Conditions: Melanoma and Brain Metastases
Keywords: BRAF V600E mutation brain metastases BRAF V600K mutation Metastatic melanoma BRAF inhibitor brain neoplasms GSK2118436
Allocation: RANDOMIZED | Intervention model: SINGLE_GROUP
Enrollment: 6
Healthy volunteers: no

Brief summary:
This is a global, multi-centre, open-label, study of GSK2118436 conducted in up to 30 evaluable subjects with resectable, BRAF V600E or V600K mutation-positive metastatic melanoma to the brain. All subjects in this study are required to have accessible extracranial metastases and are agreeable to undergo repetitive biopsies. The first cohort of 15 subjects will receive dabrafenib orally 150mg twice daily (BID) for 7 to 14 days prior to surgery (Cohort A); the second cohort of 15 subjects will receive the combination of dabrafenib 150 mg BID and trametinib 2 mg once daily for 7 to 14 days prior to surgery (Cohort B). The primary purpose of this study is to determine levels and distribution of dabrafenib, its metabolites, and trametinib (Cohort B only) in parenchymal brain metastases, extracranial metastases, and peripheral blood (plasma) within two cohorts of subjects with BRAF V600E/K mutation-positive melanoma that has metastasized to the brain. All subjects will be followed for survival and new anti-cancer therapy for a total of two years or until death or the subject wishes to withdraw from further follow-up.

Detailed description:

Arms:
arm 1: The first cohort of 15 subjects will receive oral dabrafenib 150 mg twice daily orally for 7 to 14 days prior to surgery in Cohort A; Subjects will be treated for at least 7 days prior to craniotomy, but not more than 14 days. Subjects in either cohort with intracranial and/or extracranial metastases remaining after surgery may resume treatment with the combination of dabrafenib 150 mg BID and trametinib 2 mg once daily no earlier than 72 hours after surgery arm 2: The second cohort of 15 subjects will receive dabrafenib 150 mg twice daily combined with trametinib 2 mg once daily (Cohort B) orally for 7 to 14 days prior to surgery; Subjects will be treated for at least 7 days prior to craniotomy, but not more than 14 days. Subjects in either cohort with intracranial and/or extracranial metastases remaining after surgery may resume treatment with the combination of dabrafenib 150 mg BID and trametinib 2 mg once daily no earlier than 72 hours after surgery

Interventions: intervention 1: Dabrafenib 150 mg intervention 2: Trametinib 2.0 mg
Intervention descriptions: intervention 1: Dabrafenib will be provided for oral administration as 50 mg and 75 mg capsules. Dabrafenib will be dosed orally with approximately 200 mL of water, twice a day. Dabrafenib should be administered under fasting conditions. intervention 2: Trametinib study treatment will be provided as 0.5 mg and 2.0 mg tablets. should be taken orally with approximately 200 mL of water under fasting conditions, either one hour before or two hours after a meal.

Protocol document:
Prot_000.pdf: 
2011N129968_03
CONFIDENTIAL
The GlaxoSmithKline group of companies
BRV116521
1
TITLE PAGE
Division: Worldwide Development
Information Type: Protocol Amendment
Title:
An Open-Label, Multicentre, Corollary Study of Pre-Operative 
Therapy with Dabrafenib and the Combination of Dabrafenib 
with Trametinib in Subjects with BRAF Mutation-Positive 
Metastatic Melanoma to the Brain
Compound Number:
GSK1120212+GSK2118436
Development Phase:
IIB
Effective Date:
15-APR-2015
Protocol Amendment Number:  03
Author (s):
 
 
 
1 GlaxoSmithKline Research & Development Limited, Collegeville, PA, US
2 University of Texas M D Anderson Cancer Center Houston, TX, US
3 The Melanoma Institute Australia, University of Sydney, Australia
4 University of Pittsburgh Cancer Institute, Pittsburgh, PA, US
5 GlaxoSmithKline Research & Development Limited, Research Triangle Park, NC, US
Copyright 2015 the GlaxoSmithKline group of companies.  All rights reserved.  
Unauthorised copying or use of this information is prohibited.
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2011N129968_03
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Revision Chronology
GlaxoSmithKline
Document Number
Date
Version
2011N129968_00
2012-MAY-23
Original
2011N129968_01
2013-AUG-28
Amendment No. 1
Clarified age requirement and other eligibility criteria; reduced dabrafenib monotherapy 
cohort to 15 subjects and included cohort of 15 subjects who will be treated with 
dabrafenib and trametinib; changed post-op treatment to dabrafenib plus trametinib; 
updated dose modification guidelines; updated contraindicated and cautionary 
medications; updated translational research to include assessment of mRNA and miRNA 
expression, and, when feasible, for DNA methylation and copy number variation; 
clarified post-craniotomy assessment schedule.
2011N129968_02
2013-NOV-08
Amendment No. 2
Updated medical monitor contact information; revised IND number to reflect submission 
to dabrafenib + trametinib IND; Added ophthalmic examinations to be performed at the 
Screening Visit, Week 4 Visit, and as clinically indicated; updated dose modification 
guidelines for QTc prolongation; removed collection of alcohol information at baseline; 
updated guidelines for missed doses of trametinib
2011N129968_03
2015-APR-15
Amendment No. 3
Revised Author list. Updated medical monitor contact information. Changed the resection 
of extracranial metastases to optional from required; analyses related to the concordance 
of cranial to extracranial have been categorized as exploratory.  Sequence of enrollment 
for first 10 patients changed to 5 for cohort A and 5 for cohort B. (Sequence for next 20 
defined as groups of 5 in same order).  Interim review planned after first 10 patients. 
Exclusion criteria have been amended to no longer include presence of leptomeningeal 
disease or dural metastases; or history of another active malignancy within the past 5 
years; or any malignancy with a confirmed activating RAS mutation. Papsmear no 
longer required prior to enrollment. Clarified that SUVmax is recorded for PET-CT 
scans, not size of tumor lesions. Clarified that FDG-PET may not be performed in lieu of 
bone scans. Removed 18-NaF- PET as an alternate to bone scans.  Option to use core 
biopsy for extracranial tumor added. Allow option to collect the optional extracranial 
tissue 1 day craniotomy procedure. Third optional extracranial biopsy corrected from 
every 8 weeks to at study discontinuation. Revised guidelines for visual changes for the 
dabrafenib and trametinib combination arm to replace CSR with RPED and align with 
asset standard language.


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SPONSOR INFORMATION PAGE
Clinical Study Identifier:
BRV116521
Sponsor Legal Registered Address:
GlaxoSmithKline Research & Development Limited
980 Great West Road
Brentford
Middlesex, TW8 9GS
UK
Sponsor Contact Address
GlaxoSmithKline Research & Development Limited
1250 South Collegeville Road
Collegeville, PA 19426, USA
Telephone Number: 
In some countries, the clinical trial sponsor may be the local GlaxoSmithKline Affiliate 
Company (or designee). Where applicable, the details of the Sponsor and contact person 
will be provided to the relevant regulatory authority as part of the clinical trial 
submission.
Medical Monitor and Sponsor Contact Information:
Role
Name
Day Time 
Phone 
Number
After-hours 
Phone/Cell/
Pager 
Number
Fax Number
Address
Primary 
Medical 
Monitor
 
 
MD
 
 
GlaxoSmithKline
5 Crescent Drive
NY 0400
Philadelphia, PA  19112 USA
Secondary 
Medical 
Monitor
 MD
Novartis Oncology 
Stockley Park West 
Building 11
UB11 1 BT
Uxbridge, UK
Regulatory Agency Identifying Number(s): 
IND No.: 113,557
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INVESTIGATOR PROTOCOL AGREEMENT PAGE
For protocol BRV116521
I confirm agreement to conduct the study in compliance with the protocol, as amended by 
this protocol amendment.
I acknowledge that I am responsible for overall study conduct. I agree to personally 
conduct or supervise the described study.
I agree to ensure that all associates, colleagues and employees assisting in the conduct of 
the study are informed about their obligations. Mechanisms are in place to ensure that site 
staff receives the appropriate information throughout the study. 
Investigator Name:
Investigator Address:
Investigator Phone Number:
Investigator Signature
Date


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TABLE OF CONTENTS
PAGE
LIST OF ABBREVIATIONS...........................................................................................10
PROTOCOL SUMMARY...............................................................................................13
1.
INTRODUCTION....................................................................................................16
1.1.
Background ................................................................................................16
1.2.
Dabrafenib..................................................................................................18
1.3.
Trametinib...................................................................................................19
1.4.
Dabrafenib Combined with Trametinib........................................................20
1.5.
Study Rationale ..........................................................................................20
2.
OBJECTIVES AND ENDPOINTS...........................................................................21
3.
STUDY DESIGN ....................................................................................................24
3.1.
Discussion of Design ..................................................................................26
3.1.1.
Dose Rationale ............................................................................26
3.1.2.
Treatment Duration and Timing Rationale....................................27
4.
SUBJECT SELECTION AND DISCONTINUATION/ COMPLETION 
CRITERIA ..............................................................................................................28
4.1.
Subject Selection Criteria............................................................................28
4.1.1.
Number of Subjects .....................................................................28
4.1.2.
Inclusion Criteria..........................................................................28
4.1.3.
Exclusion Criteria.........................................................................29
4.2.
Permanent Discontinuation from Study Treatment and Subject 
Completion Criteria.....................................................................................31
4.2.1.
Subject Completion......................................................................32
5.
STUDY TREATMENTS..........................................................................................32
5.1.
Investigational Products..............................................................................32
5.1.1.
Dabrafenib...................................................................................32
5.1.2.
Trametinib....................................................................................33
5.1.3.
Study Treatment Dosage and Administration...............................33
5.2.
Handling and Storage of Study Treatment ..................................................33
5.3.
Treatment Assignment................................................................................34
5.4.
Blinding.......................................................................................................34
5.5.
Product Accountability ................................................................................34
5.6.
Treatment Compliance................................................................................34
5.7.
Dose Modification Guidelines......................................................................34
5.7.1.
Dose Levels of Dabrafenib and Trametinib ..................................35
5.7.2.
General Guidelines for Clinically Significant Toxicities .................36
5.7.3.
Guidelines for Cardiovascular Adverse Events ............................37
5.7.3.1.
Left Ventricular Ejection Fraction (LVEF)....................37
5.7.3.2.
Hypertension ..............................................................38
5.7.3.2.1.
Monitoring of Hypertension.....................38
5.7.3.2.2.
Management of Hypertension.................38
5.7.3.3.
Guidelines for Prolonged QTc ....................................40
5.7.4.
Guidelines for Skin-related Adverse Events.................................40


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5.7.4.1.
Rash...........................................................................40
5.7.4.2.
Guidelines for Hand-foot Skin Reactions 
(HFSR).......................................................................43
5.7.4.3.
Guidelines for cuSCC.................................................44
5.7.5.
Guidelines for Other Adverse Event of Special Interest................44
5.7.5.1.
Guidelines for Pyrexia ................................................44
5.7.5.2.
Guidelines for Diarrhea...............................................46
5.7.5.3.
Guidelines for Renal Insufficiency...............................48
5.7.5.4.
Guidelines for Visual Changes ...................................49
5.7.5.5.
Guidelines for Pneumonitis.........................................51
5.7.6.
Liver Chemistry Stopping and Follow-Up Criteria.........................52
5.7.6.1.
Liver Chemistry Stopping Criteria ...............................52
5.7.6.2.
Liver Chemistry Monitoring Criteria.............................53
5.7.6.3.
Liver Event Follow Up Assessments...........................54
6.
CONCOMITANT MEDICATIONS AND NON-DRUG THERAPIES .........................55
6.1.
Permitted Medications and Non-Drug Therapies.........................................55
6.2.
Prohibited Medications and Non-Drug Therapies........................................55
6.3.
Medications to be Used with Caution..........................................................56
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 .....................................................59
7.1.
Critical Baseline Assessments....................................................................63
7.1.1.
Baseline Assessment of Target and Non-target Lesions..............63
7.2.
Efficacy.......................................................................................................64
7.2.1.
Efficacy Endpoints .......................................................................64
7.2.2.
Efficacy Assessment....................................................................64
7.2.3.
Assessment of Treatment Response in Intracranial and 
Extracranial Metastases...............................................................65
7.2.4.
Assessment Guidelines ...............................................................65
7.2.5.
Guidelines for Evaluation of Disease ...........................................66
7.2.5.1.
Measurable and Non-measurable Definitions .............66
7.2.6.
Response Criteria........................................................................67
7.2.6.1.
Evaluation of extracranial target lesions .....................67
7.2.6.2.
Evaluation of intracranial or extracranial non-
target lesions..............................................................68
7.2.6.3.
New intracranial and/or extracranial lesions ...............68
7.2.6.4.
Evaluation of overall extracranial response ................68
7.3.
Safety .........................................................................................................69
7.3.1.
Adverse Events............................................................................70
7.3.1.1.
Definition of an AE......................................................70
7.3.1.2.
Definition of a SAE .....................................................71
7.3.1.3.
Laboratory and Other Safety Assessment 
Abnormalities Reported as AEs and SAEs .................72
7.3.1.4.
Disease-Related Events and/or Disease-
Related Outcomes Not Qualifying as SAEs ................72
7.3.1.5.
Time Period and Frequency of Detecting AEs 
and SAEs ...................................................................73
7.3.1.6.
Prompt Reporting of SAEs and Other Events to 
GSK ...........................................................................73


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7.3.1.7.
Regulatory reporting requirements for SAEs ..............74
7.3.2.
Pregnancy Testing, Prevention and Reporting.............................75
7.3.2.1.
Pregnancy Test and Prevention .................................75
7.3.2.2.
Pregnancy Reporting..................................................76
7.3.3.
Laboratory Assessments .............................................................76
7.3.4.
Physical Examinations.................................................................77
7.3.5.
Neurological Examinations ..........................................................77
7.3.6.
Dermatologic Examinations .........................................................78
7.3.7.
Vital Signs....................................................................................78
7.3.8.
Performance Status.....................................................................78
7.3.9.
Electrocardiogram (ECG).............................................................78
7.3.10.
Echocardiograms.........................................................................79
7.3.11.
Ophthalmic Examination..............................................................79
7.4.
Pharmacokinetics .......................................................................................79
7.4.1.
Pharmacokinetic Endpoints .........................................................79
7.4.2.
Brain Tumor Sample Collection for Pharmacokinetics .................80
7.4.3.
CSF Collection for Pharmacokinetics...........................................80
7.4.4.
Extracranial Tumor Sample Collection for 
Pharmacokinetics ........................................................................80
7.4.5.
Blood Sample Collection for Pharmacokinetics............................81
7.4.6.
Pharmacokinetic Sample Analysis ...............................................81
7.4.7.
Meals and Dietary Restrictions ....................................................81
7.5.
Pharmacodynamics ....................................................................................81
7.5.1.
Pharmacodynamic Analysis of Brain Metastases.........................82
7.5.2.
Pharmacodynamic Analysis of Extracranial Metastases ..............82
7.6.
Pharmacogenetics......................................................................................82
7.7.
Translational Research...............................................................................83
7.7.1.
Prevalence of BRAF and Other Mutations in Brain 
Metastases and Extracranial Metastases.....................................83
7.7.2.
Tumor Biomarker Analysis...........................................................83
7.7.3.
Immunologic Monitoring...............................................................84
7.7.4.
T-Cell Receptor Sequencing........................................................85
7.7.5.
Tumor Infiltrating Lymphocyte Analysis........................................85
7.8.
Days 1-3 Post-Craniotomy..........................................................................85
7.9.
Post-Craniotomy Safety Assessments........................................................86
7.10.
Post-Craniotomy Disease Assessments .....................................................86
7.11.
Discontinuation Visit ...................................................................................86
7.12.
Survival Follow-up Visits.............................................................................86
8.
DATA MANAGEMENT ...........................................................................................86
9.
DATA ANALYSIS AND STATISTICAL CONSIDERATIONS...................................87
9.1.
Study Design Considerations......................................................................87
9.1.1.
Sample Size Assumptions ...........................................................87
9.1.2.
Sample Size Re-estimation..........................................................87
9.2.
Data Analysis Considerations .....................................................................87
9.2.1.
Analysis Populations....................................................................87
9.2.2.
Analysis Data Sets.......................................................................87
9.2.3.
Interim Review.............................................................................88
9.2.4.
Key Elements of Analysis Plan ....................................................88
9.2.4.1.
Primary Analysis.........................................................89
9.2.4.1.1.
Pharmacokinetics ...................................89


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9.2.4.2.
Secondary Analyses...................................................89
9.2.4.2.1.
Pharmacokinetics in CSF .......................89
9.2.4.2.2.
Pharmacodynamics ................................89
9.2.4.2.3.
Mutational Analysis.................................89
9.2.4.2.4.
Exploratory Biomarkers (others) .............90
9.2.4.2.5.
Change from Baseline to Pre-
Surgery in Intracranial Target 
Lesions...................................................90
9.2.4.2.6.
Maximum Change from Baseline 
in Unresected Intracranial Target 
Lesions...................................................90
9.2.4.2.7.
Overall Response in Extracranial 
Lesion(s).................................................90
9.2.4.2.8.
Duration of Response.............................91
9.2.4.2.9.
Overall Survival ......................................91
9.2.4.3.
Safety Analyses..........................................................91
9.2.4.3.1.
Extent of Exposure .................................91
9.2.4.3.2.
Adverse Events ......................................91
9.2.4.3.3.
Clinical Laboratory Evaluations...............92
9.2.4.3.4.
Other Safety Measures...........................92
9.2.4.4.
Pharmacogenetic Analyses ........................................92
10. STUDY CONDUCT CONSIDERATIONS ...............................................................92
10.1.
Posting of Information on Publicly Available Clinical Trial Registers............92
10.2.
Regulatory and Ethical Considerations, Including the Informed 
Consent Process ........................................................................................92
10.3.
Quality Control (Study Monitoring) ..............................................................93
10.4.
Quality Assurance.......................................................................................93
10.5.
Study and Site Closure ...............................................................................94
10.6.
Records Retention......................................................................................94
10.7.
Provision of Study Results to Investigators, Posting of Information 
on Publicly Available Clinical Trials Registers and Publication....................95
11. REFERENCES.......................................................................................................96
APPENDICES...............................................................................................................99
Appendix 1: Pharmacogenetic Research................................................................99
Appendix 2: Cockcroft-Gault Formula...................................................................104
Appendix 3: Liver Chemistry Monitoring, Interruption Stopping and Follow-
up Criteria.................................................................................................105
Appendix 4: Country Specific Requirements.........................................................106
Appendix 5: Collection of CSF..............................................................................107
Appendix 6: Summary of Protocol Amendment Changes .....................................108


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LIST OF ABBREVIATIONS
AE
Adverse event
ALT
Alanine aminotransferase (SGPT)
ANC
Absolute neutrophil count
AST
Aspartate aminotransferase (SGOT)
ATP
Adenosine triphosphate
ATS
All treated subjects
BBB
Blood-brain barrier
BID
Twice a day
BUN
Blood urea nitrogen
CLCr
Creatinine clearance
CLL
Chronic lymphocytic leukemia
CNS
Central nervous system
CPK
Creatinine phosphokinase
CR
Complete response
CRF
Case Report Form
CSF
Cerebrospinal fluid
CSR
Central serous retinopathy
CT
Computed tomography
CTCAE v4.0
Common Terminology Criteria for Adverse Events, version 4.0 
CYP
Cytochrome P450
dL
Deciliter(s)
DNA
Deoxyribonucleic acid
ECG
Electrocardiogram
ECHO
Echocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
Electronic Case Report Form
FDA
Food and Drug Administration
EIAED
Enzyme-inducing antiepileptic drug
FDA
Food and Drug Administration
FDG
Fluorodeoxyglucose 
FFPE
Formalin fixed, paraffin embedded
FSH
Follicle Stimulating Hormone
FTIH
First time in humans
G
Gram
GCP
Good Clinical Practice
GK
Gamma knife
GLP
Good Laboratory Practice
GSK
GlaxoSmithKline
G6PD
Glucose-6-phosphate dehydrogenase
H&E
Hematoxylin and eosin
HBV
Hepatitis B Virus
hCG
Human chorionic gonadotrophin
HCV
Hepatitis C Virus
HFSR
Hand-foot skin reaction


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HIV
Human Immunodeficiency Virus
HPMC
Hydroxypropyl methyl cellulose
HRT
Hormone Replacement Therapy
IB
Investigator Brochure
ICH
International Conference on Harmonization
IHC
Immunohistochemical
IEC
Independent Ethics Committee
IND
Investigational New Drug
INR
International normalized ratio
IRB
Institutional Review Board
KA
Keratoacanthoma
kg
Kilogram
L
Liter(s)
LDH
Lactate dehydrogenase
Linac
Linear accelerator
LLN
Lower limit of normal
LVEF
Left ventricular ejection fraction
MALDI
Matrix Assisted Laser Desorption Ionization
MedDRA
Medical Dictionary for Regulatory Activities
mg
Milligrams
miRNA
MicroRNA
mL
Milliliter
mm
Millimeter
MOA
Mode of action
MRI
Magnetic resonance imaging
NA
Not applicable
NCI
National Cancer Institute 
NE
Not evaluable
nM
Nanomolar
NSAID
Non-steroidal anti-inflammatory drugs
NYHA
New York Heart Association
ORR
Overall response rate
PBMC
Peripheral blood mononuclear cell
PCR
Polymerase chain reaction
PD
Progressive disease
p-ERK
Phosphorylated ERK
PET
Positron emission tomography, FDG-PET, FDG-PET/CT unless stated 
otherwise
Pgp
p-glycoprotein
PK
Pharmacokinetic
PR
Partial response
PSA
Prostate-specific antigen
PT
Prothrombin time
PTT
Partial thromboplastin time
OCT
Optimum cutting temperature solution
QTc
Corrected QT interval on electrocardiogram


