Conditions: Melanoma
Keywords: dabrafenib MEK trametinib BRAF melanoma Oncology
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 48
Healthy volunteers: no

Brief summary:
This is a three-arm, open-label, randomised Phase II study to evaluate whether the different sequencing of dabrafenib and trametinib monotherapies and the upfront combination has an impact on translational or clinical activity in subjects with BRAF mutant metastatic unresectable stage IIIc or IV melanoma. Both dabrafenib and trametinib have demonstrated clinical activity as monotherapies and in combination in BRAF-mutant melanoma. However, duration of responses seem to be limited due to acquired drug resistance. The goal of this protocol is to study the sequential effects of BRAF and MEK inhibition on skin, blood and tumour biomarkers and to study the correlation between biomarkers and response to treatment and intrapatient toxicity. Approximately 54 eligible subjects will be randomised in the ratio of 1:1:1 to one of the three treatment arms.

Detailed description:

Arms:
arm 1: Eligible subjects will receive dabrafenib 150 milligrams (mg) twice a day (BID) continuously during 8 weeks of monotherapy treatment followed by the combination of trametinib 2 mg once daily with dabrafenib 150 mg BID until disease progression, death or unacceptable toxicity. arm 2: Eligible subjects will receive trametinib 2 mg per day continuously during 8 weeks of monotherapy treatment followed by the combination of trametinib 2 mg once daily with dabrafenib 150 mg BID until disease progression, death or unacceptable toxicity. arm 3: Eligible subjects will receive trametinib 2 mg per day plus dabrafenib 150 mg BID continuously until disease progression, death or unacceptable toxicity.

Interventions: intervention 1: Dabrafenib intervention 2: Trametinib
Intervention descriptions: intervention 1: Dabrafenib will be provided as 50 mg and 75 mg capsules. intervention 2: Trametinib study medication will be provided as 0.5 mg and 2.0 mg tablets.

Protocol document:
Prot_000.pdf: 
2012N132406_01
CONFIDENTIAL
GlaxoSmithKline group of companies
BRF116613
1
Division:  Worldwide Development
Information Type: Clinical Protocol
Title:
Phase II biomarker study evaluating the upfront combination of 
BRAF inhibitor dabrafenib with MEK inhibitor trametinib 
versus the combination after eight weeks of monotherapy with
dabrafenib or trametinib in patients with metastatic and 
unresectable stage III or IV melanoma harbouring an activating 
BRAF mutation
Compound Number:
GSK1120212+GSK2118436
Development Phase
II 
Effective Date:
28-OCT-2013
Protocol Amendment Number:  01
Description: Three-arm, open-label, randomised Phase II study to evaluate whether the 
different sequencing of dabrafenib and trametinib monotherapies and the upfront 
combination has an impact on translational or clinical activity in patients with BRAF 
mutant metastatic unresectable stage IIIc or IV melanoma.
Subject: Oncology, trametinib, dabrafenib, MEK, BRAF, melanoma
Author(s): GlaxoSmithKline: 
 
 
 Institut Gustave Roussy
Copyright 2013 the GlaxoSmithKline group of companies.  All rights reserved.  
Unauthorised copying or use of this information is prohibited.
PPD
PPD


2012N132406_01
CONFIDENTIAL
GlaxoSmithKline group of companies
BRF116613
2
Revision Chronology:
2012N132406_00
2013-APR-15
Original
2012N132406_01
2013-OCT-28
Amendment 01 
1. Update to figure 1 Trial design
to better reflect the design of the 
study
2. Replaced “treatment vials” with 
Treatment bottles” as the study 
drugs are tablets.
3. Change of brain MRI from 4 
weeks to 5 weeks before Day 1
4. Amendment and further 
clarification around the biopsies 
taken for this study as requested 
by the ANSM. This includes: a)
That the biopsies will only be 
done on cutaneous and 
subcutaneous lesions  only if 
they are easily accessible; b) 
confirmation that no deep lesion 
biopsies will be performed; c) 
clarification of who is qualified 
to perform the biopsies;  
5. Clarification regarding the 
confirmation of response
6. Clarification to the PK blood 
sampling
7. New France specific Appendix
6 added to reflect the 
monitoring required for 
Cutaneous Squamous Cell 
Carcinoma (CuSCC), new 
primary melanoma and non-
cutaneous secondary/recurrent 
malignancy as reqested by 
ANSM


PPD


2012N132406_01
CONFIDENTIAL
BRF116613
4
SPONSOR INFORMATION PAGE
Clinical Study Identifier:
BRF116613
Sponsor Legal Registered Address:
GlaxoSmithKline Research & Development Limited
980 Great West Road
Brentford
Middlesex, TW8 9GS
UK
Sponsor Contact Address
GlaxoSmithKline Research & Development Limited
Addenbrooke’s Centre for Clinical Investigation (ACCI)
Addenbrooke’s Hospital
Hills Road
Cambridge, Cambridgeshire, CB2 2GG, UK
Telephone:  
GlaxoSmithKline Research & Development Limited
Iron Bridge Road 
Stockley Park West, Uxbridge, Middlesex, UB11 1BU, UK
Telephone:  
 
GlaxoSmithKline Research & Development Limited
2301 Renaissance Boulevard
Building #510
Post Office Box 61540
King of Prussia, Pennsylvania 19406
Telephone number: 
Or
GlaxoSmithKline Research & Development Limited
1250 South Collegeville Road
Collegeville, PA 19426, USA
Telephone Number: 
GlaxoSmithKline Research & Development Limited
Five Moore Drive 
P.O. 13398
Research Triangle Park, NC 27709-3398, USA
Telephone: 
In some countries, the clinical trial sponsor may be the local GlaxoSmithKline affiliate 
company (or designee). Where applicable, the details of the Sponsor and contact person 
will be provided to the relevant regulatory authority as part of the clinical trial 
submission.
PPD
PPD
PPD
PPD
PPD


2012N132406_01
CONFIDENTIAL
BRF116613
5
Sponsor Medical Monitor Contact Information: 
Role
Name
Day Time 
Phone 
Number
After-hours 
Phone 
Number
Email
GSK Address
Primary 
Medical 
Monitor
 
 
 
GlaxoSmithKline
100 route de Versailles
78163 Marly le Roi
France
Secondary 
Medical 
Monitor
 
 
 
GlaxoSmithKline
Stockley Park West
Uxbridge, UB11 1BT
UK
Sponsor Serious Adverse Events (SAE) Contact Information:Département de 
Pharmacovigilance
GlaxoSmithKline
100 route de Versailles
78163 Marly le Roi
France
Telephone: 
Fax:
Regulatory Agency Identifying Numbers:
European Drug Regulatory Authorities Clinical Trials 
(EudraCT) Number
2012-004577-12
PPD
PPD
P
P
D
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


2012N132406_01
CONFIDENTIAL
BRF116613
6
INVESTIGATOR PROTOCOL AGREEMENT PAGE

I confirm agreement to conduct the study in compliance with the protocol.

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 receive the appropriate information throughout the 
study.
Investigator Name:  _____________________________
Investigator Signature
Date


2012N132406_01
CONFIDENTIAL
BRF116613
7
TABLE OF CONTENTS
PAGE
LIST OF ABBREVIATIONS...........................................................................................11
PROTOCOL SUMMARY...............................................................................................14
1.
INTRODUCTION....................................................................................................16
1.1.
Background ................................................................................................16
1.1.1.
The BRAF Inhibitor Dabrafenib as Monotherapy..........................16
1.1.2.
The MEK Inhibitor Trametinib as Monotherapy ............................17
1.1.3.
BRAF and MEK Inhibitors as Combination Therapy.....................18
1.2.
Study Rationale ..........................................................................................19
1.3.
Dose Rationale ...........................................................................................19
2.
OBJECTIVES AND ENDPOINTS...........................................................................20
3.
STUDY DESIGN ....................................................................................................21
4.
PATIENT SELECTION AND DISCONTINUATION/ COMPLETION 
CRITERIA ..............................................................................................................23
4.1.
Patient Selection Criteria ............................................................................23
4.1.1.
Number of Patients......................................................................23
4.1.2.
Inclusion Criteria..........................................................................23
4.1.3.
Exclusion Criteria.........................................................................24
4.2.
Permanent Discontinuation from Study Treatment and Patient 
Completion Criteria.....................................................................................27
4.2.1.
Permanent Discontinuation from Study Treatment.......................27
4.2.2.
Patient Completion and Withdrawal .............................................27
5.
STUDY TREATMENTS..........................................................................................29
5.1.
GSK Investigational Products .....................................................................29
5.1.1.
Dabrafenib...................................................................................29
5.1.2.
Trametinib....................................................................................29
5.2.
Dosage and Administration.........................................................................29
5.3.
Handling and Storage of Study Treatment ..................................................30
5.4.
Treatment Assignment................................................................................30
5.5.
Blinding.......................................................................................................30
5.6.
Product Accountability ................................................................................31
5.7.
Treatment Compliance................................................................................31
5.8.
Dose Modification Guidelines......................................................................31
5.8.1.
Dose Levels of dabrafenib and trametinib....................................33
5.8.2.
General Guidelines for Clinically Significant Toxicities .................33
5.8.3.
Guidelines for Cardiovascular Adverse Events ............................34
5.8.3.1.
Left Ventricular Ejection Fraction (LVEF)....................34
5.8.3.2.
Hypertension ..............................................................36
5.8.3.3.
Guidelines for Prolonged QTc ....................................38
5.8.3.4.
Guidelines for Valvular Toxicity ..................................38
5.8.4.
Guidelines for Skin-related Adverse Events.................................39
5.8.4.1.
Rash...........................................................................39
5.8.4.2.
Guidelines for Hand-foot Skin Reactions 
(HFSR).......................................................................40


2012N132406_01
CONFIDENTIAL
BRF116613
8
5.8.4.3.
Guidelines for cuSCC.................................................41
5.8.5.
Guidelines for Other Adverse Event of Special Interest................42
5.8.5.1.
Guidelines for Pyrexia ................................................42
5.8.5.2.
Guidelines for Diarrhoea.............................................44
5.8.5.3.
Guidelines for Renal Insufficiency...............................46
5.8.5.4.
Guidelines for Visual Changes ...................................47
5.8.5.5.
Guidelines for Pneumonitis.........................................49
5.9.
Stopping, Follow-up, and Monitoring Criteria for Hepatobiliary 
Events ........................................................................................................51
5.9.1.
Liver Chemistry Stopping Criteria ................................................51
5.9.1.1.
Liver Event Follow-up Assessments...........................52
5.9.1.2.
Liver Chemistry Monitoring Criteria.............................53
5.9.1.3.
Drug Restart/Rechallenge Following Liver 
Events that are Possibly Related to Study 
Treatment...................................................................54
5.9.1.4.
Drug Restart Following Transient Resolving 
Liver Events Not Related to Study Treatment.............54
6.
CONCOMITANT MEDICATIONS AND NON-DRUG THERAPIES .........................56
6.1.
Permitted Medications and Non-drug Therapies .........................................56
6.2.
Prohibited Medications and Non-drug Therapies ........................................56
6.3.
Medications to be used with Caution...........................................................57
6.4.
Treatment after Discontinuation of Study Treatment or Withdrawal 
from/Completion of Study ...........................................................................59
6.5.
Treatment of Study Treatment Overdose....................................................59
7.
STUDY ASSESSMENTS AND PROCEDURES .....................................................60
7.1.
Critical Baseline Assessments....................................................................64
7.1.1.
BRAF Mutation Determination .....................................................64
7.1.2.
Baseline Documentation of Target and Non-target Lesions .........64
7.2.
Biomarkers .................................................................................................65
7.2.1.
Biomarkers on blood sample........................................................65
7.2.2.
Biomarkers on tumour sample .....................................................65
7.2.3.
Biomarkers on skin sample..........................................................67
7.3.
Efficacy.......................................................................................................67
7.3.1.
Efficacy Endpoints .......................................................................67
7.3.2.
Efficacy Assessment....................................................................67
7.3.2.1.
Assessment Guidelines ..............................................68
7.3.2.2.
Follow-up Assessments for Patients 
Permanently Discontinued from both Study 
Treatments.................................................................69
7.3.2.3.
Assessment at Patient Completion.............................69
7.3.3.
Guidelines for Evaluation of Disease ...........................................69
7.3.3.1.
Measurable and Non-measurable Definitions .............69
7.3.4.
Response Criteria........................................................................70
7.3.4.1.
Evaluation of Target Lesions ......................................70
7.3.4.2.
Evaluation of Non-target Lesions................................71
7.3.4.3.
New Lesions...............................................................72
7.3.4.4.
Evaluation of Overall Response .................................72
7.3.4.5.
Evaluation of Best Overall Response .........................73
7.4.
Safety .........................................................................................................73
7.4.1.
Safety Endpoints..........................................................................73


2012N132406_01
CONFIDENTIAL
BRF116613
9
7.4.2.
Adverse Events............................................................................73
7.4.2.1.
Definition of an AE......................................................73
7.4.2.2.
Definition of an SAE ...................................................74
7.4.2.3.
Laboratory and Other Safety Assessment 
Abnormalities Reported as AEs and SAEs .................76
7.4.2.4.
Disease-related Events and/or Disease-related 
Outcomes Not Qualifying as SAEs .............................76
7.4.2.5.
Time Period and Frequency for Detecting AEs 
and SAEs ...................................................................76
7.4.2.6.
Prompt Reporting of SAEs and Other Events to 
GSK ...........................................................................77
7.4.2.7.
Regulatory Reporting Requirements for SAEs............79
7.4.3.
Pregnancy Testing, Prevention, and Reporting............................79
7.4.3.1.
Pregnancy Testing and Prevention.............................79
7.4.3.2.
Pregnancy Reporting..................................................80
7.4.4.
Laboratory Assessments .............................................................81
7.4.5.
Ophthalmic Examination..............................................................82
7.4.6.
Vital Signs....................................................................................82
7.4.7.
Physical Examinations.................................................................82
7.4.8.
Electrocardiograms (ECG)...........................................................83
7.4.9.
Echocardiograms (ECHO) ...........................................................83
7.5.
Pharmacokinetics .......................................................................................83
7.5.1.
Blood Sample Collection for Pharmacokinetics............................83
8.
DATA MANAGEMENT ...........................................................................................84
9.
DATA ANALYSIS AND STATISTICAL CONSIDERATIONS...................................85
9.1.
Hypotheses.................................................................................................85
9.2.
Study Design Considerations......................................................................85
9.2.1.
Sample Size Assumptions ...........................................................85
9.2.2.
Sample Size Sensitivity................................................................85
9.2.3.
Sample Size Re-estimation..........................................................85
9.3.
Data Analysis Considerations .....................................................................85
9.3.1.
Analysis Populations....................................................................85
9.3.2.
Analysis Data Sets.......................................................................86
9.3.3.
Treatment Comparisons ..............................................................86
9.3.4.
Interim Analysis ...........................................................................86
9.3.5.
Key Elements of Analysis Plan ....................................................86
9.3.5.1.
Biomarker Analyses....................................................87
9.3.5.2.
Efficacy Analyses .......................................................87
9.3.5.3.
Safety Analyses..........................................................88
9.3.5.4.
Pharmacokinetic/Pharmacodynamic Analyses ...........89
9.3.5.5.
Translational Research Analyses ...............................89
10. STUDY CONDUCT CONSIDERATIONS ...............................................................90
10.1.
Posting of Information on Publicly Available Clinical Trial Registers............90
10.2.
Regulatory and Ethical Considerations, Including the Informed 
Consent Process ........................................................................................90
10.3.
Quality Control (Study Monitoring) ..............................................................90
10.4.
Quality Assurance.......................................................................................91
10.5.
Study and Site Closure ...............................................................................91
10.6.
Records Retention......................................................................................91


2012N132406_01
CONFIDENTIAL
BRF116613
10
10.7.
Provision of Study Results to Investigators, Posting of Information 
on Publicly Available Clinical Trials Registers and Publication....................92
10.8.
Independent Data Monitoring Committee....................................................92
11. REFERENCES.......................................................................................................93
12. APPENDICES........................................................................................................95
Appendix 1 Eastern Cooperative Oncology Group (ECOG) Performance 
Status .........................................................................................................95
Appendix 2 Cockcroft-Gault Formula......................................................................96
Appendix 3 QT interval on electrocardiogram corrected using the Bazett’s 
formula (QTcB) ...........................................................................................97
Appendix 4 New York Heart Association (NYHA) Guidelines .................................98
Appendix 5 Liver Chemistry Monitoring, Interruption Stopping and Follow-
up Criteria...................................................................................................99
Appendix 6 Additional Monitoring for Patients Enrolled in France.........................100
Appendix 7 Summary of Changes for Amendment 01..........................................101


2012N132406_01
CONFIDENTIAL
BRF116613
11
LIST OF ABBREVIATIONS
AE
Adverse event
AJCC
American Joint Committee on Cancer
ALT
Alanine aminotransferase (SGPT)
ANC
Absolute neutrophil count
AST
Aspartate aminotransferase (SGOT)
ATP
Adenosine triphosphate
BCRP
Breast cancer resistance protein
BID
Twice a day
BUN
Blood urea nitrogen
cfDNA
Circulating cell free DNA
CI
Confidence interval
CPK
Creatine phosphokinase
CR
Complete response
Cr CL
Creatinine clearance
CRP
C-reactive protein
CSR
Central serous retinopathy
CT
Computed tomography
CTCAE
Common Terminology Criteria for Adverse Events
CYP
Cytochrome P450
DBP
diastolic blood pressure
dL
Deciliter(s)
DMSO
dimethyl sulfoxide
DNA
Deoxyribonucleic acid
DoR
Duration of Response
DTIC
dacarbazine
ECG
Electrocardiogram
ECHO
Echocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
Electronic Case Report Form
EGFR
Epidermal growth factor receptor
FDA
Food and Drug Administration
FDG-PET
Fluorodeoxyglucose positron emission tomography
FSH
Follicle-stimulating hormone
g
Gram
G6PD
glucose-6-phosphate dehydrogenase
GCP
Good Clinical Practice
GGT
Gamma-Glutamyl Transpeptidase
GSK
GlaxoSmithKline
HBV
Hepatitis B Virus
HCG
Human chorionic gonadotropin
HCV
Hepatitis C Virus
HFSR
Hand-foot skin reaction
HIV
Human Immunodeficiency Virus
HPLC
High-performance liquid chromatography


2012N132406_01
CONFIDENTIAL
BRF116613
12
HR
Hazard ratio
HRT
Hormone-replacement therapy
IB
Investigator’s Brochure
ICH
International Conference on Harmonization
IEC
Independent Ethics Committees
IHC
Immunohistochemistry
INR
International normalized ratio
ITT
Intent-to-treat
IVRS
Interactive voice response system
KA
Keratoacanthoma
L
Liter(s)
LDH
lactate dehydrogenase
LLN
Lower limit of normal
LVEF
Left ventricular ejection fraction
MedDRA
Medical Dictionary for Regulatory Activities
mg
Milligrams
mL
Milliliter
mm
Millimeter
MRI
Magnetic resonance imaging
MSDS
Material Safety Data Sheet
NA
Not applicable 
NCI
National Cancer Institute 
NE
Not evaluable
NED
no evidence of disease
NYHA
New York Heart Association
ORR
Overall response rate
OS
Overall survival
PD
Progressive disease
PFS
Progression free survival
Pg
Picogram
Pgp
P-glycoprotein
PK
Pharmacokinetic
Pmol
Picomole
PR
Partial response
PT
Prothrombin time
PTT
Partial thromboplastin time
QTc
Corrected QT interval on electrocardiogram
RAMOS
Registration and Medication Ordering System
RAP
Reporting and analysis plan
RECIST
Response Evaluation Criteria In Solid Tumours
RNA
Ribonucleic acid
RR
response rate
RVO
Retinal vein occlusion
s.d.
Standard deviation
SAE
Serious adverse event
SBP
Systolic blood pressure


2012N132406_01
CONFIDENTIAL
BRF116613
13
SCC
Squamous cell carcinoma
SD
Stable disease
SGOT
Serum Glutamic Oxaloacetic Transaminase
SGPT
Serum Glutamic Pyruvic Transaminase
SPF
Skin protection factor
SPM
Study Procedures Manual
ULN
Upper limit of normal
Trademark Information
Trademarks of the GlaxoSmithKline 
group of companies
Trademarks not owned by the 
GlaxoSmithKline group of companies
NONE
None


2012N132406_01
CONFIDENTIAL
BRF116613
14
PROTOCOL SUMMARY
Rationale
Both dabrafenib and trametinib have demonstrated clinical activity as monotherapies and 
in combination in BRAF-mutant melanoma. However, duration of responses seem to be 
limited due to acquired drug resistance.
Anti-BRAF treatments are associated with skin side effects like squamous cell carcinoma 
and keratoacanthoma as well as rash and hyperkeratosis.
Clinical data from the combination study BRF113220 suggests that both resistance and 
secondary skin tumours might be reduced by using both inhibitors simultaneously.
The goal of this protocol is to study the sequential effects of BRAF and MEK inhibition 
on skin, blood and tumour biomarkers and to study the correlation between biomarkers 
and response to treatment and intrapatient toxicity.
Objectives
Primary objective:

To evaluate biomarkers linked to treatment response, resistance and toxicity 
including skin toxicity when dabrafenib and trametinib combination is given upfront 
or as monotherapy before the combination treatment.
Secondary objectives:

To evaluate the clinical response (ORR)

To characterise the safety profile of dabrafenib and trametinib in monotherapy and/or 
in combination including incidences of squamous cell carcinoma (SCC) and other 
proliferative cutaneous lesions as well as the papulo-pustular rash.

To evaluate dabrafenib, trametinib and combination exposures in connection to 
clinical response and toxicity.
Exploratory objectives:

To evaluate changes in inflammation

To evaluate the impact of the two drugs, separately and in combination on immune 
system

To evaluate the progression-free survival (PFS) and duration of response (DoR).


2012N132406_01
CONFIDENTIAL
BRF116613
15
Study Design
This is a three-arm, open label, randomised, Phase II study comparing the upfront 
combination of dabrafenib (GSK2118436) with trametinib (GSK1120212) versus the 
combination after eight weeks of monotherapy treatment with dabrafenib or trametinib.
Approximately 54 eligible patients with histologically confirmed cutaneous melanoma 
that is either metastatic or unresectable (stage IIIc or IV) and BRAF V600E/K mutation 
positive as determined by a local laboratory will be randomised, 1:1:1 to one of the three 
treatment arms.

Arm A: dabrafenib 150mg BID continuously during eight weeks followed by 
the combination of trametinib 2mg once daily with dabrafenib 150mg BID until 
disease progression, death or unacceptable toxicity.

Arm B: trametinib 2mg/day continuously during eight weeks followed by the 
combination of trametinib 2mg once daily with dabrafenib 150mg BID until 
disease progression, death or unacceptable toxicity.

Arm C: trametinib 2mg/day plus dabrafenib 150mg BID continuously until 
disease progression, death or unacceptable toxicity.
Biomarker analysis will be performed on blood, tumour and skin samples.
Study Assessments
The ORR, PFS and duration of response endpoints will be determined using 
investigator’s lesion assessments as evaluated by the Response Evaluation Criteria in 
Solid Tumours (RECIST), version 1.1. Safety will be evaluated by clinical assessments 
including vital signs and physical examinations, 12-lead electrocardiograms (ECG), 
echocardiograms (ECHO), chemistry and haematology laboratory values and adverse 
events (AEs). Exposure to dabrafenib, dabrafenib metabolites, and trametinib will be 
evaluated by measuring drug and metabolite plasma concentrations.


2012N132406_01
CONFIDENTIAL
BRF116613
16
1.
INTRODUCTION
1.1.
Background
Cutaneous melanoma is the most aggressive form of all skin cancers. Worldwide, it is 
currently expected that approximately 132,000 people will be diagnosed with melanoma 
each year and some 37,000 people are expected to die of the disease annually. The 
median survival time for patients with Stage IV melanoma remains short at 
approximately 6 months with 26% of patients alive at 1-year (Korn, 2008); the estimated 
5-year survival rate is < 10% (Huncharek, 2001). Median progression free survival (PFS) 
is also short at 1.7 months and only 14.5% of patients are progression-free at 6 months 
(Korn, 2008).
The RAS/RAF/MEK/ERK pathway (i.e., the MAP kinase pathway) is a critical 
proliferation pathway in many human cancers. Oncogenic mutations in both RAS and 
BRAF signal through the extracellular signal regulated kinases MEK1 and MEK2.  
BRAF mutations have been identified at a high frequency in specific cancers, including 
up to 60% of melanoma tumours (Davies, 2002). In melanoma, more than 80% of the 
BRAF mutations cause a substitution of the amino acid glutamate (E) for valine (V) at 
position 600 (V600E) of the BRAF protein, whereas approximately 3-20% of melanoma 
mutations are a substitution of lysine (K) for valine at position 600 (V600K) (Gorden,
2003; Libra, 2005). Both mutations cause constitutive activation of BRAF, which in turn
activates the MAP kinase pathway.
Dabrafenib is a potent and selective RAF kinase inhibitor of human wild type BRAF and 
CRAF enzymes as well as the mutant forms BRAFV600E, BRAFV600K and 
BRAFV600D. The mode of action of dabrafenib is consistent with competitive inhibition 
of adenosine triphosphate (ATP) binding. By contrast, trametinib is a reversible, highly 
selective, allosteric inhibitor of MEK1 and MEK2. Trametinib is non-competitive 
towards ATP and inhibits both MEK activation and kinase activity. Because BRAF and 
MEK are in the same pathway, and because MEK is a substrate of activated BRAF, 
inhibiting both proteins simultaneously rather than individually could provide more 
effective pathway inhibition and also decrease the likelihood of developing resistance. 
Data generated in cell line, mouse xenograft, and rat safety models with BRAF and MEK 
inhibitor combinations suggest enhanced effects on efficacy and less potential for 
proliferative skin lesions or stimulation of dormant tumours containing RAS mutations 
compared to treatment with a BRAF inhibitor alone. 
Based on the demonstrated efficacy of both dabrafenib and trametinib as monotherapies 
along with preliminary clinical data suggesting that the combination may prevent 
resistance and improve efficacy, phase III clinical studies of the dabrafenib/trametinib 
combination are being initiated in advanced melanoma and as adjuvant therapy for high-
risk Stage III disease.
1.1.1.
The BRAF Inhibitor Dabrafenib as Monotherapy
Dabrafenib, a selective BRAF inhibitor, has shown activity with a manageable safety 
profile in phase 1 and 2 studies in patients with BRAF V600E/K-mutation positive 
metastatic melanoma. The BREAK-3 (BRF113683) global phase III trial was conducted 


2012N132406_01
CONFIDENTIAL
BRF116613
17
in patients with BRAF V600E mutation-positive advanced or metastatic melanoma 
randomised (3:1) to receive treatment with either dabrafenib (150 mg , twice daily [BID]) 
or dacarbazine (DTIC) (Hauschild, 2012). Patients were randomised by disease stage 
(unresectable Stage III, IVM1a and IVM1b versus IVM1c). Patients randomised to the 
DTIC arm were allowed to crossover to receive dabrafenib after confirmation of 
progressive disease (PD). The primary endpoint was progression free survival (PFS) 
based on investigator assessment in the intent-to-treat (ITT) population comprised of all 
randomised patients, regardless of whether or not treatment was administered. Secondary 
endpoints were overall survival (OS), overall response rate (ORR) in both groups and 
after crossover, PFS for patients randomised to the DTIC treatment groups after 
crossover, duration of response, safety/tolerability and BRAF mutation assay validation.
Two hundred and fifty patients were enrolled; including 187 that were randomised to 
dabrafenib and 63 to DTIC. At the time of data cut-off for the primary analysis, 141 
patients were on study treatment (dabrafenib n=127; DTIC n=14) including 21/28 DTIC 
patients that crossed over to dabrafenib. Median age was 52 years; 31% had an Eastern 
Cooperative Oncology Group (ECOG) performance status ≤1, 66% were M1c, and 33% 
lactate dehydrogenase (LDH) greater than the upper limit of normal (>ULN) (Hauschild, 
2012).
At the time of the primary analysis, there were 118 events (77 dabrafenib and 41 DTIC). 
The hazard ratio (HR) for PFS was 0.30 (95% confidence interval (CI): 0.18-0.53; 
p<0.0001). Median PFS was 5.1 months for dabrafenib and 2.7 months for DTIC by 
investigator assessment. OS data were immature. Confirmed response rate (RR) was 53% 
for dabrafenib and 19% for DTIC. Benefits in PFS and RR were observed in all 
subgroups evaluated. 
The most frequent adverse events (AEs) (≥20%) in the dabrafenib arm were 
hyperkeratosis (37%), headache (32%), pyrexia (28%), arthralgia (27%), skin papillomas 
(24%), alopecia (22%), palmar-plantar erythrodysaesthesia syndrome (2%). Serious 
adverse events (SAEs) (>1%) on the dabrafenib arm included pyrexia (4%), squamous 
cell carcinomas (6%), and new primary melanomas (2%).
Further evidence for the safety and efficacy of dabrafenib has been established in a large 
(N=172) study of patients (BREAK-MB) with both controlled and uncontrolled brain 
metastases (Long, 2012). Activity in patients with the V600K mutation was also seen.
1.1.2.
The MEK Inhibitor Trametinib as Monotherapy
Trametinib is a reversible, highly selective allosteric inhibitor of MEK1/2 activation and 
kinase activity. A Phase 3 trial, METRIC (MEK114267), was conducted in patients with 
BRAF V600E/K mutation positive advanced or metastatic melanoma. Patients were 
randomised 2:1 to trametinib (2mg once daily) or chemotherapy (DTIC or paclitaxel). 
Patients were stratified by baseline LDH level and prior chemotherapy; patients in the 
chemotherapy arm were allowed to crossover to receive trametinib after confirmation of 
PD. The primary endpoint was PFS in patients with BRAF V600E mutation-positive 
metastatic melanoma and no prior brain metastases; PFS was also evaluated in the ITT 


2012N132406_01
CONFIDENTIAL
BRF116613
18
population. Secondary endpoints were OS, ORR in the primary and ITT population and 
safety in the safety population (Flaherty, 2012b).
Three hundred and twenty-two patients were randomised to trametinib (n=214) or 
chemotherapy (n=108); 273 patients were BRAF V600E mutation-positive with no prior 
brain metastases. Median age was 54 years; all had an ECOG performance status of 0 
(64%) or 1 (36%), and 65% were M1c (Flaherty, 2012b).
The HR for the primary population for PFS by investigator was 0.44 (95% CI 0.31–0.64; 
p<0.0001) in favour of trametinib with a median PFS of 4.8 months vs. 1.4 months with 
chemotherapy. The confirmed ORR was 24% with trametinib and 7% with 
chemotherapy. HR for interim OS was 0.53 (95% CI 0.30–0.94; p=0.0181), in favour of 
trametinib. 
The most frequent AEs (≥20%) with trametinib were skin rash (57%), diarrhoea (43%), 
fatigue (26%), and oedema (26%). Known MEK inhibitor class effects were observed in 
this study including chorioretinopathy (<1%) and decreased ejection fraction (7%).
1.1.3.
BRAF and MEK Inhibitors as Combination Therapy
A 4-part Phase I/II study (BRF113220) investigating the dabrafenib/trametinib 
combination is being conducted in patients with V600 BRAF mutation-positive solid 
tumours. 
In Part B, patients were treated on 4 escalating dose levels of dabrafenib/trametinib (mg 
BID/mg once daily): 75/1, 150/1, 150/1.5, 150/2. Demographic and efficacy data for the 
melanoma patients and safety data for all 125 Part B patients were reported (Flaherty, 
2012a). 
Among 77 treatment-naïve patients with BRAF V600 mutation-positive melanoma and 
measurable disease according to Response Evaluation Criteria in Solid Tumours version 
1.1(RECIST 1.1), median age was 52 years, 61% male, 57% ECOG performance status 
of 0, 91% V600E, 65% M1c stage, 26% prior brain metastases, and 52% LDH > ULN. 
Confirmed ORR was 56% (95% CI: 44.1%-67.2%) with 4 complete response (CR), 39 
partial response (PR), 29 stable disease (SD) and3 PD. Confirmed response rates for each 
dose level tested in Part B were 67% (n=6), 64% (n=22), 44% (n=25), and 63% (n=24), 
respectively. Median PFS was 7.4 months overall (95% CI: 5.5-9.2), and 10.8 months 
(95% CI: 5.3, not reached) in the cohort treated with 150/2. Median duration of response 
for the entire cohort was 11.3 months (95% CI: 9.2, not reached) with a median duration 
on treatment of 10.7 months (including 38% of patients ongoing at the time of the 
analysis). The most common adverse events (AE) were pyrexia (52%), rash (45%), chills 
(38%), fatigue (37%), and nausea (34%). There were two grade 5 adverse events (AEs), 
pneumonia and hyponatraemia. The most common Grade 3/4 AEs were pyrexia (n=6, 
5%), fatigue (n=6, 5%) and dehydration (n=6, 5%). Skin toxicity ≥ Grade 2 occurred in 
17 (14%) patients. Cutaneous squamous cell carcinoma occurred in 3 (2%) patients and 
actinic keratoses in 2 (2%). The most common treatment related AEs (≥20%, all grades) 
among patients in Part B receiving 150 mg BID dabrafenib and 2 mg once daily 


2012N132406_01
CONFIDENTIAL
BRF116613
19
trametinib (n=79) were pyrexia (58%), skin toxicities including rash (42%), chills (37%), 
fatigue (38%) and nausea (34%).
The Part C data for the randomised comparison of two of dabrafenib/trametinib 
combination schedules versus dabrafenib monotherapy in 162 patients were reported 
(Flaherty, 2012a). The data showed that the combination of the full dose of dabrafenib 
(150 mg BID) and trametinib (2 mg once daily) is well tolerated and is more efficacious 
than dabrafenib monotherapy or a combination of 150 mg BID dabrafenib and 1 mg once 
daily trametinib in BRAF mutation-positive melanoma patients who have not been 
previously treated with a BRAF-inhibitor.
1.2.
Study Rationale
Both dabrafenib and trametinib have demonstrated clinical activity as monotherapies and 
in combination in BRAF-mutant melanoma. However, duration of responses seem to be 
limited due to acquired drug resistance (Flaherty, 2012b; Hauschild, 2012). 
Anti-BRAF treatments are associated with skin side effects like squamous cell carcinoma 
and keratoacanthoma as well as rash and hyperkeratosis (Chapman, 2011; Hauschild, 
2012).
Clinical data from the combination study BRF113220 suggests that both resistance and 
secondary skin tumours might be reduced by using both inhibitors simultaneously
(Flaherty, 2012a).
The goal of this protocol is to study the sequential effects of BRAF and MEK inhibition 
on skin, blood and tumour biomarkers and to study the correlation between biomarkers 
and response to treatment and intrapatient toxicity.
1.3.
Dose Rationale
Dabrafenib and trametinib will be co-administered at their recommended monotherapy 
doses of 150 mg BID and 2.0 mg once daily, respectively. As monotherapies, these dose 
levels achieved > 80% target inhibition, and in the Phase III setting demonstrated 
confirmed response rates of 50% and 22%, respectively, in patients with V600 mutation-
positive melanoma (Flaherty, 2012b; Hauschild, 2012). This combination dose is further 
supported by the PK and safety data obtained in Parts A, B and C of the combination 
study BRF113220 which showed no clinically meaningful drug-drug interaction and 
showed an acceptable safety profile for the proposed combination dose level (Flaherty, 
2012a).


2012N132406_01
CONFIDENTIAL
BRF116613
20
2.
OBJECTIVES AND ENDPOINTS
Table 1 lists the study objectives and corresponding endpoints.
Table 1
Study Objectives and Endpoints
Objectives
Endpoints
Primary
To evaluate biomarkers linked to treatment response, 
resistance and toxicity including skin toxicity when 
dabrafenib and trametinib combination is given upfront or as 
monotherapy before the combination treatment.
Percentage Change of  of Erk phosphorylation score 
from baseline 
Secondary
1.
To evaluate the clinical response (ORR)
2.
To characterise the safety profile of dabrafenib 
and trametinib in monotherapy and/or in 
combination including incidences of squamous cell 
carcinoma (SCC) and other proliferative 
cutaneous lesions as well as the papulo-pustular 
rash. 
3.
To evaluate dabrafenib, trametinib and 
combination exposures in connection to clinical 
response and toxicity.
4.
Overall response rate (ORR; defined as the 
percentage of patients with a confirmed 
complete response [CR] or partial response 
[PR] at any time per Response Evaluation 
Criteria in Solid Tumours [RECIST], 
version 1.1.
5.
Safety as measured by clinical assessments 
including vital signs and physical 
examinations, ECOG performance status, 
12-lead electrocardiograms (ECG), 
echocardiogram (ECHO), chemistry and 
haematology laboratory values, incidence of 
squamous cell carcinoma and 
keratoacanthoma (KA), and adverse events 
(AEs) graded according to the Common 
Terminology Criteria for Adverse Events  
(CTC-AE), version 4.0
6.
Plasma PK/PD evaluation
Exploratory
7.
To evaluate changes in inflammation
8.
To evaluate the impact of the two drugs, 
separately and in combination on immune system
9.
To evaluate the progression-free survival (PFS) 
and duration of response (DoR).
10. Inflammatory markers
11. T cell function by blood immunomonitoring 
and lymphocyte infiltration of tumours and 
skin
12. Progression-free survival (PFS; defined as 
the time from randomisation until the earliest 
date of disease progression or death due to 
any cause) and Duration of response (DoR; 
defined as the time from first documented 
evidence of CR or PR until disease 
progression or death due to any cause 
among patients who achieve an overall 
response).
Refer to Section 9 for further details on endpoint definitions.


2012N132406_01
CONFIDENTIAL
BRF116613
21
3.
STUDY DESIGN
Figure 1
Study Schema
Treatment Period 2
Treatment Period 1
n=54
Time (weeks)
Day 1
8
1:1:1
R
a
n
d
o
m
i
s
a
t
i
o
n
S
c
r
e
e
n
i
n
g
Stage IIIC/IV 
Melanoma
BRAF 
V600E/K
-4
2
10
X
X
X
X
P
r
o
g
r
e
s
s
i
o
n
Trametinib 2mg daily 
Dabrafenib 150mg BID
Dabrafenib 150mg BID
Trametinib 2mg daily 
Dabrafenib 150mg BID
Trametinib 2mg daily 
Biopsy
X
This is a three-arm, open label, randomised, Phase II study comparing the upfront 
combination of dabrafenib (GSK2118436) with trametinib (GSK1120212) versus the 
combination after eight weeks of monotherapy treatment with dabrafenib or trametinib.
Approximately 54 eligible patients with histologically confirmed cutaneous melanoma 
that is either metastatic or unresectable (stage IIIc or IV) and BRAF V600E/K mutation 
positive as determined by a local laboratory will be randomised, 1:1:1 to one of the three 
treatment arms.

Arm A: dabrafenib 150mg BID continuously during eight weeks followed by 
the combination of trametinib 2mg once daily with dabrafenib 150mg BID until 
disease progression, death or unacceptable toxicity.

Arm B: trametinib 2mg/day continuously during eight weeks followed by the 
combination of trametinib 2mg once daily with dabrafenib 150mg BID until 
disease progression, death or unacceptable toxicity.

Arm C: trametinib 2mg/day plus dabrafenib 150mg BID continuously until 
disease progression, death or unacceptable toxicity.
Monitoring will be performed throughout the study according to the Time and Events 
Table (Table 19). Protocol specified guidelines for dose adjustments, interruptions and 
discontinuation due to AEs/liver toxicity are provided in Section 5.8, and Section 5.9,
respectively. The visits allow a window of +/- 7 days. Dose interruptions should not alter 
the assessment schedule for any subsequent treatment period.


2012N132406_01
CONFIDENTIAL
BRF116613
22
Biomarker analysis will be performed on blood, tumour and skin samples according to 
the Time and Events Table (Table 19).
Clinical responses will be evaluated using RECIST 1.1 criteria every 8 weeks. The 
response evaluation may be performed earlier if clinically indicated (for example, if 
patient has symptomatic deterioration suggesting rapid disease progression or to confirm 
clinical response at 4 weeks after achieving response).
Patients who show either radiographic or clinical progression of disease according to the 
investigator during the monotherapy treatment period in arm A or B will be able to go on
to the combination treatment before completion of the 8 weeks monotherapy treatment. 
Patients will be treated with the combination treatment until disease progression, 
unacceptable toxicity or withdrawal from study whichever comes first.
The study will be considered completed when all patients ended study treatment either 
through progression, death or withdrawal from study for any reason.
Protocol waivers or exemptions are not allowed with the exception of immediate safety 
concerns. Therefore, adherence to the study design requirements, including those 
specified in the Time and Events Table (Table 19), are essential and required for study 
conduct.
Supplementary study conduct information not mandated to be present in this protocol will 
be provided in the Study Procedures Manual (SPM). The SPM will provide the site 
personnel with administrative and detailed technical information that does not impact 
patient safety.


2012N132406_01
CONFIDENTIAL
BRF116613
23
4.
PATIENT SELECTION AND DISCONTINUATION/ 
COMPLETION CRITERIA
4.1.
Patient Selection Criteria
4.1.1.
Number of Patients
Approximately 54 patients will be randomised 1:1:1 into the three treatment arms.  See 
Section 9.2.1 for sample size assumptions.
4.1.2.
Inclusion Criteria
Specific information regarding warnings, precautions, contraindications, adverse events, 
and other pertinent information on the GSK investigational products dabrafenib 
(GSK2118436) and trametinib (GSK1120212) that may impact patient eligibility is 
provided in the Investigator Brochures (IBs).
Deviations from inclusion criteria are not allowed because they can potentially jeopardize 
the scientific integrity of the study, regulatory acceptability or patient safety. Therefore, 
adherence to the criteria as specified in the protocol is essential.
Patients eligible for enrolment in the study must meet all of the following criteria:
1.
Signed written informed consent;
2.
≥18 years of age;
3.
Histologically confirmed cutaneous melanoma that is either Stage IIIc (unresectable) 
or Stage IV (metastatic) (according to American Joint Committee on Cancer (AJCC)
staging 7th edition). 
4.
BRAF V600E/K mutation-positive confirmed by a local laboratory.
5.
Accessible melanoma tumours for biopsies (locally advanced primary melanoma or 
metastases)
6.
Measurable disease according to Response Evaluation Criteria in Solid Tumours 
(RECIST 1.1) (Eisenhauer, 2009) on not biopsied lesions. Refer to Section 7.3.3.1
for the definition of a measureable lesion.
7.
All prior anti-cancer treatment-related toxicities (except alopecia) must be Grade 1 
according to the Common Terminology Criteria for Adverse Events version 4 
(CTCAE version 4.0) at the time of randomisation.
8.
Able to swallow and retain orally administered medication and does not have any 
clinically significant gastrointestinal abnormalities that may alter absorption such as 
malabsorption syndrome or major resection of the stomach or bowels.
9.
Women of childbearing potential must have a negative serum pregnancy test within 
14 days prior to randomisation and agree to use effective contraception, as defined in 
Section 7.4.3.1, throughout the treatment period, and for 4 months after the last dose 
of study treatment. 


2012N132406_01
CONFIDENTIAL
BRF116613
24
10. Eastern Cooperative Oncology Group (ECOG) Performance Status score of 0 or 1. 
Refer to Appendix 1 for details.
11. Adequate baseline organ function as defined in Table 2.
Table 2
Definitions for Adequate Baseline Organ Function
System
Laboratory Values
Hematologic
ANC
1.2 × 109/L
Haemoglobin
9 g/dL 
Platelet count
75 x 109/L
PT/INR and PTTa
1.5 x ULN
Hepatic
Albumin
2.5 g/dL
Total bilirubin
1.5 x ULN
AST and ALT
2.5 x ULN 
Renal
Calculated creatinine clearanceb
50 mL/min
Cardiac
Left Ventricular Ejection fraction (LVEF)c
≥ LLN by ECHO 
a.
Abbreviations: ALT = alanine transaminase; ANC = absolute neutrophil count; AST = aspartate aminotransferase; 
INR = international normalized ratio; LLN = lower limit of normal; PT = prothrombin time; PTT = partial 
thromboplastin time; ULN = upper limit of normal.
b.
Patients receiving anticoagulation treatment may be allowed to participate with INR established within the 
therapeutic range prior to randomisation. PT and PTT >1.5 ULN are permitted in these patients.
c.
Calculate creatinine clearance using standard Cockcroft-Gault formula (Appendix 2). Creatinine clearance must 
be 50 mL/min to be eligible. 
d.
ECHO scans must be used throughout the study
12. In France, a patient 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 patient safety. 
Therefore, adherence to the criteria as specified in the protocol is essential.
Patients meeting any of the following criteria must not be enrolled in the study:
1.
Prior treatment with a BRAF or MEK inhibitor 
2.
Any major surgery, extensive radiotherapy, chemotherapy with delayed toxicity, 
biologic therapy, or immunotherapy within 21 days prior to randomisation and/or 
daily or weekly chemotherapy without the potential for delayed toxicity within 14 
days prior to randomisation.
3.
Taken an investigational drug within 28 days or 5 half-lives (minimum 14 days), 
whichever is shorter, prior to randomisation
4.
Current use of a prohibited medication as described in Section 6.2.


