A Phase I, First Time in Human, Open-Label, Dose Escalation Study to Investigate the Safety, Pharmacokinetics, and Pharmacodynamics of Anti-Her3 Monoclonal Antibody GSK2849330 in Subjects With Advanced Her3-Positive Solid Tumors
Phase: PHASE1
Conditions: Cancer, Neoplasms
Sponsor: GlaxoSmithKline

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The GlaxoSmithKline group of companies
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TITLE PAGE
Division: Worldwide Development
Information Type: Protocol Amendment
Title:
A Phase I, first time in human, open-label, dose escalation study 
to investigate the safety, pharmacokinetics, and 
pharmacodynamics of anti-HER3 monoclonal antibody 
GSK2849330 in subjects with advanced HER-3 positive solid 
tumors
Compound Number:
GSK2849330
Development Phase:
I
Effective Date:
09-JAN-2015
Description: This is a Phase I, first time in human (FTIH), open-label, multi-center,
dose-escalation study of the anti-HER3 monoclonal antibody, GSK2849330 administered 
to subjects with HER3-expressing or HER3 and NRG1-expressing solid tumors. The 
study will be conducted in two parts. Part 1 will include dose escalation and 
pharmacokinetic (PK)/ pharmacodynamic (PD) cohorts to evaluate safety, PK, and PD to 
guide selection of dose regimen(s) for Part 2. Part 2 will include at least 4 molecularly-
defined tumor histology groups that will be studied to further characterize safety, PK, PD, 
and evaluate initial clinical activity of GSK2849330.
Protocol Amendment Number:  2
Author(s):
Oncology Biomarkers, UP, USA
Biopharm Clinical Pharmacology, UM, USA 
Biopharm R&D, UM, USA
Global Oncology Data Sciences, RTP, USA
Oncology R&D, RTP, USA
Clin Pharm Mod & Sim, RTP, USA
Oncology R&D, UP, USA
Oncology Clinical Statistics, UP, USA
Copyright 2015 the GlaxoSmithKline group of companies.  All rights reserved.  
Unauthorised copying or use of this information is prohibited.
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The GlaxoSmithKline group of companies
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Revision Chronology
GlaxoSmithKline
Document Number
Date
Version
2012N152466_00
2013-AUG-06
Original
2012N152466_01
2014-SEP-10
Amendment No. 1
Four molecularly-defined, tumor histology groups were added for study during Part 2: 
Group 1 will include subjects with HER3-expressing melanoma, Group 2 will include 
subjects with HER3-expressing gastric/gastroesophageal cancer, Group 3 will include 
subjects with HER3 and NRG1-expressing cancers of the head and neck, and Group 4 
will include subjects with HER3 and NRG1-expressing non-small cell lung carcinoma 
(NSCLC).
Additional inclusion criteria for subjects in Part 2 were added to clarify the number of 
prior lines of therapy allowed for study entry and to require subjects to undergo pre and 
on-treatment tumor biopsies.
References to cohorts of subjects in Part 2 were removed and replaced with groups of 
subjects.
An additional cohort of subjects was added to Part 1. This cohort will receive weekly 
treatment with 30 mg/kg GSK2849330, with an option to reduce dosing frequency to 
every 2 weeks after 24 weeks.
The approximate number of subjects in Part 1 was changed from 10 to 13, to 
accommodate the additional weekly cohort. The anticipated number of subjects in Part 1 
is now 34.
The rationale for adding a weekly dosing regimen was added.
Clarification regarding ECHO as the preferred method of LVEF assessment has been 
added.
The exclusion criteria for subjects with untreated brain or meningeal metastases and 
subjects treated for stable brain metastases were clarified.
PK sampling times were revised for subjects in Part 1enrolled under this amendment and 
for subjects enrolled in Part 2.
An Efficacy Population was defined.
Recent findings on the biodistribution of GSK2849330 in mice were added.
Preclinical and nonclinical findings on HER3 antibodies from recent studies and abstracts 
were added, including the rationale for the tumor types selected for Part 2.
The predicted half-life of GSK2849330 was changed from 8-9 days to 7 days at 
30 mg/kg. The expected dosing frequency was changed from 2 weeks to 1-2 weeks.
Preliminary noncompartmental and population PK parameters for the 1.4 mg/kg, 
3 mg/kg, and 10 mg/kg doses were added.
The definitions for subject and study completion were clarified.

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The timing for disease assessment at the end of the study was clarified.
The timing for serum samples for immunogenicity at the end of the study was clarified.
Permitted and prohibited medications (growth factors, anticoagulants, and 
corticosteroids) were clarified.
The recommendations for management of diarrhea were expanded.
The requirement for a sample for selected cytokines in subjects experiencing suspected 
infusion-related reactions was added.
The criterion for withholding of study treatment for QTc prolongation was clarified.
Vials containing 5 mL of investigational product were introduced, and 1-mL vials will 
also continue to be used.
References to “randomization” were changed to “enrollment.”
Several authors to the protocol were changed.
Minor grammatical and formatting changes were made throughout the document.
2012N152466_02
2015-JAN-09
Amendment No. 2
The inclusion criteria were modified for Molecularly Defined Tumor Histology Groups 1, 
2 and 4 in Part 2 to remove the statement that subjects would be eligible for inclusion into 
the study if they had not received standard therapy when such therapy was not available 
to them commercially or via a clinical trial. 
The definition of DLT for subjects with thrombocytopenia was expanded to include 
Grade 3 events of thrombocytopenia associated with bleeding in addition to all Grade 4 
events.
The statements regarding obtaining paired tumor biopsies have been modified to include
that all biopsies should be obtained from tumor easily accessible to biopsy using a 
procedure that is safe for the subject.
The total volume of blood to be collected within the first 30 days of participation has 
been modified to account for the increased PK sampling.
Inconsistencies were corrected in the Time and Events Tables in Section 7.
Minor grammatical and formatting changes were made throughout the document.

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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
Fax Number
GSK Address
Primary 
Medical 
Monitor
MD, MS,MBA
1250 South Collegeville Road
Mailstop UP4410
Collegeville, PA 19426, USA
Secondary 
Medical 
Monitor
 
MD
 
 
Gunnels Wood Road
Stevenage Herts, SG1 2NY
Tertiary 
Medical 
Monitor
MD, 
PhD
1250 South Collegeville Road
Mailstop UP4410
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):  NA
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INVESTIGATOR PROTOCOL AGREEMENT PAGE
For protocol HER117158 
I confirm agreement to conduct the study in compliance with the protocol, as amended by 
this protocol amendment.
I acknowledge that I am responsible for overall study conduct. I agree to personally 
conduct or supervise the described study.
I agree to ensure that all associates, colleagues and employees assisting in the conduct of 
the study are informed about their obligations. Mechanisms are in place to ensure that site 
staff receives the appropriate information throughout the study. 
Investigator Name:
Investigator Address:
Investigator Phone Number:
Investigator Signature
Date

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TABLE OF CONTENTS
PAGE
LIST OF ABBREVIATIONS...........................................................................................12
PROTOCOL SYNOPSIS...............................................................................................16
1.
INTRODUCTION....................................................................................................32
1.1.
Background ................................................................................................32
1.2.
GSK2849330..............................................................................................33
1.2.1.
GSK2849330 - Background .........................................................33
1.2.2.
Pre-clinical Pharmacokinetics of GSK2849330 ............................33
1.2.3.
Nonclinical Safety of GSK2849330 ..............................................34
1.2.4.
Pre-clinical Activity and Pharmacodynamics of 
GSK2849330...............................................................................35
1.2.4.1.
In vitro studies ............................................................35
1.2.4.2.
Studies in vivo ............................................................36
1.3.
HER3 antibodies in Clinical Trials ...............................................................36
1.4.
Summary of Risk Management...................................................................37
2.
OBJECTIVE(S) AND ENDPOINT(S) ......................................................................38
2.1.
Part 1: Dose Escalation and PK-PD Cohorts ..............................................38
2.2.
Part 2: Molecularly Defined Tumor Histology Groups..................................39
3.
INVESTIGATIONAL PLAN.....................................................................................40
3.1.
Discussion of Study Design ........................................................................40
3.2.
Pre-Screening.............................................................................................41
3.3.
Part 1: Dose-Escalation Phase ...................................................................41
3.3.1.
Dose-Limiting Toxicity..................................................................44
3.3.2.
Maximum Tolerated Dose............................................................44
3.4.
Part 2: Molecularly-Defined Tumor Histology Groups .................................45
3.5.
Intra-subject Dose-Escalation .....................................................................45
3.6.
Rationale ....................................................................................................45
3.6.1.
Rationale for Study ......................................................................45
3.6.2.
Rationale for Population...............................................................46
3.6.3.
Rationale for Dose.......................................................................48
3.6.4.
Rationale for Endpoints................................................................53
3.7.
Study Treatment .........................................................................................53
3.7.1.
Treatment Assignment.................................................................53
3.7.2.
Dosage and Administration of Study Treatment(s).......................54
3.7.3.
Blinding........................................................................................54
3.8.
Safety Management Guidelines..................................................................54
3.8.1.
Liver Chemistry Stopping Criteria ................................................54
3.8.1.1.
Liver Chemistry Follow-up Procedures .......................55
3.8.2.
QTc Stopping Criteria ..................................................................57
3.8.3.
Left Ventricular Ejection Fraction (LVEF) Stopping Criteria..........57
3.8.3.1.
LVEF Stopping Criteria...............................................57
3.9.
Guidelines for Events of Special Interest and Dose Modifications...............58
3.9.1.
Management of Infusion Reactions..............................................58
3.9.2.
Allergic Reaction Monitoring and Management............................59
3.9.3.
Diarrhea Management .................................................................59

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3.9.4.
Dose Modifications ......................................................................60
3.9.5.
Dose Reductions .........................................................................60
4.
INVESTIGATIONAL PRODUCT(S) ........................................................................60
4.1.
Description of Investigational Product(s).....................................................61
4.2.
Preparation/Handling/Storage of GSK2849330 GSK Investigational 
Product.......................................................................................................61
4.3.
Product Accountability ................................................................................62
4.4.
Treatment Compliance................................................................................62
4.5.
Treatment of Investigational Product Overdose ..........................................62
5.
STUDY POPULATION...........................................................................................63
5.1.
Number of Subjects ....................................................................................63
5.2.
Subject Selection Criteria............................................................................63
5.2.1.
Pre-screening Inclusion Criteria for Part 1....................................63
5.2.2.
Pre-screening for Part 2...............................................................64
5.2.3.
Screening Inclusion Criteria for Parts 1 and 2..............................64
5.2.4.
Inclusion Criteria for Part 2 ONLY................................................66
5.2.5.
Screening Exclusion Criteria for Parts 1 and 2.............................67
6.
COMPLETION OR WITHDRAWAL OF SUBJECTS...............................................68
6.1.
Screen and Baseline Failures .....................................................................68
6.2.
Subject Completion Criteria ........................................................................69
6.3.
Permanent Discontinuation from Study Treatment......................................69
6.4.
Study Completion .......................................................................................69
6.5.
Treatment after the End of the Study ..........................................................70
7.
STUDY ASSESSMENTS AND PROCEDURES .....................................................70
7.1.
Time and Events Tables .............................................................................71
7.2.
Demographic/Medical History and Baseline Assessments..........................93
7.2.1.
Critical Baseline Assessments.....................................................93
7.3.
Safety Evaluations......................................................................................93
7.3.1.
Physical Examinations.................................................................93
7.3.2.
ECOG Performance Status..........................................................93
7.3.3.
Vital Signs....................................................................................93
7.3.4.
Electrocardiogram........................................................................94
7.3.5.
Echocardiogram and/or Multi-gated Acquisition (MUGA) 
Scans ..........................................................................................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............................97
7.4.2.
Pharmacokinetic Sample Analysis ...............................................97
7.5.
Immunogenicity...........................................................................................97
7.5.1.
Blood Sample Collection..............................................................97
7.5.2.
Sample Analysis ..........................................................................98
7.6.
Translational Research...............................................................................98
7.6.1.
Tumor Biomarker Analysis...........................................................99
7.6.1.1.
Tumor Tissue for Pre-screening Assessments 
and Exploratory Research ..........................................99
7.6.1.2.
Tumor Biopsies ..........................................................99
7.6.2.
Skin Biopsies.............................................................................100

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7.6.3.
Blood Samples ..........................................................................100
7.6.3.1.
Circulating Cell-free DNA (cfDNA) Analysis..............101
7.6.3.2.
Cytokines Analysis ...................................................101
7.7.
Pharmacogenetics (PGx)..........................................................................101
7.8.
Evaluation of Anti-Cancer Activity .............................................................102
8.
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS...................................102
8.1.
Definition of an AE....................................................................................102
8.2.
Definition of an SAE..................................................................................103
8.2.1.
Sentinel Events..........................................................................104
8.3.
Laboratory and Other Safety Assessment Abnormalities Reported 
as AEs and SAEs .....................................................................................105
8.3.1.
Cardiovascular Events...............................................................105
8.4.
Disease-Related Events and/or Disease-Related Outcomes Not 
Qualifying as SAEs...................................................................................106
8.5.
Time Period and Frequency of Detecting AEs and SAEs..........................106
8.5.1.
Method of Detecting AEs and SAEs...........................................106
8.5.2.
Prompt Reporting of SAEs and Other Events to GSK ................107
8.5.3.
Regulatory Reporting Requirements for SAEs ...........................109
9.
LIVER CHEMISTRY FOLLOW-UP PROCEDURES.............................................109
9.1.
Liver Chemistry Testing Procedures .........................................................109
9.2.
Liver Chemistry Monitoring Criteria...........................................................110
9.3.
Drug Restart/Rechallenge Following Liver Events that are Possibly 
Related to Study Drug(s) ..........................................................................110
9.4.
Drug Restart Following Transient, Resolving Liver Events Not 
Related to Study Drug(s) ..........................................................................111
10. CONCOMITANT MEDICATIONS AND NON-DRUG THERAPIES .......................112
10.1.
Permitted Medication(s)............................................................................112
10.2.
Prohibited Medication(s) ...........................................................................112
11. LIFESTYLE AND/OR DIETARY RESTRICTIONS................................................113
11.1.
Contraception ...........................................................................................113
11.1.1.
Female Subjects........................................................................113
11.1.2.
Male Subjects............................................................................114
11.2.
Lactation Restrictions................................................................................114
12. DATA MANAGEMENT .........................................................................................114
13. DATA ANALYSIS AND STATISTICAL CONSIDERATIONS.................................115
13.1.
Hypothesis(es)..........................................................................................115
13.1.1.
Part 1: Dose-Escalation Phase ..................................................115
13.1.2.
Part 2: Molecularly-Defined Tumor Histology Groups ................115
13.2.
Sample Size Determination ......................................................................115
13.2.1.
Part 1: Dose-Escalation Phase ..................................................115
13.2.2.
Part 2: Molecularly-Defined Tumor Histology Groups ................116
13.3.
Sample Size Sensitivity.............................................................................117
13.3.1.
Sample Size Re-estimation........................................................117
13.4.
Data Analysis Considerations ...................................................................117
13.4.1.
Analysis Populations..................................................................117
13.4.2.
Analysis Data Sets.....................................................................117

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13.4.3.
Withdrawal.................................................................................118
13.4.4.
Missing Data..............................................................................118
13.4.5.
Derived and Transformed Data..................................................118
13.4.6.
Assessment Windows................................................................118
13.4.7.
Other Issues ..............................................................................118
13.5.
Treatment Comparisons ...........................................................................118
13.5.1.
Primary Comparisons of Interest................................................118
13.5.2.
Other Comparisons of Interest...................................................118
13.6.
Interim Analysis ........................................................................................119
13.6.1.
Part 1: Dose-Escalation .............................................................119
13.6.2.
Part 2: Molecularly Defined Tumor Histology Groups.................119
13.7.
Key Elements of Analysis Plan .................................................................120
13.7.1.
Anti-Cancer Activity Analyses ....................................................121
13.7.2.
Safety Analyses.........................................................................121
13.7.2.1.
Extent of Exposure ...................................................121
13.7.2.2.
Adverse Events ........................................................122
13.7.2.3.
Clinical Laboratory Evaluations ................................122
13.7.2.4.
Other Safety Measures.............................................122
13.7.3.
Pharmacokinetic Analyses.........................................................122
13.7.3.1.
Pharmacokinetic Parameters....................................122
13.7.3.2.
Statistical Analysis of Pharmacokinetic Data ............123
13.7.3.3.
Population Pharmacokinetics ...................................124
13.7.4.
Immunogenicity Analyses ..........................................................124
13.7.5.
Pharmacokinetic/Pharmacodynamic Analyses...........................124
13.7.5.1.
Translational Research Analyses .............................124
13.7.5.2.
Novel Biomarker(s) Analyses ...................................124
13.7.6.
Pharmacogenetic Analyses .......................................................125
14. STUDY CONDUCT CONSIDERATIONS .............................................................125
14.1.
Posting of Information on Clinicaltrials.gov................................................125
14.2.
Regulatory and Ethical Considerations, Including the Informed 
Consent Process ......................................................................................125
14.3.
Urgent Safety Measures ...........................................................................125
14.4.
Quality Control (Study Monitoring) ............................................................125
14.5.
Quality Assurance.....................................................................................126
14.6.
Study and Site Closure .............................................................................126
14.7.
Records Retention....................................................................................127
14.8.
Provision of Study Results to Investigators, Posting of Information 
on Publicly Available Clinical Trials Registers and Publication..................127
15. REFERENCES.....................................................................................................129
16. APPENDICES......................................................................................................133
16.1.
Appendix 1: Liver Chemistry Monitoring, Interruption Stopping and 
Follow-up Criteria......................................................................................133
16.2.
Appendix 2: Country Specific Requirements.............................................134
16.3.
Appendix 3: ECOG Performance Status ...................................................135
16.4.
Appendix 4: Estimated Glomerular Filtration Rate Using the 
Modification of Diet in Renal Disease (MDRD) Equation...........................136
16.5.
Appendix 5: RECIST 1.1 Guidelines for Evaluation of Disease.................137
16.6.
Appendix 6: Modified irRC from RECIST 1.1 ............................................141
16.7.
Appendix 7: mRECIST Criteria .................................................................144

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16.8.
Appendix 8: Pharmacogenetics (PGx) ......................................................150
16.9.
Appendix 9: Management of Diarrhea.......................................................155
16.10. Appendix 10: Protocol Amendment Changes............................................159

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LIST OF ABBREVIATIONS
ABC’s
Airway, breathing, and circulation from basic life support
ADA
Anti-drug antibodies
ADCC
Antibody-dependent cell-mediated cytotoxicity
AE(s)
Adverse event(s)
ALK
Anaplastic lymphoma kinase
ALP
Alkaline phosphatase
ALT
Alanine aminotransferase
ANC
Absolute neutrophil count
AST
Aspartate aminotransferase
AUC(0-)
Area under the concentration-time curve from time zero (pre-dose) 
extrapolated to infinite time
AUC(0-x)
Area under the concentration-time curve from zero (pre-dose) to some 
fixed nominal time x
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
BQL
Below the quantification limit
BRAF
V-raf murine sarcoma viral oncogene homolog B1
BUN
Blood urea nitrogen
CAF
Cytokines and angiogenic factors
CBC
Complete blood count
CDC
Complement dependent cytotoxicity
CfDNA
Circulating cell free DNA
CI
Confidence Interval
CL
Systemic clearance of parent drug
Cmax
Maximum observed concentration 
CPK
Creatinine phosphokinase
Cτ
Pre-dose (trough) concentration at the end of the dosing interval
CO2
Carbon dioxide
CPMS
Clinical Pharmacokinetics Modeling and Simulation
CPR
Cardio pulmonary resuscitation
CR
Complete response
CRC
Colorectal cancer
CRM
Continuous reassessment method
CSR
Clinical study report
CT
Computed tomography
CV
Coefficient of variance
DLT(s)
Dose-limiting toxicity
DMPK
Drug Metabolism and Pharmacokinetics
DNA
Deoxyribonucleic acid
EC
Ethics committee

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ECG(s)
Electrocardiogram
ECHO
Echocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
Electronic case report form
EDTA
Ethylenediamine tetraacetic acid
ECD
Extracellular domain
FACTS
Fixed and Adaptive Clinical Trial Simulator
FDA
Food and Drug Administration
FFPE
Formalin fixed paraffin-embedded
FSH
Follicle stimulating hormone
FTIH
First time in human
GCP
Good Clinical Practice
GGT
Gamma glutamyltransferase
GI
Gastrointestinal 
GLP
Good Laboratory Practice
GSK
GlaxoSmithKline
HBV
Hepatitis B virus
HCC
Hepatocellular carcinoma
HCV
Hepatitis C virus
HED
Human equivalent dose
HER3
Human epidermal growth Factor Receptor 3
HPLC
High-performance liquid chromatography
HIV
Human immunodeficiency virus
h/hr
Hour(s)
HR
Heart rate
HRT
Hormone replacement therapy
IB
Investigator’s Brochure
IC50
Half maximal inhibitory concentration
ICF
Informed consent form
ICH
International Conference on Harmonization
IDSL
International Data Standards Library
IEC
Independent ethics committee
Ig
Immunoglobulin
IHC
Immunohistochemistry
INR
International normalization ratio
IP
Investigational product
IRB
Institutional Review Board
irCR
Immune related complete response
irPD
Immune-related progressive disease
irPR
Immune related partial response
irRC
Immune related response criteria
irSD
Immune-related stable disease
irSLD
Immune-related sum of lesion diameters
IV
Intravenous
IVRS
Interactive voice response system
kg
Kilogram

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Km
Concentration at half maximal activity or rate 
L
Liter
LDH
Lactate dehydrogenase
LH
Luteinizing hormone
LLN
Lower limit of normal
LSLV
Last subject’s last visit
LVEF 
Left Ventricular Ejection Fraction
mAb
Monoclonal antibody
MRI
Magnetic resonance imaging
µg
Microgram
MCH
Mean corpuscular hemoglobin
MCHC
Mean corpuscular hemoglobin concentration
MCV
Mean corpuscular volume
MDRD
Modification of diet in renal disease
MedDRA
Medical Dictionary for Regulatory Activities
mg
Milligrams
mL
Milliliter
M
Micromolar
mRECIST
Modified Response Evaluation Criteria in Solid Tumors
MRT
Mean residence time
MSDS
Material Safety Data Sheet
msec
Milliseconds
MTD
Maximum tolerated dose
MUGA
Multi gated acquisition scan
NA
Not applicable
NCI-CTCAE
National Cancer Institute - Common Terminology Criteria for Adverse 
Events
N-CRM
Neuenschwander-Continuous Reassessment Method
NE
Not evaluable
ng
Nanogram
NK
Natural killer cells
NOAEL
No observed adverse effect level
NRG1
Neuregulin 1
NSAID
Nonsteroidal anti-inflammatory drug
NSCLC
Non-small cell lung cancer
NYHA
New York Heart Association
ORR
Overall response rate
OTC
Over the counter
PBL
Peripheral blood leukocytes
PBMC
Peripheral blood mononuclear cells
PCI
Potential clinical importance
PD
Progressive disease or pharmacodynamic
PES
Polyethersulfone
PFS
Progression-free survival
pg
Picogram
PGx
Pharmacogenetics

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PK
Pharmacokinetic
pM
Picomolar
PO
Polyolefin
PR
Partial response
PT
Prothrombin time
PTEN
Phosphatase and tensin homolog
PTT
Partial thromboplastin time
PVC
Polymerizing vinyl chloride
Q
Distributional clearance
qRT-PCR
Quantitative real time polymerase chain reaction
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
RAMOS
Registration and Medication Ordering System
RAP
Reporting and Analysis Plan
RBC
Red blood cells
RNA
Ribonucleic acid
RTK(s)
Receptor tyrosine kinase(s)
SAE
Serious adverse event(s)
SC
Subcutaneous
SD
Stable disease or standard deviation
SPM
Study Procedures Manual
t1/2
Elimination half-life
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
V
Volume of distribution
Vm
Maximal rate 
WBC
White blood cells
Trademark Information
Trademarks of the GlaxoSmithKline 
(GSK) group of companies
Trademarks not owned by the 
GlaxoSmithKline group of companies
NONE
Facts
WinNonlin

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PROTOCOL SYNOPSIS
TITLE
A phase I, first time in human (FTIH), open-label, dose 
escalation study to investigate the safety, 
pharmacokinetics (PK), and pharmacodynamics (PD) of 
anti-HER3 monoclonal antibody (mAb) GSK2849330 in 
subjects with advanced HER3-positive solid tumors
PROTOCOL NUMBER
HER117158
CLINICAL PHASE
I
COMPOUND(S)
GSK2849330
STUDY RATIONALE
GSK2849330 is a humanized glycoengineered 
IgG1/IgG3 mAb with enhanced Fc-effector function 
potency, directed against HER3 (ErbB3), a signaling and 
drug resistance target expressed on a wide range of solid 
tumors. This FTIH, open-label, dose escalation study 
will assess the safety, PK, PD, and preliminary clinical 
effect of GSK2849330 in subjects with HER3-
expressing or HER3 and NRG1 expressing solid tumors.
STUDY OBJECTIVES, 
ENDPOINTS AND 
HYPOTHESES
Primary Objective Part 1:
To determine the safety and tolerability of 
GSK2849330 in subjects with advanced HER3-
positive solid tumors.
Primary Objective Part 2:
To evaluate the safety of GSK2849330 in a larger 
population of subjects in molecularly-defined 
tumor histology groups at the dose regimen(s) 
recommended for further exploration in Part 1.
Secondary Objectives, Part 1:
To characterize the PK of GSK2849330 following 
intravenous (IV) administration.
To evaluate preliminary evidence of target 
engagement and PD effects of GSK2849330.
To determine the recommended dose regimen(s) of
GSK2849330 for further exploration in Part 2.
To evaluate the immunogenicity of GSK2849330 
following IV administration.
Secondary Objectives, Part 2:
To evaluate preliminary evidence of clinical 
benefit.
To further characterize target engagement and PD 

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effects of GSK2849330.
To further characterize the PK of GSK2849330.
To characterize relationship between GSK2849330 
PK, markers of target engagement, and/or PD 
markers.
To evaluate the immunogenicity of GSK2849330 
following IV administration.
Exploratory Objectives Part 1: 
To further evaluate preliminary evidence of target 
engagement and PD effects of GSK2849330.
To explore relationships between GSK2849330 
PK, markers of target engagement, and /or PD 
markers.
To explore preliminary clinical tumor outcomes 
after treatment with GSK2849330.
Exploratory Objectives Part 2: 
To explore additional measures of clinical benefit.
To further characterize target engagement and PD 
effects of GSK2849330.
To explore the relationship between pre-treatment 
HER3 or HER3/NRG1 expression levels and 
clinical outcome.
To identify molecular features potentially 
predictive of response to GSK2849330.
Pharmacogenetic (PGx) objectives Parts 1 and 2:
To investigate the relationship between genetic 
variants in candidate genes and safety, tolerability, 
PK, PD, and/or efficacy of GSK2849330.
Primary Endpoints Parts 1 and 2:
Adverse events (AEs), serious adverse events 
(SAEs), dose limiting toxicities (DLTs), and 
changes in laboratory values, electrocardiograms 
(ECGs), and vital signs.
Secondary Endpoints Part 1:
PK parameter values for GSK2849330.
Total and phospho-HER3 from tumor tissue.
Safety, tolerability, PK, and available PD data.
Antibodies to GSK2849330 assessed in serum.
Secondary Endpoints Part 2:
Overall response rate (ORR), tumor markers, and 
other measures of clinical benefit.

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Total and phospho-HER3 from tumor tissue.
PK parameter values for GSK2849330.
Antibodies to GSK2849330 in serum.
Exploratory Endpoints Part 1:
Pre- and post- treatment biomarkers (cells, 
proteins, ribonucleic acid [RNA] and/or 
deoxyribonucleic acid [DNA]) from circulation, 
skin, and/or tumor tissue.
Additional target engagement and PD markers in 
circulation, skin, and/or tumor.
Preliminary evidence of clinical benefit as assessed 
by ORR, tumor markers, and other measures of 
clinical benefit.
Exploratory Endpoints Part 2:
Progression free survival (PFS), ORR according to 
immune-related response criteria (irRC) and 
modified Response Evaluation Criteria in Solid 
Tumors (mRECIST) where applicable, and other 
tumor markers and measures of clinical benefit.  
Pre- and post- treatment biomarkers (cells, 
proteins, RNA and/or DNA) from circulation, 
and/or tumor tissue.
Pre-treatment HER3 expression or HER3 and 
NRG1 levels, efficacy outcome parameters.
Prediction analysis of biomarkers (cells, DNA, 
RNA or protein) in tumor, and/or circulation with 
efficacy endpoints.
PGx exploratory Endpoints Parts 1 and 2:

Genetic variations in selected candidate genes, 
such as the FC-receptor family, safety, 
tolerability, PK, PD, and/or efficacy endpoints.
STUDY DESIGN
This is a FTIH, open-label, dose-escalation study of 
GSK2849330 administered to subjects with HER3-
expressing or HER3 and NRG1 expressing solid tumors. 
The study will be conducted in two parts.
Part 1 will include dose escalation and PK/PD cohorts to 
evaluate safety, PK and PD to guide selection of dose 
regimen(s) for Part 2.
The starting dose is 1.4 mg/kg, administered once-
weekly, to be studied in a single patient (Cohort 1).  If 
no DLTs are observed, dose escalation will progress to 
3, 10, and 30 mg/kg, at a planned dosing frequency of 

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every two weeks, followed by a 30 mg/kg weekly 
cohort, with three subjects studied at each dose level 
(except 1.4 mg/kg).  In the cohort treated with 
30 mg/kg/wk, the option to reduce the dosing frequency 
to every 2 weeks after 24 weeks of treatment may be 
exercised.  The study team, in discussion with the 
investigator(s), may select lower doses or alternative 
schedules besides those listed above, based on emerging 
safety, tolerability, and PK findings.
The occurrence of any DLTs will be evaluated using a 
Neuenschwander-Continuous Reassessment Method (N-
CRM) to provide a model-based recommendation for 
dose escalation decisions.  Dose escalation decisions, 
and any modifications to the proposed nominal dose 
levels or interval, will be based principally on review of 
safety data, including the output from the N-CRM, and 
will be supported by review of available PK and PD 
data.
Once a dose escalation cohort has been filled, additional 
subjects may be enrolled into the PK/PD cohorts (at any 
dose level determined to be tolerable).  Subjects in the 
PK/PD cohort must consent to a pre- and on-treatment 
biopsy, which will provide information on target 
engagement and tumor-based PD markers.  Blood 
samples will be obtained to evaluate GSK2849330 PK 
and circulating PD markers.  Safety, PK and PD data 
from Part 1 will be used to support the dose regimen 
selection for Part 2.  
In Part 2, at least 4 molecularly-defined tumor histology 
groups will be enrolled at the dose regimen(s) selected 
based on Part 1 data. The objective of Part 2 is to 
evaluate safety in a larger population in molecularly-
defined, tumor histology groups of subjects at the 
recommended dose regimen(s). Part 2 will also evaluate 
PD markers in paired tumor biopsies and assess 
preliminary evidence of clinical benefit.  Selection of the 
tumor types for focus in Part 2 was based on available 
preclinical and external data.
NUMBER OF SUBJECTS
Part 1:  Approximately 13 subjects will be enrolled to 
complete the planned dose escalation. If DLTs are 
observed, additional subjects may be enrolled in dose 
escalation to establish the MTD or the dose for further 
exploration in Part 2, as guided by the N-CRM. A target 
maximum of 21 subjects with evaluable pre- and on-
treatment tumor biopsies will be enrolled in the PK/PD 

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cohorts. Additional subjects may be enrolled, if 
warranted, to provide sufficient safety, PK, or PD data to 
select the recommended dose for study in Part 2.
Part 2:  At least 4 molecularly defined tumor histology 
groups will be studied. A minimum of 12 and a 
maximum of 30 subjects will be enrolled in each of the 
groups. Futility criteria will be evaluated as data accrues, 
and enrollment in a group will be halted if futility 
criteria are met for that group.
INCLUSION/EXCLUSION 
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 [GlaxoSmithKline 
Document number 2013N168399_01].
Deviations from inclusion/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.
Pre-screening Inclusion Criteria for Part 1
Subjects will be eligible for inclusion in pre-screening 
for the study (See Section 3.2) only if all of the 
following criteria apply:
1. Males and females ≥18 years of age (at the time 
consent is obtained).
2. Written informed consent provided.
3. Performance Status score of 0 or 1 according to 
the Eastern Cooperative Oncology Group 
(ECOG) scale (see Appendix 3).
4. Sufficient archival tumor specimen is available 
for HER3 IHC analysis, or subject is willing to 
undergo a fresh tumor biopsy (using a procedure 
that is safe for the subject) for HER3 IHC 
analysis (see Section 7.6.1.1 for details).
5. Histologically or cytologically confirmed 
diagnosis of one of the following solid tumor 
malignancies for which no standard therapeutic 
alternatives exist:

Bladder cancer

Breast cancer

Castrate-resistant prostate cancer

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
Cervical cancer

Colorectal cancer (CRC)

Gastric cancer

Hepatocellular carcinoma (HCC)

Melanoma

Non-small cell lung cancer (NSCLC)

Ovarian cancer

Pancreatic cancer

Squamous cell cancers of the head and 
neck region (SCCHN)(including parotid 
and nasopharynx)
Pre-screening for Part 2
Subjects with melanoma, gastric/gastroesophageal 
cancer, head and neck cancer, or NSCLC who appear to 
meet all inclusion and exclusion criteria may be pre-
screened for the study provided that sufficient tumor 
specimen either from archival Formalin-fixed, paraffin-
embedded (FFPE) tissue or tissue obtained by biopsy 
(using a procedure that is safe for the subject) is 
available for analyzing HER3 by IHC or HER3 by IHC 
and NRG1 by RNA analysis.
Screening Inclusion Criteria for Parts 1 and 2
Subjects eligible for enrollment in the study must meet 
all of the following criteria:
1. Males and females ≥18 years of age (at the time 
consent is obtained).
2. Written informed consent provided.
3. For subjects enrolled in Part 1: subjects must 
have tumors with documented HER3 expression 
(2+ or 3+) on the cell surface of the invasive 
component of the tumor using an analytically 
validated IHC assay by central laboratory   (see 
Section 7.6.1.1 for details). Subjects enrolled in 
Part 2 must meet inclusion criterion 9 listed 
below.
4. ECOG performance status of 0 or 1 (see 
Appendix 3).
5. Adequate baseline organ function defined by: 

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SYSTEM
LABORATORY 
VALUES
Hematologic
  ANC
1.5  × 109/L
  Hemoglobin
9 g/dL 
  Platelets
75  × 109/L
  PT/INR and PTT  1.3 × ULN  
Hepatic
  Albumin
2.5 g/dL
  Total bilirubin
1.5  × ULN 
  AST and ALT
2.5  × ULN
Renal
Serum creatinine
OR
Estimated 
glomerular 
filtration rate or 
24-hour urine 
creatinine 
clearancea
ULN
OR
50 mL/min
Cardiac
LVEF
50% by ECHO or 
MUGAb
a.
Estimated glomerular filtration as 
calculated by the Modification of Diet 
in Renal Disease (MDRD) equation 
(Appendix 4). When both a calculated 
and 24-hour creatinine clearance are 
available, the 24-hour value will be 
used.
b. ECHO is the preferred method. 
MUGA should be performed only if 
evaluation by ECHO is not available
6. If the subjects is female, she must be of non-
childbearing potential, i.e., have a current tubal 
ligation, hysterectomy, ovariectomy or be post 
menopausal, or if she is of childbearing potential, 
she 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 11.1.1, from the time of the first dose of 
study treatment until 45 days or 5 half-lives 
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treatment.
7. Men with a female partner of childbearing 
potential must have either had a prior vasectomy 
or agree to use effective contraception as 
described in Section 11.1.2 from the time of the 
first dose of study treatment until 45 days or 
5 half-lives (whichever is longer) after the last 
dose of study treatment to allow for clearance of 
GSK2849330 from seminal fluid.
8. Subjects enrolled as part of the PK/PD cohort 
(Part 1) must agree to undergo pre- and on-
treatment tumor biopsies, using a procedure that 
is safe for the subject.
Inclusion Criteria for Part 2 ONLY
As listed above for Part 1, with the exception of 
criterion 3 which should be replaced with the following 
criterion 9 and the addition of criteria 10 and 11.
9. For Group 1: subjects with previously treated, 
unresectable stage III or IV melanoma with 
documented HER3 expression (3+) on the cell 
surface of the invasive component of the tumor
using an analytically validated IHC assay by 
central laboratory.

Subjects must have received no more than 
3 prior lines of systemic therapy and have 
disease progression on or after last prior 
treatment (based on RECIST v1.1).

Subjects with BRAF V600 
mutations who already received or 
were intolerant of prior BRAF 
inhibitor therapy may be included. 

Subjects may be included if they 
had prior immune therapy, or 
were intolerant of prior immune 
therapy.
For Group 2: Subjects with previously treated, 
unresectable stage III or IV gastric or 
gastroesophageal junction (GEJ) adenocarcinoma 
with documented HER3 expression (3+) on the 
cell surface of the invasive component of the 
tumor using an analytically validated IHC assay by 
central laboratory.

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
Subjects must have no more than 3 prior 
lines of systemic therapy and have 
disease progression on or after last prior 
treatment (based on RECIST v1.1).

Subjects with HER2 positive 
disease may be included if they 
had already received prior anti-
HER2 therapy, or were intolerant 
of prior anti-HER2 therapy.
For Group 3: Subjects with previously treated, 
unresectable stage III or IV cancers of the head 
and neck with documented HER3 expression on 
the cell surface of the tumor ( 1+) and NRG1 
expression using analytically validated assays by 
central laboratory.

Subjects must have no more than 3 prior 
lines of systemic therapy and have 
disease progression on or after last prior 
treatment (based on RECIST v1.1).

Subjects with locoregional recurrences 
amenable to resection/surgery or 
additional radiation are excluded.
For Group 4: Subjects with previously treated, 
unresectable stage III or IV NSCLC with 
documented HER3 expression on the cell surface 
of the tumor ( 1+) and NRG1 expression using 
analytically validated assays by central 
laboratory.

Subjects must have no more than 3 prior 
lines of systemic therapy and have 
disease progression on or after last prior 
treatment (based on RECIST v1.1).

Subjects with anaplastic lymphoma 
kinase (ALK) translocation who already 
received or were intolerant of prior anti-
ALK therapy may be included. 

Subjects with EGFR mutation positive 
disease (e.g., exon 19 deletion and exon 
21 L858R) who already received or were 
intolerant of prior EGFR inhibitors may 
be included. 
Additional tumor histology groups predicted to 
be sensitive to the study drug based on 
biomarkers (e.g.., HER3 mutations, NRG 
translocations) supported by preclinical or 
clinical data may be added based on emerging 

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data.  
10. Subjects must have at least one measurable 
lesion per RECIST v1.1.
NOTE: If the only site of measurable disease has 
been previously irradiated, documented 
progression of disease and a 4-week interval 
since completion of radiotherapy is required.
NOTE: In subjects with 1 measurable lesion, a 
measurable lesion may be biopsied at Screening 
and Day 15; however that lesion must not be 
selected as a target lesion for disease assessment.
11. Subjects must have disease amendable to biopsy
using a procedure that is safe for the subject, and
agree to undergo pre- and on-treatment tumor 
biopsies (until the participating centers receive 
written notification from the Sponsor that paired 
tumor biopsies are no longer required).
Screening Exclusion Criteria for Parts 1 and 2
Subjects meeting any of the following criteria must not 
be enrolled in the study:
1.
Subjects with leptomeningeal or brain metastases 
or spinal cord compression.

Subjects with untreated brain or meningeal 
metastases are not eligible (computed 
tomography [CT] scans are not required to 
rule this out unless there is a clinical 
suspicion of central nervous system [CNS] 
disease).

Subjects with treated and radiologic or 
clinical evidence of stable brain metastases 
(confirmed by 2 scans at least 4 weeks 
apart), with no evidence of cavitation or 
hemorrhage in the brain lesion are eligible 
providing that they are asymptomatic and do 
not require corticosteroids. Subjects are not 
permitted to receive enzyme inducing anti-
epileptic drugs.
2.
Prior HER3- directed treatment (HER2- or EGFR-
directed treatment is acceptable).
3.
Use of an investigational anti-cancer drug within 

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28 days or 5 half-lives, whichever is longer, 
preceding the first dose of GSK2849330 OR 
chemotherapy within the last 3 weeks (6 weeks for 
prior nitrosourea or mitomycin C) OR any major 
surgery, radiotherapy, immunotherapy or any other 
anti-cancer therapy within the last 4 weeks except 
as noted above. 
4.
Unresolved toxicity greater than NCI-CTCAE, 
version 4.0 [NCI, 2009] Grade 1 from previous 
anti-cancer therapy except alopecia and stable 
anemia (i.e., untransfused Hb 9.0 g/dL without 
the need for supportive transfusion within 2 weeks 
of screening) at the time of treatment allocation.
5.
Known or suspected hypersensitivity reaction to 
prior biologic therapy (e.g., therapeutic monoclonal 
antibody) that in the opinion of the investigator is a 
contraindication to their participation in the study.
6.
Current use of a prohibited medication or requires 
any of these medications during treatment (Section 
10.2).
7.
History or evidence of significant cardiovascular 
risk including any of the following:

LVEF<50%

A QT interval corrected for HR (QTc) 
480 msec (≥500 msec for subjects with 
bundle branch block)

History or evidence of current clinically 
significant uncontrolled arrhythmias.
Exception: Subjects with controlled atrial 
fibrillation for >30 days prior to enrollment 
are eligible.

History of acute coronary syndromes 
(including myocardial infarction and 
unstable angina), coronary angioplasty, or 
stenting within 6 months prior to enrollment.

History or evidence of current ≥ Class II 
congestive heart failure as defined by New 
York Heart Association (NYHA).
8.
Known Human Immunodeficiency Virus (HIV), 
hepatitis B virus (HBV), or hepatitis C virus 
(HCV) infection (with the exception of chronic or 
cleared HBV and HCV infection which will be 

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allowed). 
9.
Evidence of another active malignancy (excludes 
non-melanoma skin cancer). Consult GSK Medical 
Monitor if unsure whether second malignancies 
meet requirements specified above.
10.
Psychological, familial, sociological, or 
geographical conditions that do not permit 
compliance with the protocol.
11. Concurrent medical condition that in the 
investigator’s opinion would jeopardize 
compliance with the protocol.
12. Lactating female.
13. Receiving chronic immunosuppressive therapies
(includes daily steroid doses in excess of 
20 mg/day of prednisone).

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STUDY TREATMENT 
DOSE/ROUTE/REGIMEN
GSK2849330 will be given by IV infusion over 1 hour.  
If an infusion-related reaction occurs during 
administration, the infusion rate may be reduced or halted 
at the discretion of the investigator and/or medical 
monitor, and the subject will receive appropriate medical 
treatment. The infusion may be restarted according to the 
judgment of the investigator. Upon restart, the infusion 
rate should be half of the infusion rate at the time the 
infusion was paused. For subsequent infusions, the 
investigator may provide premedication with 
antihistamines, acetaminophen, and/or corticosteroids 
and may reduce the starting infusion rate.
A subject that exhibits signs or symptoms of severe 
hypersensitivity or anaphylaxis will receive appropriate 
medical treatment and remain on study at the discretion 
of the investigator and after discussion with the GSK 
medical monitor.  In accordance with the preparedness 
for treatment of anaphylaxis, emergency resuscitation 
equipment, advanced cardiac life support equipment, and 
medications must be readily accessible during 
GSK2849330 administration.
SAFETY ASSESSMENTS
Measurements to evaluate safety will include weight, 
height, heart rate (HR), blood pressure (BP), temperature, 
echocardiogram (ECHO) or multi gated acquisition scan 
(MUGA) including calculation of left ventricular ejection 
fraction (LVEF), clinical laboratory tests, 12-lead ECG, 
ECOG performance status, and complete 
physical/neurological examination. AEs and laboratory 
results will be graded according to the NCI-CTCAE v4.0 
[NCI, 2009]. Planned time points for all safety 
assessments are listed in the Time and Events Tables 
(Section 7.1).
PHARMACOKINETIC/ 
PHARMACODYNAMIC 
ASSESSMENT(S)
For all subjects in the dose escalation cohorts in Part 1, 
blood samples for analysis of GSK2849330 
concentrations will be collected on Day 1: pre-dose and 
at 1 hour and 6 hours after the end of infusion and at 
Day 8, Day 15, and Day 29 after the first dose of 
GSK2849330. If a subject’s duration of infusion is 
3 hours or longer, the 6 hour time point is optional.  On 
days of dosing, the sample will be drawn pre-dose. 
Additionally the first subject in Cohort 1 will have PK 
samples taken at 24 hours (Day 2) and 72 hours (Day 4) 
after the end of infusion.
For cohorts enrolled under Amendment 1 of this protocol, 
more frequent PK samples will be collected including: 

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On Day 1 samples will be collected pre-dose and at 
1 hour, 6 hours and 24 hours after the end of infusion. 
Pre-dose samples will be collected on Day 4, Day 8 and 
weekly through Day 57 with additional 1 hour post-dose 
samples collected on Days 29 and 57.  Pre-dose samples 
will also be collected on Day 71, Day 85, and every 12 
weeks thereafter
For all subjects in the Part 1 PK/PD cohorts, blood 
samples for analysis of GSK2849330 concentrations will 
be collected on Day 1 pre-dose and at 1 hour, 6 hours and 
24 hours after the end of infusion. Pre-dose samples will 
be collected on Day 4, Day 8 and weekly through Day 57 
with additional 1 hour post-dose samples collected on 
Days 29 and 57. Pre-dose samples will also be collected 
on Day 71, Day 85, and every 12 weeks thereafter.
If a subject’s duration of infusion is 3 hours or longer the 
6 hour time point is optional.
For the molecularly defined tumor histology groups
enrolled in Part 2, blood samples for analysis of 
GSK2849330 concentrations will be collected on Day 1 
pre-dose and at 1 hour after the end of infusion; and pre-
dose on Day 15, Day 29, Day 43, Day 57, Day 71, 
Day 85, and every 12 weeks thereafter.
For all subjects in Part 1 and Part 2, if treatment 
continues beyond 1 year, samples will be collected every 
24 weeks. An additional PK sample will also be taken 
45 days or 5 half -lives (whichever is longer) after the last 
dose of study treatment. Unless stated otherwise, on days 
of dosing, PK samples will be drawn pre-dose.
Blood samples will also be collected pre-dose, during 
treatment, and at disease progression to explore 
circulating markers of PD activity according to the 
schedule outlined in the Time and Events Tables (Section 
7.1).
Samples for immunogenicity assessment will be obtained 
according to the schedule outlined in the Time and 
Events Tables. (Section 7.1). 
CLINICAL ACTIVITY 
ASSESSMENT
Disease assessment will be performed every 8 to 9 weeks 
in all subjects (Parts 1 and 2).  Disease progression and 
response evaluations will be determined according to the 
definitions established in the Response Evaluation 
Criteria in Solid Tumors (RECIST 1.1).  Exploratory 
assessment of response according to irRC and mRECIST 
should also be recorded in applicable tumor types.  

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Subjects whose disease responds [either complete 
response (CR) or partial response (PR)] should have a 
confirmatory disease assessment performed at least 
4 weeks after the date of assessment during which the 
response was demonstrated. RECIST 1.1 criteria will be 
employed to evaluate futility in Part 2.
TRANSLATIONAL 
RESEARCH
Comparative examination of pre-treatment, on- treatment 
and post-treatment markers (which may include DNA, 
RNA, protein, cell, blood or tissue examination) may be 
performed to uncover known or novel candidate 
biomarkers/profiles which could be used to predict 
response to treatment with GSK2849330, measure PD 
and/or response to treatment, or provide new insights into 
cancer and medically related conditions.
STATISTICAL 
METHODS
The total number of subjects in the Part 1 dose escalation 
will depend on the number of dose escalations needed, 
but the minimum number of subjects anticipated to 
complete dose escalation is 13. A target maximum of 21 
additional subjects with evaluable pre- and on-treatment 
tumor biopsies may be enrolled in the PK/PD cohorts.  
Cohort size is based on feasibility and the objective to 
provide an initial characterization of safety and PK/PD 
information that will inform dose regimen selection for 
Part 2.
In Part 2, at least 12 and up to 30 subjects will be 
enrolled in each group.  Each group will include a futility 
analysis, whereby no additional subjects will be enrolled 
in a group if futility criteria are met, as defined in Section 
13.6.2. 
The null hypothesis is:
The alternative hypothesis is:
Starting with a group of 12 subjects and allowing for a 
maximum sample size of 30, this design will have a 
type I error rate (α) of 0.15 and 94% power. Group 
enrollment will be stopped early for futility if the 
predictive probability of success is less than 6%.The 
Bayesian Prior was Beta (0.2, 0.8), a weak prior with a 
mean response rate of 20%. The group outcome will be 
declared successful if the posterior probability of 

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(P>0.10│observed data) is ≥ 80%.
Under the null hypothesis, the expected sample size is 
20 subjects and the probability of early termination is 
77%. Under the alternative hypothesis, the expected 
sample size is 29 subjects and the probability of early 
termination is 5%.
The All Treated Population is defined as all subjects 
who receive at least one dose of GSK2849330. Safety 
will be evaluated based on this analysis population.
The Efficacy Population will consist of all subjects from 
the All Treated Population for whom at least one post-
dose tumor assessment by CT scan has been performed.
The PK Population will consist of all subjects from the 
All Treated Population for whom at least one post-dose 
PK sample is obtained and analyzed.
Additional details of the statistical analysis plan will be 
provided in the reporting and analysis plan (RAP).

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1.
INTRODUCTION
1.1.
Background
Many tumor types are characterized by dysregulation of the human epidermal growth 
factor receptor (HER) family of tyrosine kinase receptors, which includes HER1 (EGFR), 
HER2 (ErbB2), HER3 (ErbB3), and HER4 (ErbB4) [Kolibaba, 1997].  Both EGFR and 
HER2 are established pharmacologic targets in the treatment of cancer; emerging 
evidence also suggests that HER3 is an important therapeutic target.  HER3 is expressed 
in a broad range of solid tumors, with varying prevalence depending on primary tumor 
type and histology. HER3 is a potent mediator of downstream signaling when 
heterodimerized with other receptor tyrosine kinases (RTK).  The heterodimerization 
partners include other HER family members, such as EGFR, HER2, and HER4, as well 
as other RTK classes, including cMET and IGF-1R.  Intracellular tyrosine sites on HER3 
can be phosphorylated by an activated partner protein allowing recruitment of adaptor 
proteins and downstream activation of the MAPK and AKT signaling pathways.
While the HER3 gene is not frequently amplified in human cancers, HER3 protein 
expression has been associated with aggressive histopathological characteristics and 
poorer survival in various tumor types including melanoma, ovarian, gastric and 
colorectal carcinomas [Reschke, 2008; Tanner, 2006; Hayashi, 2008; Beji, 2011]. In 
melanoma cases with high HER3 expression as determined by immunohistochemistry 
(IHC), the probability of tumor-related death was almost three times higher than in cases 
with low HER3 staining [Reschke, 2008]. In gastric cancer, HER3 overexpression was 
associated with a significantly worse survival (P =0.0000) and was an independent 
prognostic factor in a multivariate analysis (hazard ratio 2.382; p = 0.048) [Hayashi, 
2008] In a recent meta-analysis that included 12 clinical studies (3 colorectal cancer 
[CRC], 2 gastric cancer, 2 breast cancer, and 1 each for melanoma, ovarian cancer, head 
and neck cancer, pancreatic cancer, and cervical cancer) HER3 over-expression, as 
determined by immunohistochemistry (IHC), was significantly associated with poorer 
overall survival at both 3 and 5 years [Ocana, 2013]. Recently, somatic mutations of 
HER3 have been described in ~11% of screened gastric and colon cancers [Jaiswal, 
2013].  These mutations promote oncogenic signaling in a ligand-independent manner in 
vitro, suggesting functional relevance, and provide a potential targeted population for 
clinical studies.
HER3 is also increasingly recognized as an important mediator of drug resistance 
following treatment with inhibitors of multiple key cancer pathways, including EGFR, 
HER2, IGF-1R, PI3K, RAF and MAPK [Amin, 2010; Zhang, 2014; Kugel, 2014]. This 
role has important implications for the potential utility of anti-HER3 therapeutics in 
combination with inhibitors of these pathways. The development of therapeutic agents 
targeting HER3, either as single agents or in combination with other anti-cancer agents, 
may provide clinical benefit for subjects with cancers exhibiting HER3 expression.

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1.2.
GSK2849330
1.2.1.
GSK2849330 - Background
An overview of the pre-clinical studies of GSK2849330 is provided below.  Detailed 
information concerning the biology, pharmacology, pharmacokinetics (PK), and safety 
can be found in the Investigators’ Brochure (IB) [GlaxoSmithKline Document number 
2013N168399_01].
GSK2849330 is a humanized IgG1/IgG3 monoclonal antibody (mAb) with a molecular 
mass of approximately 145 kDa.  GSK2849330 selectively binds HER3 at Domain III 
which resides in the extracellular domain (ECD) of the protein. HER3 sequences are 99% 
identical (99% homologous) between human and cynomolgus monkey, and 91% identical 
(94% homologous) between human and rat or mouse. The binding affinity of 
GSK2849330 for HER3 across these species is comparable: human: 2.1 nM; cynomolgus 
monkey: 1.7 nM; mouse: 4.1 nM; rat: 3.4 nM. In addition to directly blocking the 
heregulin (NRG1) ligand binding to the HER3 ECD, the antibody also sterically prevents 
the receptor from adopting the extended conformation that is required for dimerization, a 
prerequisite for receptor activation.
GSK2849330 is a glycoengineered antibody with enhanced potency for antibody-
dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity 
(CDC).  ADCC causes tumor cell lysis upon binding of antibody to target, followed by 
engagement of cytotoxic T-cells and natural killer (NK) effector cells via their FcRIIIA
receptors.  Perforin, granulysin and serine proteases released from cytoplasmic granules 
within cytotoxic T-cells and NK cells produce tumor cell lysis.  CDC, considered one of 
the most powerful cell-killing mechanisms of antibodies [Walport, 2001], results from 
assembly of the ‘membrane attack complex’ that punches holes in the target cell 
membrane leading to tumor cell lysis.  Compared with a wild-type antibody, 
GSK2849330 has a 16-18 fold greater binding affinity to human FcRIIIA (responsible 
for initiating ADCC) and a 17-fold higher affinity to human complement protein (C1q, 
responsible for initiating CDC). These increased binding affinities translated to enhanced 
potency of GSK2849330, compared to wild type antibody, in cell based assays for ADCC 
and CDC (see IB for details).
In summary, there are three main potential antitumor modes of action when GSK2849330 
is administered as monotherapy:  a) inhibition of signaling; b) ADCC and c) CDC.  The 
latter two mechanisms provide an opportunity for differentiation from non-ADCC and 
CDC- enhanced HER3-directed mAbs in clinical development, based on direct killing of 
both dividing and non-dividing cells, which may be independent of inhibition of 
downstream signaling.
1.2.2.
Pre-clinical Pharmacokinetics of GSK2849330
The preclinical PK of GSK2849330 has been investigated following intravenous (IV) 
administration in the mouse, monkey and rat.  Details of the preclinical PK are provided 
in Section 3.6.3 and the IB [GlaxoSmithKline Document number 2013N168399_01 ].

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1.2.3.
Nonclinical Safety of GSK2849330
GSK2849330 toxicology studies were conducted in rats and monkeys, which were shown 
to be suitable species based on similar HER3 tissue expression, protein sequence 
homology, and binding affinity of GSK2849330 for HER3.  IHC assessment of HER3 
distribution in normal human tissues showed specific positive staining in the majority of 
tissues examined and was characterized by cytoplasmic staining of epithelial cells, nerve 
fibers/ganglia, and focal areas of cells in the spleen.  Membrane staining of epithelial 
cells was observed inconsistently only in the mammary gland ducts, cornea, esophagus, 
epidermis, tonsil, cervix and endometrium.  These results are consistent with results 
previously published where HER3 expression in human tissue was examined by IHC 
[Prigent, 1992] and through the evaluation of a microarray gene expression database
[Gene Logic, Ocimum Biosolutions, LLC, Houston, TX, USA, Uhlen, 2010].  
Furthermore, HER3 receptor protein has been shown by IHC to be associated with 
peripheral nerves and Schwann cells in particular [Carroll, 1997]. A similar distribution 
of epithelial cell and peripheral nerve HER3 expression was observed in tissues from 
untreated monkeys using IHC.
In the good laboratory practice (GLP) toxicology studies, GSK2849330 was well 
tolerated in rats and monkeys following weekly IV dosing for 1 month up to and 
including the top doses studied, 500 mg/kg and 300 mg/kg, respectively.
In monkeys, dose-dependent, abnormal fecal consistency (beginning following a single 
dose) occurred at 30 mg/kg/dose, continued into a 4-week recovery period in monkeys 
given 300 mg/kg/dose and was not associated with effects on food consumption or body 
weight.  Mucosal ulcers (mild, multifocal), associated with neutrophilic inflammation, 
occurred in the cecum and colon in one of three females given 300 mg/kg/dose after 4 
weekly repeat doses.  No ulcerations of the cecum/colon were present in recovery 
monkeys; however, reversibility was not clearly demonstrated based on low incidence 
and persistent systemic exposure in the study. Abnormal fecal consistency and ulceration 
of the cecum/colon occurred at 1X and10X the maximum planned clinical dose 
(30 mg/kg), respectively.
In rats, decreases in prostate weight (with no microscopic correlate) and minimal to 
marked lobuloalveolar atrophy of the male mammary gland were observed at doses 
≥5 mg/kg/dose. There was a minimal decrease in the mean serum testosterone and 
luteinizing hormone (LH) concentrations in male rats given 500 mg/kg/day.  Decreases in 
prostate weight and serum testosterone/LH concentrations were reversed following a 4-
week off-treatment period, and lobuloalveolar atrophy was persistent over the same 
period, in rats given 500 mg/kg/dose. In the male rat, both the prostate and mammary 
gland are androgen dependent tissues and the mammary gland is unique in that it 
undergoes androgen-dependent development and maintains a sexually dimorphic 
appearance [Lucas, 2007]. Changes in the prostate and male rat mammary gland of rats 
are likely pharmacologically mediated effects of HER3 receptor inhibition with either 
direct effects on cell growth and differentiation or effects mediated by inhibited or 
reduced androgen receptor signaling.  The effect on male rat mammary gland is not 
considered to be relevant to the risk assessment for the adult human male or female that is 
not pregnant or lactating.