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RAP
Reporting and Analysis Plan
RECIST
Response Evaluation Criteria In Solid Tumours
RPED
Retinal pigment epithelial detachment
RNA
Ribonucleic acid
RPPA
Reverse phase protein arrays
RVO
Retinal vein occlusion
SAE
Serious adverse event(s)
SCC
Squamous cell carcinoma
SD
Stable disease
SGOT
Serum glutamic oxaloacetic transaminase (AST)
SGPT
Serum glutamic pyruvic transaminase (ALT)
SPM
Study procedures manual
SRS
Stereotactic radiosurgery
SUV
Standard uptake value
TID
Three times a day
TIL
Tumor infiltrating lymphocyte
TMZ
Temozolamide
L
Microliter
M
Micromolar
ULN
Upper limit of normal
US/USA
United States
WBRT
Whole-brain radiation therapy
Trademark Information
Trademarks of the GlaxoSmithKline 
group of companies
Trademarks not owned by the 
GlaxoSmithKline group of companies
MEKINIST
None
TAFINLAR


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PROTOCOL SUMMARY
Rationale
Cutaneous melanoma is the most aggressive form of skin cancer, with approximately 
132,000 new cases and approximately 37,000 disease-related deaths worldwide each 
year. One of the most common complications of advanced melanoma is the development 
of brain metastasis.  Brain involvement is detected in up to 80% of advanced melanoma 
patients in autopsy series, and up to 55% of advanced melanoma patients will die as a 
direct result of uncontrolled and progressive brain metastases.  The prognosis of 
melanoma patients with brain metastasis is generally very poor, with a median overall 
survival ranging from 2.8 to 4 months. While local treatment options are generally 
preferred, the need for effective systemic treatments to also control peripheral melanoma 
manifestations and to ultimately prolong the overall survival of patients with melanoma 
metastatic to the brain is still very much unmet. 
Dabrafenib (GSK2118436, TAFINLA™), a 4-(3-aminosulfonylphenyl)-5-(pyrimidin-3-
yl) thiazole, is a potent and selective inhibitor of BRAF kinase activity with a mode of 
action (MOA) consistent with adenosine triphosphate (ATP)-competitive inhibition.  In 
May 2013, dabrafenib monotherapy was approved by the United States Food and Drug 
Administration (FDA) for the treatment of patients with unresectable or metastatic 
melanoma with BRAF V600E mutation as detected by an FDA-approved test.   Clinical 
activity was reported in patients with BRAF V600E or K-mutation positive melanoma 
brain metastases [Long, 2012].
The clinical activity in the brain metastases may have resulted from the activity of the 
parent or of one (or more) of the metabolites of dabrafenib.  In preclinical studies, 
dabrafenib failed to penetrate the intact blood-brain-barrier (BBB) but disruption of the 
BBB in patients with brain metastases may allow penetration of dabrafenib or its 
metabolites into the brain.  In the Phase I trial with GSK2118436, as well in a Phase I 
trial with the BRAF inhibitor vemurafenib, correlative studies demonstrated the critical 
need to achieve specific parent drug concentrations in the plasma to achieve inhibition of 
signalling by the mutant BRAF V600E protein in extracranial metastases, which 
correlated with the achievement of clinical responses.  
Trametinib (GSK1120212, MEKINIST™) is an orally available, small molecule, 
selective inhibitor of MEK1 and MEK2 that was approved in May 2013 by the United 
States FDA for the treatment of patients with unresectable or metastatic melanoma with 
BRAF V600E or V600K mutations as detected by an FDA-approved test.  
In phase II studies, it was shown that dabrafenib can be safely combined with trametinib, 
and the anti-tumor activity of the combination of both agents given continuously at full 
approved dose levels for monotherapy was superior when compared to single-agent 
dabrafenib.   Several phase III trials evaluating the safety and efficacy of the combination 
are currently ongoing. 
In order to facilitate the understanding of dabrafenib and dabrafenib in combination with 
trametinib as a treatment option for patients with brain metastases, there is a critical need 


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to improve the understanding of the levels of the dabrafenib parent compound, its 
metabolites, and trametinib that are achieved in the central nervous system (CNS), the 
relationship of intracerebral concentrations to plasma levels, and pharmacodynamic 
effects in the brain metastases.
Objective(s)
The primary objective of this study is to determine levels and distribution of dabrafenib, 
its metabolites, and trametinib (Cohort B only) in parenchymal brain metastases, 
extracranial metastases (when available), and peripheral blood (plasma) within two 
cohorts of subjects with BRAF V600E/K mutation-positive melanoma that has 
metastasized to the brain. 
The secondary objectives of this study are to determine: the levels of dabrafenib , its 
metabolites, and trametinib (as appropriate) in the cerebrospinal fluid (CSF) ) and in 
extracranial metastases where possible; the activation status of the RAS-RAF-MEK-ERK 
signalling pathway in brain metastases and extracranial metastases; the activation status 
of other pro-survival signalling pathways in brain metastases and extracranial metastases; 
the relationship between these pharmacokinetic and pharmacodynamic measures and 
early clinical responsiveness of the brain metastases; the degree of concordance with 
respect to the presence of BRAF mutations in both the brain and extra-cranial metastases 
from the same subjects, the presence of other mutations that may be uniquely present and 
novel only for brain metastases; and the safety and tolerability of pre-operative treatment 
with dabrafenib or dabrafenib combined with trametinib prior to resection of brain 
metastases, as well as the surgical outcomes from the craniotomy itself.  Efficacy will be 
assessed in terms of change from baseline to pre-surgery in the sum of the longest 
diameters of intracranial target lesions, maximum change from baseline in the sum of 
longest diameters of unresected intracranial target lesions, overall extracranial response 
rate in unresected lesions, and overall survival.  
The exploratory objectives of this study are to determine, in available samples, the degree 
of concordance with respect to the presence of BRAF mutations in both the brain and 
extra-cranial metastases from the same subjects; the presence of other mutations that may 
be uniquely present and novel only for brain metastases; and to compare the status of 
signalling pathways and the immune response in brain metastases and extra-cranial 
metastases.
Study Design
This is a global, multi-centre, open-label, study that will be conducted evaluable subjects 
with resectable, BRAF V600E or V600K mutation-positive metastatic melanoma to the 
brain. The first cohort of 5 subjects will receive dabrafenib orally 150mg twice daily 
(BID) for 7 to 14 days prior to surgery (Cohort A); the second cohort of 5 subjects will 
receive the combination of dabrafenib 150 mg BID and trametinib 2 mg once daily for 7 
to 14 days prior to surgery (Cohort B).  An interim analysis will be performed after 
cohorts A and B have each enrolled 5 patients (with cohort A enrolling the first 5 patients 
and cohort B the second 5) to assess variability in PK results and determine whether 
projected total sample size of 30 subjects will be adequate or sample size will require 


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readjustment. Accrual will continue during this formal review.   If variance in results 
suggests that a total sample size of 30 subjects is adequate, the planned assignment of 
subsequent patients to the two cohorts will be in groups of 5 with the first 5 subjects 
enrolling in cohort A, then the next 5 enrolling in cohort B; alternating between cohorts 
until up to 30 patients have been enrolled.  Study treatment will be taken the night prior 
to surgery, but not on the day of surgery.  Samples of the resected brain tumor(s) will be 
utilized for pharmacokinetic and pharmacodynamic analyses.  Optional samples of 
accessible extracranial metastases may be collected prior to starting treatment and on the 
same day as the resection of the brain metastases.  PK and PD levels in extracranial 
metastases if available will be compared with those observed in resected brain 
metastases.  Plasma will be collected from all subjects on the day of the craniotomy for 
pharmacokinetic analysis, to determine the correlation with levels achieved in the brain 
and extracranial tumors.  Optional CSF collected on the day of surgery will also undergo 
pharmacokinetic analysis, and results will be compared to plasma and intracranial 
pharmacokinetic levels.  Radiographic assessment of early clinical responses by positron 
emission tomography-computed tomography (PET-CT) and magnetic resonance imaging 
(MRI) will be performed in all subjects and compared with pharmacokinetic and 
pharmacodynamic analyses.  Tissues and blood will also be utilized for exploratory 
translational objectives.
After surgery, all subjects with remaining intracranial and/or extracranial metastases will 
be able to resume treatment with the combination of dabrafenib and trametinib no earlier 
than 72 hours after surgery, provided the subject is able to tolerate oral medications and 
felt to be appropriate for treatment by the Principal Investigator.  Subjects who resume 
treatment will be evaluated for safety 4 weeks after restarting treatment and every 4 
weeks thereafter.  Efficacy will be assessed 8 weeks after restarting treatment and every 8 
weeks thereafter.  Subjects will be permitted to remain on treatment until disease 
progression, unacceptable toxicity, investigator discretion, subject/proxy request, or 
administrative reasons.  An optional tumor biopsy may be collected for subjects who 
discontinue treatment due to disease progression or recurrence.
Subjects who do not continue treatment after the craniotomy procedure will be evaluated 
for safety at the discontinuation visit 4 weeks after the procedure.
All subjects who permanently discontinue study treatment will be followed for survival 
and new anti-cancer therapy for a total of two years or until death or the subject wishes to 
withdraw from further follow-up.  The study will be considered closed once the last 
subject reaches this milestone.


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1.
INTRODUCTION
1.1.
Background
Cutaneous melanoma is the most aggressive form of skin cancer, with approximately 
132,000 new cases and approximately 37,000 disease-related deaths worldwide each 
year.  The prognosis of melanoma is primarily dependent on the disease stage at the time 
of initial diagnosis. The high risk of developing distant tumor metastases, and particularly 
brain metastases, negatively impacts the prognosis of advanced stage disease. In fact, 
after lung-, breast-, and cancer of unknown primary origin, melanoma results in the 
fourth highest number of patients who develop central nervous system (CNS) metastases 
detected by imaging each year (10% of all brain metastases) [Majer, 2007]. Moreover, 
autopsy series indicate that up to 75% of subjects who die from melanoma show evidence 
of metastatic disease in the CNS [McWilliams, 2008].  It is of major clinical relevance 
that subjects with malignant melanoma who initially respond to aggressive systemic 
therapy often relapse with metastases in the CNS.
The prognosis of melanoma patients with brain metastasis is generally very poor, with a 
median overall survival ranging from 2.8 to 4 months; up to 55% of these subjects will 
ultimately die as a direct result of their brain metastases [McWilliams, 2008; Staudt, 
2010].  The initial clinical management of melanoma brain lesions depends largely on the 
number and size of the lesion(s), the presence of concurrent extracranial metastatic 
disease, and the patient’s performance status.  The neurological symptoms associated 
with melanoma brain metastasis can be severe and therefore, the supportive care is of 
particular clinical importance. The use of corticosteroids to reduce intracerebral edema is 
well established, and high initial doses can be frequently weaned as anti-tumor therapy is 
delivered. Anti-convulsants are primarily used in subjects with symptomatic brain 
metastases and documented seizures since several studies have demonstrated the lack of 
use of these medications in a prophylactic setting [McWilliams, 2008]. While local 
treatment options are generally preferred [Staudt, 2010] the need for effective systemic 
treatments to also control peripheral melanoma manifestations is still very much unmet. 
Neurosurgical tumor resection usually followed by radiotherapy is the current gold 
standard in the local control of melanoma brain metastases [Fife, 2004; Samlowski, 
2007].  Unfortunately, only a small proportion of patients are suitable candidates for 
surgical tumor resection, and the overall survival in these patients remains poor [Davies, 
2011].  Similar rates of local tumor control of brain metastases have been demonstrated 
for stereotactic radiosurgery (SRS), using either linear accelerator (Linac-) or gamma-
knife (GK) based treatment approaches [Majer, 2007]. Patients who are not suitable for 
neurosurgical resection or SRS, including those with poor prognostic factors 
(uncontrolled primary tumor and/or extracranial metastases, or those patients with either 
>3 or surgically inaccessible lesions) are frequently treated with palliative whole-brain 
radiation therapy (WBRT). 
So far, the efficacy of systemic treatment approaches, and especially chemotherapy, in 
the treatment of melanoma metastatic to the brain is limited. Most attempts to control the 
progression of metastatic brain lesions with single-agent or combination regimens alone 
or in combination with local modalities, have been largely unsuccessful [McWilliams, 


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2008; Samlowski, 2007].  Although multiple chemotherapeutic agents such as the 
nitrosoureas carmustine and fotemustine or the dacarbazine analogue temozolamide 
(TMZ) can theoretically penetrate the blood-brain-barrier, only limited activity against 
melanoma CNS metastases has been demonstrated  in clinical trials [McWilliams, 2008].  
The convincing efficacy data that led to the regulatory approval of TMZ for the use in 
subjects with primary brain tumors were not reproduced for the treatment of melanoma 
brain metastases in a phase II study [Agarwala, 2004].  In this study, the response rate 
was low (7% in patients with no prior systemic treatment, 6% in those who had 
previously received systemic treatment), and the progression-free survival (1.2 months in 
patients with no prior systemic treatment, 1.2 months in those who had previously 
received systemic treatment) as well as the overall survival (3.5 months in patients with 
no prior systemic treatment, 2.2 months in those who had previously received systemic 
treatment) were short.  However, multiple trials are currently ongoing to assess the 
efficacy of novel targeted- and immnuo-therapeutic agents alone or in combination with 
other systemic or localized treatment modalities in the clinical management of melanoma 
metastatic to the brain.
The RAS/RAF/MEK/ERK pathway is a critical proliferation pathway in many human 
cancers, including melanoma.  This pathway can be constitutively activated by alterations 
in specific proteins, including BRAF, which phosphorylates MEK1 and MEK2 on two 
regulatory serine residues.  Approximately 90% of all identified BRAF mutations that 
occur in human cancer result in a V600-E or -K amino acid substitution [Wan, 2004; 
Wellbrock, 2004]. This mutation appears to mimic regulatory phosphorylation and 
increases BRAF activity approximately >10-fold compared to wild type [Davies, 2002]. 
BRAF mutations have been identified at a high frequency in specific cancers, including 
approximately 40-60% of melanoma [Hocker, 2007].  The frequency of this activating 
mutation and the pathway addiction to which it leads make mutated BRAF an extremely 
attractive target especially in melanoma. So far, only one putative RAF kinase small-
molecule inhibitor, sorafenib, has achieved regulatory approval (for renal cell and 
hepatocellular carcinoma).  However, sorafenib failed to demonstrate activity in 
melanoma as a single agent [Eisen, 2006] or in combination with systemic chemotherapy 
[Flaherty, 2013].  Clinical benefit from sorafenib in metastatic melanoma patients did not 
correlate with the presence of the activating V600E BRAF-mutation [Eisen, 2006], 
indicating that the compound lacks specificity and potency against BRAF kinase.  The 
clinical activity of sorafenib is most likely due to inhibition of targets other than BRAF.  
The selective small molecule BRAF-inhibitor vemurafenib received FDA-approval in 
August of 2011, as the first molecularly-targeted agent for unresectable or metastatic 
melanoma harboring BRAF V600E mutations. In the pivotal Phase III study, treatment 
with vemurafenib resulted in a significant (p<0.001) improvement of progression-free 
survival (HR 0.26) and overall survival (HR 0.37) in the interim data analysis compared 
to DTIC chemotherapy [Chapman, 2011].  In addition to a strict dependence on BRAF 
mutation status for activity, vemurafenib also has notable pharmacologic requirements in 
that the drug failed to achieve clinical responses until doses were reached that achieved > 
80% inhibition of phosphorylated (activated) ERK (p-ERK) levels in the tumors [Bollag, 
2010]. This correlated with the achievement of plasma level that also induced tumor 
regression in preclinical models [Flaherty, 2010].


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1.2.
Dabrafenib
Dabrafenib (GSK2118436), a 4-(3-aminosulfonylphenyl)-5-(pyrimidin-3-yl) thiazole, is a 
potent and selective inhibitor of BRAF kinase activity with a mode of action (MOA) 
consistent with adenosine triphosphate (ATP)-competitive inhibition.  Excluding RAF 
enzymes, GSK2118436 demonstrated IC50 values <100 nM against only 8 kinases from 
~300 protein and lipid kinases tested.  GSK2118436 has demonstrated inhibition of a 
downstream pharmacodynamic biomarker (pERK) in tumor cell lines, demonstrated anti-
proliferative activity against multiple BRAF mutant tumor cell lines, and achieved 
biomarker inhibition and tumor regression in BRAF mutant xenograft models.  
Dabrafenib is metabolized sequentially to 3 metabolites, hydroxyl-dabrafenib 
(GSK2285403), carboxy-dabrafenib (GSK2298683), and desmethyl –dabrafenib 
(GSK2167542).  Hydroxy- and desmethyl-dabrafenib are believed to contribute to the 
clinical activity of dabrafenib, although contribution of each metabolite to the overall 
clinical activity is unknown and dependent on potency and relative exposure.  Additional 
background information is provided in the Investigator’s Brochure (IB) 
[GlaxoSmithKline Document Number CM2010/00010/03].
More than 700 patients have been treated to-date with dabrafenib monotherapy. Common 
AEs occurring in at least 20% of patients include hyperkeratosis, headache, pyrexia, 
arthralgia, alopecia, and palmar-plantar erythrodysesthesia syndrome.  . Most cases of 
pyrexia have been mild, self limited, and have responded to anti-pyretic therapy.   
However, cases of complex pyrexia have been reported as serious adverse events (SAEs) 
in which patients have presented with high fever (up to 105 -106 degrees F), with severe 
rigors, and in some instances, hypotension.  Most cases of pyrexia have presented within 
the first two months of therapy.  A variety of skin effects have been noted in BRAF 
inhibitor treated patients including rash, hyperkeratosis, actinic keratosis, seborrheic 
keratosis, hand-foot skin reactions (HFSR), papillomas and cutaneous squamous cell 
carcinomas (SCC).   Squamous cell cancers related to BRAF inhibitor therapy often have 
characteristic of keratoacanthoma type of SCC, which traditionally have a relatively 
benign prognosis.  Among the rare AEs, renal insufficiency/failure was recently 
identified as a potential adverse drug reaction associated with dabrafenib.  Most cases of 
renal insufficiency have been in the setting of dehydration and/or pyrexia; however there 
have been reports of acute renal failure suggestive of intrinsic renal disease.  Dabrafenib, 
like other BRAF inhibitors, has been associated with reports of uveitis, with an incidence 
of 1%.
BRF113683 (BREAK-3) was a phase III clinical trial in subjects with BRAF V600E-
mutation positive metastatic melanoma.  250 subjects were randomly assigned to receive 
either dabrafenib (187 patients) or dacarbazine (63 patients). Median progression-free 
survival was 5.1 months for dabrafenib and 2·7 months for dacarbazine, with a hazard 
ratio (HR) of 0·30 (95% CI 0·18–0·51; p<0·0001). The most common adverse events 
with dabrafenib were skin-related toxicities: fever, fatigue, arthralgia, and headache [Data 
from this trial were the basis for the recent FDA approval of dabrafenib as treatment for 
patients with unresectable or metastatic melanoma with BRAF V600E mutation as 
detected by an FDA-approved test.


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BRF113929 (BREAK-MB) was a phase II clinical trial in subjects with BRAF V600E/K-
mutation positive melanoma that had metastasized to the brain.  172 subjects were 
enrolled; 89 (52%) had not received prior local treatment to the brain (Cohort A) and 83 
(48%) had progressive brain metastases after prior local intervention (Cohort B).   Of the 
74 subjects with V600E mutation-positive melanoma, 29 (39·2%, 95% CI 28·0–51·2) 
achieved an overall intracranial response, as did 20 (30·8%, 19·9–43·4) of 65 subjects in 
Cohort B. One (6·7%, 0·2–31·9) of 15 subjects with V600K mutation-positive melanoma 
achieved an overall intracranial response in Cohort A, as did four (22·2%, 6·4–47·6) of 
18 subjects patients in Cohort B. Treatment-related adverse events of grade 3 or worse 
occurred in 38 (22%) patients. Eleven (6%) patients developed squamous-cell carcinoma. 
Four grade 4 treatment-related adverse events occurred in Cohort A: one blood amylase 
increase, one convulsion, one lipase increase, and one neutropenia. Two grade 4 events 
occurred in Cohort B: one agranulocytosis and one intracranial hemorrhage. 51 (30%) 
patients had a serious adverse event. The most frequent serious adverse events were 
pyrexia (6%), intracranial hemorrhage (6%) and squamous-cell carcinoma (6%) [Long, 
2012].
1.3.
Trametinib
Trametinib (GSK1120212), a pyrido-pyrimidine derivative, is a potent and highly 
selective allosteric i.e. non-ATP competitive inhibitor of MEK1 and MEK2 activation 
and kinase activity. In the pivotal study MEK114267 (METRIC), 322 patients who had 
metastatic melanoma with a V600E or V600K BRAF mutation were randomized in a 2:1 
ratio to receive trametinib (2 mg orally) once daily or chemotherapy (either intravenous 
dacarbazine, 1000 mg per square meter of body-surface area or paclitaxel 175 mg per 
square meter every 3 weeks.)  Median progression-free survival was 4.8 months in the 
trametinib group and 1.5 months in the chemotherapy group (hazard ratio 0.45; 95% 
confidence interval [CI], 0.33 to 0.63; P<0.001). At 6 months, the rate of overall survival 
was 81% in the trametinib group and 67% in the chemotherapy group despite crossover 
(hazard ratio, 0.54; 95% CI, 0.32 to 0.92; P = 0.01).  Rash, diarrhea, and peripheral 
edema were the most common toxic effects in the trametinib group and were managed 
with dose interruption and dose reduction; asymptomatic and reversible reduction in the 
cardiac ejection fraction and ocular toxic effects occurred infrequently. Secondary skin 
neoplasms were not observed [Flaherty, 2012a].  Data from this trial were the basis for 
the approval of trametinib for patients with unresectable or metastatic melanoma with 
BRAF V600E or V600K mutations as detected by an FDA-approved test.
Trametinib monotherapy has been evaluated in well over 500 patients. Common AEs 
include rash, lymphedema, and diarrhea.  In addition, a decrease in left-ventricular 
ejection fraction (LVEF) has been observed in approximately 10% of subjects receiving 
trametinib.  Most of these cases were associated with no symptoms. Consequently, strict 
monitoring has been in place along with guidelines on management of patients with 
decreased LVEF. 