2012N132406_01
CONFIDENTIAL
BRF116613
25
5.
Refusal of tumour and skin biopsies.
6.
History of another malignancy. 
Exception: Patients, who have been disease-free for 3 years, or patients with a 
history of completely resected non-melanoma skin cancer, and/or patients with 
indolent second malignancies are eligible.
7.
Any serious and/or unstable pre-existing medical conditions (aside from malignancy 
exceptions specified above), psychiatric disorders, or other conditions that could 
interfere with the patient’s safety, obtaining informed consent, or compliance with 
study procedures. 
8.
Known Human Immunodeficiency Virus (HIV), Hepatitis B Virus (HBV), or 
Hepatitis C Virus (HCV) infection (with the exception of chronic or cleared HBV 
and HCV infection which will be allowed). 
9.
A history of glucose-6-phosphate dehydrogenase (G6PD) deficiency.
10. Brain metastases are excluded unless:
a.
All known lesions were previously treated with surgery or stereotactic 
surgery (whole-brain radiation is not allowed unless given after definitive 
treatment with surgery or stereotactic surgery), OR
b.
Brain lesion(s), if still present, must be confirmed stable (i.e., no increase in 
lesion size) for ≥ 12 weeks prior to randomisation (stability must be 
confirmed with two consecutive magnetic resonance image (MRI) or 
computed tomography (CT) scans with contrast, AND
c.
Asymptomatic with no corticosteroid requirements for ≥ 4 weeks prior to 
randomisation, AND
d.
No enzyme inducing anticonvulsants for ≥ 4 weeks prior to randomisation
In addition, for patients that had brain metastases but currently have no evidence of 
disease (NED), NED for ≥12 weeks is required and must be confirmed by two 
consecutive scans, separated by ≥6 weeks, prior to randomisation.
11. A history or evidence of cardiovascular risk including any of the following:
a.
LVEF < LLN
b.
A QT interval corrected for heart rate using the Bazett’s formula (QTcB; 
Appendix 3) 480 msec;
c.
A history or evidence of current clinically significant uncontrolled 
arrhythmias;
Exception: Patients with atrial fibrillation controlled for > 30 days prior to 
randomisation are eligible.
d.
A history (within 6 months prior to randomisation) of acute coronary 
syndromes (including myocardial infarction or unstable angina), coronary 
angioplasty;


2012N132406_01
CONFIDENTIAL
BRF116613
26
e.
A history or evidence of current Class II congestive heart failure as defined 
by the New York Heart Association (NYHA) guidelines (Appendix 4);
f.
Treatment refractory hypertension defined as a blood pressure of systolic> 
140 mmHg and/or diastolic > 90 mm Hg which cannot be controlled by 
anti-hypertensive therapy;
g.
Patients with intra-cardiac defibrillators or permanent pacemakers;
h.
Known cardiac metastases;
i.
Abnormal cardiac valve morphology (≥grade 2) documented by 
echocardiogram (patients with grade 1 abnormalities [i.e., mild 
regurgitation/stenosis] can be entered on study). Patients with moderate 
valvular thickening should not be entered on study.
12. A history or current evidence/risk of retinal vein occlusion (RVO) or central serous 
retinopathy (CSR) including: 
a.
Presence of predisposing factors to RVO or CSR (e.g., uncontrolled 
glaucoma or ocular hypertension, uncontrolled hypertension, uncontrolled 
diabetes mellitus, or a history of hyperviscosity or hypercoagulability 
syndromes); or
b.
Visible retinal pathology as assessed by ophthalmic examination that is 
considered a risk factor for RVO or CSR such as:
i.
Evidence of new optic disc cupping;
ii.
Evidence of new visual field defects on automated perimetry;
iii.
Intraocular pressure >21 mmHg as measured by tonography.
13. Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs 
chemically related to the study treatments, their excipients, and/or dimethyl sulfoxide 
(DMSO).
14. Pregnant or lactating females
15. Interstitial lung disease or pneumonitis


2012N132406_01
CONFIDENTIAL
BRF116613
27
4.2.
Permanent Discontinuation from Study Treatment and 
Patient Completion Criteria
4.2.1.
Permanent Discontinuation from Study Treatment
Patients will receive study treatment when on combination therapy until disease 
progression, death or unacceptable adverse event, including haematologic or other non-
haematologic toxicity, and/or meeting stopping criteria for liver chemistry defined in
Section 5.9.1. A patient will be allowed to continue on monotherapy (either dabrafenib or 
trametinib) if only one study drug is permanently discontinued.
Note: Continuation of combination study treatment beyond radiographic or clinical 
disease progression (as defined by RECIST 1.1) may be possible if the investigator 
determines that patient has clear evidence of clinical benefit from study treatment, 
continuing study drugs may be in the best interest for the patient and the patient is willing 
to continue on study drugs. In this case, consultation between the investigator and the 
GSK Medical Monitor is mandatory. If continuing the patient on study treatment is 
agreed then all study procedures, including tumour assessments, must be followed as 
scheduled (Table 19). In addition, after each tumour assessment, the investigators must 
confirm with the GSK Medical Monitor that the patient is still benefiting from study 
treatment and therefore can continue receiving study treatment.
In addition study treatment may be permanently discontinued for any of the following 
reasons:

deviation(s) from the protocol

request of the patient or proxy

investigator’s discretion

patient is lost to follow-up

study is closed or terminated.
The primary reason study treatment was permanently discontinued must be documented 
in the patient’s medical records and in the electronic case record form (eCRF). 
If the patient voluntarily discontinues from treatment due to toxicity, ‘adverse event’ will 
be recorded as the primary reason for permanently discontinuation on the eCRF.
Once a patient has permanently discontinued from study treatment, the patient will not be 
allowed to be retreated.
All patients who discontinue from study treatment will have safety assessments as 
specified in Time and Events Table (Table 19) under End-of-study visit.
4.2.2.
Patient Completion and Withdrawal
A patient will be considered to have completed the study if the patient has disease 
progression or dies during the study treatment.
A patient will be considered to have withdrawn from the study if the patient has stopped 
study treatment due to toxicity, has withdrawn consent or if the study is 


2012N132406_01
CONFIDENTIAL
BRF116613
28
closed/terminated. The investigator should attempt to complete the End-of-study 
assessments as detailed in the Times and Events Table (Table 19).
There is no survival follow-up on patients. For patients who did not progress on study 
drug but withdrew due to toxicity the individual’s observation will be censored.


2012N132406_01
CONFIDENTIAL
BRF116613
29
5.
STUDY TREATMENTS
The term ‘study treatment’ is used throughout the protocol to describe any combination 
of products received by the patient as per the protocol design. Study treatment may 
therefore refer to the individual study treatments or the combination of those study 
treatments.
5.1.
GSK Investigational Products
5.1.1.
Dabrafenib
Dabrafenib will be provided as 50 mg and 75 mg capsules. Each capsule will contain 50 
mg or 75 mg of free base (present as the mesylate salt). Dabrafenib will be provided to 
sites by GSK. The contents of the label will be in accordance with all applicable 
regulatory requirements.
5.1.2.
Trametinib
Trametinib study medication will be provided as 0.5 mg and 2.0 mg tablets. Each tablet 
will contain 0.5 mg or 2.0 mg of trametinib parent (present as the DMSO solvate). 
Trametinib will be provided to sites by GSK. The contents of the label will be in
accordance with all applicable regulatory requirements.
Under normal conditions of handling and administration, investigational product is not 
expected to pose significant safety risks to site staff. Material Safety Data Sheets (MSDS) 
describing the occupational hazards and recommended handling precautions will be 
provided to site staff if required by local laws or will otherwise be available from GSK 
upon request.
5.2.
Dosage and Administration
Please refer to Section 5.8 for rules for dose modifications.
No special preparation of study medication is required.
Study treatments will be administered as follows:
Dabrafenib, 150 mg, BID
Trametinib, 2.0 mg, once daily
Both study treatments should be administered in the morning at approximately the same 
time every day. The second dose of dabrafenib (150 mg) should be administered 
approximately 12 hours after the morning dose. Study medication should be taken orally 
with approximately 200 mL of water under fasting conditions, either 1 hour before or 2 
hours after a meal. During the combination therapy, if administration of trametinib is 
interrupted or permanently discontinued, administration of dabrafenib may be continued. 
If administration of dabrafenib is interrupted, administration of trametinib may continue. 
If a patient vomits after taking study medication, the patient should be instructed not to 
retake the dose and should take the next dose as originally scheduled. 


2012N132406_01
CONFIDENTIAL
BRF116613
30
If a patient misses a dose, the patient may take the dose immediately if the next dose is 
scheduled for at least 6 hours later. If the next scheduled dose is due in less than 6 hours, 
the patient should skip the dose and resume dosing at the next scheduled dose.
Patients should abstain from ingestion of any food or drink containing grapefruit and 
grapefruit juice, Seville oranges, or pomelos within 7 days prior to randomisation until 
treatment discontinuation, as these have been shown to inhibit CYP3A4 activity.
Patients should start treatment as soon as possible after randomisation but no later than 72 
hours post-randomisation.
5.3.
Handling and Storage of Study Treatment
Dabrafenib, trametinib must be dispensed and administered in accordance with the 
protocol, and only to patients enrolled in the study. Dabrafenib and trametinib must be 
stored in a secure area under the appropriate physical conditions for the product. Study 
medication is to be stored at the temperature specified on the label. Maintenance of a 
temperature log (manual or automated) is required. Access to and administration of 
dabrafenib and trametinib will be limited to the investigator and authorized site staff. 
Procedures for final disposition of unused study treatments will be provided in the SPM. 
5.4.
Treatment Assignment
Patients will be identified by a unique patient number that will remain consistent for the 
duration of the study.
Upon completion of all the required screening assessments, eligible patients will be 
registered into RAMOS (Registration and Medication Ordering System), the GSK 
interactive voice response system (IVRS), by the investigator or authorized site staff.
RAMOS allows study sites to register and randomise patients, and also records 
stratification information.
Randomisation will be done centrally using a randomisation schedule generated by the 
GSK Biostatistical Department, which will assign patients in a 1:1:1 ratio to:
Dabrafenib monotherapy followed by dabrafenib and trametinib combination 
therapy;
Trametinib monotherapy followed by dabrafenib and trametinib combination 
therapy;
Dabrafenib and trametinib combination therapy
Once a randomisation number has been assigned it must not be re-assigned even in cases 
of errors. 
5.5.
Blinding
This is an open-label study


2012N132406_01
CONFIDENTIAL
BRF116613
31
5.6.
Product Accountability
In accordance with local regulatory requirements, the investigator, designated site staff, 
or head of the medical institution (where applicable) must document the amount of 
investigational product dispensed and/or administered to study patients, the amount 
returned by study patients, and the amount received from and returned to GSK, when 
applicable. Product accountability records must be maintained throughout the course of 
the study. Refer to the SPM for further detailed instructions on product accountability.
5.7.
Treatment Compliance
Patients will be instructed to return treatment bottles at each visit. Compliance with 
dabrafenib and trametinib will be assessed through querying the patient during the site 
visits and documented in the source documents and eCRF. 
A record of the number of dabrafenib and trametinib tablets dispensed to and taken by 
each patient must be maintained and reconciled with study treatment and compliance 
records. Treatment start and stop dates, including dates for treatment delays and/or dose 
reductions will also be recorded in the CRF. The investigator will make every effort to 
bring non-compliant patients into compliance. 
5.8.
Dose Modification Guidelines
The severity of AEs will be graded using the CTCAE, version 4.0. The section includes:
general guidelines for clinically significant toxicities related to study treatments 
and 
specific guidelines for adverse events of special interest, which are events that 
have been observed with higher frequency or severity in patients receiving 
dabrafenib, trametinib, or a combination of both therapies.
Note: With the exception of pyrexia (likely related to dabrafenib), the guidance suggests 
that both therapies be reduced simultaneously in response to toxicities that are considered 
by the investigator to be treatment related.


2012N132406_01
CONFIDENTIAL
BRF116613
32
Table 3
Categories of Dose Modification Guidelines
Adverse Event
Dabrafenib
Trametinib
Section
General Guidelines for Clinically 
Significant Toxicities
X
X
Section 5.8.2
Guidelines for Specific Adverse Events
Cardiovascular Adverse Events
LVEF
X
X
Section 5.8.3.1
Hypertension 
X
X
Section 5.8.3.2
Prolonged QTc
X
X
Section 5.8.3.3
Skin –Related Adverse Events (Except cuSCC)a
Rash
X
X
Section 5.8.4.1
Hand-Foot Skin Reaction
X
X
Section 5.8.4.2
Other Adverse Events
Pyrexia
X
Section 5.8.5.1
Diarrhea
X
X
Section 5.8.5.2
Renal Insufficiency
X
X
Section 5.8.5.3
Visual Changes
X
X
Section 5.8.5.4
Pneumonitis
X
X
Section 5.8.5.5
Liver Chemistry Stopping Criteria
X
X
Section 5.9
e.
aRefer to Section 5.8.4.3 for management of cuSCC


2012N132406_01
CONFIDENTIAL
BRF116613
33
5.8.1.
Dose Levels of dabrafenib and trametinib
The dose levels for this study are provided in Table 4. 
Table 4
Dose Level Reduction Guidelines
Dose Level
Dabrafenib
Dose/Schedule
Trametinib
Dose/Schedule
Starting Dose
150 mg BID
2 mg once daily
-1 (1st Dose reduction)
100 mg BID
1.5 mg once daily
-2 (2nd Dose reduction)
75 mg BID
1.0 mg once daily
Abbreviation: BID = twice daily
If an AE resolves to grade 1 or baseline at the reduced dose level, and no additional 
toxicities are seen after 4 weeks of study treatment at the reduced dose, the dose may be 
increased to the previous dose level. 
A dose reduction below 75 mg BID for dabrafenib and 1 mg once daily for trametinib is 
not allowed. If a dose reduction below 75 mg BID for dabrafenib is required, dabrafenib 
will be permanently discontinued, but the patient will be allowed to continue trametinib. 
If a dose reduction below1.0 mg once daily for trametinib is required, then trametinib will 
be permanently discontinued, but these patients will be allowed to continue dabrafenib.
Note: Approval from the GSK Medical Monitor is required to restart study 
treatment after ≥21 days of interruption.
5.8.2.
General Guidelines for Clinically Significant Toxicities
General guidelines regarding management and dose reduction for adverse events that are 
considered by the investigator to be related to study treatment and which do not have 
specific guidelines (Table 3) are provided in Table 5.


2012N132406_01
CONFIDENTIAL
BRF116613
34
Table 5
Dose Modification Guidelines for Events Considered Related to Study 
Treatment
CTCAE Grade
Action and Dose Modification
Grade 1 
Continue study treatment at current dose level
Monitor closely 
Provide supportive care according to institutional standards
Grade 2 
Interrupt study treatment if clinically indicated
Monitor closely 
Provide supportive care according to institutional standards
When toxicity resolves to grade 1 or baseline, restart study 
treatment at current dose level
Grade 3 
Interrupt study treatment if clinically indicated
Monitor closely 
Provide supportive care according to institutional standards
When toxicity resolves to grade 1 or baseline, restart study 
treatment reduced by one dose level 
If the grade 3 toxicity recurs, interrupt study treatment
When toxicity resolves to grade 1 or baseline, restart study 
treatment reduced by another dose level 
Grade 4 
Interrupt study treatment 
Monitor closely 
Provide supportive care according to institutional standards
Restart with study treatment reduced by one dose level once 
toxicity resolves to grade 1 or baseline
If the grade 4 toxicity recurs, either permanently discontinue 
study treatment or, if the patient is clinically benefiting, discuss 
continuation of study treatment with the GSK medical monitor. 
5.8.3.
Guidelines for Cardiovascular Adverse Events
Cardiovascular adverse events have been seen in patients receiving either dabrafenib, 
trametinib or both in combination. (See the IBs for additional information.) 
5.8.3.1.
Left Ventricular Ejection Fraction (LVEF)
Decreases of the left-ventricular-ejection-fraction (LVEF) have been observed in patients 
receiving trametinib monotherapy and in combination with dabrafenib. Therefore, 
ECHOs must be performed to assess cardiac ejection fraction at regular intervals as 
outlined in the Time and Events Table (Table 19). If possible ECHO assessment should 
be performed by the same operator throughout the study. Dose modification guidance and 
stopping criteria for LVEF decrease are provided in Table 6.


2012N132406_01
CONFIDENTIAL
BRF116613
35
Table 6
Dose Modification Guidelines and Stopping Criteria for LVEF Decrease
Clinic
LVEF-drop (%) or CTCAE 
grade
Action and Dose Modification
Asymptomatic
Absolute decrease of >10% in 
LVEF compared to baseline and
ejection fraction below the 
institution’s LLN
Interrupt study treatment and repeat ECHO 
within 2 weeksa
If the LVEF recovers within 4 weeks (defined 
as LVEF ≥LLN and absolute decrease ≤10% 
compared to baseline) 
Consult with the GSK medical monitor 
and request approval for restart 
Restart with trametinib or placebo 
reduced by one dose level
Restart dabrafenib at previous dose level
Repeat ECHO 2 , 4 , 8 and 12 weeks 
after re-start; continue in intervals of 12 weeks 
thereafter
If LVEF does not recover within 4 weeks
Consult with cardiologist
Permanently discontinue study 
treatment
Repeat ECHO after 2, 4, 8, 12, and 16 
weeks or until resolution
Consult with GSK medical monitor
Symptomaticb
Grade 3: resting LVEF 39-20% 
or >20% absolute reduction from 
baseline
Permanently discontinue study treatment. 
Consult with cardiologist
Repeat ECHO after 2, 4, 8, 12, and 16 weeks 
or until resolution
Grade 4: resting LVEF <20%
Abbreviations: CTCAE = Common Terminology Criteria for Adverse Events; ECHO = echocardiogram; GSK = 
GlaxoSmithKline; LLN = lower limit of normal; LVEF = left ventricular ejection fraction; 
a.
If ECHO does not show LVEF recovery after 2 weeks, repeat ECHO 2 weeks later.
b.
Symptoms may include: dyspnea, orthopenea, and other signs and symptoms of pulmonary congestion and 
oedema.


2012N132406_01
CONFIDENTIAL
BRF116613
36
5.8.3.2.
Hypertension
Increases in blood pressure have been observed in patients receiving trametinib. 
Recommendations for blood pressure monitoring and management are provided in this 
section.
Monitoring of Hypertension
All blood pressure assessments should be performed under the following optimal 
conditions:
the patient has been seated with back support, ensuring that legs are uncrossed 
and flat on the floor
the patient is relaxed comfortably for at least 5 minutes
restrictive clothing has been removed from the cuff area and the right cuff size has 
been selected
the patients arm is supported so that the middle of the cuff is at heart level
the patient remains quiet during the measurement. 
In patients with an initial blood pressure 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 blood pressure measurement. The averaged value should be recorded in the eCRF.
Persistent hypertension is defined as an increase of systolic blood pressure (SBP) > 140 
mm Hg and/or diastolic blood pressure (DBP) > 90 mm Hg in three consecutive visits 
with blood pressure assessments from two readings collected as described above. Visits 
to monitor increased blood pressure can be scheduled independently from the per-
protocol visits outlined in the Time and Events Table (Table 19). Ideally, subsequent 
blood pressure assessments should be performed within one week. 
Asymptomatic hypertension is defined as an increase of SBP >140 mm Hg and/or DBP 
>90 mm Hg in the absence of headache, light-headedness, vertigo, tinnitus, episodes of 
fainting or other symptoms indicative of hypertension that resolve after the blood 
pressure is controlled within the normal range. 
Management of Hypertension
For patients experiencing an increase in systolic and/or diastolic blood pressure that is 
persistent and may be associated with the study treatment, recommendations for the 
clinical management of hypertension are described in Table 7.


2012N132406_01
CONFIDENTIAL
BRF116613
37
Table 7
Management and Dose Modification Guidelines for Hypertension
Hypertension
Action and Dose Modification
Scenario A:
Asymptomatic and persistenta SBP of ≥140 and 
<160 mmHg, or DBP ≥90 and <100 mmHg, 
or 
Clinically significant increase in DBP of 20 mmHg 
(but still below 110 mmHg).
Continue study treatmentat the current 
dose 
Adjust current or initiate new 
antihypertensive medication
Titrate antihypertensive medication(s) 
during the next 2 weeks as indicated to achieve 
well-controlledb BP
If BP is not well controlled within 2 weeks, 
consider referral to a specialist and go to 
scenario (B).
Scenario B:
Asymptomatic SBP ≥160 mmHg, or DBP 
≥100 mmHg, 
or 
Failure to achieve well-controlled BP within 2 
weeks in Scenario A
Interrupt study treatment if clinically 
indicated
Adjust current or initiate new 
antihypertensive medication(s)
Titrate antihypertensive medication(s) 
during the next 2 weeks as indicated to achieve 
well-controlled BP
Once BP is well controlledb, restart study 
treatment reduced by one dose level
Scenario C:
Symptomaticc hypertension 
or 
Persistentd SBP ≥160 mmHg, or DBP ≥100 mmHg, 
despite antihypertensive medication and dose reduction 
of study treatment
Interrupt study treatment 
Adjust current or initiate new 
antihypertensive medication(s)
Titrate antihypertensive medication during 
the next 2 weeks as indicated to achieve well-
controlled BP
Referral to a specialist for further 
evaluation and follow-up is recommended
Once BP is well controlled, restart study 
treatment reduced by one dose level
Scenario D:
Refractory hypertension unresponsive to above 
interventions or hypertensive crisis.
Permanently discontinue study treatment
Continue follow-up per protocol.
Abbreviations: BP = blood pressure; DBP = diastolic blood pressure; mmHg = millimetres mercury; SBP = systolic 
blood pressure;
a.
Hypertension detected in two separate readings during up to three consecutive visits
b.
Well-controlled blood pressure defined as SBP ≤140 mm Hg and DBP ≤90 mm Hg in two separate readings 
during up to three consecutive visits.
c.
Symptomatic hypertension defined as hypertension aggravated by symptoms (e.g., headache, light-headedness, 
vertigo, tinnitus, episodes of fainting) that resolve after the blood pressure is controlled within the normal range.
d.
Persistent hypertension is defined as asymptomatic hypertension after initially successful anti-hypertensive 
intervention.


2012N132406_01
CONFIDENTIAL
BRF116613
38
5.8.3.3.
Guidelines for Prolonged QTc
Guidelines for dose modification and stopping criteria due to QTC-prolongation are 
provided in Table 8.
Table 8
Withholding and Stopping Criteria for QTc-Prolongation
QTc-Prolongationa
Action and Dose Modification
QTcB ≥501 msec

Interrupt study treatment until QTcB prolongation 
resolves to grade 1 or baseline

Restart at current dose levelb

If event recurs, permanently discontinue study treatment
Abbreviations: msec = milliseconds; QTcB = QT interval on electrocardiogram corrected using the Bazett’s formula
a.
Based on average QTc value of triplicate ECGs. For example, if an ECG demonstrates a prolonged QT interval, 
obtain two or more ECGs over a brief period, and then use the averaged QTc values of the three ECGs to 
determine if study treatments should be interrupted or discontinued.
b.
If the QTc prolongation resolves to grade 1 or baseline, the patient may resume study treatment if the investigator 
and GSK medical monitor agree that the patient will benefit from further treatment.
5.8.3.4.
Guidelines for Valvular Toxicity

Patients who have an asymptomatic, moderate regurgitation or stenosis by ECHO 
(Grade 2 mitral/tricuspid/aortic valvular toxicity per CTCAE v4.0) should 
temporarily discontinue study treatment and have a repeat evaluation by ECHO 
within 1 week. ECHO should be repeated every 1-2 weeks for 4 weeks or until valve 
recovery to baseline. 
o
If the valve recovers to baseline any time during the next 4 weeks, after 
consultation and approval of the GSK medical monitor, the patient may be 
restarted on dabrafenib at a reduced dose(s). For such patients, monitoring of the 
valve via ECHO will then be performed 2 and 4 weeks after rechallenge, and 
every 4 weeks thereafter for 12 weeks and then per protocol.
o
If repeat ECHO does not reveal valve recovery to baseline within 4 weeks, 
then the patient should permanently discontinue study treatment. The valve 
should continue to be monitored via ECHO every 4 weeks for 16 weeks or until 
resolution. 

Patients with a Grade 3 or 4 (symptomatic, severe regurgitation/stenosis by imaging, 
with symptoms controlled by medical intervention) valvular toxicity must 
discontinue study treatment. Valvular toxicity should continue to be monitored every 
4 weeks for 16 weeks or until resolution. If recovery occurs (return to baseline via 
imaging AND symptom resolution) within 4 weeks, the patient may restart 
dabrafenib at a reduced dose after consultation and approval of the GSK medical 
monitor. For such patients, monitoring of the valve via ECHO will then be 
performed 2 and 4 weeks after rechallenge, and every 4 weeks thereafter for 12 
weeks and then per protocol.


2012N132406_01
CONFIDENTIAL
BRF116613
39
ECHO must be performed at baseline and at follow-up visit(s). Copies of all ECHO(s) 
and cardiology consultations performed on patients who experience a valvular toxicity 
will be required by GSK for review.
5.8.4.
Guidelines for Skin-related Adverse Events
Cutaneous adverse events have been observed in patients receiving dabrafenib, trametinib 
or both therapies in combination (see the Investigator Brochures for more information). 
Recommendations for supportive care and guidelines for dose modifications are provided 
(Section 5.8.4.1, Section 5.8.4.2 , and Section 5.8.4.3). The institutional standards for the 
management of skin-related AEs can differ from these guidelines. In this case, best 
clinical judgment should be applied and a consultation with the GSK Medical Monitor 
may be required. In addition, biopsies of any new skin lesions especially those suspicious 
of cuSCC for further study should be taken at the investigator’s discretion. 
5.8.4.1.
Rash
Rash is a frequent AE observed in patients receiving trametinib, dabrafenib, or the 
combination of both therapies. Guidelines for rash management are based on experience 
with other MEK inhibitors and epidermal growth factor receptor (EGFR) inhibitors and 
are provided below (Table 9 and Table 10).
Table 9
Guidelines for Supportive Care of Rash
Type of Care
Action
Prevention/Prophylaxisa

Avoid unnecessary exposure to sunlight

Apply broad-spectrum sunscreen (containing titanium dioxide or zinc 
oxide) with a skin protection factor (SPF) ≥15 at least twice daily.

Use thick, alcohol-free emollient cream (e.g., glycerine and cetomacrogol 
cream) on dry areas of the body at least twice daily.
Symptomatic Careb

Pruritic lesions: cool compresses and oral antihistamine therapies 

Papulopustular rash: topical steroids and antibiotics and antibiotics

Fissuring lesions: , silver nitrate, or zinc oxide cream 

Desquamation: thick emollients and mild soap 

Paronychia: antiseptic bath, local potent corticosteroids in addition to oral 
antibiotics; if no improvement, consult dermatologist or surgeon 

Infected lesions: appropriate bacterial/fungal culture-driven systemic or 
topical antibiotics 
Abbreviations: BID = twice daily; SPF = skin protection factor
a.
Rash prophylaxis is recommended for the first 6 weeks of study treatment
b.
Patients who develop rash/skin toxicities should be seen by a qualified physician and should receive evaluation 
for symptomatic/supportive care management
Guidelines for management and dose reduction for rash considered to be related to study 
treatment are provided in Table 10.


2012N132406_01
CONFIDENTIAL
BRF116613
40
Table 10
Management and Dose Modification Guidelines for Rash
CTCAE Grade
Adverse Event Management
Action and Dose Modification
Grade 1
Initiate prophylactic and symptomatic 
treatment measuresa
Use moderate strength topical steroidb 
Reassess after 2 weeks

Continue study treatment

If rash does not recover to 
baseline within 2 weeks despite 
best supportive care, continue 
topical steroid, consider using 
more potent topical steroids
Grade 2
Initiate prophylactic and symptomatic 
treatment measures
Use moderate strength topical steroidb
Use systemic tetracycline
Reassess after 2 weeks

Continue study treatment

If no recovery to ≤grade 1 
within 2 weeks, reduce study 
treatment by one dose level. If 
rash recovers to ≤grade 1 within 
2 weeks, increase dose to 
previous dose level
Grade ≥3
Use moderate strength topical steroidsb
PLUS oral 
Use antibiotic
Consult dermatologist 

Interrupt study treatment until 
rash recovers to grade ≤1

Restartc with study treatment 
reduced by one dose leveld

If no recovery to grade ≤2 within 
4 weeks, permanently
discontinue study treatment
Abbreviations: CTCAE = Common Terminology Criteria for Adverse Events
a.
Rash prophylaxis is recommended for the first 6 weeks of study treatment 
b.
Moderate-strength topical steroids: hydrocortisone 2.5% cream or fluticasone prioprionate 0.5% cream
c.
Approval of GSK medical monitor is required to restart study treatment after >4 weeks of interruption.
d.
Escalation of study treatment to previous dose level may be considered if no rash is evident 4 weeks after 
restarting study treatment
5.8.4.2.
Guidelines for Hand-foot Skin Reactions (HFSR)
Episodes of Hand-foot Skin Reaction (HFSR) have been observed in patients receiving 
dabrafenib. Guidelines for management of HFSR are based on experience with other 
kinase inhibitors (Lacouture, 2008; McLellan, 2011) and are listed Table 11.


2012N132406_01
CONFIDENTIAL
BRF116613
41
Table 11
Management and Dose modification Guidelines for Hand-Foot Skin 
Reaction (HFSR)
CTCAE Grade
Adverse Event Management
Action and Dose Modification
Grade 1a

Life style changes 
recommendedb

Initiate symptomatic treatmentc if 
clinically appropriate

Continue study treatment at current 
dose level
Grade 2

Life style changes 
recommendedb

Initiate symptomatic treatmentc

Interrupt study treatment until 
recovery to ≤grade 1d

Recovery to ≤grade 1 within 7 days: 
Restart study treatment at previous 
dose level

No recovery to grade ≤1 within 7 days 
or ≥ 2nd occurrence: restart with 
study treatment reduced by one 
dose levele
Grade ≥3

Life style changes 
recommendedb

Initiate symptomatic treatmentc

Consult dermatologist

Interrupt study treatment until 
recovery to ≤ grade 1

Restart with study treatment reduced 
by one dose levele

If 3rd occurrence, discontinue study 
treatment permanently 
Abbreviations: CTCAE = Common Terminology Criteria for Adverse Events
a.
A full-body skin examination and a removal of pre-existing calluses and keratotic skin is recommended prior to 
initiation of study treatment
b.
Life-style changes: (1)reduce exposure of hands and feet to hot water, (2) avoid traumatic activity including 
vigorous exercise especially in the first 4 weeks after start of study treatment, (3) avoid constrictive footwear, (4) 
avoid excessive friction on the skin, when applying topical treatments, (5) wear thick cotton socks and gloves, 
and shoes with padded insoles
c.
Symptomatic Treatments: (1) use moisturizing creams frequently and especially on hands and feet (2) consider 
topical keratolytics: urea 20-40 % cream, or salicylic acid 6%, or tazarotene 0.1% cream, or fluorouracil 5% 
cream; (3) erythrematous areas: clobetasol propionate 0.05% ointment; (4) Pain: topical lidocaine 2%, and / or 
systemic pain medication such as nonsteroidal anti-inflammatory drugs, codeine, and pregabalin 
c.
Symptoms usually resolve within 2-4 weeks of treatment cessation. Approval of GSK medical monitor is required 
to restart study treatment after ≥21 days of interruption
d.
Escalation of study treatment to the previous dose level is allowed if no HFSR is observed in the 4 weeks 
subsequent to dose reduction. 
5.8.4.3.
Guidelines for cuSCC
Cutaneous squamous cell carcinoma have been observed in patients treated with 
dabrafenib and the combination of dabrafenib and trametinib (see dabrafenib and 
trametinib combination IB). These treatment-related cuSCC should be surgically 
removed according to institutional practice. Dose modifications or interruptions of the 
study treatment are not required for cuSCC. Occurrence of cuSCC must be reported as an 
SAE.


2012N132406_01
CONFIDENTIAL
BRF116613
42
5.8.5.
Guidelines for Other Adverse Event of Special Interest
5.8.5.1.
Guidelines for Pyrexia
Episodes of pyrexia have been observed in patients receiving dabrafenib monotherapy or 
in combination with trametinib (see dabrafenib and dabrafenib and trametinib 
combination IBs). In a minority of cases the pyrexia was accompanied by symptoms such 
as severe chills, dehydration, hypotension, dizziness or weakness. 
Pyrexia accompanied by hypotension, dehydration requiring IV fluids, or severe 
rigors/chills should be reported as an SAE per Section 7.4.2.2. 
Patients should be instructed on the importance of immediately reporting febrile episodes. 
In the event of a fever, the patient should be instructed to take non-steroidal anti-pyretics 
as appropriate to control fever. In patients experiencing pyrexia associated with rigors, 
severe chills, dehydration, hypotension, etc., renal function should be monitored carefully 
(see Section 5.8.5.3). 
Guidelines regarding management and dose reduction for pyrexia considered to be 
related to study treatment are provided in Table 12.


2012N132406_01
CONFIDENTIAL
BRF116613
43
Table 12
Management and Dose Modification Guidelines for Pyrexia
Adverse 
Event
Adverse Event Management
Action and Dose Modification
Pyrexiaa
1st Eventb:

Clinical evaluation for infection and 
hypersensitivityc

Laboratory work-upc

Hydration as requiredd

Administer anti-pyretic treatment if clinically 
indicated and continue prophylactic 
treatmente
2nd Eventg

Clinical evaluation for infection and 
hypersensitivityc

Laboratory work-upc

Hydration as requiredd

Within 3 days of onset of pyrexia

Optimize anti-pyretic therapy

Consider oral corticosteroids (i.e., 
prednisone 10 mg) for at least 5 days 
or as clinically indicatedf
Subsequent Events: 

Clinical evaluation for infection and 
hypersensitivityc

Laboratory work-upc

Hydration as requiredd

within 3 days of onset of pyrexia:

Optimize oral corticosteroid dose as 
clinically indicated for recalcitrant 
pyrexiaf

If corticosteroids have been tapered 
and pyrexia recurs, restart steroids 

If corticosteroids cannot be tapered 
consult medical monitor
1st Event: 

Interrupt dabrafenib

Continue trametinib

Once pyrexia resolves to baseline, 
restart dabrafenib at the same 
dose level

If fever was associated with 
dehydration or hypotension, 
reduce dabrafenib by one 
dose level
2nd Event:

Interrupt dabrafenib

Continue trametinib

Once pyrexia resolves to baseline, 
restart dabrafenib at the same 
dose level

If fever was associated with 
dehydration or hypotension, 
reduce dabrafenib by one 
dose level
Subsequent Events:

Interrupt dabrafenib

Continue trametinib

Once pyrexia resolves to baseline, 
restart dabrafenib reduced by one 
dose levelg

If dabrafenib must be reduced to 
<75 mg BID, permanently 
discontinue dabrafenib


2012N132406_01
CONFIDENTIAL
BRF116613
44
a.
Pyrexia is defined as a body temperature equal to or above 38.5º Celsius or 101.3º Fahrenheit. 
b.
For patients experiencing pyrexia complicated by rigors, severe chills, etc., a clinical evaluation and laboratory 
work-up is mandatory for each event; anti-pyretic treatment should be started immediately at the first occurrence 
and prophylactic anti-pyretic treatment is recommended
c.
Thorough clinical examination for signs and symptoms of infection or hypersensitivity is required; laboratory work-
up should include full-blood-count, electrolytes, creatinine, blood urea nitrogen (BUN), C-reactive protein (CRP), 
liver-function tests, blood culture, and urine culture.
d.
Oral hydration should be encouraged in patients without evidence of dehydration. Intravenous hydration is 
recommended in patients experiencing pyrexia complicated by dehydration/hypotension.
e.
Anti-pyretic treatment may include acetaminophen, ibuprofen, or suitable anti-pyretic medication according to 
institutional standards. Prophylactic anti-pyretic treatment may be discontinued after three days in the absence of 
pyrexia
f.
In patient experiencing pyrexia complicated by rigors, severe chills, etc., which cannot be controlled with anti-
pyretic medication, oral corticosteroids should be started at the 2nd event and doses should be gradually increased 
for subsequent events.
g.
Dabrafenib should be reduced by one dose level after three episodes of pyrexia complicated by rigors, severe 
chills, etc., which cannot be managed by best supportive care and increasing doses of oral steroids. Escalation of 
dabrafenib is allowed if no episode of pyrexia is observed in the 4 weeks subsequent to dose reduction.
5.8.5.2.
Guidelines for Diarrhoea
Episodes of diarrhoea have occurred in patients receiving dabrafenib, trametinib, or both 
therapies in combination. Other, frequent causes for diarrhoea including concomitant 
medications (e.g., stool softeners, laxatives, antacids, etc.), infections by C. difficile or 
other pathogens, partial bowel obstruction, etc., should be clinically excluded.
Guidelines regarding management and dose reduction for diarrhoea considered to be 
related to study treatment by the investigator are provided in Table 13.


2012N132406_01
CONFIDENTIAL
BRF116613
45
Table 13
Management and Dose Modification Guidelines for Diarrhoea
CTCAE Grade
Adverse Event Management
Action and Dose Modification
Uncomplicated 
Diarrhoeaa
Grade 1 or 2
Diet: stop all lactose containing products; 
eat small meals, BRAT-diet (banana, rice, 
apples, toast) recommended
Hydration: 8-10 large glasses of clear 
liquids per day (e.g., Gatorade or broth)
Loperamidec: initially 4 mg, followed by 2 
mg every four hours or after every unformed 
stool; maximum 16 mg/day. Continue until 
diarrhoea free for 12 hours
Diarrhoea > 24h: loperamide 2 mg every 
two hours; maximum 16 mg/day. Consider 
adding oral antibiotics
Diarrhoea > 48h: loperamide 2 mg every 
two hours; maximum 16 mg/day. Add 
budesonide or other second-line therapies 
(otreotide, or tincture of opium) and oral 
antibiotics
Continue study treatment
If diarrhoea is grade 2 for > 48h, 
interrupt study treatment until diarrhoea 
resolves to grade ≤1
Restart study treatment at the same 
dose level
Uncomplicated 
Diarrhoeaa
Grade 3 or 4
Any Complicated 
Diarrhoeab
Clinical evaluation mandatory
Loperamidec: initially 4 mg, followed by 2 
mg every four hours or after every unformed 
stool; maximum 16 mg/day. Continue until 
diarrhoea free for 12 hours
Oral antibiotics and second-line therapies 
if clinically indicated
Hydration: intravenous fluids if clinically 
indicated
Antibiotics (oral or intravenous) if clinically 
indicated
Intervention should be continued until the 
patient is diarrhoea free for ≥ 24 hours
Intervention may require hospitalization for 
patients at risk of life-threatening complications
Interrupt study treatment until 
diarrhoea resolves to grade ≤1
Restart with study treatment reduced 
by one dose leveld
If 3 dose reductions of study treatment 
are clinically indicated, permanently 
discontinue study treatment
Abbreviation: CTCAE = Common Terminology Criteria for Adverse Events
a. Uncomplicated diarrhoea defined by the absence of symptoms such as, cramping, nausea/vomiting ≥grade 2, 
decreased performance status, pyrexia, sepsis, neutropenia grade ≥3, frank bleeding, and/or dehydration requiring 
intravenous fluid substitution
b. Complicated diarrhoea defined by the presence of symptoms such as, cramping, nausea/vomiting ≥grade 2, 
decreased performance status, pyrexia, sepsis, neutropenia grade ≥3, frank bleeding, and/or dehydration requiring 
intravenous fluid substitution
c. Loperamide should be made available prior to start of study treatment so loperamide administration can begin at 
the first signs of diarrhoea
d. Escalation of study treatment to previous dose level is allowed after consultation with the medical monitor and in 
the absence of another episode of complicated or severe diarrhoea in the 4 weeks subsequent to dose reduction.


2012N132406_01
CONFIDENTIAL
BRF116613
46
5.8.5.3.
Guidelines for Renal Insufficiency
Cases of renal insufficiency have occurred in patients receiving dabrafenib and the 
combination of dabrafenib and trametinib. Prior to start of study treatment, concomitant 
medications should be reviewed for the potential risk of inducing nephrotoxicity and 
concomitant medications should be modified if clinically possible. 
Guidelines regarding management and dose reduction for renal insufficiency considered 
to be related to study treatment by the investigator are provided in Table 14.
Table 14
Management and Dose Modification Guidelines for Renal 
Insufficiency
Serum Creatinine Level
Adverse Event Management
Action and Dose Modification
Serum creatinine increase 
>0.2 mg/dL (18 umol/L)
but
0.5 mg/dL (44 umol/L) 
above baseline
Recheck serum creatinine within 
1 week
Serum creatinine increase > 1 
week: contact GSK Medical Monitor
If pyrexia is present, treat pyrexia 
as per guidelinesa
Continue study treatmentat 
the same dose level
Serum creatinine increase 
>0.5 mg/dL (44 umol/L) 
above baseline 
or 
serum creatinine >2 mg/dL 
(> 177 umol/L)
Monitor serum creatinine ≥ 2-
times per week 
Hospitalization may be necessary 
if serum creatinine cannot be 
monitored frequently
If pyrexia is present, treat pyrexia 
per guidelinesa
Consult nephrologist if clinically 
indicated
Perform renal biopsy if clinically 
indicated, for example:
Renal insufficiency persists 
despite volume repletion
Patient has new rash or 
signs of hypersensitivity (such as 
elevated eosinophil count)
Interrupt study treatment until 
serum creatinine recovers to 
baseline
Restart with study treatmentb
Abbreviations: GSK = GlaxoSmithKline; NSAIDS = non-steroidal anti-inflammatory drugs
a.
NSAIDs can induce renal insufficiency, especially in patients with dehydration; encourage oral fluids or consider 
intravenous fluids as clinically indicated. See guidelines for pyrexia 5.8.5.1.
b.
Investigator may restart at either the same or a reduced dose level. Escalation of study treatment to previous 
dose level is allowed if another episode of renal insufficiency does not occur after 4 weeks of dose reduction. 
Consultation with GSK Medical Monitor is required before restarting study treatment if there is evidence of 
thrombotic microangiography.


2012N132406_01
CONFIDENTIAL
BRF116613
47
5.8.5.4.
Guidelines for Visual Changes
Episodes of visual changes have been observed in patients receiving dabrafenib, 
trametinib or the combination of both therapies. The causal relationship between a 
change in vision and the study treatment should be carefully explored and an 
ophthalmologist should be consulted. Special attention should be given to retinal (e.g., 
CSR) or retinal vein abnormalities (e.g., RVO). For events of visual changes regardless 
of severity, a blood sample for PK analysis must be drawn as close as possible to the time 
of the event.
Guidelines regarding management and dose reduction for visual changes considered to be 
related to study treatment are provided in Table 15.


2012N132406_01
CONFIDENTIAL
BRF116613
48
Table 15
Management and Dose Modification Guidelines for Visual Changes
CTCAE Gradea
Adverse Event Management
Action and Dose Modification
Grade 1
Consult ophthalmologist within 7 
days of onset
Exclude CSR or RVO
Consult retinal specialist in case of 
CSR or RVO
Report RVO as SAE
Continue follow up examination(s) 
by retinal specialist for CSR and RVO
Continue study treatmentat the same 
dose level until ophthalmologic examination 
can be conductedb
If ophthalmologic examination cannot be 
performed within 7 days of onset, interrupt 
study treatment until CSR and RVO can be 
excluded and symptoms resolve
Restart study treatment at same dose 
level
CSR: Interrupt study treatment until 
symptoms resolve and exam by retinal 
specialist shows resolution
Restart with study treatment reduced by 
one dose level
RVO: Permanently discontinue study 
treatment
Grade 2 and
Grade 3
Consult ophthalmologist 
immediately 
Exclude CSR and RVO
Consult retinal specialist in case of 
RVO or CSR for follow-up exam
Report RVO as SAE
Continue follow up examination(s) 
by retinal specialist for CSR and RVO
Interrupt study treatmentuntil signs and 
symptoms have resolved to baseline
Restart with study treatment reduced by 
one dose level
CSR: Interrupt study treatment until 
symptoms resolve and exam by retinal 
specialist shows resolution Restart study 
treatment reduced by one dose level
RVO: Permanently discontinue study 
treatment
Grade 4
Consult ophthalmologist 
immediately 
Exclude CSR and RVO
Report RVO as SAE
Continue follow up examination(s) 
by retinal specialist for CSR and RVO
Permanently discontinue study 
treatment
Abbreviations: CSR = central serous retinopaty; CTCAE = Common Terminology Criteria for Adverse Events; RVO = 
retinal vein occlusion; SAE = serious adverse event
a.
Refers to CTCAE Version 4.0 ‘Eye disorders – Other, specify
b.
If visual changes are clearly unrelated to study treatment (e.g., allergic conjunctivitis), monitor closely but 
ophthalmic examination is not required.


2012N132406_01
CONFIDENTIAL
BRF116613
49
5.8.5.5.
Guidelines for Pneumonitis
Pneumonitis has been observed in patients receiving trametinib. To reduce the risk of 
pneumonitis, patients will be monitored closely for symptoms, evaluated with imaging 
and functional tests. Dose modification and supportive care guidelines for pneumonitis 
are described in Table 16.


2012N132406_01
CONFIDENTIAL
BRF116613
50
Table 16
Management and Dose Modification Guidelines for Pneumonitis
CTCAE 
Grade
Adverse Event Management
Action and Dose Modification
Grade 1
CT scan (high-resolution with lung 
windows) recommended
Clinical evaluation and laboratory work-up 
for infection
Monitoring of oxygenation via pulse-
oximetry recommended 
Consultation of pulmonologist 
recommended
Continue study treatment at current 
dose
Grade 2
CT scan (high-resolution with lung 
windows)
Clinical evaluation and laboratory work-up 
for infection
Consult pulmonologist
Pulmonary function tests -if < normal, 
repeat every 8 weeks until ≥ normal
Bronchoscopy with biopsy and/or BAL 
recommended
Symptomatic therapy including 
corticosteroids if clinically indicated
Interrupt study treatment until 
recovery to grade ≤1
Restart with study treatment 
reduced by one dose level
Escalation to previous dose level 
after 4 weeks and consultation with 
medical monitor possible
If no recovery to grade ≤1 within 4 
weeks, permanently discontinue study 
treatment
Grade 3
CT scan (high-resolution with lung 
windows)
Clinical evaluation and laboratory work-up 
for infection
Consult pulmonologist
Pulmonary function tests-if < normal, 
repeat every 8 weeks until ≥ normal
Bronchoscopy with biopsy and/or BAL if 
possible
Symptomatic therapy including 
corticosteroids as clinically indicated
Interrupt study treatment until 
recovery to grade ≤1
After consultation with medical 
monitor, study treatmentmay be 
restarted reduced by one dose level
If no recovery to grade ≤1 within 4 
weeks, permanently discontinue study 
treatment
Grade 4
Same as grade 3
Permanently discontinue study 
treatment
Abbreviations: BAL= broncioalveolar lavage; CT = computed tomography; CTCAE = Common Terminology Criteria for 
Adverse Events


2012N132406_01
CONFIDENTIAL
BRF116613
51
5.9.
Stopping, Follow-up, and Monitoring Criteria for 
Hepatobiliary Events
5.9.1.
Liver Chemistry Stopping Criteria
These liver chemistry stopping and follow-up criteria have been designed to assure 
patient safety and evaluate liver event etiology in alignment with the FDA Guidance for 
Industry – Drug-Induced Liver Injury: Premarketing Clinical Evaluation (July 2009, 
www.fda.gov). Liver chemistry stopping criteria 1-5 are defined as:
1.
ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin) (or ALT3xULN and 
INR>1.5, if INR measured)
NOTE: If serum bilirubin fractionation is not immediately available, study treatment 
should be discontinued if ALT 3xULN and bilirubin 2xULN. 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 5xULN.
3.
ALT  3xULN if associated with symptoms (new or worsening) believed to be 
related to  hepatitis (such as fatigue, nausea, vomiting, right upper quadrant pain or 
tenderness, or jaundice) or believed to be related to hypersensitivity (such as fever, 
rash or eosinophilia).
4.
ALT 3xULN persists for 4 weeks
5.
ALT 3xULN and cannot be monitored weekly for 4 weeks
When any of the liver chemistry stopping criteria 1 - 5 is met, do the following:

Immediately discontinue patient from study treatment 

Report the event to GSK within 24 hours of learning its occurrence

Complete the liver event CRF and SAE data collection tool if the event also meets 
the criteria for an SAE All events of ALT 3xULN and bilirubin 2xULN (>35% 
direct bilirubin) (or ALT3xULN and INR>1.5, if INR measured; INR measurement 
is not required and the threshold value stated will not apply to patients receiving 
anticoagulants), termed ‘Hy’s Law’, must be reported as an SAE.
NOTE: if serum bilirubin fractionation is not immediately available, study treatment 
should be discontinued if ALT 3xULN and bilirubin 2xULN. Serum bilirubin 
fractionation should be performed if testing is available. If testing is unavailable,
record presence of detectable urinary bilirubin on dipstick, indicating direct 
bilirubin elevations and suggesting liver injury

Complete the liver imaging and/or liver biopsy CRFs if these tests are performed

Perform liver event follow up assessments, and monitor the patient until liver 
chemistries resolve, stabilize, or return to baseline values as described below


2012N132406_01
CONFIDENTIAL
BRF116613
52

Withdraw the patient from the study after completion of the liver chemistry 
monitoring (unless further safety follow up is required or GSK Medical Governance 
approval of drug restart is granted, as described in Section 5.9.1.3).

