Clinical trial NCT01376310
Conditions: Cancer
Sponsor: Novartis Pharmaceuticals
Start date: 2010-11-02; Completion date: 2018-01-18
Enrollment: 159 participants; Allocation: NON_RANDOMIZED; Intervention model: SINGLE_GROUP

Brief summary:
This was an open-label study to permit subjects with solid tumors or leukemia, who were clinically benefitting on another GSK sponsored trial with GSK1120212 either monotherapy or in combination continued access to GSK1120212.

Detailed description:

Arms: arm 1: Subjects on GSK1120212 Monotherapy who have been treated less than 24 weeks in their parent study. arm 2: Subjects on GSK monotherapy who have been treated for 24 weeks or greater in their parent study. Also, subjects entering this study from any GSK1120212 combo trial.
Interventions: intervention 1: GSK1120212 intervention 2: Docetaxel + GSK1120212 intervention 3: Erlotinib + GSK1120212 intervention 4: Pemetrexed + GSK1120212 intervention 5: Carboplatin + GSK1120212 intervention 6: Nab-paclitaxel + GSK1120212 intervention 7: Gemcitabine + GSK1120212 intervention 8: Everolimus + GSK1120212
Intervention descriptions: intervention 1: up to 2 mg/day intervention 2: dose as defined in the dose escalation protocol. intervention 3: dose as defined in the dose escalation protocol. intervention 4: dose as defined in the dose escalation protocol intervention 5: dose as defined in the dose escalation protocol intervention 6: dose as defined in the dose escalation protocol intervention 7: dose as defined in the dose escalation protocol intervention 8: dose as defined in the dose escalation protocol

Protocol documents:
Prot_000.pdf: 
RM2010/00127/07
CONFIDENTIAL
The GlaxoSmithKline group of companies
MEK114375
1
TITLE PAGE
Division: Worldwide Development
Information Type: Protocol Amendment
Title:
A rollover study to provide continued treatment with 
GSK1120212 to subjects with solid tumors or leukemia
Compound Number:    GSK1120212 / NCT01376310
Effective Date:              06-FEB-2014
 
Protocol Amendment Number:  7
Subject: GSK1120212 (Trametinib), MEK inhibitor, solid tumors, leukemia, safety, 
cancer.
Author:
 
Copyright 2014 the GlaxoSmithKline group of companies.  All rights reserved.  
Unauthorised copying or use of this information is prohibited.




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Revision Chronology:
RM2010/00127/00
2010-NOV-15
Original
RM2010/00127/01
2011-MAY-26
Amendment No.:1





Removed reference to “a GSK-
sponsored” GSK1120212 study
throughout document as subjects 
may be transitioned to the 
rollover study from studies 
conducted/sponsored by other 
groups such as NCI

Revised the following sections to
reflect revision in study
objective stating intent of study 
is to allow subjects to continue 
treatment if clinically benefitting 
(allowing for continued 
treatment for subjects who have 
clinically progressed if agreed 
upon by treating physician and 
GSK Medical Monitor :  
description, protocol summary, 
objective, study design, and 
inclusion criteria (#4)

Added Section 5.7.6.1, French
specific QTc stopping criteria

Revised text in Section 5.1 and
Section 7.1 to clarify
administration of GSK1120212 


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in a fasting state as “1 hour 
before or 2 hours after a meal”.

Revised list of References and 
removed those references not 
cited in protocol

Added country specific 
requirements for Australia 
(investigational product 
availability) and France (QTc 
stopping criteria)
RM2010/00127/02
2011-DEC-15
Amendment 2:

 
 
 
 
 

Updated the fax number for the 
Primary Medical Monitor

Section 1.1, Background: 
revised to reflect updated 
information from 
Investigator’s Brochure

Section 1.2, Summary of Risk 
Management: inserted new 
section and text to include risk 
management of potential risks 
of ocular toxicity, cardiac 
function and GI toxicity and 
cutaneous toxicity.

Section 1.2, Study Rationale: 
renumbered to Section 1.3.

Section 5.1, GSK1120212 GSK 
Investigational Product:  title 
of section revised to 
“Investigational Product”; 
inserted new table for 
GSK1120212 GSK 
Investigational Product 
(Commercial Image Product).

Section 5.7.7.1 Left Ventricular 
Ejection Fraction Stopping 


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Criteria: revised to provide a 
parameter for LVEF when 
lower limit of normal does not 
exist

Section 8.2.1 Cohort A, Section 
8.2.2 Cohort B, and Section 
8.3 Final Visit:  clarified text 
describing timing of ECHO or 
MUGA scans to clearly 
indicate that ECHO or MUGA 
should be performed 12 weeks 
from date of last assessment 
and not from the date of 
transition to rollover unless 
ECHO or MUGA is performed 
at that time.

Section 12, References: revised 
citation for GSK1120212 IB 
version 03, issued on 
23 Jun 2011

Section 13.1 and Section 13.2, 
Time and Events Tables for 
Cohort A and Cohort B, 
respectively:  table revised to 
show liver function tests (AST, 
ALT, alkaline phosphatase and 
total bilirubin) as separate 
assessments from rest of 
clinical chemistry laboratory 
tests.  Footnote added to clarify 
tests included in liver function 
tests; footnotes renumbered due 
to insertion of new footnote.

Appendix 7 added to capture 
changes in Amendment 02.
RM2010/00127/03
2012-FEB-06
Amendment No. 3: 

Abbreviations: updated to 
include abbreviations used in 
revised text

Protocol Summary: revised to 
reflect changes made in the 
Background section

Section 1.1, Background, 


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paragraph 2:  revised text 
describing GSK1120212 in 
regards to its inhibitory activity 
and kinase activity

Section 4.1.3, Exclusion 
Criteria:  added criteria 
outlining additional criteria to 
be used in assessing the 
cardiovascular risk of a subject 
at the time of determining 
eligibility for treatment with 
GSK1120212

Section 5.4, Handling and 
Storage of Study Treatment: 
revised temperature for storage 
of GSK1120212 based on 
clarification received from 
GSK Pharmaceutical 
Development.

Section 5.7.1, Monitoring and 
Management of Hypertension:  
added new section with 
guidelines for monitoring and 
managing hypertension in 
subjects undergoing treatment 
with GSK1120212

Section 7.1, Meals and Dietary 
Restrictions:  revised to clarify 
that fasting times were based 
upon the time of meal rather 
than dosing of GSK1120212 
and for consistency with 
Section 5.1

Appendix 1, Footnote #9: 
revised to clarify when an 
ECHO or MUGA scan should 
be performed during the Final 
Study Visit

Appendix 2, Footnote #9: 
revised to clarify when an 
ECHO or MUGA scan should 
be performed during the Final 
Study Visit


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RM2010/00127/04
2012-SEP-12
Amendment No. 4: United Kingdom 
(UK) only.  

Abbreviations: updated to
include abbreviations used
in revised text.

Page 14: Study Design
revised to clarify how
long subjects may
continue to receive
treatment in the
MEK114375 study once
GSK1120212 is
commercially available.

Section 3: Study Design
revised to clarify how
long subjects may
continue to receive
treatment in the
MEK114375 study once
GSK1120212 is
commercially available.

Section 5.7.7.1: Revised to
include the UK (QTc
stopping criteria)

Section 13.5 Appendix 5:
Country Specific
Requirements: page
revised to include UK
specific requirements
regarding QTc withdrawal
criteria and study duration
RM2010/00127/05
2012-SEP-25
Amendment No. 5:

Page 1: Subject: added
‘trametinib’ the commercial
name of GSK1120212.

Section 4.1.2: Inclusion Criteria
Bullet #7:  revised the time
span for female contraceptive
use as standard language
requirement.

Section 4.1.3: Exclusion
Criteria revised to be more in


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line with the criteria of the 
parent studies from which the 
subject is transitioning.

Section 5.7.7: QTc Withdrawal 
Criteria revised to show 
specific actions for a Grade 3 or 
Grade 4 prolonged QTc event 
at the request of the FDA.

Section 6.2: Prohibited 
Medications and Non-Drug 
Therapies revised by removing 
medications and non-drug 
therapies that are no longer 
prohibited.

Section 7.3:  Contraception 
Requirements, Section 7.3.1: 
Female Subjects revised the 
time span for female 
contraceptive use as standard 
language requirement.

Section 12: References updated 
to include the most recent 
edition date of Investigator’s 
Brochure.

Section 13.1: Appendix 1: Time 
and Event Table for Cohort A 
deleted ECHO/MUGA Scan at 
8 weeks to match the language 
in the body of the protocol and 
revised footnote #8 to match.  
Additionally revised footnote 
#6 to reflect the change in the 
upper limit of the QTc interval.

Section 13.2: Appendix 2: Time 
and Event Table for Cohort B: 
Footnote #6 revised to reflect 
the change in the upper limit of 
the QTc interval.
RM2010/00127/06
2013-FEB-14
Amendment No.: 6

Revised Section: 3.1 Cohorts, 
Section 13.1 Time & Events 
Table Cohort A footnote # 20 
and Section 13.2 Time & Event 


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Table Cohort B footnote #20 to 
provide  clarification on 
decreasing interim visit 
schedule for those subject on 
study >52 weeks.

Revised language to 
incorporate standard language 
changes in Section: 4.1.2 
Inclusion Criteria, Section 
5.7.1.2 Managing 
Hypertension, Section 5.7.7 
QTc Withdrawal Criteria, 
Section 5.7.8.1 Left Ventricular 
Ejection Fraction Stopping 
Criteria, and Section 8.5.5 
Pregnancy.

Section 5.1. Investigational 
Product: Table 1 GSK1120212 
GSK Investigational Product: 
Deleted description of the 1mg 
tablet as this strength is no 
longer available for use.

Section 7.2.Contraception 
Requirements:  Section 7.3.2 
Male Subjects: Deleted as it no 
longer applies.

Made administrative changes 
for typographical (punctuation) 
omissions and errors.
RM2010/00127/07
2014-FEB-06
Amendment No.: 7 

 
 
 
 
 
  
 


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
 

 
 
 
 
 

List of Abbreviations:  Added 
Retinal Pigment Epithelial 
Detachment (RPED).

Section 4.1.3. Exclusion 
Criteria:  Deleted criterion #2 
as local access to commercially
available GSK1120212 is no 
longer considered a major 
exclusion to enroll in study.

Section 5.1. Investigational 
Product, Table 1 
GSK1120212GSK 
Investigational Product:  Table 
1 was deleted.  Protocol tables 
and table references throughout 
the protocol were renumbered 
accordingly. 

Section 5.4. Handling and 
Storage of Study Treatment:  
Revised section to reference the 
label and the Study Procedure 
Manual for study treatment 
storage conditions.

Section5.7.5. Stopping Criteria 
for Visual Changes:  Paragraph
#1 revised to reflect current


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standard language.

Section 5.7.5 Stopping Criteria 
for Visual Changes: Grade 1 
visual changes: Grade 2 or 3 
visual changes; Grade 4 visual 
changes: Revised to reflect 
current standard language.

Section 8.4.2. Ophthalmologic
Examinations:  revised to 
reflect current standard 
language.

Section 12 References:  Added 
Investigator’s Brochure, 5th
edition, 25 September 2013 to
Clinical Investigator’s Brochure
reference.

Section13.1. Appendix 1: Time 
and Events Table for Cohort A: 
Annotation #12 corrected 
symbol from > to ≥.

Section13.2. Appendix 2: Time 
and Events Table for Cohort B: 
Annotation #12 corrected 
symbol from > to ≥.

Made administrative changes 
for typographical (punctuation) 
omissions and errors.




RM2010/00127/07
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SPONSOR/MEDICAL MONITOR INFORMATION PAGE
Clinical Study Identifier:
MEK114375
GlaxoSmithKline
Five Moore Drive 
P.O. 13398
Research Triangle Park, NC 27709-3398, USA
Telephone: 
In some countries, the clinical trial sponsor may be the local GlaxoSmithKline affiliate 
company (or designee). Where applicable, the details of the Sponsor and contact person 
will be provided to the relevant regulatory authority as part of the clinical trial 
submission.
Sponsor Medical Monitor Contact Information: 
Role
Name
Day Time 
Phone 
Number
After-hours 
Phone/Cell
/
Pager 
Number
Fax 
Number
GSK Address
Primary 
Medical 
Monitor
, 
MD, PhD
GlaxoSmithKline
1250 South Collegeville 
Road, 
Mailstop UP 4410
Collegeville, PA  19426-0989, 
US
Secondary 
Medical 
Monitor
, MD
GlaxoSmithKline
1250 South Collegeville 
Road, 
Mailstop UP 4210
Collegeville, PA  19426-0989, 
US
Regulatory Agency Identifying Numbers:  
US IND #102,175
EudraCT # 2010-023015-33






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INVESTIGATOR AGREEMENT PAGE
For protocol MEK114375
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 clinical 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 Signature
Date


RM2010/00127/07
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TABLE OF CONTENTS
PAGE
LIST OF ABBREVIATIONS...........................................................................................18
PROTOCOL SUMMARY...............................................................................................21
1.
INTRODUCTION....................................................................................................22
1.1.
Background ................................................................................................22
1.2.
Summary of Risk Management...................................................................23
1.3.
Study Rationale ..........................................................................................24
2.
OBJECTIVE ...........................................................................................................24
2.1.
Primary.......................................................................................................24
3.
STUDY DESIGN ....................................................................................................24
3.1.
Cohorts.......................................................................................................25
3.2.
Discussion of Design ..................................................................................26
3.2.1.
Dose Rationale ............................................................................26
4.
SUBJECT SELECTION AND DISCONTINUATION/ COMPLETION 
CRITERIA ..............................................................................................................27
4.1.
Subject Selection Criteria............................................................................27
4.1.1.
Number of Subjects .....................................................................27
4.1.2.
Inclusion Criteria..........................................................................27
4.1.3.
Exclusion Criteria.........................................................................28
4.1.4.
Permanent Discontinuation from Study Treatment and 
Subject Completion Criteria .........................................................29
4.1.4.1.
Permanent Discontinuation from Study 
Treatment...................................................................29
4.1.4.2.
Subject Completion Criteria........................................30
5.
STUDY TREATMENTS..........................................................................................30
5.1.
Investigational Product................................................................................31
5.2.
Other Approved Anti-Cancer Agents (Cohort B)..........................................32
5.3.
Administration of Study Treatment..............................................................32
5.4.
Handling and Storage of Study Treatment ..................................................32
5.5.
Treatment Assignment................................................................................32
5.6.
Dose Modifications .....................................................................................32
5.6.1.
GSK1120212 Dose Modification..................................................33
5.6.2.
Dose Modification: Other Approved Anti-Cancer Agent(s) ...........33
5.7.
Guidelines for Events of Special Interest ....................................................34
5.7.1.
Monitoring and Management of Hypertension..............................34
5.7.1.1.
Monitoring of Hypertension.........................................34
5.7.1.2.
Management of Hypertension.....................................34
5.7.2.
Management of Dermatological AEs............................................35
5.7.2.1.
Supportive Measures for Rash ...................................35
5.7.2.2.
Prophylactic Treatment of Rash..................................36
5.7.2.3.
Reactive Management of Rash...................................36
5.7.3.
Management of Diarrhea .............................................................38
5.7.4.
Management of Pneumonitis .......................................................39


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5.7.5.
Stopping Criteria for Visual Changes ...........................................43
5.7.6.
Liver Chemistry Stopping Criteria ................................................44
5.7.6.1.
Liver Event Follow-Up Assessments ..........................46
5.7.6.2.
Liver Chemistry Monitoring Criteria.............................47
5.7.7.
QTc Withdrawal Criteria...............................................................47
5.7.7.1.
French and the United Kingdom Specific QTc 
Stopping Criteria.........................................................48
5.7.8.
Criteria for Evaluating Cardiac Function and Electrical 
Activity .........................................................................................48
5.7.8.1.
Left Ventricular Ejection Fraction Stopping 
Criteria........................................................................48
5.8.
Blinding.......................................................................................................49
5.9.
Product Accountability ................................................................................49
5.10.
Treatment Compliance................................................................................49
6.
CONCOMITANT MEDICATIONS AND NON-DRUG THERAPIES .........................49
6.1.
Permitted Medications ................................................................................50
6.1.1.
Drug to Be Used with Caution......................................................50
6.1.1.1.
GSK1120212 as a Victim............................................50
6.1.1.2.
GSK1120212 as a Perpetrator ...................................51
6.2.
Prohibited Medications and Non-Drug Therapies........................................51
6.3.
Treatment after Discontinuation of Study Treatment or 
Discontinuation from /Completion of Study .................................................52
6.4.
Treatment of Study Treatment Overdose....................................................52
6.4.1.
GSK1120212...............................................................................52
6.4.2.
Other Anti-Cancer Agent(s) .........................................................53
7.
LIFESTYLE OR DIETARY RESTRICTIONS ..........................................................53
7.1.
Meals and Dietary Restrictions ...................................................................53
7.2.
Activity ........................................................................................................53
7.3.
Contraception Requirements ......................................................................53
7.3.1.
Female Subjects..........................................................................53
8.
STUDY ASSESSMENTS AND PROCEDURES .....................................................54
8.1.
Transition Visit ............................................................................................54
8.2.
Continuous Dosing Treatment Period .........................................................55
8.2.1.
Cohort A ......................................................................................55
8.2.2.
Cohort B ......................................................................................56
8.3.
Final Study Visit..........................................................................................57
8.4.
Safety .........................................................................................................57
8.4.1.
Physical Examinations.................................................................58
8.4.1.1.
Assessment of Skin Changes.....................................58
8.4.2.
Ophthalmologic Examinations......................................................58
8.4.3.
Vital Signs....................................................................................58
8.4.4.
Electrocardiograms......................................................................58
8.4.5.
Echocardiograms/MUGA Scans ..................................................59
8.4.6.
Clinical Laboratory Assessments .................................................59
8.5.
Adverse Events...........................................................................................60
8.5.1.
Definition of an AE.......................................................................60
8.5.2.
Definition of a SAE.......................................................................61
8.5.3.
Laboratory and Other Safety Assessment Abnormalities 
Reported as AEs and SAEs.........................................................62


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8.5.3.1.
Disease-Related Events and/or Disease-
Related Outcomes Not Qualifying as SAEs ................63
8.5.4.
Time Period and Frequency of Detecting AEs and SAEs.............63
8.5.4.1.
Prompt Reporting of Serious Adverse Events 
and Other Events to GSK ...........................................64
8.5.4.2.
Regulatory reporting requirements for SAEs ..............65
8.5.5.
Pregnancy ...................................................................................65
8.5.6.
Optional Tumor and/or Skin Biopsy and Biomarker 
Assessments ...............................................................................65
8.5.7.
Optional Tumor Biopsy ................................................................65
8.5.8.
Optional Skin Biopsy....................................................................66
8.5.9.
Optional Blood Sampling for Biomarker Analysis .........................66
8.5.9.1.
Optional Circulating Free DNA (cfDNA)......................66
9.
DATA MANAGEMENT ...........................................................................................66
10. DATA ANALYSIS AND STATISTICAL CONSIDERATIONS...................................67
10.1.
Hypotheses.................................................................................................67
10.2.
Study Design Considerations......................................................................67
10.2.1.
Sample Size Considerations........................................................67
10.2.2.
Sample Size Re-estimation..........................................................67
10.3.
Data Analysis Considerations .....................................................................67
10.3.1.
Analysis Populations....................................................................67
10.3.2.
Analysis Data Sets.......................................................................67
10.3.3.
Interim Analysis ...........................................................................67
10.3.4.
Key Elements of Analysis Plan ....................................................67
10.3.5.
Safety Analyses...........................................................................68
10.3.5.1.
Extent of Exposure .....................................................68
10.3.5.2.
Adverse Events ..........................................................68
10.3.5.3.
Clinical Laboratory Evaluations ..................................68
10.3.5.4.
Other Safety Measures...............................................69
10.3.5.5.
Clinical Activity Analyses ............................................69
11. STUDY CONDUCT CONSIDERATIONS ...............................................................69
11.1.
Posting of Information on Clinicaltrials.gov..................................................69
11.2.
Regulatory and Ethical Considerations, Including the Informed 
Consent Process ........................................................................................69
11.3.
Urgent Safety Measures .............................................................................70
11.4.
Quality Control (Study Monitoring) ..............................................................70
11.5.
Quality Assurance.......................................................................................70
11.6.
Study and Site Closure ...............................................................................70
11.7.
Records Retention......................................................................................71
11.8.
Provision of Study Results to Investigators, Posting to the Clinical 
Trials Register and Publication ...................................................................71
12. REFERENCES.......................................................................................................73
13. APPENDICES........................................................................................................74
13.1.
Appendix 1: Time and Events Table for Cohort A .......................................74
13.2.
Appendix 2: Time and Events Table for Cohort B .......................................76
13.3.
Appendix 3:  NYHA Functional Classification System .................................78
13.4.
Appendix 4:  Liver Chemistry Stopping and Follow-up Criteria....................79


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13.5.
Appendix 5:  Country Specific Requirements..............................................80
13.6.
Appendix 6:  Protocol Changes...................................................................81


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LIST OF ABBREVIATIONS 
ADL
Activities of daily living
AE(s)
Adverse Event(s)
ALT
Alanine aminotransferase (SGPT)
AST
Aspartate aminotransferase (SGOT)
ATS
All Treated Subjects
-HCG
Beta-Human Chorionic Gonadotropin
BID
Twice daily
BP
Blood pressure
BUN
Blood urea nitrogen
C
Degrees Celsius
cfDNA
Circulating free DNA
cm
Centimeter(s)
CPK
Creatine phosphokinase
CPP
Calcium phosphate product
CR 
Complete response
CSR
Central serous retinopathy
CT
Computed tomography
CYP
Cytochrome
DBP
Diastolic blood pressure
DHEA
Dehydroepiandrosterone
dL
Deciliter
DLT
Dose-limiting toxicity
DNA
Deoxyribonucleic acid
ECG(s)
Electrocardiogram(s)
ECHO(s)
Echocardiogram(s)
eCRF(s)
Electronic case report form(s)
EIAED(s)
Enzyme-inducing anti-epileptic drug(s)
ERK
Extracellular signal-regulated kinase
F
Degrees Fahrenheit
FDA
Food and Drug Administration
fl oz
Fluid ounces
GCP
Good Clinical Practice
G-CSF
Granulocyte-cell stimulating factor
GM-CSF
Granulocyte-macrophage-cell stimulating factor
GSK
GlaxoSmithKline
IB
Investigator’s Brochure
ICH
International Conference on Harmonization
IDSL
Integrated Data Standards Library
IEC
Independent Ethics Committee
IgM
Immunoglobulin M
IND
Investigational New Drug
INR
International normalized ratio
IP
Investigational product
IRB
Institutional Review Board


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IV
Intravenous
IVRS
Interactive voice response system
kg
Kilogram(s)
LDH
Lactate dehydrogenase
LLN
Lower limit of normal
LVEF
Left ventricular ejection fraction
MAA
Marketing Application Authorization
MAPK
Mitogen-activated protein kinase
MedDRA
Medical dictionary for regulatory activities
MEK
Mitogen-activated protein kinase
MHRA
Medicines and Healthcare products Regulatory Agency
mg
Milligrams
mL
Milliliter
mmHg
Millimeters of mercury
MRI
Magnetic resonance imaging
MSDS
Material Safety Data Sheet
msec
Milliseconds
MTD
Maximum tolerated dose
MUGA
Multiple-gated acquisition scan
NC
North Carolina
NCCN
National Comprehensive Cancer Network
NCI-CTCAE
National Cancer Institute – Common Toxicity Criteria for 
Adverse Events
NSCLC
Non-small cell lung cancer
NYHA
New York Heart Association
PA
Pennsylvannia
PD
Progressive disease or pharmacodynamic
P-gp
P-glycoprotein
PK
Pharmacokinetic
PR
Partial response
PT
Prothrombin time
PTT
Partial thromboplastin time
QTcB
QT duration corrected for heart rate by Bazett’s formula
QTcF
QT duration corrected for heart rate by Fridericia’s formula
RAMOS
Registration and Medication Ordering System
RAP
Reporting and Analysis Plan
RECIST
Response Evaluation Criteria in Solid Tumors
RNA
Ribonucleic acid
RP2D
Recommended Phase II dose
RPED
Retinal Pigment Epithelial Detachment
RVO
Retinal vein occlusion
SAE
Serious adverse event(s)
SBP
Systolic blood pressure
SD
Stable disease
SPF
Skin protection factor
SPM
Study Procedures Manual


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TSH
Thyroid stimulating hormone
UK
United Kingdom
ULN
Upper limit of normal
US/USA
United States of America
WBC
White blood cells
WNL
Within normal limits
Trademark Information
Trademarks of the GlaxoSmithKline 
group of companies
Trademarks not owned by the 
GlaxoSmithKline group of companies
NONE
None


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PROTOCOL SUMMARY
Rationale
GSK1120212 is a potent, reversible and highly selective inhibitor of MEK1/MEK2 
activation and kinase activity.  This multicenter, non-randomized, open-label rollover 
study will provide continued access to GSK1120212 to subjects with solid tumors or 
leukemia who have previously participated in a GSK1120212 study and who are 
clinically benefitting from continued treatment and have an acceptable safety profile with 
GSK1120212.
Objectives
The primary objective of the study is to provide continued treatment with GSK1120212 
for subjects with solid tumors or leukemia who have previously participated in a 
GSK1120212 study and who are clinically benefitting from continued treatment and have 
an acceptable safety profile with GSK1120212.
Study Design
This Phase II, multicenter, non-randomized, open-label, rollover study is designed to 
provide continued access to GSK1120212 to subjects with solid tumors or leukemia who 
have previously participated in a GSK1120212 study (parent study) and who are 
clinically benefitting from continued treatment and have an acceptable safety profile with 
GSK1120212.  Subjects will be enrolled into the appropriate cohort based upon the 
treatment received in their parent study.  Enrollment into this study will be dependent 
upon the site’s agreement to participate in this study.  It is estimated that approximately 
250 subjects will be enrolled in this study. Subjects may continue treatment in the 
rollover study until no longer clinically benefitting, unacceptable toxicity, withdrawal of 
consent, or have access to local commercial supply of GSK1120212.
Study Assessments
Safety will be evaluated through routine physical examinations, vital sign measurements, 
12-lead electrocardiograms, echocardiograms or multiple-gated acquisition scans, clinical 
laboratory tests, and monitoring of adverse events.  Additional safety assessments may be 
necessary if a combination treatment regimen is administered to address specific safety 
concerns with the other agent(s) being administered.
Assessment of clinical activity will be performed throughout the study using local 
standard of care imaging practices and the appropriate assessment criteria as determined 
by the investigator to determine continued study participation and treatment with 
GSK1120212.  Only subjects considered by the investigator to be receiving clinical 
benefit may continue on study treatment.


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1.
INTRODUCTION
1.1.
Background
The RAS/RAF/MEK/ERK or MAPK pathway is a critical signal transduction cascade 
implicated in the uncontrolled proliferation of many human cancers.  Multiple genetic 
alterations in components of this cascade resulting in constitutive pathway activation 
have been well characterized over the past several decades [Davies, 2002; Allen, 2003].   
Given the critical location of MEK in this signalling pathway, it has been recognized as 
an important target for anti-cancer therapy.  Drug development efforts to inhibit MEK 
demonstrated clinical benefit, although with limited success.  For example, PD-0325901, 
CI-1040, and AZD6244, have achieved objective responses in melanoma, pancreatic 
cancer, and non-small cell lung cancer [LoRusso, 2010; LoRusso, 2005; 
GlaxoSmithKline Document Number RM2007/00642/03; Tzekova, 2008], but none have 
demonstrated significant single-agent activity in these tumor types. 
GSK1120212 is a potent, reversible, highly selective allosteric inhibitor of MEK1/MEK2 
activation and kinase activity.  The specificity of GSK1120212 to MEK1 and MEK2 
was confirmed against a large panel of kinases and no significant inhibitory activity 
was measured. A detailed summary of in vitro and in vivo non-clinical pharmacology 
studies is provided in the GSK1120212 Investigator Brochure (IB) 
[GlaxoSmithKline Document Number HM2009/00151/02].
As of 14 April 2011, 657 subjects with cancer have received at least one dose of 
GSK1120212 in 14 ongoing Phase I/II/III clinical studies.  Six of the 14 studies 
administer GSK1120212 as monotherapy, whereas the other 8 studies are designed 
to administer GSK112012 as combination therapy.  As of 14 April 2011, 206 
subjects in MEK111054, the first-time-in-human (FTIH) study of GSK1120212, had 
been dosed with GSK1120212.  Dose-related MAP kinase inhibition was 
demonstrated between daily doses of 0.5 and 2.0 mg with immunohistochemistry on 
tumor biopsies.  Modulation of MAP kinase pathways was consistent with changes 
observed with fluorodeoxyglucose-positron emission tomography imaging.  Based 
on the AEs observed in the FTIH MEK111054 study, the maximum tolerated dose 
(MTD) was determined to be 3.0 mg once-daily and the recommended Phase II dose 
(RP2D) of GSK1120212 was identified as 2.0 mg once-daily.  An unconfirmed 
response rate of 43% (6 out of 14 subjects) had an objective response, including 
2 complete responses (CRs) was observed.    The recommended monotherapy dose 
(2 mg once-daily) was well-tolerated.  Most notable adverse events (AEs) at this dose 
(n = 96) included class effects of rash (78%; 4% Grade 3) and diarrhea (54%; 1% 
Grade 3).  In all subjects dosed (n = 206), 5 cases of Grade 3 left ventricular systolic 
dysfunction, 3 cases of central serous retinopathy (CSR), and 1 case of retinal vein 
occlusion (RVO) were observed.  Among the 5 left ventricular ejection fraction 
(LVEF) cases, only 2 were considered related to study treatment and neither subject 
was symptomatic.  All 3 cases of CSR resolved upon study treatment interruption, 
and the subject with RVO has experienced significant improvement in visual acuity 
after intraocular bevacizumab treatments.


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GSK1120212 is absorbed rapidly with median tmax generally occurring within 1 to 
3 hours after administration of GSK1120212.  After repeat dosing (Study Day 15), 
the mean area under the concentration-time curve (AUC(0-)) and maximum 
observed concentrations (Cmax) increased in a dose proportional manner (i.e., a 
2-fold increase in dose resulted in a 2-fold increase in exposure).  Between-subject 
variability (CV%) in exposure ranged from 27 to 50% for Cmax and 20 to 41% for 
area under the concentration-time curve from time zero (pre-dose) to 24 hrs after 
the last dose of study treatment (AUC(0-24)) across all dosing regimens.  
GSK1120212 accumulates with repeat dose with an effective half-life (t1/2) of 
approximately 5 days.
Further information on the safety, PK, and efficacy is described in the IB for 
GSK1120212 [GlaxoSmithKline Document Number HM2009/00151/02].
1.2.
Summary of Risk Management
The assessment of the risk of GSK1120212 is based on clinical data from the 
ongoing FTIH study in which subjects have been dosed daily for >21 days, as well as 
preclinical toxicity data.  In study MEK111054, the most common AEs experienced 
by 20% of all subjects with daily dosing were rash, diarrhea, fatigue, nausea, 
peripheral edema, and vomiting.  Rash and diarrhea are common, class-effect 
toxicities for MEK inhibitors.  In addition, visual impairment and LVEF reduction, 
although observed at lower frequencies, are also considered class-effect toxicities as 
they have been observed with GSK1120212 as well as other MEK inhibitors.  
Systemic toxicity of GSK1120212 has been evaluated following oral dosing in rats 
and dogs for up to 13 weeks.  In the most sensitive non-clinical species, rat, the 
principal adverse effects seen in oral toxicity studies of up to 13 weeks with daily 
dosing were skin and stomach erosions, skin ulcerations, which were secondary to 
reduced proliferation, altered phosphate homeostasis that resulted in soft tissue 
mineralization, hepatocellular necrosis, bone marrow degeneration/necrosis and 
ovarian perturbations.  The skin and stomach findings and phosphatemia 
demonstrated reversibility with 4 weeks of recovery.  Additional details are 
provided in the IB for GSK1120212 [GlaxoSmithKline Document Number 
HM2009/00151/02].
Procedures to minimize or monitor potential risks are listed below:

To reduce the risk of ocular toxicity, subjects with history of RVO, or CSR, 
subjects with predisposing factors for RVO or CSR or predisposing retinal 
pathology as determined by ophthalmologic exams are excluded.  
Ophthalmologic exams will be performed at baseline and as clinically 
warranted.

To monitor cardiac function, echocardiogram (ECHO) or multigated 
acquisition (MUGA) scans will be performed.

To reduce the risk of excessive gastrointestinal (GI) toxicity (diarrhea) and 
cutaneous toxicity (rash), subjects will be monitored closely and supportive 
care guidelines will be implemented.


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1.3.
Study Rationale
This open-label rollover study will permit subjects with solid tumors or leukemia, who 
are currently receiving GSK1120212 either as monotherapy or as part of a combination 
regimen in a GSK1120212 study that has met its study objective(s), to continue receiving 
treatment with GSK1120212.  In addition, this study will continue to collect safety 
information. Subject may continue treatment in this study if they are demonstrating 
clinical benefit as well as an acceptable safety profile with GSK1120212.
2.
OBJECTIVE
2.1.
Primary
The primary objective of the study is to provide continued treatment with GSK1120212 
for subjects who have previously participated in a GSK1120212 study and who continue 
to receive clinical benefit as well as have an acceptable safety profile with GSK1120212.
3.
STUDY DESIGN
This Phase II, multicenter, non-randomized, open-label, rollover study is designed to 
provide continued access to GSK1120212 to subjects who have previously participated in 
a GSK1120212 study (parent study).  All subjects enrolling in this study must be
receiving clinical benefit from continued treatment as well as have an acceptable safety 
profile with GSK1120212 to be eligible.  Subjects will be stratified into the appropriate 
cohort (see Section 3.1) based upon the treatment received in their parent study.  
Enrollment into this study will be dependent upon the site’s agreement to participate in 
this study.
Subjects must provide written informed consent prior to any study-related assessment or 
procedure being performed or treatment with GSK1120212 for this study.  After 
informed consent is obtained, subjects will be evaluated for study eligibility.
Protocol waivers or exemptions are not allowed.  Therefore, adherence to the study 
design requirements, including those specified in Appendix 1: Time and Events Table for 
Cohort A or Appendix 2: Time and Events Table for Cohort B, is essential.
The study will consist of a transition visit, continuous dosing treatment period, and a final 
study visit. 
Safety assessments will be performed throughout the study including the evaluation of 
physical examinations, vital sign measurements (blood pressure [BP], pulse rate, and 
temperature), 12-lead electrocardiograms (ECGs), echocardiograms (ECHOs) or MUGA 
scans, clinical laboratory assessments, and monitoring of AEs.  Additional safety 
assessments may be necessary if a combination treatment regimen is administered to 
address specific safety concerns with the other agent(s).


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Assessment of clinical activity will be performed using local standard of care imaging 
practices and the appropriate assessment criteria (e.g. Response Evaluation Criteria in 
Solid Tumors [RECIST] 1.1) as determined by the investigator to determine continued 
study participation and treatment with GSK1120212.  Only subjects who continue to 
receive clinical benefit as determined by the investigator as well as having an acceptable 
toxicity safety profile will be allowed to continue treatment on study.
Subjects may continue treatment in this rollover study until lack of clinical benefit,
unacceptable toxicity, withdrawal of consent, or have access to local commercial supply 
of GSK1120212.
Refer to Appendix 1: Time and Events Table for Cohort A or Appendix 2: Time and 
Events Table for Cohort B for timing of all assessments.
NOTE:  Subjects participating in a BRAF/MEK combination study (receiving 
GSK1120212 in combination with GSK2118436 [a BRAF inhibitor]) should continue 
treatment in the GSK2118436 rollover study, BRF114144.
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.
3.1.
Cohorts
Cohort A:
Cohort A will consist of subjects who have completed <24 weeks of treatment with 
GSK1120212 monotherapy during their participation in the parent study.  It is anticipated 
that subjects in this cohort will have participated in a clinical pharmacology or another 
short-term study of GSK1120212.  Subjects will complete the Transition Visit and return 
for their next scheduled visit (Study Week 4), and then every 4 weeks thereafter.  
Subjects who have tolerated therapy well with limited toxicities and remain on study 
treatment >52 weeks may have the frequency of their interim visits decreased with 
approval and direction from the GSK Medical Monitor.
Subjects will receive GSK1120212 as an oral, daily dose of 2 mg or less.  Protocol 
specified guidelines for dose modifications and treatment discontinuation criteria are 
provided in Section 5.6 and Section 5.7, respectively.  If there are any uncertainties about 
the dose to be administered in this study, the GSK Medical Monitor should be consulted.  
Once treatment with GSK1120212 is discontinued the subject is to be withdrawn from 
the rollover study.
Cohort B:
Cohort B will consist of subjects who have completed 24 weeks of treatment with 
GSK1120212 (either as monotherapy or combination therapy with an approved anti-
cancer agent) during their participation in the parent study.  Subjects who transition from 
a combination study may continue to receive GSK1120212 in combination with the 
approved anti-cancer agent defined by the parent study or if, in the opinion of the 


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investigator, the subject has received maximum benefit or is experiencing unacceptable 
toxicity from the approved anti-cancer agent, then treatment with the approved anti-
cancer agent may be discontinued and the subject may remain on study for continued 
treatment with GSK1120212 alone.  Once treatment with GSK1120212 is discontinued 
the subject is to be withdrawn from the rollover study.
Subjects will complete the Transition Visit assessments and then return for their next 
scheduled visit (Study Week 3 or 4), then every 3 or 4 weeks thereafter (depending on the 
schedule used in the parent study).  Subjects who have tolerated therapy well with 
limited toxicities and remain on study treatment >52 weeks may have the frequency of 
their interim visits decreased with approval and direction from the GSK Medical 
Monitor.  
All subjects will receive GSK1120212 at the current dose level administered in the parent 
study at the time of the Transition Visit.  If this starting dose of GSK1120212 is below 
the recommended Phase 2 dose (RP2D) previously defined for the given treatment 
regimen (e.g., dose modification following recovery from toxicity), the investigator, after 
consultation with the GSK Medical Monitor, may consider escalating the dose to the 
RP2D.  If there are any uncertainties about the dose(s) to be administered in this study, 
the GSK Medical Monitor should be consulted.
3.2.
Discussion of Design
The purpose of this study is to allow for continued treatment with GSK1120212 in 
subjects with solid tumors or leukemia who have participated in a GSK1120212 study of 
GSK1120212 and meet the protocol requirements for transitioning to the rollover study.  
Subjects will be closely monitored for known dose-limiting toxicities associated with 
GSK1120212.  The schedule of assessments and procedures to be performed during this 
study is provided in Appendix 1: Time and Events Table for Cohort A and Appendix 2: 
Time and Events Table for Cohort B.  To manage known side effects, and unless 
otherwise stated, supportive care therapies, such as growth colony stimulating factors, 
will be allowed and dosed in accordance with local institutional practices.  The details 
regarding dose modifications of GSK1120212 and guidance on additional assessments 
and procedures following events of special interest can be found in Section 5.6 and 
Section 5.7, respectively.
3.2.1.
Dose Rationale
For this study, the dose of study treatment to be administered to subjects will be 
individualized based upon the dose/regimen received during their participation in the 
parent study at the time of transition to the rollover study.  
1.
Subjects who have received <24 weeks of GSK1120212 monotherapy in the parent 
study (Cohort A) will receive the same continuous dosing regimen of GSK1120212 
at completion of the parent study. Subjects must be at a starting dose of 2 mg or less 
once-daily in the rollover study. 