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1.4.
Dabrafenib Combined with Trametinib
In a recent study of dabrafenib in combination with trametinib in patients without CNS 
metastases, a confirmed ORR of 76% was reported in patients with BRAF V600E/K-
mutation-positive metastatic melanoma who were treated in the dabrafenib 150 mg BID 
combined with trametinib 2 mg once daily dose cohort.  In this same cohort, efficacy 
outcomes were significantly improved when compared with dabrafenib monotherapy 
(ORR: 76% vs 54%; p=0.026; median PFS=9.4 vs 5.8 mo, HR 0.39; 95% CI (0.25, 0.62), 
p<0.0001) [Flaherty, 2012b].
1.5.
Study Rationale
The current systemic therapeutic options for the management of melanoma metastatic to 
the CNS are limited and there is a high unmet medical need for additional treatment 
modalities.  Although local therapies such as neurosurgical resection, SRS, and WBRT 
are considered standard, the ability of these modalities to control intracranial disease 
progression, and to improve neurological signs and symptoms, is limited to sub-
populations of melanoma patients with limited tumor burden. In addition, CNS 
progression of melanoma is rarely independent of extracranial progression and therefore, 
innovative treatment approaches for patients with melanoma metastatic to the brain 
should ideally address both intracranial and extracranial disease [Cranmer, 2010].
Although encouraging results have been observed in BREAK-MB, the interpretation of 
this trial, and the design of future clinical trials for subjects with melanoma brain 
metastases with BRAF mutations, will be strengthened by an improved understanding of 
the pharmacokinetics and pharmacodynamic effects of dabrafenib in brain metastases.  In 
preclinical studies, dabrafenib did not penetrate the intact blood-brain-barrier (BBB) 
following single dose administration in mice without brain metastases.  It is currently 
unknown  if the activity of dabrafenib in subjects with established brain metastases is due 
to BBB penetration of dabrafenib or one (or more) of its metabolites, and the relationship 
between the levels achieved in brain metastases and peripheral exposure in plasma and 
extracranial metastases.  The degree of inhibition of BRAF achieved in brain metastases 
with doses of dabrafenib that were selected for their peripheral pharmacokinetic and 
pharmacodynamic characteristics is also unknown.  We have designed this corollary 
study of pre-operative treatment of dabrafenib 150 mg BID monotherapy and dabrafenib 
150 mg BID combined with trametinib 2 mg once daily in subjects with BRAF V600E or 
V600K-mutation positive melanoma with resectable brain metastases to address these 
important questions.


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2.
OBJECTIVES AND ENDPOINTS
Table 1 lists the study objectives and corresponding endpoints.
Table 1
Study Objectives and Endpoints
Objectives
Endpoints
Primary
The primary objective of this study is to 
determine levels and tissue distribution of 
dabrafenib, its metabolites and trametinib in 
parenchymal brain metastases peripheral 
blood (plasma) and, when possible, in 
extracranial metastases within two cohorts of 
subjects with BRAF V600E/K mutation-positive 
metastatic melanoma to the brain following 
pre-operative treatment.
Concentrations and tissue distribution of 
dabrafenib, its metabolites hydroxy-, 
carboxy- and desmethyl-dabrafenib and 
trametinib (Cohort B only) in parenchymal 
brain metastases, peripheral blood 
(plasma) and, when possible, in 
extracranial metastases.
Secondary
The secondary objectives are as follows:
Determine the levels of dabrafenib, its 
metabolites and trametinib in the CSF in 
subjects who undergo resection of BRAF 
V600E/K mutation-positive metastatic 
melanoma to the brain following pre-operative 
treatment.
Determine the activation status of the MAPK 
pathway following pre-operative treatment in 
resected brain and, when available,
extracranial metastases.  Activation of the 
MAPK kinase pathway will also be determined 
in samples of readily accessible extracranial 
metastases obtained prior to starting 
treatment.  
Comparison of pharmacokinetics and 
pharmacodynamics to tumor response.
Concentrations of dabrafenib, its 
metabolites hydroxy-, carboxy- and 
desmethyl-dabrafenib) and trametinib 
(Cohort B only) in CSF samples.
When available, changes in MAPK pathway 
markers in paired extracranial biopsies 
taken pre-treatment, during craniotomy, and 
at disease progression, and changes in 
markers between post-operative intracranial 
and extracranial biopsies.
Changes in the radiographic characteristics 
of the tumors will be compared to (1) levels 
of dabrafenib, its metabolites and trametinib 
(where appropriate) in the brain 
metastases, plasma, and CSF, and (2) 
MAPK pathway activation status in tumors 
at the time of surgery.  When available, 
results will also be compared to the 
analysis of early clinical responses in 
extracranial metastases, as determined by 
the PET-CT imaging.


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Objectives
Endpoints
The clinical response objectives are to 
evaluate efficacy of study treatment in 
resected and unresected lesions.
The safety objective is to further characterize 
the safety profile of study treatment in subjects 
with melanoma brain metastases. 
Efficacy as measured by:

change from baseline to pre-
surgery in the sum of the longest 
diameters of intracranial target 
lesions,

maximum change from baseline in 
the sum of longest diameters of 
unresected intracranial target 
lesions, 

overall extracranial response rate 
in unresected lesions, and

overall survival
Safety as measured by clinical 
assessments including vital signs and 
physical examinations, 12-lead 
electrocardiograms (ECG), echocardiogram 
(ECHO), chemistry and hematology 
laboratory values, and adverse events 
(AEs).  
Exploratory
The exploratory research objectives are as 
follows:
Characterize the prevalence of BRAF and 
other mutations in melanoma brain metastases 
and extracranial metastases when available.
Evaluate the baseline and changes in the 
expression and activation of proteins and 
transcriptional cell signaling networks, 
including the MAPK kinase pathway, in readily 
accessible extracranial metastases when 
available in patients treated with dabrafenib 
and dabrafenib plus trametinib and compare 
changes where appropriate. 
Quantitative analysis of DNA from the brain 
and extracranial metastases to determine 
the degree of concordance of BRAF 
mutations between the two samples.   
Additional mutations found in the analysis 
of tumor samples will be summarized.  
The expression and activation of protein 
signaling pathways and transcriptional 
networks, including the MAPK pathway, will 
be evaluated  when available in extracranial 
biopsies taken pre-treatment, at/near the 
time of craniotomy, and at disease 
progression to understand changes induced 
by the given treatments and their 
correlation with other molecular features 
(i.e. mutations) and treatment outcomes.  


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Objectives
Endpoints
Compare the status of protein and 
transcriptional signaling pathways, including 
the the MAPK kinase pathway, in the brain 
metastases and readily accessible extracranial 
metastases when available.
The expression and activation of protein 
signaling pathways and transcriptional 
networks, including the MAPK pathway, in 
intracranial and, when available,
extracranial biopsies collected at/near the 
time of craniotomy, and/or at disease 
progression, will be compared to identify 
differential molecular features and 
treatment effects.   
Results will also be compared to the 
analysis of early clinical responses in 
extracranial metastases, as determined by 
the PET-CT imaging, and drug levels in 
blood and tissue samples.
Encouraging efficacy has been reported in subjects with BRAF V600E/K-mutation 
positive melanoma that has metastasized to the brain who were treated with dabrafenib 
monotherapy; however, the degree of BRAF inhibition achieved in brain metastases with 
doses of dabrafenib that were selected for their peripheral pharmacokinetic and 
pharmacodynamic characteristics is unknown.  Thus, it is critical to better understand 
whether levels and distribution of dabrafenib and/or trametinib in intracranial lesions 
differ from extracranial lesions and plasma.  A secondary question would be to 
understand whether there is a variation of distribution of drug between intracranial 
tumors and plasma and, when possible, extracranial tumors and CSF.  Potential intra-
cohort variability and the small cohort sample sizes preclude any meaningful inter-cohort 
analysis, thus, there are no planned statistical comparisons between Cohort A and Cohort 
B.  


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3.
STUDY DESIGN
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 is 
provided in the accompanying Study Procedures Manual (SPM).  The SPM will provide 
the site personnel with administrative and detailed technical information that does not 
impact subject safety.
This international, multi-centre, open-label study will be conducted in up to 30 evaluable 
subjects with untreated, resectable brain metastases and when possible, readily accessible 
(i.e. cutaneous, subcutaneous, or superficial lymph node) extracranial metastases.  
Subjects with metastatic melanoma (Stage IV) and evidence of untreated brain metastases 
will be screened for eligibility.  Subjects must have clinically certified testing results that 
indicate the presence of a BRAF mutation involving the V600 codon (V600E or V600K) 
in a sample of tumor tissue obtained at any time during the subject’s disease course.  
Eligible subjects will have at least one intracranial metastasis of between 1.0 – 4.0 cm 
that is considered surgically resectable by a neurosurgeon but that does not require 
immediate removal for subject safety or symptom relief.  Eligible subjects must not have 
received any prior radiation or surgical treatments to the brain in the region of the tumor 
(s) that will be resected to address the primary endpoint of the study.  
This is a global, multi-centre, open-label, study that will be conducted in up to 30 
evaluable subjects with resectable, BRAF V600E or V600K mutation-positive metastatic 
melanoma to the brain.  Subjects in Cohort A will receive dabrafenib orally 150mg twice 
daily (BID) for 7 to 14 days prior to surgery (Cohort A); Subjects in Cohort B (the 
second cohort of 2 cohorts) will receive the combination of dabrafenib 150 mg BID and 
trametinib 2 mg once daily for 7 to 14 days prior to surgery (Cohort B).  An interim 
analysis will be performed after cohorts A and B have each enrolled 5 patients (with 
cohort A enrolling the first 5 patients and cohort B the second 5). After the first 10 
subjects have been enrolled the planned assignment of subsequent patients to the two 
cohorts will be in groups of 5 beginning with Cohort A then switching to the Cohort B 
until up to 30 patients have been enrolled.  Subjects will be treated for at least 7 days 
prior to craniotomy, but not more than 14 days. This 7-14 day window is allowed for 
scheduling purposes, or if the interim or later analyses determines this duration is needed 
to meet the primary endpoint.  The last dose of study treatment will be given the night 
prior to the craniotomy.  The timing of the last dose prior to surgery may also be adjusted 
based on interim or later analyses to meet primary endpoint.  Protocol specified 
guidelines for dose adjustments, interruptions and discontinuation due to adverse events 
are provided in Section 5.7.  If available, subjects will undergo biopsy of an easily 
accessible extracranial metastasis within 14 days before starting treatment.  All subjects 
will have an MRI of the brain and whole-body PET-CT imaging within 14 days before 
starting study treatment.  All subjects will undergo physical exam and routine lab testing 
prior to starting therapy.  Subjects will initiate study treatment on Day 1.  On the day 
prior to the craniotomy, subjects will be assessed by physical exam and lab testing.  MRI 


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of the brain and whole-body PET-CT imaging will also be performed between 1 to 3 days 
prior to surgery. On the day of surgery, blood samples will be collected for 
pharmacokinetic analysis.  Two samples will be collected prior to surgery, and two 
samples will be collected after surgery; all samples will be separated in time by at least 1 
hour.  Optional collection of CSF will be obtained in the operating room on the day of 
brain metastasis resection; this procedure is described in Section 6.5 of the protocol.  
Portions of the resected brain metastasis(es) that in the clinical judgment of the 
neurosurgeon performing the operation are not required to be submitted for pathological 
confirmation of melanoma brain metastasis will be divided into sections to be used for 
pharmacokinetic, pharmacodynamic, and exploratory translational research studies. 
Optional collection of an easily accessible extracranial metastasis may be performed after 
the PET-CT scan and up to 1 day after the removal of brain metastasis(es); which will be 
similarly divided for studies.  The time of collection of brain metastasis, the plasma 
samples, and the optional extracranial metastasis(es) and CSF will be recorded for the 
purpose of the pharmacokinetic analysis, as well as the time the last dose of study 
treatment was taken.
Subjects in either cohort with intracranial and/or extracranial metastases remaining after 
surgery may resume treatment with the combination of dabrafenib 150 mg BID and 
trametinib 2 mg once daily no earlier than 72 hours after surgery at the discretion of the 
Principal Investigator.  Subjects continuing on treatment will be evaluated for safety 4 
weeks after restarting treatment, and every 4 weeks thereafter.  These subjects will be 
evaluated for efficacy eight weeks after restarting treatment, and every 8 weeks 
thereafter.  
Subjects who do not continue treatment after the craniotomy procedure will be evaluated 
for safety at the discontinuation visit 4 weeks after the craniotomy.
All subjects who permanently discontinue study treatment will be followed for survival 
and new anti-cancer therapy for a total of two years or until death or the subject wishes to 
withdraw from further follow-up.  The study will be considered closed once the last 
subject reaches this milestone. 
This trial will prospectively evaluate the levels of dabrafenib and its metabolites that are 
achieved in melanoma brain metastases, the relationship between the drug levels 
achieved in the brain metastases and in the plasma, and the activation of the MAPK 
pathway and other cell signalling networks in the brain metastases.  In subjects receiving 
dabrafenib in combination with trametinib, drug levels of trametinib will also be 
assessed, where feasible.  Subjects may also undergo optional biopsies of readily 
accessible extracranial tumors (i.e. skin, subcutaneous, superficial lymph nodes) prior to 
initiating treatment and on the same day as the craniotomy.  The activation status of the 
MAPK and other cellular signalling pathways will be determined in the pre- and post-
treatment specimens to determine the degree of pathway inhibition achieved in the 
extracranial metastases, which will be compared to the activation status of the pathway in 
the brain metastases at the time of resection.  The levels of dabrafenib and its metabolites 
will also be determined in the available extracranial metastases for comparison to the 
pharmacodynamic effects, and for comparison to the levels achieved in the brain 
metastases and the plasma.  For subjects who consent to the optional procedure, we will 


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also determine the levels of dabrafenib and its metabolites in the CSF, which will be 
collected at the time of the craniotomy, and will be compared to the levels in the plasma 
and in the brain metastases.  Exploratory studies of the activation status of other pro-
survival pathways as well as for the prevalence of BRAF and activating mutations in 
other oncogenes will also be performed on the tissues obtained from the study.  The study 
also incorporates imaging to detect early clinical responsiveness of the brain and 
extracranial lesions, for correlation with the results of the pharmacokinetic and 
pharmacodynamic studies, and the pathologic and immunological features of the tumor.
Figure 1
Study Schema
3.1.
Discussion of Design
The trial will evaluate the pharmacokinetics, pharmacodynamics, exploratory 
translational research, and safety endpoints of preoperative treatment of dabrafenib and 
dabrafenib combined with trametinib in subjects with resectable metastatic melanoma to 
the brain.
3.1.1.
Dose Rationale
Dabrafenib 150 mg BID was  studied in Phase II and Phase III studies of patients with 
metastatic melanoma (including patients with melanoma that has metastasized to the 
brain), and was the basis for the dose level described in the current US Prescribing 
Information.  
The dose combination of dabrafenib 150 mg BID combined with trametinib 2 mg once 
daily was clinically active and well-tolerated in a phase II study [Flaherty, 2012b], and is 
presently under study in three pivotal phase III trials. 


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3.1.2.
Treatment Duration and Timing Rationale
The goals of the study include both pharmacokinetic and pharmacodynamic evaluations.  
Thus, the duration of pre-operative treatment is designed to result in surgery prior to 
significant tumor tissue degradation due to apoptosis and/or necrosis.  Based on 
pharmacokinetic analyses from the FTIH study, dabrafenib exposure decreases with time 
and is near steady state after about 14 days of dosing.  However, two of the dabrafenib 
metabolites accumulate with repeat dosing due to their long half-life and are generally 
stable after one week of dosing.  Based on these PK data and the analysis of a selected 
number of tumor tissue biopsies performed between 8 to 15 days of treatment, it is 
estimated that the ideal duration of treatment will be 7 to 14 days.  In the initial phase of 
the trial, the treatment duration goal will be for 7 days, with 24-48 hour variance allowed 
for scheduling conflicts.  Study treatment will be taken until the evening before surgery.  
Concentrations of dabrafenib and hydroxyl-dabrafenib should be in the terminal, linear 
phase during surgery while concentrations of carboxy-dabrafenib and desmethyl-
dabrafenib should be fairly constant.  This will allow better estimations of brain to 
plasma equilibrium. A sample quality review will take place after 3 subjects have been 
treated to allow for evaluation of modifiable treatment logistics and the ability to 
complete the primary objective of the study. This sample quality review will include an 
assessment of the quality of the tissue samples from the resected brain and optional 
extracranial metastases for the planned pharmacokinetic and pharmacodynamic analyses.
In addition, the results of the pharmacokinetic analysis of dabrafenib and its metabolites 
for the first 3 subjects will be reviewed. Adjustments may be made to the duration of the 
treatment before surgery, and/or the timing of the last dose of dabrafenib that is 
administered prior to surgery, based on the review of the results by the participating 
investigators. Subject safety and any unexpected toxicities will also be reviewed.
Accrual will continue during this formal review. Additional analyses will be performed 
after the last patient in the dabrafenib cohort reaches the 4-week post-craniotomy 
assessment or withdraws from the study, whichever comes first.
Among all subjects treated with dabrafenib 150 mg BID on the phase I study, the most 
common adverse events documented to occur or start within the first 15 days on drug 
were pyrexia (19%; all grade 1 or 2), headache (17%; 1 grade 3), anemia (16%; 1 grade 
3, 1 grade 4), and rash (14%; all grade 1-2).  There were 2 cases of neutropenia (both 
grade 2), and no cases of thrombocytopenia.  Of note, based on the adverse event 
reporting in that trial, it is not possible to tell if the grade 4 anemia actually occurred 
during the first 15 day or it rather started within this timeframe and at some point reached 
grade 4.  In that same trial, 36 subjects underwent a total of 51 invasive procedures.  The 
majority (n=28) of the procedures were biopsies or removal of cutaneous lesions.  Other 
significant procedures included hemicolectomy (n=2), laminectomy (n=1), and tibia 
hardware replacement with debridement (n=1).  One subject underwent gamma knife 
treatment of a brain metastasis.  Three subjects underwent resection of intracranial 
lesions, one of whom underwent evacuation of an intracerebral hematoma that developed 
in the setting of disease progression more than 10 days after discontinuation of 
dabrafenib.  Adverse events occurring within 15 days of surgery included the single 
intracerebral hemorrhage described above, one post-procedural complication 
(inflammation of a biopsy site), and one post-procedural pain.  There were no wound 
healing or infectious adverse events observed [GlaxoSmithKline Document Number 
CM2010/00010/03]. 


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4.
SUBJECT SELECTION AND DISCONTINUATION/ 
COMPLETION CRITERIA
4.1.
Subject Selection Criteria
4.1.1.
Number of Subjects
Up to 30 evaluable subjects (up to 15 per cohort) will be enrolled in this study.  An 
interim analysis will be performed after both cohorts A and B have enrolled 5 subjects. 
Subjects may have received prior treatment for brain metastatses.  If subjects do not 
complete the full pre-operative treatment regimen, or if their samples cannot be 
evaluated, they will be replaced with another subject until a total of 15 subjects per cohort 
have been treated and evaluated.
See Section 9.1.1 for sample size assumptions.
4.1.2.
Inclusion Criteria
Specific information regarding warnings, precautions, contraindications, adverse events, 
and other pertinent information on study treatment  that may impact subject eligibility is 
provided in the GSK2118436 IB [GlaxoSmithKline Document Number 
CM2010/00010/03] and the GSK1220212 + GSK2118436 IB [GlaxoSmithKline 
Document Number 2011N126811_01]
Deviations from inclusion criteria are not allowed because they can potentially jeopardize 
the scientific integrity of the study, regulatory acceptability or subject safety.  Therefore, 
adherence to the criteria as specified in the protocol is essential.
Subjects eligible for enrolment in the study must meet all of the following criteria:
1.
Signed written informed consent
2.
Histologically-confirmed metastatic melanoma (Stage IV), carrying BRAF V600E or 
V600K mutation as determined by testing certified for clinical diagnostic purposes. 
Previously performed certified BRAF testing is acceptable.  If no prior BRAF 
mutation testing results are available, testing of a distant metastasis is preferred, but 
testing of a regional metastasis or primary tumor is also acceptable.
3.
At least one previously untreated intracranial lesion ≥ 1.0 cm but ≤ 4.0 cm that can 
be treated with surgical resection in the opinion of the treating physicians, and for 
which immediate local therapy is not clinically indicated.
4.
Age > 18 years of age.
5.
Able to swallow and retain oral medication 
6.
Women with child-bearing potential must be willing to practice acceptable methods 
of birth control during the study (See Section 7.3.2).
7.
Women of childbearing potential must have a negative serum pregnancy test within 
14 days of first dose of study treatment. 


