), 
protein and/or transcription (RNA)  profiles 
with response

Evaluate transcriptional and/or protein 
changes upon GSK2816126 treatment

Deoxyribonucleic acid (DNA), ribonucleic 
acid (RNA) and protein markers in tumor 
and blood

Pharmacogenomic (PGx) analysis of 
whole blood


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Part 2 Objectives
Part 2 Endpoints
Hypothesis
In Part 2, the overall response rate (p) of GCB-DLBCL and tFL patients will be assessed for 
each EZH2 mutation status cohort (wild type and mutant), and also for MM patients. 

For each of the GCB-DLBCL and tFL cohort, the null and alternative hypotheses of the 
overall response rate are as following:
The null hypothesis is:
H0: p≤20%
The alternative hypothesis is:
HA: p≥40%

For MM cohort:
The null hypothesis is:
H0: p≤10%
The alternative hypothesis is:
HA: p≥25%
The primary objective of Part 2 is to determine whether administration of GSK2816126 has a 
potentially clinically meaningful response rate. 

In subjects with GCB-DLBCL, this will be determined in each EZH2 mutation status 
cohort (wild type and mutant) by testing the null hypothesis that the response rate is 
≤10%, with about 90% power when the true response rate is 30%.  

In subjects with tFL, this will be determined in each EZH2 mutation status cohort by 
testing the null hypothesis that the response rate is ≤5%, with about 80% power when 
the true response rate is 25%. 

In subjects with MM, this will be determined by testing the null hypothesis that the 
response rate is ≤5%, with about 85% power when the true response rate is 20%.
Section 3.1
Study Schematic
Rationale for Change: Upated study schematic to include Part 1 expansion cohort.


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Part 1
Accelerated Dose Titration followed by 3+3 Dose Escalation
To determine the safety and tolerability of GSK2816126 in subjects with relapsed/refractory 
DLBCL, transformed FL, other NHLs, solid tumors and MM 
Part 1 will include a cohort expansion at MTD or any dose level to enroll subjects with GCB-DLBCL 
and solid tumors with EZH2 inhibitor sensitizing mutations or prostate cancer 

Section 3.2
Discussion of Study Design
Rationale for Change – Updated to include expansion of any dose level during dose 
escalation to 12 subjects.  At MTD, included Part 1 expansion cohort/analysis plan to 
include approximately 27 GCB-DLBCL subjects and approximately 15 subjects with 
solid tumors containing EZH2-sensitive mutations or prostate cancer to explore 
additional safety and preliminary efficacy. Updated in line with updates made through the 
protocol.
REVISED TEXT
After the accelerated dose titration, subjects will be enrolled in a standard 3+3 dose 
escalation design. Dose escalation will continue until a recommended Phase 2 dose
(RP2D) is determined or until a maximum tolerated dose (MTD) or a dose of 3000 mg 
twice-weekly is reached [Maximum Feasible Dose (MFD)]. After the RP2D (or 
MTD/MFD) has been determined in Part1, then. Any dose level during Part 1 dose 
escalation may be expanded up to 12 subjects to explore safety and preliminary efficacy.  
At MTD/RP2D the cohort may be expanded to enroll approximately 27 GCB-DLBCL 
subjects and approximately 15 subjects with solid tumors containing EZH2-sensitive 
mutations or prostate cancer to explore additional safety and preliminary efficacy. Based 
on results of the Part 1 analysis in totality, Part 2 expansion cohorts may will be opened. 
In Part 2, and subjects with will be assigned to one of four cohorts based on disease and 
EZH2 mutation status.
Safety assessments will be performed weekly for the first 4 weeks and then at regular 
intervals as outlined in the Time and Events Table (Section 7.1). 
Disease response in lymphoma and solid tumor subjects will be assessed as described in 
the T&E table (Section 7.1).  
Futility and Efficacy analysis will be performed on GCB-DLBCL subjects enrolled at the 
MTD/RP2D in cohort expansion of Part 1 as listed in Section 12.2.1.2.


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Section 3.3.2 3+3 Dose Escalation Phase
Rationale for Change: Added definition of evaluable subject during dose escalation 
andmoved text for PK/PD cohort to Part 2 of the study.
REVISED TEXT
An evaluable subject in Table 2 is defined as a subject who has been on study for at least 
28 days (one cycle).  Evaluation of safety data from at least 1 subject during the 
accelerated dose titration or at least 3 subjects in the standard dose titration who have 
completed 28 days of dosing on study (one cycle) is required prior to defining a new dose 
and starting the next cohort. Once a higher dose has been cleared, subjects at lower dose 
levels who remain on study drug and have not experienced dose limiting toxicity will be 
allowed to escalate up to that level.
Reverting from 3+3 Dose Escalation to Accelerated Dose Titration: Once Grade 2 
toxicity is seen in one subject, there are 2 scenarios where the accelerated dose escalation 
may be resumed.
1) If two additional subjects are added at the dose where Grade 2 toxicity was seen 
in the initial subject and if no Grade 2 or higher toxicity is seen in either of the 2 
new subjects, the accelerated dose escalation may be resumed, or
2) If the 3+3 method is used and, at the next higher dose, the 3 subjects do not have 
a grade 2 or higher toxicity, the accelerated dose escalation may be resumed.  
(Before any decision is made to reinitiate accelerated dose titration a discussion 
between the investigators and  the GSK medical monitor is required)
Part 1 PK/PD cohorts:  Any dose level may be expanded up to 12 subjects in order to 
collect adequate data on safety, pharmacokinetics, or pharmacodynamics. Urine, bile, and 
additional blood samples may be collected following repeated administration for drug 
metabolite profiling and to obtain information on renal excretion of GSK2816126.  
Initially, optional pre- and post-treatment tumor biopsies will be requested.  At MTD, 
mandatory collection of pre- and post-treatment tumor biopsies will be required for 
enrollment in a PK/PD cohort.  Mandatory biopsies may be instituted at lower dose levels 
once evidence of target engagement has been demonstrated in surrogate tissue (e.g. 
H3K27me3 from PBMCs in blood); or if sufficient evidence of target engagement (e.g. 
dose dependence) is not observed in PD assay from surrogate tissue.  Additional subjects 
may be enrolled at previously completed dose levels for the purpose of obtaining 
additional PK or PD data. A reduced PK schedule may be used in subjects enrolled to 
obtain additional PD data. These subjects may have the dose escalated to a higher 
completed dose level (not exceeding the MTD) once the necessary PK/PD procedures 
have been completed.
Section 3.3.5 Intra-subject Dose Escalation
Rationale for Change: Included additional text to clarify PK/PD and safety assessments 
for subjects who are approved for intra-subject dose escalation


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REVISED TEXT
Decision on intra-subject dose escalation will be made after review of all safety data and 
approval by a GSK Medical Monitor and discussion with the investigator.  In this case, 
the subject may begin dosing at the higher dose level as it will have already been 
demonstrated to be tolerable and monitoring will be performed as described in the 
protocol. Subjects approved for intra-subject dose escalation may require additional 
limited PK and/or PD sampling as determined by GSK Clinical Pharmacology.  
Additional safety assessments may be specified at the time of the dose escalation or 
schedule modification based on the safety profile in previous subjects at the higher dose 
level.
Section 3.3.7 Part 1: Futility and Efficacy Analysis for GCB-DLBCL Subjects
Rationale for Change: Text added to Section 3.3.7 and Section 3.4 include the patient 
populations to be enrolled in Part 1 expansion cohort and Part 2 and the statistical 
analysis that will be performed.  GCB-DLBCL cohort expansion was added into Part 1 
dose escalation phase. The study design was based on predictive probability methodology 
(Lee, 2008) to allow interim futility/efficacy assessment by comparing the overall 
responses with the pre-specified futility and efficacy stopping criteria, in order to 
enabling early decision of opening Part 2 expansion phase or terminating the trial. 
Additional details were moved to Section 12, Data Analysis and Statistical 
Considerations,  of the protocol.
REVISED TEXT
There will be a GCB-DLBCL expansion cohort enrolled after the completion of dose 
escalation in Part 1. For the GCB-DLBCL expansion cohort in Part 1, futility and 
efficacy evaluation of overall response data will be performed in order to support the 
early decision regarding opening Part 2 dose expansion. The methodology is based on the 
Bayesian predictive probability of success if enrollment continues until all planned 
subjects are recruited [Lee, 2008]. Details of the predictive probability methodology, 
futility and efficacy evaluation are explained in Section 12.2.1.2. In summary, a 
minimum of 13 and maximum of 27 GCB-DLBCL patients will be enrolled. Once 13 
GCB-DLBCL patients at MTD/RP2D have been enrolled (including patients in dose 
escalation phase) and have completed  response assessments of safety and efficacy, 
response data will be reviewed on an ongoing basis for evidence of futility or efficacy. 
For futility/efficacy analysis, subjects evaluable for response assessment will be defined 
by any or all of the following criteria:

Subjects who have at least two post-baseline radiological disease assessments and 
have been on study for at least 28 days (one cycle.)


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
Subjects who have progressed or have died or have withdrawn for study treatment 
due to any reason.
Interim analysis (IA) of futility and efficacy can be conducted at any time after 13 GCB-
DLBCL subjects have enrolled and are evaluable for response assessment. If the 
thresholds for futility are met, the Part 1 expansion cohort may be stopped based upon the 
evaluation of the totality of the data. If the efficacy thresholds are reached, then Part 2 
expansion may be opened. If neither futility nor efficacy thresholds are met at any interim 
analysis, and the totality of the data does not support continuation of the trial, then the 
trial may be terminated. All available data will be considered in making decision of 
termination or continuation of the trial.
Section 3.4
Part 2: Expansion Cohorts
Rationale for Change: Due to the improvement of response rates of cancer treatments 
over time, the study designs in Part 2 expansion phase based on predictive probability 
method were revised by updating the null and alternative hypothesis, to align with the 
current typical response rates. The sample size and futility stopping criteria for each 
cohort (GCB-DLBCL mutant and wild type, tFL mutant and wild type, and MM) are 
updated. Additional details were moved to Section 12, Data Analysis and Statistical 
Considerations,  of the protocol.
REVISED TEXT
Part 2:  Expansion Cohorts in both wild type and EZH2 mutation-positive GCB-
DLBCL and tFL subjects, and subjects with MM 
The primary objective of Part 2 is to investigate whether administration of GSK2816126 
at the RP2D has a potentially clinically meaningful activity for more tumor types, if 
notable response rate is observed in Part 1 expansion cohort of GCB-DLBCL patients.  
Expansion cohorts will be enrolled in Part 2, including GCB-DLBCL and tFL patients 
with mutant and wild type EZH2 and  patients with MM. Similar to Part 1 expansion 
design, Part 2 expansion  design is planned based on predictive probability methodology. 
Rather than early stop for either futility or efficacy, Part 2 allows early stop for futility 
only. For each expansion cohort of GCB-DLBCL and tFL patients, a minimum of 10 and 
maximum of 32 patients will be enrolled at the RP2D. For MM cohort, a minimum of 14 
and maximum of 40 patients will be enrolled at the RP2D. Interim analysis of response 
data will start from minimum number of patients enrolled and at any time thereafter. 
Details of Part 2 designs and stopping criteria are elaborated in Section 12.2.  All 
available data will be considered in making decision of termination or continuation of the 
trial.
It is noted that patients with GCB-DLBCL, tFL and MM enrolled at MTD/RP2D in the 
previous stages of the trial (dose escalation and cohort expansion in Part 1) will be 
included for the Part 2 analysis.


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Lymphoma subjects will be enrolled based on EZH2 mutation status.  There will be up to
30 subjects per group in both GCB-DLBCL cohorts, up to 16 subjects per group in both 
tFL cohort s, and up to 37 subjects with MM.  Multiple myeloma subjects will be selected 
independent of their EZH2 mutation status.
Further evaluation of futility:
The methodology is based on the predictive probability of success if enrollment continues 
until all planned subjects are recruited [Lee, 2008]. The predictive probability design is 
similar to a Green-Dahlberg design in that it allows for early stopping for futility.  The 
differences are that the predictive probability design allows for evaluation of stopping 
rules after each subject, rather than at only two stages, once a minimum number of 
subjects are evaluable.  In this particular study, we will stop only for futility.  While the 
two designs have similar type I and type II error rates, the probability of early termination 
is greater with the predictive probability design.
In both GCB-DLBCL mutation status cohorts, after,  12 subjects have been enrolled in 
each cohort to examine safety and efficacy, the number of observed confirmed responses 
will guide further enrollment according to the rules summarized in Figure1..A maximum
of 30 subjects per cohort will be enrolled at the RP2D.  All available data will be 
considered in making enrollment decisions.
Figure 1
Diagram of Stopping Rules for GCB-DLBCL Cohort Expansion: 
GSK2816126
Number of Responses
Number of 
Subjects
0
1
2
3
4
5
≥6
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30


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Figure 1Legend:  The shaded regions are the specific regions for stopping the study for futility.  For instance, if there is 
only one response in fourteen subjects, then the predictive probability for success will be 5.0% or less (the futility 
criterion) and the study may be stopped.
In both tFL mutation status cohorts, after 12 subjects have been enrolled to examine 
safety and efficacy, the number of observed confirmed responses will guide further 
enrolment according to the rules summarized in Figure 2.  A maximum of 16 subjects 
will be enrolled at the RP2D.  All available data will be considered in making enrollment 
decisions.
Figure 2
Diagram of Stopping Rules for tFL Cohort Expansion: GSK2816126
Number of Responses
Number of 
Subjects
0
1
2
3
12
13
14
15
16
Figure2 Legend:  The shaded regions are the specific regions for stopping the study for futility.  For instance, if there is 
no response in twelve subjects, then the predictive probability for success will be 1% or less (the futility criterion) and 
the study may be stopped.
For the MM cohort: After 13 subjects have been enrolled to examine safety and efficacy, 
the number of observed confirmed responses will guide further enrollment 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.
Figure 3
Diagram of Stopping Rules for MM Cohort Expansion
Number of 
Subjects
0
1
2
3
4
13
14
15
16
17
18
19
20
21
22
23


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Number of 
Subjects
0
1
2
3
4
24
25
26
27
28
29
30
31
32
33
34
35
36
37
The shaded regions are the specific regions for stopping the study for futility.  For instance, if there is no response in 
13 subjects, then the predictive probability for success will be 1% or less (the futility criterion) and the study may be 
stopped.
Section 3.4.1 Part 2 PK/PD cohort
Rationale for Change: Part 1 will focus on completion of the Part 1 expansion cohort.  
Potential to enroll subjects into a PK/PD cohort was moved to Part 2 of the study.  Text 
was added to clarify that this cohort may be enrolled at the RP2D.
REVISED TEXT
In Part 2 a cohort of up to 12 subjects may be enrolled at RP2D to collect adequate data 
on safety, pharmacokinetics, or pharmacodynamics. Urine, bile, and additional blood 
samples may be collected following repeated administration for drug metabolite profiling 
and to obtain information on renal excretion of GSK2816126.  Mandatory collection of 
pre- and post-treatment tumor biopsies will be required for enrollment in a PK/PD cohort.
Section 3.5.2 Rationale for Population
Rationale for Change:  Included text to add  Part 1 expansion cohorts of GCB-DLBCL 
and solid tumor subjects and rationale for inclusion of these tumor types.


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REVISED TEXT
Therefore, the study includes subjects with nNon-Hodgkin’s Lymphoma and enriched for 
subsets (GCB-DLBCL, tFL) as well as multiple myeloma and solid tumors that have 
relapsed or are refractory to prior treatment with standard of care or do not have standard 
of care available or refuse standard of care therapy. 
Part 1 will be comprised of 2 phases: 

Part 1 dose escalation which will include subjects with MM, 
relapsed/refractory tFL andDLBCL, other NHLs and solid tumors , and

Part 1 cohort expansion at the highest tolerated dose/MTD which will include 
a cohort ofsubjects with relapsed/refractory GCB-DLBCL and a cohort of 
subjects with prostate cancer or solid tumors containing EZH2 inhibitior 
sensitizing mutations. 
Part 2 will be comprised of cohort expansions in subjects with GCB-DLBCL, 
transformed follicular lymphoma and multiple myeloma. 
EZH2 and H3K27me3 are dysregulated in nearly all cancers through numerous pathways 
including 1) recurrent gain-of-function heterozygous mutations in germinal center B-cell 
(GCB) DLBCL, FL, melanoma, and parathyroid adenoma, 2) EZH2 over-expression in 
numerous other aggressive tumors including those from prostate, breast, lung, liver, 
bladder, head and neck, skin, and kidney, and 3) inactivating mutations in UTX.  H3K27 
demethylase that acts in opposition to EZH2, described in numerous tumor types 
including transitional cell bladder carcinoma, esophageal squamous cell carcinoma, renal 
cell carcinoma, multiple myeloma, and subgroup 4 medulloblastoma (McCabe, 2014). 
Furthermore, data from prostate, breast, and several other tumor types have demonstrated 
that increased EZH2 expression correlates with increased aggressiveness of tumors and 
poor prognosis [GlaxoSmithKline Document Number 2013N169204_04, 2017]


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McCabe 2014
With regard to haematological indications for GSK2816126, preclinical studies 
demonstrate that B-cell lymphomas of DLBCL with EZH2 activating mutations are the 
most sensitive to GSK2816126. Approximately 22% of GCB-DLBCL tumors have an 
EZH2-activating mutation, whereas ABC DLBCL does not contain EZH2- activating 
mutations (McCabe MT & Creasy 2014). Early follicular lymphoma lesions have been 


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shown to have EZH2 mutations, as well as mutations in other genes that disrupt 
chromatin structure [Friedberg Blood. 2015;125(1):40-47]. 
Of particular interest is that there is some data to suggest that certain tumor types may 
respond to EZH2 inhibitors regardless of EZH2 inhibitor sensitizing status.  Data 
presented at ASH Lymphoma Biology  2016 (Morschhauser F 2016) suggests that 
patients who have DLBCL(both GCB or nonGCB) and EZH2 mutated FL who are 
treated with the EZH2 targeted agent tazemetostat can achieve responses, providing proof 
of concept in DLBCL.  Patients with GCB-DLBCL were analysed by EZH2-mutation 
status. Of patients with EZH2 mutation 1/5 had a PR (ORR=20%). Of those without a 
mutation, 3/19 had PR or CR (ORR=15.7%; 2 with CR). Therefore, Part 1 cohort 
expansion in GCB-DLBCL will enroll patients regardless of EZH2 related mutation 
status.
Neuroendocrine prostate cancer (NEPC) is a subtype of castration-resistant prostate 
cancer associated with aggressive clinical features and poor overall survival 
(Wang 2014). Mounting evidence suggests that NEPC evolves from prostate 
adenocarcinoma as one mechanism of resistance to androgen. Data from metastatic 
biopsies obtained from patients progressing on abiraterone or enzalutamide suggests that 
at least 10% of patients with late-stage castration-resistant prostate adenocarcinoma 
(CRPC) eventually develop small-cell NEPC. NEPC cancer is driven by N-Myc. N-Myc 
in turn drives EZH2, making neuroendocrine prostate cancer sensitive to inhibition 
(Dardenne 2016). Additionally, EZH2 has been described as an epigenetic driver of 
aggressive prostate cancer. EZH2 dysregulation may be involved in the progression from 
early prostate cancer to late (Yang, 2013).  One of the most prevalent genetic 
modifications observed in prostate cancer is the fusion between the TMPRSS2 and ERG 
genes, resulted from an abnormal translocation on chromosome 21. Detected in more 
than half of all prostate tumors, this fusion gene consisting of the androgen-responsive 
TMPRSS2 promoter and the ERG coding region is able to substantially upregulate ERG 
expression, which has been proven to induce cell proliferation and invasion (Kumar-
Sinha, 2008). Notably, it has been demonstrated that ERG can directly activate EZH2, 
which synergistically result in cancer progression through histone methylation linked de-
differentiation (Yu, 2010b). Several studies have also confirmed that expression of EZH2 
shows a correlated pattern with the stage of prostate cancer development (Berezovska, 
2006; Saramaki., 2006; Hoffmann, 2007).Therefore, subjects with prostate cancer will be 
enrolled regardless of EZH2 related mutation status.
This study of GSK2816126 will focus primarily on the GCB-DLBCL NHL in order to 
ascertain a clinical benefit in a defined tumor type, for which there is high probability of 
potential benefit. However, solid tumors with changes to EZH2 inhibitor sensitizing 
mutations will be evaluated. These will be targeted as it is felt that they are most likely to 
show benefit. The exception in the solid tumor cohort will be prostate cancer, for which 
no mutation status will be required.


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Section 3.5.3 Rationale for Dose and Schedule
Rationale for Change: Restructured section. Included text to update monitoring and risk 
mitigation strategy for infusion reactions in line with updates made through the protocol.
REVISED TEXT
The doses of GSK2816126 for evaluation in this study were selected based on available 
preclinical biology, toxicology, and pharmacokinetic data as well as predicted 
pharmacokinetic and response information for humans.  Refer to the IB for more 
information [GlaxoSmithKline Document Number 2013N169204_04, 2017
2013N169204_00, 2013].
Predicted Effective Dose
The potential therapeutic dose for GSK2816126 in human was derived using available 
preclinical, PK and efficacy data from Karpas-422 and Pfeiffer tumor xenograft studies. 
Based on PK/PD modeling of Karpas-422 and Pfeiffer xenograft data, tumor eradication 
with GSK2816126 could be achieved in mice with an average total blood concentration 
target over the dosing interval of 1 ug/mL or an average free concentration of 16ng/mL. 
This free concentration is similar to the in vitro exposure producing 50% of the maximum 
effect (EC50) obtained in Karpas-422 or Pfeiffer cell lines and to the average free 
concentration obtained with 50 mg/kg dosed daily in Karpas-422 xenograft model where 
more than 90% tumor growth inhibition was observed. This average free concentration 
could be achieved on average with twice-weekly administration of 950 mg in humans. 
Due to species differences in protein binding and blood to plasma partitioning, a dose of 
up to 2700 mg could be needed to achieve the average total blood concentration target of 
1 ug/mL.
Starting Dose and Infusion Duration
Three approaches have been considered to establish the starting dose for GSK2816126 in 
heme hematological malignancies assuming a 70 kg adult with a surface area of 1.7 m2. 
An infusion duration of 2-hours is proposed for this clinical study. This infusion duration 
is shorter than the infusion duration used in animals but can be justified based on the 
following points:

With infusion of a volume of 250 mL over 2 hours, GSK2816126 doses up to 
1250 mg will provide infusion concentration up to the infusion concentration of 
5 mg/mL used in dogs while doses up to 2500 mg will provide infusion 
concentration up to the concentration of 10 mg/mL used in rats. A 3000 mg dose 
would provide an infusion concentration of 12 mg/mL.

The infusion will be performed into a larger (central) vein in humans than in 
animals. A shorter infusion duration and higher local blood flow would lead to a
shorter exposure of the local area of the vein to high concentrations of 
GSK2816126.

The main factor for the long infusion duration in animals was the histamine-


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release like reaction. Subjects will be monitored during the infusion for evidence 
of  histamine release related symptoms/infusion reactions and treated as needed 
with supportive care per local standard of care (e.g., corticosteroids, oxygen, 
epinephrine, diuretics, IV fluid). The infusion duration can be lengthened with 
restart of the infusion or at the next infusion.  Premedications (antihistamines or 
similar) may be provided at the next infusion or prior to treatment of new 
subjects.Subjects will be monitored during the infusion for evidence of histamine 
release related symptoms and treated as needed with anti-histamines.  Subsequent 
subjects treated at that dose or higher doses will be treated .  If necessary based on 
emerging clinical data, the infusion duration can be lengthened.
Taking all three approaches into consideration and the shorter infusion duration of 2-
hours, a starting dose of 50 mg twice-weekly as a 2-hour infusion is proposed. This dose 
provides a predicted total blood AUC of 1.43g.h/mL and a total blood Cmax of 0.428
g/mL. The AUC is 38-fold lower than the AUC (0-24hr) for the rat STD10 of 100 
mg/kg, 18-fold lower than the AUC at the lowest tested dose in rat (30 mg/kg), and 56-
fold lower than the AUC for the dog HNSTD of 100 mg/kg. The Cmax is 18-fold lower 
than the Cmax for the rat STD10 of 100mg/kg, 6.9-fold lower than the Cmax at the 
lowest tested dose in rat (30 mg/kg), and 23-fold lower than the Cmax for the dog 
HNSTD of 100 mg/kg. The starting dose of 50 mg will provide a suitable safety margin 
for the anticipated toxicities, while minimizing the number of subjects with aggressive 
lymphomas exposed to sub-therapeutic doses.
Predicted Effective Dose and Dosing Frequency
The potential therapeutic dose for GSK2816126 in human was derived using available 
preclinical, PK and efficacy data from Karpas-422 and Pfeiffer tumor xenograft studies. 
Based on PK/PD modeling of Karpas-422 and Pfeiffer xenograft data, tumor eradication 
with GSK2816126 could be achieved in mice with an average total blood concentration 
target over the dosing interval of 1 ug/mL or an average free concentration of 16ng/mL. 
This free concentration is similar to the in vitro exposure producing 50% of the maximum 
effect (EC50) obtained in Karpas-422 or Pfeiffer cell lines and to the average free 
concentration obtained with 50 mg/kg dosed daily in Karpas-422 xenograft model where 
more than 90% tumor growth inhibition was observed. This average free concentration 
could be achieved on average with twice-weekly administration of 950 mg in humans. 
Due to species differences in protein binding and blood to plasma partitioning, a dose of 
up to 2700 mg could be needed to achieve the average total blood concentration target of 
1 ug/mL.
The rationale for the proposed schedule of twice weekly, 3 weeks on / 1 week off for 
each 28-day cycle is based on preclinical in vivo observations.  Briefly, mice with Pfeiffer 
tumor xenograft were treated daily with 50 mg/kg for 10 days. Tumor H3K27 tri-
methylation levels were measured and tri-methylation inhibition was observed up to 5 
days after the last administration.  Using in vivo murine tumor xenograft models, 
schedules with progressively longer dosing intervals (i.e., from daily to once or twice-
weekly to intermittent twice-weekly dosing with 2 weeks on/ 1 week off) were evaluated.  
Similar tumor growth inhibition were observed for the same total weekly dose, regardless 
of dosing frequency, except for lower tumor growth inhibition being observed with once 
weekly dosing.  Taken together, these data support a schedule of 3 weeks on / 1 week off. 


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Additional schedules may be explored based on safety, tolerability, PK and 
pharmacodynamics.
Taken together, these data support a schedule of twice weekly, 3 weeks on / 1 week off. 
Additional schedules may be explored based on safety, tolerability, PK and 
pharmacodynamics.
Section 3.7
Dosage and Administration of Study Treatment
Rationale for change:  Administrative change to clarify  infusion duration per protocol.
REVISED TEXT
Investigational product (IP) details are provided in Table 5. It will be diluted in saline or 
D5W to a fixed 250 mL volume. This volume will be infused over a minimum of 2 hours 
(and/or up to 4 hours). Additional details are provided in the SPM. 
Section 3.8.1 QTcF Stopping Criteria
Rationale for Change: Clarified that QTcF would be used for eligibility and stopping 
criteria decision making. QT corrected by Friedericia’s method provides a better 
assessment of QT interval at the extremes of heart rate. This is a more accepted 
correction method that is being employed in Oncology studies and the ECG machines 
centrally provided for GSK studies provides the QTcF values on the reads. This leads to 
uniform correction of QT and standardization across studies.
REVISED TEXT
The QTcF is the QT interval corrected for heart rate according Fridericia’s formula 
(QTcF). 

For eligibility and withdrawal, subjects QTcF value will be used. 

For purposes of data analysis, QTcF values will  be used.
If a subject that meets the corrected QT (QTcF)1 interval duration criteria below, study 
treatment(s) will be withheld.  

QTcF interval (corrected for HR) ≥500 msec; IP GSK2816126 will be permanently 
discontinued.

QTcF interval increase from baseline ≥60 msec and maximum QTQTcF < 500 msec; 
GSK2816126IP may be restarted at a 33% reduction in doseone dose level lower
once the QTcF returns to baseline.  If QTcF prolongation meeting stopping criteria 
recurs after re-challenge, GSK2816126 IP must be permanently discontinued.
1Based on average QTcF value of triplicate electrocardiograms (ECGs) to include manual 
over-read.  For example, if an ECG demonstrates a prolonged QTQTcCF 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 QTcF values of the 3 ECGs to determine whether the subjects 
should have study treatment discontinued.


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The QTc is the QT interval corrected for heart rate according to either Bazett’s formula 
(QTcB), Fridericia’s formula (QTcF), or another method, machine or manual over read. 