Do not restart investigational product unless written approval is granted by GSK 
Medical Governance (details for restarting investigational product are described in 
Section 5.9.1.3), whereupon the patient continues in the study after completion of the 
liver chemistry monitoring described in Section 5.9.1.2). 
In addition, for patients meeting liver stopping criterion 1: 

Make every reasonable attempt to have patients return to clinic within 24 hours for 
repeat liver chemistries, liver event follow up assessments (refer to Section 5.9.1.1), 
and close monitoring

A specialist or hepatology consultation is recommended

Monitor patients twice weekly until liver chemistries (ALT, AST, alkaline 
phosphatase, bilirubin) resolve, stabilize or return to within baseline values.
For patients meeting any of the liver stopping criteria 2-5:

Make every reasonable attempt to have patients return to clinic within 24-72 hrs for 
repeat liver chemistries and liver event follow up assessments (refer to Section 
5.9.1.1)

Monitor patients weekly until liver chemistries (ALT, AST, alkaline phosphatase, 
bilirubin) resolve, stabilize or return to within baseline values; 

Patients meeting criterion 5 should be monitored as frequently as possible.
5.9.1.1.
Liver Event Follow-up Assessments
For patients meeting any of the liver chemistry stopping criteria 1- 5, make every attempt 
to carry out the liver event follow up assessments described below:

Viral hepatitis serology including:

Hepatitis A IgM antibody

Hepatitis B surface antigen and Hepatitis B Core Antibody (IgM) 

Hepatitis C RNA 

Cytomegalovirus IgM antibody

Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, obtain 
heterophile antibody or monospot testing)

Hepatitis E IgM antibody.

Blood sample for pharmacokinetic (PK) analysis, obtained within 10 days of last 
dose. Record the date/time of the PK blood sample draw and the date/time of the last 
dose of study treatment prior to blood sample draw on the CRF. If the date or time of 
the last dose is unclear, provide the patient’s best approximation. If the date/time of 


2012N132406_01
CONFIDENTIAL
BRF116613
53
the last dose cannot be approximated OR a PK sample cannot be collected in the 
time period indicated above, do not obtain a PK sample. Instructions for sample 
handling and shipping are in the SPM.

Serum creatine phosphokinase (CPK) and lactate dehydrogenase (LDH).

Fractionate bilirubin, if total bilirubin 2xULN.

Obtain complete blood count with differential to assess eosinophilia.

Record the appearance or worsening of clinical symptoms of hepatitis, or 
hypersensitivity, such as fatigue, nausea, vomiting, right upper quadrant pain or 
tenderness, pyrexia, rash or eosinophilia as relevant on the AE form. Please note that 
treatment with trametinib often associates with rash which is usually acneiform and 
affects the scalp, face, neck, chest, and upper back. Discuss with GSK Medical 
Monitor as needed.

Record use of concomitant medications such as acetaminophen, herbal remedies, 
other over the counter medications, or putative hepatotoxins, on the concomitant 
medications form.

Record alcohol use on the liver event alcohol intake form.
The following assessments are required for patients with ALT 3xULN and bilirubin 
2xULN (>35% direct) but are optional for other abnormal liver chemistries:

Anti-nuclear antibody, anti-smooth muscle antibody, and Type 1 anti-liver kidney 
microsomal antibodies and quantitative total immunoglobulin G (IgG or gamma 
globulins).

Liver imaging (ultrasound, magnetic resonance, or computerized tomography) to 
evaluate liver disease.

Serum acetaminophen adduct high-performance liquid chromatography (HPLC) 
assay (quantifies potential acetaminophen contribution to liver injury in patients with 
definite or likely acetaminophen use in the preceding week (James, 2009).

Only in those with underlying chronic hepatitis B at study entry (identified by 
positive hepatitis B surface antigen): quantitative hepatitis B DNA and hepatitis delta 
antibody. NOTE: if hepatitis delta antibody assay cannot be performed, it can be 
replaced with a PCR of hepatitis D RNA virus (where needed) – as outlined in: 
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1153793/.
5.9.1.2.
Liver Chemistry Monitoring Criteria
For patients with ALT ≥3xULN but <5xULN and bilirubin <2xULN, without hepatitis 
symptoms or rash, and who can be monitored weekly for 4 weeks, the following actions 
should be taken:

Notify the GSK Medical Monitor within 24 hours of learning of the abnormality 
to discuss patient safety

Continue study treatment 


2012N132406_01
CONFIDENTIAL
BRF116613
54

Return weekly for repeat liver chemistries (ALT, AST, alkaline phosphatase, 
bilirubin) until they resolve, stabilize or return to within baseline values 

If at any time the patient meets any of the liver chemistry stopping criteria 1 – 5, 
proceed as described above

If, after 4 weeks of monitoring, ALT <3xULN and bilirubin <2xULN, monitor 
patients twice monthly until liver chemistries normalize or return to within 
baseline values. 

Refer to Appendix 5 for an algorithm of liver chemistry monitoring, stopping, 
and follow-up criteria.
5.9.1.3.
Drug Restart/Rechallenge Following Liver Events that are Possibly 
Related to Study Treatment
Approval by GSK for study treatment restart can be considered where:
The patient is receiving compelling benefit, benefit of drug restart exceeds risk, and no 
effective alternative therapy is available. Ethics Committee or Institutional Review Board 
approval of study treatment restart/rechallenge must be obtained, as required.
If the restart/rechallenge is approved by GSK in writing, the patient must be provided 
with a clear description of the possible benefits and risks of drug administration, 
including the possibility of recurrent, more severe liver injury or death.
The patient must also provide signed informed consent specifically for the study 
treatment restart/rechallenge. Documentation of informed consent must be recorded in 
the study chart.
Study treatment must be administered at the dose specified by GSK.
Patients approved by GSK for restart/rechallenge of study treatment must return to the 
clinic twice a week for liver chemistry tests until stable, liver chemistries have been 
demonstrated and then laboratory monitoring may resume as per protocol. 
5.9.1.4.
Drug Restart Following Transient Resolving Liver Events Not Related 
to Study Treatment
Approval by GSK for drug restart can be considered where:

Liver chemistries have a clear underlying cause (e.g., biliary obstruction, 
hypotension and liver chemistries have improved to normal or are within 1.5 x 
baseline and ALT <3xULN). Ethics Committee or Institutional Review Board 
approval of study treatment restart/rechallenge must be obtained, as required.

If restart of study treatment is approved by GSK in writing, the patient must be 
provided with a clear description of the possible benefits and risks of drug 
administration, including the possibility of recurrent, more severe liver injury or 
death.


2012N132406_01
CONFIDENTIAL
BRF116613
55

The patient must also provide signed informed consent specifically for the 
restart. Documentation of informed consent must be recorded in the study chart.

Study treatment must be administered at the dose specified by GSK.

Patients approved by GSK for restarting study treatment must return to the clinic 
once a week for liver chemistry tests until stable liver chemistries have been 
demonstrated, and then laboratory monitoring may resume as per protocol. If 
protocol defined stopping criteria for liver chemistry elevations are met, study 
treatment must be stopped.


2012N132406_01
CONFIDENTIAL
BRF116613
56
6.
CONCOMITANT MEDICATIONS AND NON-DRUG 
THERAPIES
6.1.
Permitted Medications and Non-drug Therapies
The investigator must be informed as soon as possible about any medication taken from 
the time of screening until 30 days after the last dose of study treatment with the 
exception of new anti-cancer therapy, if taken after study treatment discontinuation; these 
will be documented until study completion/withdrawal or death. Any concomitant 
medication(s), including dietary supplements, taken during the study will be recorded in 
the eCRF. The minimum requirement is that drug name, dose, the dates of administration 
and reason for medications are to be recorded. Additionally, a complete list of all prior 
anti-cancer therapies will be recorded in the eCRF. 
Patients should receive full supportive care during the study, including transfusions of 
blood and blood products, and treatment with antibiotics, anti-emetics, anti-diarrhoeals, 
and analgesics, and other care as deemed appropriate, and in accordance with their 
institutional guidelines. Use of anticoagulants such as warfarin is permitted provided that 
INR is monitored in accordance with local institutional practice. 
While patients are on study treatment, palliative radiation therapy is permitted for non-
target lesions that are either new or present at baseline. The total dose may not exceed 30 
Gy.
6.2.
Prohibited Medications and Non-drug Therapies
The use of certain medications and illicit drugs within 28 days or 5 half lives, whichever 
is shorter, prior to randomisation and for the duration of the study will not be allowed. 
The GSK medical monitor can approve the use of a prohibited medication if it is required 
for a single use (such as for a procedure) while treatment with study drug is interrupted. 
The following medications or non-drug therapies are also prohibited while on treatment 
in this study:
Other anti-cancer therapies;
Other investigational drugs;
Antiretroviral drugs (Note: Patients with known HIV are ineligible for study 
participation);
Herbal remedies (e.g., St. John’s wort);
Drugs that are strong inhibitors or inducers of CYP3A and CYP2C8 (for 
examples see Table 17) may only be used under special circumstances (e.g. as a 
single use for a procedure) while treatment with study drug is interrupted as they 
may alter dabrafenib and/or trametinib concentrations; consider therapeutic 
substitutions for these medications. Approval of the GSK medical monitor is 
required in these situations. A partial list of these medications is provided in 
Table 17. The list may be modified based on emerging data. Refer to the SPM 
for the most current list.


2012N132406_01
CONFIDENTIAL
BRF116613
57
Table 17
Drugs that are Strong Inhibitors or Inducers of CYP3A and CYP2C8
Class/Therapeutic Area
Drugs/Agents
Antibiotics
Clarithromycin, rifamycin class agents (e.g.,  rifampin, rifabutin, 
rifapentine), telithromycin, troleandomycin
Antidepressant
Nefazodone
Antifungals
Itraconazole, ketoconazole, posaconazole, voriconazole
Hyperlipidemia
Gemfibrozil
Miscellaneous
Amiodarone, bosentan, carbamazepine, conivaptan, mibefranil, 
phenobarbital, phenytoin, s-mephenytoin 
6.3.
Medications to be used with Caution
The following medications should be used with caution as their concentrations may be 
altered by dabrafenib or trametinib or they may alter dabrafenib or trametinib 
concentrations:

Drugs that are mild/moderate inhibitors or inducers of CYP3A and CYP2C8 as 
they may alter concentrations of dabrafenib.

Dabrafenib has been shown to induce CYP3A4 in vivo and may induce 
CYP2B6. Other enzymes such as CYP2C8, CYP2C9, and CYP2C19 may also 
be affected.  Co-administration of dabrafenib and medications which are 
affected by the induction of these enzymes (including warfarin) may result in 
loss of efficacy.  If co-administration of these medications is necessary, 
investigators should monitor patients for loss of efficacy or consider 
substitutions of these medications. A partial list of these medications is provided 
in Table 18 and in the SPM.


2012N132406_01
CONFIDENTIAL
BRF116613
58
Table 18
Medications to be used with Caution
USE WITH CAUTION: Concentrations of these drugs may be increased or decreased by dabrafenib
Class/Therapeutic Area
Mild/Moderate CYP3A and CYP2C8
Antiarrhythmics
Diltiazem, verapamil
Antibiotic
Erythromycin
Antifungal
Fluconazole
Miscellaneous
Aprepitant, cimetidine, montelukast
USE WITH CAUTION: Co-administration of these drugs with study treatment may result in loss of 
efficacy.  Monitor patients for loss of efficacy or substitute with another medication.
Class/Therapeutic Area
CYP3A4, CYP2B6, CYP2C8, CYP2C9, or CYP2C19 Substrates that 
May be Affected by Induction 
Analgesics
Alfentanil, buprenorphine, celecoxib, codeine, fentanyl, methadone, 
oxycodone
Antiarrhythmics
Disopyramide, dronedarone, mexiletine, propafenone, quinidine
Antibiotics
Chloramphenicol, doxycycline, erythromycin, moxifloxacin 
Anticoagulants/ Antiplatelets
Cilostazole, warfarin
Anticonvulsants
Divalproex, lamotrigine, valproate, zonisamide
Antidepressants and 
Antipsychotics
Aripiprazole, bupropion, buspirone, desipramine, haloperidol, mirtazapine, 
pimozide, quetiapine, trazodone, amitriptyline, clomipramine, imipramine
Antidiabetics
Glyburide, saxagliptin, tolbutamide, nateglinide, pioglitazone, repaglinide, 
rosiglitazone
Antifungals
Caspofungin, fluconazole, terbinafine
Antihistamines
Astemizole, chlorpheniramine, ebastine
Antihypertensives
Amlodipine, diltiazem, felodipine, nifedipine, nilvadipine, nisoldipine, 
verapamil
Antimigraine Agents
Diergotamine, eletriptan, ergotamine
Corticosteroids
Dexamethasone, methylprednisolone, oral budesonide
Erectile Dysfunction Agents
Sildenafil, tadalafil, vardenafil
HMG-CoA Reductase 
Inhibitors
Atorvastatin, lovastatin, simvastatin, cerivastatin
Hypnotics and Sedatives
Alprazolam, brotizolam, diazepam, estazolam, midazolam, triazolam, 
zolpidem, zopiclone
Immunosuppressants
Everolimus, sirolimus, tacrolimus
Miscellaneous
Aprepitant, cisapride, darifenacin, disopyramide, leflunomide, 
methohexital, oral contraceptives, quinine, ranitidine, solifenacin, 
sulfasalazine, tramadol, tolvaptan, chloroquine, zopiclone
Selective Aldosterone 
Blockers
Eplerenone
Abbreviations: CYP = cytochrome P450; HMG-CoA = 3-hydroxy-3-methylglutaryl-coenzyme A.
Questions regarding concomitant medications should be directed to the GSK Medical 
Monitor for clarification.


2012N132406_01
CONFIDENTIAL
BRF116613
59
6.4.
Treatment after Discontinuation of Study Treatment or 
Withdrawal from/Completion of Study
The investigator is responsible for ensuring that consideration has been given for the 
post-study care of the patient’s medical condition whether or not GSK is providing 
specific post-study treatment.
Post-study treatment will not be provided as part of the protocol. Upon discontinuation 
from assigned study treatment, patients may receive additional (non-protocol) anti-cancer 
therapy at the discretion of the treating physician.
6.5.
Treatment of Study Treatment Overdose
In the event of a dabrafenib overdose, defined as administration of more than 300 mg as a 
single dose or 600 mg per day (the highest dose tested in clinical studies to date), and/or a 
trametinib overdose, defined as administration of more than 3.0 mg once daily (the 
maximum tolerated dose defined in the MEK111054 Study), the investigator should 
contact the GSK Medical Monitor immediately and closely monitor the patient for 
AEs/SAEs and laboratory abnormalities. GSK does not recommend specific treatment. 
The investigator will use clinical judgment to treat any overdose. 
Decisions regarding dose modifications or interruptions should be made by the 
investigator in consultation with the GSK Medical Monitor based on the clinical 
evaluation of the patient.
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.
Information regarding the quantity of the excess dose as well as the duration of the 
overdosing should be documented in the eCRF.


2012N132406_01
CONFIDENTIAL
BRF116613
60
7.
STUDY ASSESSMENTS AND PROCEDURES
A signed, written informed consent form must be obtained from the patient prior to any 
study-specific procedures or assessments.
Procedures conducted as part of the patient’s routine clinical management (e.g., imaging) 
and obtained prior to signing of informed consent may be used for screening or baseline 
purposes provided the procedure meets the protocol-defined criteria and has been 
performed within the timeframe specified in the protocol.
Refer to the Time and Events Table (Table 19) for the timing of all assessments. 
Assessments must be performed on a calendar schedule; delays in treatment 
administration will not delay performance of assessments. Details on efficacy and safety 
assessments are presented in Section 7.3 and Section 7.4, respectively. Further details of 
study procedures and assessments can be found in the SPM
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.
The investigator may discuss with the GSK Medical Monitor the possibility of continuing 
study treatment for a patient who is receiving benefit but has met the RECIST 1.1 criteria 
for disease progression.


2012N132406_01
CONFIDENTIAL
BRF116613
61
Table 19
Time and Events
Study Assessments1
Screening
(28 days 
except where 
noted)2
Day 1
Every 4 Weeks
(7 days)
Every 8 Weeks
(7 days)
Every 12 Weeks
(7 days)
End of Study20
Clinical assessments
Informed consent3
X
Inclusion/Exclusion criteria
X
X
Demographic data
X
Past and current medical conditions including 
cardiovascular medical and family history, risk factors
X
Disease characteristics4
X
Prior anti-cancer therapies
X
Performance status (ECOG)
X
X
X
Brain MRI/CT5
X
(5 weeks)
Lesion assessment (including skin lesion 
photography)6
X
(5 weeks)
Week 8 and every 8 weeks thereafter 
through week 56 and then every 12 
weeks thereafter until determination of 
progressive disease
Randomisation7
X
Safety Assessments
Vital signs8
X
X
X
Physical examination9,23
X
X (short)
X
Ophthalmic examination10
X
Adverse events11
X
X
X
X
ECG12
X 
(5 weeks)
X
(only at Week 4)
X
X
ECHO13
X 
(5 weeks)
X
(only at Week 4)
X
Dermatology assessment23
X
X
(only at week 2, 8, 10)
X
(at PD)
Concomitant medications14
X
X
X
X
Laboratory Assessments
Chemistry and Haematology15
X
X
X


2012N132406_01
CONFIDENTIAL
BRF116613
62
Study Assessments1
Screening
(28 days 
except where 
noted)2
Day 1
Every 4 Weeks
(7 days)
Every 8 Weeks
(7 days)
Every 12 Weeks
(7 days)
End of Study20
Serum pregnancy test16
X
Coagulation
X
Study Treatments
Dispensation of medication17
X
X
Assessment of compliance18
X
Biomarker Samples
Tumour biopsy21, 22, 
X
X
(only at week 2, 8, 10)
X
(at PD)
Skin biopsy21, 22
X
X
(only at week 2, 8, 10)
X
(at PD)
Blood sample for biomarker
X
X
(only at week 2, 8, 10)
X
(at PD)
Blood sample for PK19
X
(only at week 2, 8, 10)
X
(at PD)
Blood sample for cfDNA21
X
Abbreviations: cfDNA = cell-free deoxyribonucleic acid; CNS = central nervous system; CT = computed tomography; ECG = electrocardiogram; ECHO = echocardiogram; ECOG = 
Eastern Cooperative Oncology Group; LDH = lactate dehydrogenase; LLN = lower limit of normal; LVEF = left ventricular ejection fraction; MRI = magnetic resonance imaging; PD = 
progressive disease; PK = pharmacokinetics; RAMOS = Registration and Medication Ordering System; RECIST = Response Evaluation Criteria in Solid Tumours; SPM = study 
procedures manual.
1.
All assessments mandated throughout the study must be performed on a calendar schedule; delays in treatment administration will not delay performance of assessments. 
2.
Screening procedures may be performed up to 28 days prior to randomisation. Screening procedures that have a larger visit window are indicated in parentheses.
3.
Informed consent must be given prior to performance of any study-related procedures. Informed consent can be obtained at any time before Day 1.
4.
Disease characteristics will include date of diagnosis, primary tumour type, histology, stage, etc.
5.
Baseline MRI (preferred) or CT (only if MRI contraindicated or unavailable) of the brain must be performed on all patients to rule out current leptomeningeal metastases, brain 
metastases, or spinal cord compression secondary to metastasis. Post-baseline scans should be performed in all patients with documented metastases at baseline and as 
clinically indicated (e.g., symptoms suggestive of CNS progression) in all patients. 
6.
Lesion assessments must be done for chest, abdomen, pelvis, and any area of known disease. Lesion assessment by contrast CT (preferred) or MRI must be performed within 5
weeks prior to randomisation and at the times indicated until disease progression, death, or withdrawal of consent, whichever occurs first. (See Section 7.3.3 for instructions 
regarding chest X-Rays and CT assessment.) Target and non-target lesions must be identified at the time of screening and the same lesions must be re-assessed at each 
timepoint in a consistent manner according to RECIST, version 1.1. The same diagnostic method, including use of contrast when applicable, must be used throughout the study 
to evaluate each lesion. Lesion measurements will be taken using ruler or calipers. The Week 8 assessment for patients in arms A & B should be done before starting the 
combination treatment. If the last assessment was > 8 weeks prior to study withdrawal and disease progression had not been documented, a disease assessment should be 
obtained.


2012N132406_01
CONFIDENTIAL
BRF116613
63
7.
Randomisation will occur via RAMOS on Day 1.
8.
Refer to Section 7.4.6 for details regarding vital sign measurements. 
9.
A complete physical examination will be performed at Screening and End-of-study; brief physical examinations will be performed at all other timepoints as indicated. In females, 
genitourinary exam should include a visual inspection of the cervix. If the patient has had a genitourinary and rectal exam within 6 months of screening the genitourinary and 
rectal exam do not need to be repeated. Refer to Section 7.4.7 for details.
10.
An ophthalmic examination will be performed at Screening; additional ophthalmic examinations will be performed only as symptomatically warranted. Refer to Section 7.4.5 for 
details. 
11.
Adverse events will be recorded from the time the first dose of study treatment is administered until 30 days after discontinuation of study treatment. Serious adverse events will 
be collected over the same time period as AEs except SAEs assessed as related to study participation (e.g., protocol-mandated procedures, invasive tests, or change in existing 
therapy), study treatment, or a GSK concomitant medication which must be recorded from the time a patient consents to participate in the study up to and including any follow-up 
contact. 
12.
At each timepoint listed, a single 12-lead ECG will be performed by qualified site personnel after the patient has rested in a semi-recumbent or supine position for at least 5 
minutes. 
13.
While on treatment, patients who have an asymptomatic, absolute decrease in LVEF of > 10% compared to screening and whose ejection fraction is below the institution’s LLN, 
must be followed according to LVEF guidelines for study drug management and requirements for subsequent ECHO. 
14.
All medications the patient takes during the study from the time of screening until 30 days after the last dose of study treatment will be recorded.
15.
Analysis of clinical chemistry and haematology samples will be performed by the local lab. Screening labs performed within 2 weeks prior to randomisation do not need to be 
repeated.
16.
Serum pregnancy test is required at Screening. Subsequent tests may be urine tests, and should be performed as clinically indicated.
17.
A 4-week supply of study medication should be dispensed at each scheduled study visit as of Day 1. Patients should be provided with dosing instructions. Patients should start 
treatment as soon as possible after randomisation but no later than 72 hours post-randomisation.
18.
Patients should be instructed to return study drug vials at each visit; compliance will be assessed through querying the patient and through pill count at the time of new 
dispensation. Dose modifications and interruptions must be recorded.
19.
The date and exact time of PK sample collection and most recent dose will be recorded. Details of collection procedures, including dosing instructions for morning and afternoon 
visits, will be provided in the SPM.
20.
End of study assessments do not need to be repeated if performed within 4 weeks
21.
Biomarker-related sampling to be conducted at randomisation to avoid biomarker sample collection for ineligible patients
22.
Biopsies are to be taken at the judgement of the investigator at the various time-points to ensure that any potential risk or impact to the patients are kept to a minimum, All 
biopsies, be they from cutaneous or sub-cutaneous lesions, are to be performed only if the lesions are easily accessible.Biopsies are to be performed by either the investigator, a 
dermatologist, a surgeon or a physician qualified in radiology if an ultrasound-led biopsy is necessary.
23.
For Subjects enrolled in France, refer to the Appendix 6: Additional Monitoring for Patients Enrolled in France


2012N132406_01
CONFIDENTIAL
BRF116613
64
7.1.
Critical Baseline Assessments
Baseline assessments comprise clinical examination with detailed skin examination and 
standardised skin photos (face, trunk, limbs, scalp, nails, hand and feet). The 
dermatologic assessment will be reproduced at each biomarker sampling at week 2, 8, 10 
and at disease progression. Efficacy assessments conducted at baseline are described in 
Section 7.3.2, tumour tissue and biomarker assessments are described in Section 7.2. 
Safety assessments conducted at baseline and during treatment are described in Section 
7.4. Cardiovascular medical history/risk factors will be assessed at baseline.
7.1.1.
BRAF Mutation Determination
The conduct of the BRAF-mutation screening prior to the baseline assessments is the 
responsibility of the investigator and must be performed in a local laboratory. Testing for 
BRAF mutation for enrolment in the trial can occur any time prior to dosing.
7.1.2.
Baseline Documentation of Target and Non-target Lesions
All baseline lesion assessments, including brain MRI/CT to rule out brain metastases, 
must be performed within 5 weeks prior to randomisation.
Lymph nodes that have a short axis of < 10 mm are considered non-pathological 
and should not be recorded or followed.
Pathological lymph nodes with a short axis of < 15 mm but 10 mm are 
considered non-measurable.
Pathological lymph nodes with a short axis of 15 mm are considered 
measurable and can be selected as target lesions. Lymph nodes should not be 
selected as target lesions when other suitable target lesions are available. 
Measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in total, 
representative of all involved organs, should be identified as target lesions, and 
recorded and measured at baseline. These lesions should be selected on the basis 
of their size (i.e., lesions with the longest diameter) and their suitability for 
accurate repeated measurements (i.e., either by imaging techniques or 
clinically). 
Note: Cystic lesions thought to represent cystic metastases should not be 
selected as target lesions when other suitable target lesions are available.
Note: Measurable lesions that have been previously irradiated and have not been 
shown to be progressing following irradiation should not be considered as target 
lesions. 
Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue 
components, that can be evaluated by CT or MRI can be considered measurable. 
Bone scans, fluorodeoxyglucose positron emission tomography (FDG-PET) 
scans or X-rays are not considered adequate imaging techniques to measure 
bone lesions.


2012N132406_01
CONFIDENTIAL
BRF116613
65
All other lesions (or sites of disease) should be identified as non-target and should 
also be recorded at baseline. Non-target lesions will be grouped by organ. 
Measurements of these lesions are not required, but the presence or absence of 
each should be noted throughout follow-up. 
7.2.
Biomarkers
Comparative examination of pre-dosing profiles of patients may uncover known or novel 
candidate biomarkers/profiles which could be used to predict response to study 
treatments or provide new insights into melanoma and medically related conditions. 
Comparative examination of post-dosing profiles in conjunction with pre-dosing profiles 
may yield known and novel candidate biomarkers/profiles and new insights which relate 
to the action of the study treatments and changes contributing to the development of 
resistance.
Novel candidate biomarkers and subsequently discovered biomarkers of the biological 
response associated with melanoma or medically related conditions and/or the action of 
the study treatments may be identified by application of DNA/gene, RNA and protein 
analysis of tumour tissue.
Unless stated otherwise, these investigations may be performed irrespective of whether a 
response to study treatment is observed.
Biopsies will be performed on cutaneous or sub-cutaneous lesions that are easily 
accessible and will NOT be performed on any deep lesions. If possible biopsies should be 
taken from the same lesion/location. Key biopsies are taken at randomisation, week 2, 
week 8, and week 10. Additional patients might be recruited to ensure a sufficient 
number of patients in each arm providing these three key biopsies.
7.2.1.
Biomarkers on blood sample
Biomarkers include, but are not limited to:

LDH

CRP

Osteopontin

Circulating cell-free DNA (cfDNA)

Protein S 100

Lymphocyte subpopulations

Inflammatory cytokines (e.g. TNF-α, IL-1)
7.2.2.
Biomarkers on tumour sample
The exploratory research objectives of this study include further characterisation of the 
patient population through analysis of tumour DNA, RNA and protein, or other 
aberrations from tumour tissue and to determine whether these are associated with 
clinical outcome in response to therapy and/or to toxicity.


2012N132406_01
CONFIDENTIAL
BRF116613
66
Biomarkers in the melanoma tumour samples:
Biomarkers include, but are not limited to:
Immunohistochemistry (IHC) on fixed tumour samples:
P-ERK
P-MEK
Ki-67
P-AKT
P-S6
PTEN
eIF4E and P-eIF4E
eIF4G
CDK4
c-Met
EGFR
P-EGFR
Mutations screening:
A panel of genes relevant in melanoma biology (up to 400 genes potentially involved 
ontogeny or resistance) such as BRAF, MEK1 and 2, HRAS, NRAS,KRAS, PTEN, KIT,
NRAS, STK11, TP53, MNK1 CDK4, CDKN2ATGFBR1, EGF will be assessed on limited 
quantity of DNA using IonTorrent technology. This analysis should allow a sensitivity of 
mutation detection up to 10% of mutated DNA extracted from FFPE or frozen samples 
collected at base line or after (e.g. at recurrence).
For samples with sufficient amount of DNA, according to method available (currently 
3µg) the whole exome analysis will be performed.
Additional analysis of chromosomal abnormalities by CGH array and transcriptome 
analysis with Gen Expression microarray will be performed on frozen samples
Biomarkers in skin tumours induced by kinase inhibitors (papillomas, KA and 
SCC):
Biomarkers include, but are not limited to:

Fixed samples: P-ERK and P-MEK

Mutations screening: mutational hotspot for the three RAS genes, TGFBR1, 
TP53, BRAF

HPV DNA and RNA


2012N132406_01
CONFIDENTIAL
BRF116613
67
7.2.3.
Biomarkers on skin sample
Biomarkers include, but are not limited to:
Fixes samples: P-ERK, P-MEK, P-AKT, eiF4E and P-eiF4E, P-S6, HPV DNA, 
Ki-67
Frozen samples: kinome analysis
7.3.
Efficacy
7.3.1.
Efficacy Endpoints
The efficacy endpoints of this study are:

Overall response rate (ORR), defined as the percentage of patients with a 
confirmed or unconfirmed CR or PR at any time per RECIST, version 1.1 
(Eisenhauer, 2009).

Progression-free survival (PFS), defined as the time from randomisation until 
the earliest date of disease progression or death due to any cause.

Duration of response, defined as the time from first documented evidence of CR 
or PR until disease progression or death due to any cause among patients who 
achieve an overall response (i.e., unconfirmed or confirmed CR or PR)
7.3.2.
Efficacy Assessment
Disease progression and response evaluations will be determined according to the 
definitions established in RECIST version 1.1 (Eisenhauer, 2009).
Refer to the Time and Events table (Table 19) for the schedule of efficacy assessments. 
Assessments must be performed on a calendar schedule and should not be affected by 
dose interruptions/delays.
The following scans/assessments are required at baseline: contrast CT (preferred method) 
of chest/abdomen/pelvis or MRI of abdomen/pelvis and any area of known disease, skin 
lesion photography, and clinical disease assessment for palpable lesions. Exception: If a 
chest CT cannot be performed, chest X-ray can be used only to document the absence of 
disease (no tumour lesions) or the presence of new lesions. If lesions are detected at 
baseline by chest X-ray, chest CT must be done to properly document these lesions at 
baseline and in follow-up tumour assessments. At each post-baseline assessment, 
evaluations of the sites of disease identified by these scans are required. 
A brain MRI (preferred) or CT scan is required for all patients at baseline to rule out 
brain metastases. If clinically indicated, a CT or MRI scan of affected bone areas will be 
required at baseline. Bone lesions, if present, will continue to be followed consistently 
throughout the study until disease progression, death, or withdrawal of consent. 
Confirmation of response (i.e., CR and PR) is not necessary per RECIST, version 1.1, as 
the primary endpoint of the study is not overall best response. 
Scans will be assessed by investigators and will not be collected for central review.


2012N132406_01
CONFIDENTIAL
BRF116613
68
7.3.2.1.
Assessment Guidelines
Please note the following:
The same diagnostic method, including use of contrast when applicable, must be 
used throughout the study to evaluate lesions. 
The same diagnostic method, including use of contrast when applicable, must be 
used throughout the study to evaluate a lesion. Contrast agents must be used in 
accordance with the Image Acquisition Guidelines.All measurements should be 
taken and recorded in millimeters (mm), using a ruler or calipers.
Ultrasound is not a suitable modality of disease assessment. If new lesions are 
identified by ultrasound, confirmation by CT or MRI is required.
Fluorodeoxyglucose-positron emission tomography (FDG-PET) is generally not 
suitable for ongoing assessments of disease. It can, however, be useful in 
confirming new sites of disease when a positive FDG-PET scan correlates with 
the new site of disease present on CT/MRI or when a baseline FDG-PET was 
previously negative for the site of the new lesion. Fluorodeoxyglucose (FDG)-
PET may also be used in lieu of a standard bone scan providing coverage allows 
interrogation of all likely sites of bone disease and FDG-PET is performed at all 
assessments.
If PET/CT is performed then the CT component can only be used for standard 
response assessments if performed to diagnostic quality, which includes the 
required anatomical coverage and prescribed use of contrast. The method of 
assessment should be noted as CT in the eCRF.
Clinical Examination: Clinically detected lesions will only be considered measurable 
when they are superficial (e.g., skin nodules). In the case of skin lesions, documentation 
by colour photography, including a ruler/calipers to measure the size of the lesion, is 
required.
CT and MRI: Contrast enhanced CT with 5 mm contiguous slices is recommended.
Minimum size of a measurable baseline lesion should be twice the slice thickness, with a 
minimum lesion size of 10 mm when the slice thickness is 5 mm. Magnetic resonance 
imaging (MRI) is acceptable, but when used, the technical specification of the scanning 
sequences should be optimised for the evaluation of the type and site of disease and 
lesions must be measured in the same anatomic plane by use of the same imaging 
examinations. Whenever possible, the same scanner should be used.
X-ray: In general, X-ray should not be used for target lesion measurements owing to 
poor lesion definition. Lesions on chest X-ray may be considered measurable if they are 
clearly defined and surrounded by aerated lung; however chest CT is preferred over chest 
X-ray [Eisenhauer, 2009].
Brain Scan: Contrast enhanced MRI is preferable to contrast enhanced CT for 
assessment of brain lesion(s). 
Bone Scan (typically bone scintigraphy): If a bone scan is performed and a new 
lesion(s) is equivocal, then correlative imaging (i.e., X-ray, CT, or MRI) is required to 
demonstrate malignant characteristics of the lesion(s). 


2012N132406_01
CONFIDENTIAL
BRF116613
69
Note: Positron emission tomography (PET; FDG or fluoride) may be used in lieu of a 
standard bone scan providing coverage allows interrogation of all likely sites of bone 
disease and PET is performed at all assessments.
7.3.2.2.
Follow-up Assessments for Patients Permanently Discontinued from
both Study Treatments 
All patients who permanently discontinue both study treatments without disease 
progression will be withdrawn from study and progression data will be censored.
7.3.2.3.
Assessment at Patient Completion
If the last radiographic assessment was more than 8 weeks prior to study withdrawal and 
progressive disease had not been documented, a disease assessment should be obtained at 
the time of withdrawal.
7.3.3.
Guidelines for Evaluation of Disease
7.3.3.1.
Measurable and Non-measurable Definitions
Measurable lesion(s):
A non-nodal lesion that can be accurately measured in at least one dimension (the longest 
dimension) of:

10 mm with MRI or CT when the scan slice thickness is 5 mm. If the slice 
thickness is >5 mm, the minimum size of a measurable lesion must be at least 
double the slice thickness (e.g., if the slice thickness is 10 mm, a measurable 
lesion must be 20 mm).

10 mm caliper/ruler measurement by clinical exam or medical photography. 

20 mm by chest x-ray.
Additionally, lymph nodes can be considered pathologically enlarged and measurable if:
The short axis measures 15 mm when assessed by CT or MRI (the slice 
thickness is recommended to be 5 mm). At baseline and follow-up, only the 
short axis will be measured.
Non-measurable lesion(s): 
All lesions other than those considered measurable, including lesions too small to be 
considered measurable (i.e., longest diameter < 10 mm or pathological lymph nodes with 
a short axis of 10 mm but < 15 mm) as well as truly non-measurable lesions, which 
include: leptomeningeal disease, ascites, pleural or pericardial effusions, inflammatory 
breast disease, lymphangitic involvement of the skin or lung, and abdominal 
masses/abdominal organomegaly identified by physical examination that is not 
measurable by reproducible imaging techniques.


2012N132406_01
CONFIDENTIAL
BRF116613
70
Measurable disease: 
The presence of at least one measurable lesion. Palpable lesions that are not measurable 
by radiologic or photographic evaluations may not be used as the only measurable lesion.
Non-measurable only disease: 
The presence of only non-measurable lesions. Note: Non-measurable only disease is not 
allowed per protocol.
7.3.4.
Response Criteria
7.3.4.1.
Evaluation of Target Lesions
Definitions for assessment of response for target lesion(s) are as follows:
Complete Response (CR): Disappearance of all target lesions. Any pathological 
lymph nodes must have a short axis of <10 mm.
Partial Response (PR): At least a 30% decrease in the sum of the diameters of 
target lesions, taking as a reference, the baseline sum of the diameters (i.e., 
percent change from baseline).
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for progressive disease (PD).
Progressive Disease (PD): At least a 20% increase in the sum of the diameters of 
target lesions, taking as a reference, the smallest sum of diameters recorded
since the treatment started (i.e., percent change from nadir, where nadir is 
defined as the smallest sum of diameters recorded since treatment start). In 
addition, the sum must have an absolute increase from nadir of 5 mm.
Not Applicable (NA): No target lesions at baseline.
Not Evaluable (NE): Cannot be classified by one of the 5 preceding definitions.


2012N132406_01
CONFIDENTIAL
BRF116613
71
Note:
If lymph nodes are documented as target lesions the short axis is added into the 
sum of the diameters (i.e., sum of diameters is the sum of the longest diameters 
for non-nodal lesions and the short axis for nodal lesions). When lymph nodes 
decrease to non-pathological size (short axis < 10 mm), they should still have a 
measurement reported in order not to overstate progression.
If at a given assessment timepoint all target lesions identified at baseline are not
assessed, the sum of the diameters cannot be calculated for purposes of assessing 
CR, PR, or SD, or for use as the nadir for future assessments. The sum of the 
diameters of the assessed lesions and the percent change from nadir should, 
nevertheless, be calculated to ensure that PD has not been documented. If an 
assessment of PD cannot be made, the response assessment should be NE.
All lesions (nodal and non-nodal) should have their measurements recorded even 
when very small (e.g., 2 mm). If lesions are present but too small to measure, 5 
mm should be recorded and should contribute to the sum of the diameters, unless 
it is likely that the lesion has disappeared in which case 0 mm should be 
reported.
If a lesion disappears and reappears at a subsequent timepoint it should continue 
to be measured. The response at the time when the lesion reappears will depend 
upon the status of the other lesions. For example, if the disease had reached a 
CR status then PD would be documented at the time of reappearance; if the 
response status was PR or SD, the diameter of the reappearing lesion should be 
added to the remaining diameters and response determined based on percent 
change from baseline and percent change from nadir.
7.3.4.2.
Evaluation of Non-target Lesions
Definitions for assessment of response for non-target lesion(s) are as follows:
Complete Response (CR): The disappearance of all non-target lesions. All lymph 
nodes identified as a site of disease at baseline must be non-pathological (i.e., a 
short axis of <10 mm).
Non-CR/Non-PD: The persistence of 1 or more non-target lesion(s) or lymph 
nodes identified as a site of disease at baseline with a short axis of 10 mm.
Progressive Disease (PD): Unequivocal progression of existing non-target lesions. 
Not Applicable (NA): No non-target lesions at baseline.
Not Evaluable (NE): Cannot be classified by one of the 4 preceding definitions.
Note:
In the presence of measurable disease, progression on the basis of solely non-
target disease requires substantial worsening such that even in the presence of 


2012N132406_01
CONFIDENTIAL
BRF116613
72
SD or PR in target disease, the overall tumour burden has increased sufficiently 
to merit discontinuation of therapy.
Sites of non-target lesions, which are not assessed at a particular timepoint based 
on the assessment schedule, should be excluded from the response determination 
(i.e., non-target response does not have to be NE). 
7.3.4.3.
New Lesions
New malignancies denoting disease progression must be unequivocal. Lesions identified 
in follow-up in an anatomical location not scanned at baseline are considered new 
lesions.
Any equivocal new lesions should continue to be followed. Treatment can continue at the 
discretion of the investigator until the next scheduled assessment. If at the next 
assessment the new lesion is considered to be unequivocal, progression should be 
documented.
7.3.4.4.
Evaluation of Overall Response
Table 20 presents the overall response at an individual timepoint for all possible 
combinations of tumour responses in target and non-target lesions with or without the 
appearance of new lesions for patients with measurable disease at baseline.
Table 20
Evaluation of Overall Response for Patients with Measurable 
Disease at Baseline
Target Lesions
Non-target Lesions
New Lesions
Overall Response
CR
CR or NA
No
CR
CR
Non-CR/Non-PD or NE
No
PR
PR
Non-PD or NA or NE
No
PR
SD
Non-PD or NA or NE
No
SD
NE
Non-PD or NA or NE
No
NE
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD
Any
Any
Yes
PD
Abbreviations: CR = complete response; NA = not applicable; NE = not evaluable; PD = progressive disease; PR = 
partial response; SD = stable disease.
Note:

Patients with a global deterioration of health status requiring treatment 
discontinuation without objective evidence of disease progression at that time 
should be classified as having "symptomatic deterioration." Objective response 


2012N132406_01
CONFIDENTIAL
BRF116613
73
status is determined by evaluations of disease burden. Every effort should be 
made to document the objective progression even after treatment 
discontinuation. 

In some circumstances, it may be difficult to distinguish residual disease from 
normal tissue. When the evaluation of CR depends on this determination, it is 
recommended that the residual lesion be investigated (e.g., fine needle 
aspirate/biopsy) to confirm the CR.
7.3.4.5.
Evaluation of Best Overall Response
The best overall response is the best response recorded from the start of the treatment 
until disease progression, death, or withdrawal of consent, whichever occurs first. Best 
overall response will be determined programmatically by GSK based on the 
investigator’s assessment of response at each timepoint. 

To be assigned a status of SD, follow-up disease assessment must have met the 
SD criteria at least once after randomisation for a minimum of 49 days. 

If the minimum time for SD is not met, best response will depend on the 
subsequent assessments. For example, if an assessment of PD follows the 
assessment of SD and SD does not meet the minimum time requirement, the best 
response will be PD. Alternatively, patients lost to follow-up after an SD 
assessment not meeting the minimum time criteria will be considered NE.
7.4.
Safety
7.4.1.
Safety Endpoints
The secondary objectives of the study include characterising the safety of dabrafenib and 
trametinib combination therapy. As a consequence, clinical assessments including vital 
signs and physical examinations, ECOG, 12-lead ECG, ECHO, chemistry and 
haematology laboratory values, and AEs will be monitored and evaluated.
7.4.2.
Adverse Events
The investigator or site staff will be responsible for detecting, documenting, and reporting 
events that meet the definition of an AE or SAE as outlined in Section 7.4.2.1 and 
Section 7.4.2.2, respectively.
7.4.2.1.
Definition of an AE
Any untoward medical occurrence in a patient or clinical investigation patient, 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 unfavourable 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 


2012N132406_01
CONFIDENTIAL
BRF116613
74
also includes failure to produce expected benefits, abuse, or misuse. Examples of events 
meeting the definition of an AE include:

Exacerbation of a chronic or intermittent pre-existing condition including either 
an increase in frequency and/or Grade of the condition;

New conditions detected or diagnosed after study treatment administration even 
though it may have been present prior to the start of the study;

Signs, symptoms, or the clinical sequelae of a suspected interaction; and

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 unless this is an intentional overdose taken with possible 
suicidal/self-harming intent. This should be reported regardless of sequelae). 

‘Lack of efficacy’ or ‘failure of expected pharmacological action’ per se is not 
to be reported as an AE or SAE. Any signs, symptoms, and/or clinical sequelae 
resulting from ‘lack of efficacy’ will, however, be reported as an AE or SAE, if 
they fulfil the definition of an AE or SAE. 
Events that do not meet the definition of an AE include:

Medical or surgical procedure (e.g., endoscopy, appendectomy); the condition 
that leads to the procedure is an AE;

Situations where an untoward medical occurrence did not occur (e.g., 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; and/or

The disease/disorder being studied, or expected progression, signs, or symptoms 
of the disease/disorder being studied, unless more severe than expected for the 
patient’s condition. 
7.4.2.2.
Definition of an SAE
A serious adverse event (SAE) is any untoward medical occurrence that, at any dose:
a.
Results in death;
b.
Is life-threatening;
Note: The term 'life-threatening' in the definition of 'serious' refers to an event in 
which the patient 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, hospitalisation signifies that the patient has been detained (i.e., 
usually involving at least one overnight stay) at the hospital or emergency ward for 
observation and/or treatment that would not have been appropriate in the physician’s 
office or out-patient setting. Complications that occur during hospitalisation are AEs. 