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Dose selection for Cohort A was based on the preliminary results from the first-time-
in-human trial, MEK111054 [GlaxoSmithKline Document Number 
RM2007/00642/03].  Based on the preliminary AEs observed and protocol-defined 
dose-finding criteria in MEK111054, the single-agent maximum tolerated dose 
(MTD) was established at 3 mg once-daily, and the current recommended Phase II 
dose as monotherapy is 2 mg once-daily.
2.
Subjects who have received 24 weeks of continuous treatment with GSK1120212
as monotherapy or combination therapy with another approved anti-cancer agent 
(Cohort B) will continue treatment in the rollover study at the current dose level 
administered in the parent study at the time of transition to the rollover study.  If a 
subject required a dose modification while receiving treatment in the parent study, 
the subject will enter the rollover study and continue treatment on the modified dose 
unless after consultation with the GSK Medical Monitor it is appropriate to escalate 
the dose.  
4.
SUBJECT SELECTION AND DISCONTINUATION/ 
COMPLETION CRITERIA
4.1.
Subject Selection Criteria
4.1.1.
Number of Subjects
Approximately 250 subjects from approximately 80 investigative sites will be 
transitioned to this study from other GSK1120212 studies.
4.1.2.
Inclusion Criteria
Specific information regarding warnings, precautions, contraindications, AEs, and other 
pertinent information on GSK1120212 or other approved agent(s) that may impact 
subject eligibility is provided in the IB for GSK1120212 
[GlaxoSmithKline Document Number HM2009/00151/02] or any subsequent IB 
supplements or in the Prescribing Information for any approved agent(s) administered as 
part of a combination treatment regimen, as applicable.
Deviations from inclusion criteria are not allowed because they can potentially jeopardize 
the scientific integrity of the study, regulatory acceptability, or subject safety.  Therefore, 
adherence to the criteria as specified in the protocol is essential.
A subject will be eligible for inclusion in this study only if all of the following criteria 
apply:
1.
Has provided signed informed consent for this study.
2.
Has demonstrated compliance during the parent study with study treatment(s), 
treatment visit schedules, and the requirements and restrictions listed in the consent 
form.


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3.
Is currently participating in GSK1120212 study and is receiving treatment with 
GSK1120212.
4.
Is currently receiving clinical benefit as determined by the investigator from previous 
treatment with GSK1120212 either as monotherapy or as part of a combination 
treatment regimen.
5.
Continued ability to swallow and retain orally administered study treatment(s) and 
does not have any clinically significant GI abnormalities that may alter absorption 
such as malabsorption syndrome or major resection of the stomach or bowels.
6.
Female subjects of childbearing potential, as defined in the parent study, must 
be willing to continue practicing the same acceptable method of contraception 
as used in the parent study during the rollover study and for at least 4 months 
after the last dose of GSK1120212.
7.
Female subjects of childbearing potential, as defined in parent study, must have 
negative serum pregnancy tests at the time of transition to this study.
8.
Subjects enrolled in France: In France, a subject will be eligible for inclusion in 
this study only if either affiliated to or a beneficiary of a social security 
category.
4.1.3.
Exclusion Criteria
Deviations from exclusion criteria are not allowed because they can potentially 
jeopardize the scientific integrity of the study, regulatory acceptability, or subject safety.  
Therefore, adherence to the criteria as specified in the protocol is essential.
Subjects meeting any of the following criteria must not be enrolled in this study:
1. Permanent discontinuation of GSK1120212 in the parent study due to toxicity or 
disease progression.
2. Current use of a prohibitive medication(s) as listed in Section 6.2.
NOTE: Use of anticoagulants such as warfarin is permitted; however, the 
international normalization ratio (INR) must be monitored in accordance 
with local institutional practice.
3. Any unresolved toxicity that meets the study treatment discontinuation or 
study withdrawal criteria from the parent study at the time of transition to 
this study.
4. Bazett-corrected QT (QTcB) interval ≥501 msec at the time of transition to 
this study
5. Left ventricular ejection fraction (LVEF) < institutional lower limit of 
normal (LLN) by ECHO (preferred) or MUGA scan at the time of transition 
to this study.
6.
Nursing female.
7. Any serious and/or unstable pre-existing medical, psychiatric disorder or 
other conditions at the time of transition to this study that could interfere 


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with subject’s safety, obtaining informed consent or compliance to the study 
procedures, in the opinion of the investigator or GSK Medical Monitor.
4.1.4.
Permanent Discontinuation from Study Treatment and Subject 
Completion Criteria
4.1.4.1.
Permanent Discontinuation from Study Treatment
Subjects will receive study treatment until death or unacceptable AE, including meeting 
stopping criteria for liver chemistry defined in Section 5.7.4 or for hematologic and other 
non-hematologic toxicity.  In addition, study treatment may be permanently discontinued 
for any of the following reasons:

Deviation(s) from the protocol

Clinically significant AE leading to interruption of treatment for 
>21 consecutive days.  
NOTE:  If the investigator and GSK Medical Monitor agree that continued 
treatment will benefit the subject, then the subject may continue treatment, with 
or without a dose reduction, with the approval of the GSK Medical Monitor.

Disease progression (including death due to disease progression)

Request of the subject or proxy (withdrawal of consent by the subject)

Investigator’s discretion

Subject is lost to follow-up

Study is closed or terminated (such as when GSK1120212 becomes locally 
available as commercial product to the subject for continued treatment)
The primary reason study treatment was permanently discontinued must be documented 
in the subject’s medical records and electronic case report form (eCRF).
Once a subject has permanently discontinued from GSK1120212, the subject will not be 
allowed to be retreated.
All subjects who discontinue study treatment will have safety assessments performed at 
the Final Study Visit within approximately 28 days (7 days) of last dose of study 
treatment(s) as specified in Appendix 1: Time and Events Table for Cohort A or 
Appendix 2: Time and Events Table for Cohort B.
If the subject withdraws consent for further study treatment, a Final Study Visit should be 
completed (see Appendix 1: Time and Events Table for Cohort A or Appendix 2: Time 
and Events Table for Cohort B).  If the subject withdraws consent for further treatment 
and data collection, then no additional study visits or data collection should occur.
If the subject discontinues from treatment due to toxicity, ‘AE’ will be recorded as the 
primary reason for permanent discontinuation in the eCRF.


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In the event that a subject is prematurely discontinued from the study at any time due to 
an AE (as defined in Section 8.5.1, “Definition of an AE”) or serious AE (SAE) (as 
defined in Section 8.5.2, “Definition of a SAE”), the procedures stated in Section 8.5, 
(“Adverse Events”) must be followed.  All subjects who have a Grade 3 or 4 clinical or 
laboratory abnormality at the time of withdrawal from the study must be followed until 
resolution to Grade 2 or less, unless it is unlikely to improve because of underlying 
disease.
If the subject discontinues from study treatment due to disease progression, ‘Disease 
Progression’ will be recorded as the primary reason for permanent study treatment 
discontinuation in the eCRF.
If the subject discontinues study treatment due to death, ‘Death’ will be recorded as the 
primary reason for permanent study treatment discontinuation in the eCRF.  The cause of 
death should also be documented in the eCRF
4.1.4.2.
Subject Completion Criteria
A subject will be considered to have completed the study if the subject progresses during 
study treatment or at the Final Study Visit, or dies.
A subject will be considered to have withdrawn from the study if the subject has not died 
or progressed and is lost to follow-up, has withdrawn consent, or at the investigator’s 
discretion is no longer being followed. 
The end of study is defined as the last subject, last visit.
5.
STUDY TREATMENTS
The term ‘study treatment’ is used throughout the protocol to describe any combination 
of products received by the subject as per the protocol design. Study treatment may 
therefore refer to the individual study treatments or the combination of those study 
treatments.


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5.1.
Investigational Product
Table 1
GSK1120212 GSK Investigational Product
Commercial Image Product
Product 
name :
GSK1120212 0.5 mg Tablet
GSK11210212 2 mg Tablet
Formulation 
description:
Each tablet contains GSK1120212B equivalent 
to 0.5 mg of GSK1120212 as drug substance 
blended with inert ingredients (mannitol, 
sodium lauryl sulfate, colloidal silicon dioxide, 
microcrystalline cellulose, hypromellose, 
croscarmellose sodium, and magnesium 
stearate) and compressed into tablets.  The 
tablets are then coated with yellow opaque 
film* (*Opadry yellow, a titanium dioxide-based 
formulation with yellow iron oxide as 
colorant).
Each tablet contains GSK1120212B 
equivalent to 2 mg of GSK1120212 as 
drug substance blended with inert 
ingredients (mannitol, sodium lauryl 
sulfate, colloidal silicon dioxide, 
microcrystalline cellulose, hypromellose, 
croscarmellose sodium, and magnesium 
stearate) and compressed into tablets.
The tablets are then coated with pink 
opaque film* (*Opadry Pink, a titanium 
dioxide-based formulation with red iron 
oxide as colorant).
Dosage form 
:
Tablet
Tablet
Unit dose 
strength(s):
Tablet strength: 0.5 mg
Tablet strength: 2 mg
Physical 
Description:
Yellow, modified oval, biconvex, film-coated 
tablets (4.85 x 8.86 mm)
Pink, biconvex, round film-coated tablets 
7.5 mm in diameter
Route/
Administrati
on: 
Oral/once-daily single dose
Oral/once-daily single dose
Dosing 
Instructions:
GSK1120212 should be administered with approximately 240 mL (8 fl oz) of water, under 
fasting conditions, either 1 hour before or 2 hours after a meal
GSK1120212 will be provided to sites by GSK. The contents of the label will be in 
accordance with all applicable regulatory requirements.  No special preparation of 
GSK1120212 is required.
GSK1120212 must be dispensed or administered only to subjects enrolled in the study 
and in accordance with the protocol.  Only authorized site staff may supply or administer 
GSK1120212.
Under normal conditions of handling and administration, study treatment is not expected 
to pose significant safety risks to site staff.  A Material Safety Data Sheet (MSDS) 
describing the occupational hazards and recommended handling precautions will be 
provided to the site staff if required by local laws or will otherwise be available from 
GSK upon request.
Adequate precautions are to be taken to avoid direct contact with the study treatment.  
The occupational hazards and recommended handling procedures are provided in the 
MSDS.


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5.2.
Other Approved Anti-Cancer Agents (Cohort B)
When the treatment regimen to be administered includes an approved anti-cancer agent(s) 
in combination with GSK1120212, the sites will be responsible for obtaining the 
necessary drug supply for the approved anti-cancer agent(s) through commercial means; 
the drug(s) will not be supplied by GSK.  The use of an anti-cancer agent(s) in 
combination with GSK1120212 that was not part of the parent study is not permitted.  
Refer to the Prescribing Information for each approved anti-cancer agent for information 
regarding the physical and chemical properties, storage, and dosing/administration 
guidelines.
5.3.
Administration of Study Treatment
If a subject vomits after taking study treatment(s), the subject should be instructed NOT 
to retake the dose and should take the next scheduled dose of study treatment(s).  If 
vomiting persists, the subject should contact the investigator.
If subject misses a dose of study treatment(s), the subject should be instructed to skip the 
missed dose and not make it up, then take the next scheduled dose.
5.4.
Handling and Storage of Study Treatment
GSK1120212 must be stored in an opaque bottle, protected from light and moisture
in a secure area under the appropriate physical conditions for the product at the 
temperature specified on the label. Maintenance of a temperature log (manual or 
automatic) is required.  Access to and administration of the GSK1120212 will be 
limited to the investigator and authorized site staff.  GSK1120212 must be dispensed or 
administered only to subjects enrolled in the study and in accordance with the protocol.
Additional guidance can be found in the SPM.
5.5.
Treatment Assignment
Subjects will be identified by a new, unique subject number assigned upon enrollment 
into this study that will remain consistent for the duration of the study.
Subject/treatment numbers originally assigned to subjects during their participation in the 
parent study will be recorded in the eCRF, but will not be used to identify subjects in the 
rollover 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.  
5.6.
Dose Modifications
At each study visit, subjects should be carefully evaluated for evidence of treatment-
related toxicity.  The investigator should use clinical judgment to determine which study 


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treatment may be contributing to the treatment-emergent toxicity and make the 
appropriate dosing adjustments, which may include reducing the dose of 1 or all study 
treatments.
Guidelines for GSK1120212 dose modifications are provided below.  Investigators 
should also refer to the GSK1120212 IB [GlaxoSmithKline Document Number 
HM2009/00151/02] or the prescribing information for the appropriate approved anti-
cancer combination agent for detailed information regarding warnings, precautions, 
contraindications, AEs, and recommendations for supportive care in the event of drug-
related toxicity. 
5.6.1.
GSK1120212 Dose Modification
For clinically significant toxicities that are considered related to GSK1120212 (i.e., 
diarrhea, peripheral and periorbital edema), except for rash (Section 5.7.1), ejection 
fraction changes (Section 5.7.8.1), pneumonitis (Section 5.7.4), or visual changes 
(Section 5.7.5), the dose modification guidelines for GSK1120212 are provided in Table 
2  All dose modifications (delays or reductions) will be recorded on the appropriate 
eCRF.
Table 2
Dose Modifications for GSK1120212
TOXICITYa
GSK1120212
Grade 1
Continue GSK1120212 at current dose level.  Consider supportive care 
recommendations provided in Section 5.7.
Grade 2
Withhold treatment with GSK1120212 until toxicity resolves to Grade 1 or baseline.  
Upon resolution, restart GSK1120212 at current dose level.  Consider supportive 
care recommendations provided in Section 5.7. Consider dose reduction if toxicity 
is intolerable to the subject.
Grade 3
Withhold GSK1120212 until toxicity resolves to Grade 1 or baseline.  Upon 
resolution, consider reducing dose of GSK1120212 by ≥0.5 mg.  Consider 
supportive care recommendations provided in Section 5.7. 
Grade 4
Permanently discontinue treatment with GSK1120212.
a.
Considered related to study treatment.
Treatment with GSK1120212 may be delayed for up to 21 days to allow resolution of 
toxicity or based on investigator discretion.  If the investigator and the GSK Medical 
Monitor conclude that continued treatment will benefit a subject who has experienced a 
treatment delay >21 days, then the subject may continue GSK1120212 therapy with the 
approval of the GSK Medical Monitor.
A maximum of 2 dose reductions of GSK1120212 is permitted.  If a third dose reduction 
is required, treatment with GSK1120212 should be discontinued.
5.6.2.
Dose Modification: Other Approved Anti-Cancer Agent(s)
If an approved anti-cancer agent(s) is being taken in combination with GSK1120212 at 
the time of transition to the rollover study, treatment will continue with the current dose 


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administered in the parent study.  Any dose modification(s) required while on study 
should be made according to the administration and/or dose modification guidelines 
presented in the protocol of the parent study or in the package insert for the agent, 
whichever is appropriate.  If, in the opinion of the investigator, the subject has received 
maximum benefit from the additional approved anti-cancer agent(s), then treatment with 
the approved anti-cancer agent(s) may be discontinued.
5.7.
Guidelines for Events of Special Interest
The severity of AEs will be graded utilizing the NCI-CTCAE, version 4.0
[NCI, 2009].  Guidelines for dose modifications and interruptions for management of 
common toxicities associated with the study treatment are provided in this section. 
5.7.1.
Monitoring and Management of Hypertension
5.7.1.1.
Monitoring of Hypertension
All BP assessments should be performed under optimal conditions i.e. after (1) 
subject has been seated with back support, ensuring that legs are uncrossed and flat 
on the floor, (2) subject is relaxed comfortably for at least 5 minutes, (3) 
preparatory steps including removal of any restrictive clothing over the cuff area 
and selection of the proper cuff size have been ensured, (4) the arm is supported so 
that the middle of the cuff is at the heart level, and (5) the subject remains quiet 
during the measurement.  In subjects with an initial BP reading within the 
hypertensive range, a second reading should be taken at least 1 minute later, with 
the 2 readings averaged to obtain a final BP measurement. 
Persistent hypertension is defined as an increase of systolic blood pressure (SBP) 
>140 mm Hg and/or diastolic blood pressure (DBP) >90 mmHg in up to 3 
subsequent visits with BP assessments from 2 readings under the optimal conditions 
described above.  Visits to monitor increased BP should be scheduled independently 
from the per-protocol visits outlined in the time-and-events schedule; ideally, 
subsequent BP assessments should be performed within 7 days.
Asymptomatic hypertension is defined as an increase of SBP >140 mmHg and/or 
DBP > 90 mmHg in the absence of headache, light-headedness, vertigo, tinnitus, 
episodes of fainting or other symptoms indicative of hypertension which would 
disappear after the BP is controlled within the normal range. 
5.7.1.2.
Management of Hypertension
For subjects experiencing an increase in SBP and/or DBP that is persistent and may 
be associated with the study treatment, recommendations for the clinical 
management of hypertension are described below:


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Hypertension
(A)  Asymptomatic and persistent1
SBP of 140 and <160 mmHg, or DBP 
90 and <100 mmHg, or a clinically 
significant increase in DBP of 
20 mmHg (but still below 100 mmHg).
Step 1. Continue study treatment at the current dose. 
Step 2. Adjust current or initiate new antihypertensive 
medication(s).
Step 3. Titrate antihypertensive medication(s) during next 2 weeks 
as indicated to achieve well-controlled2 BP.  If BP is not well-
controlled within 2 weeks, consider referral to a specialist and go 
to scenario (B).
(B) Asymptomatic SBP 160 mmHg, 
or DBP 100 mmHg, or failure to 
achieve well-controlled BP within 2 
weeks in scenario (A).
Step 1.Consider reducing or interrupting study treatment, as 
clinically indicated.
Step 2. Adjust current or initiate new antihypertensive 
medication(s). 
Step 3. Titrate antihypertensive medication(s) during next 2 weeks 
as indicated to achieve well-controlled BP. 
Step 4. Once BP is well-controlled2, restart study treatment dose-
reduced by one dose level
(C) Symptomatic hypertension or 
recurring3 SBP 160 mmHg, or DBP 
100 mmHg, despite modification of 
antihypertensive medication(s)
Step 1. Interrupt study treatment.
Step 2. Adjust current or initiate new antihypertensive 
medication(s). 
Step 3. Titrate antihypertensive medication(s) during next 2 weeks 
as indicated to achieve well-controlled BP.  Referral to a specialist 
for further evaluation and follow-up is also recommended.
Step 4. Once BP is well-controlled, restart study treatment dose-
reduced by one dose level
(D) Refractory hypertension 
unresponsive to above interventions.
Permanently discontinue study treatment and continue follow-up 
per protocol.
1.
Hypertension detected in 2 separate readings during up to 3 subsequent visits
2.
BP reading of SBP 140 mmHg and DBP 90 mmHg in 2 separate readings during up to 3 subsequent 
visits
3.
Persistent asymptomatic hypertension after initially successful anti-hypertensive intervention.
5.7.2.
Management of Dermatological AEs
5.7.2.1.
Supportive Measures for Rash
General considerations in rash management:

Encourage subjects to avoid unnecessary exposure to sunlight.


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
Employ a proactive approach (i.e., prophylactic treatment; see below for 
recommendations).

If a subject develops rash, verify treatment intervention and follow steps 
outlined under “Reactive Management”.
5.7.2.2.
Prophylactic Treatment of Rash
The exact prophylactic regimen should be based on the investigator’s experience; 
however, the following regimen is recommended: 

Broad-spectrum sunscreen (containing titanium dioxide or zinc oxide) with an 
skin protection factor (SPF) ≥15;

Thick, alcohol-free emollient cream (e.g. glycerine and cetomacrogel cream) on 
dry areas of the body;

Mild topical steroid (1% hydrocortisone cream), with escalation to higher 
strength and/or oral steroid as detailed below.

Offer topical antibiotics or oral doxycycline 100 mg twice daily (BID) or oral 
minocycline 100 mg BID for the first 2 to 3 weeks of GSK1120212 
administration.  
Topical agents should be applied on a daily basis starting on Study Day 1 of study 
treatment, and more often as needed.  Oral antibiotics should be started on Study Day 1.
5.7.2.3.
Reactive Management of Rash
It is strongly recommended that subjects who develop dermatological reactions receive 
evaluations for management on the specific side effect. 

For pruritic lesions, the use of cool compresses and oral antihistamine agents 
may be helpful.  

For fissuring, the use of Monsel’s solution, silver nitrate, or zinc oxide cream is 
advised.  

For desquamation, thick emollients and mild soap are recommended.  

For paronychia, antiseptic bath and local potent corticosteroids in addition to 
oral antibiotics are recommended and, if no improvement is seen, a dermatology 
or surgery consultation is recommended.  

For infected lesions, bacterial and fungal culturing followed by the appropriate 
culture-driven systemic or topical antibiotics is indicated.
Consider the following algorithm in a stepwise manner (Table 3).


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Table 3
Guidelines for Skin Rash Management
Step
Grade
Severity 
Management 
GSK1120212 
Dose Adjustment
1
Mild

Localized

Minimally 
symptomatic

No impact on 
activities of 
daily living 
(ADL)

No sign of 
superinfection

Initiate prophylactic regimen if not already 
started.  Consider using moderate 
strength topical steroids (e.g. 
hydrocortisone 2.5% cream or fluticasone 
propionate 0.5% cream)

Reassess after 2 weeks; if rash worsens 
or does not improve, proceed to step 2.

Continue 
current dose.

Reassess 
after 2 weeks; 
if rash 
worsens or 
does not 
improve, 
proceed to 
step 2.
2
Moderate

Generalized

Mild symptoms 
(e.g., pruritis, 
tenderness)

Minimal impact 
on ADL

No sign of 
superinfection

Initiate prophylactic regimen if not already 
started, but using moderate strength 
topical steroids (e.g. hydrocortisone 2.5% 
cream or fluticasone propionate 0.5% 
cream)

Reassess after 2 weeks; if rash worsens 
or does not improve, proceed to step 3

Reduce dose 
by ≥0.5mg 

Consider 
holding 
treatment until 
rash improves

Reassess 
after 2 weeks; 
if rash 
worsens or 
does not 
improve, 
proceed to 
step 3
3
Severe

Generalized

Severe 
symptoms (e.g. 
pruritis, 
tenderness)

Significant 
impact on ADL

Sign of or 
potential for 
superinfection

Initiate prophylactic regimen if not already 
started, but using moderate strength 
topical steroids PLUS methylprednisolone 
dose pack.

Consider obtaining dermatology 
consultation.

Manage rash per dermatologist’s 
recommendation.

Hold treatment 
until rash 
improves 
(moderate, 
mild) or 
resolves, then 
follow steps 
outlined for the 
appropriate 
grading. 

Reassess 
after 2 weeks; 
if rash 
worsens or 
does not 
improve, 
discontinue 
treatment with 
GSK1120212.  
For subjects with an extensive or symptomatic Grade 3 or 4 dermatologic events, or for 
subjects with chronic, persistent or recurring lower grade skin events, a dermatology 
consultation is encouraged.


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5.7.3.
Management of Diarrhea
General considerations for diarrhea management:
Rule out other or concomitant causes.  These include medications (e.g., stool softeners, 
laxatives, antacids, etc), infection by C. difficile or Candida species, partial bowel 
obstruction, malabsorption/lactose intolerance, fecal impaction, diets high in fiber or 
lactose.
For uncomplicated Grade 1 to 2 diarrhea (i.e., mild to moderate defined as 
NCI-CTCAE [NCI, 2009] Grade 1 or 2 with no complicating signs or symptoms):

Administer standard dose of loperamide:

Initial dose of 4 mg followed by 2 mg every 4 hours or after every 
unformed stool; maximum of 16 mg (8 tablets) per day.

Continuation of loperamide is suggested until diarrhea-free for 12 hours

Dietary modifications: stop all lactose containing products and eat small meals. 
A BRAT (banana, rice, apples, toast) diet may be helpful.

Hydration: drink 8 to 10 large glasses of clear liquids per day (e.g., Gatorade or 
broth)

Consider a temporary GSK1120212 dose interruption until symptoms have 
resolved to baseline or Grade 1.  Re-treatment with GSK1120212 may then be 
resumed at 100% of current dose level.

If mild to moderate diarrhea persists for >24 hours, administer loperamide 2 mg 
every 2 hours; maximum 16 mg (8 tablets) per day.  Consider adding oral 
antibiotics.

If mild to moderate diarrhea persists after 48 hours total treatment with 
loperamide, start second-line agents (octreotide, budesonide or tincture of 
opium).  Consider adding oral antibiotics.
Grade 3 to 4 diarrhea or complicated Grade 1 to 2 diarrhea (i.e., cramping, 
nausea/vomiting ≥Grade 2, decreased performance status, fever, sepsis, Grade 3 or 4 
neutropenia, frank bleeding and/or dehydration):

Subject must call the investigator immediately for any complicated severe 
diarrhea event.

Discontinue GSK1120212 treatment and hold until symptoms resolve to 
Grade 1 or baseline.  Consider re-starting therapy at a reduced dose level.

If loperamide has not been initiated, initiate loperamide immediately.  Initial 
dose 4 mg followed by 2 mg every 2 hours or after every unformed stool; 
maximum of 16 mg (8 tablets) per day.

For dehydration, use IV fluids as appropriate; if severe dehydration, administer 
octreotide.


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
Administer antibiotics as needed (e.g. fluoroquinolones), especially if diarrhea is 
persistent beyond 24 hours or there is fever or Grade 3 or 4 neutropenia.

Intervention should be continued until the subject is diarrhea free for at least 
24 hours.
Intervention may require hospitalization for subjects most at risk for life-threatening 
complications.
5.7.4.
Management of Pneumonitis
To reduce the risk of pneumonitis, subjects will be monitored closely for symptoms, 
evaluated with imaging and/or functional studies, and stopping/interruption criteria will 
be implemented.  Dose modification and supportive care guidelines for pneumonitis will 
also be implemented.


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Table 4
Pneumonitis Guidelines for GSK1120212
Grade
Required Investigations
Management
Dose Adjustment 
for GSK1120212
1
CT scans with lung windows (high resolution CT 
recommended). 
Consider evaluation by pulmonologist. 
Consider room air O2 saturation at rest via pulse 
oximetry reading (times 2, 5 minutes apart).  
Repeat every 8 to 12 weeks until values return to 
WNL
No specific therapy is 
required.
Administer 100% of 
study treatment dose.
2
CT scan with lung windows (high resolution CT 
recommended).
Consider evaluation by pulmonologist.  
Consider pulmonary function tests including: 
spirometry, DLCO, and room air O2 saturation at 
rest via pulse oximetry reading (times 2, 
5 minutes apart).  Repeat every 8 to 12 weeks 
until values return to WNL. 
Consider a bronchoscopy with biopsy and/or 
bronchoalveolar lavage.
Symptomatic only. 
Consider corticosteroids 
if symptoms are 
troublesome and 
infective origin is ruled 
out.  Taper as medically 
indicated.
Hold treatment until 
recovery to Grade 1, 
then reduce by 0.5 
mg.  Discontinue 
treatment if no 
recovery to Grade 1 
within 4 weeks.  May 
consider escalation to 
pre-event dose after 
discussion with GSK 
Medical Monitor.
3
CT scan with lung windows (high resolution CT 
recommended). 
Evaluation by pulmonologist.
Required pulmonary function tests including: 
spirometry, DLCO, and room air O2 saturation at 
rest via pulse oximetry reading (times 2, 
5 minutes apart). Repeat every 8 to 12 weeks 
until values return to WNL.
Bronchoscopy with biopsy and/or bronchoalveolar 
lavage is recommended.
Consider corticosteroids 
if infective origin is ruled 
out. Taper as medically 
indicated.
Hold treatment until 
recovery to Grade 1. 
Discontinue treatment 
if no recovery to 
Grade 1 within 
4 weeks.  May 
consider restarting 
GSK1120212 at a 
dose reduced by 0.5 
mg after discussion 
with GSK Medical 
Monitor if there is 
clinical benefit.
4
CT scan with lung windows (high resolution CT 
recommended). 
Evaluation by pulmonologist.
Required pulmonary function tests including: 
spirometry, DLCO, and room air O2 saturation at 
rest via pulse oximetry reading (times 2, 
5 minutes apart).  Repeat every 8 to 12 weeks 
until values return to WNL.
Bronchoscopy with biopsy and/or bronchoalveolar 
lavage is recommended.
Consider corticosteroids 
if infective origin is ruled 
out. Taper as medically 
indicated.
Discontinue treatment.


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Table 5
Pneumonitis Guidelines for GSK1120212 and Gemcitabine 
Combination Therapy
Worst Grade 
Pneumonitis
Required Investigations
Management of 
Pneumonitis
Dose Adjustment 
for GSK1120212
Dose Adjustment 
for Gemcitabine
Grade 1
CT scans with lung windows 
(high resolution CT scan is 
recommended). Consider 
evaluation by pulmonologist.  
Consider room air O2 
saturation at rest via pulse 
oximetry reading (times 2, 
5 mins apart).  Repeat every 8 
to 12 weeks until return to 
within normal limits (WNL).
No specific 
therapy is 
required.
Administer 100% of 
study treatment dose.
Hold treatment 
until improvement 
in CT scan results, 
then re-start at 
same dose level.
Grade 2
CT scan with lung windows 
(high resolution CT scan is 
recommended). Consider 
evaluation by pulmonologist.  
Consider pulmonary function 
tests including: spirometry, 
DLCO, and room air O2 
saturation at rest via pulse 
oximetry reading (times 2, 
5 mins apart).  Repeat every 8 
to 12 weeks until return to 
WNL. Consider a 
bronchoscopy with biopsy 
and/or BAL. 
Symptomatic 
only. Consider 
corticosteroids if 
symptoms are 
troublesome and 
infective origin is 
ruled out.  Taper 
as medically 
indicated.
Reduce by 0.5mg 
until recovery to 
Grade 1. Treatment 
may also be 
interrupted if 
symptoms are 
troublesome. 
Discontinue treatment 
if no recovery to 
Grade 1 within 
4 weeks.  May 
consider escalation to 
pre-event dose after 
discussion with GSK 
Medical Monitor.
Hold treatment 
until recovery to 
Grade 1, then re-
start with at least 
25% dose 
reduction.
Discontinue 
treatment if no 
recovery to 
Grade 1 within 
4 weeks.
Grade 3
CT scan with lung windows 
(high resolution CT scan is 
recommended).  Evaluation by 
pulmonologist.  Required 
pulmonary function tests 
including: spirometry, DLCO, 
and room air O2 saturation at 
rest via pulse oximetry reading 
(times 2, 5 mins apart). 
Repeat at least every 8 weeks 
until return to WNL. 
Bronchoscopy with biopsy 
and/or BAL is recommended.
Consider 
corticosteroids if 
infective origin is 
ruled out. Taper 
as medically 
indicated.
Hold treatment until 
recovery to 
Grade 1. May 
restart study 
treatment within 
4 weeks at a reduced 
dose (by 0.5mg) if 
symptoms improve 
and evidence of 
clinical benefit after 
discussion with GSK 
Medical Monitor.
Hold treatment 
until recovery to 
Grade 1, then re-
start with at least 
25% dose 
reduction.  
Discontinue study 
treatment if no 
recovery to 
Grade 1 within 
4 weeks.
Grade 4
CT scan with lung windows 
(high resolution CT 
recommended).  Evaluation by 
pulmonologist.  Required 
pulmonary function tests 
including: spirometry, DLCO, 
and room air O2 saturation at 
rest via pulse oximetry reading 
(times 2, 5 mins apart).  
Repeat at least every 8 weeks 
until return to WNL.  
Bronchoscopy with biopsy 
and/or BAL is recommended if 
possible.
Consider 
corticosteroids if 
infective origin is 
ruled out. Taper 
as medically 
indicated.
Discontinue 
treatment.
Discontinue 
treatment.


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Table 6
Pneumonitis Guidelines for GSK1120212 and Everolimus 
Combination Therapy
Worst Grade 
Pneumonitis
Required Investigations
Management of 
Pneumonitis
Dose Adjustment 
for GSK1120212
Dose Adjustment 
for Everolimus
Grade 1
CT scans with lung windows (high
resolution CT scan is 
recommended). Consider 
evaluation by pulmonologist.  
Consider room air O2 saturation at 
rest via pulse oximetry reading 
(times 2, 5 mins apart).  Repeat 
every 8 to 12 weeks until return to 
WNL.
No specific 
therapy is 
required.
Administer 100% 
of study treatment 
dose.
Administer 100% 
of study treatment 
dose.
Grade 2
CT scan with lung windows (high 
resolution CT scan is 
recommended). Consider 
evaluation by pulmonologist.  
Consider pulmonary function tests 
including: spirometry, DLCO, and 
room air O2 saturation at rest via 
pulse oximetry reading (times 2, 
5 mins apart).  Repeat every 8 to 
12 weeks until return to WNL. 
Consider a bronchoscopy with 
biopsy and/or BAL. 
Symptomatic 
only. Consider 
corticosteroids if 
symptoms are 
troublesome and 
infective origin is 
ruled out.  Taper 
as medically 
indicated.
Reduce by 0.5mg 
until recovery to 
Grade 1. 
Treatment may 
also be interrupted 
if symptoms are 
troublesome. 
Discontinue 
treatment if no 
recovery to 
Grade 1 within 
4 weeks.  May 
consider escalation 
to pre-event dose 
after discussion 
with GSK Medical 
Monitor.
Reduce study 
treatment dose by 
1 dose level until 
recovery to 
≤Grade 1.  Study 
treatment may also 
be interrupted if 
symptoms are 
troublesome.  
Subjects will 
discontinue study 
treatment if they 
fail to recover to 
≤Grade 1 within 
4 weeks.
Grade 3
CT scan with lung windows (high 
resolution CT scan is 
recommended).   Evaluation by 
pulmonologist.  Required 
pulmonary function tests including: 
spirometry, DLCO, and room air O2 
saturation at rest via pulse oximetry 
reading (times 2, 5 mins apart). 
Repeat at least every 8 weeks until 
return to WNL. Bronchoscopy with 
biopsy and/or BAL is 
recommended.
Consider 
corticosteroids if 
infective origin is 
ruled out. Taper 
as medically 
indicated.
Hold treatment 
until recovery to 
Grade 1. May 
restart study 
treatment within 
4 weeks at a 
reduced dose (by 
0.5mg) if symptom 
improve and 
evidence of clinical 
benefit after 
discussion with 
GSK Medical 
Monitor.
Hold treatment 
until recovery to 
≤Grade 1.  May 
restart study 
treatment within 
4 weeks at a 
reduced dose (by 
one level) if 
evidence of clinical 
benefit.
Grade 4
CT scan with lung windows (high 
resolution CT scan recommended).  
Evaluation by pulmonologist.  
Required pulmonary function tests 
including: spirometry, DLCO, and 
room air O2 saturation at rest via 
pulse oximetry reading (times 2, 
5 mins apart).  Repeat at least 
every 8 weeks until return to WNL. 
Bronchoscopy with biopsy and/or 
BAL is recommended if possible.
Consider 
corticosteroids if 
infective origin is 
ruled out. Taper 
as medically 
indicated.
Discontinue 
treatment.
Discontinue 
treatment.


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5.7.5.
Stopping Criteria for Visual Changes
Episodes of visual changes have been observed in subjects receiving trametinib, and 
ocular adverse events are known to be related to trametinib. An ophthalmologist 
should be consulted if changes in vision develop.  If the visual changes are clearly 
unrelated to study treatment (e.g., allergic conjunctivitis), then monitor closely as it 
may be reasonable to defer ophthalmic examination. Special attention should be 
given to retinal findings (e.g., retinal pigment epithelial detachment (RPED) or 
retinovascular abnormalities (i.e., branch or central retinal vein occlusions (RVO)).  
For events of visual changes (regardless of severity) for which an ophthalmic 
examination is conducted, a blood sample for PK analysis must be drawn as close as 
possible to the time of the event.
Visual change events should be graded using Table 7 based on the NCI-CTCAE, version 
4.0 [NCI, 2009]).
Table 7
Grading of Visual Changes
Grade
Description
1
Asymptomatic or symptomatic but not limiting activities of daily living (ADL); clinical or 
diagnostic observations only; intervention not indicated
2
Symptomatic with moderate decrease in visual acuity (20/40 or better); limiting instrumental 
ADL;  local or non-invasive intervention indicated (e.g., topical or oral agents)
3
Symptomatic with marked decrease in visual acuity or marked visual field defect (worse than 
20/40 but better than 20/200 in the affected eye); Severe pain or medically significant but not 
immediately sight-threatening; operative intervention indicated; disabling; limiting self care ADL
4
Sight-threatening consequences; urgent intervention indicated; blindness (20/200 or worse) in 
the affected eye
Grade 1 visual changes:

For Grade 1 visual changes that do not affect vision and which, in the option of 
the treating physician, are clearly unrelated to study treatment (e.g., 
conjunctivitis), treatment with GSK1120212 may continue with close 
observation.

If attribution to study treatment is unclear, immediately refer the subject for 
ophthalmic exam; if a dilated fundus examination cannot be performed 
within 7 days of onset, interrupt treatment with GSK1120212 until RPED 
and RVO can be excluded by retina specialist/ophthalmologist. Follow the 
guidance below depending on the results.
If a retinal abnormality is noted, interrupt treatment with GSK1120212 
immediately and referral to a retinal specialist should be considered for further 
evaluation.
  If RPED suspected or diagnosed (asymptomatic; clinical or diagnostic 
observations only) continued treatment with retinal evaluation   monthly 
until resolved.  Report as an SAE.  If worsens see grade 2-3 guidance.


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
If RVO is diagnosed, report as a SAE and permanently discontinue 
treatment with GSK1120212

If there is no evidence of RPED or RVO, resume treatment with GSK1120212 
at the same dose level.
Grade 2 or Grade 3 visual changes:

Immediately interrupt treatment with GSK1120212 and refer subject to an 
ophthalmologist for evaluation with an ophthalmic exam.  For all subjects with 
findings consistent with RPED or RVO based on the ophthalmic exam, referral 
to retinal specialist, if available, should be considered for further evaluation.

If RVO is diagnosed report as a SAE and permanently discontinue 
GSK1120212

If RPED is diagnosed (symptomatic with mild to moderate decrease in 
visual acuity; limiting instrumental ADL, perform retinal evaluation 
monthly and if improves to ≤ Grade 1, resume treatment with 
GSK1120212 at lower dose (reduced by 0.5 mg) or discontinue in 
subjects taking GSK1120212 1 mg daily.

If RPED and RVO are excluded and visual changes are clearly 
unrelated to study treatment, restart GSK1120212 at the same dose 
level.
Grade 4 visual changes:

Interrupt GSK1120212, consult ophthalmologist immediately and report as 
SAE.

If RPED and RVO are excluded, may consider restarting GSK1120212 at 
same or reduced dose after discussion with the study medical monitor

If RPED or RVO diagnosed permanently discontinue treatment with 
GSK1120212.
5.7.6.
Liver Chemistry Stopping Criteria
Phase II liver chemistry stopping and follow-up criteria have been designed to assure 
subject safety and evaluate liver event etiology in alignment with the United States Food 
and Drug Administration (US FDA) premarketing clinical liver safety guidance.  Phase II 
liver chemistry stopping criteria 1 to 5 are defined as follows:
1. Alanine aminotransferase (ALT) 3 times upper limit of normal (ULN) and
bilirubin 2 times ULN (>35% direct bilirubin) (or ALT 3 times ULN and 
INR >1.5, if INR is measured).