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In the 4-week GLP toxicity study in monkeys, there were no GSK2849330-related effects 
on cardiac histology or cardiovascular measurements (qualitative electrocardiogram 
[ECG] waveform evaluation including corrected QT interval duration [QTc], 
echocardiographic measures of left ventricular structure and function and 
clinicopathologic evaluation of serum cardiac troponin I). Additionally there were no 
GSK2849330-related effects on serum cardiac troponin I or cardiac histology in the 4-
week GLP toxicity study in rats.
In the 4-week GLP toxicity study in monkeys, anti-drug antibodies (ADA) were detected 
in 4 of 6 monkeys given 3 mg/kg/dose with an associated decrease in GSK2849330 
exposure.  In monkeys given 30 mg/kg/dose, ADA were detected in 1 of 6 monkeys at 
the end of a 6-week off-treatment period. In the 4-week GLP toxicity study in rats, ADA 
were detected in 5 of 6 rats given 5 mg/kg/dose at the end of a 6-week off-treatment 
period, where GSK2849330 exposure was not clearly affected. ADA were not detected in 
monkeys at doses 30 mg/kg/dose during the dosing period and were not identified 
during the dosing period in rats at any dose; therefore, sufficient exposure to 
GSK2849330 was maintained at the no observed adverse effect level (NOAEL) doses 
and above in the toxicology studies in monkeys and rats to assess for potential adverse 
effects.  Induction of antibody formation in animals when using humanised protein is not 
predictive of a potential for antibody formation in humans.
The NOAEL in the monkey was 30 mg/kg/week (area under the concentration-time curve 
from zero to 168 hr [AUC0-168] 102 mg.h/mL, range 68.5 to 115 mg.h/mL; maximum 
observed concentration [Cmax] 1.26 mg/mL, range 1.10 to 1.39 mg/mL (gender-averaged 
based on Week 4 values)]. The NOAEL in the rat was 500 mg/kg/week [AUC0-168 573 
mg.h/mL, range 465 to 617 mg.h/mL; Cmax 13.1 mg/mL, range 11.4 to 15.1 mg/mL 
(gender-averaged based on Day 22)].
1.2.4.
Pre-clinical Activity and Pharmacodynamics of GSK2849330
1.2.4.1.
In vitro studies
GSK2849330 is a potent antagonist of HER3 signaling as evidenced by its ability to 
inhibit NRG1-induced HER3 receptor phosphorylation in various cancer cell lines (half 
maximal inhibitory concentration [IC50] 2.5-30 ng/mL[17.2-207 pM]), and NRG1-
induced AKT phosphorylation in BxPC3 pancreatic cancer cell lines (IC50 11 ng/mL 
[76 pM]).  GSK2849330 is also able to inhibit NRG1-induced proliferation of BxPC3 
cells in a concentration dependent manner (33% inhibition at 10 g/mL [69 nM]).
ADCC assays using both high- and low-expressing HER3 human target cells 
demonstrated the increased potency and target cytotoxicity achieved with the ADCC-
enhanced GSK2849330 compared to the WT parental antibody.  For example, when a 
CHL-1 human melanoma cell line was used as target cells and human peripheral blood 
leukocytes (PBLs) as effector cells, the potency of GSK2849330 was 245-764 pg/mL 
(1.7-5.3 pM) versus 35 ng/mL (241 pM) for the WT antibody. The efficacy of 
GSK2849330 was also tested against cynomolgus HER3 (transduced into human 
HEK293 cells) in combination with cynomolgus PBLs as effector cells.  In this assay, 

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GSK2849330 had IC50=454-910 pg/mL (3.76-7.5 pM) whereas parental WT antibody 
had IC50=4.2-5.5 ng/mL (29-38 pM).
GSK2849330 caused concentration-dependent complement-mediated cell lysis of 
HEK293 cells transduced with full length human HER3.  CDC activity level was 
proportional to HER3 protein expression on the cell surface, suggesting threshold HER3 
expression amounts may be required to engage effective CDC activity.  The level of 
ADCC killing may also be related to the amount of HER3 expression on the cell 
membrane [Bossenmaier, 2012].
1.2.4.2.
Studies in vivo
GSK2849330 or variants have been evaluated for anti-tumor activity in melanoma and 
pancreatic cancer cell line xenograft tumor models   Twice weekly IP dosing with 
GSK2849330 at 0.5 to 50 mg/kg/dose, resulted in dose-dependent and statistically 
significant decreases (p<0.001 at ≥5 mg/kg) in tumor growth rates in a human melanoma 
cell line (CHL-1) subcutaneous xenograft model.  Significant inhibition of tumor growth 
was also observed in subcutaneous pancreatic (BxPC3) cancer cell line xenograft models 
and in a syngeneic mouse melanoma (lung colonization) model.  Since xenograft studies 
were carried out in immune-compromised CB17 SCID mice, which lack T and B cells, 
and the disposition and nature of Fcreceptor subtypes in mouse are different to that 
observed in human [Smith, 2012], the effects of GSK2849330 on tumor growth in these 
mouse models are expected to result mainly from HER3 signaling inhibition (e.g., ligand 
blocking/inhibition of heterodimerization) rather than an effect of the other potential (cell 
killing) modes of action for GSK2849330.  In agreement with this hypothesis, 
GSK2849330 and Fc-disabled variant of GSK2849330 showed similar tumor growth 
inhibition in CHL-1 tumor xenograft.
1.3.
HER3 antibodies in Clinical Trials
Although this is the FTIH study for GSK2849330, there is relevant experience for 
targeted inhibition of HER3 in cancer subjects. Initial clinical data from Phase I studies 
of other monoclonal antibodies targeting HER3 have been reported. Two of the 
antibodies, MM-121 and U3-1287, are non-enhanced human or humanized IgG1 
antibodies.  One antibody, RG7116, is a glycoengineered humanized IgG1 antibody 
reported to have enhanced potency for ADCC activity.  Another antibody, LJM716, is a 
fully human monoclonal antibody that inhibits both ligand-dependent and -independent 
activation of HER3. These antibodies have been administered in clinical trials at doses up 
to 40 mg/kg weekly IV without dose limiting toxicities (DLTs) and without reaching a 
maximum tolerated dose (MTD).  The majority of adverse events (AEs) have been 
Grade 1 or 2 with GI toxicity and fatigue predominating across studies.  Infusion 
reactions, although seen, were reportedly not severe [Arnedos, 2013 Lorusso, 2013, 
Meulendijks, 2013, Denlinger, 2011, Reynolds, 2014].

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1.4.
Summary of Risk Management
The anticipated AEs based on preclinical studies include:
Gastrointestinal (GI): Mild GI hazard/diarrhea (multifocal ulceration of the cecum 
and colon, and abnormal fecal consistency), was observed as discussed in 
Section 1.2.3.  High-grade diarrhea has not been reported with other HER3-
targeting agents that have already been tested in the clinic; however precautions 
have been added to the protocol in the event that unexpected GI toxicity is 
observed with GSK2849330.  Medical history, physical examination and clinical 
laboratory assessments will be used to identify and assess toxicity in the GI 
tract.  Supportive therapy will be provided according to the diarrhea 
management guidelines provided in Section 3.9.3 and standard medical practice.  
Treatment with GSK2849330 will be withheld for clinically significant toxicity.
Prostate: Reversible decreases in prostate weight and serum testosterone and LH 
concentrations were seen in rats given GSK2849330.  Decreases in prostate 
weight may represent inhibited or reduced androgen receptor activation. No 
clinical consequences are expected from decreased prostate volume and no 
clinical signals relating to prostate have emerged from ongoing studies with 
other agents that target HER3.  However, serial measurement of testosterone and 
LH will be performed in male study subjects to explore for clinical correlation.
Further information on these potential risks can be found in Section 1.2.3 and the IB for 
GSK2849330 [GlaxoSmithKline Document number 2013N168399_01]

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2.
OBJECTIVE(S) AND ENDPOINT(S)
2.1.
Part 1: Dose Escalation and PK-PD Cohorts
Objective
Endpoint
Primary
To determine the safety and 
tolerability of GSK2849330 in 
subjects with advanced HER3-
positive solid tumors.
AEs, serious adverse events (SAEs), DLTs, and 
changes in laboratory values, electrocardiograms 
(ECGs), and vital signs.
Secondary
To characterize the PK of 
GSK2849330 following IV 
administration.
PK parameter values for GSK2849330.
To evaluate preliminary evidence 
of target engagement and PD 
effects of GSK2849330
Total and phospho-HER3 from tumor tissue
To determine the recommended 
dose regimen(s) of GSK2849330 
for further exploration in Part 2.
Safety, tolerability, PK, and available PD data.
To evaluate the immunogenicity of 
GSK2849330 following IV 
administration.
Antibodies to GSK2849330 assessed in serum
Exploratory
To further evaluate preliminary 
evidence of target engagement 
and PD effects of GSK2849330.
Pre- and post- treatment biomarkers (cells, proteins, 
ribonucleic acid [RNA] and/or deoxyribonucleic acid 
[DNA]) from circulation, skin, and/or tumor tissue.
To explore relationships between 
GSK2849330 PK, markers of 
target engagement, and /or PD 
markers.
GSK2849330 concentration-time profile and PK 
parameters, target engagement and PD markers in 
circulation, skin, and/or tumor
To explore preliminary clinical 
tumor outcomes after treatment 
with GSK2849330.
Preliminary evidence of clinical benefit as assessed by 
overall response rate (ORR), tumor markers, and other 
measures of clinical benefit  
Pharmacogenetic (PGx) Exploratory
To investigate the relationship 
between genetic variants in 
candidate genes and safety, 
tolerability, PK, PD, and/or efficacy 
of GSK2849330.
Genetic variations in selected candidate genes, such 
as the FCreceptor family, safety, tolerability, PK, PD, 
and/or efficacy endpoints.

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2.2.
Part 2: Molecularly Defined Tumor Histology Groups
Objective
Endpoint
Primary
To evaluate the safety of 
GSK2849330 in a larger population 
of subjects in molecularly-defined 
tumor histology groups at the dose 
regimen(s) recommended for 
further exploration in Part 1.
AEs, SAEs, DLTs, and changes in laboratory values, 
ECGs, and vital signs.
Secondary
To evaluate preliminary evidence of 
clinical benefit.
ORR, tumor markers, and other measures of clinical 
benefit.
To further characterize target 
engagement and PD effects of 
GSK2849330.
Total and phospho-HER3 from tumor tissue.
To further characterize the PK of 
GSK2849330.
PK parameter values for GSK2849330.
To characterize the relationship 
between GSK2849330 PK, markers 
of target engagement, and/or PD
markers.
PK parameter values for GSK2849330
To evaluate the immunogenicity of 
GSK2849330 following IV 
administration.
Antibodies to GSK2849330 in serum
Exploratory
To explore additional measures of 
clinical benefit.
Progression free survival (PFS), ORR according to 
immune-related response criteria (irRc) and modified 
Response Evaluation Criteria in Solid Tumors 
mRECIST where applicable, and other tumor markers 
and measures of clinical benefit  
To further characterize target 
engagement and PD effects of 
GSK2849330.
Pre- and post- treatment biomarkers (cells, proteins, 
RNA and/or DNA) from circulation and/or tumor tissue.
To explore relationship between 
pre-treatment HER3 or 
HER3/NRG1expression levels and 
clinical outcome.
Pre-treatment HER3 expression or HER3 and NRG1 
levels, efficacy outcome parameters.
To identify molecular features 
potentially predictive of response to 
GSK2849330.
Prediction analysis of biomarkers (cells, DNA, RNA or 
protein) in tumor, and/or circulation with efficacy 
endpoints.

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Objective
Endpoint
Pharmacogenetic (PGx) Exploratory
To investigate the relationship 
between genetic variants in 
candidate genes and safety, 
tolerability, PK, PD, and/or efficacy 
of GSK2849330.
Genetic variations in selected candidate genes, such 
as the FCreceptor family, safety, tolerability, PK, PD, 
and/or efficacy endpoints.
3.
INVESTIGATIONAL PLAN
3.1.
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 Tables (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, FTIH, open-label, multi-center, dose-escalation study of the anti-HER3 
antibody, GSK2849330, in subjects with advanced solid tumors expressing HER3 (see 
Inclusion Criteria 3 and 9). The study will be conducted in two parts as depicted below.
Part 1
Dose Escalation Cohorts
To determine the safety, tolerability, PK and preliminary PD of GSK2849330, in support of 
selection of the recommended dose(s) and regimen(s) for further exploration in subjects with 
advanced solid tumors with HER3 expression
PK/PD Cohorts
Subjects that agree to give pre- and on- treatment tumor biopsies will be enrolled in the 
PK/PD cohorts to support selection of the recommended dose(s) and regimen(s) for Part 2.  
Up to 3 subjects with evaluable pre- and on-treatment tumor biopsies will be enrolled at each 
dose level after that dose is determined tolerable.

Part 2
Molecularly-Defined Tumor Histology Groups
To determine safety and preliminary evidence of clinical benefit of GSK2849330, and to 
further evaluate the PK and PD of GSK2849330 at the recommended Part 2 dose(s) and 
regimen(s) in subjects with selected HER3 or HER3 and NRG1 expressing tumor types.

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3.2.
Pre-Screening
Subjects will be required to undergo pre-screening to determine if their tumor is HER3 
expressing or HER3 and NRG1 expressing (details regarding HER3 and NRG1 
expression requirements will be described in the SPM).  Subjects with study eligible 
advanced solid tumors will sign a separate Informed Consent Form (ICF) to allow for 
pre-screening of archival tumor or tissue from fresh tumor biopsies (obtained using a 
procedure that is safe for the subject) for HER3 expression by IHC, or for HER3 
expression by IHC and NRG1 expression by quantitative real-time polymerase chain 
reaction (qRT-PCR) assay.
3.3.
Part 1: Dose-Escalation Phase
Accelerated dose titration will be used based upon the favorable pre-clinical safety and 
clinical experience to date with other HER3-targeted therapies (see Section 1.3 and 
Section 3.6.3). A single subject in Cohort 1 will receive a dose of 1.4 mg/kg weekly, in 
order to obtain PK samples at defined intervals to guide the dose regimen(s) for 
subsequent cohorts.
The subject in Cohort 1 must complete a full 28 days of dosing, and the safety and PK 
data will be reviewed prior to starting Cohort 2.  If the first subject becomes unevaluable 
for reasons other than toxicity, another subject will be recruited.  Additional subjects may 
also be enrolled at 1.4 mg/kg weekly as part of the PK/PD cohorts as described below. 
The dose-escalation decision and rationale will be documented in writing with copies 
maintained at each study site and in the master study files at GlaxoSmithKline (GSK).
Starting with Cohort 2, the dose escalation will continue using the Neuenschwander-
continuous reassessment method (N-CRM) [Neuenschwander, 2008] with 3 subjects in 
each cohort as described below. After the first subject is dosed in Cohort 2 and in all 
subsequent cohorts, the second and third subjects will not be dosed until the first subject 
has been observed for at least 24 hours for evidence of unanticipated acute toxicity.
Neuenschwander-Continuous Reassessment Method (N-CRM) in Dose Escalation
The decision regarding escalation to the next dose levels of GSK2849330 will be guided 
by a Bayesian adaptive method called N-CRM. N-CRM is an alternative to the traditional 
3+3 design. It is a modified version of the original Continual Reassessment Method 
(CRM) proposed by [O’Quigley, 1990]. The traditional 3+3 design only uses the safety 
information from the current dose and ignores the information from previous cohorts.  In 
contrast, the N-CRM model incorporates information from all previous subjects and dose 
levels as the study progresses, resulting in a more accurate and reliable prediction of dose 
effects on the future subjects. In this case the 3+3 design and N-CRM collect the same 
safety information (occurrence of a DLT), but utilize different decision making processes 
to support dose escalation decisions.
The N-CRM method assumes that the probability of experiencing a DLT is related to 
dose according to a logistic regression model. The model actively seeks a dose level that 
produces a pre-specified probability of a DLT occurring by using safety data from all 

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enrolled subjects to compute a more precise dose-toxicity curve. The model is carried out 
using Bayesian methods, which requires an initial estimation of prior distribution which 
characterizes the shape of the dose-toxicity curve. In this case, a weakly informative prior 
was selected based on clinical experience reported to date for anti-HER3 mAbs (which 
have not been associated with reported DLTs) and the nonclinical safety data for 
GSK2849330.
As the study progresses, the absence or presence of DLTs in subjects enrolled at each 
dose level provides additional information for the model and results in an adjustment of 
the estimation of distribution to characterize the shape of the dose-toxicity curve (also 
called posterior distribution). The posterior distribution is then evaluated to identify the 
dose closest to the acceptable toxicity interval, which is pre-specified as the interval from 
16% - 33% DLT rate. This range was selected as the equivalent of between a 1 out of 6 
and 1 out of 3 (or 2 out of 6) toxicity rate which guides the traditional 3+3 dose escalation 
decision.
Implementation of N-CRM: The N-CRM model implementation will be performed 
using Fixed and Adaptive Clinical Trial Simulator (FACTS) (Version 2.3 or higher) from 
Tessella.
Bayesian Prior
The N-CRM methodology requires that a Bayesian prior for the toxicity curve be pre-
specified.  The Bayesian prior used for this design was determined using the quantile 
method.  For each dose, an estimate of the median probability of DLT was specified, 
along with a 95% credible interval. The 95% credible intervals are intentionally wide due 
to limited information about the toxicity profile of GSK2849330 in humans.  Table 1
shows the median prior probability of experiencing a DLT at the given cumulative dose 
along with a 95% credible interval around the median:
Table 1
Table of Specified Prior Probability of DLT (with 95% Credible 
Interval)
Anticipated 
Dose
(mg/kg)
2.5% Quantile for 
Probability of DLT
Median for 
Probability of 
DLT
97.5% Quantile for 
Probability of DLT
1.4
0.0009739
0.00415
0.5
3
0.002085
0.00851
0.6
10
0.006915
0.02891
0.7
30
0.02046
0.08198
0.8
The 2.5% quantile and median of the prior distribution are based on Roche RGA7116 
study human safety data [Meulendijks, 2013] conservatively treating AEs that resulted in 
discontinuation as if they were DLTs.  The 97.5% quantile of the prior distribution is 
increased by empirical adjustment to weaken the prior by inflation of variance.

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Dose recommendation: Dose recommendation output from the N-CRM model will be 
based on the posterior probabilities that the DLT rate for each escalation dose lies in one 
of the following categories:

[0%,16%) range of minimal toxicity

[16%, 33%) range of acceptable toxicity

[33%, 60%) range of excessive toxicity

[60%, 100%) range of unacceptable toxicity
After each cohort, a recommendation will be made to either: 1) escalate to the next dose 
or regimen, 2) de-escalate, 3) recruit more subjects at the current dose, or 4) stop.  The 
recommended dose will be the one with the highest probability of having a DLT rate in 
the acceptable toxicity range [16%, 33%), subject to the constraint that no dose may be 
skipped during dose escalation. The recommended dose has an additional requirement 
that the sum of the posterior probabilities of the DLT rate lying in the excessive toxicity 
or unacceptable toxicity range must be less than 25%. Additional subjects may also be 
enrolled at any specified dose level to further characterize the safety, as with traditional 
dose-escalation methods.
Prior to dose escalation/de-escalation, a meeting will be convened to discuss available 
safety, and the recommendation from the N-CRM model. The data will be reviewed by 
the investigator(s) and GSK study team which may include the Medical Monitor, 
statistician, and pharmacokineticist. The dose escalation rationale and decision for the 
subsequent cohort will be documented in writing with copies maintained at each site and 
in the GSK study files.
The initial dose levels to be evaluated are outlined in Section 3.6.3.
Additional subjects may also be enrolled at any specified dose level to further 
characterize safety. Additional doses and schedules and loading doses may be explored, 
following the rules outlined for dose escalation, based on emerging safety, PK, and PD 
data.
PK/PD cohort(s): Once a given dose escalation cohort is filled, additional subjects may 
be enrolled into a PK/PD cohort (at any dose level determined to be tolerable) to allow 
for the collection of data on the PD effects of GSK2849330 as well as additional PK data.
Subjects enrolled in the PK/PD cohorts must meet all of the relevant inclusion and 
exclusion criteria, have disease that is amenable to biopsy, and also agree to have pre-
and on-treatment biopsies (using a procedure that is safe for the subject) in addition to the 
other study procedures. Subjects will be enrolled in PK/PD cohorts in order to obtain 
evaluable pre- and on-treatment biopsy pairs per dose level (see SPM for additional 
details). Subjects who do not agree to, or who are unable to safely provide pre- and on-
treatment biopsies in the PD expansion may be enrolled in dose escalation cohorts in 
Part 1 as they become available.

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Subjects enrolled in the PK/PD cohorts may have their dose escalated to a higher 
completed dose level (not exceeding the MTD) once the necessary PK/PD procedures 
have been completed and once other criteria for intra-subject dose-escalation have been 
met (see Section 3.5). See the PK/PD cohorts Time and Events (Table 9, Table 10) for 
study assessments specific to the PK/PD cohorts.
The final recommended Part 2 dose regimen(s) will be based on an overall assessment of 
safety taking into consideration all available data including PK, PD, and the 
recommendation from the N-CRM model.
3.3.1.
Dose-Limiting Toxicity
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 unless it can be clearly established that 
the event is unrelated to treatment:
a.
Grade 3 or greater non-hematologic toxicity as described in Common National 
Cancer Institute-Terminology Criteria for Adverse Events (NCI-CTCAE) version 4.0 
[NCI, 2009] that cannot be controlled with routine supportive measures (e.g.,
antiemetics, antidiarrheals, antihistamines).
b.
Grade 4 neutropenia lasting >5 days.
c.
Febrile neutropenia, of any grade or duration as defined by NCI-CTCAE version 4.0 
[NCI, 2009].
d.
Grade 4 thrombocytopenia, or Grade 3 thrombocytopenia associated with bleeding.
e.
Alanine aminotransferase (ALT) >3x upper limit of normal (ULN) with bilirubin 
>2x ULN.
f.
Any Grade 2 or greater NCI-CTACAE version 4.0 [NCI, 2009] toxicity that in the 
judgment of the investigator and GSK Medical Monitor, would be considered dose-
limiting.
g.
Grade 3 or greater decrease in left ventricular ejection fraction (LVEF).
3.3.2.
Maximum Tolerated Dose
In the context of the N-CRM approach as described in Section 3.3, the MTD is defined as 
the dose with the highest posterior probability of subjects experiencing a DLT, in the first 
28 days on treatment in the target interval [16%, 33%]. These probabilities 16% and 33% 
were chosen to be consistent with the traditional 3+3 design toxicity boundary which is 
1/6 and 1/3.
Additional dosing schedules with lower dose intensity may be explored as long as they do 
not exceed the MTD.

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3.4.
Part 2: Molecularly-Defined Tumor Histology Groups
Part 2 can begin once the recommended dose and schedule is identified in Part 1. It is 
possible that more than one dose and/or schedule will be evaluated in Part 2 if available 
PK, PD and safety data suggest that multiple doses and schedules have desirable biologic 
activity or if an MTD cannot be established.
The selected dose level(s) will be evaluated in Part 2 for confirmation of safety and 
tolerability, as well as preliminary assessment of clinical benefit, in at least 4 
molecularly-defined tumor histology groups of subjects with HER3 or HER3 and NRG1 
expressing tumors  Group 1 will include subjects with HER3- expressing melanoma. 
Group 2 will include subjects with HER3-expressing gastric cancer. Group 3 will include 
subjects with HER3 expressing and NRG1-expressing cancers of the head and neck. 
Group 4 will include subjects with HER3 expressing and NRG1-expressing NSCLC. All 
subjects must have archival tissue available for HER3 and if required NRG1 testing or be 
willing to undergo a tumor biopsy using a procedure that is safe for the subject, to 
provide a sample for testing.
Each group will initially enroll 12 subjects with the option of expanding to a maximum of 
30 subjects if futility criteria are not met using well established  methodology of [Lee, 
2008] (See Section 13.2.2 and Section 13.6.2 for additional details).
Subjects will be required to have disease amenable to biopsy and agree to pre-and on-
treatment tumor biopsies, using a procedure that is safe for the subject. Pre-and on-
treatment biopsies are mandatory for all subjects in all groups. GSK will closely monitor 
and evaluate the collection of evaluable biopsies and will notify the participating centers 
of any change to the collection requirements for any or all groups.
3.5.
Intra-subject Dose-Escalation
A subject’s dose level may be increased up to the highest dose level that has previously 
been confirmed by the investigator and GSK medical monitor as not exceeding the MTD.  
Intra-subject dose escalations will be allowed in both Part 1 and Part 2 (if multiple 
doses/regimens demonstrate a better PK profile or clinical activity) provided that the 
subject has completed at minimum, the first 28 days of treatment with no sign or 
evidence of disease progression, no toxicity greater than Grade 2 or the occurrence of 
significant AEs, and prior approval has been obtained from a GSK medical monitor. 
Subjects will be permitted to increase dose levels multiple times provided the above 
criteria are met. Any dose escalations must be agreed upon by the investigator and GSK 
medical monitor, and must be documented on an Intra-subject Dose Escalation Request 
Form (see the SPM) with copies maintained at the site and in the study files.
3.6.
Rationale
3.6.1.
Rationale for Study
HER3 expression is seen across a wide variety of solid malignancies and is associated 
with poor prognosis. Up-regulation of HER3 expression and activity is also associated 

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with resistance to multiple pathway inhibitors. GSK2849330, a monoclonal antibody 
targeting HER3, is a new agent for subjects whose tumors express HER3 and/or its 
ligand, NRG1.  GSK2849330 has a unique pharmacologic profile compared to other 
HER3 antibodies with multiple modes of action including inhibition of tumor signaling 
and increased potential for direct cell killing via enhanced ADCC and CDC activities.   
(See Section 1.2.1 for details).
There is considerable unmet medical need across these tumor types where high HER3 
expression is seen. The purpose of the dose escalation is to evaluate safety, PK, and 
initial PD of the drug in subjects with HER3 expressing tumors.  Following dose 
escalation in Part 1, at least 4 molecularly-defined tumor histology groups will be 
enrolled in Part 2. Preliminary clinical activity, biomarkers of target engagement, 
downstream signalling, ADCC, and CDC will be evaluated.
3.6.2.
Rationale for Population
Subjects will be selected on the basis of HER3 expression on the cell membrane of the 
tumor because higher levels of target expression on the cell surface is required for 
ADCC, CDC and signaling inhibition functions of the antibody. High HER3 expression 
has been demonstrated in the tumor histologies being considered for this trial [Ocana, 
2013].
Study eligibility for Part 1 is based on HER3 protein expression using an analytically 
validated IHC assay. For some groups in Part 2, study eligibility is further defined by 
NRG1 expression.
HER3 is expressed in a broad range of solid tumors, including melanoma, gastric cancer, 
NSCLC, and squamous cell carcinoma of the head and neck (SCCHN). Upon ligand 
binding, HER3 heterodimerizes with other members of the HER family and acts as a 
mediator of drug resistance to various cancer therapies [Amin, 2010; Zhang, 2014; 
Kugel, 2014]. Phosphorylation of intracellular sites of HER3 leads to activation of 
PI3K/AKT and MEK/MAPK and JAK/STAT signaling. GSK2849330 has demonstrated 
inhibition of HER3 activity and tumor growth in mouse xenograft models.
For Part 2 of the study, 4 tumor types were selected for inclusion: 2 tumor types with 
high levels of HER3 expression (melanoma and gastric cancer) and 2 tumor types with 
high levels of NRG1 (ligand for HER3) expression (cancers of the head and neck and 
NSCLC).
Melanoma
In melanoma, overexpression of HER3 is associated with advanced disease and decreased 
survival [Reschke, 2008; Ueno, 2008]. Treatment of melanoma is underexplored in the 
development of HER3 inhibitors.
In CHL-1, BRAF wild-type melanoma cell line mouse xenograft model GSK2849330 
treatment decreased phospho-HER3, total HER3, phospho-AKT and tumor growth.

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HER3 inhibition restored the sensitivity of trametinib and dabrafenib (MEK and BRAF 
inhibitors, respectively) in NRG1-treated BRAF mutant melanoma cell lines.
Gastric cancer
Both HER2 and HER3 expression are probable prognostic markers in patients with 
gastric cancer [Park, 2006; García, 2003; Piontek, 1993; Hayashi, 2008; Zhang, 2009; 
Wu, 2014; Sato, 2013].
Approximately 30% to 60% of gastric cancers express HER3 [Hayashi, 2008]. HER3 
mutations are present in approximately 11% of gastric cancers. In a gastric cancer 
xenograft model, HER3 antibodies reported to reduce tumor growths.  In NCI-N87, an 
ERBB2 amplified gastric cancer cell line, GSK2849330 treatment restored sensitivity to 
lapatinib lost due to the addition of NRG1.
Cancers of the Head and Neck
A subset of head and neck cancer cell lines with sensitivity to lapatinib has elevated 
expression of NRG1 and activation of HER3 [Wilson, 2011]. High NRG1 expression in 
these cancers is associated with activation of HER3 and may be used as a predictive 
biomarker for HER3-targeted therapies [Shames, 2013].
A combination of EGFR and HER3 inhibition caused tumor regression in head and neck 
xenograft models [Zhang, 2014].
NSCLC
NRG1 overexpression was identified as a biomarker for efficacy in patients treated with 
HER-3 antibody MM-121 [Sequist, 2014]. In a phase 2 trial of patritumab, a HER3-
targeted antibody, in combination with erlotinib, an EGFR inhibitor, in erlotinib-naive 
patients with advanced NSCLC, PFS was significantly improved only in the subgroup of 
patients with high NRG1 expression [Mendell-Harary, 2014;Von Pawel, 2014].  
Furthermore, one PR was confirmed in a patient with NSCLC who expressed high levels 
of NRG1 in a phase 1 study of HER3 antibody AV-203 that included subjects with 
advanced or metastatic colorectal cancer, NSCLC, and SCCHN, and other solid tumors 
[Sarantopoulos, 2014]. Recently, NRG1 gene fusion has been reported in a subset of 
invasive mucinous lung adenocarcinoma.
Nonclinical data also demonstrated NRG1 induced activation of HER3 signalling 
adversely affect the activity of agents that target the MEK/MAPK and PI3K/AKT 
signalling pathways. In KRAS mutant NSCLC cell lines, the combined inhibition of 
MEK and HER3 synergistically induced cell death.  HER3 is upregulated in response to 
AKT inhibition in some NSCLC cell lines. In vitro studies of patritumab showed that 
only cell lines expressing NRG1 responded to treatment, as manifested by decreases in 
HER3 and AKT phosphorylation [Schneider, 2014].

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3.6.3.
Rationale for Dose
The proposed doses of GSK2849330 are based on available preclinical biology, 
toxicology, and PK data as well as predicted PK and pharmacologic response information 
for humans and are consistent with International Conference on Harmonisation (ICH) 
guidelines for FTIH oncology studies.  Guidance for first in human studies with 
biologics, expert viewpoints on FTIH oncology studies with molecularly targeted 
therapeutics [LeTourneau, 2010], and recent preliminary safety data reported for anti-
HER3 mAbs were also considered when proposing doses of GSK2849330 (refer to 
Section 1.3 for details).
In nonclinical GLP toxicology studies, GSK2849330 was given as a once-weekly IV 
infusion to rats and cynomolgus monkeys for up to 4 weeks with up to 6-week off-
treatment period.  In the rat, there were no adverse findings up to and including the top 
dose studied (500 mg/kg/wk). In monkeys, abnormal fecal consistency was observed in 
male animals at the top dose studied (300 mg/kg/wk) and in female animals at ≥ 
30 mg/kg/wk.  In a single monkey in the top dose group (300 mg/kg/wk), mild cecal and 
colonic ulcers were observed at terminal necropsy.  The NOAEL, STD10 (severely toxic 
dose in 10% of animals [rat], and HNSTD (highest non-severely toxic dose 
[cynomologus moneky]), and HED (human equivalent dose) corresponding to the STD10 
or NHSTD are summarized in Table 2.
Table 2
NOAEL, NSTD10 (rat), and HNSTD (primate) from GLP Toxicology 
Studies and HED Predictionsa
NOAEL Dose
(mg/kg/wk)
NOAEL AUC
(0-168 h)
(mg*hr/mL)
STD10 or HNSTD 
Dose
(mg/kg/wk)
Human Equivalent 
Dose
(mg/kg/wk)
Rat
500
573
≥500
≥81
Cyno
30
102
≥300
≥97
AUC = area under the concentration-time curve; Cyno = cynomolgus monkey; HED = human equiv. dose 
HNSTD = highest non-severely toxic dose; NOAEL = no observed adverse effect level; STD10 = severely 
toxic dose in 10% of animals.
a.
HED corresponding to the STD10 (rat) or HNSTD (Cyno) as calculated scaled using scaling factor 
described in the FDA FTIH guidance 
Refer to Section 1.2 and the IB [GlaxoSmithKline Document number 2013N168399_01] 
for additional information on the preclinical biology and toxicology studies. 
Starting Dose 
The proposed starting dose is 1.4 mg/kg, administered once-weekly.  According to 
ICHS9 guidance, calculating a starting dose based on HNSTD/6 in the most relevant 
species (cynomologous monkey) yields a starting dose of ~16 mg/kg/wk.  We selected a 
more conservative starting dose of 1.4 mg/kg/wk, slightly above the MABEL calculated 
from tumor xenograft studies, which in turn suggests that clinical activity may be 
observed at dose levels of 1.2 mg/kg and higher.

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Table 3
Dose Levels
Cohort
Dose 
N
Dose Escalation 
Cohorts
N
PK-PD 
Cohorts
1
1.4 mg/kg weekly
1 (minimum)
up to 3
2
3 mg/kg every 2 weeks
3 (minimum)
up to 3
3
10 mg/kg every 2 weeks
3 (minimum)
up to 3
4
30 mg/kg every 2 weeks
3 (minimum)
up to 3
5
30 mg/kg weekly (optional change to every 2 weeks 
after 24 weeks of treatment)
3 (minimum)
up to 3
Additional optional cohorts may be enrolled at different dose levels and  intensities
Maximum Proposed Dose
The maximum proposed dose of 30 mg/kg for weekly, bi-weekly or every three week 
dosing was selected based on PK-PD extrapolations which predict target engagement > 
90% and tumor saturation should be achieved at or below this dose, and based on 
practical considerations (e.g., drug product supply and production capacity) Emerging 
PK, safety and tolerability data may cause the proposed maximum dose to be adjusted
downward (see Section 3.3 for details of the N-CRM model assessment of safety data).
Dose Escalation
The proposed dose escalation scheme is based on a half-log step size, with the exception 
of the 30 mg/kg/wk dose and the nominal doses shown in Table 3 represent the maximum 
dose which may be selected. The study team, in discussion with the investigator(s), may 
select other doses or alternative schedules besides those shown, based on emerging 
safety, tolerability, PK and/or PD data.
Dosing Interval 
The predicted half-life for GSK2849330 after the first dose is ~7 days and increases to 
~10 to 14 days after repeated dosing and is expected to support dosingfrequency from 
weekly to every three weeks.  However, at lower doses, including the proposed starting 
dose, the contribution of target mediated clearance may yield a half-life somewhat shorter 
than projected for higher dose levels.  With this consideration, the initial dosing 
frequency for the first subject will be once-weekly. PK data will be evaluated from the 
first week of dosing for the first subject, so that adjustments in the dosing interval can be 
made if appropriate (see the Time and Events Tables Section 7.1 and Section 7.4 for the 
specific PK assessment schedule for the first subject).  
If the half-life appears to be generally in line with expectations, the dosing interval for 
higher dose cohorts is anticipated to be every week or every 2 weeks.  A general 
guideline is shown in Table 4.  Additional schedules may be explored based on safety, 
tolerability, PK and PD.

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Table 4
Dosing Interval Guidance
Observed half-life
Likely dose interval*
<3 days
Once-weekly
4-8 days
Every week or every 
2weeks
> 9 days
Every 3 weeks
*Final selection of dose interval for cohorts will take into consideration the half-life together with safety, 
tolerability, PK and available PD data.
It is recognized that increasing the dose can allow for extension of the dosing interval 
with equivalent safety and efficacy, assuming that 1) toxicity is not limited by Cmax and 
2) efficacy is related to overall exposure (AUC) or time above a given concentration.  
Both assumptions appear reasonable for GSK2849330 based on 1) preclinical safety data 
and 2) preclinical efficacy data and knowledge of the mechanism of action.  Based on 
human PK predictions from cynomolgus monkey data, a dose of 2.9 mg/kg every 3 
weeks IV may provide the same exposure in 3 weeks as 3 doses of 1.2mg/kg every week 
IV at steady state.  Using these principles, it is anticipated that the dosing schedule may 
be lengthened as appropriate based on accrual of PK and/or PD information.
Additional context for the proposed doses are provided in the following sections.
Human Pharmacokinetic Extrapolation
Human plasma PK was predicted based on extrapolation from PK data of GSK2849330 
in cynomolgus monkeys dosed with 1, 10 or 100 mg/kg as a single IV dose (n= 3 female 
and n= 3 male per group).  The estimated terminal half-life from the high dose (100 
mg/kg) in a 3-kg cynomolgus monkey was 100-114 hours with central volume of 
distribution of 140 mL (8% coefficient of variance [CV]) and target mediated clearance 
equilibrium constant 7.2 μg/mL (57% CV).  Single species allometric scaling from 3 kg 
cynomolgus monkey to a 60 kg human predicts a terminal half-life in humans of 
approximately 197-224 hours (~8-9 days) with central volume of distribution 
approximately 2.9 L and equilibrium constant approximately 3.7 μg/mL (57% CV), 
assuming the same level of target in cynomolgus and human.
Preliminary Human Pharmacokinetic Profile
Arithmetic mean preliminary non-compartmental PK parameters as of September 2014
are listed in Table 5 below for dose-escalation cohorts in this trial dosed GSK2849330 at 
1.4 mg/kg, 3 mg/kg or, 10 mg/kg.

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Table 5
Preliminary non-compartmental Pharmacokinetic Profile
Parameter 
Unit 
n 
Treatment (mg/kg)  
Estimate (CV%)
AUC(0,336) 
h*µg/mL 
1 
1.4 
3123 
3 
3 
8880 (25.7) 
3 
10 
28100 (27.8) 
t1/2 (24, 168) 
hr 
1/3 
1.4 
78.7 
t1/2 (24, 336) 
hr 
1/3 
3 
119 
3 
10 
134 (32.0) 
Cmax
µg/mL 
1 
1.4 
29.8 
3 
3 
64.7 (30.2) 
3 
10 
234 (2.65) 
tmax
hr
1 
1.4 
1 
3 
3 
1 [1-6]a
3 
10 
1[1-6] a
AUC = area under the concentration-time curve; Cmax = maximum observed concentration; CV = coefficient of 
variance; t1/2 = plasma elimination half-life; tmax = time to maximum observed concentration.  
Preliminary non-compartmental PK analysis for subjects in dose-escalation cohorts.  
a denotes median [range] 
Preliminary population PK parameters based on nominal dose and PK sample time as of 
September 2014 are listed in Table 6 below for dose-escalation cohorts at 1.4 mg/kg 
(n=1), 3 mg/kg (n=2) or, 10 mg/kg (n=2). The data are modelled according to a two 
compartment PK model with peripheral Target Mediated Drug Disposition. The value of 
KM (concentration at half maximal saturation of peripheral target mediated drug 
disposition) is based on Biacore in vitro binding data together with an assumed 4/h rate of 
internalization and degradation based on semi-quantitative in vitro pulse chase 
experiment. One subject was excluded from the 3 mg/kg cohort because the dose was 
delayed; and another subject was excluded from the 10 mg/kg cohort because the 
infusion was terminated early so the total dose of GSK849330 administered was 
uncertain.

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Table 6
Preliminary Population PK Parameters
Parameter 
Unit 
Estimate
%RSE
%CV
CL 
mL/h 
11.4
39.1 
31.3
V1 
mL 
2830
6.64 
VM 
µg/h 
198
40.6 
KM
µg/mL 
0.513 
Q
mL/h 
79.0 
19.1 
V2
mL 
3420
13.7 
D1
h 
1 
SG1 (proportional)
0.0626 
62.9 
The compartmental and non-compartmental model parameters suggest a catabolic half-
life of (V1/CL)xln(2) = 172 hours. 
Predicted Effective Dose 
The potential therapeutic dose range for GSK2849330 in humans was derived using 
available preclinical in vitro and in vivo PK and efficacy data.  In addition, data from 
mouse in vivo CHL-1 xenograft efficacy studies were evaluated to predict the potential 
minimum clinically efficacious dose.  PK/PD modeling of CHL-1 xenograft data in SCID 
mice suggests that anti-tumor efficacy (based on tumor growth curves) may be achieved 
with systemic plasma trough concentrations of GSK2849330 maintained at ≥ 20 μg/mL.  
The predicted human equivalent dose to achieve a similar trough concentration in 90% of 
the population is approximately 1.4-3 mg/kg/wk. This dose is also in line with that 
projected, based on in vitro potency data, to engage HER3 and inhibit signaling 
(approximately 0.9 to 5.6 mg/kg).  It is anticipated that optimal anti-tumor activity will 
require full target engagement and that ADCC and CDC enhancements may further 
increase the anti-tumor activity of GSK2849330.  However, it is also recognized that 
saturation of target throughout the tumor in the clinical setting may require doses higher 
than those projected based on preclinical extrapolations, due to factors in the tumor 
microenvironment such as vascular perfusion heterogeneity which may limit mAb intra-
tumoral distribution.  Recognizing these factors, the top proposed dose for evaluation is 
30 mg/kg, a dose which is also viewed as the highest dose feasible based on practical 
considerations.

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A loading dose scenario is predicted to maintain an accumulated steady state trough 
concentration if the dosing interval is less than or equal to the elimination half-life.  
Accordingly, a 30 mg/kg weekly IV dose cohort has been added to the dose escalation 
portion of the study.
3.6.4.
Rationale for Endpoints
The safety endpoints for all parts of the study (as described in Section 2.1 and Section 
2.2) are designed to maximize subject safety, to allow for the identification and 
monitoring of emerging safety signals, and to allow for the identification of DLTs for 
determination of a MTD and/or recommended dose for further exploration.
Efficacy endpoints (as described in Section 2.1 and Section 2.2) will be collected to 
evaluate preliminary evidence of clinical benefit from treatment with GSK2849330.
Non-compartmental PK parameter values for GSK2849330 following IV administration, 
including 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-t)], Area 
under the concentration-time curve over the dosing interval [AUC(0-τ)], Cmax and time 
of occurrence of Cmax (tmax) and mean residence time (MRT) of GSK2849330 together 
with population compartmental PK parameters including clearance (CL), systemic 
volume of distribution (V), distributional clearance (Q), maximal rate (Vm), and 
concentration at half maximal rate (Km) according to a Michaelis-Menten approximation 
of systemic target mediated clearance [Gibiansky, 2008], were selected to characterize 
the PK activity of GSK2849330.
Tumor, skin, and circulating biomarkers were selected based on the mechanism of action 
of GSK2849330, preclinical evidence in addition to clinical evidence reported in agents 
of the same class and in those affecting similar pathways.  The objective is to characterize 
the PD effect of GSK2849330 and to obtain preliminary data on the relationship between 
HER3 expression levels (e.g., IHC 2+ and 3+), NRG1 expression, other potential 
predictive biomarkers including expression of other RTKs, mutations, immune associated 
markers, and efficacy outcome.
3.7.
Study Treatment
3.7.1.
Treatment Assignment

Subjects will be identified by a unique subject number that will remain consistent 
for the duration of the study.

Upon completion of all the required screening assessments, eligible subjects will 
be registered into RAMOS (Registration and Medication Ordering System), the 
GSK interactive voice response system (IVRS) by the investigator or authorized 
site staff.  All enrolled subjects will receive GSK2849330.

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3.7.2.
Dosage and Administration of Study Treatment(s)
GSK2849330 will be given by IV infusion over a 1-hour period. If an infusion-related 
reaction occurs during administration, the infusion rate may be reduced or halted at the 
discretion of the investigator and/or GSK medical monitor, depending on the severity of 
the symptoms; the subject will receive appropriate medical treatment. When the subject’s 
condition is stable, the infusion may be restarted according to the judgment of the 
investigator. Upon restart, the infusion rate should be half of the infusion rate at the time 
the infusion was paused.
Guidance for the monitoring and managing of infusion related reactions and 
allergic/hypersensitivity reactions, including anaphylaxis, are outlined in Section 3.9.1
and Section 3.9.2.
Subjects should be monitored for at least 1 hour after the completion of the infusion and 
may be discharged if considered clinically stable and all other study procedures have 
been completed.
Guidelines for dosage modifications are provided in Section 3.9.4.
The dose of study treatment is discussed in Section 3.3 and Section 3.4.
3.7.3.
Blinding
This is an open-label study.
3.8.
Safety Management Guidelines
3.8.1.
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.  Study treatment(s) will be stopped if any of the following liver 
chemistry stopping criteria is/are met:
1.
ALT 3 times ULN and bilirubin 2 times ULN (or ALT 3 times ULN and 
international normalization ratio [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).
2.
ALT 5 times ULN.
3.
ALT 3 times ULN if associated with the appearance or worsening of rash or 
hepatitis symptoms (fatigue, nausea, vomiting, right upper quadrant pain, tenderness 
or jaundice) or hypersensitivity (such as fever, rash or eosinophilia, other than that 
as described in Section 3.9.1 and Section 3.9.2).

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4.
ALT 3 times ULN persists for 4 weeks.
5.
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.
3.8.1.1.
Liver Chemistry Follow-up Procedures
Refer to the diagram in Appendix 1 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 3.8.1.

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 electronic case report forms (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, aspartate aminotransferase 
[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 
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.

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In addition, for all subjects with ALT 3 times ULN, every attempt must be made to 
also obtain the following:

Viral hepatitis serology including:

Hepatitis A Immunoglobulin M (IgM) antibody.

Hepatitis B surface antigen and hepatitis B core antibody (IgM).

Hepatitis C RNA.

Cytomegalovirus IgM antibody.

Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, obtain 
heterophile antibody or monospot testing).

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 30 days of last dose.  Record the 
date/time of the PK blood sample draw and the date/time of the last dose of study 
treatment(s) 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 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 (other than as described in Section 3.9.1 and Section 3.9.2) 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, magnetic resonance imaging [MRI] or computed 
tomography [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 high-performance 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]).
3.8.2.
QTc Stopping Criteria
If a subject meets the QTc1 interval duration criteria below, study treatment(s) will be 
withheld.  

QT interval corrected for heart rate (HR) by Fredericia’s formula (QTcF) >530 msec
1Based on average QTc value of triplicate ECGs to include manual over-read.  For example, if an ECG 
demonstrates a prolonged QT interval, obtain 2 additional ECGs over a brief period (e.g., within 
approximately 10 minutes of the abnormal ECG, if possible, and approximately 10 minutes apart from each 
other), and then use the averaged QTc values of the 3 ECGs to determine whether the subject should have 
study treatment(s) withheld.
If the QTc prolongation resolves to Grade 1 or baseline, the subject may be re-started on 
the study treatment(s) if the investigator and GSK Medical Monitor agree that the subject 
will benefit from further treatment.
Refer to Appendix 2 for country-specific QTc stopping criteria.
3.8.3.
Left Ventricular Ejection Fraction (LVEF) Stopping Criteria
3.8.3.1.
LVEF Stopping Criteria
Echocardiography (ECHO) or multi gated acquisition scan (MUGA) must be performed 
at Screening and as outlined in the Time and Events Tables (Section 7.1). Subjects who 
have an asymptomatic, absolute decrease of >15% in LVEF compared with baseline or an 
absolute decrease of >10% in LVEF compared with baseline and the ejection fraction is 
below 50% should temporarily discontinue GSK2849330 and have a repeat evaluation of 
LVEF within 1 week.  ECHO should be repeated every 1 to 2 weeks for 4 weeks or until 
LVEF recovery to within15% of baseline or to above 50% and within 10% of baseline 
depending on which stopping criteria above were met.

If the LVEF recovers (defined as absolute decrease 15% compared to baseline 
or 50% and absolute decrease 10% compared with baseline) at any time 
during the next 4 weeks, after consultation and approval of the GSK Medical 
Monitor, the subject may be restarted on GSK2849330 at a reduced dose.  For 
such subjects, monitoring of LVEF will be performed 2, 4, and 8 weeks after 
rechallenge, and then per protocol.

If repeat LVEF does not recover within 4 weeks, treatment with GSK2849330 
should be permanently discontinued.  Ejection fraction should be monitored 
every 4 weeks for a total of 16 weeks or until resolution.
Subjects with Grade 3 or 4 (symptomatic) left ventricular systolic dysfunction must 
discontinue treatment with GSK2849330.  Ejection fraction should be monitored every 
4 weeks for a total of 16 weeks or until resolution. If recovery occurs (LVEF 50% and 

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symptom resolution) within 4 weeks, treatment with GSK2849330 may be restarted at a 
reduced dose if the subject is receiving clinical benefit and in consultation with the GSK 
Medical Monitor.
Copies of all ECHOs/MUGAs and cardiology consultations performed on subjects who
experience a >15% decrease in LVEF from baseline or >10% decrease in LVEF from 
baseline and whose cardiac ejection fraction is < 50% will be required by GSK for 
review.  Instructions for submitting qualifying ECHOs are provided in the SPM.
3.9.
Guidelines for Events of Special Interest and Dose 
Modifications
The severity of AEs will be graded utilizing NCI-CTCAE, version 4.0 [NCI, 2009]. 
Guidelines for dose modifications and interruptions for management of common 
toxicities associated with the study treatment(s) are provided in this section.
In subjects experiencing suspected infusion-related reactions, a whole blood sample for 
selected cytokines (including but not limited to TNF alpha, IL-6, and tryptase) should be 
drawn within 24 hours and submitted to the central laboratory for analysis (see SPM for 
instructions).
3.9.1.
Management of Infusion Reactions
As there is a risk of infusion reactions during administration of IV immunoglobulins, 
including monoclonal antibodies, subjects will be monitored for signs and symptoms of 
an infusion-related reaction (including Grade 1 to 2 fever, chills, headache, nausea, 
malaise) during infusion and for a minimum of 1 hour after the first administration of 
GSK2849330.
If an infusion-related reaction occurs during administration, the infusion rate may be 
reduced or halted at the discretion of the investigator and/or GSK medical monitor, 
depending on the severity of the symptoms and the subject will receive appropriate 
medical treatment. For subsequent infusions, the investigator may provide premedication 
with antihistamines, acetaminophen, and/or corticosteroids and may reduce the starting 
infusion rate.
Treatment may include:

Fevers/Myalgia:  Initiate treatment with acetaminophen (paracetamol). If
subject’s fever does not respond to acetaminophen, consideration should be given 
to the use of a nonsteroidal anti-inflammatory drug (NSAID) such as 
indomethacin. Consider pre-medication with acetaminophen for subsequent 
doses.

Chills/rigors: Use warming blankets as initial intervention; consider IV 
meperidine (pethidine) if chills persist.

Nausea/vomiting: Consider treatment with 5-HT3 antagonists, prochlorperazine, 
lorazepam; some agents may cause hypotension and altered mental status; 
therefore, these agents should be used with caution.

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3.9.2.
Allergic Reaction Monitoring and Management
As GSK2849330 is a fully humanized antibody, it is considered unlikely for acute 
allergic reactions to occur in response to GSK2849330 exposure; however, all subjects 
will be monitored carefully for evidence of allergic response. A subject that exhibits signs 
or symptoms of severe hypersensitivity or anaphylaxis will receive appropriate medical 
treatment and remain on study at the discretion of the investigator and after discussion 
with the GSK medical monitor.
In accordance with the preparedness for treatment of anaphylaxis, emergency 
resuscitation equipment, advanced cardiac life support equipment, and medications must 
be readily accessible during GSK2849330 administration.
It is important to recognize early signs of an anaphylaxis reaction and appropriate 
treatment must begin immediately to prevent progression to severe anaphylaxis. Subjects 
will be closely monitored in an appropriate setting for early signs of dyspnea and edema. 
Antihistamines, such as diphenhydramine; and corticosteroids such as prednisolone may 
be given to reduce symptoms.
If more severe clinical signs arise, immediate assessment of the ABC's (airway, 
breathing, and circulation from Basic Life Support) will be done in all suspected 
anaphylactic reactions. Cardio-Pulmonary Resuscitation (CPR) will be initiated if 
needed. Epinephrine will be given by injection without delay. Emergency interventions 
may include endotracheal intubation or tracheostomy. Treatment for shock will include 
IV fluids and medications that support the actions of the heart and circulatory system.
3.9.3.
Diarrhea Management
If episodes of diarrhea occur, causes for the diarrhea other than the study treatment such 
as concomitant medications (e.g., stool softeners, laxatives, antacids, etc.), infections by 
Clostridium. difficile or other pathogens, partial bowel obstruction, etc., should be ruled 
out. Subjects should be instructed to first notify their physician/healthcare provider at 
onset of diarrhea of any severity. Supportive measures depend on the severity of the 
diarrhea and could include the following as clinically indicated:

Dietary modifications (e.g. small, frequent meals, low fiber, and lactose-
avoidance; addition of foods rich in potassium)

Maintain hydration with clear liquids or IV fluids as needed

Loperamide and/or oral antibiotics

Second-line agents

Hold GSK2849330
Additional recommended guidelines for the treatment of study treatment induced diarrhea 
are provided in Benson, et.al. [Benson, 2004] and in Appendix 9.

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3.9.4.
Dose Modifications
In the event of a toxicity that meets the guidelines for DLT (Section 3.3.1) or is otherwise 
considered to be clinically significant by the treating physician, treatment will be stopped 
and supportive therapy administered as clinically indicated. If clinically significant drug-
related toxicity is present, treatment should be delayed until the toxicity resolves (with or 
without supportive therapy) to baseline or Grade 1. If the toxicity does not resolve to 
Grade 1 or baseline within 2 weeks, withdrawal from the trial is recommended unless 
otherwise agreed to by a GSK Medical Monitor and the investigator based on evidence of 
clinical benefit.
For subjects enrolled in the 30 mg/kg weekly dosing cohort, the dosing frequency may be 
reduced to every 2 weeks at the discretion of the investigator for a toxicity that does not 
automatically necessitate a dose reduction.
3.9.5.
Dose Reductions
Part 1: A subject who experiences a toxicity at any time during treatment with 
GSK2849330 that either meets the guidelines for DLT (Section 3.3.1) or is otherwise 
considered to be clinically significant by the treating physician, should have their dose 
reduced to the previously tested next lower dose level. Any subject who experiences one 
or more recurrent clinically significant toxicities after the initial dose reduction may have 
one further dose reduction except where noted otherwise. Subjects who continue to 
experience clinically significant toxicity despite two dose reductions (i.e., unacceptable 
toxicity) will be discontinued from the study.
Part 2: Subjects who begin the selected dose and require a dose reduction (due to 
tolerability/toxicity issues), should be dose reduced to one level below the recommended 
Part 2 dose. Further dose reductions should be discussed with the GSK Medical Monitor.
4.
INVESTIGATIONAL PRODUCT(S)
The term ‘study treatment’ is used throughout the protocol to describe the investigational 
product (IP) received by the subject as per the protocol design.  The study was initiated 
with vials containing 1 mL of IP. Vials containing 5 mL were later introduced, and for 
the remainder of the study, both 1-mL and 5-mL vials will be available.

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4.1.
Description of Investigational Product(s)
Product name :
GSK2849330 solution for infusion 100 mg/mL
Formulation description:
Solution containing 100 mg/mL GSK2849330 in 
vials containing 1 mL for injection
or
Solution containing 100 mg/mL GSK2849330 in 
vials containing 5 mL for injection
Dosage form :
Solution for Infusion. The solution is stored at 2-
8C.
Unit dose strength(s)/Dose 
Level(s):
IV/100 mg/mL (refer to Section 3.3 and Section 3.4
for dose levels)
Physical Description: 
GSK2849330 solution for infusion is clear to 
opalescent, pale yellow or pale brown in color.
Route/
Administration/ Duration:
Delivered as an IV solution (see Section 3.7.2).
Dosing instructions:
Dilute GSK2849330 solution into a 0.9% sodium 
chloride IV bag to the appropriate concentration for 
the dose. Deliver the entire contents of the IV bag to 
the subject.
Manufacturer/ Source of 
Procurement:
GSK
GSK2849330 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 GSK2849330 GSK 
Investigational Product
Preparation
Dilute GSK2849330 solution into a 0.9% sodium chloride IV bag to the appropriate 
concentration for the dose. Deliver the entire contents of the IV bag to the subject. The 
administration kits can be polymerizing vinyl chloride (PVC) or polyolefin (PO) plastics. 
A 0.22-M polyethersulfone (PES) filtration set will be used for this study.
Handling
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.
Take adequate precautions to avoid direct eye or skin contact and the generation of 
aerosols or mists.
In the case of unintentional occupational exposure notify the study monitor, the GSK 
Medical Monitor and/or the study manager.

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Refer to the SPM for detailed procedures for the disposal and/or return of unused study 
treatments.
Storage
GSK2849330 must be stored in a secure area under the appropriate physical conditions 
for the product.  Access to and administration of the GSK2849330 will be limited to the 
investigator and authorized site staff.  GSK2849330 must be dispensed or administered 
only to subjects enrolled in the study and in accordance with the protocol.
GSK2849330 is to be stored at a temperature range of 2C to 8C.  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
GSK2849330 will be administered IV to subjects at the study site.  Administration will 
be documented in the source documents and reported in the eCRF.
Treatment start and stop dates, including dates and reasons for treatment delays and/or 
dose modifications will also be recorded in the dosing eCRF.
4.5.
Treatment of Investigational Product Overdose
In the event of an overdose (defined as administration of more than the highest protocol-
specified dose) of GSK2849330, the investigator should:

contact the GSK Medical Monitor immediately

closely monitor the subject for AEs/SAEs and laboratory abnormalities for at 
least 45 days or 5 half-lives (whichever is longer) for GSK2849330

obtain a plasma sample for PK analysis within 30 days 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.
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.

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5.
STUDY POPULATION
5.1.
Number of Subjects
The number of dose levels and the level at which the MTD is reached cannot be 
determined in advance.  An adequate number of subjects will be enrolled into the study to 
establish the recommended dose(s) for further study.  It is estimated that approximately 
13 subjects will be enrolled in Part 1 dose escalation if there are no DLTs observed; if 
there are any DLTs observed, more than 13 subjects can be enrolled in dose escalation.
Up to an additional 21 subjects with evaluable pre- and on-treatment paired biopsies can 
be enrolled for the purpose of the PK/PD cohorts in Part 1. Therefore, up to 
approximately 34 subjects may be enrolled into Part 1 (dose-escalation and PK/PD 
cohorts) of the study; however; additional dose escalation cohorts may be enrolled to 
allow for further evaluation of additional dose levels/regimens if warranted.
In Part 2 of the study, there will be at least 4 molecularly-defined tumor histology 
groups. It is estimated that a minimum of 12 subjects will be enrolled in each group with 
a maximum of approximately 30 subjects if futility criteria are not met. 
Therefore,approximately120 subjects may be enrolled in Part 2 and approximately 
154 subjects may be enrolled in the entire study; however, this number will be 
considerably fewer if futility conditions are met for any group in Part 2 (see Section 3.4, 
Section 13.2.2, and Section 13.6.2). Additional groups of tumor histologies predicted to 
be sensitive to the study drug based on emerging nonclinical or clinical data may be 
added to Part 2.
In Part 1 (dose escalation) of the study, if subjects prematurely discontinue for reasons 
other than toxicity, additional subjects may be enrolled as replacement subjects and 
assigned to the same treatment cohort at the discretion of the Sponsor in consultation with 
the investigator.  Subjects may also be replaced in Part 2 of the study for the purpose of 
testing futility or to facilitate collection of sufficient tumor biopsies for exploratory 
analyses.
5.2.
Subject Selection 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.
Deviations from inclusion/exclusion criteria are not allowed because they can potentially 
jeopardize the scientific integrity of the study, regulatory acceptability or subject safety.  
Therefore, adherence to the criteria as specified in the protocol is essential.
5.2.1.
Pre-screening Inclusion Criteria for Part 1
Subjects will be eligible for inclusion in pre-screening for the study (See Section 3.2) 
only if all of the following criteria apply:

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1. Males and females ≥18 years of age (at the time consent is obtained).
2. Written informed consent provided.
3. Performance Status score of 0 or 1 according to the Eastern Cooperative 
Oncology Group (ECOG) scale (see Appendix 3).
4. Sufficient archival tumor specimen is available for HER3 IHC analysis, or subject 
is willing to undergo a fresh tumor biopsy (using a procedure that is safe for the 
subject) for HER3 IHC analysis (see Section 7.6.1.1 for details).
5. Histologically or cytologically confirmed diagnosis of one of the following solid 
tumor malignancies for which no standard therapeutic alternatives exist:

Bladder cancer

Breast cancer

Castrate-resistant prostate cancer

Cervical cancer

Colorectal cancer (CRC)

Gastric cancer

Hepatocellular carcinoma (HCC)

Melanoma

Non-small cell lung cancer (NSCLC)

Ovarian cancer

Pancreatic cancer

Squamous cell cancers of the head and neck region (SCCHN) (including 
parotid and nasopharynx)
5.2.2.
Pre-screening for Part 2
Subjects with melanoma, gastric/gastroesophageal cancer, head and neck cancer, or 
NSCLC who appear to meet all inclusion and exclusion criteria may be pre-screened for 
the study provided that sufficient tumor specimen, either from archival FFPE tissue or 
tissue obtained by biopsy (using a procedure that is safe for the subject) is available for 
analyzing HER3 by IHC or HER3 by IHC and NRG1 by RNA analysis.
5.2.3.
Screening Inclusion Criteria for Parts 1 and 2
Subjects eligible for enrollment in the study must meet all of the following criteria:
1. Males and females ≥18 years of age (at the time consent is obtained).
2. Written informed consent provided.
3. For subjects enrolled in Part 1:subjects must have tumors with documented HER3 
expression (2+ or 3+) on the cell surface of the invasive component of the tumor 
using an analytically validated IHC assay by central laboratory   (see Section 
7.6.1.1 for details). Subjects enrolled in Part 2 must meet inclusion criterion 9 
listed below.

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4. ECOG performance status of 0 or 1 (see Appendix 3).
5. Adequate baseline organ function defined by: 
SYSTEM
LABORATORY VALUES
Hematologic
  ANC
1.5 × 109/L
  Hemoglobin
9 g/dL 
  Platelets
75  × 109/L
PT/INR and  
1.3 × ULN
Hepatic
  Albumin
2.5 g/dL
  Total bilirubin
1.5  × ULN
 AST and ALT
2.5  × ULN
Renal
Serum creatinine
OR
Estimated glomerular filtration rate or 
24-hour urine creatinine clearancea
ULN
OR
50 mL/min
Cardiac
LVEF
50% by ECHOb or MUGA
ALT = alanine aminotransferase; ANC = absolute neutrophil count; AST = aspartate aminotransferase; 
ECHO = echocardiogram; INR = international normalized ratio; LVEF = left ventricular ejection 
fraction; MUGA = multiple-gated acquisition scan; PT = prothrombin time; PTT = partial thromboplastin 
time; ULN = upper limit of normal. 
a. Estimated glomerular filtration rate will be calculated by the Modification of Diet in Renal Disease 
(MDRD) equation (Appendix 4). When both a calculated and 24-hour creatinine clearance are 
available, the 24-hour value will be used.
b. ECHO is the preferred method. MUGA should be performed only if evaluation by ECHO is not 
available.
.
6. If the subject is female, she must be of non-childbearing potential, i.e., have a 
current tubal ligation, hysterectomy, ovariectomy or be post menopausal, or if she 
is of childbearing potential, she 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 11.1.1, from the time of the first dose of study treatment until 
45 days or 5 half-lives (whichever is longer) after the last dose of study treatment.
7. Men with a female partner of childbearing potential must have either had a prior 
vasectomy or agree to use effective contraception as described in Section 11.1.2  
from the time of the first dose of study treatment until 45 days or 5 half-lives 
(whichever is longer) after the last dose of study treatment to allow for clearance 
of GSK2849330 in seminal fluid.
8. Subjects enrolled as part of the PK/PD cohort (Part 1) must agree to undergo pre-
and on-treatment tumor biopsies, using a procedure that is safe for the subject.