2012N132406_01
CONFIDENTIAL
BRF116613
75
If a complication prolongs hospitalisation or fulfills any other serious criteria, the 
event is serious. When in doubt as to whether ‘hospitalisation’ occurred or was 
necessary, the AE should be considered serious.
Hospitalisation for elective treatment of a pre-existing condition that did not worsen 
from baseline is not considered an AE.
d.
Results in disability/incapacity; and/or
Note: The term disability means a substantial disruption of a person’s ability to 
conduct normal life functions. This definition is not intended to include experiences 
of relatively minor medical significance such as uncomplicated headache, nausea, 
vomiting, diarrhoea, influenza, and/or 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. Medical or scientific judgment should be 
exercised in deciding whether reporting is appropriate in other situations, such as 
important medical events that may not be immediately life-threatening or result in 
death or hospitalisation but may jeopardize the patient 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 
hospitalisation, or development of drug dependency or drug abuse.
f.
Protocol-specific SAEs: 

All events of possible drug-induced liver injury with hyperbilirubinemia 
defined as ALT 3 x ULN and total bilirubin 2 x ULN (>35% direct) or ALT 
3 x ULN and INR >1.5 (if INR is measured) or termed ‘Hy’s Law’ events (INR 
measurement is not required and the threshold value stated will not apply to 
patients receiving anticoagulants).
Note: Bilirubin fractionation 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 patient meets the criterion of total bilirubin 2 x ULN, then 
the event is still reported as an SAE. If INR is obtained, include values on the 
SAE form. International normalized ratio (INR) elevations >1.5 suggest severe 
liver injury. 

Any new malignancy with a histology different from the primary tumour, 
including cutaneous squamous cell carcinoma

Laboratory abnormalities as referenced in Section 7.4.2.3.

LVEF that meets stopping criteria Section 5.8.3.1

CSR or RVO


2012N132406_01
CONFIDENTIAL
BRF116613
76

Pyrexia accompanied by ≥ Grade 3 hypotension or hypotension that is 
clinically significant in the judgement of the investigator, or dehydration 
requiring IV fluids, or severe rigors/chills.
7.4.2.3.
Laboratory and Other Safety Assessment Abnormalities Reported as 
AEs and SAEs
Any abnormal laboratory test results (haematology, clinical chemistry, or urinalysis), or 
other safety assessments (e.g., ECGs, radiological scans, vital sign measurements, etc.) 
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 AEs or 
SAEs, in accordance with the definitions provided. 
In addition, an associated AE or SAE is to be recorded for any laboratory test result or 
other safety assessment that led to an intervention, including permanent discontinuation 
of study treatment and/or dose modification/interruption. 
Any new primary cancer must be reported as an SAE. 
Any clinically significant safety assessments that are associated with the disease/disorder 
being studied, unless judged by the investigator to be more severe than expected for the 
patient's condition, are not to be reported as AEs or SAEs. 
7.4.2.4.
Disease-related Events and/or Disease-related Outcomes Not 
Qualifying as SAEs
An event which is part of the natural course of the disease under study (i.e., disease 
progression or hospitalisation 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 and 
does not need to be reported as an SAE. If however, if the underlying disease (i.e., 
progression) is greater than that which would normally be expected for the patient, or if 
the investigator considers that there was a causal relationship between treatment with 
study medication(s) or protocol design/procedures and disease progression, then this must 
be reported as an SAE. 
7.4.2.5.
Time Period and Frequency for 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. 
Adverse events (AEs) will be collected from the time the first dose of study treatment is 
administered until 30 days after discontinuation of study treatment regardless of initiation 
of a new anti-cancer therapy or transfer to hospice. 
Serious adverse events (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 a GSK concomitant medication, must be recorded from the time a patient 
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 7.4.2.6. 


2012N132406_01
CONFIDENTIAL
BRF116613
77
After study treatment discontinuation, the investigator will monitor all AEs/SAEs that are 
ongoing until resolution or stabilisation of the event or until the patient is lost to follow-
up. At any time after 30 days from the last dose of study treatment, the investigator may 
report any AE that he/she believes is possibly related to study treatment. 
7.4.2.6.
Prompt Reporting of SAEs and Other Events to GSK
Serious adverse events (SAEs), pregnancies, and liver function abnormalities meeting 
pre-defined criteria will be reported promptly by the investigator to GSK as described in 
Table 21 once the investigator determines that the event meets the protocol-definition for 
that event.


2012N132406_01
CONFIDENTIAL
BRF116613
78
Table 21
Time Frames for Reporting SAEs and Other Events
Initial Reports
Follow-up Information on a Previous 
Report
Type of Event
Time Frame
Documents
Time Frame
Documents
All SAEs
24 hours
SAE data collection
tool
24 hours
Updated SAE data 
collection tool “CV 
events” and/or “death” 
data collection tool(s) 
if applicable
Pregnancy
2 weeks
Pregnancy notification 
form
2 weeks
Pregnancy follow-up 
form
Liver Chemistry Abnormalities:
ALT 3 x ULN PLUS
total bilirubin 2 x ULN (> 
35% direct) or ALT 3 x 
ULN and INR > 1.5, if INR 
measureda
24 hoursb
SAE data collection 
tool,
liver event eCRF 
form, and liver 
imaging and/or biopsy 
eCRFs, if applicablec
24 hours
Updated SAE data 
collection tool and 
updated liver event 
eCRF formc
ALT 8 x ULN; ALT 3 x 
ULN with hepatitis or rash 
or 3 x ULN but < 5 x 
ULN that persists 4 
weeks
24 hoursb
Liver event eCRF 
formc
24 hours 
Updated liver event 
eCRF formc
ALT 5 x ULN PLUS
total bilirubin < 2 x ULN
24 hoursb
Liver event eCRF 
form does not need 
completing unless 
elevations persist for 
2 weeks or patient 
cannot be monitored 
weekly for 2 weeksc
24 hours
ALT 5 x ULN PLUS
total bilirubin < 2 x ULN 
that persists 2 weeks
24 hoursb
Liver event eCRF 
formc
24 hours
Updated liver event 
eCRF formc
ALT 3 x ULN but < 5 x 
ULN PLUS total bilirubin 
< 2 x ULN
24 hoursb
Liver event eCRF 
form does not need 
completing unless 
elevations persist for 
4 weeks or patient 
cannot be monitored 
weekly for 4 weeksc


2012N132406_01
CONFIDENTIAL
BRF116613
79
Abbreviations: ALT = alanine transaminase; AST = aspartate aminotransferase; eCRF = electronic case report form; 
INR = international normalized ratio; SAE = serious adverse event; ULN = upper limit of normal.
a.
INR measurement is not required; if measured, the threshold value stated will not apply to patients receiving 
anticoagulants.
b.
GSK to be notified at onset of liver chemistry elevations to discuss patient safety.
c.
Liver Event Documents (i.e., “Liver Event CRF” and “Liver Imaging CRF” and/or “Liver Biopsy CRF”, as 
applicable) should be completed as soon as possible.
Liver chemistry stopping, follow-up, and monitoring criteria are provided in Section 5.9. 
Methods for detecting, recording, evaluating, and following-up on AEs and SAEs and 
procedures for completing and transmitting SAE reports to GSK are provided in the 
SPM. Procedures for post-study AEs and SAEs are provided in the SPM.
7.4.2.7.
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 patients 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 
regulatory authorities, Independent Ethics Committees (IEC) and investigators.
Investigator safety reports will be prepared for suspected unexpected serious adverse 
reactions according to local regulatory requirements and GSK policy and will be 
forwarded to investigators as necessary.
An investigator who receives an investigator safety report describing an 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.
7.4.3.
Pregnancy Testing, Prevention, and Reporting
7.4.3.1.
Pregnancy Testing and Prevention
The need for a screening pregnancy test depends on whether a female patient is of 
childbearing potential or non-childbearing potential.
A female of non-childbearing potential (i.e., physiologically incapable of becoming 
pregnant) is defined as any female who has had a hysterectomy, bilateral oophorectomy 
(ovariectomy) or bilateral tubal ligation, or is post-menopausal. 
A practical definition accepts menopause after 1 year without menses with an appropriate 
clinical profile, e.g., age appropriate, >45 years in the absence of hormone-replacement 
therapy (HRT). In questionable cases, the patient must have a follicle-stimulating 
hormone (FSH) value >40 mIU/mL and an estradiol value <40 pg/mL (<140 pmol/L).
A female of child-bearing potential is defined as any female who does not meet the 
criteria of non-childbearing potential as described in the previous paragraph. 
If a female patient is of childbearing potential, she must have a serum -human chorionic 
gonadotropin (HCG) pregnancy test performed within 14 days prior to randomisation. 
Patients with a positive pregnancy test result must be excluded from the study. Patients 
with a negative pregnancy test result must agree to use an effective contraception method 


2012N132406_01
CONFIDENTIAL
BRF116613
80
as described below throughout the treatment period and until 4 months after the last dose 
of study treatment.

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 less than 1% per year.

Vasectomised partner who is sterile prior to the female patient’s entry and is the 
sole sexual partner for that female.

Complete abstinence from sexual intercourse for 14 days prior to randomisation, 
throughout the treatment period, and for at least 4 months after the last dose of 
study treatment.
Note: Abstinence is acceptable only when in line with the preferred and usual 
lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, 
symptothermal, post-ovulation methods) and withdrawal are not acceptable 
methods of contraception.

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 interactions with dabrafenib. 
Female patients who are nursing must discontinue prior to randomisation and must 
refrain from nursing throughout the treatment period and for 4 months after the last dose 
of study treatment.
7.4.3.2.
Pregnancy Reporting
Any pregnancy that occurs during study participation must be reported using a clinical 
trial pregnancy form. To ensure patient safety, each pregnancy must be reported to GSK 
within 2 weeks of learning of its occurrence. The pregnancy must be followed-up to 
determine outcome (including premature termination) and status of mother and child. 
Pregnancy complications and elective terminations for medical reasons must be reported 
as an AE or SAE. Spontaneous abortions must be reported as an SAE.
Any SAE occurring in association with a pregnancy brought to the investigator’s 
attention after the patient has completed the study and considered by the investigator as 
possibly related to 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 patients who become pregnant while the patient is enrolled in the 
study. Pregnancy information must be reported to GSK as described above.


2012N132406_01
CONFIDENTIAL
BRF116613
81
7.4.4.
Laboratory Assessments
All protocol-required laboratory assessments must be conducted in accordance with the 
Time and Events Schedule (Table 19). Only local laboratory assessments are undertaken 
during the course of the trial and its data must be recorded in the patients CRF.
Clinical chemistry and haematology parameters to be tested are listed in Table 22. 
Female patients of child-bearing potential will have a serum pregnancy test at Screening; 
urine pregnancy testing may be done during study treatment, if necessary.
Table 22
Clinical Chemistry and Haematology Parameters
Clinical Chemistry Parameters

Albumin

Alkaline Phosphatase

Alanine Transaminase (ALT) or Serum Glutamic Pyruvic Transaminase (SGPT)

Aspartate Aminotransferase (AST) or Serum Glutamic Oxaloacetic Transaminase (SGOT)

Gamma-Glutamyl Transpeptidase (GGT)

Blood Urea Nitrogen (BUN) or urea

Calcium

Creatininec

Lactate Dehydrogenase (LDH)

Phosphate

Potassium

Sodium

Total Bilirubinb

Total Protein
Haematology Parameters

White Blood Cell (WBC) Count 

Hemoglobin

International Normalized Ratio (INR; at Screening only)a

Platelet Count

Prothrombin Time (PT; at Screening only)a

Partial Thromboplastin Time (PTT; at Screening only)a

Automated WBC Differential (expressed as %): 
o
Basophils 
o
Eosinophils
o
Lymphocytes
o
Monocytes
o
Neutrophils
a.
Coagulation panel to be done at Screening only.
b.
Bilirubin fractionation is recommended if total bilirubin is > 2 x the upper limit of normal (ULN).
c.
If serum creatinine is > 1.5 mg/dL, creatinine clearance should be calculated using the standard Cockcroft-Gault 
formula (Appendix 2).


2012N132406_01
CONFIDENTIAL
BRF116613
82
For patients with a history of chronic HBV and/or HCV, the following tests will be
performed at Screening:

Viral hepatitis serology;

Hepatitis B surface antigen and Hepatitis B core antibody (IgM); and/or 

Hepatitis C RNA.
7.4.5.
Ophthalmic Examination
Patients are required to have a standard ophthalmic examination performed by an 
ophthalmologist at baseline and as clinically warranted per protocol’s guidance (Section 
5.8.5.4). The exam will include indirect and/or direct fundoscopic examination, visual 
acuity (with correction), visual field examination, and tonometry, with special attention to 
retinal abnormalities that are predisposing factors for RVO or CSR.
In patients with clinical suspicion of RVO or CSR, fluorescent angiography and/or 
optical coherence tomography are highly recommended.
7.4.6.
Vital Signs
Vital sign measurements will include systolic and diastolic blood pressure, body 
temperature, pulse rate, body weight, and height (only at Screening). Body temperature, 
weight and height measurements should be recorded in the metric scale. 
All blood pressure assessments should be performed under optimal conditions i.e. after (i) 
patient has been seated with back support, ensuring that legs are uncrossed and flat on the 
floor, (ii) patient is relaxed comfortably for at least 5 minutes, (ii) preparatory steps 
including removal of any restrictive clothing over the cuff area and selection of the right 
cuff size have been ensured, (iii) the arm is supported so that the middle of the cuff is at 
the heart level, and (iv) the patient remains quiet during the measurement. In patients 
with an initial blood pressure 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 
blood pressure measurement. Only the averaged value should be entered in the eCRF.
7.4.7.
Physical Examinations
Complete physical examination will include assessments of eyes, neurological and 
cardiovascular systems, lungs, abdomen, and any other areas with signs and symptoms of 
disease, and of the head, neck, ears, nose, mouth, throat, thyroid, lymph nodes, 
extremities, and a full skin exam to assess cutaneous malignancies and proliferative skin 
diseases. Complete physical examinations will also include thorough genitourinary 
(pelvic) and rectal exams to assess secondary malignancies. In females, the pelvic exam 
must visualize the cervix. Pap smear and colposcopy are performed at the investigator’s 
discretion. Rectal exam must include digital rectal exam and visual inspection of the anus 
and perianal area. Brief physical examinations will include assessment of head, neck, 
eyes, skin, neurological and cardiovascular systems, lungs, abdomen, and any other areas 
with signs and symptoms of disease. Refer to the Time and Events Table (Table 19) for 
when to perform a complete or a brief physical examination.


2012N132406_01
CONFIDENTIAL
BRF116613
83
Dermatologic skin exams may be referred to a dermatologist, if needed. 
If possible, the same physician should perform each examination for the duration of the 
study to ensure consistency between evaluations (i.e., if the patient is referred to a 
Dermatologist for the Screening examination, the Dermatologist should do all follow-up 
dermatologic skin assessments). 
7.4.8.
Electrocardiograms (ECG)
Twelve (12)-lead ECGs will be obtained using an ECG machine that automatically 
calculates heart rate and measures PR, QRS, QT, RR and QTcB intervals. 
At each assessment, a single 12-lead ECG will be performed by qualified site personnel 
after the patient has rested in a semi-recumbent or supine position for at least 5 minutes. 
See Section 5.8.3.3 for instructions if QTc withholding criteria are met.
7.4.9.
Echocardiograms (ECHO)
Echocardiograms (ECHO) will be performed to assess cardiac ejection fraction and 
cardiac valve morphology. If possible, ECHO should be performed by the same person 
throughout the study for a patient. The echocardiographer’s evaluation should include an 
evaluation for left ventricular ejection fraction and both right and left-sided valvular 
lesions.
7.5.
Pharmacokinetics
As part of the secondary objectives of this study, concentrations of trametinib and of 
dabrafenib and its metabolites (GSK2285403, GSK2298683, and GSK2167542) will be 
determined at each time point during treatment when the skin and tumour biopsies are 
performed. During the monotherapy treatment in arm A and B, only trametinib or 
dabarafenib and its metabolites will be measured. During combination, both drugs and 
metabolites will be measured.
7.5.1.
Blood Sample Collection for Pharmacokinetics
Blood samples for PK analyses of dabrafenib, trametinib, and metabolites of dabrafenib 
will be collected at the same day as the tumour and skin biopsies are performed during 
treatment (Week 2, 8 and 10). Patients with morning clinic visits will be instructed to 
withhold their morning dose, and samples will be collected prior to dabrafenib and 
trametinib administration; for patients with afternoon clinic visits, patients will take their 
morning doses as usual, and samples will be collected 4-8 hours following dabrafenib and 
trametinib administration. Date and exact time of pharmacokinetic sample and of most 
recent dose will be recorded.. No more than 25 mL of blood will be collected over the 
duration of the study for PK blood sample collection, including any extra assessments 
that may be required.
Details of PK blood sample collection (including volume to be collected), processing, 
storage, and shipping procedures will be provided in the SPM.


2012N132406_01
CONFIDENTIAL
BRF116613
84
8.
DATA MANAGEMENT
For this study, patient data will be entered into GSK defined Inform eCRFs, transmitted 
electronically to GSK or designee and combined with data provided from other sources in 
a validated data system.
Management of clinical data will be performed in accordance with applicable GSK 
standards and data cleaning procedures to ensure the integrity of the data, e.g., removing 
errors and inconsistencies in the data. Adverse events, concomitant medications terms 
and other anti-cancer therapies will be coded using Medical Dictionary for Regulatory 
Activities (MedDRA) and an internal validated medication dictionary, GSKDrug.
eCRFs (including queries and audit trails) will be retained by GSK and copies will be 
sent to the investigator to maintain as the investigator copy. In all cases, patient initials 
will not be collected or transmitted to GSK in accordance with GSK policy.


2012N132406_01
CONFIDENTIAL
BRF116613
85
9.
DATA ANALYSIS AND STATISTICAL CONSIDERATIONS
9.1.
Hypotheses
The primary objective of this trial is to evaluate the percentage reduction of pERK score 
from baseline and characterise safety and efficacy of different treatment sequence with 
the pERK score changes. The primary end point will be analysed with a descriptive intent 
only. Hence no hypothesis testing will be performed.
9.2.
Study Design Considerations
9.2.1.
Sample Size Assumptions
Based on feasibility a sample size of 54 patients will be enrolled in this trial in 1:1:1 ratio 
to one of the three treatment arms allowing a total of 20% early dropout rate. Assuming 
as large as 30% standard deviation (s.d.) of percentage reduction of pERK score from 
baseline, 15 patients per treatment arm will be sufficient to ensure that the 95% 
confidence interval (CI) will be the mean 16.61%. With 15 patients per treatment arm,
the study will have >97% power to detect 80% reduction of pERK score from baseline to 
Week 2 within a treatment group (with s.d.=70%, alpha=0.05, two sided paired t-test).
9.2.2.
Sample Size Sensitivity
The effect of changes in the assumed standard deviation on the precision (i.e., half-width 
of the 95% CI for percent reduction of pERK score from Baseline at Week 2 within a 
treatment group) is summarised in Table 23.
Table 23
Effects of changes in the assumption of standard deviation
Standard Deviation (%)
Precision (Half-width of 95% CI of % 
reduction of pERK score from baseline 
within a treatment group)
10
5.538
20
11.076
30
16.613
40
22.151
50
27.689
9.2.3.
Sample Size Re-estimation
Sample size re-estimation is not planned for this study.
9.3.
Data Analysis Considerations
9.3.1.
Analysis Populations
The Intent-to-Treat Population (ITT) will consist of all randomised patients whether or 
not randomised treatment was administered. This population will be based on the 


2012N132406_01
CONFIDENTIAL
BRF116613
86
treatment to which the patient was randomised and will be the primary population for the 
analysis of efficacy data. Any patient who receives a treatment randomisation number 
will be considered to have been randomised. 
The Safety Population will consist of all patients who received at least one dose of 
randomised treatment and will be based on the actual treatment received. This population 
will be used for the analysis of clinical safety data.
The Biomarker Population will consist of all patients with biopsy performed at 
screening and at least once during treatment. 
9.3.2.
Analysis Data Sets
The primary dataset for efficacy (ORR, PFS and DoR) will be comprised of the ITT 
population as defined in Section 9.3.1
The primary dataset for assessing safety will be the Safety Population as defined in 
Section 9.3.1.
The primary dataset for biomarker analysis will be the Biomarker Population as defined 
in Section 9.3.1.
Details on the handling of missing data are provided in the Reporting and analysis plan 
(RAP).
9.3.3.
Treatment Comparisons
This is a descriptive study and there will be no treatment comparison. Biomarker, 
efficacy and safety endpoints will be evaluated for each treatment arm.
9.3.4.
Interim Analysis
No interim analyses will be performed for this study.
9.3.5.
Key Elements of Analysis Plan
The final analysis will be performed after the last patient has the week 16 efficacy 
assessment.
Data will be listed and summarised according to the GSK reporting standards, where 
applicable. Complete details will be documented in the RAP. Any deviations from, or 
additions to, the original analysis plan described in this protocol will be documented in 
the RAP and final study report.
Demographic and baseline characteristics will be summarised.
Percentage reduction in pERK biomarker score from baseline to Week 2 will be 
calculated within a treatment group.
ORR will be determined based on confirmed responses. Details on the determination of 
tumour response are given in Section 7.3.4.


2012N132406_01
CONFIDENTIAL
BRF116613
87
PFS analysis will be performed if there is sufficient number of events at the time of final 
analysis. For the analysis of PFS, if the patient received subsequent anti-cancer therapy 
prior to the date of documented progression or death, progression free-survival will be 
censored at the last adequate assessment (e.g. assessment where visit level response is 
CR, PR, or SD) prior to the initiation of therapy. Otherwise, if the patient does not have a 
documented date of progression or death progression-free survival will be censored at the 
date of the last adequate assessment. Further details on rules for censoring will be 
provided in the RAP.
Duration of response analysis will be performed if there is sufficient number of 
responders. 
Additional details on biomarker analyses are provided in Section 9.3.5.1. Similarly 
additional details on efficacy and safety analyses are provided in Section 9.3.5.2. and in 
Section 9.3.5.3 respectively.
9.3.5.1.
Biomarker Analyses
Biomarker endpoints are defined in Section 2. Percentage reduction of pERK score from 
baseline is the primary endpoint of this study. Change in biomarker status is most 
prominent within two weeks of start of treatment. Patients from arm A and arm B will be 
given combination therapy starting from week 9 after completion of 8 weeks of 
monotherapy. Therefore, changes in biomarker between screening and week 2 as well as 
between week 8 and week 10 will be summarised. In addition, effect of change of 
biomarker status on ORR will be determined. Further details will be provided in the RAP.
9.3.5.2.
Efficacy Analyses
Efficacy endpoints are described in Section 2 and Section 7.3. The ITT population will 
be used for the analysis of efficacy data.
The ORR endpoint will be tabulated based on number and percentage of patients 
attaining a confirmed overall best response of CR or PR in the ITT population. Patients 
with unknown or missing response data, including those who withdraw from the study 
without an assessment, will be treated as non-responders (i.e., they will be included in the 
denominator when calculating the percentage). No imputation will be performed for 
missing lesion assessment or tumour response data.
Overall response rates (ORR) for each treatment group will be provided along with the 
corresponding 95% CI. However, ORR will not be compared between treatment groups.
PFS and DoR are exploratory endpoints and will be analyzes provided there is sufficient 
number of events at the time of final analysis.
PFS will be evaluated for each treatment group. The date of objective disease progression 
will be defined as the earliest date of radiological or photographic disease progression as 
assessed by the investigator using RECIST, version 1.1. For patients who have not 
progressed or died at the time of the PFS analysis, censoring will be performed using the 
date of the last disease assessment. In addition, patients who start a new anti-cancer 


2012N132406_01
CONFIDENTIAL
BRF116613
88
therapy prior to a PFS event will be censored at the date of the last disease assessment 
prior start of new anti-cancer therapy, respectively. Further details on censoring rules will 
be outlined in the RAP.
DoR will include patients from the ITT population who achieve a confirmed best 
response of CR or PR and will only be analyzed provided a sufficient number of patients 
respond to warrant such an analysis. Censoring rules for duration of response will follow 
the rules for PFS and will be outlined in detail in the RAP.
9.3.5.3.
Safety Analyses
Safety endpoints are described in Section 2 and Section 7.4.
The Safety Population will be used for the analysis of safety data. Complete details of the 
safety analyses will be provided in the RAP.
Extent of Exposure
The number of patients administered study treatment will be summarised according to the 
duration of therapy. 
Adverse Events
Adverse events (AEs) will be coded using the standard GlaxoSmithKline Medical 
Dictionary for Regulatory Activities (MedDRA) and grouped by system organ class. AEs 
will be graded by the investigator according to the NCI-CTCAE (version 4). 
Events will be summarised by frequency and proportion of total patients, by system organ 
class and preferred term. Separate summaries will be given for all AEs, drug-related AEs, 
serious AEs and AEs leading to discontinuation of study treatment.
If the AE is listed in the NCI CTCAE (version 4) table, the maximum grade will be 
summarised.
Characteristics (e.g. number of occurrences, action taken, grade, etc) of the following 
AEs of special interest (e.g. diarrhoea and dash) will be summarised separately as 
detailed in the RAP.
The incidence of deaths and the primary cause of death will be summarised.
Clinical Laboratory Evaluations
Haematology and clinical chemistry data will be summarised at each scheduled 
assessment according to NCI CTCAE grade (version 4). The proportion of values lying 
outside the reference range will also be presented for laboratory tests that are not graded 
because there are no associated NCI CTCAE criteria. Summaries will include data from 
scheduled assessments only, and all data will be reported according to the nominal visit 
date for which it was recorded (i.e. no visit windows will be applied). Unscheduled data 
will be included in “overall” and “any post-screening” summaries which will capture a 


2012N132406_01
CONFIDENTIAL
BRF116613
89
worst case across all scheduled and unscheduled visits post first dose of study treatment. 
Further details will be provided in the RAP.
Other Safety Measures
The results of scheduled assessments of vital signs, 12-lead ECG, ECHO and ECOG 
performance status will be summarised. Summaries will include data from scheduled 
assessments only. All data will be reported according to the nominal visit date for which 
it was recorded (i.e. no visit windows will be applied). Unscheduled data will be included 
in ‘worse case’ summaries which will capture a worst case across all scheduled and 
unscheduled visits after the first dose of study treatment. All data will be listed. Further 
details will be provided in the RAP.
9.3.5.4.
Pharmacokinetic/Pharmacodynamic Analyses
If data warrant, exploratory analyses will be performed to examine the relationship 
between plasma concentration of dabrafenib and/or trametinib and pharmacodynamic 
endpoints such as tumour size, biomarker changes and other clinical and safety measures.
Initially, the relationships will be explored graphicially. If these exploratory graphical 
analyses suggest a relationship between pharmacodynamic endpoints and concentration 
or pharmacokinetic parameters, PK/PD models may be derived and evaluated. Additional 
exploratory analyses may be performed to further characterize biomarkers. 
Further details of PK/PD analyses will be described under a separate RAP. Results of the 
PK/PD analyses may be included in a report separate from the clinical study report.
9.3.5.5.
Translational Research Analyses
The results of translational research investigations will be reported separately from the
main clinical study report. All endpoints of interest from all comparisons will be 
descriptively and/or graphically summarised as appropriate to the data.
Further details on the translational research analyses will described under a separate 
RAP.


2012N132406_01
CONFIDENTIAL
BRF116613
90
10.
STUDY CONDUCT CONSIDERATIONS
10.1.
Posting of Information on Publicly Available Clinical Trial 
Registers
Study information from this protocol will be posted on publicly available clinical trial 
registers before enrolment of patients begins.
10.2.
Regulatory and Ethical Considerations, Including the 
Informed Consent Process
Prior to initiation of a study site, GSK will obtain favourable opinion/approval from the 
appropriate regulatory agency to conduct the study in accordance with ICH Good Clinical 
Practice (GCP) and applicable country-specific regulatory requirements.
The study will be conducted in accordance with all applicable regulatory requirements.
The study will be conducted in accordance with ICH Good Clinical Practice (GCP), all 
applicable patient privacy requirements, and the ethical principles that are outlined in the 
Declaration of Helsinki 2008, including, but not limited to:

Institutional Review Board (IRB)/Independent Ethics Committee (IEC) review 
and favourable opinion/approval of study protocol and any subsequent 
amendments.

Patient informed consent.

Investigator reporting requirements.
GSK will provide full details of the above procedures, either verbally, in writing, or both.
Written informed consent must be obtained from each patient prior to participation in the 
study.
10.3.
Quality Control (Study Monitoring)
In accordance with applicable regulations, GCP, and GSK procedures, the site will be 
contacted prior to the start of the study to review with the site staff the protocol, study 
requirements, and their responsibilities to satisfy regulatory, ethical, and GSK 
requirements. When reviewing data collection procedures, the discussion will include 
identification, agreement and documentation of data items for which the CRF will serve 
as the source document.
The investigator and the head of the medical institution (where applicable) agrees to 
allow the monitor direct access to all relevant documents and to allocate their time and 
the time to their staff to monitor to discuss findings and any issues.
Monitoring visits will be conducted in a manner to ensure that the:
Data are authentic, accurate, and complete.
Safety and rights of patients are being protected.


2012N132406_01
CONFIDENTIAL
BRF116613
91
Study is conducted in accordance with the currently approved protocol and any 
other study agreements, ICH GCP, and all applicable regulatory requirements.
10.4.
Quality Assurance
To ensure compliance with GCP and all applicable regulatory requirements, GSK may 
conduct a quality assurance assessment and/or audit of the site records, and the regulatory 
agencies may conduct a regulatory inspection at any time during or after completion of 
the study. In the event of an assessment, audit or inspection, the investigator (and 
institution) must agree to grant the advisor(s), auditor(s) and inspector(s) direct access to 
all relevant documents and to allocate their time and the time of their staff to discuss the 
conduct of the study, any findings/relevant issues and to implement any corrective and/or 
preventative actions to address any findings/issues identified
10.5.
Study and Site Closure
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.
10.6.
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 


2012N132406_01
CONFIDENTIAL
BRF116613
92
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.
10.7.
Provision of Study Results to Investigators, Posting of 
Information on Publicly Available Clinical Trials Registers 
and Publication
Where required by applicable regulatory requirements, an investigator signatory will be 
identified for the approval of the clinical study report. The investigator will be provided 
reasonable access to statistical tables, figures, and relevant reports and will have the 
opportunity to review the complete study results at a GSK site or other mutually-
agreeable location.
GSK will also provide the investigator with the full summary of the study results. The 
investigator is encouraged to share the summary results with the study patients, as 
appropriate.
GSK aims to post a results summary to the GSK Clinical Study Register and other 
publicly available registers no later than 8 months after the last patient’s last visit (LSLV) 
[this applies to each data analysis phase for studies with multiple phases, e.g., primary 
analysis, follow up analysis etc]. In addition, the aim is to submit a manuscript to a peer-
reviewed journal for publication within 18 months of LSLV. GSK also aims to publish 
the full study protocol on the GSK Clinical Study Register at the time the results of the 
study are published as a manuscript in the scientific literature. 
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. 
A manuscript will be progressed for publication in the scientific literature if the results 
provide important scientific or medical knowledge.
10.8.
Independent Data Monitoring Committee
No Independent Data Monitoring Committee (IDMC) will be utilized in this study.


2012N132406_01
CONFIDENTIAL
BRF116613
93
11.
REFERENCES
Chapman, P. B., A. Hauschild, C. Robert, J. B. Haanen, P. Ascierto, J. Larkin, R. 
Dummer, C. Garbe, A. Testori, M. Maio, D. Hogg, P. Lorigan, C. Lebbe, T. Jouary, D. 
Schadendorf, A. Ribas, S. J. O'Day, J. A. Sosman, J. M. Kirkwood, A. M. Eggermont, B. 
Dreno, K. Nolop, J. Li, B. Nelson, J. Hou, R. J. Lee, K. T. Flaherty and G. A. McArthur 
(2011). "Improved survival with vemurafenib in melanoma with BRAF V600E 
mutation." N Engl J Med 364(26): 2507-16.
Davies, H., G. R. Bignell, C. Cox, P. Stephens, S. Edkins, S. Clegg, J. Teague, H. 
Woffendin, M. J. Garnett, W. Bottomley, N. Davis, E. Dicks, R. Ewing, Y. Floyd, K. 
Gray, S. Hall, R. Hawes, J. Hughes, V. Kosmidou, A. Menzies, C. Mould, A. Parker, C. 
Stevens, S. Watt, S. Hooper, R. Wilson, H. Jayatilake, B. A. Gusterson, C. Cooper, J. 
Shipley, D. Hargrave, K. Pritchard-Jones, N. Maitland, G. Chenevix-Trench, G. J. 
Riggins, D. D. Bigner, G. Palmieri, A. Cossu, A. Flanagan, A. Nicholson, J. W. Ho, S. Y. 
Leung, S. T. Yuen, B. L. Weber, H. F. Seigler, T. L. Darrow, H. Paterson, R. Marais, C. 
J. Marshall, R. Wooster, M. R. Stratton and P. A. Futreal (2002). "Mutations of the 
BRAF gene in human cancer." Nature 417(6892): 949-54.
Eisenhauer, E. A., P. Therasse, J. Bogaerts, L. H. Schwartz, D. Sargent, R. Ford, J. 
Dancey, S. Arbuck, S. Gwyther, M. Mooney, L. Rubinstein, L. Shankar, L. Dodd, R. 
Kaplan, D. Lacombe and J. Verweij (2009). "New response evaluation criteria in solid 
tumours: revised RECIST guideline (version 1.1)." Eur J Cancer 45(2): 228-47.
Flaherty, K. T., C. Robert, P. Hersey, P. Nathan, C. Garbe, M. Milhem, L. V. Demidov, J. 
C. Hassel, P. Rutkowski, P. Mohr, R. Dummer, U. Trefzer, J. M. Larkin, J. Utikal, B. 
Dreno, M. Nyakas, M. R. Middleton, J. C. Becker, M. Casey, L. J. Sherman, F. S. Wu, D. 
Ouellet, A. M. Martin, K. Patel and D. Schadendorf (2012b). "Improved survival with 
MEK inhibition in BRAF-mutated melanoma." N Engl J Med 367(2): 107-14.
Flaherty, K. T., J. R. Infante, A. Daud, R. Gonzalez, R. F. Kefford, J. Sosman, O. Hamid, 
L. Schuchter, J. Cebon, N. Ibrahim, R. Kudchadkar, H. A. Burris, 3rd, G. Falchook, A. 
Algazi, K. Lewis, G. V. Long, I. Puzanov, P. Lebowitz, A. Singh, S. Little, P. Sun, A. 
Allred, D. Ouellet, K. B. Kim, K. Patel and J. Weber (2012a). "Combined BRAF and 
MEK inhibition in melanoma with BRAF V600 mutations." N Engl J Med 367(18): 
1694-703.
Gorden, A., I. Osman, W. Gai, D. He, W. Huang, A. Davidson, A. N. Houghton, K. 
Busam and D. Polsky (2003). "Analysis of BRAF and N-RAS mutations in metastatic 
melanoma tissues." Cancer Res 63(14): 3955-7.
Hauschild, A., J. J. Grob, L. V. Demidov, T. Jouary, R. Gutzmer, M. Millward, P. 
Rutkowski, C. U. Blank, W. H. Miller, Jr., E. Kaempgen, S. Martin-Algarra, B. 
Karaszewska, C. Mauch, V. Chiarion-Sileni, A. M. Martin, S. Swann, P. Haney, B. 
Mirakhur, M. E. Guckert, V. Goodman and P. B. Chapman (2012). "Dabrafenib in 
BRAF-mutated metastatic melanoma: a multicentre, open-label, phase 3 randomised 
controlled trial." Lancet 380(9839): 358-65.


2012N132406_01
CONFIDENTIAL
BRF116613
94
Huncharek, M., J. F. Caubet and R. McGarry (2001). "Single-agent DTIC versus 
combination chemotherapy with or without immunotherapy in metastatic melanoma: a 
meta-analysis of 3273 patients from 20 randomized trials." Melanoma Res 11(1): 75-81.
James, L. P., L. Letzig, P. M. Simpson, E. Capparelli, D. W. Roberts, J. A. Hinson, T. J. 
Davern and W. M. Lee (2009). "Pharmacokinetics of acetaminophen-protein adducts in 
adults with acetaminophen overdose and acute liver failure." Drug Metab Dispos 37(8): 
1779-84.
Korn, E. L., P. Y. Liu, S. J. Lee, J. A. Chapman, D. Niedzwiecki, V. J. Suman, J. Moon, 
V. K. Sondak, M. B. Atkins, E. A. Eisenhauer, W. Parulekar, S. N. Markovic, S. Saxman 
and J. M. Kirkwood (2008). "Meta-analysis of phase II cooperative group trials in 
metastatic stage IV melanoma to determine progression-free and overall survival 
benchmarks for future phase II trials." J Clin Oncol 26(4): 527-34.
Lacouture, M. E., S. Wu, C. Robert, M. B. Atkins, H. H. Kong, J. Guitart, C. Garbe, A. 
Hauschild, I. Puzanov, D. T. Alexandrescu, R. T. Anderson, L. Wood and J. P. Dutcher 
(2008). "Evolving strategies for the management of hand-foot skin reaction associated 
with the multitargeted kinase inhibitors sorafenib and sunitinib." Oncologist 13(9): 1001-
11.
Libra, M., G. Malaponte, P. M. Navolanic, P. Gangemi, V. Bevelacqua, L. Proietti, B. 
Bruni, F. Stivala, M. C. Mazzarino, S. Travali and J. A. McCubrey (2005). "Analysis of 
BRAF mutation in primary and metastatic melanoma." Cell Cycle 4(10): 1382-4.
Long, G. V., U. Trefzer, M. A. Davies, R. F. Kefford, P. A. Ascierto, P. B. Chapman, I. 
Puzanov, A. Hauschild, C. Robert, A. Algazi, L. Mortier, H. Tawbi, T. Wilhelm, L. 
Zimmer, J. Switzky, S. Swann, A. M. Martin, M. Guckert, V. Goodman, M. Streit, J. M. 
Kirkwood and D. Schadendorf (2012). "Dabrafenib in patients with Val600Glu or 
Val600Lys BRAF-mutant melanoma metastatic to the brain (BREAK-MB): a 
multicentre, open-label, phase 2 trial." Lancet Oncol 13(11): 1087-95.
McLellan, B. and H. Kerr (2011). "Cutaneous toxicities of the multikinase inhibitors 
sorafenib and sunitinib." Dermatologic Therapy 24: 396-400.


2012N132406_01
CONFIDENTIAL
BRF116613
95
12.
APPENDICES
Appendix 1 Eastern Cooperative Oncology Group (ECOG) Performance 
Status
CCI - This section contained Clinical Outcome Assessment data collection questionnaires or indices, which are protected by 
third party copyright laws and therefore have been excluded.


2012N132406_01
CONFIDENTIAL
BRF116613
96
Appendix 2 Cockcroft-Gault Formula
To determine eligibility for the study, investigators should calculate a patient’s creatinine 
clearance by the Cockcroft-Gault formula as follows [Cockcroft, 1976]:
CrCl for males (mL/min) =
(140 - age [years]) × (weight [kg])
72 × (serum creatinine [mg/dL])
CrCL for females 
(mL/min) =
0.85 × (140 - age [years]) × (weight 
[kg])
72 × (serum creatinine [mg/dL])
For SI units:
CrCl for males (mL/min) =
(140 - age [years]) × (weight [kg]) × 
1.23
(serum creatinine [mol/L])
CrCL for females 
(mL/min) =
(140 - age [years]) × (weight [kg]) × 
1.05
(serum creatinine [mol/L])
CrCl = creatinine clearance; SI = Système International d’Unités.
Reference
Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. 
Nephron 1976; 16(1):31-41.


2012N132406_01
CONFIDENTIAL
BRF116613
97
Appendix 3 QT interval on electrocardiogram corrected using the Bazett’s 
formula (QTcB)
Bazett's formula used to correct QT interval for heart rate is:
RR
QT
QTcB 
where QTcB is the QT interval corrected for heart rate, RR is the interval from the onset 
of one QRS complex to the onset of the next QRS complex, measured in seconds, often 
derived from the heart rate (HR) as 60/HR, and QT is the QT interval measured in 
milliseconds. 
Reference
Bazett HC. An analysis of the time-relations of electrocardiograms. Heart 1920; 7: 353-
370. 


2012N132406_01
CONFIDENTIAL
BRF116613
98
Appendix 4 New York Heart Association (NYHA) Guidelines
The New York Heart Association Functional Classification provides a simple way of 
classifying the extent of heart failure [The Criteria Committee of the New York Heart 
Association 1994]. It places patients in 1 of 4 categories based on the level of limitation 
experienced during physical activity:
Functional Capacity
Objective Assessment
Class I: Patients with cardiac disease but without resulting 
limitation of physical activity. Ordinary physical activity does not 
cause undue fatigue, palpitation, dyspnea, or anginal pain.
A: No objective evidence of 
cardiovascular disease.
Class II: Patients with cardiac disease resulting in slight limitation 
of physical activity. They are comfortable at rest. Ordinary physical 
activity results in fatigue, palpitation, dyspnea, or anginal pain.
B: Objective evidence of minimal 
cardiovascular disease.
Class III: Patients with cardiac disease resulting in marked 
limitation of physical activity. They are comfortable at rest. Less 
than ordinary physical activity causes fatigue, palpitation, dyspnea, 
or anginal pain.
C: Objective evidence of moderately 
severe cardiovascular disease.
Class IV: Patients with cardiac disease resulting in inability to carry 
on any physical activity without discomfort. Symptoms of heart 
failure or the anginal syndrome may be present even at rest. If any 
physical activity is undertaken, discomfort is increased.
D: Objective evidence of severe 
cardiovascular disease.
Reference
The Criteria Committee of the New York Heart Association. Nomenclature and criteria 
for diagnosis of diseases of the heart and great vessels. 9th ed. Boston, Mass: Little, 
Brown, & Co; 1994:253-256.


2012N132406_01
CONFIDENTIAL
BRF116613
99
Appendix 5 Liver Chemistry Monitoring, Interruption 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
IP may be re-challenged if protocol provides this option.


2012N132406_01
CONFIDENTIAL
BRF116613
100
Appendix 6 Additional Monitoring for Patients Enrolled in France
Evaluation for Cutaneous Squamous Cell Carcinoma (cuSCC), New Primary 
Melanoma, and Non-cutaneous Secondary/Recurrent Malignancy Following 
Discontinuation of Dabrafenib
Patients should be monitored for cuSCC, new primary melanoma, and non-cutaneous 
secondary/recurrent malignancies. Dermatological examinations should be performed 
prior to initiation of therapy with dabrafenib, monthly throughout treatment, and for 6 
months following discontinuation of dabrafenib or until initiation of another anti-
neoplastic therapy, whichever comes first. Cases should be managed by dermatological 
excision and dabrafenib treatment should be continued without any dose adjustment. 
Patients should be instructed to immediately inform their physician if new lesions 
develop.
Non-cutaneous secondary/recurrent malignancy
Prior to initiation of dabrafenib treatment patients should undergo a head and neck 
examination with minimally visual inspection of oral mucosa and lymph node palpation, 
as well as chest/abdomen Computerised Tomography (CT) scan. Refer to Section 7.47
and Time and events table (Table 19). During treatment patients should be monitored as 
clinically appropriate which may include a head and neck examination every 3 months 
and a chest/abdomen CT scan every 6 months. Anal examinations and pelvic 
examinations (for women) are recommended as per Section 7.4.7 and the Time and 
Events table (Table 19), or when considered clinically indicated. Complete blood cell 
counts should be performed as clinically indicated. Following discontinuation of 
dabrafenib and completion in study, monitoring for non-cutaneous secondary/recurrent 
malignancies should continue for up to 6 months or until initiation of another anti-
neoplastic therapy, whichever comes first as per the SmPC fro Dabrafenib. Abnormal 
findings should be managed according to clinical practices.
Any cuSCC, new primary melanomas, and or non-cutaneous secondary/recurrent 
malignancy should be reported as a protocol-specific SAEs and treated according to 
standard clinical practice. Refer to Section 7.4.2.2.


2012N132406_01
CONFIDENTIAL
BRF116613
101
Appendix 7 Summary of Changes for Amendment 01
Previous - 3. STUDY DESIGN
Figure 2
Study Schema
Treatment Period 2
Treatment Period 1
n=54
Time (weeks)
0
8
1:1:1
R
a
n
d
o
m
i
s
a
t
i
o
n
S
c
r
e
e
n
i
n
g
Stage 
IIIC/IV 
Melanoma
BRAF 
V600E/K
-4
2
10
X
X
X
X
P
r
o
g
r
e
s
s
i
o
n
Trametinib2mg daily 
Dabrafenib 150mg BID
Dabrafenib 150mg 
BID
Trametinib2mg daily 
Dabrafenib 150mg BID
Trametinib2mg daily 
Biopsy
X
Revised- 3. STUDY DESIGN
Figure 3
Study 
Schema
Treatment Period 2
Treatment Period 1
n=54
Time (weeks)
Day 1
8
1:1:1
R
a
n
d
o
m
i
s
a
t
i
o
n
S
c
r
e
e
n
i
n
g
Stage IIIC/IV 
Melanoma
BRAF 
V600E/K
-4
2
10
X
X
X
X
P
r
o
g
r
e
s
s
i
o
n
Trametinib 2mg daily 
Dabrafenib 150mg BID
Dabrafenib 150mg BID
Trametinib 2mg daily 
Dabrafenib 150mg BID
Trametinib 2mg daily 
Biopsy
X


2012N132406_01
CONFIDENTIAL
BRF116613
102
Rationale: Amendment to figure 1.in order to be better aligned with the study design 
with regards to timelines.
Previous
5.7 Treatment Compliance
Patients will be instructed to return treatment vials at each visit. 
Revised
5.7 Treatment Compliance
Patients will be instructed to return treatment bottles at each visit. 
Rationale: Clarification of text. The study medication will be in bottles and not vials
Previous
7.2 Biomarkers
If possible biopsies should be taken from the same organ. Key biopsies are screening, 
week 2 and week 10. Additional patients might be recruited to ensure a sufficient number 
of patients in each arm providing these three key biopsies.
Revised
7.2 Biomarkers
Biopsies will be performed on cutaneous or sub-cutaneous lesions that are easily 
accessible and will NOT be performed on any deep lesions. If possible biopsies should be 
taken from the same lesion/location. Key biopsies are taken at randomisation, week 2, 
week 8, and week 10. Additional patients might be recruited to ensure a sufficient 
number of patients in each arm providing these three key biopsies.
Rationale: Amendment and further clarification around the biopsies taken for this study 
as requested by the ANSM. 