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8.
Must be able to understand and comply with protocol requirements and instructions.
9.
Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 [Oken, 
1982].
10. Must have adequate organ function as defined by the following screening values in 
Table 2:
Table 2
Definitions for Adequate Baseline Organ Function
System
Laboratory Values
Hematologic
ANC
1.2 × 109/L
Hemoglobin
9 g/dL 
Platelet count
100 x 109/L
PT/INRa and PTT
1.3 x ULN
Hepatic
Total bilirubin
1.5 x ULN
AST and ALT
2.5 x ULN 
Renal
Serum creatinineb
1.5 mg/dL 
Cardiac
Left Ventricular Ejection fraction (LVEF)c
≥ LLN by ECHO 
1.
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.  
a.
Subjects receiving anticoagulation treatment may be allowed to participate with INR established within the 
therapeutic range prior to randomization.  
b.
If serum creatinine is > 1.5 mg/dL, calculate creatinine clearance using standard Cockcroft-Gault formula 
(Appendix 2).  Creatinine clearance must be 50 mL/min to be eligible. 
4.1.3.
Exclusion Criteria
Deviations from exclusion criteria are not allowed because they can potentially 
jeopardize the scientific integrity of the study, regulatory acceptability or subject safety.  
Therefore, adherence to the criteria as specified in the protocol is essential.
Subjects meeting any of the following criteria must not be enrolled in the study:
1.
Neurological symptoms related to brain metastasis that are not controlled with a 
stable or decreasing dose of oral steroids for at least 7 days prior to starting study 
treatment.  
2.
Prior whole brain radiation (WBRT). Prior treatment with stereotactic radiosurgery is 
permitted so long as there is one evaluable lesion which has not been treated with 
SRS.
3.
Previous treatment with a BRAF or MEK inhibitor.
4.
Cancer therapy (chemotherapy with delayed toxicity, extensive radiation therapy, 
immunotherapy, biologic therapy, or major surgery) or investigational anti-cancer 


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drugs within the last 3 weeks, or chemotherapy without delayed toxicity within the 
last 2 weeks, preceding the first dose of study treatment.
5.
Current or expected use of a prohibited medication as described in Section 6.2, 
including enzyme-inducing antiepileptic drugs (EIAEDs) during treatment with 
dabrafenib. 
6.
Presence of leptomeningeal disease or dural metastases.
7.
History of another active malignancy within the past 5 years, or any malignancy with 
a confirmed activating RAS mutation.  Please note prospective RAS mutation testing 
is not required, however, if results of previous RAS testing are known, they must be 
used in assessing eligibility.  Subjects with a history of completely resected non-
melanoma skin cancer are eligible.  
8.
Known allergies against contrast agents required for MRI of intracranial lesions, or 
other contraindications for MRI, i.e., pacemaker. 
9.
Current use of therapeutic warfarin. Low-molecular-weight heparin and prophylactic 
low-dose warfarin are permitted.
10. Unresolved toxicity of National Cancer Institute Common Terminology Criteria for 
Adverse Events, version 4.0 (CTCAE v4.0) [NCI, 2009] Grade 2 or higher from 
previous anti-cancer therapy, except alopecia.
11. Presence of active gastrointestinal disease or other condition that will interfere 
significantly with the absorption of drugs.  
12. History of a prior symptomatic stroke, dementia, or other significant central 
neurologic condition (i.e. multiple sclerosis).
13. A history of known Human Immunodeficiency Virus (HIV), Hepatitis B Virus 
(HBV), or Hepatitis C Virus (HCV) infection.
14. Current acute infection requiring intravenous antibiotics.
15. A history or evidence of cardiovascular risk, including any of the following cardiac 
abnormalities:

A QT interval corrected for heart rate using Bazett’s Formula; (QTcB) interval 
480 msecs; 

A history of acute coronary syndromes (including myocardial infarction or 
unstable angina), coronary angioplasty, or stenting within 6 months prior to 
randomization; 

A history or evidence of current Class II, III, or IV heart failure as defined by 
the New York Heart Association (NYHA) guidelines; 

Abnormal cardiac valve morphology (≥ Grade 2) documented by 
echocardiogram (ECHO) (subjects with Grade 1 abnormalities [i.e., mild 
regurgitation/stenosis] can be entered on study).  Subjects with moderate 
valvular thickening should not be entered on study. 

History of or evidence of clinically significant uncontrolled cardiac arrhythmias; 


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
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;

Patients with intra-cardiac defibrillators or permanent pacemakers;
16. A history or current evidence/risk of retinal vein occlusion (RVO) or 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.
17. Pregnant, lactating or breastfeeding females
18. Any serious and/or unstable pre-existing medical, psychiatric disorder or other 
conditions that could interfere with subject’s safety, obtaining informed consent or 
compliance to the study procedures.  
19. Have a known immediate or delayed hypersensitivity reaction or idiosyncrasy to 
drugs chemically related to dabrafenib, trametinib or their excipients that 
contraindicate their participation.
4.2.
Permanent Discontinuation from Study Treatment and 
Subject Completion Criteria
All subjects will receive study treatment until the day prior to the resection of their brain 
metastasis (es), or until unacceptable adverse event, including meeting stopping criteria 
for hematologic and other non-hematologic toxicity.  Subjects who have additional 
melanoma metastases after resection of their brain metastasis (es) and optional sampling 
of easily accessible extracranial metastases may resume treatment with the combination 
of dabrafenib 150 mg BID and trametinib 2 mg once daily no earlier than  72 hours after 
completion of their surgical procedures, at the discretion of the treating physician.  
Subjects will be permitted to receive the combination of dabrafenib 150 mg BID and 
trametinib 2 mg once daily until disease progression, death, or unacceptable AE, 
including hematologic or other non-hematologic toxicity, and/or meeting stopping criteria 
for liver chemistry defined in Section 5.7.6.  In addition, study treatment may be 
permanently discontinued at any time for any of the following additional reasons:

deviation(s) from the protocol

request of the subject or proxy

investigator’s discretion

subject is lost to follow-up


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
study is terminated.
The primary reason that study treatment was permanently discontinued must be 
documented in the subject’s medical records and eCRF. 
If the subject voluntarily discontinues from treatment due to toxicity, ‘adverse event’ will 
be recorded as the primary reason for permanent discontinuation on the eCRF.   
Once a subject has permanently discontinued from study treatment, the subject will not 
be allowed to be retreated. 
All subjects who discontinue from study treatment will have safety assessments at the 
time of discontinuation and follow-up as specified in Time and Events Table (Table 19) 
and Section 7.11.
All subjects will be followed for survival and new anti-cancer therapy for a total of two 
years or until the subject wishes to withdraw from further follow-up.
4.2.1.
Subject Completion
A subject will be considered to have completed the study if the subject dies during the 
study, during the follow-up period or has been in survival follow-up for 2 years.  The 
cause of death will be recorded in the eCRF. A subject will be considered to have
withdrawn from the study if the subject has not died and is lost to follow-up, has 
withdrawn consent, is no longer being followed at the investigator’s discretion, or if the 
study is terminated. 
5.
STUDY TREATMENTS
The term ‘study treatment’ is used throughout the protocol to describe any combination 
of products received by the subject per the protocol design. Study treatment may 
therefore refer to the individual study treatments or the combination of those study 
treatments.
5.1.
Investigational Products
5.1.1.
Dabrafenib
Dabrafenib will be provided to sites by GSK. The contents of the label will be in 
accordance with all applicable regulatory requirements.
Dabrafenib study treatment will be provided for oral administration as 50 mg and 75 mg 
capsules.  Each capsule contains 50 mg or 75 mg as free base (present as the mesylate 
salt).  Under normal conditions of handling and administration, investigational product is 
not expected to pose significant safety risks to site staff.  A Material Safety Data Sheet 
(MSDS) describing the occupational hazards and recommended handling precautions will 
be provided to site staff upon request.


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5.1.2.
Trametinib
Trametinib will be provided to sites by GSK.  The contents of the label will be in 
accordance with all applicable regulatory requirements. 
Trametinib study treatment 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).  The 
inactive ingredients will include mannitol, sodium lauryl sulfate, colloidal silicon 
dioxide, microcrystalline cellulose, hypromellose, croscarmellose sodium, magnesium 
stearate, and film coating (Opadry, a titanium dioxide-based formulation with yellow or 
red iron oxide as colorant).  Both tablet strengths are biconvex film coated tablets with a 
different shape and size to facilitate the visual identification.  The 0.5 mg strength is a 
4.8x8.7 mm yellow, oval tablet, and the 2.0 mg strength is a 7.5 mm diameter, pink, 
round tablet.
5.1.3.
Study Treatment Dosage and Administration
Both study treatment cohorts should take their assigned treatment in the morning at 
approximately the same time every day.   Study treatment should be taken orally with 
approximately 200 mL of water under fasting conditions, either one hour before or two 
hours after a meal.  The second dose of dabrafenib (150 mg) should be administered 
approximately 12 hours after the morning dose.  
If a subject vomits after taking study medication, the subject should be instructed not to 
retake the dose and should take the next scheduled dose.  
If a subject misses a dose of dabrafenib, the subject should not double the next regularly 
scheduled dose.  However, the subject can take the missed dose immediately if the next 
scheduled dose is at least 6 hrs later.  The subject should take the next dose at the usual 
time.  
If a subject misses a dose of trametinib, the subject should not double the next regularly 
scheduled dose.  However, the subject can take the missed dose immediately if the next 
scheduled dose is at least 12 hrs later.  The subject should take the next dose at the usual 
time.
Refer to Section 5.7 for information on dose modifications of study treatment.
5.2.
Handling and Storage of Study Treatment
No special preparation of study treatment is required.
Dabrafenib and trametinib must be dispensed and administered in accordance with the 
protocol, and only to subjects enrolled in the study.  Dabrafenib and trametinib must be 
stored in a secure area under the appropriate physical conditions for the product at the 
temperature specified on the label.  Maintenance of a temperature log (manual or 
automated) is required.  Access to and administration of study treatment will be limited to 
the investigator and authorized site staff.
Procedures for final disposition of unused study treatments will be provided in the SPM.


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5.3.
Treatment Assignment
Subjects will be identified by a unique subject number for the duration of the study. Each 
site will be given a subject number range. The first 5 enrolled subjects will receive 
dabrafenib 150 mg twice daily (Cohort A).  The second 5 enrolled subjects will receive 
dabrafenib 150 mg twice daily in combination with trametinib 2 mg once daily (Cohort 
B).  After the first 10 subjects have been enrolled the planned assignment of subsequent 
patients to the two cohorts will be in groups of 5 beginning with Cohort A then switching 
to the Cohort B until up to 30 patients have been enrolled.
Upon completion of all the required screening assessments, eligible subjects will be 
registered into RAMOS (Registration and Medication Ordering System), the GSK 
interactive voice response system (IVRS), by the investigator or authorized site staff.  
Study-specific instructional worksheets will be provided for the use of RAMOS. All calls 
to RAMOS are confirmed with a fax, which will be sent to the site upon completion of 
each call. 
Subjects who begin, but discontinue treatment prior to the planned pre-operative 
treatment duration, or who fail to undergo surgical resection and collection of their brain 
metastasis (es) and extracranial metastases for pharmacokinetic analysis (the primary 
objective of the study will be replaced in the study.  Once 30 subjects have completed the 
treatment and assessments described in the protocol, the study will be closed to further 
enrolment. 
5.4.
Blinding
This is an open-label study.
5.5.
Product Accountability
In accordance with local regulatory requirements, the investigator, designated site staff, 
or head of the medical institution (where applicable) must document the amount of 
investigational product dispensed and/or administered to study subjects, the amount 
returned by study subjects, and the amount received from and returned to GSK, when 
applicable.  Product accountability records must be maintained throughout the course of 
the study.  Refer to the SPM for further detailed instructions on product accountability.
5.6.
Treatment Compliance
Compliance with study treatment will be assessed through querying the subject during the 
site visits and documented in the source documents and electronic case report form 
(eCRF). A record of the number of dabrafenib capsules and trametinib tablets dispensed 
to and taken by each subject must be maintained and reconciled with study treatment and 
compliance records.  Treatment start and stop dates, including dates of dose 
modifications and/or interruptions will also be recorded in the eCRF.
5.7.
Dose Modification Guidelines
The severity of AEs will be graded using the CTCAE, version 4.0.  The section includes:


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
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 subjects receiving 
dabrafenib, trametinib, or a combination of both therapies.
With the exceptions of pyrexia which is likely related to dabrafenib, and LVEF decrease, 
retinal vein occlusion (RVO), central serous retinopathy (CSR), and retinal pigment 
epithelial detachment (RPED) which are likely related to trametinib, guidance suggests 
that both therapies be reduced simultaneously in response to toxicities that are considered 
by the investigator to be treatment related.
Table 3
Categories of Dose Modification Guidelines
Adverse Event
Dabrafenib
Trametinib
Section
General Guidelines for Clinically 
Significant Toxicities
X
X
Section 5.7.2
Guidelines for Specific Adverse Events
Cardiovascular Adverse Events
LVEF
X
Section 5.7.3.1
Hypertension 
X
X
Section 5.7.3.2
Prolonged QTc
X
X
Section 5.7.3.3
Skin–Related Adverse Events (Except cuSCC)a
Rash
X
X
Section 5.7.4.1
Hand-Foot Skin Reaction
X
X
Section 5.7.4.2
Other Adverse Events
Pyrexia
X
Section 5.7.5.1
Diarrhea
X
X
Section 5.7.5.2
Renal Insufficiency
X
X
Section 5.7.5.3
Visual Changes
X
X
Section 5.7.5.4
Pneumonitis
X
X
Section 5.7.5.5
Liver Chemistry Stopping Criteria
X
X
Section 5.7.6.1
a.
Refer to Section 5.7.4.3 for management of cuSCC.
5.7.1.
Dose Levels of Dabrafenib and Trametinib
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
1.
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.


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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 subjects 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 subjects will be allowed to continue dabrafenib.
Note: Approval from the GSK Medical Monitor is required to restart study 
treatment after ≥21 days of interruption. 
5.7.2.
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 (see Table 3) are provided in Table 5.
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 

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 subject is clinically benefiting, discuss 
continuation of study treatment with the GSK medical monitor.  
For adverse events of abdominal pain or suspected pancreatitis, amylase and lipase laboratory samples should be 
collected.


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5.7.3.
Guidelines for Cardiovascular Adverse Events
Cardiovascular adverse events have been seen in subjects receiving, trametinib or 
dabrafenib in combination with trametinib. 
5.7.3.1.
Left Ventricular Ejection Fraction (LVEF)
Decreases of the left-ventricular-ejection-fraction (LVEF) have been observed in subjects 
receiving trametinib monotherapy and in combination with dabrafenib. Therefore, 
ECHOs must be performed to assess cardiac ejection fraction in regular intervals as 
outlined in the Time and Events Table (Table 19).  Dose modification guidance and 
stopping criteria for LVEF decrease are provided in Table 6.
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 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 trametinib
Repeat ECHO after 2, 4, 8, 12, and 16 
weeks or until resolution
Consult with GSK medical monitorc
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%


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1.
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, orthopnea, and other signs and symptoms of pulmonary congestion and 
edema.
c.
Once LVEF recovers, restarting dabrafenib monotherapy can be considered in consultation with GSK medical 
monitor.
5.7.3.2.
Hypertension
Increases in blood pressure have been observed in subjects receiving trametinib. 
Recommendations for blood pressure monitoring and management are provided in 
Section 5.7.3.2.1 and Section 5.7.3.2.2, respectively. 
5.7.3.2.1.
Monitoring of Hypertension
All blood pressure assessments should be performed under the following optimal 
conditions:

the subject has been seated with back support, ensuring that legs are uncrossed 
and flat on the floor

the subject 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 subjects arm is supported so that the middle of the cuff is at heart level

the subject remains quiet during the measurement. 
In subjects 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. 
5.7.3.2.2.
Management of Hypertension
For subjects 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 below:


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Table 7
Management and Dose Modification Guidelines for Hypertension
Hypertension
Action and Dose Modification
(Scenario A)

Asymptomatic and persistent a SBP of ≥140 and 
<160 mmHg, or DBP ≥90 and <100 mmHg, 
or 

Clinically significant increase in DBP of 20 mmHg 
(but still below 100 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-controlled b 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 controlled b, restart study 
treatment reduced by one dose level
(Scenario C)

Symptomatic c hypertension 
or 

Persistent 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.
1.
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.


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5.7.3.3.
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 all study treatments until QTcB prolongation 
resolves to grade 1 or baseline

Recommend testing serum potassium, calcium, 
phosphorus and magnesium. If abnormal, correct per 
routine clinical practice to within normal limits.

Review concomitant medication usage for a prolonged 
QTc.

Restart at current dose levelb

If event recurs, permanently discontinue study 
treatments.
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 subject may resume study treatment if the investigator 
and GSK medical monitor agree that the subject will benefit from further treatment.
5.7.4.
Guidelines for Skin-related Adverse Events
Cutaneous adverse events have been observed in subjects 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 5.7.4.1, Section 5.7.4.2 , and Section 5.7.4.3). 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, the Sponsor may require biopsies 
of any new skin lesions especially those suspicious of cuSCC for further study.  
5.7.4.1.
Rash
Rash is a frequent AE observed in subjects receiving trametinib, dabrafenib, or the 
combination of both therapies. Guidelines for rash management are based on experience 
with other MEK inhibitors and EGFR inhibitors [Balagula, 2010; Lacouture, 2011] and 
are provided below (Table 9 and Table 10).


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Table 9
Guidelines for Supportive Care of Rash
Type of Care
Action
Prevention/Prophylaxis:
Start from Day 1

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.
Prevention/Prophylaxis:
Start from Day 29 and 
implement for a total of 6 
weeks

Topical steroids and antibiotics should be applied at least twice daily 
starting on Day 29 of study treatment, to body areas such as face, 
chest, and upper back.  

Use mild-strength topical steroid  (hydrocortisone 1% cream) 
and

topical antibiotic (e.g., clindamycin) or oral antibiotics (e.g., doxycycline 
100 mg BID, minocycline 100 mg BID)
Symptomatic Carea

Pruritic lesions: cool compresses and oral antihistamine therapies 

Fissuring lesions: Monsel’s solution, 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 
1.
Abbreviations:  BID = twice daily; SPF = sun protection factor
a.
Subjects 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.


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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 measures

Use moderate strength topical 
steroida 

Reassess after 2 weeks

Continue study treatment

If rash does not recover to baseline 
within 2 weeks despite best 
supportive care, reduce study 
treatment by one dose levelc
Grade 2

Initiate prophylactic and 
symptomatic treatment measures

Use moderate strength topical 
steroida

Reassess after 2 weeks

Reduce study treatment by one 
dose level

If rash recovers to ≤grade 1 
within 2 weeks, increase dose 
to previous dose level

If no recovery to ≤grade 1 
within 2 weeks, interrupt study 
treatment until recovery to 
≤grade 1

Restart study treatment at  
reduced dose levelb
Grade ≥3

Use moderate strength topical 
steroidsa PLUS oral methyl-
prednisolone dose pack

Consult dermatologist 

Interrupt study treatment until rash 
recovers to grade ≤1

Restartb with study treatment 
reduced by one dose levelc

If no recovery to grade ≤2 within 4 
weeks, permanently discontinue 
study treatment
1.
Abbreviations:  CTCAE = Common Terminology Criteria for Adverse Events
a.
Moderate-strength topical steroids: hydrocortisone 2.5% cream or fluticasone prioprionate 0.5% cream
b.
Approval of GSK medical monitor is required to restart study treatment after ≥21 days of interruption.
c.
Escalation of study treatment to previous dose level may be considered if no rash is evident 4 weeks after 
restarting study treatment


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5.7.4.2.
Guidelines for Hand-foot Skin Reactions (HFSR)
Episodes of Hand-Foot Skin Reaction (HFSR) have been observed in subjects receiving 
dabrafenib. Guidelines for management of HFSR are based on experience with other 
kinase inhibitors [Lacouture, 2008; McLellan, 2011] and are listed Table 11.
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 1d

Restart with study treatment reduced 
by one dose levele

If 3rd occurrence, discontinue study 
treatment permanently 
1.
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 
d.
Approval of GSK medical monitor is required to restart study treatment after ≥21 days of interruption
e.
Escalation of study treatment to the previous dose level is allowed if no HFSR is observed in the 4 weeks 
subsequent to dose reduction. 


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5.7.4.3.
Guidelines for cuSCC
Cutaneous squamous cell carcinoma has been observed in subjects treated with 
dabrafenib and the combination of dabrafenib and trametinib. 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. Submit tumor tissue from cuSCC or 
other suspected new primary cancers for analysis (including RAS-mutation status and 
other mutations as appropriate) as directed in the SPM.
5.7.5.
Guidelines for Other Adverse Event of Special Interest
5.7.5.1.
Guidelines for Pyrexia
Episodes of pyrexia have been observed in subjects 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 ≥ Grade 3 hypotension, or hypotension that is clinically 
significant in the judgment of the investigator, or dehydration requiring IV fluids, or 
severe rigors/chills should be reported as an SAE per Section 7.3.2.2. 
Subjects should be instructed on the importance of immediately reporting febrile 
episodes.  In the event of a fever, the subject should be instructed to take non-steroidal 
anti-pyretics as appropriate to control fever.  In subjects experiencing pyrexia associated 
with rigors, severe chills, dehydration, hypotension, etc., renal function should be 
monitored carefully (see Section 5.7.5.3). 
Guidelines regarding management and dose reduction for pyrexia considered to be 
related to study treatment are provided in Table 12.