For eligibility and withdrawal, ideally the same QT correction 
formula will be used for all subjects. However, because this is not 
always possible, the same QT correction formula must be used for 
each individual subject to determine eligibility for and withdrawal 
from the study. 
For purposes of data analysis, QTcB, QTcF, another QT correction formula, or a
composite of available values will be used.
Section 3.8.2.1
Management of Infusion Site Reactions
Infusion Site Related Reaction
Rationale for Change:  Included text to update monitoring and risk mitigation strategy 
for infusion reactions in line with updates made through the protocol.
Infusion Site (Histamine) Related Reaction
Grade 1: 
Continue infusion and closely monitor the subject 
Grade 2/3:
Temporarily interrupt study medication and:
-
Administer diphenhydramine 50 mg or similar 
anti-histamine 
-
Provide supportive care per local standard of 
care (e.g., corticosteroids, oxygen, 
epinephrine, diuretics, IV fluid)
-
May resume infusion once resolved to ≤</=
grade 1*
-
For grade 3 reactions, corticosteroids may be 
considered 
Grade 4:
-
Discontinue infusion.  Administer 
diphenhydramine, corticosteroids and 
supportive care per local standard of careas 
above
-
May consider restarting study treatment at a 
reduced dose or dose level pre-event based on 
discussion with GSK Medical Monitor
*Recommend following institutional guidelines for re-starting after infusion reactions 
seen with cytotoxic therapy. A general guideline would be as follows:
- Restart under observation at an infusion rate of 25% of the original rate for the 
first 30 minutes


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- If no reaction, increase infusion rate by 25% of the original rate every half hour 
until full dose administered
- If Grade 1 reaction, continue at the rate at which the reaction occurs
-If Grade 2 or 3 infusion related reaction consider premedication for all 
subsequent infusions per local standard of care.
Section 3.8.3 Dose Adjustment for Non-Hematologic Toxicity
REVISED TEXT
Rationale for Change: Dose escalation has been completed, therefore; updated dose 
adjustments to include reducing by dose level instead of reducing by percentage of 
received dose were updated in Section 3.4.8.1, Section 3.8.4.2 and Section 3.9.1.
Table 4
Dose Adjustment Guideline for Drug Related Non-Hematologic 
Toxicity
Worst Grade
Dose Adjustment
G1
No change in dose
G2
Continue dosing with no change OR
Consider holding for up to 2  weeks for toxicity to resolve to baseline or ≤ Grade 1, then 
continue at the same dose OR dose reduce by at least 25%to 1 dose level lower per dose 
escalation scheme if the toxicity is considered a DLT.
G3 and 4
Hold for up to 2 weeks for toxicity to resolve to baseline or ≤Grade 1, then dose reduce by 
at least 25%.to 1 dose level lower per dose escalation scheme
If no recovery to ≤Grade 1* or baseline after 14 days, patient should be withdrawn.
If the non-hematologic toxicity or event resolves to baseline or Grade 1 within 14 days 
of stopping therapy, treatment with GSK2816126 may be restarted at 1with at least 
25%dose level lower than the current dose reduction. For a non-DLT, the treatment with 
GSK2816126 could restart at a full dose, if deemed appropriate.
If the non-hematologic toxicity does not resolve to Grade 1 or baseline within 14 days, 
the subject should be withdrawn from the treatment permanently (Section 6.3).  However, 
if the investigator and GSK Medical Monitor agree that further treatment will benefit the 
subject, treatment can restart with at least 25% dose reduction1 dose level lower and 
under weekly clinical monitoring.  If the toxicity resolves to Grade 1 or baseline, the 
dose may be resumed to the initial dose level.


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Section 3.8.4.1
For subjects with lymphoma and multiple myeloma:
REVISED TEXT
When the treatment resumes, the dose may be adjusted based on platelet count, i.e., dose 
can be reduced by at least 25% increments up to twice1 or 2 dose levels when the platelet 
count ≤25 x 109/L (G4 thrombocytopenia) and it is not attributed to the disease. If a 
subject has persistent G4 thrombocytopenia for 4 weeks not attributed to disease or 
requires platelet transfusions for bleeding in the absence of the disease, the subject will 
be withdrawn from the study.
Section 3.8.4.2
For subjects with solid tumors:
REVISED TEXT
- Grade 3 (platelet count between 25,000 to <50,000): After discussion with medical 
monitor and using sound clinical judgement, continue at same dose or consider dose 
interruption untiladjust dose (e.g. consider missing one dose or till count recovery to 
Grade 2 or less). Monitor platelet countCBC at least a minimum of twice a weekly, more 
frequently if necessary.
- Grade 4 (platelet count below 25,000): Interrupt study medication and monitor CBC 
platelet count every 2-3 days. If platelet counts recover to Grade 2, discuss with medical 
monitor resuming treatment at the same or adjusted dose based on sound clinical 
judgement. Platelet transfusion is allowed based on institutional guidelines. In case of 
platelet transfusion, hold drug for at least 7 days from day of transfusion, and if platelet 
counts recover to Grade 2 consider initiating treatment at a lower dose using sound 
clinical judgement and after consulting with the GSK medical monitor. Discontinue 
treatment if drug has to be held for >14 days or greater than 2 dose reductions required.
Section 3.9.1 Dose Modifications
REVISED TEXT
Dose reductions for GSK2816126 will depend on their starting dose.  If a subject has a 
dose reduction for toxicity the dose will be reduced by one dose level by a minimum of 
25%.  Approval from the GSK Medical Monitor is required to restart a dose after 14 days 
of dose interruption.  Following a dose reduction subjects may be re-escalated to a higher 
dose level with the approval of the GSK Medical Monitor if the toxicity has resolved.
Section 5.1
Number of Subjects
Rationale for Change: updated total number of subjects to be enrolled based on added 
Part 1 expansion cohorts and revised subject numbers in Part 2.


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REVISED TEXT
A maximum of approximately 250169 subjects will be enrolled.   See Section 12.2 for 
sample size assumptions.
The number of dose levels and the level at which the RP2D (or MTD or MFD) is reached 
cannot be determined in advance.  An adequate number of subjects will be enrolled into 
the study to establish the recommended dose(s) for further study.  It is estimated that 
approximately 40 subjects will be enrolled into Part 1 dose-escalation of the study.  
Additionally i n Part 1 cohort expansion, approximately 27 GCB-DLBCL subjects and 
approximately 15 solid tumor subjects containing EZH2 inhibitor sensitizing mutations or 
subjects with prostate cancer will be enrolled. 
Approximately up to 129 168 subjects will be enrolled in Part 2 in five expansion 
cohorts: two GCB-DLBCL cohorts with up to 320 subjects from the EZH2 wild-type 
population, and up to 320 subjects from the EZH2 mutation positive population, and two 
tFL cohorts with up to 3216 subjects from the EZH2 wild-type population and up to 3216
subjects from the EZH2 mutation positive population and up to 3740 subjects in the MM 
cohort.  Additional subjects/cohorts may be enrolled to allow for evaluation of additional 
dose levels. 
Section 5.2.1 Part 1 Inclusion Criteria
Rationale for Change – see rationale for updates to inclusion and exclusion noted 
under Synopsis.
REVISED TEXT
3. Tumor type criteria

Relapsed/refractory non-Hodgkin’s lymphoma (NHL) that meets one of the 
following criteria:
o
Germinal Center B cell Diffuse large B cell lymphoma (GCB-
DLBCL) or transformed follicular lymphoma relapsed after, or 
refractory to at least one prior chemotherapy regimen (e.g., rituximab, 
cyclophosphamide, doxorubicin, vincristine, prednisone [R-CHOP]) 
AND  not a candidate for standard salvage regimens or autologous or 
allogeneic stem cell transplant. (e.g., due to age, comorbid conditions 
or failure to respond to salvage chemotherapy).  Local confirmation of 
lymphoma subtype GCB-DLBCL is allowed for enrollment but must 
be confirmed through central laboratory testing.
o
DLBCL or transformed FL relapsed after or refractory to at least two 
prior chemotherapy regimens.
o
Other NHLs that have failed at least one prior line of therapy and for 
which there is no standard salvage regimen.

Relapsed and/or refractory MM that have failed prior standard therapy and 
for which there is no standard salvage regimen.


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
Solid tumors [RECIST evaluable, with the exception of castrate resistant 
prostate cancer (CRPC) at least one and not more than three standard of care 
chemotherapeutic regimens, or tumor for which there is no approved therapy, 
or for which standard therapy is refused.

Solid tumors that meet the following criteria:
o
Measurable disease by RECIST 1.1 in at least 1 site

For Castrate Resistant Prostate Cancer (CRPC) measurable 
disease can also include PSA level (see below)
o
Disease progressionevaluable, with the exception of castrate resistant 
prostate cancer (CRPC) with the last line of therapy and at least one 
prior standard of care chemotherapeutic regimens, or tumor for which 
there is no approved therapy, or for which standard therapy is 
unsuitable or refused.
o
Mutation Status:

Solid tumor types, other than prostate, must have one of the 
following EZH2 inhibitor sensitizing mutations as determined 
via local testing:

An activating mutation in EZH2 (Y641F/C/S/H/N, 
A677V/G, and/or A687V 

Loss of a component of the SWI/SNF complex, 
including, but not limited to, ARID1A, SMARCB1 
(aka SNF5/INI1/BAF47), SMARCA4 (aka BRG1), or 
PBRM1 (aka PB1) as determined by molecular testing 
(bi-allelic loss or mutation) or immunohistochemistry

Loss of BAP1 (ubiquitin carboxy-terminal hydrolase) 
as determined by molecular testing (bi-allelic loss or 
mutation) or immunohistochemistry
o
CRPC subjects:

Must have measurable disease by either:

RECIST1.1 (see Appendix 5) or,

A minimum PSA of 5 ng/mL 

Disease progression on last line of therapy and must have 
progressed on abiraterone, enzalutamide, or taxane 
chemotherapy

Patients may continue GnRH agonists

Small cell prostate cancer is eligible


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4. For all subjects: Availability of archival tissue, or willingness to undergo fresh 
biopsy if archival tissue is not available as described in Section 
7.6.1.1,Section 7.6.1.2 and Section 7.6.5.: 
5. Must have a pre-existing central venous access such as a port, Hickmann 
catheter, or a peripherally inserted central catheter (PICC line) or be willing 
and able to have one inserted.
6. ECOG Performance Status of 0 or 1 (see Appendix 2).
7. Men with a female partner of childbearing potential must have either had a 
prior bilateral vasectomy with resultant azoospermia, bilateral orchiectomy, or 
must agree to use one of the contraception methods listed in Section 10.1 from 
the time of the first dose of study medication until 3 monthsat least 2 weeks 
(14 days) after the last dose of study treatment due to long elimination 
phase.for clearance of any altered sperm.
8. A female subject is eligible to participate if she is of:Women of 
childbearing potential must have a negative serum pregnancy test within 7 
days of first dose of study treatment and agree to use effective contraception, 
as defined in Section 10.1, during the study and for at least two weeks (14 
days)  following the last dose of study treatment.

Non-childbearing potential as defined in Section 10.1.1

Child bearing potential as defined in Section 10.1.1 and agree to use 
effective contraception, as defined in Section 10.1, for an appropriate 
period of time (as determined by the product label) prior to the start of 
dosing to sufficiently minimize the risk of pregnancy and for at least 2 
weeks (14 days) following the last dose of study treatment. Women of 
childbearing potential must have a negative serum pregnancy test within 
7 days of first dose of study treatment followed by negative urine or serum 
pregneancy test once every 4 weeks (prior to next dose cycle) thereafter.
9.
Adequate organ system function as defined below:
System
LABORATORY VALUES
Hematologic
  ANC
1.2 x 109/L  
  Hemoglobin
9 g//dL 
  Platelets
75x 109/L  
 Platelets for Subjects with MM
≥ 50,000 (transfusion independent)
 PT/INR and PTT
≤1.5 x ULN
Hepatic
  Albumin
2.5 g/dL
  Total bilirubin
1.5 times ULN
 AST and ALT
2.5  times ULN without liver metastases
5 times ULN if documented liver metastases
Renal
Serum Creatinine
1.5 mg/dL 
Or


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System
LABORATORY VALUES
Calculate Creatinine Clearancea, b  OR            
24 hr urine Creatinine Clearance
50 mL/min                                                              
≥50mL/min
Reproductive/Endocrine for CRPC only
Testosterone 
<50ng/dL (only for subjects with CRPC)
Cardiac
Left Ventricular Ejection Fraction (LVEF)
≥LLN (minimum of 50% LVEF) by ECHO  or MUGAc
Abbreviation(s): ANC, absolute neutrophil count; ALT, alanine aminotransferase; AST, aspartate aminotransferase; 
CRPC, castration resistant prostate cancer ECHO, echocardiogram; INR, international normalization ratio, MUGA, 
multigated (radionuclide) angiogram; PT, prothrombin time, PTT, partial thromboplastin time, ULN, upper limit of 
normal , LLN, lower limit of normal.
a.
Calculated by Cockcroft-Gault formula
b.
For MM subjects, adequate renal function is defined as serum creatinine ≤ 2.5 mg/dL OR
calculated creatinine clearance (either calculated or obtained via 24 hr urine collection) ≥ 30 
mL/min.ECHO is the preferred method
c.
ECHO is the preferred method and should always be used if available
NOTE:  Laboratory results obtained during Screening should be used to determine 
eligibility criteria.  In situations where laboratory results are outside the permitted range, 
the investigator may opt to retest the subject and the subsequent within range screening 
result may be used to confirm eligibility.  Subjects requiring transfusions to meet 
eligibility criteria are not eligible.
Section 5.2.2 Part 2 Inclusion Criteria
REVISED TEXT
1. In addition to inclusion criteria listed for Part 1, Part 2 will enroll GCB-DLBCL, tFL 
and MM subjects only.
2. Relapsed and/or refractory MM or tFL that have failed prior standard therapy and for 
which there is no standard salvage regimen
Section 5.2.3 Part 1 and 2 Exclusion Criteria 
REVISED TEXT
Subjects meeting any of the following criteria must not be enrolled in the study:
1. Currently rReceiving any cancer therapy within 2 weeks of first dose  (chemotherapy, 
radiation therapy, immunotherapy or biologic therapy(including surgery, and/or 
tumor embolization)).(permitting corticosteroids Corticosteroids to control systemic 
or local symptoms, up to a dose of 10 mg prednisone or equivalent daily and stable 
for at least 7 days prior to enrolment)
Note: the following are allowed:

Corticosteroids to control systemic or local symptoms, up to a dose of 10 
mg prednisone or equivalent daily and stable for at least 7 days prior to 
enrollment.


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
Subjects with prostate cancer may remain on GnRH agonists. Other 
hormonal therapies (e.g., bicalutamide, abiraterone and enzlutimide) for 
prostate cancer must be stopped 4 weeks prior to enrolment.  
Note: the following are NOT allowed:

Chemotherapy regimens with delayed toxicity within the last 3 weeks.

Nitrogen mustards, Melphalan,  Monoclonal antibody or Nitrosourea 
within the last 6 weeks.

Hormonal (e.g. anti androgen) therapies for prostate cancer must be 
stopped 4 to 6 weeks prior to enrolment. Subjects with prostate cancer 
may remain on luteinizing hormone releasing hormone (LHRH) agonists. 
Subjects with prostate cancer amy also remain on low dose prednisone or 
prednisolone (up to 10 mg/day) and still be eligible for this study.
2. Any major surgery, radiotherapy or immunotherapy within the 4 weeks prior to first 
dose of study drug, or palliative radiotherapy to a single symptomatic lesion within 
the 2 weeks prior to first dose of study drugs.
3. Subjects with prior allogeneic transplant are excluded: however, subjects who have 
previously received an autologous stem cell transplant are allowed if a minimum of 
100 days has elapsed from the time of transplant and the subject has recovered from 
transplant-associated toxicities prior to the first dose of GSK2816126
Subjects who have previously received an autologous stem cell transplant are 
allowed if a minimum of 100 days has elapsed from the time of transplant and 
the subject has recovered from transplant-associated toxicities prior to the first 
dose of GSK2816126
4. Received an investigational anti-cancer drug within 64 weeks, or within 5 half-lives 
(whichever is shorter) of the first dose of study drug.  At minimum ofleast 14 days 
must have passed between the last dose of prior investigational agent and the first 
dose of study drug. 
5. Current use of a prohibited medication or expected to require any of these 
medications during treatment with study drugs (see Section 9).
6. Known HIV, or serological evidence for Hepatitis B (positive HBsAg) or chronic
Hepatitis C infection.

Subjects who are negative for HBsAg, but HBcAb positive, a HBV DNA 
(viral load) test will be performed and if positive negative are eligiblewill be 
excluded.  

Subjects with positive Hepatitis C antibody serology, but with a negative 
HCV RNA test results are eligible.  
7. Concurrent use of therapeutic warfin is allowed. However, anticoagulants that do not 
have reversal agents available are prohibited (see Section 9.2). Current use of 


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therapeutic warfarin.  Therapeutic dosing of warfarin is defined as resulting in an 
(International normalization ratio) INR >1.3.  Low molecular weight heparin is 
permitted.  
8. Chemotherapy regimens with delayed toxicity within the 3 weeks prior to first dose 
of study drug. These include, but are not limited to, monoclonal antibody, 
immunotherapy, therapy, and nitrogen mustards 
8. Unresolved toxicity greater than Grade 1 National Cancer Institute – Common 
Terminology Criteria for Adverse Events (NCI-CTCAE) version 4 from previous 
anti-cancer therapy, with the exception of alopecia and peripheral neuropathy [NCI-
CTCAE, 2009]. 

Lymphoma subjects with ≤Grade 3 lymphopenia can be enrolled at the 
discretion of the investigator
9. Packed red blood cell or platelet transfusion within 7 days of screening laboratory 
tests.
10. Psychological, familial, sociological or geographical conditions that do not permit 
compliance with the protocol.
11. Cardiac exclusion criteria:

History of acute coronary syndromes (including myocardial infarction and 
unstable angina), coronary angioplasty, or stenting within the past 6 months 
prior to first dose of study drug.

QTcF interval >450 msec 

Uncontrolled arrhythmias.  Subjects with rate controlled atrial fibrillation for 
>1 month prior to first dose of study drugs may be eligible.

Class II, III or IV heart failure as defined by the New York Heart Association 
(NYHA) functional classification system. 
12. Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs 
chemically related to the study drug or their excipients.
13. Pregnant or lactating female.
14. Unwillingness or inability to follow the procedures outlined in the protocol.
15. Uncontrolled diabetes or other medical condition that may interfere with assessment 
of toxicity.
16. Central nervous system (CNS) metastases, with the following exception:
i. Subjects who have  previously treated CNS metastases, are 
asymptomatic, and have no requirement for steroids at least 14 
days prior to first dose of study drug.
ii. Subjects with carcinomatous meningitis are excluded regardless of 
clinical stability.
17. Invasive malignancy or history of invasive malignancy other than disease under 
study, except as noted below:


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i. Any other invasive malignancy from which the subject has been 
disease-free for more than 2 years and, in the opinion of the 
principal investigator and GSK Medical Monitor, will not affect 
the evaluation of the effects of this clinical trial treatment on 
currently targeted malignancy, can be included in this clinical trial.
ii. Curatively treated non-melanoma skin cancer and any carcinoma-
in-situ.
Section 6.3
Permanent Discontinuation from Study Treatment
Rationale for Change: Clarify the assessments to occur and timing of the post study 
treatment Follow Up Visit visit for subjects who discontinue from study treatment.
REVISED TEXT

Intercurrent illness that prevents further administration of study treatment(s)

Subject is lost to follow-up 

or Sstudy is closed or terminated

Female subject who becomes pregnant while on study treatment
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/disease assessments 
at the post study treatment Follow Up Visit as specified in the Time and Events Tables.
Section 7.2
Demographic/Medical History and Baseline Assessments
Rationale for Change: Clarified baseline assessments required based on tumor type.
REVISED TEXT

Disease characteristics for all subjects including: 

Date of initial diagnosis 

Initial diagnosis tumor histology

ECOG performance status at initial diagnosis

LDH level at initial diagnosis

Tumor location involvement at initial diagnosis 

Previous cancer treatments (e.g., cytotoxics, radiotherapy, maintenance, surgery)

Ongoing toxicities related to previous treatment


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
Best response to previous treatment(s)

Date of relapse/refractory diagnosis

Tumor histology (if relapse/refractory tumor biopsy completed). For Part 2
subjects, tumor biopsy is mandatory for inclusion. See Section 7.6.5. 

Ann Arbor stage of relapse/refractory diagnosis for NHL

ECOG performance score at time of first relapse/refractory diagnosis (as 
applicable)

LDH level at time of first relapse/refractory diagnosis (as applicable) 

Diagnostic quality CT imaging with contrast within 28 days of first dose of study 
treatment identifying nodes, nodal masses, spleen/liver nodules and, if applicable 
measurable extra nodal disease. Diagnostic quality CT imaging is the preferred 
method of disease assessment. If PET/CT has been performed within this window, 
diagnostic CT will not be required.  See Section 7.7 for further information.

If completed and will be utilized for assessment of disease, PET imaging within 28 
days of first dose of study treatment. Images may be obtained from standalone PET 
scanners or via combination PET/CT scanners.  Standalone PET does not replace 
diagnostic CT.  See Section 15.4 for further information.

For NHL, unilateral or bilateral bone marrow biopsy within 35 days prior to 
commencing study therapy. 

Clinical laboratory tests:  hematology, clinical chemistry, coagulation parameters 

Serum beta-human chorionic gonadotropin (-HCG) pregnancy test for female 
subjects of childbearing potential only 

12-lead ECG

ECHO or MUGA

Review of concomitant medications

Baseline assessments for subjects with GCB-DLBCL

Ann Arbor stage of initial diagnosis for NHL

Ann Arbor stage of relapse/refractory diagnosis for NHL

GCB testing confirming status

LDH level at initial diagnosis

LDH level at time of first relapse/refractory diagnosis (as applicable)


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Section 7.3.3 Vital Signs
REVISED TEXT
Vital sign measurements will include systolic and diastolic BP, temperature, respiration 
rate and pulse rate.  Vital signs should be measured after resting for at least 5 minutes in a 
semi-supine position.  Vital signs will be measured more frequently if warranted by 
clinical condition of the subject.  On days where vital signs are measured multiple times 
(Cycle 1 Day 1), temperature does not need to be repeated unless clinically indicated.  
Refer to the SPM for details regarding measurement of vital signs.
Section 7.3.4 Safety Electrocardiogram
Rationale for Change: Updated to clarify timing of safety ECGs, review by 
investigator, and definition of baseline timepoint.  Clarified that QTcF would be used for 
eligibility and stopping criteria decision making. QT corrected by Friedericia’s method 
provides a better assessment of QT interval at the extremes of heart rate. This is a more 
accepted correction method that is being employed in Oncology studies and the ECG 
machines centrally provided for GSK studies provides the QTcF values on the reads. This 
leads to uniform correction of QT and standardization across studies.
REVISED TEXT
Safety tTwelve-lead ECGs will be obtained in triplicate over a brief (e.g., 5-10 minute) 
recording period at designated time points during the study using an ECG machine that 
automatically calculates the HR and measures PR, QRS, QT, and QTc intervals.  At each 
assessment, a 12-lead ECG will be performed by qualified personnel at the site after the 
subject has at least a 5 minute rest and is in a semi-[recumbent or supine] position. Refer 
to the SPM for details regarding ECG procedures.
Standard 12-lead ECGs (safety ECGs) will be performed as part of the real-time 
assessment of subjects. 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
The QTc is the QT interval corrected for heart rate according to Fredericia’s formula 
(QTcF).

For eligibility and withdrawal, QTcF will be used for all subjects

For purposes of data analysis, QTcF values 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 C1D1 predose QTcF 
results.  If these results are not available, then the mean of QTcF of the screening 
triplicate ECG results would be used.


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Timings for in-house on-drug ECGs on Day 1 only are pre-infusion, post-infusion, before 
bed (between 9-10pm) and before discharge the next morning. These ECGs are in 
addition to the Holter monitoring.  Subjects will not be discharged from their overnight 
stay in the Phase I unit after dose 1 until the QTcF is <500 msec.
Section 7.3.5 Holter Monitoring
REVISED TEXT
In addition to the 12-lead safety ECGs performed during the study, continuous 12-lead 
Holter ECGs (obtained via a Holter monitor) will be acquired for a total of approximately 
24 hours beginning an hour before the first infusion.  Subjects will be monitored
overnight in the CRU.  The Holter monitor-derived ECGs will not provide real-time 
assessment of cardiac rhythm and morphology but will be analyzed retrospectively and 
included in the DLT and concentration QT analysis. 
Refer to Section 3.8.1 for QTc interval withdrawal criteria and additional readings that 
may be necessary.  Refer to the SPM for details regarding Holter monitoring procedures.
Section 7.3.6 Laboratory Assessments
Rationale for Change: Updated to clarify reporting of abnormal laboratory values as 
Adverse Events. Clarified clinical laboratory tests to be taken (table 8).
REVISED TEXT
All protocol required laboratory assessments, as defined in Table 8 should be performed 
according to the Time and Events Table (Section 7.1).  Details for the preparation and 
shipment of samples will be provided in the SPM.
Abnormal laboratory results that are considered by the investigator to be clinically 
significant should be recorded on the eCRF as AEs.   All laboratory tests with values that 
are significantly abnormal during participation in the study or within 30 days after the last 
dose of study treatment should be repeated until the values return to normal or baseline.  
If such values do not return to normal within a period judged reasonable by the 
investigator, the etiology should be identified and the sponsor notified.
Hematology, clinical chemistry, urinalysis and additional parameters to be tested are 
listed below and are to be performed at the institutions local laboratory:


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Table 8
List of Clinical Laboratory Tests
Hematology
Platelet Count
RBC Indices:
Automated WBC Differential:
RBC Count
MCV
Neutrophils
WBC Count (absolute) 
MCH
Lymphocytes
Reticulocyte Count
MCHC
Monocytes
Hemoglobin
Eosinophils
Hematocrit
Basophils
Clinical Chemistry
BUN
Potassium
AST
Total and direct bilirubin
Creatinine
Chloride
ALT
Uric Acid
Sodium
Calcium
Alkaline phosphatase
Total Protein
Magnesium
Glucose
LDH
PO4
FSH and estradiol (as needed in women of non-child bearing potential and all peri menopausal womenonly)
Pregnancy test for females (serum B-HCG at screening, Urine or serum B-HCG during Continuation Phase)
Abbreviation(s): ALT, alanine aminotransferase; AST, aspartate aminotransferase; BUN, blood urea nitrogen; FSH, 
follicle stimulating hormone; LDH, lactate dehydrogenase; MCH, mean corpuscular hemoglobin;  MCHC, mean 
corpuscular hemoglobin concentration; MCV, mean corpuscular volume; PO4, phosphate; RBC, red blood cell;  WBC, 
white blood cell.
Section 7.3.7 Pregnancy Testing and Reporting
REVISED TEXT
Any pregnancy that occurs during study participation must be reported using a clinical 
trial pregnancy notification and follow –up form.  To ensure subject safety, each 
pregnancy must be reported to GSK within 2 weeks of learning of its occurrence.  The 
pregnancy must be followed up to determine outcome (including premature termination) 
and status of mother and child.  While pregnancy itself is not considered to be an AE or 
SAE, pregnancy complications and elective terminations for medical reasons must be 
reported as an AE or SAE.  Spontaneous abortions must be reported as an SAE.
Section 7.4.1 Blood Sample Collection for Pharmacokinetics
Rationale for Change: In Section7.4.1, Section 7.4.2 and Section 7.4.3, clarified the 
number of subjects and timing of assessments.
REVISED TEXT
For at least 4 sSubjects participating in the Part 2 Part 1 PK/PD expansion cohort, 
additional blood samples will be collected for metabolite profiling.
Section 7.4.2 Bile Sample Collection for Pharmacokinetics
REVISED TEXT
For at least 4 sSubjects participating in the Part 12 PK/PD expansion cohort, bile samples 
for analysis of GSK2816126 and its metabolites maywill be collected via the Entero-Test 


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[Guiney, 2011] over the time period specified in the Time and Events Table (see 
Section 7.1).
Section 7.4.3 Urine Sample Collection for Pharmacokinetics
REVISED TEXT
Urine maywill be collected for metabolic profiling in at least 4 subjects in the PK/PD 
expansion cohort of Part 21 at the time points indicated in the Time and Events Schedule 
(Section 7.1).
Section 7.4.4 Plasma Sample for CYP3A4 Enzyme Activity
REVISED TEXT
Plasma collected in the Part 2 PK/PD expansion cohort may be analyzed for 4β-
hydroxycholesterol (as well as cholesterol) as a potential in vivo marker of CYP3A4 
enzyme activity and the results will be reported under a separate Mechanistic Safety and 
Disposition Drug Metabolism and Pharmacokinetics (DMPK) protocol. Samples 
collected pre-treatment and at steady-state will be compared to evaluate this potential 
biomarker. 
Section 7.4.5 Pharmacokinetic Sample Analysis
REVISED TEXT
Blood sample analysis will be performed under the management of Bioanalysistical
Immunogenicity and Biomarker,Science and Toxicokinetics, In Vitro In Vivo Translation
Drug Metabolism and Pharmacokinetics, Platform Technology and Science, GSK.  
Concentrations of GSK2816126 will be determined in blood samples using the most 
current approved and validated analytical methodology. Blood raw data will be stored in 
the Good Laboratory Practices (GLP) Archives, GSK. Once the blood has been analyzed 
for GSK2816126, any remaining blood may be analyzed qualitatively for circulating 
metabolites and the results reported under a separate DMPK protocol.
If dry blood matrix samples are collected, they will be analyzed under the management of 
Bioanalysis Immunogenicity and Biomarker, In Vitro In Vivo Translation Bioanalytical 
Science and Toxicokinetics, Drug Metabolism and Pharmacokinetics, Platform 
Technology and Science, GSK. Concentrations of GSK2816126 will be determined in 
dry blood matrix samples using a validated analytical methodology. Dried blood matrix 
raw data will be stored in the Good Laboratory Practices (GLP) Archives, GSK.
Urine sample analysis may be performed under the management of Bioanalytical
Bioanalysis Immunogenicity and Biomarker, In Vitro In Vivo Translation Science and 
Toxicokinetics, Drug Metabolism and Pharmacokinetics, Platform Technology and 
Science, GSK.  Concentrations of GSK2816126 may be determined in urine samples 
using an investigative analytical methodology.  Urine raw data will be stored in the GLP 
Archives, GSK.