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5.2.4.
Inclusion Criteria for Part 2 ONLY
As listed above for Part 1, with the exception of criterion 3 which should be replaced 
with the following criterion 9 and the addition of criteria 10 and 11.
9. For Group 1: subjects with previously treated, unresectable stage III or IV 
melanoma with documented HER3 expression (3+) on the cell surface of the 
invasive component of the tumor using an analytically validated IHC assay by 
central laboratory.

Subjects must have no more than 3 prior lines of systemic regimens and 
have disease progression on or after last prior treatment (based on 
RECIST v1.1).

Subjects with BRAF V600 mutations who already received or were 
intolerant of prior BRAF inhibitor therapy may be included. 

Subjects may be included if they had prior immune therapy, or were 
intolerant of prior immune therapy.
For Group 2: Subjects with previously treated, unresectable stage III or IV gastric 
or gastroesophageal junction (GEJ) adenocarcinoma with documented HER3 
expression (3+) on the cell surface of the invasive component of the tumor using an 
analytically validated IHC assay by central laboratory.

Subjects must have no more than 3 prior lines of systemic regimens and 
have disease progression on or after last prior treatment (based on 
RECIST v1.1).

Subjects with HER2 positive disease may be included if they had prior 
anti-HER2 therapy or were intolerant of prior anti-HER2 therapy.
For Group 3: Subjects with previously treated, unresectable stage III or IV 
cancers of the head and neck with documented HER3 expression on the cell 
surface of the tumor ( 1+) and NRG1 expression using analytically validated 
assays by central laboratory.

Subjects must have no more than 3 prior lines of systemic therapy and 
have disease progression on or after last prior treatment (based on 
RECIST v1.1).

Subjects with locoregional recurrences amenable to definite surgery or 
additional radiation are excluded.
For Group 4: Subjects with previously treated, unresectable stage III or IV 
NSCLC with documented HER3 expression on the cell surface of the tumor (1+) 
and NRG1 expression using analytically validated assays by central laboratory.

Subjects must have no more than 3 prior lines of systemic regimens and 
have disease progression on or after last prior treatment (based on 
RECIST v1.1).

Subjects with anaplastic lymphoma kinase (ALK) translocation who 
already received or were intolerant of prior anti-ALK therapy may be 
included. 

Subjects with EGFR mutations (e.g., exon 19 deletion and exon 21 
L858R) who have documented progression (based on RECIST 1.1) or who 
were intolerant of prior EGFR inhibitors may be included. 

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Additional tumor histology groups predicted to be sensitive to the study drug 
based on biomarkers (e.g., HER3 mutations, NRG translocations) supported by 
preclinical or clinical data may be added based on emerging data.
10. Subjects must have at least one measurable lesion per RECIST v1.1.
NOTE: If the only site of measurable disease has been previously irradiated, 
documented progression of disease and a 4-week interval since completion of 
radiotherapy is required.
NOTE: In subjects with >1 measurable lesion, a measurable lesion may be 
biopsied at Screening and Day 15; however that lesion must not be selected as a 
target lesion for disease assessment.
11. Subjects must have disease amendable to biopsy and agree to undergo pre- and 
on-treatment tumor biopsies using a procedure that is safe for the subject (until 
the participating centers receive written notification from the Sponsor that paired 
tumor biopsies are no longer required).
5.2.5.
Screening Exclusion Criteria for Parts 1 and 2
Subjects meeting any of the following criteria must not be enrolled in the study:
1.
Subjects with leptomeningeal or brain metastases or spinal cord compression.

Subjects with untreated brain or meningeal metastases are not eligible 
(computed tomography [CT] scans are not required to rule this out unless 
there is a clinical suspicion of central nervous system [CNS] disease).

Subjects with treated and radiologic or clinical evidence of stable brain 
metastases (confirmed by 2 scans at least 4 weeks apart), with no evidence 
of cavitation or hemorrhage in the brain lesion are eligible providing that 
they are asymptomatic and do not require corticosteroids. Subjects are not 
permitted to receive enzyme inducing anti-epileptic drugs.
2.
Prior HER3- directed treatment (HER2- or EGFR-directed treatment is 
acceptable).
3. Use of an investigational anti-cancer drug within 28 days (or 5 half-lives, 
whichever is longer) preceding the first dose of GSK2849330 OR chemotherapy 
within the last 3 weeks (6 weeks for prior nitrosourea or mitomycin C) OR any 
major surgery, radiotherapy, immunotherapy or any other anti-cancer therapy 
within the last 4 weeks, except as noted above.
4. Unresolved toxicity greater than NCI-CTCAE, version 4.0 [NCI, 2009] Grade 1 
from previous anti-cancer therapy except alopecia and stable anemia (i.e., 
untransfused Hb 9.0 g/dL without the need for supportive transfusion within 
2 weeks of screening) at the time of treatment allocation.

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5. Known or suspected hypersensitivity reaction to prior biologic therapy (e.g.,
therapeutic monoclonal antibody) that in the opinion of the investigator is a 
contraindication to their participation in the study.
6. Current use of a prohibited medication or requires any of these medications 
during treatment (Section 10.2).
7. History or evidence of significant cardiovascular risk including any of the 
following:

LVEF <50%

A QT interval corrected for HR (QTc) 480 msec (≥500 msec for subjects 
with bundle branch block)

History or evidence of current clinically significant uncontrolled 
arrhythmias.
Exception: Subjects with controlled atrial fibrillation for >30 days prior to 
enrollment are eligible.

History of acute coronary syndromes (including myocardial infarction and 
unstable angina), coronary angioplasty, or stenting within 6 months prior 
to enrollment.

History or evidence of current ≥ Class II congestive heart failure as 
defined by New York Heart Association (NYHA).
8. Known human immunodeficiency virus (HIV), hepatitis B virus (HBV), or 
hepatitis C virus (HCV) infection (with the exception of chronic or cleared HBV 
and HCV infection which will be allowed).
9. Evidence of another active malignancy (excludes non-melanoma skin cancer). 
Consult GSK Medical Monitor if unsure whether second malignancies meet 
requirements specified above.
10. Psychological, familial, sociological, or geographical conditions that do not 
permit compliance with the protocol.
11. Concurrent medical condition that in the investigator’s opinion would jeopardize 
compliance with the protocol.
12. Lactating female.
13. Receiving chronic immunosuppressive therapies (includes daily steroid doses in 
excess of 20 mg/day of prednisone).
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 
and the reason for screen failure will be transmitted to GSK.

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6.2.
Subject Completion Criteria
In Part 1, a subject will be considered to have completed the study if they complete 
screening assessments and at least one study treatment followed by at least 28 days of 
observation. In Part 2, a subject will be considered to have completed the study if they 
have completed at least one on-treatment disease assessment.
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 3.8.1  . 
In addition, study treatment may be permanently discontinued for any of the following 
reasons:

major deviations(s) from the protocol

request of the subject or proxy (withdrawal of consent by subject or proxy)

investigator’s discretion

a dose delay for toxicity of > 2 weeks unless the investigator or GSK Medical 
Monitor agree that further treatment may benefit the subject

intercurrent illness that prevents further administration of study treatment

subject is lost to follow-up, or the 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, ‘AE’ will be 
recorded as the primary reason for permanent 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 assessments at the 
time of discontinuation and during post-study treatment follow-up as specified in Time 
and Events Tables (see Section 7.1).
6.4.
Study Completion
The study will be considered complete that is, having met the study objectives, after 70% 
of the subjects have died or 2 years after the last subject is enrolled. Upon completion of 
the study, if subjects are still continuing to receive benefit from GSK2849330, plans will 
be developed to provide continued access for those subjects if warranted.
Per the EU Clinical Trial Directive, the end of the study is defined as the last subject’s 
last visit (LSLV).

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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. Procedures conducted as part 
of the subject’s routine clinical management (e.g., blood count, ECG, ECHO/MUGA) 
obtained prior to their signing the informed consent may be utilized for screening or 
baseline purposes provided these procedures are conducted as specified in the protocol 
and have been performed within the protocol-specified timeframe.  However physical 
exam, medical history, ECOG performance status, and vital signs must be conducted 
after the informed consent is signed regardless of when these procedures may have been 
performed as part of routine clinical management.
The timing of each assessment is listed in the Time and Events Tables (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 safety, PK, PD/biomarker, 
immunogenicity, imaging or other assessments.  Changes in timing, addition, or removal 
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. Up to approximately 
350mL of blood will be collected over a 30-day period, including any extra assessments 
that may be required.
Whenever vital signs, 12-lead ECGs and blood draws are scheduled for the same nominal 
time, the assessments should occur in the following order: 12-lead ECG, vital signs, 
blood draws.  The timing of the assessments should allow the blood draw to occur at the 
exact nominal time.  Detailed procedures for obtaining each assessment are provided in 
the SPM.
After a subject has provided written informed consent for pre-screening, the investigator 
or other study personnel will determine if the subject is eligible for pre-screening in the 
study.  This will be done by reviewing the pre-screening inclusion criteria (Section 5.2.1) 
and completing all of the pre-screening assessments outlined in the Time and Events 
Table (Section 7.1).  Pre-screening assessments may be carried out over more than one 
day.
If during pre-screening the subject is determined to have the required HER3 or HER3 and 
NRG1 levels of expression then after a subject has provided written informed consent for 
the study and within 14 days of the first dose of study treatment, the investigator or other 
study personnel will determine if the subject is eligible for enrollment in the study.  This 
will be done by reviewing the inclusion and exclusion criteria and completing all of the 

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screening assessments outlined in the Time and Events Tables (Section 7.1).  Screening 
assessments may be carried out over more than one day provided that all required 
assessments are completed within14 days prior to the first dose of study treatment.
7.1.
Time and Events Tables
This section consists of the Time and Events Tables and supplemental footnotes to 
describe assessment windows and sequencing of study-specific assessments and 
procedures.

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Table 7
Time and Events for Part 1 (Dose Escalation Cohorts, every 2 week dosing schedule)
Pre-
screening
Screening
First Treatment Period (28 
days)
Day 29
Continuation Phase
Follow-up1
Post-study2
Day 1
Day 8 
Day 15 
-14 day 
window3
1 day window for each visit
3 day window for each 
visit
+ 7 day window 
Informed consent
X
X
Archival tissue 
X
Tumor biopsy
X4
X5
X6 pre-
dose
X7
Skin biopsy
X pre-
dose
X pre-dose
Baseline 
demographics
X
X
Medical history
X
X
X
Concurrent 
medication
Continuous
Pregnancy test8
X3
X pre-dose
Every 4 weeks
X
X
Physical examination
X
X9
X
X
Every 4 weeks
X
Height (at screening 
only) and weight
X
X
X
Weight: Every 4 weeks
X
ECOG 
X
X9
X
Every 4 weeks
X
Vital signs (BP, pulse 
rate, Temperature)
X
X10
X
X
X
Every 2 weeks 
X
12-lead ECG
X
X10
X
X
Every 4 weeks
X
Hematology/Clinical 
Chemistry
X
X9
X
X
X
Every 2 weeks
X
Coagulation 
parameters: PT, INR, 
PTT
X
As Clinically Indicated

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Pre-
screening
Screening
First Treatment Period (28 
days)
Day 29
Continuation Phase
Follow-up1
Post-study2
Day 1
Day 8 
Day 15 
-14 day 
window3
1 day window for each visit
3 day window for each 
visit
+ 7 day window 
Urinalysis
X
X
Every 4 weeks
X
ECHO11
X
X
Every 8 weeks
X
PK (Blood)12
X
X
X
X
Every 12 weeks
X
X
Safety cytokines20
In the event of infusion reaction
Circulating cell free 
DNA (cfDNA)
X pre-
dose
X7
Testosterone and 
LH13
X pre-
dose
X
Every 8 weeks
Whole blood/serum 
/cellular markers14
X
X
X
X
X7
GSK2849330 IV 
infusion15
X
X
X
Every 2 weeks15
AE assessment
Continuous
Serum sample for 
Immunogenicity
X pre-
dose
X
X
X16
X16
PGx sample
X pre-
dose17
Tumor markers 18
X
Every 8 weeks
Disease 
assessment19
X3
Every 8 weeks
X21
1.
The Follow-up visit should be approximately 28 days after the last dose of study treatment.
2.
The Post-study visit should be at least 45 days or 5 half-lives (whichever is longer) after the last dose of study treatment.
3.
Within 14 days prior to first dose except for pregnancy test (7 days) and Disease Assessment within 28 days prior to the first dose.
4.
Separate pre-screening consent required for fresh biopsy and fresh biopsy is only collected at pre-screening if archived tissue is not available.
5.
Fresh pre- and on-treatment tumor biopsy is optional, but strongly encouraged for dose escalation cohorts; if adequate fresh biopsy tumor tissue is acquired 
during pre-screening, then this does not need to be repeated during the screening period.  Archival tumor tissue is not acceptable to serve as pre-treatment 
tumor tissue.

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6.
Tumor biopsy is optional on Day 15 for dose escalation cohort subjects and required for the PK/PD cohorts. Biopsy must be collected prior to study treatment 
administration on Day 15 dose (pre-dose). 
7.
Collected at progression. Tumor biopsy is optional and only collected for subjects with disease progression on study treatment. The tumor specimen may be 
collected at any time after study treatment discontinuation, but must occur prior to the start of any subsequent anticancer therapy.
8.
Perform only in women of child-bearing potential.  Serum pregnancy test should be conducted at the Screening, Follow-up, and Post-study visits.  Urine 
pregnancy test should be conducted pre-dose on Day 29 and every 4 weeks from Day 29 in the continuation phase of the study.
9.
If the screening visit was completed within 72 hours of the first dose, this assessment does not need to be repeated on Day 1.
10. Collect at pre-dose and at 1, 2, 4, and 6 hours after the start of the first infusion.
11. ECHO is preferred; however, if echocardiography is not available, or if reliable echocardiographic analysis of LVEF is unable to be obtained due to technical 
factors, a MUGA scan may be performed.  Regardless, the method used at Baseline should be used for the remaining assessments in the study. 
Assessments should be performed more frequently than every 8 weeks if clinically indicated.
12. Blood samples for analysis of GSK2849330 concentrations will be collected on Day 1: pre-dose and at 1hour (15-minute window), and 6 hour (1-hour 
window) after the end of infusion. If a subject’s duration of infusion is 3 hours or longer the 6-hour time point is optional. Additional PK samples will be 
collected at Day 8, Day 15, and Day 29. Additional PK samples will also be taken every 12 weeks from the first dose within 1 year of starting treatment and if 
treatment continues after 1 year samples will be collected every 24 weeks. An additional PK sample will also be taken at the Follow-up and Post-study visits. 
Unless stated otherwise, on days of dosing sample will be drawn pre-dose. For the first subject in Cohort 1, additional PK samples will be taken at 24 hours 
(Day 2 [8-hours window]) and at 72 hours (Day 4 [24-hour window]) after the end of infusion of the first dose of GSK2849330.
13. To be conducted in male subjects only.
14. Whole blood for soluble markers from plasma, serum, and/or cellular markers.  Blood samples will be collected on Day 1: pre-dose and at 1 hour (15-minute 
window) and 6 hours (1-hour window) after the end of infusion.  If a subject’s duration of infusion is 3 hours or longer the 6 hour time point is optional. A pre-
dose blood sample should be collected on Day 8, Day 15 and Day 29 for all cohorts. An additional sample will also be collected at progression.
15. For any subjects receiving a weekly dosing schedule, the study treatment dosing window is 2 days.  The study treatment dosing window for all other dosing 
schedules (e.g., an every 2 week or every 3 week dosing schedule) is 3 days. If dosing does not occur on the intended day, all other 
assessments/subsequent visits should be changed accordingly relative to when the dose was received.  Subsequent cohorts may receive different dosing 
schedules use the appropriate Time and Events Table as applicable.
16. After the first treatment period, immunogenicity samples will be collected every 12 weeks from the first dose within one year of treatment. If treatment 
continues after 1 year, samples will be collected every 24 weeks. An immunogenicity sample must be collected at both the Follow up and the Post-study visit. 
17. It is preferred that the PGx sample be taken pre-dose on Day 1; however, it may be obtained anytime after informed consent has been given for PGx 
research.
18. See Section 7.8 and collect all tumor markers applicable for the subject’s primary tumor type.
19. Confirmatory assessments will occur at least 4 weeks after assessments demonstrating CR or PR. Confirmatory assessments may be conducted at a 
subject’s next regularly scheduled visit as appropriate.

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20. A blood sample for select serum safety markers (including but not limited to TNF alpha, IL-6, and tryptase) should be drawn within 24 hours of suspected 
infusion-related reactions.
21. For subjects who discontinue the study prior to disease progression, disease assessment must be performed either at the Follow-up visit or at the Post-Study 
visit prior to the start of any subsequent anticancer therapy.

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Table 8
Time and Events for Part 1 (Dose Escalation Cohorts, every week dosing schedule)
Pre-
screen
Screen
First Treatment Period (28 days)
Day 29
Continuation 
Phase
Follow-
up1
Post-
study2
Day 1
Day 2
Day 4
Day 8 
Day 15 
Day 22
-14 day 
window3
1 day window for each visit
2 day 
window for 
each visit
+ 7 day window 
Informed consent
X
X
Archival tissue 
X
Tumor biopsy
X4
X5
X6 pre-
dose
X7
Skin biopsy
X pre-
dose
X pre-
dose
Baseline 
demographics
X
X
Medical history
X
X
X
Concurrent 
medication
Continuous
Pregnancy test8
X3
X pre-
dose
Every 4 weeks
X
X
Physical examination
X
X9
X
X
Every 4 weeks
X
Height (at screening 
only) and weight
X
X
X
Weight: Every 
4 weeks
X
ECOG 
X
X9
X
Every 4 weeks
X
Vital signs (BP, pulse 
rate, Temperature)
X
X10
X
X
X
X
Every week22 
X
12-lead ECG
X
X 10
X
X
Every 4 weeks
X
Hematology/Clinical 
Chemistry
X
X9
X
X
X
X
Every week22
X

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Pre-
screen
Screen
First Treatment Period (28 days)
Day 29
Continuation 
Phase
Follow-
up1
Post-
study2
Day 1
Day 2
Day 4
Day 8 
Day 15 
Day 22
-14 day 
window3
1 day window for each visit
2 day 
window for 
each visit
+ 7 day window 
Coagulation 
parameters: PT, INR, 
PTT
X
As clinically indicated
Urinalysis
X
X
Every 4 weeks
X
ECHO11
X
X
Every 8 weeks
X
PK (Blood)12
X
X
X
X
X
X
X
X12
X
X
Safety cytokines20
In the event of infusion reaction
Circulating cell free 
DNA (cfDNA)
X pre-
dose
X7
Testosterone and 
LH13
X pre-
dose
X
Every 8 weeks
Whole blood/serum 
/cellular markers14
X
X
X
X
X7
GSK2849330 IV 
infusion15
X
X
X
X
X
Every week15
AE assessment
Continuous
Serum sample for 
Immunogenicity
X pre-
dose
X16
X16
PGx sample
X pre-
dose17
Tumor markers 18
X
Every 8 weeks
Disease 
assessment19
X3
Every 8 weeks
X21
1.
The Follow-up visit should be approximately 28 days after the last dose of study treatment.
2.
The Post-study visit should be at least 45 days or 5 half-lives (whichever is longer) after the last dose of study treatment.

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3.
Within 14 days prior to first dose except for pregnancy test (7 days) and Disease Assessment within 28 days prior to the first dose.
4.
Separate pre-screening consent required for fresh biopsy and fresh biopsy is only collected at pre-screening if archived tissue is not available.
5.
Fresh pre- and on-treatment tumor biopsy is optional, but strongly encouraged for dose escalation cohorts; if adequate fresh biopsy tumor tissue is acquired 
during pre-screening, then this does not need to be repeated during the screening period.  Archival tumor tissue is not acceptable to serve as pre-treatment 
tumor tissue.
6.
Tumor biopsy is optional on Day 15 for dose escalation cohort subjects and required for the PK/PD cohorts. Biopsy must be collected prior to study treatment 
administration on Day 15 dose (pre-dose). 
7.
Collected at progression. Tumor biopsy is optional and only collected for subjects with disease progression on study treatment. The tumor specimen may be 
collected at any time after study treatment discontinuation, but must occur prior to start of any subsequent anticancer therapy.
8.
Perform only in women of child-bearing potential.  Serum pregnancy test should be conducted at the Screening, Follow-up, and Post-study visits.  Urine 
pregnancy test should be conducted pre-dose on Day 29 and every 4 weeks from Day 29 in the continuation phase of the study.
9.
If the screening visit was completed within 72 hours of the first dose, this assessment does not need to be repeated on Day 1.
10. Collect at pre-dose and at1, 2, 4, and 6 hours after the start of the first infusion.
11. ECHO is preferred; however, if echocardiography is not available, or if reliable echocardiographic analysis of LVEF is unable to be obtained due to technical 
factors, a MUGA scan may be performed.  Regardless, the method used at Baseline should be used for the remaining assessments in the study. 
Assessments should be performed more frequently than every 8 weeks if clinically indicated.
12. Blood samples for analysis of GSK2849330 concentrations will be collected on Day 1: pre-dose and at 1 hour (15-minute window), 6 hours (1-hour 
window) and 24 hours (8-hour window) after the end of infusion. Pre-dose samples will also be collected on Day 4 (1-day window), Day 8 (1-day 
window) and weekly through Day 57 with additional 1-hour post-dose samples collected on Days 29 and 57. Pre-dose samples will also be collected on 
Day 71, Day 85 and every 12 weeks thereafter.  If treatment continues after 1 year, samples will be collected every 24 weeks. An additional PK sample will 
also be taken at the Follow-up and Post-study visits.
13. To be conducted in male subjects only.
14. Whole blood for soluble markers from plasma, serum, and/or cellular markers.  Blood samples will be collected on Day 1: pre-dose and at 1 hour (15-minute 
window) and 6 hours (1-hr window) after the end of infusion.  If a subject’s duration of infusion is 3 hours or longer the 6-hour time point is optional. A pre-
dose blood sample should be collected on Day 8, Day 15 and Day 29 for all cohorts. An additional sample will also be collected at progression.
15. For any subjects receiving a weekly dosing schedule, the study treatment dosing window is 2 days.  The study treatment dosing window for all other dosing 
schedules (e.g., an every 2 week or every 3 week dosing schedule) is 3 days. If dosing does not occur on the intended day, all other 
assessments/subsequent visits should be changed accordingly relative to when the dose was received Subsequent cohorts may receive different dosing 
schedules use the appropriate Time and Events Table as applicable.
16. An immunogenicity sample must be collected at the Follow-up and Post-study visits. 
17. It is preferred that the PGx sample be taken pre-dose on Day 1; however, it may be obtained anytime after informed consent has been given for PGx 
research.
18. See Section 7.8 and collect all tumor markers applicable for the subject’s primary tumor type.

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19. Confirmatory assessments will occur at least 4 weeks after assessments demonstrating CR or PR. Confirmatory assessments may be conducted at a 
subject’s next regularly scheduled visit as appropriate.
20. A blood sample for select serum safety biomarkers (including but not limited to TNF alpha, IL-6, and tryptase) should be drawn within 24 hours of suspected 
infusion-related reactions.
21. For subjects who discontinue the study prior to disease progression, disease assessment must be performed either at the Follow-up visit or at the Post-Study 
visit prior to the start of any subsequent anticancer therapy.
22. Assessments to be performed weekly while receiving weekly dosing and bi-weekly if switched to a bi-weekly dosing regimen.

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Table 9
Time and Events for Part 1 PK/PD Cohorts (every 2 week dosing schedule)
Pre-
screening
Screening
First Treatment Period (28 days)
Day 29
Continuation Phase
Follow-
up1
Post-
study2
First Week
Day 15
Day 1
Day 2
Day 4
Day 8
- 14 day 
window3
1 day window for each visit
3 day window for each 
visit
+ 7 day window
Informed consent
X
X
Archival tissue 
X
Tumor biopsy
X4
X5
X6 pre-
dose
X7
Skin biopsy
X pre-
dose
X pre-dose
Baseline 
demographics
X
X
Medical history
X
X
X
Concurrent Medication
Continuous
X
Pregnancy test8
X3
X pre-
dose
Every 4 weeks
X
X
Physical examination
X
X9
X
X
Every 4 weeks
X
Height (at screening 
only) and weight
X
X
X
Weight: Every 4 weeks
X
ECOG 
X
X9
X
Every 4 weeks
X
Vital signs (BP, pulse 
rate, Temperature)
X
X10
X
X
Every 2 weeks
X
12-lead ECG
X
X10
X
X
Every 4 weeks
X
Hematology/Clinical 
Chemistry
X
X9
X
X
X
Every 2 weeks
X
Coagulation 
parameters: PT, INR, 
PTT
X
As clinically indicated

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Pre-
screening
Screening
First Treatment Period (28 days)
Day 29
Continuation Phase
Follow-
up1
Post-
study2
First Week
Day 15
Day 1
Day 2
Day 4
Day 8
- 14 day 
window3
1 day window for each visit
3 day window for each 
visit
+ 7 day window
Urinalysis
X
X
Every 4 weeks
X
ECHO11
X
X
Every 8 weeks
X
PK (Blood)12
X
X
X
X
X
X
X12
X
X
Safety cytokines20
In the event of infusion reaction
cfDNA
X pre-
dose
X7
Testosterone and LH13
X pre-
dose
X
Every 8 weeks
Whole blood/serum 
/cellular markers14
X
X
X
X
X
X7
GSK2849330 IV 
infusion15
X
X
X15
Every 2 weeks15 
AE assessment 
Continuous
Serum sample for 
Immunogenicity
X pre-
dose
X16
X16
PGx Sample17
X pre-
dose
Tumor markers 18
X
Every 8 weeks
Disease assessment19
X3
Every 8 weeks
X21
1.
The Follow-up visit should be approximately 28 days after the last dose of study treatment.
2.
The Post-study visit should be at least 45 days or 5 half-lives (whichever is longer) after the last dose of study treatment.
3.
Within 14 days prior to first dose except for pregnancy test (7 days) and Disease Assessment within 28 days prior to the first dose.
4.
Separate pre-screening consent required for fresh biopsy and fresh biopsy is only collected at pre-screening if archived tissue is not available.
5.
Fresh tumor biopsy is required for the PK/PD cohort; if adequate tumor biopsy is obtained during pre-screening, then this does not need to be repeated. 
Archival tumor tissue is not acceptable to serve as pre-treatment tumor tissue.
6.
Tumor biopsy is required on Day 15 pre-dose for PK/PD cohort. Biopsy must be collected prior to administration of Day 15 dose.

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7.
Collected at progression. Tumor biopsy is optional and only collected from subjects with disease progression on study treatment. The tumor specimen may be 
collected at any time after study treatment discontinuation, but must occur prior to start of any subsequent anticancer therapy.
8.
Perform only in women of child-bearing potential. Serum pregnancy test should be conducted at the Screening, Follow-up, and Post-study visits.  Urine 
pregnancy test should be conducted pre-dose on Day 29 and every 4 weeks from Day 29 in the continuation phase of the study.
9.
If the screening visit was completed within 72 hours of the first dose, this assessment does not need to be repeated on Day 1.
10. Collect at pre-dose and at 1, 2, 4, and 6 hours after the start of the first infusion 
11. ECHO is preferred; however, if echocardiography is not available, or if reliable echocardiographic analysis of LVEF is unable to be obtained due to technical 
factors, a MUGA scan may be performed.  Regardless, the method used at Baseline should be used for the remaining assessments in the study. 
Assessments should be performed more frequently than every 8 weeks if clinically indicated.
12. Blood samples for analysis of GSK2849330 concentrations will be collected Day 1: pre-dose and at1 hour (15-minute window), 6 hours (1-hour window) 
and 24 hours (8-hour window) after the end of infusion. Pre-dose samples will also be collected on Day 4 (1-day window), Day 8 (1-day window) and
weekly through Day 57 with additional 1-hour post-dose samples collected on Days 29 and 57. Pre-dose samples will also be collected on Day 71, Day 85 
and every 12 weeks thereafter.
13. To be conducted in male subjects only.
14. Whole blood for soluble markers from plasma, serum, and/or cellular markers.  Blood samples will be collected on Day 1: pre-dose and at 1 hour (15-minute 
window), 6 hours (1-hour window), and 24 hours (Day 2 [8-hr window]) after the end of infusion. If a subject’s duration of infusion is 3 hours or longer the 
6 hour time point is optional. A pre-dose blood sample should be collected on Day 8, Day 15 and Day 29 for all cohorts. An additional sample will be collected 
at progression.
15. The study treatment dosing window is 3 days for subjects on an every 2 week dosing schedule. If dosing does not occur on the intended day, all other 
assessments/subsequent visits should be changed accordingly relative to when the dose was received.  Subsequent cohorts may receive different dosing 
schedules. Use the appropriate Time and Events Table as applicable.
16. An immunogenicity sample will be collected at the Follow-up and Post-study visits.
17. It is preferred that the PGx sample be taken pre-dose on Day 1; however, it may be obtained anytime after informed consent has been given for PGx 
research.
18. See Section 7.8 and collect all tumor markers applicable for the subject’s primary tumor type.
19. Confirmatory assessments will occur at least 4 weeks after assessments demonstrating CR or PR. Confirmatory assessments may be conducted at a 
subject’s next regularly scheduled visit as appropriate.
20. A blood sample for select serum safety markers (including but not limited to TNF alpha, IL-6, and tryptase) should be drawn within 24 hours of suspected 
infusion-related reactions.
21. For subjects who discontinue the study prior to disease progression, disease assessment must be performed either at the Follow-up visit or at the Post-Study 
visit prior to the start of any subsequent anticancer therapy.

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Table 10
Time and Events for Part 1 PK/PD Cohorts (every week dosing schedule)
Pre-
screening
Screening
First Treatment Period (28 days)
Day 29
Continuation 
Phase
Follow
-up1
Post-
study2
First Week
Day 15
Day 22
Day 1
Day 2
Day 4
Day 8
- 14 day 
window3
1 day window for each visit
2 day 
window for 
each visit
+ 7 day window
Informed consent
X
X
Archival tissue 
X
Tumor biopsy
X4
X5
X6 pre-
dose
X7
Skin biopsy
X pre-
dose
X pre-
dose
Baseline 
demographics
X
X
Medical history
X
X
X
Concurrent 
Medication
Continuous
X
Pregnancy test8
X3
X pre-
dose
Every 4 weeks
X
X
Physical examination
X
X9
X
X
Every 4 weeks
X
Height (at screening 
only) and weight
X
X
X
Weight: Every 4 
weeks
X
ECOG 
X
X9
X
Every 4 weeks
X
Vital signs (BP, pulse 
rate, Temperature)
X
X10
X
X
X
X
Every week22 
X
12-lead ECG
X
X10
X
X
Every 4 weeks
X
Hematology/Clinical 
Chemistry
X
X9
X
X
X
X
Every week22
X

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Pre-
screening
Screening
First Treatment Period (28 days)
Day 29
Continuation 
Phase
Follow
-up1
Post-
study2
First Week
Day 15
Day 22
Day 1
Day 2
Day 4
Day 8
- 14 day 
window3
1 day window for each visit
2 day 
window for 
each visit
+ 7 day window
Coagulation 
parameters: PT, INR, 
PTT
X
As Clinically Indicated
Urinalysis
X
X
Every 4 weeks
X
ECHO11
X
X
Every 8 weeks
X
PK (Blood)12
X
X
X
X
X
X
X
X12
X
X
Safety cytokines20
In the event of infusion reaction
cfDNA
X pre-
dose
X7
Testosterone and 
LH13
X pre-
dose
X
Every 8 
weeks 
Whole blood/serum 
/cellular markers14
X
X
X
X
X
X7
GSK2849330 IV 
infusion15
X
X15
X
X
X15
Every week15 
AE assessment 
Continuous
Serum sample for 
Immunogenicity
X pre-
dose
X16
X16
PGx Sample17
X pre-
dose
Tumor markers 18
X
Every 8 
weeks
Disease 
assessment19
X3
Every 8 
weeks
X21
1.
The Follow-up visit should be approximately 28 days after the last dose of study treatment.
2.
The Post-study visit should be at least 45 days or 5 half-lives (whichever is longer) after the last dose of study treatment.

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3.
Within 14 days prior to first dose except for pregnancy test (7 days) and Disease Assessment within 28 days prior to the first dose.
4.
Separate pre-screening consent required for fresh biopsy and fresh biopsy is only collected at pre-screening if archived tissue is not available.
5.
Fresh tumor biopsy is required for the PK/PD cohort; if adequate tumor biopsy is obtained during pre-screening, then this does not need to be repeated. 
Archival tumor tissue is not acceptable to serve as pre-treatment tumor tissue.
6.
Tumor biopsy is required on Day 15 pre-dose for PK/PD cohort. Biopsy must be collected prior to administration of Day 15 dose. 
7.
Collected at progression. Tumor biopsy is optional and only collected from subjects with disease progression on study treatment. The tumor specimen may be 
collected at any time after study treatment discontinuation, but must occur prior to start of any subsequent anticancer therapy.
8.
Perform only in women of childbearing potential. Serum pregnancy test should be conducted at the Screening, Follow-up, and Post-study visits.  Urine 
pregnancy test should be conducted pre-dose on Day 29 and every 4 weeks from Day 29 in the continuation phase of the study.
9.
If the screening visit was completed within 72 hours of the first dose, this assessment does not need to be repeated on Day 1.
10. Collect at pre-dose and at 1, 2, 4, and 6 hours after the start of infusion. For subjects on a weekly dosing schedule, vital signs should be conducted weekly at 
each dosing visit in clinic.
11. ECHO is preferred; however, if echocardiography is not available, or if reliable echocardiographic analysis of LVEF is unable to be obtained due to technical 
factors, a MUGA scan may be performed.  Regardless, the method used at Baseline should be used for the remaining assessments in the study. 
Assessments should be performed more frequently than every 8 weeks if clinically indicated.
12. Blood samples for analysis of GSK2849330 concentrations will be collected Day 1: pre-dose and at1 hour (15-minute window), 6 hours (-1-hr window) 
and 24 hours (8-hour window) after the end of infusion. Pre-dose samples will also be collected on Day 4(1-day window), Day 8 (1-day window ) and 
weekly through Day 57 with additional 1-hour post-dose samples collected on Days 29 and 57. Pre-dose samples will also be collected on Day 71, Day 85 
and every 12 weeks thereafter.
13. To be conducted in male subjects only.
14. Whole blood for soluble markers from plasma, serum, and/or cellular markers.  Blood samples will be collected on Day 1: pre-dose and at 1 hour (15-minute 
window), 6 hour (1-hour window), and 24 housr(Day 2 [8-hour window]) after the end of infusion. If a subject’s duration of infusion is 3 hours or longer the 
6 hour time point is optional. A pre-dose blood sample should be collected on Day 8, Day 15 and Day 29 for all cohorts. An additional sample will be collected 
at progression.
15. For the subjects receiving a weekly dosing schedule, the study treatment dosing window is 2 days The study treatment dosing window is 3 days for 
subjects on an every 2 week dosing schedule. If dosing does not occur on the intended day, all other assessments/subsequent visits should be changed 
accordingly relative to when the dose was received.  Subsequent cohorts may receive different dosing schedules. Use the appropriate Time and Events Table 
as applicable.
16. An immunogenicity sample must be collected at the Follow-up and Post-study visits.
17. It is preferred that the PGx sample be taken pre-dose on Day 1; however, it may be obtained anytime after informed consent has been given for PGx 
research.
18. See Section 7.8 and collect all tumor markers applicable for the subject's primary tumor type.

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19. Confirmatory assessments will occur at least 4 weeks after assessments demonstrating CR or PR. Confirmatory assessments may be conducted at a 
subject’s next regularly scheduled visit as appropriate.
20. A blood sample for select serum safety markers (including but not limited to TNF alpha, IL-6, and tryptase) should be drawn within 24 hours of suspected 
infusion-related reactions.
21. For subjects who discontinue the study prior to disease progression,disease assessment must be performed either at the Follow-up visit or at the Post-Study 
visit prior to the start of any subsequent anticancer therapy.
22. Assessments to be performed weekly while receiving weekly dosing and bi-weekly if switched to a bi-weekly dosing regimen.

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Table 11
Time and Events for Part 1 PK/PD Cohorts (every 3 week dosing schedule)
Pre-
screening
Screening
First Treatment Period (21 days)
Continuation Phase
Follow-
up1
Post-
study2
First Week
Day 1
Day 2
Day 4
Day 8
Day 22
- 14 day 
window3
1 day window for each 
visit
3 day window for each 
visit
+7 day window
Informed consent
X
X
Archival tissue 
X
Tumor biopsy
X4
X5
X6pre-dose
X7
Skin biopsy
X pre-dose
X pre-dose
Baseline 
demographics
X
X
Medical history
X
X
X
Concurrent 
medication
Continuous
X
Pregnancy test8
X3
X pre-dose
Every 3 weeks 
X
X
Physical examination
X
X9
X
Every 3 weeks 
X
Height (at screening 
only) and weight
X
X
X
Weight: Every 3 weeks
X
ECOG 
X
X9
X
Every 3 weeks
X
Vital signs (BP, pulse 
rate, Temperature)
X
X10
X
X
Every 3 weeks 
X
12-lead ECG
X
X10
X
Every 3 weeks
X
Hematology/Clinical 
Chemistry
X
X9
X
X
Every 3 weeks
X
Coagulation 
parameters: PT, INR, 
PTT
X
As Clinically Indicated
Urinalysis
X
X
Every 3 weeks
X
ECHO11
X
X
Every 9 weeks from day 22
X

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Pre-
screening
Screening
First Treatment Period (21 days)
Continuation Phase
Follow-
up1
Post-
study2
First Week
Day 1
Day 2
Day 4
Day 8
Day 22
- 14 day 
window3
1 day window for each 
visit
3 day window for each 
visit
+7 day window
PK (Blood)12
X
X
X
X
X
Day 43 and every 12 weeks  
X
X
Safety cytokines20
In the event of infusion reaction
cfDNA
X pre-dose
X7
Testosterone and 
LH13
X pre-dose
X
Every 9 weeks from day 22
Whole blood/serum 
/cellular markers14
X
X
X
X
Day 43
X7
GSK2849330 IV 
infusion15
X
X
Every 3 weeks15 
AE assessment 
Continuous
Serum sample for 
Immunogenicity
X pre-dose
  
X16
X16
PGx Sample17
X pre-dose
Tumor markers 18
X
Every 9 weeks
Disease assessment19
X3
Every 9 weeks
X21
1.
The Follow-up visit should be approximately 28 days after the last dose of study treatment.
2.
The Post-study visit should be at least 45 days or 5 half-lives (whichever is longer) after the last dose of study treatment.
3.
Within 14 days prior to first dose except for pregnancy test (7 days) and disease assessment within 28 days prior to the first dose.
4.
Separate pre-screening consent required for fresh biopsy and fresh biopsy is only collected at pre-screening if archived tissue is not available.
5.
Fresh tumor biopsy is required for the PK/PD cohort; if adequate tumor biopsy is obtained during pre-screening, then this does not need to be repeated. 
Archival tumor tissue is not acceptable to serve as pre-treatment tumor tissue.
6.
Tumor biopsy is required on Day 22 pre-dose for PK/PD cohort. Biopsy must be collected prior to administration of Day 22 dose. 
7.
Collected at progression. Tumor biopsy is optional and only required from subjects with disease progression on study treatment. The tumor specimen may be 
collected at any time after study treatment discontinuation, but must occur prior to start of any subsequent anticancer therapy.
8.
Perform only in women of childbearing potential.  Serum pregnancy test should be conducted at the Screening, Follow-up, and Post-study visits.  Urine 
pregnancy test should be conducted pre-dose on Day 22 and every 3 weeks from Day 22 in the continuation phase of the study.
9.
If the screening visit was completed within 72 hours of the first dose, this assessment does not need to be repeated on Day 1.

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10. Collect at pre-dose and at 1, 2, 4, and 6 hours after the start of the first infusion.
11. ECHO is preferred; however, if echocardiography is not available, or if reliable echocardiographic analysis of LVEF is unable to be obtained due to technical 
factors, a MUGA scan may be performed.  Regardless, the method used at Baseline should be used for the remaining assessments in the study.
Assessments should be performed more frequently than every 9 weeks if clinically indicated.
12. Blood samples for analysis of GSK2849330 concentrations will be collected on Day 1: pre-dose and at 1 hour (15-minute window) and 6 hours (1-hour 
window) after the end of infusion. If a subject’s duration of infusion is 3 hours or longer the 6-hour time point is optional. Additional PK samples will be 
collected at 24 hours (Day 2 [8-hr window]) and 72 hours (Day 4 [24-hour window]) after the end of infusion, and at Day 8 (1-day window and weekly 
through Day 57 with additional 1 hour post-dose samples collected on Days 29 and 57. Additional PK samples will also be taken every 12 weeks from the 
first dose within 1 year of starting treatment and if treatment continues after 1 year, samples will be collected every 24 weeks. An additional PK sample will be 
collected at the Post-study visit. On days of dosing sample will be drawn pre-dose.
13. To be conducted in male subjects only.
14. Whole blood for soluble markers from plasma, serum, and/or cellular marker.  Blood samples will be collected on Day 1: pre-dose and at 1 hour (15-minute 
window), 6 hours (1-hourwindow), and 24 hours (Day 2 [8-hour window]) after the end of infusion. If a subject’s duration of infusion is 3 hours or longer 
the 6-hour time point is optional. A pre-dose blood sample should be collected on Day 8, Day 22 and Day 43 for all cohorts. An additional blood sample 
should be collected at progression.
15. The study treatment dosing window is 3 days for an every 3-week dosing schedule. If dosing does not occur on the intended day, all other 
assessments/subsequent visits should be changed accordingly relative to when the dose was received.
16.   An immunogenicity sample will be collected at the Follow-up and Post-study visits.
17. It is preferred that the PGx sample be taken pre-dose on Day 1; however, it may be obtained anytime after informed consent has been given for PGx 
research.
18. See Section 7.8 and collect all tumor markers applicable for the subject’s primary tumor type.
19. Confirmatory assessments will occur at least 4 weeks after assessments demonstrating CR or PR. Confirmatory assessments may be conducted at a 
subject’s next regularly scheduled visit as appropriate.
20. A blood sample for select serum safety markers (including but not limited to TNF alpha, IL-6, and tryptase) should be drawn within 24 hours of suspected 
infusion-related reactions.
21. For subjects who discontinue the study prior to disease progression,disease assessment must be performed either at the Follow-up visit or at the Post-Study 
visit prior to the start of any subsequent anticancer therapy.

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Table 12
Time and Events for Part 2 Molecularly Defined Tumor Histology Groups
Pre-
Screen
Screen
First Treatment Period (28 days)
Day 29
Continuation 
Phase
Follow up1
Post study2
Day 1
Day 8 
Day 15 
Day 22
-14 day 
window3
1 day window for each visit
2day window for 
each visit
+ 7 day window 
Informed consent
X
X
Archival tissue 
X
Tumor biopsy
X4
X5
X6 pre-
dose
X7
Baseline demographics
X
X
Medical history
X
X
X
Concurrent medication
Continuous
Pregnancy test8
X3
X pre-
dose
Every 4 weeks
X
X
Physical examination
X
X9
X
X
Every 4 weeks
X
Height (at screening 
only) and weight
X
X
X
Weight: Every 4 
weeks
X
ECOG 
X
X9
X
Every 4 weeks
X
Vital signs (BP, pulse 
rate, Temperature)
X
X10
X22
X
X22
X
Every week 22 
X
12-lead ECG
X
X10
X
X
Every 4 weeks
X
Hematology/Clinical 
Chemistry
X
X9
X22
X
X22
X
Every week22
X
Coagulation 
parameters: PT, INR, 
PTT
X
As Clinically Indicated
Urinalysis
X
X
Every 4 weeks
X
ECHO11
X
X
Every 8 weeks
X

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Pre-
Screen
Screen
First Treatment Period (28 days)
Day 29
Continuation 
Phase
Follow up1
Post study2
Day 1
Day 8 
Day 15 
Day 22
-14 day 
window3
1 day window for each visit
2day window for 
each visit
+ 7 day window 
PK (Blood)12
X
X
X
X12
X
X
Safety cytokines20
In the event of an infusion reaction
Circulating cell free 
DNA (cfDNA)
X pre-
dose
X7
Testosterone and LH13
X pre-
dose
X
Every 8 weeks
Whole blood/serum 
/cellular markers14
X
X22
X
X
X7
GSK2849330 IV 
infusion15
X
X22
X
X22
X
Everyweek15,22
AE assessment
Continuous
Serum sample for 
Immunogenicity
X pre-
dose
X16
X16
PGx sample
X pre-
dose17
Tumor markers 18
X
Every 8 weeks
Disease assessment19
X3
Every 8 weeks
X21
1.
The Follow-up visit should be approximately 28 days after the last dose of study treatment.
2.
The Post-study visit should be at least 45 days or 5 half-lives (whichever is longer) after the last dose of study treatment.
3.
Within 14 days prior to first dose except for pregnancy test (7 days) and Disease Assessment within 28 days prior to the first dose.
4.
Separate pre-screening consent required for fresh biopsy and fresh biopsy is only collected at pre-screening if archived tissue is not available.
5.
Fresh pre- and on-treatment tumor biopsy is required; if adequate fresh biopsy tumor tissue is acquired during pre-screening, then this does not need to be 
repeated during the screening period.  Archival tumor tissue is not acceptable to serve as pre-treatment tumor tissue.
6.
Tumor biopsy is required on Day 15. Biopsy must be collected prior to study treatment administration on Day 15 dose (pre-dose).
7.
Collected at progression. Tumor biopsy is optional and only collected from subjects with disease progression on study treatment. The tumor specimen may be 
collected at any time after study treatment discontinuation, but must occur prior to start of any subsequent anticancer therapy.

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8.
Perform only in women of child-bearing potential.  Serum pregnancy test should be conducted at the Screening, Follow-up, and Post-study visits.  Urine 
pregnancy test should be conducted pre-dose on Day 29 and every 4 weeks from Day 29 in the continuation phase of the study.
9.
If the screening visit was completed within 72 hours of the first dose, this assessment does not need to be repeated on Day 1.
10. For vitals: collect at pre-dose and at 1, 2, 4, and 6 hours after the start of the first infusion. For ECG: collect at pre-dose and 2 hours after the start of the first 
infusion
11. ECHO is preferred; however, if echocardiography is not available, or if reliable echocardiographic analysis of LVEF is unable to be obtained due to technical 
factors, a MUGA scan may be performed.  Regardless, the method used at Baseline should be used for the remaining assessments in the study. 
Assessments should be performed more frequently than every 8 weeks if clinically indicated.
12. Blood samples for analysis of GSK2849330 concentrations will be collected on Day 1: pre-dose and at 1 hour (15-minute window), after the end of infusion, 
and pre-dose on Day 15, Day 29, Day 43, Day 57, Day 71, Day 85, and every 12 weeks thereafter. If treatment continues after 1 year, samples will be 
collected every 24 weeks. An additional PK sample will also be taken at the Follow-up or Post-study visits. Unless stated otherwise, on days of dosing sample 
will be drawn pre-dose. 
13. To be conducted in male subjects only.
14. Whole blood for soluble markers from plasma, serum, and/or cellular markers.  Blood samples will be collected on Day 1: pre-dose and at 1 hour (15-minute 
window) and 6 hours (1-hour window) after the end of infusion.  If a subject’s duration of infusion is 3 hours or longer, the 6-hour time point is optional. A 
pre-dose blood sample should be collected on Day 8, Day 15 and Day 29 for all cohorts. An additional sample will also be collected at progression.
15. For the subjects receiving a weekly dosing schedule, the study treatment dosing window is 2 days.  The study treatment dosing window for all other dosing 
schedules (e.g., an every 2-week or every 3-week dosing schedule) is 3 days. If dosing does not occur on the intended day, all other 
assessments/subsequent visits should be changed accordingly relative to when the dose was received.
16. An immunogenicity sample must be collected at the Follow-up and Post-study visits. 
17. It is preferred that the PGx sample be taken pre-dose on Day 1; however, it may be obtained anytime after informed consent has been given for PGx 
research.
18. See Section 7.8 and collect all tumor markers applicable for the subject’s primary tumor type.
19. Confirmatory assessments will occur at least 4 weeks after assessments demonstrating CR or PR. Confirmatory assessments may be conducted at a 
subject’s next regularly scheduled visit as appropriate.
20. A blood sample for select serum safety markers (including but not limited to TNF alpha, IL-6, and tryptase) should be drawn within 24 hours of suspected 
infusion-related reactions.
21. For subjects who discontinue the study prior to disease progression,disease assessment must be performed either at the Follow-up visit or at the Post-Study 
visit prior to the start of any subsequent anticancer therapy.
22. Assessments to be performed weekly while receiving weekly dosing and bi-weekly if switched to a bi-weekly dosing regimen.

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7.2.
Demographic/Medical History and Baseline Assessments
Demographic data will include gender, age, race, height, and weight. Medical, surgical, 
and treatment history including date [month (if available) and year] of first diagnosis, 
best response to prior systemic therapy, histology, molecular characteristics and current 
sites of disease will be taken as part of the medical history and disease status. Details 
concerning concomitant medication will be recorded starting from screening through the 
follow-up visit. At a minimum, the drug name, route of administration, dose and 
frequency of dosing, along with start and stop dates/times should be recorded.
7.2.1.
Critical Baseline Assessments
Cardiovascular medical history/risk factors will be assessed at baseline.
7.3.
Safety Evaluations
Measurements used to evaluate safety will include physical examinations, vital signs (BP, 
temperature and pulse rate), 12-lead ECGs, echocardiography, clinical laboratory tests, , 
and monitoring for AEs.  Planned time points for all safety assessments are provided in 
the Time and Events Tables (Section 7.1).
Additional, unplanned safety assessments may be performed during the course of the 
study as clinically indicated in the judgment of the investigator.  Additional time points 
for safety tests may also be added during the course of the study based on newly available 
data to ensure appropriate safety monitoring.
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), 
spine and long bones, lymph nodes and extremities.  Height (at screening only) and 
weight will also be measured and recorded.
7.3.2.
ECOG Performance Status
The performance status will be assessed using the ECOG scale (Appendix 3) as specified 
in the Time and Events Tables (Section 7.1).
7.3.3.
Vital Signs
Vital sign measurements will include systolic and diastolic blood pressure (BP), 
temperature, and pulse rate.  Vital signs will be measured more frequently if warranted by 
clinical condition of the subject.  On days where vital signs are measured multiple times, 
temperature does not need to be repeated unless clinically indicated.  Refer to the SPM 
for details regarding measurement of vital signs.

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If a subject develops a fever within the immediate post-infusion period, refer to Section 
3.9.1 and Section 3.9.2 for management of infusion reactions and allergic reactions.
7.3.4.
Electrocardiogram
Single 12-lead ECGs will be obtained 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.
All ECGs will be single assessments unless clinically significant abnormality is observed, 
in which case repeat ECG twice more, for a total of 3 ECGs within approximately 5-
15 minutes. Manual calculation for all 3 ECGs should be done using Fridericia’s formula 
(QTcF=QT/(RR)1/3) in view of the complex relationship between QT and RR. Any 
clinical decisions should be based on the average of all 3 ECGs.
Refer to Section 3.8.2 for QTc withdrawal criteria.
Refer to the SPM for details regarding ECG procedures.
7.3.5.
Echocardiogram and/or Multi-gated Acquisition (MUGA) Scans
ECHO will be performed to assess cardiac ejection fraction as noted in the Time and 
Events Tables Section 7.1. Should electrocardiography not be available or if 
echocardiographic analysis of LVEF is unable to be obtained due to technical factors, a 
MUGA scan may be performed.  However, whichever method is used at baseline should 
be used for the remaining assessments in the study. Additional ECHO assessments may 
be performed if clinically warranted.  The evaluation of the echocardiographer should 
include an evaluation for LVEF.
Copies of all ECHOs performed on subjects who experience an absolute decrease >15% 
in LVEF compared to baseline or an absolute decrease >10% in LVEF compared to 
baseline concurrent with LVEF <50% may be required by GSK for review.
7.3.6.
Laboratory Assessments
All protocol required laboratory assessments, as defined in Table 13), should be 
performed according to the Time and Events Tables (Section 7.1).  Details for the 
preparation and shipment of samples will be provided in the SPM.
At the discretion of the investigator, additional laboratory samples may be taken as 
clinically necessary. If additional non-protocol specified laboratory assessments are 
performed at the institution’s local laboratory and result in a change in subject 
management or are considered clinically significant by the investigator (for example SAE 
or AE or dose modification) the results must be recorded in the subject’s eCRF.

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All abnormal laboratory tests with values that are clinically significant during study 
participation or within 28 days after the last dose of study treatment should be repeated 
until the values return to within normal range or baseline or the subject starts subsequent 
treatment.  All subjects who have a Grade 3 or 4 laboratory abnormality at time of study 
withdrawal must be followed until resolution to Grade 2 or less, unless it is unlikely to 
improve due to underlying disease or subsequent therapy.  
Hematology, clinical chemistry, urinalysis and additional parameters to be tested are 
listed below:
Table 13
List of Clinical Laboratory Tests
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) or urea
Potassium
AST
Total and direct bilirubin
Creatinine
Chloride
ALT
Uric Acid
Glucose, fasting
Total carbon 
dioxide (CO2)
Gamma glutamyl transferase 
(GGT)
Albumin
Sodium
Calcium
Alkaline phosphatase
Total Protein
Magnesium
Phosphate
Routine Urinalysis
Specific gravity
pH, glucose, protein, blood and ketones by dipstick
Microscopic examination (if blood or protein is abnormal)
Other tests
PT, INR, PTT 
Testosterone (male subjects only)
Luteinizing Hormone (LH) (male subjects only)
Follicle stimulating hormone (FSH) and estradiol (as needed in women of non-child bearing potential only)
7.3.7.
Pregnancy Testing and Reporting
All pregnancies in female subjects and/or female partners of male subjects will be 
collected after the start of dosing and until the post-study visit.
The need for a screening pregnancy test depends on whether a female subject is of 
childbearing potential or non-childbearing potential.

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If a female subject is of childbearing potential, she must have a serum Beta-human 
chorionic gonadotropin (-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 below during the study until 45 days or 
5 half-lives (whichever is longer) following the last dose of study treatment.  Additional 
pregnancy tests will be performed as outlined in the Times and Events Table (see Section 
7.1).
Any pregnancy that occurs during study participation must be reported using a clinical 
trial pregnancy form.  To ensure subject safety, each pregnancy must be reported to GSK 
within 2 weeks of learning of its occurrence.  The pregnancy must be followed up to 
determine outcome (including premature termination) and status of mother and child.  
Pregnancy complications and elective terminations for medical reasons must be reported 
as an AE or SAE.  Spontaneous abortions must be reported as an SAE.
Any SAE occurring in association with a pregnancy brought to the investigator’s 
attention after the subject has completed the study and considered by the investigator as 
possibly related to the study treatment, must be promptly reported to GSK.
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
For subjects enrolled in Part 1, dose escalation Cohorts 1-4, blood samples for analysis of 
GSK2849330 concentrations will be collected on Day 1: pre-dose and at 1 hour and 
6 hoursafter the end of infusion and at Day 8, Day 15, and Day 29 after the first dose of 
GSK2849330. If a subject’s duration of infusion is 3 hours or longer, the 6-hour time 
point is optional.  On days of dosing, the sample will be drawn pre-dose. Additionally the 
first subject in Cohort 1 will have PK samples taken at 24 hour (Day 2) and 72 hour 
(Day 4) after the end of infusion.
For cohorts enrolled under Amendment 1 of this protocol, more frequent PK samples will 
be collected on Day 1: pre-dose and at 1 hour, 6 hours and 24 hours after the end of 
infusion;. Pre-dose samples will also be collected on Day 4, Day 8, and weekly through 
Day 57 with additional 1 hour post-dose samples collected on Days 29 and 57. Pre-dose 
samples will also be collected on Day 71, Day 85, and every 12 weeks thereafter. 
For all subjects in the Part 1 PK/PD cohorts, blood samples for analysis of GSK2849330 
concentrations will be collected on scheduled dosing Days 1: pre-dose and at 1 hour, 
6 hours and 24 hours after the end of infusion. Pre-dose samples will also be collected on 
Day 4, Day 8, and weekly through Day 57 with additional 1 hour post-dose samples 
collected on Days 29 and 57. Pre-dose samples will also be collected on Day 71, Day 85 
and every 12 weeks thereafter.

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For the molecularly defined tumor histology groups in Part 2, blood samples for analysis 
of GSK2849330 concentrations will be collected on Day 1: pre-dose and at 1 hour after 
the end of infusion; and pre-dose on Day 15, Day 29, Day 43, Day 57, Day 71, Day 85, 
and every 12 weeks thereafter.
For all subjects (Part 1 and Part 2), if treatment continues beyond 1 year, samples will be 
collected every 24 weeks. An additional PK sample will also be taken at the Follow-up 
visit (28 days after the last dose of study treatment),and/or the Post study visit (45 days or 
5 half-lives [whichever is longer] after the last dose of study treatment). Unless stated 
otherwise, on days of dosing PK samples will be drawn pre-dose.
See the Time and Events Tables Section 7.1 and the SPM for additional details on the PK 
sample timing.
7.4.1.
Blood Sample Collection for Pharmacokinetics
Blood samples for PK analysis of GSK2849330 will be collected at the time points 
indicated in the Time and Events Tables (Section 7.1).  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.
Once preliminary PK data have been reviewed, the planned sample collection times may 
be revised and provided to sites in writing.  Changes in PK sample collection times will 
not constitute a protocol amendment.
Details of PK blood sample collection (including volume to be collected), processing, 
storage and shipping procedures are provided in the SPM.
7.4.2.
Pharmacokinetic Sample Analysis
Plasma analysis will be performed under the management of Bioanalytical Science and 
Toxicokinetics, Drug Metabolism and Pharmacokinetics (DMPK), GSK.  Concentrations 
of GSK2849330 will be determined in plasma samples using the currently approved 
analytical methodology.  Raw data will be stored in the GLP Archives, GSK.
7.5.
Immunogenicity
7.5.1.
Blood Sample Collection
Serum samples for determination of anti- GSK2849330 antibodies will be taken from all 
subjects in this study at the time-points specified in the Time and Events Tables in 
Section 7.1.

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7.5.2.
Sample Analysis
Samples will be analyzed for the presence of anti-GSK2849330 antibodies using a 
validated immunoelectrochemiluminescenceassay. The assay involves screening, 
confirmation and titration steps (tiered-testing approach). Confirmed positive samples 
will be titrated to obtain the titer of the anti-GSK2849330 antibodies. Further antibody 
characterization may be performed, if needed. Results will be reported at the end of the 
study. Details on sample preparation, storage and analysis will be given in the SPM.
7.6.
Translational Research
Unless stated otherwise, these investigations may be performed irrespective of whether a 
response to GSK2849330 is observed.
Comparative examination of pre-dosing profiles of participants may uncover known or 
novel candidate biomarkers/profiles which could be used to predict response to treatment 
with GSK2849330 or provide new insights into cancer and medically related conditions.  
Comparative examination of post-dosing profiles with pre-dosing profiles may yield 
known and novel candidate biomarkers/profiles and new insights which relate directly or 
indirectly to the mechanism of action of GSK2849330.
All samples may be retained for a maximum of 15 years after the last subject completes 
the study.
Novel candidate biomarkers and subsequently discovered biomarkers of the biological 
response associated with cancer or medically related conditions and/or the action of 
GSK2849330 may be identified by application of:

DNA/gene, RNA, protein and cell population analysis of tumor/skin tissue.

Circulating cell free-DNA analysis of blood/plasma.

Circulating/peripheral biomarkers 
o
Cytokines and Angiogenic Factors (CAF) analysis of plasma
o
Proteome analysis of plasma
o
Complement CH50 analysis of serum
o
Peripheral blood mononuclear cell (PBMC) count analysis of whole blood
RNA transcriptome research and/or RNA expression research on whole of a subset of 
RNA species are included as relevant for the study.

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7.6.1.
Tumor Biomarker Analysis
7.6.1.1.
Tumor Tissue for Pre-screening Assessments and Exploratory 
Research
Tumor tissue taken from a metastatic site (preferably) or obtained at the time of primary 
cancer diagnosis (biopsy or from definitive surgery) is required to be submitted for 
analysis to one or more of the central laboratories, including Ventana Medical Systems to 
determine HER3 and NRG1 expression. If archival tumor tissue is not available, a fresh 
biopsy using a procedure that is safe for the subject is required for HER3 and NRG1 
testing.
Refer to the SPM for further details on tumor tissue sample requirements preparation and 
shipping.
Additional exploratory research may include the evaluation of intra-tumoral molecular 
profiles (to include RNA, DNA/gene, protein, and cell populations) that may uncover 
known or novel candidate biomarkers/profiles that could be used to predict response to 
GSK2849330 or possibly glean biological information into its mechanisms of action.
Histological features may be evaluated to include but are not limited to the enumeration 
of cell type populations such as lymphocytes.
7.6.1.2.
Tumor Biopsies
Every effort should be made to collect pre- and on-treatment tumor biopsies using a 
procedure that is safe for the subject.  Image guidance has been shown to significantly 
increase the probability of success in obtaining tumor biopsies and is required for all 
percutaneous pre- and on-treatment biopsies in this study (with the exception of 
melanoma skin lesions or cutaneous metastases of other solid tumors).
Tumor biopsies are optional for subjects in the dose escalation cohorts, but strongly 
encouraged.  All subjects enrolled in PK/PD cohorts in Part 1 and in each of the 
molecularly defined tumor histology groups in Part 2 must agree to pre and on-treatment 
tumor biopsies (using a procedure that is safe for the subject) for assessment of PD effect.
GSK will closely monitor and evaluate the collection of evaluable biopsies and will 
notify the participating centers of any change to the collection requirements for any or all 
groups.
Tumor biopsies for PD analyses will be collected at the time points listed in the Time and 
Events Tables Section 7.1.
Tumor biopsies should be obtained upon disease progression, using a procedure that is 
safe for the subject, if the subject provides consent, and if the tumor is in a biopsy-
accessible location.  Once preliminary PK and PD data have been reviewed, the planned 
tumor biopsy collection times may be revised and provided to sites in writing.  Changes 
in sample collection times will not constitute a protocol amendment.