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NOTE: If serum bilirubin fractionation is not immediately available, study 
treatment(s) should be discontinued if ALT 3 times ULN and bilirubin 2 times 
ULN.  Serum bilirubin fractionation should be performed if testing is available.  If 
testing is unavailable, record presence of detectable urinary bilirubin on dipstick, 
indicating direct bilirubin elevations and suggesting liver injury.
2. ALT 5 times ULN.
3. ALT 3 times ULN if associated with the appearance or worsening of symptoms 
of hepatitis or hypersensitivity such as fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, fever, rash or eosinophilia.
4. ALT 3 times ULN persists for 4 weeks.
5. ALT 3 times ULN and cannot be monitored weekly for 4 weeks.
When any of the liver chemistry stopping criteria 1 through 5 is met, do the 
following:

Immediately discontinue study treatment(s).

Report the event to GSK within 24 hours of learning its occurrence.

Complete the liver event eCRF and SAE data collection tool if the event also meets 
the criteria for an SAE.  

All events of ALT 3 times ULN and bilirubin 2 times ULN (>35% direct 
bilirubin) (or ALT times ULN and INR >1.5, if INR is measured; INR 
measurement is not required and the threshold value stated will not apply to 
subjects receiving anticoagulants), termed ‘Hy’s Law’, must be reported as an 
SAE (excluding studies of hepatic impairment or cirrhosis).

NOTE: if serum bilirubin fractionation is not immediately available, study 
drug(s) should be discontinued if ALT 3 times ULN and bilirubin 2 times 
ULN.  Serum bilirubin fractionation should be performed if testing is available.  
If testing is unavailable, record presence of detectable urinary bilirubin on 
dipstick, indicating direct bilirubin elevations and suggesting livery injury.

Complete the liver imaging and/or liver biopsy eCRFs if these tests are performed.

Perform liver event follow-up assessments, and monitor the subject until liver 
chemistries resolve, stabilize, or return to baseline values as described below.

Withdraw the subject from the study (unless further safety follow-up is required) 
after completion of the liver chemistry monitoring as described below.

Do not rechallenge with study treatment(s).
In addition, for criterion 1:

Make every reasonable attempt to have subjects return to clinic within 24 hours for 
repeat liver chemistries, liver event follow-up assessments (refer to Section 5.7.6.1), 
and close monitoring.

A specialist or hepatology consultation is recommended.


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
Monitor subjects twice weekly until liver chemistries (ALT, aspartate 
aminotransferase [AST], alkaline phosphatase, and bilirubin) resolve, stabilize or 
return to within baseline values.
In addition, for subjects meeting any of the criteria 2 to 5:

Make every reasonable attempt to have subjects return to clinic within 24 to 
72 hours for repeat liver chemistries and liver event follow-up assessments (refer to 
Section 5.7.6.1)

Monitor subjects weekly until liver chemistries (ALT, AST, alkaline phosphatase, 
bilirubin) resolve, stabilize or return to within baseline values; 

Any subject who meets criterion 5 should be monitored as frequently as 
possible.
5.7.6.1.
Liver Event Follow-Up Assessments
For subjects meeting any of the liver chemistry stopping criteria 1 through 5, make every 
attempt to carry out the liver event follow-up assessments described below:

Viral hepatitis serology including:

Hepatitis A Immunoglobulin M (IgM) antibody

Hepatitis B surface antigen and Hepatitis B Core Antibody (IgM)

Hepatitis C RNA.

Cytomegalovirus IgM antibody

Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, obtain 
heterophile antibody or monospot testing).  

Hepatitis E IgM antibody 

Blood sample for PK analysis, obtained within 96 hours of last dose of study 
treatment(s).  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 in the SPM. 

Serum creatine phosphokinase (CPK) and lactate dehydrogenase (LDH).

Fractionate bilirubin, if total bilirubin 2 times ULN.

Obtain complete blood count with differential to assess eosinophilia.

Record the appearance or worsening of clinical symptoms of hepatitis, or 
hypersensitivity, such as fatigue, nausea, vomiting, right upper quadrant pain or 
tenderness, fever, rash or eosinophilia as relevant on the AE report form.


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
Record use of concomitant medications, acetaminophen, herbal remedies, other over 
the counter medications, or putative hepatotoxins, on the concomitant medications 
report form.

Record alcohol use on the liver event alcohol intake case report form.
The following assessments are required for subjects with ALT 3 times ULN and 
bilirubin 2 times 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, magnetic resonance imaging [MRI], or computerized 
tomography [CT]) to evaluate liver disease.
5.7.6.2.
Liver Chemistry Monitoring Criteria
For subjects with ALT 3 times ULN but <5 times ULN and bilirubin <2 times ULN, 
without hepatitis symptoms or rash, and who can be monitored weekly for 4 weeks, the 
following actions should be taken:

Notify the GSK Medical Monitor within 24 hours of learning of the abnormality to 
discuss subject safety.

Continue study treatment(s).

Return weekly for repeat liver chemistries (ALT, AST, alkaline phosphatase, 
bilirubin) until they resolve, stabilize or return to within baseline. 

If at any time the subject meets any of the liver chemistry stopping criteria 1 to 5, 
proceed as described above.

If, after 4 weeks of monitoring, ALT <3 times ULN and bilirubin <2 times ULN, 
monitor subjects twice monthly until liver chemistries normalize or return to within 
baseline values. 
Refer to Appendix 4 for algorithm of liver chemistry stopping and follow-up criteria.
5.7.7.
QTc Withdrawal Criteria
QTc should be assessed at the frequency shown in Appendix 1: Time and Events Table 
for Cohort A or Appendix 2: Time and Events Table for Cohort B.
A subject who experiences a QTc prolongation1 defined as QTcB ≥501 msec or 
uncorrected QT>600 msec or (QTcB>530  msec or QTcB>530 msec for subjects 
with bundle branch block will have study treatment with GSK1120212 withheld:
1 based on average QTc value of triplicate ECGs (confirmed via 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.


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If the QTc prolongation resolves to grade 1 (450 - 480 msec) or baseline, the subject 
may be re-started on the study treatment at current dose level if the investigator and 
GSK Medical Monitor agree that the subject will benefit from further treatment.  If the 
event does not resolve or recurs, permanently discontinue study treatment.
5.7.7.1.
French and the United Kingdom Specific QTc Stopping Criteria
In line with local requirements, a subject in France or the United Kingdom that meets 
the QTc1 criteria below will have study treatment withheld:
QTcB >500 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 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.
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.
5.7.8.
Criteria for Evaluating Cardiac Function and Electrical Activity
5.7.8.1.
Left Ventricular Ejection Fraction Stopping Criteria
ECHO or MUGA scans should include an evaluation for LVEF and both right- and left-
sided valvular lesions.  For each subject, the same procedure should be performed at the 
time of transition and at the Final Study Visit to allow direct comparison.  Additional 
ECHO assessments may be performed if clinically warranted.
Subject who have an asymptomatic, absolute decrease of >10% in LVEF compared with 
baseline (baseline value from parent study) and the ejection fraction is below the 
institution’s LLN should have treatment with GSK1120212 withheld and a repeat 
evaluation of LVEF within 2 weeks.  

If the LVEF recovers (defined as LLN and absolute decrease 10% compared 
with baseline [baseline value from parent study]) at any time during the next 
4 weeks, after consultation and approval of the GSK Medical Monitor, the 
subject may be restarted on GSK1120212 at a reduced dose.  For such subjects, 
monitoring of LVEF will be performed 2 and 4 weeks after rechallenge, and 
every 4 weeks thereafter for 12 weeks, and then per protocol.

If repeat LVEF does not recover within 4 weeks, treatment with GSK1120212 
should be permanently discontinued and have a cardiology consult.  Ejection 
fraction should be monitored in 2 weeks and then every 4 weeks for a total of 16 
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Subjects with symptomatic Grade 3 (resting LVEF 39-20% or >20% absolute 
reduction from baseline) or symptomatic Grade 4 (resting LVEF <20%) left 
ventricular systolic dysfunction must discontinue treatment with GSK1120212 and have 
a cardiology consult. Ejection fraction should be monitored at 2 weeks, at 4 weeks, and 
then every 4 weeks for a total of 16 weeks or until resolution.  Symptomatic Grade 3 
and symptomatic Grade 4 left ventricular systolic dysfunctions are to be reported as 
SAEs.
The same procedure (either ECHO or MUGA, although ECHO is preferred) should be 
performed at baseline and at follow-up visit(s).  Copies of all ECHOs and/or MUGA 
scans performed on subjects who experience an absolute decrease >10% in LVEF 
compared to baseline and LVEF <LLN (or <50% when LLN does not exist) will be 
required by GSK for review.  Instructions for submission of qualifying ECHOs/MUGA 
scans are provided in the SPM.
5.8.
Blinding
This is an open-label study.
5.9.
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 GSK 
investigational product (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 IP accountability.
5.10.
Treatment Compliance
Compliance with GSK1120212 and other investigational or approved anti-cancer agent(s) 
used in combination with GSK1120212 dosing will be assessed through pill counts, and 
querying the subject during the site visits and documented in the source documents and 
eCRF.
A record of the number of GSK1120212 tablets and other investigational or approved 
anti-cancer agent(s) used in combination with GSK1120212 dosing dispensed to and 
taken by each subject must be maintained and reconciled with study treatment and 
compliance records.  Treatment start and stop dates, including dates for treatment 
interruptions and/or dose reductions will also be recorded in the eCRF.
6.
CONCOMITANT MEDICATIONS AND NON-DRUG 
THERAPIES
Subjects will be instructed to inform the investigator prior to starting any new 
medications from the time of the Transition Visit until the end of the study (Final Study 
Visit).  Any concomitant medication(s), including herbal preparations, taken at the time 
of transition from the parent study and during the study will be recorded in the eCRF.


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If future changes are made to the list of permitted/prohibited medications, formal 
documentation will be provided by GSK and stored in the study file.  Any such changes 
will be communicated to the investigative sites in the form of a letter.
6.1.
Permitted Medications
All concomitant medications taken during the study will be recorded in the eCRF with 
information regarding reason for use, route of administration and dates of administration.
The following will be recorded on the concomitant medications eCRF page:

A complete list of prescription and over-the-counter medications (including herbal 
remedies) taken at the time of transition to the rollover study.

All concomitant medications taken during the study will also be recorded in the 
eCRF.
Subjects should receive full supportive care during the study including transfusions of 
blood and blood products, and treatment with antibiotics, anti-emetics, anti-diarrheals, 
and analgesics, and other care as deemed appropriate, and in accordance with their 
institutional guidelines.  
Acetaminophen at doses of 2 grams/day is permitted.  Use of anticoagulants such as 
warfarin is also permitted provided that INR is monitored according to local standard 
clinical practice.  
Supplementation with growth factors such as granulocyte colony-stimulating factor 
(G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), and 
erythropoietin-based agents are allowed as clinically indicated.  Growth factors will be 
administered according to the National Comprehensive Cancer Network (NCCN) 
Clinical Practice Guidelines in Oncology version 1, 2010.
6.1.1.
Drug to Be Used with Caution
Medications that may alter the elimination of GSK1120212 (Table 8) or medications that 
may have their elimination altered by GSK1120212 (Table 9) should be administered 
WITH CAUTION.
6.1.1.1.
GSK1120212 as a Victim
Drugs that potently inhibit or induce CYP3A4 should be administered WITH 
CAUTION as it may increase or decrease exposure to GSK1120212.  Table 8 provides a 
list of possible medications including, but not limited to, those drug substances that may 
alter GSK1120212 elimination.


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Table 8
Drugs Potentially Affecting GSK1120212 Elimination Resulting in 
Increased or Decreased GSK1120212 Exposure
Drug Class
Generic Drug Name
Drugs that may increase exposure of GSK1120212 (CYP3A4 inhibitors)
Antivirals
amprenavir, atazanavir,  fosamprenavir, indinavir, lopinavir, nelfinavir,  ritonavir, saquinavir
Antibiotics
clarithromycin, erythromycin, telithromycin, troleandomycin 
Antifungals
fluconazole, itraconazole, ketoconazole, voriconazole
Antidepressants
nefazodone
Calcium Channel 
Blockers
mibefradil, diltiazem, verapamil
Miscellaneous
aprepitant
Drugs that may decrease exposure of GSK1120212 (CYP3A4 inducers)
Antivirals
efavirenz, nevirapine,
Antibiotic
rifampin
Anticonvulsants
carbamazepine, phenobarbital, phenytoin
6.1.1.2.
GSK1120212 as a Perpetrator
Drugs with a narrow therapeutic index that are substrates of CYP2C8 should be used 
WITH CAUTION (Table 9).
Table 9
Drug Metabolism Potentially Affected by GSK1120212 Resulting in 
Increased Exposure of These Substrates
Drug Class
Generic Drug Name
Substrates for CYP2C8
HMG CoA-reductase inhibitors
cerivastatin
Thiazolidinediones
repaglinide, rosiglitazone, pioglitazone
Miscellaneous
chloroquine, zopiclone
6.2.
Prohibited Medications and Non-Drug Therapies
The use of certain medications, and illicit drugs within 5 half-lives or 28 days (if the drug 
is a potential enzyme inducer) prior to the first dose of study treatment(s) and for the 
duration of the study will not be allowed.  If a prohibited medication is required for single 
use (such as for a procedure) while study treatment(s) is held, the GSK Medical Monitor 
can approve such use.
The following medications or non-drug therapies are prohibited while participating in this 
study: 

Other anti-cancer agents (e.g., chemotherapy, immunotherapy, biologic therapy, 
and/or hormone therapy other than for replacement)

Other non-drug anti-cancer therapy (e.g. radiation therapy, surgery, and/or 
tumor embolization)
NOTE: Subjects may receive palliative radiation treatment during this study.  The 
study treatment must be held for at least 2 days prior to the start of palliative 
radiation treatment and for at least 2 days after palliative treatment or longer 


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(depending upon the extent of palliative treatment and recovery from any acute 
toxicities to Grade 1).

Herbal products include, but are not limited to:

marijuana
Questions regarding concomitant medications should be directed to the GSK Medical 
Monitor for clarification.
6.3.
Treatment after Discontinuation of Study Treatment or 
Discontinuation from /Completion of Study
The investigator is responsible for ensuring that consideration has been given for the 
post-study care of the subject’s medical conditions whether or not GSK is providing 
specific post-study treatment.
Subjects will receive standard of care treatment as determined by their healthcare 
provider after withdrawal from this study.
Post-study treatment will not be provided as part of the protocol.  Upon discontinuation 
from assigned study treatment, subjects may receive additional (non-protocol) therapy at 
the discretion of the treating physician.  New therapy should be documented in the eCRF. 
Every effort should be made to complete the required post-treatment follow-up 
evaluations prior to initiating further anti-cancer therapy or dosing of an investigational 
agent (see Appendix 1: Time and Events Table for Cohort A or Appendix 2: Time and 
Events Table for Cohort B for Final Study Visit assessments and procedures).  
6.4.
Treatment of Study Treatment Overdose
6.4.1.
GSK1120212
In the event of a GSK1120212 overdose defined as administration of more than the 
highest dose administered in clinical studies to date, the investigator should contact the 
GSK Medical Monitor immediately and closely monitor the subject for AEs/SAEs and 
laboratory abnormalities.
Subjects suspected of overdose should be monitored until study treatment(s) can no 
longer be detected systemically (at least 7 days).
Decisions regarding dose interruptions or modifications will be made by the investigator 
in consultation with the GSK Medical Monitor based on the clinical evaluation of the 
subject.
A plasma sample for PK analysis may be requested by the GSK Medical Monitor on a 
case-by-case basis.  This plasma sample should be collected as soon as possible, but 
within 7 days from the date of the last dose of on-study dosing.


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Information regarding the quantity of the excess dose as well as the duration of the 
overdosing should be documented in the eCRF.
6.4.2.
Other Anti-Cancer Agent(s)
In the event of an overdose of another anti-cancer agent(s) used in combination with 
GSK1120212, the investigator should contact the GSK Medical Monitor immediately and 
closely monitor the subject for AE/SAEs and laboratory abnormalities based upon the 
prescribing information for the agent(s).
Information regarding the quantity of the excess dose as well as the duration of the 
overdosing should be documented in the eCRF.
7.
LIFESTYLE OR DIETARY RESTRICTIONS
7.1.
Meals and Dietary Restrictions
GSK1120212 should be administered with approximately 240 mL (8 fl oz) of water, 
under fasting conditions, either 1 hour before or 2 hours after a meal.
If diet recommendations change with emerging data (i.e. the planned food-effect study) 
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 without 
amendment to the protocol.
7.2.
Activity
Subjects should abstain from strenuous exercise for 48 hours prior to each blood 
collection for clinical laboratory tests.
7.3.
Contraception Requirements
7.3.1.
Female Subjects
Females of non-childbearing potential (i.e., physiologically incapable of becoming 
pregnant), as defined in the parent study, are any female who has had a documented 
hysterectomy, bilateral oophorectomy (ovariectomy), or bilateral tubal ligation; or post-
menopausal.
Female subjects of childbearing potential, as defined in the parent study and determined 
not to be post-menopausal, must continue to use the same adequate method of 
contraception as used in the parent study during the rollover study and for 4 months*
following the last dose of study treatment(s).
GSK acceptable contraceptive methods, when used consistently and in accordance with 
both the product label and the instructions of the physician, are as follows:

An intrauterine device with a documented failure rate of <1% per year


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
Vasectomized partner who is sterile prior to the female subject’s entry in the 
study and is the sole sexual partner for that female.

Complete abstinence from sexual intercourse for 14 days prior to the first dose 
of study treatment, through the dosing period, and for at least 4 months* after
the last dose of study treatment

Double-barrier contraception: condom and occlusive cap (diaphragm or 
cervical/vault caps) with a vaginal spermicidal agent 
(foam/gel/cream/suppository).
NOTE:  Hormonal-based methods (e.g., oral contraceptives) are not permitted due 
to potential drug-drug interaction with GSK1120212.
*NOTE:  Contraception requirement may last for a time period longer than what is 
required for single-agent GSK1120212 since female subjects may be exposed to 
cytotoxic chemotherapy during study treatment.  Investigators should reference the 
product label for the appropriate chemotherapeutic agent(s) for additional 
clarification.
Refer to Section 8.5.5 for details on reporting any pregnancy that occurs during 
participation in the rollover study.
8.
STUDY ASSESSMENTS AND PROCEDURES
The study specific assessments and procedures are outlined in Appendix 1: Time and 
Events Table for Cohort A and Appendix 2: Time and Events Table for Cohort B.  
Further details of study assessments and procedures are provided in the SPM.  
A signed, written informed consent form must be obtained from the subject prior to any 
study-specific procedures or assessments.
Approximately 3 teaspoons (15 mL) of blood will be collected at each study visit. The 
total amount of blood collected for the duration of the study is dependent on the length of 
individual subject participation in the study.
Investigators may be requested to perform additional safety tests during the course of the 
study based on newly available data to ensure appropriate safety monitoring.  
Appropriate local regulatory and ethical approvals should be obtained before any 
additional testing is performed.
If vital signs, ECGs and blood draws are scheduled for the same nominal time, the ECG 
will be obtained first, followed by the vital signs, and then blood draws.
8.1.
Transition Visit
For this study, the Transition Visit may occur on the same day as the last study visit on 
the parent study.  The results of any specified study assessments performed on the day of 
the Transition Visit will serve as the baseline value for said assessment.
At the Transition Visit, the following assessments will be performed:


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
Demographic data, including date of birth, ethnicity, sex, and race.

Subject-related data from parent study, including parent study protocol number, 
parent study subject treatment number, previous subject number assigned in parent 
study, start date and dose of GSK1120212 treatment regimen in parent study, dose of 
GSK1120212 and other study treatment(s), if applicable, at time of transition to this 
study; and best response based on last disease assessment in parent study.

Complete physical examination, including height and weight.

Vital signs (BP, temperature, respiratory rate, and pulse rate)

Clinical laboratory tests:  hematology and clinical chemistry

Serum beta-human Chorionic Gonadotropin (-hCG) pregnancy test for female 
subjects of childbearing potential only

12-lead ECG

ECHO (preferred) or MUGA scan (if ECHO or MUGA scan was performed within 
12 to 16 weeks of transition to rollover study as part of the parent study assessments, 
the results of that assessment may be recorded as transition values for the rollover 
study)

Review of concomitant medications
8.2.
Continuous Dosing Treatment Period
8.2.1.
Cohort A
The following assessments must be performed every 4 weeks while receiving treatment:

Vital signs (BP, temperature, respiratory rate, and pulse rate)

Clinical laboratory tests: hematology and clinical chemistry(for the first 2 years of 
treatment with GSK1120212, including time on parent study)
The following assessments must be performed at Week 8 while receiving treatment:

Complete physical examination
The following assessment must be performed while receiving treatment:

ECHO (preferred) or MUGA scan should be performed within 12 weeks from 
the date of the subject’s last ECHO or MUGA scan which may have been 
performed in the parent study or at the time of transition to the rollover study.

Subsequent ECHO (preferred) or MUGA scans must be performed every 
12 weeks thereafter while the subject is receiving treatment.
NOTE:  Refer to Section 5.7.5 for stopping criteria and follow-up for 
abnormal results).


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The following assessments must be performed every 12 weeks while receiving treatment:

Complete physical examination (after Week 8)

12-lead ECG (for first 2 years of treatment with GSK1120212, including time on 
parent study)

Clinical laboratory tests:  hematology and clinical chemistry (>2 years of treatment 
with GSK1120212, including time on parent study)
The following assessments must be performed every 24 weeks while receiving treatment:

12-lead ECG (>2 years of treatment with GSK1120212, including time on parent 
study)
The following assessments must be performed continuously while receiving treatment:

Review of Concomitant Medications

Assessment of study treatment(s) compliance

Assessment of AEs
8.2.2.
Cohort B
The following assessments must be performed every 3 or 4 weeks (depending on 
schedule used in parent study) while receiving treatment:

Vital signs (BP, temperature, respiratory rate, and pulse rate)

Clinical laboratory tests:  hematology and clinical chemistry (for first 2 years of 
treatment with GSK1120212, including time on parent study)
The following assessments must be performed every 9 or 12 weeks (depending on 
schedule used in parent study) while receiving treatment:

12-lead ECG (for first 2 years of treatment with GSK1120212, including time on 
parent study)

Clinical laboratory tests: hematology and clinical chemistry (>2 years of treatment 
with GSK2118436, including time on parent study)
The following assessments must be performed every 12 weeks while receiving treatment:

Complete physical examination
The following assessments must be performed while receiving treatment:

ECHO (preferred) or MUGA scan should be performed within 12 weeks 
from the date of the subject’s last ECHO or MUGA scan which may have 
been performed in the parent study or at the time of transition to the 
rollover study.


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
Subsequent ECHO (preferred) or MUGA scans must be performed every 
12 weeks thereafter while the subject is receiving treatment.
NOTE:  Refer to Section 5.7.5 for stopping criteria and follow-up for 
abnormal results).
The following assessments must be performed every 24 weeks while receiving treatment:

12-lead ECG (>2 years of treatment with GSK1120212, including time on parent 
study)
The following assessments must be performed continuously while receiving treatment:

Review of Concomitant Medications

Assessment of study treatment(s) compliance

Assessment of AEs
8.3.
Final Study Visit
If a subject is withdrawn from study treatment, the following assessments will be 
performed within 28 days (7 days) from the last dose of study treatment(s) and prior to 
initiating any other treatment for cancer:

Complete physical examination

Vital signs (BP, temperature, respiratory rate, and pulse rate)

Clinical laboratory tests:  hematology and clinical chemistry

12-lead ECG

ECHO (preferred) or MUGA scan (only required if there was an abnormal finding 
reported from the last ECHO or MUGA scan performed)

Review of concomitant medications

Assessment of AEs
8.4.
Safety
Measurements used to evaluate safety will include physical examinations, vital signs (BP, 
temperature, respiratory rate, and pulse rate), 12-lead ECGs, ECHO or MUGA scan, 
clinical laboratory tests (hematology and clinical chemistry), and monitoring for AEs.  
Planned time points for all safety assessments are listed in Appendix 1: Time and Events 
Table for Cohort A and Appendix 2: Time and Events Table for Cohort B.
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.


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NOTE:  Baseline will refer to time of first dose of study treatment(s) on the rollover 
study as baseline for some AEs may have occurred in parent study as AE continued at the 
time of transition to the rollover study).  This definition of baseline will be applicable to 
other assessments (i.e., physical examination findings, laboratory values) for this study 
when baseline reference is used.
8.4.1.
Physical Examinations
Complete physical examinations will be performed at the time points outlined in 
Appendix 1: Time and Events Table for Cohort A or Appendix 2: Time and Events Table 
for Cohort B.  Height and weight will also be measured and recorded at the initial 
physical examination only.
8.4.1.1.
Assessment of Skin Changes
All physical examinations should include examination of skin and assessment of any skin 
changes.  Post-baseline skin examinations by a referral dermatologist or other appropriate 
physician should be conducted if clinically indicated.  Biopsy of skin lesions related to 
treatment may be performed if clinically indicated.
8.4.2.
Ophthalmologic Examinations
All subjects transitioning to the rollover study are expected to have had a standard 
ophthalmic exam performed by an ophthalmologist during Screening in their parent 
study.  Ophthalmologic examinations will be conducted during the rollover study if 
clinically indicated (refer to Section 5.7.5 for stopping criteria for visual changes).  If an 
ophthalmologic examination is necessary, it should include dilated indirect fundoscopic 
examination, best corrected visual acuity, visual field examination, tonometry, slit lamp 
biomicroscopic examination and direct fundoscopy, with special attention to retinal 
abnormality. Optical coherence tomography is strongly recommended at scheduled 
visits, and if retinal abnormalities are suspected. Other types of ancillary testing 
including color fundus photography and fluorescein angiography are also 
recommended if clinically indicated.
8.4.3.
Vital Signs
Vital sign measurements (BP, temperature, respiratory rate, and pulse rate) will be taken 
at the time points outlined in Appendix 1: Time and Events Table for Cohort A or 
Appendix 2: Time and Events Table for Cohort B.  Vital signs will be measured more 
frequently if warranted by clinical condition of the subject.  Refer to the SPM for details 
regarding measurement of vital signs.
8.4.4.
Electrocardiograms
Single 12-lead ECGs will be obtained at each time point during the study according to 
Appendix 1: Time and Events Table for Cohort A or Appendix 2: Time and Events Table 
for Cohort B using an ECG machine that automatically calculates the heart rate and 
measures RR, PR, QRS, QT and QTc intervals.


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If there are any clinically significant abnormalities including, but not limited to, 
QTcB >500 msec, confirm with 2 additional ECGs taken at least 5 minutes apart.
Refer to Section 5.7.7 for QTc withdrawal criteria and additional readings that may be 
necessary.  Refer to the SPM for details regarding ECG procedures.
8.4.5.
Echocardiograms/MUGA Scans
ECHO or MUGA scans (preferably ECHO) will be performed to assess cardiac ejection 
fraction and cardiac valve abnormalities at the time points specified in Appendix 1: Time 
and Events Table for Cohort A or Appendix 2: Time and Events Table for Cohort B.  The 
procedure (either ECHO or MUGA, although ECHO is preferred) to document the 
subject’s baseline LVEF status must be used consistently throughout the study. If 
possible, it is also preferred that interpretation of LVEF status be performed consistently 
by the same reviewer throughout the study.
Copies of all ECHOs and/or MUGA scans performed on subjects who experience an 
absolute >10% decrease in LVEF compared to baseline and LVEF <LLN will be required 
by GSK for review.  Instructions for submission of qualifying ECHOs/MUGA scans are 
provided in the SPM
Refer to Section 5.7.8.1 for details regarding LVEF evaluation.
8.4.6.
Clinical Laboratory Assessments
Clinical laboratory tests (Table 10) will be performed as outlined in Appendix 1: Time 
and Events Table for Cohort A or Appendix 2: Time and Events Table for Cohort B.  At 
the discretion of the investigator, additional laboratory samples may be taken as clinically 
necessary.
Whenever possible, every effort should be made to ensure that laboratory results 
submitted to GSK are from the designated central laboratory.  If laboratory assessments 
are performed at the institution’s local laboratory, please refer to the SPM for appropriate 
and handling of samples to avoid duplicate and/or additional blood draws.
All laboratory tests with values that are significantly abnormal during study participation 
or within 30 days after the last dose of study treatment(s) should be repeated until the 
values return to within normal range or baseline.  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.  If such values 
do not return to within normal range within a period judged reasonable by the 
investigator, the etiology should be identified and the GSK Medical Monitor notified.


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Table 10
List of Clinical Laboratory Assessments
Hematology
Platelet Count 
Automated WBC Differential:
White blood cell (WBC) Count (absolute) 
Neutrophils
Hemoglobin
Lymphocytes
Monocytes
Eosinophils
Basophils
Clinical Chemistry
Blood urea nitrogen (BUN)
Potassium
Creatinine
Inorganic phosphorus
Sodium
Magnesium
Albumin
Chloride
Calcium
LDH
Bicarbonate
Glucose
Liver Function Tests
AST
ALT
Alkaline Phosphatase
Total bilirubin (bilirubin fractionation recommended if total bilirubin >2 times ULN)
Other tests
Serum -hCG pregnancy (female subjects of childbearing potential only; performed only at baseline unless clinically 
indicated)
8.5.
Adverse Events
AEs and SAEs will be monitored from the time of consent until 30 days after the last 
dose of study treatment(s).  All AEs and SAEs must be recorded and reported as detailed 
in the following sections and in the SPM.  At the time of consent, all ongoing AEs that 
began during participation in the parent study must be recorded in the eCRF.
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 8.5.1 and 
Section 8.5.2, respectively.
8.5.1.
Definition of an AE
Any untoward medical occurrence in a subject or clinical investigation subject, 
temporally associated with the use of a medicinal product, whether or not considered 
related to the medicinal product.
Note: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a medicinal product.  For marketed medicinal products, this 
also includes failure to produce expected benefits, abuse, or misuse. Examples of events 
meeting the definition of an AE include:

Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or grade of the condition


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
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). 
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.
8.5.2.
Definition of a SAE
A SAE is any untoward medical occurrence that, at any dose:
a.
Results in death
b.
Is life-threatening
NOTE:  The term 'life-threatening' in the definition of 'serious' refers to an event in 
which the subject was at risk of death at the time of the event.  It does not refer to an 
event, which hypothetically might have caused death, if it were more severe.
c.
Requires hospitalization or prolongation of existing hospitalization
NOTE:  In general, hospitalization signifies that the subject has been detained 
(usually involving at least an overnight stay) at the hospital or emergency ward for 
observation and/or treatment that would not have been appropriate in the physician’s 
office or outpatient setting. Complications that occur during hospitalization are AEs. 
If a complication prolongs hospitalization or fulfils any other serious criteria, the 
event is serious.  When in doubt as to whether “hospitalization” occurred or was 
necessary, the AE should be considered serious.
Hospitalization for elective treatment of a pre-existing condition that did not worsen 
from baseline is not considered an AE.
d.
Results in disability/incapacity, or


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NOTE:  The term disability means a substantial disruption of a person’s ability to 
conduct normal life functions.  This definition is not intended to include experiences 
of relatively minor medical significance such as uncomplicated headache, nausea, 
vomiting, diarrhea, influenza, and accidental trauma (e.g. sprained ankle) which may 
interfere or prevent everyday life functions but do not constitute a substantial 
disruption.
e.
Is a congenital anomaly/birth defect.
f.
Medical or scientific judgement should be exercised in deciding whether reporting is 
appropriate in other situations, such as important medical events that may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize 
the subject or may require medical or surgical intervention to prevent one of the 
other outcomes listed in the above definition. These should also be considered 
serious. Examples of such events are invasive or malignant cancers, intensive 
treatment in an emergency room or at home for allergic bronchospasm, blood 
dyscrasias or convulsions that do not result in hospitalization, or development of 
drug dependency or drug abuse.
g.
All events of possible drug-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) termed ‘Hy’s Law’ events (INR 
measurement is not required and the threshold value stated will not apply to subjects 
receiving anticoagulants.
NOTE: Bilirubin fractionation is performed if testing is available.  If testing is 
unavailable, record presence of detectable urinary bilirubin on dipstick indicating 
direct bilirubin elevations and suggesting liver injury.  If testing is unavailable and a 
subject meets the criterion of total bilirubin 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
h.
Protocol-specific SAEs: LVEF meeting the stopping criteria (see Section 5.7.8).
i.
Additionally, new primary cancers and laboratory abnormalities as referenced in 
Section 8.5.3 are considered to be serious events by virtue of being medically 
important. These should be reported in the same manner as other SAEs.
8.5.3.
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.  
All events of possible drug-induced liver injury with hyperbilirubinemia (defined as ALT 
3 times ULN plus bilirubin 2 times ULN and/or INR >1.5) or Hy’s Law events, 
require immediate study treatment cessation and reporting as an SAE.


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NOTE: bilirubin fractionation is performed if testing is available. If testing is unavailable, 
record presence of detectable urinary bilirubin on dipstick indicating direct bilirubin 
elevations and suggesting liver injury.
If testing is unavailable and a subject meets the criterion of total bilirubin 2.0 times 
ULN, then the event is still reported as an SAE. If INR is obtained, include values on the 
SAE form. INR elevations >1.5 suggest severe liver injury.
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.
8.5.3.1.
Disease-Related Events and/or Disease-Related Outcomes Not 
Qualifying as SAEs
An event which is part of the natural course of the disease under study (i.e., disease 
progression or hospitalization due to disease progression) does not need to be reported as 
an SAE. Death due to disease under study is to be recorded on the Death eCRF form.  
However, if the underlying disease (i.e., progression) is greater than that which would 
normally be expected for the subject, or if the investigator considers that there was a 
causal relationship between treatment with study treatment(s) or protocol 
design/procedures and the disease progression, then this must be reported as a SAE.
8.5.4.
Time Period and Frequency of Detecting AEs and SAEs
The investigator or site staff is responsible for detecting, documenting and reporting 
events that meet the definition of an AE or SAE.
AEs will be collected from the time the first dose of study treatment is administered until 
30 days following discontinuation of study treatment regardless of initiation of a new 
cancer therapy or transfer to hospice.
SAEs will be collected over the same time period as stated above for AEs.  In addition, 
any SAE assessed as related to study participation (e.g., protocol-mandated procedures, 
invasive tests, or change in existing therapy), study treatment or GSK concomitant 
medication must be recorded from the time a subject consents to participate in the study 
up to and including any follow-up contact. All SAEs will be reported to GSK within 
24 hours, as indicated in Section 8.5.4.1.
After discontinuation of study treatment, the investigator will monitor all AEs/SAEs that 
are ongoing until resolution or stabilization of the event or until the subject is lost to 
follow-up.  At any time after 30 days the investigator may report any AE that they 
believe possibly related to study treatment.


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8.5.4.1.
Prompt Reporting of Serious Adverse Events and Other Events to GSK
SAEs, pregnancies, and liver function abnormalities meeting pre-defined criteria will be 
reported promptly by the investigator to GSK as described in the following table once the 
investigator determines the event meets the protocol definition for that event.
Initial Reports
Follow-up Information on a Previous 
Report
Type of Event
Time Frame
Documents
Time Frame
Documents
All SAEs
24 hours
SAE data collection 
tool
24 hours
Updated SAE data 
collection tool 
Pregnancy
2 Weeks
Pregnancy 
Notification Form
2 Weeks
Pregnancy Follow up 
Form
Liver chemistry abnormalities Phase II:
ALT 3 times ULN and 
bilirubin 2 times ULN 
(>35% direct) (or ALT 3 
times ULN and INR >1.5, 
if INR measured)3
24 hours1
SAE data collection 
tool.
Liver Event eCRF 
and liver imaging 
and/or biopsy CRFs if 
applicable2
24 hours
Updated SAE data 
collection tool. 
Updated Liver Event 
eCRF2
ALT 5 times ULN; ALT 
3 times ULN with 
hepatitis or rash or 3 
times ULN 4 weeks
24 hours1
Liver Event eCRF2
24 hours
Updated Liver Event 
eCRF2
ALT 3 times ULN and <5 
times ULN and bilirubin <2 
times ULN
24 hours1
Liver Event eCRF 
does not need 
completing unless 
elevations persist  for 
4 weeks or subject 
cannot be monitored 
weekly for 4 weeks2
ALT 3 times ULN and <5 
times ULN and bilirubin <2 
times ULN
24 hours1
Liver event eCRF 
does not need 
completing unless 
elevations persist for 
4 weeks or subject 
cannot be monitored 
weekly for 4 weeks2
1.
GSK to be notified at onset of liver chemistry elevations to discuss subject safety.
2.
Liver event documents should be completed as soon as possible
3.
INR measurement is not required; if measured, the threshold value stated will not apply to subjects receiving 
anticoagulants.
Methods for detecting, recording, evaluating, and following up on AEs and SAEs are 
provided in the SPM.


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8.5.4.2.
Regulatory reporting requirements for SAEs
Prompt notification of SAEs by the investigator to GSK is essential so that legal 
obligations and ethical responsibilities towards the safety of subjects are met.
GSK has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a product under clinical investigation.  GSK will 
comply with country specific regulatory requirements relating to safety reporting to the 
regulatory authority, IRB/IEC and investigators.
Investigator safety reports are prepared for suspected unexpected serious adverse 
reactions according to local regulatory requirements and GSK policy and are forwarded 
to investigators as necessary.
An investigator who receives an investigator safety report describing a SAE(s) or other 
specific safety information (e.g. summary or listing of SAEs) from GSK will file it with 
the IB and will notify the IRB/IEC, if appropriate according to local requirements.
8.5.5.
Pregnancy
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 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 a 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.
8.5.6.
Optional Tumor and/or Skin Biopsy and Biomarker Assessments
All sites are required to participate in the collection of tumor or skin biopsies and tumor 
marker sampling; however, participation by the individual subject is optional.  Samples 
will only be collected only from subjects who provide consent for tumor biopsy, skin 
biopsy and/or blood sampling for tumor marker assessment at the time of transition to 
this study.  If consent is provided, tumor tissue sample(s), skin sample(s), and/or blood 
samples (2 x 10 mL) will be collected at the time of disease progression.
Further details on tissue and/or blood requirements for specific tumor biopsy or tumor 
marker assessments will be provided in the SPM.
8.5.7.
Optional Tumor Biopsy
Some subjects may have had pre- and/or post-dose tumor biopsies collected during their 
participation in their parent study. However, an additional tumor tissue sample from a 


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lesion not required for disease assessment may be requested during this study.  Total 
mutations in BRAF, MEK1 or 2, PIK3Ca, PTEN and other genes may be assessed.
8.5.8.
Optional Skin Biopsy
Some subjects may have had skin biopsies collected during their participation in their 
parent study.  However, additional biopsy or initial biopsies in or around skin lesions that 
change on treatment may be taken during this study.  Testing of these biopsies may 
include analysis of proteins related to the action of GSK1120212.  Deoxyribonucleic acid 
(DNA) analysis of these biopsy specimens will be restricted to cancer-related genes.
8.5.9.
Optional Blood Sampling for Biomarker Analysis
In subjects whose disease may be followed by well-characterized tumor markers, 
assessment of clinical activity should include results of tumor marker measurements.
Blood samples may be collected for analysis of potential surrogate markers of 
GSK1120212 activity (e.g. interleukin-8) at the time of disease progression.  Additional 
blood proteins or tumor DNA related to the activity of GSK1120212 may be analyzed.  
Biomarker sample collection may be altered or terminated based on emerging data.  
Tumor marker values will be recorded in the eCRF.5
8.5.9.1.
Optional Circulating Free DNA (cfDNA)
Blood samples may be collected for the analysis of circulating free-DNA (cfDNA).   
Tumor-specific cfDNA has the potential to be a useful biomarker of therapeutic response 
to correlate increasing cfDNA levels with increasing tumor burden.
9.
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 
coded using Medical Dictionary for Regulatory Activities (MedDRA) and an internal 
validated medication dictionary, GSK Drug.  Electronic CRFs (including queries and 
audit trails) will be retained by GSK, and copies will be sent to the investigator to 
maintain as the investigator copy.
Laboratory data (i.e., hematology and clinical chemistry) will be stored in a database 
maintained by the central laboratory and transferred to GSK at agreed times.
In all cases, subject initials will not be collected or transmitted to GSK according to GSK 
policy.