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The urine and bile samples may be analyzed for compound-related metabolites and the 
results will be reported under a separate DMPK protocol.
Plasma analysis for 4β-hydroxycholesterol and cholesterol may be conducted and the 
results reported under a separate DMPK protocol.
Section 7.6
Translational Research

Rationale for Change: In Section 7.6, provided additional clarity on the biomarker 
assessments required per protocol.
REVISED TEXT
Translational or biomarker research may be performed on archival tissue, tumor biopsies, 
blood samples or other surrogate tissue (e.g. skin or hair) collected at various times 
throughtout theon study, to better understand DLBCL, transformed FL, MM, mechanism 
of action and response to GSK2816126. The successful collection of quality tissue 
specimens will be critical to furthering our understanding of EZH2 biology and 
identifying the best way to treat patients with an EZH2 inhibitor.
Section 7.6
Translational Research
REVISED TEXT
Novel candidate biomarkers and subsequently discovered biomarkers of the biological 
response associated with lymphoma, or other cancers, or medically related conditions 
and/or the action of GSK2816126 may be identified by application of the following.
DNA/gene, RNA and protein analysis of blood and tumor tissue including but not limited 
to the following analyses:

Confirmation of GCB-subtype DLBCL status by IHC analysis using the standard 
methods or  tumor GEP signature

Confirmation of EZH2 WT status by targeted sequencing of EZH2 gene

Subject tumors determined to be wild-type for the seven pre-defined 
EZH2 mutations assessed in the screening assay maywill be 
evaluated for the presence of additional, undefined, mutations in the 
EZH2 gene

DNA analyses may be performed for somatic mutations in genes of interest 
(including, but not limited to, EZH2, and UTX, BAP1, ARID1A, SMARCB1, 
SMARCA4, and PBRM1)) by next-generation sequencing or alternative 
methodology.  Translocations including, but not limited to, BCL-2, BCL-6 and c-
MYC, which have been observed in DLBCL, may also be assessed

Circulating cell free-DNA (cfDNA) analysis of blood/plasma


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
Circulating biomarker (DNA, RNA and/or protein) analysis of plasma

RNA transcriptome analysis of blood and/or tissue samples.

Measurement of the levels of a subset of RNA species oin blood and/or tissue 
samples

Analysis of protein expression by IHC or an alternative method may also be 
performed for proteinsgenes of interest. including, but not limited to, JARID-2
Section 7.6.1 Tumor Biomarker Analysis
REVISED TEXT
To evaluate candidate biomarkers and identify novel predictors of sensitivity and/or 
resistance to GSK2816126, DNA, RNA or protein measurements will be assessed in 
archival tumor tissue or fresh biopsies.  Specific tests, exploratory analyses and tissue 
requirements for each tumor type are indicated below and/or Table 6.   
DLBCL/tFL patients: A requirement for inclusion in this study is availability of archival 
tissue, or willingness to undergo fresh biopsy for the following:

Confirmation of GCB-subtype DLBCL status by analysis of tumor by IHC using 
the standard methods (DLBCL subjects)

Confirmation of EZH2 WT status by targeted sequencing of EZH2 gene (DLBCL 
and tFL subjects)

DNA, RNA or protein measurements to identify predictors of sensitivity or 
resistance to GSK2816126

All other patients will be asked to submit an archival tumor specimen for 
retrospective DNA, RNA or protein testing of potential markers of sensitivity 
and/or resistance; however this will not be an eligibility requirement.
Section 7.6.1.1
GCB-DLBCL Subtyping (DLBCL subjects only)
REVISED TEXT
Central confirmation of GCB DLBCL status will be confirmed by an IHC test utilizing 
the Choi algorithm [Choi, 2009] in part 1 and 2.
Local testing, in advance of central confirmation  may be performed to determine GCB 
status for enrollment using the Choi algorithm or a suitable alternative algorithm.  
Section 7.6.1.2
EZH2 Mutation Analysis (required for study entry in Part 2 
for GCB-DLBCL and tFL subjects only)
REVISED TEXT
Screening for eligibilityfor Part 2 of the study will be conducted using either an NGS-
based gene panel or a custom quantitative real time polymerase chain reaction (RT-PCR) 


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test based on TaqMan PCR chemistry.  BothThe tests detects 7 known activating 
mutations in the EZH2 gene: Y641F (c.1937A>T); Y641N (c.1936T>A); Y641S 
(c.1937A>C); Y641H (c.1936T>C); Y641C (c.1937A>G); A677G (c.2045C>G); and 
A687V (c.2075C>T) .( AltheaDX , 2014).
EZH2 mutation analysis on archival tumor samples or fresh biopsies from subjects 
enrolled in Part 1 may also be performed, though the presence of an EZH2 mutation is 
not required for study entry in Part 1. 
Retention of screen-failure tumor tissue: all or a portion of archival or fresh biopsy tissue 
from screen-failure subjects, used for central testing of GCB-DLBCL or EZH2 mutation 
status, will be retained.  This tissue may be used in the validation of potential diagnostic 
assays to detect EZH2 mutations and/or for GCB-DLBCL subtyping.
Section 7.6.2 Circulating cell free DNA/RNA Analysis
REVISED TEXT
Plasma samples maywill be analyzed to investigate mutations, including but not limited 
to EZH2, in cfDNA.
Tumor-specific cfDNA levels detected in plasma or serum have been found to correlate 
with increasing tumor burden and decline following therapy.  Furthermore, cfDNA in 
cancer subjects can harbor many genetic alterations (mutations, microsatellite alterations, 
aberrant methylation), which are generally consistent with the tumor. Thus, tumor-
specific circulating cfDNA has the potential to be a useful biomarker of therapeutic 
response as well as offering a less invasive blood based technique for identifying and 
selecting subjects for certain treatments.  Given the promise of cfDNA blood based test 
for subject selection, this test will be explored to determine whether EZH2 mutations in 
cfDNA correlate with that in the tumor tissue from which it is derived. This test will also 
be explored to correlate increasing cfDNA levels with increasing tumor burden.
Tumor-specific circulating cell-free deoxyribonucleic acid (cfDNA) levels detected in 
plasma or serum have been found to correlate with increasing tumor burden and decline 
following therapy.  Furthermore, cfDNA in cancer participants can harbor many genetic 
alterations (mutations, microsatellite alterations, aberrant methylation), which are 
generally consistent with the tumor. Additionally exosomes, released from tumors cells 
into circulation, which contain both DNA and RNA are increasingly being recognized as 
important source of cancer biomarkers.  Thus, tumor-specific circulating cfDNA and 
exosomes have the potential to be a useful source of biomarkers of therapeutic response 
as well as offering a less invasive blood based technique for identifying and selecting 
participants for certain treatment.  Methylation status of cfDNA may also be investigated.


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Section 7.6.4 RNA Expression Research of a Subset of RNA Species
REVISED TEXT
Transcriptional (RNA) analyses may be performed to better understand changes in gene 
expression profile upon treatment with GSK2816126 in tumor tissue and/or blood..  
Blood and tissue samples will be collected for RNA expression analyses of a subset of 
RNA species.
RNA expression studies may be conducted using RNA-seq, quantitative RT-PCR, and/or 
alternative equivalent technologies, which can facilitate the simultaneous measurement of 
the relative abundances of RNA species resulting in a RNA expression profile for each 
blood and tumor tissue sample. The RNAs assayed may be those involved in tumor 
pathogenesis, the absorption, distribution, metabolism, or excretion of GSK2816126, or 
in the subject’s response to GSK2816126. In addition, continuing research may identify 
other proteins or regulatory RNAs that may be involved in response to GSK2816126 or 
tumor pathogenesis. The RNAs that code for these proteins and/or regulatory RNAs may 
also be studied. This will enable the evaluation of changes in RNA expression profiles 
that may correlate with biological response relating to specific lymphoma, other cancers, 
and medically related conditions or the action of GSK2816126.
Section 7.6.5 Tumor Tissue collection
REVISED TEXT
Part 1:

DLBCL subjects:  the availability of archived tissue (or willingness to undergo 
fresh biopsy) is required for determination of EZH2 mutation status, and/or GCB-
subtype.

All other subjects:  an archival tumor specimen (or willingness to undergo fresh 
biopsy) for retrospective DNA, RNA or protein testing of potential markers of 
sensitivity and/or resistance. however, this will not be an eligibility requirement. 
Subjects for whom archived tissue is not available and biopsies are not feasible 
will be eligible for enrolment and participation in the study at the discretion of the 
GSK medical monitor. Contact GSK medical monitor for confirmation of 
enrollement and sudy entry if biopsies are not feasible.

Pre and post treatment biopsies for PD and translational research activities are 
optional for all subjects.
Part 2:

DLBCL cohorts:  a fresh tumor biopsy is required for all screened subjects to 
determine EZH2 mutation status and GCB-subtype.  


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
tFL cohorts:  a fresh tumor biopsy is required for all screened subjects to 
determine EZH2 mutation status. 

MM cohort:  an archival tumor specimen or fresh tumor biopsy is required.

PK/PD cohorts: Pre treatment and post treatment biopsies are required

Pre and post treatment biopsies for PD and translational research activities are 
optional for all other subjects.
Retention of screen-failure tumor tissue: all or a portion of archival or fresh biopsy tissue 
from screen-failure subjects, used for central testing of GCB-DLBCL or EZH2 mutation 
status, will be retained.  This tissue may be used in the validation of potential diagnostic 
assays to detect EZH2 mutations and/or for GCB-DLBCL subtyping.
The availability of archived tissue (or willingness to undergo fresh biopsy) is required for 
all screened lymphoma subjects for determination of EZH2 mutation status, and/or GCB-
subtype of DLBCL subjects.
A tumor biopsy at progression for biomarker research is recommended for all subjects.
For Part 1 PK/PD cohorts, pre-treatment and post-treatment tumor biopsies will be 
initially optional.  At MTD, mandatory collection of pre- and post-treatment tumor 
biopsies will be required for further enrollment of subjects in a PK/PD cohort.  
Mandatory biopsies may be instituted: at lower dose levels once evidence of target 
engagement has been demonstrated in surrogate tissue (H3K27me3 from PBMCs in 
blood); or if sufficient evidence of target engagement (e.g. dose dependence) is not 
observed in PD assay from surrogate tissue.  Optional tumor biopsies may be requested 
for all or a portion of subjects in Part 2. Subjects for whom biopsies are not feasible will 
be eligible for enrollment and participation in study at the discretion of the GSK medical 
monitor.  Contact GSK medical monitor for confirmation of enrollment and study entry if 
biopsies are not feasible.
A tumor biopsy at progression for biomarker research is recommended for all subjects.
Further details on sample requirements and collection will be provided in the SPM.
Section 7.6.6 Blood collection
REVISED TEXT
Blood samples will be collected at multiple time points from all subjects on study (Parts 1 
and 2) for pharmacodynamic and exploratory biomarker testing (Section 7.1).
A change in frequency of blood biomarker sampling times may be implemented based on 
emerging data.  This would be determined by GSK and documented in formal 
communication to sites for implementation but would not require a protocol amendment.
Further details on sample requirements and collection will be provided in the SPM.


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Section 7.7
Evaluation of Anti-Cancer Activity
Rationale for Change: Clarifiations to the timing of disease assessments and Response 
Criteria to be used per tumor types. Added response criteria for subjects enrolled with 
prostate cancer.
REVISED TEXT
Disease assessment may include imaging and physical examination (as indicated for 
palpable/superficial lesions). Refer to Appendix 4 for more details on response 
assessment criteria. 

Disease assessment for lymphomas will be completed within 4 weeks of first dose 
of GSK2816126 and repeated 8 weeks after dosing is initiated, every 12 weeks 
thereafter, and at the final study visit. 

Disease assessment for solid tumors will be completed withinat 48 weeks of first 
dose of GSK2816126 and repeated every 8 weeks after dosing is 
initiatedthereafter, and at the final study visit. 

Disease assessment for MM will be completed within 4 weeks of first dose of 
GSK2816126, week 4 and repeated every 6weeks thereafter.  
Section 7.7
Evaluation of Anti-Cancer Activity
REVISED TEXT
For subjects with NHL, the following B symptoms should be assessed at the time points 
in the Time and Events Table (Section 7.1): 

night sweats without signs of infection

unintentional weight loss of ≥10% within the previous 6 months

recurrent, unexplained fever of greater than 38oC for 2 weeks without signs of 
infection
If a lymphoma subject had involvement of bone marrow at baseline, and a CR is 
suspected, a bone marrow biopsy must be obtained as described in Section 7.2.1. A repeat 
bone marrow biopsy will be performed within 8 weeks of the imaging confirmed CR in 
accordance with the response guidelines. (SeeAppendix 4: Section 15.4 for additional 
details). 
Tumor response will be assessed as outlined above and in the Time and Events Schedule 
by the investigator using:

Lymphoma Subjects: Revised Response Criteria for Malignant Lymphoma 
(RRCLM)(Appendix 4)

Solid Tumor RECIST 1.1 (Appendix 5)


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
Multiple Myeloma: International Myeloma Working Group (IMWG) 
(Appendix 6)

Prostate: RECIST 1.1 and PSA (Appendix 7)
Section 7.8
Genetic Research
REVISED TEXT
The information regarding genetic research is included in Appendix 8 Appendix 6.
Section 8.3.1 Liver Chemistry Stopping Criteria
Rationale for Change: The Liver Events section was reorganized with updated tables and 
figures. Stopping/monitoring criteria for subjects with baseline ALT ≤2.5xULN have not 
changed. Stopping/monitoring criteria rules were further clarified for subjects with 
documented liver metastases/tumor infiltration at baseline and entry criteria 
ALT>2.5xULN but ≤5xULN.  Study treatment restart/rechallange criteria was added. 
Details moved to Appendix 3.
REVISED TEXT
Liver chemistry threshold stopping criteria have been designed to assure subject safety 
and to evaluate liver event etiology during administration of study treatment(s) and the 
follow-up period (in alignment with the FDA premarketing clinical liver safety 
guidance).  Study treatment(s) will be stopped if any of the following liver chemistry 
stopping criteria is/are met:
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid
ances/UCM174090.pdf
See Figure 1 and Figure 2 for liver stopping criteria for subjects without and with liver 
metastases, respectively. The algorithms are best read from left to right.


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Figure 1
Phase I/II Liver Chemistry Stopping and Increased Monitoring 
Algorithm for Subjects WITH entry criteria ALT ≤2.5xULN
Liver Safety Required Actions and Follow up Assessments Section can be found in 
Appendix 3


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Figure 2
Phase I/II Liver Chemistry Stopping and Increased Monitoring 
Algorithm including Subjects WITH documented liver metastases/tumor 
infiltration at baseline AND entry criteria ALT>2.5xULN but ≤5xULN
Liver Safety Required Actions and Follow up Assessments Section can be found in 
Appendix 3
Section 8.3.1.1
Study Treatment Restart or Rechallenge
If subject meets liver chemistry stopping criteria do not restart/rechallenge subject with 
study treatment unless:

GSK Medical Governance approval is granted

Ethics and/or Institutional Review Board (IRB) approval is obtained, if 
required, and

Separate consent for treatment restart/rechallenge is signed by the subject
Refer to Appendix 3 for full guidance

ALT 3 times ULN and bilirubin 2 times ULN (or ALT 3 times ULN and 
INR >1.5)
NOTE: Serum bilirubin fractionation should be performed if testing is available.  If 
fractionation is unavailable, urinary bilirubin is to be measured via dipstick (a 
measurement of direct bilirubin, which would suggest liver injury).


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
ALT 5 times ULN.

ALT 3 times ULN if associated with the appearance or worsening of rash or 
hepatitis symptoms (fatigue, nausea, vomiting, right upper quadrant pain or 
tenderness or jaundice) or hypersensitivity (such as fever, rash or eosinophilia).

ALT 3 times ULN persists for 4 weeks.

ALT 3 times ULN and cannot be monitored weekly for 4 weeks.
Subjects with ALT 3 times ULN and <5 times ULN and bilirubin <2 times ULN, 
who do not exhibit hepatitis symptoms or rash, can continue study treatment(s) as 
long as they can be monitored weekly for 4 weeks.  See following section for details 
on weekly follow-up procedures for these subjects.
Liver Chemistry Follow-up Procedures
Refer to the diagram in Appendix 3 for a visual presentation of the procedures listed 
below.
The procedures listed below are to be followed if a subject meets the liver chemistry 
stopping criteria defined in Section 8.3.1:
Immediately and permanently withdraw the subject from study treatment. 
Notify the GSK Medical Monitor within 24 hours of learning of the abnormality to 
confirm the subject’s study treatment(s) cessation and follow-up.
Complete the “Safety Follow-Up Procedures” listed below.
Complete the liver event eCRFs.  If the event also meets the criteria of a SAE (see 
Section 8.2) the SAE data collection tool will be completed separately with the 
relevant details.
Upon completion of the safety follow-up permanently withdraw the subject from the 
study and do not rechallenge with study treatment(s).
Safety Follow-Up Procedures for subjects with ALT 3 times ULN:
Monitor subjects weekly until liver chemistries (ALT, AST, alkaline phosphatase 
[ALP], and bilirubin) resolve, stabilize or return to within baseline values.
Safety Follow-Up Procedures for subjects with ALT 3 times ULN and bilirubin 
2 times ULN (or ALT 3 times ULN and INR >1.5):
This event is considered an SAE (see Section 8.2). Serum bilirubin fractionation 
should be performed if testing is available.  If fractionation is unavailable, urinary 
bilirubin is to be measured via dipstick (a measurement of direct bilirubin, which 
would suggest liver injury).
Make every reasonable attempt to have subjects return to the clinic within 24 hours 


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for repeat liver chemistries, additional testing, and close monitoring (with specialist 
or hepatology consultation recommended).
Monitor subjects twice weekly until liver chemistries (ALT, AST, alkaline 
phosphatase, bilirubin) resolve, stabilize or return to within baseline values.
In addition, for all subjects with ALT 3 times ULN, every attempt must be made to 
also obtain the following:

Viral hepatitis serology including:
o
Hepatitis A Immunoglobulin M (IgM) antibody.
o
Hepatitis B surface antigen and Hepatitis B Core Antibody.
o
Hepatitis C RNA.
o
Cytomegalovirus IgM antibody.
o
Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, obtain 
heterophile antibody or monospot testing).
o
Hepatitis E IgM antibody (if subject resides outside the United States (US) or 
Canada, or has traveled outside US or Canada in past 3 months).

Blood sample for PK analysis, obtained within 96 hours of last dose.  Record the 
date/time of the PK blood sample draw and the date/time of the last dose of study 
treatment(s) prior to blood sample draw on the eCRF.  If 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 included in the SPM.

Serum creatine phosphokinase and lactate dehydrogenase.

Fractionate bilirubin, if total bilirubin 2 times ULN.

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, on the AE eCRF.

Record use of concomitant medication(s), acetaminophen, herbal remedies, other 
over-the-counter medication(s), or putative hepatotoxins on the Concomitant 
Medications eCRF.

Record alcohol use on the Liver Events eCRF.

The following are required for subjects with ALT 3 times ULN and bilirubin 2 
times ULN but are optional for other abnormal liver chemistries:

Anti-nuclear antibody, anti-smooth muscle antibody, and Type 1 anti-liver kidney 
microsomal antibodies.

Liver imaging (ultrasound, MRI or CT scan) to evaluate liver disease.

Liver Imaging and/or Liver Biopsy eCRFs are also to be completed if these tests are 
performed.


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
Serum acetaminophen adduct HPLC assay (quantifies potential acetaminophen 
contribution to liver injury in subjects with definite or likely acetaminophen use in 
the preceding week [James, 2009]).
Only in those with underlying chronic hepatitis B at study entry (identified by positive 
hepatitis B surface antigen):  quantitative hepatitis B DNA and hepatitis delta antibody.  
NOTE:  if hepatitis delta antibody assay cannot be performed, it can be replaced with a 
PCR of hepatitis D RNA virus (where needed) – as outlined in: .
Rationale for Change: Removal of section as there have been no pre-defined disease-
related events.
Section 8.4
Disease-Related Events and/or Disease-Related Outcomes Not 
Qualifying as SAEs
An event which is part of the natural course of the disease under study (i.e., disease 
progression or hospitalization due to disease progression) does not need to be reported as 
a SAE.  Death due to disease under study is to be recorded on the Death eCRF.  
However, if the underlying disease (i.e., progression) is greater than that which would 
normally be expected for the subject, or if the investigator considers that there was a 
causal relationship between treatment with study treatment(s) or protocol design or 
procedures and the disease progression, then this must be reported as a SAE.
Section 9.1
Permitted Medications
Rationale for Change; The section was updated to clarify permitted medications for use 
during the study.
REVISED TEXT
Subjects should receive full supportive care during the study, including transfusions of
blood and blood products, and treatment with antibiotics, antiemetics, antidiarrheals, and 
analgesics, and other care as deemed appropriate and in accordance with their 
institutional guidelines and considering the list of contra-indicated medicines included in 
Section 9 of the protocol.
Palliative radation and/or surgical intervention is permitted after discussion with the GSK 
medical monitor and documenting the treatment in the eCRF. 
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 


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be permitted (for example to address pain management) and should be discussed with the 
GSK medical monitor prior to intervention to determine appropriate dosing and schedule. 
The only caveat is that subjects should not receive those medications listed as prohibited 
in Section 9.2
Questions regarding concomitant medications should be directed to the GSK Medical 
Monitor for clarification.
Section 9.2
Prohibited and Ccautionary Mmedications
Rationale for Change; Section 9.2, Section 9.3 and Section 9.4 were  updated with most 
recent drug interaction data, including updating the prohibited and cautionary medication 
tables. Use of therapeutic warfarin was clarified and additional monitoring for bleeding 
added. Use of anticoagulants that do not have reversal agents available were included as 
prohibited. Based on review of QTc data from the study with the GSK co-chairs of the 
QT panel and Global Safety Board, it was agreed that the restriction on the administration 
of drugs possibly associated with Torsade de Pointes could be relaxed and will be 
included as medications to be used with caution (Table 14). Additional ECG assessments 
will be recommended when these medications are initiated after Cycle 1. Exclusion and 
withdrawal criteria for cardiac monitoring will remain as stated in the protocol (e.g., 
patients with a QTc > 450 msec are excluded from entry and patients > 500 msec will be 
withdrawn as dictated by the protocol).
REVISED TEXT
Subjects should not receive those medications listed as prohibited in Section 9.2
Subjects should not receive other anti-cancer therapy, (including chemotherapy, radiation 
therapy, immunotherapy, biologic therapy, investigational therapy,and hormone therapy 
(other than leuprolide or other GnRH angonists for mCRPC), surgery or tumour 
embolizationother than for replacement) 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. Subjects should not receive any other investigational anti-cancer drugs within 28 
days or five half-lives, whichever is shorter with a minimum of 14 days, preceding the 
first dose of GSK2816126.
Warfarin used for therapeutic doses of anticoagulation is Concurrent use of therapeutic 
warfarin may be allowed. However, increased monitoring of INR and bleeding with dose 
titration for warfarin is recommended due to potential increase in warfarin concentration 
when administered with study treatment GSK2816126. Anticoagulants that do not have 
reversal agents available are prohibitedPROHIBITED from 14 days prior to the first dose 
of study drug through completion of the Final Study Visit.  Prophylactic warfarin (e.g., to 
maintain central venous access patency) is permitted.  


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Section 9.2.1 Drugs that may alter the Pharmacokinetics of GSK2816126
It has been demonstrated in vitro that GSK2816126 is metabolized by CYP3A enzymes., 
hHoowever, turnover in human liver microsomes and hepatocytes was low and the 
relative contribution of this pathway to the elimination of GSK2816126 is presently 
unknown. GSK2816126 has also been shown to be a substrate of P-gp and BCRP 
transporters. and may be a substrate for OATP transporters.
Therefore, substances that potently inhibit or induce CYP3A, P-gp or BCRP or OATP 
(Table 9) should be avoided during the course of the study where possible as these drugs 
could lead to higher/lower exposure in subjects, potentially leading to alterations of the 
pharmacologic effects of GSK2816126.  
The impact of inhibition of P-gp or BCRP onby GSK2816126 pharmacokinetics has not 
been assessed in humans. Drugs that are mild to moderate inhibitors of P-gp and BCRP 
should be administered with caution because they may alter GSK2816126 levels (Table 
10).
Table 9
Prohibited Drugs Potentially Affecting GSK2816126 
Pharmacokinetics Resulting in Increased or Decreased GSK2816126 Exposure
PROHIBITED – strong inducers/inhibitors of CYP3A, CYP2C8, Pgp, Bcrp, or OATP since levels of 
GSK2816126 may be decreased/increased
Strong CYP2C8/3A/Pgp/Bcrp Inhibitor/Inducer
Therapeutic Area
clarithromycin, telithromycin, rifamycin class agents
(e.g.  rifampin, rifabutin, rifapentine) troleandomycin
Antibiotics
itraconazole, ketoconazole
Antifungals
Nefazodone
Antidepressants
Amprenavir, atazanivir delaviridine, fosamprenavir 
indinavir, lopinavir,nelfinavir, ritonavir, saquinavir, 
tipranivir
Antiretrovirals, Protease Inhibitors
Gemfibrozil 
Hyperlipidemia
carbamazepine, cyclosporine, phenobarbital, 
amiodarone
Miscellaneous


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Table 10
Use with Caution Drugs Potentially Affecting GSK2816126 
Pharmacokinetics Resulting in Increased or Decreased GSK2816126 Exposure
USE WITH CAUTION – Potential for Inducers/inhibitors of CYP3A, CYP2C8, Pgp and BCRPcrp since 
levels of GSK2816126 may be decreased/increased
Mild/Moderate CYP3A or Pgp Inhibitor/Inducer
Therapeutic Area
erythromycin
Antibiotic
fluconazole, voriconazole
Antifungal
diltiazem, verapamil
Antiarrhythmics
Cortisone (>50 mg), hydrocortisone (>40 mg), 
prednisone or prednisolone (>10 mg), 
methylprednisolone or triamcinolone (>8 mg), 
betamethasone or dexamethasone (>1.5 mg)
Glucocorticoids (oral)
aprepitant, cimetidine, montelukast, 
Miscellaneous
2.
NOTE:  Topical or inhaled steroids are permitted.
Section 9.3
Drugs that may have their Pharmacokinetics altered by GSK2816126
REVISED TEXT
The potential for pharmacokinetic interactions with drugs likely to be co-administered 
with GSK2816126 in vivo has not been assessed. In vitro data suggests that GSK2816126 
has the potential to inhibit CYP2C8, CYP2C9, CYP2C19, and CYP3A (IC50’s <9 µM). 
GSK2816126 does not appear to be an inhibitor of CYP1A2 or CYP2D6. GSK2816126 
is also an in vitro inhibitor of human transporters BCRP, OATP1B1, OATP1B3, OCT2, 
MATE1 and MATE2-K (IC50 values of 21, 13, 34, 2.88, 0.025 and 0.95 M, 
respectively) In addition, GSK2816126 was shown to activate human PXR (EC50 = 6.3 
M) and, therefore, may have the potential to induce CYP enzymes.  A further in vitro 
study showed induction of CYP3A4 mRNA with a calculated EC50 of 4.22-5.43 M and 
Emax of 3.22-16.5-fold.GSK2816126 has also been shown to activate human PXR which 
is known to induce several drug metabolizing enzymes, primarily CYP3A4.  
These results suggest that narrow therapeutic index medications that are substrates of 
CYP2C8, CYP2C9, CYP2C19 and CYP3A4, and/or transporters BCRP, OATP, OCT2, 
MATE1 and MATE2-K should be prohibited as their levels may be increased, and could 
lead to adverse effect (Table 11). Cco-administration of sensitive substrates of these 
CYPs and/or transportersand narrow therapeutic index medications metabolized by 
CYP2C9 should be used with cautionprohibited as their levels may be increased or 
decreased (Table 11Table 12)). Discussion by the PI/staff with the GSK medical 
monitor(s) must occur before use of these drugs.
In addition, narrow therapeutic index medications metabolized by CYP2C8, CYP2C19 
and CYP3A4 should also be prohibited as their levels may be increased or decreased 
(Table 11). However, sensitive medications metabolized by CYP2C8, CYP2C19 and 
CYP3A4 may be administered with caution (Table 12). 