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Biopsies may be analyzed for genetic markers (mutations in genes to potentially include 
but not limited to PIK3CA, PTEN, and BRAF), DNA, RNA or protein levels that may 
indicate a PD response, or correlate with a tumor response, to GSK2849330.  Protein 
levels that may be analyzed include, but are not limited to, markers of the HER3 pathway 
such as HER3, phospho-HER3 and HER3 ligands (neuregulins); markers of cell 
proliferation such as Ki67; markers of ADCC such as perforin and granzyme B; markers 
of the CDC pathway; and markers of tumor resistance such as the PTEN protein. 
Additional analyses may include the evaluation of histological features to include but are 
not limited to the enumeration of cell type populations such as lymphocytes.
Details on tumor biopsy collection, processing, storage and shipping procedures are 
provided in the SPM.
7.6.2.
Skin Biopsies
For subjects in Part 1 of the study, every effort should be made to collect pre- and on-
treatment skin biopsies for analysis of RNA or protein levels that may indicate a PD 
response to GSK 2849330.  Protein levels that may be analyzed include, but are not 
limited to, markers of the HER3 pathway such as HER3 and phospho-HER3.
All subjects enrolled in dose escalation and PK/PD cohorts in Part 1 must agree to pre 
and on-treatment skin biopsies for assessment of PD effect.
Refer to Time and Events Tables in Section 7.1 for details on time points. 
Details on skin biopsy collection, processing, storage and shipping procedures are 
provided in the SPM.
7.6.3.
Blood Samples
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 well as 
markers of activity and resistance based on changes that occur during treatment.
Blood samples will be collected for analysis of potential surrogate markers of 
GSK2849330 activity.  These analyses may include, but are not limited to measurement 
of specific blood proteins and cell populations (e.g., PBMCs: CD16, CD56, CD69, 
CD107, CD19, CD8, CD4, CD3, CD14), complement activity (e.g., CH50), 
inflammatory cytokines (e.g., IFN, TNFIL-2, IL-6), growth factors, soluble HER3, or 
mutations in circulating free tumor DNA (Refer to Section 7.6.3.1).
Blood samples drawn for investigating both predictive and PD biomarkers will be by 
study part and subject cohort or group:
Details on sample collection, processing, storage and shipping procedures are provided in 
the SPM.

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7.6.3.1.
Circulating Cell-free DNA (cfDNA) Analysis
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 mutations in cfDNA 
that may include but are not limited to PIK3CA, PTEN, and BRAF, correlate with the 
mutations in the tumor. This test will also be explored to correlate increasing cfDNA 
levels with increasing tumor burden. These mutations will be specific to the primary 
tumor types enrolled in the study.
7.6.3.2.
Cytokines Analysis
A panel of inflammatory cytokines which may include but are not limited to IFN, 
TNF, IL6, IL2, and MCP-1 will be evaluated in plasma and correlated with clinical 
outcome of treatment with GSK2849330.
7.7.
Pharmacogenetics (PGx)
An important objective of the clinical study is PGx research.  Participation in PGx is 
optional but all subjects who are eligible for the clinical study will be given the 
opportunity to participate.  Subjects may decline participation without effect on their 
medical care or care during the clinical study.  A separate consent signature is required 
for PGx research.
Subjects who provide consent will have a blood sample taken for analysis.  The 
presence/absence of genetic variations in selected candidate genes, such as but not 
limited to the FCreceptor family, in DNA from blood may be analyzed to determine 
their relationship with response (safety, tolerability, PK and efficacy to treatment with 
GSK2849330).
Information regarding PGx research is included in Appendix 8.  The IRB/EC and, where 
required, the applicable regulatory agency must approve the PGx assessments before 
these can be conducted at the site.  The approval(s) must be in writing and will clearly 
specify approval of the PGx assessments (i.e., approval of Appendix 8).  In some cases, 
approval of the PGx assessments can occur after approval is obtained for the rest of the 
study.  If so, then the written approval will clearly indicate approval of the PGx 
assessments is being deferred and the study, except for PGx assessments, can be initiated.  
When PGx assessments will not be approved, then the approval for the rest of the study 
will clearly indicate this and therefore PGx assessments will not be conducted.

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7.8.
Evaluation of Anti-Cancer Activity
Disease assessment may include imaging (e.g., CT scan, MRI, bone scan, plain 
radiography) and physical examination (as indicated for palpable/superficial lesions). 
Disease assessment will be completed within 4 weeks prior to the first dose of 
GSK2849330, then every 8 or 9 weeks thereafter, and at the final study visit.  See the 
Time and Events Tables (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, progressive disease 
(PD) has not been documented, and the subject has not started subsequent anti-cancer 
therapy, a disease assessment should be obtained at the Follow-up visit or the Post-study 
visit.
In addition to the above, a MRI with contrast should be considered to rule out the 
presence of brain metastases.  CT scans with and without contrast may be performed if a 
MRI is contraindicated or otherwise unavailable.
For purposes of determining futility, disease progression and response evaluations will be 
determined according to the definitions established in the Response Evaluation Criteria in 
Solid Tumors (RECIST 1.1) [Eisenhauer, 2009] (see Appendix 5).  Exploratory 
assessment of response according to immune-related response criteria (Appendix 6) and 
mRECIST (Appendix 7) [Lencioni, 2010] should also be recorded. Subjects whose 
disease responds (either CR or PR) should have a confirmatory disease assessment 
performed at least 4 weeks after the date of assessment during which the response was 
demonstrated.  More frequent disease assessments may be performed at the discretion of 
the investigator.  To ensure comparability between the baseline and subsequent 
assessments, the same method of assessment, the same technique and the same 
radiologist should be used when assessing response. Images should be retained until 
study completion to facilitate central review if requested. Tumor markers should be 
followed serially per institutional guidelines and recorded in the eCRF where part of 
standard practice.
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 

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associated with the use of a medicinal product.  For marketed medicinal products, this 
also includes failure to produce expected benefits, abuse, or misuse. Examples of events 
meeting the definition of an AE include:

Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or grade of the condition

New conditions detected or diagnosed after study treatment administration even 
though it may have been present prior to the start of the study

Signs, symptoms, or the clinical sequelae of a suspected interaction

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
treatment or a concomitant medication (overdose per se will not be reported as an 
AE/SAE).
“Lack of efficacy” or “failure of expected pharmacological action” per se is not to be 
reported as an AE or SAE.  However, any signs and symptoms and/or clinical sequelae 
resulting from “lack of efficacy” will be reported as an AE or SAE, if they fulfill the 
definition of an AE or SAE.
Events that do not meet the definition of an AE include:

Medical or surgical procedure (e.g., endoscopy, appendectomy); the condition that 
leads to the procedure is an AE.

Situations where an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).

Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present 
or detected at the start of the study that do not worsen.

The disease/disorder being studied or expected progression, signs, or symptoms of 
the disease/disorder being studied, unless more severe than expected for the subject’s 
condition.
8.2.
Definition of an SAE
A SAE is any untoward medical occurrence that, at any dose:
Results in death
a.
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.
b.
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.
c.
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.
d.
Is a congenital anomaly/birth defect.
e.
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.
f.
Protocol-Specific SAEs:

All events of possible study treatment-induced liver injury with 
hyperbilirubinemia defined as ALT 3 times ULN and bilirubin ≥2 times ULN 
(>35% direct) (or ALT ≥3 times ULN and INR >1.5, if INR is measured) or 
termed ‘Hy’s Law’ events (INR measurement is not required and the threshold 
value stated will not apply to 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.
LVEF (Section 3.8.3.1): meeting stopping criteria.
8.2.1.
Sentinel Events
A Sentinel Event is a GSK-defined SAE that is not necessarily drug-related but has been 
associated historically with adverse reactions for other drugs and is therefore worthy of 
heightened pharmacovigilance.  The GSK Medical Monitor is accountable for reviewing 
all SAEs for possible Sentinel Events which is mandated at GSK.  The GSK medical 
monitor may request additional clinical information on an urgent basis if a possible 

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Sentinel Event is identified on SAE review.  The current GSK-defined Sentinel Events 
are listed below:

Acquired long QT syndrome

Agranulocytosis/severe neutropenia 

Anaphylaxis & anaphylactoid reactions (see Section 3.9.2 on Allergic Reaction 
Management)

Hepatotoxicity

Acute renal failure

Seizure

Stevens-Johnson syndrome/toxic epidermal necrosis
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.
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

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
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.
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 electronic case 
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.
8.5.
Time Period and Frequency of Detecting AEs and SAEs
The investigator or site staff is responsible for detecting, documenting and reporting 
events that meet the definition of an AE or SAE.
AEs will be collected from the time the first dose of study treatment is administered until 
28 days following discontinuation of study treatment.
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 8.5.2.
After discontinuation of study treatment, the investigator will monitor all AEs/SAEs that 
are ongoing until resolution or stabilization of the event or until the subject is lost to 
follow-up.  At any time after 28 days the investigator may report any AE that they 
believe possibly related to study treatment.
8.5.1.
Method of Detecting AEs and SAEs
Care must be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended 
and non-leading verbal questioning of the subject is the preferred method to inquire about 
AE occurrence. Appropriate questions include:
“How are you feeling?” or for pediatric studies, “How does your child seem to feel?”

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“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?”
8.5.2.
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:
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.
See Section 3.8.1 for liver chemistry stopping criteria and follow up procedures.

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Methods for detecting, recording, evaluating, and following up on AEs and SAEs are 
provided in the SPM.
8.5.3.
Regulatory Reporting Requirements for SAEs
Prompt notification of SAEs by the investigator to GSK is essential so that legal 
obligations and ethical responsibilities towards the safety of subjects are met.
GSK has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a product under clinical investigation.  GSK will 
comply with country specific regulatory requirements relating to safety reporting to the 
regulatory authority, IRB/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.
LIVER CHEMISTRY FOLLOW-UP PROCEDURES
9.1.
Liver Chemistry Testing Procedures
For subjects meeting any of the liver chemistry stopping criteria in Section 3.8.1, make 
every attempt to carry out the liver event follow-up assessments described below:

Viral hepatitis serology, including:

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, then obtain 
heterophile antibody or monospot testing)

Blood sample for PK analysis, obtained within 10 days of the last dose of study
drug(s). Record the date and time of the PK blood sample draw and the date and 
time of the last dose of study drug(s) prior the 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 or time of the last dose cannot be approximated, or if 
a PK sample cannot be collected within the 10-day period following the last 
dose, do not obtain a PK sample.  Instructions for sample handling and shipping 
are found in the SPM.

Serum creatinine phosphokinase (CPK) and lactate dehydrogenase (LDH).

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
Fractionate bilirubin, if total bilirubin 2 X ULN.

Obtain a complete blood count (CBC) with differential to assess eosinophilia.

Record the appearance or worsening of clinical symptoms indicative of hepatitis 
or hypersensitivity, such as fatigue, nausea, vomiting, right upper quadrant pain 
or tenderness, fever, rash or eosinophilia as relevant on the AE eCRF.

Record the use of concomitant medications, including acetaminophen, herbal 
remedies or any other over the counter (OTC) medications, or any putative 
hepatotoxins, on the concomitant medication eCRF.

Record alcohol use on the liver event alcohol intake eCRF.
The following assessments are required for subjects with ALT 3 X ULN and bilirubin 
2X ULN (>35% direct) but are optional for other abnormal liver chemistries:

Anti-nuclear antibody, anti-smooth muscle antibody, and Type 1 anti-liver 
kidney microsomal antibodies.

Liver imaging (ultrasound, MRI or CT) to evaluate liver disease.
9.2.
Liver Chemistry Monitoring Criteria
For subjects with ALT 3 X ULN but <5X ULN and bilirubin <2 X ULN, without 
symptoms indicative of hepatitis or rash, and who can be monitored safety for 4 weeks, 
the following actions should be taken:

Notify the GSK Medical Monitor within 24 hours of learning of the abnormality 
to discuss subject safety.

Continue administration of study drug(s).

Evaluate liver chemistries (ALT, AST, alkaline phosphatase, bilirubin) weekly 
until they resolve, stabilize or return to within baseline levels.

If at any time the subject meets any of the liver chemistry stopping criteria 1 to 5 
(Section 3.8.1), then proceed as described in Section 9).

If, after 4 weeks of monitoring, ALT <3X ULN and bilirubin <2 X ULN, then 
monitor subjects twice monthly until liver chemistries normalize or return to 
within baseline values.
9.3.
Drug Restart/Rechallenge Following Liver Events that are 
Possibly Related to Study Drug(s)
Approval by the GSK Medical Monitor to restart/rechallenge study drug(s) may be 
considered where:

The subject is receiving compelling benefit, the benefit exceeds the risk, and no 
effective alternative therapy is available.  Approval of restart/rechallenge by the 
IRB or Independent Ethics Committee (IEC) must be obtained, as required.

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
If the restart/rechallenge is approved by GSK in writing, then the subject must 
be provided with a clear description of the possible benefits and risks of 
administration of study drug(s), including the possibility of a recurrence, a more 
severe liver injury or death.

The subject must also provide signed informed consent specifically for the study 
drug(s) restart/rechallenge.  Documentation of the informed consent must be 
recorded in the subject’s study chart.

Study drug(s) must be administered at the dose specified by the GSK Medical 
Monitor.

Subjects approved by GSK for restart/rechallenge of study drug(s) must return 
to the clinic twice a week for evaluation of liver chemistry tests until stable liver 
chemistries have been demonstrated and laboratory monitoring may resume per 
protocol.
9.4.
Drug Restart Following Transient, Resolving Liver Events 
Not Related to Study Drug(s)
Approval by the GSK Medical Monitor to restart study drug(s) may be considered where:

Liver chemistry abnormalities 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 <3X ULN.  Approval of restart by the IRB or 
IEC may be required.

If the restart/rechallenge is approved by GSK in writing, then the subject must 
be provided with a clear description of the possible benefits and risks of 
administration of study drug(s), including the possibility of a recurrence, a more 
severe liver injury or death.

The subject must also provide signed informed consent specifically for the study 
drug(s) restart/rechallenge.  Documentation of the informed consent must be 
recorded in the subject’s study chart.

Study drug(s) must be administered at the dose specified by the GSK Medical 
Monitor.

Subjects approved by GSK for restart/rechallenge of study drug(s) must return 
to the clinic once a week for evaluation of liver chemistry tests until stable liver 
chemistries have been demonstrated and laboratory monitoring may resume per 
protocol.

If protocol-defined stopping criteria for liver chemistry abnormalities are met, 
study drug(s) administration must stop.

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10.
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.
10.1.
Permitted Medication(s)
Subjects should receive full supportive care during the study, including transfusion of 
blood and blood products, and treatment with antibiotics, antiemetics, antidiarrheals, and 
analgesics, as appropriate.  Growth factors (e.g., G-CSF) are not permitted during the 
DLT observation period in Part 1, but may be allowable beyond the DLT observation 
period in Part 1, in the PK/PD cohorts or in Part 2 after discussion with the GSK medical 
monitor.
The use of anticoagulant and antiplatelet agents are permitted. However, prior to 
undergoing tumor biopsy, it is recommended that subjects be off agents such as coumadin 
or heparin for 5 days and then recheck labs prior to biopsy procedure.  It is further 
recommended that subjects be off of NSAIDs for at least 48 hours.  If institution 
guidelines require these agents be held longer than the recommended number of days/ 
hours, then follow institution guidelines.  If there are risks of stopping these medications, 
contact the GSK Medical Monitor.
10.2.
Prohibited Medication(s)
Subjects should not receive other anticancer therapy (cytotoxic, surgery, tumor 
embolization, biologic, radiation, or hormone other than replacement) except where noted 
in the eligibility criteria while on treatment in this study.
If corticosteroids are needed for chronic conditions, doses below 20 mg/day of 
prednisone or the equivalent are allowed. Corticosteroids exceeding this level are 
generally not allowed except as infusion pre-medication.

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11.
LIFESTYLE AND/OR DIETARY RESTRICTIONS
11.1.
Contraception
11.1.1.
Female Subjects
A female of non-childbearing potential (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 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.
Female subjects of childbearing potential must not become pregnant during the study and 
so must be sexually inactive by abstinence or use contraceptive methods with a failure 
rate of <1%.
Abstinence
Sexual inactivity by abstinence must be consistent with the preferred and usual lifestyle 
of the subject.  Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-
ovulation methods) and withdrawal are not acceptable methods of contraception. 
Complete abstinence from sexual intercourse for 14 days prior to first dose of study 
treatment, through the dosing period, and for at least 45 days or 5 half-lives (whichever is 
longer) after the last dose of study treatment.
Contraceptive Methods with a Failure Rate of <1%

Oral contraceptives (either combined or progesterone only) if not contraindicated for 
this subject population or per local practice.

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.

Intrauterine device or intrauterine system that meets the <1% failure rate as stated in 
the product label.

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
Male partner sterilization (vasectomy with documentation of azoospermia) prior to 
the female subject's entry into the study, and this male is the sole partner for that 
subject.  For this definition, “documented” refers to the outcome of the 
investigator's/designee’s medical examination of the subject or review of the 
subject's medical history for study eligibility, as obtained via a verbal interview with 
the subject or from the subject’s medical records.

Double-barrier method: condom and occlusive cap (diaphragm or cervical/vault 
caps) plus vaginal spermicidal agent (foam/gel/film/cream/suppository).
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.
11.1.2.
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:

Abstinence, defined as sexual inactivity consistent with the preferred and usual 
lifestyle of the subject.  Periodic abstinence (e.g., calendar, ovulation, 
symptothermal, post-ovulation methods) and withdrawal are not acceptable methods 
of contraception.
Complete abstinence from sexual intercourse for 14 days prior to first dose of study 
treatment, through the dosing period, and for at least 45 days or 5 half-lives 
(whichever is longer) after the last dose of study treatment.

Condom (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).
11.2.
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 
45 days or 5 half-lives (whichever is longer) following the last dose of study treatment.
12.
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.
Management of clinical data will be performed in accordance with applicable GSK 
standards and data cleaning procedures to ensure the integrity of the data, e.g. removing 
errors and inconsistencies in the data.  AEs and concomitant medications terms will be 

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coded using Medical Dictionary for Regulatory Activities (MedDRA) and an internal 
validated medication dictionary, GSK Drug.  eCRFs, including queries and audit trails, 
will be retained by GSK, and copies will be sent to the investigator to maintain as the 
investigator copy.
When laboratory samples (i.e., hematology and clinical chemistry) are analyzed by a 
central laboratory the results will be stored in a database maintained by the central 
laboratory and transferred to GSK at agreed times.  When laboratory samples are 
analyzed by a local laboratory, the laboratory normal ranges will be provided to GSK and 
the results will be entered into the eCRF.
In all cases, subject initials will not be collected or transmitted to GSK according to GSK 
policy.
13.
DATA ANALYSIS AND STATISTICAL CONSIDERATIONS
13.1.
Hypothesis(es)
13.1.1.
Part 1: Dose-Escalation Phase
With respect to primary objectives and endpoints, no specific hypotheses are being tested
during the dose escalation portion of this study. The primary focus will be on determining 
the safety profile of GSK2849330 and recommended dose for further exploration. Most 
of the analyses will be descriptive or exploratory.
13.1.2.
Part 2: Molecularly-Defined Tumor Histology Groups
For the groups in Part 2, hypothesized clinical benefit rates are provided in Section 
13.2.2. A test that the clinical benefit rate is less than or equal to the null hypothesis rate 
versus the clinical benefit rate is greater than or equal to the alternative rate is being 
performed using the stopping rules provided. Descriptive statistics will be used to 
describe the observed response rates at the dose used in each of the groups.
13.2.
Sample Size Determination
13.2.1.
Part 1: Dose-Escalation Phase
The total number of subjects in the Part 1 dose escalation will depend on the number of 
dose escalations needed, but the minimum number of subjects anticipated to complete 
dose escalation is 13 and the anticipated number of subjects is approximately 34 subjects. 
The selection of sample size 34 is based on the goal of fully exploring available dose 
ranges for purposes of selecting an appropriate regimen(s) for Part 2.  This will include a 
number of cohorts to establish an initial understanding of the dose-response relationship 
as well as to evaluate a range of PD biomarkers that may reveal the biological activity of 
GSK2849330. The initial cohort (1.4 mg/kg) will have 1 subject and Cohorts 2 through 5 
will have 3 subjects in the dose escalation phase and up to an additional 3 subjects with 

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evaluable pre- and on-treatment paired biopsies in each of these cohorts for the PK/PD 
cohorts. See Section 3.3 and Table 3 for additional details. The actual number of cohorts
and subjects will depend in part on the observed toxicity and the PK and PD observed
during the dose escalation.
Simulations were conducted to determine the average sample size and percentage of time 
each dose was selected under 3 different scenarios: almost no toxicity scenario, little 
toxicity scenario and moderate toxicity scenario. For each scenario, 5000 clinical trials 
were simulated using the planned doses.  Details are provided in Table 14.
The specified prior probabilities discussed in Section 3.3 were used to determine an 
explicit equation for the prior distribution using the FACTS software.  The parameters 
(s.d.) of the explicit distribution are =-5.334(1.9913), ln()=-0.0579 (0.1018), and 
ρ=-0.9977 where and ln() are distributed as bivariate normal with correlation ρ.
Table 14
Simulation Results for Various Scenarios
Dose
(mg/kg)
Scenario 1: Almost No
Toxicity
Scenario 2: Little 
Toxicity
Scenario 3: Moderate
Toxicity
True DLT 
Rate
Percent of 
Trials 
Selecting 
Dose as 
MTD (%)
True DLT 
Rate
Percent of 
Trials 
Selecting 
Dose as 
MTD (%)
True DLT 
Rate
Percent of 
Trials 
Selecting 
Dose as 
MTD (%)
1.4
0.00005
0
0.0005
0.8
0.05
5.2
3
0.0005
0
0.1
10
0.1
14.2
10
0.005
0.2
0.2
33
0.2
37.4
30
0.055
99.8
0.25
56.2
0.3
43.2
The average sample size over the 5000 clinical trials simulated under Scenarios 1-3 was
15.2, 15.5, and 15.1 respectively.
13.2.2.
Part 2: Molecularly-Defined Tumor Histology Groups
Once the recommended dose(s) and schedule(s) is/are confirmed from Part 1, at least 12 
and up to 30 subjects per group will be enrolled at that dose(s) in Part 2, guided by 
decision rules defined in Section 13.6.2. These guidelines are based on the predictive 
probabilities of success if enrollment were to continue to 30 subjects using the 
methodology of [Lee, 2008].   
The null hypothesis is:
The alternative hypothesis is:

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Starting with a group of 12 subjects and allowing for a maximum sample size of 30, this 
design will have a type I error rate (α) of 0.15 and 94% power. Group enrollment will be 
stopped early for futility if the predictive probability of success is less than 6%. The trial 
would not stop early for success. The Bayesian Prior was Beta (0.2, 0.8), a weak prior 
with a mean response rate of 20%. The group outcome will be considered successful if 
the posterior probability of (P >0.10│observed data) is ≥80%. The futility boundary
described in Section 13.6.2 was calculated based on the optimizing criterion of 
maximizing the power under the alternative hypothesis.
Under the null hypothesis, the expected sample size is 20 subjects and the probability of
early termination is 77%. Under the alternative hypothesis, the expected sample size is 
29 subjects and the probability of early termination is 5%.
13.3.
Sample Size Sensitivity
No analysis of sample size sensitivity was performed.
13.3.1.
Sample Size Re-estimation
Sample size re-estimation is not planned for this study.
13.4.
Data Analysis Considerations
Data will be listed and summarized according to GSK integrated data standards library 
(IDSL) reporting standards where applicable. Complete details will be provided in the 
RAP.
13.4.1.
Analysis Populations
The All Treated Population is defined as all subjects who receive at least one dose of 
GSK2849330. Safety will be evaluated based on this analysis population.
The Efficacy Population will consist of all subjects from the All Treated Population for 
whom at least one post-dose tumor assessment by CT scan has been performed.
The PK Population will consist of all subjects from the All Treated Population for whom 
at least one post-dose PK sample is obtained and analyzed.
Additional analysis populations may be defined in the RAP.
13.4.2.
Analysis Data Sets
The construction of datasets relating to the reporting and analysis of study data will be 
performed in accordance with all applicable GSK standards and procedures.

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13.4.3.
Withdrawal
Reason for subject withdrawal will be listed.
13.4.4.
Missing Data
Missing data will not be imputed. Where appropriated, available data will be summarized 
over specified intervals (e.g., from start of treatment until withdrawal from study) using 
suitable summary statistics.
13.4.5.
Derived and Transformed Data
The PK parameters, AUC, Cmax, and MRT will be log-transformed prior to analysis.
13.4.6.
Assessment Windows
Safety assessments that occur prior to the administration of study drug will be considered 
screening assessments. Safety assessments that occur after dosing has begun will be 
considered as having occurred while on treatment.
Disease assessments will be distinguished as belonging to either screening, continued 
therapy or post-study phases of the study.
13.4.7.
Other Issues
Data from participating centers will be pooled prior to analysis. It is anticipated that 
subject accrual may be limited across centers and summaries of data by center would 
likely not be informative. Therefore, these summaries will not be provided.
Demographic and baseline characteristics will be summarized.
For PK analyses, assay values below the quantitative limit (BQL) will be handled as 
described in the GSK CPK/M&S PK methods.
13.5.
Treatment Comparisons
13.5.1.
Primary Comparisons of Interest
Several dose levels and regimens of GSK2849330 are being investigated. No formal 
comparisons will be performed regarding differences between the dose levels. Safety, 
PK, PD biomarker, and clinical benefit summaries will be provided by dose level of 
GSK2849330.
13.5.2.
Other Comparisons of Interest
In Part 1, PK parameters including, but not limited to, AUC(0-t), AUC(0-τ), AUC(0-∞),
Cmax, tmax, and MRT of GSK2849330 will be descriptively compared between dose 

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levels in tabular or graphic formats. In Part 2, other safety, PK and clinical activity data 
than the primary endpoints will also be evaluated and compared between different 
treatment groups.

PK: PK parameters including, but not limited to, AUC(0-t), AUC(0-τ), AUC(0-
∞), Cmax, tmax, and MRT of GSK2849330 will be descriptively compared 
between dose levels in tabular or graphic formats.

PD biomarker: Changes from baseline in PD markers, the markers of 
inflammatory response activation from blood and markers in skin and tumor 
biopsies will be evaluated and summarized for each dose cohort or group.

Clinical anti-cancer activity:  The number of CRs, PRs, stable diseases (SDs) and 
PDs for each dose cohort or group will be listed using RECIST, irRC, and 
mRECIST and summarized if appropriate.
13.6.
Interim Analysis
Ongoing examination of safety, PK and PD data will occur while the study is being 
conducted. In Part 1, PK parameters will also be evaluated and compared among different 
treatment cohorts.
13.6.1.
Part 1: Dose-Escalation
In Part 1 (Dose-Escalation), an interim analysis will be performed to determine if a dose-
escalation is appropriate and to be informed of the data reviewed to support the dose-
escalation decision following the completion of each dose cohort.  The primary driver for 
the dose-escalation decision(s) in Part 1 will be safety and tolerability of each dose 
cohort.  Further details regarding such analyses will be provided in the RAP.
13.6.2.
Part 2: Molecularly Defined Tumor Histology Groups
For each of the groups in Part 2, response data will be reviewed on an ongoing basis. 
After the initial 12 subjects have been enrolled at the recommended dose, the number of 
responses observed will be compared with the stopping rules provided in Table 15 and 
Figure 1 below.

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Table 15
xStopping rules for each expansion group
Number of Subjects Enrolled
Stop for Futility if ≤ this number of 
responders is observed
12
0
16
1
22
2
27
3
30
4
Figure 1
Diagram of Stopping Rules for each Group
13.7.
Key Elements of Analysis Plan
Data will be listed and summarized according to the GSK reporting standards, where 
applicable.  Complete details will be documented in the RAP.  Any deviations from, or 

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additions to, the original analysis plan described in this protocol will be documented in 
the RAP and final study report.
As it is anticipated that accrual will be spread thinly across centers and summaries of data 
by center would be unlikely to be informative, data from all participating centers will be 
pooled prior to analysis.
All data up to the time of study completion/withdrawal from study will be included in the 
analysis, regardless of duration of treatment.
As the duration of treatment for a given subject will depend on efficacy and tolerability, 
the duration of follow-up will vary between subjects.  Consequently there will be no 
imputation for missing data.
Demographic and baseline characteristics will be summarized.
13.7.1.
Anti-Cancer Activity Analyses
The Efficacy Population will be used for anti-cancer activity analyses. Since this is a 
Phase I study, anti-cancer activity will be evaluated based on clinical evidence and 
response criteria. Where appropriate, the lesion data will be listed for each subject. The 
percent change from baseline will be calculated for each subject and listed, along with 
their ORR, CR, PR, SD and PD according to standard RECIST 1.1 (See Appendix 5).  
mRECIST and irRc will be calculated and listed as applicable. Response data will be 
summarized by cohort or group. If data warrant, the response data will be summarized 
by dose level. Response-evaluable subjects are defined as subjects with a pre-dose and at
least 1 post-dose disease assessment. Correlation analysis may be conducted to explore 
any relationship between the subject’s tumor type specific markers and tumor response 
based on RECIST, version [1.1], mRECIST and irRc.  Other measures of clinical benefit 
specific to the groups in Part 2 will be summarized by group as appropriate.
Full details will be specified in the RAP.
13.7.2.
Safety Analyses
The All Treated Population will be used for the analysis of safety data. All serially 
collected safety endpoints (e.g., laboratory tests, vital signs, ECGs) will be summarized 
according to the scheduled, nominal visit at which they were collected and across all on-
treatment time points using a “worst-case” analysis.
DLTs will be listed for each subject and summarized according to GSK IDSL standards. 
All other relevant safety data will be listed and summarized according to the GSK IDSL 
standards as well. Complete details of the safety analyses will be provided in the RAP.
13.7.2.1.
Extent of Exposure
Extent of exposure of GSK2849330 will depend on tolerability of the subjects to the 
doses administered and the course of their disease.

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The number of subjects administered study treatment will be summarized according to 
the duration of therapy.
13.7.2.2.
Adverse Events
AEs will be coded using the standard MedDRA and grouped by system organ class. AEs 
will be graded by the investigator according to the NCI-CTCAE, (version 4.0) [NCI, 
2009]. Summaries of the number of toxicity grades for both laboratory and non-
laboratory data will be presented.
Events will be summarized by frequency and proportion of total subjects, by system 
organ class and preferred term.  Separate summaries will be given for all AEs, treatment-
related AEs, SAEs and AEs leading to discontinuation of study treatment.  AEs, if listed 
in the NCI-CTCAE (version 4.0) [NCI, 2009] will be summarized by the maximum 
grade.  Otherwise, the AEs will be summarized by maximum intensity.
The incidence of deaths and the primary cause of death will be summarized.
DLTs will be listed for each subject and summarized by dose cohort according to IDSL 
standards.
13.7.2.3.
Clinical Laboratory Evaluations
Clinical laboratory evaluations will be performed on the days specified in the Time and 
Events Tables Section 7.1.
Hematology and clinical chemistry data will be summarized using frequencies and 
proportions according to NCI-CTCAE (version 4.0) [NCI, 2009].  Laboratory test results 
outside the reference ranges that do not have associated NCI-CTCAE criteria will be 
summarized at each scheduled assessment. Results will be flagged using toxicity grades, 
if available, or as normal or abnormal (high or low) with reference to standard reference 
ranges.  Further details will be provided in the RAP.
13.7.2.4.
Other Safety Measures
Data for vital signs, ECGs, and ECHOs will be summarized based on predetermined 
criteria identified to be of potential clinical importance (PCI). Vital signs will be listed 
for each subjects at all measured time points. A descriptive summary including change 
from baseline pre-dose will also be presented. Individual profiles of BP will be plotted by 
time. Further details will be provided in the RAP.
13.7.3.
Pharmacokinetic Analyses
13.7.3.1.
Pharmacokinetic Parameters
PK analysis will be the responsibility of the Clinical Pharmacology Modeling and 
Simulation (CPMS) Department, GSK.

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PK analysis of drug concentration-time data will be conducted by non-compartmental 
methods and exploratory compartmental methods under the direction of CPMS, 
Quantitative Sciences, GSK.  The following PK parameters will be determined if data 
permit:

Cmax

tmax

area under the plasma concentration-time curve (AUC(0-t), AUC(0-τ) (repeat 
dosing) and/or area under the concentration-time curve from time zero (pre-
dose) extrapolated to infinite time [AUC(0-∞)] (single dose)

apparent terminal phase elimination rate constant (z) (single dose)

apparent terminal phase half-life (t½) (single dose)

apparent MRT

population pharmacokinetic parameters including CL, Q, V, Vm and Km
13.7.3.2.
Statistical Analysis of Pharmacokinetic Data
Statistical analyses of the non-compartmental PK parameters data will be the 
responsibility of Oncology, Clinical Statistics, GSK.  Statistical analysis of the 
exploratory compartmental PK parameters data will be the responsibility of CPMS, 
Quantitative Sciences, GSK. Plasma GSK2849330 concentration-time data from dose 
escalation will be analyzed by non-compartmental methods with WinNonlin [Version 
number 5.2].
From the plasma concentration-time data, the following PK parameters will be 
determined, as data permit: Cmax, tmax, AUC(0-t) and AUC(0-), apparent terminal 
phase half-life (t1/2), and MRT. Trough concentration (Cτ) samples collected on the 
specified days will be used to assess attainment of steady state.
Plasma concentration-time data will be listed by dose and summarized using descriptive 
statistics (n, mean, standard deviation SD, median, minimum and maximum) by planned 
relative assessment time. Mean and/or median values will be plotted over time. Individual 
plasma and urinary (if available) PK parameters values as well as descriptive summary 
(mean, SD, median, minimum, maximum, geometric mean, and the standard deviation, 
95% confidence interval (CI) of log-transformed parameters (if applicable) by dose 
cohort or group will be reported.
Cmax and AUC (AUC(0-∞), and AUC(0-τ)) will be plotted as a function of the dose 
administered.
Further exploratory statistical analysis of any or all the pharmacokinetic endpoints may 
be performed as appropriate including dose proportionality.
PK data will be presented in graphical and/or tabular form and will be summarized 
descriptively.

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13.7.3.3.
Population Pharmacokinetics
Statistical analysis of the population PK parameter data will be the responsibility of 
CPMS, Quantitative Sciences, GSK.
Plasma concentration-time data from the groups in Part 2 may be combined with data 
from dose escalation and further analyzed using a population approach. A nonlinear 
mixed effect model may be used to determine population PK parameters and important 
covariates (biomarker, or disease related covariates).
PK data will be presented in graphical and/or tabular form and will be summarized 
descriptively.
13.7.4.
Immunogenicity Analyses
The immunogenicity assessment will include the incidence (confirmed positive results 
only) and titers of anti-GSK2849330 binding antibodies at any time point post baseline. 
Full details will be provided in the RAP.
13.7.5.
Pharmacokinetic/Pharmacodynamic Analyses
Data permitting, exploratory population covariate PK/PD/biomarker analyses will be 
provided.
13.7.5.1.
Translational Research Analyses
The results of translational research investigations will be reported in or separately from
the main clinical study report (CSR).  All endpoints of interest from all comparisons will 
be descriptively and/or graphically summarized as appropriate to the data.
Data permitting, the results of secondary translational research objectives will be reported 
in the main CSR. 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.
Further details on the translational research analyses will be addressed in the RAP.
13.7.5.2.
Novel Biomarker(s) Analyses
The results of these biomarker investigations may be reported separately from the main 
CSR.  All endpoints of interest from all comparisons will be descriptively and/or 
graphically summarized as appropriate to the data.
Additional exploratory analyses may be performed to further characterize the novel 
biomarker.

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13.7.6.
Pharmacogenetic Analyses
Further details on PGx analyses will be addressed in Appendix 8 and the PGx RAP.
14.
STUDY CONDUCT CONSIDERATIONS
14.1.
Posting of Information on Clinicaltrials.gov
Study information from this protocol will be posted on publicly available clinical trial 
registers before enrollment of subjects begins.
14.2.
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 Conference 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.
14.3.
Urgent Safety Measures
If an event occurs that is related to the conduct of the study or the development of the IP, 
and this new event is likely to affect the study of subjects, the Sponsor, and the 
investigator will take appropriate urgent safety measures to protect subjects against any 
immediate hazard.
The Sponsor will work with the investigator to ensure the IRB/EC is notified.
14.4.
Quality Control (Study Monitoring)
In accordance with applicable regulations, Good Clinical Practice (GCP) and GSK 
procedures, the site will be contacted prior to the start of the study to review with the site 

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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.
14.5.
Quality Assurance
To ensure compliance with ICH GCP and all applicable regulatory requirements, GSK 
may conduct quality assurance audits of the site.  Regulatory agencies may conduct a 
regulatory inspection at any time during or after completion of the study.  In the event of 
an audit or inspection, the investigator (and institution) must agree to grant the auditor(s) 
and inspector(s) direct access to all relevant documents and to allocate their time and the 
time of their staff to discuss any findings/relevant issues.
14.6.
Study and Site Closure
The end of the study will be defined as the date of the LSLV enrolled.
Upon completion or termination of the study, the monitor will conduct site closure 
activities with the investigator or site staff (as appropriate), in accordance with applicable 
regulations, ICH GCP, and GSK Standard Operating Procedures.
GSK reserves the right to temporarily suspend or terminate the study at any time for 
reasons including (but not limited to) safety issues, ethical issues, or severe 
noncompliance.  If GSK determines that such action is required, GSK will discuss the 
reasons for taking such action with the investigator or head of the medical institution 
(where applicable).  When feasible, GSK will provide advance notice to the investigator 
or head of the medical institution of the impending action.
If a study is suspended or terminated for safety reasons, GSK will promptly inform all 
investigators, heads of the medical institutions (where applicable),and/or institutions 
conducting the study.  GSK will also promptly inform the relevant regulatory authorities 
of the suspension/termination along with the reasons for such action.  Where required by 
applicable regulations, the investigator or head of the medical institution must inform the 
IRB/EC promptly and provide the reason(s) for the suspension/termination.

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

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for publication no later than 18 months after the 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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15.
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Arnedos M, Denlinger CS, Harb WA, et al. A Phase 1 Study of MM-121 in combination 
with multiple anticancer therapies in patients with advanced solid tumors. Paper 
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Beji A, Horst D, Engel J, Kirchner T, Ullrich A. Toward the prognostic significance and 
therapeutic potential of HER3 receptor tyrosine kinase in human colon cancer. Clin 
Cancer Res. Feb 15 2011;18(4):956-968.
Benson AB, 3rd, Ajani JA, Catalano RB, et al. Recommended guidelines for the 
treatment of cancer treatment-induced diarrhea. J Clin Oncol. Jul 15 2004;22(14):2918-
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Bossenmaier B, Friess T, Gerdes C, et al. GE-huMab-HER3, a novel humanized, 
glycoengineered HER3 antibody with enhanced ADCC and superior preclinical in vitro 
and in vivo efficacy Paper presented at: AACR Annual Meeting 2012; Chicago, IL.
Carroll SL, Miller ML, Frohnert PW, Kim SS, Corbett JA. Expression of neuregulins and 
their putative receptors, ErbB2 and ErbB3, is induced during Wallerian degeneration. J of 
Neuroscience. March 1, 1997: 17(5):1642–1659.
Denlinger CS, Keedy VL, Cleary JM, et al. Phase I Dose escalation study of MM-121, a 
fully human monoclonal antibody to ErbB3, in patients with advanced solid tumors. 
Paper presented at: AACR, 2011; Orlando.
Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid 
tumours: revised RECIST guideline (version 1.1). Eur J Cancer. Jan 2009;45(2):228-247.
García I, del Casar JM, Corte MD, Allende MT, García-Muñiz JL, Vizoso F. Epidermal 
growth factor receptor and c-erbB-2 contents in unresectable (UICC R1 or R2) gastric 
cancer. Int J Biol Markers. 2003 Jul-Sep;18(3):200-6.
Gibiansky L, Gibiansky E, Kakkar T, Ma P. Approximations of the target-mediated drug 
disposition model and identifiability of model parameters. J Pharmacokinet 
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GlaxoSmithKline Document Number 2013N168399_01 Version 01.  GSK2849330 
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Hayashi M, Inokuchi M, Takagi Y, et al. High expression of HER3 is associated with a 
decreased survival in gastric cancer. Clin Cancer Res. Dec 1 2008;14(23):7843-7849.

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Jaiswal BS, Kljavin NM, Stawiski EW, et al. Oncogenic ERBB3 mutations in human 
cancers. Cancer Cell. May 13 2013;23(5):603-617.
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9 1997;1333(3):F217-248.
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ERBB3 antibody inhibits the adaptive response to RAF inhibitor. Cancer Res. 2014 Aug 
1;74(15):4122-32.
Lee JJ, Liu DD. A predictive probability design for phase II cancer clinical trials. Clin 
Trials. 2008;5(2):93-106.
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carcinoma. Semin Liver Dis. Feb 2010;30(1):52-60.
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molecularly targeted agents evaluated in first-in-human phase I cancer clinical trials. J 
Clin Oncol. Mar 10 2010;28(8):1401-1407.
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HER3 monoclonal antibody, in patients with advanced solid tumors. Clin Cancer Res. 
Jun 1 2013;19(11):3078-3087.
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mammary gland: morphologic changes as an indicator of systemic hormonal 
perturbations induced by xenobiotics. Toxicol Pathol. Feb 2007;35(2):199-207.
Mendell-Harary J, Ruhe J, Schneider M, et al. Identification of a predictive biomarker for 
patritumab, an anti-HER3 monoclonal antibody, in advanced NSCLC. J Clin Oncol 32, 
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Neuenschwander B, Branson M, Gsponer T.  Critical aspects of the Bayesian approach to 
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Ocana A, Vera-Badillo F, Seruga B, Templeton A, Pandiella A, Amir E. HER3 
overexpression and survival in solid tumors: a meta-analysis. J Natl Cancer Inst. 
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Park DJ, Lenz HJ. Determinants of chemosensitivity in gastric cancer. Curr Opin 
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1992;7(7):1273-1278.
Reschke M, Mihic-Probst D, van der Horst EH, et al. HER3 is a determinant for poor 
prognosis in melanoma. Clin Cancer Res. Aug 15 2008;14(16):5188-5197.
Reynolds KL, Juric D, Baselga J, et al. A phase 1 study in patients with esophageal 
squamous cell carcinoma, head and neck cancer, or HER2-overexpressing metastatic 
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study of AV-203, a monoclonal antibody against ERBB3, in patients with metastatic or 
advanced solid tumors. J Clin Oncol. 32:5s, 2014 (suppl; abstr 11113).
Sato Y, Yashiro M, Takakura N. Heregulin induces resistance to lapatinib-mediated 
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Schneider M, Blum S, Wenzl C, et al. Heregulin expression level as a predictive 
biomarker for patritumab efficacy. J Clin Oncol. 32:5s, 2014 (suppl; abstr 2618).
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EGFR wild-type NSCLC patients. J Clin Oncol. 32:5s, 2014 (suppl; abstr 8051).
Shames DS, Carbon J, Walter K, et al. High heregulin expression is associated with 
activated HER3 and may define an actionable biomarker in patients with squamous cell 
carcinomas of the head and neck. PLoS One. 2013;8(2):e56765.
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Tanner B, Hasenclever D, Stern K, et al. ErbB-3 predicts survival in ovarian cancer. J 
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induced activation of ErbB3 by EGFR tyrosine kinase activity promotes tumor growth 
and metastasis in melanoma cells. Int J Cancer. 2008 Jul 15;123(2):340-7.
Uhlen M, Oksvold P, Fagerberg L, Lundberg E, Jonasson K, Forsberg M, Zwahlen M, 
Kampf C, Wester K, Hober S, Wernerus H, Björling L, Ponten F. Towards a knowledge-
based Human Protein Atlas. Nat Biotechnol. 2010 28(12):1248-50.
Von Pawel J, Tseng J, Dediu M, et al. J Clin Oncol 32:5s, 2014 (suppl; abstr 8045). 
Phase 2 HERALD study of patritumab with erlotinib in advanced NSCLC subjects. J 
Clin Oncol. 32:5s, 2014 (suppl; abstr 8045).
Walport MJ. Complement. First of two parts. N Engl J Med. Apr 5 2001;344(14):1058-
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Wilson TR, Lee DY, Berry L, Shames DS, Settleman J. Neuregulin-1-mediated autocrine 
signaling underlies sensitivity to HER2 kinase inhibitors in a subset of human cancers. 
Cancer Cell. 2011 Aug 16;20(2):158-72.
Wu X, Chen Y, Li G, et al. Her3 is associated with poor survival of gastric 
adenocarcinoma: Her3 promotes proliferation, survival and migration of human gastric 
cancer mediated by PI3K/AKT signalling pathway. Med Oncol. 2014 Apr;31(4):903.
Zhang L, Castanaro C, Luan B, et al. ERBB3/HER2 signaling promotes resistance to 
EGFR blockade in head and neck and colorectal cancer models. Mol Cancer Ther. 2014 
May;13(5):1345-55.
Zhang XL, Yang YS, Xu DP, et al. Comparative study on overexpression of HER2/neu 
and HER3 in gastric cancer. World J Surg. 2009 Oct;33(10):2112-8.

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16.
APPENDICES
16.1.
Appendix 1: Liver Chemistry Monitoring, Interruption 
Stopping and Follow-up Criteria
Phase I Liver Safety Algorithm

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16.2.
Appendix 2: Country Specific Requirements
Specific QTc Stopping Criteria:
If specified by local requirements, a subject that meets the criteria QTc1 below will have 
study treatment withheld:
The QT interval 
corrected for heart 
rate by Bazett’s 
formula (QTcB) > 
500 msec
1Based on average corrected QT (QTc) interval value of triplicate ECGs to include 
manual over-read.  For example, if an ECG demonstrates a prolonged QT interval, obtain 
2 more ECGs over a brief period, and then use the averaged QTc values of the 3 ECGs to 
determine whether the subjects should have study treatment withheld.
In addition, for subjects in designated countries, study treatment must be withheld for an 
increase in QTc >60 msec from baseline.
If the QTc prolongation resolves to Grade 1 or baseline, the subject may be re-started on 
the study treatment if the investigator and GSK Medical Monitor agree that the subject 
will benefit from further treatment.
No other known country specific requirements are currently required.

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16.3.
Appendix 3: ECOG Performance Status
CCI - This section contained Clinical Outcome Assessment data collection questionnaires or indices, which are 
protected by third party copyright laws and therefore have been excluded.

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16.4.
Appendix 4: Estimated Glomerular Filtration Rate Using the 
Modification of Diet in Renal Disease (MDRD) Equation
Background
The Modification of Diet in Renal Disease (MDRD) equation provides an estimate of 
glomerular filtration rate (GFR), using values for a subject’s serum creatinine, age, sex, 
and race (Levey, 1999).
MDRD Equation when creatinine is expressed in mg/dL:
Estimated GFR (ml/min/1.73 m2) = 186 x (serum creatinine)-1.154 x (age)-0.203 x 
(0.742 if female) x (1.212 if black)
MDRD Equation when creatinine is expressed in µmol/L:
Estimated GFR (ml/min/1.73 m2) = 32788 x (serum creatinine)-1.154 x (age)-0.203 x 
(0.742 if female) x (1.212 if black)
Reference
Levey AS, Bosch JP, Lewis JB, Greene T, Rogers N, Roth D. A more accurate method to 
estimate glomerular filtration rate from serum creatinine: a new prediction equation. Modification 
of Diet in Renal Disease Study Group. Ann Intern Med. 130(6):461-70. (1999)
Glomerular Filtration Rate Interpretation
Table 16
Kidney function using GFR estimates
Stage GFR
Equation (age in years for ≥ 18)
1
90+
Normal kidney function
2
60 - 89 Mildly reduced kidney function
3
30 - 59 Moderately reduced kidney function
4
15 - 29 Severely reduced kidney function
5
<15
Very severe, or endstage kidney failure
Website to calculate the glomerular filtration rate
http://nephron.org/MDRD_GFR.cgi

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16.5.
Appendix 5: RECIST 1.1 Guidelines for Evaluation of 
Disease
Measurable and Non-measurable Definitions
Measurable lesion:
A non nodal lesion that can be accurately measured in at least one dimension (longest 
dimension) of

10 mm with MRI or CT when the scan slice thickness is no greater than 5 mm.  If 
the slice thickness is greater than 5 mm, the minimum size of a measurable lesion 
must be at least double the slice thickness (e.g., if the slice thickness is 10 mm, a 
measurable lesion must be 20 mm).

10 mm caliper/ruler measurement by clinical exam or medical photography.

20 mm by chest x-ray.
Additionally lymph nodes can be considered pathologically enlarged and measurable if

15 mm in the short axis when assessed by CT or MRI (slice thickness 
recommended to be no more than 5 mm).  At baseline and follow-up, only the short 
axis will be measured [Eisenhauer, 2009].
Non-measurable lesion: 
All other lesions including lesions too small to be considered measurable (longest 
diameter <10 mm or pathological lymph nodes with ≥ 10 mm and <15 mm short axis) as 
well as truly non-measurable lesions, which include: leptomeningeal disease, ascites, 
pleural or pericardial effusions, inflammatory breast disease, lymphangitic involvement 
of the skin or lung, abdominal masses/abdominal organomegaly identified by physical 
exam that is not measurable by reproducible imaging techniques [Eisenhauer, 2009].
Measurable disease:  The presence of at least one measurable lesion.  Palpable lesions 
that are not measurable by radiologic or photographic evaluations may not be utilized as 
the only measurable lesion.
Non-Measurable only disease:  The presence of only non-measurable lesions.  
Response Criteria
Evaluation of target lesions
Definitions for assessment of response for target lesion(s) are as follows:

CR:  Disappearance of all target lesions.  Any pathological lymph nodes must be 
<10 mm in the short axis.

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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
SD:  Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify 
for PD.

PD:  At least a 20% increase in the sum of the diameters of target lesions, taking as a 
reference, the smallest sum of diameters recorded since the treatment started (e.g.,
percent change from nadir, where nadir is defined as the smallest sum of diameters 
recorded since treatment start). In addition, the sum must have an absolute increase 
from nadir of 5 mm.

Not Applicable (NA): No target lesions at baseline.

Not Evaluable (NE): Cannot be classified by one of the five preceding definitions.
NOTE:

If lymph nodes are documented as target lesions the short axis is added into the sum 
of the diameters (e.g., sum of diameters is the sum of the longest diameters for non-
nodal lesions and the short axis for nodal lesions).  When lymph nodes decrease to 
non-pathological size (short axis <10 mm) they should still have a measurement 
reported in order not to overstate progression.

If at a given assessment time point all target lesions identified at baseline are not 
assessed, sum of the diameters cannot be calculated for purposes of assessing CR, 
PR, or SD, or for use as the nadir for future assessments.  However, the sum of the 
diameters of the assessed lesions and the percent change from nadir should be 
calculated to ensure that progression has not been documented.  If an assessment of 
PD cannot be made, the response assessment should be NE.

All lesions (nodal and non-nodal) should have their measurements recorded even 
when very small (e.g., 2 mm).  If lesions are present but too small to measure, 5 mm 
should be recorded and should contribute to the sum of the diameters, unless it is 
likely that the lesion has disappeared in which case 0 mm should be reported.

If a lesion disappears and reappears at a subsequent time point it should continue to 
be measured.  The response at the time when the lesion reappears will depend upon 
the status of the other lesions.  For example, if the disease had reached a CR status 
then PD would be documented at the time of reappearance.  However, if the response 
status was PR or SD, the diameter of the reappearing lesion should be added to the 
remaining diameters and response determined based on percent change from baseline 
and percent change from nadir.
Evaluation of non-target lesions
Definitions for assessment of response for non-target lesions are as follows:

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.

PD: Unequivocal progression of existing non-target lesions. 

Not Applicable (NA): No non-target lesions at baseline.

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
Not Evaluable (NE): Cannot be classified by one of the four preceding definitions.
NOTE:

In the presence of measurable disease, progression on the basis of solely non-target 
disease requires substantial worsening such that even in the presence of SD or PR in 
target disease, the overall tumor burden has increased sufficiently to merit 
discontinuation of therapy.

In the presence of non-measurable only disease consideration should be given to 
whether or not the increase in overall disease burden is comparable in magnitude to 
the increase that would be required to declare PD for measurable disease.

Sites of non-target lesions, which are not assessed at a particular timepoint based on 
the assessment schedule, should be excluded from the response determination (e.g., 
non-target response does not have to be "Not Evaluable").
New lesions
New malignancies denoting disease progression must be unequivocal.  Lesions identified 
in follow-up in an anatomical location not scanned at baseline are considered new 
lesions.
Any equivocal new lesions should continue to be followed.  Treatment can continue at 
the discretion of the investigator until the next scheduled assessment.  If at the next 
assessment the new lesion is considered to be unequivocal, progression should be 
documented.
Evaluation of overall response
Table 17 presents the overall response at an individual time point for all possible 
combinations of tumor responses in target and non-target lesions with or without the 
appearance of new lesions for subjects with measurable disease at baseline.
Table 17
Evaluation of Overall Response for Subjects with Measurable 
Disease at Baseline
Target Lesions
Non-Target Lesions
New Lesions
Overall Response
CR
CR or NA
No
CR
CR
Non-CR/Non-PD or 
NE
No
PR
PR
Non-PD or NA or NE
No
PR
SD
Non-PD or NA or NE
No
SD
NE
Non-PD or NA or NE
No
NE
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD
Any
Any
Yes
PD
CR=complete response, PR = partial response, SD=stable disease, PD=progressive disease, 
NA= Not applicable, and NE=Not Evaluable

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Table 18 presents the overall response at an individual time point for all possible 
combinations of tumor responses in non-target lesions with or without the appearance of 
new lesions for subjects with non-measurable only disease at baseline.
Table 18
Evaluation of Overall Response for Subjects with Non-Measurable 
Only Disease at Baseline
Non-Target Lesions
New Lesions
Overall Response
CR
No
CR
Non CR/Non PD
No
Non CR/Non PD
NE
No
NE
Unequivocal PD
Yes or No
PD
Any
Yes
PD
CR=complete response,  PD=progressive disease, and NE=Not Evaluable
NOTE:

Subjects with a global deterioration of health status requiring discontinuation of 
treatment without objective evidence of disease progression at that time should be 
classified as having "symptomatic deterioration." Objective response status is 
determined by evaluations of disease burden. Every effort should be made to 
document the objective progression even after discontinuation of treatment.

In some circumstances, it may be difficult to distinguish residual disease from 
normal tissue. When the evaluation of CR depends on this determination, it is 
recommended that the residual lesion be investigated (fine needle aspirate/biopsy) to 
confirm the CR.
Evaluation of best overall response
The best overall response is the best response recorded from the start of the treatment 
until disease progression/recurrence and will be determined programmatically by GSK 
based on the investigators assessment of response at each time point.

To be assigned a status of SD, follow-up disease assessment must have met the SD 
criteria at least once after first dose at a minimum interval of 8 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.
Confirmation Criteria:
To be assigned a status of PR or CR, a confirmatory disease assessment should be 
performed no less than 4 weeks (28 days) after the criteria for response are first met.
References:
Eisenhauer EA, Therasse P, Bogaerts J, et al.  New response evaluation criteria in solid 
tumours:  Revised RECIST guidelines (version 1.1). Eur J Cancer. 2009; 45: 228-2.

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16.6.
Appendix 6: Modified irRC from RECIST 1.1
Modified immune-related response criteria (irRC)
Modified irRC is modified from RECIST 1.1 based on immune-related response criteria 
[Wolchok, 2009].
Measurable lesions/non-Measurable lesions
The definition of measurable lesions and non-measurable lesions are based on RECIST 
1.1. [Eisenhauer, 2009]
Index lesions
All target lesions from RECIST 1.1 assessment will be referred to as index lesions in the 
modified irRC. 
Non-index lesions
All non-target lesions from RECIST 1.1 assessment will be referred to as non-index 
lesions in the modified irRC. 
Measurable and Non-measurable new lesions
New lesions will be classified as measurable and non-measurable lesions based on 
RECIST 1.1. For measurable new lesions, measurement will be recorded in CRF. 
Calculation of immune-related Sum of Lesion Diameters (irSLD)

irSLD at baseline is the sum of diameters for all index lesions at baseline prior to 
treatment on Day 1. 

irSLD at post-baseline assessment: at each post-baseline disease assessment, the 
diameters of the index lesions and of new measurable lesions are added together 
to provide the irSLD, see below
irSLD = SLDindex + SLDnew, measurable
Definition of Index Lesion Response

Immune-related complete response (irCR), which is defined as complete 
disappearance of all index lesions. Lymph nodes that shrink to <10 mm in short 
axis are considered normal.

Immune-related partial response (irPR), which is defined as a decrease, 
relative to baseline, of 30% or greater in the sum of the diameters of all index and 
all new measurable lesions, in the absence of irCR.

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o
Note: the appearance of new measurable lesion is factored into the irSLD, 
but does not automatically qualify as progressive disease until the irSLD 
increase by 20% when compared to irSLD at nadir.

Immune-related stable disease (irSD), which is defined as not meeting the 
criteria for irCR or irPR, in the absence of immune-related progressive disease 
(irPD).

Immune-related progressive disease (irPD), which is defined as at least a 20% 
increase in the sum of the diameters of all index and all new measurable lesions 
when compared to irSLD at nadir.
Definition of Non-index Lesion Response

irCR, which is defined as complete disappearance of all non-index lesions. 
Lymph nodes that shrink to <10 mm short axis are considered normal.

irPR, non-index lesions are not considered in the definition of irPR, this term does 
not apply.

irSD, non-index lesions are not considered in the definition of irSD, this term does 
not apply.

irPD, increase in number or size of non-index lesions does not constitute 
progressive disease unless/until irSLD increase by 20% compared to nadir.
Impact of New Lesions on modified irRC
New lesions alone do not qualify as progressive disease. However their contribution to 
total tumor burden is included in the irSLD which in turn feeds into the modified irRC for 
tumor response.
Definition of Overall Response using modified irRC

irCR, defined as complete disappearance of all index and non-index lesions, 
together with no new measurable or non-measurable lesions. All lymph nodes 
short axes must be <10 mm.  Must be confirmed no less than 4 weeks from the 
date of the documentation of irCR.

irPR, defined as a decrease of 30% or greater in the sum of lesion diameters of all 
index lesions and new measurable lesions (irSLD) relative to baseline, in the 
absence of irCR.  Must be confirmed no less than 4 weeks from the date of the
documentation of irPR.

irSD, defined as failure to meet the criteria for irCR or irPR, in the absence of 
irPD.

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
irPD, defined as at least 20% increase in the irSLD of all index lesions and new 
measurable lesions over the nadir irSLD. It is highly recommended to confirm 
irPD no less than 4 weeks later.
Modified Immune-related overall response
Index 
lesion 
Non-
Index 
New, 
Measur
able 
New, 
non-
measura
ble 
% change in irSLD (index 
and measurable new 
lesions)
Overall 
Respons
e 
irCR
irCR
Absent
Absent
100% reduction from 
baseline 
irCR*
irCR
Non-irCR
Absent
Any 
100% reduction from 
baseline
irPR*
irCR
Any
Absent 
Present 
100% reduction from 
baseline
irPR*
irPR
Any
Any
Any
>=30% reduction from 
baseline and <20% increase 
from nadir 2
irPR*
irSD
Any
Any
Any
<30% reduction from 
baseline and <20% increase 
from nadir
irSD*
irPD
Any
Any
Any
>= 20% increase from nadir
irPD*#
*irCR, irPR and irPD must be confirmed no less than 4 weeks later.
Use lowest recorded tumor burden for this calculation.
References:
Eisenhauer EA, Therasse P, Bogaerts J, et al.  New response evaluation criteria in solid 
tumours:  Revised RECIST guidelines (version 1.1). Eur J Cancer. 2009; 45: 228-2.
Wolchok JD, Hoos A, O’Day S, et al. Guidelines for the evaluation of immune therapy 
activity in solid tumors: immune-related response criteria. Clin Cancer Res
2009;15:7412-7420.