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10.
DATA ANALYSIS AND STATISTICAL CONSIDERATIONS
10.1.
Hypotheses
No statistical hypotheses are being tested.  Only descriptive methods will be used in 
analysis of the data obtained from this study.
10.2.
Study Design Considerations
10.2.1.
Sample Size Considerations
As this is a roll-over study, no specific sample size considerations are required.  The 
sample size will be based on the number of subjects completing their parent study of 
GSK1120212 and are eligible for inclusion in this rollover study.
10.2.2.
Sample Size Re-estimation
Sample size re-estimation is not planned for this study.
10.3.
Data Analysis Considerations
10.3.1.
Analysis Populations
The All-Treated Subjects (ATS) Population will consist of all subjects that receive at 
least one dose of GSK1120212.  Safety and response data will be evaluated based on this 
population.
10.3.2.
Analysis Data Sets
Construction of data sets relating to the reporting and analysis of study data will be 
performed in accordance with all applicable GSK Integrated Data Standards Library 
(IDSL) standards and procedures.
10.3.3.
Interim Analysis
No formal interim analysis is planned for this study.
10.3.4.
Key Elements of Analysis Plan
The final analysis will take place after the last subject last visit has occurred.
Data will be listed and summarized by cohort and for total subjects according to the GSK 
reporting standards, where applicable.  Complete details will be documented in the 
Reporting and Analysis Plan (RAP).  Any deviations from, or additions to, the original 
analysis plan described in this protocol will be documented in the RAP and final study 
report.


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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.  Summaries may be provided grouped by appropriate subject 
populations and/or cohorts.
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 by cohort and for total 
subjects.  The ATS population will be used for the analysis of safety data.  Complete 
details of the safety analyses will be provided in the RAP.
10.3.5.
Safety Analyses
10.3.5.1.
Extent of Exposure
The number of subjects administered study treatment(s) will be listed and summarized by 
cohort according to the duration of therapy.
10.3.5.2.
Adverse Events
Adverse events (AEs) will be coded using MedDRA and grouped by system organ class.  
AEs will be graded by the investigator according to the NCI-CTCAE (version 4.0)
[NCI, 2009].
Events will be summarized by frequency, cohort and proportion of total subjects, by 
system organ class and preferred term. Separate summaries will be given for all AEs, 
drug-related AEs, serious AEs and AEs leading to discontinuation of study treatment(s).
If the AE is listed in the NCI-CTCAE (version 4.0) [NCI, 2009] table, the maximum 
grade will be summarized.
Characteristics (e.g. number of occurrences, action taken, grade, etc) of the following 
AEs of special interest will be summarized separately: rash, visual changes, diarrhea, 
pneumonitis, and LVEF.
The incidence of deaths and the primary cause of death will be summarized by cohort and 
for total subjects.
10.3.5.3.
Clinical Laboratory Evaluations
Hematology and clinical chemistry data will be listed for each subject and summarized at 
each scheduled assessment according to NCI-CTCAE grade (version 4.0)
[NCI, 2009].  The proportion of values lying outside the reference range will also be 


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presented for laboratory tests that are not graded because there are no associated NCI-
CTCAE criteria.  Summaries will include data from scheduled assessments only, and all 
data will be reported according to the nominal visit date for which it was recorded (i.e., 
no visit windows will be applied).  Unscheduled data will be included in “overall” and 
“any post-screening” summaries which will capture a worst case across all scheduled and 
unscheduled visits post first dose of study treatment(s).  Further details will be provided 
in the RAP.
10.3.5.4.
Other Safety Measures
The results of scheduled assessments of vital signs, 12-lead ECG, and ECHO/MUGA 
scan, will be listed for each subject and summarized by cohort.  All data will be reported 
according to the nominal visit date for which it was recorded (i.e. no visit windows will 
be applied).  Further details will be provided in the RAP.
10.3.5.5.
Clinical Activity Analyses
No efficacy analysis is planned for this study.  To assess clinical activity, the overall 
response based on investigator assessments will be listed and summarized by cohort.  If 
the data warrant, the response data will be summarized by cohort.
11.
STUDY CONDUCT CONSIDERATIONS
11.1.
Posting of Information on Clinicaltrials.gov
Study information from this protocol will be posted on clinicaltrials.gov before enrolment 
of subjects begins.
11.2.
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 (ICH) Good Clinical Practice (GCP) and applicable country-specific 
regulatory requirements including a US IND.
The study will be conducted in accordance with all applicable regulatory requirements.
The study will be conducted in accordance with ICH GCP, all applicable subject privacy 
requirements, and the ethical principles that are outlined in the Declaration of Helsinki 
2008, including, but not limited to:

IRB/IEC review and 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.


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Written informed consent must be obtained from each subject prior to participation in the 
study.  The consent process will be conducted during the Transition Visit.
11.3.
Urgent Safety Measures
If an event occurs that is related to the conduct of the study or the development of the IP, 
and this new event is likely to affect the study of subjects, the Sponsor, and the 
investigator will take appropriate urgent safety measures to protect subjects against any 
immediate hazard.
The Sponsor will work with the investigator to ensure the IEC/IRB is notified.
11.4.
Quality Control (Study Monitoring)
In accordance with applicable regulations, ICH GCP, and GSK procedures, the site will 
be contacted prior to the start of the study to review with the site staff the protocol, study 
requirements, and their responsibilities to satisfy regulatory, ethical, and GSK 
requirements.  When reviewing data collection procedures, the discussion will include 
identification, agreement and documentation of data items for which the eCRF will serve 
as the source document.
The investigator and the head of the medical institution (where applicable) agrees to 
allow the monitor direct access to all relevant documents and to allocate their time and 
the time to their staff to monitor to discuss findings and any issues.
Monitoring visits will be conducted in a manner to ensure that the:

Data are authentic, accurate, and complete.

Safety and rights of subjects are being protected.

Study is conducted in accordance with the currently approved protocol and any other 
study agreements, ICH GCP, and all applicable regulatory requirements.
11.5.
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.
11.6.
Study and Site Closure
The end of the study will be defined as the date of the last visit of the last subject 
enrolled.


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Upon completion or termination of the study, the monitor will conduct site closure 
activities with the investigator or site staff (as appropriate), in accordance with applicable 
regulations, ICH GCP, and GSK Standard Operating Procedures.
GSK reserves the right to temporarily suspend or terminate the study at any time for 
reasons including (but not limited to) safety issues, ethical issues, or severe 
noncompliance.  If GSK determines that such action is required, GSK will discuss the 
reasons for taking such action with the investigator or head of the medical institution 
(where applicable).  When feasible, GSK will provide advance notice to the investigator 
or head of the medical institution of the impending action.
If a study is suspended or terminated for safety reasons, GSK will promptly inform all 
investigators, heads of the medical institutions (where applicable),and/or institutions 
conducting the study.  GSK will also promptly inform the relevant regulatory authorities 
of the suspension/termination along with the reasons for such action.  Where required by 
applicable regulations, the investigator or head of the medical institution must inform the 
IRB/IEC promptly and provide the reason(s) for the suspension/termination.
11.7.
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.
11.8.
Provision of Study Results to Investigators, Posting to the 
Clinical Trials Register and Publication
Where required by applicable regulatory requirements, an investigator signatory will be 
identified for the approval of the clinical study report.  The investigator will be provided 


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reasonable access to statistical tables, figures, and relevant reports and will have the 
opportunity to review the complete study results at a GSK site or other mutually-
agreeable location.
GSK will also provide the investigator with the full summary of the study results.  The 
investigator is encouraged to share the summary results with the study subjects, as 
appropriate.
The results summary will be posted to the Clinical Study Register at the time of the first 
regulatory approval or within 12 months of any decision to terminate development. In 
addition, a manuscript will be submitted to a peer-reviewed journal for publication within 
12 months of the first approval or within 12 months of any decision to terminate 
development. When manuscript publication in a peer-reviewed journal is not feasible, 
further study information will be posted to the GSK Clinical Study Register to 
supplement the results summary.


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12.
REFERENCES
Allen LF, Sebolt-Leopold J, Meyer MB. CI-140 (PD184352), a targeted signal 
transduction inhibitor of MEK (MAPKK). Seminars in Oncology. 2003; 30:105-166. 
Davies H, Bignell, GR, Cox, C, Stephens, P, Edkins, S, et al. Mutations of the BRAF 
gene in human cancer. Nature. 2002; 417:949-954. 
Friday BB, Adjei AA. Advances in targeting the Ras/Raf/MEK/Erk mitogen-activated 
protein kinase cascade with MEK inhibitors for cancer therapy. Clin Cancer Res. 2008; 
14:342-346.
GlaxoSmithKline Document Number HM2009/00151/02. Clinical Investigator Brochure 
for GSK1120212, 3rd edition. 23-Jun-2011. 4th edition. 05-Sep-2012. 5th edition. 25-Sep-
2013.
GlaxoSmithKline Document Number RM2007/00642/03. MEK111054: An open-label, 
multiple-dose, dose escalation study to investigate the safety, pharmacokinetics, and 
pharmacodynamics of the MEK inhibitor GSK1120212 in subjects with solid tumors or 
lymphoma. Dated: 10-Jun-2009. 
LoRusso PM, Adjei AA, Varterasian M, Gadgeel S, Reid J, et al. Phase I and 
pharmacodynamic study of the oral MEK inhibitor CI-1040 in patients with advanced 
malignancies. J Clin Oncol. 2005; 23:5281-93.
LoRusso PM, Krishnamurthi SS, et al.  Phase I pharmacokinetic and pharmacodynamic 
study of the oral MAPK/ERK kinase inhibitor PD-0325901 in patients with advanced 
cancers. Clin Cancer Res. 2010; 16:1924-1937.
NCI Common Terminology Criteria for Adverse Events, Version 4, DCTD, NCI, NIH, 
DHHS, 28 May 2009.
The Criteria Committee of the New York Heart Association (NYHA).  Nomenclature and 
Criteria for Diagnosis of Diseases of the Heart and Great Vessels. 9th Ed. Boston, Mass:  
Little, Brown & Co.;  1994:253-256.
Tzekova V, Cebotaru C, et al. Efficacy and safety of AZD6244 (ARRY-142886) as 
second/third-line treatment of patients (pts) with advanced non-small cell lung cancer 
(NSCLC). J Clin Oncol. 2008;26:431s.


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13.
APPENDICES
13.1.
Appendix 1: Time and Events Table for Cohort A
Assessment/
Procedure18
Transition Visit1
Continuous Dosing
Treatment Period20
Final Study Visit
Every 4 
weeks17
(7 days)
Week 817
(7 days)
Every 12 weeks17
(7 days)
Every 24 weeks17
(7 days)
With 28 days of Last Dose of 
Study Treatment(s)
(7 days)19
Informed Consent2
X
Demographics and Parent 
Study Data
X
Physical  Exam3
X
X
X
X
Pregnancy test4
X
Vital Signs5
X
X
X
12-Lead ECG6
X
X7
X7
X
ECHO/MUGA scan
X
X8
X9
Clinical Chemistry10
X
X11
X11
X
Hematology10
X
X11
X11
X
Liver Function Tests10,12
X
X
X
X
Tumor Tissue /Skin Biopsy or 
Blood Sample for Biomarker 
Analysis13
O
cfDNA Sample13
O
AE Monitoring14, 15
Continuous
Review of Concomitant 
Medications16
Continuous
GSK1120212 Dosing
Continuous


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Abbreviations:  O, optional
1.
All subjects transitioning from parent study will begin the rollover study based on the last treatment visit completed during the parent study.  All Transition Visit 
assessments/procedures must be completed prior to the first dose of study treatment(s).  Assessments/procedures may be used to fulfill the requirements of both the parent 
study and this study.  Results from the parent study should be recorded in the eCRF as transition values.
2.
Informed consent must be obtained prior to performing any assessments or procedures for this study and before treatment with GSK1120212 is to be continued.
3.
Physical examination will be completed at the Transition Visit, Week 8 and every 12 weeks thereafter while on treatment, and at the Final Study Visit. Height (cm) and weight 
(kg) will be measured only at the Transition Visit.
4.
Serum β–hCG pregnancy tests will be performed on female subjects of childbearing potential only at the time of transition from the parent study.
5.
Vital signs (BP, temperature, respiratory rate, and pulse rate) should be taken in a semi-supine position and after the subject has rested for at least 5 minutes prior to the 
reading.  Vital signs may be measured more frequently as clinically indicated.
6.
A single 12-Lead ECG will be performed using a standard 12-lead ECG machine.  All ECGs will be taken in a supine position after resting in that position for at least 10 
minutes prior to testing.  QTc interval must not be >500 msec.
7.
12-lead ECGs will be performed every 12 weeks (at a minimum or more frequently per local practice) for the first 2 years of treatment (including time on parent study).  After 
2 years of treatment 12-lead ECGs will be performed every 24 weeks for the duration of treatment.
8.
ECHO or MUGA scan should be performed every 12 weeks (at a minimum or more frequently per local practice).  If LVEF decreases 20 percentage points, repeat testing 
is required within 2 weeks.  If decline is sustained, the investigator, in consultation with GSK Medical Monitor, should consider withdrawal of subject from the study.
9.
ECHO is only required at the Final Study Visit if an abnormal finding is reported from the last ECHO or MUGA scan performed
10. Refer to Section 8.4.5 for complete list of clinical laboratory assessments to be performed.
11. Hematology and clinical chemistry laboratory assessments will be performed every 4 weeks (at a minimum or more frequently per local practice) for the first 2 years of 
treatment (including time on parent study).  After 2 years hematology and clinical chemistry laboratory assessments will be performed every 12 weeks for the duration of 
treatment.
12. Liver function tests (AST, ALT, alkaline phosphatase and total bilirubin) will be performed every 4 weeks (depending on the scheduled used in the parent study; at a minimum 
or more frequently per local practice) for the first 2 years of treatment (including time on parent study).  After 2 years liver function tests will be performed every 12 weeks 
(depending on schedule used in the parent study) for the duration of treatment.  Bilirubin fractionation is recommended if total bilirubin is ≥2 times ULN.
13. Optional tumor tissue, skin or blood sample from a lesion not required for disease assessment and/or optional blood sample for cfDNA may be obtained if subject has 
provided consent.
14. AEs/SAEs will be monitored and recorded beginning on the time of consent until 30 days after the last dose of GSK1120212.
15. All ongoing (unresolved) AEs at the time of the transition to this study will be recorded in the eCRF.
16. All concomitant medication(s) at the time of the transition to this study will be recorded in the eCRF.
17. The Week 8”, “Every 12 Weeks” or “Every 24 Weeks” columns are NOT a separate visit but instead a listing of assessments required to be completed at week 8 and every
12 or 24 weeks or every second or third clinic visit that is recurring at 4-week intervals, respectively.
18. After a subject has been on study for a total of 2 years, including time on parent study, the frequency of assessments will be modified.  If more frequent assessments are 
needed, these should be done per local practice.
19. The Final Study Visit should occur within 28 days (7 days) following the last dose of study treatment(s) and prior to initiating any new treatment.
20. Subjects who have tolerated therapy well with limited toxicities and remain on study treatment >52 weeks may have the frequency of their interim visits decreased with 
approval and direction from the GSK Medical Monitor.


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13.2.
Appendix 2: Time and Events Table for Cohort B
Assessment/
Procedure18
Transition Visit1
Continuous Dosing 
Treatment Period20
Final Study Visit
Every 3 or 4 
weeks17
(7 days)
Every 9 or 12 
weeks17
(7 days)
Every 12 weeks17
(7 days)
Every 24 weeks17
(7 days)
With 28 days of Last Dose of 
Study Treatment(s)
(7 days)19
Informed Consent2
X
Demographics and Parent 
Study Data
X
Physical  Exam3
X
X
X
Pregnancy test4
X
Vital Signs5
X
X
X
12-Lead ECG6
X
X7
X7
X
ECHO/MUGA scan
X
X8
X9
Clinical Chemistry10
X
X11
X11
X
Hematology10
X
X11
X11
X
Liver Function Tests10,12
X
X
X
X
Tumor Tissue /Skin Biopsy or 
Blood Sample for Biomarker 
Analysis13
O
cfDNA Sample13
O
AE Monitoring14, 15
Continuous
Review of Concomitant 
Medications16
Continuous
GSK1120212 Dosing
Continuous


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Abbreviations:  O, optional
1.
All subjects transitioning from parent study will begin the rollover study based on the last treatment visit completed during the parent study.  All Transition Visit 
assessments/procedures must be completed prior to the first dose of study treatment(s).  Assessments/procedures may be used to fulfill the requirements of both the parent study 
and this study.  Results from the parent study should be recorded in the eCRF as transition values.
2.
Informed consent must be obtained prior to performing any assessments or procedures for this study and before treatment with GSK1120212 is to be continued.
3.
Height (cm) and weight (kg) will be measured only at the Transition Visit.
4.
Serum β–hCG pregnancy tests will be performed on female subjects of childbearing potential only at the time of transition from the parent study.
5.
Vital signs (BP, temperature, respiratory rate, and pulse rate) should be taken in a semi-supine position and after the subject has rested for at least 5 minutes prior to the reading.  
Vital signs may be measured more frequently as clinically indicated.
6.
A single 12-Lead ECG will be performed using a standard 12-lead ECG machine.  All ECGs will be taken in a supine position after resting in that position for at least 10 minutes 
prior to testing.  QTc interval must not be >500 msec.
7.
12-lead ECGs will be performed every 9 or 12 weeks (depending on the schedule used in the parent study; at a minimum or more frequently per local practice) for the first 2 years 
of treatment (including time on parent study).  After 2 years of treatment 12-lead ECGs will be performed every 24 weeks for the duration of treatment.
8.
ECHO or MUGA scan should be performed every 12 weeks (at a minimum or more frequently per local practice).  If LVEF decreases 20 percentage points, repeat testing is 
required within 2 weeks.  If decline is sustained, the investigator, in consultation with GSK Medical Monitor, should consider withdrawal of subject from the study.
9.
ECHO is only required at the Final Study Visit if an abnormal finding is reported from the last ECHO or MUGA scan performed
10. Refer to Section 8.4.5 for complete list of clinical laboratory assessments to be performed.
11. Hematology and clinical chemistry laboratory assessments will be performed every 3 or 4 weeks (depending on the scheduled used in the parent study; at a minimum or more 
frequently per local practice) for the first 2 years of treatment (including time on parent study).  After 2 years hematology and clinical chemistry laboratory assessments will be 
performed every 9 or 12 weeks (depending on schedule used in the parent study) for the duration of treatment.
12. Liver function tests (AST, ALT, alkaline phosphatase and total bilirubin) will be performed every 3 or 4 weeks (depending on the scheduled used in the parent study; at a minimum 
or more frequently per local practice) for the first 2 years of treatment (including time on parent study).  After 2 years liver function tests will be performed every 9 or 12 weeks 
(depending on schedule used in the parent study) for the duration of treatment.  Bilirubin fractionation is recommended if total bilirubin is ≥2 times ULN.
13. Optional tumor tissue, skin or blood sample from a lesion not required for disease assessment and/or optional blood sample for cfDNA may be obtained if subject has provided 
consent.  
14. AEs/SAEs will be monitored and recorded beginning on the time of consent until 30 days after the last dose of GSK1120212.
15. All ongoing (unresolved) AEs at the time of the transition to this study will be recorded in the eCRF.
16. All concomitant medication(s) at the time of the transition to this study will be recorded in the eCRF.
17. The “Every 9 Weeks”, “Every 12 Weeks” or “Every 24 Weeks” columns are NOT a separate visit but instead a listing of assessments required to be completed every 9, 12 or 
24 weeks or every second or third clinic visit that is recurring at 3 or 4-week intervals, depending on the schedule used in the parent study.
18. After a subject has been on study for a total of 2 years, including time on parent study, the frequency of assessments will be modified.  If more frequent assessments are needed, 
these should be done per local practice.
19. The Final Study Visit should occur within 28 days (7 days) following the last dose of study treatment(s) and prior to initiating any new treatment.
20. Subjects who have tolerated therapy well with limited toxicities and remain on study treatment >52 weeks may have the frequency of their interim visits decreased with 
approval and direction from the GSK Medical Monitor.


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13.3.
Appendix 3:  NYHA Functional Classification System
The New York Heart Association (NYHA) Functional Classification: Class I, II, III 
or IV Heart Failure [NYHA, 1994] provides a simple way of classifying the extent of 
heart failure.  It places subjects in one of 4 categories based on the level of limitation 
experienced during physical activity:
Class
Symptoms
Class I
(Mild)
No limitation of physical activity.  Ordinary physical activity does not cause 
undue fatigue, palpitation or dyspnea (shortness of breath).
Class II
(Mild)
Slight limitation of physical activity.  Comfortable at rest, but ordinary 
physical activity results in fatigue, palpitation or dyspnea.
Class III
(Moderate)
Marked limitation of physical activity.  Comfortable at rest, but less than 
ordinary physical activity results in fatigue, palpitation or dyspnea.
Class IV
(Severe)
Unable to carry out any physical activity without discomfort.  Symptoms of 
cardiac insufficiency at rest.  If any physical activity is undertaken, discomfort 
is increased.


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13.4.
Appendix 4:  Liver Chemistry Stopping and Follow-up 
Criteria
Phase II Liver Safety Algorithms
ALT>3xULN
plus Bilirubin>2xULN 
(>35% direct) (or plus
INR>1.5, if measured)*
No
Yes
Yes
•Instruct subject to stop investigational product (IP)
•Notify GSK + arrange clinical followup within 24-72h
•Perform liver chemistries and liver event follow up 
assessments (serology, PK sample etc as in protocol) 
•Complete liver event CRF, SAE data collection tool if 
appropriate, + liver imaging +/or biopsy CRFs if these 
tests performed.
•Obtain weekly liver chemistries [**as far as possible] 
until resolved, stabilised or returned to baseline 
•Withdraw subject from study after liver chemistry 
monitoring complete + do not re-challenge with IP
•Instruct subject to stop investigational product (IP)
•Notify GSK + arrange clinical followup within 24h
•Perform liver chemistries and liver event follow up 
assessments (serology, PK sample etc as in protocol) 
•Report as an SAE (excl. hepatic impairment or cirrhosis 
studies)+ and complete liver event CRF, SAE data 
collection tool, + liver imaging +/or biopsy CRFs if tests 
performed.
•Obtain twice weekly liver chemistries until resolved, 
stabilised or returned to baseline values
•Consultation with hepatologist/specialist recommended
•Withdraw subject from study after liver chemistry 
monitoring complete + do not re-challenge with IP
ALT>5xULN
Hepatitis 
symptoms
or rash?
No
Able to 
monitor weekly                       
for 4 wks?
No
Notify GSK within 24h to 
discuss subject safety
Continue IP
Check liver chemistry 
weekly for 4 weeks
No
No**
Yes
Yes
Continue IP
Obtain twice monthly liver 
chemistries until normalised
or back to baseline values
Yes
Yes
ALT>3xULN or bilrubin >2xULN?
Yes
*INR value not applicable to patients on anticoagulants


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13.5.
Appendix 5:  Country Specific Requirements
Australia: Supply of GSK1120212 should continue until the drug is available under 
subsidy on the Pharmaceutical Benefits Scheme (PBS).
France and the United Kingdom:  French and United Kingdom specific QTc Stopping 
Criteria has been added to Section 5.7.1.1.
 
 
 
 
 
 
  
 
 
No other known country specific requirements are currently required.


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FRENCH ADMINISTRATIVE CONSIDERATIONS 
This appendix includes all the requirements of the French law (n° 2004-806 of 9th August 
2004), and identifies, item per item, the mandatory modifications or additional information to 
the study protocol. 
1. Concerning the « STUDY POPULATION»  
• In line with the local regulatory requirements, the following text in section  «OTHER 
STUDY ELIGIBILITY CRITERIA CONSIDERATIONS » is added : 
A subject will be eligible for inclusion in this study if he /she is either affiliated to or 
beneficiary of a social security category. 
It is the investigator’s responsibility to ensure and to document (in source document - 
patient notes) that the patient is either affiliated to or beneficiary of a social security 
category. 
≈≈≈≈≈≈≈≈≈≈≈≈ 
2. Concerning the “DATA ANALYSIS AND STATISTICAL 
CONSIDERATIONS” and specially in the “SAMPLE SIZE 
ASSUMPTION” 
The expected number of patients to be recruited in France is declared to the 
French regulatory authority. 
≈≈≈≈≈≈≈≈≈≈≈≈ 
3. Concerning the “STUDY CONDUCT CONSIDERATIONS” 
• In section “Regulatory and Ethical Considerations, Including the Informed 
Consent Process” 
⇒ Concerning the process for informing the patient or his/her legally 
authorized representative, the following text is added :  
French Patient Informed Consent form is a document in triplicate which 
summarizes the main features of the study and allows collection of the 
patient's written consent. It also contains a reference to the authorisation 
of Afssaps and the approval from the French Ethic committee and the 
maintenance of confidentiality of the returned consent form by GSK 
France. 
 
⇒ Concerning the management of the Patient Informed Consent forms, the 
following text is added : 
The first copy of the Patient Informed Consent form is kept by the 
investigator. The second copy is kept by the Medical Direction of 
GlaxoSmithKline France and the last copy is given to the patient or 
his/her legally authorized representative. 
The second copy of all the consent forms will be collected by the 
investigator under the Clinical Research Assistant’s (CRA's) control, and 
placed in a sealed envelope bearing only: 
♦ the study number,  
♦ the identification of the Centre : name of the principal investigator and 
centre number), 
♦ the number of informed consents, 


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♦ the date,  
♦ and the principal investigator’s signature. 
Then, the CRA hands the sealed envelope over to the Medical Direction, 
for confidential recording, under the responsibility of the Medical Director. 
-*-*-*-*-*-*-*- 
• In 
section 
concerning 
the 
“ NOTIFICATION 
TO 
THE 
HOSPITAL 
DIRECTOR ” the following text is added: 
In accordance with Article L1123-13 of the Public Health Code, the 
Hospital Director is informed of the commitment to the trial in his 
establishment. The Hospital Director is supplied with the protocol and any 
information needed for the financial disposition, the name of the 
investigator(s), the number of sites involved in his establishment and the 
estimated time schedule of the trial (R.1123-63). 
≈≈≈≈≈≈≈≈≈≈≈≈ 
• In 
section 
concerning 
the 
“ INFORMATION 
TO 
THE 
HOSPITAL 
PHARMACIST ” the following text is added: 
In accordance with Article R.1123-64 of the Public Health Code, the 
Hospital Pharmacist is informed of the commitment to the trial in his 
establishment. The Pharmacist is supplied with a copy of the protocol 
(which allows him to dispense the drug(s) of the trial according to the trial 
methodology), all information concerning the product(s) of the trial (e.g. 
included in the CIB), the name of the investigator(s), the number of sites 
involved in his establishment and the estimated time schedule of the trial. 
≈≈≈≈≈≈≈≈≈≈≈≈ 
• In section “ DATA MANAGEMENT ” the following text is added: 
Within the framework of this clinical trial, data regarding the identity of the 
investigators and/or co-investigators and/or the pharmacist if applicable, 
involved in this clinical trial, and data regarding the patients recruited in 
this clinical trial (patient number, treatment number, patient status with 
respect to the clinical trial, dates of visit, medical data) will be collected 
and computerized in GSK data bases by GlaxoSmithKline Laboratory or 
on its behalf, for reasons of follow up, clinical trial management and using 
the results of said clinical trial. According to the Act n° 78-17 of 6th 
January 1978 further modified, each of these people aforesaid has a right 
of access, correction and opposition on their own data through 
GlaxoSmithKline Laboratory (Clinical Operations Department). 
≈≈≈≈≈≈≈≈≈≈≈≈ 
4. . Concerning the « SAE »  
 In section “TRANSMISSION OF THE SAE REPORTS”:  
In case of paper CRF, the SAE Reports have to be transmitted to the 
GSK France Drug Safety Department, which name, address and phone 
number are:  
Département de Pharmacovigilance 
Laboratoire GlaxoSmithKline 
100 Route de Versailles 
78163 MARLY LE ROI 
Tel : 
 Fax : 
 


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13.6.
Appendix 6:  Protocol Changes
AMENDMENT 7
Where the Amendment Applies
Amendment 07 applies to all sites that are or will be conducting this study. 
Summary of Amendment Changes with Rationale
In this amendment, standard language changes based on CIB V 05 report date 25 Sept 
2013 were made to Stopping Criteria for Visual Changes and Ophthalmologic 
Examinations.  Exclusion Criteria number 2 was deleted as local commercial availability 
of the study drug is no longer considered to be a major exclusion criterion.  Table 1
GSK1120212 Investigation Product (description) was deleted as only the commercial 
drug is now being used in studies.  Tables and table references throughout the protocol 
were renumbered accordingly.  The Handling and Storage of Study Treatment was 
revised to refer investigators to the drug label and SPM for detailed handling and storage 
directions.  CIB V 05 report date 25 Sep 2013 was added to the CIB reference.  Authors, 
Sponsor Signatory and Sponsor/Medical Monitor Information pages were revised to
reflect changes in GSK study team members.  Administrative changes were made for 
typographical (punctuation) omissions and errors.
Title Page
PREVIOUS TEXT:
Author:
REVISED TEXT:
Author:
 
                    


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Sponsor Signatory Page
PREVIOUS TEXT:
, MD
 
, 
GlaxoSmithKline
REVISED TEXT:
, MD, PhD
 
 
  GlaxoSmithKline
Sponsor/Medical Monitor Information Page
PREVIOUS TEXT:
Sponsor Medical Monitor Contact Information: 
Role
Name
Day Time 
Phone 
Number
After-hours 
Phone/Cell
/
Pager 
Number
Fax 
Number
GSK Address
Primary 
Medical 
Monitor
, 
MD, PhD
GlaxoSmithKline
1250 South Collegeville 
Road, 
Mailstop UP 4215
Collegeville, PA  19426, US
Secondary 
Medical 
Monitor
 
, MD, 
PhD
GlaxoSmithKline
1250 South Collegeville 
Road
Mailstop: UP 4340
Collegeville, PA 19426, US
Tertiary 
Medical 
Monitor
 
, MD
GlaxoSmithKline
1250 South Collegeville 
Road
Mailstop: UP4340
Collegeville, PA 19426, US


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REVISED TEXT:
Sponsor Medical Monitor Contact Information: 
Role
Name
Day Time 
Phone 
Number
After-hours 
Phone/Cell
/
Pager 
Number
Fax 
Number
GSK Address
Primary 
Medical 
Monitor
, 
MD, PhD
GlaxoSmithKline
1250 South Collegeville 
Road, 
Mailstop UP 4410
Collegeville, PA  19426-0989, 
US
Secondary 
Medical 
Monitor
, MD
GlaxoSmithKline
1250 South Collegeville 
Road, 
Mailstop UP 4210
Collegeville, PA  19426-0989, 
US
List of Abbrevations
ADDED:
RPED
Retinal Pigment Epithelial Detachment
Section 4.1.3. Exclusion Criteria #2
PREVIOUS TEXT:
1. Permanent discontinuation of GSK1120212 in the parent study due to toxicity or 
disease progression.
2. Local access to commercially available GSK1120212.
3. Current use of a prohibitive medication(s) as listed in Section 6.2.
NOTE: Use of anticoagulants such as warfarin is permitted; however, the 
international normalization ratio (INR) must be monitored in accordance with 
local institutional practice.
4. Any unresolved toxicity that meets the study treatment discontinuation or study 
withdrawal criteria from the parent study at the time of transition to this study.
5. Bazett-corrected QT (QTcB) interval ≥501 msec at the time of transition to 
this study


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6. Left ventricular ejection fraction (LVEF) < institutional lower limit of 
normal (LLN) by ECHO (preferred) or MUGA scan at the time of transition 
to this study.
7.
Nursing female.
8. Any serious and/or unstable pre-existing medical, psychiatric disorder or 
other conditions at the time of transition to this study that could interfere 
with subject’s safety, obtaining informed consent or compliance to the study 
procedures, in the opinion of the investigator or GSK Medical Monitor.
REVISED TEXT:
1. Permanent discontinuation of GSK1120212 in the parent study due to toxicity or 
disease progression.
2. Current use of a prohibitive medication(s) as listed in Section 6.2.
NOTE: Use of anticoagulants such as warfarin is permitted; however, the 
international normalization ratio (INR) must be monitored in accordance 
with local institutional practice.
3. Any unresolved toxicity that meets the study treatment discontinuation or 
study withdrawal criteria from the parent study at the time of transition to 
this study.
4. Bazett-corrected QT (QTcB) interval ≥501 msec at the time of transition to 
this study
5. Left ventricular ejection fraction (LVEF) < institutional lower limit of 
normal (LLN) by ECHO (preferred) or MUGA scan at the time of transition 
to this study.
6.
Nursing female.
7. Any serious and/or unstable pre-existing medical, psychiatric disorder or 
other conditions at the time of transition to this study that could interfere 
with subject’s safety, obtaining informed consent or compliance to the study 
procedures, in the opinion of the investigator or GSK Medical Monitor.


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Section 5.1. Investigational Product, Table 1
PREVIOUS TEXT:
Table 1
GSK1120212 GSK Investigational Product
Investigational Product
Product name :
GSK1120212
Formulation 
description:
Each tablet is blended with inert ingredients (mannitol, sodium lauryl sulfate, colloidal silicon 
dioxide, microcrystalline cellulose, hypromellose, croscarmellose sodium, and magnesium 
stearate) and compressed into tablets.  Tablets are then coated with either a white or pink 
opaque film* (*Opadry White or Pink, a titanium dioxide-based formulation with iron oxide as 
colorant as applicable).
Dosage form :
Tablet
Unit dose 
strength(s):
0.5 mg
2.0 mg
Physical 
Description: 
0.5mg: White, oval, biconvex film-coated tablet with dose proportional diameter
2.0 mg: Pink, round, biconvex film-coated tablet with dose proportional diameter
Route/Regimen: 
Oral/Cohort A: Subjects will receive GSK1120212 2.0 mg or less once-daily.  Cohort B: 
Subjects will receive continuous oral dosing of GSK1120212 at the current dose administered 
in the parent study at the time of transition to the rollover study.
Dosing Instructions:
GSK1120212 should be administered with approximately 240 mL (8 fl oz) of water, under 
fasting conditions, either 1 hour before or 2 hours after a meal. 
REVISED TEXT:
Table 1
GSK1120212 GSK Investigational Product
Commercial Image Product
Product name 
:
GSK1120212 0.5 mg Tablet
GSK11210212 2 mg Tablet
Formulation 
description:
Each tablet contains GSK1120212B equivalent 
to 0.5 mg of GSK1120212 as drug substance 
blended with inert ingredients (mannitol, 
sodium lauryl sulfate, colloidal silicon dioxide, 
microcrystalline cellulose, hypromellose, 
croscarmellose sodium, and magnesium 
stearate) and compressed into tablets.  The 
tablets are then coated with yellow opaque 
film* (*Opadry yellow, a titanium dioxide-based 
formulation with yellow iron oxide as 
colorant).
Each tablet contains GSK1120212B 
equivalent to 2 mg of GSK1120212 as drug 
substance blended with inert ingredients 
(mannitol, sodium lauryl sulfate, colloidal 
silicon dioxide, microcrystalline cellulose, 
hypromellose, croscarmellose sodium, and 
magnesium stearate) and compressed into 
tablets. The tablets are then coated with 
pink opaque film* (*Opadry Pink, a titanium 
dioxide-based formulation with red iron 
oxide as colorant).
Dosage form :
Tablet
Tablet
Unit dose 
strength(s):
Tablet strength: 0.5 mg
Tablet strength: 2 mg
Physical 
Description:
Yellow, modified oval, biconvex, film-coated 
tablets (4.85 x 8.86 mm)
Pink, biconvex, round film-coated tablets 
7.5 mm in diameter
Route/
Administratio
n: 
Oral/once-daily single dose
Oral/once-daily single dose
Dosing 
Instructions:
GSK1120212 should be administered with approximately 240 mL (8 fl oz) of water, under 
fasting conditions, either 1 hour before or 2 hours after a meal


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Section 5.4. Handling and Storage of Study Treatment
PREVIOUS TEXT:
GSK1120212 must be stored in a secure area under the appropriate physical conditions 
for the product. Access to and administration of the GSK1120212 will be limited to the 
investigator and authorized site staff.  GSK1120212 must be dispensed or administered 
only to subjects enrolled in the study and in accordance with the protocol.
GSK1120212 is to be stored at a temperature up to 25°C in an opaque bottle, protected 
from light and moisture.  Maintenance of a temperature log (manual or automated) is 
required.
REVISED TEXT:
GSK1120212 must be stored in an opaque bottle, protected from light and moisture
in a secure area under the appropriate physical conditions for the product at the 
temperature specified on the label. Maintenance of a temperature log (manual or 
automatic) is required.  Access to and administration of the GSK1120212 will be 
limited to the investigator and authorized site staff.  GSK1120212 must be dispensed or 
administered only to subjects enrolled in the study and in accordance with the protocol. 
Additional guidance can be found in the SPM.
Section 5.7.5. Stopping Criteria for Visual Changes, paragraph 1
PREVIOUS TEXT:
For all visual changes, regardless of grade, a blood sample for PK analysis must be drawn 
as close as possible to the time of the event.  Visual change events should be graded using 
Table 8 based on the NCI-CTCAE, version 4.0 [NCI 2009]).
REVISED TEXT:
Episodes of visual changes have been observed in subjects receiving trametinib, and 
ocular adverse events are known to be related to trametinib. An ophthalmologist 
should be consulted if changes in vision develop.  If the visual changes are clearly 
unrelated to study treatment (e.g., allergic conjunctivitis), then monitor closely as it 
may be reasonable to defer ophthalmic examination. Special attention should be 
given to retinal findings (e.g., retinal pigment epithelial detachment (RPED) or 
retinovascular abnormalities (i.e., branch or central retinal vein occlusions (RVO).  
For events of visual changes (regardless of severity) for which an ophthalmic 
examination is conducted, a blood sample for PK analysis must be drawn as close as 
possible to the time of the event.
Visual change events should be graded using Table 7 based on the NCI-CTCAE, version 
4.0 [NCI 2009]).


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Section 5.7.5. Stopping Criteria for Visual Changes, Grade 1, Grade 2 or 3 
and Grade 4 Visual Changes
PREVIOUS TEXT:
Grade 1 visual changes:

For Grade 1 visual changes that do not affect vision and which, in the option 
of the treating physician, are clearly unrelated to study treatment (e.g., 
conjunctivitis), treatment with GSK1120212 may continue with close 
observation.

If attribution to study treatment is unclear, immediately refer the subject for 
ophthalmic exam; if an ophthalmic exam cannot be performed within 7 
days, interrupt treatment with GSK1120212 until exam can be 
performed and follow the guidance below depending on the results.
If a retinal abnormality is noted, interrupt treatment with GSK1120212 
immediately and referral to a retinal specialist should be considered for 
further evaluation.

If RVO is diagnosed, report as a SAE and permanently discontinue 
treatment with GSK1120212

If CSR is diagnosed, interrupt treatment with GSK1120212 until signs and 
symptoms have resolved.  Resume treatment with GSK1120212 at a dose 
reduced by 1 dose level.