2012N132406_01
CONFIDENTIAL
BRF116613
103
Previous
7.3.2 Efficacy Assessment
Confirmation of response (i.e., CR and PR) is not necessary per RECIST, version 1.1, as 
the primary efficacy endpoint of the study is PFS.
Revised
7.3.2 Efficacy Assessment
Confirmation of response (i.e., CR and PR) is not necessary per RECIST, version 1.1, as 
the primary endpoint of the study is not overall best response. 
Rationale: Clarification regarding the confirmation of response.
Previous
7.5.1 Blood Sample Collection for Pharmacokinetics
Blood samples for PK analyses of dabrafenib, trametinib, and metabolites of dabrafenib 
will be collected pre-dose and at the same time as the tumour and skin biopsies are 
performed during treatment (Week 2, 8 and 10). The actual date and time of each blood 
sample collection will be recorded. No more than 25 mL of blood will be collected over 
the duration of the study for PK blood sample collection, including any extra assessments 
that may be required.
Revised
7.5.1 Blood Sample Collection for Pharmacokinetics
Blood samples for PK analyses of dabrafenib, trametinib, and metabolites of dabrafenib 
will be collected at the same day as the tumour and skin biopsies are performed during 
treatment (Week 2, 8 and 10). Patients with morning clinic visits will be instructed to 
withhold their morning dose, and samples will be collected prior to dabrafenib and 
trametinib administration; for patients with afternoon clinic visits, patients will take their 
morning doses as usual, and samples will be collected 4-8 hours following dabrafenib and 
trametinib administration. Date and exact time of pharmacokinetic sample and of most 
recent dose will be recorded.. No more than 25 mL of blood will be collected over the 
duration of the study for PK blood sample collection, including any extra assessments 
that may be required.
Rationale: Clarification of the PK blood sampling.


2012N132406_01
CONFIDENTIAL
BRF116613
104
Previous - Table 24 Time and Events 
Table 25
Time and Events
Study Assessments1
Screening
(28 days 
except where 
noted)2
Day 1
Every 4 Weeks
(7 days)
Every 8 Weeks
(7 days)
Every 12 Weeks
(7 days)
End of Study20
Clinical assessments
Informed consent3
X
Inclusion/Exclusion criteria
X
X
Demographic data
X
Past and current medical conditions including 
cardiovascular medical and family history, risk factors
X
Disease characteristics4
X
Prior anti-cancer therapies
X
Performance status (ECOG)
X
X
X
Brain MRI/CT5
X
Lesion assessment (including skin lesion 
photography)6
X
(5 weeks)
Week 8 and every 8 weeks thereafter 
through week 56 and then every 12 
weeks thereafter until determination of 
progressive disease
Randomisation7
X
Safety Assessments
Vital signs8
X
X
X
Physical examination9
X
X (short)
X
Ophthalmic examination10
X
Adverse events11
X
X
X
X
ECG12
X 
(5 weeks)
X
(only at Week 4)
X
X
ECHO13
X 
(5 weeks)
X
(only at Week 4)
X
Dermatology assessment
X
X
(only at week 2, 8, 10)
X
(at PD)
Concomitant medications14
X
X
X
X
Laboratory Assessments


2012N132406_01
CONFIDENTIAL
BRF116613
105
Study Assessments1
Screening
(28 days 
except where 
noted)2
Day 1
Every 4 Weeks
(7 days)
Every 8 Weeks
(7 days)
Every 12 Weeks
(7 days)
End of Study20
Chemistry and Haematology15
X
X
X
Serum pregnancy test16
X
Coagulation
X
Study Treatments
Dispensation of medication17
X
X
Assessment of compliance18
X
Biomarker Samples
Tumour biopsy21
X
X
(only at week 2, 8, 10)
X
(at PD)
Skin biopsy21
X
X
(only at week 2, 8, 10)
X
(at PD)
Blood sample for biomarker
X
X
(only at week 2, 8, 10)
X
(at PD)
Blood sample for PK19
X
(only at week 2, 8, 10)
X
(at PD)
Blood sample for cfDNA21
X
Abbreviations: cfDNA = cell-free deoxyribonucleic acid; CNS = central nervous system; CT = computed tomography; ECG = electrocardiogram; ECHO = echocardiogram; ECOG = 
Eastern Cooperative Oncology Group; LDH = lactate dehydrogenase; LLN = lower limit of normal; LVEF = left ventricular ejection fraction; MRI = magnetic resonance imaging; PD = 
progressive disease; PK = pharmacokinetics; RAMOS = Registration and Medication Ordering System; RECIST = Response Evaluation Criteria in Solid Tumours; SPM = study 
procedures manual.
1.
All assessments mandated throughout the study must be performed on a calendar schedule; delays in treatment administration will not delay performance of assessments. 
2.
Screening procedures may be performed up to 28 days prior to randomisation. Screening procedures that have a larger visit window are indicated in parentheses.
3.
Informed consent must be given prior to performance of any study-related procedures. Informed consent can be obtained at any time before Day 1.
4.
Disease characteristics will include date of diagnosis, primary tumour type, histology, stage, etc.
5.
Baseline MRI (preferred) or CT (only if MRI contraindicated or unavailable) of the brain must be performed on all patients to rule out current leptomeningeal metastases, brain 
metastases, or spinal cord compression secondary to metastasis. Post-baseline scans should be performed in all patients with documented metastases at baseline and as 
clinically indicated (e.g., symptoms suggestive of CNS progression) in all patients. 
6.
Lesion assessments must be done for chest, abdomen, pelvis, and any area of known disease. Lesion assessment by contrast CT (preferred) or MRI must be performed within 4 
weeks prior to randomisation and at the times indicated until disease progression, death, or withdrawal of consent, whichever occurs first. (See Section 7.3.3 for instructions 
regarding chest X-Rays and CT assessment.) Target and non-target lesions must be identified at the time of screening and the same lesions must be re-assessed at each 
timepoint in a consistent manner according to RECIST, version 1.1. The same diagnostic method, including use of contrast when applicable, must be used throughout the study to 
evaluate each lesion. Lesion measurements will be taken using ruler or calipers. The Week 8 assessment for patients in arms A & B should be done before starting the 


2012N132406_01
CONFIDENTIAL
BRF116613
106
combination treatment. If the last assessment was > 8 weeks prior to study withdrawal and disease progression had not been documented, a disease assessment should be 
obtained.
7.
Randomisation will occur via RAMOS on Day 1.
8.
Refer to Section 7.4.6 for details regarding vital sign measurements. 
9.
A complete physical examination will be performed at Screening and End-of-study; brief physical examinations will be performed at all other timepoints as indicated. In females,
genitourinary exam should include a visual inspection of the cervix. If the patient has had a genitourinary and rectal exam within 6 months of screening the genitourinary and rectal 
exam do not need to be repeated. Refer to Section 7.4.7 for details.
10. An ophthalmic examination will be performed at Screening; additional ophthalmic examinations will be performed only as symptomatically warranted. Refer to Section 7.4.5 for 
details. 
11. Adverse events will be recorded from the time the first dose of study treatment is administered until 30 days after discontinuation of study treatment. Serious adverse events will 
be collected over the same time period as AEs except SAEs assessed as related to study participation (e.g., protocol-mandated procedures, invasive tests, or change in existing 
therapy), study treatment, or a GSK concomitant medication which must be recorded from the time a patient consents to participate in the study up to and including any follow-up 
contact. 
12. At each timepoint listed, a single 12-lead ECG will be performed by qualified site personnel after the patient has rested in a semi-recumbent or supine position for at least 5 
minutes. 
13. While on treatment, patients who have an asymptomatic, absolute decrease in LVEF of > 10% compared to screening and whose ejection fraction is below the institution’s LLN, 
must be followed according to LVEF guidelines for study drug management and requirements for subsequent ECHO. 
14. All medications the patient takes during the study from the time of screening until 30 days after the last dose of study treatment will be recorded.
15. Analysis of clinical chemistry and haematology samples will be performed by the local lab. Screening labs performed within 2 weeks prior to randomisation do not need to be 
repeated.
16. Serum pregnancy test is required at Screening. Subsequent tests may be urine tests, and should be performed as clinically indicated.
17. A 4-week supply of study medication should be dispensed at each scheduled study visit as of Day 1. Patients should be provided with dosing instructions. Patients should start 
treatment as soon as possible after randomisation but no later than 72 hours post-randomisation.
18. Patients should be instructed to return study drug vials at each visit; compliance will be assessed through querying the patient and through pill count at the time of new 
dispensation. Dose modifications and interruptions must be recorded.
19. The date and exact time of PK sample collection and most recent dose will be recorded. Details of collection procedures, including dosing instructions for morning and afternoon 
visits, will be provided in the SPM.
20. End of study assessments do not need to be repeated if performed within 4 weeks
21. Biomarker-related sampling to be conducted at randomisation to avoid biomarker sample collection for ineligible patients


2012N132406_01
CONFIDENTIAL
BRF116613
107
Revised - Table 26
Time and Events
Table 27
Time and Events
Study Assessments1
Screening
(28 days 
except where 
noted)2
Day 1
Every 4 Weeks
(7 days)
Every 8 Weeks
(7 days)
Every 12 Weeks
(7 days)
End of Study20
Clinical assessments
Informed consent3
X
Inclusion/Exclusion criteria
X
X
Demographic data
X
Past and current medical conditions including 
cardiovascular medical and family history, risk factors
X
Disease characteristics4
X
Prior anti-cancer therapies
X
Performance status (ECOG)
X
X
X
Brain MRI/CT5
X
(5 weeks)
Lesion assessment (including skin lesion 
photography)6
X
(5 weeks)
Week 8 and every 8 weeks thereafter 
through week 56 and then every 12 
weeks thereafter until determination of 
progressive disease
Randomisation7
X
Safety Assessments
Vital signs8
X
X
X
Physical examination9,23
X
X (short)
X
Ophthalmic examination10
X
Adverse events11
X
X
X
X
ECG12
X 
(5 weeks)
X
(only at Week 4)
X
X
ECHO13
X 
(5 weeks)
X
(only at Week 4)
X
Dermatology assessment23
X
X
(only at week 2, 8, 10)
X
(at PD)
Concomitant medications14
X
X
X
X


2012N132406_01
CONFIDENTIAL
BRF116613
108
Study Assessments1
Screening
(28 days 
except where 
noted)2
Day 1
Every 4 Weeks
(7 days)
Every 8 Weeks
(7 days)
Every 12 Weeks
(7 days)
End of Study20
Laboratory Assessments
Chemistry and Haematology15
X
X
X
Serum pregnancy test16
X
Coagulation
X
Study Treatments
Dispensation of medication17
X
X
Assessment of compliance18
X
Biomarker Samples
Tumour biopsy21, 22, 
X
X
(only at week 2, 8, 10)
X
(at PD)
Skin biopsy21, 22
X
X
(only at week 2, 8, 10)
X
(at PD)
Blood sample for biomarker
X
X
(only at week 2, 8, 10)
X
(at PD)
Blood sample for PK19
X
(only at week 2, 8, 10)
X
(at PD)
Blood sample for cfDNA21
X
Abbreviations: cfDNA = cell-free deoxyribonucleic acid; CNS = central nervous system; CT = computed tomography; ECG = electrocardiogram; ECHO = echocardiogram; ECOG = 
Eastern Cooperative Oncology Group; LDH = lactate dehydrogenase; LLN = lower limit of normal; LVEF = left ventricular ejection fraction; MRI = magnetic resonance imaging; PD = 
progressive disease; PK = pharmacokinetics; RAMOS = Registration and Medication Ordering System; RECIST = Response Evaluation Criteria in Solid Tumours; SPM = study
procedures manual.
1.
All assessments mandated throughout the study must be performed on a calendar schedule; delays in treatment administration will not delay performance of assessments. 
2.
Screening procedures may be performed up to 28 days prior to randomisation. Screening procedures that have a larger visit window are indicated in parentheses.
3.
Informed consent must be given prior to performance of any study-related procedures. Informed consent can be obtained at any time before Day 1.
4.
Disease characteristics will include date of diagnosis, primary tumour type, histology, stage, etc.
5.
Baseline MRI (preferred) or CT (only if MRI contraindicated or unavailable) of the brain must be performed on all patients to rule out current leptomeningeal metastases, brain 
metastases, or spinal cord compression secondary to metastasis. Post-baseline scans should be performed in all patients with documented metastases at baseline and as 
clinically indicated (e.g., symptoms suggestive of CNS progression) in all patients. 
6.
Lesion assessments must be done for chest, abdomen, pelvis, and any area of known disease. Lesion assessment by contrast CT (preferred) or MRI must be performed 
within 5 weeks prior to randomisation and at the times indicated until disease progression, death, or withdrawal of consent, whichever occurs first. (See Section 7.3.3 for 
instructions regarding chest X-Rays and CT assessment.) Target and non-target lesions must be identified at the time of screening and the same lesions must be re-
assessed at each timepoint in a consistent manner according to RECIST, version 1.1. The same diagnostic method, including use of contrast when applicable, must be used 


2012N132406_01
CONFIDENTIAL
BRF116613
109
throughout the study to evaluate each lesion. Lesion measurements will be taken using ruler or calipers. The Week 8 assessment for patients in arms A & B should be done 
before starting the combination treatment. If the last assessment was > 8 weeks prior to study withdrawal and disease progression had not been documented, a disease 
assessment should be obtained.
7.
Randomisation will occur via RAMOS on Day 1.
8.
Refer to Section 7.4.6 for details regarding vital sign measurements. 
9.
A complete physical examination will be performed at Screening and End-of-study; brief physical examinations will be performed at all other timepoints as indicated. In 
females, genitourinary exam should include a visual inspection of the cervix. If the patient has had a genitourinary and rectal exam within 6 months of screening the 
genitourinary and rectal exam do not need to be repeated. Refer to Section 7.4.7 for details.
10. An ophthalmic examination will be performed at Screening; additional ophthalmic examinations will be performed only as symptomatically warranted. Refer to Section 7.4.5 
for details. 
11. Adverse events will be recorded from the time the first dose of study treatment is administered until 30 days after discontinuation of study treatment. Serious adverse events 
will be collected over the same time period as AEs except SAEs assessed as related to study participation (e.g., protocol-mandated procedures, invasive tests, or change in 
existing therapy), study treatment, or a GSK concomitant medication which must be recorded from the time a patient consents to participate in the study up to and including 
any follow-up contact. 
12. At each timepoint listed, a single 12-lead ECG will be performed by qualified site personnel after the patient has rested in a semi-recumbent or supine position for at least 5 
minutes. 
13. While on treatment, patients who have an asymptomatic, absolute decrease in LVEF of > 10% compared to screening and whose ejection fraction is below the institution’s 
LLN, must be followed according to LVEF guidelines for study drug management and requirements for subsequent ECHO. 
14. All medications the patient takes during the study from the time of screening until 30 days after the last dose of study treatment will be recorded.
15. Analysis of clinical chemistry and haematology samples will be performed by the local lab. Screening labs performed within 2 weeks prior to randomisation do not need to be 
repeated.
16. Serum pregnancy test is required at Screening. Subsequent tests may be urine tests, and should be performed as clinically indicated.
17. A 4-week supply of study medication should be dispensed at each scheduled study visit as of Day 1. Patients should be provided with dosing instructions. Patients should 
start treatment as soon as possible after randomisation but no later than 72 hours post-randomisation.
18. Patients should be instructed to return study drug vials at each visit; compliance will be assessed through querying the patient and through pill count at the time of new 
dispensation. Dose modifications and interruptions must be recorded.
19. The date and exact time of PK sample collection and most recent dose will be recorded. Details of collection procedures, including dosing instructions for morning and 
afternoon visits, will be provided in the SPM.
20. End of study assessments do not need to be repeated if performed within 4 weeks
21. Biomarker-related sampling to be conducted at randomisation to avoid biomarker sample collection for ineligible patients
22. Biopsies are to be taken at the judgement of the investigator at the various time-points to ensure that any potential risk or impact to the patients are kept to a minimum, All 
biopsies, be they from cutaneous or sub-cutaneous lesions, are to be performed only if the lesions are easily accessible.Biopsies are to be performed by either the 
investigator, a dermatologist, a surgeon or a physician qualified in radiology if an ultrasound-led biopsy is necessary.
23. For Subjects enrolled in France, refer to the Appendix 6: Additional Monitoring for Patients Enrolled in France


2012N132406_01
CONFIDENTIAL
BRF116613
110
Rationale: Change of brain MRI from 4 weeks to 5 weeks before Day 1; Amendment of 
the the time and events table to be in alignment with footnote 21 which states that the 
biopsies will be taken at the randomisation visit and not the screening visit.; Amendment 
and further clarification around the biopsies taken for this study as requested by the 
ANSM. This includes: a) That the biopsies will only be done on cutaneous and 
subcutaneous lesions only if they are easily accessible; b) confirmation that no deep 
lesion biopsies will be performed; c) clarification of who is qualified to perform the 
biopsies; refer to footnote 22.; The addition of footnote 23 refering to the Appendix 6, 
Additional Monitoring for patients enrolled in France.
Previous
No Appendix 6 - Additional Monitoring for Patients Enrolled in France
Evaluation for Cutaneous Squamous Cell Carcinoma (cuSCC), New Primary 
Melanoma, and Non-cutaneous Secondary/Recurrent Malignancy Following 
Discontinuation of Dabrafenib
Revised
Addition of  Appendix 6  - Additional Monitoring for Patients Enrolled in France
Evaluation for Cutaneous Squamous Cell Carcinoma (cuSCC), New Primary 
Melanoma, and Non-cutaneous Secondary/Recurrent Malignancy Following 
Discontinuation of Dabrafenib
Rationale: New France specific Appendix 6  added to reflect the monitoring required for 
Cutaneous Squamous Cell Carcinoma (CuSCC), new primary melanoma and non-
cutaneous secondary/recurrent malignancy as reqested by ANSM.

SAP_001.pdf: 
CONFIDENTIAL
The GlaxoSmithKline group of companies
BRF116613
1
Division: Worldwide Development
Retention Category: GRS019
Information Type:  Clinical Pharmacology Reporting and Analysis Plan
Title:
Reporting and Analysis Plan for BRF116613: A Phase II 
biomarker study evaluating the upfront combination of BRAF 
inhibitor dabrafenib with MEK inhibitor trametinib versus the 
combination after eight weeks of monotherapy with dabrafenib 
or trametinib in patients with metastatic and unresectable stage 
III or IV melanoma harbouring an activating BRAF mutation
Compound Number:
GSK1120212 + GSK2118436
Effective Date:
06-JAN-2015
Description: The purpose of this reporting and analysis plan (RAP) is to describe the 
planned analyses and output to be included in the Study Report for Protocol 
BRAF116613.  This RAP is intended to describe the biomarker, safety, efficacy analyses 
required for the study. This document will be provided to the study team members to 
convey the content of the Statistical Analysis Complete (SAC) deliverable.
Identifier/Version Number:  NA
Subject:  Oncology, GSK2118436, GSK1120212, BRAF, melanoma 
Author’s Name and Functional Area: 
 
Clinical Statistics US
Approved by Email:
Operational Study Lead
Oncology Statistics and Programming
Oncology PK Analyst
Oncology Biomarkers 
Oncology Data Management 
Oncology Clinical Investigator Lead
The Discovery Statistics and Programming (or designee) will give final approval
  
Clinical Statistics US 
06-JAN-2015
Copyright 2015 the GlaxoSmithKline group of companies. All rights reserved.  
Unauthorised copying or use of this information is prohibited
PPD
PP
D
PPD
PPD
PPD
PPD
PPD
PPD
PPD


CONFIDENTIAL
BRF116613
2
TABLE OF CONTENTS
PAGE
1.
INTRODUCTION......................................................................................................7
2.
STUDY OBJECTIVES AND ENDPOINTS................................................................7
2.1.
Study Objective.............................................................................................7
2.1.1.
Primary Objective ..........................................................................7
2.1.2.
Secondary Objectives....................................................................7
2.1.3.
Exploratory Objectives...................................................................7
2.2.
Study Endpoints............................................................................................8
2.2.1.
Primary Endpoint ...........................................................................8
2.2.2.
Secondary Endpoints.....................................................................8
2.2.3.
Exploratory Endpoints....................................................................8
2.3.
Statistical Hypothesis....................................................................................8
3.
STUDY DESIGN ......................................................................................................9
4.
PLANNED ANALYSES ..........................................................................................10
4.1.
Interim Analysis ..........................................................................................10
4.2.
Final Analyses ............................................................................................10
5.
SAMPLE SIZE CONSIDERATIONS.......................................................................10
5.1.
Sample Size Assumptions ..........................................................................10
5.2.
Sample Size Sensitivity...............................................................................10
5.3.
Sample Size Re-estimation.........................................................................11
6.
ANALYSIS POPULATIONS ...................................................................................11
7.
TREATMENT COMPARISONS..............................................................................11
8.
GENERAL CONSIDERATIONS FOR DATA ANALYSES.......................................11
8.1.
Reporting Conventions ...............................................................................11
8.2.
Multicentre Studies .....................................................................................12
8.3.
Examination of Subgroups..........................................................................12
8.4.
Multiple Comparisons and Multiplicity .........................................................12
9.
DATA HANDLING CONVENTIONS .......................................................................12
9.1.
Premature Withdrawal and Missing Data ....................................................12
9.2.
Derived and Transformed Data...................................................................14
9.2.1.
Reference dates ..........................................................................14
9.2.2.
Study Day for Safety Measures ...................................................14
9.2.3.
Study Day for Efficacy..................................................................14
9.2.4.
Duration and Elapsed Time .........................................................14
9.2.5.
Imputation of Partial Dates...........................................................15
9.2.6.
Imputation of Missing Exposure End Dates..................................22
9.2.7.
Baseline Definition.......................................................................22
9.2.8.
Change from baseline..................................................................23
9.2.9.
Multiple Assessments ..................................................................24
9.2.10.
Actual Treatment .........................................................................24
9.3.
Study Time Periods ....................................................................................24


CONFIDENTIAL
BRF116613
3
9.3.1.
Time in relation to treatment ........................................................24
9.3.2.
Study time periods for concomitant medications ..........................25
9.4.
Values of Potential Clinical Importance.......................................................26
9.4.1.
Laboratory Parameters ................................................................26
9.4.2.
ECG Parameters: ........................................................................26
9.4.3.
Vital signs ....................................................................................27
9.4.4.
Left Ventricular Ejection Fraction .................................................28
10. STUDY POPULATION...........................................................................................28
10.1.
Disposition of Subjects................................................................................28
10.2.
Protocol Deviations.....................................................................................29
10.3.
Demographic and Baseline Characteristics.................................................29
10.4.
Treatment Compliance................................................................................30
10.5.
Concomitant Medications............................................................................31
11. PHOSPHORYLATION OF ERK ENDPOINT ANALYSIS........................................31
11.1.
Interim Analysis ..........................................................................................31
11.2.
Investigator Assessment of H-Score...........................................................32
11.2.1.
Primary p-ERK Biomarker Analyses: ...........................................32
11.2.2.
Exploratory Predictive p-ERK Analyses .......................................34
11.2.2.1.
Change from baseline ................................................34
11.2.2.2.
Baseline .....................................................................34
12. SAFETY ANALYSES .............................................................................................34
12.1.
Extent of Exposure .....................................................................................35
12.2.
Adverse Events...........................................................................................36
12.3.
Adverse Events of Special Interest .............................................................37
12.4.
Deaths and Serious Adverse Events...........................................................39
12.5.
Adverse Events Leading to Discontinuation of Study Treatment 
and/or Withdrawal from the Study and Other Significant Adverse 
Events ........................................................................................................40
12.6.
Pregnancies................................................................................................40
12.7.
Clinical Laboratory Evaluations...................................................................40
12.7.1.
Analyses of Liver Function Tests .................................................41
12.8.
Other Safety Measures...............................................................................42
13. EFFICACY .............................................................................................................44
13.1.
Primary Efficacy Analyses ..........................................................................44
13.2.
Secondary Efficacy Analyses......................................................................44
13.3.
Exploratory Efficacy Analyses.....................................................................45
13.3.1.
Progression-Free Survival ...........................................................45
13.3.2.
Duration of Response ..................................................................46
14. PHARMACOKINETIC ANALYSES.........................................................................47
14.1.
Drug Concentration Measures ....................................................................47
14.2.
Population Pharmacokinetic Analyses ........................................................47
15. PHARMACOKINETIC/PHARMACODYNAMIC ANALYSES ...................................48
16. BIOMARKER ANALYSES......................................................................................48
17. REFERENCES.......................................................................................................49


CONFIDENTIAL
BRF116613
4
18. ATTACHMENTS ....................................................................................................50
18.1.
Table of Contents for Data Display Specifications.......................................50
18.1.1.
Study Population (Section 1)........................................................51
18.1.1.1.
Tables ........................................................................51
18.1.1.2.
ICH Listings................................................................53
18.1.1.3.
Other Study Population Listings..................................54
18.1.2.
Efficacy (Section 2)......................................................................56
18.1.2.1.
Tables ........................................................................56
18.1.2.2.
Figures .......................................................................57
18.1.2.3.
ICH Listings................................................................58
18.1.3.
Safety (Section 3) ........................................................................59
18.1.3.1.
Tables ........................................................................59
18.1.3.2.
Figures .......................................................................64
18.1.3.3.
ICH Listings................................................................65
18.1.3.4.
Other Study Population Listings..................................67
18.1.4.
Pharmacokinetics (Section 4) ......................................................68
18.1.4.1.
Tables ........................................................................68
18.1.4.2.
Figures .......................................................................69
18.1.4.3.
ICH Listings................................................................71
18.1.5.
Biomarker (Section 5) ..................................................................72
18.1.5.1.
Tables ........................................................................72
18.1.5.2.
Figures .......................................................................76
18.1.5.3.
Listings.......................................................................77
18.2.
Mock-Ups for Select Displays .....................................................................78
18.2.1.
Study Population Mock-Ups.........................................................78
18.2.2.
Safety Mock-Ups .........................................................................80
18.2.3.
Immunohistochemistry Mock-Ups ................................................92


CONFIDENTIAL
BRF116613
5
LIST OF ABBREVIATIONS
ADaM
Analysis Data Model
AE
Adverse Event
ALT
Alanine aminotransferase (SGPT)
ANOVA
Analysis of variance
aPTT
Activated Partial thromboplastin time
AST
Aspartate aminotransferase (SGOT)
ATC
Anatomical Therapeutic Chemical 
BLDPROD
Blood and Blood Supportive Care Products
BP
Blood Pressure
BUN
Blood Urea Nitrogen
CDISC
Clinical Data Interchange Standards Consortium 
CI
Confidence Interval
cfDNA
Circulating free DNA
Conmed
Concomitant Medication
CPMS
Clinical Pharmacology Modelling and Simulation
CR
Complete response
CRF
Case Report Form
CSR
Clinical Study Report
CTX
Anti-Cancer Therapy
CTCAE
Common Terminology Criteria for Adverse Events
DoR
Duration of Response
ECG
Electrocardiogram
ECHO
Echocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
Electronic Case Report Form
ERK
Extracellular signal-regulated kinase
EXENDT
Exposure end date
GCT
Gamma-Glutamyl Transpeptidase
GLS
Geometric Least Squares
GSK
GlaxoSmithKline
HGB
Hemoglobin
IDSL
Integrated data standards library
INR
International normalized ratio
ITT
Intent-to-Treat
KA
Keratocanthoma
LDH
Lactate Dehydrogenase
LLN
Lower limit of Normal
LVEF
Left ventricular ejection fraction
MedDRA
Medical Dictionary for Regulatory Affairs
MRI
Magnetic resonance imaging
MUGA
Multiple gated acquisition scan
NCI
National Cancer Institute 
NEWCTXDT
New Anti-Cancer Start Date
NQ
Lower limit of quantification
ONCSURV
Overall Survival Analysis Dataset
ONCTTE
Oncology time to event analysis dataset


CONFIDENTIAL
BRF116613
6
ORR
Overall response rate
PcD
Pharmacodynamic
PD
Progressive disease
p-ERK
ERK phosphorylation
PFS
Progression Free Survival
PK
Pharmacokinetic
PR
Partial response
PT
Preferred Term
PrT
Prothrombin time
QTc
Corrected QT interval on electrocardiogram
QTcB
Bazett’s Corrected QT interval on electrocardiogram
QTcF
Friderica’s Corrected QT interval on electrocardiogram
RADIO
Radiotherapy
RAP
Reporting and analysis plan
RECIST
Response Evaluation Criteria In Solid Tumors
RUCAM
Roussel Uclaf Causality Assessment Method
SAC
Statistical Analysis Complete
SAE
Serious adverse event(s)
SCC
Squamous cell carcinoma
SD
Stable disease
SGOT
Serum glutamic oxaloacetic transaminase (AST)
SGPT
Serum glutamic pyruvic transaminase (ALT)
SLD
Sum of Lesion Diameters
SOC
System Organ Class
SRT
Safety Review Team
STD
Standard Deviation
TTE
Time to Event
ULN
Upper limit of normal
WBC
White Blood Count
Trademark Information
Trademarks of the GlaxoSmithKline 
group of companies
Trademarks not owned by the 
GlaxoSmithKline group of companies
None
NONMEM
SAS


CONFIDENTIAL
BRF116613
7
1.
INTRODUCTION
This reporting and analysis plan (RAP) details all planned analyses required for a Clinical 
Study Report of study BRF116613. This is a phase II study to evaluate the biomarkers 
linked to treatment response, safety, and efficacy of GSK1120212 and GSK2118436 as 
either a combined treatment or monotherapy.
Revision Chronology:
2012N132406_00
2013-15-APR
Original
2012N132406_01
2013-28-OCT
Amendment No. 01
All decisions regarding primary/final analysis, as defined in this RAP document, have 
been made prior to Database Freeze (unblinding) of the study data.
2.
STUDY OBJECTIVES AND ENDPOINTS
2.1.
Study Objective
2.1.1.
Primary Objective

To evaluate biomarkers linked to treatment response, resistance and toxicity 
including skin toxicity when dabrafenib and trametinib combination is given 
upfront or as monotherapy before the combination treatment.
2.1.2.
Secondary Objectives

To evaluate the clinical response.

To characterize the safety profile of dabrafenib and trametinib in monotherapy 
and/or in combination including incidences of squamous cell carcinoma (SCC) 
and other proliferative cutaneous lesions as well as the papulo-pustular rash.

To evaluate dabrafenib, trametinib, and combination exposures in connection to 
clinical response and toxicity.
2.1.3.
Exploratory Objectives

To evaluate changes in inflammation

To evaluate the impact of the two drugs, separately and in combination, on 
immune markers

To evaluate the progression-free survival (PFS) and duration of response (DoR).


CONFIDENTIAL
BRF116613
8
2.2.
Study Endpoints
2.2.1.
Primary Endpoint

Percentage Change of Extracellular signal-regulated kinase (ERK) 
phosphorylation (p-ERK) score from baseline
2.2.2.
Secondary Endpoints

Overall response rate (ORR; defined as the percentage of patients with a 
confirmed or unconfirmed complete response [CR] or partial response [PR] at any 
time per Response Evaluation Criteria in Solid Tumors [RECIST], version 1.1).

Safety as measured by clinical assessments including vital signs and physical 
examinations, Eastern Cooperative Oncology Group (ECOG) performance status, 
12-lead electrocardiograms (ECG), echocardiogram (ECHO), chemistry and 
haematology laboratory values, incidence of squamous cell carcinoma and 
keratoacanthoma (KA), and adverse events (AEs) graded according to the 
Common Terminology Criteria for Adverse Events (CTC-AE), version 4.0

Plasma pharmacokinetic (PK)/ pharmacodynamic (PcD) evaluation
2.2.3.
Exploratory Endpoints

Inflammatory markers 

T cell function by blood immunomonitoring and lymphocyte infiltration of tumors
and skin

Progression-free survival (PFS; defined as the time from randomization until the 
earliest date of disease progression or death due to any cause) and Duration of 
response (DoR; defined as the time from first documented evidence of CR or PR 
until disease progression or death due to any cause among patients who achieve 
an overall response).
2.3.
Statistical Hypothesis
The primary objective of this trial is to evaluate the percentage reduction of p-ERK score
from baseline and characterize safety and efficacy of different treatment sequence with
the p-ERK score changes. The primary end point will be analyzed with a descriptive 
intent only. Hence no hypothesis testing will be performed.


CONFIDENTIAL
BRF116613
9
3.
STUDY DESIGN
This is a three-arm, open label, randomized, Phase II study comparing the upfront 
combination of dabrafenib (GSK2118436) with trametinib (GSK1120212) versus the 
combination after eight weeks of monotherapy treatment with dabrafenib or trametinib.
Approximately 54 eligible patients with histological confirmed cutaneous melanoma that 
is either metastatic or unresectable (stage IIIc or IV) and BRAF V600E/K mutation 
positive as determined by a local laboratory will be randomized, 1:1:1 to one of the three 
treatment arms.

Arm A: dabrafenib 150mg BID continuously during eight weeks followed by the 
combination of trametinib 2mg once daily with dabrafenib 150mg BID until 
disease progression, death or unacceptable toxicity.

Arm B: trametinib 2mg/day continuously during eight weeks followed by the 
combination of trametinib 2mg once daily with dabrafenib 150mg BID until 
disease progression, death or unacceptable toxicity.

Arm C: trametinib 2mg/day plus dabrafenib 150mg BID continuously until 
disease progression, death or unacceptable toxicity.
Monitoring will be performed throughout the study according to the Time and Events 
Table in the protocol.  
Biomarker analysis will be performed on blood, tumor and skin samples according to the 
Time and Events Table in the protocol.
Clinical responses will be evaluated using RECIST 1.1 criteria every 8 weeks. The 
response evaluation may be performed earlier if clinically indicated (for example, if 


CONFIDENTIAL
BRF116613
10
patient has symptomatic deterioration suggesting rapid disease progression or to confirm
clinical response at 4 weeks after achieving response).
Patients who show either radiographic or clinical progression of disease according to the 
investigator during the monotherapy treatment period in arm A or B will be able to go on 
to the combination treatment before completion of the 8 weeks monotherapy treatment. 
Patients will be treated with the combination treatment until disease progression; 
unacceptable toxicity or withdrawals from study whichever comes first.
The study will be considered completed when all patients ended study treatment either 
through progression, death or withdrawal from study for any reason.
4.
PLANNED ANALYSES
4.1.
Interim Analysis
No interim analyses will be performed for this study.
4.2.
Final Analyses
The final analysis will be performed after the last patient has the week 16 efficacy 
assessment.
5.
SAMPLE SIZE CONSIDERATIONS
5.1.
Sample Size Assumptions
Based on feasibility a sample size of 54 patients will be enrolled in this trial in 1:1:1 ratio 
to one of the three treatment arms allowing a total of 20% early dropout rate. Assuming 
as large as 30% standard deviation (s.d.) of percentage reduction of p-ERK score from 
baseline, 15 subjects per treatment arm will be sufficient to ensure that the 95% 
confidence interval (CI) will be the mean ± 16.61%. With 15 patients per treatment arm, 
the study will have > 97% power to detect 80% reduction of p-ERK score from baseline 
to Week 2 within a treatment group (with standard deviation (STD) =70%, alpha=0.05, 
two sided paired t-test).
5.2.
Sample Size Sensitivity
The effect of changes in the assumed standard deviation on the precision (i.e., half-width 
of the 95% CI for percent reduction of p-ERK score from Baseline at Week 2 within a 
treatment group) is summarized in Table 1.


CONFIDENTIAL
BRF116613
11
Table 1
Effects of changes in the assumption of standard deviation
Standard Deviation (%)
Precision (Half-Width of 95% CI of % reduction of pERK score 
from baseline within a treatment group
10
5.538
20
11.076
30
16.613
40
22.151
50
27.689
5.3.
Sample Size Re-estimation
Sample size re-estimation is not planned for this study
6.
ANALYSIS POPULATIONS
The Intent-to-Treat Population (ITT) will consist of all randomized patients whether or 
not randomized treatment was administered. This population will be based on the 
treatment to which the patient was randomized and will be the primary population for the 
analysis of efficacy data. Any patient who receives a treatment randomization number 
will be considered to have been randomized.
The Safety Population will consist of all patients who received at least one dose of 
randomized treatment and will be based on the actual treatment received.  This 
population will be used for the analysis of clinical safety data.
The Biomarker Population will consist of all patients with biopsy performed at 
screening and at least once during treatment.
7.
TREATMENT COMPARISONS
This is a descriptive study and there will be no treatment comparison. Biomarker, 
efficacy and safety endpoints will be evaluated for each treatment arm.
Depending on the treatment arm, the treatment descriptor will either be listed as 
GSK2118436 BID 8W then GSK1120212 QD + GSK2118436 BID for Arm A, 
GSK1120212 QD 8W then GSK1120212 QD + GSK2118436 BID for Arm B, or 
GSK1120212 QD+ GSK2118436 BID for Arm C.
8.
GENERAL CONSIDERATIONS FOR DATA ANALYSES
8.1.
Reporting Conventions
Data will be listed and summarized according to GlaxoSmithKline (GSK) current 
reporting standards where applicable.  Integrated Data Standards Library (IDSL) 
standards will be followed, as appropriate. Reporting and analyses will be performed 


CONFIDENTIAL
BRF116613
12
using SAS, Version 9.2 or higher.  These SAS programs will be imported into HARP and 
the final output will be produced by running drivers in HARP.  Final delivery of all 
statistical displays will be generated using Clinical Data Interchange Standard 
Consortium (CDISC) standards.  Other software may be used as needed.
Deviations from the analysis in the RAP will be identified in the Clinical Study Report 
(CSR).
Unless otherwise stated, all listings will be sorted by centre, subject number, and visit.  
Unless otherwise stated, continuous variables will be summarized with the statistics 
mean, median, standard deviation, minimum, and maximum.  Categorical variables will 
be summarized with frequency counts and percentages.
Unscheduled visits will be included in the listing using actual time and in calculation of 
maximum or minimum value over time. However, unscheduled visits will not be included 
in summaries by planned time. 
For summary by planned time, not all plan times are needed to be included in the 
summary table.  
8.2.
Multicentre Studies
Data from all participating centres, if applicable, will be pooled prior to analysis.  It is 
anticipated that patient accrual will be spread thinly across centres and summaries of data 
by centre would be unlikely to be informative and will not, therefore, be provided.  
However, a summary of subject recruitment by centre will be produced.
8.3.
Examination of Subgroups
Exploratory subgroup analyses may be performed, if appropriate.  Variables that form the 
basis of subgroup analyses of some biomarker, safety, and efficacy data including, but 
not limit to, baseline ECOG performance status, number of prior chemotherapies, age, 
gender, race and tobacco use.
8.4.
Multiple Comparisons and Multiplicity
Adjustment for multiple comparisons is not needed for this study.  As there is a single 
primary endpoint, percentage Change of Erk phosphorylation score from baseline, the 
nominal levels of significance for the primary analysis will not be affected by multiple 
comparisons. 
9.
DATA HANDLING CONVENTIONS
9.1.
Premature Withdrawal and Missing Data
Patients will receive study treatment when on combination therapy until disease 
progression, death or unacceptable adverse event, including haematologic or other 
nonhaematologic toxicity, and/or meeting stopping criteria for liver chemistry.  All 


CONFIDENTIAL
BRF116613
13
patients will be followed for survival until death, or withdrawal from the study, 
whichever comes first.  A patient will be allowed to continue on monotherapy (either 
dabrafenib or trametinib) if only one study drug is permanently discontinued.
Note: Continuation of combination study treatment beyond radiographic or clinical 
disease progression (as defined by RECIST 1.1) may be possible if the investigator 
determines that patient has clear evidence of clinical benefit from study treatment, 
continuing study drugs may be in the best interest for the patient and the patient is willing 
to continue on study drugs. In this case, consultation between the investigator and the 
GSK Medical Monitor is mandatory. If continuing the patient on study treatment is 
agreed then all study procedures, including tumor assessments, must be followed as 
scheduled. In addition, after each tumor assessment, the investigators must confirm with 
the GSK Medical Monitor that the patient is still benefiting from study treatment and 
therefore can continue receiving study treatment.
In addition study treatment may be permanently discontinued for any of the following 
reasons:

deviation(s) from the protocol

request of the patient or proxy

investigator’s discretion

patient is lost to follow-up

study is closed or terminated.
A patient will be considered to have completed the study if the patient has disease 
progression or dies during the study treatment.  Patients who withdraw from the study 
will be included in analyses up to the time of withdrawal, regardless of the duration of 
treatment.
A patient will be considered to have withdrawn from the study if the patient has stopped 
study treatment due to toxicity, has withdrawn consent, or if the study is 
closed/terminated. 
As the length of treatment for any patient will depend on the efficacy and toxicity of the 
treatment, the duration of follow-up will vary among patients.  Consequently, there will 
be no imputation for missing data. Answers such as “Not applicable” and “Not 
evaluable” are not considered to be missing data and should be displayed as such.
Subjects with unknown or missing best response will be assumed to be non-responders 
and will be included in the denominator when calculating percentages. 
Subjects with the designation of treatment relationship for adverse events (AEs) and 
serious adverse events (SAEs) missing will have the worst case assumed to impute the 
relationship: if the relationship to study treatment is missing, it will be assumed to be 
“Yes” for summary of drug-related AE or SAE. 
In the event that the study is prematurely discontinued, all available data will be listed 
and a review will be carried out by the study team to assess which statistical analyses are
still considered appropriate.


CONFIDENTIAL
BRF116613
14
9.2.
Derived and Transformed Data
The following sections provide a general description of the derived and transformed 
variables used to describe and analyze the data.  Separate analysis dataset specifications 
provide full details on all data derivations and transformations including descriptions of 
standard integrated data standards library (IDSL) algorithms including standard 
Oncology algorithms.  The analysis dataset specifications will clearly communicate the 
content and source of the datasets supporting the statistical analyses. 
9.2.1.
Reference dates
There are three reference dates:

Because age is an eligibility requirement, the reference date for age is the date of 
screening.

The safety reference date is the treatment start date, and will be used to calculate 
study day for safety measures.  

The efficacy reference date is the date of randomization and will be used to 
calculate study day for efficacy measures and baseline characteristics (such as 
time since initial diagnosis), as well as efficacy durations.
9.2.2.
Study Day for Safety Measures
If the date of interest occurs on or after the safety reference date then the safety study day 
will be calculated as (date of interest - safety reference date) + 1.  If the date of interest 
occurs before the safety reference date then the safety study day will be calculated as 
(date of interest – safety reference date).  There is no safety study day 0.
9.2.3.
Study Day for Efficacy
If the date of interest occurs on or after the efficacy reference date then efficacy study day 
will be calculated as (date of interest - efficacy reference date) + 1.  If the date of interest 
occurs prior to the efficacy reference date then efficacy study day will be calculated as 
(date of interest – efficacy reference date).  There is no efficacy study day 0.  
9.2.4.
Duration and Elapsed Time
Durations (e.g., the duration of an adverse event, duration of exposure, etc.) are 
calculated as the stop date minus the start date plus one.
For elapsed time (e.g., the time since initial diagnosis):

If the reference date is on or after the event date, then the elapsed time is the 
reference date minus the event date + 1.

If the reference date is before the event date then the elapsed time is the 
reference date minus the event date.


CONFIDENTIAL
BRF116613
15
When reporting time to event (TTE) durations such as duration of response (DOR) in 
months, divide the number of days by 30.4375; to report in weeks divide the number of 
days by 7; to report in years divide the number of days by 365.25.  These algorithms for 
time to event return decimal numbers, and ignore the actual numbers of days in the 
months or years between start date and stop date.  The "year" used in these algorithms is 
365.25 days long, and the "month" is one twelfth of that year.
For converting all other durations (e.g. duration of adverse events, duration of exposure, 
age) to weeks, months or years use the following:

To report the duration in weeks divide the number of days by 7.

To report the duration in months use:
( YEAR(stopdate+1) - YEAR(startdate) ) * 12 + ( MONTH(stopdate+1) -
month(startdate) -1 ) + ( DAY(stopdate+1) >= DAY(startdate) )

To report the duration in years use:
intck('year', startdate, stopdate+1) - ( month(stopdate+1)<month(startdate) or
(month(stopdate+1)=month(startdate) and day(stopdate+1)<day(startdate)) )
The algorithms above for age and duration return whole numbers for months and years, 
accurately accounting for the actual numbers of days in the months or years between the 
start date and the stop date.
9.2.5.
Imputation of Partial Dates
Imputed partial dates will not be used to derive study day, duration (e.g. duration of 
adverse events), or elapsed time variables.  In addition, imputed dates are not used for 
deriving the last contact date in overall survival analysis dataset (ONCSURV).
With the exception of new anti-cancer start date (NEWCTXDT) on the Oncology time to 
event analysis dataset (ONCTTE) [,][and] exposure end date (EXENDT) on the Exposure 
analysis dataset, [and other variables and datasets] imputed dates will also not be stored 
on datasets.  
Imputed dates will not be displayed in listings.  However, where necessary, display 
macros may impute dates as temporary variables for the purpose of sorting data in listings 
only.  In addition partial dates may be imputed for ‘slotting’ data to study time periods 
(Section 9.3) or for specific analysis purposes as outlined below.  
The partial date imputation will follow Analysis Data Model (ADaM) conventions. The 
ADaM approach is to populate the numeric date variables with the imputed date and add 
a flag variable to the dataset that indicates the level of imputation.  The flag variable can 
contain the values: blank, 'D', 'M', 'Y'. 
Blank: indicates that no imputation was done
D='Day': indicates that the day portion of the date is imputed


CONFIDENTIAL
BRF116613
16
M='Month': indicates that the month and day portions of the date are imputed
Y='Year': indicates that the entire date (year, month, and day) is imputed
Example of Date Variables: Date of new anti-cancer therapy 
NEWCTXD_ - character date variable
NEWCTXDT - numeric date variable
NEWCDTFL - flag variable
Details on imputing partial dates for specific datasets are outlined below.
Adverse Events (AE):
Imputations in AE are used for slotting events to the appropriate study time periods and 
for sorting in data listings.
Dataset
Date
Missing 
Element
Rule
Adverse 
Events 
(AE)
Start 
Date
day, 
month, 
and 
year

No Imputation for completely missing dates
day, 
month

If study treatment start date is missing (i.e. subject did not start 
study treatment), then set start date = January 1.