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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

Blood sample for cytokine analysise

Administer anti-pyretic treatment if clinically 
indicated and continue prophylactic 
treatmentf
2nd Eventg

Clinical evaluation for infection and 
hypersensitivityc

Laboratory work-upc

Hydration as requiredd

Blood sample for cytokine analysise

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

Blood sample for cytokine analysise

within 3 days of onset of pyrexia:

Optimize oral corticosteroid dose as 
clinically indicated for recalcitrant 
pyrexiag

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 levelh

If dabrafenib must be reduced to 
<75 mg BID, permanently 
discontinue dabrafenib


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a.
Pyrexia is defined as a body temperature equal to or above 38.5 Celsius or 101.3○Fahrenheit. 
b.
For subjects 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.  For subjects experiencing rigors/chills without pyrexia, 
work-up and supportive care, including interruption of study treatment, are 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, BUN, CRP, liver-function tests, blood culture, and urine 
culture.
d.
Oral hydration should be encouraged in subjects without evidence of dehydration.  Intravenous hydration is 
recommended in subjects experiencing pyrexia complicated by dehydration/hypotension.
e.
Blood samples for cytokine analysis should be taken immediately at the start of fever (i.e., when the subject is 
being evaluated for fever), and after the fever has disappeared (i.e., during the next routine visit).  Blood samples 
for cytokine analysis must be sent to the central laboratory
f.
Anti-pyretic treatment may include ibuprofen, or suitable anti-pyretic medication according to institutional 
standards. Acetaminophen should be used with caution, especially in subjects with elevated liver enzymes.  
Prophylactic anti-pyretic treatment may be discontinued after three days in the absence of pyrexia
g.
In subject 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.
h.
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.
5.7.5.2.
Guidelines for Diarrhea
Episodes of diarrhea have occurred in subjects receiving dabrafenib, trametinib, or both 
therapies in combination. Other, frequent causes for diarrhea 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 diarrhea considered to be 
related to study treatment by the investigator are provided in Table 13.


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Table 13
Management and Dose Modification Guidelines for Diarrhea
CTCAE Grade
Adverse Event Management
Action and Dose Modification
Uncomplicated 
Diarrheaa
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 diarrhea free for 12 hours

Diarrhea > 24h: loperamide 2 mg every 
two hours; maximum 16 mg/day.  Consider 
adding oral antibiotics

Diarrhea > 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 diarrhea is grade 2 for > 48h, 
interrupt study treatment until diarrhea 
resolves to grade ≤1

Restart study treatment at the same 
dose level
Uncomplicated 
Diarrheaa
Grade 3 or 4
Any Complicated 
Diarrheab

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 diarrhea 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 
subject is diarrhea free for ≥ 24 hours

Intervention may require hospitalization for 
subjects at risk of life-threatening 
complications

Interrupt study treatment until diarrhea 
resolves to grade ≤1

Restart with study treatment reduced 
by one dose level d

If 3 dose reductions of study treatment 
are clinically indicated, permanently 
discontinue study treatment
1.
Abbreviation:  CTCAE = Common Terminology Criteria for Adverse Events
a.
Uncomplicated diarrhea 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 diarrhea 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 diarrhea
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 diarrhea in the 4 weeks subsequent to dose reduction.


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5.7.5.3.
Guidelines for Renal Insufficiency
Cases of renal insufficiency have occurred in subjects 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

Subject 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
1.
Abbreviations:  GSK = GlaxoSmithKline; NSAIDS = non-steroidal anti-inflammatory drugs
a.
NSAIDs can induce renal insufficiency, especially in subjects with dehydration; encourage oral fluids or consider 
intravenous fluids as clinically indicated. See guidelines for pyrexia 5.7.5.1.
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 microangiopathy.


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5.7.5.4.
Guidelines for Visual Changes
Episodes of visual changes have been observed in subjects receiving trametinib, 
dabrafenib, and combination therapy. An ophthalmologist should be consulted if changes 
in vision develop. However, if the visual changes are clearly unrelated to study treatment 
(e.g., allergic conjunctivitis), then monitor closely as it may be reasonable to defer 
ophthalmic examination.
Treatment with dabrafenib has been associated with the development of uveitis, including 
iritis. Monitor patients for visual signs and symptoms (such as, change in vision, 
photophobia and eye pain) during therapy. Special attention should be given to retinal 
findings (e.g., retinal pigment epithelial detachment (RPED) or retinovascular
abnormalities (i.e., branch or central retinal vein occlusions (RVO). For events of visual 
changes (regardless of severity) for which an ophthalmic examination is conducted, a 
blood sample for PK analysis must be drawn as close as possible to the time of the event.
Guidelines regarding management and dose reduction for visual changes and/or 
ophthalmic examination findings considered to be related to study treatment are provided 
in Table 15.


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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


If dilated fundus examination cannot 
be performed within 7 days of onset, 
interrupt trametinib until RPED and 
RVO can be excluded by retina 
specialist/ophthalmologist. If subject is 
receiving trametinib/dabrafenib 
combination therapy dabrafenib may 
be continued.

If RPED and RVO excluded, continue 
(or restart) trametinib at same dose 
level

If RPED suspected or diagnosed: see 
RPED dose modification table Y 
below; report as SAE if diagnosed.

If RVO diagnosed:  Permanently 
discontinue trametinib and report 
as SAE.
Grade 2 and
Grade 3

Consult ophthalmologist 
immediately

Interrupt trametinib. If subject is 
receiving trametinib/dabrafenib 
combination therapy dabrafenib 
may be continued.


If RPED and RVO excluded, restart 
trametinib at same dose level. 

If RPED diagnosed, see RPED dose 
modification table below; report as 
SAE.

If RVO diagnosed: Permanently 
discontinue trametinib and report 
as SAE

Grade 4

Consult ophthalmologist 
immediately 

Interrupt trametinib. If subject is 
receiving trametinib/dabrafenib 
combination therapy dabrafenib 
may be continued.


If RPED and RVO excluded, may 
consider restarting trametinib at same 
or reduced dose after discussion with 
study medical monitor

If RVO or RPED diagnosed, 
permanently discontinue 
trametinib and report as SAE.
1.
Abbreviations:  CSR = central serous retinopathy; 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.


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5.7.5.5.
Guidelines for Pneumonitis
Pneumonitis has been observed in subjects receiving trametinib. To reduce the risk of 
pneumonitis, subjects 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.
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
1.
Abbreviations:  BAL= bronchoalveolar lavage; CT = computed tomography; CTCAE = Common Terminology 
Criteria for Adverse Events


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5.7.6.
Liver Chemistry Stopping and Follow-Up Criteria
5.7.6.1.
Liver Chemistry Stopping Criteria
These liver chemistry stopping and follow up criteria have been designed to assure 
subject safety and evaluate liver event aetiology in alignment with the FDA Guidance for 
Industry – Drug-Induced Liver Injury: Premarketing Clinical Evaluation (July 2009, 
www.fda.gov).
Phase II liver chemistry stopping criteria 1-5 are defined as follows:
1. Alanine aminotransferase (ALT) 3xULN and bilirubin 2xULN (>35% direct 
bilirubin) (or ALT3xULN and international normalized ratio (INR)>1.5, if INR 
measured)
NOTE: If serum bilirubin fractionation is not immediately available, study drug 
should be discontinued if ALT 3xULN and bilirubin 2xULN. Serum bilirubin 
fractionation should be performed if testing is available.  If testing is not available, 
record presence of detectable urinary bilirubin on dipstick, indicating direct 
bilirubin elevations and suggesting liver injury.
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, 
tenderness or jaundice), or 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 investigational product

Report the event to GSK within 24 hours of learning its occurrence

Complete the liver event case report form (CRF) and serious adverse event (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 subjects receiving 
anticoagulants), termed ‘Hy’s Law’, must be reported as an SAE (excluding 
studies of hepatic impairment or cirrhosis).

NOTE: If serum bilirubin fractionation is not immediately available, and if ALT 
3xULN and bilirubin 2xULN, discontinue subject from study treatment. 
Serum bilirubin fractionation should be performed if testing is available. If 
testing is unavailable, record presence of detectable urinary bilirubin on 
dipstick, indicating direct bilirubin elevations and suggesting liver injury


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
Complete the liver imaging and/or liver biopsy CRFs (provided by GSK) if these 
tests are performed

Perform liver event follow up assessments, and monitor the subject until liver 
chemistries resolve, stabilize, or return to baseline values as described below

Withdraw the subject from the study (unless further safety follow up is required) 
after completion of the liver chemistry monitoring as described below.  

For studies where survival or progression is an endpoint, follow-up for overall 
survival or progression is required following discontinuation from study treatment. 

Do not rechallenge with investigational product.
In addition, for subjects meeting liver stopping criterion 1: 

Make every reasonable attempt to have subjects return to clinic within 24 hours for 
repeat liver chemistries, liver event follow up assessments (refer to Section 5.7.6.3), 
and close monitoring

A specialist or hepatology consultation is recommended

Monitor subjects twice weekly until liver chemistries (ALT, AST, alkaline 
phosphatase, bilirubin) resolve, stabilize or return to within baseline values.
In addition, for subjects meeting any of the criteria 2 - 5:

Make every reasonable attempt to have subjects return to clinic within 24-72 hrs for 
repeat liver chemistries and liver event follow up assessments (refer to Section 
5.7.6.3)

Monitor subjects weekly until liver chemistries (ALT, AST, alkaline phosphatase, 
bilirubin) resolve, stabilize or return to within baseline values; 

Subjects meeting criterion 5 should be monitored as frequently as possible.
5.7.6.2.
Liver Chemistry Monitoring Criteria
For subjects with ALT 3xULN but <5xULN and bilirubin <2xULN, without hepatitis 
symptoms or rash, and who can be monitored weekly for 4 weeks, the following actions 
should be taken:

Notify the GSK Medical Monitor within 24 hours of learning of the abnormality to 
discuss subject safety

Continue study treatment

Return weekly for repeat liver chemistries (ALT, AST, alkaline phosphatase, 
bilirubin) until they resolve, stabilize or return to within baseline 

If at any time the subject meets any of the liver chemistry stopping criteria 1 – 5, 
proceed as described above

If, after 4 weeks of monitoring, ALT <3xULN and bilirubin <2xULN, monitor 
subjects twice monthly until liver chemistries normalize or return to within baseline 
values. 
Refer to Appendix 3 for an algorithm of liver chemistry monitoring, interruption, 
stopping and follow-up criteria.


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5.7.6.3.
Liver Event Follow Up Assessments
For subjects 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 96 hours of last 
dose.  Record the date/time of the PK blood sample draw and the date/time of the last 
dose of study treatment prior to blood sample draw on the CRF.  If the date or time 
of the last dose is unclear, provide the subject’s best approximation.  If the date/time 
of the last dose cannot be approximated OR a PK sample cannot be collected in the 
time period indicated above, do not obtain a PK sample.  Instructions for sample 
handling and shipping are in the SPM.

Serum creatine phosphokinase (CPK) and lactate dehydrogenase (LDH).

Fractionate bilirubin, if total bilirubin 2xULN.

Obtain complete blood count with differential to assess eosinophilia.

Record the appearance or worsening of clinical symptoms of hepatitis, or 
hypersensitivity, such as fatigue, nausea, vomiting, right upper quadrant pain or 
tenderness, fever, rash or eosinophilia as relevant on the AE report form.

Record use of concomitant medications, acetaminophen, herbal remedies, other over 
the counter medications, or putative hepatotoxins, on the concomitant medications 
report form.

Record alcohol use on the liver event alcohol intake case report form.
The following assessments are required for subjects with ALT 3xULN and bilirubin 
2xULN (>35% direct), but are optional for other abnormal liver chemistries:

Anti-nuclear antibody, anti-smooth muscle antibody, 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.


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
Serum acetaminophen adduct assay (quantifies potential acetaminophen contribution 
to liver injury, detectable by HPLC assay more than 1 week following 
acetaminophen use).

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 polymerase chain reaction (PCR) of hepatitis D RNA virus (where 
needed) – as outlined in: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1153793/
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.  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, and the dates 
of administration are to be recorded.  Additionally, a complete list of all prior surgical 
procedures will be recorded in the eCRF.
Subjects should receive full supportive care during the study, including transfusions of 
blood and blood products, and treatment with antibiotics, anti-emetics, anti-diarrheals, 
and analgesics, and other care as deemed appropriate, and in accordance with their 
institutional guidelines.  Use of anticoagulants such as warfarin is permitted provided that 
INR is monitored in accordance with local institutional practice.  
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 randomization and for the duration of the study will not be allowed. 
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: Subjects with known HIV are ineligible for study 
participation);

Herbal remedies (e.g., St. John’s wort);

Dabrafenib is metabolized primarily by Cytochrome P450 (CYP) 2C8 and 
CYP3A4.  Co-administration of dabrafenib with ketoconazole, a CYP3A4 
inhibition, or with gemfibrozil, a CYP2C8 inhibitor, resulted in increases in 
dabrafenib AUC of 71% and 47%, respectively.  Drugs that are strong inhibitors 


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or inducers of CYP3A and CYP2C8 (see list in Table 1) 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 concentrations; consider 
therapeutic substitutions for these medications.  Approval of the GSK medical 
monitor is required in these situations. The list may be modified based on 
emerging data. Refer to the SPM for the most current list. 
Table 17
Prohibited Medications
PROHIBITED – strong inducers of CYP3A or CYP2C8, since concentrations of dabrafenib may be 
decreased
Class/Therapeutic Area
Drugs/Agents
Antibiotics
Rifamycin class agents (e.g.,  rifampin, rifabutin, rifapentine), 
Anticonvulsant
Carbamazepine, oxcarbazepine phenobarbital, phenytoin, s-mephenytoin 
Miscellaneous
bosentan, St-John’s wort
PROHIBITED – Strong inhibitors of CYP3A, or CYP2C8 since concentrations of dabrafenib may be 
increased
Class/Therapeutic Area
Drugs/Agents
Antibiotics
Clarithromycin, telithromycin, troleandomycin
Antidepressant
Nefazodone
Antifungals
Itraconazole, ketoconazole, posaconazole, voriconazole
Hyperlipidemia
Gemfibrozil
Antiretroviral
ritonavir, saquinavir, atazanavir
Miscellaneous
Conivaptan 
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 they may alter dabrafenib concentrations:

Drugs that are moderate inhibitors or inducers of CYP3A and CYP2C8 as they 
may alter concentrations of dabrafenib.

Dabrafenib has been shown to induce CYP3A4 and CYP2C9 in vivo using 
midazolam (CYP3A4 substrate) and S-warfarin (CYP2C9 substrate).  
Dabrafenib is an in vitro inducer of CYP2B6 and other enzymes such as 
CYP2C8, CYP2C19, UDP-glucuronyl transferases. Transporters may also be 
affected.  Co-administration of dabrafenib and medications which are affected 
by the induction of these enzymes (including warfarin) and transporters may 
result in loss of efficacy.  If co-administration of these medications is necessary,
investigators should monitor subjects 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.

Therapeutic level dosing of warfarin can be used with approval by the GSK 
Medical Monitor and close monitoring of PT/INR by the site. Exposure 
decreased by 37% due to enzyme induction when on treatment, thus warfarin 


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dosing may need to be adjusted based upon PT/INR. Consequently, when 
discontinuing dabrafenib, warfarin exposure may be increased and thus close 
monitoring via PT/INR and warfarin dose adjustments must be made as 
clinically appropriate. Prophylactic low dose warfarin may be given to maintain 
central catheter patency. 

Dabrafenib solubility is pH-dependent with decreased solubility at higher pH. 
Drugs such as proton pump inhibitors that inhibit gastric acid secretion to 
elevate gastric pH may decrease the solubility of dabrafenib and reduce its 
bioavailability. No clinical study has been conducted to evaluate the effect of pH 
on dabrafenib pharmacokinetics. In an ad-hoc analysis, no differences in Cmax 
and AUC were noted between subjects who reported taking pH-elevating 
products relative to other subjects. Due to the theoretical risk that pH-elevating 
agents may decrease oral bioavailability and exposure to dabrafenib, these 
medicinal products that increase gastric pH should be used with caution when 
administered with dabrafenib.


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Table 18
Medications to be used with Caution
USE WITH CAUTION:  Moderate  inhibitors of CYP3A, or CYP2C8 since concentrations of 
dabrafenib may be increased
Class/Therapeutic Area
Moderate CYP3A and CYP2C8 Inhibitors
Antiarrhythmics
Diltiazem, verapamil
Antibiotic
Erythromycin
Antifungal
Fluconazole
Miscellaneous
Aprepitant
USE WITH CAUTION: Co-administration of these drugs with study treatment may result in loss of 
efficacy.  Monitor subjects for loss of efficacy or substitute with another medication.
Class/Therapeutic Area
CYP3A4, CYP2B6, CYP2C8, CYP2C9, CYP2C19 or Transporter 
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, rosuvastatin, pravastatin
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
USE WITH CAUTION: Co-administration of drugs that increase gastric pH should be used with 
caution when administered with dabrafenib.
pH altering agents
Dexlansoprazole. esomeprazole, famotidine, ilaprazole, lansoprazole, 
omeprazole, pantoprazole, rabeprazole, ranitidine
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.


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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 subject’s medical condition whether or not GSK is providing 
specific post-study treatment.
Please refer to Section 7.12 for follow-up assessment of subjects who are to be followed 
up for disease progression and/or survival after permanently discontinuing study 
treatment
6.5.
Treatment of Study Treatment Overdose
In the event of a dabrafenib overdose, defined as administration of more than 300mg as a 
single dose or 600mg daily (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 subject 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 interruptions or modifications should be made by the 
investigator in consultation with the Medical Monitor based on the clinical evaluation of 
the subject.
A plasma sample for PK analysis may be requested by the 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. 
7.
STUDY ASSESSMENTS AND PROCEDURES
A signed, written informed consent form must be obtained from the subject prior to any 
study-specific procedures or assessments.
Refer to the Time and Events Table for the timing of all assessments (Table 19).  Details 
on efficacy and safety assessments are presented in Section 7.2 and Section 7.3, 
respectively.  Further details of study procedures and assessments can be found in the 
study procedures manual (SPM).
Procedures conducted as part of the subject’s routine clinical management (e.g., blood 
count, imaging study) and obtained prior to signing of informed consent may be utilized 
for screening or baseline purposes provided the procedure meets the protocol-defined 
criteria and has been performed in the timeframe of the study. Investigators may be 
requested to perform additional safety tests during the course of the study based on newly 
available data to ensure appropriate safety monitoring.  Appropriate local regulatory and 
ethical approvals should be obtained before any additional testing is performed.


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Table 19
Time and Events Table
Study Assessments1
Screen2
1 to 3 Days 
prior to 
surgery
Day 
prior to 
surgery
Day 
of surgery
Day 3
after surgery
Every 4 weeks 
after restart
Every 8 weeks 
after restart
Discontinuation
Survival
Informed consent
X
Inclusion/exclusion criteria3
X
Demographic data
X
Serum pregnancy test4
X
Register subject
X
Disease characteristics5
X
Prior anti-cancer therapy, 
radiotherapy, surgical procedures
X
Past and current medical 
conditions, family history
X
Past and current tobacco 
consumption
X
Dispense oral study treatment, 
assess compliance6
X
X
X
X
Neurological assessment
X
X
X
Height/weight7
X
X
X
Blood pressure, vital signs8
X
X
X
X
Performance status (ECOG)
X
X
X
Physical examination9
X
X
X
Dermatologic assessment10
X
X
X
ECG11
X
ECHO12
X
X
Ophthalmic examination
X
X (only week 4)
Concomitant medications
X
X
X
Blood products and blood 
supportive care products
X
X
X
Adverse events13
X
Chemistry and Haematology14
X
X
X
X
Coagulation
X
X


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Study Assessments1
Screen2
1 to 3 Days 
prior to 
surgery
Day 
prior to 
surgery
Day 
of surgery
Day 3
after surgery
Every 4 weeks 
after restart
Every 8 weeks 
after restart
Discontinuation
Survival
PET-CT/CT, disease assessment15
X
X
X
X
MRI Brain16
X
X
X
X
X
Biopsy extracranial metastasis(es)
(Optional) 19
X
X19
X19
Removal of brain metastasis(es)
X
Plasma collection for PK studies17
X
CSF collection for PK studies 
(Optional)
X
Photographic skin lesion 
assessment18
X
X
X
Blood Sample for immunologic 
monitoring20
X
X
X
Pharmacogenetics
X


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1. MRI = magnetic resonance imaging; ECOG = Eastern Cooperative Oncology Group; ECG = electrocardiogram; ECHO = echocardiogram; PK = pharmacokinetic.
2. Screening procedures may be performed up to 14 days prior to first dose of study drug, except for ECG and echocardiogram, which may be performed up to 28 days prior to 
the first dose of study drug.  Tumor biopsy may be performed up to 14 days prior to the first dose of the study drug.  Testing results for BRAF V600E and V600K mutation via 
a CLIA-certified testing center at any time prior to enrolment is acceptable.
3. Only subjects who meet all inclusion and exclusion criteria will be eligible to enter into the study.
4. A negative serum pregnancy test will be required within the 14 days prior to the first dose of study treatment.  Subsequent tests may be urine tests, and should be performed 
as clinically indicated.
5. Disease characteristics: Record date of diagnosis, primary tumor type, histology, stage, etc.
6. Record dose reductions, dose interruptions/delays and/or dose escalations.  Subject treatment diary to be reviewed for dosing compliance.
7. Measurements should be in Metric scale.  Height is only measured at screening.
8. Record body temperature, pulse rate, respirations.
9. Physical examination performed at visits listed.
10. Dermatologic exams should be performed by the Investigator, or may be referred to a dermatologist, at the discretion of the Investigator.  If possible, the same physician 
should perform each exam for the duration of the study (i.e. if the subject is referred to a dermatologist for the screening exam, the dermatologist should do all follow-up 
dermatologic assessments) to ensure consistency between evaluations. 
11. ECG assessments must be performed within 28 days prior to starting treatment.  Two copies of the ECG tracing should be obtained at the time of the ECG, one to be kept in 
the study file for retrospective collection by the sponsor if necessary.  
12. Echocardiogram assessments must be performed within 28 days prior to starting treatment, and then repeated at Week 8 and every 16 weeks thereafter.
13. Adverse events assessment should be continuous. 
14. Chemistry and hematology evaluations are performed by the central laboratory. 
15. PET-CT imaging will be performed on all subjects within 14 days of starting treatment.  Imaging is repeated 1-3 days prior to surgery (optimally 1 day prior to surgery).  After 
surgery, disease assessments will be performed by CT will be performed every 8 weeks. 
16. Contrast-enhanced MRI will be performed on all subjects within 14 days of starting treatment.  Imaging is repeated 1-3 days prior to surgery; day 3 after surgery and every 8 
weeks thereafter. 
17. A total of 4 PK samples will be obtained on the day of surgery.  Two samples should be obtained prior to surgery and separated by at least 1 hr. Two samples should be 
obtained after surgery and separated by at least one hour.  The date and time of PK samples and of the dose taken the evening before must be recorded.
18. Skin photography of new non-melanoma skin lesions or non-melanoma lesions that change during treatment must be obtained at each reassessment while the subject is on 
study medication. 
19. Optional collection of extracranial tumor may be performed after the PET-CT scan and up to 1 day after the removal of brain metastasis(es), and at the time of disease 
progression 
20. 1 genomic DNA Yellow/ACD tube at baseline; 3 x 10cc red top serum tubes and 10 x 10 cc heparin/green top tubes for peripheral blood mononuclear cell PBMC isolation at 
baseline, Week 4 and 8 post-craniotomy.