If there is no evidence of RVO or CSR, resume treatment with GSK1120212 
at the same dose level.  
Grade 2 or Grade 3 visual changes:

Immediately interrupt treatment with GSK1120212 and refer subject to an 
ophthalmologist for evaluation with an ophthalmic exam.  For all subjects 
with findings consistent with RVO or CSR based on the ophthalmic exam, 
referral to retinal specialist, if available, should be considered for further 
evaluation.

If RVO is diagnosed, report as a SAE and permanently discontinue 
GSK1120212

If CSR is diagnosed, interrupt treatment with GSK1120212 until signs 
and symptoms have resolved and then resume treatment with 
GSK1120212 at reduced dose by at least one dose level.

If there is no evidence of RVO or CSR, interrupt treatment with 
GSK1120212 until signs and symptoms have returned to Grade 1 or 
resolved.  Resuming treatment with GSK1120212 at the same dose level 
may be considered if visual changes are clearly unrelated to study 
treatment.


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Grade 4 visual changes:

requires permanent discontinuation of treatment with GSK1120212.
REVISED TEXT:
Grade 1 visual changes:

For Grade 1 visual changes that do not affect vision and which, in the option 
of the treating physician, are clearly unrelated to study treatment (e.g., 
conjunctivitis), treatment with GSK1120212 may continue with close 
observation.

If attribution to study treatment is unclear, immediately refer the subject for 
ophthalmic exam; if a dilated fundus examination cannot be performed 
within 7 days of onset, interrupt treatment with GSK1120212 until 
RPED and RVO can be excluded by retina specialist/ophthalmologist. 
Follow the guidance below depending on the results.
If a retinal abnormality is noted, interrupt treatment with GSK1120212 
immediately and referral to a retinal specialist should be considered for 
further evaluation.

  If RPED suspected or diagnosed (asymptomatic; clinical or diagnostic 
observations only) continued treatment with retinal evaluation   monthly 
until resolved.  Report as an SAE.  If worsens see grade 2-3 guidance.

If RVO is diagnosed, report as a SAE and permanently discontinue 
treatment with GSK1120212

If there is no evidence of RPED or RVO, resume treatment with 
GSK1120212 at the same dose level.
Grade 2 or Grade 3 visual changes:

Immediately interrupt treatment with GSK1120212 and refer subject to an 
ophthalmologist for evaluation with an ophthalmic exam.  For all subjects 
with findings consistent with RPED or RVO based on the ophthalmic exam, 
referral to retinal specialist, if available, should be considered for further 
evaluation.

If RVO is diagnosed report as a SAE and permanently discontinue 
GSK1120212

If RPED is diagnosed (symptomatic with mild to moderate decrease 
in visual acuity; limiting instrumental ADL), perform retinal 
evaluation monthly and if improves to ≤ Grade 1, resume treatment 
with GSK1120212 at lower dose (reduced by 0.5 mg) or discontinue 
in subjects taking GSK1120212 1 mg daily.

If RPED and RVO, are excluded and visual changes are clearly 
unrelated to study treatment restart GSK1120212 at the same dose.


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Grade 4 visual changes:

Interupt GSK1120212, consult ophthalmologist immediately and report 
as as SAE.

If RPED and RVO are excluded, may consider restarting GSK1120212 
at same or reduced dose after discussion with the study medical monitor

If RPED or RVO diagnosed permanently discontinue treatment with 
GSK1120212.
Section 8.4.2. Ophthalmologic Examinations
PREVIOUS TEXT:
All subjects transitioning to the rollover study are expected to have had a standard 
ophthalmic exam performed by an ophthalmologist during Screening in their parent 
study.  Ophthalmologic examinations will be conducted during the rollover study if 
clinically indicated (refer to Section 5.7.5 for stopping criteria for visual changes).  If an 
ophthalmologic examination is necessary, it should include indirect fundoscopic 
examination, visual acuity, visual field examination, tonometry, and direct fundoscopy, 
with special attention to retinal abnormality that are predisposing factors for RVO or 
CSR.
For subjects with clinical suspicion of RVO or CSR, additional color fundus photos are 
recommended if they can be acquired, and fluorescein angiography and/or optical 
coherence tomography are highly recommended.
REVISED TEXT:
All subjects transitioning to the rollover study are expected to have had a standard 
ophthalmic exam performed by an ophthalmologist during Screening in their parent 
study.  Ophthalmologic examinations will be conducted during the rollover study if 
clinically indicated (refer to Section 5.7.5 for stopping criteria for visual changes).  If an 
ophthalmologic examination is necessary, it should include dilated indirect fundoscopic 
examination, best corrected visual acuity, visual field examination, tonometry, slit 
lamp biomicroscopic examination and direct fundoscopy, with special attention to 
retinal abnormality. Optical coherence tomography is strongly recommended at 
scheduled visits, and if retinal abnormalities are suspected. Other types of ancillary 
testing including color fundus photography and fluorescein angiography are also 
recommended if clinically indicated.
Section 12. References
PREVIOUS TEXT:
GlaxoSmithKline Document Number HM2009/00151/02. Clinical Investigator Brochure 
for GSK1120212, 3rd edition. 23-Jun-2011. 4th edition. 05-Sep-2012


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REVISED TEXT:
GlaxoSmithKline Document Number HM2009/00151/02. Clinical Investigator Brochure 
for GSK1120212, 3rd edition. 23-Jun-2011. 4th edition. 05-Sep-2012. 5th edition. 25-Sep-
2013.
Section 13.1. Appendix 1: Time and Events Table for Cohort A, annotation 
#12
PREVIOUS TEXT:
12.  Liver function tests (AST, ALT, alkaline phosphatase and total bilirubin) will be 
performed every 4 weeks (depending on the scheduled used in the parent study; at a 
minimum or more frequently per local practice) for the first 2 years of treatment 
(including time on parent study).  After 2 years liver function tests will be performed 
every 12 weeks (depending on schedule used in the parent study) for the duration of 
treatment.  Bilirubin fractionation is recommended if total bilirubin is >2 times ULN
REVISED TEXT:
12.  Liver function tests (AST, ALT, alkaline phosphatase and total bilirubin) will be 
performed every 4 weeks (depending on the scheduled used in the parent study; at a 
minimum or more frequently per local practice) for the first 2 years of treatment 
(including time on parent study).  After 2 years liver function tests will be performed 
every 12 weeks (depending on schedule used in the parent study) for the duration of 
treatment.  Bilirubin fractionation is recommended if total bilirubin is ≥ 2 times ULN
Section 13.2. Appendix 2: Time and Events Table for Cohort B, annotation 
#12
PREVIOUS TEXT:
12.  Liver function tests (AST, ALT, alkaline phosphatase and total bilirubin) will be 
performed every 3 or 4 weeks (depending on the scheduled used in the parent study; at a 
minimum or more frequently per local practice) for the first 2 years of treatment 
(including time on parent study).  After 2 years liver function tests will be performed 
every 9 or 12 weeks (depending on schedule used in the parent study) for the duration of 
treatment.  Bilirubin fractionation is recommended if total bilirubin is >2 times ULN
REVISED TEXT:
12.  Liver function tests (AST, ALT, alkaline phosphatase and total bilirubin) will be 
performed every 3 or 4 weeks (depending on the scheduled used in the parent study; at a 
minimum or more frequently per local practice) for the first 2 years of treatment 
(including time on parent study).  After 2 years liver function tests will be performed 
every 9 or 12 weeks (depending on schedule used in the parent study) for the duration of 
treatment.  Bilirubin fractionation is recommended if total bilirubin is ≥2 times ULN


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AMENDMENT 6
Where the Amendment Applies
Amendment 06 applies to all sites that are or will be conducting this study. 
Summary of Amendment Changes with Rationale
In this amendment, standard language changes based on CIB V 04 report date 05 Sep 
2012 were made to QTc Withdrawal Criteria, LVEF Stopping Criteria, Management of 
Hypertension, Inclusion Criteria, Pregnancy and Contraception.  The requirements for 
male contraception were deleted from the Inclusion Criteria and sections on Pregnancy 
and Contraception as the use of contraception with female partners of childbearing 
potential is not recommended based on the absence of genotoxicity, no effects on male 
reproductive tissues in nonclinical toxicity studies, and the minimal potential for 
trametinib exposure of females via semen. The decreased frequency of interim visits for 
those subjects who have been on study >52 weeks was more clearly define to be for those 
subjects who have in addition to being on study >52 weeks have also tolerated therapy 
well with limited toxicities and to be with the approval and direction of the GSK medical 
monitor. The 1mg tablet was deleted from Table 1 GSK1120212 Investigational Product 
as the 1mg tablet is no longer available.  Typographical errors were corrected.
Section 3.1. Cohorts
PREVIOUS TEXT:
Cohort A:
Cohort A will consist of subjects who have completed <24 weeks of treatment with 
GSK1120212 monotherapy during their participation in the parent study.  It is anticipated 
that subjects in this cohort will have participated in a clinical pharmacology or another 
short-term study of GSK1120212.  Subjects will complete the Transition Visit and return 
for their next scheduled visit (Study Week 4), and then every 4 weeks thereafter.  
Subjects who remain on study treatment >52 weeks may have the frequency of their 
interim visits decreased with approval from the GSK Medical Monitor.
Subjects will receive GSK1120212 as an oral, daily dose of 2 mg or less.  Protocol 
specified guidelines for dose modifications and treatment discontinuation criteria are 
provided in Section 5.6 and Section 5.7, respectively.  If there are any uncertainties about 
the dose to be administered in this study, the GSK Medical Monitor should be consulted.  
Once treatment with GSK1120212 is discontinued the subject is to be withdrawn from 
the rollover study.
Cohort B:
Cohort B will consist of subjects who have completed 24 weeks of treatment with 
GSK1120212 (either as monotherapy or combination therapy with an approved anti-
cancer agent) during their participation in the parent study.  Subjects who transition from 


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a combination study may continue to receive GSK1120212 in combination with the 
approved anti-cancer agent defined by the parent study or if, in the opinion of the 
investigator, the subject has received maximum benefit or is experiencing unacceptable 
toxicity from the approved anti-cancer agent, then treatment with the approved anti-
cancer agent may be discontinued and the subject may remain on study for continued 
treatment with GSK1120212 alone.  Once treatment with GSK1120212 is discontinued 
the subject is to be withdrawn from the rollover study.
Subjects will complete the Transition Visit assessments and then return for their next 
scheduled visit (Study Week 3 or 4), then every 3 or 4 weeks thereafter (depending on the 
schedule used in the parent study).  Subjects who remain on study treatment >52 weeks 
may have the frequency of their interim visits decreased with approval from the GSK 
Medical Monitor.  
All subjects will receive GSK1120212 at the current dose level administered in the parent 
study at the time of the Transition Visit.  If this starting dose of GSK1120212 is below 
the recommended Phase 2 dose (RP2D) previously defined for the given treatment 
regimen (e.g., dose modification following recovery from toxicity), the investigator, after 
consultation with the GSK Medical Monitor, may consider escalating the dose to the 
RP2D.  If there are any uncertainties about the dose(s) to be administered in this study, 
the GSK Medical Monitor should be consulted.
REVISED TEXT
Cohort A:
Cohort A will consist of subjects who have completed <24 weeks of treatment with 
GSK1120212 monotherapy during their participation in the parent study.  It is anticipated 
that subjects in this cohort will have participated in a clinical pharmacology or another 
short-term study of GSK1120212.  Subjects will complete the Transition Visit and return 
for their next scheduled visit (Study Week 4), and then every 4 weeks thereafter.  
Subjects who have tolerated therapy well with limited toxicities and remain on study 
treatment >52 weeks may have the frequency of their interim visits decreased with 
approval and direction from the GSK Medical Monitor.
Subjects will receive GSK1120212 as an oral, daily dose of 2 mg or less.  Protocol 
specified guidelines for dose modifications and treatment discontinuation criteria are 
provided in Section 5.6 and Section 5.7, respectively.  If there are any uncertainties about 
the dose to be administered in this study, the GSK Medical Monitor should be consulted.  
Once treatment with GSK1120212 is discontinued the subject is to be withdrawn from 
the rollover study.
Cohort B:
Cohort B will consist of subjects who have completed 24 weeks of treatment with 
GSK1120212 (either as monotherapy or combination therapy with an approved anti-
cancer agent) during their participation in the parent study.  Subjects who transition from 
a combination study may continue to receive GSK1120212 in combination with the 
approved anti-cancer agent defined by the parent study or if, in the opinion of the 
investigator, the subject has received maximum benefit or is experiencing unacceptable 


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toxicity from the approved anti-cancer agent, then treatment with the approved anti-
cancer agent may be discontinued and the subject may remain on study for continued 
treatment with GSK1120212 alone.  Once treatment with GSK1120212 is discontinued 
the subject is to be withdrawn from the rollover study.
Subjects will complete the Transition Visit assessments and then return for their next 
scheduled visit (Study Week 3 or 4), then every 3 or 4 weeks thereafter (depending on the 
schedule used in the parent study).  Subjects who have tolerated therapy well with 
limited toxicities and remain on study treatment >52 weeks may have the frequency of 
their interim visits decreased with approval and direction from the GSK Medical 
Monitor.  
All subjects will receive GSK1120212 at the current dose level administered in the parent 
study at the time of the Transition Visit.  If this starting dose of GSK1120212 is below 
the recommended Phase 2 dose (RP2D) previously defined for the given treatment 
regimen (e.g., dose modification following recovery from toxicity), the investigator, after 
consultation with the GSK Medical Monitor, may consider escalating the dose to the 
RP2D.  If there are any uncertainties about the dose(s) to be administered in this study, 
the GSK Medical Monitor should be consulted.
Section 4.1.2. Inclusion Criteria, #6
PREVIOUS TEXT:
A subject will be eligible for inclusion in this study only if all of the following criteria 
apply:
1. Has provided signed informed consent for this study.
2. Has demonstrated compliance during the parent study with study treatment(s), 
treatment visit schedules, and the requirements and restrictions listed in the consent 
form.
3. Is currently participating in GSK1120212 study and is receiving treatment with 
GSK1120212.
4. Is currently receiving clinical benefit as determined by the investigator from previous 
treatment with GSK1120212 either as monotherapy or as part of a combination 
treatment regimen.
5. Continued ability to swallow and retain orally administered study treatment(s) and 
does not have any clinically significant GI abnormalities that may alter absorption 
such as malabsorption syndrome or major resection of the stomach or bowels.
6. Male subjects with a female partner of childbearing potential must be willing to 
continue practicing the same acceptable method of contraception as used in the parent 
study during the rollover study and for at least 16 weeks after the last dose of 
GSK1120212. 
7. Female subjects of childbearing potential, as defined in the parent study, must be 
willing to continue practicing the same acceptable method of contraception as used in 


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the parent study during the rollover study and for at least 4 months after the last dose 
of GSK1120212.
8. Female subjects of childbearing potential, as defined in parent study, must have 
negative serum pregnancy tests at the time of transition to this study.
9. Subjects enrolled in France: In France, a subject will be eligible for inclusion in this 
study only if either affiliated to or a beneficiary of a social security category.
REVISED TEXT:
A subject will be eligible for inclusion in this study only if all of the following criteria 
apply:
1. Has provided signed informed consent for this study.
2. Has demonstrated compliance during the parent study with study treatment(s), 
treatment visit schedules, and the requirements and restrictions listed in the consent 
form.
3. Is currently participating in GSK1120212 study and is receiving treatment with 
GSK1120212.
4. Is currently receiving clinical benefit as determined by the investigator from previous 
treatment with GSK1120212 either as monotherapy or as part of a combination 
treatment regimen.
5. Continued ability to swallow and retain orally administered study treatment(s) and 
does not have any clinically significant GI abnormalities that may alter absorption 
such as malabsorption syndrome or major resection of the stomach or bowels.
6. Female subjects of childbearing potential, as defined in the parent study, must 
be willing to continue practicing the same acceptable method of contraception as 
used in the parent study during the rollover study and for at least 4 months after 
the last dose of GSK1120212.
7. Female subjects of childbearing potential, as defined in parent study, must have 
negative serum pregnancy tests at the time of transition to this study.
8. Subjects enrolled in France: In France, a subject will be eligible for inclusion in 
this study only if either affiliated to or a beneficiary of a social security category.


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Section 5.1. Investigational Product: Table 1
PREVIOUS TEXT:
Table 12
GSK1120212 GSK Investigational Product
Investigational Product
Product name :
GSK1120212
Formulation 
description:
Each tablet is blended with inert ingredients (mannitol, sodium lauryl sulfate, colloidal silicon 
dioxide, microcrystalline cellulose, hypromellose, croscarmellose sodium, and magnesium 
stearate) and compressed into tablets.  Tablets are then coated with either a white or pink 
opaque film* (*Opadry White or Pink, a titanium dioxide-based formulation with iron oxide as 
colorant as applicable).
Dosage form :
Tablet
Unit dose 
strength(s):
0.5 mg
1.0 mg
2.0 mg
Physical 
Description: 
0.5mg: White, oval, biconvex film-coated tablet with dose proportional diameter
1.0 mg: White, round, biconvex film-coated tablet with dose proportional diameter
2.0 mg: Pink, round, biconvex film-coated tablet with dose proportional diameter
Route/Regimen: 
Oral/Cohort A: Subjects will receive GSK1120212 2.0 mg or less once-daily.  Cohort B: 
Subjects will receive continuous oral dosing of GSK1120212 at the current dose administered 
in the parent study at the time of transition to the rollover study.
Dosing Instructions:
GSK1120212 should be administered with approximately 240 mL (8 fl oz) of water, under 
fasting conditions, either 1 hour before or 2 hours after a meal. 
REVISED TEXT:
Table 13
GSK1120212 GSK Investigational Product
Investigational Product
Product name :
GSK1120212
Formulation 
description:
Each tablet is blended with inert ingredients (mannitol, sodium lauryl sulfate, colloidal silicon 
dioxide, microcrystalline cellulose, hypromellose, croscarmellose sodium, and magnesium 
stearate) and compressed into tablets.  Tablets are then coated with either a white or pink 
opaque film* (*Opadry White or Pink, a titanium dioxide-based formulation with iron oxide as 
colorant as applicable).
Dosage form :
Tablet
Unit dose 
strength(s):
0.5 mg
2.0 mg
Physical 
Description: 
0.5mg: White, oval, biconvex film-coated tablet with dose proportional diameter
2.0 mg: Pink, round, biconvex film-coated tablet with dose proportional diameter
Route/Regimen: 
Oral/Cohort A: Subjects will receive GSK1120212 2.0 mg or less once-daily.  Cohort B: 
Subjects will receive continuous oral dosing of GSK1120212 at the current dose administered 
in the parent study at the time of transition to the rollover study.
Dosing Instructions:
GSK1120212 should be administered with approximately 240 mL (8 fl oz) of water, under 
fasting conditions, either 1 hour before or 2 hours after a meal. 


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Section 5.7.1.2. Managing Hypertension
PREVIOUS TEXT:
For subjects experiencing an increase in SBP and/or DBP that is persistent and may 
be associated with the study treatment, recommendations for the clinical 
management of hypertension are described below:
Hypertension
(A)  Asymptomatic and persistent1
SBP of 140 and <160 mmHg, or DBP 
90 and <100 mmHg, or a clinically 
significant increase in DBP of 
20 mmHg (but still below 100 mmHg).
Step 1. Continue study treatment at the current dose. 
Step 2. Adjust current or initiate new antihypertensive medication(s).
Step 3. Titrate antihypertensive medication(s) during next 2 weeks 
as indicated to achieve well-controlled2 BP.  If BP is not well-
controlled within 2 weeks, consider referral to a specialist and go to 
scenario (B).
(B) Asymptomatic SBP 160 mmHg, or 
DBP 100 mmHg, or failure to achieve 
well-controlled BP within 2 weeks in 
scenario (A).
Step 1.Consider reducing or interrupting study treatment, as 
clinically indicated.
Step 2. Adjust current or initiate new antihypertensive medication(s). 
Step 3. Titrate antihypertensive medication(s) during next 2 weeks 
as indicated to achieve well-controlled BP. 
Step 4. Once BP is well-controlled, restart study treatment dose-
reduced 
(C) Symptomatic hypertension or 
recurring3 SBP 160 mmHg, or DBP 
100 mmHg, despite modification of 
antihypertensive medication(s)
Step 1. Interrupt study treatment.
Step 2. Adjust current or initiate new antihypertensive medication(s). 
Step 3. Titrate antihypertensive medication(s) during next 2 weeks 
as indicated to achieve well-controlled BP.  Referral to a specialist 
for further evaluation and follow-up is also recommended.
Step 4. Once BP is well-controlled, restart study treatment dose-
reduced. 
(D) Refractory hypertension 
unresponsive to above interventions.
Discontinue study treatment and continue follow-up per protocol.
Hypertension detected in 2 separate readings during up to 3 subsequent visits
a.
BP reading of SBP 140 mmHg and DBP 90 mmHg in 2 separate readings during up to 3 subsequent visits
b.
Persistent asymptomatic hypertension after initially successful anti-hypertensive intervention.


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REVISED TEXT:
For subjects experiencing an increase in SBP and/or DBP that is persistent and may 
be associated with the study treatment, recommendations for the clinical 
management of hypertension are described below:
Hypertension
(A)  Asymptomatic and persistent1
SBP of 140 and <160 mmHg, or DBP 
90 and <100 mmHg, or a clinically 
significant increase in DBP of 
20 mmHg (but still below 100 mmHg).
Step 1. Continue study treatment at the current dose. 
Step 2. Adjust current or initiate new antihypertensive medication(s).
Step 3. Titrate antihypertensive medication(s) during next 2 weeks 
as indicated to achieve well-controlled2 BP.  If BP is not well-
controlled within 2 weeks, consider referral to a specialist and go to 
scenario (B).
(B) Asymptomatic SBP 160 mmHg, or 
DBP 100 mmHg, or failure to achieve 
well-controlled BP within 2 weeks in 
scenario (A).
Step 1.Consider reducing or interrupting study treatment, as 
clinically indicated.
Step 2. Adjust current or initiate new antihypertensive medication(s). 
Step 3. Titrate antihypertensive medication(s) during next 2 weeks 
as indicated to achieve well-controlled BP. 
Step 4. Once BP is well-controlled2, restart study treatment dose-
reduced by one dose level
(C) Symptomatic hypertension or 
recurring3 SBP 160 mmHg, or DBP 
100 mmHg, despite modification of 
antihypertensive medication(s)
Step 1. Interrupt study treatment.
Step 2. Adjust current or initiate new antihypertensive medication(s). 
Step 3. Titrate antihypertensive medication(s) during next 2 weeks 
as indicated to achieve well-controlled BP.  Referral to a specialist 
for further evaluation and follow-up is also recommended.
Step 4. Once BP is well-controlled, restart study treatment dose-
reduced by one dose level
(D) Refractory hypertension 
unresponsive to above interventions.
Permanently discontinue study treatment and continue follow-up per 
protocol.
1.
Hypertension detected in 2 separate readings during up to 3 subsequent visits
2.
BP reading of SBP 140 mmHg and DBP 90 mmHg in 2 separate readings during up to 3 subsequent visits
3.
Persistent asymptomatic hypertension after initially successful anti-hypertensive intervention.


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Section 5.7.7 QTc Withdrawal Criteria
PREVIOUS TEXT:
QTc should be assessed at the frequency shown in Appendix 1: Time and Events Table 
for Cohort A or Appendix 2: Time and Events Table for Cohort B.
A subject that experiences a Grade 3 (QTcB ≥501 msec on at least two separate 
ECGs) or Grade 4 (QTcB≥501 or >60 msec change from baseline and Torsade de 
pointes or polymorphic ventricular tachycardia or signs/symptoms of serious 
arrhythmia) prolongation of the corrected QT1 interval will have study treatment 
with GSK1120212 withheld:
1 based on average QTc value of triplicate ECGs (confirmed via 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.
If the QTc prolongation resolves to grade 1 (450 - 480 msec) or baseline, the subject 
may be re-started on the study treatment at current dose level if the investigator and 
GSK Medical Monitor agree that the subject will benefit from further treatment.
REVISED TEXT:
QTc should be assessed at the frequency shown in Appendix 1: Time and Events Table 
for Cohort A or Appendix 2: Time and Events Table for Cohort B.
A subject who experiences a QTc prolongation1 defined as QTcB ≥501 msec or 
uncorrected QT>600 msec or QTcB>530  msec for subjects with bundle branch 
block will have study treatment with GSK1120212 withheld:
1 based on average QTc value of triplicate ECGs (confirmed via 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.
If the QTc prolongation resolves to grade 1 (450 - 480 msec) or baseline, the subject 
may be re-started on the study treatment at current dose level if the investigator and 
GSK Medical Monitor agree that the subject will benefit from further treatment.  If the 
event does not resolve or recurs, permanently discontinue study treatment.


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Section 5.7.8.1 Left Ventricular Ejection Fraction Stopping Criteria, Second 
Paragraph, Bullet #2 and Third Paragraph
PREVIOUS TEXT:
Subject who have an asymptomatic, absolute decrease of >10% in LVEF compared with 
baseline (baseline value from parent study) and the ejection fraction is below the 
institution’s LLN should have treatment with GSK1120212 withheld and a repeat 
evaluation of LVEF within 2 weeks.  

If the LVEF recovers (defined as LLN and absolute decrease 10% compared 
with baseline [baseline value from parent study]) at any time during the next 
4 weeks, after consultation and approval of the GSK Medical Monitor, the 
subject may be restarted on GSK1120212 at a reduced dose.  For such subjects, 
monitoring of LVEF will be performed 2 and 4 weeks after rechallenge, and 
every 4 weeks thereafter for 12 weeks, and then per protocol.

If repeat LVEF does not recover within 4 weeks, treatment with GSK1120212 
should be permanently discontinued.  Ejection fraction should be monitored in 
2 weeks and then 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 GSK1120212. Ejection fraction should be monitored at 
2 weeks, at 4 weeks, and then every 4 weeks for a total of 16 weeks or until resolution.  
Evaluation by a cardiologist should be considered.
REVISED TEXT
Subject who have an asymptomatic, absolute decrease of >10% in LVEF compared with 
baseline (baseline value from parent study) and the ejection fraction is below the 
institution’s LLN should have treatment with GSK1120212 withheld and a repeat 
evaluation of LVEF within 2 weeks.  

If the LVEF recovers (defined as LLN and absolute decrease 10% compared 
with baseline [baseline value from parent study]) at any time during the next 
4 weeks, after consultation and approval of the GSK Medical Monitor, the 
subject may be restarted on GSK1120212 at a reduced dose.  For such subjects, 
monitoring of LVEF will be performed 2 and 4 weeks after rechallenge, and 
every 4 weeks thereafter for 12 weeks, and then per protocol.

If repeat LVEF does not recover within 4 weeks, treatment with GSK1120212 
should be permanently discontinued and have a cardiology consult.  Ejection 
fraction should be monitored in 2 weeks and then every 4 weeks for a total of 16 
weeks or until resolution.


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Subjects with symptomatic Grade 3 (resting LVEF 39-20% or >20% absolute 
reduction from baseline) or symptomatic Grade 4 (resting LVEF<20%) left 
ventricular systolic dysfunction must discontinue treatment with GSK1120212 and have 
a cardiology consult. Ejection fraction should be monitored at 2 weeks, at 4 weeks, and 
then every 4 weeks for a total of 16 weeks or until resolution.  Symptomatic Grade 3 
and symptomatic Grade 4 left ventricular systolic dysfunctions are to be reported as 
SAEs.
Section 7.3. Contraception Requirements
PREVIOUS TEXT:
7.3.2. Male Subjects
Male subjects with a female partner of childbearing potential must have had a prior 
vasectomy or must agree to use the same method of contraception as used in the parent 
study during the rollover study and for 16 weeks after the last dose of study treatment(s).
REVISED TEXT:
None
Section 8.5.5. Pregnancy
PREVIOUS TEXT:
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 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 a 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.
REVISED TEXT
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 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 a 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.


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Section 13.1. Appendix 1: Time and Events Table Cohort A, Footnotes #14, 
#17 and #20
PREVIOUS TEXT:
Assessment/
Procedure18
Transition 
Visit1
Continuous Dosing
Treatment Period20
Final Study Visit
Every 4 
weeks17
(7 days)
Week 817
(7 days)
Every 12 
weeks17
(7 days)
Every 24 
weeks17
(7 days)
With 28 days of 
Last Dose of Study 
Treatment(s)
(7 days)19
Informed Consent2
X
Demographics 
and Parent Study 
Data
X
Physical  Exam3
X
X
X
X
Pregnancy test4
X
Vital Signs5
X
X
X
12-Lead ECG6
X
X7
X7
X
ECHO/MUGA 
scan
X
X8
X9
Clinical 
Chemistry10
X
X11
X11
X
Hematology10
X
X11
X11
X
Liver Function 
Tests10,12
X
X
X
X
Tumor Tissue 
/Skin Biopsy or 
Blood Sample for 
Biomarker 
Analysis13
O
cfDNA Sample13
O
AE Monitoring14, 15
Continuous
Review of 
Concomitant 
Medications16
Continuous
GSK1120212 
Dosing
Continuous


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Abbreviations:  O, optional
1.
All subjects transitioning from parent study will begin the rollover study based on the last treatment visit 
completed during the parent study.  All Transition Visit assessments/procedures must be completed prior to 
the first dose of study treatment(s).  Assessments/procedures may be used to fulfill the requirements of both 
the parent study and this study.  Results from the parent study should be recorded in the eCRF as transition 
values.
2.
Informed consent must be obtained prior to performing any assessments or procedures for this study and 
before treatment with GSK1120212 is to be continued.
3.
Physical examination will be completed at the Transition Visit, Week 8 and every 12 weeks thereafter while 
on treatment, and at the Final Study Visit. Height (cm) and weight (kg) will be measured only at the Transition 
Visit.
4.
Serum β–hCG pregnancy tests will be performed on female subjects of childbearing potential only at the time 
of transition from the parent study.
5.
Vital signs (BP, temperature, respiratory rate, and pulse rate) should be taken in a semi-supine position and 
after the subject has rested for at least 5 minutes prior to the reading.  Vital signs may be measured more 
frequently as clinically indicated.
6.
A single 12-Lead ECG will be performed using a standard 12-lead ECG machine.  All ECGs will be taken in a 
supine position after resting in that position for at least 10 minutes prior to testing.  QTc interval must not be 
>500 msec.
7.
12-lead ECGs will be performed every 12 weeks (at a minimum or more frequently per local practice) for the 
first 2 years of treatment (including time on parent study).  After 2 years of treatment 12-lead ECGs will be 
performed every 24 weeks for the duration of treatment.
8.
ECHO or MUGA scan should be performed every 12 weeks (at a minimum or more frequently per local 
practice).  If LVEF decreases 20 percentage points, repeat testing is required within 2 weeks.  If decline is 
sustained, the investigator, in consultation with GSK Medical Monitor, should consider withdrawal of subject 
from the study.
9.
ECHO is only required at the Final Study Visit if an abnormal finding is reported from the last ECHO or 
MUGA scan performed
10. Refer to Section 8.4.5 for complete list of clinical laboratory assessments to be performed.
11. Hematology and clinical chemistry laboratory assessments will be performed every 4 weeks (at a minimum 
or more frequently per local practice) for the first 2 years of treatment (including time on parent study).  After 
2 years hematology and clinical chemistry laboratory assessments will be performed every 12 weeks for the 
duration of treatment.
12. Liver function tests (AST, ALT, alkaline phosphatase and total bilirubin) will be performed every 4 
weeks (depending on the scheduled used in the parent study; at a minimum or more frequently per 
local practice) for the first 2 years of treatment (including time on parent study).  After 2 years liver 
function tests will be performed every 12 weeks (depending on schedule used in the parent study) for 
the duration of treatment.  Bilirubin fractionation is recommended if total bilirubin is >2 times ULN.
13. Optional tumor tissue, skin or blood sample from a lesion not required for disease assessment and/or 
optional blood sample for cfDNA may be obtained if subject has provided consent.
14. AEs/SAEs will be monitored and recorded beginning on the time of consent until 30 days after the last dose 
of GSK2118436.
15. All ongoing (unresolved) AEs at the time of the transition to this study will be recorded in the eCRF.
16. All concomitant medication(s) at the time of the transition to this study will be recorded in the eCRF.
17. The “Every 8 Weeks”, “Every 12 Weeks” or “Every 24 Weeks” columns are NOT a separate visit but instead 
a listing of assessments required to be completed every 8, 12 or 24 weeks or every second or third clinic visit 
that is recurring at 4-week intervals, respectively.
18. After a subject has been on study for a total of 2 years, including time on parent study, the frequency of 
assessments will be modified.  If more frequent assessments are needed, these should be done per local 
practice.
19. The Final Study Visit should occur within 28 days (7 days) following the last dose of study treatment(s) and 
prior to initiating any new treatment.
20. Subjects who remain on study treatment >52 weeks may have the frequency of their interim visits decreased 
with approval from the GSK Medical Monitor.


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REVISED TEXT:
Assessment/
Procedure18
Transition 
Visit1
Continuous Dosing
Treatment Period20
Final Study Visit
Every 4 
weeks17
(7 days)
Week 817
(7 days)
Every 12 
weeks17
(7 days)
Every 24 
weeks17
(7 days)
With 28 days of 
Last Dose of Study 
Treatment(s)
(7 days)19
Informed Consent2
X
Demographics 
and Parent Study 
Data
X
Physical  Exam3
X
X
X
X
Pregnancy test4
X
Vital Signs5
X
X
X
12-Lead ECG6
X
X7
X7
X
ECHO/MUGA 
scan
X
X8
X9
Clinical 
Chemistry10
X
X11
X11
X
Hematology10
X
X11
X11
X
Liver Function 
Tests10,12
X
X
X
X
Tumor Tissue 
/Skin Biopsy or 
Blood Sample for 
Biomarker 
Analysis13
O
cfDNA Sample13
O
AE Monitoring14, 15
Continuous
Review of 
Concomitant 
Medications16
Continuous
GSK1120212 
Dosing
Continuous


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Abbreviations:  O, optional
1.
All subjects transitioning from parent study will begin the rollover study based on the last treatment visit 
completed during the parent study.  All Transition Visit assessments/procedures must be completed prior to 
the first dose of study treatment(s).  Assessments/procedures may be used to fulfill the requirements of both 
the parent study and this study.  Results from the parent study should be recorded in the eCRF as transition 
values.
2.
Informed consent must be obtained prior to performing any assessments or procedures for this study and 
before treatment with GSK1120212 is to be continued.
3.
Physical examination will be completed at the Transition Visit, Week 8 and every 12 weeks thereafter while 
on treatment, and at the Final Study Visit. Height (cm) and weight (kg) will be measured only at the Transition 
Visit.
4.
Serum β–hCG pregnancy tests will be performed on female subjects of childbearing potential only at the time 
of transition from the parent study.
5.
Vital signs (BP, temperature, respiratory rate, and pulse rate) should be taken in a semi-supine position and 
after the subject has rested for at least 5 minutes prior to the reading.  Vital signs may be measured more 
frequently as clinically indicated.
6.
A single 12-Lead ECG will be performed using a standard 12-lead ECG machine.  All ECGs will be taken in a 
supine position after resting in that position for at least 10 minutes prior to testing.  QTc interval must not be 
>500 msec.
7.
12-lead ECGs will be performed every 12 weeks (at a minimum or more frequently per local practice) for the 
first 2 years of treatment (including time on parent study).  After 2 years of treatment 12-lead ECGs will be 
performed every 24 weeks for the duration of treatment.
8.
ECHO or MUGA scan should be performed every 12 weeks (at a minimum or more frequently per local 
practice).  If LVEF decreases 20 percentage points, repeat testing is required within 2 weeks.  If decline is 
sustained, the investigator, in consultation with GSK Medical Monitor, should consider withdrawal of subject 
from the study.
9.
ECHO is only required at the Final Study Visit if an abnormal finding is reported from the last ECHO or 
MUGA scan performed
10. Refer to Section 8.4.5 for complete list of clinical laboratory assessments to be performed.
11. Hematology and clinical chemistry laboratory assessments will be performed every 4 weeks (at a minimum 
or more frequently per local practice) for the first 2 years of treatment (including time on parent study).  After 
2 years hematology and clinical chemistry laboratory assessments will be performed every 12 weeks for the 
duration of treatment.
12. Liver function tests (AST, ALT, alkaline phosphatase and total bilirubin) will be performed every 4 
weeks (depending on the scheduled used in the parent study; at a minimum or more frequently per 
local practice) for the first 2 years of treatment (including time on parent study).  After 2 years liver 
function tests will be performed every 12 weeks (depending on schedule used in the parent study) for 
the duration of treatment.  Bilirubin fractionation is recommended if total bilirubin is >2 times ULN.
13. Optional tumor tissue, skin or blood sample from a lesion not required for disease assessment and/or 
optional blood sample for cfDNA may be obtained if subject has provided consent.
14. AEs/SAEs will be monitored and recorded beginning on the time of consent until 30 days after the last dose 
of GSK1120212.
15. All ongoing (unresolved) AEs at the time of the transition to this study will be recorded in the eCRF.
16. All concomitant medication(s) at the time of the transition to this study will be recorded in the eCRF.
17. The “‘Week 8”, “Every 12 Weeks” or “Every 24 Weeks” columns are NOT a separate visit but instead a listing 
of assessments required to be completed at week 8, and every 12 or 24 weeks or every second or third 
clinic visit that is recurring at 4-week intervals, respectively.
18. After a subject has been on study for a total of 2 years, including time on parent study, the frequency of 
assessments will be modified.  If more frequent assessments are needed, these should be done per local 
practice.
19. The Final Study Visit should occur within 28 days (7 days) following the last dose of study treatment(s) and 
prior to initiating any new treatment.
20. Subjects who have tolerated therapy well with limited toxicities and remain on study treatment >52 
weeks may have the frequency of their interim visits decreased with approval and direction from the GSK 
Medical Monitor.