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16.7.
Appendix 7: mRECIST Criteria
Definition of Measurable and Non-measurable Disease
Measurable disease: The presence of at least one measurable lesion.
Measurable lesion:

RECIST 1.0: lesions that can be accurately measured in at least one dimension, 
with the longest diameter (LD) being:
o
≥20 mm with conventional techniques (medical photograph [skin or oral 
lesion], palpation, plain X-ray, CT, or MRI),
OR
o
≥10 mm with spiral CT scan.

mRECIST:  intrahepatic lesions that show intratumoral arterial enhancement on 
contrast-enhanced CT or MRI (i.e.,. viable lesions), and that can be accurately 
measured in at least one dimension with the longest diameter being ≥10 mm 
with contrast-enhanced spiral CT scan or contrast-enhanced dynamic MRI.
Non-measurable lesion: All other lesions including lesions too small to be considered 
measurable (longest diameter <20 mm with conventional techniques or <10 mm with 
spiral CT scan) including bone lesions, leptomeningeal disease, ascites, pleural or 
pericardial effusions, lymphangitis cutis/pulmonis, abdominal masses not confirmed and 
followed by imaging techniques, cystic lesions, or disease documented by indirect 
evidence only (e.g., by lab values).  Malignant portal vein thrombosis should be 
considered as non-measurable lesions.  Porta hepatis lymph nodes with a short axis less 
than 20 mm are considered reactive and not malignant.
Methods of Measurement
The same diagnostic method must be used throughout the study to evaluate a lesion.
Conventional CT and MRI: Minimum sized lesion should be twice the reconstruction 
interval. The minimum size of a baseline lesion may be 20 mm, provided the images are 
reconstructed contiguously at a minimum of 10 mm. CT is preferred, and when used, 
lesions must be measured in the same anatomic plane by use of the same imaging 
sequences on subsequent examinations. Whenever possible, the same scanner should be 
used.
Spiral CT: Minimum size of a baseline lesion may be 10 mm, provided the images are 
reconstructed contiguously at 5 mm intervals. This specification applies to the tumors of 
the chest, abdomen, and pelvis.
Chest X-ray: Lesions on chest X-ray are acceptable as measurable lesions when they are 
clearly defined and surrounded by aerated lung. However, MRI is preferable.

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Clinical Examination: Clinically detected lesions will only be considered measurable by 
RECIST criteria when they are superficial (e.g., skin nodules and palpable lymph nodes). 
In the case of skin lesions, documentation by color photography - including a ruler and 
subject study number in the field of view to estimate the size of the lesion is required.
Selection and Baseline Documentation of Target and Non-Target Lesions
Target Lesion Definition
‘Typical’ Target Lesions
Intrahepatic lesions that meet the following criteria are considered ‘typical’ target 
lesions:

Lesions that show typical features of HCC in contrast-enhanced spiral CT or 
MRI studies (i.e., hypervascularity in the arterial phase with wash-out in the 
portal or late venous phase)

Lesions that are measurable (as defined above)

Lesions that are suitable for repeated measurements

Other Target Lesions (‘atypical’ and extrahepatic lesions)

‘Atypical’ and extrahepatic lesions that are measurable and suitable for repeated 
measurements are considered target lesions
Target Lesion Selection

The selection of target lesions will be guided initially by the presence of ‘typical’ 
intrahepatic lesions:
If ‘Typical’ intrahepatic lesions are present:
o
Up to 5 of these ‘typical’ intrahepatic lesions should be selected as target 
lesions at baseline.  Measurement of viable tumor diameter will be applied 
to these lesions. All intrahepatic lesions beyond these 5 should be 
considered as non-target lesions.
o
In addition, up to 5 measurable, extrahepatic lesions per organ should be 
selected as target lesions at baseline.  Measurement of longest tumor 
diameter will be applied to these lesions.  All extrahepatic lesions beyond 
the up-to-10 selected target lesions should be considered as non-target 
lesions.
If no ‘Typical’ intrahepatic lesions are present:
o
In case measurable intrahepatic HCC lesions are present at baseline but do 
not meet the criteria for ‘typical’ lesions, due to atypical vascular patterns, 
these measurable intrahepatic lesions as well as measurable extrahepatic 
lesions should be assessed at baseline.  Up to a maximum of 5 lesions per 
organ and 10 lesions in total, representative of all involved organs, should 

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be identified as target lesions and recorded and measured.  A measurement 
of longest diameter will be applied to these lesions.
Non-Target Lesions

Measurable lesions other than the target lesions and all sites of non-measurable 
(evaluable) disease will be identified as non-target lesions.  Measurements of these 
lesions are not required, but the presence or absence of each should be noted 
throughout follow-up.  Non-target lesions may include:
Intrahepatic lesions:

Not well-delineated HCC lesions including infiltrative-type and diffuse HCC

HCC lesions with atypical contrast-agent enhancement patterns

HCC lesions showing local recurrence after previous loco-regional treatment 
without meeting the criteria for ‘viable’ lesions (i.e., lack of clear-cut 
hypervascular recurrence and/or well-delineation from the surrounding liver 
tissue)

Portal vein tumor invasion and/or thrombosis

Porta hepatis lymph node(s) considered as malignant (i.e., >20 mm in the short 
axis)

Intrahepatic viable lesions in excess of the 5 lesions in the liver selected as target 
lesions
Extrahepatic lesions:

Extrahepatic lesions in excess of the 5 lesions per organ selected as target 
lesions

Non-measurable but evaluable disease (i.e., cutaneous or bone lesions, etc.)
Calculation of Sum of Target Lesions

Documentation of indicator lesion(s) should include date of assessment, description 
of lesion site, dimensions, and type of diagnostic study used to follow lesion(s).

All measurements should be taken and recorded in metric notation, using a ruler or 
callipers.
If ‘Typical’ intrahepatic lesions are present:
The sum of the viable diameters of all ‘typical’ intrahepatic target lesions (up to 5 lesions 
total) and of the longest overall diameters of extrahepatic target lesions (5 per organ) up 
to a maximum of 10 target lesions in total will be calculated and reported as the baseline 
sum.  This baseline sum will be used as the reference for determining tumor response.  
Note the longest viable diameter may not be on the same section of liver as the longest 
overall diameter.

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If no ‘Typical’ intrahepatic lesions are present:
The sum of the longest overall diameters for all target lesions up to a maximum of 10 
target lesions in total will be calculated and reported as the baseline sum of the longest 
diameters, which will be used as reference to characterize the objective tumor response 
according to RECIST 1.0.
In case of an initial tumor shrinkage, the smallest sum of (1) viable diameters (for 
‘typical’ intrahepatic lesions) or of (2) longest diameters (for ‘atypical’ intra- and 
extrahepatic lesions) recorded following baseline will be used as reference to determine 
disease progression.
Response Criteria
Disease assessments are to be performed every 6 weeks after initiating treatment.  
However, subjects experiencing a partial or complete response must have a 
confirmatory disease assessment at least 28 days later. Assessment should be
performed as close to 28 days later (as scheduling allows), but no earlier than 28 days.
Definitions for assessment of response for target lesion(s) are as follows:
Complete Response (CR) – both of the following criteria must be met:

For ‘typical’ intrahepatic target- and non-target lesions, complete disappearance 
of any intratumoral contrast-agent enhancement in the arterial phase of spiral CT 
or dynamic MRI
AND

For ‘atypical’ intra- and extrahepatic target- and non-target lesions, complete 
disappearance of all evidence of target- and non-target lesions in spiral CT or 
MRI
Partial Response (PR) –

A decrease of >30% in the sum of the longest diameters of all target lesions 
(defined below), with the baseline sum of the longest diameters of all target 
lesions as reference.

The “sum of the longest diameters of all target lesions” is defined as the sum of 
the following:

The sum of the longest viable diameters of ‘typical’ intrahepatic target 
lesions
AND

The sum of the longest overall diameters of ‘atypical’ intra- and extrahepatic 
target lesions.
Stable Disease (SD) – neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD.

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Progressive Disease (PD) – one or more of the following criteria must be met:

For ‘typical’ intrahepatic target lesions, increase of >20% in the sum of the 
longest viable diameters of target lesions, taking as reference the smallest sum of 
viable diameters of target lesions recorded since the treatment started
OR

For ‘atypical’ intra- and extrahepatic lesions increase of >20% in the sum of the 
longest diameters of target lesions, taking as reference the smallest sum of the 
diameters of target lesions recorded since the treatment started
OR

New hepatic lesion with the longest diameter of at least 10 mm with the vascular 
pattern characteristic for HCC, i.e., hypervascularization in the arterial phase with 
wash-out in the portal venous (or late venous) phase of contrast-enhanced spiral 
CT or MRI imaging
OR

New hepatic lesion larger than 10 mm without the vascular pattern characteristic 
for HCC, but evidence of growth of at least 10 mm in subsequent scans.  Note: 
individual radiological events will be adjudicated retrospectively as PD at the 
time when it was first detected by imaging techniques, if the criteria are fulfilled 
(≥ 20 mm) on subsequent radiological testing
OR

Unequivocal progression of existing non-measurable lesions. However, any new 
or worsening of pre-existing effusion (ascites, pleural effusion, etc.) will not be 
considered progression unless there is cyto-pathological confirmation of 
malignancy
OR

Appearance of one or more new extrahepatic lesions of any size
OR

Unequivocal progression of existing intra- or extrahepatic non-target lesion(s)

In the absence of clinical progression or concurrent progression in target lesions, 
progression of non-target lesions that is equivocal should be confirmed by a 
repeat evaluation at 3-6 weeks.  If the progression is confirmed, the date of the 
first (equivocal) assessment will be taken as the date of progression

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Evaluation of Overall Response for mRECIST-Based Response
The overall response is the best response recorded from the start of the treatment until 
disease progression/recurrence is documented. In general, the subject's best response 
assignment will depend on the achievement of both measurement and confirmation 
criteria.
The following table presents the evaluation of best overall response for all possible 
combinations of tumor responses in target and non-target lesions with or without the 
appearance of new lesions.
Target Lesions
Non-Target Lesions
New Lesions
Overall Response
CR
CR
No
CR
CR
Incomplete response/SD
No
PR
PR
Non-PD
No
PR
SD
Non-PD
No
SD
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD
Any
Any
Yes
PD
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". 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 complete response depends on this 
determination, it is recommended that the residual lesion be investigated (fine needle 
aspirate/biopsy) to confirm the complete response status.
Confirmation Criteria

To be assigned a status of PR or CR, a confirmatory disease assessment should be 
performed no less than 28 days after the criteria for response are first met.

To be assigned a status of SD, follow-up measurements must have met the SD 
criteria at least once after study entry at a minimum interval of 12 weeks.
References:
Lencioni R, Llovet JM. Modified RECIST (mRECIST) assessment for hepatocellular 
carcinoma. Semin Liver Dis. Feb 2010;30(1):52-60.

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16.8.
Appendix 8: Pharmacogenetics (PGx)
PGx Research
PGx – Background
PGx is the study of variability in drug response due to hereditary factors in different 
populations.  There is increasing evidence that an individual's genetic composition (i.e., 
genotype) may impact the PK (absorption, distribution, metabolism, and elimination), PD 
(relationship between concentrations and pharmacologic effects or the time course of 
pharmacologic effects) and/or clinical outcome (in terms of efficacy and/or safety and 
tolerability). Some reported examples of PGx analysis include:
Drug
Disease
Gene
Outcome
Abacavir
HIV
[Hetherington, 
2002; Mallal, 
2002]
HLA-B*5701
Individuals with HLA-B*5701 variant may be at 
increased risk for experiencing hypersensitivity 
to abacavir.  Clinical assays are available for 
HLA-B*5701 but none has been validated. 
HLA-B*5701 screening would supplement but 
never replace abacavir clinical risk 
management strategies aimed at minimizing 
rare but serious outcomes associated with 
abacavir hypersensitivity.
Carbamazepin
e
Seizure, 
Bipolar 
disorders & 
Analgesia 
[Chung, 2010; 
Ferrell ,2008] 
HLA-B*1502
Independent studies indicated that patients of 
East Asian ancestry who carry HLA-B*15:02
are at higher risk of Stevens-Johnson 
Syndrome and toxic epidermal necrolysis.  
Regulators, including the US FDA and the 
Taiwanese TFDA, have updated the 
carbamazepine drug label to indicate that 
patients with ancestry in genetically at risk 
populations should be screened for the 
presence of HLA-B*1502 prior to initiating 
treatment with carbamazepine..
Warfarin
Cardiovascular
[Neergard, 
2006;
Wilke, 2005]
CYP2C9
SAEs experienced by some subjects on 
warfarin may be explained by variations in the 
CYP2C9 gene that influences the degree of 
anticoagulation achieved.

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Drug
Disease
Gene
Outcome
Irinotecan
Cancer
[FDA News 
Release, 
2005]
UGT1A1
Variations in the UGT1A1 gene can influence 
a patient’s ability to break down irinotecan, 
which can lead to increased blood levels of the 
drug and a higher risk of side effects. A dose 
of irinotecan that is safe for one patient with a 
particular UGT1A1 gene variation, might be 
too high for another subject without this 
variation, raising the risk of certain side 
effects.  A genetic blood test (Invader 
UGT1A1molecular assay) is available that can 
detect variations in the gene.
A key component to successful PGx research is the collection of samples during the 
conduct of clinical studies.
Regarding the pharmacology of GSK2849330, of specific interest are genetic 
polymorphisms of Fc receptors which modify affinity of the receptor(s) for binding to 
IgG antibodies [Hogarth, 2012]. FcγRIIIa polymorphisms have been described (Val158 
or Phe158) which exhibit different affinities for IgG and consequent downstream effector 
cell functionality such as ADCC. Furthermore, these polymorphisms are clinically 
important as they have been shown to affect the efficacy of therapeutic antibodies in 
patients [Hogarth, 2012].
Collection of whole blood may enable PGx analysis to be conducted if at any time it 
appears that there is a potential unexpected or unexplained variation in handling or 
response to GSK2849330.
PGx Research Objectives
The objective of the PGx research (if there is a potential unexpected or unexplained 
variation) is to investigate a possible genetic relationship to handling or response to 
GSK2849330.  If at any time it appears there is potential variability in response in this 
clinical study or in a series of clinical studies with GSK2849330 that may be attributable 
to genetic variations of subjects, the following objectives may be investigated:

Relationship between genetic variants and the PK and/or PD of study treatment

Relationship between genetic variants and safety and/or tolerability of study 
treatment

Relationship between genetic variants and efficacy of study treatment
Study Population
Any subject who has given informed consent to participate in the clinical study, has met 
all the entry criteria for the clinical study, and receives study treatment may take part in 
the PGx research.  Any subject who has received an allogeneic bone marrow transplant 
must be excluded from the PGx research.

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Subject participation in the PGx research is voluntary and refusal to participate will not 
indicate withdrawal from the clinical study.  Refusal to participate will involve no penalty 
or loss of benefits to which the subject would otherwise be entitled.
Study Assessments and Procedures
Blood samples can be taken for PGx assessments.
If taking blood samples: in addition to any blood samples taken for the clinical study, a 
whole blood sample (~10 mL) will be collected for the PGx research using a tube 
containing Ethylenediaminetetraacetic acid (EDTA).  It is recommended that the blood 
sample be taken at the first opportunity after a subject has been enrolled and provided 
informed consent for PGx research, but may be taken at any time while the subject is 
participating in the clinical study.
The PGx sample is labeled (or “coded”) with a study specific number that can be traced 
or linked back to the subject by the investigator or site staff. Coded samples do not carry 
personal identifiers (such as name or social security number). The blood sample is taken 
on a single occasion unless a duplicate sample is required due to inability to utilize the 
original sample.
The DNA extracted from the blood sample may be subjected to sample quality control 
analysis. This analysis will involve the genotyping of several genetic markers to confirm 
the integrity of individual samples. If inconsistencies are noted in the analysis, then those 
samples may be destroyed.
The need to conduct PGx analysis may be identified after a study (or set of studies) of 
GSK2849330 has been completed and the study data reviewed. In some cases, the 
samples may not be studied. e.g., no questions are raised about how people respond to 
GSK2849330.
Samples will be stored securely and may be kept for up to 15 years after the last subject 
completes the study or GSK may destroy the samples sooner. GSK or those working with 
GSK (for example, other researchers) will use samples collected from the study for the 
purpose stated in this protocol and in the informed consent form.
Subjects can request their sample to be destroyed at any time.
Subject Withdrawal from Study
If a subject who has consented to participate in PGx research and has a sample taken for 
PGx research withdraws from the clinical study for any reason other than lost to follow-
up, the subject will be given the following options:

The sample is retained for PGx research.

Any PGx sample is destroyed.

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If a subject withdraws consent from the PGx research or requests sample destruction for 
any reason, the investigator must complete the appropriate documentation to request 
sample destruction within the timeframe specified by GSK and maintain the 
documentation in the site study records.  In either case, GSK will only keep study
information collected/generated up to that point.
Screen and Baseline Failures
If a blood sample for PGx research has been collected and it is determined that the 
subject does not meet the entry criteria for participation in the clinical study, then the 
investigator must complete the appropriate documentation to request sample destruction 
within the timeframe specified by GSK and maintain the documentation in the site study 
records.
PGx Analyses
Specific sections of DNA may be selected from areas of the genome (e.g., candidate 
genes) known to encode the drug target, drug metabolizing enzymes, areas associated 
with mechanisms underlying AEs, and those linked to study disease and, thus, linked to 
drug response.
The candidate genes that may be investigated in this study include the following: the 
GSK Absorption, Distribution, Metabolism and Excretion genes. These play a central 
role in drug PK and PD.  In addition, continuing research may identify other enzymes, 
transporters, proteins, or receptors that may be involved in response to GSK2849330.  
The genes that may code for these proteins may also be studied.
Genome-wide scans involving a large number of polymorphic markers (e.g., single 
nucleotide polymorphisms) located throughout the genome. This approach is often 
employed when potential genetic effects are not well understood.
The results of PGx investigations will be reported either as part of the main clinical study 
report or as a separate report.  All endpoints of interest from all comparisons will be 
descriptively and/or graphically summarized as appropriate to the data. In all cases, 
appropriate statistical methods will be used to analyze the genetic markers in the context 
of other clinical data.  Statistical methods may include, but are not limited to Hardy-
Weinberg Equilibrium testing, Comparison of Demographic and Baseline Characteristics 
by Genotype, Evaluation of Genotypic Effects, Evaluation of Treatment by Genotype and 
Gene-Gene Interaction, Linkage Disequilibrium, Multiple Comparison and Multiplicity 
and/or Power and Sample Size Considerations.  Detailed description of the analyses to be 
conducted will be documented in the PGx RAP.
Informed Consent
Subjects who do not wish to participate in the PGx research may still participate in the 
clinical study.  PGx informed consent must be obtained prior to any blood/saliva being 
taken for PGx research.

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Provision of Study Results and Confidentiality of Subject’s PGx Data
GSK may summarize the cumulative PGx research results in the CSR.
In general, GSK does not inform the investigator, subject or anyone else (e.g., family 
members, study investigators, primary care physicians, insurers, or employers) of the 
PGx research results unless required by law.  The information generated from PGx 
research is preliminary in nature, and the significance and scientific validity of the results 
are undetermined at such an early stage of research.
References
Chung WH, Hung SL, Chen YT. Genetic predisposition of life-threatening antiepileptic-
induced skin reactions.  Expert Opin. Drug Saf. 2010; 9: 15-21.
Ferrell PB, McLeod HL.  Carbamazepine, HLA-B*1502 and risk of Stevens-Johnson 
syndrome and toxic epidermal necrolysis: US FDA recommendations.  
Pharmacogenomics. 2008; 9: 1543-46.
Hetherington S, Hughes AR, Mosteller M, Shortino D, Baker KL, Spreen W, Lai E, 
Davies K, Handley A, Dow DJ, Fling ME, Stocum M, Bowman C, Thurmond LM, Roses 
AD. Genetic variations in HLA-B region and hypersensitivity reactions to abacavir. 
Lancet. 2002; 359:1121-2.
Hogarth PM, Pietersz GA. Fc receptor-targeted therapies for the treatment of 
inflammation, cancer and beyond. Nat Rev Drug Discov. Apr 2012;11(4):311-331.
Mallal S, Nolan D, Witt C, Masel G, Martin AM, Moore C, Sayer D, Castley A, Mamotte 
C, Maxwell D, James I. Association between presence of HLA-B*5701, HLA-DR7, and 
HLA-DQ3 and hypersensitivity to HIV-1 reverse-transcriptase inhibitor abacavir. Lancet. 
2002; 359:727-32.
Neergard. Reducing the risk of blood thinners. Associated press, September 2006. 
U.S. Food and Drug Administration, FDA Clears Genetic Test That Advances 
Personalized Medicine Test Helps Determine Safety of Drug Therapy 22 August 2005, 
http://www.fda.gov/bbs/topics/NEWS/2005/NEW01220.html
Wilke RA, Musana AK, Weber WW. Cytochrome P450 gene-based drug prescribing, 
and factors impacting translation into routine clinical practice. Personalized Med. 2005; 
2: 213–224.

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16.9.
Appendix 9: Management of Diarrhea
In rare cases, diarrhea can be debilitating, and potentially life threatening if accompanied 
by dehydration, renal insufficiency, and/or electrolyte imbalances.
Standardized and universal guidelines have been developed by an American Society of 
Clinical Oncology (ASCO) panel for treating chemotherapy-induced diarrhea (Benson, 
2004). Presented in the sections below are the recommended guidelines for the 
management of diarrhea published by the ASCO panel (Benson, 2004).
Early identification and intervention is critical for the optimal management of diarrhea.  
A subject’s baseline bowel patterns should be established so that changes in patterns can 
be identified while subject is on treatment.
Subjects should be instructed to first notify their physician/healthcare provider at 
onset of diarrhea of any severity.
An assessment of frequency, consistency and duration as well as knowledge of other 
symptoms such as fever, cramping, pain, nausea, vomiting, dizziness and thirst should be 
taken at baseline. Consequently subjects at high risk of diarrhea can be identified.  
Subjects should be educated on signs and symptoms of diarrhea with instructions to 
report any changes in bowel patterns to the physician.
It is recommended that subjects keep a diary and record the number of diarrhea episodes 
and its characteristics. They should also include information on any dietary changes or 
other observations such as over the counter (OTC) medications, including herbal 
supplements, that may be useful in the evaluation of their diarrhea history.
Definitions
National Cancer Institute (NCI) guidelines define diarrhea compared to baseline (Table 
19).
Table 19
Grading of Diarrhea
Adverse 
Event Grade
Diarrhea
1
Increase of <4 stools/day over baseline; mild increase in ostomy output compared 
to baseline
2
Increase of 4-6 stools/day over baseline; moderate increase in ostomy output 
compared to baseline;
3
Increase of ≥7 stools/day over baseline; incontinence; hospitalization indicated; 
severe increase in ostomy output compared to baseline; limiting self care activities 
of daily living (ADL)
4
Life-threatening consequences; urgent intervention indicated
5
Death

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Uncomplicated diarrhea is considered mild-to-moderate and defined as CTCAE 
Grade 1 or 2 with no complicating signs or symptoms.
Complicated diarrhea is severe and defined as any CTCAE Grade 3 or 4 diarrhea, or 
Grade 1 or 2 with one or more of the following signs or symptoms:

Moderate to severe abdominal cramping 

Nausea/vomiting ≥Grade 2

Decreased performance status

Fever

Sepsis

Neutropenia

Frank bleeding (red blood in stool)

Dehydration
Management of Uncomplicated Mild to Moderate Diarrhea
Recommendation: Initial management of mild to moderate diarrhea should include 
dietary modifications (e.g., eliminating all lactose-containing products and high osmolar 
dietary supplements), and the patient should be instructed to record the number of stools 
and report symptoms of life-threatening sequelae (e.g., fever or dizziness on standing). 
Loperamide should be started at an initial dose of 4 mg followed by 2 mg every 4 hours 
or after every unformed stool (not to exceed 16 mg/day).
If diarrhea resolves with loperamide, the patients should be instructed to continue dietary 
modifications and to gradually add solid foods to their diet. In the case of chemotherapy-
induced diarrhea, patients may discontinue loperamide when they have been diarrhea-free 
for at least 12 hours.
If mild to moderate diarrhea persists for more than 24 hours, the dose of loperamide 
should be increased to 2 mg every 2 hours, and oral antibiotics may be started as 
prophylaxis for infection.
If mild to moderate chemotherapy-induced diarrhea has not resolved after 24 hours on 
high-dose loperamide (48 hours total treatment with loperamide), it should be 
discontinued and the patient should be started on a second-line antidiarrheal agent such as 
subcutaneous (SC) octreotide (100- to 150-g starting dose, with dose escalation as 
needed) or other second-line agents (e.g., oral budesonide or tincture of opium). In the 
case of chemotherapy-induced diarrhea, the patient should be seen in the physician’s 
office or outpatient center for further evaluation, including complete stool and blood 
work-up. Stool work-up should include evaluation for pathogens. Fluids and electrolytes 
should be replaced as needed.

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Aggressive Management of Complicated Cases
Recommendation: Aggressive management of complicated cases should involve IV 
fluids; octreotide at a starting dose of 100 to 150 g SC tid or IV (25 to 50 g/h) if the 
patient is severely dehydrated, with dose escalation up to 500 g until diarrhea is 
controlled, and administration of antibiotics (e.g., fluoroquinolone). This may require 
admission to the hospital; for select patients, diarrhea may be managed with intensive 
home nursing or in a day hospital. Stool work-up (evaluation for blood, fecal leukocytes, 
C. difficile, Salmonella, Escherichia coli, Campylobacter, and infectious colitis), 
complete blood count, and electrolyte profile should be performed. This may not be 
appropriate for radiotherapy-induced diarrhea. Any patient with chemotherapy-induced 
diarrhea who progresses to Grade 3 or 4 diarrhea after 24 or 48 hours on loperamide 
should also be treated as described above. Continue intervention as described until the 
patient has been diarrhea-free for 24 hours.
These recommendations for the aggressive management of complicated cases of 
chemotherapy-induced diarrhea are based on evidence that the GI syndrome is an 
indicator that the patient may be at serious risk for dehydration and/or infection and other 
potentially life-threatening complications. Moreover, loperamide, even at high-doses, 
may be less effective in patients with Grade 3 or 4 diarrhea. Therefore, it is appropriate to 
start immediate octreotide therapy (either SC or IV if the patient is already severely 
dehydrated) along with antibiotics.

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Figure 2
Algorithm for the management of diarrhea
References
1. Benson A, Jaffer AA, Catalano RB, et al.  recommended guidelines for the treatment 
of cancer treatment-inducted diarrhea.  Journal of Clinical Oncology. 2004; 22:2918-
2926.
2. National Cancer Institute. Nutrition in cancer care (PDQ®). 
http://www.cancer.gov/cancertopics/pdq/supportivecare/nutrition/Subject.

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16.10.
Appendix 10: Protocol Amendment Changes
Amendment 1
Where the Amendment Applies
This amendment applies to all sites and countries.
Summary of Amendment Changes with Rationale
Typographical and formatting errors have been corrected and minor clarifications have 
been made throughout the document. These corrections have not been listed in this 
appendix, unless the correction changed the context or meaning of the text.
Addition of Groups to Part 2 and Changes to Inclusion and Exclusion Criteria
Four molecularly-defined, tumor histology groups were added for study during Part 2: 
Group 1 will include subjects with HER3-expressing melanoma, Group 2 will include 
subjects with HER3-expressing gastric/gastroesophageal cancer, Group 3 will include 
subjects with HER3 and NRG1-expressing cancers of the head and neck, and Group 4 
will include subjects with HER3 and NRG1-expressing non-small cell lung carcinoma 
(NSCLC).
Additional inclusion criteria for subjects in Part 2 were added to clarify the number of 
prior lines of therapy allowed for study entry and to require subjects to undergo pre and 
on-treatment tumor biopsies.
Additional tumor histology groups of subjects predicted to be sensitive to the study drug 
based on emerging biomarkers may be added 
References to cohorts of subjects in Part 2 were removed and replaced with groups of 
subjects as subjects.
The exclusion criteria for subjects with untreated brain or meningeal metastases and 
subjects treated for stable brain metastases were clarified.
Sample Size, Power, and Stopping Rules
The approximate number of subjects in Part 1 was changed from 10 to 13, to 
accommodate the additional weekly cohort. The anticipated number of subjects in Part 1 
is now 34.
New Cohort in Part 1
An additional cohort of subjects was added to Part 1. This cohort will receive weekly 
treatment with 30 mg/kg GSK2949330, with an option to reduce dosing frequency to 
every 2 weeks after 24 weeks.

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Concomitant Medications
Permitted and prohibited medications (growth factors, anticoagulants, and 
corticosteroids) were clarified.
Pharmacokinetic Parameters and Sampling Times
A rationale for adding a weekly dosing regimen was added.
PK sampling times were revised for subjects in Part 1enrolled under this amendment and 
for subjects enrolled in Part 2.
The predicted half-life of GSK2849330 was changed from 8-9 days to 7 days at 
30 mg/kg. The expected dosing frequency was changed from 2 weeks to 1-2 weeks.
Preliminary noncompartmental and population PK parameters for the 1.4 mg/kg, 
3 mg/kg, and 10 mg/kg doses were added.
Efficacy Population
An Efficacy Population was defined.
New Nonclinical and Preclinical Findings
Recent findings on the biodistribution of GSK2849330 in mice were added.
Preclinical and nonclinical findings on HER3 antibodies from recent studies and abstracts 
were added, including the rationale for the tumor types selected for Part 2.
Study Completion
The definitions for subject and study completion were clarified.
Disease Assessment
The timing for disease assessment at the end of the study was clarified.
Serum Samples for Immunogenicity
The timing for serum samples for immunogenicity at the end of the study was clarified.
Management of Diarrhea and other Toxicities
The recommendations for management of diarrhea were expanded.
Infusion Reactions
The requirement for a sample for selected cytokines in subjects experiencing suspected 
infusion-related reactions was added.

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Vials and Preparation of Investigational Product
Vials containing 5 mL of investigational product were introduced, and 1-mL vials will 
also continue to be used.
Safety Assessments
Clarification regarding ECHO as the preferred method of LVEF assessment has been 
added.
The criterion for withholding of study treatment for QTc prolongation was clarified.
List of Specific Changes
Title Page, Description
REVISED TEXT (new text bold and underlined, deleted text in strikethrough)
This is a Phase I, first time in human (FTIH), open-label, multi-center, dose-escalation 
study of the anti-HER3 monoclonal antibody, GSK2849330 administered to subjects with 
HER3-expressing or HER3 and NRG1-expressing solid tumors. The study will be 
conducted in two parts. Part 1 will include dose escalation and pharmacokinetic (PK)/ 
pharmacodynamic (PD) cohorts to evaluate safety, PK, and PD to guide selection of dose 
regimen(s) for Part 2. Part 2 will include up to 3 cohorts which may include tumor type 
specific cohorts and/or a histology-independent cohort of subjectsPart 2 will include at 
least 4 molecularly-defined tumor histology groups that will be studied to further 
characterize safety, PK, PD, and evaluate initial clinical activity of GSK2849330.
Title Page, Authors
REVISED TEXT (new text bold and underlined, deleted text in strikethrough)
Oncology R&D, UP, USA
Global Clinical Safety & Pharmacovigilance, USA
Biopharm R&D, Stevenage, UK
Oncology R&D, UP, USA
Projects Clinical Platforms and Sciences, RTP, 
USA
Oncology Biomarkers, UP, USA
Biopharm Clinical Pharmacologyand Biometrics, UM, 
USA
Global Clinical Operational Sciences, RTP, USA
Biopharm R&D, UM, USA
Global Oncology Data Sciences, RTP, USA
Biopharm R&D, UM, USA
Oncology R&D, UP, USA
Oncology Clinical Statistics, UP, USA
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD

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Sponsor Signatory
REVISED TEXT (new text bold and underlined, deleted text in strikethrough)
Mark J. Cornfeld, M.D., MPH
Li Yan, MD, PhD
Sponsor/Medical Monitor Information Page
REVISED TEXT (new text bold and underlined, deleted text in strikethrough)
Role
Name
Day Time 
Phone 
Number
After-hours 
Phone/Cell/
Pager 
Number
Fax Number
GSK Address
Primary 
Medical 
Monitor
 MD
 
MD
1250 South Collegeville Road
Mailstop UP4400UP4410
Collegeville, PA 19426, USA
Secondary 
Medical 
Monitor
MD
 
 
 
709 Swedeland Road
King of Prussia, PA 19406
Gunnels Wood Road
Stevenage Herts, SG1 2NY
Tertiary 
Medical 
Monitor
MD, 
PhD
1250 South Collegeville 
Road
Mailstop UP4410
Collegeville, PA 19426, USA
Protocol Synopsis, Study Rationale
REVISED TEXT (new text bold and underlined, deleted text in strikethrough
GSK2849330 is a humanized glycol-engineered IgG1/IgG3 mAb with enhanced Fc-
effector function potency, directed against HER3 (Erb3), a signalling and drug resistance 
target expressed on a wide range of solid tumors. This FTIH, open-label, dose escalation 
study will assess the safety, PK, PD, and preliminary clinical effect of GSK2849330 in 
subjects with HER3-expressing or HER3 and NRG1 expressing solid tumors.
Protocol Synopsis, Study Objectives, Endpoints and Hypotheses
REVISED TEXT (new text bold and underlined, deleted text in strikethrough)
Primary Objective Part 2:
To evaluate the safety of GSK2849330 in a larger cohort population of subjects in 
molecularly-defined tumor histology groups at the dose regimen(s) recommended for 
further exploration in Part 1.
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD

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Exploratory Objectives Part 2:
To explore relationship between pre-treatment HER3 or HER3/NRG1 expression levels
and clinical outcome.
Exploratory Endpoint Part 2
Progression-free survival (PFS), ORR according to immune-related response criteria 
(irRC) ad modified Response Evaluation Criteria in Solid Tumors (mRECIST) where 
applicable, and other tumor markers and measures of clinical benefit.
Protocol Synopsis, Study Design
REVISED TEXT (new text bold and underlined, deleted text in strikethrough)
This is a FTIH, open-label, dose-escalation study of GSK2849330 administered to 
subjects with HER3-expressing or HER3 and NRG1 expressing solid tumors. The study 
will be conducted in two parts.
Part 1 will include dose escalation and PK/PD cohorts to evaluate safety and PK and PD 
to guide selection of dose regimen(s) for Part 2.
The starting dose is 1.4 mg/kg, administered once-weekly, to be studied in a single 
patient (Cohort 1).  If no DLTs are observed, dose escalation will progress to 3, 10, and 
30 mg/kg, at a planned dosing frequency of every two weeks, followed by a 30 mg/kg 
weekly cohort with three subjects studied at each dose level (except 1.4 mg/kg).  In the 
cohort treated with 30 mg/kg/wk, the option to reduce the dosing frequency to every 
2 weeks after 24 weeks of treatment may be exercised. The study team, in discussion 
with the investigator(s), may select lower doses or alternative schedules besides 
those listed above, based on emerging safety, tolerability and PK findings.
The occurrence of any DLTs will be evaluated using a Neuenschwander-Continuous 
Reassessment Method (N-CRM) to provide a model-based recommendation for dose 
escalation decisions.  Dose escalation decisions, and any modifications to the proposed 
nominal dose levels or interval, will be based principally on review of safety data, 
including the output from the N-CRM, and will be supported by review of available PK 
and PD data.
Once a dose escalation cohort has been filled, additional subjects may be enrolled into the 
PK/PD cohorts (at any dose level determined to be tolerable).  Subjects in the PK/PD 
cohort must consent to a pre- and on-treatment biopsy, which will provide information on 
target engagement and tumor-based PD markers.  Blood samples will be obtained to 
evaluate GSK2849330 PK and circulating PD markers.  Safety, PK and PD data from 
Part 1 will be used to support the dose regimen selection for Part 2  
In Part 2, up to 3 cohorts which may include tumor type specific cohorts and/or a 
histology-independent cohort of subjects,at least 4 molecularly-defined tumor 
histology groups will be enrolled at the dose regimen(s) selected based on Part 1 data.  
The objective of Part 2 is to evaluate safety in a larger cohortpopulation in molecularly 

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defined, tumor histology groups of subjects at the recommended dose regimen, Part 2 
will and also to evaluate PD markers in paired tumor biopsies and assess preliminary 
evidence of clinical benefit.  Selection of the tumor types for focus in Part 2  will bewas
based on available preclinical and external data. and relevant PD and initial clinical 
benefit information gained from Part 1.
Protocol Synopsis, Number of Subjects
REVISED TEXT (new text bold and underlined, deleted text in strikethrough)
Part 1:  Approximately 10 13 subjects will be enrolled to complete the planned dose 
escalation.  If DLTs are observed, additional subjects may be enrolled in dose escalation 
to establish the MTD or the dose for further exploration in Part 2, as guided by the N-
CRM.  A target minimum of 9 additional subjects and a target maximum of 21 subjects 
with evaluable pre- and on-treatment tumor biopsies will be enrolled in the PK/PD 
cohorts. Additional subjects may be enrolled, if warranted, to provide sufficient safety, 
PK, or PD data to select the recommended dose for study in Part
Part 2:  A minimum of 12 and a maximum of 30 subjects will be enrolled in each 
expansion cohort in Part 2 of the groups.  Up to 3 expansion cohorts will be studied.  
Futility criteria will be evaluated as data accrues; enrollment in a cohort will be halted if 
futility criteria conditions are met for that cohort.  Futility criteria will be evaluated as 
data accrues, and enrollment in a group will be halted if futility criteria conditions 
are met for that group.
Protocol Synopsis, Inclusion/Exclusion Criteria
REVISED TEXT (new text bold and underlined, deleted text in strikethrough)
Pre-screening Inclusion Criteria for Parts 1 and 2
Subjects will be eligible for inclusion in pre-screening for the study (See Section 3.2) 
only if all of the following criteria apply:
1. Males and females ≥18 years of age (at the time consent is obtained).
2. Written informed consent provided.
3. Performance Status score of 0 or 1 according to the Eastern Cooperative 
Oncology Group (ECOG) scale (see Appendix 3).
4. Sufficient archival tumor specimen is available for HER3 IHC analysis, or subject 
is willing to undergo a fresh tumor biopsy for HER3 IHC analysis (see Section 
7.6.1.1 for details).
5. Histologically or cytologically confirmed diagnosis of one of the following solid 
tumor malignancies for which no standard therapeutic alternatives exist:

Bladder cancer

Breast cancer

Castrate-resistant prostate cancer

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
Cervical cancer

Colorectal cancer (CRC)

Gastric cancer

Hepatocellular carcinoma (HCC)

Melanoma

Non-small cell lung cancer (NSCLC)

Ovarian cancer

Pancreatic cancer

Squamous cell cancers of the head and neck region (SCCHN)(including 
parotid and nasopharynx)
Pre-screening for Part 2
Subjects with either melanoma, gastric/gastroesophageal cancer, head and neck 
cancer, or NSCLC who appear to meet all inclusion and exclusion criteria may be 
pre-screened for the study provided that sufficient tumor specimen is available for 
analyzing HER3 by IHC or HER3 by IHC and NRG1 by RNA analysis.
Protocol Synopsis, Screening Inclusion Criteria for Parts 1 and 2, Criterion 3
REVISED TEXT (new text bold and underlined, deleted text in strikethrough)
3. For subjects enrolled in Part 1:subjects Subjects must have tumors with 
documented HER3 expression (2+ or 3+) on the cell surface of the invasive 
component of tumor (either on archival tissue or fresh tumor biopsy) using an 
analytically validated IHC assay by central laboratory (see Section 7.6.1.1 for 
details). Subjects enrolled in Part 2 must meet inclusion criterion 9 listed 
below.
Protocol Synopsis, Screening Inclusion Criteria for Parts 1 and 2, Criterion 5,
REVISED TEXT (new text bold and underlined, deleted text in strikethrough)
5. Adequate baseline organ function defined by: 
SYSTEM
LABORATORY VALUES
Hematologic
  ANC
1.5 x 109/L
  Hemoglobin
9 g/dL 
  Platelets
75 x 109/L
 PT/INR and PTT  
1.3x ULN
Hepatic
  Albumin
2.5 g/dL
  Total bilirubin
1.5 X ULN 
 AST and ALT
2.5 X ULN

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SYSTEM
LABORATORY VALUES
Renal
Serum creatinine
OR
Estimated glomerular 
filtration rate or 24-hr 
urine creatinine 
clearancea
ULN
OR
50 mL/min
Cardiac
LVEF
50% by ECHO or MUGAb
a.
Estimated glomerular filtration as calculated 
by the Modification of Diet in Renal Disease 
(MDRD) equation (Appendix 4). When both a 
calculated and 24-hr creatinine clearance are 
available, the 24-hr value will be used.
b.
ECHO is the preferred method. MUGA 
should be performed only if evaluation by 
ECHO is not available.
Protocol Synopsis, Inclusion Criteria for Part 2 ONLY
NEW TEXT (new text bold and underlined, deleted text in strikethrough)
As listed above for Part 1, with the exception of criterion 3 which should be replaced 
with the following criterion 9 and the addition of criteria 10 and 11.
Criterion 9
9. For Group 1: subjects with previously treated, unresectable stage III or IV 
melanoma with documented HER3 expression (3+) on the cell surface of the 
invasive component of the tumor (either on archival tumor or fresh tumor 
biopsy) using an analytically validated IHC assay by central laboratory.

Subjects must have no more than 3 prior lines of systemic regimens 
and have disease progression on or after last prior treatment (based 
on RECIST v1.1 ).

Subjects with BRAF V600 mutations who already received or 
were intolerant of prior BRAF inhibitor therapy may be 
included. BRAF V600 inhibitor-naïve subjects will be eligible if 
a BRAF inhibitor is not available to them commercially or via 
a clinical trial.

Subjects may be included if they had prior immune therapy, 
were intolerant of prior immune therapy, or if such therapy is 
not available to them commercially or via a clinical trial.

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For Group 2: Subjects with previously treated, unresectable stage III or IV 
gastric or gastroesophageal junction (GEJ) adenocarcinoma with 
documented HER3 expression (3+) on the cell surface of the invasive 
component of the tumor (either on archival tumor or fresh tumor biopsy) 
using an analytically validated IHC assay by central laboratory.

Subjects must have no more than 3 prior lines of systemic regimens 
and have disease progression on or after last prior treatment (based 
on RECIST v1.1.).

Subjects with HER2 positive disease may be included if they had prior 
anti-HER2 therapy or were intolerant of prior anti-HER2 therapy or 
if such therapy is not available to them commercially or via a clinical 
trial.
For Group 3: Subjects with previously treated, unresectable stage III or IV 
cancers of the head and neck with documented HER3 expression ( 1+) and 
NRG1 expression on the cell surface of the tumor (either on archival tumor 
or fresh tumor biopsy) using analytically validated assays by central 
laboratory.

Subjects must have no more than 3 prior lines of systemic therapy and 
have disease progression on or after last prior treatment (based on 
RECIST v1.1 ).

Subjects with locoregional recurrences amenable to definite surgery 
or additional radiation are excluded.
For Group 4: Subjects with previously treated, unresectable stage III or IV 
NSCLC with documented HER3 expression ( 1+) and NRG1 expression on 
the cell surface of the tumor (either on archival tumor or fresh tumor biopsy) 
using analytically validated assays by central laboratory.

Subjects must have no more than 3 prior lines of systemic regimens 
and have disease progression on or after last prior treatment (based 
on RECIST v1.1. ).

Subjects with anaplastic lymphoma kinase (ALK) translocation who 
already received or were intolerant of prior anti-ALK therapy may be 
included.Anti-ALK therapy-naïve subjects will be eligible for the 
study if such a therapy is not available to them commercially or via a 
clinical trial.

Subjects with EGFR mutations (e.g., exon 19 deletion and exon 21 
L858R) who have documented progression (based on RECIST 1.1 
criteria) or who were intolerant of prior EGFR inhibitors may be 
included. EGFR inhibitor-naive subjects will be eligible for the study 
if such a therapy is not available to them commercially or via a 
clinical trial.

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Additional groups of subjects predicted to be sensitive to the study drug 
based on biomarker (eg, HER3 mutations, NRG fusions) identified with 
preclinical or clinical data may be added based on emerging data.
Criterion 10
Subjects must have at least one measurable lesion per RECIST v1.1.
NOTE: If the only site of measurable disease has been previously irradiated, 
documented progression of disease and a 4-week interval since completion of 
radiotherapy is required.
NOTE: In subjects with 1 measurable lesion, a measurable lesion may be 
biopsied at Screening and Day 15; however that lesion must not be selected 
as a target lesion for disease assessment.
Criterion 11
Subjects must have disease amendable to biopsy and agree to undergo pre-
and on-treatment tumor biopsies (until the participating centers receive 
written notification from the Sponsor that paired tumor biopsies are no 
longer required for any/all groups).
Protocol Synopsis, Screening Exclusion Criteria Parts 1 and 2, Criterion 1
REVISED TEXT (new text bold and underlined, deleted text in strikethrough)
1. Subjects with leptomeningeal or brain metastases or spinal cord compression.

Subjects with untreated brain or meningeal metastases are not eligible 
(computed tomography [CT] scans are not required to rule this out 
unless there is a clinical suspicion of central nervous system [CNS] 
disease).

Subjects with treated and radiologic or clinical evidence of stable 
brain metastases (confirmed by 2 scans at least 4 weeks apart), with 
no evidence of cavitation or hemorrhage in the brain lesion are 
eligible providing that they are asymptomatic and do not require 
corticosteroids. Subjects are not permitted to receive enzyme inducing 
anti-epileptic drugs.
Protocol Synopsis, Screening Exclusion Criteria Parts 1 and 2, Criterion 3
REVISED TEXT (new text bold and underlined, deleted text in strikethrough)
3. Use of an investigational anti-cancer drug within 28 days or 5 half-lives, 
whichever is longer, preceding the first dose of GSK2849330 OR chemotherapy 
within the last 3 weeks (6 weeks for prior nitrosourea or mitomycin C) OR any 
major surgery, radiotherapy, immunotherapy or any other anti-cancer therapy 
within the last 4 weeks except as noted above.

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Protocol Synopsis, Screening Exclusion Criteria Parts 1 and 2, Criterion 7
REVISED TEXT (new text bold and underlined, deleted text in strikethrough)
14. History or evidence of significant cardiovascular risk including any of the following:

LVEF<50%

A QT interval corrected for HR using Fredericia’s formula (QTcF) 480 msec 
(≥500 msec for subjects with bundle branch block)

History or evidence of current clinically significant uncontrolled arrhythmias.
Exception: Subjects with controlled atrial fibrillation for >30 days prior to 
enrollment are eligible.

History of acute coronary syndromes (including myocardial infarction and unstable 
angina), coronary angioplasty, or stenting within 6 months prior to enrollment.

History or evidence of current ≥ Class II congestive heart failure as defined by New 
York Heart Association (NYHA).
Protocol Synopsis, Pharmacokinetic/Pharmacodynamic Assessments
REVISED TEXT (new text bold and underlined, deleted text in strikethrough)
For all subjects in the dose escalation cohorts in Part 1, blood samples for analysis of 
GSK2849330 concentrations will be collected on Day 1: pre-dose and at 1 hour and 
6 hours after the end of infusion and at Day 8, Day 15, and Day 29 after the first dose of 
GSK2849330. If a subject’s duration of infusion is 3 hours or longer, the 6 hour time 
point is optional.  On days of dosing, the sample will be drawn pre-dose. Additionally the 
first subject in Cohort 1 will have PK samples taken at 24 hours (Day 2) and 72 hours 
(Day 4) after the end of infusion.
For cohorts enrolled under Amendment 1 of this protocol, more frequent PK 
samples will be collected including: On Day 1 pre-dose, 1 hour, 6 hours and 
24 hours after the end of infusion. Pre-dose samples will be collected on Day 4, 
Day 8 and weekly through Day 57 with additional 1 hour post-dose samples 
collected on Days 29 and 57.  Pre-dose samples will also be collected on Day 71, 
Day 85, and every 12 weeks thereafter.
For all subjects in the Part 1 PK/PD cohorts, blood samples for analysis of GSK2849330 
concentrations will be collected on Day 1 pre-dose, and at 1 hour, 6 hours and 
24 hours after the end of infusion. Pre-dose samples will be collected on Day 4, 
Day 8 and weekly through Day 57 with additional 1 hour post-dose samples 
collected on Days 28 and 57.  Pre-dose samples will also be collected on Day 71, 
Day 85, and every 12 weeks thereafter. and 1 hr and 6 hr after the end of infusion and 
at 24 hr (Day 2), 72 hr (day 4), and 168 hr (Day 8) after the end of infusion. If a subject’s 
duration of infusion is 3 hours or longer the 6 hr time point is optional. Additional PK 
samples will be drawn pre-dose on Days 22 and 43 (after the first dose) for subjects on an 
every 3 week dosing schedule or pre-dose on Days 15 and 29 (after the first dose) for 
subjects on an every 2 week dosing schedule.

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If a subject’s duration of infusion is 3 hours or longer the 6 hour time point is 
optional.
For the expansion cohorts subjects enrolled in Part 2, blood samples for analysis of 
GSK2849330 concentrations will be collected on Day 1: pre-dose and at 1 hour after the 
end of infusion; and pre-dose on Day 15, Day 29, day 43, Day 57, Day 85, and every 
12 weeks thereafter. with an additional PK sample pre-dose on Days 22 and 43 (after the 
first dose) for subjects on an every 3 week dosing schedule or pre-dose on Days 15 and 
29 (after the first dose) for subjects on an every 2 week dosing schedule.
For all subjects in Part 1 and Part 2, additional PK samples will also be taken every 12 
weeks from the first dose within 1 year of starting treatment and if treatment continues 
after beyond 1 year, samples will be collected every 24 weeks. An additional PK sample 
will also be taken 45 days or 5 half lives (whichever is longer) after the last dose of study 
treatment.  Unless stated otherwise, onOn days of dosing, PK samples will be drawn 
pre-dose.
Blood samples will also be collected pre-dose, during treatment, and at disease 
progression to explore circulating markers of PD activity according to the schedule 
outlined in the Time and Events Tables (Section 7.1).
Samples for immunogenicity assessment will be obtained according to the schedule 
outlined in the Time and Events Tables (Section 7.1).
Protocol Synopsis, Statistical Methods
REVISED TEXT (new text bold and underlined, deleted text in strikethrough)
The total number of subjects in the Part 1 dose escalation will depend on the number of 
dose escalations needed, but the minimum number of subjects anticipated to complete 
dose escalation is 1013. A target minimum of 9 additional subjects and a target maximum 
of 21 additional subjects with evaluable pre- and on-treatment tumor biopsies willmay be 
enrolled in the PK/PD cohorts.  Cohort size is based on feasibility and the objective to 
provide an initial characterization of safety and PK/PD information that will inform dose 
regimen selection for Part 2. 
In Part 2, at least 12 and up to 30 subjects will be enrolled in each expansion 
cohortgroup.  Each cohortgroup in Part 2 will include a futility analysis, whereby no 
additional subjects will be enrolled in a cohort group if futility criteria are met, as 
defined in Section 13.6.2. 
The null hypothesis is:
H0:  p 10%
The alternative hypothesis is:
H0:  p 30%

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Starting with a cohortgroup of 12 subjects and allowing for a maximum sample size of 
30, this design will have a type I error rate (α) of 0.15 and 94 % power. CohortGroup
enrollment is will be stopped early for futility if the predictive probability of success is 
less than 6 %.The Bayesian Prior was Beta (0.2, 0.8), a weak prior with a mean response 
rate of 20%. The cohortgroup outcome will be declared successful if the posterior 
probability of (P>0.10 observed data) is ≥ 80%.
Under the null hypothesis, the expected sample size is 20 subjects and the probability of 
early termination is 77 %. Under the alternative hypothesis, the expected sample size is 
29 subjects and the probability of early termination is 5 %.
The All Treated Population is defined as all subjects who receive at least one dose of 
GSK2849330. Safety and clinical activity will be evaluated based on this analysis 
population.
The Efficacy Population will consist of all subjects from the All Treated Population 
for whom at least one post-dose tumor assessment by CT scan has been performed.
The PK Population will consist of all subjects from the All Treated Population for whom 
at least one post-dose PK sample is obtained and analyzed.
Additional details of the statistical analysis plan will be provided in the reporting and 
analysis plan (RAP).
Section 1.2.1, 1st paragraph
REVISED TEXT (new text bold and underlined, deleted text in strikethrough)
An overview of the pre-clinical studies of GSK2849330 is provided below.  Detailed 
information concerning the biology, pharmacology, pharmacokinetics (PK), and safety 
can be found in the Investigators’ Brochure (IB) [GlaxoSmithKline Document number 
2013N168399_01].
GSK2849330 is a humanized IgG1/IgG3 monoclonal antibody (mAb) with a molecular 
mass of approximately 145 kDa.  GSK2849330 selectively binds HER3 at Domain III 
which resides in the extracellular domain (ECD) of the protein. HER3 sequences are 99% 
identical (99% homologous) between human and cynomolgus monkey, and 91% identical 
(94% homologous) between human and rat or mouse. The binding affinity of 
GSK2849330 for HER3 across these species is comparable: human: 2.1 nM; cynomolgus 
monkey: 1.7 nM; mouse: 4.1 nM; rat: 3.4 nM.In addition to directly blocking the 
heregulin (NRG1) ligand (heregulin) binding to the HER3 ECD, the antibody also 
sterically prevents the receptor from adopting the extended conformation that is required 
for dimerization, a prerequisite for receptor activation.
Section 1.2.3, Title
REVISED TEXT (new text bold and underlined, deleted text in strikethrough)
PreclinicalNonclinical Safety of GSK2849330

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Section 1.2.4.1
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GSK2849330 is a potent antagonist of HER3 signaling as evidenced by its ability to 
inhibit heregulinNRG1-induced HER3 receptor phosphorylation in various tumor cancer
cell lines (half maximal inhibitory concentration [IC50] 2.5-30 ng/mL [17.2-207 pM]), 
and heregulinNRG1-induced AKT phosphorylation in BxPC3 pancreatic tumor cells
cancer cell lines (IC50 11 ng/mL [76 pM]).  GSK2849330 is also able to inhibit NRG1-
induced proliferation of BxPC3 cells in a concentration dependent manner (33% 
inhibition at 10 g/mL [69 nM]).
ADCC assays using both high- and low-expressing HER3 human target cells 
demonstrated the increased potency and target cytotoxicity achieved with the ADCC-
enhanced GSK2849330 compared to the WT parental antibody.  For example, when a
CHL-1 human melanoma cells were cell line was used as target cells and human 
peripheral blood leukocytes (PBLs) as effector cells, the potency of GSK2849330 was 
245-764 pg/mL (1.7-5.3 pM) versus 35 ng/mL (241 pM) for the WT antibody. The 
efficacy of GSK2849330 was also tested against cynomolgus HER3 (transduced into 
human HEK293 cells) in combination with cynomolgus PBLs as effector cells.  In this 
assay, GSK2849330 had IC50=454-910 pg/mL (3.76-7.5 pM) whereas parental WT 
antibody had IC50=4.2-5.5 ng/mL (29-38 pM).
GSK2849330 caused concentration-dependent complement-mediated cell lysis of 
HEK293 cells transduced with BacMam expressing full length human HER3.  CDC 
activity level was proportional to HER3 protein expression on the cell surface, suggesting 
threshold HER3 expression amounts may be required to engage effective CDC activity.  
The level of ADCC killing may also be related to the amount of HER3 expression on the 
cell membrane [Bossenmaier, 2012].
Section 1.2.4.2 Studies in vivo
REVISED TEXT (new text bold and underlined, deleted text in strikethrough)
GSK2849330 or variants have been evaluated for anti-tumor activity in melanoma and 
pancreatic cancer cell line xenograft tumor avariety of tumor engraftment models 
including melanoma, pancreatic and gastric cancer. For example, twice Twice weekly IP 
dosing with GSK2849330 at 0.5 to 50 mg/kg/dose, resulted in dose-dependent and 
statistically significant decreases (p<0.001 at ≥5 mg/kg) in tumor growth rates in a human 
melanoma cell line (HER3+CHL-1) subcutaneous xenograft model. These studies were 
carried out in immune-compromised, CB17 SCID mice which lack T and B cells and in 
which advanced xenografts (~200 mm3) had been allowed to establish.  Significant 
inhibition of tumor growth was also observed in subcutaneous and orthotopic pancreatic 
(HER3+ BxPC3) cancer cell line xenograft models and in a syngeneic mouse melanoma 
(lung colonization) model. A more limited effect on tumor growth was observed in a 
HER2 amplified gastric cancer cell line (NCI-N87) tumor xenograft model with HER3 
mAb monotherapy.  Because Since xenograft studies were carried out in immune-
compromised CB17 SCID mice, which lack T and B cells, and the disposition and 
nature of Fcreceptor subtypes in mouse are different to that observed in human [Smith, 

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2012], the effects of GSK2849330 on tumor growth in these mouse models are expected 
to result mainly from HER3 signaling inhibition (eg, ligand blocking/inhibition of 
heterodimerization) rather than an effect of the other potential (cell killing) modes of 
action for GSK2849330. Indeed, similar effects on inhibition of CHL-1 tumor xenograft 
growth in this model were observed with a wild-type and an Fc-disabled variant of 
GSK2849330. In agreement with this hypothesis, GSK2849330 and Fc-disabled 
variant of GSK2849330 showed similar tumor growth inhibition in CHL-1 tumor 
xenograft.
Section 1.3 HER3 Antibodies in Clinical Trials
REVISED TEXT (new text bold and underlined, deleted text in strikethrough)
Although this is the FTIH study for GSK2849330, there is relevant experience for 
targeted inhibition of HER3 in cancer subjects. Initial clinical data from Phase I studies 
of threeother monoclonal antibodies targeting HER3 have been reported. Two of the 
antibodies, MM-121 and U3-1287, are non-enhanced human or humanized IgG1 
antibodies.  One antibody, RG7116, is a glycoengineered humanized IgG1 antibody 
reported to have enhanced potency for ADCC activity. Another antibody, LJM716, is a 
fully human monoclonal antibody that inhibits both ligand-dependent and -
independent activation of HER3. These antibodies have been administered in clinical 
trials at doses up to 40 mg/kg (loading dose) + 20 mg/kg weekly IV without dose limiting 
toxicities (DLTs) and without reaching a maximum tolerated dose (MTD). These 
therapies have been well-tolerated. The majority of adverse events (AEs) have been 
Grade 1 or 2 with GI toxicity and fatigue predominating across studies.  Infusion 
reactions, although seen, were reportedly not severe [Arnedos, 2013 Lorusso, 2013, 
Meulendijks, 2013, Denlinger, 2011, Reynolds 2014].

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Section 2.1, Part 1: Dose Escalation and PK-PD Cohorts-Exploratory Endpoint
REVISED TEXT (new text bold and underlined, deleted text in strikethrough)
Objective
Endpoint
Primary
To determine the safety and 
tolerability of GSK2849330 in 
subjects with advanced HER3-
positive solid tumors.
AEs, serious adverse events (SAEs), DLTs, and 
changes in laboratory values, electrocardiograms 
(ECGs), and vital signs.
Secondary
To characterize the PK of 
GSK2849330 following IV 
administration.
To evaluate preliminary 
evidence of target engagement 
and PD effects of GSK2849330.
To determine the recommended 
dose regimen(s) of 
GSK2849330 for further 
exploration in Part 2.
To evaluate the immunogenicity 
of GSK2849330 following IV 
administration.
PK parameter values for GSK2849330.
Total and phospho-HER3 from tumor tissue.
Safety, tolerability, PK, and available PD data.
Antibodies to GSK2849330 assessed in serum.
Exploratory
To further evaluate preliminary 
evidence of target engagement 
and PD effects of GSK2849330.
To explore relationships 
between GSK2849330 PK, 
markers of target engagement, 
and /or PD markers.
To explore preliminary clinical 
tumor outcomes after treatment 
with GSK2849330.
Pre- and post- treatment biomarkers (cells, 
proteins, ribonucleic acid [RNA] and/or 
deoxyribonucleic acid [DNA]) from circulation, skin, 
and/or tumor tissue.
GSK2849330 concentration-time profile and PK 
parameters, target engagement and PD markers in 
circulation, skin, and/or tumor.
Preliminary evidence of clinical benefit as 
assessed by overall response rate (ORR), tumor 
markers, and other measures of clinical benefit 
Pharmacogenetic (PGx) Exploratory
To investigate the relationship 
between genetic variants in 
candidate genes and safety, 
tolerability, PK, PD, and/or 
efficacy of GSK2849330.
Genetic variations in selected candidate genes, 
such as the FCreceptor family, safety, tolerability, 
PK, PD, and/or efficacy endpoints.

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Section 2.2, Title
REVISED TEXT (new text bold and underlined, deleted text in strikethrough)
Part 2: Expansion CohortsMolecularly-Defined Tumor Histology Groups
Objective
Endpoint
Primary
To evaluate the safety of 
GSK2849330 in a larger cohort
population of subjects in 
molecularly-defined tumor 
histology groups at the dose 
regimen(s) recommended for 
further exploration in Part 1.
AEs, SAEs, DLTs, and changes in laboratory 
values, ECGs, and vital signs.
Secondary
To evaluate preliminary 
evidence of clinical benefit.
ORR, tumor markers, and other measures of 
clinical benefit.
To further characterize target 
engagement and PD effects of 
GSK2849330.
Total and phospho-HER3 from tumor tissue.
To further characterize the PK of 
GSK2849330.
To characterize the relationship
between GSK2849330 PK, 
markers of target engagement, 
and/or PD markers.
PK parameter values for GSK2849330
To evaluate the immunogenicity 
of GSK2849330 following IV 
administration.
Antibodies to GSK2849330 in serum
Exploratory

To explore additional measures 
of clinical benefit.

Progression free survival (PFS), ORR according 
to immune-related response criteria (irRc) and 
modified Response Evaluation Criteria in Solid 
Tumors mRECIST where applicable, and other 
tumor markers and measures of clinical benefit  

To further characterize target 
engagement and PD effects of 
GSK2849330.
Pre- and post- treatment biomarkers (cells, 
proteins, RNA and/or DNA) from circulation, skin,
and/or tumor tissue.
To explore relationship between 
pre-treatment HER3 and 
NRG1expression levels and 
clinical outcome.
Pre-treatment HER3 and NRG1 expression 
levels, efficacy outcome parameters.