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7.1.
Critical Baseline Assessments
Subjects with histologically-confirmed metastatic melanoma (Stage IV) to the brain will 
be screened for eligibility within 28 days prior to the first dosing day.
Testing for BRAF V600E and V600K mutations may be performed at each participating 
site using a certified clinical test.  Prior CLIA-certified testing result for the presence of a 
BRAF V600E or V600K mutation in a tumor sample from the subject will be acceptable 
for screening.
Cardiovascular medical history/risk factors will be assessed at baseline.
The assessments of brain and (optional) extracranial metastases conducted at baseline and 
during the study are described in Section 7.1.1.
The safety assessments conducted at baseline and during the study are described in 
Section 7.3.
The pharmacokinetic assessments are described in Section 7.3.11.
The pharmacodynamic assessments are described in Section 7.5.
Exploratory research assessments are described in Section 7.7.
7.1.1.
Baseline Assessment of Target and Non-target Lesions
All baseline lesion assessments must be performed within 14 days of the first dose of 
study treatment. 
All brain metastases that are planned for surgical resection and are ≥ 1.0 cm should be 
defined as target lesions, with their size by MRI.
All other intracranial lesions should be identified as non-target and should also be 
recorded at baseline. Measurements of non-target lesions are not required, but the 
presence or absence of each should be noted throughout follow-up. 
For subjects with extracranial metastases, up to a maximum of 2 lesions per organ and 5 
lesions in total should be identified as target lesions.  These lesions should be selected on 
the basis of their size (lesions with the longest diameter) and their suitability for accurate 
repeat measurements (either by imaging techniques or clinically).  Extracranial lesions 
that are identified for optional biopsy after treatment should be identified as target lesions 
if the lesion is assessable for response.
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 <15 mm and but 10 
mm short axis are considered non measurable.  Pathological lymph nodes with 15 mm 
short axis are considered measurable and can be selected as target lesions. However 
lymph nodes should not be selected as target lesions when other suitable target lesions are 
available.  


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Note: Cystic lesions thought to represent cystic metastases should not be selected as 
target lesions when other suitable target lesions are available.
Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue components, 
that can be evaluated by CT or MRI can be considered measurable.   Bone scans, FDG-
PET scans or X-rays are not considered adequate imaging techniques to measure bone 
lesions.  Lytic bone lesions or mixed lytic-blastic lesions will not be considered for 
response by PET-CT.
All other lesions (or sites of disease, excluding the brain) 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.
Efficacy
7.2.1.
Efficacy Endpoints
Efficacy is a secondary objective for this trial.  Efficacy endpoints include:

Overall Survival: defined as the time from first dose of study treatment until death 
due to any cause.

Overall Extracranial Response Rate: defined as the percentage of subjects with 
CR or PR at anytime as per modified Response Evaluation Criteria in Solid 
Tumors (RECIST) 1.1 [Eisenhauer, 2009].

Change from baseline to pre-surgery in the sum of longest diameters of 
intracranial target lesions.

Maximum change from baseline in the sum of longest diameters of unresected 
intracranial target lesions.
7.2.2.
Efficacy Assessment
Disease progression and response will be determined according to the definitions 
established in modified RECIST 1.1 guidelines.
See the Time and Events Table (Table 19) for the schedule of efficacy assessments.  
Assessments must be performed on a calendar schedule and will not be affected by dose 
interruptions/delays.  For post-baseline assessments, a window of 7 days is permitted to 
allow for flexible scheduling.


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7.2.3.
Assessment of Treatment Response in Intracranial and 
Extracranial Metastases
For this study, treatment responses will be assessed in both the brain and extracranial 
metastases when feasible and will be considered separately.  PET-CT imaging will be 
performed within 14 days before the start of treatment, and 1 to 3 days prior to resection 
of brain metastasis(es).  Changes in tumor size of the intracranial target lesions will be 
assessed by MRI of the brain and changes in SUVmax in total-body PET-CT imaging; 
changes in changes in SUVmax of extracranial target lesions will be assessed by total-
body PET-CT.
Given the planned surgical intervention for brain metastases after 7-14 days of treatment, 
response may be evaluated in extracranial lesions. 
7.2.4.
Assessment Guidelines
Please note the following:

The same diagnostic method, including use of contrast when applicable, must be 
used throughout the study to evaluate a lesion.

All measurements should be taken and recorded in millimeters (mm), using a ruler or 
calipers.

Ultrasound is not a suitable modality of disease assessment.  If new lesions are 
identified by ultrasound, confirmation by CT or MRI is required.

Fluorodeoxyglucose (FDG)-PET can be useful in confirming new sites of disease 
where a positive FDG-PET scans correlates with the new site of disease present on 
CT/MRI or when a baseline FDG-PET was previously negative for the site of the 
new lesion. If PET/CT is performed then the CT component can only be used for 
standard response assessments if performed to diagnostic quality, which includes the 
required anatomical coverage and prescribed use of contrast.  The method of 
assessment should be noted as CT on the 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 color photography, including a ruler/calipers to measure the size of the lesion, is 
required [Eisenhauer, 2009].
CT and MRI: Contrast enhanced CT with 5mm contiguous slices is recommended.
Minimum size of a measurable baseline lesion should be twice the slice thickness, with a 
minimum lesion size of 10 mm when the slice thickness is 5 mm. MRI is acceptable, but 
when used, the technical specification of the scanning sequences should be optimized for 
the evaluation of the type and site of disease and lesions must be measured in the same 
anatomic plane by use of the same imaging examinations. Whenever possible, the same 
scanner should be used [Eisenhauer, 2009].
X-ray: In general, X-ray should not be used for target lesion measurements owing to 
poor lesion definition.  Lesions on chest X-ray may be considered measurable if they are 


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clearly defined and surrounded by aerated lung; however chest CT is preferred over chest 
X-ray [Eisenhauer, 2009].
Brain Scan:  If brain scans are required, then contrast enhanced MRI is preferable to 
contrast enhanced CT.
Bone Scan (typically bone scintigraphy):  If a bone scan is performed and a new 
lesion(s) is equivocal, then correlative imaging (i.e., X-ray, CT, or MRI) is required to 
demonstrate malignant characteristics of the lesion(s).  
Note:  PET [FDG or fluoride] may be used in lieu of a standard bone scan providing 
coverage allows interrogation of all likely sites of bone disease and PET is performed at 
all assessments.
7.2.5.
Guidelines for Evaluation of Disease
7.2.5.1.
Measurable and Non-measurable Definitions
Measurable lesion:
A non nodal lesion that can be accurately measured in at least one dimension (longest 
dimension) of:

10 mm with MRI or CT when the scan slice thickness is no greater than 5mm.  If 
the slice thickness is greater than 5mm, the minimum size of a measurable lesion 
must be at least double the slice thickness (e.g., if the slice thickness is 10 mm, a 
measurable lesion must be 20 mm).

10 mm 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

15mm in the short axis when assessed by CT or MRI (slice thickness recommended 
to be no more than 5mm).  At baseline and follow-up, only the short axis will be 
measured [Eisenhauer, 2009].
Non-measurable lesion:
All other lesions including lesions too small to be considered measurable (longest 
diameter <10 mm or pathological lymph nodes with ≥ 10 mm and <15 mm short axis) as 
well as truly non-measurable lesions, which include: leptomeningeal disease, ascites, 
pleural or pericardial effusions, inflammatory breast disease, lymphangitic involvement 
of the skin or lung, abdominal masses/abdominal organomegaly identified by physical 
exam that is not measurable by reproducible imaging techniques [Eisenhauer, 2009].
Measurable disease: The presence of at least one measurable lesion.  Palpable lesions 
that are not measurable by radiologic or photographic evaluations may not be utilized as 
the only measurable lesion.


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Non-Measurable-only disease: The presence of only non-measurable lesions. Note: 
non-measurable only disease is not allowed per protocol.
7.2.6.
Response Criteria
7.2.6.1.
Evaluation of extracranial target lesions
Definitions for assessment of response for extracranial target lesion(s) are as follows:

Complete Response (CR):  Disappearance of all target lesions.  Any pathological 
lymph nodes must be <10mm in the short axis.

Partial Response (PR):  At least a 30% decrease in the sum of the diameters of target 
lesions, taking as a reference, the baseline sum of the diameters (e.g. percent change 
from baseline).

Stable Disease (SD):  Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for progressive disease.

Progressive Disease (PD): At least a 20% increase in the sum of the diameters of 
target lesions, taking as a reference, the smallest sum of diameters recorded since the 
treatment started (e.g. percent change from nadir, where nadir is defined as the 
smallest sum of diameters recorded since treatment start). In addition, the sum must 
have an absolute increase from nadir of 5mm.

Not Applicable (NA): any target lesions at baseline.

Not Evaluable (NE):  cannot be classified by one of the five preceding definitions.
Note:

If lymph nodes are documented as target lesions, the short axis is added into the sum 
of the diameters (e.g. sum of diameters is the sum of the longest diameters for non-
nodal lesions and the short axis for nodal lesions).  When lymph nodes decrease to 
non-pathological size (short axis <10mm) they should still have a measurement 
reported in order not to overstate progression.

If at a given assessment time point all target lesions identified at baseline are not
assessed, sum of the diameters cannot be calculated for purposes of assessing CR, 
PR, or SD, or for use as the nadir for future assessments.  However, the sum of the 
diameters of the assessed lesions and the percent change from nadir should be 
calculated to ensure that progression has not been documented.  If an assessment of 
PD cannot be made, the response assessment should be NE.

All lesions (nodal and non-nodal) should have their measurements recorded even 
when very small (e.g. 2 mm).  If lesions are present but too small to measure, 5 mm 
should be recorded and should contribute to the sum of the diameters, unless it is 
likely that the lesion has disappeared in which case 0 mm should be reported.

If a lesion disappears and reappears at a subsequent time point it should continue to 
be measured.  The response at the time when the lesion reappears will depend upon 
the status of the other lesions.  For example, if the disease had reached a CR status 


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then PD would be documented at the time of reappearance.  However, if the response 
status was PR or SD, the diameter of the reappearing lesion should be added to the 
remaining diameters and response determined based on percent change from baseline 
and percent change from nadir.
7.2.6.2.
Evaluation of intracranial or extracranial non-target lesions
Definitions for assessment of response for non-target lesions are as follows:

Complete Response (CR):  The disappearance of all non-target lesions. All lymph 
nodes identified as a site of disease at baseline must be non-pathological (e.g. <10 
mm short axis).

Non-CR/Non-PD:  The persistence of 1 or more non-target lesion(s) or lymph nodes 
identified as a site of disease at baseline ≥ 10 mm short axis.

Progressive Disease (PD): Unequivocal progression of existing non-target lesions. 

Not Applicable (NA): any non-target lesions at baseline.

Not Evaluable (NE):  cannot be classified by one of the four preceding definitions.
Note:

In the presence of measurable disease, progression on the basis of solely non-target 
disease requires substantial worsening such that even in the presence of SD or PR in 
target disease, the overall tumor burden has increased sufficiently to merit 
discontinuation of therapy.

Sites of non-target lesions, which are not assessed at a particular time point based on 
the assessment schedule, should be excluded from the response determination (e.g. 
non-target response does not have to be "Not Evaluable"). 
7.2.6.3.
New intracranial and/or extracranial 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.
7.2.6.4.
Evaluation of overall extracranial response
Table 20 presents the overall response at an individual time point for all possible 
combinations of tumor responses in target and non-target lesions with or without the 
appearance of new lesions for subjects with measurable extracranial disease at baseline.


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Table 20
Evaluation of Overall Extracranial Response for Subjects with 
Measurable Disease at Baseline
Target Lesions
Non-Target Lesions
New Lesions
Overall Response
CR
CR or NA
No
CR
CR
Non-CR/Non-PD or NE
No
PR
PR
Non-PD or NA or NE
No
PR
SD
Non-PD or NA or NE
No
SD
NE
Non-PD or NA or NE
No
NE
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD
Any
Any
Yes
PD
CR=complete response, PR = partial response, SD=stable disease, PD=progressive disease, NA= Not applicable, 
and NE=Not Evaluable
Note:

Subjects with a global deterioration of health status requiring discontinuation of 
treatment without objective evidence of disease progression at that time should 
be classified as having "symptomatic deterioration." Objective response status is 
determined by evaluations of disease burden. Every effort should be made to 
document the objective progression even after discontinuation of treatment.  

In some circumstances, it may be difficult to distinguish residual disease from 
normal tissue. When the evaluation of CR depends on this determination, it is 
recommended that the residual lesion be investigated (fine needle 
aspirate/biopsy) to confirm the CR.
The best overall response is the best response recorded from the start of the treatment 
until disease progression/recurrence and will be determined programmatically by GSK 
based on the investigator’s assessment of response at each time point. 

To be assigned a status of SD, follow-up disease assessment must have met the SD 
criteria at least once after first dose at a minimum interval of 56 days.

If the minimum time for SD is not met, best extracranial response will depend on 
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, subjects lost to follow-up after an SD assessment not meeting the 
minimum time criteria will be considered not evaluable.
7.3.
Safety
The safety endpoint of this study is the evaluation of safety assessments during treatment 
with dabrafenib or the combination of dabrafenib with trametinib, as measured by the 
nature and frequency of adverse events, laboratory abnormalities, vital signs, 
echocardiograms, 12-lead electrocardiograms (ECG), and clinical monitoring 
/observation.


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7.3.1.
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.
7.3.1.1.
Definition of an AE
Any untoward medical occurrence in a subject or clinical investigation subject, 
temporally associated with the use of a medicinal product, whether or not considered 
related to the medicinal product.
Note: An AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally 
associated with the use of a medicinal product.  For marketed medicinal products, this 
also includes failure to produce expected benefits, abuse, or misuse. Examples of events 
meeting the definition of an AE include:

Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or grade of the condition

New conditions detected or diagnosed after study treatment administration even 
though it may have been present prior to the start of the study

Signs, symptoms, or the clinical sequelae of a suspected interaction

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
treatment or a concomitant medication (overdose per se will not be reported as an 
AE/SAE) 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.  However, any signs and symptoms and/or clinical sequelae 
resulting from “lack of efficacy” will 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 a 
lead to the procedure is an AE.

Situations where an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).

Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present 
or detected at the start of the study that do not worsen.

The disease/disorder being studied or expected progression, signs, or symptoms of 
the disease/disorder being studied, unless more severe than expected for the subject’s 
condition. 


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7.3.1.2.
Definition of a SAE
A serious adverse event is any untoward medical occurrence that, at any dose:
a.
Results in death
b.
Is life-threatening
NOTE:  The term 'life-threatening' in the definition of 'serious' refers to an event in 
which the subject was at risk of death at the time of the event.  It does not refer to an 
event, which hypothetically might have caused death, if it were more severe.
c.
Requires hospitalization or prolongation of existing hospitalization
NOTE:  In general, hospitalization signifies that the subject has been detained 
(usually involving at least an overnight stay) at the hospital or emergency ward for 
observation and/or treatment that would not have been appropriate in the physician’s 
office or outpatient setting. Complications that occur during hospitalization are AEs. 
If a complication prolongs hospitalization or fulfils any other serious criteria, the 
event is serious.  When in doubt as to whether “hospitalization” occurred or was 
necessary, the AE should be considered serious.
Hospitalization for elective treatment of a pre-existing condition that did not worsen 
from baseline is not considered an AE.
d.
Results in disability/incapacity, or
NOTE:  The term disability means a substantial disruption of a person’s ability to 
conduct normal life functions.  This definition is not intended to include experiences 
of relatively minor medical significance such as uncomplicated headache, nausea, 
vomiting, diarrhea, influenza, and accidental trauma (e.g. sprained ankle) which may 
interfere or prevent everyday life functions but do not constitute a substantial 
disruption.
e.
Is a congenital anomaly/birth defect. 
f.
Medical or scientific judgment should be exercised in deciding whether reporting is 
appropriate in other situations, such as important medical events that may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize 
the subject or may require medical or surgical intervention to prevent one of the 
other outcomes listed in the above definition. These should also be considered 
serious. Examples of such events are invasive or malignant cancers, intensive 
treatment in an emergency room or at home for allergic bronchospasm, blood 
dyscrasias or convulsions that do not result in hospitalization, or development of 
drug dependency or drug abuse.
g.
Protocol-Specific SAEs:

All events of possible drug-induced liver injury with hyperbilirubinaemia 
defined as ALT 3xULN and bilirubin 2xULN (>35% direct) (or ALT 
3xULN and INR>1.5, if INR measured) or termed ‘Hy’s Law’ events (INR 
measurement is not required and the threshold value stated will not apply to 
subjects receiving anticoagulants).


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
NOTE: bilirubin fractionation is performed if testing is available. If testing is 
unavailable, record presence of detectable urinary bilirubin on dipstick 
indicating direct bilirubin elevations and suggesting liver injury. If testing is 
unavailable and a subject meets the criterion of total bilirubin 2xULN, then the 
event is still reported as an SAE. If INR is obtained, include values on the SAE 
form. INR elevations >1.5 suggest severe liver injury

Protocol-specific SAEs: 

SCC, 

Pyrexia accompanied by ≥ Grade 3 hypotension, or hypotension that is 
clinically significant in the judgment of the investigator, or dehydration 
requiring IV fluids, or severe rigors/chills should be reported as an SAE ;

CSR and RVO

Additionally, new primary cancers (excluding basal cell carcinoma) and 
laboratory abnormalities as referenced in Section 7.3.1.3 are considered to be 
serious events by virtue of being medically important. These should be reported 
in the same manner as other serious adverse events.  Please refer to Section 
5.7.4.3.
7.3.1.3.
Laboratory and Other Safety Assessment Abnormalities Reported as 
AEs and SAEs
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis), or 
other safety assessments (e.g., ECGs, radiological scans, vital signs measurements) 
including those that worsen from baseline, and events  felt to be clinically significant in 
the medical and scientific judgment of the investigator are to be recorded as an AE or 
SAE, in accordance with the definitions provided.  
In addition, an associated AE or SAE is to be recorded for any laboratory test result or 
other safety assessment that led to an intervention, including permanent discontinuation 
of study treatment, dose reduction, and/or dose interruption/delay.  
However, any clinically significant safety assessments that are associated with the 
underlying disease, unless judged by the investigator to be more severe than expected for 
the subject's condition, are not to be reported as AEs or SAEs.  
7.3.1.4.
Disease-Related Events and/or Disease-Related Outcomes Not 
Qualifying as SAEs
An event which is part of the natural course of the disease under study (i.e., disease 
progression or hospitalization due to disease progression) does not need to be reported as 
an SAE. Death due to disease under study is to be recorded on the Death eCRF form.  
However, if the underlying disease (i.e., progression) is greater than that which would 
normally be expected for the subject, or if the investigator considers that there was a 
causal relationship between treatment with study medication(s) or protocol 
design/procedures and the disease progression, then this must be reported as an SAE.


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7.3.1.5.
Time Period and Frequency of Detecting AEs and SAEs
The investigator or site staff is responsible for detecting, documenting and reporting 
events that meet the definition of an AE or SAE. 
AEs will be collected from the time the first dose of study treatment is administered until 
30 days following discontinuation of study treatment regardless of initiation of a new 
cancer therapy or transfer to hospice. 
SAEs will be collected over the same time period as stated above for AEs.  In addition, 
any SAE assessed as related to study participation (e.g., protocol-mandated procedures, 
invasive tests, or change in existing therapy), study treatment or GSK concomitant 
medication must be recorded from the time a subject consents to participate in the study 
up to and including any follow-up contact. All SAEs will be reported to GSK within 24 
hours, as indicated in Section 7.3.1.6. 
After discontinuation of study treatment, the investigator will monitor all AEs/SAEs that 
are ongoing until resolution or stabilization of the event or until the subject is lost to 
follow-up.  At any time after 30 days the investigator may report any adverse event that 
they believe possibly related to study treatment.
7.3.1.6.
Prompt Reporting of SAEs and Other Events to GSK
SAEs, pregnancies, and liver function abnormalities meeting pre-defined criteria will be 
reported promptly by the investigator to GSK as described in the following table once the 
investigator determines the event meets the protocol definition for that event.