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Section 13.2 Appendix 2: Time and Events Table Cohort B, Footnote #20
PREVIOUS TEXT:
Assessment/
Procedure18
Transition 
Visit1
Continuous Dosing 
Treatment Period20
Final Study Visit
Every 3 or 4 
weeks17
(7 days)
Every 9 or 
12 weeks17
(7 days)
Every 12 
weeks17
(7 days)
Every 24 
weeks17
(7 days)
With 28 days of 
Last Dose of Study 
Treatment(s)
(7 days)19
Informed Consent2
X
Demographics 
and Parent Study 
Data
X
Physical  Exam3
X
X
X
Pregnancy test4
X
Vital Signs5
X
X
X
12-Lead ECG6
X
X7
X7
X
ECHO/MUGA 
scan
X
X8
X9
Clinical 
Chemistry10
X
X11
X11
X
Hematology10
X
X11
X11
X
Liver Function 
Tests10,12
X
X
X
X
Tumor Tissue 
/Skin Biopsy or 
Blood Sample for 
Biomarker 
Analysis13
O
cfDNA Sample13
O
AE Monitoring14, 15
Continuous
Review of 
Concomitant 
Medications16
Continuous
GSK1120212 
Dosing
Continuous


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Abbreviations:  O, optional
1.
All subjects transitioning from parent study will begin the rollover study based on the last treatment visit completed 
during the parent study.  All Transition Visit assessments/procedures must be completed prior to the first dose of 
study treatment(s).  Assessments/procedures may be used to fulfill the requirements of both the parent study and 
this study.  Results from the parent study should be recorded in the eCRF as transition values.
2.
Informed consent must be obtained prior to performing any assessments or procedures for this study and before 
treatment with GSK1120212 is to be continued.
3.
Height (cm) and weight (kg) will be measured only at the Transition Visit.
4.
Serum β–hCG pregnancy tests will be performed on female subjects of childbearing potential only at the time of 
transition from the parent study.
5.
Vital signs (BP, temperature, respiratory rate, and pulse rate) should be taken in a semi-supine position and after 
the subject has rested for at least 5 minutes prior to the reading.  Vital signs may be measured more frequently as 
clinically indicated.
6.
A single 12-Lead ECG will be performed using a standard 12-lead ECG machine.  All ECGs will be taken in a 
supine position after resting in that position for at least 10 minutes prior to testing.  QTc interval must not be 
>500 msec.
7.
12-lead ECGs will be performed every 9 or 12 weeks (depending on the schedule used in the parent study; at a 
minimum or more frequently per local practice) for the first 2 years of treatment (including time on parent study).  
After 2 years of treatment 12-lead ECGs will be performed every 24 weeks for the duration of treatment.
8.
ECHO or MUGA scan should be performed every 12 weeks (at a minimum or more frequently per local practice).  
If LVEF decreases 20 percentage points, repeat testing is required within 2 weeks.  If decline is sustained, the 
investigator, in consultation with GSK Medical Monitor, should consider withdrawal of subject from the study.
9.
ECHO is only required at the Final Study Visit if an abnormal finding is reported from the last ECHO or MUGA 
scan performed
10. Refer to Section 8.4.5 for complete list of clinical laboratory assessments to be performed.
11. Hematology and clinical chemistry laboratory assessments will be performed every 3 or 4 weeks (depending on 
the scheduled used in the parent study; at a minimum or more frequently per local practice) for the first 2 years of 
treatment (including time on parent study).  After 2 years hematology and clinical chemistry laboratory 
assessments will be performed every 9 or 12 weeks (depending on schedule used in the parent study) for the 
duration of treatment.
12. Liver function tests (AST, ALT, alkaline phosphatase and total bilirubin) will be performed every 3 or 4 
weeks (depending on the scheduled used in the parent study; at a minimum or more frequently per local 
practice) for the first 2 years of treatment (including time on parent study).  After 2 years liver function 
tests will be performed every 9 or 12 weeks (depending on schedule used in the parent study) for the 
duration of treatment.  Bilirubin fractionation is recommended if total bilirubin is >2 times ULN.
13. Optional tumor tissue, skin or blood sample from a lesion not required for disease assessment and/or optional 
blood sample for cfDNA may be obtained if subject has provided consent.  
14. AEs/SAEs will be monitored and recorded beginning on the time of consent until 30 days after the last dose of 
GSK1120212.
15. All ongoing (unresolved) AEs at the time of the transition to this study will be recorded in the eCRF.
16. All concomitant medication(s) at the time of the transition to this study will be recorded in the eCRF.
17. The “Every 9 Weeks”, “Every 12 Weeks” or “Every 24 Weeks” columns are NOT a separate visit but instead a 
listing of assessments required to be completed every 9, 12 or 24 weeks or every second or third clinic visit that is 
recurring at 3 or 4-week intervals, depending on the schedule used in the parent study.
18. After a subject has been on study for a total of 2 years, including time on parent study, the frequency of 
assessments will be modified.  If more frequent assessments are needed, these should be done per local 
practice.
19. The Final Study Visit should occur within 28 days (7 days) following the last dose of study treatment(s) and prior 
to initiating any new treatment.
20.
Subjects who remain on study treatment >52 weeks may have the frequency of their interim visits decreased with 
approval from the GSK Medical Monitor.


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REVISED TEXT
Assessment/
Procedure18
Transition 
Visit1
Continuous Dosing 
Treatment Period20
Final Study Visit
Every 3 or 4 
weeks17
(7 days)
Every 9 or 
12 weeks17
(7 days)
Every 12 
weeks17
(7 days)
Every 24 
weeks17
(7 days)
With 28 days of 
Last Dose of Study 
Treatment(s)
(7 days)19
Informed Consent2
X
Demographics 
and Parent Study 
Data
X
Physical  Exam3
X
X
X
Pregnancy test4
X
Vital Signs5
X
X
X
12-Lead ECG6
X
X7
X7
X
ECHO/MUGA 
scan
X
X8
X9
Clinical 
Chemistry10
X
X11
X11
X
Hematology10
X
X11
X11
X
Liver Function 
Tests10,12
X
X
X
X
Tumor Tissue 
/Skin Biopsy or 
Blood Sample for 
Biomarker 
Analysis13
O
cfDNA Sample13
O
AE Monitoring14, 15
Continuous
Review of 
Concomitant 
Medications16
Continuous
GSK1120212 
Dosing
Continuous


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Abbreviations:  O, optional
1.
All subjects transitioning from parent study will begin the rollover study based on the last treatment visit completed 
during the parent study.  All Transition Visit assessments/procedures must be completed prior to the first dose of 
study treatment(s).  Assessments/procedures may be used to fulfill the requirements of both the parent study and 
this study.  Results from the parent study should be recorded in the eCRF as transition values.
2.
Informed consent must be obtained prior to performing any assessments or procedures for this study and before 
treatment with GSK1120212 is to be continued.
3.
Height (cm) and weight (kg) will be measured only at the Transition Visit.
4.
Serum β–hCG pregnancy tests will be performed on female subjects of childbearing potential only at the time of 
transition from the parent study.
5.
Vital signs (BP, temperature, respiratory rate, and pulse rate) should be taken in a semi-supine position and after 
the subject has rested for at least 5 minutes prior to the reading.  Vital signs may be measured more frequently as 
clinically indicated.
6.
A single 12-Lead ECG will be performed using a standard 12-lead ECG machine.  All ECGs will be taken in a 
supine position after resting in that position for at least 10 minutes prior to testing.  QTc interval must not be 
>500 msec.
7.
12-lead ECGs will be performed every 9 or 12 weeks (depending on the schedule used in the parent study; at a 
minimum or more frequently per local practice) for the first 2 years of treatment (including time on parent study).  
After 2 years of treatment 12-lead ECGs will be performed every 24 weeks for the duration of treatment.
8.
ECHO or MUGA scan should be performed every 12 weeks (at a minimum or more frequently per local practice).  
If LVEF decreases 20 percentage points, repeat testing is required within 2 weeks.  If decline is sustained, the 
investigator, in consultation with GSK Medical Monitor, should consider withdrawal of subject from the study.
9.
ECHO is only required at the Final Study Visit if an abnormal finding is reported from the last ECHO or MUGA 
scan performed
10. Refer to Section 8.4.5 for complete list of clinical laboratory assessments to be performed.
11. Hematology and clinical chemistry laboratory assessments will be performed every 3 or 4 weeks (depending on 
the scheduled used in the parent study; at a minimum or more frequently per local practice) for the first 2 years of 
treatment (including time on parent study).  After 2 years hematology and clinical chemistry laboratory 
assessments will be performed every 9 or 12 weeks (depending on schedule used in the parent study) for the 
duration of treatment.
12. Liver function tests (AST, ALT, alkaline phosphatase and total bilirubin) will be performed every 3 or 4 
weeks (depending on the scheduled used in the parent study; at a minimum or more frequently per local 
practice) for the first 2 years of treatment (including time on parent study).  After 2 years liver function 
tests will be performed every 9 or 12 weeks (depending on schedule used in the parent study) for the 
duration of treatment.  Bilirubin fractionation is recommended if total bilirubin is >2 times ULN.
13. Optional tumor tissue, skin or blood sample from a lesion not required for disease assessment and/or optional 
blood sample for cfDNA may be obtained if subject has provided consent.  
14. AEs/SAEs will be monitored and recorded beginning on the time of consent until 30 days after the last dose of 
GSK1120212.
15. All ongoing (unresolved) AEs at the time of the transition to this study will be recorded in the eCRF.
16. All concomitant medication(s) at the time of the transition to this study will be recorded in the eCRF.
17. The “Every 9 Weeks”, “Every 12 Weeks” or “Every 24 Weeks” columns are NOT a separate visit but instead a 
listing of assessments required to be completed every 9, 12 or 24 weeks or every second or third clinic visit that is 
recurring at 3 or 4-week intervals, depending on the schedule used in the parent study.
18. After a subject has been on study for a total of 2 years, including time on parent study, the frequency of 
assessments will be modified.  If more frequent assessments are needed, these should be done per local 
practice.
19. The Final Study Visit should occur within 28 days (7 days) following the last dose of study treatment(s) and prior 
to initiating any new treatment.
20.
Subjects who have tolerated therapy well with limited toxicities and remain on study treatment >52 weeks 
may have the frequency of their interim visits decreased with approval and direction from the GSK Medical 
Monitor.


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AMENDMENT 5
Where the Amendment Applies
Amendment 05 applies to all sites that are or will be conducting this study. 
Summary of Amendment Changes with Rationale
In this amendment, actions regarding study treatment, GSK1120212 (Trametinib), should 
the subject experience a Grade 3 or Grade 4 prolongation of the QTc interval was 
provided in greater detail at the request of the FDA.  The time span for females to use 
contraception was revised; prohibited medications and non-drug therapies were revised to 
reflect recent changes in the standard language. Additionally, the Exclusion Criteria were 
revised to be more in line with those of the subject’s parent study and less restrictive for 
eligible subjects who are transitioning to the MEK114375 study.  Trametinib, the 
commercial name of GSK1120212, was added to the subject line on the title page.
Title Page
PREVIOUS TEXT:
GSK1120212, MEK inhibitor, solid tumors, leukemia, safety, cancer
REVISED TEXT
GSK1120212 (Trametinib), MEK inhibitor, solid tumors, leukemia, safety, cancer
Section 4.1.2 Inclusion Criteria, Bullet #7
PREVIOUS TEXT:
7.   Female subjects of childbearing potential, as defined in the parent study, must be 
willing to continue practicing the same acceptable method of contraception as used in the 
parent study during the rollover study and for at least 30 days after the last dose of 
GSK1120212.
REVISED TEXT:
7.   Female subjects of childbearing potential, as defined in the parent study, must be 
willing to continue practicing the same acceptable method of contraception as used in the 
parent study during the rollover study and for at least 4 months after the last dose of 
GSK1120212.


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Section 4.1.3 Exclusion Criteria
PREVIOUS TEXT:
Subjects meeting any of the following criteria must not be enrolled in this study:
1. Permanent discontinuation of GSK1120212 in the parent study due to toxicity or 
disease progression.
2. Local access to commercially available GSK1120212.
3. Current use of a prohibitive medication(s) as listed in Section 6.2.

NOTE: Use of anticoagulants such as warfarin is permitted; however, the 
international normalization ratio (INR) must be monitored in accordance 
with local institutional practice.
4. Any unresolved toxicity that meets the study treatment discontinuation or study 
withdrawal criteria from the parent study at the time of transition to this study.
5. Evidence of severe or uncontrolled systemic diseases (e.g. unstable, or 
uncompensated respiratory, hepatic, renal or metabolic disease)
6. History or evidence of cardiovascular risk including any of the following: 

Bazett-corrected QT (QTcB) interval 480 msec at the time of transition 
to this study

History or evidence of current clinically significant uncontrolled 
arrhythmias
i. Exception: Subjects with controlled atrial fibrillation for >30 
days prior to transition to this study are eligible.

History of acute coronary syndromes (including myocardial infarction 
and unstable angina), coronary angioplasty, or stenting within 6 
months prior to transition to this study

History or evidence of current Class II congestive heart failure as 
defined by the New York Heart Association (NYHA; Appendix 3)

Treatment refractory hypertension defined as a BP reading of systolic 
>140 mmHg and/or diastolic >90 mmHg which cannot be controlled 
by antihypertensive therapy

Subjects with intra-cardiac defibrillator or permanent pacemaker

Cardiac metastases
7. Left ventricular ejection fraction (LVEF) < institutional lower limit of normal 
(LLN) by ECHO (preferred) or MUGA scan at the time of transition to this study.
8. Symptomatic or untreated leptomeningeal or brain metastases or spinal cord 
compression at the time of transition to this study.

NOTE: Subjects are not permitted to receive enzyme-inducing anti-
epileptic (EIAEDs).


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9. Nursing female.
10. Any serious and/or unstable pre-existing medical, psychiatric disorder or other 
conditions at the time of transition to this study that could interfere with subject’s 
safety, obtaining informed consent or compliance to the study procedures, in the
opinion of the investigator or GSK Medical Monitor.
REVISED TEXT:
Subjects meeting any of the following criteria must not be enrolled in this study:
1. Permanent discontinuation of GSK1120212 in the parent study due to toxicity or 
disease progression.
2. Local access to commercially available GSK1120212.
3. Current use of a prohibitive medication(s) as listed in Section 6.2.

NOTE: Use of anticoagulants such as warfarin is permitted; however, the 
international normalization ratio (INR) must be monitored in accordance 
with local institutional practice.
4. Any unresolved toxicity that meets the study treatment discontinuation or study 
withdrawal criteria from the parent study at the time of transition to this study.
5. Bazett-corrected QT (QTcB) interval 501 msec at the time of transition to this 
study
6. Left ventricular ejection fraction (LVEF) < institutional lower limit of normal 
(LLN) by ECHO (preferred) or MUGA scan at the time of transition to this study.
7. Nursing female.
8. Any serious and/or unstable pre-existing medical, psychiatric disorder or other 
conditions at the time of transition to this study that could interfere with subject’s 
safety, obtaining informed consent or compliance to the study procedures, in the 
opinion of the investigator or GSK Medical Monitor.
Section 5.7.7 QTc Withdrawal Criteria
PREVIOUS TEXT:
QTc should be assessed at the frequency shown in Appendix 1: Time and Events Table 
for Cohort A or Appendix 2: Time and Events Table for Cohort B.
A subject that meets the QTc1 criteria below will have study treatment with GSK1120212 
withheld:

QTcB >530 msec, or uncorrected QT >600 msec
1 based on average QTc value of triplicate ECGs (confirmed via 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.


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If the QTc prolongation resolves to <500 msec, 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.
REVISED TEXT:
QTc should be assessed at the frequency shown in Appendix 1: Time and Events Table 
for Cohort A or Appendix 2: Time and Events Table for Cohort B.
A subject that experiences a Grade 3 (QTcB ≥501 msec on at least two separate 
ECGs) or Grade 4 (QTcB ≥501 or >60 msec change from baseline and Torsade de 
pointes or polymorphic ventricular tachycardia or signs/symptoms of serious 
arrhythmia) prolongation of the corrected QT1 interval will have study treatment 
with GSK1120212 withheld:
1 based on average QTc value of triplicate ECGs (confirmed via 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.
If the QTc prolongation resolves to grade 1 (450 – 480 msec) or baseline, the subject 
may be re-started on the study treatment at current dose level, if the investigator and 
GSK Medical Monitor agree that the subject will benefit from further treatment.
Section 6.2 Prohibited Medications and Non-Drug Therapies, 2nd Paragraph
PREVIOUS TEXT:
The following medications or non-drug therapies are prohibited while participating in this 
study: 

Other anti-cancer agents (e.g., chemotherapy, immunotherapy, biologic therapy, 
and/or hormone therapy other than for replacement)

Other non-drug anti-cancer therapy (e.g. radiation therapy, surgery, and/or 
tumor embolization)
NOTE: Subjects may receive palliative radiation treatment during this study.  The 
study treatment must be held for at least 2 days prior to the start of palliative 
radiation treatment and for at least 2 days after palliative treatment or longer 
(depending upon the extent of palliative treatment and recovery from any acute 
toxicities to Grade 1).

Enzyme-inducing anti-epileptic drugs (EIAEDs)

Herbal products include, but are not limited to:

St. John’s Wort

kava

ephedra (ma huang)

gingko biloba


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
dehydroepiandrosterone (DHEA)

yohimbe

saw palmetto 

ginseng

marijuana
REVISED TEXT:
The following medications or non-drug therapies are prohibited while participating in this 
study: 

Other anti-cancer agents (e.g., chemotherapy, immunotherapy, biologic therapy, 
and/or hormone therapy other than for replacement)

Other non-drug anti-cancer therapy (e.g. radiation therapy, surgery, and/or 
tumor embolization)
NOTE: Subjects may receive palliative radiation treatment during this study.  The 
study treatment must be held for at least 2 days prior to the start of palliative 
radiation treatment and for at least 2 days after palliative treatment or longer 
(depending upon the extent of palliative treatment and recovery from any acute 
toxicities to Grade 1).

Herbal products include, but are not limited to:

marijuana
Section 7.3 Contraceptive Requirements: 7.3.1 Female Subjects, 2nd
Paragraph & Bullet #3 of the 3rd Paragraph
PREVIOUS TEXT:
Female subjects of childbearing potential, as defined in the parent study and determined 
not to be post-menopausal, must continue to use the same adequate method of 
contraception as used in the parent study during the rollover study and for 30 days* 
following the last dose of study treatment(s).
GSK acceptable contraceptive methods, when used consistently and in accordance with 
both the product label and the instructions of the physician, are as follows:

An intrauterine device with a documented failure rate of <1% per year

Vasectomized partner who is sterile prior to the female subject’s entry in the 
study and is the sole sexual partner for that female.

Complete abstinence from sexual intercourse for 14 days prior to the first dose 
of study treatment, through the dosing period, and for at least 30 days* after the 
last dose of study treatment


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
Double-barrier contraception: condom and occlusive cap (diaphragm or 
cervical/vault caps) with a vaginal spermicidal agent 
(foam/gel/cream/suppository).
REVISED TEXT:
Female subjects of childbearing potential, as defined in the parent study and determined 
not to be post-menopausal, must continue to use the same adequate method of 
contraception as used in the parent study during the rollover study and for 4 months* 
following the last dose of study treatment(s).
GSK acceptable contraceptive methods, when used consistently and in accordance with 
both the product label and the instructions of the physician, are as follows:

An intrauterine device with a documented failure rate of <1% per year

Vasectomized partner who is sterile prior to the female subject’s entry in the 
study and is the sole sexual partner for that female.

Complete abstinence from sexual intercourse for 14 days prior to the first dose 
of study treatment, through the dosing period, and for at least 4 months* after 
the last dose of study treatment

Double-barrier contraception: condom and occlusive cap (diaphragm or 
cervical/vault caps) with a vaginal spermicidal agent 
(foam/gel/cream/suppository).
Section 12:  References
PREVIOUS TEXT:
GlaxoSmithKline Document Number HM2009/00151/02. Clinical Investigator Brochure 
for GSK1120212, 3rd edition. 23-Jun-2011
REVISED TEXT:
GlaxoSmithKline Document Number HM2009/00151/02. Clinical Investigator Brochure 
for GSK1120212, 3rd edition. 23-Jun-2011. 4th edition. 05-Sep-2012.


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Section 13.1 Appendix 1: Time and Events Table for Cohort A
PREVIOUS TEXT:
Assessment/
Procedure18
Transition 
Visit1
Continuous Dosing
Treatment Period20
Final Study Visit
Every 4 
weeks17
(7 days)
Week 817
(7 days)
Every 12 
weeks17
(7 days)
Every 24 
weeks17
(7 days)
With 28 days of 
Last Dose of Study 
Treatment(s)
(7 days)19
Informed Consent2
X
Demographics 
and Parent Study 
Data
X
Physical  Exam3
X
X
X
X
Pregnancy test4
X
Vital Signs5
X
X
X
12-Lead ECG6
X
X7
X7
X
ECHO/MUGA 
scan
X
X8
X8
X9
Clinical 
Chemistry10
X
X11
X11
X
Hematology10
X
X11
X11
X
Liver Function 
Tests10,12
X
X
X
X
Tumor Tissue 
/Skin Biopsy or 
Blood Sample for 
Biomarker 
Analysis13
O
cfDNA Sample13
O
AE Monitoring14, 15
Continuous
Review of 
Concomitant 
Medications16
Continuous
GSK1120212 
Dosing
Continuous


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Abbreviations:  O, optional
1.
All subjects transitioning from parent study will begin the rollover study based on the last treatment visit 
completed during the parent study.  All Transition Visit assessments/procedures must be completed prior to 
the first dose of study treatment(s).  Assessments/procedures may be used to fulfill the requirements of both 
the parent study and this study.  Results from the parent study should be recorded in the eCRF as transition 
values.
2.
Informed consent must be obtained prior to performing any assessments or procedures for this study and 
before treatment with GSK1120212 is to be continued.
3.
Physical examination will be completed at the Transition Visit, Week 8 and every 12 weeks thereafter while 
on treatment, and at the Final Study Visit. Height (cm) and weight (kg) will be measured only at the Transition 
Visit.
4.
Serum β–hCG pregnancy tests will be performed on female subjects of childbearing potential only at the time 
of transition from the parent study.
5.
Vital signs (BP, temperature, respiratory rate, and pulse rate) should be taken in a semi-supine position and 
after the subject has rested for at least 5 minutes prior to the reading.  Vital signs may be measured more 
frequently as clinically indicated.
6.
A single 12-Lead ECG will be performed using a standard 12-lead ECG machine.  All ECGs will be taken in a 
supine position after resting in that position for at least 10 minutes prior to testing.  QTc interval must not be 
>480 msec.
7.
12-lead ECGs will be performed every 12 weeks (at a minimum or more frequently per local practice) for the 
first 2 years of treatment (including time on parent study).  After 2 years of treatment 12-lead ECGs will be 
performed every 24 weeks for the duration of treatment.
8.
ECHO or MUGA scan should first be performed at Week 8 and then every 12 weeks (at a minimum or more 
frequently per local practice).  If LVEF decreases 20 percentage points, repeat testing is required within 
2 weeks.  If decline is sustained, the investigator, in consultation with GSK Medical Monitor, should consider 
withdrawal of subject from the study.
9.
ECHO is only required at the Final Study Visit if an abnormal finding is reported from the last ECHO or 
MUGA scan performed
10. Refer to Section 8.4.5 for complete list of clinical laboratory assessments to be performed.
11. Hematology and clinical chemistry laboratory assessments will be performed every 4 weeks (at a minimum 
or more frequently per local practice) for the first 2 years of treatment (including time on parent study).  After 
2 years hematology and clinical chemistry laboratory assessments will be performed every 12 weeks for the 
duration of treatment.
12. Liver function tests (AST, ALT, alkaline phosphatase and total bilirubin) will be performed every 4 
weeks (depending on the scheduled used in the parent study; at a minimum or more frequently per 
local practice) for the first 2 years of treatment (including time on parent study).  After 2 years liver 
function tests will be performed every 12 weeks (depending on schedule used in the parent study) for 
the duration of treatment.  Bilirubin fractionation is recommended if total bilirubin is >2 times ULN.
13. Optional tumor tissue, skin or blood sample from a lesion not required for disease assessment and/or 
optional blood sample for cfDNA may be obtained if subject has provided consent.
14. AEs/SAEs will be monitored and recorded beginning on the time of consent until 30 days after the last dose 
of GSK2118436.
15. All ongoing (unresolved) AEs at the time of the transition to this study will be recorded in the eCRF.
16. All concomitant medication(s) at the time of the transition to this study will be recorded in the eCRF.
17. The “Every 8 Weeks”, “Every 12 Weeks” or “Every 24 Weeks” columns are NOT a separate visit but instead 
a listing of assessments required to be completed every 8, 12 or 24 weeks or every second or third clinic visit 
that is recurring at 4-week intervals, respectively.
18. After a subject has been on study for a total of 2 years, including time on parent study, the frequency of 
assessments will be modified.  If more frequent assessments are needed, these should be done per local 
practice.
19. The Final Study Visit should occur within 28 days (7 days) following the last dose of study treatment(s) and 
prior to initiating any new treatment.
20. Subjects who remain on study treatment >52 weeks may have the frequency of their interim visits decreased
with approval from the GSK Medical Monitor.


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REVISED TEST:
Assessment/
Procedure18
Transition 
Visit1
Continuous Dosing
Treatment Period20
Final Study Visit
Every 4 
weeks17
(7 days)
Week 817
(7 days)
Every 12 
weeks17
(7 days)
Every 24 
weeks17
(7 days)
With 28 days of 
Last Dose of Study 
Treatment(s)
(7 days)19
Informed Consent2
X
Demographics 
and Parent Study 
Data
X
Physical  Exam3
X
X
X
X
Pregnancy test4
X
Vital Signs5
X
X
X
12-Lead ECG6
X
X7
X7
X
ECHO/MUGA 
scan
X
X8
X9
Clinical 
Chemistry10
X
X11
X11
X
Hematology10
X
X11
X11
X
Liver Function 
Tests10,12
X
X
X
X
Tumor Tissue 
/Skin Biopsy or 
Blood Sample for 
Biomarker 
Analysis13
O
cfDNA Sample13
O
AE Monitoring14, 15
Continuous
Review of 
Concomitant 
Medications16
Continuous
GSK1120212 
Dosing
Continuous


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Abbreviations:  O, optional
1.
All subjects transitioning from parent study will begin the rollover study based on the last treatment visit 
completed during the parent study.  All Transition Visit assessments/procedures must be completed prior to 
the first dose of study treatment(s).  Assessments/procedures may be used to fulfill the requirements of both 
the parent study and this study.  Results from the parent study should be recorded in the eCRF as transition 
values.
2.
Informed consent must be obtained prior to performing any assessments or procedures for this study and 
before treatment with GSK1120212 is to be continued.
3.
Physical examination will be completed at the Transition Visit, Week 8 and every 12 weeks thereafter while 
on treatment, and at the Final Study Visit. Height (cm) and weight (kg) will be measured only at the Transition 
Visit.
4.
Serum β–hCG pregnancy tests will be performed on female subjects of childbearing potential only at the time 
of transition from the parent study.
5.
Vital signs (BP, temperature, respiratory rate, and pulse rate) should be taken in a semi-supine position and 
after the subject has rested for at least 5 minutes prior to the reading.  Vital signs may be measured more 
frequently as clinically indicated.
6.
A single 12-Lead ECG will be performed using a standard 12-lead ECG machine.  All ECGs will be taken in a 
supine position after resting in that position for at least 10 minutes prior to testing.  QTc interval must not be 
>500 msec.
7.
12-lead ECGs will be performed every 12 weeks (at a minimum or more frequently per local practice) for the 
first 2 years of treatment (including time on parent study).  After 2 years of treatment 12-lead ECGs will be 
performed every 24 weeks for the duration of treatment.
8.
ECHO or MUGA scan should be performed every 12 weeks (at a minimum or more frequently per local 
practice).  If LVEF decreases 20 percentage points, repeat testing is required within 2 weeks.  If decline is 
sustained, the investigator, in consultation with GSK Medical Monitor, should consider withdrawal of subject 
from the study.
9.
ECHO is only required at the Final Study Visit if an abnormal finding is reported from the last ECHO or 
MUGA scan performed
10. Refer to Section 8.4.5 for complete list of clinical laboratory assessments to be performed.
11. Hematology and clinical chemistry laboratory assessments will be performed every 4 weeks (at a minimum 
or more frequently per local practice) for the first 2 years of treatment (including time on parent study).  After 
2 years hematology and clinical chemistry laboratory assessments will be performed every 12 weeks for the 
duration of treatment.
12. Liver function tests (AST, ALT, alkaline phosphatase and total bilirubin) will be performed every 4 
weeks (depending on the scheduled used in the parent study; at a minimum or more frequently per 
local practice) for the first 2 years of treatment (including time on parent study).  After 2 years liver 
function tests will be performed every 12 weeks (depending on schedule used in the parent study) for 
the duration of treatment.  Bilirubin fractionation is recommended if total bilirubin is >2 times ULN.
13. Optional tumor tissue, skin or blood sample from a lesion not required for disease assessment and/or 
optional blood sample for cfDNA may be obtained if subject has provided consent.
14. AEs/SAEs will be monitored and recorded beginning on the time of consent until 30 days after the last dose 
of GSK2118436.
15. All ongoing (unresolved) AEs at the time of the transition to this study will be recorded in the eCRF.
16. All concomitant medication(s) at the time of the transition to this study will be recorded in the eCRF.
17. The “Every 8 Weeks”, “Every 12 Weeks” or “Every 24 Weeks” columns are NOT a separate visit but instead 
a listing of assessments required to be completed every 8, 12 or 24 weeks or every second or third clinic visit 
that is recurring at 4-week intervals, respectively.
18. After a subject has been on study for a total of 2 years, including time on parent study, the frequency of 
assessments will be modified.  If more frequent assessments are needed, these should be done per local 
practice.
19. The Final Study Visit should occur within 28 days (7 days) following the last dose of study treatment(s) and 
prior to initiating any new treatment.
20. Subjects who remain on study treatment >52 weeks may have the frequency of their interim visits decreased 
with approval from the GSK Medical Monitor.


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Section 13.2 Appendix 2: Time and Events Table for Cohort B, Footnote #6
PREVIOUS TEXT:
6.
A single 12-Lead ECG will be performed using a standard 12-lead ECG machine.  All ECGs will be taken in a 
supine position after resting in that position for at least 10 minutes prior to testing.  QTc interval must not be 
>480 msec.
REVISED TEXT:
6.  A single 12-Lead ECG will be performed using a standard 12-lead ECG machine.  All ECGs will be taken in a 
supine position after resting in that position for at least 10 minutes prior to testing.  QTc interval must not be 
>500 msec.


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AMENDMENT 4
Where the Amendment Applies
Amendment 04 applies to all sites located in the UK that are or will be conducting this 
study. 
Summary of Amendment Changes with Rationale
 
 
 
 
 
List of Specific Changes
Abbreviations
Added abbreviations for the United Kingdom (UK), Medicines and Healthcare 
products Regulatory Agency (MHRA) and Marketing Application Authorization 
(MAA).
Study Design, page 14
PREVIOUS TEXT
This Phase II, multicenter, non-randomized, open-label, rollover study is designed to 
provide continued access to GSK1120212 to subjects with solid tumors or leukemia who 
have previously participated in a GSK1120212 study (parent study) and who are 
clinically benefitting from continued treatment and have an acceptable safety profile with 
GSK1120212.  Subjects will be enrolled into the appropriate cohort based upon the 
treatment received in their parent study.  Enrollment into this study will be dependent 
upon the site’s agreement to participate in this study.  It is estimated that approximately 
250 subjects will be enrolled in this study. Subjects may continue treatment in the 
rollover study until no longer clinically benefitting, unacceptable toxicity, withdrawal of 
consent, or commercial supply of GSK1120212 becomes available to the subject.
REVISED TEXT
This Phase II, multicenter, non-randomized, open-label, rollover study is designed to 
provide continued access to GSK1120212 to subjects with solid tumors or leukemia who 
have previously participated in a GSK1120212 study (parent study) and who are 
clinically benefitting from continued treatment and have an acceptable safety profile with 
GSK1120212.  Subjects will be enrolled into the appropriate cohort based upon the 
treatment received in their parent study.  Enrollment into this study will be dependent 


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upon the site’s agreement to participate in this study.  It is estimated that approximately 
250 subjects will be enrolled in this study. Subjects may continue treatment in the 
rollover study until no longer clinically benefitting, unacceptable toxicity, withdrawal of 
consent, or have access to local commercial supply of GSK1120212 becomes available 
to the subject..
Section 3 Study Design, paragraph 7
PREVIOUS TEXT
Subjects may continue treatment in this rollover study until lack of clinical benefit,
unacceptable toxicity, withdrawal of consent, or commercial supply of GSK1120212 
becomes available to the subject.
REVISED TEXT
Subjects may continue treatment in this rollover study until lack of clinical benefit,
unacceptable toxicity, withdrawal of consent, or have access to local commercial supply 
of GSK1120212 becomes available to the subject.
Section 5.7.7.1 French and the United Kingdom Specific QTc Stopping 
Criteria
PREVIOUS TEXT
Section 5.7.7.1 French Specific QTc Stopping Criteria
In line with local requirements, a subject in France that meets the QTc1 criteria below will 
have study treatment withheld:
QTcB >500 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 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.
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.
REVISED TEXT
Section 5.7.7.1 French and United Kingdom Specific QTc Stopping Criteria
In line with local requirements, a subject in France or the United Kingdom that meets 
the QTc1 criteria below will have study treatment withheld:
QTcB >500 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 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.


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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.
Section 13.5 Appendix 5 Country Specific Requirements
PREVIOUS TEXT
France:  French specific QTc Stopping Criteria has been added to Section 5.7.7.1.
REVISED TEXT
France and the United Kingdom:  French and United Kingdom specific QTc Stopping 
Criteria has been added to Section 5.7.7.1.
Section 13.5 Appendix 5 Country Specific Requirements
PREVIOUS TEXT
None
REVISED TEXT
 
 
 
 
 
 
  
 
 


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AMENDMENT 3
Where the Amendment Applies
This amendment applies to all site and countries.
Summary of Amendment Changes with Rationale
In this amendment, new hypertension guidelines were added based on recent reports of 
hypertensive events in subjects receiving GSK1120212.  In addition, the exclusion 
criteria based on cardiovascular risk was expanded to include additional criteria based 
upon recent cardiac events reported in an ongoing MEK study.  The protocol section 
providing background information on GSK1120212 was also revised to remove text that 
does not correctly summarize the mechanism of action noted preclinically; additional text 
was inserted to provide a more accurate description of the specificity of GSK1120212.  
Other changes were made to correct inconsistencies between sections regarding 
administration of GSK1120212 and the need to perform an ECHO or MUGA at the final 
study visit outlined in the study assessments section and the Time and Events Tables.
List of Specific Changes
Abbreviations
Added abbreviations for diastolic blood pressure (DBP) and systolic blood pressure 
(SBP).
Protocol Summary – Rationale
PREVIOUS TEXT
GSK1120212 is a potent and highly selective inhibitor of MEK kinase activity.  This 
multicenter, non-randomized, open-label rollover study will provide continued access to 
GSK1120212 to subjects with solid tumors or leukemia who have previously participated 
in a GSK1120212 study and who are clinically benefitting from continued treatment and 
have an acceptable safety profile with GSK1120212.
REVISED TEXT
GSK1120212 is a potent, reversible and highly selective inhibitor of MEK1/MEK2 
activation and kinase activity.  This multicenter, non-randomized, open-label rollover 
study will provide continued access to GSK1120212 to subjects with solid tumors or 
leukemia who have previously participated in a GSK1120212 study and who are 
clinically benefitting from continued treatment and have an acceptable safety profile with 
GSK1120212.


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Section 1.1 Background, Paragraph 2
PREVIOUS TEXT
GSK1120212 is a reversible, highly selective allosteric inhibitor of MEK1/MEK2 
activation and kinase activity.  A detailed summary of in vitro and in vivo non-clinical 
pharmacology studies is provided in the GSK1120212 Investigator Brochure (IB) 
[GlaxoSmithKline Document Number HM2009/00151/02].
REVISED TEXT
GSK1120212 is a potent, reversible and highly selective allosteric inhibitor of 
MEK1/MEK2 activation and kinase activity.  The specificity of GSK1120212 to MEK1 
and MEK2 was confirmed against a large panel of kinases and no significant 
inhibitory activity was measured. A detailed summary of in vitro and in vivo non-
clinical pharmacology studies is provided in the GSK1120212 Investigator Brochure (IB) 
[GlaxoSmithKline Document Number HM2009/00151/02].
Section 4.1.3 Exclusion Criteria
The new criteria were inserted with some original criteria placed within this new criteria 
as sub-bullets; subsequent criteria were renumbered as appropriate.
PREVIOUS TEXT
5.
Evidence of severe or uncontrolled systemic diseases (e.g. unstable or 
uncompensated respiratory, hepatic, renal, metabolic or cardiac disease).
6.
Bazett-corrected QT (QTcB) interval >530 msec or uncorrected QT >600 msec at the 
time of transition to this study.  
7. Left ventricular ejection fraction (LVEF) < institutional lower limit of normal (LLN) 
by ECHO (preferred) or MUGA scan at the time of transition to this study.
8. Evidence of current Class II, III, or IV heart failure as defined by the New York Heart 
Association (NYHA) functional classification system at the time of transition to this 
study (Appendix 3).
REVISED TEXT
5.
Evidence of severe or uncontrolled systemic diseases (e.g. unstable, or 
uncompensated respiratory, hepatic, renal or metabolic or cardiac disease).
6.
History or evidence of cardiovascular risk including any of the following: 

Bazett-corrected QT (QTcB) interval 480 msec at the time of transition to this 
study

Bazett-corrected QT (QTcB) interval 480 msec at the time of transition to 
this study

History or evidence of current clinically significant uncontrolled 
arrhythmias


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Exception: Subjects with controlled atrial fibrillation for >30 days prior to 
transition to this study are eligible.

History of acute coronary syndromes (including myocardial infarction and 
unstable angina), coronary angioplasty, or stenting within 6 months prior to 
transition to this study

History or evidence of current Class II congestive heart failure as defined 
by the New York Heart Association (NYHA; Appendix 3)

Treatment refractory hypertension defined as a BP reading of systolic 
>140 mmHg and/or diastolic >90 mmHg which cannot be controlled by 
antihypertensive therapy

Subjects with intra-cardiac defibrillator or permanent pacemaker

Cardiac metastases
7. Left ventricular ejection fraction (LVEF) < institutional lower limit of normal (LLN) 
by ECHO (preferred) or MUGA scan at the time of transition to this study.
8. Evidence of current Class II, III, or IV heart failure as defined by the New York Heart 
Association (NYHA) functional classification system at the time of transition to this 
study (Appendix 3).
Section 5.4 Handling and Storage of Study Treatment
The storage temperature for GSK1120212 was clarified by GSK Pharmaceutical 
Development and is consistent with information provided in IND and IMPD for 
GSK1120212.
PREVIOUS TEXT 
GSK1120212 is to be stored at a temperature up to 30°C in an opaque bottle.  
Maintenance of a temperature log (manual or automated) is required.
REVISED TEXT
GSK1120212 is to be stored at a temperature up to 3025°C in an opaque bottle, 
protected from light and moisture.  Maintenance of a temperature log (manual or 
automated) is required.
Section 5.7.1 Monitoring and Management of Hypertension
New section was inserted and subsequent sections were renumbered in Section 5.7.