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Table 11
Prohibited Drugs Potentially Affected by GSK2816126
PROHIBITED – highly sensitive and/or low therapeutic index 
CYP3A/CYP2C8/CYP2C9/CYP2C19/OCT2/MATE substrates since levels of these drugs may be 
increased
CYP3A Substrate
Therapeutic Area
alprazolam, diazepam, midazolam, triazolam
Hypnotics and Sedatives
diergotamine, ergotamine, eletriptan
Antimigraine agents
duloxetine, pimozide, buspirone
Antidepressant, Antipsychotics, Antianxiety agents
cyclosporine, sirolimus, tacrolimus
Immunosuppressive agents
astemizole
Antihistamine
sildenafil, tadalafil, vardenafil
Erectile Dysfunction agents
eplerenone
Selective Aldosterone Blockers
tizanidine
Muscle Relaxant
quinidine
Antiarrhythmics
CYP2C8, CYP2C9 and CYP2C19 Substrate
Amiodarone
Antiarrhythmics
Paclitaxel
Anticancer
tolbutamide, nateglinide
amitryptyline, 
Antidiabetic
amitriptyline, clomipramine, imipramine
Antidepressants
phenytoin, s-mephenytoin
Anticonvulsants
Warfarin, acenocoumarol 
Anticoagulant
Cyclophosphamide
Immunosuppressant
OCT2, MATE1, MATE2-K Substrate
Cisplatin
Anticancer
Dofetilide, pilsicainide, procainamide
Antiarrhythmics
Table 12
Use with Caution - Drugs Potentially Affected by GSK2816126
USE WITH CAUTION – Monitor for side effects since levels of these drugs may be increased. 
Consider dose reduction.
CYP2C8/9/19/3A/OATP1B1/OATP1B3 Substrate
Therapeutic Area
felodipine
Calcium Channel Blockers
lovastatin, rosuvastatin, atorvastatin, fluvastatin
HMG-CoA Reductase Inhibitors
oral budesonide
Corticosteroids
fentanyl, alfentanil
Analgesics
Warfarin*, cilostazole
Anticoagulants and Antiplatelets
Rosiglitazone, repaglinide
Antidiabetics
OCT2, MATE1, MATE2-K Substrate
captopril
Anti-Hypertensive
ganciclovir, tenofovir
Antiviral
gabapentin,
Anticonvulsants


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USE WITH CAUTION – Monitor for side effects since levels of these drugs may be increased. 
Consider dose reduction.
certirizine, ranitidine
H2 Blocker
metformin
Antidiabetics
atecegatran metoxil
Anticoagulants
glycopyrronium
Respiratory, COPD
pindolol, triamterene
Antihypertension
varenicline
Others
USE WITH CAUTION – Monitor for loss of efficacy or substitute another medication
Substrates of CYP3A4/CYP2B6 that are affected 
by induction 
Therapeutic Area
ciprofloxacin, levofloxacin, moxifloxacin, gatifloxacin, 
gemifloxacin, doxycycline, chloramphenicol, 
erythromycin
Antibiotics
caspofungin, fluconazole, terbinafine
Antifungals
enalapril, diltiazem, amlodipine, nifedipine, 
nisoldipine
Antihypertensives
amitriptyline, nortriptyline, desipramine, imipramine, 
protriptyline, clomipramine, doxepin
Antidepressants
glipizide, glyburide, tolbutamide, tolazamide, 
chlorpropamide
Antidiabetics
zonisamide, valproate, divalproex
Anticonvulsants
buspirone
Antidepressant, Antipsychotics, Antianxiety agents
buprenorphine, naloxone, naltrexone, nalmefene
Opioid agonist/antagonists
aprepitant, clofibrate, disopyramide, tramadol, 
methohexital, estazolam, galantamine, haloperidol,
leflunomide, solifenacin, sulfasalazine, 
Miscellaneous
*Concurrent use of therapeutic warfarin may be  allowed. Increased monitoring of INR and bleeding with 
dose titration of warfarin is recommended due to potential increase in warfarin concentration when co-
administered with GSK2816126. However, anticoagulants that do not have reversal agents available are 
prohibited
Section 9.4
Drugs and QT prolongation
REVISED TEXT
Co-administration of medications that are known to prolong the QT interval or have aand 
have a possible risk of causing Torsades de Pointes (latest list available on 
www.crediblemeds.org) are PROHIBITED for 5 half-lives of the drug with a minimum 
of 14 days 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 requires the use of 
amiodarone, which should be used as per local clinical guidelines). The medications with 
a risk of torsade de pointes are provided in Table 13.


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Co-administration of medication that are known to prolong the QT interval and have a 
possible risk of causing Torsades de Pointes “possible-torsadogenic medication”are to be 
used with Extreme Caution beginning 14 days prior the first dose of study drug until 
discontinuation from the study. On starting cautionary medications such as in Table 14, 
additional ECG monitoring should be implemented after cycle 1.  Additional ECGs 
should be taken at the next scheduled study visit following the initiation of the “possible-
torsadogenic medication”.  If there are no abnormalities, regular cardiac safety 
monitoring can be resumed per Table 6.  If there are abnormalities, implement additional 
cardiotoxcity monitoring as addressed in Section 3.8.1. and contact GSK Medical 
Monitor.
while the medications with a possible risk of torsade de pointes are provided in Table 14
(but are not limited to): Neither list is all inclusive and subject to change based on 
evolving data. Both tables are taken from the www.crediblemeds.org website available as 
of 09-Jan-2017.  Latest list of medications is available on www.crediblemeds.org 
website.
Questions regarding concomitant medications whould be directed to the GSK Medical 
Monitor.
Table 13
Drugs with known to prolong the QT interval and have a Risk of 
Torsades de Pointes that are not permittedPROHIBITED for Co-Administration 
with GSK2816126
Generic Name
Drug Class
Generic Name
Drug Class
Amiodarone
Anti-arrhythmic
Haloperidol
Anti-psychotic
Anagrelide
Phosphodiesterase 3 
inhibitor
Ibogaine(only on non 
US Market)
Psychedelic
Arsenic trioxide
Anti-cancer
Ibutilide
Anti-arrhythmic
Astemizole 
(Removed from US 
Market)
Antihistamine
Levofloxacin
Antibiotic
Azithromycin
Antibiotic
Levomepromazine(Only 
on Non  US Market)
Antipsychotic
Bepridil (Removed 
from US Market)
Anti-anginal
Levomethadyl acetate
(Removed from US
Market)
Opiate
Chloroquine
Anti-malarial
Levosulpiride (only on 
non US Market)
Antipsychotic
Chlorpromazine
Anti-psychotic / Anti-
emetic
Mesoridazine 
(Removed from US 
Market)
Anti-psychotic
Cilostazol
Phosphodiesterase 3 
inhibitor
Methadone
Opiate
Ciprofloxacin
Antibiotic
Moxifloxacin
Antibiotic
Cisapride 
(Removed from US 
Market)
GI stimulant
Ondansetron
Anti-emetic


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Generic Name
Drug Class
Generic Name
Drug Class
Citalopram
Anti-depressant, SSRI
Oxaliplatin
Antineoplastic Agent
Clarithromycin
Antibiotic
Papaverine HCL (Intra-
coronary)
Vasodilator, Coronary
Cocaine
Local anesthetic
Pentamidine
Antibiotic
Disopyramide
Anti-arrhythmic
Pimozide
Anti-psychotic
Dofetilide
Anti-arrhythmic
Probucol (Removed 
from US Market)
Antilipemic
Domperidone 
(Only oOn non US 
Market)
Anti-nausea
Procainamide (Oral off 
US mkt)
Anti-arrhythmic
Donepezil
Cholinesterase inhibitor
Propofol
Anaesthetic, general
Dronedarone
Anti-arrhythmic
Quinidine
Anti-arrhythmic
Droperidol
Anti-psychotic / Anti-
emetic
Roxithromycin (Only on 
Non US Market)
Antibiotic
Erythromycin
Antibiotic
Sevoflurane
Anesthetic, general
Escitalopram
Anti-depressant, SSRI
Sotalol
Anti-arrhythmic
Flecainide
Anti-arrhythmic
Sparfloxacin (Removed 
from US Market)
Antibiotic
Fluconazole
Antifungal
Sulpiride (Only non US 
Market)
Anti-psychotic, 
atypical
Gatifloxacin 
(Removed from 
Market)
Antibiotic
Sulyopride (Only on 
Non US Market)
Anti-psychotic, 
atypical
Grepafloxacin (Off 
market worldwide)
Antibiotic
Terlipressin (Only on 
non US Market)
Vasoconstrictor
Halofantrine
Anti-malarial
Terfenadine (Removed 
from US Market)
Antihistamine
Thioridazine
Anti-psychotic
Vandetanib
Anti-cancer
Data Source: : www.crediblemeds.org (9 January 2017 27 February 2015)
Table 14
Drugs Known to prolong the QT interval with a Possible Risk of 
Torsades de Pointes that are are Permitted for co-administration with Extreme 
CautionProhibited
Generic Name
Drug Class
Generic Name
Drug Class
Alfuzosin
Alpha1-blocker
Mirabegron
Beta3 adrenergic 
antagonist
Apomorphine
Dopamine agonist
Mirtazapine
Anti-depressant, Tetracyclic
Aripiprazole
Anti-psychotic, atypical
Moexipril/HCTZ
Anti-hypertensive
Atazanavir
Anti-viral
Nicardipine
Anti-hypertensive
Artenimol+piperaqui
ne
Antimalarial
Nilotinib
Kinase inhibitor
Asenapine
Anti-psychotic, atypical
Norfloxacin
Antibiotic
Atomoxetine
Norepinephrine reuptake 
Nortriptyline
Antibiotic


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Generic Name
Drug Class
Generic Name
Drug Class
inhibitor
Bedaquiline
Antibiotic
Ofloxacin
Antibiotic
Bendamustine
Alkylating agent
Olanzapine
Anti-psychotic, atypical
Bortezomib
Proteasome inhibitor
Osimertinib
Tyrsine kinase inhibitor
Bosutinib
Tyrosine kinase inhibitor
Oxytocin
Oxytocic
Buprenorphine
Opioid receptor modulator
Paliperidone
Anti-psychotic, atypical
Capecitabine
Anticancer
Panobinostat
Histone deacetylase 
inhibitor
Ceritinib
Kinase inhibitor
Pasireotide
Somatostatin analog
Clomipreamine
Antidepressant, Tricyclic
Pazopanib
Tyrosine kinase inhibitor
Clozapine
Anti-psychotic, atypical
Perflutren lipid 
microspheres
Imaging contrast agent
Crizotinib
Kinase inhibitor
Perphenazine
Antipsychotic
Cyamemazine 
(cyamepromazine)(
Only on Non US 
Market)
Antipsychotic
Pipamperone (On 
non US Market)
Antipsychotic
Dabrafenib
Anti-cancer
Promethazine
Anti-psychotic / Anti-emetic
Dasatinib
Tyrosine kinase inhibitor
Quetiapine
Anti-psychotic, atypical
Degarelix
Gonadotropin Releasing 
Hormone
Ranolazine
Anti-anginal
Delamanid (Only on 
Non US Market)
Antibiotic
Rilpivirine
Anti-viral
Desipramine
Antidepressant, Tricyclic
Risperidone
Anti-psychotic, atypical
Dexmedetomidine
Sedative
Roxithromycin (On 
non US Market)
Antibiotic
Dihydroartemisinin+
piperaquine
Anti-malarial
Romidepsin
Histone deacetylase 
inhibitor
Dolasetron
Anti-emeticnausea
Saquinavir
Anti-viral
Efavirenz
Antiretroviral
Sertindole (On non 
US Market)
Anti-psychotic, atypical
Eribulin mesylate
Anti-cancer
Solifenacin
Muscle Relaxant
Ezogabine 
(Retigabine)
Anticonvulsant
Sorafenib
Tyrosine kinase inhibitor
Famotidine
H2-receptor antagonist
Sunitinib
Anti-cancer
Felbamate
Anti-convulsant
Tacrolimus
Immunosuppressant
Fingolimod
Sphingosine phospate 
receptor modulator
Tamoxifen
Anti-cancer
Flupentixol (Only on 
Non US Market)
Dopamine 2 and 5HT2a 
antagonist
Telavancin
Antibiotic
Foscarnet
Anti-viral
Telithromycin
Antibiotic
Fosphenytoin
Anti-convulsant
Tetrabenazine 
(Orphan drug in US)
Monoamine Transporter 
Inhibitor
Gatifloxacin 
(Removed from US 
Market)
Antibiotic
Tiapride (Only on 
Non US Market)
Selective D2, D3 dopamine 
antogonist
Gemifloxacin
Antibiotic
Tizanidine
Muscle relaxant
Granisetron
Anti-emeticnausea
Tolterodine
Muscle relaxant
Hydrocodone-ER
Analgesic
Toremifene
Estrogen 
agonist/antagonist


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Generic Name
Drug Class
Generic Name
Drug Class
Iloperidone
Anti-psychotic, atypical
Trimipramine
Antidepressant, Tricyclic
Imipramine 
(melipramine)
Antidepressant, Tricyclic
Tropisetron (only on 
Non US Market)
Antiemetic
Isradipine
Anti-hypertensive
Vardenafil
Phosphodiesterase inhibitor
Lapatinib
Anti-cancer
Vemurafenib
Kinase Inhibitor
Lenvatinib
Anticancer
Venlafaxine
Anti-depressant, SNRI
Leuprolide
Gonadotropin Receptor 
Anonist
Vorinostat
Anti-CancerHistone 
deacetylase inhibitor
Lithium
Anti-mania
Zipracidone
Anti-psychotic, atypical
Melperone (Only on 
Non US Market)
Antipsychotic, atypical
Zotepine (Only on 
Non US Market)
Anti-psychotic, atypical
Mifepristone
Progesterone antagonist
Data Source: : www.crediblemeds.org (27 February 
20159 January 2017)
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. Intravenous administration of 
these drugs are not permitted. 
Section 10.1.1Female Subjects
Rationale for Change: Update to reflect current GSK guidance and document standards 
and to align with Inclusion criteria. 
REVISED TEXT
A female of non-childbearing potential is defined as:

Post menopausal women (including all women 60 years of age or older) with 1 
year without menses with an appropriate clinical profile (e.g. age appropriate, 
>45 years) in the absence of hormone replacement therapy (HRT) or medical 
suppression of the menstral cycle (e.g. leuprolide treatment). In questionable 
cases for women <60 years of age, a blood sample with simultaneous follicle 
stimulating hormone (FSH) and estradiol falling into the central laboratory’s 
post-menopausal reference range is confirmatory [Kronenberg, 2008; Strauss and 
Barbieri, 2004].  Females under 60 years of age, who are on hormone 
replacement therapy (HRT) and whose menopausal status is in doubt, will be 
required to use one of the contraceptive methods listed below 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 2-4 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 


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HRT during the study without use of a contraceptive method.  If laboratory 
values for FSH and estradiol are drawn and the results do not confirm menopause 
on a potential subject that otherwise met the specifications for being post 
menopausal as defined below without question, the subject may still enroll in the 
study as a female of non-childbearing potential if approved by the medical 
monitor and the safety physician..

Females under 60 year of age with a documented bilateral tubal ligation or 
salpingectomy, hysteroscopic tubal occlusion procedure with follow up 
confirmation of bilateral tubal occlusion, hysterectomy or bilateral oophorectomy 
(surgical menopause) and no plans to utilize assisted reproductive techiniques 
(e.g., in vitro fertilization or donor embryo transfer).
(i.e., physiologically incapable of becoming pregnant) is defined as any female who has 
had a hysterectomy, bilateral oophorectomy (ovariectomy) or bilateral tubal ligation, or is 
post-menopausal. 
A practical definition accepts menopause after 1 year without menses with an appropriate 
clinical profile, e.g., age appropriate, >45 years in the absence of hormone replacement 
therapy (HRT).  In questionable cases, the subject must have a follicular stimulating 
hormone (FSH) value >40 mIU/mL and an estradiol value <40 pg/mL (<140 pmol/L).
A female of childbearing potential is defined as any female who does not meet the 
criteria of non-childbearing potential as described in the previous paragraph and to also 
include:

Females with functioning ovaries (i.e. post menarche, premenopausal women with 
no documented impairment of oviduct or uterine function that would cause 
sterility).

Females with oligomenorrhea, females who are peri-menopausal and young 
females who have begun to menstrusate.
Female subjects of childbearing potential must not become pregnant during the study and 
so must be sexually inactive by abstinence or use non-hormonal contraceptive methods 
with a failure rate of <1%  per year  when used consistently and correctly and , when 
applicable, in accordance with the product label.  These are defined below.
Requirements for Female Subjects of Reproductive Potential:  Contraceptive 
Methods with a Failure Rate of <1% per year:

GSK2816126 is a potential CYP3A enzyme inducer which may decrease the efficacy 
of oralhormonal contraceptives.  Therefore the use of oralhormonal contraceptives is 
excluded except when used with the double barrier method.

Oral contraceptives alone are not adequate in use with this compound.

Contraceptive subdermal implant


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
Double-barrier method: condom and occlusive cap (diaphragm or cervical/vault 
caps) plus vaginal spermicidal agent (foam/gel/film/cream/suppository). 

Estrogenic vaginal ring if not contraindicated for this subject population or per local 
practice. 

Percutaneous contraceptive patches if not contraindicated for this subject population 
or per local practice. Implants of levonorgestrel if not contraindicated for this subject 
population or per local practice.  Injectable progesterone if not contraindicated for 
this subject population or per local practice.

Non-hormonal iIntrauterine 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 and/or semen analysis of the subject or 
review of the subject's medical history for study eligibilityor medical history 
interview provided by the subject or her partner., 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.
Section 10.1.2Male Subjects
Rationale for Change: Update to reflect current GSK guidance and document standards 
and to align with Inclusion criteria. 
REVISED TEXT
To prevent pregnancy in a female partner or to prevent exposure of any partner to the 
study treatment from a male subject’s semen, male subjects must use one of the following 
contraceptive methods from the time of first dose of study medication until at least 
2 weeks (14 days) following last dose of study medication:

Vasecetomy with documentation of azoospermia or bilateral orchiectomy.  The 
documentation on male sterility can come from the site personnel’s; review of 
subjects medical records, medical examination and/or semen analysis, or medical 
history interview provided by the subject or his partner.

Abstinence from penile-vaginal intercourse, 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.


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
Complete abstinence from sexual intercourse for 14 days prior to first dose of study 
treatment, through the dosing period, and for at least one week after the last dose of 
study treatment.

Male cCondom plus partner use of a highly effective contraceptive (< 1% rate of 
failure per year as stated in the product label) 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. (during non-vaginal intercourse with 
any partner - male or female) OR

Double-barrier method: condom and occlusive cap (diaphragm or cervical/vault 
caps) plus spermicidal agent (foam/gel/film/cream/suppository) (during sexual 
intercourse with a female)
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.
Section 10.4
Sun and UV Exposure Restrictions
Rationale for Change: Clarified the time period subjects should minimize exposure to 
sunlight.
REVISED TEXT
Prior to starting study drug, subjects should be instructed to follow the below procedures 
from the time of first dose of study medication until at least 2 weeks (14 days) following 
last dose of study medication due to long elimination phase of GSK2816126:

Minimize or avoid prolonged exposure to natural or artificial sunlight
(e.g., tanning beds, sunlamps, UVA or UVB treatments)

Wear loose fitting clothing with long sleeves, sunglasses, and broad rim hat that
protect the skin from sun exposure AND use a broad spectrum sunscreen (e.g.,
UVA and UVB protective with minimum SPF 30) on any uncovered areas of the
body if outdoors
Section 12.1.1Part 1: Dose-Escalation Phase
Rationale for Change: Updated Section 12 to include - GCB-DLBCL cohort expansion 
added into Part 1 dose escalation phase. The study design was based on predictive 
probability methodology (Lee, 2008) to allow interim futility/efficacy assessment by 
comparing the overall responses with the pre-specified futility and efficacy stopping 
criteria, in order to enabling early decision of opening Part 2 expansion phase or 
terminating the trial.  Due to the improvement of response rates of cancer treatments over 
time, the study designs in Part 2 expansion phase based on predictive probability method 
were revised by updating the null and alternative hypothesis, to align with the current 
typical response rates. The sample size and futility stopping criteria for each cohort 
(GCB-DLBCL mutant and wild type, tFL mutant and wild type, and MM) are updated


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REVISED TEXT
No formal statistical hypotheses are being tested in Part 1.  Analysis of the data obtained 
from Part 1 will only utilize descriptive methods.
No formal statistical hypotheses are being tested for the dose escalation in Part 1. 
Analysis of the data obtained from dose escalation of Part 1 will utilize descriptive 
methods only. 
The cohort expansion of GCB-DLBCL subjects in Part 1 will assess the overall response 
rate (p) of GCB-DLBCL patients. The null and alternative hypotheses for the overall 
response rate are detailed below:
The null hypothesis is:
H0: p≤20%
The alternative hypothesis is:
HA: p≥40%
For cohort expansion of solid tumor subjects in Part 1, there is no formal statistical 
hypothesis are being tested. Analysis of the data obtained from solid tumor expansion 
will utilize descriptive methods only. 
Section 12.1.2Part 2: Expansion Cohorts
REVISED TEXT
The null hypothesis and alternative hypothesis for the four expansion cohorts of GCB-
DLBCL and tFL patients in Part 2 are same as those in Part 1. That is, for each cohort:
The null hypothesis is:
H0: p≤20%
The alternative hypothesis is:
HA: p≥40%
For MM cohort, the null hypothesis is:
H0: p≤10%
The alternative hypothesis is:
HA: p≥25%


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For Part 2, hypothesized response rates are provided in Section 12.2.2. In this case, a test 
that the response rate is less than or equal to the null hypothesis rate is being performed 
using the stopping rules provided in Section 3.4.  Descriptive statistics will be used to 
describe the observed response rates at the RP2D dose used in the expanded cohorts.
Section 12.2
Sample Size Determination
REVISED TEXT
The sample size planned for Part 1 arises from the predefined criteria for dose selection 
and is not driven by statistical considerations. 
In addition, Part 1 expansion may include up to 27 GCB-DLBCL subjects at MTD/RP2D 
twice-weekly for 3 out of 4 weeks followed by 1 week off. This will allow 
futility/success analysis with type I error rate no more than 0.1and at least 80% of power. 
Additionally, 15 subjects with solid tumors or prostate cancer may be enrolled for the 
evaluation of safety, futility and efficacy. 
The additional 129 168 subjects in Part 2 of the study (which includes approximately 
30up to 32 subjects each for the EZH2 mutant and EZH2 WT GCB-DLBCL populations, 
and 16 subjects each for the up to 32 subjects each for EZH2 mutant and EZH2 WT tFL 
populations as well as up to 3740 MM subjects) will provide additional safety and 
tolerability information about the treatment and a better precision around the response 
rate estimate.
Approximately 168 subjects will be enrolled in Part 2 in five expansion cohorts: two 
GCB-DLBCL cohorts with up to 32 subjects from the EZH2 wild-type population, and 
up to 32 subjects from the EZH2 mutation positive population, and two tFL cohorts with 
up to 32 subjects from the EZH2 wild-type population and up to 32 subjects from the 
EZH2 mutation positive population and up to 40 subjects in the MM cohort.  Additional 
subjects/cohorts may be enrolled to allow for evaluation of additional dose levels. 
Section 12.2.1Part 1: Dose-Escalation Phase
REVISED TEXT
12.2.1.1
Dose Escalation in Part 1
The total number of subjects to be enrolled for dose escalation in Part 1 will depend on 
the number of subjects needed to characterize individual dose cohorts. The sample size is 
not driven by statistical considerations. However, it is anticipated that approximately 
40 subjects will be enrolled.  Given true incidence rates of DLTs, the associated 
probabilities of escalating to the next dose in a 3+3 scheme are provided for reference 
below in Table 15.


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Table 15
Statistical Basis for Phase I Dose Escalation in a 3+3 Scheme
True incidence of dose-limiting toxicity
10%
20%
30%
40%
50%
60%
Probability of escalating the dose
0.91
0.71
0.49
0.31
0.17
0.08
Section 12.2.1.2
Cohort Expansion in Part 1
For GCB-DLBCL expansion cohort in Part 1, futility and efficacy evaluation of response 
data will be performed in order to support the early decision of Part 2 expansion. The 
sample size and stopping rules are based on the predictive probability methodology of 
Lee & Liu [Lee, 2008]. The predictive probability design is similar to a two-stage design 
in that it allows for early termination of the trial due to either futility or efficacy.  The 
differences are that the predictive probability design allows for evaluation of stopping 
rules on an on-going basis, once a minimum number of subjects are evaluable, rather than 
at only two stages. While the two designs have comparable type I error rates and power, 
the probability of early termination is greater with the predictive probability design 
compared with two-stage design.
The detailed decision rules of the design for Part 1 expansion cohort are listed in Table 
16. The decision rules to stop the trial for either futility or efficacy were constructed as 
follows:

If Predictive probability of response greater than the null hypothesis<θL, then stop the 
trial and reject the alternative hypothesis (i.e., claim futility); and 

If Predictive probability of response greater than the null hypothesis >θU, then stop 
the trial and reject the null hypothesis (i.e., declare efficacy);

Otherwise continue enrollment,
Where θL and θU are prespecified lower and upper limit of probabilities for establishing 
stopping criteria in terms of futility and efficacy, respectively.
The hypothesis of overall response rate (p) of GCB-DLBCL subjects for the cohort 
expansion design are detailed below. 
The null hypothesis is:
H0: p≤20%
The alternative hypothesis is:
HA:p≥40%
As listed in Table 16, the futility/efficacy evaluation will start with 13 subjects and allow 
for maximum of 27 subjects (including GCB-DLBCL subjects enrolled at the RP2D in 
the dose escalation phase.) This design will have a type I error rate () of 0.087 and a 


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power of 0.803.  In this particular expansion part, the trial is designed to allow stopping 
for both futility and efficacy.  The trial may be stopped early for futility if the predictive 
probability of the overall response rate greater than the null hypothesis of 20%  is very 
low, i.e.below 5.0% for this design, and may be stopped early for efficacy if the 
predictive probability of the overall response rate greater than 20%  is very high, i.e. 
90.0% or above.  The type I error rate, power, and predictive probability of success were 
derived by explicitly stating null and alternative hypothesis of response rate, the 
minimum and maximum sample size, futility and efficacy stopping boundaries and the 
selection of the optimizing criterion as the maximization of power under the alternative 
hypothesis.  The Bayesian prior used in determining the design was Beta (0.15, 0.85), a 
distribution with a mean response rate of 15%.  Under the null hypothesis, that is, if the 
true response rate is 20%, the expected sample size of the design is 16.48 subjects and 
probability of early termination (PET) is 96.3%.  Under the alternative hypothesis, that is, 
if the true response rate is at least 40%, the expected sample size of the design is 16.98 
subjects and PET is 94.7%.
The input parameters for finding the design shown in Table 16 are:
Nmin
13
Cohort
1
Nmax
27
theta_Lbegin
0.05
theta_Lend
0.05
theta_Lstep
0.001
theta_Upper
0.9
theta_Tbegin
0.9
theta_Tend
0.9
theta_Tstep
0.001
p_0
0.2
p_1
0.4
Prior a0
0.15
Prior b0
0.85
Type I Error
0.1
Power
0.8


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Table 16
Stopping Rules for GSK2816126 Part 1 GCB-DLBCL Cohort 
Expansion 
No. of Subjects 
Evaluated for Response
Stopping  Criteria [1]
Stop for Futility if No. of 
Responders (CR+PR) Less 
Than or Equal To This 
Number
Declaration of Efficacy if No. 
of Responders (CR+PR) 
Greater Than or Equal To This 
Number
13
2
6
14
2
7
15
2
7
16
3
7
17
3
7
18
3
8
19
4
8
20
4
8
21
5
8
22
5
9
23
5
9
24
6
9
25
6
9
26
7
9
27
8
9
[1]:  The specific criteria for stopping the GCB-DLBCL expansion cohort for futility or efficacy.  For instance, if there are 
20 subjects, then the trial may be stopped for futility if No. of Responders ≤ 4, or Part 2 opened for efficacy if No. of 
Responders ≥8.
Section 12.2.2
Part 2: Expansion Cohort
REVISED TEXT
An initial dose escalation will be used to establish the RP2D for GSK2816126.  Once the 
final dose is confirmed, at least 12 and up to 30 subjects in both GCB-DLBCL mutation 
status cohorts, up to 16 subjects in both tFL mutation status cohorts and up to 37 subjects 
with MM will be enrolled at that dose, using decision rules defined in in Figure 1, Figure 
2 and Figure 3. The sample size and stopping rules are based on the methodology of Lee 
& Liu [Lee, 2008].
Upon completion of cohort expansion in Part 1 and the totality of data supports opening 
Part 2, GCB-DLBCL and tFL patients in both mutation status, as well as patients with 
MM will be enrolled at RP2D for Part 2 study. There are 5 cohorts in Part 2, i.e. 2 cohorts 
for GCB-DLBCL patients (mutant and wild type), 2 cohorts for tFL petients (mutant and 
wild type), and 1 cohort for MM patients.