Else if study treatment start date is not missing:
o
If year of start date = year of study treatment start date 
then

If stop date contains a full date and stop 
date is earlier than study treatment start 
date then set start date = January 1.

Else set start date = study treatment start 
date.
o
Else set start date = January 1.
day

If study treatment start date is missing (i.e. subject did not start 
study treatment), then set start date = 1st of month.

Else if study treatment start date is not missing:
o
If month and year of start date = month and year of 
study treatment start date then

If stop date contains a full date and stop 
date is earlier than study treatment start 
date then set start date= 1st of month.

Else set start date = study treatment start 
date.
o
Else set start date = 1st of month.
End 
Date

No imputation for partial end dates will be performed


CONFIDENTIAL
BRF116613
17
Anti-Cancer Therapy (CTX) and Radiotherapy (RADIO):
Start and end dates are generally not imputed.  If start or end dates need to be imputed for 
an analysis (e.g. to calculate duration or elapsed time as covariates for efficacy analyses), 
the rules for imputation will be defined within the algorithm of the derived covariate.  
Additionally, post treatment CTX and RADIO start dates may be imputed to determine 
date of new anti-cancer therapy. In this case only, NEWCTXDT (not all CTX and 
RADIO start dates) will be stored on appropriate efficacy datasets.  Imputed partial dates 
will not be used to derive ATMPCTX (time since most recent prior therapy).  In addition, 
the CTXTRTCD variable, and not any variables which use imputed partial dates, will be 
used to differentiate prior and follow-up CTX and RADIO. 
Dataset
Date
Missing 
Element
Rule
Anti-Cancer 
Therapy (CTX)
Radiotherapy 
(RADIO)
Start 
Date
day, 
month, 
and year
No Imputation for completely missing dates
day, 
month
If partial date contains a year only set to January 1st.
day
If partial date contains a month and year set to the 1st
of the month.
End 
Date
No imputation for partial end dates will be performed
Surgery:
SURGERY date is generally not imputed.  If SURGERY date needs to be imputed for an 
analysis (e.g. to calculate duration, elapsed time as covariates for efficacy analyses, or if 
surgery is on a lesion being tracked), the rules for imputation will be defined within the 
algorithm of the derived covariate.  Additionally, post treatment SURGERY dates maybe 
imputed (where applicable) to determine date of new anti-cancer therapy. In this case 
only, NEWCTXDT (not specific SURGERY date) will be stored on appropriate efficacy 
datasets.  The SPCATCD variable, and not any variables which use imputed partial dates, 
will be used to differentiate prior, on, and follow-up SURGERY data. The derived 
ATTYPE and ATTYPECD variables are not needed for reporting of data because 
SPCATCD can be used. Therefore, imputed dates are not needed for derivation of 
ATTYPE and ATTYPECD.


CONFIDENTIAL
BRF116613
18
Dataset
Missing Element
Rule
Surgery
day, month, and 
year

No Imputation for completely missing dates
day, month

If partial date contains a year only set to January 1st.
day

If partial date contains a month and year set to the 1st
of the month
Concomitant Medication (Conmed) and Blood and Blood Supportive Care 
Products:
Impute start and end dates for use in derivation of the reference variables 
(CONMEDS.CMSTRF/BLDPROD.BLSTRF, 
CONMEDS.CMENRF/BLDPROD.BLENRF), but do not permanently store the imputed 
start and end dates in the CONMEDS and BLDPROD AR datasets. The reference 
variables will be used to differentiate before, during and after for the concomitant 
medication start and end dates. The derived ATTYPE and ATTYPECD variables are not 
needed for reporting of data.
Dataset
Date
Missing 
Element
Rule
Concomitant 
Medication 
(Conmed)
Blood and 
Blood 
Supportive 
Care Products 
(BLDPROD)
Start 
Date
day, 
month, 
and year

No Imputation for completely missing dates
day, 
month

If study treatment start date is missing (i.e. subject 
did not start study treatment), then set start date = 
January 1. 

Else if study treatment start date is not missing: 
o
If year of start date = year of study treatment 
start date then 

If stop date contains a full date and 
stop date is earlier than study 
treatment start date then set start 
date = January 1. 

Else set start date = study treatment 


CONFIDENTIAL
BRF116613
19
start date. 
o
Else set start date = January 1.
day

If study treatment start date is missing (i.e. subject 
did not start study treatment), then set start date = 
1st of month. 

Else if study treatment start date is not missing: 
o
If month and year of start date = month and 
year of study treatment start date then 

If stop date contains a full date and 
stop date is earlier than study 
treatment start date then set start 
date= 1st of month. 

Else set start date = study treatment 
start date.
o
Else set start date = 1st of month.
End 
Date
day, 
month, 
and year

No Imputation for completely missing dates
day, 
month

If partial end date contains year only, set end date = 
earliest of December 31 or date of last contact. 
day

If partial end date contains month and year, set end 
date = earliest of last day of the month or date of last 
contact (MSTONE.LCONTDT).
ONCTTE, RESP2, and RESP2EX1:
Start dates for follow-up CTX, RADIO (where applicable), and SURGERY (where 
applicable) will be temporarily imputed in order to define event and censoring rules for 
progression-free survival, response rate, or duration of response (i.e. start date for new 
anti-cancer therapy).  Dates will only be imputed when a month and year are available 
but the day is missing.  The imputed date(s) will not be stored on the CTX, RADIO, or 
SURGERY datasets.  The following rules will be used to impute the date when partial 
start dates are present on CTX RADIO, and/or SURGERY:
Dataset
Date
Missing 
Element
Rule
Anti-Cancer 
Therapy (CTX)
Where 
applicable: 
Radiotherapy 
Start 
Date
day, month, 
and year

No Imputation for completely missing dates


CONFIDENTIAL
BRF116613
20
(RADIO)
Surgery 
day, month

No imputation for missing day and month 
(note the eCRF should only allow for missing 
day)
day

If partial date falls in the same month as the last 
dose of study treatment, then assign to earlier 
of (date of last dose of study treatment+1, last 
day of month). 

If partial date falls in the same month as the 
subject’s last assessment and the subject’s last 
assessment is PD, then assign to earlier of (date 
of PD+1, last day of month). 

If both rules above apply, then assign to latest 
of the 2 dates 

Otherwise, impute missing day to the first of 
the month.
End 
Date

No imputation for partial end dates will be 
performed
NEWCTXDT is derived as the earliest date of new anti-cancer therapy (e.g. 
chemotherapy), radiotherapy (where applicable), or cancer related surgical procedure 
(where applicable) and will include imputed dates.  If NEWCTXDT is an imputed date, 
then the flag variable NEWCDTFL is assigned the value of 'D' to indicate that the day 
portion of the date is imputed (following ADaM convention). 
As multiple dates are used to derive NEWCTXDT ensure that NEWCDTFL is only set to 
‘D’ if the derived date is imputed.  For example if the date of new radiotherapy is 
imputed but the date of new anti-cancer therapy is prior to date of new radiotherapy and 
the new anti-cancer therapy date is not a partial date then the NEWCDTFL should be set 
to missing as the date used for NEWCTXDT is not an imputed date.
Covariates:
If the algorithms for covariates (e.g. prognostic factors) include any partial dates, then the 
algorithms must specify the date imputation rules used in the derivations. The following 
imputation rules are the standard rules to be used when algorithms for covariates require 
date imputations.


CONFIDENTIAL
BRF116613
21
Variable 
Example of when to impute
Rule
Prior CTX start date
Prior RADIO start date

Impute to derive duration 
o
Duration of prior 
[Herceptin] Therapy

Only impute when a month and 
year are available but the day is 
missing. 

Impute to first day of the 
month. 

Do not store imputed date 

Use only for relevant efficacy 
analyses (i.e. not to be used for 
general radiotherapy or anti-
cancer therapy summaries)
Prior CTX end date
Prior RADIO end date

Impute to derive elapsed time 
and duration 
o
Duration of prior 
[Herceptin] Therapy 
o
Time from Last dose 
of [Herceptin] to 
Randomization

Only impute when a month and 
year are available but the day is 
missing. 

Impute to last day of the 
month, also must be prior to 
'start' 
o
if 'start' is the first of 
the month assign to 
'start', else assign to 
'start'-1), where 'start' 
is either the date of 
randomization or the 
start of study 
treatment. 

Do not store imputed date

Use only for relevant efficacy 
analyses (i.e. not to be used for 
general radiotherapy or anti-
cancer therapy summaries)
Any DISCHA1 dates. 
For example: 

DIAGDT 

LSTRECDT 

LPROGDT

Impute to derive elapsed time 
o
Time from initial 
diagnosis to 
randomization for use 
as a covariate 
o
Time from 
progression on last 
therapy until 
randomization for use 
as a covariate

If both month and day are 
missing, impute to January 1st 

else if day is missing, impute to 
first day of the month. 

Do not store imputed date 

Use only for relevant efficacy 
analyses (i.e. not to be used for 
general disease characteristic 
summaries)


CONFIDENTIAL
BRF116613
22
9.2.6.
Imputation of Missing Exposure End Dates
In general, completely missing dates are not imputed. However, subjects in oncology 
trials may still be on study treatment when analyses are performed and so may have 
missing exposure end dates in their last dosing record. Missing exposure end dates for 
subjects who are still on study treatment at the time of an analysis will be imputed.  For 
subjects with missing exposure end dates at the time of data cutoff, the exposure end date 
will be imputed to the earliest of:  the date of the data cutoff, the date of withdrawal from 
the study, or the death date.  The imputed exposure end date will be used to calculate 
cumulative dose and exposure duration.  The imputed exposure end date will be stored in 
the EXPOSURE analysis dataset (EXENDT) and an exposure end date imputation flag 
variable will be derived indicating which exposure end date records are imputed.  
Imputed exposure end dates will also be stored on the MSTONE analysis dataset 
(MSTENDT).
For subjects who have missing end dates in their last exposure record because they are 
still on study treatment, the on-therapy indicator variables ATTYPE and ATTYPECD are 
assigned to on-therapy for all records where the 'dataset'.'date' is after or on the study 
treatment start date.
9.2.7.
Baseline Definition
Baseline will be defined as the most recent non-missing value prior to the first dose of 
study treatment.  For laboratory data, baseline will be defined as the most recent non-
missing value from a central laboratory prior to the first dose of study treatment.
The following table indicates the baseline day to be used in any change from baseline 
listings / summaries / graphical presentations or as a covariate in a statistical analysis:


CONFIDENTIAL
BRF116613
23
Parameter 
Baseline Days Collected
Baseline To Be Used in 
Analysis / Summaries
Screening1
Day 1
Safety :
ECOG
X
Screening
Brain Magnetic Resonance 
Imaging (MRI) /Computed 
Tomography (CT)
X
(5 weeks)
Screening
Lesion Assessment
X
(5 weeks)
Screening
Vital Signs
X
Screening2
Physical examination
X
Screening2
Ophthalmic examination
X
Screening2
ECG
X
(5 weeks)
Screening
ECHO
X
(5 weeks)
Screening
Chemistry and 
Haematology3
X
PD : 
Tumor
X
Day 1
Skin
X
Day 1
Blood sample for biomarker
X
Day 1
Blood sample for circulating 
free DNA (cfDNA)
X
Day 1
Clinical Activity:
Disease Assessment 
X
Screening
1.
≤ 28 days before 1st dose except where noted
2.
Use the mean of replicate assessments at any given time point as the value for that time point in all summaries, 
figures and statistical analyses.
3.
Screening labs performed within 2 weeks prior to randomization do not need to be repeated
9.2.8.
Change from baseline
Change from baseline will be presented for safety data as described in Section 12.
Change from baseline is calculated as:

For records occurring after baseline:  (visit value) – baseline value.
Percent change from baseline is calculated as:

For records occurring after baseline:  ((change from baseline) / baseline value) * 
100
If either the baseline or visit value is missing, the change from baseline and/or percent 
change from baseline is set to missing as well.


CONFIDENTIAL
BRF116613
24
9.2.9.
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).  Unscheduled data is 
included only in summary sections and in shift summaries of laboratory (e.g., vital 
signs/ECG) data labelled worst- case.  For summaries that collapse data across multiple 
planned time intervals, select the worst-case data at each collapsed interval.
If multiple assessments on different days are reported for the same scheduled assessment, 
then the latest assessment for that scheduled assessment will be analyzed.  
If multiple assessments are reported on the same date for the same scheduled planned 
time, then the worst-case result will be analyzed, with the exception of laboratory data 
reported from both central and local laboratories.  If laboratory data is reported from both 
central and local laboratories with the same date, then the central laboratory data will be 
analyzed to provide consistency with measurements from other subjects.  For example, 
for ECG data where 3 assessments are collected for each scheduled planned time, the first 
3 measures will be used to compute the mean values for ECG intervals at each scheduled 
planned time.
Data from all assessments (scheduled and unscheduled), including multiple assessments, 
will be included in listings.   
9.2.10.
Actual Treatment
The subjects’ actual treatment will be derived from exposure data and stored in variables 
ATRTCD and ATRTGRP.  If a subject’s actual treatment is the same as the assigned 
treatment, then actual treatment is the assigned treatment.  If a subject receives a study 
treatment that is different from the assigned treatment for the entire time of treatment, 
then actual treatment is the different treatment (the treatment actually received).
9.3.
Study Time Periods
Data from all assessments (scheduled and unscheduled), including multiple assessments, 
will be included in listings.  Summaries by planned time will include data from scheduled 
assessments 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, when 
summarized, will be included only in calculation of the maximum or minimum value 
over time such as worst case post-baseline. 
9.3.1.
Time in relation to treatment
Adverse events, serious adverse events, death, laboratory data, vitals, ECG, 
ECHO/Multiple gated acquisition scan (MUGA), and questionnaire data (ECOG, 
FACIT-F, FKSI-19, SQLQ, CTSQ, MRU, and KPS), will be assigned to the study time 
periods defined below.  Partial dates will be imputed into full dates, if applicable, for 
slotting data to the appropriate categories below (see Section 9.2.5).  Flag variables 
(ATTYPECD/ATTYPE) indicating the study time periods will be added to these datasets.


CONFIDENTIAL
BRF116613
25
Pre-therapy is defined as the time prior to the subject’s first dose of study treatment.  
On-therapy is defined as the time from first dose of study treatment to the last dose date 
of study treatment.  
Post-therapy is defined as any time beyond the on-therapy period.
9.3.2.
Study time periods for concomitant medications
Concomitant Medication and Blood and Blood Supportive Care Product start and end 
dates will be assigned to study time periods in relation to first dose of study treatment as 
defined below.  The start date references time flag variables (CMSTRF, BLSTRF) and 
end date reference time flag variables (CMENRF and BLENRF) will be added to the 
CONMEDS and BLDPROD datasets, respectively.

Start relative to treatment (CMSTRF and BLSTRF, respectively):  Assign to 
'BEFORE" if start date is prior to study treatment start date or if subject has not 
taken any study treatment or (start date is missing and end date is before study 
treatment start date).  Else assign to 'DURING' if the start date falls into the on-
therapy period as defined above or if subject is ongoing (not all study treatment 
discontinuation records completed) or start date is missing.  Else assign to 
'AFTER' if start date is after the on-therapy period (defined above).

End relative to treatment (CMENRF and BLENRF, respectively):  Assign to 
'BEFORE" if end date is prior to study treatment start date or if subject has not 
taken any study treatment.  Else assign to 'DURING' if start date falls into the 
on-therapy period as defined above or if subject is ongoing (not all study 
treatment discontinuation records completed) or (end date is missing and –STRF 
not ‘AFTER’).  Else assign to 'AFTER' if start date is after the on-therapy period 
(defined above) or (end date is missing and –STRF=’AFTER’). 
Only on-therapy blood and blood supportive care products that start after the start of 
study treatment are included in the Blood Products and Blood Supportive Care Product 
summaries. Therefore, for summary tables, include BLDPROD records where BLSTRF 
in ('DURING') and BLENRF in ('DURING','AFTER'). All data will be reported in 
listings. 
CONMEDS.CMSTRF and CONMEDS.CMENRF are used to select data to include in 
the Concomitant Medication summaries as follows:

Summary of Concomitant Medications: This summary will contain medications 
including those with start date prior to study treatment start date and continue 
(missing end date or end date after study treatment start date) on therapy. Note that 
any medications with start date and end date prior to study treatment start date will be 
excluded. In addition, any medication that was started during post-therapy (see above 
for definition of post-therapy) will be excluded. Include CONMED records where 
CMSTRF in ('BEFORE','DURING') and CMENRF in ('DURING','AFTER').

Summary of Concomitant Medications with On-Therapy Onset: This summary will 
contain medications with start date after study treatment start date.  In addition, any 


CONFIDENTIAL
BRF116613
26
medication that was started during post-therapy (see above for definition of post-
therapy) will be excluded. Include CONMED records where CMSTRF in 
('DURING') and CMENRF in ('DURING','AFTER').
9.4.
Values of Potential Clinical Importance
9.4.1.
Laboratory Parameters
Reference ranges for all laboratory parameters collected throughout the study are 
provided by the laboratory.  A laboratory value that is outside the reference range is 
considered either high abnormal (value above the upper limit of the reference range) or 
low abnormal (value below the lower limit of the reference range).  Note: a high 
abnormal or low abnormal laboratory value is not necessarily of clinical concern.  The 
laboratory reference ranges will be provided on the listings of laboratory data.  Clinical 
laboratory test results outside of the reference range will be flagged in the listings.
To identify laboratory values of potential clinical importance, National Cancer Institute 
Common Terminology Criteria for Adverse Events (NCI-CTCAE v4.0) will be used to 
assign grades to the relevant laboratory parameters.  NCI-CTCAE v4.0 can be found at
http://ctep.cancer.gov/reporting/ctc.html.
For laboratory data which are not listed in the NCI CTCAE v4.0, a summary of values 
outside the normal range will be provided.
Vital signs in the following ranges will be flagged as being of clinical concern in the 
corresponding listings:
9.4.2.
ECG Parameters:
The following criteria will be used to flag electrocardiogram (ECG) values that are values 
of potential clinical importance: 
To identify corrected QT interval on electrocardiogram (QTc) (Bazett’s [QTcB] or 
Fridericia’s [QTcF]) values of potential clinical importance, NCI-CTCAE v4.0 will be 
used to assign grades (see adverse event ‘Electrocardiogram QT corrected interval 
prolonged’).  Note that there is a slight inconsistency between CTCAE v4 and ICH E14 
(Absolute QTc interval prolongation).  It was decided to align with CTCAE for the 
oncology standard categories.
ECG Parameter
Potential Clinical Importance (PCI) Range
Unit
Absolute QTcF [QTcB] 
interval
>=450 to <481 (Grade 1)
>=481 to <501 (Grade 2)
>=501 (Grade 3)
Msec
Increase from baseline 
QTcF [QTcB]
Increase of >=31 to <=60
Increase of >60
Msec


CONFIDENTIAL
BRF116613
27
The following criteria will be used to flag other ECG values that are values of potential 
clinical importance: 
ECG Parameter
Potential Clinical Importance (PCI) Range
Unit
PR interval
<110 (L) and >220 (H)
Msec
QRS interval
<75 (L) and >110 (H)
Msec
9.4.3.
Vital signs
The following criteria will be used to flag vital sign values that are values of potential 
clinical importance: 
To identify heart rate values of potential clinical importance, NCI-CTCAE v4.0 will be 
used to assign categories that align with the grades for ‘Sinus bradycardia’, ‘Sinus 
tachycardia’, ‘Supraventricular tachycardia’, and ‘Ventricular tachycardia’.
Vital Sign Parameter
Potential Clinical Importance (PCI) Range
Unit
Decrease from baseline 
Heart Rate
Decrease to <60
bpm
Increase from baseline 
Heart Rate
Increase to >100
bpm
To identify blood pressure values of potential clinical importance, NCI-CTCAE v4.0 will 
be used to assign categories that align with the grades for ‘Hypertension’.
Vital Sign Parameter
Potential Clinical Importance (PCI) Range
Unit
Increase from baseline 
Systolic Blood Pressure
>=120 to <140 (Grade 1)
>=140 to <160 (Grade 2)
>=160 (Grade 3)
mmHg
Increase from baseline 
Diastolic Blood Pressure
>=80 to <90 (Grade 1)
>=90 to <100 (Grade 2)
>=100 (Grade 3)
mmHg


CONFIDENTIAL
BRF116613
28
To identify temperature values of potential clinical importance, NCI-CTCAE v4.0 will be 
used to assign categories that align with the grades for ‘Hypothermia’ and ‘Fever’.
Vital Sign Parameter
Potential Clinical Importance (PCI) Range
Unit
Increase from baseline 
temperature
Increase to >= 38
Degrees C
Decrease from baseline 
Diastolic Blood Pressure
Decrease to <= 35
Degrees C
9.4.4.
Left Ventricular Ejection Fraction
The following criteria will be used to flag left ventricular ejection fraction (LVEF) values 
that are values of potential clinical importance: 
To identify LVEF values of potential clinical importance, NCI-CTCAE v4.0 will be used 
to assign categories that align with the grades for ‘Ejection fraction decreased’.
LVEF Parameter
Potential Clinical Importance (PCI) Range
Unit
Absolute change from 
baseline LVEF

No change or any increase

Any decrease
o
>0-<10 decrease
o
10-19 decrease
o
>=20 decrease
o
>=10 decrease and >= LLN
o
>=10 decrease and below LLN
o
>=20 decrease and >= LLN
o
>=20 decrease and below LLN
%
Relative change from 
baseline LVEF

>=20 decrease and >= LLN

>=20 decrease and below LLN
%
10.
STUDY POPULATION
Unless otherwise stated, all tables and listings in this section will be based on the ITT 
population, and all summaries and data listings will use treatment labels as specified in 
Section 7.
The lists of displays for Study Population, including population to use for each display, 
are shown in Section 18.1 of the RAP.
10.1.
Disposition of Subjects
A summary of the number of subjects in each of the analysis populations described in 
Section 6 will be provided.  In addition, the number of subjects enrolled by centre will be 
summarized by treatment group using the ITT population. A listing of subjects excluded 
from analysis populations will also be provided.


CONFIDENTIAL
BRF116613
29
A summary of subject status and reason for study withdrawal will be provided.  This 
display will show the number and percentage of subjects who withdrew from the study, 
including primary and secondary reasons for study withdrawal.  Reasons for study 
withdrawal will be presented in the order they are displayed in the electronic case report 
form (eCRF).
A summary of study treatment status will be provided.  This display will show the 
number and percentage of subjects who discontinued study treatment (or have treatment 
ongoing or completed the study) and a summary of the primary and secondary reasons for 
discontinuation of study treatment.  Reasons for study treatment discontinuation will be 
presented in the order they are displayed in the eCRF.  A listing of study treatment 
discontinuation will be generated.  The listing will include last dose date, and reasons for 
study treatment discontinuation as well as study period of discontinuation. 
10.2.
Protocol Deviations
All protocol deviations will be summarized and listed and will include 
inclusion/exclusion deviations as well as other deviations.  A separate summary and 
listing of inclusion/exclusion deviations will also be provided.
10.3.
Demographic and Baseline Characteristics
The demographic characteristics (e.g. age, race, ethnicity, sex, height, and body weight) 
will be summarized and listed. Age, height and weight will be summarized using the 
mean, standard deviation, minimum, median, and maximum.  In addition, age will also be 
categorized and summarized by 18-64, 65-74, and > 74.  A separate age group 
breakdown table with age ranges of 18-64, 65-84, and > 84 will be created for use in any 
European submissions.  The count and percentage will be computed for sex and ethnicity.
Race and racial combinations will be summarized and listed.
Disease history and characteristics (time since initial diagnosis in weeks, stage at initial 
diagnosis, date of initial diagnosis) at initial diagnosis and screening (BRAF mutation 
determination, and Baseline determination of target and non-target lesions), will be listed. 
Separate summaries of disease characteristics at initial diagnosis and screening will be 
provided.  Medical conditions present at screening will be listed and will be summarized
for both cancer-related and non-cancer related medical conditions.
A summary of disease burden at baseline will be produced.  Information on metastatic 
disease at screening will be summarized and listed.  
Substance use, including and not-limited to smoking history, alcohol use, and caffeine 
use, will be summarized and listed.
Prior anti-cancer therapy including chemotherapy, hormonal therapy, immunotherapy, 
biologic therapy, and small molecule targeted therapy will be coded using GSK Drug 
coding dictionary, and the following summary tables will be provided:


CONFIDENTIAL
BRF116613
30

Summary of prior anti-cancer therapy, in which the number and percentage of 
subjects who received anti-cancer therapy prior to the study will be displayed for 
each type of anti-cancer therapy. The types of anti-cancer therapy will be sorted in 
descending order from highest total incidence to the lowest total incidence. 

Summary of dictionary coded prior anti-cancer therapy, in which the number and 
percentage of subjects with each dictionary coded anti-cancer therapy will be 
displayed.

Summary of number of prior anti-cancer therapy regimens.

Summary of best response to most recent prior anti-cancer therapy for metastatic 
disease.  
The relationship between Anatomical Therapeutic Chemical (ATC) level 1, ingredient, 
and verbatim text for anti-cancer therapy will be provided. 
Prior anti-cancer radiotherapy will be listed. 
Prior surgical procedures will be listed and summarized. Separate summaries will be 
provided for cancer related and non-cancer related surgical procedures. 
10.4.
Treatment Compliance
A listing of planned and actual treatments will be produced. 
A listing of drug accountability data (dispensed and returned) will be produced.
For dabrafenib and trametinib, the number of capsules dispensed and returned at each 
visit interval according to the eCRF will be listed.  An assessment of percentage 
compliance during each visit interval will be calculated and listed.  For each subject, an 
assessment of overall percentage compliance will be calculated looking at the entire 
interval of dosing (i.e. number of days between start of investigational product and stop 
of investigational product).  The formula to calculate compliance is as follows:
Where 
in the visit 
interval.
Compliance will be considered unknown if it cannot be calculated because of missing 
data.  The calculated percentage compliances will be summarized for the subjects in the 
ITT population.  Percentage overall compliance will be summarized using the mean, 
standard deviation, minimum, median, and maximum.  In additional, percentage overall 
compliance will be categorized and summarized by < 80%, 80%-105%, and >105%. 
A listing of overall compliance will be produced.


CONFIDENTIAL
BRF116613
31
In addition, summaries of study treatment exposure and dose modifications (e.g. number 
of dose reductions, number of dose interruptions) will further characterize compliance. 
These analyses are described in the Extent of Exposure section (Section 12.1).
10.5.
Concomitant Medications
Concomitant medications will be coded using GSK Drug coding dictionary, summarized, 
and listed.  The summary of concomitant medications will show the number and 
percentage of subjects taking concomitant medications by Ingredient. Multi-ingredient 
products will be summarized by their separate ingredients rather than as a combination of 
ingredients.  Anatomical Therapeutic Chemical (ATC) classification Level 1 (Body 
System) information will be included on the listing but not in the summary.
In the summary of concomitant medications, each subject is counted once within each 
unique ingredient. For example, if a subject takes Amoxicillin on two separate occasions, 
the subject is counted only once under the ingredient “Amoxicillin”.
In the summary of concomitant medications, the ingredients will be summarized by the 
base only, using CMBASECD and CMBASE. [OR In the summary of concomitant 
medications, the ingredients will be summarized by the combination of base and salts, 
using CMCOMPCD and CMCOMP.]  
Blood products or blood supportive care products with onset date within the on-therapy 
window will be included in the summary tables. The frequency and percentage of 
subjects using blood products and blood supportive care products after the start of study 
medication will be provided.  Supporting listings will also be provided.
Follow-up anti-cancer therapy will be listed.
11.
PHOSPHORYLATION OF ERK ENDPOINT ANALYSIS
The primary objective of this trial is to evaluate the percentage reduction of p-ERK score 
from baseline and characterize safety and efficacy of different treatment sequence with 
the p-ERK score changes. The primary end point will be analyzed with a descriptive 
intent only. Hence no hypothesis testing will be performed.  The Biomarker Population 
will be used for the reporting and the analysis of the primary endpoint, and all members 
of the biomarker population will have a positive BRAF V600E/K mutation.
We also will conduct an exploratory sensitivity analysis among all subjects with BRAF 
V600E mutation based on central lab testing for primary P-ERK Biomarker Analyses 
listed in Section 11.2.1.  A summary will be created that lists the samples obtained for 
Immuohistochemistry Analysis.  The lists of displays for P-ERK, including population to 
use for each display, are shown in Section 18.1.5 of the RAP.
11.1.
Interim Analysis
No formal interim analysis will be conducted in this study.


CONFIDENTIAL
BRF116613
32
11.2.
Investigator Assessment of H-Score
The primary endpoint analysis will be the evaluation of the percentage change of the 
mean Phosphorylated Extracellular Signal-regulated Kinase (p-ERK) H-Score from 
baseline.  At the beginning of IP treatment, the p-ERK H-Score will be determined for all 
participants in the biomarker population.  
Change in biomarker status is most prominent within two weeks of start of treatment. 
Patients from arm A and arm B will be given combination therapy starting from week 9 
after completion of 8 weeks of monotherapy. Therefore, changes in biomarker between 
screening and week 2 as well as between week 8 and week 10 will be summarized and 
listed.  All visits for biomarker samples have a window of ± 7 days.
More specifically, the procedure for calculating the p-ERK score is shown below:

Intra-tumoral expression levels of ERK, a tumor tissue biomarker, will be 
measured using immunohistochemistry methods that incorporated both intensity 
and distribution of staining. A value designated the H-Score will be derived by 
summing the percentages of cells staining at each intensity multiplied by the 
weighted intensity of staining (0, 1+, 2+, 3+: 3+ indicates the strongest staining, 
2+ indicates medium staining, 1+ indicates weak staining, and 0 indicates no 
staining).  H-Scores range from a minimum score of 0 to a maximum score of 
300; the maximum score indicates the strongest expression.   We will also collect 
a summary staining score for the tumor tissue which has potential values of 0 (no 
staining), 1+ (weak staining), 2+ (medium staining), and 3+ (strong staining). 
All p-ERK H-Score data will be recorded on the eCRF, including data on % positivity for 
all participants in the biomarker population, which is calculated using the equation 
below:   
Summary statistics, graphics, and statistical modeling will be conducted on the biomarker 
population for each arm of the study.
11.2.1.
Primary p-ERK Biomarker Analyses:
Analyses from this section will utilize p-ERK H-scores from pre-dose, 2-week, 8-week, 
and 10-week biopsies. Summary statistics (mean, standard deviation, median, minimum, 
and maximum) will be reported at each time point and for change (actual and percent 


CONFIDENTIAL
BRF116613
33
changes) from baseline to two weeks in Arm C and for change from 8-week and 10-week 
in Arms A and B for p-ERK using H-score values.
Depending upon data availability, log2-transformed values of p-ERK H-Score results will 
be analyzed by analysis of variance (ANOVA) for each cohort.  In some cases, it is 
possible for p-ERK H-Scores to have a value of zero, and if these zero H-Scores are 
present in the data, we will add an offset of one to all values before conducting any log2-
transformations.  This analysis will consider time and treatment as the fixed effect, and 
subject as a random effect. The H-Score calculation at either screening (analysis for 
combo arm) or week 8 (analysis from monotherapy arms) is the test comparison and the 
H-Score calculation at either week 2 (analysis for combo arm) or week 10 (analysis from 
monotherapy arms) is the reference calculation. The analysis will be performed using the 
mixed linear models procedure within the SAS/STAT module of the SAS system. Point 
and (1-2α*) interval estimates of the difference in least-square (LS) means of the test less 
the reference treatment will be derived using SAS code such as that described below:
proc mixed;
class trt time subject;
model HScore = time trt;
random subject;
lsmeans trt;
estimate ‘B vs. A’ trt -1 1 / cl alpha=0.05
run;
(In this code, trt, HScore, and time refer to treatment given, H-Score Value, and the time 
of H-Score analysis, respectively).
For each primary endpoint, results from these analyses will be exponentiated to obtain 
point and 90% confidence interval estimates of the appropriate test to reference ratios of 
geometric least-squares (GLS) means.
Assumptions underlying these analyses will be assessed. If the assumptions are seriously 
violated, then nonparametric methods will be considered.
The mean and median Intra-tumoral expression levels of ERK over time will be plotted, 
with treatment highlighted using appropriate graphical techniques (e.g. trellis, plotting 
symbol, and colour). 
For further exploratory purposes and if data warrant, multivariate proportional Cox 
models examining the relationships between PFS and DoR and decreases in H-Score 
from none or mono therapy to combo therapy may be examined with age, sex, ECOG 
status, initial drug exposure (combo therapy vs. monotherapy), and BRAF mutation type
(V600E vs. V600K) as potential covariates using backward selection.  If multivariate 
proportional Cox models are developed, a listing containing the values for each variable 
as part of the Cox model will be created.


CONFIDENTIAL
BRF116613
34
11.2.2.
Exploratory Predictive p-ERK Analyses
The objective of the statistical analysis outlined in this section is to characterize potential 
of p-ERK to be a predictive biomarker assessed from tumor tissue and biological 
response as measured by changes in tumor volume. 
11.2.2.1.
Change from baseline
Depending upon data availability, exploratory analyses may be performed to examine 
potential relationships between decrease from baseline H-score from tumor biopsies, and 
tumor response. 
Tumor response will be quantified using change from baseline of tumor measurements 
(% change sum of lesion diameters [SLD]).  Percent change from baseline for 
sum of 
lesion diameters is set to missing if any target lesions at baseline are missing or not 
measured at post baseline observation.  Correlation between decrease in H-score and 
%SLD will be evaluated using Spearman’s correlation coefficient. A scatter plot will be 
created for each treatment arm.
Summaries of the relationship between change in H-score and CR/PR/ Stable Disease 
(SD)/ Progressive Disease (PD) (without confirmation) will be assessed if data permit 
(i.e. if there are enough subjects with CR, PR etc.). 
11.2.2.2.
Baseline
Depending upon data availability, exploratory analyses may be performed to examine 
potential relationships between baseline of H-score from tumor biopsies, and tumor 
response. 
Tumor response will be quantified using change from baseline of tumor measurements 
(%SLD). Correlation matrices of baseline p-ERK H-Score and %SLD will be reported
(Spearman’s R, N, and p-value). A scatter plot will be created for each treatment arm.
Summaries of the relationship between baseline H-score and CR/PR/SD/PD (without 
confirmation) will be assessed if data permit (i.e. if there are enough subjects with CR, 
PR etc.). 
12.
SAFETY ANALYSES
Safety data will be summarized and listed by, or under the direct auspices of, the 
Discovery Biometrics Programmer and reviewed by the Discovery Biometrics 
Statistician, GlaxoSmithKline.  Select safety data will be presented graphically.
Unless otherwise specified, all the safety analyses will be based on the Safety population 
as defined in Section 6 and summaries will include all events or assessments collected 
during the study. All the analyses will be performed by treatment arm. 
The lists of displays for safety analyses, including population to use for each display, are
shown in Section 18.1.3 of the RAP.   


CONFIDENTIAL
BRF116613
35
12.1.
Extent of Exposure
Extent of exposure to dabrafenib and trametinib will be summarized separately.
The duration of exposure to study treatment in weeks (from first day to last day of 
treatment) will be summarised. Descriptive statistics including mean, median, standard 
deviation, minimum, and maximum will be calculated for time on study treatment. 
Moreover, time on study treatment will be categorized in different time period:  < 2 
months, 2 months to 4 months, >4 months to 8 months and >8 months. 
The subject daily dose, defined as the cumulative dose divided by the duration of 
exposure for each subject, will be summarized. In addition, summary of the population 
level daily dose will also be provided. In this analysis, a dose on each day for each 
subject will be treated as an observation and the summary will be based on the dose on 
each individual day for all subjects.
Example of population level daily dose:

Take 2 Subjects
o
Subject 1 dose dates:

150 mg BID 01JAN2014-10JAN2014 

150 mg BID 13JAN2014-22JAN2014
o
Subject 2 dose dates:

150 mg BID 01JAN2014-10JAN2014

100 mg BID 11JAN2014-20JAN2014
o
Population level daily dose  (See equation below):
Dose reductions will be summarised by number of reductions and reasons for reductions.  
Dose escalations will be summarised by number of escalations and reasons for escalation.  
Dose interruptions will be summarised by number of interruptions, reasons for the 
interruptions, and interruption duration (days).  The mean, standard deviation, median, 
minimum value, and maximum value will be computed for the duration of interruptions 
as well as the number and percentage of the interruptions ≤ 7, 8 -14, 15 - 21 and >21 
days. The summaries of dose modifications will be provided only if the data warrant.
All the dose reductions, dose escalations and dose interruptions will be listed separately.
The cumulative exposure plot will be provided showing the proportion of subjects on 
treatment over time.


CONFIDENTIAL
BRF116613
36
12.2.
Adverse Events
An overview summary of AEs, including counts and percentages of subjects with any 
AE, AEs related to study treatment, AEs leading to permanent discontinuation of study 
treatment, AE leading to dose reductions, AEs leading to dose interruptions, SAEs, SAEs 
related to study treatment, fatal SAEs, and fatal SAEs related to study treatment will be 
produced.
A summary of non-serious AEs that occurred in strictly 5% of the subjects or above will 
be provided (no rounding for the percentage will be used in terms of 5% threshold, e.g. 
event with 4.9% incidence rate should not be included in this table). The summary will be 
displayed by System Organ Class (SOC) and Preferred Term (PT).  Another summary 
will be created that highlights the number of subjects with Non-Serious AE, total number 
of exposed subjects, and  number of non-serious AEs for any European submissions.
The relationship between Medical Dictionary for Regulatory Affairs (MedDRA) SOC, 
PT, and Verbatim Text will be displayed.
Adverse events (AEs) will be graded according to the CTCAE, Version 4.0. Adverse 
events will be coded to the preferred term (PT) level using the MedDRA dictionary. 
A summary of number and percentage of subjects with any adverse events by maximum 
grade will be produced. AEs will be sorted by Preferred term (PT) in descending order of 
total incidence first and then by each treatment arm. The summary will use the following 
algorithms for counting the subject:

Preferred term row: Subjects experiencing the same AE preferred term several 
times with different grades will only be counted once with the maximum grade.

Any event row: Each subject with at least one adverse event will be counted only 
once at the maximum grade no matter how many events they have.
In addition, the frequency and percentage of AEs (all grades) will be summarized and 
displayed in two ways: 1) in descending order of total incidence first and then by each
treatment arm by PT only and 2) in descending order of total incidence first and then by 
each treatment arm by System Organ Classes (SOC) and PT. In the SOC row, the number 
of subjects with multiple events under the same system organ class will be counted once.  
A separate summary will be provided for study treatment-related AEs.  A study 
treatment-related AE is defined as an AE for which the investigator classifies the 
relationship to study treatment as “Yes”.  A worst case scenario approach will be taken to 
handle missing relatedness data, i.e. the summary table will include events with the 
relationship to study treatment as ‘Yes’ or missing. The summary table will be displayed 
in descending order of total incidence first and then by each treatment arm by PT only.


CONFIDENTIAL
BRF116613
37
12.3.
Adverse Events of Special Interest
A comprehensive list of MedDRA terms based on clinical review will be used to identify 
each adverse event of special interest. Change to the MedDRA dictionary may occur 
between the start of the study and the time of reporting and/or emerging data from on-
going studies may highlight additional adverse events of special interest, therefore the list 
of MedDRA terms to be used for each event of interest and the specific adverse events of 
interest will be based on the safety review team agreement at the time of reporting.  The 
list of MedDRA terms for each adverse event of special interest will be provided.
For subjects receiving dabrafenib monotherapy, the adverse events of special interest 
include but not be limited to the following:

Cutaneous squamous cell carcinoma (cuSCC) including keratoacanthoma (KA), 

Pyrexia events

Treatment-emergent malignancies (excluding cuSCC/KA, and cancer under 
study)

Renal failure/acute renal failure events

Uveitis 

Hypersensitivity events

Pancreatitis events

Hyperglycemia events
For subjects receiving trametinib monotherapy, the adverse events of special interest 
include but not be limited to the following:

Skin-related toxicities (including rash)

Diarrhoea

Left Ventricular dysfunction  (including ejection fraction decreasing)

Ocular Events

Pneumonitis

Hepatic disorders

Hypertension

Oedema

Hypersensitivity

Bleeding events
For subjects receiving dabrafenib and trametinib in either the combination arm of after 8 
weeks of monotheraoy, the adverse events of special interest include but not be limited to 
the following:


CONFIDENTIAL
BRF116613
38

Cutaneous squamous cell carcinoma (cuSCC) including keratoacanthoma (KA), 

Pyrexia events

Treatment-emergent malignancies (excluding cuSCC/KA, and  cancer under 
study)

Renal failure/acute renal failure events

Uveitis 

Hypersensitivity events

Pancreatitis events

Hyperglycaemia events

Skin-related events (exclude SCC, KA)

Diarrhoea 

Cardiac-related events

Ocular events

Pneumonitis events

Hepatic events

Oedema events

Hemorrhages events

Hypertension 

Neutropenia events

Pulmonary embolism events
All AEs of special interest will be summarized by categories of AE of special interest, 
preferred term and maximum toxicity grade in one table per treatment regimen 
(dabrafenib monotherapy, trametinib monotherapy, and dabrafenib plus trametinib 
combotherapy).  AEs of special interest will be sorted by categories and then by preferred 
term in descending order based on incidence. 
The following displays will be provided for selected AEs of special interest occur in > 5
subjects per treatment regimen: 

Summary of characteristics of AE of special interest, which will summarize 
event characteristics (serious, study treatment-related, fatal), number of 
occurrences, number of subjects, maximum toxicity, outcome, and action 
taken. The worst case approach will be applied at subject level for the event 
outcome and maximum grade, i.e. a subject will only be counted once as the 
worst case from all the events experienced by the subject. For action taken to 
a event, subject will be counted once under each action, e.g. if a subject has a 
event leading to both study treatment discontinuation and dose reduction, the 


CONFIDENTIAL
BRF116613
39
subject will be counted once for study treatment discontinuation and dose 
reduction, respectively.  

Summary of onset and duration. Time to onset (days) and duration of first 
occurrence (days) will be summarized. In addition to descriptive statistics 
(mean, median, min, max), time to onset will be summarized in categories of  
0-2 weeks, >2-4 weeks, >4-8 weeks, >8-12 weeks, >12-18weeks, >18-24 
weeks, and >24 weeks, and duration of first occurrence will be summarized in 
categories of 1-5 days, 6-10days, >10 days.   

Cumulative incidence plot.
Listing will be provided which profiles all categories of AEs of special interest per 
treatment regimens.  Other AEs of special interest may be added later. Depending on the 
number of events, summary and/or listing may be provided appropriately.
12.4.
Deaths and Serious Adverse Events
In the event that a subject has withdrawn consent, no data after the withdrawal of consent 
date from this subject including death is supposed to appear in the database, which should 
be part of the data cleaning process.  All deaths occurring any time from the time of 
informed consent to the clinical cut-off date will be summarised based on the number and 
percentage of subjects. This summary will classify subjects by time of death relative to 
the last dose of medication (> 30 days or 30 days) and primary cause of death (disease 
under study, SAE related to study treatment, or other). A supportive listing will be 
generated to provide subject-specific details on subjects who died. 
All SAEs will be tabulated based on the number and percentage of subjects who 
experienced the event.  Separate summaries will also be provided for study treatment-
related SAEs and fatal SAEs. The summary tables will be displayed in descending order 
of total incidence first and then by each treatment arm for each PT term.
A study treatment-related SAE is defined as an SAE for which the investigator classifies 
the relationship to study treatment as “Yes”.  A worst case scenario approach will be 
taken to handle missing data, i.e. the summary table will include events with the 
relationship to study treatment as ‘Yes’ or missing.  
SAEs are included in the listing of all adverse events. Separate supportive listings with 
subject-level details will be generated for:

Fatal SAEs 

Non-Fatal SAEs.

Another summary will be included which summarizes the number of subjects 
with serious AE, total number of exposed subjects, number of serious AEs, 
number of drug-related serious AEs, number of fatal serious AEs, and number of 
drug-related fatal serious AEs, for any European submissions.


CONFIDENTIAL
BRF116613
40
12.5.
Adverse Events Leading to Discontinuation of Study 
Treatment and/or Withdrawal from the Study and Other 
Significant Adverse Events
The following categories of AEs will be summarized separately in descending order of 
total incidence first and then by each treatment arm for each PT term, and separate 
supportive listings will be generated with subject level details for those subjects:

AEs Leading to Discontinuation of Study Treatment 

AEs leading to Withdrawal from the Study

AEs Leading to Dose Interruptions

AEs Leading to Dose Reductions
12.6.
Pregnancies
While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication or elective termination of a pregnancy for medical reasons will be recorded 
as an AE or SAE as described in the protocol. If subjects and subjects’ spouse become 
pregnant while on the study, the information will be included in the SAE narratives and 
no separate table or listing will be produced.
12.7.
Clinical Laboratory Evaluations
The assessment of laboratory toxicities will examine the following laboratory tests: 
Hematology: Hemoglobin (HGB), White Blood Cell (WBC) count, and Platelet count. 
Automated WBC differential (expressed as absolute count) for basophils, eosinophilis, 
lymphocytes, monocytes, and total neutrophilis.
Clinical Chemistry: Sodium, Potassium, Calcium, Albumin, Total Protein, Blood Urea 
Nitrogen (BUN), Creatinine, Estimated Creatinine Clearance, Lactate Dehydrogenase 
(LDH), Gamma-Glutamyl Transpeptidase (GCT), phosphate, and C-Reactive Protein 
(CRP). BUN, LDH, CRP, Total Protein, and Estimated Creatinine Clearance are not 
gradable by CTCAE v4.0. For Sodium, Potassium, and Calcium, two bi-directional 
parameters (hyper and hypo), the tests will be graded by CTCAE v4.0 in both directions.
Liver Function Tests: Aspartateaminotransferase (AST) or Serum Glutamic Oxaloacetic 
Transaminase (SGOT), Alanine aminotransferase (ALT) or Serum Glutamic Pyruvic 
Transaminase (SGPT), Alkaline phosphatase, Total bilirubin (total) and Direct bilirubin
(only recorded when Total bilirubin ≥ 2*ULN). All these tests are gradable by CTCAE 
v4.0.
Coagulation Tests: Prothrombin time (PrT), International Normalized Ratio (INR), and 
Activated Partial thromboplastin time (aPTT).  All tests at screening only.
Laboratory grades will be reported using the Common Terminology Criteria for Adverse 
Events (CTCAE v4.0).