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NEW TEXT
Section 5.7.1
Monitoring and Management of Hypertension
Section 5.7.1.1
Monitoring of Hypertension
All BP assessments should be performed under optimal conditions i.e. after (1) 
subject has been seated with back support, ensuring that legs are uncrossed and flat 
on the floor, (2) subject is relaxed comfortably for at least 5 minutes, (3) 
preparatory steps including removal of any restrictive clothing over the cuff area 
and selection of the proper cuff size have been ensured, (4) the arm is supported so 
that the middle of the cuff is at the heart level, and (5) the subject remains quiet 
during the measurement.  In subjects with an initial BP reading within the 
hypertensive range, a second reading should be taken at least 1 minute later, with 
the 2 readings averaged to obtain a final BP measurement. 
Persistent hypertension is defined as an increase of systolic blood pressure (SBP) 
>140 mm Hg and/or diastolic blood pressure (DBP) >90 mmHg in up to 3 
subsequent visits with BP assessments from 2 readings under the optimal conditions 
described above.  Visits to monitor increased BP should be scheduled independently 
from the per-protocol visits outlined in the time-and-events schedule; ideally, 
subsequent BP assessments should be performed within 7 days.
Asymptomatic hypertension is defined as an increase of SBP >140 mmHg and/or 
DBP > 90 mmHg in the absence of headache, light-headedness, vertigo, tinnitus, 
episodes of fainting or other symptoms indicative of hypertension which would 
disappear after the BP is controlled within the normal range. 
Section 5.7.1.2
Management of Hypertension
For subjects experiencing an increase in SBP and/or DBP that is persistent and may 
be associated with the study treatment, recommendations for the clinical 
management of hypertension are described below:


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Hypertension
(A). Asymptomatic and persistent1 SBP of 140 
and <160 mmHg, or DBP 90 and <100 mmHg, or 
a clinically significant increase in DBP of 
20 mmHg (but still below 100 mmHg).
Step 1. Continue study treatment at the current dose. 
Step 2. Adjust current or initiate new antihypertensive 
medication(s).
Step 3. Titrate antihypertensive medication(s) during next 
2 weeks as indicated to achieve well-controlled2 BP. I f 
BP is not well-controlled within 2 weeks, consider 
referral to a specialist and go to scenario (B).
(B). Asymptomatic SBP 160 mmHg, or DBP 
100 mmHg, or failure to achieve well-controlled 
BP within 2 weeks in scenario (A).
Step 1.Consider reducing or interrupting study treatment, 
as clinically indicated.
Step 2. Adjust current or initiate new antihypertensive 
medication(s). 
Step 3. Titrate antihypertensive medication(s) during next 
2 weeks as indicated to achieve well-controlled BP. 
Step 4. Once BP is well-controlled, restart study 
treatment dose-reduced 
(C). Symptomatic hypertension or recurring3 SBP 
160 mmHg, or DBP 100 mmHg, despite 
modification of antihypertensive medication(s)
Step 1. Interrupt study treatment.
Step 2. Adjust current or initiate new antihypertensive 
medication(s). 
Step 3. Titrate antihypertensive medication(s) during next 
2 weeks as indicated to achieve well-controlled BP.  
Referral to a specialist for further evaluation and follow-
up is also recommended.
Step 4. Once BP is well-controlled, restart study 
treatment dose-reduced 
(D). Refractory hypertension unresponsive to 
above interventions.
Discontinue study treatment and continue follow-up per 
protocol.
1.
Hypertension detected in 2 separate readings during up to 3 subsequent visits
2.
BP reading of SBP 140 mmHg and DBP 90 mmHg in 2 separate readings during up to 3 subsequent 
visits
3.
Persistent asymptomatic hypertension after initially successful anti-hypertensive intervention


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Section 7.1 Meals and Dietary Restrictions
PREVIOUS TEXT
GSK1120212 should be taken orally, once-daily with approximately 8 fl oz of water.  
Subjects should fast for at least 1 hour before and for at least 2 hours after dosing with
GSK1120212. 
REVISED TEXT
GSK1120212 should be administered taken orally, once-daily with approximately 
240 mL (8 fl oz) of water, under fasting conditions, either.  Subjects should fast for at 
least 1 hour before or and for at least 2 hours after a meal dosing with GSK1120212.
Appendix 1: Time and Events Table for Cohort A, Footnote #9
PREVIOUS TEXT
9.
ECHO is only required at the Final Study Visit if an abnormal finding is reported at a 
prior visit.
REVISED TEXT
9.
ECHO is only required at the Final Study Visit if an abnormal finding is reported at a 
prior visit from the last ECHO or MUGA scan performed.
Appendix 2: Time and Events Table for Cohort B, Footnote #9
PREVIOUS TEXT
9.
ECHO is only required at the Final Study Visit if an abnormal finding is reported at a 
prior visit.
REVISED TEXT
9.
ECHO is only required at the Final Study Visit if an abnormal finding is reported at a 
prior visit from the last ECHO or MUGA scan performed.


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AMENDMENT 2
Where the Amendment Applies
This amendment applies to all site and countries.
Summary of Amendment Changes with Rationale
In this amendment, the background information and risk management sections of the 
protocol were revised to provide updated safety information included in the most recent 
version of the GSK1120212 IB.  In addition, since the new commercial image 
investigational product will be administered to subjects participating in this protocol, it 
was necessary to add the product description.
The language describing the timing of the ECHOs and MUGA scans was revised to 
further clarify that ECHO/MUGA should be completed 12 weeks from the subject’s last 
scan not necessarily 12 weeks from the date of the transition visit.
Administrative changes were made to update contact information for the primary and 
secondary medical monitors.
List of Specific Changes
Sponsor Medical Monitor Contact Information: 
updated Fax number for primary Medical Monitor.
Section 1.1 Background, Paragraph 2
PREVIOUS TEXT
A detailed summary of in vitro and in vivo non-clinical pharmacology studies is provided 
in the GSK1120212 Investigator Brochure (IB) [GlaxoSmithKline Document Number 
HM2009/00151/].
REVISED TEXT
A detailed summary of in vitro and in vivo non-clinical pharmacology studies is provided 
in the GSK1120212 Investigator Brochure (IB) [GlaxoSmithKline Document Number 
HM2009/00151/02].
Section 1.1 Background, Paragraphs 3 to 6
PREVIOUS TEXT
The safety, pharmacokinetic (PK) and pharmacodynamic (PD) profiles and activity of 
GSK1120212 administered either as monotherapy or in combination with other anti-
cancer agents are currently being evaluated in multiple clinical trials involving subjects 


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with a variety of cancers.  The investigator should refer to the GSK1120212 IB 
[GlaxoSmithKline Document Number HM2009/00151/] for detailed information 
regarding ongoing GSK1120212 clinical studies, PK in the target disease population, as 
well as observed safety and efficacy findings. 
The adverse event (AE) profile of GSK1120212 observed to date is comparable to other 
MEK inhibitors [Friday, 2008].  For example, rash and diarrhea, experienced by 70% and 
41% of subjects, respectively, are the most common toxicities reported in the first-time-
in-human study, MEK111054 [GlaxoSmithKline Document Number RM2007/00642/03].  
Rash was considered a dose-limiting toxicity (DLT) in 2 subjects (Grade 2 and Grade 3), 
whereas a DLT for Grade 3 diarrhea occurred once.   Other AEs commonly reported 
(≥20%) include fatigue, nausea, peripheral edema, and vomiting.  Although observed at 
lower frequencies, visual impairment and left ventricular ejection fraction (LVEF) 
reduction have been observed with GSK1120212 as well as other MEK inhibitors.  
Visual impairment includes 2 cases of dose-limiting Grade 2 central serous retinopathy 
(CSR) and 1 case of Grade 3 retinal vein occlusion (RVO).  Pneumonitis has also been 
seen in subjects treated with GSK1120212 in combination with gemcitabine.
GSK1120212 has demonstrated anti-tumor activity in a variety of solid tumors as well as 
in 1 subject with acute myelogenous leukemia.  Importantly, 1 out of 2 subjects with 
KRAS-mutant metastatic non-small cell lung cancer (NSCLC) has achieved a partial 
response (PR; 49% tumor reduction) and one out of 18 advanced pancreatic subjects has 
a sustained PR (on study >40 weeks) following treatment with GSK1120212 
monotherapy.  
Although tumor response appears to higher in those subjects whose cancer harbors 
mutations in the MAPK signalling pathway, clinical benefit is still observed in subjects 
with wild-type disease or disease where the mutation status is unknown.  For example, 
multiple NSCLC and pancreatic cancer subjects have achieved stable disease (SD).  
REVISED TEXT
The safety, pharmacokinetic (PK) and pharmacodynamic (PD) profiles and activity of 
GSK1120212 administered either as monotherapy or in combination with other anti-
cancer agents are currently being evaluated in multiple clinical trials involving subjects 
with a variety of cancers.  The investigator should refer to the GSK1120212 IB 
[GlaxoSmithKline Document Number HM2009/00151/] for detailed information 
regarding ongoing GSK1120212 clinical studies, PK in the target disease population, as 
well as observed safety and efficacy findings. 


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The adverse event (AE) profile of GSK1120212 observed to date is comparable to other 
MEK inhibitors [Friday, 2008].  For example, rash and diarrhea, experienced by 70% and 
41% of subjects, respectively, are the most common toxicities reported in the first-time-
in-human study, MEK111054 [GlaxoSmithKline Document Number RM2007/00642/03].  
Rash was considered a dose-limiting toxicity (DLT) in 2 subjects (Grade 2 and Grade 3), 
whereas a DLT for Grade 3 diarrhea occurred once.   Other AEs commonly reported 
(≥20%) include fatigue, nausea, peripheral edema, and vomiting.  Although observed at 
lower frequencies, visual impairment and left ventricular ejection fraction (LVEF) 
reduction have been observed with GSK1120212 as well as other MEK inhibitors.  
Visual impairment includes 2 cases of dose-limiting Grade 2 central serous retinopathy 
(CSR) and 1 case of Grade 3 retinal vein occlusion (RVO).  Pneumonitis has also been 
seen in subjects treated with GSK1120212 in combination with gemcitabine.
GSK1120212 has demonstrated anti-tumor activity in a variety of solid tumors as well as 
in 1 subject with acute myelogenous leukemia.  Importantly, 1 out of 2 subjects with 
KRAS-mutant metastatic non-small cell lung cancer (NSCLC) has achieved a partial 
response (PR; 49% tumor reduction) and one out of 18 advanced pancreatic subjects has 
a sustained PR (on study >40 weeks) following treatment with GSK1120212 
monotherapy.  
Although tumor response appears to higher in those subjects whose cancer harbors 
mutations in the MAPK signalling pathway, clinical benefit is still observed in subjects 
with wild-type disease or disease where the mutation status is unknown.  For example, 
multiple NSCLC and pancreatic cancer subjects have achieved stable disease (SD).
As of 14 April 2011, 657 subjects with cancer have received at least one dose of 
GSK1120212 in 14 ongoing Phase I/II/III clinical studies.  Six of the 14 studies 
administer GSK1120212 as monotherapy, whereas the other 8 studies are designed 
to administer GSK112012 as combination therapy.  As of 14 April 2011, 206 
subjects in MEK111054, the first-time-in-human (FTIH) study of GSK1120212, had 
been dosed with GSK1120212.  Dose-related MAP kinase inhibition was 
demonstrated between daily doses of 0.5 and 2.0 mg with immunohistochemistry on 
tumor biopsies.  Modulation of MAP kinase pathways was consistent with changes 
observed with fluorodeoxyglucose-positron emission tomography imaging.  Based 
on the AEs observed in the FTIH MEK111054 study, the maximum tolerated dose 
(MTD) was determined to be 3.0 mg once-daily and the recommended Phase II dose 
(RP2D) of GSK1120212 was identified as 2.0 mg once-daily.  An unconfirmed 
response rate of 43% (6 out of 14 subjects) had an objective response, including 2 
complete responses (CRs) was observed.    The recommended monotherapy dose (2 
mg once-daily) was well-tolerated.  Most notable adverse events (AEs) at this dose 
(n = 96) included class effects of rash (78%; 4% Grade 3) and diarrhea (54%; 1% 
Grade 3).  In all subjects dosed (n = 206), 5 cases of Grade 3 left ventricular systolic 
dysfunction, 3 cases of central serous retinopathy (CSR), and 1 case of retinal vein 
occlusion (RVO) were observed.  Among the 5 left ventricular ejection fraction 
(LVEF) cases, only 2 were considered related to study treatment and neither subject 
was symptomatic.  All 3 cases of CSR resolved upon study treatment interruption, 
and the subject with RVO has experienced significant improvement in visual acuity 
after intraocular bevacizumab treatments.


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GSK1120212 is absorbed rapidly with median tmax generally occurring within 1 to 
3 hours after administration of GSK1120212.  After repeat dosing (Study Day 15), 
the mean area under the concentration-time curve (AUC0-)) and maximum 
observed concentrations (Cmax) increased in a dose proportional manner (i.e., a 2-
fold increase in dose resulted in a 2-fold increase in exposure).  Between-subject 
variability (CV%) in exposure ranged from 27 to 50% for Cmax and 20 to 41% for 
area under the concentration-time curve from time zero (pre-dose) to 24 hrs after 
the last dose of study treatment (AUC(0-24)) across all dosing regimens.  
GSK1120212 accumulates with repeat dose with an effective half-life (t1/2) of 
approximately 5 days.
Further information on the safety, PK, and efficacy is described in the IB for 
GSK1120212 [GlaxoSmithKline Document Number HM2009/00151/02].
Section 1.2 Summary of Risk Management
Added new Section 1.2 and renumbered old Section 1.2 to Section 1.3.
NEW TEXT
The assessment of the risk of GSK1120212 is based on clinical data from the 
ongoing FTIH study in which subjects have been dosed daily for >21 days, as well as 
preclinical toxicity data.  In study MEK111054, the most common AEs experienced 
by 20% of all subjects with daily dosing were rash, diarrhea, fatigue, nausea, 
peripheral edema, and vomiting.  Rash and diarrhea are common, class-effect 
toxicities for MEK inhibitors.  In addition, visual impairment and LVEF reduction, 
although observed at lower frequencies, are also considered class-effect toxicities as 
they have been observed with GSK1120212 as well as other MEK inhibitors.  
Systemic toxicity of GSK1120212 has been evaluated following oral dosing in rats 
and dogs for up to 13 weeks.  In the most sensitive non-clinical species, rat, the 
principal adverse effects seen in oral toxicity studies of up to 13 weeks with daily 
dosing were skin and stomach erosions, skin ulcerations, which were secondary to 
reduced proliferation, altered phosphate homeostasis that resulted in soft tissue 
mineralization, hepatocellular necrosis, bone marrow degeneration/necrosis and 
ovarian perturbations.  The skin and stomach findings and phosphatemia 
demonstrated reversibility with 4 weeks of recovery.  Additional details are 
provided in the IB for GSK1120212 [GlaxoSmithKline Document Number 
HM2009/00151/02HM2009/00151/].
Procedures to minimize or monitor potential risks are listed below:

To reduce the risk of ocular toxicity, subjects with history of RVO, or CSR, 
subjects with predisposing factors for RVO or CSR or predisposing retinal 
pathology as determined by ophthalmologic exams are excluded.  
Ophthalmologic exams will be performed at baseline and as clinically 
warranted.

To monitor cardiac function, echocardiogram (ECHO) or multigated 
acquisition (MUGA) scans will be performed.


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
To reduce the risk of excessive gastrointestinal (GI) toxicity (diarrhea) and 
cutaneous toxicity (rash), subjects will be monitored closely and supportive 
care guidelines will be implemented.
Section 5.1 GSK1120212 GSK Investigational Product
Changed title of Section 5.1 from GSK1120212 GSK Investigational Product to 
Investigational Product.  Labelled the original table as Table 1 (previously unlabelled) 
and inserted Table 2, a new table for GSK1120212 GSK Investigational Product 
(Commercial Image Product).
PREVIOUS TEXT
Product name :
GSK1120212
Formulation 
description:
The drug substance is blended with inert ingredients (mannitol, sodium lauryl sulfate, 
colloidal silicon dioxide, microcrystalline cellulose, hypromellose, croscarmellose 
sodium, and magnesium stearate) and compressed into tablets.  The tablets are then 
coated with either a white or pink opaque film* (*Opadry White or Pink, a titanium 
dioxide-based formulation with iron oxide as colorant as applicable).
Dosage form :
Tablet
Unit dose 
strength(s)/ 
Dosage levels
0.5 mg
1.0 mg
2.0 mg
Physical 
Description: 
0.5mg: White, oval, biconvex film-coated tablet with dose proportional diameter
1.0 mg: White, round, biconvex film-coated tablet with dose proportional diameter
2.0 mg: Pink, round, biconvex film-coated tablet with dose proportional diameter
Route/Regimen: 
Oral/Cohort A: Subjects will receive GSK1120212 2.0 mg or less once-daily.  Cohort 
B: Subjects will receive continuous oral dosing of GSK1120212 at the current dose 
administered in the parent study at the time of transition to the rollover study.
Dosing 
Instructions:
GSK1120212 should be administered with approximately 240 mL (8 fl oz) of water, 
under fasting conditions, either 1 hour before or 2 hours after a meal. 
REVISED and NEW TEXT
Section 5.1 GSK1120212 GSK Investigational Product


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Table 1
GSK1120212 GSK Investigational Product
Product name :
GSK1120212
Formulation 
description:
The drug substance is blended with inert ingredients (mannitol, sodium lauryl sulfate, 
colloidal silicon dioxide, microcrystalline cellulose, hypromellose, croscarmellose 
sodium, and magnesium stearate) and compressed into tablets.  The tablets are then 
coated with either a white or pink opaque film* (*Opadry White or Pink, a titanium 
dioxide-based formulation with iron oxide as colorant as applicable).
Dosage form :
Tablet
Unit dose 
strength(s)/ 
Dosage levels
0.5 mg
1.0 mg
2.0 mg
Physical 
Description: 
0.5mg: White, oval, biconvex film-coated tablet with dose proportional diameter
1.0 mg: White, round, biconvex film-coated tablet with dose proportional diameter
2.0 mg: Pink, round, biconvex film-coated tablet with dose proportional diameter
Route/Regimen: 
Oral/Cohort A: Subjects will receive GSK1120212 2.0 mg or less once-daily.  Cohort 
B: Subjects will receive continuous oral dosing of GSK1120212 at the current dose 
administered in the parent study at the time of transition to the rollover study.
Dosing 
Instructions:
GSK1120212 should be administered with approximately 240 mL (8 fl oz) of water, 
under fasting conditions, either 1 hour before or 2 hours after a meal. 
Table 2
GSK1120212 GSK Investigational Product (Commercial Image 
Product)
Commercial Image Product
Product name :
GSK1120212 0.5 mg Tablet
GSK11210212 2 mg Tablet
Formulation 
description:
Each tablet contains GSK1120212B equivalent to 
0.5 mg of GSK1120212 as drug substance 
blended with inert ingredients (mannitol, sodium 
lauryl sulfate, colloidal silicon dioxide, 
microcrystalline cellulose, hypromellose, 
croscarmellose sodium, and magnesium stearate) 
and compressed into tablets.  The tablets are then 
coated with yellow opaque film* (*Opadry yellow, 
a titanium dioxide-based formulation with yellow 
iron oxide as colorant as applicable).
Each tablet contains GSK1120212B 
equivalent to 2 mg of GSK1120212 as drug 
substance blended with inert ingredients 
(mannitol, sodium lauryl sulfate, colloidal 
silicon dioxide, microcrystalline cellulose, 
hypromellose, croscarmellose sodium, and 
magnesium stearate) and compressed into 
tablets. The tablets are then coated with pink 
opaque film* (*Opadry Pink, a titanium dioxide-
based formulation with red iron oxide as 
colorant).
Dosage form :
Tablet
Tablet
Unit dose 
strength(s):
Tablet strength: 0.5 mg
Tablet strength: 2 mg
Physical 
Description:
Yellow, modified oval, biconvex, film-coated 
tablets (4.85 x 8.86 mm)
Pink, biconvex, round film-coated tablets 
7.5 mm in diameter
Route/
Administration: 
Oral/once-daily single dose
Oral/once-daily single dose
Dosing 
Instructions:
GSK1120212 should be administered with approximately 240 mL (8 fl oz) of water, under fasting 
conditions, either 1 hour before or 2 hours after a meal. 


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Section 5.7.7.1, Left Ventricular Ejection Fraction Stopping Criteria, 4th 
paragraph:
PREVIOUS TEXT
The same procedure (either ECHO or MUGA, although ECHO is preferred) should be 
performed at baseline and at follow-up visit(s).  Copies of all ECHOs and/or MUGA 
scans performed on subjects who experience an absolute decrease >10% in LVEF 
compared to baseline and LVEF <LLN will be required by GSK for review.  Instructions 
for submission of qualifying ECHOs/MUGA scans are provided in the SPM.
REVISED TEXT
The same procedure (either ECHO or MUGA, although ECHO is preferred) should be 
performed at baseline and at follow-up visit(s).  Copies of all ECHOs and/or MUGA 
scans performed on subjects who experience an absolute decrease >10% in LVEF 
compared to baseline and LVEF <LLN (or <50% when LLN does not exist) will be 
required by GSK for review.  Instructions for submission of qualifying ECHOs/MUGA 
scans are provided in the SPM.
Section 8.2.1 Cohort A:
PREVIOUS TEXT
The following assessments must be performed at Week 8 while receiving treatment:

Complete physical examination

ECHO (preferred) or MUGA scan (see Section 5.7.4 for stopping criteria and follow-
up for abnormal results) 
The following assessments must be performed every 12 weeks while receiving treatment:

Complete physical examination (after Week 8)

ECHO (preferred) or MUGA scan (after Week 8) 

12-lead ECG  (for first 2 years of treatment with GSK1120212, including time on 
parent study)

Clinical laboratory tests:  hematology and clinical chemistry (>2 years of treatment 
with GSK1120212, including time on parent study)
REVISED TEXT
The following assessments must be performed at Week 8 while receiving treatment:

Complete physical examination

ECHO (preferred) or MUGA scan (see Section 5.7.4 for stopping criteria and follow-
up for abnormal results) 


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The following assessment must be performed while receiving treatment:

ECHO (preferred) or MUGA scan should be performed within 12 weeks 
from the date of the subject’s last ECHO or MUGA scan which may have 
been performed in the parent study or at the time of transition to the rollover 
study.

Subsequent ECHO (preferred) or MUGA scans must be performed every 
12 weeks thereafter while the subject is receiving treatment.
NOTE:  Refer to Section 5.7.4 for stopping criteria and follow-up for 
abnormal results).
The following assessments must be performed every 12 weeks while receiving treatment:

Complete physical examination (after Week 8)

ECHO (preferred) or MUGA scan (after Week 8) 

12-lead ECG  (for first 2 years of treatment with GSK1120212, including time on 
parent study)

Clinical laboratory tests:  hematology and clinical chemistry (>2 years of treatment 
with GSK1120212, including time on parent study)
Section 8.2.2 Cohort B:
PREVIOUS TEXT
The following assessments must be performed every 12 weeks while receiving treatment:

Complete physical examination

ECHO (preferred) or MUGA scan (see Section 5.7.7)
REVISED and NEW TEXT
The following assessments must be performed every 12 weeks while receiving treatment:

Complete physical examination

ECHO (preferred) or MUGA scan (see Section 5.7.7)
The following assessment must be performed while receiving treatment:

ECHO (preferred) or MUGA scan should be performed within 12 weeks 
from the date of the subject’s last ECHO or MUGA scan which may have 
been performed in the parent study or at the time of transition to the 
rollover study.


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
Subsequent ECHO (preferred) or MUGA scans must be performed every 
12 weeks thereafter while the subject is receiving treatment.
NOTE:  Refer to Section 5.7.4 for stopping criteria and follow-up for 
abnormal results).
Section 8.3 Final Visit
PREVIOUS TEXT
If a subject is withdrawn from study treatment, the following assessments will be 
performed within 28 days (7 days) from the last dose of study treatment(s) and prior to 
initiating any other treatment for cancer:

Complete physical examination

Vital signs (BP, temperature, respiratory rate, and pulse rate)

Clinical laboratory tests:  hematology and clinical chemistry

12-lead ECG

ECHO (preferred) or MUGA scan (only required if there was an abnormal finding 
reported at a prior visit)

Review of concomitant medications

Assessment of AEs
REVISED TEXT
If a subject is withdrawn from study treatment, the following assessments will be 
performed within 28 days (7 days) from the last dose of study treatment(s) and prior to 
initiating any other treatment for cancer:

Complete physical examination

Vital signs (BP, temperature, respiratory rate, and pulse rate)

Clinical laboratory tests:  hematology and clinical chemistry

12-lead ECG

ECHO (preferred) or MUGA scan (only required if there was an abnormal finding 
reported at a prior visit reported from the last ECHO or MUGA scan performed)

Review of concomitant medications

Assessment of AEs


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Section 12 References
PREVIOUS TEXT
GlaxoSmithKline Document Number HM2009/00151/01. Clinical Investigator Brochure 
for GSK1120212, 2nd edition. 04-Jun-2010.
REVISED TEXT
GlaxoSmithKline Document Number HM2009/00151/02. Clinical Investigator Brochure 
for GSK1120212, 3rd edition. 23-Jun-2011.


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Section 13.1 Appendix 1: Time and Events Table for Cohort A
PREVIOUS TEXT
Assessment/
Procedure17
Transition Visit1
Continuous Dosing 
Treatment Period19
Final Study Visit
Every 4 
weeks16
(7 days)
Week 816
(7 days)
Every 12 weeks16
(7 days)
Every 24 weeks16
(7 days)
With 28 days of Last Dose of 
Study Treatment(s)
(7 days)18
Informed Consent2
X
Demographics and Parent 
Study Data
X
Physical  Exam3
X
X
X
X
Pregnancy test4
X
Vital Signs5
X
X
X
12-Lead ECG6
X
X7
X7
X
ECHO/MUGA scan
X
X8
X8
X9
Clinical Chemistry10
X
X11
X11
X
Hematology10
X
X11
X11
X
Tumor Tissue /Skin 
Biopsy or Blood Sample 
for Biomarker Analysis12
O
cfDNA Sample12
O
AE Monitoring13,14
Continuous
Review of Concomitant 
Medications15
Continuous
GSK1120212 Dosing
Continuous


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Abbreviations:  O, optional
1.
All subjects transitioning from parent study will begin the rollover study based on the last treatment visit completed during the parent study.  All Transition Visit 
assessments/procedures must be completed prior to the first dose of study treatment(s).  Assessments/procedures may be used to fulfill the requirements of both the parent 
study and this study.  Results from the parent study should be recorded in the eCRF as transition values.
2.
Informed consent must be obtained prior to performing any assessments or procedures for this study and before treatment with GSK1120212 is to be continued.
3.
Physical examination will be completed at the Transition Visit, Week 8 and every 12 weeks thereafter while on treatment, and at the Final Study Visit. Height (cm) and weight 
(kg) will be measured only at the Transition Visit.  
4.
Serum β–hCG pregnancy tests will be performed on female subjects of childbearing potential only at the time of transition from the parent study.
5.
Vital signs (BP, temperature, respiratory rate and pulse rate) should be taken in a semi-supine position and after the subject has rested for at least 5 minutes prior to the 
reading.  Vital signs may be measured more frequently as clinically indicated.
6.
A single 12-Lead ECG will be performed using a standard 12-lead ECG machine.  All ECGs will be taken in a supine position after resting in that position for at least 10 
minutes prior to testing.  QTc interval must not be >480 msec.  
7.
12-lead ECGs will be performed every 12 weeks (at a minimum or more frequently per local practice) for the first 2 years of treatment (including time on parent study).  After 
2 years of treatment 12-lead ECGs will be performed every 24 weeks for the duration of treatment.
8.
ECHO or MUGA scan should first be performed at Week 8 and then every 12 weeks (at a minimum or more frequently per local practice).  If LVEF decreases 20 percentage 
points, repeat testing is required within 2 weeks.  If decline is sustained, the investigator, in consultation with GSK Medical Monitor, should consider withdrawal of subject 
from the study.
9.
ECHO is only required at the Final Study Visit if an abnormal finding is reported at a prior visit.
10. Refer to Section 8.4.5 for complete list of clinical laboratory assessments to be performed.
11. Hematology and clinical chemistry laboratory assessments will be performed every 4 weeks (at a minimum or more frequently per local practice) for the first 2 years of 
treatment (including time on parent study).  After 2 years hematology and clinical chemistry laboratory assessments will be performed every 12 weeks for the duration of 
treatment.
12. Optional tumor tissue, skin or blood sample from a lesion not required for disease assessment and/or optional blood sample for cfDNA may be obtained if subject has 
provided consent.  
13. AEs/SAEs will be monitored and recorded beginning on the time of consent until 30 days after the last dose of GSK2118436.
14. All ongoing (unresolved) AEs at the time of the transition to this study will be recorded in the eCRF.
15. All concomitant medication(s) at the time of the transition to this study will be recorded in the eCRF.
16. The “Every 8 Weeks”, “Every 12 Weeks” or “Every 24 Weeks” columns are NOT a separate visit but instead a listing of assessments required to be completed every 8, 12 or 
24 weeks or every second or third clinic visit that is recurring at 4-week intervals, respectively.
17. After a subject has been on study for a total of 2 years, including time on parent study, the frequency of assessments will be modified.  If more frequent assessments are 
needed, these should be done per local practice.
18. The Final Study Visit should occur within 28 days (7 days) following the last dose of study treatment(s) and prior to initiating any new treatment.
19. Subjects who remain on study treatment >52 weeks may have the frequency of their interim visits decreased with approval from the GSK Medical Monitor.


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REVISED TEXT
Assessment/
Procedure18
Transition Visit1
Continuous Dosing
Treatment Period20
Final Study Visit
Every 4 
weeks17
(7 days)
Week 817
(7 days)
Every 12 weeks17
(7 days)
Every 24 weeks17
(7 days)
With 28 days of Last Dose of 
Study Treatment(s)
(7 days)19
Informed Consent2
X
Demographics and Parent 
Study Data
X
Physical  Exam3
X
X
X
X
Pregnancy test4
X
Vital Signs5
X
X
X
12-Lead ECG6
X
X7
X7
X
ECHO/MUGA scan
X
X8
X8
X9
Clinical Chemistry10
X
X11
X11
X
Hematology10
X
X11
X11
X
Liver Function Tests10,12
X
X
X
X
Tumor Tissue /Skin Biopsy 
or Blood Sample for 
Biomarker Analysis13
O
cfDNA Sample13
O
AE Monitoring14, 15
Continuous
Review of Concomitant 
Medications16
Continuous
GSK1120212 Dosing
Continuous


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Abbreviations:  O, optional
1.
All subjects transitioning from parent study will begin the rollover study based on the last treatment visit completed during the parent study.  All Transition Visit 
assessments/procedures must be completed prior to the first dose of study treatment(s).  Assessments/procedures may be used to fulfill the requirements of both the parent 
study and this study.  Results from the parent study should be recorded in the eCRF as transition values.
2.
Informed consent must be obtained prior to performing any assessments or procedures for this study and before treatment with GSK1120212 is to be continued.
3.
Physical examination will be completed at the Transition Visit, Week 8 and every 12 weeks thereafter while on treatment, and at the Final Study Visit. Height (cm) and weight 
(kg) will be measured only at the Transition Visit.
4.
Serum β–hCG pregnancy tests will be performed on female subjects of childbearing potential only at the time of transition from the parent study.
5.
Vital signs (BP, temperature, respiratory rate and pulse rate) should be taken in a semi-supine position and after the subject has rested for at least 5 minutes prior to the 
reading.  Vital signs may be measured more frequently as clinically indicated.
6.
A single 12-Lead ECG will be performed using a standard 12-lead ECG machine.  All ECGs will be taken in a supine position after resting in that position for at least 10 
minutes prior to testing.  QTc interval must not be >480 msec.
7.
12-lead ECGs will be performed every 12 weeks (at a minimum or more frequently per local practice) for the first 2 years of treatment (including time on parent study).  After 
2 years of treatment 12-lead ECGs will be performed every 24 weeks for the duration of treatment.
8.
ECHO or MUGA scan should first be performed at Week 8 and then every 12 weeks (at a minimum or more frequently per local practice).  If LVEF decreases 20 percentage 
points, repeat testing is required within 2 weeks.  If decline is sustained, the investigator, in consultation with GSK Medical Monitor, should consider withdrawal of subject 
from the study.
9.
ECHO is only required at the Final Study Visit if an abnormal finding is reported at a prior visit.
10. Refer to Section 8.4.5 for complete list of clinical laboratory assessments to be performed.
11. Hematology and clinical chemistry laboratory assessments will be performed every 4 weeks (at a minimum or more frequently per local practice) for the first 2 years of 
treatment (including time on parent study).  After 2 years hematology and clinical chemistry laboratory assessments will be performed every 12 weeks for the duration of 
treatment.
12. Liver function tests (AST, ALT, alkaline phosphatase and total bilirubin) will be performed every 4 weeks (depending on the scheduled used in the parent study; 
at a minimum or more frequently per local practice) for the first 2 years of treatment (including time on parent study).  After 2 years liver function tests will be 
performed every 12 weeks (depending on schedule used in the parent study) for the duration of treatment.  Bilirubin fractionation is recommended if total 
bilirubin is >2 times ULN.
13. Optional tumor tissue, skin or blood sample from a lesion not required for disease assessment and/or optional blood sample for cfDNA may be obtained if subject has 
provided consent.
14. AEs/SAEs will be monitored and recorded beginning on the time of consent until 30 days after the last dose of GSK2118436.
15. All ongoing (unresolved) AEs at the time of the transition to this study will be recorded in the eCRF.
16. All concomitant medication(s) at the time of the transition to this study will be recorded in the eCRF.
17. The “Every 8 Weeks”, “Every 12 Weeks” or “Every 24 Weeks” columns are NOT a separate visit but instead a listing of assessments required to be completed every 8, 12 or 
24 weeks or every second or third clinic visit that is recurring at 4-week intervals, respectively.
18. After a subject has been on study for a total of 2 years, including time on parent study, the frequency of assessments will be modified.  If more frequent assessments are 
needed, these should be done per local practice.
19. The Final Study Visit should occur within 28 days (7 days) following the last dose of study treatment(s) and prior to initiating any new treatment.
20. Subjects who remain on study treatment >52 weeks may have the frequency of their interim visits decreased with approval from the GSK Medical Monitor.


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Section 13.2  Appendix 2: Time and Events Table for Cohort B
PREVIOUS TEXT
Assessment/
Procedure17
Transition Visit1
Continuous Dosing 
Treatment Period19
Final Study Visit
Every 3 or 4 
weeks16
(7 days)
Every 9 or 12 
weeks16
(7 days)
Every 12 weeks16
(7 days)
Every 24 weeks16
(7 days)
With 28 days of Last Dose of 
Study Treatment(s)
(7 days)18
Informed Consent2
X
Demographics and Parent 
Study Data
X
Physical  Exam3
X
X
X
Pregnancy test4
X
Vital Signs5
X
X
X
12-Lead ECG6
X
X7
X7
X
ECHO/MUGA scan
X
X8
X9
Clinical Chemistry10
X
X11
X11
X
Hematology10
X
X11
X11
X
Tumor Tissue /Skin 
Biopsy or Blood Sample 
for Biomarker Analysis12
O
cfDNA Sample12
O
AE Monitoring13, 14
Continuous
Review of Concomitant 
Medications15
Continuous
GSK1120212 Dosing
Continuous


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Abbreviations:  O, optional
1.
All subjects transitioning from parent study will begin the rollover study based on the last treatment visit completed during the parent study.  All Transition Visit 
assessments/procedures must be completed prior to the first dose of study treatment(s).  Assessments/procedures may be used to fulfill the requirements of both the parent 
study and this study.  Results from the parent study should be recorded in the eCRF as transition values.
2.
Informed consent must be obtained prior to performing any assessments or procedures for this study and before treatment with GSK1120212 is to be continued.
3.
Height (cm) and weight (kg) will be measured only at the Transition Visit.
4.
Serum β–hCG pregnancy tests will be performed on female subjects of childbearing potential only at the time of transition from the parent study.
5.
Vital signs (BP, temperature, respiratory rate, and pulse rate) should be taken in a semi-supine position and after the subject has rested for at least 5 minutes prior to the 
reading.  Vital signs may be measured more frequently as clinically indicated.
6.
A single 12-Lead ECG will be performed using a standard 12-lead ECG machine.  All ECGs will be taken in a supine position after resting in that position for at least 10 
minutes prior to testing.  QTc interval must not be >480 msec.
7.
12-lead ECGs will be performed every 9 or 12 weeks (depending on the schedule used in the parent study; at a minimum or more frequently per local practice) for the first 2 
years of treatment (including time on parent study).  After 2 years of treatment 12-lead ECGs will be performed every 24 weeks for the duration of treatment.
8.
ECHO or MUGA scan should be performed every 12 weeks (at a minimum or more frequently per local practice).  If LVEF decreases 20 percentage points, repeat testing is 
required within 2 weeks.  If decline is sustained, the investigator, in consultation with GSK Medical Monitor, should consider withdrawal of subject from the study.
9.
ECHO is only required at the Final Study Visit if an abnormal finding is reported at a prior visit.
10. Refer to Section 8.4.5 for complete list of clinical laboratory assessments to be performed.
11. Hematology and clinical chemistry laboratory assessments will be performed every 3 or 4 weeks (depending on the scheduled used in the parent study; at a minimum or 
more frequently per local practice) for the first 2 years of treatment (including time on parent study).  After 2 years hematology and clinical chemistry laboratory assessments 
will be performed every 9 or 12 weeks (depending on schedule used in the parent study) for the duration of treatment.
12. Optional tumor tissue, skin or blood sample from a lesion not required for disease assessment and/or optional blood sample for cfDNA may be obtained if subject has 
provided consent.  
13. AEs/SAEs will be monitored and recorded beginning on the time of consent until 30 days after the last dose of GSK1120212.
14. All ongoing (unresolved) AEs at the time of the transition to this study will be recorded in the eCRF.
15. All concomitant medication(s) at the time of the transition to this study will be recorded in the eCRF.
16. The “Every 9 Weeks”, “Every 12 Weeks” or “Every 24 Weeks” columns are NOT a separate visit but instead a listing of assessments required to be completed every 9, 12 or 
24 weeks or every second or third clinic visit that is recurring at 3 or 4-week intervals, depending on the schedule used in the parent study.
17. After a subject has been on study for a total of 2 years, including time on parent study, the frequency of assessments will be modified.  If more frequent assessments are 
needed, these should be done per local practice.
18. The Final Study Visit should occur within 28 days (7 days) following the last dose of study treatment(s) and prior to initiating any new treatment.
19. Subjects who remain on study treatment >52 weeks may have the frequency of their interim visits decreased with approval from the GSK Medical Monitor.


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REVISED TEXT
Assessment/
Procedure18
Transition Visit1
Continuous Dosing 
Treatment Period20
Final Study Visit
Every 3 or 4 
weeks17
(7 days)
Every 9 or 12 
weeks17
(7 days)
Every 12 weeks17
(7 days)
Every 24 weeks17
(7 days)
With 28 days of Last Dose of 
Study Treatment(s)
(7 days)19
Informed Consent2
X
Demographics and Parent 
Study Data
X
Physical  Exam3
X
X
X
Pregnancy test4
X
Vital Signs5
X
X
X
12-Lead ECG6
X
X7
X7
X
ECHO/MUGA scan
X
X8
X9
Clinical Chemistry10
X
X11
X11
X
Hematology10
X
X11
X11
X
Liver Function Tests10,12
X
X
X
X
Tumor Tissue /Skin Biopsy 
or Blood Sample for 
Biomarker Analysis13
O
cfDNA Sample13
O
AE Monitoring14, 15
Continuous
Review of Concomitant 
Medications16
Continuous
GSK1120212 Dosing
Continuous


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Abbreviations:  O, optional
1.
All subjects transitioning from parent study will begin the rollover study based on the last treatment visit completed during the parent study.  All Transition Visit 
assessments/procedures must be completed prior to the first dose of study treatment(s).  Assessments/procedures may be used to fulfill the requirements of both the 
parent study and this study.  Results from the parent study should be recorded in the eCRF as transition values.
2.
Informed consent must be obtained prior to performing any assessments or procedures for this study and before treatment with GSK1120212 is to be continued.
3.
Height (cm) and weight (kg) will be measured only at the Transition Visit.
4.
Serum β–hCG pregnancy tests will be performed on female subjects of childbearing potential only at the time of transition from the parent study.
5.
Vital signs (BP, temperature, respiratory rate, and pulse rate) should be taken in a semi-supine position and after the subject has rested for at least 5 minutes prior to the 
reading.  Vital signs may be measured more frequently as clinically indicated.
6.
A single 12-Lead ECG will be performed using a standard 12-lead ECG machine.  All ECGs will be taken in a supine position after resting in that position for at least 10 
minutes prior to testing.  QTc interval must not be >480 msec.
7.
12-lead ECGs will be performed every 9 or 12 weeks (depending on the schedule used in the parent study; at a minimum or more frequently per local practice) for the first 
2 years of treatment (including time on parent study).  After 2 years of treatment 12-lead ECGs will be performed every 24 weeks for the duration of treatment.
8.
ECHO or MUGA scan should be performed every 12 weeks (at a minimum or more frequently per local practice).  If LVEF decreases 20 percentage points, repeat 
testing is required within 2 weeks.  If decline is sustained, the investigator, in consultation with GSK Medical Monitor, should consider withdrawal of subject from the study.
9.
ECHO is only required at the Final Study Visit if an abnormal finding is reported at a prior visit.
10. Refer to Section 8.4.5 for complete list of clinical laboratory assessments to be performed.
11. Hematology and clinical chemistry laboratory assessments will be performed every 3 or 4 weeks (depending on the scheduled used in the parent study; at a minimum or 
more frequently per local practice) for the first 2 years of treatment (including time on parent study).  After 2 years hematology and clinical chemistry laboratory 
assessments will be performed every 9 or 12 weeks (depending on schedule used in the parent study) for the duration of treatment.
12. Liver function tests (AST, ALT, alkaline phosphatase and total bilirubin) will be performed every 3 or 4 weeks (depending on the scheduled used in the parent 
study; at a minimum or more frequently per local practice) for the first 2 years of treatment (including time on parent study).  After 2 years liver function tests 
will be performed every 9 or 12 weeks (depending on schedule used in the parent study) for the duration of treatment.  Bilirubin fractionation is recommended 
if total bilirubin is >2 times ULN.
13. Optional tumor tissue, skin or blood sample from a lesion not required for disease assessment and/or optional blood sample for cfDNA may be obtained if subject has 
provided consent.  
14. AEs/SAEs will be monitored and recorded beginning on the time of consent until 30 days after the last dose of GSK1120212.
15. All ongoing (unresolved) AEs at the time of the transition to this study will be recorded in the eCRF.
16. All concomitant medication(s) at the time of the transition to this study will be recorded in the eCRF.
17. The “Every 9 Weeks”, “Every 12 Weeks” or “Every 24 Weeks” columns are NOT a separate visit but instead a listing of assessments required to be completed every 9, 12 
or 24 weeks or every second or third clinic visit that is recurring at 3 or 4-week intervals, depending on the schedule used in the parent study.
18. After a subject has been on study for a total of 2 years, including time on parent study, the frequency of assessments will be modified.  If more frequent assessments are 
needed, these should be done per local practice.
19. The Final Study Visit should occur within 28 days (7 days) following the last dose of study treatment(s) and prior to initiating any new treatment.
20. Subjects who remain on study treatment >52 weeks may have the frequency of their interim visits decreased with approval from the GSK Medical Monitor.