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Objective
Endpoint
To identify molecular features 
potentially predictive of 
response to GSK2849330.
Prediction analysis of biomarkers (cells, DNA, 
RNA or protein) in tumor,skin, and/or circulation 
with efficacy endpoints.
Pharmacogenetic (PGx) Exploratory
To investigate the relationship 
between genetic variants in 
candidate genes and safety, 
tolerability, PK, PD, and/or 
efficacy of GSK2849330.
Genetic variations in selected candidate genes, 
such as the FCreceptor family, safety, 
tolerability, PK, PD, and/or efficacy endpoints.
Section 3.1 Discussion of Study Design
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Protocol waivers or exemptions are not allowed.  Therefore, adherence to the study 
design requirements, including those specified in the Time and Events Tables (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, FTIH, open-label, multi-center, dose-escalation study of the anti-HER3 
antibody, GSK2849330, in subjects with advanced solid tumors expressing HER3 (see 
Inclusion Criteria 3 and 9). The study will be conducted in two parts as depicted below.  
Part 1
Dose Escalation Cohorts
To determine the safety, tolerability, PK and preliminary PD of GSK2849330, in support of 
selection of the recommended dose(s) and regimen(s) for further exploration in subjects with 
advanced solid tumors with HER3 expression
PK/PD Cohorts
Subjects that agree to give pre- and on- treatment tumor biopsies will be enrolled in the PK/PD 
cohorts to support selection of the recommended dose(s) and regimen(s) for Part 2.  Up to 3 
subjects with evaluable pre- and on-treatment tumor biopsies will be enrolled at each dose level 
after that dose is determined tolerable.

Part 2
Expansion Cohort Molecularly-Defined Tumor Histology Groups
To determine safety and preliminary evidence of clinical benefit of GSK2849330, and to further 
evaluate the PK and PD of GSK2849330 at the recommended Part 2 dose(s) and regimen(s) in 
subjects with selected HER3 or HER3 and NRG1 expressing tumor types.

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Section 3.2 Pre-Screening
REVISED TEXT (new text bold and underlined, deleted text in strikethrough)
Subjects will be required to undergo pre-screening to determine if their tumor is HER3 
expressing or HER3 and NRG1 expressing (2+ or 3+ by IHC; details regarding HER3 
and NRG1 expression requirements will be described in the SPM).  Subjects with study 
eligible advanced solid tumors (see Pre-Screening Inclusion Criteria 5)will sign a 
separate Informed Consent Form (ICF) to allow for pre-screening of archival tumor or 
tissue from fresh tumor biopsies for HER3 expression by IHC or for HER3 by IHC and 
NRG1 expression by quantitative real-time reverse transcription polymerase chain 
reaction (qRT-PCR) assay.
Section 3.3 Part 1: Dose-Escalation Phase, 3rd paragraph
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Starting with Cohort 2, the dose escalation will continue using the Neuenschwander-
continuous reassessment method (N-CRM) [Neuenschwander, 2008] with 3 subjects in 
each cohort as described below.After the first subject is dosed in Cohorts 2 through 4,and 
all subsequent cohorts, the second and third subjects will not be dosed until the first 
subject has been observed for at least 24 hours for evidence of unanticipated acute 
toxicity.
Section 3.3 Part 1: Dose-Escalation Phase, Dose Recommendation
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Dose recommendation: Dose recommendation output from the N-CRM model will be 
based on the posterior probabilities that the DLT rate for each escalation dose lies in one 
of the following categories:

[0%,16%) range of minimal toxicity

[16%, 33%) range of acceptable toxicity

[33%, 60%) range of excessive toxicity

[60%, 100%) range of unacceptable toxicity
After each cohort, a recommendation will be made to either: 1) escalate to the next dose 
or regimen, 2) de-escalate, 3) recruit more subjects at the current dose, or 4) stop.  The 
recommended dose will be the one with the highest probability of having a DLT rate in 
the acceptable toxicity range [16%, 33%), subject to the constraint that no dose may be 
skipped during dose escalation. The recommended dose has an additional requirement 
that the sum of the posterior probabilities of the DLT rate lying in the excessive toxicity 
or unacceptable toxicity range must be less than 25%. Additional subjects may also be 
enrolled at any specified dose level to further characterize the safety, as with traditional 
dose-escalation methods.

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Prior to dose escalation/de-escalation, a meeting will be convened to discuss available 
safety, and the recommendation from the N-CRM model. The data will be reviewed by 
the investigator(s) and GSK study team which may include the Medical Monitor, 
statistician, and pharmacokineticist. The dose escalation rationale and decision for the 
subsequent cohort will be documented in writing with copies maintained at each site and 
in the GSK study files.
The final recommended Part 2 dose regimen(s) will be based on an overall assessment of 
safety taking into consideration all available data including PK, PD, and the 
recommendation from the N-CRM model.
Table 2
Dose Levels
Dose 
Level
Dose 
N
Dose Escalation 
Cohorts
Na
PK-PD 
Cohorts
1
1.4 mg/kg weekly
1 (minimum)
up to 3
2
3 mg/kg every 2 weeks
3 (minimum)
up to 3
3
10 mg/kg every 2 weeks
3 (minimum)
up to 3
4
30 mg/kg every 2 weeks
3 (minimum)
up to 3
5 
(Optional)
Lower dose and/or extended 
interval
NA
up to 3
6 
(Optional)
Lower dose and/or extended 
interval
NA
up to 3
7 
(Optional)
Lower dose and/or extended 
interval
NA
up to 3
a) A sufficient number of subjects will be enrolled in the PK/PD cohorts to obtain up to 3 
evaluable pre- and on-treatment biopsy pairs per dose level (see the SPM for additional 
details).
The initial dose levels to be evaluated are outlined in Section 3.6.3.
Additional subjects may also be enrolled at any specified dose level to further 
characterize safety. Additional doses and schedules and loading doses may be explored, 
following the rules outlined for dose escalation, based on emerging safety, PK and PD 
data. following the rules outlined for dose escalation. Subjects enrolled in the PK/PD 
cohorts will have assessments as required below and detailed in the PK/PD cohort Time 
and Events Table 6 and Table 7 (see Section 7.1). 
PK/PD cohort(s): Once a given dose escalation cohort is filled, additional subjects may 
be enrolled into a PK/PD cohort (at any dose level determined to be tolerable) to allow 
for the collection of data on the PD effects of GSK2849330 as well as additional PK data. 

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All subjects in cohorts 5 through 7, as depicted in Table 2, must be enrolled in the PK/PD 
cohorts. 
Subjects enrolled in the PK/PD cohorts must meet all of the relevant inclusion and 
exclusion criteria, have disease that is amenable to biopsy, and also agree to have pre-
and on-treatment biopsies in addition to the other study procedures. Subjects will be 
enrolled in PK/PD cohorts in order to obtain up to 3 evaluable pre- and on-treatment 
biopsy pairs per dose level (see SPM for additional details). Subjects who do not agree to, 
or who are unable to provide pre- and on-treatment biopsies in the PD expansion may be 
enrolled in dose escalation cohorts in Part 1 as they become available.
Subjects enrolled in the PK/PD cohorts may have their dose escalated to a higher 
completed dose level (not exceeding the MTD) once the necessary PK/PD procedures 
have been completed and once other criteria for intra-subject dose-escalation have been 
met (see Section 3.5). See the PK/PD cohorts Time and Events (Table 6 and Table 7
Table 9, Table 10) for study assessments specific to the PK/PD cohorts.
The final recommended Part 2 dose regimen(s) will be based on an overall 
assessment of safety taking into consideration all available data including PK, PD, 
and the recommendation from the N-CRM model
Section 3.4, Title
REVISED TEXT (new text bold and underlined, deleted text in strikethrough)
Part 2:Expansion CohortMolecularly-Defined Tumor Histology Groups
REVISED TEXT (new text bold and underlined, deleted text in strikethrough)
Part 2 can begin once the recommended dose and schedule is identified in Part 1. It is 
possible that more than one dose and/or schedule will be evaluated in Part 2 if available 
PK, PD and safety data suggest that multiple doses and schedules have desirable biologic 
activity or if an MTD cannot be established
The selected dose level(s) will be evaluated in Part 2 for confirmation of safety and 
tolerability, as well as preliminary assessment of clinical benefit, in one or more 
expansion cohorts at least 4 molecularly-defined tumor histology groups of subjects 
with HER3 or HER3 and NRG1 expressing tumors (see Inclusions Criteria 3). The 
expansion cohorts may include tumor type specific cohorts, and/or a histology-
independent cohort of subjects with any of the following tumor types: castrate-resistant 
prostate cancer, melanoma, CRC, non-small cell lung cancer (NSCLC), cervical cancer, 
squamous cancers of the head and neck region (including parotid and nasopharynx), 
ovarian cancer, breast cancer, bladder cancer, gastric cancer, pancreatic cancer, and 
hepatocellular carcinoma (HCC). All subjects must have archival tissue available for 
HER3 testing, or be willing to undergo a tumor biopsy to provide a sample for HER3 
testing. Group 1 will include subjects with HER3-expressing melanoma. Group 2 
will include subjects with HER3-expressing gastric cancer. Group 3 will include 
subjects with HER3 expressing and NRG1-expressing cancers of the head and neck. 
Group 4 will include subjects with HER3 expressing and NRG1-expressing NSCLC. 

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All subjects must have archival tissue available for HER3 and if required NRG1 
testing or be willing to undergo a tumor biopsy to provide a sample for testing.
Subjects will be enrolled in up to 3 expansion cohorts. The first 2 expansion cohorts may 
be opened in parallel.  The third may only be opened if futility is not established in both 
of the first 2 expansion cohorts.  Expansion cohorts will initially enroll 12 subjects with 
the option of expanding to a maximum of 30 subjects if futility criteria are not met using 
the methodology of [Lee, 2008] (See Section 13.2.2 and Section 13.6.2 for additional 
details). Response will be defined either as Complete Response (CR) or Partial Response 
(PR) as per RECIST 1.1 guidelines.
A sufficient number of subjects with disease amenable to biopsy will be enrolled to 
facilitate obtaining a minimum of 9 evaluable pre- and on-treatment biopsy pairs in each 
of the expansion cohorts.  
Each group will initially enroll 12 subjects with the option of expanding to a 
maximum of 30 subjects if futility criteria are not met using well established  
methodology of [Lee, 2008] (See Section 13.2.2 and Section 13.6.2 for additional
details).
Subjects will be required to have disease amenable to biopsy and agree to pre-and 
on-treatment tumor biopsies. Pre-and on-treatment biopsies are mandatory for all 
subjects in all groups. GSK will closely monitor and evaluate the collection of 
evaluable biopsies and will notify the participating centers of any change to the 
collection requirements for any or all groups.
Section 3.5 Intra-subject Dose Escalation
REVISED TEXT (new text bold and underlined, deleted text in strikethrough)
A subject’s dose level may be increased up to the highest dose level that has previously 
been confirmed by the investigator and GSK medical monitor as not exceeding the MTD 
Intra-subject dose escalations will be allowed in both Part 1 and Part 2 (if multiple 
doses/regimens demonstrate a better PK profile or clinical activity) provided that the 
subject has completed at least 1 post-baseline efficacy assessment without toxicity greater 
than Grade 2 or the occurrence of significant AEs, and prior approval has been obtained 
from a GSK medical monitor. Subjects will be permitted to increase dose levels multiple 
times provided the above criteria are met. Any dose escalations must be agreed upon by 
the investigator and GSK medical monitor, and must be documented on a dose escalation 
decision form (see the SPM) with copies maintained at the site and in the study files.
Section 3.6.1 Rationale for Study
REVISED TEXT (new text bold and underlined, deleted text in strikethrough)
HER3 expression is seen across a wide variety of solid malignancies and is associated 
with poor prognosis. Up-regulation of HER3 expression and activity is also associated 
with resistance to multiple pathway inhibitors. GSK2849330, a monoclonal antibody 
targeting HER3, is a new agent for subjects whose tumors express HER3 and/or its 

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ligand, NRG1. GSK2849330 possesses has a unique pharmacologic profile compared 
to other HER2 antibodies with multiple potential modes of action including inhibition 
of tumor signaling and increased potential for direct cell killing via enhanced ADCC and 
CDC activities. GSK2849330 has a unique pharmacologic profile compared to non-
enhanced HER3 antibody based therapies and small molecule inhibitors of HER3 (See 
Section 1.2.1 for details).
There is considerable unmet medical need across these tumor types where high 
HER3 expression is seen. The purpose of the dose escalation is to evaluate safety, 
PK, and initial PD of the drug in subjects with HER3 expressing tumors.  Following 
dose escalation in Part 1, at least 4 molecularly defined tumor histology groups will 
be enrolled in Part 2. Preliminary clinical activity, biomarkers of target 
engagement, downstream signalling, ADCC, and CDC will be evaluated.
Section 3.6.2 Rationale for Population
REVISED TEXT (new text bold and underlined, deleted text in strikethrough)
Subjects will be selected on the basis of HER3 expression on the cell membrane of the 
invasive component of tumor because higher levels of target expression on the cell 
surface is required for ADCC, CDC and signaling inhibition functions of the 
antibody. High , irrespective of the mechanism(s) by which clinical benefit may be 
achieved, target expression is an absolute pre-requisite for antibody engagement.  HER3 
expression has been demonstrated in up to two-thirds of the tumor histologies being 
considered for this trial [Ocana, 2013].
Study eligibility for Part 1 is based on HER3 protein expression using an 
analytically validated IHC assay. For some groups in Part 2, study eligibility is 
further defined by NRG1 expression.
HER3 expression for study eligibility is defined by an IHC score of 2+ or 3+ as this is 
expected to provide the optimal expression levels at which clinical efficacy and PD effect 
will be observed based on preclinical data (refer to Section 1.2.4). HER3 is expressed in 
a broad range of solid tumors, including melanoma, gastric cancer, NSCLC, and 
squamous cell carcinoma of the head and neck (SCCHN). Upon ligand binding, 
HER3 heterodimerizes with other members of the HER family and acts as a 
mediator of drug resistance to various cancer therapies [Amin, 2010]. 
Phosphorylation of intracellular sites of HER3 leads to activation of PI-3K/AKT 
and MEK/MAPK and JAK/STAT signaling. GSK2849330 has demonstrated 
inhibition of HER3 activity and tumor growth in mouse xenograft models.
For Part 2 of the study, 4 tumor types were selected for inclusion: 2 tumor types 
with high levels of HER3 expression (melanoma and gastric cancer) and 2 tumor 
types with high levels of NRG1 (ligand for HER3) expression (head and neck 
cancers and NSCLC).

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Melanoma
In melanoma, overexpression of HER3 is associated with advanced disease and 
decreased survival [Reschke, 2008; Ueno, 2008]. Treatment of melanoma is 
underexplored in the development of HER3 inhibitors.
In CHL-1, BRAF wild-type melanoma cell line mouse xenograft model GSK2849330 
treatment decreased phospho-HER3, total HER3, phospho-AKT and tumor growth.
HER3 inhibition restored the sensitivity of trametinib and dabrafenib (MEK and 
BRAF inhibitors, respectively) in NRG1-treated BRAF mutant melanoma cell lines.
Gastric cancer
Both HER2 and HER3 expression are probable prognostic markers in patients with 
gastric cancer [Park, 2006;García, 2003;Piontek, 1993; Hayashi, 2008; Zhang, 2009; 
Wu, 2014; Sato, 2013].
Approximately 30% to 60% of gastric cancers express HER3 [Hayashi, 2008]. 
HER3 mutations are present in approximately 11% of gastric cancers. In a gastric 
cancer xenograft model, HER3 antibodies reported to reduce tumor growths.  In 
NCI-N87, an ERBB2 amplified gastric cancer cell line, GSK2849330 treatment 
restored sensitivity to lapatinib lost due to the addition of NRG1.
Cancers of the Head and Neck
A subset of head and neck cancer cell lines with sensitivity to lapatinib has elevated 
expression of NRG1 and activation of HER3 [Wilson, 2011]. High NRG1 expression 
in these cancers is associated with activation of HER3 and may be used as a 
predictive biomarker for HER3-targeted therapies [Shames, 2013].
A combination of EGFR and HER3 inhibition caused tumor regression in head and 
neck xenograft models [Zhang, 2014].
NSCLC
NRG1 overexpression was identified as a biomarker for efficacy in patients treated 
with HER-3 antibody MM-121 [Sequist, 2014]. In a phase 2 trial of patritumab, a 
HER3-targeted antibody, in combination with erlotinib, an EGFR inhibitor, in 
erlotinib-naive patients with advanced NSCLC, PFS was significantly improved 
only in the subgroup of patients with high NRG1 expression [Mendell-Harary, 2014; 
Von Pawel , 2014].  Furthermore, one PR was confirmed in a patient with NSCLC 
who expressed high levels of NRG1 in a phase 1 study of HER3 antibody AV-203 
that included subjects with advanced or metastatic colorectal cancer, NSCLC, and 
SCCHN, and other solid tumors [Sarantopoulos, 2014]. Recently, NRG1 gene fusion 
has been reported in a subset of invasive mucinous lung adenocarcinoma.
Nonclinical data also demonstrated NRG1 induced activation of HER3 signalling 
adversely affect the activity of agents that target the MEK/MAPK and PI-3K/AKT 

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signalling pathways. In KRAS mutant NSCLC cell lines, the combined inhibition of 
MEK and HER3 synergistically induced cell death HER3 is upregulated in response 
to AKT inhibition in some NSCLC cell lines. In vitro studies of patritumab showed 
that only cell lines expressing NRG1 responded to treatment, as manifested by 
decreases in HER3 and AKT phosphorylation [Schneider, 2014].
Section 3.6.3 Rationale for Dose, Dose Escalation
REVISED TEXT (new text bold and underlined, deleted text in strikethrough)
The proposed dose escalation scheme is based on a half-log step size, with the exception 
of the 30 mg/kg/wk dose and the nominal doses shown in Table 2 Table 3 represent the 
maximum dose which may be selected.  The study team, in discussion with the 
investigator(s), may select lowerother doses or alternative schedules besides those 
shown, than those shown based on emerging safety, tolerability, PK and/or PD data.  
Additional cohorts may be added to the dose escalation to accommodate intermediate 
dose levels and slower progression up the dose escalation.  
Dosing Interval 
The predicted half-life for GSK2849330 is ~8-9 7 days at 30mg/kg and is expected to 
support an every two week (or longer) dosing frequency.  However, at lower doses, 
including the proposed starting dose, the contribution of target mediated clearance may 
yield a half-life somewhat shorter than projected for higher dose levels.  With this 
consideration, the initial dosing frequency for the first subject will be once-weekly. PK 
data will be evaluated from the first week of dosing for the first subject, so that 
adjustments in the dosing interval can be made if appropriate (see the Time and Events 
Tables Section 7.1 and Section 7.4 for the specific PK assessment schedule for the first 
subject).  
If the half-life appears to be generally in line with expectations, the dosing interval for 
higher dose cohorts is anticipated to be every week or every 2 weeks or every 3 weeks.  
A general guideline is shown in Table 4.  Additional schedules may be explored based on 
safety, tolerability, PK and PD.
Table 4
Dosing Interval Guidance
Observed half-life
Likely dose interval*
<3 days
Once-weekly
4-8 days
Every week or every 
2 weeks
> 9 days
Every 3 weeks
*Final selection of dose interval for cohorts will take into consideration the half-life together with safety, 
tolerability, PK and available PD data.
It is recognized that increasing the dose can allow for extension of the dosing interval 
with equivalent safety and efficacy, assuming that 1) toxicity is not limited by Cmax and 
2) efficacy is related to overall exposure (AUC) or time above a given concentration.  
Both assumptions appear reasonable for GSK2849330 based on 1) preclinical safety data 

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and 2) preclinical efficacy data and knowledge of the mechanism of action.  Based on 
human PK predictions from cynomolgus monkey data, a dose of 2.9 mg/kg every 3 
weeks IV may provide the same exposure in 3 weeks as 3 doses of 1.2mg/kg every week 
IV at steady state.  Using these principles, it is anticipated that the dosing schedule may 
be lengthened as appropriate based on accrual of PK and/or PD information.
Additional context for the proposed doses are provided in the following sections.
Human Pharmacokinetic Extrapolation
Human plasma PK was predicted based on extrapolation from PK data of GSK2849330 
in cynomolgus monkeys dosed with 1, 10 or 100 mg/kg as a single IV dose (n= 3 female 
and n= 3 male per group).  The estimated terminal half-life from the high dose (100 
mg/kg) in a 3-kg cynomolgus monkey was 100-114 hours with central volume of 
distribution of 140 mL (8% coefficient of variance [CV]) and target mediated clearance 
equilibrium constant 7.2 μg/mL (57% CV).  Single species allometric scaling from 3 kg 
cynomolgus monkey to a 60 kg human predicts a terminal half-life in humans of 
approximately 197-224 hours (~8-9 days) with central volume of distribution 
approximately 2.9 L and equilibrium constant approximately 3.7 μg/mL (57% CV), 
assuming the same level of target in cynomolgus and human.
Preliminary Human Pharmacokinetic Profile
Preliminary non-compartmental PK parameters are listed in Table 5 below for 
dose-escalation cohorts in this trial dosed GSK2849330 at 1.4 mg/kg, 3 mg/kg or, 
10 mg/kg.

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Table 5
Preliminary non-compartmental Pharmacokinetic Profile
Parameter 
Unit 
n 
Treatment (mg/kg)  
Estimate (CV%)
AUC(0,336) 
hr*µg/mL 
1 
1.4 
3123 
3 
3 
8880 (25.7) 
3 
10 
28100 (27.8) 
t1/2 (24, 168) 
hr 
1/3 
1.4 
78.7 
t1/2 (24, 336) 
hr 
1/3 
3 
119 
3 
10 
134 (32.0) 
Cmax
µg/mL 
1 
1.4 
29.8 
3 
3 
64.7 (30.2) 
3 
10 
234 (2.65) 
tmax
hours 
1
1.4 
1 
3 
3 
1 [1-6]a
3 
10 
1[1-6] a
AUC = area under the concentration-time curve; Cmax = maximum observed concentration; CV = coefficient 
of variance; t1/2 = plasma elimination half-life; tmax = time to maximum observed concentration.  
Preliminary non-compartmental PK analysis for subjects in dose-escalation cohorts.  
a denotes median [range]
Preliminary population PK parameters based on nominal dose and PK sample time 
are listed in Table 6 below for dose-escalation cohorts at 1.4 mg/kg (n=1), 3 mg/kg 
(n=2) or, 10 mg/kg (n=2). The data are modelled according to a two compartment 
PK model with peripheral Target Mediated Drug Disposition. One subject was 
excluded from the 3 mg/kg cohort because the dose was delayed; and another 
subject was excluded from the 10 mg/kg cohort because the infusion was terminated 
early so the total dose of GSK849330 administered was uncertain.

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Table 6
Preliminary Population PK Parameters
Parameter 
Unit 
Estimate
%RSE
%CV
CL 
mL/h 
11.4
39.1 
32.1 
V1 
mL 
2460
6.64 
VM 
µg/h 
198
40.6 
KM
µg/mL 
0.513 
Q
mL/h 
79.0 
19.1 
V2
mL 
2500
13.7 
D1
h 
1 
SG1 (proportional)
0.0626 
62.9 
The compartmental and non-compartmental model parameters suggest a catabolic 
half-life of (V1/CL)xln(2) = 150 hours. Considering GSK2849330 as an IgG1-IgG3 
fusion with Fc located in the IgG3 region, it is plausible that the elimination half-life 
is in accordance with the well-known fact that IgG3 elimination half-life is about 
7 days (e.g., Stapleton 2011 and references therein).
Predicted Effective Dose 
The potential therapeutic dose range for GSK2849330 in humans was derived using 
available preclinical in vitro and in vivo PK and efficacy data.  In addition, data from 
mouse in vivo CHL-1 xenograft efficacy studies were evaluated to predict the potential 
minimum clinically efficacious dose.  PK/PD modeling of CHL-1 xenograft data in SCID 
mice suggests that anti-tumor efficacy (based on tumor growth curves) may be achieved 
with systemic plasma trough concentrations of GSK2849330 maintained at ≥ 20 μg/mL.  
The predicted human equivalent dose to achieve a similar trough concentration is 
approximately 1.2 mg/kg/wk. This dose is also in line with that projected, based on in 
vitro potency data, to engage HER3 and inhibit signaling (approximately 0.9 to 
5.6 mg/kg).  It is anticipated that optimal anti-tumor activity will require full target 
engagement and that ADCC and CDC enhancements may further increase the anti-tumor 
activity of GSK2849330.  However, it is also recognized that saturation of target 
throughout the tumor in the clinical setting may require doses higher than those projected 
based on preclinical extrapolations, due to factors in the tumor microenvironment such as 
vascular perfusion heterogeneity which may limit mAb intra-tumoral distribution.  
Recognizing these factors, the top proposed dose for evaluation is 30 mg/kg, a dose 
which is also viewed as the highest dose feasible based on practical considerations.

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A loading dose scenario is predicted to maintain an accumulated steady state trough 
concentration if the dosing interval is less than or equal to the elimination half-life.  
Accordingly, a 30 mg/kg weekly IV dose cohort has been added to the dose 
escalation portion of the study.
Section 3.6.4 Rationale for Endpoints, 4th paragraph 
REVISED TEXT (new text bold and underlined, deleted text in strikethrough)
Tumor, skin, and circulating biomarkers were selected based on the mechanism of action 
of GSK2849330, preclinical evidence in addition to clinical evidence reported in agents 
of the same class and in those affecting similar pathways.The objective is to characterize 
the PD effect of GSK2849330 and to obtain preliminary data on the relationship between 
HER3 expression levels (i.e., IHC 2+ and 3+), NRG1 expression, other potential 
predictive biomarkers including HER3 ligands, expression of other RTKs, mutations, 
immune associated markers, and efficacy outcome.
Section 3.9.1.1 Liver Chemistry Follow-up Procedures 
REVISED TEXT
Serum acetaminophen adduct high-performance 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]). NOTE: not required 
in China
Section 3.9.2 QTc Stopping Criteria
REVISED TEXT
If a subject meets the QTc1 interval duration criteria below, study treatment(s) will be 
withheld.  

QT interval corrected for heart rate (HR) by Fredericia’s formula (QTcF) >530 msec
1Based on average QTc value of triplicate ECGs to include manual over-read.  For example, if an ECG 
demonstrates a prolonged QT interval, obtain 2 additional ECGs over a brief period (e.g., within 
approximately 10 minutes of the abnormal ECG, if possible, and approximately 10 minutes apart from each 
other), and then use the averaged QTc values of the 3 ECGs to determine whether the subject should have 
study treatment(s) withheld.
If the QTc prolongation resolves to Grade 1 or baseline, the subject may be re-started on 
the study treatment(s) if the investigator and GSK Medical Monitor agree that the subject 
will benefit from further treatment.
For subjects recruited in France, please refer Refer to Appendix 2 for the French specific
country-specific QTc stopping criteria.
Section 3.10 Guidelines for Events of Special Interest and Dose Modifications, 2nd 
paragraph

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NEW TEXT (new text bold and underlined, deleted text in strikethrough)
In subjects experiencing suspected infusion-related reactions, a whole blood sample 
for selected cytokines (including but not limited to TNF alpha, IL-6, and tryptase) 
should be drawn within 24 hours and submitted to the central laboratory for 
analysis (see SPM for instructions).
Section 3.10.1 Management of Infusion Reactions
REVISED TEXT
As there is a risk of infusion reactions during administration of IV immunoglobulins, 
including monoclonal antibodies, subjects will be monitored for signs and symptoms of 
an infusion-related reaction (including Grade 1 to 2 fever, chills, headache, nausea, 
malaise) during infusion and for a minimum of 1 hour after the first administration of 
GSK2849330.
If an infusion-related reaction occurs during administration, the infusion rate may be 
reduced or halted at the discretion of the investigator and/or GSK medical monitor, 
depending on the severity of the symptoms and the subject will receive appropriate 
medical treatment. For subsequent infusions, the investigator may provide premedication 
with antihistamines, acetaminophen
Treatment may include:

Fevers/Myalgia:  Use acetaminophen.Initiate treatment with acetaminophen 
(paracetamol). If subject’s fever does not respond to acetaminophen, consider a 
nonsteroidal anti-inflammatory drug (NSAID) such as indomethacin. Consider 
pre-medicate premedication with acetaminophen (paracetamol) for subsequent 
doses.

Chills/rigors: Use warning blankets as initial maneuver intervention;, consider IV 
meperidine (pethidine) if chills persist.

Nausea/vomiting: Consider treatment with 5-HT3 antagonists, 
prochlorperazine, lorazepam; some agents may cause hypotension and altered 
mental status, therefore, these agents should be used with caution.
3.10.2 Title
REVISED TEXT
Allergic Reaction Monitoring and Management
Section 3.10.3 Diarrhea Management 
REVISED TEXT (new text bold and underlined, deleted text in strikethrough)

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If episodes of diarrhea occur, causes for the diarrhea other than the study treatment such 
as concomitant medications (e.g., stool softeners, laxatives, antacids, etc.), infections by 
Clostridium. difficile or other pathogens, partial bowel obstruction, etc., should be ruled 
out. Subjects should be instructed to first notify their physician/healthcare provider 
at onset of diarrhea of any severity. Supportive measures depend on the severity of 
the diarrhea and could should include the following as clinically indicated:

Dietary modifications (e.g., small, frequent meals, low fiber, and lactose-
avoidance, and addition of foods rich in potassium)

Maintain hydration with clear liquids or IV fluids as needed

Loperamide and/or oral antibiotics

Second-line agents

Hold GSK2849330
Additional recommended guidelines for the treatment of study treatment induced diarrhea 
are provided in Benson, et.al. [Benson, 2004] and in Appendix 9
Section 3.10.4 Dose Modifications, 1st paragraph
REVISED TEXT (new text bold and underlined, deleted text in strikethrough)
In the event of a toxicity that meets the guidelines for DLT (Section 3.3.1.) severity 
criteria of DLT or is otherwise considered to be clinically significant by the treating 
physician, treatment will be stopped and supportive therapy administered as clinically 
indicated. If clinically significant drug-related toxicity is present, treatment should be 
delayed until the toxicity resolves (with or without supportive therapy) to baseline or 
≤Grade 1. If the toxicity does not resolve to ≤Grade 1 or baseline within 2 weeks, 
withdrawal from the trial is recommended unless otherwise agreed to by a GSK Medical 
Monitor and the investigator based on evidence of clinical benefit.
For subjects enrolled in the 30 mg/kg weekly dosing cohort, the dosing frequency may be 
reduced to every 2 weeks at the discretion of the investigator for a toxicity that does not 
automatically necessitate a dose reduction.
Section 3.10.4 Dose Modifications, 2nd paragraph
NEW TEXT (new text bold and underlined, deleted text in strikethrough)
For subjects enrolled in the 30 mg/kg weekly dosing cohort, the dosing frequency 
may be reduced to every 2 weeks at the discretion of the investigator for a toxicity 
that does not automatically necessitate a dose reduction.

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Section 3.10.5 Dose Reductions
REVISED TEXT (new text bold and underlined, deleted text in strikethrough)
Part 1: A subject who experiences a toxicity at any time during treatment with 
GSK2849330 that either meets the guidelines for DLT  (Section 3.3.1) or is otherwise 
considered to be clinically significant by the treating physician, should meeting the 
definition of a DLT at any time during treatment with GSK2849330 will have their dose 
reduced to the previously tested next lower dose level. Any subject who experiences one 
or more recurrent clinically significant toxicities after the initial dose reduction may have 
one further dose reduction except where noted otherwise. Subjects who continue to 
experience clinically significant toxicity despite two dose reductions (i.e., unacceptable 
toxicity) will be discontinued from the study.
Part 2: Subjects who begin the selected dose and require a dose reduction (due to 
tolerability/toxicity issues), should be dose reduced to one level below the recommended 
Part 2 dose. Further dose reductions should be discussed with the GSK Medical Monitor
Section 4: Investigational Products
REVISED TEXT (new text bold and underlined, deleted text in strikethrough)
The term ‘study treatment’ is used throughout the protocol to describe the investigational 
product (IP) received by the subject as per the protocol design The study was initiated 
with vials containing 1 mL of IP. Vials containing 5 mL were later introduced, and 
for the remainder of the study, both 1-mL and 5-mL vials will be available.
Section 4.1 Description of Investigational Product(s), Table
REVISED TEXT (new text bold and underlined, deleted text in strikethrough)
Product name :
GSK2849330 solution for infusion 100 mg/mL
Formulation description:
Solution containing 100 mg/mL GSK2849330 in vials 
containing 1 mL for injection
or
Solution containing 100 mg/mL GSK2849330 in vials 
containing 5 mL for injection
Dosage form :
Solution for Infusion. The solution is stored at 2-8C.
Unit dose strength(s)/Dose Level(s):
IV/100 mg/mL (refer to Section 3.3 and Section 3.4 for 
dose levels)
Physical Description: 
GSK2849330 solution for infusion is clear to opalescent, 
pale yellow or pale brown in color.
Route/
Administration/ Duration:
Delivered as an IV solution (see Section 3.8).
Dosing instructions:
Dilute GSK2849330 solution into a 0.9% sodium chloride 
IV bag to the appropriate concentration for the dose. 
Deliver the entire contents of the IV bag to the subject.
Manufacturer/ Source of Procurement:
GSK

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Section 4.2 Preparation/Handling/Storage of GSK2849003 GSK Investigational 
Product, Preparation
REVISED TEXT (new text bold and underlined, deleted text in strikethrough)
Preparation
Dilute GSK2849330 solution into a 0.9% sodium chloride IV bag to the appropriate 
concentration for the dose. Deliver the entire contents of the IV bag to the subject.The 
administration kits can be polymerizing vinyl chloride (PVC), polyolefin (PO) plastics or 
0.22M polyethersulfone (PES).  A filtration set will not be used for this study. A 0.22-
M polyethersulfone (PES) filtration set will be used for this study.
Section 5.1 Number of Subjects
REVISED TEXT (new text bold and underlined, deleted text in strikethrough)
The number of dose levels and the level at which the MTD is reached cannot be 
determined in advance.  An adequate number of subjects will be enrolled into the study to 
establish the recommended dose(s) for further study.  It is estimated that approximately 
1013 subjects will be enrolled in Part 1 dose escalation if there are no DLTs observed; if 
there are any DLTs observed, more than 10 13 subjects can be enrolled in dose 
escalation. Up to an additional 21 subjects with evaluable pre- and on-treatment paired 
biopsies can be enrolled for the purpose of the PK/PD cohorts in Part 1. Therefore, up to 
approximately 31 34 subjects may be enrolled into Part 1 (dose-escalation and PK/PD 
cohorts) of the study; however additional dose escalation cohorts may be enrolled to 
allow for further evaluation of additional dose levels/regimens if warranted.
In Part 2 of the study, there will be at least 4 molecularly-defined tumor histology 
expansion groups.  It is estimated that a minimum of 12 subjects will be enrolled in each 
expansion group with a maximum of approximately 30subjects if futility criteria are 
not met.  Part 2 (expansion cohorts) with a maximum of approximately 90 subjects if all 
three expansion cohorts are opened and futility criteria were not met.  Therefore, up to 
approximately 121 120 subjects may be enrolled in Part 2 and approximately 
154 subjects may be enrolled in the entire study; however, this number will be 
considerably fewer if futility conditions are met for any group in the expansion phase (see 
Section 3.4, Section 13.2.2, and Section 13.6.2). Additional subjects/cohorts may be 
enrolled to allow for further evaluation of additional dose levels if warranted. Additional 
groups of tumor histologies predicted to be sensitive to the study drug based on 
emerging nonclinical or clinical data may be added to Part 2.
In Part 1 (dose escalation) of the study, if subjects prematurely discontinue for reasons 
other than toxicity, additional subjects may be enrolled as replacement subjects and 
assigned to the same treatment cohort at the discretion of the Sponsor in consultation with 
the investigator.  Subjects may also be replaced in Part 2 of the study for the purpose of 
testing futility or to facilitate collection of sufficient tumor biopsies for exploratory 
analyses.

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Section 5.2.1, Pre-screening Inclusion Criteria for Part 1
REVISED TEXT
Pre-screening Inclusion Criteria for Parts 1 and 2
Subjects will be eligible for inclusion in pre-screening for the study (See Section 3.2) 
only if all of the following criteria apply:
1. Males and females ≥18 years of age (at the time consent is obtained).
2. Written informed consent provided.
3. Performance Status score of 0 or 1 according to the Eastern Cooperative 
Oncology Group (ECOG) scale (see Appendix 3).
4. Sufficient archival tumor specimen is available for HER3 IHC analysis, or subject 
is willing to undergo a fresh tumor biopsy for HER3 IHC analysis (see Section 
7.6.1.1 for details).
5. Histologically or cytologically confirmed diagnosis of one of the following solid 
tumor malignancies for which no standard therapeutic alternatives exist:

Bladder cancer

Breast cancer

Castrate-resistant prostate cancer

Cervical cancer

Colorectal cancer (CRC)

Gastric cancer

Hepatocellular carcinoma (HCC)

Melanoma

Non-small cell lung cancer (NSCLC)

Ovarian cancer

Pancreatic cancer

Squamous cell cancers of the head and neck region (SCCHN)(including 
parotid and nasopharynx)
Section 5.2.2 Pre-screening for Part 2
NEW TEXT (new text bold and underlined, deleted text in strikethrough)
Subjects with either melanoma, gastric/gastroesophageal cancer, head and neck 
cancer, or NSCLC who appear to meet all inclusion and exclusion criteria may be 
pre-screened for the study provided that sufficient tumor specimen is available for 
analyzing HER3 by IHC or HER3 by IHC and NRG1 by RNA analysis.

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Section 5.2.3 Screening Inclusion Criteria for Parts 1 and 2, Criterion 3
REVISED TEXT (new text bold and underlined, deleted text in strikethrough)
15. For subjects enrolled in Part 1:subjects Subjects must have tumors with 
documented HER3 expression (2+ or 3+) on the cell surface of the invasive 
component of tumor (either on archival tissue or fresh tumor biopsy) using an 
analytically validated IHC assay by central laboratory (see Section 7.6.1.1 for 
details). Subjects enrolled in Part 2 must meet inclusion criterion 9 listed below.
Section 5.2.3 Screening Inclusion Criteria for Parts 1 and 2, Criterion 5 
REVISED TEXT (new text bold and underlined, deleted text in strikethrough)
5. Adequate baseline organ function defined by: 
SYSTEM
LABORATORY VALUES
Hematologic
  ANC
1.5 x 109/L
  Hemoglobin
9 g/dL 
  Platelets
75 x 109/L
PT/INR and  
1.3x ULNc
Hepatic
  Albumin
2.5 g/dL
  Total bilirubin
1.5 X ULN
 AST and ALT
2.5 X ULN
Renal
Serum creatinine
OR
Estimated glomerular filtration rate or 
24-hr urine creatinine clearancea
ULN
OR
50 mL/min
Cardiac
LVEF
50% by ECHO or MUGA
ALT = alanine aminotransferase; ANC = absolute neutrophil count; AST = aspartate aminotransferase; 
ECHO = echocardiogram; INR = international normalized ratio; LVEF = left ventricular ejection 
fraction; MUGA = multiple-gated acquisition scan; PT = prothrombin time; PTT = partial thromboplastin 
time; ULN = upper limit of normal.
a.Estimated glomerular filtration rate will be calculated by the Modification of Diet in Renal Disease 
(MDRD) equation (Appendix 4). When both a calculated and 24-hr creatinine clearance are available, 
the 24-hr value will be used.
bECHO is the preferred method. MUGA should be performed only if evaluation by ECHO is not 
available...

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Section 5.2.4 Inclusion Criteria for Part 2 ONLY
NEW TEXT (new text bold and underlined, deleted text in strikethrough)
As listed above for Part 1, with the exception of criterion 3 which should be replaced 
with the following criterion 9 and the addition of criteria 10 and 11.
Criterion 9
9. For Group 1: subjects with previously treated, unresectable stage III or IV 
melanoma with documented HER3 expression (3+) on the cell surface of the 
invasive component of the tumor (either on archival tumor or fresh tumor 
biopsy) using an analytically validated IHC assay by central laboratory.

Subjects must have no more than 3 prior lines of systemic regimens 
and have disease progression on or after last prior treatment (based 
on RECIST v1.1 ).
o
Subjects with BRAF V600 mutations who already received or 
were intolerant of prior BRAF inhibitor therapy may be 
included.BRAF V600 inhibitor-naïve subjects will be eligible if 
a BRAF inhibitor is not available to them commercially or via 
a clinical trial.

Subjects may be included if they had prior immune therapy, were 
intolerant of prior immune therapy, or if such therapy is not available 
to them commercially or via a clinical trial.
For Group 2: Subjects with previously treated, unresectable stage III or IV 
gastric or gastroesophageal junction (GEJ) adenocarcinoma with 
documented HER3 expression (3+) on the cell surface of the invasive 
component of the tumor (either on archival tumor or fresh tumor biopsy) 
using an analytically validated IHC assay by central laboratory.

Subjects must have no more than 3 prior lines of systemic regimens 
and have disease progression on or after last prior treatment (based 
on RECIST v1.1 ).

Subjects with HER2 positive disease may be included if they had prior 
anti-HER2 therapy or were intolerant of prior anti-HER2 therapy or 
if such therapy is not available to them commercially or via a clinical 
trial.
For Group 3: Subjects with previously treated, unresectable stage III or IV 
cancers of the head and neck with documented HER3 expression ( 1+) and 
NRG1 expression on the cell surface of the tumor (either on archival tumor 
or fresh tumor biopsy) using analytically validated assays by central 
laboratory.

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
Subjects must have no more than 3 prior lines of systemic therapy and 
have disease progression on or after last prior treatment (based on 
RECIST v1.1).

Subjects with locoregional recurrences amenable to definite surgery 
or additional radiation are excluded.
For Group 4: Subjects with previously treated, unresectable stage III or IV 
NSCLC with documented HER3 expression ( 1+) and NRG1 expression on 
the cell surface of the tumor (either on archival tumor or fresh tumor biopsy) 
using analytically validated assays by central laboratory.

Subjects must have no more than 3 prior lines of systemic regimens 
and have disease progression on or after last prior treatment (based 
on RECIST v1.1.).

Subjects with anaplastic lymphoma kinase (ALK) translocation who 
already received or were intolerant of prior anti-ALK therapy may be 
included.Anti-ALK therapy-naïve subjects will be eligible for the 
study if such a therapy is not available to them commercially or via a 
clinical trial.

Subjects with EGFR mutations (e.g., exon 19 deletion and exon 21 
L858R) who have documented progression (based on RECIST 1.1 
criteria) or who were intolerant of prior EGFR inhibitors may be 
included.EGFR inhibitor-naive subjects will be eligible for the study if 
such a therapy is not available to them commercially or via a clinical 
trial.
Additional tumor histology groups   predicted to be sensitive to the study 
drug based on biomarkers (e.g., HER3 mutations, NRG translocations ) 
supported by preclinical or clinical data may be added based on emerging 
data.
Criterion 10
Subjects must have at least one measurable lesion per RECIST v1.1.
NOTE: If the only site of measurable disease has been previously irradiated, 
documented progression of disease and a 4-week interval since completion of 
radiotherapy is required.
NOTE: In subjects with 1 measurable lesion, a measurable lesion may be 
biopsied at Screening and Day 15; however that lesion must not be selected 
as a target lesion for disease assessment.
Criterion 11
Subjects must have disease amendable to biopsy and agree to undergo pre-
and on-treatment tumor biopsies (until the participating centers receive 

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written notification from the Sponsor that paired tumor biopsies are no 
longer required).
Section 5.2.5 Screening Exclusion Criteria Parts 1 and 2, Criterion 1
REVISED TEXT (new text bold and underlined, deleted text in strikethrough)
1. Subjects with leptomeningeal or brain metastases or spinal cord compression.

Subjects with untreated brain or meningeal metastases are not eligible 
(computed tomography [CT] scans are not required to rule this out 
unless there is a clinical suspicion of central nervous system [CNS] 
disease.

Subjects with treated and radiologic or clinical evidence of stable 
brain metastases (confirmed by 2 scans at least 4 weeks apart), with 
no evidence of cavitation or hemorrhage in the brain lesion are 
eligible providing that they are asymptomatic and do not require 
corticosteroids. Subjects are not permitted to receive enzyme inducing 
anti-epileptic drugs.
Section 5.2.5 Screening Exclusion Criteria Parts 1 and 2, Criterion 3
REVISED TEXT (new text bold and underlined, deleted text in strikethrough)
3. Use of an investigational anti-cancer drug within 28 days or 5 half-lives, 
whichever is longer, preceding the first dose of GSK2849330 OR chemotherapy 
within the last 3 weeks (6 weeks for prior nitrosourea or mitomycin C) OR any 
major surgery, radiotherapy, immunotherapy or any other anti-cancer therapy 
within the last 4 weeks except as noted above.
Section 5.2.5 Screening Exclusion Criteria Parts 1 and 2, Criterion 7
REVISED TEXT (new text bold and underlined, deleted text in strikethrough)
7.
History or evidence of significant cardiovascular risk including any of the 
following:

LVEF <50%

A QT interval corrected for HR using the Fredericia’s formula (QTc) 
480 msec (≥500 msec for subjects with bundle branch block)

History or evidence of current clinically significant uncontrolled 
arrhythmias.
Exception: Subjects with controlled atrial fibrillation for >30 days prior to 
enrollment are eligible.

History of acute coronary syndromes (including myocardial infarction and 
unstable angina), coronary angioplasty, or stenting within 6 months prior 
to enrollment.

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
History or evidence of current ≥ Class II congestive heart failure as 
defined by New York Heart Association (NYHA).
Section 6.2 Subject Completion Criteria
REVISED TEXT (new text bold and underlined, deleted text in strikethrough)
A subject will be considered to have completed the study if they complete screening 
assessments and one study treatment. In Part 1, a subject will be considered to have 
completed the study if they complete screening assessments and at least one study 
treatment followed by at least 28 days of observation. In Part 2, a subject will be 
considered to have completed the study if they have completed at least one on-
treatment disease assessment.
Section 6.3 Permanent Discontinuation from Study Treatment
REVISED TEXT (new text bold and underlined, deleted text in strikethrough)
Subjects will receive study treatment until disease progression, death or unacceptable 
toxicity, including meeting stopping criteria for liver chemistry defined in Section 3.9.1  
.In addition, study treatment maywill be permanently discontinued for any of the 
following reasons

major deviations(s) from the protocol

request of the subject or proxy (withdrawal of consent by subject or proxy)

investigator’s discretion

a dose delay for toxicity of > 2 weeks unless the investigator or GSK Medical 
Monitor agree that further treatment may benefit the subject

intercurrent illness that prevents further administration of study treatment

subject is lost to follow-up, or the 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, ‘AE’ will be 
recorded as the primary reason for permanent 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 assessments at the 
time of discontinuation and during post-study treatment follow-up as specified in Time 
and Events Tables (see Section 7.1).

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Section 6.4 Study Completion
REVISED TEXT (new text bold and underlined, deleted text in strikethrough)
The study will be considered completed, that is, having met the study objectives, 
after 70% of the subjects have died or 2 years after the last subject is enrolled. Upon 
completion of the study, if subjects are still continuing to receive benefit from 
GSK2849330, plans will be developed to provide continued access for those subjects
if warranted.
Per the EU Clinical Trial Directive, the end of the study is defined as the last subject’s 
last visit (LSLV).
Section 7 Study Assessments and Procedures 
REVISED TEXT (new text bold and underlined, deleted text in strikethrough)
A signed, written informed consent form must be obtained from the subject prior to any 
study-specific procedures or assessments being performed. Procedures conducted as part 
of the subject’s routine clinical management (e.g., blood count, ECG, ECHO/MUGA) 
obtained prior to their signing the informed consent may be utilized for screening or 
baseline purposes provided these procedures are conducted as specified in the protocol 
and have been performed within the protocol-specified timeframe.  However physical 
exam, medical history, ECOG performance status, and vital signs must be conducted 
after the informed consent is signed regardless of when these procedures may have been 
performed as part of routine clinical management.
The timing of each assessment is listed in the Time and Events Tables (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 safety, PK, PD/biomarker, 
immunogenicity, imaging or other assessments.  Changes in timing, addition, or removal 
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. No more than 200 mL of 
blood will be collected over a 30-day period, including any extra assessments that may be 
required.
Whenever vital signs, 12-lead ECGs and blood draws are scheduled for the same nominal 
time, the assessments should occur in the following order: 12-lead ECG, vital signs, 
blood draws.  The timing of the assessments should allow the blood draw to occur at the 
exact nominal time.  Detailed procedures for obtaining each assessment are provided in 
the SPM.
After a subject has provided written informed consent for pre-screening, the 
investigator or other study personnel will determine if the subject is eligible for pre-
screening in the study.  This will be done by reviewing the pre-screening inclusion 
criteria (Section 5.2.1) and completing all of the pre-screening assessments outlined 

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in the Time and Events Table (Section 7.1).  Pre-screening assessments may be carried 
out over more than one day.
If during pre-screening the subject is determined to have the required a tumor 
expressing HER3 or HER3 and NRG1 levels of expression (see Inclusion criteria 3),
then after a subject has provided written informed consent for the study and within 
14 days of the first dose of study treatment, the investigator or other study personnel will 
determine if the subject is eligible for enrollment in the study. .This will be done by 
reviewing the inclusion and exclusion criteria and completing all of the screening 
assessments outlined in the Time and Events Tables (Section 7.1).  Screening 
assessments may be carried out over more than one day provided that all required 
assessments are completed within14 days prior to the first dose of study treatment.

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Section 7.1 Time and Events Tables
REVISED TEXT (new text bold and underlined, deleted text in strikethrough)
Table 7
Time and Events for Part 1 (Dose Escalation Cohorts, every 2 week dosing schedule)
Pre-
screening
Screening
First Treatment Period (28 days)
Day 29
Continuation Phase
Follow-
up1
Post-
study2
Day 1
Day 8 
Day 15 
-14 day 
window3
1 day window for 
each visit
1 day 
window 
3 day window for each 
visit
7 day 
window 
+ 7 day 
window 
Informed consent
X
X
Archival tissue 
X
Tumor biopsy
X4
X5
X6 pre-dose
X7
Skin biopsy
X pre-dose
X pre-dose
Baseline demographics
X
X
Medical history
X
X
X
X
Concurrent medication
Continuous
X
Pregnancy test8
X3
X pre-
dose
Every 4 weeks from day 29
X
X
Physical examination
X
X9
X
X
Every 4 weeks from day 29
X
Height (at screening 
only) and weight
X
X
X
Weight: Every 4 weeks from 
first dose
X
ECOG 
X
X
X9
X
Every 4 weeks from first 
dose
X
Vital signs (BP, pulse 
rate, Temperature)
X
X10
X
X
X
Every 2 weeks from day 2910
X
12-lead ECG
X
X10
X
X
Every 4 weeks from day 29
X
Hematology/Clinical 
Chemistry
X
X9
X
X
X
Every 2 weeks from day 29
X

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Pre-
screening
Screening
First Treatment Period (28 days)
Day 29
Continuation Phase
Follow-
up1
Post-
study2
Day 1
Day 8 
Day 15 
-14 day 
window3
1 day window for 
each visit
1 day 
window 
3 day window for each 
visit
7 day 
window 
+ 7 day 
window 
Coagulation 
parameters PT, INR, 
PTT
X
As Clinically Indicated
Urinalysis
X
X
Every 4 weeks from day 29
X
ECHO11
X
X
Every 8 weeks
X
PK (Blood)12
X
X
X
X
Every 12 weeks from the first 
dose
X7
X
Circulating cell free 
DNA (cfDNA)
X pre-dose
X7
Testosterone and LH13
X pre-dose
X
Every 8 weeks from day 29
Whole blood/serum 
/cellular markers14
X
X
X
X
X7
GSK2849330 IV 
infusion15
X
X
X
Every 2 weeks15from the first 
dose
AE assessment 
Continuous
Serum sample for 
Immunogenicity
X pre-dose
X
X
Every 12 weeks16 from the
first dose
X16
PGx sample
X pre-
dose17
Tumor markers 18
X
Every 8 weeks from the first 
dose
Disease assessment19
X3
Every 8 weeks from the first 
dose
X21
1.
The Follow-up visit should be approximately 28 days after the last dose of study treatment.
2.
The Post-study visit should be at least 45 days or 5 half-lives (whichever is longer) after the last dose of study treatment.
3.
Within 14 days prior to first dose except for pregnancy test (7 days) and Disease Assessment within 28 days prior to the first dose.
4.
Separate pre-screening consent required for fresh biopsy and fresh biopsy is only collected at pre-screening if archived tissue is not available.

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5.
Fresh pre- and on-treatment tumor biopsy is optional, but strongly encouraged for dose escalation cohorts; if adequate fresh biopsy tumor tissue is acquired 
during pre-screening, then this does not need to be repeated on Day 1.  Archival tumor tissue is not acceptable to serve as pre-treatment tumor tissue.
6.
Tumor biopsy is optional on Day 15 for dose escalation cohort subjects and required for the PK/PD cohorts. Biopsy must be collected prior to study treatment 
administration on Day 15 dose (pre-dose). 
7.
Collected at progression. Tumor biopsy is optional and only collected for subjects with disease progression on study treatment. The tumor 
specimen may be collected at any time after study treatment discontinuation, but must occur prior to the start of any subsequent anticancer 
therapy.
8.
Perform only in women of child-bearing potential.  Serum pregnancy test should be conducted at the Screening, Follow-up, and Post-study visits.  Urine 
pregnancy test should be conducted pre-dose on Day 29 and every 4 weeks from Day 29 in the continuation phase of the study.
9.
If completed within 72 hours of the first dose, this assessment does not need to be repeated on Day 1.
10. Collect at pre-dose,and at 1, 2, 4, and 6 hours after the start of infusion. For subjects in Cohort 1 on a weekly dosing schedule vital signs should be conducted 
weekly at each dosing visit in clinic.
11. ECHO is preferred; however, if echocardiography is not available, or if reliable echocardiographic analysis of LVEF is unable to be obtained due to technical 
factors, a MUGA scan may be performed.  Regardless, the method used at Baseline should be used for the remaining assessments in the study. 
Assessments should be performed more frequently than every 8 weeks if clinically indicated.
12. Blood samples for analysis of GSK2849330 concentrations will be collected on Day 1: pre-dose and at 1hour (15-minute window), and 6 hours (1-hour 
window) after the end of infusion. If a subject’s duration of infusion is 3 hours or longer the 6-hour time point is optional. Additional PK samples will be 
collected at Day 8, Day 15, and Day 29. Additional PK samples will also be taken every 12 weeks from the first dose within 1 year of starting treatment and if 
treatment continues after 1 year samples will be collected every 24 weeks. An additional PK sample will also be taken at the Post-study visit. On days of 
dosing sample will be drawn pre-dose.Unless stated otherwise, on days of dosing sample will be drawn pre-dose. For the first subject in Cohort 1 
additional PK samples will be taken at 24 hours (Day 2 [8-hour window]) and at 72 hours (Day 4 [24-hour window]) after the end of infusion of the first 
dose of GSK2849330. 
13. To be conducted in male subjects only.
14. Whole blood for soluble markers from plasma, serum, and/or cellular markers.  Blood samples will be collected on Day 1: pre-dose and at 1 hour (15-minute 
window) and 6 hour (1-hour window) after the end of infusion.  If a subject’s duration of infusion is 3 hours or longer the 6-hour time point is optional. A pre-
dose blood sample should be collected on Day 8, Day 15 and Day 29 for all cohorts. An additional sample will also be collected at progression.
15. For the subject(s) in Cohorts 1 and 5, and any subjects receiving a weekly dosing schedule, the study treatment dosing window is 2 days.  The study 
treatment dosing window for all other dosing schedules (e.g., an every 2-week or every 3 week dosing schedule) is 3 days. If dosing does not occur on the 
intended day, all other assessments/subsequent visits should be changed accordingly relative to when the dose was received. Subject (s) in Cohort 1 will 
receive the dose weekly in clinic.  Cohorts 2-4 will receive the dose every 2 weeks.  Subsequent cohorts may receive different dosing schedules. Use the 
appropriate Time and Events Table as applicable.
16. After the first treatment period, immunogenicity samples will be collected every 12 weeks from the first dose within one year of treatment. If treatment 
continues after 1 year, samples will be collected every 24 weeks. An immunogenicity sample must also be collected at the Post-study visit. 

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17. It is preferred that the PGx sample be taken pre-dose on Day 1; however, it may be obtained anytime after informed consent has been given for PGx 
research.
18. See Section 7.8 and collect all tumor markers applicable for the subject’s primary tumor type.
19. Confirmatory assessments will occur at least 4 weeks after assessments demonstrating CR or PR. Confirmatory assessments may be conducted at a 
subject’s next regularly scheduled visit as appropriate.
20. A blood sample for select serum safety markers (including, but not limited to TNF alpha, IL-6, and tryptase) should be drawn within 24 hours of 
suspected infusion-related reactions.
21. Disease assessment must be performed either at the Follow up visit or at the Post-Study visit prior to the start of any subsequent anti-cancer 
therapy.
NEW TEXT
Table 8
Time and Events for Part 1 (Dose Escalation Cohorts, every week dosing schedule)
Pre-
screen
Screen
First Treatment Period (28 days)
Day 29
Continuation 
Phase
Follow-
up1
Post-
study2
Day 1
Day 2
Day 4
Day 8 
Day 15 
Day 22
-14 day 
window3
1 day window for each visit
2 day 
window for 
each visit
+ 7 day window 
Informed consent
X
X
Archival tissue 
X
Tumor biopsy
X4
X5
X6 pre-
dose
X7
Skin biopsy
X pre-
dose
X pre-
dose
Baseline 
demographics
X
X
Medical history
X
X
X

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Pre-
screen
Screen
First Treatment Period (28 days)
Day 29
Continuation 
Phase
Follow-
up1
Post-
study2
Day 1
Day 2
Day 4
Day 8 
Day 15 
Day 22
-14 day 
window3
1 day window for each visit
2 day 
window for 
each visit
+ 7 day window 
Concurrent 
medication
Continuous
Pregnancy test8
X3
X pre-
dose
Every 4 
weeks
X
X
Physical 
examination
X
X9
X
X
Every 4 
weeks
X
Height (at 
screening only) and 
weight
X
X
X
Weight: Every 
4 weeks
X
ECOG 
X
X9
X
Every 4 
weeks
X
Vital signs (BP, 
pulse rate, 
Temperature)
X
X10
X
X
X
X
Every week22 
X
12-lead ECG
X
X10
X
X
Every 4 
weeks
X
Hematology/ 
Clinical Chemistry
X
X9
X
X
X
X
Every week22
X
Coagulation 
parameters: PT, 
INR, PTT
X
As clinically indicated
Urinalysis
X
X
Every 4 
weeks
X
ECHO11
X
X
Every 8 
weeks
X

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Pre-
screen
Screen
First Treatment Period (28 days)
Day 29
Continuation 
Phase
Follow-
up1
Post-
study2
Day 1
Day 2
Day 4
Day 8 
Day 15 
Day 22
-14 day 
window3
1 day window for each visit
2 day 
window for 
each visit
+ 7 day window 
PK (Blood)12
X
X
X
X
X
X
X
X12
X
X
Safety cytokines20
In the event of infusion reaction
Circulating cell 
free DNA (cfDNA)
X pre-
dose
X7
Testosterone and 
LH13
X pre-
dose
X
Every 8
Whole blood/serum 
/cellular markers14
X
X
X
X
X7
GSK2849330 IV 
infusion15
X
X
X
X
X
Every week15
AE assessment
Continuous
Serum sample for 
Immunogenicity
X pre-
dose
X16
X16
PGx sample
X pre-
dose17
Tumor markers 18
X
Every 8 
weeks
Disease 
assessment19
X3
Every 8 
weeks
X21
1.
The Follow-up visit should be approximately 28 days after the last dose of study treatment.
2.
The Post-study visit should be at least 45 days or 5 half-lives (whichever is longer) after the last dose of study treatment.
3.
Within 14 days prior to first dose except for pregnancy test (7 days) and Disease Assessment within 28 days prior to the first dose.
4.
Separate pre-screening consent required for fresh biopsy and fresh biopsy is only collected at pre-screening if archived tissue is not available.