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For each of GCB-DLBCL and tFL cohorts, at least 10 subjects and up to 32 subjects will 
be enrolled at the RP2D (including subjects enrolled in the previous stage), using 
decision rules defined in Table 17. The sample size and stopping rules are based on the 
methodology of Lee & Liu [Lee, 2008]. 
The assumptions underlying the design are detailed below for both GCB-DLBCL and tFL
cohorts. The null hypothesis is:
H0: p≤2010%
The alternative hypothesis is:
HA:p≥4010%
For GCB-DLBCL cohorts, starting with 12 subjects and allowing for a maximum sample 
size of 30, this design will have a type I error rate () of 0.062 and 88.9% power when 
the true response rate is 30%.  The trial is not designed to stop early for efficacy, but is 
designed to stop early for futility if the predictive probability of success is 5.0% or less.  
The type I error rate, power, and predictive probability of success to stop early for futility 
were derived from explicitly stating the minimum and maximum sample size, futility 
stopping rate and selection of the optimizing criterion as the maximization of power 
under the alternative hypothesis.  The Bayesian prior used in determining the design was 
Beta (0.15, 0.85), a distribution with a mean response rate of 15%.  Under the null 
hypothesis, if the true response rate is 10%, the expected sample size of the design is 18 
subjects per expansion cohort and probability of early termination (PET) is 88.7%.  
Under the alternative hypothesis, if the true response rate is 30%, the expected sample 
size of the design is 29 subjects per expansion cohort and PET is 8.8%.
The assumptions underlying the design are detailed below for both tFL cohorts. The null 
hypothesis is:
H0: p≤5%
The alternative hypothesis is:
HA;p>5%
For tFL cohorts, starting with 12 subjects and allowing for a maximum sample size of 16, 
this design will have a type I error rate () of 0.043 and 80.1% power when the true 
response rate is 25%.  The trial is not designed to stop early for efficacy, but is designed 
to stop early for futility if the predictive probability of success is about 1.0% or less.  The 
type I error rate, power, and predictive probability of success to stop early for futility 
were derived from explicitly stating the minimum and maximum sample size, futility 
stopping rate and selection of the optimizing criterion as the minimization of the power 
under the alternative hypothesis.  The Bayesian prior used in determining the design was 
Beta (0.05, 0.95), a distribution with a mean response rate of 5%.  Under the null 
hypothesis, if the true response rate is 5%, the expected sample size of the design is 14 
subjects per expansion cohort and probability of early termination (PET) is 83.3%.  


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Under the alternative hypothesis, if the true response rate is 30%, the expected sample 
size of the design is 16 subjects per expansion cohort and PET is 8.5%.
As listed in Table 17, the futility/efficacy evaluation will start with 10 subjects and until 
maximum of 32 subjects. This design allows to stop early for futility only. The design 
will have a type I error rate () of 0.066 and a power of 0.801.  The trial may be stopped 
early for futility if the predictive probability of the overall response rate greater than the 
null hypothesis of 20%  is below 10% for this design. The type I error rate, power, and 
predictive probability of success were derived by explicitly stating null and alternative 
hypothesis of response rate, the minimum and maximum sample size, futility and efficacy 
stopping boundaries and the selection of the optimizing criterion as the maximization of 
power under the alternative hypothesis.  The Bayesian prior used in determining the 
design was Beta (0.15, 0.85), a distribution with a mean response rate of 15%.  Under the 
null hypothesis, that is, if the true response rate is 20%, the expected sample size of the 
design is 16.06 subjects and probability of early termination (PET) is 90.8%.  Under the 
alternative hypothesis, that is, if the true response rate is at least 40%, the expected 
sample size of the design is 29.16 subjects and PET is 18.1%.
The input parameters for the design shown in Table 17 are:
Nmin
10
Cohort
1
Nmax
32
theta_Lbegin
0.1
theta_Lend
0.1
theta_Lstep
0.001
theta_Upper
1
theta_Tbegin
0.9
theta_Tend
0.9
theta_Tstep
0.001
p_0
0.2
p_1
0.4
Prior a0
0.15
Prior b0
0.85
Type I Error
0.1
Power
0.8


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Table 17
Stopping Rules for GSK2816126 GCB-DLBCL and tFL Cohort 
Expansion in Part 2
Number of evaluable subjects
Stop for Futility if No. of Responders (CR+PR) Less Than 
or Equal To This Number
10
1
11
1
12
2
13
2
14
2
15
3
16
3
17
3
18
3
19
4
20
4
21
4
22
5
23
5
24
5
25
6
26
6
27
6
28
7
29
7
30
8
31
8
32
9
For MM cohort, at least 14 subjects and up to 40 subjects will be enrolled at the RP2D, 
using decision rules defined in Table 18. The sample size and stopping rules are based on 
the methodology of Lee & Liu [Lee, 2008]. The assumptions underlying the design are 
detailed below for MM subjects. The null hypothesis underlying the design is:
H0: p≤105%
The alternative hypothesis is:
HA; p255%


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The input parameters for the design shown in Table 18 are:
Nmin
14
Cohort
1
Nmax
40
theta_Lbegin
0.1
theta_Lend
0.1
theta_Lstep
0.001
theta_Upper
1
theta_Tbegin
0.9
theta_Tend
0.9
theta_Tstep
0.001
p_0
0.1
p_1
0.25
Prior a0
0.1
Prior b0
0.9
Type I Error
0.1
Power
0.8
Table 18
Stopping Rules for GSK2816126 Cohort Expansion of MM Subjects 
in Part 2
Number of evaluable subjects
Stop for Futility if No. of Responders (CR+PR) Less 
Than or Equal To This Number
14
1
15
1
16
1
17
1
18
1
19
1
20
1
21
2
22
2
23
2
24
2
25
2
26
2
27
3
28
3


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Number of evaluable subjects
Stop for Futility if No. of Responders (CR+PR) Less 
Than or Equal To This Number
29
3
30
3
31
3
32
4
33
4
34
4
35
4
36
4
37
5
38
5
39
5
40
6
As listed in Table 18, the futility/efficacy evaluation will start with 14 subjects until 
maximum of 40 subjects (including MM subjects enrolled at the RP2D in the dose 
escalation phase, if any). This design allows to stop early for futility only. The design will 
have a type I error rate () of 0.072 and a power of 0.814.  The trial may be stopped early 
for futility if the predictive probability of the overall response rate greater than the null 
hypothesis of 10%  is below 10% for this design. The type I error rate, power, and 
predictive probability of success were derived by explicitly stating null and alternative 
hypothesis of response rate, the minimum and maximum sample size, futility and efficacy 
stopping boundaries and the selection of the optimizing criterion as the maximization of 
power under the alternative hypothesis.  The Bayesian prior used in determining the 
design was Beta (0.10, 0.90), a distribution with a mean response rate of 10%.  Under the 
null hypothesis, that is, if the true response rate is 10%, the expected sample size of the 
design is 20.82 subjects and probability of early termination (PET) is 89.0%.  Under the 
alternative hypothesis, that is, if the true response rate is at least 25%, the expected 
sample size of the design is 36.56 subjects and PET is 16.7%.
Starting with 13 subjects and allowing for a maximum sample size of 37, this design will 
have a type I error rate () of 0.032 and about 85% power when the true response rate is 
20%.  The trial is not designed to stop early for efficacy, but is designed to stop early for 
futility if the predictive probability of success is about 1.0% or less.  The type I error rate, 
power, and predictive probability of success to stop early for futility were derived from 
explicitly stating the minimum and maximum sample size, futility stopping rate and 
selection of the optimizing criterion as the minimization of the power under the 
alternative hypothesis.  The Bayesian prior used in determining the design was Beta 
(0.20, 0.80), a distribution with a mean response rate of 20%.  Under the null hypothesis, 
if the true response rate is 5%, the expected sample size of the design is 22 subjects and 
probability of early termination (PET) is 91%. Under the alternative hypothesis, if the 


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true response rate is 20%, the expected sample size of the design is 36 subjects per 
expansion cohort and PET is 10%.
Section 12.3.3.1
Primary Comparisons of Interest
REVISED TEXT
All available data, including adverse events, changes in laboratory values and other safety 
parameters will be evaluated for each dose cohort in Part 1, in addition to futility and 
success analyses, and for each expansion cohort in Part 2.
Section 12.3.4
Interim Analysis
REVISED TEXT
12.3.4.1
Part 1
No formal interim analysis will be performed for Part 1 of the study.  Safety, PK, and PD 
marker data will be examined during Part 1. Prior to determining the GSK2816126 dose 
for the next cohort, exploratory analyses will be conducted to assess the relationship of 
GSK2816126 dose levels with safety, PK and PD parameters using all data from 
available cohorts. 
Futility and efficacy interim analysis of overall response rate will be performed 
continuously for GCB-DLBCL expansion cohort in Part 1 of the study, after 13 subjects 
have been enrolled.  In addition, safety, PK, and PD marker data will be examined during 
Part 1. Prior to determining the GSK2816126 dose for the next cohort, exploratory 
analyses will be conducted to assess the relationship of GSK2816126 dose levels with 
safety, PK and PD parameters using all data from available cohorts. If success criteria are 
reached at an interim analysis for GCB-DLBCL at MTDRP2D twice-weekly every 3 out 
of 4 weeks followed by 1 week off, and the totality of data support opening Part 2, then 
Part 2 will begin and Part 1 expansion will close. 
Full details of procedures and of the analyses planned at the interim analysis will be 
provided in the Reporting and Analysis Plan (RAP).
Section 12.3.4
Interim Analysis
REVISED TEXT
Section 12.3.4.2
Part 2
For each expansion cohort, after the initial 12 10 subjects have enrolled at the RP2D 
dose, response data will be reviewed on an ongoing basis and the number of responses 
observed will be compared with the stopping rules provided in Section 3.412.2.2.. In 


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addition, safety, PK, and PD marker data will be analyzed. Full details of procedures and 
of the analyses planned at the interim analysis will be provided in the Reporting and 
Analysis Plan (RAP).
Section 12.4.1.4
Efficacy Analyses
REVISED TEXT
Anti-tumor activity for lymphoma subjects will be assessed based on the Response 
Criteria listed in Section 15.4.  Anti-tumor activity for subjects with solid tumors will be 
assessed based on the Response Criteria listed in 15.5. Anti-tumor activity for subjects 
with MM will be assessed based on the Response Criteria listed in 15.6.  Anti-tumor 
activity for subjects with prostate cancer will be assessed based on the Response Criteria 
listed in 15.7. The response data will be summarized by study part, and cohort within Part 
2.  Full details will be specified in the RAP.
Section 14
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Rationale for Change: Included new references and reformatted list. Moved references 
for appendices to the appropriate appendix.
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Section 15.3
Appendix 3: Liver Chemistry Monitoring, Interruption Stopping and 
Follow-up Criteria
Rationale for Change: The Liver Events section was reorganized with updated tables and 
figures. Stopping/monitoring criteria for subjects with baseline ALT ≤2.5xULN have not 
changed. Stopping/monitoring criteria rules were further clarified for subjects with 
documented liver metastases/tumor infiltration at baseline and entry criteria 
ALT>2.5xULN but ≤5xULN.  Study treatment restart/rechallange criteria was added. 
Details added to Appendix 3.
REVISED TEXT
Section 15.3.1Liver Safety Stopping Criteria and Required Action 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.


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Phase I/II liver chemistry stopping criteria and required follow up assessments 
Liver Chemistry Stopping Criteria – Liver Stopping Event
Subject with entry criteria ALT≤ 2.5 x ULN
ALT-absolute
ALT 5xULN
ALT Increase
ALT 3xULN persists for 4 weeks
Bilirubin1, 2
ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin) 
INR2
ALT 3xULN and INR>1.5, if INR measured
Cannot Monitor
ALT 3xULN and cannot be monitored weekly for 4 weeks
Symptomatic3
ALT 3xULN associated with symptoms (new or worsening) believed to be related 
to liver injury or hypersensitivity
Liver Chemistry Stopping Criteria – Liver Stopping Event
Including subjects with documented liver metastases/tumor infiltration at baseline AND 
entry criteria ALT>2.5 x ULN but ≤5 x ULN
ALT-absolute
Both ALT 5xULN and 2x baseline value
ALT Increase
Both ALT 3xULN and ≥ 1.5x baseline value that persists for 4 weeks
Bilirubin1, 2
ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin) 
INR2
ALT 3xULN and INR>1.5, if INR measured
Cannot Monitor
Both ALT 3xULN and ≥ 1.5x baseline value that cannot be monitored for 4 weeks
Symptomatic3
Both ALT 3xULN and ≥ 1.5x baseline value associated with symptoms (new or 
worsening) believed to be related to liver injury or hypersensitivity
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

Viral hepatitis serology4

Blood sample for pharmacokinetic (PK) analysis, 
obtained approximately 48h after last dose5

Serum creatine phosphokinase (CPK) and lactate 
dehydrogenase (LDH).


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
Perform liver event follow up assessments 

Monitor the subject until liver chemistries
resolve, stabilize, or return to within baseline 
(see MONITORING below)

Do not restart/rechallenge subject with 
study treatment unless allowed per protocol 
and GSK Medical Governance approval is 
granted (refer to Appendix 3)

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

Fractionate bilirubin, if total bilirubin2xULN

Obtain complete blood count with differential to 
assess eosinophilia

Record the appearance or worsening of clinical 
symptoms of liver injury, or hypersensitivity, on the 
AE report form

Record use of concomitant medications on the 
concomitant medications report form including 
acetaminophen, herbal remedies, other over the 
counter medications

Record alcohol use on the liver event alcohol 
intake case report form
For bilirubin or INR criteria:

Anti-nuclear antibody, anti-smooth muscle 
antibody, Type 1 anti-liver kidney microsomal 
antibodies, and quantitative total immunoglobulin 
G (IgG or gamma globulins).

Serum acetaminophen adduct high pressure liquid 
chromatography (HPLC) assay (quantifies 
potential acetaminophen contribution to liver injury 
in subjects with definite or likely acetaminophen 
use in the preceding week [James, 2009]).

Liver imaging (ultrasound, magnetic resonance, or 
computerised tomography) and /or liver biopsy to 
evaluate liver disease; complete Liver Imaging 
and/or Liver Biopsy eCRF forms.
1.
Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin fractionation is not 
immediately available, discontinue study treatment for that subject if ALT 3xULN and bilirubin 2xULN. 
Additionally, if serum bilirubin fractionation testing is unavailable, record presence of detectable urinary 
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 


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eosinophilia)
4.
Includes: Hepatitis A IgM antibody; Hepatitis B surface antigen and Hepatitis B Core Antibody (IgM); Hepatitis C 
RNA; Cytomegalovirus IgM antibody; Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, obtain 
heterophile antibody or monospot testing); Hepatitis E IgM antibody 
5.
Record the date/time of the PK blood sample draw and the date/time of the last dose of study treatment prior to 
blood sample draw on the eCRF. If the date or time of the last dose is unclear, provide the subject’s best 
approximation. If the date/time of the last dose cannot be approximated OR a PK sample cannot be collected in 
the time period indicated above, do not obtain a PK sample. Instructions for sample handling and shipping are in 
the SRM.
Phase I/II Oncology liver chemistry increased monitoring criteria with continued 
therapy
Liver Chemistry Increased Monitoring Criteria – Liver Monitoring Event
Criteria
Actions
Subject with entry criteria ALT≤2.5x ULN
ALT 3xULN but <5xULN and
bilirubin <2xULN, without symptoms believed 
to be related to liver injury or hypersensitivity 
and who can be monitored weekly for 4 weeks
Subject with documented liver 
metastases/tumor infiltration at baseline 
AND entry criteria ALT>2.5 x ULN but ≤5 x 
ULN
ALT ≥3x ULN and 1.5x baseline value but ALT 
<5x ULN and 2x baseline value and bilirubin 
<2xULN, without symptoms believed to be 
related to liver injury, or hypersensitivity and
who can be monitored weekly for 4 weeks

Notify the GSK medical monitor within 24 hours of 
learning of the abnormality to discuss subject 
safety. 

Subject can continue study treatment

Subject must return weekly for repeat liver 
chemistries (ALT, AST, alkaline phosphatase, 
bilirubin) until they resolve, stabilise or return to 
within baseline1

If at any time subject meets the liver chemistry 
stopping criteria, proceed as described above
For subjects with entry criteria ALT≤2.5 x ULN

If, after 4 weeks of monitoring, ALT <3xULN and 
bilirubin <2xULN, monitor subjects twice monthly 
until liver chemistries normalize or return to within 
baseline.
For subjects with documented liver 
metastases/tumor infiltration at baseline AND entry 
criteria ALT>2.5 x ULN but ≤5 x ULN

If, after 4 weeks of monitoring, ALT <3xULN and 
<1.5x baseline value, and bilirubin <2xULN, monitor 
subjects twice monthly until liver chemistries 
normalize or return to within baseline
1. For the purpose of these guidelines “baseline” refers to laboratory assessments performed closest and prior to first 
dose of study treatment


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References
James LP, Letzig L, Simpson PM, Capparelli E, Roberts DW, Hinson JA, Davern TJ, Lee 
WM. Pharmacokinetics of Acetaminophen-Adduct in Adults with Acetaminophen 
Overdose and Acute Liver Failure. Drug Metab Dispos 2009; 37:1779-1784.
Section 15.3.2
Liver Safety – Study Treatment Restart or Rechallenge 
Guidelines
If subject meets liver chemistry stopping criteria do not restart/rechallenge subject with 
study treatment unless:

GSK Medical Governance approval is granted (as described below),

Ethics and/or IRB approval is obtained, if required, and

Separate consent for treatment restart/rechallenge is signed by the subject
If GSK Medical Governance approval to restart/rechallenge subject with study treatment 
is not granted, then subject must permanently discontinue study treatment and may 
continue in the study for protocol-specified follow up assessments
1.
Rechallenge Following Liver Stopping Events that are Possibly 
Related to Study Treatment
Following drug-induced liver injury, drug rechallenge is associated with a 13% 
mortality across all drugs in prospective studies [Andrade, 2009]. Clinical outcomes 
vary by drug, with nearly 50% fatality with halothane readministered within one month 
of initial injury. However, some drugs seldom result in recurrent liver injury or fatality. 
Risk factors for a fatal drug rechallenge outcome include:

hypersensitivity with initial liver injury (e.g. fever, rash, eosinophilia) 
[Andrade, 2009] 

jaundice or bilirubin >2xULN with initial liver injury (direct bilirubin >35% of 
total)

subject currently exhibits severe liver injury defined by: ALT 3xULN, 
bilirubin 2xULN (direct bilirubin >35% of total), or INR1.5

serious adverse event or fatality has earlier been observed with drug 
rechallenges [Papay, 2009]

evidence of drug-related preclinical liability (e.g. reactive metabolites; 
mitochondrial impairment [Hunt, 2010])
Rechallenge refers to resuming study treatment following drug induced liver injury 
(DILI). Because of the risks associated with rechallenge after DILI this should only be 
considered for a subject for whom there is compelling evidence of benefit from a critical 


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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 
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 8 of the protocol..
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).


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
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. 

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 8.
References:
Andrade RJ, Robles M, Lucena MI. Rechallenge in drug-induced liver injury: the 
attractive hazard. Expert Opin Drug Saf. 2009;8:709-714.
Hunt, CM. Mitochondrial and immunoallergic injury increase risk of positive drug 
rechallenge after drug-induced liver injury: A systematic review. Hepatol. 2010;52:2216-
2222.
Papay JI, Clines D, Rafi R, Yuen N, Britt SD, Walsh JS, et al. Drug-induced liver injury 
following positive drug rechallenge. Regul Tox Pharm. 2009;54:84-90. 
Section 15.4
Appendix 4 Response Criteria
Rationale for Change; included missing criteria for confirmation scans for assigned PR 
and CR.


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REVISED TEXT
Complete Response
To be assigned a status of complete response, all changes must be confirmed by repeat 
assessments performed no less than four weeks after the criteria for CR were met.
1. Complete disappearance of all detectable clinical evidence of disease and disease 
related B-symptoms, if present prior to therapy. 
Partial Response 
To be assigned a status of complete response, all changes must be confirmed by repeat 
assessments performed no less than four weeks after the criteria for PR were met.
1. At least a 50% decrease from baseline in the SPD of up six of the largest 
dominant nodes or nodal masses. 
2. No increase in the size of the liver or the spleen.  No unequivocal progression in 
any nonmeasurable or nondominant site.
3. Splenic and hepatic nodules must regress by ≥50% in SPD compared to baseline. 
If only a single nodule/lesion, it must regress by ≥50% in the greatest transverse 
diameter compared to baseline. 
4. With the exception of splenic and hepatic nodules, involvement of other organs is 
accessible and no measureable disease should be present. 
5. Bone marrow assessment is not relevant for determination of a PR if the sample 
was positive prior to treatment.  However, if positive, the cell type should be 
specified. Subjects who are achieve CR criteria above, except for persistent 
morphologic bone marrow involvement will be considered partial responders. 
When the bone marrow was involved before therapy and a clinical CR was 
achieved, but no bone marrow assessment after therapy, subjects must be 
considered partial responders. 
Relapsed Disease (after CR)/Progressive Disease (after PR, SD)
Criteria for determining PD for new lesions and target lesions are shown in Table 
19Table 16
Table 1619
Criteria for determining PD for new lesions and target lesions
Cheson B, Pfister B, Juweid M, Gascoyne RD, Specht L, Horning SJ, et al. Revised 
response criteria for malignant lymphoma. J Clin Oncol 2007; 25:579-586.


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Section 15.5
Appendix 5: RECIST 1.1
Rationale for Change: Clarified that baseline bone scans are to be taken as clinically 
indicated.
REVISED TEXT
I. Efficacy Assessment

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 (bone scan as clinically indicated). 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.
A baseline bone scan should be performed as clinically indicatedis 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 1 week prior to 4 weeks after.
Section 15.5
Appendix 5: RECIST 1.1
REVISED TEXT
IIIg. Independent Review
Disease progression and response evaluations maywill be collected centrally during the 
study and may be reviewed or analyzed by an independent central reviewer. Details will 
be provided in the SPM.
Chung WH, Hung SL, Chen YT. Genetic predisposition of life-threatening antiepileptic-
induced skin reactions. Expert Opin. Drug Saf. 2010; 9: 15-21.
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).  European Journal of Cancer. 2009; 45: 228-247.


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Section 15.7
Appendix 7: Criteria for Response/Progression: Prostate Cancer 
Rationale for Change: Included criteria for response/progression for prostate cancer.
REVISED TEXT
15.7.1 Disease Progression Endpoint
The disease progression endpoint is defined by 1 or more of the following criteria:

PSA progression according to the PCWG3 criteria 
o
Subjects are not required to discontinue treatment on the basis of meeting 
PSA progression alone.
o
PSA progression [Scher2016] is defined as:

If there has been a decline from baseline: time from start of 
therapy to first PSA increase that is 25% and 2 ng/mL in 
absolute value from the nadir, and which is confirmed by a second 
value 3 or more weeks later (i.e., a confirmed rising trend) at least 
9 weeks after the start of treatment

If there has NOT been a decline from baseline: time from start of 
therapy to first PSA increase that is 25% and 2 ng/mL in 
absolute value from the baseline value, determined at least 9 weeks 
after start of treatment

Radiographic progression  by RECIST 1.1 for subjects with measurable disease. 
(Appendix 5)

Bone progression on bone scan according to the PCWG3 criteria 
o
Bone progression [Scher, 2016] will be determined as the appearance of 
2 new lesions on bone scan and at least an additional 2 bone lesions at 
the next scan (every 8 weeks). The date of progression is the date of the 
first scan that indicates the change. Subjects should not be discontinued 
from study treatment(s) due to the occurrence of bone scan changes in the 
first 12 weeks that do not meet PCWG3 guidelines for progression.
Section 15.7.2
Disease Response Endpoints 

PSA response according to the PCWG3 criteria:
o
Only subjects who have a baseline PSA value and at least one post-
baseline assessment will be included in the analysis of PSA response.
o
PSA Response Rate is defined as proportion of subjects with a decrease of 
50% in the PSA concentration from the baseline PSA value determined 
at least 9 weeks after start of treatment and confirmed after ≥4 weeks by 
an additional PSA evaluation.


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
Radiographic response By Recist 1.1 for subjects with measurable disease 
(Appendix 5).
Scher HI, Morris MJ, Stadler WM, Higano C, Basch E, Fizazi K, et al. Trial design 
and objectives for castration-resistant prostate cancer: updated recommendations from 
the Prostate Cancer Clinical Trials Working Group 3. Journal of Clinical Oncology.
2016; doi: 10.1200/JCO.2015.64.2702.
Section 7.1
Time and Events Table(s)
Rationale for Change: Table 6: Reorganized and added minor clarifications throughout. 
Added footnote to clarify timing of the post treatment Follow Up Visit. Clarified that 
assessments in the Continuation Phase that are to be done every 4 weeks should occur at 
Day 1 of the cycle.  Assessments during the continuation phase that occur less frequent 
(i.e., every 8 weeks) have a 7 day window.  ECOG assessment added to Continuation 
Phase and Follow Up Visit.  Updated requirement that no need to repeat screening labs 
(chemistry, hematology, coagulation) if done within 72 hours of first dose. Added 
clarification for tumor tissue collection for different tumor types. Under PD/PK cohort, 
added collection of blood for metabolite at Cycle 1 Day 1, urine for metabolite 0-24 hour 
collection at Cycle 1 day 1 and 0-8 hour collection at Day 15. Simplified disease 
assessments for prostate cancer. Added clarification to footnotes to support study 
assessments in table 6.
Removed collection of blood for PD (PBMC) biomarkers and added collection of Whole 
Blood for biomarkers at Cycle 1 Day1 and  Day 18 and C2D1(prior to dosing on all 
days).  Recent preclinical data suggests evaluating histone H3 lysine 27 trimethylation 
(H3K27me3) in certain blood cell populations may be a better PD biomarker then 
looking at PBMCs as a whole. To evaluate this, a novel whole blood PD assay was 
developed which allows classification of blood cell populations and quantitation of 
H3K27me3. This assay will replace the PBMC PD ELISA used prior to amendment 5 
and, as such, PBMC samples will no longer be collected


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REVISED TEXT
Table 6
Time and Events, Treatment Phase:  Screening through Day 28 (See also PK sampling table for PK sampling 
schedule on Day 1 and Day 15)
STUDY PHASE
SCREEN
First Treatment Period
Cycle 1
Continuation 
Phase
Cycle 2 and 
beyond
Follo
w-Upj
VISIT
Screen
Day 1 
and 4a
Day 8 
and 11 a
Day 15 
and 18 a
Day 
21 
VISIT WINDOW 
(days)
-14
7l
7l
Assessment (notes)
Informed consent
X
Demographic data
X
Register Record subject using IVRS system
X
X
Height/Weight (Refer to Section 7.3.1)
Measurements 
in metric scale.  
Height 
measured only 
at screening
X
X
Every 
4weeks
(Cycle Day 1)
X


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STUDY PHASE
SCREEN
First Treatment Period
Cycle 1
Continuation 
Phase
Cycle 2 and 
beyond
Follo
w-Upj
VISIT
Screen
Day 1 
and 4a
Day 8 
and 11 a
Day 15 
and 18 a
Day 
21 
VISIT WINDOW 
(days)
-14
7l
7l
Serum pPregnancy test
In females of 
child bearing 
potential, a 
serumi B-HCG
pregnancy test 
is required within 
7 days of first 
dose of study 
drug; urine or 
serumn B-HCG
test thereafter.
X
Every 4 
weeks
(Cycle Day 
1)
X
Disease characteristics (Refer to Section 7.2)
Record date of 
diagnosis, 
primary tumor 
type, histology, 
stage, etc.
X
Prior anti-cancer therapy & radiation
Record date of 
therapies
X
Prior surgical procedures
X
Past and current medical conditions
X
Alcohol consumption
X
Past and current tobacco use
X


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STUDY PHASE
SCREEN
First Treatment Period
Cycle 1
Continuation 
Phase
Cycle 2 and 
beyond
Follo
w-Upj
VISIT
Screen
Day 1 
and 4a
Day 8 
and 11 a
Day 15 
and 18 a
Day 
21 
VISIT WINDOW 
(days)
-14
7l
7l
Safety Assessments (- 1 Day)
Physical examination
X
Day 1
Day 8
Day 15
X
Every 4 
weeks
Cycle Day 1
ECOG PS
See Appendix 
2
X
X
X
X
X
X
X
Vital signs
BP, body 
temperature, 
pulse rate, 
respirations
Cycle 1 Day 1 
vitals should be 
taken at same 
time points as 
PK draws on PK 
Table 7
X
X (Day 
1 PK 
Table 7
)
X
X
X
Prior to each 
infusion
X


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STUDY PHASE
SCREEN
First Treatment Period
Cycle 1
Continuation 
Phase
Cycle 2 and 
beyond
Follo
w-Upj
VISIT
Screen
Day 1 
and 4a
Day 8 
and 11 a
Day 15 
and 18 a
Day 
21 
VISIT WINDOW 
(days)
-14
7l
7l
ECGb
Pre-infusion and at 
the end of 
infusion except on
Day 1 (Section 
7.3.4). Two 
copies of the 
ECG tracing 
should be 
obtained at the 
time of the ECG, 
one to be kept in 
the study file for 
retrospective 
collection by the 
sponsor if 
necessary.  ECG 
data should be
reviewed by 
qualified 
personnel with 
experience in this 
study population 
X
Xb
X
X
On Day 4 of 
each cycle
X