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AMENDMENT 1
WHERE THE AMENDMENT APPLIES
This amendment applies to all site and countries.
Summary of Amendment Changes with Rationale
It was noted that there was inconsistent language regarding the intent of the study stated 
in the rationale and study objective sections of the protocol.  The true intent of this 
protocol is, as stated in the rationale, to allow subjects to continue on drug who are 
clinically benefitting and have an acceptable toxicity profile.  Some subjects who have 
clinically progressed (e.g., isolated progression in brain, requiring treatment with gamma 
knife) but continue to receive benefit and who are allowed as per the primary protocol to 
continue on the study treatment if both the treating physician and GSK Medical Monitor 
agree, should have continued access to the study treatment. However, as per the above 
inclusion criteria these subjects would not be allowed to roll over to open-label rollover 
study which is inconsistent with the rationale of the study.
The directions for administering GSK1120212 in a fasting state were clarified to state 
“1 hour before or 2 hours after a meal”.
Country specific requirements for Australia and France were added in the event the 
protocol is opened in these countries.  General administrative changes (i.e., authors, 
sponsor signatory, assignment of medical monitors, etc.) were also made.  List of 
references was revised to remove documents that were not cited in document but listed 
erroneously in list of references.
List of Specific Changes
Page 1, Description
PREVIOUS TEXT
Description: GSK1120212 is an orally administered, potent and highly selective small 
molecule inhibitor of MEK1/MEK2 activation and kinase activity.  As monotherapy, 
GSK1120212 has shown an acceptable risk-benefit profile with encouraging efficacy in 
various oncologic settings.  This multicenter, non-randomized, open-label, rollover study 
is designed to provide continued access to GSK1120212 to eligible subjects who have 
previously participated in a GlaxoSmithKline (GSK)-sponsored GSK1120212 study 
(referred to as the parent study) and have no evidence of progressive disease as well as an 
acceptable safety profile with GSK1120212.  Subjects will be enrolled into an 
appropriate cohort based on the treatment received in their parent study.  Safety 
assessments (physical examinations, vital sign measurements, 12-lead 
electrocardiograms, echocardiograms or multiple-gated acquisition scans, clinical 
laboratory assessments, and monitoring of adverse events) will be evaluated throughout 
the study.  Clinical activity will be assessed using local standard of care imaging 
practices and the appropriate assessment criteria as determined by the investigator.


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REVISED TEXT
Description: GSK1120212 is an orally administered, potent and highly selective small 
molecule inhibitor of MEK1/MEK2 activation and kinase activity.  As monotherapy, 
GSK1120212 has shown an acceptable risk-benefit profile with encouraging efficacy in 
various oncologic settings.  This multicenter, non-randomized, open-label, rollover study 
is designed to provide continued access to GSK1120212 to eligible subjects who have 
previously participated in a GlaxoSmithKline (GSK)-sponsored GSK1120212 study 
(referred to as the parent study) and have no evidence of progressive disease as well as
who are clinically benefitting from continued treatment and have an acceptable 
safety profile with GSK1120212.  Subjects will be enrolled into an appropriate cohort 
based on the treatment received in their parent study.  Safety assessments (physical 
examinations, vital sign measurements, 12-lead electrocardiograms, echocardiograms or 
multiple-gated acquisition scans, clinical laboratory assessments, and monitoring of 
adverse events) will be evaluated throughout the study.  Clinical activity will be assessed 
using local standard of care imaging practices and the appropriate assessment criteria as 
determined by the investigator.
Protocol Summary 
PREVIOUS TEXT
Rationale
GSK1120212 is a potent and highly selective inhibitor of MEK kinase activity.  This 
multicenter, non-randomized, open-label rollover study will provide continued access to 
GSK1120212 to subjects with solid tumors or leukemia who have previously participated 
in a GlaxoSmithKline (GSK)-sponsored GSK1120212 study and who have no evidence 
of progressive disease as well as an acceptable safety profile with GSK1120212.
Objectives
The primary objective of the study is to provide continued treatment with GSK1120212 
for subjects with solid tumors or leukemia who have previously participated in a GSK-
sponsored GSK1120212 study and who have no evidence of progressive disease as well 
as an acceptable safety profile with GSK1120212.
Study Design
This Phase II, multicenter, non-randomized, open-label, rollover study is designed to 
provide continued access to GSK1120212 to subjects with solid tumors or leukemia who 
have previously participated in a GSK-sponsored GSK1120212 study (parent study) and 
who have no evidence of progressive disease as well as an acceptable safety profile with 
GSK1120212.  Subjects will be enrolled into the appropriate cohort based upon the 
treatment received in their parent study.  Enrollment into this study will be dependent 
upon the site’s agreement to participate in this study.  It is estimated that approximately 
250 subjects will be enrolled in this study. Subjects may continue treatment in the 
rollover study until disease progression, unacceptable toxicity, withdrawal of consent, or 
commercial supply of GSK1120212 becomes available to the subject. 


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Study Assessments
Assessment of clinical activity will be performed throughout the study using local 
standard of care imaging practices and the appropriate assessment criteria as determined 
by the investigator to determine continued study participation and treatment with 
GSK1120212.  Only subjects considered by the investigator to be without progressive 
disease may continue on study treatment
REVISED TEXT
Rationale
GSK1120212 is a potent and highly selective inhibitor of MEK kinase activity.  This 
multicenter, non-randomized, open-label rollover study will provide continued access to 
GSK1120212 to subjects with solid tumors or leukemia who have previously participated 
in a GlaxoSmithKline (GSK)-sponsored GSK1120212 study and who have no evidence 
of progressive disease and who are clinically benefitting from continued treatment 
and have an acceptable safety profile with GSK1120212.
Objectives
The primary objective of the study is to provide continued treatment with GSK1120212 
for subjects with solid tumors or leukemia who have previously participated in a GSK-
sponsored GSK1120212 study and who have no evidence of progressive disease as and 
who are clinically benefitting from continued treatment and have an acceptable 
safety profile with GSK1120212.
Study Design
This Phase II, multicenter, non-randomized, open-label, rollover study is designed to 
provide continued access to GSK1120212 to subjects with solid tumors or leukemia who 
have previously participated in a GSK-sponsored GSK1120212 study (parent study) and 
who have no evidence of progressive disease who are clinically benefitting from 
continued treatment and have an acceptable safety profile with GSK1120212.  Subjects 
will be enrolled into the appropriate cohort based upon the treatment received in their 
parent study.  Enrollment into this study will be dependent upon the site’s agreement to 
participate in this study.  It is estimated that approximately 250 subjects will be enrolled 
in this study. Subjects may continue treatment in the rollover study until disease 
progression until no longer clinically benefitting, unacceptable toxicity, withdrawal of 
consent, or commercial supply of GSK1120212 becomes available to the subject. 
Study Assessments
Assessment of clinical activity will be performed throughout the study using local 
standard of care imaging practices and the appropriate assessment criteria as determined 
by the investigator to determine continued study participation and treatment with 
GSK1120212.  Only subjects considered by the investigator to be without progressive 
disease to be receiving clinical benefit may continue on study treatment


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Section 2.1 Objectives
PREVIOUS TEXT 
The primary objective of the study is to provide continued treatment with GSK1120212 
for subjects who have previously participated in a GSK-sponsored GSK1120212 study 
and who have no evidence of progressive disease as well as an acceptable safety profile 
with GSK1120212.
REVISED TEXT
The primary objective of the study is to provide continued treatment with GSK1120212 
for subjects who have previously participated in a GSK-sponsored GSK1120212 study 
and who have no evidence of progressive disease who continue to receive clinical 
benefit as well as have an acceptable safety profile with GSK1120212.
Section 3 Study Design, Paragraph 1, Paragraph 6 and Paragraph 7 
PREVIOUS TEXT
This Phase II, multicenter, non-randomized, open-label, rollover study is designed to 
provide continued access to GSK1120212 to subjects who have previously participated in 
a GSK-sponsored GSK1120212 study (parent study).  All subjects enrolling in this study 
must have no evidence of progressive disease as well as an acceptable safety profile with 
GSK1120212 to be eligible.  Subjects will be stratified into the appropriate cohort (see 
Section 3.1) based upon the treatment received in their parent study.  Enrollment into this 
study will be dependent upon the site’s agreement to participate in this study.
Assessment of clinical activity will be performed using local standard of care imaging 
practices and the appropriate assessment criteria (e.g. Response Evaluation Criteria in 
Solid Tumors [RECIST] 1.1) as determined by the investigator to determine continued 
study participation and treatment with GSK1120212.  Only subjects without progressive 
disease as determined by the investigator as well as an acceptable toxicity safety profile 
will be allowed to continue treatment on study.
Subjects may continue treatment in this rollover study until disease progression, 
unacceptable toxicity, withdrawal of consent, or commercial supply of GSK1120212 
becomes available to the subject. 


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REVISED TEXT
This Phase II, multicenter, non-randomized, open-label, rollover study is designed to 
provide continued access to GSK1120212 to subjects who have previously participated in 
a GSK-sponsored GSK1120212 study (parent study).  All subjects enrolling in this study 
must have no evidence of progressive disease be receiving clinical benefit from 
continued treatment as well as have an acceptable safety profile with GSK1120212 to 
be eligible.  Subjects will be stratified into the appropriate cohort (see Section 3.1) based 
upon the treatment received in their parent study.  Enrollment into this study will be 
dependent upon the site’s agreement to participate in this study.
Assessment of clinical activity will be performed using local standard of care imaging 
practices and the appropriate assessment criteria (e.g. Response Evaluation Criteria in 
Solid Tumors [RECIST] 1.1) as determined by the investigator to determine continued 
study participation and treatment with GSK1120212.  Only subjects without progressive 
disease who continue to receive clinical benefit as determined by the investigator as 
well as having an acceptable toxicity safety profile will be allowed to continue treatment 
on study.
Subjects may continue treatment in this rollover study until disease progression lack of 
clinical benefit, unacceptable toxicity, withdrawal of consent, or commercial supply of 
GSK1120212 becomes available to the subject.
Section 4.1.2 Inclusion Criteria, Criteria #3
PREVIOUS TEXT
Is currently participating in a GSK-sponsored study of GSK1120212 and receiving 
treatment with GSK1120212.
REVISED TEXT
Is currently participating in GSK1120212 study and is receiving treatment with 
GSK1120212.
Section 4.1.2, Inclusion Criteria, Criteria #4
PREVIOUS TEXT
Currently has no evidence of progressive disease as determined by the investigator from 
previous treatment with GSK1120212 either as monotherapy or as part of a combination 
treatment regimen
REVISED TEXT
Is currently receiving clinical benefit as determined by the investigator from previous 
treatment with GSK1120212 either as monotherapy or as part of a combination treatment 
regimen.


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Section 4.1.2 Inclusion Criteria, Criteria #9
PREVIOUS TEXT
French Subjects: In France, a subject will be eligible for inclusion in this study only if 
either affiliated to or a beneficiary of a social security category.
REVISED TEXT
Subjects enrolled in France: In France, a subject will be eligible for inclusion in this 
study only if either affiliated to or a beneficiary of a social security category.
Section 4.1.3  Exclusion Criteria, Criteria #4
PREVIOUS TEXT
Current evidence or risk of RVO or CSR: 

Visible retinal pathology as assessed by ophthalmic exam that is considered a 
risk factor for RVO or CSR such as:

Evidence of new optic disc cupping

Evidence of new visual field defects  

Intraocular pressure >21 mmHg 
REVISED TEXT
Previous text deleted and list of exclusion criteria were renumbered.
Section 4.1.3  Exclusion Criteria, Criteria #5
PREVIOUS TEXT
Any unresolved toxicity > Grade 2, except for alopecia, (National Cancer Institute-
Common Toxicity Criteria for Adverse Events [NCI Common Terminology Criteria for 
Adverse Events, 2009], version 4.0) from parent study treatment at time of transition to 
this study.
REVISED TEXT
Any unresolved toxicity > Grade 2, except for alopecia, (National Cancer Institute-
Common Toxicity Criteria for Adverse Events [NCI Common Terminology Criteria for 
Adverse Events, 2009], version 4.0) from parent study treatment at time of transition to 
this study that meets the study treatment discontinuation or study withdrawal 
criteria from the parent study at the time of transition to this study.


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Section 4.1.3 Exclusion Criteria, Criteria #7
PREVIOUS TEXT
Bazett-corrected QT (QTcB) interval 480 msec at the time of transition to this study.  
REVISED TEXT
Bazett-corrected QT (QTcB) interval >530 msec or uncorrected QT >600 msec at the 
time of transition to this study.  
Section 4.1.3 Exclusion Criteria, Criteria #10
PREVIOUS TEXT
Symptomatic or untreated leptomeningeal or brain metastases or spinal cord compression 
at the time of transition to this study.
NOTE: Subjects are not permitted to receive enzyme-inducing anti-epileptic 
(EIAEDs).  Continued stability of brain metastases must be confirmed with imaging.
REVISED TEXT
Symptomatic or untreated leptomeningeal or brain metastases or spinal cord compression 
at the time of transition to this study.
NOTE: Subjects are not permitted to receive enzyme-inducing anti-epileptic 
(EIAEDs).  Continued stability of brain metastases must be confirmed with imaging.
Section 5.1 GSK1120212 GSK Investigational Product
PREVIOUS TEXT
Dosing 
Instructions:
GSK1120212 will be taken with approximately 240 mL (8 fl oz) of water.  
Subjects will be expected to fast for at least 1 hour before and 2 hours after 
dosing unless further instructed based on food-effect assessment. 
REVISED TEXT
Dosing 
Instructions:
GSK1120212 should be administered will be taken with approximately 
240 mL (8 fl oz) of water, under fasting conditions, either 1 hour before or 
2 hours after a meal. Subjects will be expected to fast for at least 1 hour 
before and 2 hours after dosing unless further instructed based on food-effect 
assessment. 


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Section 5.7.6.1 French Specific QTc Stopping Criteria added
NEW TEXT
In line with local requirements, a subject in France that meets the QTc1 criteria 
below will have study treatment withheld:
QTcB >500 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 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.
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.
Section 7.1 Meals and Dietary Restrictions
PREVIOUS TEXT
GSK1120212 should be taken orally, once-daily with approximately 8 fl oz of water.  
Subjects should fast from other food consumption for at least 1 hour prior to daily dosing 
through at least 2 hours after daily dosing due to a potential food-effect on GSK1120212 
absorption. GSK1120212 should be taken orally, once-daily with approximately 8 fl oz of
water.  Subjects should fast from other food consumption for at least 1 hour prior to daily 
dosing through at least 2 hours after daily dosing due to a potential food-effect on 
GSK1120212 absorption.
REVISED TEXT
GSK1120212 should be taken orally, once-daily with approximately 8 fl oz of water.  
Subjects should fast from other food consumption for at least 1 hour prior to daily dosing 
through before and for at least 2 hours after daily dosing with GSK1120212 due to a 
potential food-effect on GSK1120212 absorption.
References
DELETED TEXT
GlaxoSmithKline Document Number RM2010/00127/00.  MEK114375: An Open-Label, 
Phase Ib Continuation Study of GSK1120212 Monotherapy or GSK1120212 in 
Combination with other Anti-cancer Treatment in Patients with Solid Tumors. 2010
Lacouture ME, Basti S, Patel J, et al. The SERIES clinic: an interdisciplinary approach to 
the management of toxicities of EGFR inhibitors. J Support Oncol. 2006 May;4(5):236-8.


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Lynch TJ Jr, Kim ES, Eaby B, et al. Epidermal growth factor receptor inhibitor-
associated cutaneous toxicities: an evolving paradigm in clinical management. 
Oncologist. 2007 May;12(5):610-21. 
Pérez-Soler R, Delord JP, Halpern A, et al. HER1/EGFR inhibitor-associated rash: future 
directions for management and investigation outcomes from the HER1/EGFR inhibitor 
rash management forum. Oncologist. 2005 May;10(5):345-56.
Appendix 5: Country Specific Requirements
PREVIOUS TEXT
No known country specific requirements are currently required.
REVISED TEXT
Australia:  Supply of GSK1120212 should continue until the drug is available under 
subsidy on the Pharmaceutical Benefits Scheme (PBS).  
France:  French specific QTc Stopping Criteria has been added to Section 5.7.6.1.
No other known country specific requirements are currently required.

SAP_001.pdf: 
Clinical Development
TMT212A/Trametinib
CTMT212A2X01B (MEK114375) / NCT01376310
A Rollover Study to Provide Continued Treatment with 
Trametinib to Subjects with Solid Tumors or Leukemia
Statistical Analysis Plan (SAP)
Author:
Trial Statistician, 
Document type:
SAP Documentation
Document status:
Final 1.0
Release date:
14-Dec-2016
Number of pages:
16
Property of Novartis
Confidential
May not be used, divulged, published or otherwise disclosed
without the consent of Novartis


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Document History – Changes compared to previous final version of SAP
Date
Time 
point
Reason for 
update
Outcome for update
Section and title 
impacted 
(Current)


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Table of contents
Table of contents .................................................................................................................3
Introduction ................................................................................................................................6
1.1
Study design.............................................................................................................6
1.2
Study objectives and endpoints ...............................................................................7
2
Statistical methods...............................................................................................................7
2.1
Data analysis general information ...........................................................................7
2.1.1
General definitions..................................................................................7
2.2
Analysis sets ............................................................................................................9
2.3
Subject disposition, demographics and other baseline characteristics ..................10
Subject disposition.................................................................................................10
2.4
Treatments (study treatment, rescue medication, concomitant therapies, 
compliance)............................................................................................................10
2.4.1
Study treatment / compliance................................................................10
2.4.2
Prior, concomitant and post therapies ...................................................11
2.5
Analysis of the primary objective..........................................................................11
2.6
Analysis of the key secondary objective ...............................................................11
2.7
Analysis of secondary efficacy objective(s) ..........................................................11
2.8
Safety analyses.......................................................................................................11
2.8.1
Adverse events (AEs)............................................................................11
2.8.2
Deaths....................................................................................................12
2.8.3
Laboratory data .....................................................................................12
2.8.4
Other safety data ...................................................................................12
2.9
Pharmacokinetic endpoints....................................................................................12
2.10
PD and PK/PD analyses.........................................................................................12
2.11
Patient-reported outcomes .....................................................................................12
2.12
Biomarkers.............................................................................................................13
2.13
Other Exploratory analyses....................................................................................13
2.14
Interim analysis......................................................................................................13
3
Sample size calculation .....................................................................................................13
4
Change to protocol specified analyses ..............................................................................13
5
Appendix ...........................................................................................................................13
5.1
Imputation rules.....................................................................................................13
5.1.1
Study drug .............................................................................................13
5.1.2
AE date imputation ...............................................................................14
5.1.3
Concomitant medication date imputation .............................................15


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5.2
AEs coding/grading ...............................................................................................16
5.3
Laboratory parameters derivations ........................................................................16
5.4
Statistical models...................................................................................................16
5.4.1
Primary analysis ....................................................................................16
5.4.2
Key secondary analysis .........................................................................16
5.4.3
Secondary efficacy analysis ..................................................................16
6
Reference...........................................................................................................................16


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List of abbreviations
AE
Adverse Event
eCRF
Electronic Case Report Form
GSK
GlaxoSmithKline
MedDRA
Medical Dictionary for Regulatory Activities
PT
Preferred Term
RECIST
Response Evaluation Criteria in Solid Tumors
SAE
Serious Adverse Event
SOC
System Organ Class


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Introduction
This statistical analysis plan (SAP) describes all planned analyses for the clinical study report 
(CSR) of study CTMT212A2X01B, a multi-center, non-randomized, open-label, phase II, 
rollover study conducted in subjects with solid tumors or leukemia who have previously 
participated in a Trametinib study (parent study) and who are clinically benefitting from 
continued treatment and have an acceptable safety profile with Trametinib.
The content of this SAP is based on protocol CTMT212A2X01B (MEK114375) amendment 7. 
All decisions regarding final analyses, as defined in the SAP document, have been made prior 
to database lock.
1.1
Study design
This Phase II, multicenter, non-randomized, open-label, rollover study is designed to provide 
continued access to Trametinib to subjects with solid tumors or leukemia who have previously 
participated in a Trametinib study (parent study) and who are clinically benefitting from 
continued treatment and have an acceptable safety profile with Trametinib. Subjects will be 
enrolled into the appropriate cohort based upon the treatment received in their parent study. 
Enrollment into this study will be dependent upon the site’s agreement to participate in this 
study. It is estimated that approximately 250 subjects will be enrolled in this study. Subjects 
may continue treatment in the rollover study until no longer clinically benefitting, 
unacceptable toxicity, withdrawal of consent, have access to local commercial supply of 
Trametinib or the study is terminated early.
Cohort A will consist of subjects who have completed 24 weeks of treatment with 
Trametinib monotherapy during their participation in the parent study.
Cohort B will consist of subjects who have completed ≥24 weeks of treatment with 
Trametinib (either as monotherapy or combination therapy with an approved anti-cancer 
agent) during their participation in the parent study.
The study will consist of a transition visit, a continuous dosing treatment period, and a final 
study visit.  Safety assessments will be performed throughout the study, including physical 
examinations, vital sign measurements (blood pressure, pulse rate, respiratory rate and 
temperature), 12-lead electrocardiograms (ECGs), echocardiograms (ECHOs)/MUGA scan, 
clinical laboratory assessments, and monitoring of AEs. Additional safety assessments may be 
necessary for subjects on a combination treatment.  Assessment of clinical activity will be 
performed using local standard of care imaging practices and the appropriate assessment 
criteria (e.g., Response Evaluation Criteria in Solid Tumors [RECIST] 1.1) as determined by 
the investigator to determine continued study participation and treatment with trametinib.  
Only subjects who are demonstrating clinical benefit as determined by the investigator as well 
as an acceptable safety profile will be allowed to continue treatment on study and will


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continue treatment until no longer receiving clinical benefit, unacceptable toxicity, withdrawal 
of consent, or commercial supply of trametinib becomes available to the subject.
This statistical analysis plan (SAP) details the planned analyses required for a clinical study 
report.  
1.2
Study objectives and endpoints
The primary objective of this study is to provide continuing treatment with trametinib either 
as monotherapy or as part of a combination regimen for subjects with solid tumors or 
leukemia who have previously participated in a trametinib study and who continue to receive 
clinical benefit as well as have an acceptable safety profile with trametinib. There are no 
formal endpoints for this study.
2
Statistical methods
2.1
Data analysis general information
The tables, figures and listings will be generated by a designated CRO. SAS version 9.4 or 
later software will be used to perform all data analyses and to generate tables, figures and 
listings.
Data included in the analysis
The final analysis will take place after the last subject, last visit has occurred.  It is anticipated 
that this trial will remain open until local commercial supply of trametinib becomes available
or early termination of the study.
General analysis conventions
Pooling of center: Unless specified otherwise, data from all study centers will be pooled for 
the analysis. Due to expected small size of centers, no center effect will be assessed. 
Qualitative data (e.g., gender, race, etc.) will be summarized by means of contingency tables; 
a missing category will be included as applicable. Percentages will be
calculated using the number of subjects in the relevant population or subgroup as the
denominator.
Quantitative data (e.g., age, body weight, etc.) will be summarized by appropriate
descriptive statistics (i.e. mean, standard deviation, median, minimum, and maximum).
2.1.1
General definitions
Investigational drug and study treatment
Investigational drug, study drug refer to trametinib.
Study treatment refers to trametinib, trametinib + an approved anti-cancer agent.
The study treatment component refers to trametinib or an approved anti-cancer agent.


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Treatment
For presentation in the outputs, the following treatment descriptors will be used on all 
applicable summaries, figures, and listings:

Cohort A,

Cohort B.
Date of first/last administration of study drug
The date of first administration of study drug is defined as the first date when a non-zero dose 
of study drug was administered and recorded on the Study Treatment Exposure (ST 
EXPOSURE) eCRF. For simplicity, the date of first administration of study drug will also be 
referred as start date of study drug.
The date of last administration of study drug is defined as the last date when a non-zero dose 
of study drug was administered and recorded on ST EXPOSURE eCRF. 
Date of first/last administration of study treatment
The date of first administration of study treatment is derived as the first date when a non-zero 
dose of any component of study treatment was administered and recorded on the ST 
EXPOSURE eCRF. For example, if the 1st dose of study drug A is administered on 
04JAN2010, and the 1st dose of its combination partner, drug B, is administered on 
03JAN2010, the date of the first administration of study treatment is on 03JAN2010). For the 
sake of simplicity, the date of the first administration of study treatment will also be referred 
as the start of study treatment.
The date of last administration of study treatment is derived as the last date when a non -zero 
dose of any component of study treatment was administered and recorded on the Study 
Treatment Exposure eCRF . For example, if the last dose of Trametinib is administered on 
15APR2010, and the last dose of a combination partner is administered on 17MAY2010, the 
date of last administration of study treatment is then on 17MAY2010.
Study day
The study day, describes the day of the event or assessment date, relative to the reference start 
date. 
The study day is defined as:
The date of the event (visit date, onset date of an event, assessment date etc.) − 
reference start date + 1 if event is on or after the reference start date;

The date of the event (visit date, onset date of an event, assessment date etc.) − 
reference start date if event precedes the reference start date.
The reference date for all assessments is the start of study treatment. 
The study day will be displayed in the data listings. If an event starts before the reference start 
date, the study day displayed on the listing will be negative.


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Time unit
A year length is defined as 365.25 days. A month length is 30.4375 days (365.25/12). If 
duration is reported in months, duration in days will be divided by 30.4375.  If duration is 
reported in years, duration in days will be divided by 365.25.
Baseline
Baseline is defined as the most recent non-missing value prior to the first dose of study 
treatment.
On-treatment assessment/event and observation periods
Adverse events, serious adverse events, death will be assigned to the treatment periods 
defined below. Flag variables indicating the treatment period will be added to these datasets.
On-treatment is defined as the time from first dose of study treatment on this trial until the 
earliest of 30 days after the last dose of study treatment. If an event occurs on the same date as 
the first dose of study treatment on this trial, then the event will be considered as occurring 
during the on-treatment period.  
Post-treatment is defined as any time beyond the on-treatment period.
If dates are incomplete in a way that clear assignment to  on-, post-treatment period cannot be 
made, then the respective data will be assigned to the on-treatment period.  
In particular, summary tables for adverse events (AEs) will summarize only on-treatment 
events, with a start date during the on-treatment period, the so-called treatment-emergent
AEs.  
However, safety data per this analysis plan (including those from the post-treatment period)
will be listed and those collected during the pre-treatment and post-treatment period are to be 
flagged.
Windows for multiple assessments 
All data will be reported according to the nominal visit date for which it was reported (that is, 
no visit windows will be applied during dataset creation). 
2.2
Analysis sets
Safety
The Safety Set is the primary population of interest in this trial which includes all subjects 
who received at least one dose of study treatment after enrolling into the rollover protocol. 
Withdrawal of Informed Consent
Any data collected in the clinical database after a subject withdraws informed consent from all 
further participation in the trial, will not be included in the analysis data sets.  The date on 
which a subject withdraws full consent is recorded in the eCRF. 


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2.3
Subject disposition, demographics and other baseline 
characteristics
The Safety Set will be used for all baseline and demographic summaries and listings unless 
otherwise specified.
Basic demographic and background data
The demographic characteristics (e.g., age, ethnicity, sex, height, and body weight) will be 
summarized and listed.  Age will be summarized both as a continuous variable and 
categorized as < 65 and 65 years.  
Subject disposition
Subject disposition will be summarized using the Safety set. The following will be tabulated:

Number (%) of subjects, who remained in the trial at the time of data cut-off or final 
data base lock;

Number (%) of subjects who discontinued the treatment;

Number (%) of subjects with primary reason for end of treatment (based on subject
status entered in the ‘Study Treatment Discontinuation’ page);
Listings will be provided for disposition using the Safety set.
Analysis sets
Safety set is the only analysis set for this study.
2.4
Treatments (study treatment, rescue medication, concomitant 
therapies, compliance)
2.4.1
Study treatment / compliance
Dose administration data will be summarized by cohorts using the Safety Set.
Duration of exposure to study treatment
Exposure summaries will be produced by cohorts.  Duration of treatment will be summarized 
in the number of months.  The summary will include daily dose and cumulative dose.  In 
addition, a listing of exposure to trametinib, and other anti-cancer agents taken with 
trametinib will be produced.
Dose exposure
Not applicable.
Dose reductions, interruptions or permanent discontinuations


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Not applicable.
2.4.2
Prior, concomitant and post therapies
Not applicable.
2.5
Analysis of the primary objective
Not a formal endpoint and analysis is planned for the primary objective in this study.
2.6
Analysis of the key secondary objective
Not applicable.
2.7
Analysis of secondary efficacy objective(s)
Not applicable.
2.8
Safety analyses
All safety analyses will be based on the safety set. Summaries will be sorted and displayed by 
Cohort A, Cohort B.
2.8.1
Adverse events (AEs)
AE summaries will include all AEs occurring during on treatment period. All AEs collected in 
the AE (e)CRF page will be listed along with the information collected on those AEs e.g. AE 
relationship to study drug, AE outcome etc. AEs with start date outside of on-treatment period 
will be flagged in the listings. 
AEs will be summarized by number and percentage of subjects having at least one AE, having 
at least one AE in each primary system organ class (SOC) and for each preferred term (PT) 
using MedDRA coding. A subject with multiple occurrences of an AE will be counted only 
once in the respective AE category. A subject with multiple CTCAE grades for the same 
preferred term will be summarized under the maximum CTCAE grade recorded for the event.
In AE summaries, the primary system organ class (SOC) will be presented alphabetically and 
the preferred terms will be sorted within primary SOC in descending frequency. The sort 
order for the preferred term will be based on their frequency. 
The following AE summaries will be produced: AEs by SOC, PT and maximum grade, 
summarized by relationship to study drug, seriousness, leading to treatment discontinuation, 
in addition, a summary of  serious adverse events with number of occurrences will be 
produced.
2.8.1.1
Adverse events of special interest / grouping of AEs
Data analysis of AESIs
Adverse events of special interest (AESIs) are defined as AEs within the following 
categories/groupings of PTs:


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
Rash

Visual changes

Diarrhea

Pneumonitis

LVEF
AESIs are defined at the project level and may be updated based on emergent data to reflect
new AESIs of interest at the time of analysis.
For each specified AESI, number and percentage of subjects with at least one event of the 
AESI occurring during on treatment period will be summarized.
A listing of all grouping levels down to the MedDRA preferred terms used to define each 
AESI will be generated. 
2.8.2
Deaths
Separate summaries for on-treatment death and all deaths on-treatment and post-treatment
will be produced by system organ class and preferred term. All deaths will be listed, post 
treatment deaths will be flagged.
Note: The death summaries cover subjects from the Safety Set. 
2.8.3
Laboratory data
As a short close-out CSR will be produced, data will not be summarized and listed.
2.8.4
Other safety data
2.8.4.1
ECG and cardiac imaging data
As a short close-out CSR will be produced, data will not be summarized and listed.
2.8.4.2
Vital signs
As a short close-out CSR will be produced, data will not be summarized and listed.
2.9
Pharmacokinetic endpoints
Not Applicable.
2.10
PD and PK/PD analyses
Not Applicable.
2.11
Patient-reported outcomes
Not Applicable. 


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2.12
Biomarkers
Not Applicable.
2.13
Other Exploratory analyses
Not Applicable.
2.14
Interim analysis
No formal interim analysis will be performed.
3
Sample size calculation
There are no statistical hypotheses in this trial therefore there is no sample size calculation.  
The sample size will be based on the number of subjects completing their parent study of 
trametinib who are eligible for inclusion in this rollover study.  It is estimated that 
approximately 250 subjects will be enrolled
4
Change to protocol specified analyses
Clinical laboratory data, vital signs, 12-lead ECG, and ECHO/MUGA scan data will not be 
summarized and listed. 
5
Appendix
This will be used later for drafting CSR Appendix 16.1.9.
5.1
Imputation rules
5.1.1
Study drug
The following rule should be used for the imputation of the dose end date for trametinib:
Scenario 1: If the dose end date is completely missing and there is no ‘STUDY 
TREATMENT DISCONTINUATION’ page and no death date, the subject is considered as 
on-going:
The subject should be treated as on-going and the cut-off date should be used as the last 
dosing date. 
Scenario 2: If the dose end date is completely or partially missing and the EOT page is 
available:
Case 1: The dose end date is completely missing, and the EOT  completion date is complete, 
then this latter date should be used.  
Case 2: Only Year(yyyy) of the dose end date is available and yyyy < the year of EOT date:  
Use Dec31yyyy
Case 3: Only Year(yyyy) of the dose end date is available and yyyy  = the year of EOT date:


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Use EOT date
Case 4: Both Year(yyyy) and Month (mm) are available for dose end date, and yyyy  = the 
year of EOT date and mm < the month of  EOT date: 
Use last day of the Month (mm)
All other cases should be considered as a data issue and the statistician should contact the data 
manager of the study.
After imputation, compare the imputed date with start date of treatment, if the imputed date is 
< start date of treatment:
Use the treatment start date
Subjects with missing start dates are to be considered missing for all study treatment 
component related calculations and no imputation will be made. If start date is missing then 
end-date should not be imputed.
5.1.2
AE date imputation
The following missing dates will not be imputed

Missing AE start dates

AE start dates missing the year

Partial/missing AE end dates
For other type of missing dates, rules specified in Tables 5-1 to 5-3 will be used
Table 5-1
AE/Treatment Date Abbreviations 
Day
Month
Year
Partial Adverse Event Start Date
<not used>
AEM
AEY
Treatment Start Date (TRTSTD)
<not used>
TRTM
TRTY
Table 5-2 describes the possible combinations and their associated imputations. The upper 
text indicates the imputation (NC, A, B, C etc.) and the lower text the relationship of the AE 
start date to the treatment start date (TRTSTD).
Table 5-2
Imputation algorithm
AEM MISSING
AEM < TRTM
AEM = TRTM
AEM > TRTM
AEY MISSING
NC
Uncertain
NC
Uncertain
NC
Uncertain
NC
Uncertain
AEY < TRTY
( D )
Before TRTSTD
( C )
Before TRTSTD
( C )
Before TRTSTD
( C )
Before TRTSTD
AEY = TRTY
( B )
Uncertain
( C )
Before TRTSTD
( B )
Uncertain
( A )
After TRTSTD
AEY > TRTY
( E )
After TRTSTD
( A )
After TRTSTD
( A )
After TRTSTD
( A )
After TRTSTD
The legend to the above table is shown in Table 5-3.


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Table 5-3
Imputation algorithm legends
Relationship
Before TRTSTD
Indicates AE start date prior to Treatment Start Date
After TRTSTD
Indicates AE start date after Treatment Start Date
Uncertain
Insufficient to determine the relationship of AE start date 
to Treatment Start Date
Imputation calculation
NC / Blank
No convention/imputation
( A )
01MONYYYY
( B )
TRTSTD+1
( C )
15MONYYYY
( D )
01JULYYYY
( E )
01JANYYYY
Few examples are shown in Table 5-4.
Table 5-4
Example scenarios
Partial
AE start date
Treatment
start date
Relationship 
with TRTSTD
Imputation 
Calculation
Imputed Date
12mmyyyy
20OCT2001
Uncertain
NC
<blank>
ddmmm2000
20OCT2001
Before
( D )
01JUL2000
ddmmm2002
20OCT2001
After
( E )
01JAN2002
ddmmm2001
20OCT2001
Uncertain
( B )
21OCT2001
ddSEP2001
20OCT2001
Before
( C )
15SEP2001
ddOCT2001
20OCT2001
Uncertain
( B )
21OCT2001
ddNOV2001
20OCT2001
After
( A )
01NOV2001
5.1.3
Concomitant medication date imputation
Not applicable.
5.1.3.1
Other imputations
Incomplete date of initial diagnosis of cancer and  date of most recent 
recurrence 
Missing day is defaulted to the 15th of the month and missing month and day is defaulted to 
01-Jan. 
Missing death date
All dates must be completed with day, month and year. For cases when either day is missing 
or both month and day are missing for the date of death, the following imputation rules will be 
implemented:


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
If only day is missing, then impute max [(1 mmm-yyyy), min(last contact date+1 , cutoff 
date)]. 

If both day and month are missing, then impute max [(1 Jan-yyyy, min (last contact date 
+1, cutoff date)].
5.2
AEs coding/grading
Adverse events are coded using the Medical dictionary for regulatory activities (MedDRA) 
terminology.
AEs will be assessed according to the Common Terminology Criteria for Adverse Events 
(CTCAE) version 4.00.
The CTCAE represents a comprehensive grading system for reporting the acute and late 
effects of cancer treatments. CTCAE grading is by definition a 5-point scale generally 
corresponding to mild, moderate, severe, life threatening, and death. This grading system 
inherently places a value on the importance of an event, although there is not necessarily 
proportionality among grades (a grade 2 is not necessarily twice as bad as a grade 1). The 
CTCAE grade of 5 (death) is not used; rather, ‘fatal’ is collected as AE outcome and death 
information is also collected on a separate (e)CRF page.
5.3
Laboratory parameters derivations
Not applicable.
5.4
Statistical models
5.4.1
Primary analysis
Not Applicable.
5.4.2
Key secondary analysis
Not applicable.
5.4.3
Secondary efficacy analysis
Not Applicable.
6
Reference
None.