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5.
Fresh pre- and on-treatment tumor biopsy is optional, but strongly encouraged for dose escalation cohorts; if adequate fresh biopsy tumor tissue 
is acquired during pre-screening, then this does not need to be repeated during the screening period.  Archival tumor tissue is not acceptable to 
serve as pre-treatment tumor tissue.
6.
Tumor biopsy is optional on Day 15 for dose escalation cohort subjects and required for the PK/PD cohorts. Biopsy must be collected prior to 
study treatment administration on Day 15 dose (pre-dose). 
7.
Collected at progression. Tumor biopsy is optional and only collected for subjects with disease progression on study treatment. The tumor 
specimen may be collected at any time after study treatment discontinuation, but must occur prior to start of any subsequent anticancer therapy.
8.
Perform only in women of childbearing potential.  Serum pregnancy test should be conducted at the Screening, Follow-up, and Post-study visits.  
Urine pregnancy test should be conducted pre-dose on Day 29 and every 4 weeks from Day 29 in the continuation phase of the study.
9.
If completed within 72 hours of the first dose, this assessment does not need to be repeated on Day 1.
10. Collect at pre-dose, and at 1, 2, 4, and 6 hours after the start of the first infusion.
11. ECHO is preferred; however, if echocardiography is not available, or if reliable echocardiographic analysis of LVEF is unable to be obtained due to 
technical factors, a MUGA scan may be performed.  Regardless, the method used at Baseline should be used for the remaining assessments in the 
study. Assessments should be performed more frequently than every 8 weeks if clinically indicated.
12. Blood samples for analysis of GSK2849330 concentrations will be collected on Day 1: pre-dose, and at 1 hour (15-minute window), 6 hour (1-
hour window) and 24 hours after the end of infusion. Pre-dose samples will also be collected on Day 4, Day 8 and weekly through Day 57 with 
additional 1-hour post-dose samples collected on Days 29 and 57. Pre-dose samples will also be collected on Day 71, Day 85 and every 12 weeks 
thereafter.  If treatment continues after 1 year, samples will be collected every 24 weeks. An additional PK sample will also be taken at the Follow-
up and Post-study visits.
13. To be conducted in male subjects only.
14. Whole blood for soluble markers from plasma, serum, and/or cellular markers.  Blood samples will be collected on Day 1: pre-dose and at 1 hour 
(15-minute window) and 6 hours (1-hour window) after the end of infusion.  If a subject’s duration of infusion is 3 hours or longer the 6-hour 
time point is optional. A pre-dose blood sample should be collected on Day 8, Day 15 and Day 29 for all cohorts. An additional sample will also be 
collected at progression.
15. For the subjects in Cohorts 1 and 5, and any subjects receiving a weekly dosing schedule, the study treatment dosing window is 2 days.  The 
study treatment dosing window for all other dosing schedules (e.g., an every 2 week or every 3 week dosing schedule) is 3 days. If dosing does 
not occur on the intended day, all other assessments/subsequent visits should be changed accordingly relative to when the dose was received. 
Subsequent cohorts may receive different dosing schedules. Use the appropriate Time and Events Table as applicable.
16. An immunogenicity sample must be collected at the Follow-up and Post-study visits.
17. It is preferred that the PGx sample be taken pre-dose on Day 1; however, it may be obtained anytime after informed consent has been given for 
PGx research.
18. See Section 7.8 and collect all tumor markers applicable for the subject’s primary tumor type.

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19. Confirmatory assessments will occur at least 4 weeks after assessments demonstrating CR or PR. Confirmatory assessments may be conducted 
at a subject’s next regularly scheduled visit as appropriate.
20. A blood sample for select serum safety markers (including but not limited to TNF alpha, IL-6, and tryptase) should be drawn within 24 hours of 
suspected infusion-related reactions.
21. Disease assessment must be performed either at the Follow-up visit or at the Post-Study visit prior to the start of any subsequent anticancer
therapy
22. Assessments to be performed weekly while receiving weekly dosing and bi-weekly if switched to a bi-weekly dosing regimen
REVISED TEXT (new text bold and underlined, deleted text in strikethrough)
Table 9
Time and Events for Part 1 PK/PD Cohorts (every 2 week dosing schedule)
Pre-
screening
Screening
First Treatment Period (28 days)
Day 29
Continuation Phase
Follow-
up1
Post-
study2
First Week
Day 15
Day 1
Day 2
Day 4
Day 8
- 14 day 
window3
1 day window for each 
visit
3 day window for each visit
+ 7 day 
window
Informed consent
X
X
Archival tissue 
X
Tumor biopsy
X4
X5
X6 pre-
dose
X7
Skin biopsy
X pre-
dose
X pre-
dose
Baseline 
demographics
X
X
Medical history
X
X
X
Concurrent Medication
Continuous
X
Pregnancy test8
X3
X pre-
dose
Every 4 weeks from day 29
X
X
Physical examination
X
X9
X
X
Every 4 weeks from day 29
X

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Pre-
screening
Screening
First Treatment Period (28 days)
Day 29
Continuation Phase
Follow-
up1
Post-
study2
First Week
Day 15
Day 1
Day 2
Day 4
Day 8
- 14 day 
window3
1 day window for each 
visit
3 day window for each visit
+ 7 day 
window
Height (at screening 
only) and weight
X
X
X
Weight: Every 4 weeks from 
first dose
X
ECOG 
X
X
X9
X
Every 4 weeks from day 29
X
Vital signs (BP, pulse 
rate, Temperature)
X
X10
X
X
X
X
X
Every 2 weeks from day 
2910
X
12-lead ECG
X
X10
X
X
Every 4 weeks from day 29
X
Hematology/Clinical 
Chemistry
X
X9
X
X
X
Every 2 weeks from day 29
X
Coagulation 
parameters PT, INR, 
PTT
X
As Clinically Indicated
Urinalysis
X
X
Every 4 weeks from day 29
X
ECHO11
X
X
Every 8 weeks
X
PK (Blood)12
X
X
X
X
X
X
Every 12 weeks from the 
first dose
X7
X
cfDNA
X pre-
dose
X7
Testosterone and LH13
X pre-
dose
X
Every 8 weeks from day 29
Whole blood/serum 
/cellular markers14
X
X
X
X
X
X7
GSK2849330 IV 
infusion15
X
X
X
Every 2 weeks15 from the 
first dose
AE assessment 
Continuous
Serum sample for 
Immunogenicity
X pre-
dose
X
X
Every 12 weeks16
from  the first dose
X16
X16

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Pre-
screening
Screening
First Treatment Period (28 days)
Day 29
Continuation Phase
Follow-
up1
Post-
study2
First Week
Day 15
Day 1
Day 2
Day 4
Day 8
- 14 day 
window3
1 day window for each 
visit
3 day window for each visit
+ 7 day 
window
PGx Sample17
X pre-
dose
Tumor markers 18
X
Every 8 weeks from the first 
dose
Disease assessment19
X3
Every 8 weeks from the first 
dose
1.
The Follow-up visit should be approximately 28 days after the last dose of study treatment.
2.
The Post-study visit should be at least 45 days or 5 half-lives (whichever is longer) after the last dose of study treatment.
3.
Within 14 days prior to first dose except for pregnancy test (7 days) and Disease Assessment within 28 days prior to the first dose.
4.
Separate pre-screening consent required for fresh biopsy and fresh biopsy is only collected at pre-screening if archived tissue is not available.
5.
Fresh tumor biopsy is required for the PK/PD cohort; if adequate tumor biopsy is obtained during pre-screening, then this does not need to be repeated. 
Archival tumor tissue is not acceptable to serve as pre-treatment tumor tissue.
6.
Tumor biopsy is required on Day 15 pre-dose for PK/PD cohort. Biopsy must be collected prior to administration of Day 15 dose. 
7.
Collected at progression. Tumor biopsy is optional and only collected from subjects with disease progression on study treatment. The tumor 
specimen may be collected at any time after study treatment discontinuation, but must occur prior to start of any subsequent anticancer therapy.
8.
Perform only in women of childbearing potential. Serum pregnancy test should be conducted at the Screening, Follow-up, and Post-study visits.  Urine 
pregnancy test should be conducted pre-dose on Day 29 and every 4 weeks from Day 29 in the continuation phase of the study.
9.
If completed within 72 hours of the first dose, this assessment does not need to be repeated on Day 1.
10. Collect at pre-dose, and at 1, 2, 4, and 6 hours after the start of infusion.For subjects in Cohort 1 on a weekly dosing schedule vital signs should be conducted 
weekly at each dosing visit in clinic.
11. ECHO is preferred; however, if echocardiography is not available, or if reliable echocardiographic analysis of LVEF is unable to be obtained due to technical 
factors, a MUGA scan may be performed.  Regardless, the method used at Baseline should be used for the remaining assessments in the study. 
Assessments should be performed more frequently than every 8 weeks if clinically indicated.
12. Blood samples for analysis of GSK2849330 concentrations will be collected on Day 1: pre-dose and at 1 hour (15-minute window) and 6 hours (1-hour 
window) and 24 hour after the end of infusion. If a subject’s duration of infusion is 3 hours or longer the 6 hr time point is optional. Additional PK samples will 
be collected at 24 hr (Day 2 [8 hr window]), 72 hr (Day 4 [24 hr window]) after the end of infusion, and on Day 8, Day 15, and Day 29 after the first dose of 
GSK2849330. Additional PK samples will also be taken every 12 weeks from the first dose within 1 year of starting treatment and if treatment continues after 

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1 year samples will be collected every 24 weeks. An additional PK sample will also be taken at the Post-study visit. On days of dosing sample will be drawn 
pre-dose. Pre-dose samples will also be collected on Day 4, Day 8 and weekly through Day 57 with additional 1-hour post-dose samples collected 
on Days 29 and 57. Pre-dose samples will also be collected on Day 71, Day 85 and every 12 weeks thereafter.
13. To be conducted in male subjects only.
14. Whole blood for soluble markers from plasma, serum, and/or cellular markers.  Blood samples will be collected on Day 1: pre-dose and at 1 hour (15-minute 
window), 6 hours (1-hour window), and 24 hours (Day 2 [8-hour window]) after the end of infusion. If a subject’s duration of infusion is 3 hours or longer, 
the 6-hour time point is optional. A pre-dose blood sample should be collected on Day 8, Day 15 and Day 29 for all cohorts. An additional sample will be 
collected at progression.
15. For the subject(s) in cohort 1 and any subjects receiving a weekly dosing schedule the study treatment dosing window is 2 days.  Subject(s) in Cohort 1 will 
receive the dose weekly in clinic.  The study treatment dosing window is 3 days for subjects on an every 2-week dosing schedule. If dosing does not occur 
on the intended day, all other assessments/subsequent visits should be changed accordingly relative to when the dose was received. Cohorts 2-4 will receive 
the dose every 2 weeks. Subsequent cohorts may receive different dosing schedules. Use the appropriate Time and Events Table as applicable.
16. After the first treatment period, immunogenicity samples will be collected every 12 weeks from the first dose within 1 year of treatment. If treatment continues 
1 year, samples will be collected every 24 weeks. An immunogenicity sample must also be collected at the Post-study visit will be collected at the Follow 
up and Post-study visits.
17. It is preferred that the PGx sample be taken pre-dose on Day 1; however, it may be obtained anytime after informed consent has been given for PGx 
research.
18. See Section 7.8 and collect all tumor markers applicable for the subjects’ primary tumor type.
19. Confirmatory assessments will occur at least 4 weeks after assessments demonstrating CR or PR. Confirmatory assessments may be conducted at a 
subject’s next regularly scheduled visit as appropriate.
20. A blood sample for select serum safety markers (including but not limited to TNF alpha, IL-6, and tryptase) should be drawn within 24 hours of 
suspected infusion-related reactions.
21. Disease assessment must be performed either at the Follow-up visit or at the Post-Study visit prior to the start of any subsequent anticancer 
therapy.

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NEW TEXT
Table 10
Time and Events for Part 1 PK/PD Cohorts (every week dosing schedule)
Pre-
screening
Screening
First Treatment Period (28 days)
Day 29
Continuation 
Phase
Follow-
up1
Post-
study2
First Week
Day 15
Day 22
Day 1
Day 2
Day 4
Day 8
- 14 day 
window3
1 day window for each visit
2 day 
window for 
each visit
+ 7 day window
Informed consent
X
X
Archival tissue 
X
Tumor biopsy
X4
X5
X6 pre-
dose
X7
Skin biopsy
X pre-
dose
X pre-
dose
Baseline 
demographics
X
X
Medical history
X
X
X
Concurrent Medication
Continuous
X
Pregnancy test8
X3
X pre-
dose
Every 4 
weeks
X
X
Physical examination
X
X9
X
X
Every 4 
weeks
X
Height (at screening 
only) and weight
X
X
X
Weight: Every 
4 weeks
X
ECOG 
X
X9
X
Every 4 
weeks
X
Vital signs (BP, pulse 
rate, Temperature)
X
X10
X
X
X
X
X
Every week22 
X

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Pre-
screening
Screening
First Treatment Period (28 days)
Day 29
Continuation 
Phase
Follow-
up1
Post-
study2
First Week
Day 15
Day 22
Day 1
Day 2
Day 4
Day 8
- 14 day 
window3
1 day window for each visit
2 day 
window for 
each visit
+ 7 day window
12-lead ECG
X
X10
X
X
Every 4 
weeks
X
Hematology/Clinical 
Chemistry
X
X9
X
X
X
X
Every week22
X
Coagulation 
parameters: PT, INR, 
PTT
X
As Clinically Indicated
Urinalysis
X
X
Every 4 
weeks
X
ECHO11
X
X
Every 8 
weeks
X
PK (Blood)12
X
X
X
X
X
X
X
X12
X
X
Safety cytokines20
In the event of infusion reaction
cfDNA
X pre-
dose
X7
Testosterone and LH13
X pre-
dose
X
Every 8 
weeks 
Whole blood/serum 
/cellular markers14
X
X
X
X
X
X7
GSK2849330 IV 
infusion15
X
X15
X
X
X15
Every 
week15 
AE assessment 
Continuous
Serum sample for 
Immunogenicity
X pre-
dose
X16
X16
PGx Sample17
X pre-
dose

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Pre-
screening
Screening
First Treatment Period (28 days)
Day 29
Continuation 
Phase
Follow-
up1
Post-
study2
First Week
Day 15
Day 22
Day 1
Day 2
Day 4
Day 8
- 14 day 
window3
1 day window for each visit
2 day 
window for 
each visit
+ 7 day window
Tumor markers 18
X
Every 8 
weeks
Disease assessment19
X3
Every 8 
weeks
X21
1.
The Follow-up visit should be approximately 28 days after the last dose of study treatment.
2.
The Post-study visit should be at least 45 days or 5 half-lives (whichever is longer) after the last dose of study treatment.
3.
Within 14 days prior to first dose except for pregnancy test (7 days) and Disease Assessment within 28 days prior to the first dose.
4.
Separate pre-screening consent required for fresh biopsy and fresh biopsy is only collected at pre-screening if archived tissue is not available.
5.
Fresh tumor biopsy is required for the PK/PD cohort; if adequate tumor biopsy is obtained during pre-screening, then this does not need to be repeated. 
Archival tumor tissue is not acceptable to serve as pre-treatment tumor tissue.
6.
Tumor biopsy is required on Day 15 pre-dose for PK/PD cohort. Biopsy must be collected prior to administration of Day 15 dose. 
7.
Collected at progression. Tumor biopsy is optional and only collected from subjects with disease progression on study treatment. The tumor specimen may be 
collected at any time after study treatment discontinuation, but must occur prior to start of any subsequent anticancer therapy.
8.
Perform only in women of child-bearing potential. Serum pregnancy test should be conducted at the Screening, Follow-up, and Post-study visits.  Urine 
pregnancy test should be conducted pre-dose on Day 29 and every 4 weeks from Day 29 in the continuation phase of the study.
9.
If completed within 72 hours of the first dose, this assessment does not need to be repeated on Day 1.
10. Collect at pre-dose, and at 1, 2, 4, and 6 hours after the start of infusion. For subjects on a weekly dosing schedule, vital signs should be conducted weekly at 
each dosing visit in clinic.
11. ECHO is preferred; however, if echocardiography is not available, or if reliable echocardiographic analysis of LVEF is unable to be obtained due to technical 
factors, a MUGA scan may be performed.  Regardless, the method used at Baseline should be used for the remaining assessments in the study. 
Assessments should be performed more frequently than every 8 weeks if clinically indicated.
12. Blood samples for analysis of GSK2849330 concentrations will be collected Day 1: pre-dose, and at 1 hour (15-minute window), 6 hours (1-hr window) 
and 24 hours after the end of infusion. Pre-dose samples will also be collected on Day 8 and weekly through Day 57 with additional 1-hour post-dose samples 
collected on Days 29 and 57. Pre-dose samples will also be collected on Day 71, Day 85 and every 12 weeks thereafter.
13. To be conducted in male subjects only.

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14. Whole blood for soluble markers from plasma, serum, and/or cellular markers.  Blood samples will be collected on Day 1: pre-dose and at 1 hour (15-minute 
window), 6 hours (1-hour window), and 24 hours (Day 2 [8-hour window]) after the end of infusion. If a subject’s duration of infusion is 3 hours or longer, 
the 6-hour time point is optional. A pre-dose blood sample should be collected on Day 8, Day 15 and Day 29 for all cohorts. An additional sample will be 
collected at progression.
15. For the subjects receiving a weekly dosing schedule, the study treatment dosing window is 2 days The study treatment dosing window is 3 days for 
subjects on an every 2 week dosing schedule. If dosing does not occur on the intended day, all other assessments/subsequent visits should be changed
accordingly relative to when the dose was received.  Subsequent cohorts may receive different dosing schedules. Use the appropriate Time and Events Table 
as applicable.
16. An immunogenicity sample must be collected at the Follow-up and Post-study visits.
17. It is preferred that the PGx sample be taken pre-dose on Day 1; however, it may be obtained anytime after informed consent has been given for PGx 
research.
18. See Section 7.8 and collect all tumor markers applicable for the subject’s primary tumor type.
19. Confirmatory assessments will occur at least 4 weeks after assessments demonstrating CR or PR. Confirmatory assessments may be conducted at a 
subject’s next regularly scheduled visit as appropriate.
20. A blood sample for select serum safety markers (including but not limited to TNF alpha, IL-6, and tryptase) should be drawn within 24 hours of suspected 
infusion-related reactions.
21. Disease assessment must be performed either at the Follow-up visit or at the Post-Study visit prior to the start of any subsequent anticancer therapy.
22. Assessments to be performed weekly while receiving weekly dosing and bi-weekly if switched to a bi-weekly dosing regimen.

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REVISED TEXT (new text bold and underlined, deleted text in strikethrough)
Table 11
Time and Events for Part 1 PK/PD Cohorts (every 3 week dosing schedule)
Pre-
screening
Screening
First Treatment Period (21 days)
Continuation Phase
Follow-
up1
Post-
study2
First Week
Day 1
Day 2
Day 4
Day 8
Day 22
- 14 day 
window3
1 day window for 
each visit
3 day window for each visit
+7 day 
window
Informed consent
X
X
Archival tissue 
X
Tumor biopsy
X4
X5
X6pre-dose
X7
Skin biopsy
X pre-dose
X pre-dose
Baseline 
demographics
X
X
Medical history
X
X
X
X
Concurrent 
medication
Continuous
X
Pregnancy test8
X3
X pre-dose
Every 3 weeks from day 22
X
X
Physical examination
X
X9
X
Every 3 weeks from day 22
X
Height (at screening 
only) and weight
X
X
X
Weight: Every 3 weeks from 
day 22
X
ECOG 
X
X
X9
X
Every 3 weeks from from 
day 22
X
Vital signs (BP, pulse 
rate, Temperature)
X
X10
X
X
X
X
Every 3 weeks from day 22
X
12-lead ECG
X
X10
X
Every 3 weeks from day 22
X
Hematology/Clinical 
Chemistry
X
X9
X
X
Every 3 weeks from day 22
X
Urinalysis
X
X
Every 3 weeks from day 22
X
ECHO11
X
X
Every 9 weeks from day 22
X

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Pre-
screening
Screening
First Treatment Period (21 days)
Continuation Phase
Follow-
up1
Post-
study2
First Week
Day 1
Day 2
Day 4
Day 8
Day 22
- 14 day 
window3
1 day window for 
each visit
3 day window for each visit
+7 day 
window
PK (Blood)12
X
X
X
X
X
X Day 43  and every 12 
weeks from the first dose
X7
X
cfDNA
X pre-dose
X7
Testosterone and 
LH13
X pre-dose
X
Every 9 weeks from day 22
Whole blood/serum 
/cellular markers14
X
X
X
X
Day 43
X7
GSK2849330 IV 
infusion15
X
X
Every 3 weeks15 from the 
first dose
AE assessment 
Continuous
Serum sample for 
Immunogenicity
X pre-dose
X
X
Every 12 weeks16
from thefirst dose 
X16
PGx Sample17
X pre-dose
Tumor markers 18
X
Every 9 weeks from the first 
dose
Disease assessment19
X3
Every 9 weeks from the first 
dose
1.
The Follow-up visit should be approximately 28 days after the last dose of study treatment.
2.
The Post-study visit should be at least 45 days or 5 half-lives (whichever is longer) after the last dose of study treatment.
3.
Within 14 days prior to first dose except for pregnancy test (7 days) and disease assessment within 28 days prior to the first dose.
4.
Separate pre-screening consent required for fresh biopsy and fresh biopsy is only collected at pre-screening if archived tissue is not available.
5.
Fresh tumor biopsy is required for the PK/PD cohort; if adequate tumor biopsy is obtained during pre-screening, then this does not need to be repeated. 
Archival tumor tissue is not acceptable to serve as pre-treatment tumor tissue.
6.
Tumor biopsy is required on Day 22 pre-dose for PK/PD cohort. Biopsy must be collected prior to administration of Day 22 dose. 
7.
Collected at progression. Tumor biopsy is optional and only required from subjects with disease progression on study treatment. The tumor 
specimen may be collected at any time after study treatment discontinuation, but must occur prior to start of any subsequent anticancer therapy.

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8.
Perform only in women of childbearing potential.  Serum pregnancy test should be conducted at the Screening, Follow-up, and Post-study visits.  Urine 
pregnancy test should be conducted pre-dose on Day 22 and every 3 weeks from Day 22 in the continuation phase of the study. 
9.
If completed within 72 hours of the first dose, this assessment does not need to be repeated on Day 1.
10. Collect at pre-dose, and at 1, 2, 4, and 6 hours after the start of infusion.
11. ECHO is preferred; however, if echocardiography is not available, or if reliable echocardiographic analysis of LVEF is unable to be obtained due to technical 
factors, a MUGA scan may be performed.  Regardless, the method used at Baseline should be used for the remaining assessments in the study.
Assessments should be performed more frequently than every 9 weeks if clinically indicated.
12. Blood samples for analysis of GSK2849330 concentrations will be collected on Day 1: pre-dose and at 1 hour (15-minute window) and 6 hours (1-hour 
window) after the end of infusion. If a subject’s duration of infusion is 3 hours or longer the 6 hour time point is optional. Additional PK samples will be 
collected at 24 hours (Day 2 [8-hour window]) and 72 hours (Day 4 [24-hour window]) after the end of infusion, and at Day 8, Day 22, and Day 43 [1-
day window] after the first dose of GSK2849330. Additional PK samples will also be taken every 12 weeks from the first dose within 1 year of starting 
treatment and if treatment continues after 1 year samples will be collected every 24 weeks. An additional PK sample will be collected at the Post-study visit. 
On days of dosing sample will be drawn pre-dose.
13. To be conducted in male subjects only.
14. Whole blood for soluble markers from plasma, serum, and/or cellular marker.  Blood samples will be collected on Day 1: pre-dose and at 1 hour (15-minute 
window), 6 hours (1-hour window), and 24 hours (Day 2 [8-hour window]) after the end of infusion. If a subject’s duration of infusion is 3 hours or longer 
the 6-hour time point is optional. A pre-dose blood sample should be collected on Day 8, Day 22 and Day 43 for all cohorts. An additional blood sample 
should be collected at progression.
15. The study treatment dosing window is 3 days for an every 3 week dosing schedule. If dosing does not occur on the intended day, all other 
assessments/subsequent visits should be changed accordingly relative to when the dose was received.
16. After the first treatment period, immunogenicity samples will be collected every 12 weeks from the first dose within 1 year of treatment. If treatment continues 
after 1 year, samples will be collected every 24 weeks. An immunogenicity sample must also be collected at the Post-study visit.will be collected at the
Follow-up and Post-study visits.
17. It is preferred that the PGx sample be taken pre-dose on Day 1; however, it may be obtained anytime after informed consent has been given for PGx 
research.
18. See Section 7.8 and collect all tumor markers applicable for the subjects’ primary tumor type.
19. Confirmatory assessments will occur at least 4 weeks after assessments demonstrating CR or PR. Confirmatory assessments may be conducted at a 
subject’s next regularly scheduled visit as appropriate.
20. A blood sample for select serum safety markers (including but not limited to TNF alpha, IL-6, and tryptase) should be drawn within 24 hours of 
suspected infusion-related reactions.
21. Disease assessment must be performed either at the Follow-up visit or at the Post-Study visit prior to the start of any subsequent anticancer 
therapy.

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REVISED TEXT (new text bold and underlined, deleted text in strikethrough)
Table 12
Time and Events for Part 2 Expansion Cohorts Molecularly-Defined Tumor Histology Groups
Pre-
Screen
Screen
First Treatment Period (28 days)
Day 29
Continuation Phase
Follow up1
Post study2
Day 1
Day 8 
Day 15 
Day 22
-14 day 
window3
1 day window for each visit
2day window for 
each visit
+ 7 day window 
Informed consent
X
X
Archival tissue 
X
Tumor biopsy
X4
X5
X6 pre-
dose
X7
Baseline demographics
X
X
Medical history
X
X
X
Concurrent medication
Continuous
Pregnancy test8
X3
X pre-
dose
Every 4 weeks
X
X
Physical examination
X
X9
X
X
Every 4 weeks
X
Height (at screening 
only) and weight
X
X
X
Weight: Every 4 
weeks
X
ECOG 
X
X9
X
Every 4 weeks
X
Vital signs (BP, pulse 
rate, Temperature)
X
X10
X22
X
X22
X
Every week10,22 
X
12-lead ECG
X
X10
X
X
Every 4 weeks
X22
Hematology/Clinical 
Chemistry
X
X9
X22
X
X22
X
Every week22
X22
Coagulation 
parameters: PT, INR, 
PTT
X
As Clinically Indicated
Urinalysis
X
X
Every 4 weeks
X

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Pre-
Screen
Screen
First Treatment Period (28 days)
Day 29
Continuation Phase
Follow up1
Post study2
Day 1
Day 8 
Day 15 
Day 22
-14 day 
window3
1 day window for each visit
2day window for 
each visit
+ 7 day window 
ECHO11
X
X
Every 8 weeks
X
PK (Blood)12
X
X
X
X12
X
X
Safety cytokines20
In the event of an infusion reaction
Circulating cell free 
DNA (cfDNA)
X pre-
dose
X7
Testosterone and LH13
X pre-
dose
X
Every 8 weeks
Whole blood/serum 
/cellular markers14
X
X22
X
X
X7
GSK2849330 IV 
infusion15
X
X22
X
X22
X
Everyweek15,22
AE assessment
Continuous
Serum sample for 
Immunogenicity
X pre-
dose
X16
X16
PGx sample
X pre-
dose17
Tumor markers 18
X
Every 8 weeks
Disease assessment19
X3
Every 8 weeks
X21
1.
If completed within 72 hours of the first dose, this assessment does not need to be repeated on Day 1.
2.
Collect at pre-dose, and at 1, 2, 4, and 6 hours after the start of the first infusion.
3.
ECHO is preferred; however, if echocardiography is not available, or if reliable echocardiographic analysis of LVEF is unable to be obtained due to technical 
factors, a MUGA scan may be performed.  Regardless, the method used at Baseline should be used for the remaining assessments in the study. 
Assessments should be performed more frequently than every 8 or 9weeks if clinically indicated.
4.
Blood samples for analysis of GSK2849330 concentrations will be collected on Day 1: pre-dose and at 1 hour (15-minute window), after the end of infusion, 
and pre-dose on Day 15, Day 29, Day 43, Day 57, Day 71, Day 85, and every 12 weeks thereafter. Additional PK samples will be collected pre-dose Day 
15 and Day 29 for an every 2 week dosing schedule, and pre-dose Day 22 and Day 43 for an every 3 week dosing schedule, these additional samples all 
have a 1 day window. Additional PK samples will also be taken every 12 weeks from the first dose within 1 year of starting treatment and if treatment 

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continues after 1 year, samples will be collected every 24 weeks. An additional PK sample will also be taken at the Follow-up or Post-study visits. Unless 
stated otherwise, on days of dosing sample will be drawn pre-dose.
5.
To be conducted in male subjects only.
6.
Whole blood for soluble markers from plasma, serum, and/or cellular markers.  Blood samples will be collected on Day 1: pre-dose and at 1 hour (15-
minute window) and 6 hours (1-hour window) after the end of infusion.  If a subject’s duration of infusion is 3 hours or longer the 6-hour time point is 
optional. A pre-dose blood sample should be collected on Day 8, Day 15 and Day 29 for all cohorts. On day 15 for those subjects on a 2 week dosing 
schedule and on Day 22 pre-dose for those subject s on a 3 week dosing schedule, a blood sample is required to be collected. An additional sample will also 
be collected at progression.
7.
For the subjects receiving a weekly dosing schedule, the The study treatment dosing window is 23 days.  The study treatment dosing window for all 
other dosing schedules (e.g., an every 2-week or every 3-week dosing schedule) is 3 days. If dosing does not occur on the intended day, all other 
assessments/subsequent visits should be changed accordingly relative to when the dose was received.
8.
After the first treatment period, immunogenicity samples will be collected every 12 weeks from the first dose within 1 year of treatment. If treatment continues 
after 1 year, samples will be collected every 24 weeks. An immunogenicity sample must be collected at the Follow-up and Post-study visits. 
9.
It is preferred that the PGx sample be taken pre-dose on Day 1; however, it may be obtained anytime after informed consent has been given for PGx 
research.
10. See Section 7.8 and collect all tumor markers applicable for the subject’s primary tumor type.
11. Confirmatory assessments will occur at least 4 weeks after assessments demonstrating CR or PR. Confirmatory assessments may be conducted at a 
subject’s next regularly scheduled visit as appropriate.
12. A blood sample for select serum safety markers (including but not limited to TNF alpha, IL-6, and tryptase) should be drawn within 24 hours of 
suspected infusion-related reactions.
13. Disease assessment must be performed either at the Follow-up visit or at the Post-Study visit prior to the start of any subsequent anticancer 
therapy.
14. Assessments to be performed weekly while receiving weekly dosing and bi-weekly if switched to a bi-weekly dosing regimen.

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Section 7.3.6 Laboratory Assessments, Table of Clinical Laboratory Tests
REVISED TEXT (new text bold and underlined, deleted text in strikethrough)
Table 13
List of Clinical Laboratory Tests
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) or urea
Potassium
AST
Total and direct bilirubin
Creatinine
Chloride
ALT
Uric Acid
Glucose, fasting
Total carbon 
dioxide (CO2)
Gamma glutamyl transferase 
(GGT)
Albumin
Sodium
Calcium
Alkaline phosphatase
Total Protein
Magnesium
Phosphate
Routine Urinalysis
Specific gravity
pH, glucose, protein, blood and ketones by dipstick
Microscopic examination (if blood or protein is abnormal)
Other tests
PT, INR, PTT 
Testosterone (male subjects only)
Luteinizing Hormone (LH) (male subjects only)
Follicle stimulating hormone (FSH) and estradiol (as needed in women of non-child bearing potential only)
Section 7.4 Pharmacokinetics
REVISED TEXT (new text bold and underlined, deleted text in strikethrough)
For all subjects in the dose escalation cohorts in Part 1,subjects enrolled in Part 1, dose 
escalation Cohorts 1-4, blood samples for analysis of GSK2849330 concentrations will 
be collected on Day 1: pre-dose and at 1 hour and 6 hours after the end of infusion and at 
Day 8, Day 15, and Day 29 after the first dose of GSK2849330. If a subject’s duration of 
infusion is 3 hours or longer the 6-hour time point is optional.  On days of dosing, the 
sample will be drawn pre-dose. Additionally the first subject in Cohort 1 will have PK 
samples taken at 24 hours (Day 2) and 72 hours (Day 4) after the end of infusion. 

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For subjects enrolled in the additional dose escalation cohorts enrolled under 
Amendment 1 of this protocol, more frequent PK samples will be collected on 
Day 1: pre-dose, and at 1 hour, 6 hours and 24 hours after the end of infusion;. Pre-
dose samples will also be collected on Day 4, Day 8, and weekly through Day 57 with 
additional one hour post-dose samples collected on Days 29 and 57. Pre-dose 
samples will also be collected on Day 71, Day 85, and every 12 weeks thereafter.
For all subjects in the Part 1 PK/PD cohorts, blood samples for analysis of GSK2849330 
concentrations will be collected on scheduled dosing Day 1: pre-dose and at 1 hour, 
6 hours, and 24 hours after the end of the infusion. Pre-dose samples will also be 
collected on Day 4, Day 8, and weekly through Day 57 with additional one hour 
post-dose samples collected on Days 29 and 57. Pre-dose samples will also be 
collected on Day 71, Day 85 and every 12 weeks thereafter.and 6 hr after the end of 
infusion and at 24 hr (Day 2), 72 hr (Day 4), and 168 hr (Day 8) after the end of infusion. 
If a subject’s duration of infusion is 3 hours or longer the 6 hr time point is optional. 
Additional PK samples will be drawn pre-dose on Days 22 and 43 (after the first dose) 
for subjects on an every 3 week dosing schedule or pre-dose on Days 15 and 29 (after the 
first dose) for subjects on an every 2 week dosing schedule. On days of dosing, the 
sample will be drawn pre-dose. 
For the expansion cohortsgroups in Part 2, blood samples for analysis of GSK2849330 
concentrations will be collected on Day 1: pre-dose and at 1 hour after the end of infusion 
with an additional PK samples pre-dose on Days 22 and 43 (after the first dose) for 
subjects on an every 3 week dosing schedule or pre-dose on Days 15 and 29 (after the 
first dose) for subjects on an every 2 week dosing schedule.and pre-dose on Day 15, 
Day 29, Day 43, Day 57, Day 71, Day 85 and every 12 weeks thereafter.
For all subjects (Part 1 and Part 2), if treatment continues beyond 1 year, samples will 
be collected every 24 weeks. PK samples will also be taken every 12 weeks from the 
first dose within 1 year of starting treatment and if treatment continues after 1 year 
samples will be collected every 24 weeks. An additional PK sample will also be taken at 
the Follow-up visit (28 days after the last dose of study treatment) and/or at the 
Post-study visit [45 days or 5 half-lives (whichever is longer)] after the last dose of study 
treatment. On days of dosing sample will be drawn pre-dose. Unless stated otherwise, 
on days of dosing PK samples will be drawn pre-dose.
See the Time and Events Tables Section 7.1 and the SPM for additional details on the PK 
sample timing.
Section 7.4.1 Blood Sample Collection for Pharmacokinetics
REVISED TEXT (new text bold and underlined, deleted text in strikethrough)
Blood samples of approximately 1 2mL for PK analysis of GSK2849330 will be 
collected at the time points indicated in the Time and Events Tables (Section 7.1). Each 
PK sample should be collected as close as possible to the planned time relative to the 

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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.
Section 7.6.1.1, Title
REVISED TEXT (new text bold and underlined, deleted text in strikethrough)
Tumor Tissue for Pre-screening Assessments and Exploratory Research
Section 7.6.1.1: Tumor Tissue for Pre-screening Assessments and Exploratory 
Research
REVISED TEXT (new text bold and underlined, deleted text in strikethrough)
Tumor Tissue for Pre-screening Assessments and Exploratory Research
A formalin-fixed, paraffin-embedded  Tumor tissue block taken atfrom a metastatic site 
(preferably) or obtained at the time of original primary cancer diagnosis (biopsy or from 
definitive surgery) is required to be submitted to the central laboratory (Ventana Medical 
Systems) for analysis to one or more of the central laboratories including Ventana 
Medical Systems for determining HER3 expression to determine HER3 and NRG1 
expression.  and for subsequent translational research (regardless of any local results). 
Alternatively, sites may send 15-20 freshly sectioned, unstained slides containing 5-
micron thick sections. Refer to the SPM for details on tumor tissue sample preparation 
and shipping. . If archival tumor tissue is not available, a fresh biopsy is required for 
HER3 and NRG1 testing. If archival tumor tissue is not available, a fresh biopsy is 
required for HER3 and NRG1 testing.
Section 7.6.1.2 Tumor Biopsies
REVISED TEXT (new text bold and underlined, deleted text in strikethrough)
Every effort should be made to collect pre- and on-treatment tumor biopsies.  Image 
guidance has been shown to significantly increase the probability of success in obtaining 
tumor biopsies and is required for all percutaneous pre- and on-treatment biopsies in this 
study (with the exception of melanoma skin lesions or cutaneous metastases of other 
solid tumors).
Tumor biopsies are optional for subjects in the dose escalation cohorts, but strongly 
encouraged  All subjects enrolled in PK/PD cohorts in Part 1 and in each of the 
expansion groups in Part 2 must agree to pre and on-treatment tumor biopsies for 
assessment of PD effect. GSK will closely monitor and evaluate the collection of 
evaluable biopsies and will notify the participating centers of any change to the 
collection requirements for any or all groups.
Tumor biopsies for PD analyses will be collected at the time points listed in the Time 
and Events Tables Section 7.1.
All subjects enrolled in PK/PD cohorts in Part 1, must agree to pre and on-treatment 
tumor biopsies for assessment of PD effect. Tumor biopsies are optional for subjects in 

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the dose escalation cohorts, but strongly encouraged. For subjects in Part 2 expansion 
cohorts see Section 3.4 regarding tumor biopsy requirements. Tumor biopsies for PD 
analyses will be collected at the time points listed in the Time and Events Tables Section 
7.1.
Section 7.6.2 Skin Biopsies
REVISED TEXT (new text bold and underlined, deleted text in strikethrough)
For subjects in Part 1 of the study, every effort should be made to collect pre- and on-
treatment skin biopsies for analysis of RNA or protein levels that may indicate a PD 
response to GSK 2849330.  Protein levels that may be analyzed include, but are not 
limited to, markers of the HER3 pathway such as HER3 and phospho-HER3.
All subjects enrolled in dose escalation and PK/PD cohorts in Part 1 must agree to pre 
and on-treatment skin biopsies for assessment of PD effect. For subjects in Part 2 
expansion cohorts, the consent to pre and on-treatment skin biopsies is optional. 
Refer to Time and Events Tables in Section 7.1 for details on time points. 
Details on skin biopsy collection, processing, storage and shipping procedures are 
provided in the SPM.
Section 7.8 Evaluation of Anti-Cancer Activity, 1st paragraph
REVISED TEXT (new text bold and underlined, deleted text in strikethrough)
Disease assessment may include imaging (e.g., CT scan, MRI, bone scan, plain 
radiography) and physical examination (as indicated for palpable/superficial lesions). 
Disease assessment will be completed within 4 weeks prior to the first dose of 
GSK2849330, then every 8 or 9 weeks thereafter, and at the final study visit.  See the 
Time and Events Tables (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 (PD) has not been documented, and the subject has not started subsequent 
anti-cancer therapy, a disease assessment should be obtained at the Follow-up visit or 
the Post-Study visit time of withdrawal from study.
Section 10.1 Permitted Medication(s)
REVISED TEXT (new text bold and underlined, deleted text in strikethrough)
Subjects should receive full supportive care during the study, including transfusion of 
blood and blood products, and treatment with antibiotics, antiemetics, antidiarrheals, and 
analgesics, as appropriate Growth factors (eg, G-CSF) are not permitted during dose 
escalation the DLT observation period in Part 1, but may be allowable beyond the 

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DLT observation period in Part 1, in the PK-PD cohorts or in Part 2 (expansion 
cohorts) after discussion with the GSK medical monitor.
The use of anticoagulant and antiplatelet agents are permitted. However, prior to 
undergoing tumor biopsy, it is recommended that subjects be off agents such as 
coumadin or heparin for 5 days and then recheck labs prior to biopsy procedure.  It 
is further recommended that subjects be off of NSAIDs for at least 48 hours.  If 
institution guidelines require these agents be held longer than the recommended 
number of days/ hours, then follow institution guidelines. If there are risks of 
stopping these medications, contact the GSK Medical Monitor.
Section 10.2 Prohibited Medication(s)
REVISED TEXT (new text bold and underlined, deleted text in strikethrough)
Subjects should not receive other anticancer therapy (cytotoxic, surgery, tumor 
embolization, biologic, radiation, or hormone other than replacement) except where noted 
in the eligibility criteria while on treatment in this study 
If corticosteroids are needed for chronic conditions, doses below 20 mg/day of 
prednisone or the equivalent are allowed. Corticosteroids exceeding this level are 
generally not allowed except as infusion pre-medication.
Chronic immunosuppressive therapies including daily steroid doses in excess of 20 
mg/day of prednisone are prohibited while on treatment in this study.
Section 13.1.2, Title
REVISED TEXT (new text bold and underlined, deleted text in strikethrough)
Part 2: Molecularly-Defined Tumor Histology Groups
Section 13.1.2 Molecularly-Defined Tumor Histology Groups
REVISED TEXT (new text bold and underlined, deleted text in strikethrough)
For the expansion cohorts groups in Part 2, hypothesized response rates are provided in 
Section 13.2.2. A test that the response rate is less than or equal to the null hypothesis 
rate versus the response rate is greater than or equal to the alternative rate is being 
performed using the stopping rules provided. Descriptive statistics will be used to 
describe the observed response rates at the dose used in each of the expansion
cohortsgroups.
Section 13.2.1 Part 1: Dose-Escalation Phase, 1st paragraph
REVISED TEXT (new text bold and underlined, deleted text in strikethrough)
The total number of subjects in the Part 1 dose escalation will depend on the number of 
dose escalations needed but the minimum number of subjects anticipated to complete 
dose escalation is 13 and. However, the anticipated number of subjects is approximately 
31 34 subjects. The selection of sample size 3134 is based on the goal of fully exploring 

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available dose ranges for purposes of selecting an appropriate regimen(s) for Part 2.  This 
will include a number of cohorts to establish an initial understanding of the dose -
response relationship as well as to evaluate a range of PD biomarkers that may reveal the 
biological activity of GSK2849330. The initial cohort (1.4 mg/kg) will have 1 subject and 
cohorts 2 through 4 5will have 3 subjects in the dose escalation phase and up to an 
additional 3 subjects with evaluable pre- and on-treatment paired biopsies in each of 
these cohorts for the PK/PD cohorts.  Cohorts 5 through 7 will have up to 3 subjects with 
evaluable pre- and on treatment paired biopsies in each cohort for the PK/PD cohorts. See 
Section 3.3 and Table 2Table 3 for additional details. The actual number of cohorts and 
subjects will depend in part on the observed toxicity and the PK and PD observed during 
the dose escalation.
Section 13.2.2, Title
REVISED TEXT
Part 2: Expansion Cohort Molecularly-Defined Tumor Histology Groups
Section 13.2.2 Part 2: Molecularly-Defined Tumor Histology Groups
REVISED TEXT (new text bold and underlined, deleted text in strikethrough)
Once the recommended dose(s) and schedule(s) is/are confirmed from Part 1, at least 12 
and up to 30 subjects per arm group will be enrolled at that dose(s) in the expansion 
cohortsPart 2, guided by decision rules defined in Section 13.6.2. These guidelines are 
based on the predictive probabilities of success if enrollment were to continue to 30 
subjects using the methodology of [Lee, 2008 
The null hypothesis is:
H0: p 10 %
HA: p 30 %
Starting with a cohortgroup of 12 subjects and allowing for a maximum sample size of 
30 , this design will have a type I error rate (α) of 0.15and 94% power. Cohort Group
enrollment is stopped early for futility if the predictive probability of success is less than 
6 %. The trial would not stop early for success. The Bayesian Prior was Beta (0.2, 0.8), a 
weak prior with a mean response rate of 20%. The cohort group outcome will be 
considered successful if the posterior probability of (P>0.10 observed data) is ≥ 80%. The 
futility boundary described in Section 13.6.2 was calculated based on the optimizing
criterion of maximizing the power under the alternative hypothesis.
Under the null hypothesis, the expected sample size is 20 subjects and the probability of 
early termination is 77 %. Under the alternative hypothesis, the expected sample size is 
29 subjects and the probability of early termination is 5 %.

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Section 13.4.1: Analysis Populations
REVISED TEXT (new text bold and underlined, deleted text in strikethrough)
The All Treated Population is defined as all subjects who receive at least one dose of 
GSK2849330. Safety will be evaluated based on this analysis population.
The Efficacy Population will consist of all subjects from the All Treated Population 
for whom at least one post-dose tumor assessment by CT scan has been performed.
The PK Population will consist of all subjects from the All Treated Population for whom 
at least one post-dose PK sample is obtained and analyzed.
Additional analysis populations may be defined in the RAP.
Section 13.6.2, Title
REVISED TEXT (new text bold and underlined, deleted text in strikethrough)
Part 2: Expansion Cohort Molecularly-Defined Tumor Histology Groups
Section 13.6.2 Part 2: Molecularly-Defined Tumor Histology Groups
REVISED TEXT (new text bold and underlined, deleted text in strikethrough)
For each cohortof the groups in Part 2 the expansion cohortsresponse data will be 
reviewed on an ongoing basis., after After the initial 12 subjects have enrolled at the 
recommended 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 the Table and 
Figure below.
Table 15
Stopping rules for each expansion group
Number of Subjects Enrolled
Stop for Futility if ≤ this number of 
responders is observed
12
0
16
1
22
2
27
3
30
4

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Figure 3
Diagram of Stopping Rules for each Group
Section 13.7.1 Anti-Cancer Activity Analyses
REVISED TEXT (new text bold and underlined, deleted text in strikethrough)
The All Treated Efficacy Population will be used for anti-cancer activity analyses. Since 
this is a Phase I study, anti-cancer activity will be evaluated based on clinical evidence 
and response criteria. Where appropriate, the lesion data will be listed for each subject. 
The percent change from baseline will be calculated for each subject and listed, along 
with their ORR, CR, PR, SD and PD according to standard RECIST 1.1 (See Appendix 
5).  mRECIST and irRc will be calculated and listed as applicable. Response data will be 
summarized by cohort or group.  If data warrant, the response data will be summarized 
by dose level. Response-evaluable subjects are defined as subjects with a pre-dose and at
least 1 post-dose disease assessment. Correlation analysis may be conducted to explore 
any relationship between the subject’s tumor type specific markers and tumor response 
based on RECIST, version [1.1], mRECIST and irRc.  Other measures of clinical benefit 
specific to the groups in Part 2 will be summarized by group as appropriate.
Full details will be specified in the RAP.

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References
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García I, del Casar JM, Corte MD, Allende MT, García-Muñiz JL, Vizoso F. 
Epidermal growth factor receptor and c-erbB-2 contents in unresectable (UICC R1 
or R2) gastric cancer. Int J Biol Markers. 2003 Jul-Sep;18(3):200-6.
Mendell-Harary J, Ruhe J, Schneider M, et al. Identification of a predictive 
biomarker for patritumab, an anti-HER3 monoclonal antibody, in advanced 
NSCLC. J Clin Oncol 32, 2014 (suppl; abstr e19016).
Ocana A, Vera-Badillo F, Seruga B, Templeton A, Pandiella A, Amir E. HER3 
overexpression and survival in solid tumors: a meta-analysis. J Natl Cancer Inst. 
Feb 20 2012;105(4):266-273.
Park DJ, Lenz HJ. Determinants of chemosensitivity in gastric cancer. Curr Opin 
Pharmacol. 2006 Aug;6(4):337-44.
Piontek M, Hengels KJ. [The EGF receptor and stomach cancer]. Z Gastroenterol. 
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Reynolds KL, Juric D, Baselga J, et al. A phase 1 study in patients with esophageal 
squamous cell carcinoma, head and neck cancer, or HER2-overexpressing 
metastatic breast or gastric/gastroesophageal junction cancer. Abstract 2517. 
Presented at: ASCO, 2014, Chicago.
Sarantopoulos J Gordon MS, Harvey RD, et al. First-in-human phase 1 dose-
escalation study of AV-203, a monoclonal antibody against ERBB3, in patients with 
metastatic or advanced solid tumors. J Clin Oncol. 32:5s, 2014 (suppl; abstr 11113).
Sato Y, Yashiro M, Takakura N. Heregulin induces resistance to lapatinib-mediated 
growth inhibition of HER2-amplified cancer cells. Cancer Sci. 2013 
Dec;104(12):1618-25.
Schneider M, Blum S, Wenzl C, et al. Heregulin expression level as a predictive 
biomarker for patritumab efficacy. J Clin Oncol. 32:5s, 2014 (suppl; abstr 2618).
Sequist LV, Lopez-Chavez A, Doebele R, et al. A randomized phase II trial of MM-
121, a fully human monoclonal antibody targeting ErbB3, in combination with 
erlotinib, in EGFR wild-type NSCLC patients. J Clin Oncol. 32:5s, 2014 (suppl; 
abstr 8051).
Shames DS, Carbon J, Walter K, et al. High heregulin expression is associated with 
activated HER3 and may define an actionable biomarker in patients with squamous 
cell carcinomas of the head and neck. PLoS One. 2013;8(2):e56765.
Stapleton NM, Andersen JT, Stemerding AM, et al. Competition for FcRn-mediated 
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potential. Nat Commun. 2011 Dec 20;2:599.

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Von Pawel J, Tseng J, Dediu M, et al. J Clin Oncol 32:5s, 2014 (suppl; abstr 8045). 
Phase 2 HERALD study of patritumab with erlotinib in advanced NSCLC subjects. 
J Clin Oncol. 32:5s, 2014 (suppl; abstr 8045).
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gastric cancer mediated by PI3K/AKT signalling pathway. Med Oncol. 2014 
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Zhang L, Castanaro C, Luan B, et al. ERBB3/HER2 signaling promotes resistance 
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Appendix 9 Management of Diarrhea
REVISED TEXT (new text bold and underlined, deleted text in strikethrough)
In rare cases, diarrhea can be debilitating, and potentially life threatening if 
accompanied by dehydration, renal insufficiency, and/or electrolyte imbalances.
Standardized and universal guidelines have been developed by an American Society 
of Clinical Oncology (ASCO) panel for treating chemotherapy-induced diarrhea 
(Benson 2004). Presented in the sections below are the recommended guidelines for 
the management of diarrhea published by the ASCO panel (Benson 2004).
Early identification and intervention is critical for the optimal management of 
diarrhea.  A subject’s baseline bowel patterns should be established so that changes 
in patterns can be identified while subject is on treatment.
Subjects should be instructed to first notify their physician/healthcare provider at 
onset of diarrhea of any severity.
An assessment of frequency, consistency and duration as well as knowledge of other 
symptoms such as fever, cramping, pain, nausea, vomiting, dizziness and thirst 
should be taken at baseline. Consequently subjects at high risk of diarrhea can be 
identified.  Subjects should be educated on signs and symptoms of diarrhea with 
instructions to report any changes in bowel patterns to the physician.
It is recommended that subjects keep a diary and record the number of diarrhea 
episodes and its characteristics. They should also include information on any dietary 
changes or other observations such as over the counter (OTC) medications, 
including herbal supplements, that may be useful in the evaluation of their diarrhea 
history.

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Definitions
National Cancer Institute (NCI) guidelines define diarrhea compared to baseline 
(Table 19).
Table 31
Grading of Diarrhea
Adverse 
Event 
Grade
Diarrhea
1
Increase of <4 stools/day over baseline; mild increase in ostomy output 
compared to baseline
2
Increase of 4-6 stools/day over baseline; moderate increase in ostomy 
output compared to baseline;
3
Increase of ≥7 stools/day over baseline; incontinence; hospitalization 
indicated; severe increase in ostomy output compared to baseline; 
limiting self care activities of daily living (ADL)
4
Life-threatening consequences; urgent intervention indicated
5
Death
Uncomplicated diarrhea is considered mild-to-moderate and defined as CTCAE 
Grade 1 or 2 with no complicating signs or symptoms.
Complicated diarrhea is severe and defined as any CTCAE Grade 3 or 4 diarrhea, 
or Grade 1 or 2 with one or more of the following signs or symptoms:

Moderate to severe abdominal cramping 

Nausea/vomiting ≥Grade 2

Decreased performance status

Fever

Sepsis

Neutropenia

Frank bleeding (red blood in stool)

Dehydration
Management of Uncomplicated Mild to Moderate Diarrhea
Recommendation: Initial management of mild to moderate diarrhea should include 
dietary modifications (e.g., eliminating all lactose-containing products and high 
osmolar dietary supplements), and the patient should be instructed to record the 
number of stools and report symptoms of life-threatening sequelae (e.g., fever or 
dizziness on standing). Loperamide should be started at an initial dose of 4 mg 

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followed by 2 mg every 4 hours or after every unformed stool (not to exceed 
16 mg/day).
If diarrhea resolves with loperamide, the patients should be instructed to continue 
dietary modifications and to gradually add solid foods to their diet. In the case of 
chemotherapy-induced diarrhea, patients may discontinue loperamide when they 
have been diarrhea-free for at least 12 hours.
If mild to moderate diarrhea persists for more than 24 hours, the dose of 
loperamide should be increased to 2 mg every 2 hours, and oral antibiotics may be 
started as prophylaxis for infection.
If mild to moderate chemotherapy-induced diarrhea has not resolved after 24 hours 
on high-dose loperamide (48 hours total treatment with loperamide), it should be 
discontinued and the patient should be started on a second-line antidiarrheal agent 
such as subcutaneous (SC) octreotide (100- to 150-g starting dose, with dose 
escalation as needed) or other second-line agents (e.g., oral budesonide or tincture of 
opium). In the case of chemotherapy-induced diarrhea, the patient should be seen in 
the physician’s office or outpatient center for further evaluation, including complete 
stool and blood work-up. Stool work-up should include evaluation for pathogens. 
Fluids and electrolytes should be replaced as needed.
Aggressive Management of Complicated Cases
Recommendation: Aggressive management of complicated cases should involve IV 
fluids; octreotide at a starting dose of 100 to 150 g SC tid or IV (25 to 50 g/h) if the 
patient is severely dehydrated, with dose escalation up to 500 g until diarrhea is 
controlled, and administration of antibiotics (e.g., fluoroquinolone). This may 
require admission to the hospital; for select patients, diarrhea may be managed with 
intensive home nursing or in a day hospital. Stool work-up (evaluation for blood, 
fecal leukocytes, C difficile, Salmonella, Escherichia coli, Campylobacter, and 
infectious colitis), complete blood count, and electrolyte profile should be 
performed. This may not be appropriate for radiotherapy-induced diarrhea. Any 
patient with chemotherapy-induced diarrhea who progresses to Grade 3 or 4 
diarrhea after 24 or 48 hours on loperamide should also be treated as described 
above. Continue intervention as described until the patient has been diarrhea-free 
for 24 hours.
These recommendations for the aggressive management of complicated cases of 
chemotherapy-induced diarrhea are based on evidence that the GI syndrome is an 
indicator that the patient may be at serious risk for dehydration and/or infection 
and other potentially life-threatening complications. Moreover, loperamide, even at 
high-doses, may be less effective in patients with Grade 3 or 4 diarrhea. Therefore, 
it is appropriate to start immediate octreotide therapy (either SC or IV if the patient 
is already severely dehydrated) along with antibiotics.

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Figure 2
Algorithm for the management of diarrhea

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Amendment 2
Where the Amendment Applies
This amendment applies to all sites and countries.
Summary of Amendment Changes with Rationale
Typographical and formatting errors have been corrected and minor clarifications have 
been made throughout the document. These corrections have not been listed in this 
appendix, unless the correction changed the context or meaning of the text.
Inclusion Criteria
The inclusion criteria were modified for Molecularly Defined Tumor Histology Group 1 
(melanoma), Group 2 (Gastric/GEJ), and Group 4 (NSCLC) in Part 2 to remove the 
statement that subjects would be eligibile for inclusion into the study if they had not 
received standard therapy when such therapy was not available to them commercially or 
via a clinical trial.
DLT Definition:
The definition of DLT for subjects with thrombocytopenia was expanded to include 
Grade 3 events of thrombocytopenia associated with bleeding in addition to all Grade 4 
events.
Tumor Biopsy:
The statements regarding obtaining tumor biopsy samples have beem modified to include 
that all biopsies should be obtained from tumor easily accessible to biopsy using a 
procedure that is safe for the subject.
Total Blood Volume:
The total volume of blood to be collected within the first 30 days of participation has 
been modified to account for the increased frequency of PK sampling.
Time and Events Tables:
Inconsistencies were corrected and clarifications around visit and procedure windows 
were provided.
List of Specific Changes
Title Page, Authors
REVISED TEXT (new text bold and underlined, deleted text in strikethrough)
Projects Clinical Platforms and Sciences, RTP, USA
Oncology Biomarkers, UP, USA
PPD
PPD

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Biopharm Clinical Pharmacology, UM 
Biopharm R&D, UM, USA
Global Oncology Data Sciences, RTP, USA
Oncology R&D, USA
Clin Pharm, Mod & Sim, RTP, USA
Oncology R&D, UP, USA
Oncology Clinical Statistics, UP, USA
LIST OF ABBREVIATIONS
REVISED TEXT (new text bold and underlined, deleted text in strikethrough)
FFPE
Formalin fixed, paraffin-embedded
qRT-PCR
Quantitative real time polymerase chain reaction
Protocol Synopsis, Study Rationale
REVISED TEXT (new text bold and underlined, deleted text in strikethrough)
GSK2849330 is a humanized glycol-engineered glycoengineered IgG1/IgG3 mAb with 
enhanced Fc-effector function potency, directed against HER3 (ErbB3), a signaling and 
drug resistance target expressed on a wide range of solid tumors. This FTIH, open-label, 
dose escalation study will assess the safety, PK, PD, and preliminary clinical effect of 
GSK2849330 in subjects with HER3-expressing or HER3 and NRG1 expressing solid 
tumors.
Protocol Synopsis, Number of Subjects
REVISED TEXT (new text bold and underlined, deleted text in strikethrough)
Part 2:  At least 4 molecularly defined tumor histology groups will be studied. A 
minimum of 12 and a maximum of 30 subjects will be enrolled in each of the groups. 
Futility criteria will be evaluated as data accrues, and enrollment in a group will be halted 
if futility criteria conditions are met for that group.
Protocol Synopsis, Inclusion/Exclusion Criteria- Pre-screening Inclusion Criteria 
Part 1
REVISED TEXT (new text bold and underlined, deleted text in strikethrough)
4. Sufficient archival tumor specimen is available for HER3 IHC analysis, or subject 
is willing to undergo a fresh tumor biopsy (using a procedure that is safe for the 
subject) for HER3 IHC analysis (see Section 7.6.1.1 for details).
PPD
PPD
PPD
PPD
PPD
PPD
PPD

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Protocol Synopsis, Inclusion/Exclusion Criteria- Pre-screening Inclusion Criteria 
Part 2
REVISED TEXT (new text bold and underlined, deleted text in strikethrough)
Subjects with melanoma, gastric/gastroesophageal cancer, head and neck cancer, or 
NSCLC who appear to meet all inclusion and exclusion criteria may be pre-screened for 
the study provided that sufficient tumor specimen either from archival Formalin-fixed 
paraffin-embedded (FFPE) tissue or tissue obtained by biopsy (using a procedure 
that is safe for the subject) is available for analyzing HER3 by IHC or HER3 by IHC 
and NRG1 by RNA analysis.
Screening Inclusion Criteria for Parts 1 and 2
REVISED TEXT (new text bold and underlined, deleted text in strikethrough)
Subjects eligible for enrollment in the study must meet all of the following criteria:
1. Males and females ≥18 years of age (at the time consent is obtained).
2. Written informed consent provided.
3. For subjects enrolled in Part 1: subjects must have tumors with documented 
HER3 expression (2+ or 3+) on the cell surface of the invasive component of the 
tumor (either on archival tissue or fresh tumor biopsy)using an analytically 
validated IHC assay by central laboratory   (see Section 7.6.1.1 for details). 
Subjects enrolled in Part 2 must meet inclusion criterion 9 listed below.
8. Subjects enrolled as part of the PK/PD cohort (Part 1) must agree to undergo pre-
and on-treatment tumor biopsies, using a procedure that is safe for the subject
Protocol Synopsis, Inclusion Criteria for Part 2 ONLY
REVISED TEXT (new text bold and underlined, deleted text in strikethrough)
As listed above for Part 1, with the exception of criterion 3 which should be replaced 
with the following criterion 9 and the addition of criteria 10 and 11.
9. For Group 1: subjects with previously treated, unresectable stage III or IV 
melanoma with documented HER3 expression (3+) on the cell surface of the 
invasive component of the tumor (either on archival tumor or fresh tumor 
biopsy)using an analytically validated IHC assay by central laboratory.

Subjects must have received no more than 3 prior lines of systemic 
therapy and have disease progression on or after last prior treatment 
(based on RECIST v1.1).

Subjects with BRAF V600 mutations who already received or 
were intolerant of prior BRAF inhibitor therapy may be included. 
BRAF V600 inhibitor naïve subjects will be eligible if a BRAF 
inhibitor is not available to them commerciall or via a clinical trial.

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
Subjects may be included if they had prior immune therapy, or 
were intolerant of prior immune therapy, or if such therapy is not 
available to them commercially or via a clinical trial.
For Group 2: Subjects with previously treated, unresectable stage III or IV gastric 
or gastroesophageal junction (GEJ) adenocarcinoma with documented HER3 
expression (3+) on the cell surface of the invasive component of the tumor (either 
on archival tumor or fresh tumor biopsy) using an analytically validated IHC assay 
by central laboratory.

Subjects must have no more than 3 prior lines of systemic therapy and 
have disease progression on or after last prior treatment (based on 
RECIST v1.1).

Subjects with HER2 positive disease may be included if they had 
already received prior anti-HER2 therapy, or were intolerant of 
prior anti-HER2 therapy, or if such therapy is not available to them 
commercially or via a clinical trial.  
For Group 3: Subjects with previously treated, unresectable stage III or IV 
cancers of the head and neck with documented HER3 expression on the cell 
surface of the tumor ( 1+) and NRG1 expression on the cell surface of the 
tumor (either on archival tumor or frsh tumor biopsy) using analytically validated 
assays by central laboratory.