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Initial Reports
Follow-up Information on a 
Previous Report
Type of Event
Time Frame
Documents
Time Frame
Documents
All SAEs
24 hours
SAE data 
collection tool
24 hours
Updated SAE data 
collection tool 
Pregnancy
2 Weeks
Pregnancy 
Notification Form
2 Weeks
Pregnancy Follow 
up Form
Liver chemistry abnormalities Phase II:
ALT3xULN and 
bilirubin2xULN 
(>35% direct) (or 
ALT3xULN and 
INR>1.5, if INR 
measured)3
24 hours1
SAE data 
collection tool.
Liver Event Case 
Report Form 
(CRF) and liver 
imaging and/or 
biopsy CRFs if 
applicable2
24 hours
Updated SAE data 
collection tool. 
Updated Liver 
Event CRF2
ALT5xULN; 
ALT3xULN with 
hepatitis or rash or 
3xULN 4 weeks
24 hours1
Liver Event CRF2
24 hours
Updated Liver 
Event CRF2
ALT3xULN and 
<5xULN and bilirubin 
<2xULN
24 hours1
Liver Event CRF 
does not need 
completing unless 
elevations persist  
for 4 weeks or 
subject cannot be 
monitored weekly 
for 4 weeks2
1.
GSK to be notified at onset of liver chemistry elevations to discuss subject safety.
2.
Liver Event Documents (i.e., “Liver Event CRF” and “Liver Imaging CRF” and/or “Liver Biopsy CRF”, as 
applicable) should be completed as soon as possible
3.
INR measurement is not required; if measured, the threshold value stated will not apply to subjects receiving 
anticoagulants.
Please refer to the liver chemistry stopping rules and follow-up criteria in Section 5.7.6
for additional details.
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.
7.3.1.7.
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 subjects are met.


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GSK has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a product under clinical investigation.  GSK will 
comply with country specific regulatory requirements relating to safety reporting to the 
regulatory authority, Institutional Review Board (IRB)/Independent Ethics Committee 
(IEC) and investigators.
Investigator safety reports are prepared for suspected unexpected serious adverse 
reactions according to local regulatory requirements and GSK policy and are forwarded 
to investigators as necessary.
An investigator who receives an investigator safety report describing a SAE(s) or other 
specific safety information (e.g., summary or listing of SAEs) from GSK will file it with 
the IB and will notify the IRB/IEC, if appropriate according to local requirements.
7.3.2.
Pregnancy Testing, Prevention and Reporting
7.3.2.1.
Pregnancy Test and Prevention
The need for a screening pregnancy test depends on whether a female subject 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 subject must have a follicle stimulating 
hormone (FSH) value >40 mIU/mL and an estradiol value < 40pg/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 subject is of childbearing potential, she must have a serum -hCG pregnancy 
test performed within 14 days prior to the first dose of study treatment. Subjects with 
positive pregnancy test result must be excluded from the study. Subjects with negative 
pregnancy test result must agree to use an effective contraception method as described 
below during the study until 4 weeks following 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.

Vasectomized partner who is sterile prior to the female subject’s entry and is the sole 
sexual partner for that female.

Complete abstinence from sexual intercourse for 14 days prior to first dose of study 
treatment, through the dosing period, and for at least 4 weeks after the last dose of 
study treatment.

Double-barrier contraception: condom and occlusive cap (diaphragm or 
cervical/vault caps) with a vaginal spermicidal agent (foam/gel/cream/suppository).


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Hormonal-based methods (e.g., oral contraceptives) are not permitted due to potential 
drug-drug interactions with dabrafenib.  
Female subjects who are lactating must discontinue nursing prior to the first dose of study 
treatment and must refrain from nursing throughout the treatment period and for 4 
months following the last dose of study treatment.
7.3.2.2.
Pregnancy Reporting
Any pregnancy that occurs during study participation must be reported using a clinical 
trial pregnancy form.  To ensure subject safety, each pregnancy must be reported to GSK 
within 2 weeks of learning of its occurrence.  The pregnancy must be followed up to 
determine outcome (including premature termination) and status of mother and child.  
Pregnancy complications and elective terminations for medical reasons must be reported 
as an AE or SAE.  Spontaneous abortions must be reported as an SAE.
Any SAE occurring in association with a pregnancy brought to the investigator’s 
attention after the subject has completed the study and considered by the investigator as 
possibly related to the study treatment, must be promptly reported to GSK.
In addition, the investigator must attempt to collect pregnancy information on any female 
partners of male study subjects who become pregnant while the subject is enrolled in the 
study.  Pregnancy information must be reported to GSK as described above.
7.3.3.
Laboratory Assessments
Laboratory assessments must be conducted in accordance with the Time and Events 
Table (Table 19).
Table 21
Laboratory Assessments
Hematology 
Standard Chemistry1
  Hemoglobin
  Sodium
  Hematocrit
  Potassium
  Red blood cell count
  Calcium
  Platelets
  Glucose
  White blood cell count with differential
  Blood Urea Nitrogen or Urea
      Total neutrophils
  Creatinine2
      Lymphocytes
  AST
      Monocytes
  ALT
      Eosinophils
  Alkaline phosphatase 
      Basophils
  Total bilirubin
  
  Lactate dehydrogenase
Coagulation
  Magnesium
  PT
  Phosphate
  PTT
  
  INR
  
Serum Pregnancy3
  serum β-hCG (human chorionic gonadotrophin)
1.
Chemistry evaluation of bicarbonate, chloride, and uric acid are not required where there are logistical constraints
2.
If serum creatinine is >1.5 mg/dL, calculate creatinine clearance using standard Cockcroft and Gault method 
(Appendix 2).
3.
Refer to Section 7.3.2 for further details on serum pregnancy testing.


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Prior to administration of the first dose of study treatment, results of laboratory 
assessments should be reviewed.  Any laboratory test with a value outside the normal 
range may be repeated (prior to the first dose) at the discretion of the investigator.   A 
subject with a laboratory value outside the reference range(s) may be included only if the 
investigator and GSK Medical Monitor agree that it is unlikely to introduce additional 
risk factors and will not interfere with study procedures.  However, subjects with 
laboratory values outside eligibility criteria in Section 4.1 should be excluded.
All laboratory tests with values that are significantly abnormal during participation in the 
study or within 30 days after the last dose of study treatment should be repeated until the 
values return to normal or baseline.  If such values do not return to normal within a 
period judged reasonable by the investigator, the etiology should be identified and the 
sponsor notified.
7.3.4.
Physical Examinations
A complete physical examination will include assessments of the head, eyes, ears, nose, 
throat, skin, thyroid, lungs, cardiovascular, abdomen (liver and spleen), lymph nodes, and 
extremities.  Height and weight will also be measured and recorded.  A complete physical 
exam including a thorough genitourinary examination for female subjects, inspection of 
the head and neck region, and digital rectal examination for both male and female 
subjects must be performed at Screening, and Month 12 or at discontinuation if 
discontinuation occurs prior to Month 12.  If the subject has had a genitourinary and 
rectal exam within 6 months of screening, these assessments do not need to be repeated at 
screening.  Physical examinations will be obtained at each time point as noted in the 
Time and Events Table (Table 19).
7.3.5.
Neurological Examinations
Neurological exams should be performed by the Investigator as per the Time and Events 
Table (Table 19).  Alternatively, subjects may be referred to a neurologist or 
neurosurgeon, at the discretion of the investigator.
A thorough neurological assessment is required at baseline focusing on:

mental status

cranial nerves

motor system

sensory system

the deep tendon reflexes

coordination and the cerebellum

gait


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During study conduct, an orientating neurological assessment should be conducted at the 
timepoints indicated in the Time and Events Table (Table 19) in order to detect potential 
early neurological symptoms, such as:

Headache

Nausea and/or vomiting

Vertigo and/or dizziness

Restlessness and/or irritability

Fatigue or sleeplessness 

Hearing loss

Muscle weakness

Balance problems

Speech problems

Others
7.3.6.
Dermatologic Examinations
A full skin assessment must be performed at baseline and at various timepoints 
throughout the study, as noted in the Time and Events Table (Table 19).  Dermatologic 
exams should be performed by the investigator or may be referred to a dermatologist, at 
the discretion of the investigator.  If possible, the same physician should perform each 
exam for the duration of the study (i.e., if the subject is referred to a dermatologist for the 
screening exam, the dermatologist should do all follow up dermatologic assessments) to
ensure consistency between evaluations.
7.3.7.
Vital Signs
Vital sign measurements will include temperature, respiratory rate, systolic and diastolic 
blood pressure, and pulse rate, and will be obtained at each time point as noted in the 
Time and Events Table (Table 19).
7.3.8.
Performance Status
Eastern Cooperative Oncology Group performance status should be assessed per the 
Time and Event Table (Table 19). 
7.3.9.
Electrocardiogram (ECG)
12-lead ECGs will be obtained at screening as noted in the Time and Events Table (Table 
19) during the study using an ECG machine that automatically calculates the heart rate 
and measures PR, QRS, QT, and QTc intervals.  At each assessment a 12-lead ECG will 
be performed by qualified personnel at the site after at least a five-minute rest with the 
subject in a semi-recumbent or supine position.  


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7.3.10.
Echocardiograms
ECHO should include an evaluation for LVEF and both right- and left-sided valvular 
lesions. ECHO will be performed at the time points specified in the Time and Events 
Table (Table 19).
Additional ECHO assessments may be performed if clinically warranted.
7.3.11.
Ophthalmic Examination
At certain time points in the trial and if visual changes develop, an eye exam is indicated. 
(Refer to Section 5.7.5.4 for visual changes stopping criteria). The exam will include 
best corrected visual acuity, tonometry, slit lamp biomicroscopic examination, visual 
field examination, and dilated indirect fundoscopy with special attention to retinal 
abnormalities. Optical coherence tomography is strongly recommended at scheduled 
visits, and if retinal abnormalities are suspected. Other types of ancillary testing including 
color fundus photography and fluorescein angiography are also recommended if 
clinically indicated.
7.4.
Pharmacokinetics
7.4.1.
Pharmacokinetic Endpoints

Brain tumors (All subjects):  The concentrations and tumor tissue distribution of 
dabrafenib and its metabolites, including hydroxy-, carboxy, and desmethyl-
dabrafenib, in samples of the resected brain metastases will be determined in all 
subjects. Concentration of trametinib will also be determined in Cohort B.

Plasma (All subjects): The concentrations of dabrafenib, its metabolites, including 
hydroxy-, carboxy, and desmethyl-dabrafenib, and trametinib in plasma samples 
collected on the day of the brain tumor resection will be determined.  Levels in 2 
plasma samples collected before surgery and 2 samples collected after surgery will 
be determined to allow accurate estimate of the pharmacokinetics at the time of the 
tumor resection.

Extracranial metastases (if available): The concentrations and tumor tissue 
distribution of dabrafenib, its metabolites, including hydroxy-, carboxy, and 
desmethyl-dabrafenib, and trametinib (as appropriate in Cohort B)  in samples of 
extracranial metastases collected on the same day as the brain tumor resection will be 
determined.

Cerebrospinal fluid (CSF) (in subjects who agree to optional collection of CSF): The 
concentrations of dabrafenib, its metabolites, including hydroxy-, carboxy, and 
desmethyl-dabrafenib, and trametinib (as appropriate in Cohort B), in the CSF of 
subjects who give consent for optional collection of this fluid at the time of brain 
tumor resection will be determined.


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7.4.2.
Brain Tumor Sample Collection for Pharmacokinetics
Tissue for pharmacokinetic analysis will be isolated from the remaining portion of the 
resected melanoma brain metastasis(es) that in the clinical judgment of the neurosurgeon 
is not required to be submitted for pathologic confirmation of CNS melanoma metastases.  
100 mg to 1 gm of the remaining tissue will be snap-frozen for pharmacokinetic analysis.  
If the tumor is bloody, the tissue will be blotted on gauze to dry prior to snap freezing in 
liquid nitrogen.  A second portion (up to 500 mg) of the tumor will be inserted into a 
tissue cassette, and embedded in Optimum Cutting Temperature (OCT) solution, and
frozen.  A third portion of tumor tissue (up to 100 mg) will be fixed in formalin for 
paraffin embedding (FFPE).  Additional tumor tissue may be used to establish an 
immortalized cell line and/or snap-frozen.  The remaining portion from the adjacent 
“normal” CNS tissue that has been confirmed by the neuropathologist using frozen 
sections OR the overlying normal CNS tissue that is required to be resected by the 
neurosurgeon in order to gain access to the underlying CNS melanoma metastasis will be 
processed in a similar fashion.  The time the tumor was resected will be recorded to 
facilitate the comparative pharmacokinetic analyses. Concentrations of dabrafenib, its 
metabolites, hydroxy-, carboxy, and desmethyl-dabrafenib, and trametinib (as 
appropriate) and possibly other drug-related species will be quantified in the PK tissue 
sample by an investigative LC-MS/MS method.  The spatial distribution of dabrafenib, its 
metabolites, hydroxy-, carboxy, and desmethyl-dabrafenib, and trametinib (as appropriate 
in Cohort B), and possibly other drug-related species in the tissue samples will be 
determined using an investigative matrix assisted laser desorption ionization (MALDI) 
analysis method.
7.4.3.
CSF Collection for Pharmacokinetics
Collection of CSF will be an optional procedure; subjects must provide consent for this 
procedure.  CSF will be collected either right before cutting the dura, on condition that 
there is no evidence of intracranial hypertension, or using the lumbar puncture approach 
(following completion of craniotomy and repositioning the subject while under general 
anesthesia during the same operation OR postoperatively), or accessing the Ommaya 
reservoir, if present. Three ml of CSF will be processed for pharmacokinetic analysis and 
quantified using an investigative LC-MS/MS method.  The time of CSF collection will be 
recorded for the comparative pharmacokinetic analyses.
7.4.4.
Extracranial Tumor Sample Collection for Pharmacokinetics
Optional sampling of readily accessible extracranial metastases will be performed on the 
day of the removal of the brain metastasis (es), or up to one day before or after the 
craniotomy if necessary for scheduling.  Sampling will consist of an excisional biopsy, 
core needle biopsy, or a 6 mm punch biopsy.  100 mg to 1 gm of the biopsy material of 
the extracranial metastasis (es) will be snap-frozen for pharmacokinetic analysis and 
quantified using an investigative LC-MS/MS method.  If the tumor is bloody, the tissue 
will be blotted on gauze to dry prior to snap freezing in liquid nitrogen.  A second portion 
of the tumor (up to 500 mg) will be inserted into a tissue cassette, embedded in OCT 
solution, and frozen.   A third portion of the tumor (up to 100 mg) will be fixed in 
formalin for paraffin embedding (FFPE).  Additional tumor tissue may be used to 
establish an immortalized cell line and/or snap-frozen.  The remaining portion of any 


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adjacent “normal” tissue that has been confirmed by the pathologist using frozen sections 
or the underlying normal tissue that is required to be resected in order to gain access to 
the underlying metastasis will be processed in a similar fashion.  The time of tumor 
collection will be recorded for comparative pharmacokinetic analyses.
7.4.5.
Blood Sample Collection for Pharmacokinetics
Blood samples for pharmacokinetic analysis of dabrafenib and its active metabolites, 
including hydroxy-, carboxy-, and desmethyl-dabrafenib and trametinib (as appropriate), 
will be collected on the day of surgical resection of the brain metastasis(es).  Two 
samples will be collected prior to surgery; two samples will be collected after surgery.  
Each sample must be collected at least one hour after the prior sample.  The collection 
time of each blood sample collection will be recorded.  The time of the last dose of study 
treatment will also be recorded.  Upon collection blood will be placed on wet ice.  Plasma 
will be isolated within 60 minutes of collection and frozen at -20°C
The timing of pharmacokinetic samples may be altered and/or pharmacokinetic samples 
may be obtained at additional time points to ensure thorough pharmacokinetic 
monitoring.  No more than 160 mL of blood will be collected over the duration of the 
study for pharmacokinetic blood sample collection, including any extra assessments that 
may be required.
7.4.6.
Pharmacokinetic Sample Analysis
Plasma sample analysis will be performed under the management of Bioanalytical 
Science and Toxicokinetics and tissue sample analysis, under Biotransformation and 
Drug Disposition, Drug Metabolism and Pharmacokinetics, Platform Technology and 
Science, GlaxoSmithKline. Concentrations of dabrafenib, its metabolites, hydroxy-, 
carboxy, and desmethyl-dabrafenib, and trametinib (as appropriate) will be determined in 
plasma samples using the most current approved and validated analytical methodology, 
and their presence will be determined in tissue and CSF samples using investigative assay 
methodology. Plasma raw data will be stored in the Good Laboratory Practices (GLP) 
Archives, GlaxoSmithKline.  
7.4.7.
Meals and Dietary Restrictions
Either dabrafenib monotherapy or dabrafenib combined with trametinib should be 
administered under fasting conditions, either one hour prior to or at least two hours after a 
meal.  If a subject vomits after taking study medication, the subject should be instructed 
not to retake the dose and should take the next scheduled dose.  
7.5.
Pharmacodynamics
Dabrafenib inhibits the BRAF kinase, which is a component of the RAS-RAF-MEK-
ERK signalling pathway.  Activation of the pathway may be determined by measuring 
the expression of phosphorylated (activated) proteins in the pathway, including phospho 
(p)-MEK and p-ERK.


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7.5.1.
Pharmacodynamic Analysis of Brain Metastases
After sufficient tissue is collected for necessary pathological analysis and 
pharmacokinetic analysis, up to 500 mg of tumor tissue, optimally with adjacent normal 
brain tissue, will be formalin-fixed, paraffin-embedded (FFPE).  Tissue will undergo 
immunohistochemical (IHC) analysis for the expression of p-MEK and p-ERK.
OCT-embedded tissue will be used to prepare a hematoxylin and eosin (H&E) slide for 
review.  The tissue will undergo H&E-guided macrodissection to isolate specimens 
enriched for ≥ 80% viable tumor cell content.  The tissue will be processed for reverse 
phase protein array analysis (RPPA) as previously described [Davies, 2009]. The 
quantitative ratio of p-MEK: Total MEK and p-ERK:Total ERK will be determined using 
the results of the RPPA analysis.
7.5.2.
Pharmacodynamic Analysis of Extracranial Metastases
Optional sampling of easily accessible extracranial metastases will be performed (1) prior 
to starting treatment with dabrafenib alone or in combination with trametinib, and (2) on 
the day of the craniotomy, or up to one day prior or one day after the craniotomy 
procedure if needed for scheduling.  The pre-treatment tumor sampling may include a 6 
mm punch biopsy, core needle biopsy, or an excisional biopsy.  For the pre-treatment 
sample, excisional biopsy may only be performed if another easily accessible lesion can 
be identified for sampling on the day of the craniotomy.  Approximately two-thirds of the 
pre-treatment tumor tissue will be inserted into a tissue cassette and embedded in OCT 
solution; the remaining tissue will be processed by FFPE.  Collection of the extracranial 
metastasis on the day of craniotomy is described in Section 7.4.4.  After sufficient tissue 
is collected for pharmacokinetic analysis (Section 7.4.6), approximately two-thirds of the 
tissue will be inserted into a tissue cassette and embedded in OCT solution; the remaining 
tissue will be processed for FFPE.   Tissue will undergo IHC analysis for the expression 
of p-MEK and p-ERK.  IHC staining and quantitation will be performed under the 
management of GlaxoSmithKline. 
OCT-embedded tissue will be used to prepare an H&E slide for review.  The tissue will 
undergo H&E-guided macrodissection to isolate specimens enriched for ≥ 80% viable 
tumor cell content.  The tissue will be processed for RPPA, as previously described 
[Davies, 2009].  The quantitative ratio of p-MEK: Total MEK and p-ERK:Total ERK 
will be determined using the results of the RPPA analysis.
7.6.
Pharmacogenetics
Information regarding pharmacogenetic (PGx) research is included in Appendix 1: 
Pharmacogenetic Research.


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7.7.
Translational Research
7.7.1.
Prevalence of BRAF and Other Mutations in Brain Metastases 
and Extracranial Metastases
A requirement for inclusion into the study is the presence of a BRAF mutation (V600-E 
or –K) in tumor tissue of subjects being screened.  For each subject, DNA will be 
extracted from (1) FFPE slides of the resected brain metastasis(es), and if available (2) 
FFPE slides from extracranial metastases.  All samples will be dissected to isolate DNA 
from isolates consisting of ≥90% tumor cells.  The prevalence of the known BRAF 
mutation in DNA from both tumors will be determined by mass-spectroscopy-based 
genotyping using the Sequenom platform [Davies, 2009; Davies, 2008], or by next 
generation sequencing (NGS) approach if the amount of DNA isolated is feasible for this 
analysis.  When feasible the mutational analysis will also analyze other gene, including 
but not limited to Nras, Kras, Mek1/2, Akt1/2/3, Pik3ca, c-Kit, and Egfr DNA samples 
may also be analyzed for other mutations implicated in responsiveness to BRAF 
inhibitors or melanoma pathogenesis by subsequent investigations.  DNA from frozen 
samples, or from FFPE samples if feasible, may also be analyzed using whole-genome 
and/or whole-exome sequencing, depending on the results of other molecular analyses.   
Please refer to the SPM for additional details on translational research.
7.7.2.
Tumor Biomarker Analysis
RPPA analysis will be performed using OCT-embedded tissue from brain and available 
extracranial metastases.  In addition to MEK and ERK, analysis will be performed for the 
expression of ~150 validated protein markers (http://www.mdanderson.org/education-
and-research/resources-for-professionals/scientific-resources/core-facilities-and-
services/functional-proteomics-rppa-core/index.html).  This will include analysis of the 
PI3K-AKT pathway, which has been implicated both in melanoma brain metastasis and 
in resistance to BRAF inhibitors, as well as other critical regulators of melanoma growth 
and survival [Villanueva, 2009; Davies, 2009].
FFPE tissue may undergo IHC analysis of additional markers, including Ki67 and P27, or 
other markers that are identified in ongoing or future studies. 
Tissue samples collected during the conduct of the study may also undergo analysis for 
patterns of mRNA and miRNA expression, and, when feasible, for DNA methylation and 
copy number variation. 
Cells may be isolated from fresh melanoma biopsies for the establishment of immortal 
cell lines and/or xenografts.  These cells will be used to examine mechanisms of drug 
action and resistance efficiently.  Patients will be required to sign a separate consent for 
this analysis. 
Optional tumor biopsies collected at progression will also allow for further analysis of 
changes in biomarkers to facilitate understanding of mechanisms of treatment resistance. 
Details on the analytical methods and biomarkers under study can be found in the SPM.