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STUDY PHASE
SCREEN
First Treatment Period
Cycle 1
Continuation 
Phase
Cycle 2 and 
beyond
Follo
w-Upj
VISIT
Screen
Day 1 
and 4a
Day 8 
and 11 a
Day 15 
and 18 a
Day 
21 
VISIT WINDOW 
(days)
-14
7l
7l
Holter Monitoring
Continuous 12-
lead Holter 
ECGs 
(obtained via a 
Holter monitor) 
will be 
acquired for a 
total of 
approximately 
24 hours 
beginning an 
hour before 
infusion on 
Day 1 only  
X
(Day 1)


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STUDY PHASE
SCREEN
First Treatment Period
Cycle 1
Continuation 
Phase
Cycle 2 and 
beyond
Follo
w-Upj
VISIT
Screen
Day 1 
and 4a
Day 8 
and 11 a
Day 15 
and 18 a
Day 
21 
VISIT WINDOW 
(days)
-14
7l
7l
ECHO/MUGA
At Screening 
X
Concomitant medications
See Section 9.2 
for list of 
prohibited and 
cautionary 
medications
X
X
X
X
X
continuous
Every 4 
weeks
X
Adverse events (Refer to Section 8) 
Adverse event 
assessment 
should be 
continuous
X
X
X
X
X
continuous
X


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STUDY PHASE
SCREEN
First Treatment Period
Cycle 1
Continuation 
Phase
Cycle 2 and 
beyond
Follo
w-Upj
VISIT
Screen
Day 1 
and 4a
Day 8 
and 11 a
Day 15 
and 18 a
Day 
21 
VISIT WINDOW 
(days)
-14
7l
7l
Blood Sampling: on dosing days, collect blood samples prior to dosing unless otherwise noted
Chemistry
No need to 
repeat at pre-
dose Day 1 if 
screening 
assessments 
were performed 
within 72 
hours14 days of 
first dose (- 1 
day visit window 
after screening)
X
X
X
X
X
Prior to every 
infusion
X
Hematology
No need to 
repeat at pre-
dose Day 1 if 
screening 
assessments 
were performed 
within 72 
hours14 days of 
first dose (- 1 
day visit window 
after screening)
X
X
X
X
X
Prior to every 
infusion
X


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STUDY PHASE
SCREEN
First Treatment Period
Cycle 1
Continuation 
Phase
Cycle 2 and 
beyond
Follo
w-Upj
VISIT
Screen
Day 1 
and 4a
Day 8 
and 11 a
Day 15 
and 18 a
Day 
21 
VISIT WINDOW 
(days)
-14
7l
7l
Coagulation
PT/PTT/INR.
No need to 
repeat at pre-
dose Day 1 if 
screening 
assessments 
were performed 
within 
72 hours14 days
of first dose (- 1 
day visit window 
after screening)
X
Blood sample for circulating biomarkers
A blood sample 
for circulating 
biomarkers 
should be 
obtained on Day 
1 (prior to 
treatment), Day 
21 (and at the 
time of disease 
progression)
X
X
X (at 
progre
ssion)


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STUDY PHASE
SCREEN
First Treatment Period
Cycle 1
Continuation 
Phase
Cycle 2 and 
beyond
Follo
w-Upj
VISIT
Screen
Day 1 
and 4a
Day 8 
and 11 a
Day 15 
and 18 a
Day 
21 
VISIT WINDOW 
(days)
-14
7l
7l
Blood sample for Genetic research
A 6mL blood 
sample 
should be 
collected 
after 
screening 
(preferably 
on day 1) if 
informed 
consent has 
been 
obtained for 
Genetic 
research
X


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STUDY PHASE
SCREEN
First Treatment Period
Cycle 1
Continuation 
Phase
Cycle 2 and 
beyond
Follo
w-Upj
VISIT
Screen
Day 1 
and 4a
Day 8 
and 11 a
Day 15 
and 18 a
Day 
21 
VISIT WINDOW 
(days)
-14
7l
7l
Blood for PD biomarkers
Blood samples 
for PD 
biomarkers 
should be 
obtained prior to 
dosing on D1 
(baseline), 2 
hours after the 
end of the 
infusion on day 
1, 4, 8, 11, 15, 
and 18 and at 
day 21 and 28 
visits (1-2 
days).
X
X
X
X
Whole Blood for Biomarkersg
Whole blood 
should be 
obtained prior to 
dosing on day 
1,day 18  and 
C2D1 (sample 
taken prior to 
dosing)
X (Day 
1)
X (Day 
18)
X (C2W1D1 
pre dose 
only)


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STUDY PHASE
SCREEN
First Treatment Period
Cycle 1
Continuation 
Phase
Cycle 2 and 
beyond
Follo
w-Upj
VISIT
Screen
Day 1 
and 4a
Day 8 
and 11 a
Day 15 
and 18 a
Day 
21 
VISIT WINDOW 
(days)
-14
7l
7l
PK sampling for Part 1
For details, see 
Table 7
Day 1 
(Table 
7) 
Day 4 
pre-
dose 
and 
end of 
infusion
Soon 
after 
ECG and 
PD 
biomarke
r
collection
Day 15 
(Table 7)
At 
time 
of PD
circul
ating
biom
arker 
collec
tion
Cycle 2, 4, 6 
and 12 –
pre-dose 
and within 5 
min prior to 
end of 
infusion on 
Day 4 


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STUDY PHASE
SCREEN
First Treatment Period
Cycle 1
Continuation 
Phase
Cycle 2 and 
beyond
Follo
w-Upj
VISIT
Screen
Day 1 
and 4a
Day 8 
and 11 a
Day 15 
and 18 a
Day 
21 
VISIT WINDOW 
(days)
-14
7l
7l
PK sampling for Part 2
Three samples 
to be collected 
on Day 1 and 
Day 11: 
Predose within 
60 minutes 
prior to start of 
infusion, single 
draw between 
0.5 and 1.9 h 
from start of 
infusion, single 
draw between 
3-6h following 
end of infusion.
Day 1 
and 
pre-
dose 
on Day 
4
X (after 
4th dose, 
Day 11)
pre-dose 
on Day 
15
Cycle 2, 4, 6 
and 12 –
pre-dose 
and within 5 
min prior to 
end of 
infusion on 
Day 4 


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STUDY PHASE
SCREEN
First Treatment Period
Cycle 1
Continuation 
Phase
Cycle 2 and 
beyond
Follo
w-Upj
VISIT
Screen
Day 1 
and 4a
Day 8 
and 11 a
Day 15 
and 18 a
Day 
21 
VISIT WINDOW 
(days)
-14
7l
7l
Translational Research
Tumor Tissue for EZH2 mutation and GCB confirmation 
testing (required: for all GCB DLBCL and tFL  
subjects)cArchival Tissue for mutation testing (Required: All 
DLBCL and tFL subjects Parts 1 and 2)
Availability of 
archival tissue 
(or fresh biopsy) 
is required for 
central testing of 
GCB-subtype 
(DLBCL only) 
and EZH2 
mutation status
X
Tumor tissue for solid tumors (including prostate subjects)c
Availability of 
archival tissue 
(or fresh biopsy)
X


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STUDY PHASE
SCREEN
First Treatment Period
Cycle 1
Continuation 
Phase
Cycle 2 and 
beyond
Follo
w-Upj
VISIT
Screen
Day 1 
and 4a
Day 8 
and 11 a
Day 15 
and 18 a
Day 
21 
VISIT WINDOW 
(days)
-14
7l
7l
Tumor biopsy for PD optional for Part 1 and Part 2. Required 
for Part 1 and PK/PD cohort at MTD
A tumor biopsy 
should be 
obtained at D1 
(up to -14 days) 
and after 6th
dose Day 18(+3 
day window)
X
X (After 
6th dose, 
Day 18)h
Tumor biopsy for biomarker research
Recommended  
for all subjects in 
Part 2
X (at 
pro-
gressi
on)


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STUDY PHASE
SCREEN
First Treatment Period
Cycle 1
Continuation 
Phase
Cycle 2 and 
beyond
Follo
w-Upj
VISIT
Screen
Day 1 
and 4a
Day 8 
and 11 a
Day 15 
and 18 a
Day 
21 
VISIT WINDOW 
(days)
-14
7l
7l
Additional Assessments for PD/PK Cohortm
Blood for metabolite evaluation (Part 21 PK/PD expansion 
cohort only – at least 4 subjects)
Day 1 
(Table 
7)
Day 15 
(Table 7)
Urine for PK Metabolite (Part 12 PK/PD expansion cohort 
only) at least 4 subjects)
On Day 15, 
urine samples 
should be 
collected while 
subject is in the 
office
X Day 1 
prior to 
first 
dose 
and 
from 0 
to 24h
Day 15 
from 0 to 
24 8 h


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STUDY PHASE
SCREEN
First Treatment Period
Cycle 1
Continuation 
Phase
Cycle 2 and 
beyond
Follo
w-Upj
VISIT
Screen
Day 1 
and 4a
Day 8 
and 11 a
Day 15 
and 18 a
Day 
21 
VISIT WINDOW 
(days)
-14
7l
7l
Bile for metabolite PK (Part 12 PK/PD expansion cohort only) 
– at least 4 subjects)
X (prior 
to first 
dose
Day 15
Plasma for 4-hydroxycholesterol and cholesterol assay (Part 
12 PK/PD expansion cohort only)
X (Day 
1 
pPrior 
to First 
Dose)
X 
(Day 
21 
only)


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STUDY PHASE
SCREEN
First Treatment Period
Cycle 1
Continuation 
Phase
Cycle 2 and 
beyond
Follo
w-Upj
VISIT
Screen
Day 1 
and 4a
Day 8 
and 11 a
Day 15 
and 18 a
Day 
21 
VISIT WINDOW 
(days)
-14
7l
7l
Surrogate Tissue for PD and Translational Research
A surrogate 
tissue biopsy 
should be 
obtained at D1 
(up to -14 
days) and after 
6th dose Day 
18 (+3 day 
window)
X
X
Disease Assessments for Lymphoma Subjects: Baseline disease assessments at screening and repeated 8 weeks after dosing is initiated and every 12 weeks 
thereafter
CTk
Must be 
completed within 
4 weeks of first 
dose of 
GSK2816126 
and repeated 8 
weeks after 
dosing is 
initiated.  Every 
12 weeks 
thereafter
X
X
Xd


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STUDY PHASE
SCREEN
First Treatment Period
Cycle 1
Continuation 
Phase
Cycle 2 and 
beyond
Follo
w-Upj
VISIT
Screen
Day 1 
and 4a
Day 8 
and 11 a
Day 15 
and 18 a
Day 
21 
VISIT WINDOW 
(days)
-14
7l
7l
Positron emission tomography (PET)
The use of 
standalone PET 
or PET in 
combination with 
CT scan is 
optional. 
Standalone PET 
doesse not 
replace CT
Xe
Xd,e
Xd,e
Bone Marrow biopsy (See Section 3.8.4)
See Section 7.7
X
Xf
Xf
B symptoms
See Section 7.7
X
X
X
X
X
X
Disease assessment
Baseline 
disease 
assessments at 
screening and 
repeated every 
8 weeks 
X
X
X d


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STUDY PHASE
SCREEN
First Treatment Period
Cycle 1
Continuation 
Phase
Cycle 2 and 
beyond
Follo
w-Upj
VISIT
Screen
Day 1 
and 4a
Day 8 
and 11 a
Day 15 
and 18 a
Day 
21 
VISIT WINDOW 
(days)
-14
7l
7l
Disease Assessments for Multiple Myeloma (MM) subjects: Baseline disease assessments at screening, week 4 and  then every 6 weeks there after  unless 
otherwise noted
Disease Characteristics
Every 6 weeks 
after Wk4, 
Including 
cytogenetics as 
appropriate
X
Total Protein, CRP, 2 microglobulin
Every 6 weeks 
after Wk4
X
Response Assessment
Every 6 weeks 
after Wk4; 
Response 
criteria in 
Appendix 6
SPEP, FLC assay, quantitative immunoglobulins ( IgG, IgA, 
IgM)
Not required for 
subjects with 
non-secretory 
MM
X
UPEP
Only required if 
paraprotein is 
present in urine
X


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STUDY PHASE
SCREEN
First Treatment Period
Cycle 1
Continuation 
Phase
Cycle 2 and 
beyond
Follo
w-Upj
VISIT
Screen
Day 1 
and 4a
Day 8 
and 11 a
Day 15 
and 18 a
Day 
21 
VISIT WINDOW 
(days)
-14
7l
7l
Extramedullary Disease Assessment
Only required for 
MM with 
extramedullary 
disease
X
BM aspirate and biopsy
Required for 
non-secretory 
MM, or as 
appropriate for 
other subjects
X
Day 18
Week 10, 
Day 1
Disease Assessments for Solid Tumors: Baseline disease assessments at screening  and repeated every 8 weeks after dosing is initiated
CT/MRIk
Must be 
completed within 
4 weeks of first 
dose of 
GSK2816126 
andMust be 
repeated every 
8 weeks
X
Xd
Xd


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STUDY PHASE
SCREEN
First Treatment Period
Cycle 1
Continuation 
Phase
Cycle 2 and 
beyond
Follo
w-Upj
VISIT
Screen
Day 1 
and 4a
Day 8 
and 11 a
Day 15 
and 18 a
Day 
21 
VISIT WINDOW 
(days)
-14
7l
7l
Positron emission tomography (PET)
The use of 
standalone PET 
or PET in 
combination with 
CT scan is 
optional. 
Standalone PET 
does not replace 
CT
Xe
Xe
Xd,e
Disease Assessments for Prostate Cancer: (in addition to those assessments for all solid tumor subjects): Baseline disease assessments at screening  and 
repeated as noted below after dosing is initiated
Vitamin D3 and PTH
X
X
Xd
Urinalysis
Urine microscopy
UPC
X
Xe
Xd,e
Urine electrolytes
X
PSA
Wk 9 and every 
48 weeks 
thereafter
X
Every 4 
weeks
(Cycle Day 
1)
X
ECOG Performance status 
See Appendix 
2
X
X
X
X
X


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STUDY PHASE
SCREEN
First Treatment Period
Cycle 1
Continuation 
Phase
Cycle 2 and 
beyond
Follo
w-Upj
VISIT
Screen
Day 1 
and 4a
Day 8 
and 11 a
Day 15 
and 18 a
Day 
21 
VISIT WINDOW 
(days)
-14
7l
7l
Study Medication
GSK2816126 Dosing
Dosed 2x weekly with at least 2-3 non-dosing days apart (3 weeks on/1 week off)
a.
A subject is to receive two doses per week which should be given with at least 2 non-dosing days in between on the same day of the week during Cycle 1.-3 days apart. If there is 
a need to change scheduling after Cycle 1, the scheduled days of the week can change as long as there are 2-3-4 non-dosing  days between dosesing days.  
b.
Timings for triplicate in-house on-drug ECGs are pre-infusion, at the end of infusion, before bed, and before discharge the next morning for Day 1 of cycle 1 only.  Other protocol-
mandated ECGs should be performed in triplicate pre-infusion and at the end of infusion (Section 7.3.4). Two copies of the ECG tracing should be obtained at the time of the ECG, 
one to be kept in the study file for retrospective collection by the sponsor if necessary.  ECG data should be reviewed by qualified personnel with experience in this study 
population
c.
Retention of screen-failure tumor tissue: all or a portion of archival or fresh biopsy tissue from screen-failure subjects, used for central testing of GCB-DLBCL or EZH2 mutation 
status, will be retained.  This tissue may be used in the validation of potential diagnostic assays to detect EZH2 mutations and/or for GCB-DLBCL subtyping.
d.
If the Follow-up visit ≥ 812weeks from the previous response scan time point, scans should be obtained to confirm/ evaluate response.  
e.
Standalone PET dose not replace CT.  Diagnostic CT is the preferred method of disease assessment.  PET/CT may be used as an alternative at the investigator’s discretion.  
f.
Only if initially and/or previously positive & required for CR or as clinically indicated.
g.
Whole Blood for Biomarker sample at Cycle 2 day 1 must  be taken prior to start of dosing.
h.
If tissue sample not able to be taken at C1D18, site should discuss with GSK regarding having the sample taken at the next Cycle visit
i.
Serum beta-human chorionic gonadotropin (B-HCG) pregnancy test
j.
Follow up visit should be performed 30 days from last dose of study medication
k.
Baseline brain scans are required for all subjects.  Thereafter brain scans should be conducted as clinically indicated.  Bone scans are to be conducted as clinically indicated at 
baseline and subsequent follow up timepoints.  Subjects undergoing baseline full body CT/PET will not require this additional scans, unless clinically indicated. 
l.
After Cycle 1, assessments that are conducted at less frequent intervals (i.e., every 8 weeks) will have a visit window of 7 days after Cycle 1
m.
Part 2 subjects enrolled into the PK/PD cohort will have these assessments performed in addition to all other study assessments included in the Time and Events table


2012N149024_05
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401
Table 7
Time and Events, PK Sampling Table for Part 1, Day 1 and Day 15
Duration of Infusion in hours
2
3
4
From start of infusion - 60 mins
Predose
Predose
Predose
5 mins
0.5 hr
0.5 hr
0.5 hr
5 mins
1 hr
1 hr
1 hr
- 5 mins
2 hr (prior to end of infusion)
2 hr
2 hr
- 5 mins
3 hr (prior to end of infusion)
4 hr (prior to end of infusion)
From end of infusion 5 mins
0.5 h
0.5 h
0.5 h
5 mins
1 hr
1 hr
1 hr
5 mins
2 hr
2 hr
2 hr
15 mins
4 hr
4 hr
4 hr
15 mins
6 hr
6 hr
6 hr
From start of infusion 1hour
12 hr (Day 1 only)
12 hr (Day 1 only)
12 hr (Day 1 only)
1 hour
18 hr (Day 1 only)
18 hr (Day 1 only)
18 hr (Day 1 only)
1 hour
24 hr
24 hr
24 hr
2 hour
**72 or 96 hr 
72 or 96 hr
72 or 96 hr
**72 hour sample corresponds to Cycle 1 Day 4 pre infusion sample.  EOI sample should also be taken at C1D4.


2012N149024_05
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402
15.10.
Appendix 10: Country Specific Requirements
No country-specific requirements exist.

SAP_000.pdf: 
CONFIDENTIAL
The GlaxoSmithKline group of companies
EZH117208
1
Division
:
Worldwide Development
Information Type
:
Reporting and Analysis Plan (RAP)
Title
:
Reporting and Analysis Plan for A Phase I Open-label, Dose 
Escalation Study to Investigate the Safety, Pharmacokinetics, 
Pharmacodynamics and Clinical Activity of GSK2816126 in 
Subjects with Relapsed/Refractory Diffuse Large B cell 
Lymphoma, Transformed Follicular Lymphoma, Other Non-
Hodgkin’s Lymphomas, Solid Tumors and Multiple 
Myeloma
Compound Number 
:
GSK2816126
Effective Date 
:
01-MAR-2018
Description:

The purpose of this RAP is to describe the planned analyses and output to be 
included in the Clinical Study Report for Protocol EZH117208 Amendment 04.

This RAP is intended to describe the safety, tolerability, efficacy and 
pharmacokinetic analyses required for the study. 

This RAP will be provided to the study team members to convey the content of the 
Statistical Analysis Complete (SAC) deliverable.
RAP Author(s):
Approver
Date
Approval Method
25-FEB-2018
e-Signature
Statistics Leader (Oncology, Clinical Statistics)
Copyright 2018 the GlaxoSmithKline group of companies. All rights reserved.  
Unauthorised copying or use of this information is prohibited.
PPD


CONFIDENTIAL
The GlaxoSmithKline group of companies
EZH117208
2
RAP Team Approvals:
Approver
Date
Approval Method
 
26-FEB-2018
e-Signature
Senior Clinical Development Manager
(Oncology, CPSSO)
25-FEB-2018
e-Signature
Medical Director (Oncology, Cancer 
Epigenetics)
Senior Clinical Development Scientist 
(Oncology, CPSSO)
01-MAR-2018
e-Signature
 
25-FEB-2018
e-Signature
Manager (Clinical Pharmacology
Modelling & Simulation)
26-FEB-2018
e-Signature
Principal Programmer (Oncology, Clinical 
Programming)
 
26-FEB-2018
e-Signature
Data Quality Manager (Oncology, CPSSO)
Clinical Statistics and Clinical Programming Line Approvals:
Approver
Date
Approval Method
28-FEB-2018
e-Signature
Senior Director (Oncology, Clinical Statistics)
26-FEB-2018
e-Signature
Programming Manager (Oncology, Clinical 
Programming)
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


CONFIDENTIAL
EZH117208
3
TABLE OF CONTENTS
PAGE
1.
INTRODUCTION......................................................................................................5
2.
SUMMARY OF KEY PROTOCOL INFORMATION ..................................................7
2.1.
Changes to the Protocol Defined Statistical Analysis Plan............................7
2.2.
Study Objective(s) and Endpoint(s)...............................................................7
2.3.
Study Design ..............................................................................................10
2.4.
Statistical Hypotheses.................................................................................11
3.
PLANNED ANALYSES ..........................................................................................12
3.1.
Interim Analyses .........................................................................................12
3.1.1.
Part 1: Dose Escalation Phase ....................................................12
3.1.1.1.
Displays To Be Created For Dose Escalation 
Review .......................................................................12
3.2.
Final Analyses ............................................................................................12
4.
ANALYSIS POPULATIONS ...................................................................................13
4.1.
Protocol Deviations.....................................................................................13
5.
CONSIDERATIONS FOR DATA ANALYSES AND DATA HANDLING 
CONVENTIONS.....................................................................................................14
5.1.
Study Treatment & Sub-group Display Descriptors.....................................14
5.2.
Baseline Definitions ....................................................................................14
5.3.
Multicentre Studies .....................................................................................15
5.4.
Other Considerations for Data Analyses and Data Handling 
Conventions................................................................................................15
6.
STUDY POPULATION ANALYSES .......................................................................16
6.1.
Overview of Planned Study Population Analyses........................................16
6.2.
Disposition of Subjects................................................................................16
6.3.
Protocol Deviations.....................................................................................16
6.4.
Demographic and Baseline Characteristics.................................................16
6.5.
Prior Medications........................................................................................17
6.6.
Concomitant Medications............................................................................17
6.7.
Treatment Compliance................................................................................17
7.
SAFETY ANALYSES .............................................................................................18
7.1.
Extent of Exposure .....................................................................................18
7.2.
Adverse Events Analyses ...........................................................................18
7.3.
Clinical Laboratory Analyses.......................................................................19
7.3.1.
Liver Function Analyses...............................................................21
7.4.
Other Safety Analyses ................................................................................21
8.
EFFICACY ANALYSES..........................................................................................23
9.
PHARMACOKINETIC ANALYSES.........................................................................24
9.1.
Primary Pharmacokinetic Analyses.............................................................24
9.1.1.
Endpoint / Variables.....................................................................24
9.1.1.1.
Drug Concentration Measures....................................24


CONFIDENTIAL
EZH117208
4
9.1.1.2.
Derived Pharmacokinetic Parameters.........................24
9.1.2.
Summary Measure ......................................................................25
9.1.3.
Population of Interest...................................................................25
9.1.4.
Statistical Analyses / Methods .....................................................25
9.1.4.1.
Dose proportionality....................................................25
10. PHARMACODYNAMIC ANALYSES.......................................................................27
11. REFERENCES.......................................................................................................28
12. APPENDICES........................................................................................................29
12.1.
Appendix 1: Protocol Deviation Management and Definitions for Per 
Protocol Population.....................................................................................29
12.1.1.
Exclusions from Per Protocol Population .....................................29
12.2.
Appendix 2: Schedule of Activities ..............................................................30
12.2.1.
Protocol Defined Schedule of Events...........................................30
12.3.
Appendix 3: Assessment Windows .............................................................31
12.4.
Appendix 4: Study Phases and Treatment Emergent Adverse 
Events ........................................................................................................32
12.4.1.
Study Phases ..............................................................................32
12.4.1.1.
Study Phases for Concomitant Medication .................32
12.4.2.
Treatment Emergent Flag for Adverse Events .............................32
12.5.
Appendix 5: Data Display Standards & Handling Conventions....................33
12.5.1.
Reporting Process .......................................................................33
12.5.2.
Reporting Standards....................................................................33
12.5.3.
Reporting Standards for Pharmacokinetic....................................34
12.6.
Appendix 6: Derived and Transformed Data ...............................................35
12.6.1.
General........................................................................................35
12.6.2.
Study Population..........................................................................35
12.7.
Appendix 7: Reporting Standards for Missing Data.....................................36
12.7.1.
Premature Withdrawals................................................................36
12.7.2.
Handling of Missing Data.............................................................36
12.7.2.1.
Handling of Missing and Partial Dates ........................36
12.8.
Appendix 8: Values of Potential Clinical Importance ...................................38
12.9.
Appendix 9: Abbreviations & Trade Marks ..................................................39
12.9.1.
Abbreviations...............................................................................39
12.9.2.
Trademarks .................................................................................41
12.10. Appendix 10: List of Data Displays..............................................................42
12.10.1. Data Display Numbering..............................................................42
12.10.2. Mock Example Shell Referencing ................................................42
12.10.3. Deliverables.................................................................................42
12.10.4. Study Population Tables..............................................................43
12.10.5. Efficacy Tables ............................................................................44
12.10.6. Efficacy Figures ...........................................................................44
12.10.7. Safety Tables...............................................................................45
12.10.8. Pharmacokinetic Tables...............................................................47
12.10.9. Pharmacokinetic Figures .............................................................47
12.10.10.ICH Listings .................................................................................48
12.10.11.Non-ICH Listings..........................................................................50
12.11. Appendix 11: Example Mock Shells for Data Displays ................................51


CONFIDENTIAL
EZH117208
5
1.
INTRODUCTION
The purpose of this reporting and analysis plan (RAP) is to describe the analyses to be 
included in the Clinical Study Report for Protocol
GlaxoSmithKline
Document Number
Date
Version
2012N149024_00
11-JUL-2013
Original
2012N149024_01
23-OCT-2013
Amendment No. 1 
Applies only to sites in the UK. Following review of the protocol by the MHRA, the 
following changes were  made:
1.
Removed wording from the protocol stating that GSK2816126 treatment will 
continue until commercial availability. 
2.
The stopping criterion based on QTc will be changed to ≥ 500 msec. 
3.
Added a QTc stopping criterion that patients will be withdrawn if they experience 
an increase in QTc > 60msec from baseline following dose reduction and re-challenge.  
2012N149024_02
30-OCT-2013
Amendment No.: 02
Applies to all study sites. Following review of the protocol by the Food and Drug
Administration (FDA), the following changes were made:
1.
The starting dose of GSK2816126 is reduced from 125 mg/dose to 50 mg/dose
2.
Updated Dose Limiting Tox language
3.
Revised 100% dose escalation wording
4.
Decreased QTc baseline exclusion criterion
5.
Added regular ECG monitoring timings
6.
Added blood glucose testing to our list of clinical lab tests
7.
Removed any wording pertaining to the use of central labs
8.
Removed wording from the protocol stating that GSK2816126 treatment will 
continue until commercial availability 
9.
Clarify that PET scans are optional
10.
Elaborated on CT scan timings


CONFIDENTIAL
EZH117208
6
11.
The stopping criterion based on QTc will be changed to ≥ 500 msec
12.
Added a QTc stopping criterion that subjects will be withdrawn if they experience 
an increase in QTc > 60 msec from baseline following dose reduction and re-challenge 
13.
Added explanatory language to T&E Table around coagulation, CT and 
standalone PET assessments 
14.
Changed corticosteroid exclusion criteria
2012N149024_03
03-APR-2015
Amendment No. 03
Amendment 03 applies to all study sites and includes the addition of solid tumor 
malignancies and other NHLs to Part 1 of the study, transformed follicular lymphoma 
subjects to Part 2 and multiple myeloma subjects to both Part 1 and 2.  The protocol title, 
study rationale, objectives, endpoints, hypotheses, inclusion/exclusion criteria, 
background, preclinical pharmacology and safety, risk/benefits, investigational plan, 
population rationale, T&E table, tumor biomarker analysis have all been updated to 
reflect these changes. RECIST criteria and multiple myeloma response criteria have also 
been added.  A description of genetic research has been added to the appendix.  To 
accommodate these changes we have also augmented the number of subjects, evaluation 
of futility, organ function table, data management and statistical analysis.  Other 
additions include dose adjustment for hematologic and non-hematologic toxicity, 
description of the investigational product and time windows for the PK sample collection 
table. Additions were also made to the Pharmacodynamics and Translational Research 
sections to cover potential studies in a surrogate tissue.  Updated the Prohibited Meds 
Table 13 and Table 14.  Removed PD analysis from Part 2.
2012N149024_04
17-MAR-2016
Amendment No. 4
Amendment 04 applies to all study sites and includes the following updates:
1. Updated primary and secondary medical monitor contact information
2. Extend the period of post treatment contraception for women to 2 weeks (14 days) 
(previously 1 week).
3. Updated requirement for pregnancy test to within 7 days of first dose (previously 
within 14 days of first dose) and added requirements for repeat testing every 4 
weeks.
4. Added requirement that any female subject who becomes pregnant while on study 
be withdrawn from the study.
5. Added that subjects be instructed to avoid excess exposure to sunlight and UV 
and to use protective measures if outdoors. 
6. Modified the storage period for diluted investigational product prior to infusion to 
12 hours (previously 48 hours).
7. Updated prohibited medications to clarify exclusion of IV ondansetron and
palonosetron (oral doses up to 8mg TID are permitted).