Subjects must have no more than 3 prior lines of systemic therapy and 
have disease progression on or after last prior treatment (based on 
RECIST v1.1).

Subjects with locoregional recurrences amenable to resection/surgery or 
additional radiation are excluded.
For Group 4: Subjects with previously treated, unresectable stage III or IV 
NSCLC with documented HER3 expression on the cell surface of the tumor
(1+) and NRG1 expression on the cell surface of the tumor (either on archival 
tumor or fresh tumor biopsy) using analytically validated assays by central 
laboratory.

Subjects must have no more than 3 prior lines of systemic therapy and 
have disease progression on or after last prior treatment (based on 
RECIST v1.1).

Subjects with anaplastic lymphoma kinase (ALK) translocation who 
already received or were intolerant of prior anti-ALK therapy may be 
included. Anti ALK therapy naïve subjects will be eligible for the study if 
such a therapy is not available to them commercially or via a clinical trial.

Subjects with EGFR mutation positive disease (e.g., exon 19 deletion and 
exon 21 L858R) who already received or were intolerant of prior EGFR 
inhibitors may be included. EGFR inhibitor naïve subjects will be eligible 
for the study if such a therapy is not available to them commercially or via 
a clinical trial.
Additional tumor histology groups predicted to be sensitive to the study drug 
based on emerging biomarkers (e.g.., HER3 mutations, NRG translocations) 
supported by preclinical or clinical data may be added based on emerging data.  

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10. Subjects must have at least one measurable lesion per RECIST v1.1.
NOTE: If the only site of measurable disease has been previously irradiated, 
documented progression of disease and a 4-week interval since completion of 
radiotherapy is required.
NOTE: In subjects with 1 measurable lesion, a measurable lesion may be 
biopsied at Screening and Day 15; however that lesion must not be selected as a 
target lesion for disease assessment.
11. Subjects must have disease amendable to biopsy using a procedure that is safe 
for the subject, and agree to undergo pre- and on-treatment tumor biopsies (until 
the participating centers receive written notification from the Sponsor that paired 
tumor biopsies are no longer required for any/all groups).
Section 1.2.1: GSK2849330 Background
REVISED TEXT (new text bold and underlined, deleted text in strikethrough)
GSK2849330 is a glyco-engineered glycoengineered antibody with enhanced potency 
for antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent 
cytotoxicity (CDC).  ADCC causes tumor cell lysis upon binding of antibody to target, 
followed by engagement of cytotoxic T-cells and natural killer (NK) effector cells via 
their FcRIIIA receptors.  Perforin, granulysin and serine proteases released from 
cytoplasmic granules within cytotoxic T-cells and NK cells produce tumor cell lysis.  
CDC, considered one of the most powerful cell-killing mechanisms of antibodies 
[Walport, 2001], results from assembly of the ‘membrane attack complex’ that punches 
holes in the target cell membrane leading to tumor cell lysis.  Compared with a wild-type 
antibody
Section 3.2: Pre-Screening
REVISED TEXT (new text bold and underlined, deleted text in strikethrough)
Subjects will be required to undergo pre-screening to determine if their tumor is HER3 
expressing or HER3 and NRG1 expressing (details regarding HER3 and NRG1 
expression requirements will be described in the SPM).  Subjects with study eligible 
advanced solid tumors will sign a separate Informed Consent Form (ICF) to allow for 
pre-screening of archival tumor or tissue from fresh tumor biopsies (obtained using a 
procedure that is safe for the subject) for HER3 expression by IHC, or for HER3 
expression by IHC and NRG1 expression by quantitative real-time   polymerase chain 
reaction (qRT-PCR) assay.
Section 3.3: Part 1: Dose Escalation Phase
REVISED TEXT (new text bold and underlined, deleted text in strikethrough)
Subjects enrolled in the PK/PD cohorts must meet all of the relevant inclusion and 
exclusion criteria, have disease that is amenable to biopsy, and also agree to have pre-
and on-treatment biopsies (using a procedure that is safe for the subject) in addition to 

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the other study procedures. Subjects will be enrolled in PK/PD cohorts in order to obtain 
evaluable pre- and on-treatment biopsy pairs per dose level (see SPM for additional 
details). Subjects who do not agree to, or who are unable to safely provide pre- and on-
treatment biopsies in the PD expansion may be enrolled in dose escalation cohorts in 
Part 1 as they become available.
Section 3.3.1: Dose Limiting Toxicity
REVISED TEXT (new text bold and underlined, deleted text in strikethrough)
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 unless it can be clearly established that 
the event is unrelated to treatment:
a.
Grade 3 or greater non-hematologic toxicity as described in Common National 
Cancer Institute-Terminology Criteria for Adverse Events (NCI-CTCAE) version 4.0 
[NCI, 2009] that cannot be controlled with routine supportive measures (e.g.,
antiemetics, antidiarrheals, antihistamines).
b.
Grade 4 neutropenia lasting >5 days.
c.
Febrile neutropenia, of any grade or duration as defined by NCI-CTCAE version 4.0 
[NCI, 2009].
d.
Grade 4 thrombocytopenia, or Grade 3 thrombocytopenia associated with 
bleeding.
e.
Alanine aminotransferase (ALT) >3x upper limit of normal (ULN) with bilirubin 
>2x ULN.
f.
Any Grade 2 or greater NCI-CTACAE version 4.0 [NCI, 2009] toxicity that in the 
judgment of the investigator and GSK Medical Monitor, would be considered dose-
limiting.
g.
Grade 3 or greater decrease in left ventricular ejection fraction (LVEF).
Section 3.4: Part 2: Molecularly Defined Tumor Histology Groups
REVISED TEXT (new text bold and underlined, deleted text in strikethrough)
Part 2 can begin once the recommended dose and schedule is identified in Part 1. It is 
possible that more than one dose and/or schedule will be evaluated in Part 2 if available 
PK, PD and safety data suggest that multiple doses and schedules have desirable biologic 
activity or if an MTD cannot be established.
The selected dose level(s) will be evaluated in Part 2 for confirmation of safety and 
tolerability, as well as preliminary assessment of clinical benefit, in at least 4 
molecularly-defined tumor histology groups of subjects with HER3 or HER3 and NRG1 
expressing tumors  Group 1 will include subjects with HER3- expressing melanoma. 
Group 2 will include subjects with HER3-expressing gastric cancer. Group 3 will include 
subjects with HER3 expressing and NRG1-expressing cancers of the head and neck. 
Group 4 will include subjects with HER3 expressing and NRG1-expressing NSCLC. All 

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subjects must have archival tissue available for HER3 and if required NRG1 testing or be 
willing to undergo a tumor biopsy using a procedure that is safe for the subject, to 
provide a sample for testing.
Each group will initially enroll 12 subjects with the option of expanding to a maximum of 
30 subjects if futility criteria are not met using well established  methodology of [Lee, 
2008] (See Section 13.2.2 and Section 13.6.2 for additional details).
Subjects will be required to have disease amenable to biopsy and agree to pre-and on-
treatment tumor biopsies, using a procedure that is safe for the subject. Pre-and on-
treatment biopsies are mandatory for all subjects in all groups. GSK will closely monitor 
and evaluate the collection of evaluable biopsies and will notify the participating centers 
of any change to the collection requirements for any or all groups.
Section 3.5: Intra-subject Dose Escalation
REVISED TEXT (new text bold and underlined, deleted text in strikethrough)
A subject’s dose level may be increased up to the highest dose level that has previously 
been confirmed by the investigator and GSK medical monitor as not exceeding the MTD.  
Intra-subject dose escalations will be allowed in both Part 1 and Part 2 (if multiple 
doses/regimens demonstrate a better PK profile or clinical activity) provided that the 
subject has completed at minimum, the first 28 days of treatment with no sign or 
evidence of disease progression, at least 1 post-baseline efficacy assessment without no 
toxicity greater than Grade 2 or the occurrence of significant AEs, and prior approval has 
been obtained from a GSK medical monitor. Subjects will be permitted to increase dose 
levels multiple times provided the above criteria are met. Any dose escalations must be 
agreed upon by the investigator and GSK medical monitor, and must be documented on 
an Intra-subject Dose Escalation Request Form (see the SPM) with copies maintained at 
the site and in the study files.
Section 3.6.3: Rationale for Dose: Maximum Proposed Dose:
REVISED TEXT (new text bold and underlined, deleted text in strikethrough)
The maximum proposed dose of 30 mg/kg for weekly, bi-weekly or every three week 
dosing was selected based on PK-PD extrapolations which predict target engagement > 
90% and tumor saturation should be achieved at or below this dose, and based on 
practical considerations (e.g., drug product supply and production capacity)  Emerging 
PK, safety and tolerability data may cause the proposed maximum dose to be adjusted 
downward (see Section 3.3 for details of the N-CRM model assessment of safety data).
Preliminary Human Pharmacokinetic Profile
Arithmetic mean preliminary non-compartmental PK parameters as of September 2014
are listed in Table 5 below for dose-escalation cohorts in this trial dosed GSK2849330 at 
1.4 mg/kg, 3 mg/kg or, 10 mg/kg.

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Table 5
Preliminary non-compartmental Pharmacokinetic Profile
Parameter 
Unit 
n 
Treatment (mg/kg)  
Estimate (CV%)
AUC(0,336) 
h*µg/mL 
1 
1.4 
3123 
3 
3 
8880 (25.7) 
3 
10 
28100 (27.8) 
t1/2 (24, 168) 
hr 
1/3 
1.4 
78.7 
t1/2 (24, 336) 
hr 
1/3 
3 
119 
3 
10 
134 (32.0) 
Cmax
µg/mL 
1 
1.4 
29.8 
3 
3 
64.7 (30.2) 
3 
10 
234 (2.65) 
tmax
hr
1 
1.4 
1 
3 
3 
1 [1-6]a
3 
10 
1[1-6] a
AUC = area under the concentration-time curve; Cmax = maximum observed concentration; CV = coefficient of 
variance; t1/2 = plasma elimination half-life; tmax = time to maximum observed concentration.  
Preliminary non-compartmental PK analysis for subjects in dose-escalation cohorts.  
a denotes median [range] 
Preliminary population PK parameters based on nominal dose and PK sample time as of 
September 2014 are listed in Table 6 below for dose-escalation cohorts at 1.4 mg/kg 
(n=1), 3 mg/kg (n=2) or, 10 mg/kg (n=2). The data are modelled according to a two 
compartment PK model with peripheral Target Mediated Drug Disposition. The value of 
KM (concentration at half maximal saturation of peripheral target mediated drug 
disposition) is based on Biacore in vitro binding data together with an assumed 4/h 
rate of internalization and degradation based on semi-quantitative in vitro pulse 
chase experiment. One subject was excluded from the 3 mg/kg cohort because the dose 
was delayed; and another subject was excluded from the 10 mg/kg cohort because the 
infusion was terminated early so the total dose of GSK849330 administered was 
uncertain.

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Table 6
Preliminary Population PK Parameters
Parameter 
Unit 
Estimate
%RSE
%CV
CL 
mL/h 
11.4
39.1 
31.3 
V1 
mL 
2830 2460
6.64 
VM 
µg/h 
198
40.6 
KM
µg/mL 
0.513 
Q
mL/h
79.0 
19.1 
V2
mL 
3420 2500
13.7 
D1
h 
1 
SG1 (proportional)
0.0626 
62.9 
The compartmental and non-compartmental model parameters suggest a catabolic 
half-life of (V1/CL)xln(2) = 172 hours 150 hours. Considering GSK2849330 as an 
IgG1-IgG3 fusion with Fc located in the IgG3 region, it is plausible that the 
elimination half-life is in accordance with the well-known fact that IgG3 elimination 
half-life is about 7 days (e.g., Stapleton, 2011 and references therein).
Predicted Effective Dose 
The potential therapeutic dose range for GSK2849330 in humans was derived using 
available preclinical in vitro and in vivo PK and efficacy data.  In addition, data from 
mouse in vivo CHL-1 xenograft efficacy studies were evaluated to predict the potential 
minimum clinically efficacious dose.  PK/PD modeling of CHL-1 xenograft data in SCID 
mice suggests that anti-tumor efficacy (based on tumor growth curves) may be achieved 
with systemic plasma trough concentrations of GSK2849330 maintained at ≥ 20 μg/mL.  
The predicted human equivalent dose to achieve a similar trough concentration in 90% 
of the population is approximately 1.2mg/kg/wk 1.4-3 mg/kg/wk. This dose is also in 
line with that projected, based on in vitro potency data, to engage HER3 and inhibit 
signaling (approximately 0.9 to 5.6 mg/kg).  It is anticipated that optimal anti-tumor 
activity will require full target engagement and that ADCC and CDC enhancements may 
further increase the anti-tumor activity of GSK2849330.  However, it is also recognized 
that saturation of target throughout the tumor in the clinical setting may require doses 
higher than those projected based on preclinical extrapolations, due to factors in the 
tumor microenvironment such as vascular perfusion heterogeneity which may limit mAb 
intra-tumoral distribution.  Recognizing these factors, the top proposed dose for 

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evaluation is 30 mg/kg, a dose which is also viewed as the highest dose feasible based on 
practical considerations.
A loading dose scenario is predicted to maintain an accumulated steady state trough 
concentration if the dosing interval is less than or equal to the elimination half-life.  
Accordingly, a 30 mg/kg weekly IV dose cohort has been added to the dose escalation 
portion of the study.
Section 5.2.1: Pre-screening Inclusion Criteria for Part 1
REVISED TEXT (new text bold and underlined, deleted text in strikethrough)
Subjects will be eligible for inclusion in pre-screening for the study (See Section 3.2) 
only if all of the following criteria apply:
1. Males and females ≥18 years of age (at the time consent is obtained).
2. Written informed consent provided.
3. Performance Status score of 0 or 1 according to the Eastern Cooperative 
Oncology Group (ECOG) scale (see Appendix 3).
4. Sufficient archival tumor specimen is available for HER3 IHC analysis, or subject 
is willing to undergo a fresh tumor biopsy (using a procedure that is safe for the 
subject) for HER3 IHC analysis (see Section 7.6.1.1 for details).
Section 5.2.2: Pre-Screening for Part 2
REVISED TEXT (new text bold and underlined, deleted text in strikethrough)
Subjects with either melanoma, gastric/gastroesophageal cancer, head and neck cancer, or 
NSCLC who appear to meet all inclusion and exclusion criteria may be pre-screened for 
the study provided that sufficient tumor specimen, either from archival FFPE tissue or 
tissue obtained by biopsy using a procedure that is safe for the subject is available 
for analyzing HER3 by IHC or HER3 by IHC and NRG1 by RNA analysis.
Section 5.2.3: Screening Inclusion Criteria for Parts 1 and 2
REVISED TEXT (new text bold and underlined, deleted text in strikethrough)
3. For subjects enrolled in Part 1:subjects must have tumors with documented HER3 
expression (2+ or 3+) on the cell surface of the invasive component of the tumor 
(either on archival tissue or fresh tumor biopsy)using an analytically validated 
IHC assay by central laboratory   (see Section 7.6.1.1 for details). Subjects 
enrolled in Part 2 must meet inclusion criterion 9 listed below.
8. Subjects enrolled as part of the PK/PD cohort (Part 1) must agree to undergo pre- and 
on-treatment tumor biopsies, using a procedure that is safe for the subject

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Section 5.2.4: Inclusion Criteria for Part 2 ONLY
REVISED TEXT (new text bold and underlined, deleted text in strikethrough)
As listed above for Part 1, with the exception of criterion 3 which should be replaced 
with the following criterion 9 and the addition of criteria 10 and 11.
9. For Group 1: subjects with previously treated, unresectable stage III or IV 
melanoma with documented HER3 expression (3+) on the cell surface of the 
invasive component of the tumor (either on archival tumor or fresh tumor biopsy)
using an analytically validated IHC assay by central laboratory.

Subjects must have no more than 3 prior lines of systemic regimens and 
have disease progression on or after last prior treatment (based on 
RECIST v1.1).

Subjects with BRAF V600 mutations who already received or were 
intolerant of prior BRAF inhibitor therapy may be included.  BRAF 
V600 inhibitor naïve subjects will be eligible if a BRAF inhibitor is not 
available to them commercially or via a clinical trial.

Subjects may be included if they had prior immune therapy, or were 
intolerant of prior immune therapy or if such therapy is not available to 
them commercially or via a clinical trial.
For Group 2: Subjects with previously treated, unresectable stage III or IV gastric 
or gastroesophageal junction (GEJ) adenocarcinoma with documented HER3 
expression (3+) on the cell surface of the invasive component of the tumor (either 
on archival tumor or fresh tumor biopsy) using an analytically validated IHC assay 
by central laboratory.

Subjects must have no more than 3 prior lines of systemic regimens and have 
disease progression on or after last prior treatment (based on RECIST v1.1).

Subjects with HER2 positive disease may be included if they had prior 
anti-HER2 therapy or were intolerant of prior anti-HER2 therapy or if 
such therapy is not available to them commercially or via a clinical 
trial.
For Group 3: Subjects with previously treated, unresectable stage III or IV 
cancers of the head and neck with documented HER3 expression on the cell 
surface of the tumor ( 1+) and NRG1 expression on the cell surface of the 
tumor (either on archival tumor or fresh tumor biopsy) using analytically 
validated assays by central laboratory.

Subjects must have no more than 3 prior lines of systemic therapy and 
have disease progression on or after last prior treatment (based on 
RECIST v1.1).

Subjects with locoregional recurrences amenable to definite surgery or 
additional radiation are excluded.
For Group 4: Subjects with previously treated, unresectable stage III or IV 
NSCLC with documented HER3 expression on the cell surface of the tumor
(1+) and NRG1 expression on the cell surface of the tumor (either on archival 
tumor or fresh tumor biopsy)using analytically validated assays by central 
laboratory.

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
Subjects must have no more than 3 prior lines of systemic regimens and 
have disease progression on or after last prior treatment (based on 
RECIST v1.1).

Subjects with anaplastic lymphoma kinase (ALK) translocation who 
already received or were intolerant of prior anti-ALK therapy may be 
included. Anti ALK therapy naïve subjects will be eligible for the study if 
such a therapy is not available to them commercially or via a clinical trial.

Subjects with EGFR mutations (e.g., exon 19 deletion and exon 21 
L858R) who have documented progression (based on RECIST 1.1) or who 
were intolerant of prior EGFR inhibitors may be included. EGFR inhibitor 
naïve subjects will be eligible for the study if such a therapy is not 
available to them commercially or via a clinical trial.
Additional tumor histology groups predicted to be sensitive to the study drug 
based on biomarkers (e.g., HER3 mutations, NRG translocations) supported by 
preclinical or clinical data may be added based on emerging data.
10. Subjects must have at least one measurable lesion per RECIST v1.1.
NOTE: If the only site of measurable disease has been previously irradiated, 
documented progression of disease and a 4-week interval since completion of 
radiotherapy is required.
NOTE: In subjects with ≥>1 measurable lesion, a measurable lesion may be 
biopsied at Screening and Day 15; however that lesion must not be selected as a 
target lesion for disease assessment.
11. Subjects must have disease amendable to biopsy and agree to undergo pre- and 
on-treatment tumor biopsies using a procedure that is safe for the subject (until 
the participating centers receive written notification from the Sponsor that paired 
tumor biopsies are no longer required).
Section 7.0: Study Assessments and Procedures
REVISED TEXT (new text bold and underlined, deleted text in strikethrough)
The timing of each assessment is listed in the Time and Events Tables (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 safety, PK, PD/biomarker, 
immunogenicity, imaging or other assessments.  Changes in timing, addition, or removal 
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. No more than 200mL Up 
to approximately 350mL of blood will be collected over a 30-day period, including any 
extra assessments that may be required.
Section 7.1: Time and Events Tables
REVISED TEXT (new text bold and underlined, deleted text in strikethrough)

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Table 7
Time and Events for Part 1 (Dose Escalation Cohorts, every 2 week dosing schedule)
Pre-
screening
Screening
First Treatment Period (28 
days)
Day 29
Continuation Phase
Follow-up1
Post-study2
Day 1
Day 8 
Day 15 
-14 day 
window3
1 day window for each visit
3 day window for each 
visit
+ 7 day window 
Informed consent
X
X
Archival tissue 
X
Tumor biopsy
X4
X5
X6 pre-
dose
X7
Skin biopsy
X pre-
dose
X pre-dose
Baseline 
demographics
X
X
Medical history
X
X
X
Concurrent 
medication
Continuous
Pregnancy test8
X3
X pre-dose
Every 4 weeks
X
X
Physical examination
X
X9
X
X
Every 4 weeks
X
Height (at screening 
only) and weight
X
X
X
Weight: Every 4 weeks
X
ECOG 
X
X9
X
Every 4 weeks
X
Vital signs (BP, pulse 
rate, Temperature)
X
X10
X
X
X
Every 2 weeks 
X
12-lead ECG
X
X10
X
X
Every 4 weeks
X
Hematology/Clinical 
Chemistry
X
X9
X
X
X
Every 2 weeks
X
Coagulation 
parameters: PT, INR, 
PTT
X
As Clinically Indicated

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Pre-
screening
Screening
First Treatment Period (28 
days)
Day 29
Continuation Phase
Follow-up1
Post-study2
Day 1
Day 8 
Day 15 
-14 day 
window3
1 day window for each visit
3 day window for each 
visit
+ 7 day window 
Urinalysis
X
X
Every 4 weeks
X
ECHO11
X
X
Every 8 weeks
X
PK (Blood)12
X
X
X
X
Every 12 weeks
X
X
Safety cytokines20
In the event of infusion reaction
Circulating cell free 
DNA (cfDNA)
X pre-
dose
X7
Testosterone and 
LH13
X pre-
dose
X
Every 8 weeks
Whole blood/serum 
/cellular markers14
X
X
X
X
X7
GSK2849330 IV 
infusion15
X
X
X
Every 2 weeks15
AE assessment
Continuous
Serum sample for 
Immunogenicity
X pre-
dose
X
X
Every 12 weeks16 
X16
X16
PGx sample
X pre-
dose17
Tumor markers 18
X
Every 8 weeks
Disease 
assessment19
X3
Every 8 weeks
X21
1.
The Follow-up visit should be approximately 28 days after the last dose of study treatment.
2.
The Post-study visit should be at least 45 days or 5 half-lives (whichever is longer) after the last dose of study treatment.
3.
Within 14 days prior to first dose except for pregnancy test (7 days) and Disease Assessment within 28 days prior to the first dose.
4.
Separate pre-screening consent required for fresh biopsy and fresh biopsy is only collected at pre-screening if archived tissue is not available.
5.
Fresh pre- and on-treatment tumor biopsy is optional, but strongly encouraged for dose escalation cohorts; if adequate fresh biopsy tumor tissue is acquired 
during pre-screening, then this does not need to be repeated during the screening period.  Archival tumor tissue is not acceptable to serve as pre-treatment 
tumor tissue.

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6.
Tumor biopsy is optional on Day 15 for dose escalation cohort subjects and required for the PK/PD cohorts. Biopsy must be collected prior to study treatment 
administration on Day 15 dose (pre-dose). 
7.
Collected at progression. Tumor biopsy is optional and only collected for subjects with disease progression on study treatment. The tumor specimen may be 
collected at any time after study treatment discontinuation, but must occur prior to the start of any subsequent anticancer therapy.
8.
Perform only in women of child-bearing potential.  Serum pregnancy test should be conducted at the Screening, Follow-up, and Post-study visits.  Urine 
pregnancy test should be conducted pre-dose on Day 29 and every 4 weeks from Day 29 in the continuation phase of the study.
9.
If the screening visit was completed within 72 hours of the first dose, this assessment does not need to be repeated on Day 1.
10. Collect at pre-dose and at 1, 2, 4, and 6 hours after the start of the first infusion.
11. ECHO is preferred; however, if echocardiography is not available, or if reliable echocardiographic analysis of LVEF is unable to be obtained due to technical 
factors, a MUGA scan may be performed.  Regardless, the method used at Baseline should be used for the remaining assessments in the study. 
Assessments should be performed more frequently than every 8 weeks if clinically indicated.
12. Blood samples for analysis of GSK2849330 concentrations will be collected on Day 1: pre-dose and at 1hour (15-minute window), and 6 hour (1-hour 
window) after the end of infusion. If a subject’s duration of infusion is 3 hours or longer the 6-hour time point is optional. Additional PK samples will be 
collected at Day 8, Day 15, and Day 29. Additional PK samples will also be taken every 12 weeks from the first dose within 1 year of starting treatment and if 
treatment continues after 1 year samples will be collected every 24 weeks. An additional PK sample will also be taken at the Follow-up and Post-study visits. 
Unless stated otherwise, on days of dosing sample will be drawn pre-dose. For the first subject in Cohort 1, additional PK samples will be taken at 24 hours 
(Day 2 [8-hours window]) and at 72 hours (Day 4 [24-hour window]) after the end of infusion of the first dose of GSK2849330.
13. To be conducted in male subjects only.
14. Whole blood for soluble markers from plasma, serum, and/or cellular markers.  Blood samples will be collected on Day 1: pre-dose and at 1 hour (15-minute 
window) and 6 hours (1-hour window) after the end of infusion.  If a subject’s duration of infusion is 3 hours or longer the 6 hour time point is optional. A pre-
dose blood sample should be collected on Day 8, Day 15 and Day 29 for all cohorts. An additional sample will also be collected at progression.
15. For any subjects receiving a weekly dosing schedule, the study treatment dosing window is 2 days.  The study treatment dosing window for all other dosing 
schedules (e.g., an every 2 week or every 3 week dosing schedule) is 3 days. If dosing does not occur on the intended day, all other 
assessments/subsequent visits should be changed accordingly relative to when the dose was received.  Subsequent cohorts may receive different dosing 
schedules use the appropriate Time and Events Table as applicable.
16. After the first treatment period, immunogenicity samples will be collected every 12 weeks from the first dose within one year of treatment. If treatment 
continues after 1 year, samples will be collected every 24 weeks. An immunogenicity sample must be collected at both the Follow up and the Post-study 
visit. 
17. It is preferred that the PGx sample be taken pre-dose on Day 1; however, it may be obtained anytime after informed consent has been given for PGx 
research.
18. See Section 7.8 and collect all tumor markers applicable for the subject’s primary tumor type.
19. Confirmatory assessments will occur at least 4 weeks after assessments demonstrating CR or PR. Confirmatory assessments may be conducted at a 
subject’s next regularly scheduled visit as appropriate.

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20. A blood sample for select serum safety markers (including but not limited to TNF alpha, IL-6, and tryptase) should be drawn within 24 hours of suspected 
infusion-related reactions.
21. For subjects who discontinue the study prior to disease progression, disease assessment must be performed either at the Follow-up visit or at the Post-Study 
visit prior to the start of any subsequent anticancer therapy.
Table 8
Time and Events for Part 1 (Dose Escalation Cohorts, every week dosing schedule)
Pre-
screen
Screen
First Treatment Period (28 days)
Day 29
Continuation 
Phase
Follow-
up1
Post-
study2
Day 1
Day 2
Day 4
Day 8 
Day 15 
Day 22
-14 day 
window3
1 day window for each visit
2 day 
window for 
each visit
+ 7 day window 
Informed consent
X
X
Archival tissue 
X
Tumor biopsy
X4
X5
X6 pre-
dose
X7
Skin biopsy
X pre-
dose
X pre-
dose
Baseline 
demographics
X
X
Medical history
X
X
X
Concurrent 
medication
Continuous
Pregnancy test8
X3
X pre-
dose
Every 4 weeks
X
X
Physical examination
X
X9
X
X
Every 4 weeks
X
Height (at screening 
only) and weight
X
X
X
Weight: Every 
4 weeks
X
ECOG 
X
X9
X
Every 4 weeks
X

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Pre-
screen
Screen
First Treatment Period (28 days)
Day 29
Continuation 
Phase
Follow-
up1
Post-
study2
Day 1
Day 2
Day 4
Day 8 
Day 15 
Day 22
-14 day 
window3
1 day window for each visit
2 day 
window for 
each visit
+ 7 day window 
Vital signs (BP, pulse 
rate, Temperature)
X
X10
X
X
X
X
Every week22 
X
12-lead ECG
X
X 10
X
X
Every 4 weeks
X
Hematology/Clinical 
Chemistry
X
X9
X
X
X
X
Every week22
X
Coagulation 
parameters: PT, INR, 
PTT
X
As clinically indicated
Urinalysis
X
X
Every 4 weeks
X
ECHO11
X
X
Every 8 weeks
X
PK (Blood)12
X
X
X
X
X
X
X
X12
X
X
Safety cytokines20
In the event of infusion reaction
Circulating cell free 
DNA (cfDNA)
X pre-
dose
X7
Testosterone and 
LH13
X pre-
dose
X
Every 8 weeks
Whole blood/serum 
/cellular markers14
X
X
X
X
X7
GSK2849330 IV 
infusion15
X
X
X
X
X
Every week15
AE assessment
Continuous
Serum sample for 
Immunogenicity
X pre-
dose
X16
X16
PGx sample
X pre-
dose17

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Pre-
screen
Screen
First Treatment Period (28 days)
Day 29
Continuation 
Phase
Follow-
up1
Post-
study2
Day 1
Day 2
Day 4
Day 8 
Day 15 
Day 22
-14 day 
window3
1 day window for each visit
2 day 
window for 
each visit
+ 7 day window 
Tumor markers 18
X
Every 8 weeks
Disease 
assessment19
X3
Every 8 weeks
X21
1.
The Follow-up visit should be approximately 28 days after the last dose of study treatment.
2.
The Post-study visit should be at least 45 days or 5 half-lives (whichever is longer) after the last dose of study treatment.
3.
Within 14 days prior to first dose except for pregnancy test (7 days) and Disease Assessment within 28 days prior to the first dose.
4.
Separate pre-screening consent required for fresh biopsy and fresh biopsy is only collected at pre-screening if archived tissue is not available.
5.
Fresh pre- and on-treatment tumor biopsy is optional, but strongly encouraged for dose escalation cohorts; if adequate fresh biopsy tumor tissue is acquired 
during pre-screening, then this does not need to be repeated during the screening period.  Archival tumor tissue is not acceptable to serve as pre-treatment tumor 
tissue.
6.
Tumor biopsy is optional on Day 15 for dose escalation cohort subjects and required for the PK/PD cohorts. Biopsy must be collected prior to study treatment 
administration on Day 15 dose (pre-dose). 
7.
Collected at progression. Tumor biopsy is optional and only collected for subjects with disease progression on study treatment. The tumor specimen may be 
collected at any time after study treatment discontinuation, but must occur prior to start of any subsequent anticancer therapy.
8.
Perform only in women of child-bearing potential.  Serum pregnancy test should be conducted at the Screening, Follow-up, and Post-study visits.  Urine 
pregnancy test should be conducted pre-dose on Day 29 and every 4 weeks from Day 29 in the continuation phase of the study.
9.
If the screening visit was completed within 72 hours of the first dose, this assessment does not need to be repeated on Day 1.
10. Collect at pre-dose and at1, 2, 4, and 6 hours after the start of the first infusion.
11. ECHO is preferred; however, if echocardiography is not available, or if reliable echocardiographic analysis of LVEF is unable to be obtained due to technical 
factors, a MUGA scan may be performed.  Regardless, the method used at Baseline should be used for the remaining assessments in the study. Assessments 
should be performed more frequently than every 8 weeks if clinically indicated.
12. Blood samples for analysis of GSK2849330 concentrations will be collected on Day 1: pre-dose and at 1 hour (15-minute window), 6 hours (1-hour window) 
and 24 hours (8-hour window) after the end of infusion. Pre-dose samples will also be collected on Day 4 (1-day window), Day 8 (1-day window) and 
weekly through Day 57 with additional 1-hour post-dose samples collected on Days 29 and 57. Pre-dose samples will also be collected on Day 71, Day 85 and 

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every 12 weeks thereafter.  If treatment continues after 1 year, samples will be collected every 24 weeks. An additional PK sample will also be taken at the Follow-
up and Post-study visits.
13. To be conducted in male subjects only.
14. Whole blood for soluble markers from plasma, serum, and/or cellular markers.  Blood samples will be collected on Day 1: pre-dose and at 1 hour (15-minute 
window) and 6 hours (1-hr window) after the end of infusion.  If a subject’s duration of infusion is 3 hours or longer the 6-hour time point is optional. A pre-dose 
blood sample should be collected on Day 8, Day 15 and Day 29 for all cohorts. An additional sample will also be collected at progression.
15. For any subjects receiving a weekly dosing schedule, the study treatment dosing window is 2 days.  The study treatment dosing window for all other dosing 
schedules (e.g., an every 2 week or every 3 week dosing schedule) is 3 days. If dosing does not occur on the intended day, all other assessments/subsequent 
visits should be changed accordingly relative to when the dose was received Subsequent cohorts may receive different dosing schedules use the appropriate 
Time and Events Table as applicable.
16. An immunogenicity sample must be collected at the Follow-up and Post-study visits. 
17. It is preferred that the PGx sample be taken pre-dose on Day 1; however, it may be obtained anytime after informed consent has been given for PGx research.
18. See Section 7.8 and collect all tumor markers applicable for the subject’s primary tumor type.
19. Confirmatory assessments will occur at least 4 weeks after assessments demonstrating CR or PR. Confirmatory assessments may be conducted at a subject’s 
next regularly scheduled visit as appropriate.
20. A blood sample for select serum safety biomarkers (including but not limited to TNF alpha, IL-6, and tryptase) should be drawn within 24 hours of suspected 
infusion-related reactions.
21. For subjects who discontinue the study prior to disease progression, disease assessment must be performed either at the Follow-up visit or at the Post-
Study visit prior to the start of any subsequent anticancer therapy.
22. Assessments to be performed weekly while receiving weekly dosing and bi-weekly if switched to a bi-weekly dosing regimen.

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Table 9
Time and Events for Part 1 PK/PD Cohorts (every 2 week dosing schedule)
Pre-
screening
Screening
First Treatment Period (28 days)
Day 29
Continuation Phase
Follow-
up1
Post-
study2
First Week
Day 15
Day 1
Day 2
Day 4
Day 8
- 14 day 
window3
1 day window for each visit
3 day window for each 
visit
+ 7 day window
Informed consent
X
X
Archival tissue 
X
Tumor biopsy
X4
X5
X6 pre-
dose
X7
Skin biopsy
X pre-
dose
X pre-dose
Baseline 
demographics
X
X
Medical history
X
X
X
Concurrent Medication
Continuous
X
Pregnancy test8
X3
X pre-
dose
Every 4 weeks
X
X
Physical examination
X
X9
X
X
Every 4 weeks
X
Height (at screening 
only) and weight
X
X
X
Weight: Every 4 weeks
X
ECOG 
X
X9
X
Every 4 weeks
X
Vital signs (BP, pulse 
rate, Temperature)
X
X10
X
X
X
Every 2 weeks
X
12-lead ECG
X
X10
X
X
Every 4 weeks
X
Hematology/Clinical 
Chemistry
X
X9
X
X
X
Every 2 weeks
X
Coagulation 
parameters: PT, INR, 
PTT
X
As clinically indicated

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Pre-
screening
Screening
First Treatment Period (28 days)
Day 29
Continuation Phase
Follow-
up1
Post-
study2
First Week
Day 15
Day 1
Day 2
Day 4
Day 8
- 14 day 
window3
1 day window for each visit
3 day window for each 
visit
+ 7 day window
Urinalysis
X
X
Every 4 weeks
X
ECHO11
X
X
Every 8 weeks
X
PK (Blood)12
X
X
X
X
X
X
X12
X
X
Safety cytokines20
In the event of infusion reaction
cfDNA
X pre-
dose
X7
Testosterone and LH13
X pre-
dose
X
Every 8 weeks
Whole blood/serum 
/cellular markers14
X
X
X
X
X
X7
GSK2849330 IV 
infusion15
X
X
X15
Every 2 weeks15 
AE assessment 
Continuous
Serum sample for 
Immunogenicity
X pre-
dose
X16
X16
PGx Sample17
X pre-
dose
Tumor markers 18
X
Every 8 weeks
Disease assessment19
X3
Every 8 weeks
X21
1.
The Follow-up visit should be approximately 28 days after the last dose of study treatment.
2.
The Post-study visit should be at least 45 days or 5 half-lives (whichever is longer) after the last dose of study treatment.
3.
Within 14 days prior to first dose except for pregnancy test (7 days) and Disease Assessment within 28 days prior to the first dose.
4.
Separate pre-screening consent required for fresh biopsy and fresh biopsy is only collected at pre-screening if archived tissue is not available.
5.
Fresh tumor biopsy is required for the PK/PD cohort; if adequate tumor biopsy is obtained during pre-screening, then this does not need to be repeated. 
Archival tumor tissue is not acceptable to serve as pre-treatment tumor tissue.
6.
Tumor biopsy is required on Day 15 pre-dose for PK/PD cohort. Biopsy must be collected prior to administration of Day 15 dose.

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7.
Collected at progression. Tumor biopsy is optional and only collected from subjects with disease progression on study treatment. The tumor specimen may be 
collected at any time after study treatment discontinuation, but must occur prior to start of any subsequent anticancer therapy.
8.
Perform only in women of child-bearing potential. Serum pregnancy test should be conducted at the Screening, Follow-up, and Post-study visits.  Urine 
pregnancy test should be conducted pre-dose on Day 29 and every 4 weeks from Day 29 in the continuation phase of the study.
9.
If the screening visit was completed within 72 hours of the first dose, this assessment does not need to be repeated on Day 1.
10. Collect at pre-dose and at 1, 2, 4, and 6 hours after the start of the first infusion 
11. ECHO is preferred; however, if echocardiography is not available, or if reliable echocardiographic analysis of LVEF is unable to be obtained due to technical 
factors, a MUGA scan may be performed.  Regardless, the method used at Baseline should be used for the remaining assessments in the study. 
Assessments should be performed more frequently than every 8 weeks if clinically indicated.
12. Blood samples for analysis of GSK2849330 concentrations will be collected Day 1: pre-dose and at1 hour (15-minute window), 6 hours (1-hour window) 
and 24 hours (8-hour window) after the end of infusion. Pre-dose samples will also be collected on Day 4 (1-day window), Day 8 (1-day window )and 
weekly through Day 57 with additional 1-hour post-dose samples collected on Days 29 and 57. Pre-dose samples will also be collected on Day 71, Day 85 
and every 12 weeks thereafter.
13. To be conducted in male subjects only.
14. Whole blood for soluble markers from plasma, serum, and/or cellular markers.  Blood samples will be collected on Day 1: pre-dose and at 1 hour (15-minute 
window), 6 hours (1-hour window), and 24 hours (Day 2 [8-hr window]) after the end of infusion. If a subject’s duration of infusion is 3 hours or longer the 
6 hour time point is optional. A pre-dose blood sample should be collected on Day 8, Day 15 and Day 29 for all cohorts. An additional sample will be collected 
at progression.
15. The study treatment dosing window is 3 days for subjects on an every 2 week dosing schedule. If dosing does not occur on the intended day, all other 
assessments/subsequent visits should be changed accordingly relative to when the dose was received.  Subsequent cohorts may receive different dosing 
schedules. Use the appropriate Time and Events Table as applicable.
16. An immunogenicity sample will be collected at the Follow-up and Post-study visits.
17. It is preferred that the PGx sample be taken pre-dose on Day 1; however, it may be obtained anytime after informed consent has been given for PGx 
research.
18. See Section 7.8 and collect all tumor markers applicable for the subject’s primary tumor type.
19. Confirmatory assessments will occur at least 4 weeks after assessments demonstrating CR or PR. Confirmatory assessments may be conducted at a 
subject’s next regularly scheduled visit as appropriate.
20. A blood sample for select serum safety markers (including but not limited to TNF alpha, IL-6, and tryptase) should be drawn within 24 hours of suspected 
infusion-related reactions.
21. For subjects who discontinue the study prior to disease progression, disease assessment must be performed either at the Follow-up visit or at the Post-
Study visit prior to the start of any subsequent anticancer therapy.

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Table 10
Time and Events for Part 1 PK/PD Cohorts (every week dosing schedule)
Pre-
screening
Screening
First Treatment Period (28 days)
Day 29
Continuation 
Phase
Follow-
up1
Post-
study2
First Week
Day 15
Day 22
Day 1
Day 2
Day 4
Day 8
- 14 day 
window3
1 day window for each visit
2 day 
window for 
each visit
+ 7 day window
Informed consent
X
X
Archival tissue 
X
Tumor biopsy
X4
X5
X6 pre-
dose
X7
Skin biopsy
X pre-
dose
X pre-
dose
Baseline 
demographics
X
X
Medical history
X
X
X
Concurrent 
Medication
Continuous
X
Pregnancy test8
X3
X pre-
dose
Every 4 weeks
X
X
Physical examination
X
X9
X
X
Every 4 weeks
X
Height (at screening 
only) and weight
X
X
X
Weight: Every 4 
weeks
X
ECOG 
X
X9
X
Every 4 weeks
X
Vital signs (BP, pulse 
rate, Temperature)
X
X10
X
X
X
X
Every week22 
X
12-lead ECG
X
X10
X
X
Every 4 weeks
X
Hematology/Clinical 
Chemistry
X
X9
X
X
X
X
Every week22
X

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Pre-
screening
Screening
First Treatment Period (28 days)
Day 29
Continuation 
Phase
Follow-
up1
Post-
study2
First Week
Day 15
Day 22
Day 1
Day 2
Day 4
Day 8
- 14 day 
window3
1 day window for each visit
2 day 
window for 
each visit
+ 7 day window
Coagulation 
parameters: PT, INR, 
PTT
X
As Clinically Indicated
Urinalysis
X
X
Every 4 weeks
X
ECHO11
X
X
Every 8 weeks
X
PK (Blood)12
X
X
X
X
X
X
X
X12
X
X
Safety cytokines20
In the event of infusion reaction
cfDNA
X pre-
dose
X7
Testosterone and 
LH13
X pre-
dose
X
Every 8 
weeks 
Whole blood/serum 
/cellular markers14
X
X
X
X
X
X7
GSK2849330 IV 
infusion15
X
X15
X
X
X15
Every week15 
AE assessment 
Continuous
Serum sample for 
Immunogenicity
X pre-
dose
X16
X16
PGx Sample17
X pre-
dose
Tumor markers 18
X
Every 8 
weeks
Disease assessment19
X3
Every 8 
weeks
X21
1.
The Follow-up visit should be approximately 28 days after the last dose of study treatment.
2.
The Post-study visit should be at least 45 days or 5 half-lives (whichever is longer) after the last dose of study treatment.

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3.
Within 14 days prior to first dose except for pregnancy test (7 days) and Disease Assessment within 28 days prior to the first dose.
4.
Separate pre-screening consent required for fresh biopsy and fresh biopsy is only collected at pre-screening if archived tissue is not available.
5.
Fresh tumor biopsy is required for the PK/PD cohort; if adequate tumor biopsy is obtained during pre-screening, then this does not need to be repeated. 
Archival tumor tissue is not acceptable to serve as pre-treatment tumor tissue.
6.
Tumor biopsy is required on Day 15 pre-dose for PK/PD cohort. Biopsy must be collected prior to administration of Day 15 dose. 
7.
Collected at progression. Tumor biopsy is optional and only collected from subjects with disease progression on study treatment. The tumor specimen may be 
collected at any time after study treatment discontinuation, but must occur prior to start of any subsequent anticancer therapy.
8.
Perform only in women of childbearing potential. Serum pregnancy test should be conducted at the Screening, Follow-up, and Post-study visits.  Urine 
pregnancy test should be conducted pre-dose on Day 29 and every 4 weeks from Day 29 in the continuation phase of the study.
9.
If the screening visit was completed within 72 hours of the first dose, this assessment does not need to be repeated on Day 1.
10. Collect at pre-dose and at 1, 2, 4, and 6 hours after the start of infusion. For subjects on a weekly dosing schedule, vital signs should be conducted weekly at 
each dosing visit in clinic.
11. ECHO is preferred; however, if echocardiography is not available, or if reliable echocardiographic analysis of LVEF is unable to be obtained due to technical 
factors, a MUGA scan may be performed.  Regardless, the method used at Baseline should be used for the remaining assessments in the study. 
Assessments should be performed more frequently than every 8 weeks if clinically indicated.
12. Blood samples for analysis of GSK2849330 concentrations will be collected Day 1: pre-dose and at1 hour (15-minute window), 6 hours (-1-hr window) 
and 24 hours (8-hour window) after the end of infusion. Pre-dose samples will also be collected on Day 4(1-day window), Day 8 (1-day window ) and 
weekly through Day 57 with additional 1-hour post-dose samples collected on Days 29 and 57. Pre-dose samples will also be collected on Day 71, Day 85 
and every 12 weeks thereafter.
13. To be conducted in male subjects only.
14. Whole blood for soluble markers from plasma, serum, and/or cellular markers.  Blood samples will be collected on Day 1: pre-dose and at 1 hour (15-minute 
window), 6 hour (1-hour window), and 24 housr(Day 2 [8-hour window]) after the end of infusion. If a subject’s duration of infusion is 3 hours or longer the 
6 hour time point is optional. A pre-dose blood sample should be collected on Day 8, Day 15 and Day 29 for all cohorts. An additional sample will be collected 
at progression.
15. For the subjects receiving a weekly dosing schedule, the study treatment dosing window is 2 days The study treatment dosing window is 3 days for 
subjects on an every 2 week dosing schedule. If dosing does not occur on the intended day, all other assessments/subsequent visits should be changed 
accordingly relative to when the dose was received.  Subsequent cohorts may receive different dosing schedules. Use the appropriate Time and Events Table 
as applicable.
16. An immunogenicity sample must be collected at the Follow-up and Post-study visits.
17. It is preferred that the PGx sample be taken pre-dose on Day 1; however, it may be obtained anytime after informed consent has been given for PGx 
research.
18. See Section 7.8 and collect all tumor markers applicable for the subject's primary tumor type.

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19. Confirmatory assessments will occur at least 4 weeks after assessments demonstrating CR or PR. Confirmatory assessments may be conducted at a 
subject’s next regularly scheduled visit as appropriate.
20. A blood sample for select serum safety markers (including but not limited to TNF alpha, IL-6, and tryptase) should be drawn within 24 hours of suspected 
infusion-related reactions.
21. For subjects who discontinue the study prior to disease progression,disease assessment must be performed either at the Follow-up visit or at the Post-
Study visit prior to the start of any subsequent anticancer therapy.
22. Assessments to be performed weekly while receiving weekly dosing and bi-weekly if switched to a bi-weekly dosing regimen.
Table 11
Time and Events for Part 1 PK/PD Cohorts (every 3 week dosing schedule)
Pre-
screening
Screening
First Treatment Period (21 days)
Continuation Phase
Follow-
up1
Post-
study2
First Week
Day 1
Day 2
Day 4
Day 8
Day 22
- 14 day 
window3
1 day window for each 
visit
3 day window for each 
visit
+7 day window
Informed consent
X
X
Archival tissue 
X
Tumor biopsy
X4
X5
X6pre-dose
X7
Skin biopsy
X pre-dose
X pre-dose
Baseline 
demographics
X
X
Medical history
X
X
X
Concurrent 
medication
Continuous
X
Pregnancy test8
X3
X pre-dose
Every 3 weeks 
X
X
Physical examination
X
X9
X
Every 3 weeks 
X
Height (at screening 
only) and weight
X
X
X
Weight: Every 3 weeks
X
ECOG 
X
X9
X
Every 3 weeks
X
Vital signs (BP, pulse 
rate, Temperature)
X
X10
X
X
Every 3 weeks 
X

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Pre-
screening
Screening
First Treatment Period (21 days)
Continuation Phase
Follow-
up1
Post-
study2
First Week
Day 1
Day 2
Day 4
Day 8
Day 22
- 14 day 
window3
1 day window for each 
visit
3 day window for each 
visit
+7 day window
12-lead ECG
X
X10
X
Every 3 weeks
X
Hematology/Clinical 
Chemistry
X
X9
X
X
Every 3 weeks
X
Coagulation 
parameters: PT, INR, 
PTT
X
As Clinically Indicated
Urinalysis
X
X
Every 3 weeks
X
ECHO11
X
X
Every 9 weeks from day 22
X
PK (Blood)12
X
X
X
X
X
Day 43 and every 12 weeks  
X
X
Safety cytokines20
In the event of infusion reaction
cfDNA
X pre-dose
X7
Testosterone and 
LH13
X pre-dose
X
Every 9 weeks from day 22
Whole blood/serum 
/cellular markers14
X
X
X
X
Day 43
X7
GSK2849330 IV 
infusion15
X
X
Every 3 weeks15 
AE assessment 
Continuous
Serum sample for 
Immunogenicity
X pre-dose
  
X16
X16
PGx Sample17
X pre-dose
Tumor markers 18
X
Every 9 weeks
Disease assessment19
X3
Every 9 weeks
X21
1.
The Follow-up visit should be approximately 28 days after the last dose of study treatment.
2.
The Post-study visit should be at least 45 days or 5 half-lives (whichever is longer) after the last dose of study treatment.
3.
Within 14 days prior to first dose except for pregnancy test (7 days) and disease assessment within 28 days prior to the first dose.
4.
Separate pre-screening consent required for fresh biopsy and fresh biopsy is only collected at pre-screening if archived tissue is not available.

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5.
Fresh tumor biopsy is required for the PK/PD cohort; if adequate tumor biopsy is obtained during pre-screening, then this does not need to be repeated. 
Archival tumor tissue is not acceptable to serve as pre-treatment tumor tissue.
6.
Tumor biopsy is required on Day 22 pre-dose for PK/PD cohort. Biopsy must be collected prior to administration of Day 22 dose. 
7.
Collected at progression. Tumor biopsy is optional and only required from subjects with disease progression on study treatment. The tumor specimen may be 
collected at any time after study treatment discontinuation, but must occur prior to start of any subsequent anticancer therapy.
8.
Perform only in women of childbearing potential.  Serum pregnancy test should be conducted at the Screening, Follow-up, and Post-study visits.  Urine 
pregnancy test should be conducted pre-dose on Day 22 and every 3 weeks from Day 22 in the continuation phase of the study.
9.
If the screening visit was completed within 72 hours of the first dose, this assessment does not need to be repeated on Day 1.
10. Collect at pre-dose and at 1, 2, 4, and 6 hours after the start of the first infusion.
11. ECHO is preferred; however, if echocardiography is not available, or if reliable echocardiographic analysis of LVEF is unable to be obtained due to technical 
factors, a MUGA scan may be performed.  Regardless, the method used at Baseline should be used for the remaining assessments in the study. 
Assessments should be performed more frequently than every 9 weeks if clinically indicated.
12. Blood samples for analysis of GSK2849330 concentrations will be collected on Day 1: pre-dose and at 1 hour (15-minute window) and 6 hours (1-hour 
window) after the end of infusion. If a subject’s duration of infusion is 3 hours or longer the 6-hour time point is optional. Additional PK samples will be 
collected at 24 hours (Day 2 [8-hr window]) and 72 hours (Day 4 [24-hour window]) after the end of infusion, and at Day 8 (1-day window), Day 22 (1-
day window), and Day 43 (1-day window) after the first dose of GSK2849330. Additional PK samples will also be taken every 12 weeks from the first dose 
within 1 year of starting treatment and if treatment continues after 1 year, samples will be collected every 24 weeks. An additional PK sample will be collected 
at the Post-study visit. On days of dosing sample will be drawn pre-dose.
13. To be conducted in male subjects only.
14. Whole blood for soluble markers from plasma, serum, and/or cellular marker.  Blood samples will be collected on Day 1: pre-dose and at 1 hour (15-minute 
window), 6 hours (1-hourwindow), and 24 hours (Day 2 [8-hour window]) after the end of infusion. If a subject’s duration of infusion is 3 hours or longer 
the 6-hour time point is optional. A pre-dose blood sample should be collected on Day 8, Day 22 and Day 43 for all cohorts. An additional blood sample 
should be collected at progression.
15. The study treatment dosing window is 3 days for an every 3-week dosing schedule. If dosing does not occur on the intended day, all other 
assessments/subsequent visits should be changed accordingly relative to when the dose was received.
16.   An immunogenicity sample will be collected at the Follow-up and Post-study visits.
17. It is preferred that the PGx sample be taken pre-dose on Day 1; however, it may be obtained anytime after informed consent has been given for PGx 
research.
18. See Section 7.8 and collect all tumor markers applicable for the subject’s primary tumor type.
19. Confirmatory assessments will occur at least 4 weeks after assessments demonstrating CR or PR. Confirmatory assessments may be conducted at a 
subject’s next regularly scheduled visit as appropriate.
20. A blood sample for select serum safety markers (including but not limited to TNF alpha, IL-6, and tryptase) should be drawn within 24 hours of suspected 
infusion-related reactions.

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21. For subjects who discontinue the study prior to disease progression,disease assessment must be performed either at the Follow-up visit or at the Post-
Study visit prior to the start of any subsequent anticancer therapy.
Table 12
Time and Events for Part 2 Molecularly Defined Tumor Histology Groups
Pre-
Screen
Screen
First Treatment Period (28 days)
Day 29
Continuation 
Phase
Follow up1
Post study2
Day 1
Day 8 
Day 15 
Day 22
-14 day 
window3
1 day window for each visit
2day window for 
each visit
+ 7 day window 
Informed consent
X
X
Archival tissue 
X
Tumor biopsy
X4
X5
X6 pre-
dose
X7
Baseline demographics
X
X
Medical history
X
X
X
Concurrent medication
Continuous
Pregnancy test8
X3
X pre-
dose
Every 4 weeks
X
X
Physical examination
X
X9
X
X
Every 4 weeks
X
Height (at screening 
only) and weight
X
X
X
Weight: Every 4 
weeks
X
ECOG 
X
X9
X
Every 4 weeks
X
Vital signs (BP, pulse 
rate, Temperature)
X
X10
X22
X
X22
X
Every week 10,22 
X
12-lead ECG
X
X10
X
X
Every 4 weeks
X22 
Hematology/Clinical 
Chemistry
X
X9
X22
X
X22
X
Every week22
X 22

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Pre-
Screen
Screen
First Treatment Period (28 days)
Day 29
Continuation 
Phase
Follow up1
Post study2
Day 1
Day 8 
Day 15 
Day 22
-14 day 
window3
1 day window for each visit
2day window for 
each visit
+ 7 day window 
Coagulation 
parameters: PT, INR, 
PTT
X
As Clinically Indicated
Urinalysis
X
X
Every 4 weeks
X
ECHO11
X
X
Every 8 weeks
X
PK (Blood)12
X
X
X
X12
X
X
Safety cytokines20
In the event of an infusion reaction
Circulating cell free 
DNA (cfDNA)
X pre-
dose
X7
Testosterone and LH13
X pre-
dose
X
Every 8 weeks
Whole blood/serum 
/cellular markers14
X
X22
X
X
X7
GSK2849330 IV 
infusion15
X
X22
X
X22
X
Everyweek15,22
AE assessment
Continuous
Serum sample for 
Immunogenicity
X pre-
dose
X16
X16
PGx sample
X pre-
dose17
Tumor markers 18
X
Every 8 weeks
Disease assessment19
X3
Every 8 weeks
X21
1.
The Follow-up visit should be approximately 28 days after the last dose of study treatment.
2.
The Post-study visit should be at least 45 days or 5 half-lives (whichever is longer) after the last dose of study treatment.
3.
Within 14 days prior to first dose except for pregnancy test (7 days) and Disease Assessment within 28 days prior to the first dose.
4.
Separate pre-screening consent required for fresh biopsy and fresh biopsy is only collected at pre-screening if archived tissue is not available.

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5.
Fresh pre- and on-treatment tumor biopsy is required; if adequate fresh biopsy tumor tissue is acquired during pre-screening, then this does not need to be 
repeated during the screening period.  Archival tumor tissue is not acceptable to serve as pre-treatment tumor tissue.
6.
Tumor biopsy is required on Day 15. Biopsy must be collected prior to study treatment administration on Day 15 dose (pre-dose).
7.
Collected at progression. Tumor biopsy is optional and only collected from subjects with disease progression on study treatment. The tumor specimen may be 
collected at any time after study treatment discontinuation, but must occur prior to start of any subsequent anticancer therapy.
8.
Perform only in women of child-bearing potential.  Serum pregnancy test should be conducted at the Screening, Follow-up, and Post-study visits.  Urine 
pregnancy test should be conducted pre-dose on Day 29 and every 4 weeks from Day 29 in the continuation phase of the study.
9.
If the screening visit was completed within 72 hours of the first dose, this assessment does not need to be repeated on Day 1.
10. For vitals: collect at pre-dose and at 1, 2, 4, and 6 hours after the start of the first infusion. For ECG: collect at pre-dose and 2 hours after the start of the first 
infusion
11. ECHO is preferred; however, if echocardiography is not available, or if reliable echocardiographic analysis of LVEF is unable to be obtained due to technical 
factors, a MUGA scan may be performed.  Regardless, the method used at Baseline should be used for the remaining assessments in the study. 
Assessments should be performed more frequently than every 8 weeks if clinically indicated.
12. Blood samples for analysis of GSK2849330 concentrations will be collected on Day 1: pre-dose and at 1 hour (15-minute window), after the end of infusion, 
and pre-dose on Day 15, Day 29, Day 43, Day 57, Day 71, Day 85, and every 12 weeks thereafter. If treatment continues after 1 year, samples will be 
collected every 24 weeks. An additional PK sample will also be taken at the Follow-up or Post-study visits. Unless stated otherwise, on days of dosing sample 
will be drawn pre-dose. 
13. To be conducted in male subjects only.
14. Whole blood for soluble markers from plasma, serum, and/or cellular markers.  Blood samples will be collected on Day 1: pre-dose and at 1 hour (15-minute 
window) and 6 hours (1-hour window) after the end of infusion.  If a subject’s duration of infusion is 3 hours or longer, the 6-hour time point is optional. A 
pre-dose blood sample should be collected on Day 8, Day 15 and Day 29 for all cohorts. An additional sample will also be collected at progression.
15. For the subjects receiving a weekly dosing schedule, the study treatment dosing window is 2 days.  The study treatment dosing window for all other dosing 
schedules (e.g., an every 2-week or every 3-week dosing schedule) is 3 days. If dosing does not occur on the intended day, all other 
assessments/subsequent visits should be changed accordingly relative to when the dose was received.
16. An immunogenicity sample must be collected at the Follow-up and Post-study visits. 
17. It is preferred that the PGx sample be taken pre-dose on Day 1; however, it may be obtained anytime after informed consent has been given for PGx 
research.
18. See Section 7.8 and collect all tumor markers applicable for the subject’s primary tumor type.
19. Confirmatory assessments will occur at least 4 weeks after assessments demonstrating CR or PR. Confirmatory assessments may be conducted at a 
subject’s next regularly scheduled visit as appropriate.
20. A blood sample for select serum safety markers (including but not limited to TNF alpha, IL-6, and tryptase) should be drawn within 24 hours of suspected 
infusion-related reactions.

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21. For subjects who discontinue the study prior to disease progression,disease assessment must be performed either at the Follow-up visit or at the Post-
Study visit prior to the start of any subsequent anticancer therapy.
22. Assessments to be performed weekly while receiving weekly dosing and bi-weekly if switched to a bi-weekly dosing regimen.

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Section 7.4: Pharmacokinetics
REVISED TEXT (new text bold and underlined, deleted text in strikethrough)
For the expansion molecularly defined tumor histology groups in Part 2, blood samples 
for analysis of GSK2849330 concentrations will be collected on Day 1: pre-dose and at 
1 hour after the end of infusion; and pre-dose on Day 15, Day 29, Day 43, Day 57, 
Day 71, Day 85, and every 12 weeks thereafter.
Section 7.6.1.1: Tumor Tissue for Pre-Screening Assessments and Exploratory 
Research
REVISED TEXT (new text bold and underlined, deleted text in strikethrough)
Tumor tissue taken from a metastatic site (preferably) or obtained at the time of primary 
cancer diagnosis (biopsy or from definitive surgery) is required to be submitted for 
analysis to one or more of the central laboratories, including Ventana Medical Systems to 
determine HER3 and NRG1 expression. If archival tumor tissue is not available, a fresh 
biopsy using a procedure that is safe for the subject is required for HER3 and NRG1 
testing.
Section 7.6.1.2: Tumor Biopsies
REVISED TEXT (new text bold and underlined, deleted text in strikethrough)
Every effort should be made to collect pre- and on-treatment tumor biopsies using a 
procedure that is safe for the subject.  Image guidance has been shown to significantly 
increase the probability of success in obtaining tumor biopsies and is required for all 
percutaneous pre- and on-treatment biopsies in this study (with the exception of 
melanoma skin lesions or cutaneous metastases of other solid tumors).
Tumor biopsies are optional for subjects in the dose escalation cohorts, but strongly 
encouraged.  All subjects enrolled in PK/PD cohorts in Part 1 and in each of the 
molecularly defined tumor histology groups in Part 2 must agree to pre and on-treatment 
tumor biopsies (using a procedure that is safe for the subject) for assessment of PD 
effect. GSK will closely monitor and evaluate the collection of evaluable biopsies and 
will notify the participating centers of any change to the collection requirements for any 
or all groups.
Tumor biopsies for PD analyses will be collected at the time points listed in the Time and 
Events Tables Section 7.1.
Tumor biopsies should be obtained upon disease progression, using a procedure that is 
safe for the subject, if the subject provides consent, and if the tumor is in a biopsy-
accessible location.  Once preliminary PK and PD data have been reviewed, the planned 
tumor biopsy collection times may be revised and provided to sites in writing.  Changes 
in sample collection times will not constitute a protocol amendment