CONFIDENTIAL
BRF116613
41
Summary of lab values and change from baseline by scheduled visits using mean, 
median, standard deviation, minimum and maximum will be provided.
Summaries of lab data by maximum toxicity grade will be provided.
Coagulation tests are only collected at baseline.  Therefore this/these test(s) will not 
appear in any summaries of changes from baseline.
Summaries of worst case grade increase from baseline grade will be provided for all the 
lab tests that are gradable by CTCAE v4.0. These summaries will display the number and 
percentage of subjects with a maximum post baseline grade increasing from their baseline 
grade. Any increase in grade from baseline will be summarized along with any increase 
to a maximum grade of 3 and any increase to a maximum grade of 4.  Missing baseline 
grade will be assumed as grade 0. In addition, the summary will include grade increase 
from baseline by scheduled visits. For laboratory tests that are graded for both low and 
high values, summaries will be done separately and labeled by direction, e.g. sodium will 
be summarized as hyponatremia and hypernatremia.
For lab tests that are not gradable by CTCAE v4.0, summaries of worst case changes 
from baseline with respect to normal range will be generated. Decreases to low, changes 
to normal or no changes from baseline, and increases to high will be summarized at each 
scheduled visit as well as for the worst case post baseline.  If a subject has a decrease to 
low and an increase to high during the same time interval, then the subject is counted in 
both the “Decrease to Low” categories and the “Increase to High” categories.   In 
addition, the summary will include worst case changes from baseline with respect to 
normal range by scheduled visits.
Separate summary tables for hematology, chemistry, liver function, and coagulation, 
laboratory tests will be produced.
Detailed derivation of baseline assessment is specified in Section 9.2.
Unless otherwise specified, the denominator in percentage calculation at each scheduled 
visit will be based on the number of subjects with non-missing value at each particular 
visit.
12.7.1.
Analyses of Liver Function Tests
Summaries of hepatobiliary laboratory events including possible Hy’s law cases will be 
provided in addition to what has been described above.   
Possible Hy’s law cases are defined as any elevated ALT>3 × Upper Limit Normal 
(ULN), total bilirubin≥2×ULN and ALP<3×ULN/missing. Total bilirubin≥2×ULN can 
be within 28 days following the ALT elevation and if direct bilirubin is available on the 
same day, it must be ≥35% of total bilirubin. ALP<3xULN/missing means the criteria is 
satisfied unless the ALP is >=3xULN at any time of bilirubin elevation within the 28 
days window.


CONFIDENTIAL
BRF116613
42
If data warrant, a summary of liver re-challenges, adaptations and recovery will be 
provided.
12.8.
Other Safety Measures
Vital Signs
Values of vital signs as well as the change from baseline will be summarized by 
scheduled visit using mean, median, standard deviation, minimum and maximum.  
In addition vital signs or blood pressure values will be categorized as follows:

Systolic Blood Pressure (BP) (mmHg): Grade 0 (<120), Grade 1 (≥120-<140), 
Grade 2 (≥140-<160) and Grade 3 (≥160)

Diastolic BP (mmHg): Grade 0 (<80), Grade 1 (≥80-<90), Grade 2 (≥90-<100), 
and Grade 3 (≥100)

Heart rate: <60, 60-100, and >100

Temperature: <35, 35-38, ≥38
Summaries of increase in vital signs or blood pressure from the baseline with respect to 
the categories defined above will be performed.  These summaries will display the 
number and percentage of subjects with any grade increase, increase to grade 2 and 
increase to grade 3 in the worst case post baseline only.  
Performance Status
ECOG performance status will be summarized at baseline and each post baseline 
scheduled visit.  Summaries will use frequency and percentage of subjects at each 
planned assessment time.  A summary of change from baseline by scheduled visits will 
be performed, as well as the worst case post-baseline and the best case post-baseline 
changes during the study (improved, no change, deteriorated). 
A supporting listing will also be provided.  
ECG
A summary of the number and percentage of subjects who had normal and abnormal 
(clinically significant and not clinically significant) ECG findings will be displayed by 
scheduled visits as well as for the worst case post baseline. 
The QTc values based on Bazett formula will be rounded to the integer and the values 
will be categorized into the following ranges: Grade 0 (<450), Grade 1 (450-480), Grade 
2 (481-500), and Grade 3 (≥501).  Summaries of grade increase will be provided.  These 
summaries will display the number and percentage of subjects with any grade increase, 
increase to grade 2 and increase to grade 3 in the worst case post baseline only. 


CONFIDENTIAL
BRF116613
43
The changes in QTc values will be categorized into the clinical concern ranges which are 
specific to changes in QTc: 31-60 and > 60 msec.  A summary of change in QTc value 
will display the number and percentage of subjects with a change within each range in the 
worst case post baseline only. Subjects with missing baseline values will be excluded 
from this summary.
The summaries for the QTc will use the calculated value based on Bazett formula.
Listings of abnormal ECG findings and a listing of ECG values will be provided.
LVEF
Absolute change from baseline in LVEF will be summarized in the worst case post 
baseline only. Only the post baseline assessments that used the same method (ECHO or 
MUGA) as the baseline assessments will be used to derive the change from baseline. The 
change from baseline will be categorized as follows:

Any increase

No change

Any decrease
o
0 - < 10% Decrease
o
10 - <20% Decrease
o
≥20% Decrease

≥10% decrease and ≥Lower limit of normal (LLN)

≥10% decrease and <LLN

≥20% decrease and ≥LLN

≥20% decrease and <LLN
LVEF results will also be listed with subject level details including absolute change from 
baseline.
Liver Events 
For any liver events that occur during the study, the liver event information for Roussel 
Uclaf Causality Assessment Method (RUCAM) score will be summarized, including 
whether the subject was age 55 or over, whether the subject became pregnant, liver 
imaging normal or not, a biopsy was taken or not, whether there was fasting or significant 
dietary change, whether the subject took any unconventional medications, timing when 
the event occurs (while on treatment or after stopping treatment) and summary statistics 
for time from first dose to start of liver event and time from last dose to start of liver 
event. If the number of events does not support a summary, then only listings will be 
produced.


CONFIDENTIAL
BRF116613
44
For subjects with multiple events, the first event will be used for the summary tables. All 
events with subject level details will be displayed in a supporting listing.
Ocular Exams
Baseline data will be summarized based on the number and percentage of subjects who 
receive an ocular exam.  As post baseline exams are only performed as clinically 
indicated data beyond baseline will only be listed.  
13.
EFFICACY
All efficacy analyses will be based on the ITT population as defined in Section 6 unless 
otherwise specified. All analyses will be presented by treatment arm. 
Efficacy assessments are based on RECIST 1.1, criteria to assess clinical activity and 
disease status.  Primary assessments will be based on imaging data and clinical 
assessments.  Investigator assessments will be considered as primary assessments.  
Confirmation of response (i.e., CR and PR) is not necessary per RECIST, version 1.1, as
the primary endpoint of the study is not overall best response.  The lists of displays for 
efficacy, including population to use for each display, are shown in Section 18.1.2 of the 
RAP. 
13.1.
Primary Efficacy Analyses
No primary efficacy analyses will be conducted in this study.
13.2.
Secondary Efficacy Analyses
The primary efficacy endpoint, tumor response including ORR will be reported 
separately for each treatment arm.  In addition a pooled ORR across all treatment arms 
will also be reported. 
Anti-tumor activity will be evaluated based on RECIST 1.1 criteria for solid tumors
[Eisenhauer,2009]. Since the primary endpoint of the study is not overall best response, 
we will generate displays for response irrespective of confirmation status.
The overall response rate (ORR) is defined as the percentage of subjects with a confirmed 
or unconfirmed complete or partial response by investigator assessment at any time as per 
RECIST 1.1 criteria.  Subjects with unknown or missing response will be treated as non-
responders, i.e. they will be included in the denominator when calculating the percentage.  
An exact 95% confidence interval (Clopper-Pearson) will be computed for this estimate.
All data relating to response from the Investigator will be listed including lesion 
measurements, response assessments and best response.
Waterfall plots of Investigator Assessed Percent Change from Baseline in Tumor 
Measurement at Time of Best Response will be provided with indications of subject 


CONFIDENTIAL
BRF116613
45
number below the plot. Waterfall plots will be created for each treatment arm in the 
study.
13.3.
Exploratory Efficacy Analyses
Provided that there are sufficient numbers of events at time of final analysis, we will 
examine Progression-free survival and duration of response as secondary efficacy 
endpoints.
13.3.1.
Progression-Free Survival
Progression-Free survival (PFS) is defined as the interval of time (in months) between the 
date of randomization and the earlier of the date of disease progression and the date of 
death due to any cause.  Disease progression will be based on the assessments by the 
Investigator. 
The date of documented disease progression will be defined as the date of disease 
progression based on either radiographic or clinical data. The date of death should be 
taken from the Record of Death page.  Death on study due to any cause will be included.
If there is no adequate baseline assessment, the subject will be censored at their date of 
randomization. Subjects without any adequate post baseline tumor assessments will be 
censored at the date of randomization.
Subjects who progressed or died after an extended period without adequate assessment 
will be censored at their date of last adequate assessment prior to progression or death 
even if subsequent information is available regarding progression or death.  An adequate 
assessment is defined as an assessment where the Investigator determined response is 
CR, PR, or SD.  The date of response at that assessment will be used for censoring. 
For subjects who receive subsequent anti-cancer therapy the following rules will apply:

If anti-cancer therapy is started without documented disease progression or is 
started prior to documented disease progression, then PFS will be censored at the 
date of the last adequate assessment that is no later than the date of initiation of anti-
cancer therapy (i.e. if an assessment occurs on the same day as the start of new anti-
cancer therapy the assessment will be used - as it will be assumed the assessment 
occurred prior to the administration of new anti-cancer therapy).  The date of 
response at the last adequate assessment will be used as the censoring value.

If a subject has only a baseline visit or does not have an adequate assessment that is 
no later than the date of initiation of anti-cancer therapy, PFS will be censored at the 
date of randomization.
If a subject has neither progressed nor died nor started new anti-cancer therapy, then PFS 
will be censored at the date of the last adequate assessment defined as an assessment 
where the Investigator determined response  is CR, PR, SD.  The date of response will be 
used as the censoring date.
A summary of the assignments for progression and censoring dates for PFS are specified 
in Table 2.


CONFIDENTIAL
BRF116613
46
Table 2
Assignments for Progression and Censoring Dates for PFS Analysis
Situation
Date of Progression or 
Censoring 
Outcome
No (or inadequate) baseline 
tumor assessments (or patients 
with no post-baseline 
assessments)
Randomization
Censored
Progression documented 
between scheduled visits
Date of assessment of 
progression1
Progressed
No progression (or death)
Date of last ‘adequate’ 
assessment of response2
Censored
New anticancer treatment started 
(prior to documented disease 
progression).3
Date of last ‘adequate’ 
assessment of response2 (on or 
prior to starting anti-cancer 
therapy) 
Censored
Death before first PD assessment 
Date of death
Progressed
Death between adequate 
assessment visits 
Date of death
Progressed
Death or progression after more 
than one missed visit
Date of last ‘adequate’ 
assessment of response2 (prior to 
missed assessments)
Censored
1 The earliest of (i) Date of radiological assessment showing new lesion (if progression is based on new 
lesion); or (ii) Date of radiological assessment showing unequivocal progression in non target lesions, or (iii) 
Date of last radiological assessment of measured lesions (if progression is based on increase in sum of 
measured lesions)
2 An adequate assessment is defined as an assessment where the Investigator determined response is CR, 
PR, or SD.
3 If PD and New anti-cancer therapy occur on the same day assume the progression was documented first 
e.g. outcome is progression and the date is the date of the assessment of progression).  If anti-cancer 
therapy is started prior to any adequate assessments, censoring date should be the date of randomization.
PFS will be summarized by cohort using Kaplan-Meier curves.  Median times to PFS, 1st
and 3rd quartiles along with 95% CI, if there are a sufficient number of progressions or 
deaths, will be estimated using the Brookmeyer-Crowley method [Brookmeyer,1982].  A 
figure and listing of progression-free survival time will also be provided for each 
expansion cohort.  
A supplementary table showing the details of the number at risk, number of events, and 
number censored with the event time will also be displayed for each expansion cohort.
13.3.2.
Duration of Response
Duration of response, defined as the time from first documented evidence of CR or PR 
until disease progression or death due to any cause among patients who achieve an 
overall response (i.e., unconfirmed or confirmed CR or PR) will be summarized.  
Censoring rules will follow those of the PFS analysis defined in Section 13.3.1.


CONFIDENTIAL
BRF116613
47
If sample size permits, the median duration of response will be calculated from the 
Kaplan-Meier estimates.  First and third quartiles will also be calculated along with 
associated 95% confidence intervals if there are a sufficient number of responders who 
subsequently progress or die due to any cause.  A figure and listing of duration of 
response will be provided. 
14.
PHARMACOKINETIC ANALYSES
The reconciliation of the PK Case Report Form (CRF) and SMS2000 data will be 
performed by, or under the direct auspices of, Data Sciences - Oncology, 
GlaxoSmithKline.
The merge of PK concentration data,  randomisation, and CRF data to generate a dataset 
with actual blood sampling times, actual time relative to dosing, and PK concentrations 
will be performed after DBF by, or under the direct auspices of, Oncology Quantitative 
Sciences (Programmer), GlaxoSmithKline. 
Unless otherwise stated, all tables, figures and listings in this section will be based on the 
Biomarker population as defined in Section 6, and all summaries, figures and data listings 
will use treatment labels as specified in Section 7.
The lists of displays for PK, including population to use for each display, are shown in 
Section 18.1.4 of the RAP.
14.1.
Drug Concentration Measures
Concentrations of GSK1120212 and GSK2118436 and its metabolites (GSK2284503, 
GSK2298683, and GSK2167542) will be listed and summarised by treatment group and 
nominal time. Standard summary statistics will be calculated (i.e. mean, standard 
deviation, median, minimum and maximum). Refer to the PK Guidance document 
GUI_51487 , “Non-Compartmental Analysis of Pharmacokinetic Data”, for more 
information regarding the handling of concentrations below the assay’s lower limit of 
quantification (NQ).
Individual concentration-time profiles and median/mean profiles by treatment group will 
be plotted using actual elapsed time for individual plots and nominal time for 
median/mean profiles. Each of the figures will contain one plot on the untransformed 
scale (i.e. a linear plot) and one plot on the log transformed scale (i.e. log-linear plot). See 
Pharmacokinetic Source Figures and Tables for details.
Any concentration data excluded from the derivation of PK parameters by Clinical 
Pharmacology Modelling and Simulation (CPMS) should be omitted from any figures 
and summaries, and flagged with an asterisk in the relevant data listings, with a footnote 
to indicate that these values have been omitted from subsequent analyses.  
14.2.
Population Pharmacokinetic Analyses
If data warrant, pharmacokinetic data will be analyzed using a population approach. A 
nonlinear mixed effects model will be used to determine population pharmacokinetic 


CONFIDENTIAL
BRF116613
48
parameters such as CL/F (apparent clearance following oral dosing) and other parameters 
as data permit and identify relevant covariates (e.g., age, weight, or disease related 
covariates) that explain variability. Concentration data will be pooled with data from 
other studies. Details on the population analysis will be the focus of a separate analysis 
plan and will be the responsibility of CPMS.
15.
PHARMACOKINETIC/PHARMACODYNAMIC ANALYSES
If data warrant, exploratory analyses will be performed to examine the relationship 
between plasma concentration of dabrafenib and/or trametinib and pharmacodynamic 
endpoints such as tumor size, biomarker changes and other clinical and safety measures.
Initially, the relationships will be explored graphically. If these exploratory graphical 
analyses suggest a relationship between pharmacodynamic endpoints and concentration
or pharmacokinetic parameters, PK/PD models may be derived and evaluated. Additional 
exploratory analyses may be performed to further characterize biomarkers.
Further details of PK/PD analyses will be described under a separate RAP. Results of the 
PK/PD analyses may be included in a report separate from the clinical study report.
16.
BIOMARKER ANALYSES
The results of translational research investigations not related to the H-Score of p-ERK 
will be reported separately from the main clinical study report. All endpoints of interest 
from all comparisons will be descriptively and/or graphically summarized as appropriate 
to the data. Further details on the translational research analyses will described under a 
separate RAP.


CONFIDENTIAL
BRF116613
49
17.
REFERENCES
GlaxoSmithKline Document Number 2012N132406_01.  Phase II biomarker study 
evaluating the upfront combination of BRAF inhibitor dabrafenib with MEK inhibitor 
trametinib versus the combination after eight weeks of monotherapy with dabrafenib or 
trametinib in patients with metastatic and unresectable stage III or IV melanoma 
harbouring an activating BRAF mutation.  Effective Date: 28-OCT-2013
Brookmeyer R, Crowley J. A confidence interval for the median survival time. 
Biometrics, 1982; 38:29-41.
Eisenhauer EA, Therasse P, Bogaerts J, et al.  New response evaluation criteria in solid 
tumours.  Revised RECIST guidelines (version 1.1).  Eur J Cancer. 2009; 45:228-247
GUI_51487 (4.0).  Non-Compartmental Analysis of Pharmacokinetic Data, CPMS 
Global.  Effective Date:  October, 28, 2014


CONFIDENTIAL
BRF116613
50
18.
ATTACHMENTS
18.1.
Table of Contents for Data Display Specifications
The following flexible system will be used to number the listings, tables and figures:

Study Population: 

tables, 1.xxxx

ICH-listings, 21.xxxx

Other-listings, 30.xxxx (30.0010 – 30.0110)

Efficacy: 

tables, 2.xxxx; 

figures, 12.xxxx;  

ICH-listings, 22.xxxx

Safety: 

tables, 3.xxxx; 

figures, 13.xxxx; 

ICH-listings, 23.xxxx

Other-listings, 30.xxxx (30.0240 – 30.0330)

Pharmacokinetic: 

tables, 4.xxxx; 

figures, 14.xxxx;  

ICH-listings, 24.xxxx

Biomarker: 

tables, 5.xxxx; 

figures, 15.xxxx

Listings, 25.xxxx 
Note: please specify which value will be used as baseline in the listing for lab, ECG, and 
vital sign. 
Listed below are the planned figures, tables and listings to be produced for inclusion in 
clinical study report


CONFIDENTIAL
BRF116613
51
18.1.1.
Study Population (Section 1)
18.1.1.1.
Tables
Table 
No.
Title
Population
Component / Therapeutic 
Area (hyperlinked to IDSL 
LN DB)
IDSL No. or 
Example 
Shell No.
Study-Specific  Display Notes
Deliverable 
Priority
1.0010
Summary of Study Populations
ITT
Subject 
Accountability/Oncology
POP1
Percentages for each cell are based on 'N' at 
the top of each column.
SAC
1.1010
Summary of Number of Subjects by 
Centre
ITT
Enrollment/Core
NS1
SAC
1.1110
Summary of Subject Disposition
ITT
Disposition/Core
ES8
SAC
1.1220
Summary of Study Treatment Status
ITT
Investigational Product 
Discontinuation/Core
SD4
Reasons for discontinuation will be presented 
in the order they are displayed on the eCRF.  
Only include 'Missing' rows where applicable.
SAC
1.1310
Summary of Inclusion/Exclusion 
Criteria Deviations
ITT
Inclusion & Exclusion 
Criteria/Core
IE1
SAC
1.1410
Summary of Protocol Deviations
ITT
Protocol Deviations/Core
DV1A
SAC
1.2010
Summary of Demographic 
Characteristics
ITT
Demography/Core
DM1
SAC
1.2011
Age Group Breakdown for the Trial
ITT
See Mock-Up.  Based on new EMA 
requirements.  Use combined data from all 
three arms.
SAC
1.2020
Summary of Race and Racial 
Combinations
ITT
Demography/Core
DM5
SAC
1.2110
Summary of Disease Burden at 
Baseline
ITT
Lesion Assessments/ 
Oncology
LA1
SAC
1.2120
Summary of Substance Use
ITT
Substance Use/Core
SU1
SAC
1.3110
Summary of Cancer Related Medical 
Conditions at Screening
ITT
Medical Conditions/Core
MH1
SAC
1.3112
Summary of Non-Cancer-Related 
Medical Conditions at Screening
ITT
Medical Conditions/Core
MH1
SAC


CONFIDENTIAL
BRF116613
52
Table 
No.
Title
Population
Component / Therapeutic 
Area (hyperlinked to IDSL 
LN DB)
IDSL No. or 
Example 
Shell No.
Study-Specific  Display Notes
Deliverable 
Priority
1.3210
Summary of Disease Characteristics 
at Initial Diagnosis
ITT
Disease 
Characteristics/Oncology
DC1
Sections include:  Time since initial diagnosis 
(weeks), and  Primary Tumour Type
SAC
1.3220
Summary of Disease Characteristics 
at Screening
ITT
Disease 
Characteristics/Oncology
DC2
Sections include:  Measurable disease at 
baseline, Presence of non-target lesions at 
baseline, and Stage
SAC
1.3230
Summary of Metastatic Disease at 
Screening
ITT
Metastatic 
Disease/Oncology
MD1
SAC
1.4010
Summary of Prior Anti-Cancer 
Therapy
ITT
Anti-Cancer 
Therapy/Oncology
AC2
SAC
1.4020
Summary of Prior Dictionary Coded 
Anti-Cancer Therapy
ITT
Concomitant 
Medication/Core
CM1
SAC
1.4030
Summary of Number of Prior Anti-
Cancer Therapy Regimens
ITT
Anti-Cancer Therapy/ 
Oncology
AC3
Therapies should be sorted in highest to 
lowest incidence.  Total column is required.
SAC
1.4040
Summary of Best Response to Most 
Recent Prior Anti-Cancer Therapy
ITT
Anti-Cancer Therapy/ 
Oncology
AC4
SAC
1.4110
Summary of Prior Cancer-Related 
Surgical Procedures
ITT
Surgical-Medical 
Procedures/Oncology
OSP1 
SAC
1.4110
Summary of Prior Non-Cancer 
Related Surgical Procedures
ITT
Surgical-Medical 
Procedures/Oncology
OSP1 
SAC
1.5010
Summary of Concomitant Medications 
by Ingredient
ITT
Concomitant 
Medications/Core
CM8
Medications will be sorted in descending 
order of total incidence across treatment 
groups for the ATC level 1 (CM1 only) and in 
descending order of total incidence of 
ingredient within ATC level (CM1) or overall 
(CM8).  In case of a tie, sort tied ingredients 
alphabetically.
SAC
1.5011
Summary of Blood or Blood 
Supportive Care Products while On-
Therapy
ITT
Concomitant 
Medications/Core
CM8
Medications will be sorted in descending 
order of total incidence across treatment 
groups for the ATC level 1 (CM1 only) and in 
descending order of total incidence of 
ingredient within ATC level (CM1) or overall 
(CM8).  In case of a tie, sort tied ingredients 
alphabetically.
SAC


CONFIDENTIAL
BRF116613
53
Table 
No.
Title
Population
Component / Therapeutic 
Area (hyperlinked to IDSL 
LN DB)
IDSL No. or 
Example 
Shell No.
Study-Specific  Display Notes
Deliverable 
Priority
1.6010
Summary of Overall Compliance 
Based on Exposure
ITT
Compliance
COMP1
SAC
18.1.1.2.
ICH Listings
Listing 
No.
Title
Population
Component / Therapeutic Area 
(hyperlinked to IDSL LN DB)
IDSL No. or 
Example Shell No.
Study-Specific  
Display Notes
Deliverable 
Priority
21.0010
Listing of Randomized [Planned] and 
Actual Treatments
ITT
Randomization Number/Core
TA1
SAC
21.0020
Listing of Subjects Excluded from 
Analysis Populations
ITT
Subject Accountability/Oncology
POP2
SAC
21.0030
Listing of Study Treatment 
Discontinuation Record
ITT
Investigational Product 
Discontinuation/Core
SD2
SAC
21.0040
Listing of Subjects with 
Inclusion/Exclusion Criteria Deviations
ITT
Inclusion & Exclusion Criteria/Core
IE3
SAC
21.0050
Listing of Protocol Deviations
ITT
Protocol Deviations/Core
DV2
SAC
21.0060
Listing of Demographic Characteristics
ITT
Demography/Core
DM2
SAC
21.0070
Listing of Race
ITT
Demography/Core
DM9
SAC
21.0800
Listing of Overall Compliance  
ITT
Compliance
COMP2
SAC
21.0090
Listing of Drug Accountability
ITT
Compliance
COMP3C
SAC
21.0091
Listing of Randomized and Actual 
Treatments 
ITT
Compliance
COMP2
SAC


CONFIDENTIAL
BRF116613
54
18.1.1.3.
Other Study Population Listings
Listing 
No.
Title
Population
Component / Therapeutic 
Area (hyperlinked to 
IDSL LN DB)
IDSL No. or 
Example 
Shell No.
Study-Specific Display Notes
Deliverable 
Priority
30.0010
Listing of Substance Use
ITT
Substance Use/Core
SU2
SAC
30.0020
Listing of Current Cancer Related 
Medical Conditions
ITT
Medical Conditions/Core
MH2
If conditions not coded, classification column 
will not be included on the listing.
SAC
30.0021
Listing of Past Cancer Related 
Medical Conditions
ITT
Medical Conditions/Core
MH2
If conditions not coded, classification column 
will not be included on the listing.
SAC
30.0022
Listing of Current Non-Cancer 
Related Medical Conditions
ITT
Medical Conditions/Core
MH2
If conditions not coded, classification column 
will not be included on the listing.
SAC
30.0023
Listing of  Past Non-Cancer Related 
Medical Conditions
ITT
Medical Conditions/Core
MH2
If conditions not coded, classification column 
will not be included on the listing.
SAC
30.0030
Listing of Disease Characteristics at 
Initial Diagnosis
ITT
Disease 
Characteristics/Oncology
DC3
Should include time since initial diagnosis in 
weeks, stage at initial diagnosis, and date of 
initial diagnosis
SAC
30.0040
Listing of Disease Characteristics at 
Screening
ITT
Disease 
Characteristics/Oncology
DC4
Sections include:  Measurable disease at 
baseline, Presence of non-target lesions at 
baseline, and Stage
SAC
30.0050
Listing of Metastatic Disease at 
Screening
ITT
Metastatic Disease/ 
Oncology
MD2
SAC
30.0060
Listing of Prior Anti-Cancer Therapy
ITT
Anti-Cancer 
Therapy/Oncology
AC6
SAC
30.0070
Listing of Prior Anti-Cancer 
Radiotherapy
ITT
Anti-Cancer Therapy/ 
Oncology
AC7
SAC
30.0080
Listing of Prior Cancer  Related 
Surgical Procedures
ITT
Surgical-Medical 
Procedures/Oncology
OSP3
SAC
30.0081
Listing of Prior Non-Cancer Related 
Surgical Procedures
ITT
Surgical-Medical 
Procedures/Oncology
OSP3
SAC
30.0090
Listing of Post Treatment Anti-Cancer 
Therapy
ITT
Follow-up/Oncology
FAC3
SAC


CONFIDENTIAL
BRF116613
55
Listing 
No.
Title
Population
Component / Therapeutic 
Area (hyperlinked to 
IDSL LN DB)
IDSL No. or 
Example 
Shell No.
Study-Specific Display Notes
Deliverable 
Priority
30.0100
Listing of Concomitant Medications
ITT
Concomitant 
Medications/Core
CM2
SAC
30.0101
Listing of Blood or Blood Supportive 
Care Products while On-Therapy
ITT
Concomitant 
Medications/Core
CM2
SAC
30.0110
Relationship between ATC Level 1, 
Ingredient, and Verbatim Text for 
Anti-Cancer Therapy
ITT
See Mock-
Up
Have Treatment information above columns.  
Column order is ATC Level 1, Ingredient, and 
Verbatim Text
SAC


CONFIDENTIAL
BRF116613
56
18.1.2.
Efficacy (Section 2)
18.1.2.1.
Tables
Table 
No.
Title
Population
Component / Therapeutic 
Area (hyperlinked to IDSL 
LN DB)
IDSL No. or 
Example 
Shell No.
Study-Specific  Display Notes
Deliverable 
Priority
2.0010
Summary of Investigator Assessed 
Progression-Free Survival
ITT
Time to Event/
Core Standards/
TTE1
Input dataset: ONCSURV (overall survival) or 
ONCTTE (PFS, Time to Response, etc.). If 
data warrant.
SAC
2.0011
Summary of Investigator Assessed 
Duration of Response
ITT
Time to Event/
Core Standards/
TTE1
Input dataset: ONCSURV (overall survival) or 
ONCTTE (PFS, Time to Response, etc.).  If 
data warrant
SAC
2.1010
Summary of Investigator Assessed 
Best Response with confirmation for 
Subjects with Measurable Disease at 
Baseline (RECIST 1.1 Criteria)
ITT
Response Displays/
Oncology Core/
RE1a
Input dataset:  RESP2 (investigator) or 
RESP2EX1 (independent reviewer)
SAC
2.1011
Summary of Investigator Assessed 
Best Response without confirmation 
for Subjects with Measurable 
Disease at Baseline (RECIST 1.1 
Criteria)
ITT
Response Displays/
Oncology Core/
RE1a
Input dataset:  RESP2 (investigator) or 
RESP2EX1 (independent reviewer)
SAC


CONFIDENTIAL
BRF116613
57
18.1.2.2.
Figures
Figure 
No.
Title
Population
Component / 
Therapeutic Area 
(hyperlinked to IDSL LN 
DB)
IDSL No. or 
Example 
Shell No.
Study-Specific Display Notes
Deliverable 
Priority
12.0010
Graph of Kaplan Meier Investigator Progression-
Free Survival Curves with 95% Confidence Band
ITT
Time to Event/
Core Standards/
TTE10
Input dataset: ONCSURV (overall 
survival) or ONCTTE (PFS, Time to 
Response, etc.).  If data warrant
SAC
12.0011
Graph of Kaplan Meier Investigator Duration of 
Response Curves with 95% Confidence Band
ITT
Time to Event/
Core Standards/
TTE10
Input dataset: ONCSURV (overall 
survival) or ONCTTE (PFS, Time to 
Response, etc.).  If data warrant
SAC
12.0020
Investigator Assessed Percent Change at Maximum 
Reduction from Baseline in Tumour Measurement 
for those with Dabrafenib monotherapy before 
combotherapy
ITT
Response Displays/
Oncology Core/
RE8a
Input dataset:  RESP2 (investigator) 
and RESP2EX1 (independent 
reviewer)
SAC
12.0021
Investigator Assessed Percent Change at Maximum 
Reduction from Baseline in Tumour Measurement 
for those with Trametinib monotherapy before 
combotherapy
ITT
Response Displays/
Oncology Core/
RE8a
Input dataset:  RESP2 (investigator) 
and RESP2EX1 (independent 
reviewer)
SAC
12.0022
Investigator Assessed Percent Change at Maximum 
Reduction from Baseline in Tumour Measurement 
for those assigned to combotherapy arm
ITT
Response Displays/
Oncology Core/
RE8a
Input dataset:  RESP2 (investigator) 
and RESP2EX1 (independent 
reviewer)
SAC


CONFIDENTIAL
BRF116613
58
18.1.2.3.
ICH Listings
Listing 
No.
Title
Population
Component / Therapeutic 
Area (hyperlinked to 
IDSL LN DB)
IDSL No. or 
Example 
Shell No.
Study-Specific Display Notes
Deliverable 
Priority
22.0010
Listing of Progression-Free Survival
ITT
Time to Event/
Core Standards/
TTE9
Input dataset: ONCSURV (overall survival) or 
ONCTTE (PFS, Time to Response, etc.)
SAC
22.0011
Listing of Duration of Response
ITT
Time to Event/
Core Standards/
TTE9
Input dataset: ONCSURV (overall survival) or 
ONCTTE (PFS, Time to Response, etc.)
SAC
22.0020
Listing of Investigator Assessed 
Target Lesion Assessments (RECIST 
1.1 Criteria)
ITT
Lesion Displays/
Oncology Core/
LA2
Input dataset: LESION (investigator) or 
LESIONEX1 (independent reviewer)
SAC
22.0030
Listing of Investigator Assessed Non 
Target Lesion Assessments (RECIST 
1.1 Criteria)
ITT
Lesion Displays/
Oncology Core/
LA3
Input dataset: LESION (investigator) or 
LESIONEX1 (independent reviewer)
SAC
22.0040
Listing of Investigator Assessed New 
Lesions (RECIST 1.1 Criteria)
ITT
Lesion Displays/
Oncology Core/
LA4
Input dataset: LESION (investigator) or 
LESIONEX1 (independent reviewer)
SAC
22.0050
Listing of Investigator Assessed 
Tumour Responses with confirmation 
(RECIST1.1 Criteria)
ITT
Response Displays/
Oncology Core/
RE5
Input dataset: RESP1 (investigator) or 
RESP1EX1 (independent reviewer)
SAC
22.0051
Listing of Investigator Assessed 
Tumour Responses without 
confirmation (RECIST1.1 Criteria)
ITT
Response Displays/
Oncology Core/
RE5
Input dataset: RESP1 (investigator) or 
RESP1EX1 (independent reviewer)
SAC


CONFIDENTIAL
BRF116613
59
18.1.3.
Safety (Section 3)
18.1.3.1.
Tables
Table 
No.
Title
Population
Component / Therapeutic
Area (hyperlinked to IDSL 
LN DB)
IDSL No. or 
Example Shell 
No.
Study-Specific  Display Notes
Deliverable 
Priority
3.0010
Summary of Exposure to Dabrafenib
Safety
Exposure Displays/
Oncology Core/
OEX1
SAC
3.0011
Summary of Exposure to Trametinib
Safety
Exposure Displays/
Oncology Core/
OEX1
SAC
3.0040
Summary of Dose Reductions
Safety
Dose Modifications 
Displays/
Oncology Core/
ODMOD1
SAC
3.0041
Summary of Dose Interruptions
Safety
Dose Modifications 
Displays/
Oncology Core/
ODMOD2
SAC
3.0044
Summary of Dose Escalations
Safety
Dose Modifications 
Displays/
Oncology Core/
ODMOD8
SAC
3.1010
Adverse Event Overview
Safety
Adverse Events Displays/
Core/
AE13
SAC
3.1020
Summary of All Adverse Events
Safety
Adverse Events Displays/ 
Core/ 
AE1
Displayed by SOC and PT, and sorted in 
descending order (for all patients).  Have 
4 columns (1 for each treatment arm + 
total).
SAC
3.1030
Summary of Frequent Adverse Events
Safety
Adverse Events Displays/ 
Core/ 
AE3
SAC
3.1040
Summary of Common Non-Serious Adverse 
Events
Safety
Adverse Events Displays/ 
Core/
AE1
SAC


CONFIDENTIAL
BRF116613
60
Table 
No.
Title
Population
Component / Therapeutic
Area (hyperlinked to IDSL 
LN DB)
IDSL No. or 
Example Shell 
No.
Study-Specific  Display Notes
Deliverable 
Priority
3.1041
Summary of Non-Serious Adverse Events by 
Preferred Term with Occurrences ≥ 5%
Safety
t_ae_non_ser.rtf
See Mock-Up/
SAC
3.1070
Summary of Adverse Events By Maximum 
Grade by Preferred Term
Safety
Adverse Events Displays/
Oncology Core/
OAE7
SAC
3.1071
Summary of Adverse Events By Maximum 
Grade by System Organ Class and Preferred 
Term
Safety
Adverse Events Displays/
Oncology Core/
OAE1
SAC
3.1110
Summary of Adverse Events Related to Study 
Treatment
Safety
Adverse Events Displays/
Core/
AE1
SAC
3.1120
Summary of Adverse Events Related to Study 
Treatment by Maximum Grade
Safety
Adverse Events Displays/
Oncology Core/ 
OAE7
SAC
3.1210
Summary of Serious Adverse Events by 
Preferred Term
Safety
Adverse Events Displays/ 
Core/
AE3
SAC
3.1211
Summary of Serious Adverse Events by 
Preferred Term by System Organ Class and 
Preferred Term
Safety
Adverse Events Displays/
Core/
AE1
SAC
3.1310
Summary of Serious Adverse Events Related 
to Study Treatment by Preferred Term
Safety
Adverse Events Displays/ 
Core/
AE3
SAC
3.1311
Summary of Serious Adverse Events Related 
to Study Treatment by System Organ Class 
and Preferred Term
Safety
Adverse Events Displays/
Core/
AE1
SAC
3.1600
Summary of All Adverse Events of Special 
Interest by Maximum Toxicity Grade and 
Preferred Term  for Dabrafenib Monotherapy
Safety
BRF113928 Comboin 
reporting effort, Table 
3.1711  
AESIs will be sorted by categories and 
then by preferred term in descending 
order
SAC
3.1601
Summary of Characteristics for Selected 
Adverse Events of Special Interest for 
Dabrafenib Monotherapy
Safety
Adverse Events of Special 
Interest Displays/ Core/
ESI1
SAC


CONFIDENTIAL
BRF116613
61
Table 
No.
Title
Population
Component / Therapeutic
Area (hyperlinked to IDSL 
LN DB)
IDSL No. or 
Example Shell 
No.
Study-Specific  Display Notes
Deliverable 
Priority
3.1611
Summary of Onset and Duration for  Selected 
Adverse Events of Special Interest for 
Dabrafenib Monotherapy
Safety
Adverse Events of Special 
Interest Displays/ Core/
ESI2A
SAC
3.1700
Summary of All Adverse Events of Special 
Interest by Maximum Toxicity Grade and 
Preferred Term  for Trametinib Monotherapy
Safety
BRF113928 Comboin 
reporting effort, Table 
3.1711
AESIs will be sorted by categories and 
then by preferred term in descending 
order
SAC
3.1701
Summary of Characteristics for Selected 
Adverse Events of Special Interest for 
Trametinib Monotherapy
Safety
Adverse Events of Special 
Interest Displays/ Core/
ESI1
SAC
3.1711
Summary of Onset and Duration for  Selected 
Adverse Events of Special Interest for 
Trametinib Monotherapy
Safety
Adverse Events of Special 
Interest Displays/ Core/
ESI2A
SAC
3.1800
Summary of All Adverse Events of Special 
Interest by Maximum Toxicity Grade and 
Preferred Term  for Combination Treatment
Safety
BRF113928 Comboin 
reporting effort, Table 
3.1711
AESIs will be sorted by categories and 
then by preferred term in descending 
order
SAC
3.1801
Summary of Characteristics for Selected 
Adverse Events of Special Interest for 
Combination Treatment
Safety
Adverse Events of Special 
Interest Displays/ Core/
ESI1
SAC
3.1811
Summary of Onset and Duration 
Characteristics for Selected Adverse Events 
of Special Interest for Combination Treatment
Safety
Adverse Events of Special 
Interest Displays/ Core/
ESI2A
SAC
3.2010
Summary of Deaths
Safety
Death Displays/
Oncology Core/
DTH1A
SAC
3.3010
Summary of Laboratory Values for 
Hematology Tests
Safety
Lab Displays/ Core/
LB1
SAC
3.3011
Summary of Laboratory Values for Clinical 
Chemistry Tests
Safety
Lab Displays/ Core/
LB1
SAC
3.3012
Summary of Laboratory Values for Liver 
Function Tests
Safety
Lab Displays/ Core/
LB1
SAC
3.3013
Summary of Laboratory Values for 
Coagulation Tests
Safety
Lab Displays/ Core/
LB1
SAC
3.3020
Summary of Laboratory Grade Changes from 
Baseline Grade for Hematology Tests
Safety
Lab Displays/
Oncology Core/ 
OLB9C
SAC


CONFIDENTIAL
BRF116613
62
Table 
No.
Title
Population
Component / Therapeutic
Area (hyperlinked to IDSL 
LN DB)
IDSL No. or 
Example Shell 
No.
Study-Specific  Display Notes
Deliverable 
Priority
3.3021
Summary of Laboratory Grade Changes from 
Baseline Grade for Clinical Chemistry Tests
Safety
Lab Displays/
Oncology Core/ 
OLB9C
SAC
3.3022
Summary of Laboratory Grade Changes from 
Baseline Grade for Liver Function Tests
Safety
Lab Displays/
Oncology Core/ 
OLB9C
SAC
3.3030
Summary of Laboratory Changes from 
Baseline With Respect to the Normal Range 
for Hematology Tests
Safety
Lab Displays/
Oncology Core/
OLB11C
SAC
3.3031
Summary of Laboratory Changes from 
Baseline With Respect to the Normal Range 
for Clinical Chemistry Tests
Safety
Lab Displays/
Oncology Core/
OLB11C
SAC
3.3060
Summary of Laboratory Results by Maximum 
Grade for Hematology Tests
Safety
Lab Displays/
Oncology Core/ 
OLB1
SAC
3.3061
Summary of Laboratory Results by Maximum 
Grade for Hematology Tests for Clinical 
Chemistry Tests
Safety
Lab Displays/
Oncology Core/ 
OLB1
SAC
3.3062
Summary of Laboratory Results by Maximum 
Grade for Hematology Tests for Liver 
Function Tests
Safety
Lab Displays/
Oncology Core/ 
OLB1
SAC
3.3063
Summary of Laboratory Results by Maximum 
Grade for Coagulation Tests
Safety
Lab Displays/
Oncology Core/ 
OLB1
SAC
3.4010
Summary of Vital Signs
Safety
Vital Sign Displays/ Core/
VS1
SAC
3.4020
Summary of Vital Sign Changes from 
Baseline
Safety
Vital Sign Displays/ Core/
VS1
SAC
3.4030
Summary of Changes in Heart Rate from 
Baseline
Safety
Vital Sign Displays/
Oncology Core/ 
OVT1C
SAC
3.4040
Summary of Increases in Blood Pressure 
from Baseline
Safety
Vital Sign Displays/
Oncology Core/ 
OVT2C
SAC
3.4050
Summary of Changes in Temperature from 
Baseline
Safety
Vital Sign Displays/
Oncology Core/ 
OVT1C
SAC
3.4060
Summary of Decreases in Systolic Blood 
Pressure from Baseline
Safety
Vital Sign Displays/
Oncology Core/
OVT2C
SAC


CONFIDENTIAL
BRF116613
63
Table 
No.
Title
Population
Component / Therapeutic
Area (hyperlinked to IDSL 
LN DB)
IDSL No. or 
Example Shell 
No.
Study-Specific  Display Notes
Deliverable 
Priority
3.4090
Summary of Left Ventricular Ejection Fraction 
Change from Baseline
Safety
LVEF (ECHO/MUGA) 
Displays/
Oncology Core/ 
OLVEF1B
SAC
3.4110
Summary of ECOG
Safety
Performance Status 
Displays/
Oncology Core/ 
PS1A
SAC
3.4120
Summary of Change in ECOG from Baseline
Safety
Performance Status 
Displays/
Oncology Core/ 
PS4A
SAC
3.6010
Summary of ECG findings
Safety
ECG Displays/ Core/ 
EG1
SAC
3.6030
Summary of Increases in QTc
Safety
QTc Displays/
Oncology Core/ 
OECG1C
SAC
3.6040
Summary of Amount of Increase from 
Baseline Value in QTc
Safety
QTc Displays/
Oncology Core/
OECG2C
SAC
3.8020
Summary of Hepatobiliary Laboratory 
Abnormalities
Safety
Liver Signal/Event 
Displays/
Oncology Core/ 
OLIVER1
SAC
3.8030
Summary of Liver Event Information for 
RUCAM Score
Safety
Liver Signal/Event 
Displays/
Oncology Core/ 
LIVER1
SAC
3.8040
Summary of Liver Re-Challenges, 
Adaptations, and Recovery
Safety
Liver Signal/Event 
Displays/
Oncology Core/
OLIVER4
If data warrant.  Added mock-up to 
Section 18.2.2.
SAC
3.8100
Summary of Baseline Ocular Exam
Safety
See Mockup
Have our three treatment arms as 
columns to the right of the ocular test 
result column
SAC
3.9900
Summary of Serious Adverse Events by 
Preferred Term Including Drug-Related 
Status and Fatal Status
Safety
t_ae_ser.ema.rtf
See Mockup
SAC


CONFIDENTIAL
BRF116613
64
18.1.3.2.
Figures
Figure 
No.
Title
Population
Component / Therapeutic Area 
(hyperlinked to IDSL LN DB)
IDSL No. or 
Example Shell No.
Study-Specific  
Display Notes
Deliverable 
Priority
13.0020
Plot of Cumulative Exposure to Dabrafenib
Safety
Exposure Displays/
Oncology Core/
OEX13B
SAC
13.0021
Plot of Cumulative Exposure to Trametinib
Safety
Exposure Displays/
Oncology Core/
OEX13B
SAC
13.0100
Cumulative Incidence for Selected Adverse Event 
of Special interest for Dabrafenib Monotherapy
Safety
Safety Events of Special Interest 
Statistical Display Standards
ESI9
SAC
13.0200
Cumulative Incidence for Selected Adverse Event 
of Special interest for Trametinib Monotherapy 
Safety
Safety Events of Special Interest 
Statistical Display Standards
ESI9
SAC
13.0300
Cumulative Incidence for Selected Adverse Event 
of Special interest for Combination Treatment 
Safety
Safety Events of Special Interest 
Statistical Display Standards
ESI9
SAC


CONFIDENTIAL
BRF116613
65
18.1.3.3.
ICH Listings
Listing 
No.
Title
Population
Component / Therapeutic 
Area (hyperlinked to 
IDSL LN DB)
IDSL No. or 
Example Shell 
No.
Study-Specific  Display Notes
Deliverable 
Priority
23.0020
Listing of Dose Reductions
Safety
Dose Modifications 
Displays/
Oncology Core
ODMOD10a
SAC
23.0030
Listing of Dose Interruptions
Safety
Dose Modifications 
Displays/
Oncology Core/
ODMOD11a
SAC
23.0080
Listing of Dose Escalations
Safety
Dose Modifications 
Displays/
Oncology Core/
ODMOD15a
SAC
23.0090
Listing of Relationship Between 
System Organ Class and Verbatim 
Text
Safety
Adverse Events Displays/
Core/
AE2
SAC
23.0110
Listing of All Adverse Events
Safety
Adverse Events Displays/
Oncology Core/
OAE4
SAC
23.0111
Listing of  Adverse Event Profiles for 
Dabrafenib Monotherapy
Safety
Adverse Events of Special 
Interest Displays/ Core/
ESI8
SAC
23.0112
Listing of  Adverse Event Profiles for 
Trametinib Monotherapy
Safety
Adverse Events of Special 
Interest Displays/ Core/ 
ESI8
SAC
23.0113
Listing of  Adverse Event Profiles for 
Combination Treatment
Safety
Adverse Events of Special 
Interest Displays/ Core/ 
ESI8
SAC
23.0120
Listing of Fatal Serious Adverse 
Events
Safety
Adverse Events Displays/
Oncology Core/
OAE4
SAC
23.0130
Listing of Non-Fatal Serious Adverse 
Events
Safety
Adverse Events Displays/
Oncology Core/ 
OAE4
SAC
23.0140
Listing of Adverse Events Leading to 
Permanent Discontinuation of Study 
Treatment
Safety
Adverse Events Displays/
Oncology Core/ 
OAE4
SAC