CONFIDENTIAL
EZH117208
7
2.
SUMMARY OF KEY PROTOCOL INFORMATION
2.1.
Changes to the Protocol Defined Statistical Analysis Plan
There were changes to the originally planned statistical analysis specified in the Protocol 
Amendment 4 (Dated: 17-MAR-2016).
Due to the termination of study EZH117208 resulting from no evidence of efficacy, this
RAP is developed for an abbreviated CPSR. Since Part 2 cohort expansion was not 
performed before the study closed, no statistical analysis will be performed for Part 2.
Changes from the originally planned statistical analysis specified in the protocol are 
outlined in Table 1.
Table 1
Changes to Protocol Defined Analysis Plan
Protocol
Reporting & Analysis Plan
Statistical Analysis Plan
Statistical Analysis Plan
Rationale for Changes

Statistical Analysis for Part 2

No Statistical Analysis for 
Part 2

Part 2 was not implemented

Full CSR

Abbreviated CSR

Study terminated

To evaluate the relationship 
between GSK2816126 exposure 
and safety/efficacy/PD 
parameters

Not to be performed

Abbreviated CSR

To determine the amount of 
GSK2816126 excreted in urine 
after dosing at steady state

Not to be performed

Abbreviated CSR
2.2.
Study Objective(s) and Endpoint(s)
Part 1 Objectives
Part 1 Endpoints
Primary Objectives
Primary Endpoints

To determine the safety and 
tolerability, and establish the 
recommended Phase 2 dose (RP2D)
of IV administered GSK2816126 

Adverse Events (AEs), Serious Adverse Events (SAEs), 
Dose Limiting Toxicity (DLT), withdrawals due to AEs, 
dose interruptions and reductions, and changes in safety 
assessments (e.g., clinical laboratory parameters, vital 
signs, and cardiac parameters)


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Part 1 Objectives
Part 1 Endpoints
Secondary Objectives
Secondary Endpoints

To describe the pharmacokinetics of 
GSK2816126 after single- and 
repeated administration

GSK2816126 PK parameters following single- (Day 1) 
and repeat-dose administration of GSK2816126, 
including area under the concentration-time curve 
(AUC), pre-dose (trough) concentration at the end of the 
dosing interval (C), maximum observed concentration 
(Cmax), time of occurrence of Cmax (tmax), terminal 
phase half-life (t1/2), time invariance and accumulation 
ratio

To evaluate the relationship between 
GSK2816126 exposure and
safety/efficacy/PD parameters

GSK2816126 exposure markers (dose, concentration, 
Cmax or AUC) and safety/efficacy/PD responses. 
Pharmacodynamic response assessed by change from 
baseline in tri-methylation of Histone H3K27 (H3K27me3)

To determine clinical activity of 
GSK2816126

Response rate (complete response [CR] + partial 
response [PR])

To generate samples (data reported 
separately) with which to characterize 
the metabolic profile of GSK2816126 
after repeat-dosing (In the PK/PD 
expansion cohort only)

Samples to characterize the metabolites in blood, bile 
and/or urine

To determine the amount of 
GSK2816126 excreted in urine after 
dosing at steady state

Concentration of GSK2816126 in urine measured with an 
investigational bio-analytical method and extrapolated to 
total amount excreted in urine over time using urine 
volume
Exploratory Objectives
Exploratory Endpoints

To confirm tumor EZH2 and GCB-
DLBCL status

IHC for confirmation of GCB-DLBCL status

To investigate the mechanism of 
action and additional indicators of 
sensitivity and resistance to 
GSK2816126

Tumor baseline genetic profiles, response

To generate samples (data reported 
separately) with which to investigate 
the potential for GSK2816126 to affect 
cytochrome P450 (CYP) 3A4 enzyme 
activity

Samples to assess a potential change in 4b-OH 
cholesterol to cholesterol ratio in plasma following repeat 
dosing of GSK2816126 (data reported separately)


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Part 2 Objectives
Part 2 Endpoints
Primary Objectives
Primary Endpoints

To determine clinical activity of 
GSK2816126 in cohorts of subjects 
with EZH2 mutant and wild type 
GCB-DLBCL and tFL and subjects 
with MM

Objective response rate (% of subjects achieving CR and 
PR per response criteria)
Secondary Objectives
Secondary Endpoints

To determine the safety, tolerability 
of the selected IV dose of 
GSK2816126

AEs, SAEs, DLTs, withdrawals due to AEs, dose
interruptions and reductions, and changes in safety 
assessments (e.g., clinical laboratory parameters, vital 
signs, and cardiac parameters)

To characterize the population PK of 
GSK2816126

Population PK parameters for GSK2816126 including 
clearance (CL), and volume of distribution (Vd) and 
relevant covariates which may influence exposure (e.g. 
age, weight, or disease related covariates)

To evaluate the relationship between 
exposure and safety/efficacy 
parameters 

GSK2816126 exposure markers (e.g. dose, 
concentration, Cmax, or AUC) and safety/efficacy/ 
responses

To begin to characterize the durability 
of response and progression free 
survival with GSK2816126

Duration of response (DoR)

Progression-free survival (PFS)
Exploratory Objectives
Exploratory Endpoints

To identify biomarkers predictive of 
response or resistance to 
GSK2816126

Evaluation of wild-type (WT) subject tumors for the 
presence of additional, undefined, mutations in the EZH2 
gene

To investigate the mechanism of 
action of GSK2816126 by evaluating 
changes in gene expression profiles

Deoxyribonucleic acid (DNA), ribonucleic acid (RNA) and 
protein markers in tumor and blood


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2.3.
Study Design
Overview of Study Design and Key Features
Design 
Features

This study consisted of 2 parts; Part 1 of the study was a dose escalation phase with 
cohort expansion to select the recommended Phase 2 dose (RP2D) based on the 
safety, PK, and PD profiles observed after IV administration of GSK2816126.  Eligible 
subjects with relapsed/refractory DLBCL, transformed FL malignancies, other non-
Hodgkin lymphomas (NHL), Multiple Myeloma (MM) and solid tumors would be 
enrolled in the dosing cohorts until a RP2D was determined or until a maximum 
tolerated dose (MTD) or a dose of 3000 mg was established. 

In Part 1, an accelerated dose titration was employed with one subject per dose level 
until the first instance of a ≥ Grade 2 drug related non-haematological toxicity or dose 
limiting toxicity (DLT) occurs. After the accelerated dose titration, subjects would be 
enrolled in a standard 3+3 dose escalation design. 

Any dose level during Part 1 could be expanded to explore safety and preliminary 
efficacy. At RP2D, cohort may be expanded to enroll more GCB-DLBCL subjects or 
subjects with solid tumor containing EZH2-sensitive mutations to explore safety and 
preliminary efficacy.  Subjects may continue treatment in the study until disease 
progression, unacceptable toxicity, or withdrawal of consent.  

Part 2 expansion cohorts were planned in subjects with MM, and in subjects with 
both EZH2 mutant positive and wild type GCB-DLBCL and tFL to further explore 
clinical activity at the RP2D.
Dosing

In Part 1 dose escalation, the starting dose was 50 mg, IV, twice weekly.  
Subsequent cohorts would allow up to 100% dose escalations up to 500 mg, 
then up to 50% dose escalation at each step thereafter. The maximum dose 
was 3000mg. Dose adjustments were allowed to address tolerability and safety 
issues.  Alternative schedules would be evaluated if emerging data suggest that twice 
weekly administration with 2 hour infusions would result in excessive toxicity.  

In Part 2, patients would be IV dosed RP2D twice weekly, 3 weeks on / 1 week off 
for each 28-day cycle.
Time & 
Events

Refer to Protocol Amendment 4 Section 7.1 Time and Event Table(s)
Treatment 
Assignment

This was a non-randomized open-label study.  

Randomization & Medication Ordering System (RAMOS) was used for 
Part 1
Accelerated Dose Titration 
followed by 3+3 Dose 
Escalation, with possibility 
of additional subjects 
enrolled in any dose level 
to explore safety and 
preliminary efficacy 
(N=30–40 subjects)
          Part 2
Cohort Expansion in both 
wild type and EZH2 
mutation-positive GCB-
DLBCL and tFL subjects, 
and subjects with MM 
(N=up to 69 subjects)


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Overview of Study Design and Key Features
treatment assignment.
Interim 
Analysis

For dose escalation in Part 1, there was no interim analysis.

For Part 2, interim analysis of futility for each cohort would be conducted continually 
once a minimum number of subjects for futility analysis complete response evaluation. 
These interim analyses would not be formal analyses, but would be used to support 
the decision of early termination of study EZH117208.
NOTES: 

Part 2 was not implemented, due to the business decision of study termination.
2.4.
Statistical Hypotheses
No formal statistical hypotheses are being tested for the dose escalation in Part 1. 
Analysis of the data obtained from dose escalation of Part 1 will only utilize descriptive 
methods. 


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3.
PLANNED ANALYSES
3.1.
Interim Analyses
The study will not utilize an Independent Data Monitoring Committee (IDMC).
No formal interim analysis will be performed in Part 1. Dose escalation and stopping 
rules are guidelines for decision-making and the totality of the data will be considered by 
the team when making 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 decision 
making.
3.1.1.
Part 1: Dose Escalation Phase
In the accelerated dose escalation cohorts and the 3+3 dose escalation cohorts of Part 1, 
prior to making decision of the GSK2816126 dose for the next cohort, exploratory 
analyses will be conducted to assess the relationship of GSK2816126 dose levels with 
safety, PK parameters (if data permits) using all data from available cohorts.
3.1.1.1.
Displays To Be Created For Dose Escalation Review
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.
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
3.2.
Final Analyses
The final planned primary analyses will be performed after the completion of the 
following sequential steps:
1. All subjects have completed the study, i.e. discontinued study treatment or receiving 
study treatment at the time of Sponsor’s decision of closing the study.
For Part 1 dose escalation phase, a completed subject is one who has completed the 
DLT observation period, has discontinued study treatment and completed a post-
treatment follow-up visit, or has died while receiving study treatment or is receiving 
ongoing study treatment at the time of Sponsor’s decision to close the study. 
2.
All required database cleaning activities have been completed and final database 
release and database freeze has been declared by Data Management.
3.
Randomization codes have been distributed according to RandAll NG procedures.


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4.
ANALYSIS POPULATIONS
Population
Definition / Criteria
Analyses Evaluated
Enrolled
All participants who passed screening and signed the 
Informed Consent Form.
Study Population
All Subjects
Consists of all subjects that received at least one dose of 
study treatment

Efficacy

Safety
PK
Consists of all subjects in the All Subject population for 
whom a blood sample for pharmacokinetics is analyzed and 
at least 1 non-missing values is obtained
Pharmacokinetic
Pharmacodynami
cs
Consists of subjects in the All Subjects population for whom 
a pharmacodynamics/biomarkers sample was obtained and 
analyzed 
Translational/Explorato
ry analysis, e.g. 
Somatic mutation, DNA 
and (or) RNA analysis, 
H3K27me3
NOTES:

Refer to Appendix 10: List of Data Displays which details the population used for each display.
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 (Version 2.0, 25-MAY-
2017).
o
Data will be reviewed prior to freezing the database to ensure all important 
deviations which may lead to exclusion from the analysis are captured and 
categorised on the protocol deviations dataset. 
o This dataset will be the basis for the listing of protocol deviations.


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5.
CONSIDERATIONS FOR DATA ANALYSES AND DATA
HANDLING CONVENTIONS
5.1.
Study Treatment & Sub-group Display Descriptors
Treatment Group Descriptions
RandAll NG 
Data Displays for Reporting 
Code
Description
Description
Order
B
GSK2816126 Twice-weekly by IV
50 mg
1
100 mg
2
200 mg
3
400 mg
4
800 mg
5
1200 mg
6
1800 mg
7
2400 mg
8
3000 mg
9
5.2.
Baseline Definitions
For laboratory data, baseline values are defined as the most recent, non-missing value 
from a local laboratory prior to the first dose of study treatment.
For ECG analyses, subject level baseline is defined as the mean of triplicate Cycle 1 Day 
1 (C1D1) pre-dose QTc results.
Parameter
Study Assessments Considered as Baseline
Baseline Used in 
Data Display
Screening
Day -1
Day 1 (Pre-Dose)
Efficacy
Disease Assessment
X
Screening
Safety
Vital Signs
X
X
Day 1 Pre-dose if 
collected, otherwise, 
use screening
ECG
X
X
Mean of triplicate pre-
dose measurements 
on Day 1, if not 
available, use mean 
values at screening
Clinical Chemistry, 
Hematology
X
X
Day 1 Pre-dose if 
collected, otherwise, 
use screening


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Parameter
Study Assessments Considered as Baseline
Baseline Used in 
Data Display
Screening
Day -1
Day 1 (Pre-Dose)
Coagulation
X
Screening
PK/PD
PK Concentration
X
Day 1 Pre-dose
PD Biomarker
X
Day 1 Pre-dose
Unless otherwise stated, if baseline data is missing no derivation will be performed and 
the baseline data will be set to missing.
The baseline definition will be footnoted on all change from baseline displays.
5.3.
Multicentre Studies
In this multicentre global study, enrolment will be presented by country and investigative 
site.
5.4.
Other Considerations for Data Analyses and Data Handling 
Conventions
Other considerations for data analyses and data handling conventions are outlined in the 
appendices:
Section
Component
Section 12.3
Appendix 3: Assessment Windows
Section 12.4
Appendix 4: Study Phases and Treatment Emergent Adverse Events
Section 12.5
Appendix 5: Data Display Standards & Handling Conventions
Section 12.6
Appendix 6: Derived and Transformed Data
Section 12.7
Appendix 7: Reporting Standards for Missing Data
Section 12.8
Appendix 8: Values of Potential Clinical Importance


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6.
STUDY POPULATION ANALYSES
6.1.
Overview of Planned Study Population Analyses
The study population analyses will be based on the All Subjects population, unless 
otherwise specified.
Study population analyses including analyses of subject’s disposition, protocol 
deviations, demographic and baseline characteristics, prior and concomitant medications, 
and exposure will be based on GSK Core Data Standards.  Details of the planned displays
are presented in Appendix 10: List of Data Displays.
All summary tables for study population analyses will be summarized by dose cohort and 
overall, unless otherwise specified.
6.2.
Disposition of Subjects
A summary of subject status and reason for study withdrawal will be provided. This 
display will show the number and percentage of subjects who have completed the study 
or have withdrawn from the study, including primary and secondary (if any) reasons for 
study withdrawal. Reasons for study withdrawal will be presented in the order they are 
displayed in the eCRF (Electronic Case Report Form). Subjects who die for any reason 
during on-treatment period will be considered to be complete.
Number of subjects based on the Enrolled population will be summarized by country and 
site for each dose cohort.
A listing of treatment discontinuation will be generated. The listing will include last dose 
date, and primary reasons for study treatment discontinuation.
6.3.
Protocol Deviations
Important protocol deviations will be listed and will include inclusion and exclusion 
deviations as well as other deviations. 
6.4.
Demographic and Baseline Characteristics
The demographic characteristics (e.g., age, race, ethnicity, sex, height, and baseline body 
weight) will be listed and summarized. Age, height and weight will be summarized using 
the mean, standard deviation, minimum, median, and maximum. 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 race, ethnicity and sex. The summary of demographic data will be 
displayed for each dose level and overall.
A separate summary of age ranges based on the Enrolled population will be provided. 
Age will be summarized in categories: 18-64, 65-74, 75-84 and ≥85. Race and racial 
combinations will also be summarized.


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6.5.
Prior Medications
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 summarized for solid tumors and lymphoma separately. Medical 
conditions present at screening will be summarized by past and current categories.
A summary of disease burden at screening will be produced. Information on sites of 
metastatic disease at screening will be summarized.
Prior anti-cancer therapy will be coded using GSK Drug coding dictionary and listed. A 
listing of prior anti-cancer therapy will show the relationship between Anatomical 
Therapeutic Chemical (ATC) Level 1, ingredient, and verbatim text.
Prior anti-cancer radiotherapy and prior anti-cancer surgeries will be listed.
6.6.
Concomitant Medications
Concomitant medications will be coded using GSK Drug coding dictionary, and 
summarized. The summary of concomitant medications will show the number and 
percentage of subjects taking concomitant medications by Ingredient. Multi-ingredient 
products will be summarized by their separate ingredients rather than as a combination of 
ingredients. Anatomical Therapeutic Chemical (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.
6.7.
Treatment Compliance
Summary of study treatment exposure and dose modifications (e.g., number of dose 
reductions, number of dose interruptions) will be provided. For the study treatment 
exposure, the number of cycles administered, dose intensity (dose delivered per cycle), 
and the cumulative dose received will be summarized with mean, median, standard 
deviation, minimum, and maximum. Listing of study treatment exposure will also be 
provided.


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7.
SAFETY ANALYSES
The safety analyses will be based on the All Subjects population, unless otherwise 
specified. All safety displays will use treatment labels as specified in Section 5.1. All 
summaries will be presented by dose level and overall.
7.1.
Extent of Exposure
Dose reductions will be summarised by number of reductions and reasons for reductions. 
Dose escalations will be summarised by number of escalations and reasons for escalation.
Dose interruptions will be summarised by number of interruptions and reasons for 
interruptions
All the dose reductions, dose escalations and dose interruptions will be listed separately
and will be based on GSK data standards and statistical principles.
Dose reductions, interruptions and escalations will be listed by dose level and subjects.
7.2.
Adverse Events Analyses
Adverse events analyses including the analysis of adverse events (AEs), Serious (SAEs)
and other significant AEs will be based on GSK Core Data Standards. The details of the 
planned displays are provided in Appendix 10: List of Data Displays.
Adverse events (AEs) will be graded according to the Common Terminology Criteria for 
Adverse Events (CTCAE v4.0). Adverse events will be coded to the PT level using the 
MedDRA dictionary. The relationship of AE system organ class, preferred term, and 
verbatim text will be listed.
A summary of number and percentage of subjects with any adverse events by maximum 
grade will be produced. AEs will be sorted by System Organ Class (SOC) and Preferred 
term (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.

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 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.
The relationship between MedDRA SOC, PT, and Verbatim Text will be listed.
Summary tables 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 


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relatedness data, i.e. the summary table will include events with the relationship to study 
treatment as ‘Yes’ or missing. Two summary tables for treatment-related AEs will be 
provided:

Summary of treatment-related AE by maximum toxicity grade. For each toxicity 
grade, treatment-related AEs will be displayed in descending order of total 
incidence by PT only.

Summary of treatment-related AE by frequency. Treatment-related AEs will be 
displayed in descending order of total incidence by PT only.
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., 
event 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) in descending order of 
total incidence.
A listing of all AEs will be provided. A listing of adverse events recorded as dose-
limiting toxicities will be provided. 
A listing of deaths will be generated to provide subject-specific details on subjects who 
died.
All serious adverse events (SAEs) will be tabulated based on the number and percentage 
of subjects who experienced the event. The summary tables will be displayed by SOC 
and PT in descending order of total incidence.
Separate supportive listings with subject-level details will be generated for fatal and non-
fatal SAEs, respectively. The fatal and non-fatal SAEs will be listed by dose level and 
subjects, including the relationship with treatment. A study treatment-related SAE is 
defined as an SAE for which the investigator classifies the relationship to study treatment
as “Yes”. 
7.3.
Clinical Laboratory Analyses
Laboratory evaluations including the analyses of Chemistry laboratory tests, 
Haematology laboratory tests, and liver function tests will be based on GSK Core Data 
Standards. The details of the planned displays are in Appendix 10: List of Data Displays.
The assessment of laboratory toxicities will examine the following laboratory tests: 


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Hematology
Platelet Count
RBC Indices:
Automated WBC Differential:
Red Blood Cell (RBC) Count
Mean Corpuscular Volume (MCV)
Neutrophils
White Blood Cell (WBC)
Count (absolute) 
Mean Corpuscular Hemoglobin (MCH)
Lymphocytes
Reticulocyte Count
Mean Corpuscular Hemoglobin 
Concentration (MCHC)
Monocytes
Hemoglobin
Eosinophils
Hematocrit
Basophils
Clinical Chemistry
Blood Urea 
Nitrogen (BUN)
Potassium
Alanine Aminotransferase (AST)
Total and direct bilirubin
Creatinine
Chloride
Aspartate Aminotransferase 
(ALT)
Uric Acid
Sodium
Calcium
Alkaline phosphatase
Total Protein
Magnesium
Glucose
Lactate Dehydrogenase (LDH)
Follicle Stimulating Hormone (FSH) and estradiol (as needed in women of non-child bearing potential and all 
peri menopausal women)
Pregnancy test for females (serum B-HCG at screening, Urine or serum B-HCG during Continuation Phase)
Laboratory grades will be evaluated using CTCAE v4.0. However, some tests are not 
graded using CTCAE.
For hematology, Red Blood Cell (RBC) is not gradable by CTCAE v4.0.
For clinical chemistry, BUN and creatinine clearance are not gradable by CTCAE v4.0. 
For sodium, potassium, calcium, glucose, and magnesium there will be two bi-directional 
parameters (hyper and hypo) created and the tests will be graded by CTCAE v4.0 in both 
directions.
Separate summary tables for hematology and chemical chemistry will be produced as 
detailed below. Liver function and pancreatic laboratory tests will be included with 
chemical chemistry.
Summary of worst case toxicity grade of lab values increase from baseline grade across 
all scheduled visits will be generated by dose level for all the lab tests that are gradable 
by CTCAE v4.0. Any increase to a higher grade from baseline will be summarized. 
Missing baseline grade will be assumed as grade 0. 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 change 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 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. 
Detailed derivation of baseline assessment is specified in Section 5.2.


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Unless otherwise specified, the denominator in percentage calculation at each scheduled 
visit will be based on the number of subjects with non-missing value at each visit.
Supporting listings of haematology and chemistry laboratory tests will be provided. 
A character lab value starting with ‘<X’ or ‘>X’ will be displayed in listings, but will not 
be imputed with a numeric value thus will not be included for summaries. 
7.3.1.
Liver Function Analyses
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 overall 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.
A listing of liver function tests for subjects meeting Hy’s law will be generated. A listing 
of subjects with liver function test toxicity grade >=3 will also be provided.
7.4.
Other Safety Analyses
The analyses of non-laboratory safety test results including ECGs and vital signs will be 
based on GSK Core Data Standards, unless otherwise specified. The details of the 
planned displays are presented in Appendix 10: List of Data Displays.
Vital Signs
Listing of vital signs including Systolic BP, diastolic BP, heart rate, body temperature, 
height and weight at each scheduled visit will be provided.
ECOG (Eastern Cooperative Oncology Group) Performance Status
A summary of worst case post-baseline ECOG status shift from baseline among all visits 
by dose level will be provided. A supporting listing including performance status and 
change from baseline will also be provided. 
ECG
A summary of the number and percentage of subjects who had normal and abnormal 
ECG findings will be displayed by scheduled visits as well as for the worst case post-
baseline for each dose level. A listing of abnormal ECG findings will be provided. ECG 
interval values will also be listed. 
The mean of ECG values at each collection point will be used for ECG analyses 
Summary of the worst case QTc (QTcF and QTcB) post-baseline values relative to 
baseline will be provided by dose level. The QTc values (QTcF and QTcB) will be 


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rounded to the integer and the values will be categorized into the following ranges: Grade 
0 (<450), Grade 1 (450-480), Grade 2 (481-500), and Grade 3 (≥501). 
Summary of the worst case QTc (QTcF and QTcB) increase from baseline by dose level 
will be provided. The categories of ‘Increase of <=30 msec’ ‘Increase of 31-60 msec’ and 
‘Increase of  >60 msec’ will be used. A summary of change in QTc value will display the 
number and percentage of subjects with a change within each category in the worst case 
post-baseline among all visits.
Baseline results are defined by the nearest timepoint prior to first dose.  The baseline QTc
value is determined by the mean of the triplicate Cycle 1 Day 1 (C1D1) pre-dose QTc
results.  If these results are not available, then the mean of QTc of the screening triplicate 
QTc results would be used. Subjects with a missing baseline value will be assumed to 
have a normal baseline value.
LVEF (Left Ventricular Ejection Fraction)
LVEF results will be listed with subject level details including absolute change from 
baseline. Only the post-baseline assessments that used the same method (ECHO or 
MUGA) as the baseline assessments will be used to derive the change from baseline.


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8.
EFFICACY ANALYSES
The efficacy analyses will be based on the All Subjects population. All efficacy analyses 
will be descriptive, graphically presented (where appropriate) and listed. All summaries 
and data listings will use treatment labels as specified in Section 5.1. All summaries will 
be presented by dose level and overall.
A summary of investigator-assessed best response with confirmation will be presented by 
tumor types (solid tumors and Lymphoma). Subjects with Not Evaluable or missing 
response will be treated as non-responders; and they will be included in the denominator 
when calculating the percentage.  To be assigned a status of complete response or partial 
response, all responses must be confirmed by repeat assessments performed no less than 
four weeks after the criteria for CR or PR were met (Protocol Appendix 4 (Revised 
Response Criteria for Malignant Lymphoma (RRCML) and Appendix 5 (RECIST 1.1)).
The investigator assessment of target lesion, non-target lesion and new lesion will be 
listed, separately. A listing of investigator-assessed confirmed tumor response will be 
provided. Waterfall plots of maximum investigator-assessed tumor size reduction from 
baseline will be generated for solid tumor subjects including prostate cancer and 
lymphoma subjects, respectively. 
Details of the planned displays are provided in Appendix 10: List of Data Displays.


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9.
PHARMACOKINETIC ANALYSES
9.1.
Primary Pharmacokinetic Analyses
9.1.1.
Endpoint / Variables
9.1.1.1.
Drug Concentration Measures
The GSK2816126 concentration-time data will be summarized by planned time point and 
dose cohort. Standard summary statistics will be calculated (i.e. mean, standard deviation, 
median, minimum and maximum).  
Refer to Appendix 5: Data Display Standards & Handling Conventions (Section 12.5.3
Reporting Standards for Pharmacokinetic)
9.1.1.2.
Derived Pharmacokinetic Parameters
Pharmacokinetic parameters will be calculated by standard non-compartmental analysis 
according to current working practices and using the currently supported version of 
WinNonlin Version 6.3. All calculations of non-compartmental parameters will be based 
on actual sampling times. 
Pharmacokinetic parameters listed will be determined from the plasma concentration-
time data, as data permits.
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 Cycle 1 Day 1 only
AUC(0-tau)
Area under the concentration-time curve from time zero to the predose of the next dose. 
Cmax
Maximum observed concentration, determined directly from the concentration-time data.
tmax
Time to reach Cmax, determined directly from the concentration-time data.
t½
Apparent terminal half-life will be calculated as: 
t½ = ln2 / lambda_z
λz
Apparent terminal phase elimination rate constant
C
Trough (pre-dose) concentration at the end of dosing interval on the specified days (Days 8, 
15 and 22 where available).
CL
Clearance
V
Volume
NOTES:
Additional parameters may be included as required.


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9.1.2.
Summary Measure
AUC(0-∞) and Cmax following single dose, and AUC(0- τ) and Cmax following repeat 
dose will be summarized descriptively (mean, standard deviation, median, minimum, 
maximum, geometric mean, and the standard deviation, CV% and 95% confidence 
interval (CI) of log-transformed parameters) by dose cohort.
Tmax will be summarized descriptively using non-transformed values.
In addition, the following assessments will be performed: 
9.1.3.
Population of Interest 
All pharmacokinetic analyses will be based on the PK population, unless otherwise 
specified. All summaries, figures and data listings will use treatment labels specified in 
Section 5.1.
9.1.4.
Statistical Analyses / Methods
Details of the planned displays are provided in Appendix 10: List of Data Displays and 
will be based on GSK Data Standards and statistical principles.
Unless otherwise specified, endpoints / variables defined in Section 9.1.1 will be 
summarised using descriptive statistics, graphically presented (where appropriate) and 
listed.
GSK2816126 plasma concentration-time data will be listed for each subject and 
summarized by planned time point and dose cohort. It is noted that the urine and bile 
concentration data will not be analysed due to unavailability of data.
Pharmacokinetic parameters will be listed and summarized descriptively (mean, standard 
deviation, median, minimum, maximum, geometric mean (excluding tmax and 
%AUCex), and the standard deviation, CV% and 95% confidence interval (CI) of log-
transformed parameters) by dose cohort.
The following pharmacokinetic statistical analyses will only be performed, if sufficient 
data is available (i.e. if subjects have well defined plasma profiles). 
9.1.4.1.
Dose proportionality 
If data permits, dose proportionality will be assessed using power model for:

AUC(0-∞) and Cmax on Cycle 1 Day 1 (C1D1)

AUC(0- τ) and Cmax on Cycle 1 Day 1 and Cycle 1 Day 15 (C1D15)


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Dose proportionality of GSK2816126 AUC(0-∞) and Cmax following single dose 
administration and AUC(0-) and Cmax following repeat dose administration will be 
evaluated 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.  


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10.
PHARMACODYNAMIC ANALYSES
The statistical analysis for Tri-methylated Histone H3 lysine 27 (H3K27me3) biomarker 
will be detailed and reported in a separate document and may not be included in the main 
clinical study report.


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11.
REFERENCES
GUI_137354 (2.0): Information for Authors: Reporting and Analysis Plans
GUI_51487 (5.0): Non-compartmental Analysis of Pharmacokinetic Data, CPMS Global
Kenward, M. and Roger, J. (1997). Small Sample Inference for Fixed Effects from 
Restricted Maximum Likelihood. Biometrics 53, 983-997. 
SOP_54838 (6.0): Development, Review and Approval of Reporting and Analysis Plans


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12.
APPENDICES
12.1.
Appendix 1: Protocol Deviation Management and Definitions 
for Per Protocol Population
12.1.1.
Exclusions from Per Protocol Population
There will be no Per Protocol population used for any displays or statistical analysis.


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12.2.
Appendix 2: Schedule of Activities
12.2.1.
Protocol Defined Schedule of Events
Refer to Protocol Amendment 4 Section 7.1.


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12.3.
Appendix 3: Assessment Windows
No assessment windows will be applied.


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12.4.
Appendix 4: Study Phases and Treatment Emergent 
Adverse Events
12.4.1.
Study Phases
Assessments and events will be classified according to the time of occurrence relative to 
treatment start date.
Study Phase
Definition
Pre-Treatment 
Date ≤ Study Treatment Start Date
On-Treatment
Study Treatment Start Date < Date ≤ Study Treatment Stop Date + 30 days
Post-Treatment
Date > Study Treatment Stop Date + 30 days
Some datasets include the first dosing day as On-Treatment and some exclude the first 
dosing date as On-Treatment. The first dosing day (Day 1) is considered Pre-Treatment
for ECOG, ECG, vital signs, liver events, lab tests, cardiac scan, and other safety
domains. The first dosing day (Day 1) is considered to be On-Treatment for adverse 
events and concomitant medications.
12.4.1.1.
Study Phases for Concomitant Medication
Study Phase
Definition
Prior
If medication end date is not missing and is before 28 days prior to screening visit
Concomitant
Any medication that is not a prior
NOTES: 

Refer to Appendix 7: Reporting Standards for Missing Data for handling of missing and partial dates for 
concomitant medication. Use the rules in this table if concomitant medication date is completely missing.
12.4.2.
Treatment Emergent Flag for Adverse Events
Flag
Definition
Treatment 
Emergent
If AE onset or worsening date is on or after treatment start date & on or before 
treatment stop date plus 30 days. 
NOTES: 

If the study treatment stop date is missing, then the AE will be considered to be On-Treatment.


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12.5.
Appendix 5: Data Display Standards & Handling 
Conventions
12.5.1.
Reporting Process
Software

The currently supported versions of SAS software will be used.
Reporting Area
HARP Server
: US1SALX00259
HARP Compound
: Compound: GSK2816126, Study:117208
Analysis Datasets 

Analysis datasets will be created according to Legacy GSK Analysis and Reporting (A&R) dataset 
standards
Generation of RTF Files

RTF files will be generated for SAC.
12.5.2.
Reporting Standards
General

The current GSK Integrated Data Standards Library (IDSL) will be applied for reporting, unless 
otherwise stated (IDSL Standards Location: https://spope.gsk.com/sites/IDSLLibrary/SitePages/Home.aspx):

4.03 to 4.23: General Principles

5.01 to 5.08: Principles Related to Data Listings

6.01 to 6.11: Principles Related to Summary Tables

7.01 to 7.13: Principles Related to Graphics 
Formats

GSK IDSL Statistical Principles (5.03 & 6.06.3) for decimal places (DP’s) will be adopted for reporting of 
data based on the raw data collected, unless otherwise stated.

Numeric data will be reported at the precision collected on the eCRF.

The reported precision from non eCRF sources will follow the IDSL statistical principles but may be
adjusted to a clinically interpretable number of DP’s.
Planned and Actual Time

Reporting for tables, figures and formal statistical analyses:

Planned time relative to dosing will be used in figures, summaries, statistical analyses and 
calculation of any derived parameters, unless otherwise stated.

The impact of any major deviation from the planned assessment times and/or scheduled visit days 
on the analyses and interpretation of the results will be assessed as appropriate.

Reporting for Data Listings: 

Planned and actual time relative to study drug dosing will be shown in listings (Refer to IDSL 
Statistical Principle 5.05.1).

Unscheduled or unplanned readings will be presented within the subject’s listings. 

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.


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Descriptive Summary Statistics
Continuous Data
Refer to IDSL Statistical Principle 6.06.1
Categorical Data
N, n, frequency, %
Graphical Displays

Refer to IDSL Statistical Principals 7.01 to 7.13.
12.5.3.
Reporting Standards for Pharmacokinetic
Pharmacokinetic Concentration Data
PC Windows Non-
Linear (WNL) File
PC WNL file (CSV format) for the non compartmental analysis by Clinical 
Pharmacology Modelling and Simulation function will be created according to 
GUI_51487: Non-compartmental Analysis of Pharmacokinetic Data.
Note: Concentration values will be imputed as per GUI_51487
Descriptive Summary 
Statistics, Graphical 
Displays and Listings
Refer to IDSL PK Display Standards.
Refer to IDSL Statistical Principle 6.06.1.
Note: Concentration values will be imputed as per GUI_51487 for descriptive 
summary statistics/analysis and summarized graphical displays only. 
Pharmacokinetic Parameter Data
Is NQ impacted PK 
Parameters Rule 
Being Followed
Yes, refer to GUI_51487
Descriptive Summary 
Statistics, Graphical 
Displays and Listings
Refer to IDSL PK Display Standards.
Refer to GUI_51487


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12.6.
Appendix 6: Derived and Transformed Data
12.6.1.
General
Multiple Measurements at One Analysis Time Point

Mean of the measurements will be calculated and used in any derivation of summary statistics but if 
listed, all data will be presented.

If there are two values within a time window the value closest to the target day for that window will be 
used. If values are the same distance from the target, then the mean will be taken.

Participants having both High and Low values for Normal Ranges at any post-baseline visit for safety 
parameters will be counted in both the High and Low categories of “Any visit post-baseline” row of 
related summary tables. This will also be applicable to relevant Potential Clinical Importance (PCI) 
summary tables.
Study Day

Calculated as the number of days from First Dose Date:

Ref Date = Missing              → Study Day = Missing 

Ref Date < First Dose Date → Study Day = Ref Date – First Dose Date

Ref Date≥ First Dose Date → Study Day = Ref Date – (First Dose Date) + 1    
12.6.2.
Study Population
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


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12.7.
Appendix 7: Reporting Standards for Missing Data
12.7.1.
Premature Withdrawals
Element
Reporting Detail
General

A subject will be considered to have completed the study after they have completed 
their end of study visit or if the subject dies or is still in follow-up at the time the study is 
closed or terminated, whichever is sooner.  

Withdrawn subjects may be replaced in the study at the discretion of the Sponsor in 
consultation with the investigator.

All available data from participants who were withdrawn from the study will be listed 
and all available planned data will be included in summary tables and figures, unless 
otherwise specified.

Withdrawal visits will be summarised as withdrawal visits.
12.7.2.
Handling of Missing Data
Element
Reporting Detail
General

Missing data occurs when any requested data is not provided, leading to blank fields on 
the collection instrument:
o
These data will be indicated by the use of a “blank” in subject listing displays. 
Unless all data for a specific visit are missing in which case the data is excluded 
from the table. 
o
Answers such as “Not applicable” and “Not evaluable” are not considered to be 
missing data and should be displayed as such.
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.
12.7.2.1.
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. 
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 not be 
stored on datasets. 
Imputed dates will not be displayed in listings. However, where necessary, display 
macros may impute dates as temporary variables for the purpose of sorting data in listings 
only. In addition, partial dates may be imputed for ‘slotting’ data to study time periods or 
for specific analysis purposes as outlined below. 


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Element
Reporting Detail
General

Partial dates will be displayed as captured in subject listing displays.
Adverse 
Events

The eCRF allows for the possibility of partial dates (i.e., only month and year) to be 
recorded for AE start and end dates; that is, the day of the month may be missing. In 
such a case, the following conventions will be applied for calculating the time to onset 
and the duration of the event:
o
Missing Start Day: First of the month will be used unless this is before the start 
date of study treatment; in this case the study treatment start date will be used and 
hence the event is considered On-treatment as per Appendix 4: Study Phases and 
Treatment Emergent Adverse Events.
o
Missing Stop Day: Last day of the month will be used, unless this is after the stop 
date of study treatment; in this case the study treatment stop date will be used.

Completely missing start or end dates will remain missing, with no imputation applied. 
Consequently, time to onset and duration of such events will be missing.
Concomitant 
Medications/
Medical 
History

Partial dates for any concomitant medications recorded in the CRF will be imputed 
using the following convention:
o
If the partial date is a start date, a '01' will be used for the day and 'Jan' will be 
used for the month
o
If the partial date is a stop date, a '28/29/30/31' will be used for the day (dependent 
on the month and year) and 'Dec' will be used for the month.
The recorded partial date will be displayed in listings.


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12.8.
Appendix 8: Values of Potential Clinical Importance
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. 


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12.9.
Appendix 9: Abbreviations & Trade Marks
12.9.1.
Abbreviations
Abbreviation
Description
AE
Adverse Event
ALT
Alanine aminotransferase
ANOVA
Analysis of Variance
A&R
Analysis and Reporting
AST
Aspartate aminotransferase
ATC
Anatomical Therapeutic Chemical
AUC
Area under the concentration-time curve
AUC(0-)
Area under the concentration-time curve from time zero (pre-dose) extrapolated 
to infinite time
AUC(0-t)
Area under the concentration-time curve from time zero (pre-dose) to last time 
of quantifiable concentration within a subject across all treatments
AUC(0-)
Area under the concentration-time curve over the dosing interval
A&R
Analysis and Reporting 
BUN
Blood urea nitrogen
CI
Confidence Interval
CL
Clearance
Cmax
Maximum observed concentration 
CPMS
Clinical Pharmacology Modelling & Simulation
CR
Complete response
CS
Clinical Statistics
CSR
Clinical Study Report
CTCAE
Common Terminology Criteria for Adverse Events
Ctau or C
Pre-dose (trough) concentration at the end of the dosing interval
C1D1
Cycle 1 Day 1
C1D15
Cycle 1 Day 15
DLBCL
Diffuse Large B Cell Lymphoma
DLT
Dose-limiting toxicity
DoR
Duration of response
DP
Decimal Places
ECG(s)
Electrocardiogram(s)
ECOG
Eastern Cooperative Oncology Group
eCRF
Electronic Case Report Form
EZH2
Enhancer of Zeste Homolog 2
FDA
Food and Drug Administration
FDAAA
Food and Drug Administration Clinical Results Disclosure Requirements
GCB
Germinal Center B-cell like 
GCB-DLBCL
Germinal Center B-cell-like Diffuse Large B-cell Lymphoma
GLS
Geometric least squares
GSK
GlaxoSmithKline
H3K27me3
Tri-methylated Histone H3 lysine 27
ICH
International Conference on Harmonization


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Abbreviation
Description
IDMC
Independent Data Monitoring Committee 
IDSL
Integrated Data Standards Library
IHC
Immunohistochemistry
INR
International normalization ratio
LDH
Lactate dehydrogenase
LVEF
Left ventricular ejection fraction
λz
Apparent terminal phase elimination rate constant
MCH
Mean corpuscular hemoglobin
MCHC
Mean corpuscular hemoglobin concentration
MCV
Mean corpuscular volume
MedDRA
Medical Dictionary for Regulatory Activities
MM
Multiple Myeloma
msec
Millisecond
MTD
Maximum tolerated dose
NCI-CTCAE
National Cancer Institute - Common Terminology Criteria for Adverse Events
NHL
Non-Hodgkin’s Lymphoma
PCI
Potential Clinical Importance 
PD
Pharmacodynamic
PFS
Progression-free survival
PK
Pharmacokinetic
PR
Partial response
PT
Preferred Term
QTc
Corrected QT interval duration
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 
RBC
Red blood cell
REML
Restricted maximum likelihood
RP2D
Recommended Phase 2 dose
SAC
Statistical Analysis Complete
SAE
Serious adverse event(s)
SOC
System Organ Class
SOP
Standard Operation Procedure
t1/2
Terminal phase half-life
Tau or 
Dosing interval
tFL
Transformed Follicular Lymphoma
TFL
Tables, Figures & Listings 
tmax
Time of occurrence of Cmax
V
Volume
WBC
White blood cell
WT
Wild-type


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12.9.2.
Trademarks
Trademarks of the GlaxoSmithKline 
Group of Companies
Trademarks not owned by the 
GlaxoSmithKline Group of Companies
None
SAS
WinNonlin


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12.10.
Appendix 10: List of Data Displays
12.10.1.
Data Display Numbering
The following numbering will be applied for RAP generated displays:
Section
Tables
Figures
Study Population
1.1 to 1.12
N/A
Efficacy
2.1
2.2
Safety
3.1 to 3.17
N/A
Pharmacokinetic
4.1 to 4.3
4.1
Section
Listings
ICH Listings
1 to 22
Other Listings
23 to 31
12.10.2.
Mock Example Shell Referencing
Non IDSL specifications will be referenced as indicated and example mock-up displays 
are provided in Appendix 11: Example Mock Shells for Data Displays.
Section
Figure
Table
Listing
Safety
N/A
SAFE_T1
SAFE_L2
Pharmacokinetic
N/A
PK_T1
PK_L1
NOTES: 

Non-Standard displays are indicated in the ‘IDSL /  Example Shell’ or ‘Programming Notes’ column as ‘[Non-
Standard] + Reference.’
12.10.3.
Deliverables
Delivery [Priority] [1]
Description
SAC [1]
Final Statistical Analysis Complete
NOTES: 
1.
Indicates priority (i.e. order) in which displays will be generated for the reporting effort


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12.10.4.
Study Population Tables
Study Population Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Subject Disposition
1.1.
All Subjects
ES1
Summary of Subject Disposition
ICH E3, FDAAA, EudraCT
SAC [1]
1.2.
Enrolled
NS1
Summary of Number of Participants by Country and Site ID
EudraCT/Clinical Operations
SAC [1]
Protocol Deviation
1.3.
All Subjects
DV1
Summary of Important Protocol Deviations
ICH E3
SAC [1]
Demographic and Baseline Characteristics
1.4.
All Subjects
DM1 
Summary of Demographic Characteristics
ICH E3, FDAAA, EudraCT
SAC [1]
1.5.
Enrolled
DM11
Summary of Age Ranges
EudraCT
Age categories: 18-64, 65-74, 75-84 
and ≥85
SAC [1]
1.6.
All Subjects
DM5
Summary of Race and Racial Combinations
ICH E3, FDA, FDAAA, EudraCT
SAC [1]
Prior and Concomitant Medications
1.7.
All Subjects
MH1
Summary of Current/Past Medical Conditions
ICH E3
SAC [1]
1.8.
All Subjects
CM1
Summary of Concomitant Medications
ICH E3
SAC [1]
1.9.
All Subjects
LA1
Summary of Disease Burden at Screening
SAC [1]
1.10.
All Subjects
DC2
Summary of Disease Characteristics at Screening for Subjects 
with Solid Tumors Including Prostate Cancer
SAC [1]
1.11.
All Subjects
DC2
Summary of Disease Characteristics at Screening for Subjects 
with Lymphomas
SAC [1]
Exposure and Treatment Compliance
1.12.
All Subjects
OEX5
Summary of Exposure to Study Treatment
ICH E3
Calculate dose intensity per cycle.
SAC [1]


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12.10.5.
Efficacy Tables
Efficacy: Tables
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Clinical Response
2.1.
All Subjects
RE1a
Summary of Investigator-Assessed Best Response with 
Confirmation
By dose and disease types (solid tumor 
and lymphoma). no p-values.
SAC [1]
12.10.6.
Efficacy Figures
Efficacy: Figures
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
2.1.
All Subjects
RE8b
Plot of Investigator-Assessed Percent Change at Maximum 
Reduction from Baseline in Tumor Measurement for Subjects 
with Solid Tumors Including Prostate Cancer
SAC [1]
2.2.
All Subjects
RE8b
Plot of Investigator-Assessed Percent Change at Maximum 
Reduction from Baseline in Tumor Measurement for Subjects 
with Lymphomas
SAC [1]


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12.10.7.
Safety Tables
Safety: Tables
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Adverse Events (AEs)
3.1.
All Subjects
OAE1
Summary of All Adverse Events by Maximum Grade by System 
Organ Class and Preferred Term
ICH E3
By dose, and overall. For each SOC, 
sort PT in descending order of 
incidence
SAC [1]
3.2.
All Subjects
AE3
Summary of All Adverse Events by Frequency
ICH E3
SAC [1]
3.3.
All Subjects
AE15
Summary of Common (>=5%) Non-serious Adverse Events by 
System Organ Class and Preferred Term (Number of Participant 
and Occurrences)
FDAAA, EudraCT
For each SOC, sort Preferred Terms by 
highest incidence rate
SAC [1]
3.4.
All Subjects
OAE1
Summary of Treatment-Related Adverse Events by Maximum 
Grade by System Organ Class and Preferred Term
ICH E3
For each SOC, sort PT in descending 
order of incidence
SAC [1]
3.5.
All Subjects
AE3
Summary of Treatment-Related Adverse Events by Frequency
SAC [1]
Serious and Other Significant Adverse Events
3.6.
All Subjects
AE16
Summary of Serious Adverse Events by System Organ Class 
and Preferred Term (Number of Participants and Occurrences)
FDAAA, EudraCT
For each SOC, sort PT in descending 
order of incidence
SAC [1]
3.7.
All Subjects
AE3
Summary of Serious Adverse Events by Frequency
SAC [1]
Laboratory: Chemistry 
3.8.
All Subjects
LB16
Summary of Worst Case Clinical Chemistry Toxicity Grade 
Change from Baseline Grade
ICH E3
For gradable Clinical chemistry tests. 
By dose, and overall. 
SAC [1]


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Safety: Tables
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Laboratory: Haematology
3.9.
All Subjects
LB16
Summary of Worst Case Haematology Toxicity Grade Change 
from Baseline Grade
ICH E3
For gradable Haematology tests. By 
dose, and overall.
SAC [1]
Laboratory: Hepatobiliary (Liver)
3.10.
All Subjects
OLIVER10
Summary of Hepatobiliary Laboratory Abnormalities
IDSL
SAC [1]
All Laboratory
3.11.
All Subjects
LB15
Summary of Worst Case Laboratory Changes from Baseline 
with Respect to the Normal Range
ICH E3
For non-gradable lab tests. By dose, 
and overall. 
SAC [1]
ECG
3.12.
All Subjects
EG1
Summary of ECG Findings 
IDSL
SAC [1]
3.13.
All Subjects
EG10
Summary of Maximum QTc Values Post-Baseline Relative to 
Baseline by Category
IDSL
SAC [1]
3.14.
All Subjects
EG11
Summary of Maximum Increase in QTc Values Post-Baseline 
Relative to Baseline by Category
IDSL
SAC [1]
ECOG
3.15.
All Subjects
SAFE_T1
Summary of Worst-Case ECOG Performance Status Shifts from 
Baseline
SAC [1]
Exposure
3.16.
All Subjects
ODMOD1
Summary of Dose Reductions
SAC [1]
3.17.
All Subjects
ODMOD2
Summary of Dose Interruptions


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12.10.8.
Pharmacokinetic Tables
Pharmacokinetic: Tables
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
4.1.
PK
PK01
Summary of GSK2816126 Plasma Pharmacokinetic 
Concentration-Time Data
SAC [1]
4.2.
PK
PK06
Summary of Derived GSK2816126 Plasma Pharmacokinetic 
Parameters (non-transformed and log-transformed), Subjects 
with Extensive PK Sampling
SAC [1]
4.3.
PK
PK_T1
Summary of Results of Dose Proportionality Assessment for 
AUC(0- τ) and Cmax Using Power Model – C1D1 and C1D15
SAC [1]
12.10.9.
Pharmacokinetic Figures
Pharmacokinetic: Figures
No.
Population
IDSL /
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
4.1.
PK
PK17
Mean GSK2816126 Plasma Concentration-Time Plots (Linear 
and Semi-log) for C1D1 and C1D15, Subjects with Extensive PK 
Sampling
SAC [1]


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12.10.10. ICH Listings
ICH: Listings
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Subject Disposition
1.
All Subjects
SD2
Listing of Study Treatment Discontinuation
ICH E3
SAC [1]
Protocol Deviations
2.
All Subjects
DV2
Listing of Important Protocol Deviations 
ICH E3
SAC [1]
Demographic and Baseline Characteristics
3.
All Subjects
DM2
Listing of Demographic Characteristics
ICH E3
SAC [1]
Exposure and Treatment Compliance
4.
All Subjects
OEX8b
Listing of Exposure to Study Treatment
ICH E3
SAC [1]
Adverse Events
5.
All Subjects
AE2
Listing of Relationship Between Adverse Event System Organ 
Classes, Preferred Terms, and Verbatim Text
IDSL
6.
All Subjects
OAE4
Listing of All Adverse Events
ICH E3
SAC [1]
Serious and Other Significant Adverse Events
7.
All Subjects
OAE4
Listing of Fatal Serious Adverse Events
ICH E3
SAC [1]
8.
All Subjects
OAE4
Listing of Non-Fatal Serious Adverse Events
ICH E3
SAC [1]


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49
ICH: Listings
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
9.
All Subjects
OAE4
Listing of Dose-Limiting Toxicity
SAC [1]
10.
All Subjects
DTH3
Listing of Deaths
SAC [1]
All Laboratory
11.
All Subjects
OLB7
Listing of Clinical Chemistry Laboratory Data
SAC [1]
12.
All Subjects
OLB7
Listing of Haematology Laboratory Data
SAC [1]
ECG
13.
All Subjects
EG3
Listing of ECG Interval Data
SAC [1]
14.
All Subjects
EG5
Listing of Abnormal ECG Findings
IDSL
Vital Signs
15.
All Subjects
VS4 
Listing of Vital Signs 
IDSL
SAC [1]
ECOG
16.
All Subjects
PS5A
Listing of ECOG Performance Status
SAC [1]
PK
17.
All Subjects
PK07
Listing of GSK2816126 Plasma PK Concentration-Time Data 
SAC [1]
18.
All Subjects
PK13
Listing of GSK2816126 Plasma PK Parameters Data – C1D1 
and C1D15
SAC [1]
Efficacy
19.
All Subjects
LA2
Listing of Investigator-Assessed Target Lesion Assessments 
SAC [1]
20.
All Subjects
LA3
Listing of Investigator-Assessed Non Target Lesion 
Assessments 
SAC [1]
21.
All Subjects
LA4
Listing of Investigator-Assessed New Lesions
SAC [1]


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ICH: Listings
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
22.
All Subjects
RE5
Listing of Investigator-Assessed Tumor Responses with 
confirmation
SAC [1]
12.10.11. Non-ICH Listings
Non-ICH: Listings
No.
Population
IDSL / 
Example Shell
Title
Programming Notes
Deliverable 
[Priority]
Study Population
23.
All Subjects
AC6
Listing of Prior Anti-Cancer Chemotherapy, Hormonal, 
Immunotherapy, Small Molecule Target Therapy, and Biologic 
Therapy
SAC [1]
24.
All Subjects
AC7
Listing of Prior Anti-Cancer Radiation Therapy 
SAC [1]
25.
All Subjects
OSP3
Listing of Prior Anti-Cancer Surgery
SAC [1]
Safety
26.
All Subjects
SAFE_L1
Listing of Echocardiogram Scan Results 
SAC [1]
27.
All Subjects
OAE4
Listing of Subjects with Grade 3 and Higher Adverse Events
SAC [1]
28.
All Subjects
SAFE_L2
Listing of Subjects with Liver Function Test Toxicity Grade >=3
SAC [1]
29.
All Subjects
SAFE_L2
Listing of Liver Function Tests for Subjects Meeting Potential 
Hy’s Law
SAC [1]
Efficacy
30.
All Subjects
LA5
Listing of Investigator-Assessed Lesion Assessments
SAC [1]
PK
31.
PK
PK_L1
SAS Output of Results of Dose Proportionality Assessment for 
AUC(0- τ) and Cmax Using Power Model – C1D1 and C1D15
SAC [1]


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12.11.
Appendix 11: Example Mock Shells for Data Displays
Example: SAFE_T1
Protocol: EZH117208                                                                            Page 1 of 1
Population: All Treated 
                                                Table 3.14
            Summary of Worst-case ECOG Performance Status Shifts from Baseline 
                                           
Dose: 50mg
Baseline
Performance             _________________________ Worst-Case Performance Status __________________________
Status                  0           1           2           3           4           5           Total
----------------------------------------------------------------------------------------------------------
   0                     xx (xx%)    xx (xx%)    xx (xx%)    xx (xx%)    xx (xx%)    xx (xx%)     xx  (xx%)
   1                     xx (xx%)    xx (xx%)    xx (xx%)    xx (xx%)    xx (xx%)    xx (xx%)     xx  (xx%)
   2                     xx (xx%)    xx (xx%)    xx (xx%)    xx (xx%)    xx (xx%)    xx (xx%)     xx  (xx%)
   Total                 xx (xx%)    xx (xx%)    xx (xx%)    xx (xx%)    xx (xx%)    xx (xx%)     xx  (100%)


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Example: PK_T1
Protocol: EZH117208                                                                              Page 1 of 1
Population: PK
                                                 Table 4.3
      Summary of Results of Dose Proportionality Assessment for AUC(0-inf) and Cmax Using Power Model -
                                                C1D1 and C1D15
                                                                 90% Confidence Interval
                                                                 ------------------------
                                        Number of   Estimated         90% CI       90% CI
                  Parameter              Subjects   Mean Slope           Low         High
                  -----------------------------------------------------------------------
                  AUCinf                       xx      xx.xxx          xx.xxx       xx.xxx
                  (unit)
                  Cmax                         xx      xx.xxx          xx.xxx       xx.xxx
                  (unit)


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Example: SAFE_L1
Protocol: EZH117208                                                                             Page 1 of 1
Population: All Subjects
                                                 Listing 26
                                     Listing of Echocardiogram Scan Results
                                                                       Ejection
                                                                       Fraction
                     Age(y)/                   Date/        Ejection      Range     Change
             Cent./  Sex/                      Study        Fraction      Lower       from
  Dose       Subj.   Race         Visit        Day                 %      Limit   Baseline Scan Results
  --------------------------------------------------------------------------------------------------------
  50mg     xxxxxx/  xx/          SCREENING    DDMMMYYYY/       66         55              Normal
              xxxx    F/                        xx
                     White -
                     White/Caucas
                     ian/European
                     Heritage
                                  CD-WEEK12    DDMMMYYYY/       61         55     -5.00    Abnormal, not
                                               xx                                          Clinically
                                                                                           Significant
                                  CD-WEEK21    DDMMMYYYY/       66         45      0.00    Abnormal, not
                                               xx                                          Clinically
                                                                                           Significant
                                  CD-WEEK24    DDMMMYYYY/       65         45     -1.00    Normal
                                               xx


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Example: SAFE_L2
Protocol: EZH117208                                                                            Page 1 of 1
Population: All Subjects
                                                 Listing 28
                      Listing of Subjects with Liver Function Test Toxicity Grade >=3
Dose: 50 mg
            Age(y)/                           Date of                                           NR
    Inv./   Sex/                              Collection/               ____Converted Data_____ Flag Tox
    Subj.   Race     Lab Test                 Study Day     Visit       Result  Normal Range    [1]  Gr.
    ----------------------------------------------------------------------------------------------------
    xxxxxx/ 47/      Alanine Amino            DDMMMYYYY/-10 SCREENING   xx      0 - 34               0
    xxxx    M/       Transferase (IU/L)
            White -
            White/Ca
            ucasian/
            European
            Heritage
                                              DDMMMYYYY /-1  C1D1       xx      0 - 34          H    1
                                              DDMMMYYYY /4   C1D4       xx      0 - 34         H    1
                                              DDMMMYYYY /8   C1D7       xx      0 - 34          H    1
                                                            UNSCHEDULED
                                              DDMMMYYYY /8   Worst-case  xx      0 - 34         H    1
                                                            on-therapy
                     Albumin (G/L)            DDMMMYYYY /-10 SCREENING   xx      35 - 50              0
                                              DDMMMYYYY /-1   C1D1       xx      35 - 50         L    1
                                              DDMMMYYYY /4    C1D4       xx      35 - 50         L    1
[1] Normal Range flag; H=Above range, L=Below range, M=Missing reference range, U=Unconverted lab value


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Example: PK_L1
Protocol: EZH117208                                                                              Page 1 of 1
Population: PK
                                                 Listing 31
      SAS Output of Results of Dose Proportionality Assessment for AUC(0-inf) and Cmax Using Power Model
                                                C1D1
                                    Power Model For AUCINF Parameter
                                                                              (SAS output)
                                    Power Model For Cmax Parameter
                                                                               (SAS output)