CONFIDENTIAL
BRF116613
66
Listing 
No.
Title
Population
Component / Therapeutic Area (hyperlinked 
to IDSL LN DB)
IDSL No. or 
Example Shell 
No.
Study-Specific  
Display Notes
Deliverable 
Priority
23.0150
Listing of Adverse Events Leading to 
Withdrawal from Study
Safety
Adverse Events Displays/
Oncology Core/
OAE4
SAC
23.0160
Listing of Adverse Events that Lead to 
Dose Interruptions
Safety
Adverse Events Displays/
Oncology Core/ 
OAE4
SAC
23.0211
Listing of Adverse Events that Lead to 
Dose Reductions
Safety
Adverse Events Displays/
Oncology Core/ 
OAE4
SAC
23.0250
Listing of Deaths
Safety
Death Displays/
Oncology Core/ 
DTH3
SAC
23.0290
Listing of ECOG
Safety
Performance Status Displays/
Oncology Core/ 
PS5A 
SAC


CONFIDENTIAL
BRF116613
67
18.1.3.4.
Other Study Population Listings
Listing 
No.
Title
Population
Component / Therapeutic 
Area (hyperlinked to 
IDSL LN DB)
IDSL No. or 
Example 
Shell No.
Study-Specific  Display Notes
Deliverable 
Priority
30.0240
Listing of Abnormal ECG Findings
Safety
ECG Displays/ Core/
EG5
SAC
30.0241
Listing of ECG Findings
Safety
ECG Displays/ Core/
EG5
SAC
30.0280
Listing of Left Ventricular Ejection 
Fraction Results
Safety
LVEF (ECHO/MUGA) 
Displays/
Oncology Core/
OLVEF2A
SAC
30.0291
Listing of Liver Stopping Event 
Information for RUCAM Scores
Safety
Liver Signal/Event 
Displays/
Oncology Core/
LIVER6
SAC
30.0330
Listing of Ophthalmic Exam Results
Safety
See Mockup
Replace Cohort with Treatment
SAC


CONFIDENTIAL
BRF116613
68
18.1.4.
Pharmacokinetics (Section 4)
18.1.4.1.
Tables
Table 
No.
Title
Population
Component / Therapeutic 
Area (hyperlinked to 
IDSL LN DB)
IDSL No. or 
Example 
Shell No.
Study-Specific  Display Notes
Deliverable 
Priority
4.0010
Summary of  GSK1120212 
Pharmacokinetic Concentration-Time 
Data
Biomarker
PK
PK01
Macro name: pkct1.  PK will be measured at 2 
weeks, 8 weeks, and 10 weeks into treatment
SAC
4.0011
Summary of GSK2118436 
Pharmacokinetic Concentration-Time 
Data
Biomarker
PK
PK01
Macro name: pkct1.  PK will be measured at 2 
weeks, 8 weeks, and 10 weeks into treatment
SAC
4.0012
Summary of GSK2284503 
Pharmacokinetic Concentration-Time 
Data
Biomarker
PK
PK01
Macro name: pkct1.  PK will be measured at 2 
weeks, 8 weeks, and 10 weeks into treatment
SAC
4.0013
Summary of  GSK2298683 
Pharmacokinetic Concentration-Time 
Data
Biomarker
PK
PK01
Macro name: pkct1.  PK will be measured at 2 
weeks, 8 weeks, and 10 weeks into treatment
SAC
4.0014
Summary of  GSK2167542 
Pharmacokinetic Concentration-Time 
Data
Biomarker
PK
PK01
Macro name: pkct1.  PK will be measured at 2 
weeks, 8 weeks, and 10 weeks into treatment
SAC


CONFIDENTIAL
BRF116613
69
18.1.4.2.
Figures
Figure 
No.
Title
Population
Component / Therapeutic 
Area (hyperlinked to 
IDSL LN DB)
IDSL No. or 
Example 
Shell No.
Study-Specific  Display Notes
Deliverable 
Priority
14.0010
Mean GSK1120212 Concentration-
Time Plots (Linear and Semi-log)
Biomarker
PK
PK17
Macro name: pkcf2.  Have each relevant 
combination of treatment time (weeks 2, 8, and 
10) and treatment on graph.
SAC
14.0011
Mean GSK2118436 Concentration-
Time Plots (Linear and Semi-log)
Biomarker
PK
PK17
Macro name: pkcf2.  Have each relevant 
combination of treatment time (weeks 2, 8, and 
10) and treatment on graph.
SAC
14.0012
Mean GSK2284503 Concentration-
Time Plots (Linear and Semi-log)
Biomarker
PK
PK17
Macro name: pkcf2.  Have each relevant 
combination of treatment time (weeks 2, 8, and 
10) and treatment  on graph.
SAC
14.0013
Mean GSK2298683 Concentration-
Time Plots (Linear and Semi-log)
Biomarker
PK
PK17
Macro name: pkcf2.  Have each relevant 
combination of treatment time (weeks 2, 8, and 
10) and treatment  on graph.
SAC
14.0014
Mean GSK2167542 Concentration-
Time Plots (Linear and Semi-log)
Biomarker
PK
PK17
Macro name: pkcf2.  Have each relevant 
combination of treatment time (weeks 2, 8, and 
10) and treatment  on graph.
SAC
14.0020
Median GSK1120212 Concentration-
Time Plots (Linear and Semi-log)
Biomarker
PK
PK18
Macro name: pkcf3.  Have each relevant 
combination of treatment time (weeks 2, 8, and 
10) and treatment  on graph.
SAC
14.0021
Median GSK2118436 Concentration-
Time Plots (Linear and Semi-log)
Biomarker
PK
PK18
Macro name: pkcf3.  Have each relevant 
combination of treatment time (weeks 2, 8, and 
10) and treatment  on graph.
SAC
14.0022
Median GSK2284503 Concentration-
Time Plots (Linear and Semi-log)
Biomarker
PK
PK18
Macro name: pkcf3.  Have each relevant 
combination of treatment time (weeks 2, 8, and 
10) and treatment  on graph.
SAC
14.0023
Median GSK2298683 Concentration-
Time Plots (Linear and Semi-log)
Biomarker
PK
PK18
Macro name: pkcf3.  Have each relevant 
combination of treatment time (weeks 2, 8, and 
10) and treatment  on graph.
SAC
14.0024
Median GSK2167542 Concentration-
Time Plots (Linear and Semi-log)
Biomarker
PK
PK18
Macro name: pkcf3.  Have each relevant 
combination of treatment time (weeks 2, 8, and 
10) and treatment  on graph.
SAC


CONFIDENTIAL
BRF116613
70
Figure 
No.
Title
Population
Component / Therapeutic 
Area (hyperlinked to 
IDSL LN DB)
IDSL No. or 
Example 
Shell No.
Study-Specific  Display Notes
Deliverable 
Priority
14.2010
Individual GSK1120212 
Concentration-Time Plots (Linear and 
Semi-log)
Biomarker
PK
PK16a
Macro name: pkcf1.  Will plot for visit time at 2 
weeks, 8 weeks, and 10 weeks
SAC
14.2011
Individual GSK2118436 
Concentration-Time Plots (Linear and 
Semi-log)
Biomarker
PK
PK16a
Macro name: pkcf1.  Will plot for visit time at 2 
weeks, 8 weeks, and 10 weeks
SAC
14.2012
Individual GSK2284503 
Concentration-Time Plots (Linear and 
Semi-log)
Biomarker
PK
PK16a
Macro name: pkcf1.  Will plot for visit time at 2 
weeks, 8 weeks, and 10 weeks
SAC
14.2013
Individual GSK2298683 
Concentration-Time Plots (Linear and 
Semi-log)
Biomarker
PK
PK16a
Macro name: pkcf1.  Will plot for visit time at 2 
weeks, 8 weeks, and 10 weeks
SAC
14.2014
Individual GSK2167542 
Concentration-Time Plots (Linear and 
Semi-log)
Biomarker
PK
PK16a
Macro name: pkcf1.  Will plot for visit time at 2 
weeks, 8 weeks, and 10 weeks
SAC


CONFIDENTIAL
BRF116613
71
18.1.4.3.
ICH Listings
Listing 
No.
Title
Population
Component / Therapeutic 
Area (hyperlinked to 
IDSL LN DB)
IDSL No. or 
Example 
Shell No.
Study-Specific  Display Notes
Deliverable 
Priority
24.1010
Listing of GSK1120212 
Pharmacokinetic Concentration-Time 
Data  
Biomarker
PK
PK07 
Macro name: pkcl1p or pkcl1x.  For visit, use 
week 2, week 8, and week 10 if data warrant.
SAC
24.1011
Listing of GSK2118436 
Pharmacokinetic Concentration-Time 
Data 
Biomarker
PK
PK07 
Macro name: pkcl1p or pkcl1x.  For visit, use 
week 2, week 8, and week 10 if data warrant.
SAC
24.1012
Listing of GSK2284503 
Pharmacokinetic Concentration-Time 
Data
Biomarker
PK
PK07 
Macro name: pkcl1p or pkcl1x.  For visit, use 
week 2, week 8, and week 10 if data warrant.
SAC
24.1013
Listing of GSK2298683 
Pharmacokinetic Concentration-Time 
Data 
Biomarker
PK
PK07 
Macro name: pkcl1p or pkcl1x.  For visit, use 
week 2, week 8, and week 10 if data warrant.
SAC
24.1014
Listing of GSK2167542 
Pharmacokinetic Concentration-Time 
Data 
Biomarker
PK
PK07 
Macro name: pkcl1p or pkcl1x.  For visit, use 
week 2, week 8, and week 10 if data warrant.
SAC


CONFIDENTIAL
BRF116613
72
18.1.5.
Biomarker (Section 5)
18.1.5.1.
Tables
Table 
No.
Title
Population
Component / Therapeutic 
Area (hyperlinked to 
IDSL LN DB)
IDSL No. or 
Example 
Shell No.
Study-Specific  Display Notes
Deliverable 
Priority
5.0010
Summary of Samples Obtained for P-
ERK IHC Analysis
Biomarker
See 
HScore1 
Mock-Up
Display is Built off of the Immunogenicity Display 
IMM1.  For each visit, we are looking for the number 
and percentage of people with p-ERK IHC Analysis
SAC
5.0020
Summary of p-ERK IHC Scores at 
Screening
Biomarker
See 
HScore2 
Mock-Up
Display is built off of the LA1 display.  Change the 
elements in Table to reflect p-ERK analysis
SAC
5.0021
Summary of p-ERK IHC Scores at 
Week 2
Biomarker
See 
HScore2 
Mock-Up
Display is built off of the LA1 display.  Change the 
elements in Table to reflect p-ERK analysis
SAC
5.0022
Summary of-ERK IHC Scores at 
Week 8
Biomarker
See 
HScore2 
Mock-Up
Display is built off of the LA1 display.  Change the 
elements in Table to reflect p-ERK analysis
SAC
5.0023
Summary of-ERK IHC Scores at 
Week 10
Biomarker
See 
HScore2 
Mock-Up
Display is built off of the LA1 display.  Change the 
elements in Table to reflect p-ERK analysis
SAC
5.0030
Descriptive Summary of Changes in 
H-Score from Weeks 8 to 10 among 
those with Monotherapy at Start of 
Study
Biomarker
See 
HScore3
Mock-Up
Display is built off of the descriptive summary table 
from BRF113928.
SAC
5.0031
Descriptive Summary of Changes in 
H-Score from Weeks 0 to 2 among 
those with Combotherapy at Start of 
Study
Biomarker
See 
HScore3
Mock-Up
Display is built off of the descriptive summary table 
from BRF113928.
SAC


CONFIDENTIAL
BRF116613
73
Table 
No.
Title
Population
Component / Therapeutic 
Area (hyperlinked to 
IDSL LN DB)
IDSL No. or 
Example 
Shell No.
Study-Specific  Display Notes
Deliverable 
Priority
5.0040
Mixed Model Analysis of H-Score 
Differences among the Different 
Treatment Arms Comparing or No 
Therapy to Combination Therapy
Biomarker
See 
HScore4
Mock-Up
Based off of the Tykerb Mixed Model Analyses for 
Study EGF112930.
SAC
5.0050
Multivariate Proportional Cox Model 
Examining the relationship between 
H-Score and Progression Free 
Survival
Biomarker
See 
HScore5
Mock-Up
Display is built off of the immunogenicity display 
IMM2
SAC
5.0051
Multivariate Proportional Cox Model 
Examining the relationship between 
H-Score and Duration of Response
Biomarker
See 
HScore5
Mock-Up
Display is built off of the immunogenicity display 
IMM2
SAC
5.0060
Summary of p-ERK IHC Scores at 
Screening for patients with BRAF 
V600E mutation
Biomarker
See 
HScore2 
Mock-Up
Display is built off of the LA1 display.  Change the 
elements in Table to reflect p-ERK analysis.  Only 
include patients with BRAF V600E mutation.
SAC
5.0061
Summary of p-ERK IHC Scores at 
Week 2 for patients with BRAF 
V600E mutation
Biomarker
See 
HScore2 
Mock-Up
Display is built off of the LA1 display.  Change the 
elements in Table to reflect p-ERK analysis.  Only 
include patients with BRAF V600E mutation.
SAC
5.0062
Summary of p-ERK IHC Scores at 
Week 8 for patients with BRAF 
V600E mutation
Biomarker
See 
HScore2 
Mock-Up
Display is built off of the LA1 display.  Change the 
elements in Table to reflect p-ERK analysis.  Only 
include patients with BRAF V600E mutation.
SAC
5.0063
Summary of p-ERK IHC Scores at 
Week 10 for patients with BRAF 
V600E mutation
Biomarker
See 
HScore2 
Mock-Up
Display is built off of the LA1 display.  Change the 
elements in Table to reflect p-ERK analysis.  Only 
include patients with BRAF V600E mutation.
SAC
5.0070
Descriptive Summary of Changes in 
H-Score from Weeks 8 to 10 among 
those with Monotherapy at Start of 
Study for patients with BRAF V600E 
mutation
Biomarker
See 
HScore3
Mock-Up
Display is built off of the descriptive summary table 
from BRF113928.  Only include patients with BRAF 
V600E mutation.
SAC


CONFIDENTIAL
BRF116613
74
Table 
No.
Title
Population
Component / Therapeutic 
Area (hyperlinked to 
IDSL LN DB)
IDSL No. or 
Example 
Shell No.
Study-Specific  Display Notes
Deliverable 
Priority
5.0071
Descriptive Summary of Changes in 
H-Score from Weeks 0 to 2 among 
those with Combotherapy at Start of 
Study for patients with BRAF V600E 
mutation
Biomarker
See 
HScore3
Mock-Up
Display is built off of the descriptive summary table 
from BRF113928.  Only include patients with BRAF 
V600E mutation.
SAC
5.0080
Mixed Model Analysis of H-Score 
Differences among the Different 
Treatment Arms Comparing or No 
Therapy to Combination Therapy for 
patients with BRAF V600E mutation
Biomarker
See 
HScore4
Mock-Up
Based off of the Tykerb Mixed Model Analyses for 
Study EGF112930 (Table 11.4).  Only include 
patients with BRAF V600E mutation.
SAC
5.0090
Multivariate Proportional Cox Model 
Examining the relationship between
H-Score and Progression Free 
Survival  for patients with BRAF 
V600E mutation
Biomarker
See 
HScore5
Mock-Up
Display is built off of the immunogenicity display 
IMM2
SAC
5.0091
Multivariate Proportional Cox Model 
Examining the relationship between 
H-Score and Duration of Response  
for patients with BRAF V600E 
mutation
Biomarker
See 
HScore5
Mock-Up
Display is built off of the immunogenicity display 
IMM2
SAC
5.0100
Correlation of Changes in H-Score 
after Two Weeks of Combo Therapy 
and Changes in Tumor Burden
Biomarker
See 
HScore6
Mock-Up
Will contain the clinical marker of interest, 
Treatment Arm, Spearman’s Coefficient, and 
Sample Size (N)
SAC
5.0110
Correlation of H-Score and Changes 
in Tumor Burden
Biomarker
See 
HScore6
Mock-Up
Will contain the clinical marker of interest, 
Treatment Arm, Spearman’s Coefficient, and 
Sample Size (N)
SAC
5.0120
Summary of Investigator-Assessed 
Best Response without confirmation 
per percentage change category in 
H-Score (Using RECIST 1.1. criteria)
Biomarker
See 
HScore7
Mock-Up
Display is built off of the oncology response display 
RE1a
SAC


CONFIDENTIAL
BRF116613
75
Table 
No.
Title
Population
Component / Therapeutic 
Area (hyperlinked to 
IDSL LN DB)
IDSL No. or 
Example 
Shell No.
Study-Specific  Display Notes
Deliverable 
Priority
5.0130
Summary of Investigator-Assessed 
Best Response without confirmation 
per baseline H-Score category (Using 
RECIST 1.1. criteria)
Biomarker
See 
HScore8
Mock-Up
Display is built off of the oncology response display 
RE1a
SAC


CONFIDENTIAL
BRF116613
76
18.1.5.2.
Figures
Figure 
No.
Title
Population
Component / 
Therapeutic Area 
(hyperlinked to IDSL LN 
DB)
IDSL No. or 
Example 
Shell No.
Study-Specific Display Notes
Deliverable 
Priority
15.0010
Mean p-ERK Scores – Time Plot 
(Linear and Semi Log)
Biomarker
PK17
Replace Concentration (ng/mL) with H-Score on 
the y-axis, and have maximum value as 300.  
Replace Planned Relative Time (Hours) with 
Planned Screening Time (Weeks) for the x-axis 
and have values (0, 2, 8, and 10)
SAC
15.0011
Mean p-ERK Scores – Time Plot 
(Linear and Semi Log) for patients 
with BRAF V600E mutation
Biomarker
PK17
Replace Concentration (ng/mL) with H-Score on 
the y-axis, and have maximum value as 300.  
Replace Planned Relative Time (Hours) with 
Planned Screening Time (Weeks) for the x-axis 
and have values (0, 2, 8, and 10)
SAC
15.0020
Median p-ERK Scores – Time Plot 
(Linear and Semi Log)
Biomarker
PK17
Replace Concentration (ng/mL) with H-Score on 
the y-axis, and have maximum value as 300.  
Replace Planned Relative Time (Hours) with 
Planned Screening Time (Weeks) for the x-axis 
and have values (0, 2, 8, and 10)
SAC
15.0021
Median p-ERK Scores – Time Plot 
(Linear and Semi Log) for patients 
with BRAF V600E mutation
Biomarker
PK17
Replace Concentration (ng/mL) with H-Score on 
the y-axis, and have maximum value as 300.  
Replace Planned Relative Time (Hours) with 
Planned Screening Time (Weeks) for the x-axis 
and have values (0, 2, 8, and 10)
SAC
15.0030
Scatter plot for Correlation between 
Changes in H-Score after Two 
Weeks of Combo Therapy and 
Changes in Tumor Burden
Biomarker
See HScore9
Mock-Up
Have a different color and symbol for each drug 
cohort.  Y-axis contains %SLD information and 
x-axis contains change in H-Score information.   
Example is for Illustrative purposes only and 
does not represent real data.
SAC
15.0040
Scatter plot for Correlation between 
Baseline Changes in Tumor Burden
Biomarker
See HScore9
Mock-Up
Have a different color and symbol for each drug 
cohort.  Y-axis contains %SLD information and 
x-axis contains baseline H-Score information.  
Example is for Illustrative purposes only and 
does not represent real data.
SAC


CONFIDENTIAL
BRF116613
77
18.1.5.3.
Listings
Listing 
No.
Title
Population
Component / Therapeutic 
Area (hyperlinked to 
IDSL LN DB)
IDSL No. or 
Example 
Shell No.
Study-Specific Display Notes
Deliverable 
Priority
25.0010
Listing of p-ERK Results
Biomarker
See H-
Score10 
Mock-Up
SAC
25.0020
Listing of Variables Associated with 
Multivariate Cox Modeling Analysis
Biomarker
See H-
Score11 
Mock-Up
Only develop if multivariate Cox Model 
analyses will be conducted
SAC


CONFIDENTIAL
BRF116613
78
18.2.
Mock-Ups for Select Displays
18.2.1.
Study Population Mock-Ups
Protocol: A18116378                                                                     Page 1 of 2
Population: All Treated                                                         Data as of 12JUN2013
                                                Table 1.2011
Age Group Breakdown for the Trial
Treatment: Pooled Data
Age Range
Planned Number of Subjects
Actual
Number
of Subjects
Enrolled
Adult(18-64 years) Approximately 54 subjects aged ≥ 18
40
From 65-84 years Approximately 54 subjects aged ≥ 18
14
85 years or older Approximately 54 subjects aged ≥ 18
0
PPD


CONFIDENTIAL
BRF116613
79
Protocol: BRF113928                                                                     Page 1 of 2
Population: All Treated                                                         Data as of 12JUN2013
                                                Listing 1.22
          Relationship between ATC Level 1, Ingredient, and Verbatim Text for Anti-Cancer Therapy
Treatment: GSK2118436 150mg BID
    ATC Level 1                  Ingredient                     Verbatim Text
    ----------------------------------------------------------------------------------------------------
    ANTINEOPLASTIC AND           BEVACIZUMAB                    AVASTIN
    IMMUNOMODULATING AGENTS
                                                                Avastin
                                                                BEVACIZUMAB
                                                                Bevacizumab (Avastin)
                                                                Bevacizuman
                                                                Bevicizumab
                                                                bevacizumab
                                 CARBOPLATIN                    CARBOPLATINE
                                                                Carboplatin
                                                                Carboplatine
                                                                Carplan
                                                                carboplatin
                                                                carboplatine
                                 CISPLATIN                      CisPlatin
                                                                Cisplan
                                                                Cisplatin
                                                                Cisplatine
                                                                cisplatin
                                                                cisplatine
PPD


CONFIDENTIAL
BRF116613
80
18.2.2.
Safety Mock-Ups
Protocol: A18113678                                                                     Page 1 of 2
Population: Safety                                                                Data as of 12JUN2013
                                                Table 3.1041
Summary of Non-Serious Adverse Events by Preferred Term with Occurrences ≥ 5%
System Organ Class
Preferred Term
Treatment
Number of
Subjects
with
Non-serious
AE
Total
number of
exposed
subjects
Number of
Non-serious
AE
Total number of subjects having any non-serious AE at or above >=5% Placebo
10
12
39
GSK 0.25 mg/kg
12
13
35
GSK 5 mg/kg
11
12
51
Infections and infestations
Nasopharyngitis
Placebo
4
12
5
GSK 0.25 mg/kg
3
13
4
GSK 5 mg/kg
4
12
8
PPD


CONFIDENTIAL
BRF116613
81
Protocol: TAC113886                                                                             Page 1 of 4
Population: All Treated Subjects
                                                Table 10.75
                                      Summary of Baseline Ocular Exam
                                                             0.5mg         0.5mg         0.5mg
      Ocular Test      Right or Left                         MEK/25mg AKT  MEK/50mg AKT  MEK/75mg AKT
      Type             side            Ocular Test Result    (N=9)         (N=7)         (N=4)
      -----------------------------------------------------------------------------------------------
      Direct           Left            Abnormal, affecting     1  (11%)      0             0
      fundoscopic                      vision
      exam
                                       Abnormal, but not       2  (22%)      0             0
                                       affecting vision and
                                       not requiring
                                       treatment
                                       Abnormal, not           0             1  (14%)      0
                                       affecting vision,
                                       requiring treatment
                                       Within normal limits    6  (67%)      6  (86%)      4 (100%)
                       Right           Abnormal, affecting     1  (11%)      0             0
                                       vision
                                       Abnormal, but not       1  (11%)      0             0
                                       affecting vision and
                                       not requiring
                                       treatment
                                       Abnormal, not           0             1  (14%)      0
                                       affecting vision,
                                       requiring treatment
                                       Within normal limits    7  (78%)      6  (86%)      4 (100%)


CONFIDENTIAL
BRF116613
82
Protocol: TAC113886                                                                            Page 1 of 15
Population: All Treated Subjects
                                                 
Listing 33
                                     Listing of Ophthalmic Exam Results
Centre ID/                                         Exam     Study
Subj.        Cohort              Visit             Date       Day  Eye      Result
PPD - This section has been excluded to protect patient privacy.


CONFIDENTIAL
BRF116613
83
Example OLIVER4
Protocol: XYZ100001                                                                             Page 1 of 5
Population: Safety/Other study specific
Table 8.xx
Summary of Liver Re-Challenges, Adaptations and Recovery
All Subjects 
  (N=57)
Re-Challenge [1]
  
    n
  3
    Without Dose Reduction 
  0
    With Reduced Dose
  3 (100%)
Peak ALT before Re-Challenge [1]
    n
  3
    ALT 3xULN and ALT <5xULN
  1  (33%)
    ALT 5xULN and ALT <8xULN
  1  (33%)
    ALT 8xULN
  1  (33%)
Post Re-Challenge [1]
    n
  3
    Recurrent Elevation of ALT 
  1  (33%)
    No Recurrent Elevation of ALT
  2  (67%)
    No Follow-up
  0
More Severe Elevation Following Re-Challenge[1]
    n
  3
    Yes
  0  
    No
  1  (33%)
    No Follow-up
  0
Note: This summary does not depict a true count of all re-challenges, but rather those events that meet the 
strict definition.
[1] Re-Challenge is defined for a subject with an ALT elevation, whose study treatment is interrupted/delayed 
and subsequently has an ALT value of <3xULN on or prior to re-starting study treatment.
[2] Adaptation is defined as ALT >3xULN followed by an ALT assessment returning to baseline grade or below 
without any dose interruption/delay between the ALT elevation and normalization.


CONFIDENTIAL
BRF116613
84
[3] Recovery is defined as ALT <3xULN for 2 consecutive visits or <3xULN for one visit if subject discontinued 
and no data available. Post therapy records are included to evaluate recovery.
USER ID:directory/program.sas  01JAN2002 12:01


CONFIDENTIAL
BRF116613
85
Example OLIVER4
Protocol: XYZ100001                                                                             Page 2 of 5
Population: Safety/Other study specific
Table 8.xx
Summary of Liver Re-Challenges, Adaptations and Recovery
All Subjects 
  (N=100)
Time to Dose Interruption/delay (days)
    n
  3
    Mean
33.7
    SD
21.13
    Median 
31.0
    Min.
14
    Max.
56
Duration of Interruption/delay (days)
    n
  3
    Mean
24.7
    SD 
14.98
    Median 
29.0
    Min.
  8
    Max.
37
Duration of Re-Treatment (days)
    n 
  3
    Mean
33.7
    SD
21.13
    Median 
31.0
    Min.
14
    Max.
56
Note: This summary does not depict a true count of all re-challenges, but rather those events that meet the 
strict definition.
[1] Re-Challenge is defined for a subject with an ALT elevation, whose study treatment is interrupted/delayed 
and subsequently has an ALT value of <3xULN on or prior to re-starting study treatment.
[2] Adaptation is defined as ALT >3xULN followed by an ALT assessment returning to baseline grade or below 
without any dose interruption/delay between the ALT elevation and normalization.


CONFIDENTIAL
BRF116613
86
[3] Recovery is defined as ALT <3xULN for 2 consecutive visits or <3xULN for one visit if subject discontinued 
and no data available. Post therapy records are included to evaluate recovery.
USER ID:directory/program.sas  01JAN2002 12:01


CONFIDENTIAL
BRF116613
87
Example OLIVER4
Protocol: XYZ100001                                                                             Page 3 of 5
Population: Safety/Other study specific
Table 8.xx
Summary of Liver Re-Challenges, Adaptations and Recovery
All Subjects 
  (N=100)
Time to Recurrent ALT Elevation Post Re-Challenge 
(days)[1]
    n 
  3
    Mean
239.0
    SD
154.50
    Median 
194.0
    Min.
112
    Max.
411
Adaptation [2]
    n
  3
    Without Dose Reduction
  2  (67%)  
    With Dose Reduction
  1  (33%)
Time to Adaptation (days) [2]
    n 
  3
    Mean
33.7
    SD
21.13
    Median 
31.0
    Min.
14
    Max.
56
Note: This summary does not depict a true count of all re-challenges, but rather those events that meet the 
strict definition.
[1] Re-Challenge is defined for a subject with an ALT elevation, whose study treatment is interrupted/delayed 
and subsequently has an ALT value of <3xULN on or prior to re-starting study treatment.


CONFIDENTIAL
BRF116613
88
[2] Adaptation is defined as ALT >3xULN followed by an ALT assessment returning to baseline grade or below 
without any dose interruption/delay between the ALT elevation and normalization.
[3] Recovery is defined as ALT <3xULN for 2 consecutive visits or <3xULN for one visit if subject discontinued 
and no data available. Post therapy records are included to evaluate recovery.
USER ID:directory/program.sas  01JAN2002 12:01
Example OLIVER4
Protocol: XYZ100001                                                                             Page 4 of 5
Population: Safety/Other study specific
Table 8.xx
Summary of Liver Re-Challenges, Adaptations and Recovery
All Subjects 
  (N=100)
Peak ALT before Adaptation [2]
    n
  3
    ALT 3xULN and ALT <5xULN
  2  (67%)  
    ALT 5xULN and ALT <8xULN
  1  (33%)
    ALT 8xULN
  0
Outcome of ALT Elevations
    n
  8
    Recovered [3]
  8 (100%)  
    Not Recovered
  0
    No Follow-up
  0
Outcome following ALT Elevations within 7 Days On or Prior 
to Study Treatment Discontinuation
    n
  3
    Recovered [3]
  2  (67%)  
    Not Recovered
  1  (33%)
    No Follow-up
  0
Note: This summary does not depict a true count of all re-challenges, but rather those events that meet the 
strict definition.


CONFIDENTIAL
BRF116613
89
[1] Re-Challenge is defined for a subject with an ALT elevation, whose study treatment is interrupted/delayed 
and subsequently has an ALT value of <3xULN on or prior to re-starting study treatment.
[2] Adaptation is defined as ALT >3xULN followed by an ALT assessment returning to baseline grade or below 
without any dose interruption/delay between the ALT elevation and normalization.
[3] Recovery is defined as ALT <3xULN for 2 consecutive visits or <3xULN for one visit if subject discontinued 
and no data available. Post therapy records are included to evaluate recovery.
USER ID:directory/program.sas  01JAN2002 12:01
Example OLIVER4
Protocol: XYZ100001                                                                             Page 5 of 5
Population: Safety/Other study specific
Table 8.xx
Summary of Liver Re-Challenges, Adaptations and Recovery
All Subjects 
  (N=100)
Peak ALT for Subjects with ALT Elevations within 7 Days on 
or Prior to Study Treatment Discontinuation
    n
  3
    ALT 3xULN and ALT <5xULN
  2  (67%)  
    ALT 5xULN and ALT <8xULN
  1  (33%)
    ALT 8xULN
  0
Time to First ALT Elevation(days)
    n 
  3
    Mean
33.7
    SD
21.13
    median 
31.0
    Min.
14
    Max.
56
Time to Recovery [3](days)
    n 
  3
    Mean
33.7
    SD
21.13


CONFIDENTIAL
BRF116613
90
    median 
31.0
    Min.
14
    Max.
56
Note: This summary does not depict a true count of all re-challenges, but rather those events that meet the 
strict definition.
[1] Re-Challenge is defined for a subject with an ALT elevation, whose study treatment is interrupted/delayed 
and subsequently has an ALT value of <3xULN on or prior to re-starting study treatment.
[2] Adaptation is defined as ALT >3xULN followed by an ALT assessment returning to baseline grade or below 
without any dose interruption/delay between the ALT elevation and normalization.
[3] Recovery is defined as ALT <3xULN for 2 consecutive visits or <3xULN for one visit if subject discontinued 
and no data available. Post therapy records are included to evaluate recovery.
USER ID:directory/program.sas  01JAN2002 12:01
Example EMASER
Protocol: A18116378                                                                             Page 5 of 5
Population: Safety
Table 3.9900
Summary of Serious Adverse Events by Preferred Term Including Drug-Related Status and Fatal Status
System Organ Class
Preferred Term
Treatment
Number
of
Subjects
with
Serious
AE
Total
number
of
exposed
subjects
Number
of
Serious
AEs
Number
of
Drug-
related
Serious
AEs
Number
of Fatal
Serious
AEs
Number
of Drug-
related
Fatal
Serious
AEs
Total number of subjects having any serious AE Placebo
1
12
1
0
0
0
GSK 0.25 mg/kg
0
13
0
0
0
0
GSK 5 mg/kg
1
12
1
0
0
0
Infections and infestations


CONFIDENTIAL
BRF116613
91
System Organ Class
Preferred Term
Treatment
Number
of
Subjects
with
Serious
AE
Total
number
of
exposed
subjects
Number
of
Serious
AEs
Number
of
Drug-
related
Serious
AEs
Number
of Fatal
Serious
AEs
Number
of Drug-
related
Fatal
Serious
AEs
Diverticulitis
Placebo
1
12
1
0
0
0
GSK 0.25 mg/kg
0
13
0
0
0
0
GSK 5 mg/kg
0
12
0
0
0
0
PPD


CONFIDENTIAL
BRF116613
92
18.2.3.
Immunohistochemistry Mock-Ups
Example: HScore1
Protocol: BRF116613                                                                             Page 1 of x
Population: Biomarker
Table X
Summary of Samples Obtained for p-ERK Immunohistochemistry Analysis 
Visit
Planned Time
Trt A
(N=100)
Trt B
(N=100)
Trt C
(N=100)
Visit 1
Screening
x/n (%)
x/n (%)
x/n (%)
Visit 2
Week 2
x/n (%)
x/n (%)
x/n (%)
Visit 3
Week 8 
x/n (%)
x/n (%)
x/n (%)
Visit 4
Week 10
x/n (%)
x/n (%)
x/n (%)
USER ID:directory/program.sas  01JAN2002 12:01
Example HScore2
Protocol: BRF116613                                                                             Page 1 of 1
Population: Biomarker
Table X
Summary of p-ERK Immunohistochemistry Scores at Screening
Treatment A
(N=100)
Treatment B
(N=100)
Treatment C
(N = 100)
Total
(N=200)
p-ERK IHC H-Score
   100
    98
   198
  
   
    
   
  200-300
    30 (30%)
    22 (22%)
    52 (26%)
  100-199
    55 (55%)
    67 (68%)
   122 (62%)


CONFIDENTIAL
BRF116613
93
  1-99  
    15 (15%)
     9 (9%)
    24 (12%)
  0 or Unknown
    0  (0%)
     0 (0%)       
     0 (0%)
p-ERK Score Summary Statistics
  Mean
    158
  SD
    49
  Median
    137
  Minimum
    0
  Maximum
    297
Screening Intensity 
    100
    98
   198
  3+
     0 (0%)
     0 (0%)
     0 (0%)
  2+
    55 (55%)
    69 (70%)
   124 (63%)
  1+
    35 (35%)
    35 (36%)
    70 (35%)
  0
    15 (15%)
     9 (9%)
    24 (12%)
  Unknown
     2 (2%)
     0
     2 (1%)
% Positivity
    100
    98
   198
  100
     0 (0%)
     0 (0%)
     0 (0%)
  67-99
    30 (30%)
    22 (22%)
    52 (26%)
  34-66
    55 (55%)
    67 (68%)
   122 (62%)
  1-33
    15 (15%)
     9 (9%)
    24 (12%)
  0
     2 (2%)
     0
     2 (1%)
  
   USER ID:directory/program.sas  01JAN2007 12:01


CONFIDENTIAL
BRF116613
94
Example: HScore3
Protocol: BRF116613                                                                             Page 1 of x
Population: Biomarker
Table X
Descriptive Summary of Changes in H-Score from Weeks 8 to 10 among Those 
with Monotherapy at Start of Study 
Total H-Score Changes 
Trt A
(N=18)
Trt B
(N=18)
Total
(N=36)
Any Increase or No Changes
x/n (%)
x/n (%)
x/n (%)
Total Decrease in Score of 1-100
x/n (%)
x/n (%)
x/n (%)
Total Decrease in Score of 101-200
x/n (%)
x/n (%)
x/n (%)
Total Decrease in Score of 201-300
x/n (%)
x/n (%)
x/n (%)
Unknown
x/n (%)
x/n (%)
x/n (%)
Summary Statistics for Total H-
Score Changes
Mean
Standard Deviation
Median
Minimum
Maximum
Percentage Change in H-Score
Any Increase or No Changes
Any Decrease up to 80 percent
Any Decrease > 80 percent
Summary Statistics for Percentage 
H-Score Changes
Mean
Standard Deviation
Median
Minimum
Maximum


CONFIDENTIAL
BRF116613
95
Example HScore4
Protocol: BRF116613                                                                             Page 1 of 1
Population: Biomarker
Table X
Mixed Model Analysis of H-Score Differences among the Different Treatment Arms
Comparing Monotherapy or No Therapy to Combination Therapy
Treatment Arm
Comparison
N
LS Mean 
Num.
LS Mean
Demon.
Ratio
Estimate
Lower 90% 
Confidence 
Limit
Upper 90%
Confidence
Limit 
GSK2118436 BID 8W then 
GSK1120212 QD + GSK2118436 
BID
B vs A
GSK1120212 QD 8W then 
GSK1120212 QD + GSK2118436 
BID
B vs A
GSK1120212 QD + GSK2118436 
BID
B vs A
   
Comparison for H-Score Times: B = Combo Therapy and A = Monotherapy or No Therapy (for Cohort that has 
Combination Therapy at start of study)


CONFIDENTIAL
BRF116613
96
Example HScore5
Protocol: IMM123456                                                                             Page 1 of x
Population: Safety
Table X
Multivariate Proportional Cox Model Examining the relationship between 
H-Score and Progression Free Survival/Duration of Response
Parameter
Parameter 
Estimate
P-Value
HR
Low 95% CI
High 95% CI
Decrease in H-
Score 
(Log 2 Scale)
Age
Sex
ECOG Status
Initial Combo 
therapy
V600E Status


CONFIDENTIAL
BRF116613
97
Example HScore6
Protocol: BRF116613                                                                             Page 1 of 1
Population: Biomarker
Table X
Correlation of Changes in H-Score after Two Weeks of Combo Therapy and Changes in Tumor Burden
Clinical Marker of Interest
Treatment Arm
Spearman’s 
Coefficient
N
% Change in Sum of Lesion 
Diameters
GSK2118436 BID 8W then 
GSK1120212 QD + GSK2118436 BID
% Change in Sum of Lesion 
Diameters
GSK1120212 QD 8W then 
GSK1120212 QD + GSK2118436 BID
% Change in Sum of Lesion 
Diameters
GSK1120212 QD + GSK2118436 BID
Example HScore7
Protocol: XYZ100001                                                                             Page 1 of 1
Population: Intent-to-Treat/Safety/Other study specific                             (Data as of: 30MAY2003)
Table X
Summary of Investigator/Independent Reviewer/etc.-Assessed Best Response (without or with confirmation)
per baseline H-Score Category(RECIST 1.1 Criteria)
Treatment A
(N=300)
Treatment B
(N=200)
Treatment C
(N=200)
Total
(N = 54)
p-ERK IHC H-Score btw. 200-300
  Complete Response
  22  (7%)
  10  (5%)
  10  (5%)
  Partial Response
  30 (10%)
  40 (20%)
  50 (25%)
  Stable Disease
153 (50%)
110 (55%)
100 (50%)
  Non-CR/Non-PD
       3  (1%)
       0
       0
  Progressive Disease
  70 (23%)
  33 (17%)
  33 (17%)
  Not Evaluable
  25  (9%)
   7  (3%)
   7  (3%)
Response Rate


CONFIDENTIAL
BRF116613
98
  CR+PR
  52 (17.3%)
  50 (25.0%)
  60 (30.0%)
  95% Confidence Interval
(13.2%, 22.1%)
(19.2%, 31.6%)
(23.7%, 36.9%)
p-ERK IHC H-Score btw. 100-200
  Complete Response
  22  (7%)
  10  (5%)
  10  (5%)
  Partial Response
  30 (10%)
  40 (20%)
  50 (25%)
  Stable Disease
153 (50%)
110 (55%)
100 (50%)
  Non-CR/Non-PD
       3  (1%)
       0
       0
  Progressive Disease
  70 (23%)
  33 (17%)
  33 (17%)
  Not Evaluable
  25  (9%)
   7  (3%)
   7  (3%)
Response Rate
  CR+PR
  52 (17.3%)
  50 (25.0%)
  60 (30.0%)
  95% Confidence Interval
(13.2%, 22.1%)
(19.2%, 31.6%)
(23.7%, 36.9%)
p-ERK IHC H-Score btw. 1-99
  Complete Response
  22  (7%)
  10  (5%)
  10  (5%)
  Partial Response
  30 (10%)
  40 (20%)
  50 (25%)
  Stable Disease
153 (50%)
110 (55%)
100 (50%)
  Non-CR/Non-PD
       3  (1%)
       0
       0
  Progressive Disease
  70 (23%)
  33 (17%)
  33 (17%)
  Not Evaluable
  25  (9%)
   7  (3%)
   7  (3%)
Response Rate
  CR+PR
  52 (17.3%)
  50 (25.0%)
  60 (30.0%)
  95% Confidence Interval
(13.2%, 22.1%)
(19.2%, 31.6%)
(23.7%, 36.9%)
p-ERK IHC H-Score either 0 or 
Unknown
  Complete Response
  22 (7%)
  10  (5%)
  10  (5%)
  Partial Response
  30 (10%)
  40 (20%)
  50 (25%)
  Stable Disease
153 (50%)
110 (55%)
100 (50%)
  Non-CR/Non-PD
       3  (1%)
       0
       0
  Progressive Disease
  70 (23%)
  33 (17%)
  33 (17%)
  Not Evaluable
  25  (9%)
   7  (3%)
   7  (3%)
Response Rate
  CR+PR
  52 (17.3%)
  50 (25.0%)
  60 (30.0%)
  95% Confidence Interval
(13.2%, 22.1%)
(19.2%, 31.6%)
(23.7%, 36.9%)
USER ID:directory/program.sas  16JAN2004 12:01


CONFIDENTIAL
BRF116613
99
Example HScore8
Protocol: XYZ100001                                                                             Page 1 of 1
Population: Intent-to-Treat/Safety/Other study specific                             (Data as of: 30MAY2003)
Table X
Summary of Investigator/Independent Reviewer/etc.-Assessed Best Response (without or with confirmation)
per percentage change category in H-Score (RECIST 1.1 Criteria)
Treatment A
(N=300)
Treatment B
(N=200)
Treatment C
(N=200)
Total
(N = 54)
Any Increase or No Changes
  Complete Response
  22  (7%)
  10  (5%)
  10  (5%)
  Partial Response
  30 (10%)
  40 (20%)
  50 (25%)
  Stable Disease
153 (50%)
110 (55%)
100 (50%)
  Non-CR/Non-PD
       3  (1%)
       0
       0
  Progressive Disease
  70 (23%)
  33 (17%)
  33 (17%)
  Not Evaluable
  25  (9%)
   7  (3%)
   7  (3%)
Response Rate
  CR+PR
  52 (17.3%)
  50 (25.0%)
  60 (30.0%)
  95% Confidence Interval
(13.2%, 22.1%)
(19.2%, 31.6%)
(23.7%, 36.9%)
Any Decrease up to 80 percent
  Complete Response
  22  (7%)
  10  (5%)
  10  (5%)
  Partial Response
  30 (10%)
  40 (20%)
  50 (25%)
  Stable Disease
153 (50%)
110 (55%)
100 (50%)
  Non-CR/Non-PD
       3  (1%)
       0
       0
  Progressive Disease
  70 (23%)
  33 (17%)
  33 (17%)
  Not Evaluable
  25  (9%)
   7  (3%)
   7  (3%)
Response Rate
  CR+PR
  52 (17.3%)
  50 (25.0%)
  60 (30.0%)
  95% Confidence Interval
(13.2%, 22.1%)
(19.2%, 31.6%)
(23.7%, 36.9%)
Any Decrease > 80 percent
  Complete Response
  22  (7%)
  10  (5%)
  10  (5%)
  Partial Response
  30 (10%)
  40 (20%)
  50 (25%)
  Stable Disease
153 (50%)
110 (55%)
100 (50%)
  Non-CR/Non-PD
       3  (1%)
       0
       0
  Progressive Disease
  70 (23%)
  33 (17%)
  33 (17%)
  Not Evaluable
  25  (9%)
   7  (3%)
   7  (3%)
Response Rate


CONFIDENTIAL
BRF116613
100
  CR+PR
  52 (17.3%)
  50 (25.0%)
  60 (30.0%)
  95% Confidence Interval
(13.2%, 22.1%)
(19.2%, 31.6%)
(23.7%, 36.9%)
Example HScore9
Protocol: BRF116613                                                                            Page 1 of 1
Population: Biomarker
Figure X
Scatter plot for Correlation between Decreases in H-Score after
Two Weeks of Combo Therapy and Changes in Tumor Burden
Treatment Arm:  GSK2118436 QD 8W then GSK1120212 + GSK2118436 QD


CONFIDENTIAL
BRF116613
101
Example HScore10
Protocol: IMM123456                                                                             Page 1 of x
Population: Safety
Listing X
Listing of p-ERK results
Treatment
Inv./
Subj.
BRAF 
Mutation 
Type
Planned 
Time
Study
Day
Staining 
Intensity
H-Score
Change from 
Baseline (%)
Change 
from 
Week 8 
(%)
Positivity
(%)
USER ID:directory/program.sas  01JAN2002 12:01
PPD - This section has been excluded to protect patient privacy.


CONFIDENTIAL
BRF116613
102
Example HScore11
Protocol: IMM123456                                                                             Page 1 of x
Population: Safety
Listing X
Listing of Key Variables Associated with Multivariate Cox Modelling Analysis
Treatment
Inv./Subj.
Age
Sex
Race
ECOG 
Status
BRAF 
mutation 
type
USER ID:directory/program.sas  01JAN2002 12:01
PPD - This section has been excluded to protect patient privacy.