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7.7.3.
Immunologic Monitoring
For screening potential serum biomarkers, 3 x 10cc red top serum tubes at each time 
point will be drawn, enabling multiple marker screens at each time point (Baseline, Week 
4 post-surgery,  and Week 8 post-surgery). These may include circulating cytokines, 
chemokines and growth factors, C-reactive protein, and testing LDH and autoimmune 
antibodies (if not performed directly in clinical labs). 
For assessment of anti-tumor immunity and immune suppression, up to 10 x 10cc 
heparin/green top tubes for isolation of PBMC will be drawn.  PBMC assays may include 
immune suppressive Treg and myeloid-derived suppressor cell frequency assessment (to 
determine if elevated frequencies negatively impact outcomes), testing of melanoma 
antigen-specific immunity (for example, CD8+ and CD4+ T cell responses to MART-1, 
NY-ESO-1, gp100) and other potential immune responses.  Absolute counts and 
percentages of lymphocyte and myeloid subsets may be performed.
For assessment of RNA and mRNA, up to six cc of blood will be collected in PAXgene 
tubes.  
A genomic DNA Yellow/ACD tube will be drawn to assure quality of the DNA.  
Plasma will be isolated from the green top tubes before PBMC purification, which will 
allow for miRNA studies. 
To allow for centralized processing, banking and testing of these blood samples, the 
UPCI Immunologic Monitoring Laboratory will serve as a central lab. 
Blood collected into the appropriate tubes should be sealed, wrapped and placed in the 
specimen shipper kit and shipped on the same day they are drawn by Federal Express 
overnight courier using the air bill provided in the kit. The green top tubes should be 
shipped at ambient temperature (no wet or dry ice). The red, yellow, and PAXgene RNA 
tubes should be refrigerated immediately and shipped at 2-8C. Shipments must be timed 
to arrive during normal working hours.
The laboratory will be open Monday through Friday to receive samples. Samples should 
not be shipped on Fridays, Saturdays, or the day before a legal holiday.  Ship by 
overnight courier Monday-Thursday only to:
Immunologic Monitoring and Cellular Products Laboratory
University of Pittsburgh Cancer Institute
UPCI-IMCPL, Suite L 1.26
Study Coordinator
Hillman Cancer Center
5117 Centre Avenue
Pittsburgh, PA 15213
Tel: 
Fax: 
PPD
PPD


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7.7.4.
T-Cell Receptor Sequencing
Immune profiling can provide a precise characterization of the complete immune 
repertoire in each of the tissues being collected for this study, including brain tissue, CSF, 
and blood.  Immune profiling may also contribute meaningful data to help construct 
combination or sequential therapy for BRAF inhibitors, given the frequent development 
of resistance.
Approximately 2 micrograms of extracted DNA, a 25 micron slice from an FFPE block, 
or a frozen punch biopsy (depending on available volume of tumor tissue) will be utilized 
for the immunoSEQ assay (Adaptive Biotechnologies, Seattle, WA, USA).  This assay 
employs a novel method that amplifies rearranged T-Cell Receptor 3 sequences and 
exploits the capacity of high-throughput sequencing technology to sequence tens of 
thousands of TCR CDR3 chains simultaneously.  Approximately 80% of the sample 
collected will be used for this assay; the remaining tissue will be used for tumor 
infiltrating lymphocyte analysis (Section 7.7.5).
Samples will be collected as per extracranial metastases biopsy schedule as described in 
Table 19.
7.7.5.
Tumor Infiltrating Lymphocyte Analysis
Tumors contain variable numbers of lymphocytes, referred to as tumor infiltrating 
lymphocytes (TILs). In melanoma, the intensity of this lymphocytic infiltrate is believed 
to correlate with outcome though there is some debate about the applicability of this 
finding for all melanomas present in the tissue samples from these patients.  Therefore, 
considerable research is needed to better elucidate the function and prognostic 
significance of TILs in both untreated melanoma and tumors treated with biological 
therapy [Oble, 2009].
QuanTILfy (Adaptive Biotechnologies, Seattle, WA, USA) is an assay utilized to 
measure the quantity and clonality of TILs.  This platform uses a new technology, droplet 
digital PCR, to directly measure Tumor Infiltrating Lymphocytes (TILs).  Remaining 
material from the immunoSEQ assay (FFPE or frozen tissue biopsy, Section 7.7.4) will 
be used for this assay.
Samples will be collected as per extracranial metastases biopsy schedule as described in 
Table 19.
7.8.
Days 1-3 Post-Craniotomy
Subjects will undergo follow-up imaging as part of routine surgical follow-up within 72 
hours of craniotomy.  Subjects in either cohort for whom continued treatment is 
considered appropriate by their treating investigator will be permitted to continue on the 
combination of dabrafenib 150 mg twice daily plus trametinib 2 mg once daily after no 
less than 72 hours have passed. 


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7.9.
Post-Craniotomy Safety Assessments
For subjects continuing on study treatment after the craniotomy procedure, the following 
safety assessments must be performed 4 weeks after the procedure and every 4 weeks 
thereafter (7 days): 

Complete physical examination (including weight, ECOG PS)

Vital signs (blood pressure, pulse rate, and temperature)

Clinical laboratory tests: hematology and clinical chemistry

Dermatological examination

Neurologic examination

Treatment dispensing and treatment compliance
Echocardiograms will be performed at Week 8 and every 16 weeks thereafter. 
7.10.
Post-Craniotomy Disease Assessments
Subjects continuing on study treatment after the craniotomy procedure must have 
radiologic disease assessments performed 8 weeks after the procedure and every 8 weeks 
thereafter (14 days).
7.11.
Discontinuation Visit
If a subject does not resume treatment after surgery, or discontinues study treatment after 
surgery at a time other than a regularly-scheduled follow-up visit as described in Section 
7.10, the following assessments will be performed within 28 days of the last dose of 
study treatment and prior to initiation of other anti-cancer therapy:  

Brief physical examination (including weight, ECOG PS)

Vital signs (blood pressure, pulse rate, and temperature)

Clinical laboratory tests: hematology and clinical chemistry

Dermatological examination

Neurologic examination

Radiologic assessment of disease
7.12.
Survival Follow-up Visits
If a subject discontinues study treatment and begins new anti-cancer therapy, 
investigators will report on the survival status of the subject every 8 weeks.
8.
DATA MANAGEMENT
For this study subject data will be entered into GSK defined electronic case report forms 
(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 


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ensure the integrity of the data, e.g., removing errors and inconsistencies in the data.  
Adverse events and concomitant medications terms will be coded using Medical 
Dictionary for Regulatory Activities (MedDRA) and an internal validated medication 
dictionary, GSKDrug.  In all cases, subject initials will not be collected or transmitted to 
GSK according to GSK policy.
9.
DATA ANALYSIS AND STATISTICAL CONSIDERATIONS
9.1.
Study Design Considerations
9.1.1.
Sample Size Assumptions
For the objective of estimating the levels of dabrafenib its metabolites, and trametinib in 
brain metastases, the average level for the parent drug and each metabolite along with the 
range and 95% confidence interval for the brain metastases, extracranial metastases, and 
plasma will be reported. A sample size of 15 patients per cohort was chosen to 
characterize concentrations with reasonable precision (within 0.7 standard deviation) 
within each cohort. The correlation and corresponding 95% confidence interval between 
concentrations in the brain metastases and concentrations in the plasma, and in the 
optional extracranial metastases and CSF, for the parent drug and each metabolite will 
also be estimated. Additionally,  the ratio between the concentrations in the brain 
metastases and in the extracranial metastases and the plasma concentrations within each 
subject for each metabolite will be estimated and summarized with 95% CI’s.
9.1.2.
Sample Size Re-estimation
No formal sample size re-estimation is planned.
9.2.
Data Analysis Considerations
9.2.1.
Analysis Populations
All subjects who receive at least one dose of study treatment will be evaluable for both 
efficacy and safety and will comprise the All Treated Subjects (ATS) population.
9.2.2.
Analysis Data Sets
The primary datasets for the planned pharmacokinetic, pharmacodynamic, exploratory 
translational, and early response analyses will include subjects in the ATS population 
who complete the planned surgical resection of their brain metastasis(es), and biopsies of 
extra-cranial metastases.
The datasets for assessing overall survival, extracranial response, maximum change from 
baseline in unresected intracranial lesions, and all safety endpoints will include efficacy 
and safety data collected on subjects in the ATS population.


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9.2.3.
Interim Review
There is no stopping rule to allow for early termination for lack of efficacy.  An interim 
review will take place after 5 subjects in each of Cohorts A and B have undergone a 
craniotomy and have completed one follow-up post-craniotomy assessment.  This review 
will allow for evaluation of modifiable treatment logistics and the ability to complete the 
primary objective of the study.  This interim review will include an assessment of the 
quality of the tissue samples from the resected brain and optional extracranial metastases 
for the planned pharmacokinetic and pharmacodynamic analyses.  In addition, a sample 
quality review will take place where the results of the pharmacokinetic analysis of 
dabrafenib and its metabolites for the first 3 subjects will be reviewed.  Adjustments may 
be made to the duration of the treatment before surgery, and/or the timing of the last dose 
of dabrafenib that is administered prior to surgery, based on the review of the results by 
the participating investigators.  Subject safety and any unexpected toxicities will also be 
reviewed.  Accrual will continue during this formal review.  Similar analyses will be 
performed after the last subject in Cohort A completes one post-craniotomy assessment, 
or withdraws from the study, whichever comes first.
9.2.4.
Key Elements of Analysis Plan
Data will be listed and summarized according to the GSK reporting standards, where 
applicable.  Complete details will be documented in the Reporting and Analysis Plan 
(RAP).  Any deviations from, or additions to, the original analysis plan described in this 
protocol will be documented in the RAP and final study report.
As it is anticipated that summaries of data by center would be unlikely to be informative, 
data from participating centers will be pooled prior to analysis. 
All data up to the time of study completion/withdrawal from study will be included in the 
analysis.
The length of treatment for each subject will depend on the efficacy and toxicity of the 
treatment, so the duration of treatment and follow-up will vary among subjects.  All 
available overall survival data will be analyzed using appropriate statistical methods; 
subjects with shorter treatment and follow-up due to the natural history of their disease or 
medical necessities of the treatment of their disease will not be considered to have 
missing data.  Consequently there will be no imputation of overall survival data. 
Demographic and baseline characteristics will be summarized according to current GSK 
standards.
For the analysis of overall survival, the last date of known contact will be used for those 
subjects who have not died at the time of analysis; such subjects will be considered 
censored.


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9.2.4.1.
Primary Analysis
9.2.4.1.1.
Pharmacokinetics
Pharmacokinetic analysis will be the responsibility of the Clinical Pharmacology 
Modeling & Simulation department within GlaxoSmithKline.  Levels of dabrafenib, its 
metabolites, and trametinib (Cohort B only) will be summarized for each tissue (brain 
metastases, optional assessment of extracranial metastases, and mandatory assessment of 
plasma for all subjects.  Concentrations in plasma will be summarized by nominal times 
and the average concentrations calculated and summarized.  Both absolute concentrations 
and ratios relative to plasma will be determined for the different sample types.  Total and 
free concentrations may be reported.  If necessary, the plasma concentration at time of the 
surgery or collection may be interpolated.
9.2.4.2.
Secondary Analyses
9.2.4.2.1.
Pharmacokinetics in CSF
Pharmacokinetic analysis will be the responsibility of the Clinical Pharmacology 
Modeling & Simulation department within GlaxoSmithKline.  Levels of dabrafenib, its 
metabolites, and trametinib (Cohort B only) will be summarized for CSF for subjects 
with available samples.  Concentrations in plasma will be summarized by nominal times 
and the average concentrations calculated and summarized.  Both absolute concentrations 
and ratios relative to plasma will be determined for the different sample types.  Total and 
free concentrations may be reported.  If necessary, the plasma concentration at time of the 
surgery or collection may be interpolated.
9.2.4.2.2.
Pharmacodynamics
The percent change in p-MEK, p-MEK:Total MEK ratio, p-ERK, and p-ERK:Total ERK 
ratios will be determined for the paired assessment of optional extracranial metastases 
obtained before and after treatment.  The absolute levels and ratios of p- and total-MEK 
and –ERK will also be compared to the brain metastasis tissue for those subjects.  Paired 
t-tests will be used to determine the significance of differences between samples.
Absolute levels and ratios of expression of the same markers will be determined in the 
assessment of optional extracranial metastases, and will be compared to the results 
observed in the post-treatment extracranial metastases.  In addition, results will be 
compared to a retrospective collection of BRAF V600-mutation-positive brain metastases 
that were collected independently from this study [Davies, 2009].
9.2.4.2.3.
Mutational Analysis
Paired t-tests will be used to determine if there is a significant difference in the relative 
prevalence of the BRAF V600 mutation in the brain and optional extracranial metastases.  
In addition, the presence of activating mutations in other genes (i.e. Nras, Kras, Akt1/2/3, 


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Pik3ca, c-Kit, Egfr) will be compared.  If indicated, samples may also be compared using 
whole-genome and/or whole-exome sequencing.
If there are significant differences noted, the correlation with pharmacodynamic results 
(Section 9.2.4.2.2) will be assessed.
9.2.4.2.4.
Exploratory Biomarkers (others)
The percent change of additional protein markers, as determined by IHC and/or RPPA 
will be determined for the paired pre-treatment and post-treatment extracranial 
metastases.  The absolute levels and ratios of phospho-total-proteins will be determined.  
The pre- and post-treatment levels will be compared to the brain metastasis tissue for 
those subjects.  Paired t-tests will be used to determine the significance of differences 
between samples.
In addition, results will be compared to a retrospective collection of BRAF V600-
mutation-positive brain metastases that were collected independently from this study 
[Davies, 2009].
9.2.4.2.5.
Change from Baseline to Pre-Surgery in Intracranial Target Lesions
The change from baseline to the pre-surgery intracranial disease assessment in the sum of 
the longest diameters (SLD) of intracranial target lesions will be calculated as a 
percentage change from the baseline SLD.  It will be reported for the V600E and V600K 
analysis populations for each cohort and also aggregately if appropriate.
9.2.4.2.6.
Maximum Change from Baseline in Unresected Intracranial Target
Lesions
The maximum change from baseline in the sum of the longest diameters (SLD) of 
unresected intracranial target lesions will be calculated as a percentage change from the 
baseline SLD.  It will be reported for the V600E and V600K analysis populations for 
each cohort and also aggregately if appropriate.
9.2.4.2.7.
Overall Response in Extracranial Lesion(s)
The overall extracranial response rate in unresected lesions is defined as the percentage 
of subjects with a confirmed overall CR or PR by investigator assessment using modified 
RECIST 1.1 guidelines.  Subjects who have an overall extracranial response of NE (not 
evaluable) or a missing response will be treated as non-responders, i.e. they will be 
included in the denominator when calculating the percentage.  A two-sided 95% 
confidence interval will be reported along with the point estimate. The ORR will be 
reported for the V600E and V600K analysis populations for each cohort and also 
aggregately if appropriate.


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9.2.4.2.8.
Duration of Response
The duration of extracranial response will be summarized descriptively using Kaplan-
Meier quartiles, along with two-sided 95% confidence intervals, for the V600E and 
V600K analysis populations for each cohort and also aggregately if appropriate. Only the 
subset of subjects who show a complete or partial tumor response will be included in this 
analysis. If a subject receives subsequent anti-cancer therapy prior to the date of 
documented progression or death (other than planned craniotomy), duration of 
extracranial response will be censored at the last adequate assessment (that is, the last 
assessment in which the visit level response is CR, PR, or SD) prior to the initiation of 
that anti-cancer therapy. Otherwise, if the subject does not have a documented date of 
progression or death, the duration of extracranial response will be censored at the date of 
the last adequate assessment. 
9.2.4.2.9.
Overall Survival
Overall survival (OS), defined as the time from first dose of study treatment to death for 
any reason, will be summarized using Kaplan-Meier quartile estimates along with two-
sided 95% confidence intervals. OS will be censored using the date of last known contact 
for those who are alive at the time of analysis.
9.2.4.3.
Safety Analyses
The ATS population will be used for the analysis of safety data. Complete details of the 
safety analyses will be provided in the RAP.  Safety assessments that will be summarized 
are described in Section 7.3.
9.2.4.3.1.
Extent of Exposure
The number of subjects administered study treatment will be summarized according to 
the duration of therapy.
9.2.4.3.2.
Adverse Events
Adverse events (AEs) will be coded using the standard GlaxoSmithKline Medical 
Dictionary for Regulatory Activities (MedDRA) and grouped by system organ class.  
AEs will be graded by the investigator according to NCI-CTCAE (version 4.0).
Events will be summarized by frequency and proportion of total subjects, by system 
organ class and preferred term. Separate summaries will be given for all AEs, drug-
related AEs, serious AEs and AEs leading to discontinuation of study treatment.
If the AE is listed in the NCI CTCAE Version 4.0 table, the maximum grade will be 
summarized.
Characteristics (e.g. number of occurrences, action taken, grade, etc) of AEs of special 
interest will be summarized separately.  Please refer to Section 7.3.1 for additional 
details.


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The incidence of deaths and the primary cause of death will be summarized.
9.2.4.3.3.
Clinical Laboratory Evaluations
Hematology and clinical chemistry data will be summarized at each scheduled 
assessment according to NCI CTCAE grade.  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.  Summaries will include data from scheduled 
assessments only, and all data will be reported according to the nominal visit date for 
which it was recorded (i.e. no visit windows will be applied).  Unscheduled data will be 
included in “overall” and “any post-screening” summaries which will capture a worst 
case across all scheduled and unscheduled visits post first dose of study treatment.  
Further details will be provided in the RAP.
9.2.4.3.4.
Other Safety Measures
The results of scheduled safety assessments (e.g., body weight, vital signs, 12-lead ECG, 
echocardiogram, and ECOG performance status) will be summarized.  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).  All 
data will be listed. Further details will be provided in the RAP.
9.2.4.4.
Pharmacogenetic Analyses
Further details on PGx analyses are described in Appendix 1: Pharmacogenetic Research
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 subjects 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 subject privacy requirements, and the ethical principles that are outlined in the 
Declaration of Helsinki 2008, including, but not limited to:


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
Institutional Review Board (IRB)/Independent Ethics Committee (IEC) review and 
favorable opinion/approval of study protocol and any subsequent amendments.

Subject informed consent.

Investigator reporting requirements.
GSK will provide full details of the above procedures, either verbally, in writing, or both.
Written informed consent must be obtained from each subject prior to participation in the 
study.
In approving the clinical protocol the IEC/IRB and, where required, the applicable 
regulatory agency are also approving the optional assessments e.g., PGx assessments 
described in Appendix 1:  Pharmacogenetic Research unless otherwise indicated.  Where 
permitted by regulatory authorities, approval of the optional assessments can occur after 
approval is obtained for the rest of the study.  If so, then the written approval will clearly 
indicate approval of the optional assessments is being deferred and the study, except for 
the optional assessments, can be initiated.  When the optional assessments are not 
approved, then the approval for the rest of the study will clearly indicate this and 
therefore, the optional assessments will not be conducted.
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 eCRF will serve 
as the source document.
The investigator and the head of the medical institution (where applicable) agrees to 
allow the monitor direct access to all relevant documents and to allocate their time and 
the time to their staff to monitor to discuss findings and any issues.
Monitoring visits will be conducted in a manner to ensure that the:

Data are authentic, accurate, and complete.

Safety and rights of subjects are being protected.

Study is conducted in accordance with the currently approved protocol and any other 
study agreements, ICH GCP, and all applicable regulatory requirements.
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 


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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
The study will be considered complete when all evaluable subjects have completed the 
study as per Section 4.2.1.
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 
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.


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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 subjects, 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 subject’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. 


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11.
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Bollag G, Hirth P et al. Clinical efficacy of a RAF inhibitor needs broad target blockade 
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Davies H, Bignell GR, et al. Mutations of the BRAF gene in human cancer. Nature. 
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APPENDICES
Appendix 1: Pharmacogenetic Research
Pharmacogenetics – Background
Pharmacogenetics (PGx) is the study of variability in drug response due to hereditary 
factors in populations.  There is increasing evidence that an individual's genetic 
composition (i.e., genotype) may impact the pharmacokinetics (absorption, distribution, 
metabolism, elimination), pharmacodynamics (relationship between concentrations and 
pharmacologic effects or the time course of pharmacologic effects) and/or clinical 
outcome (in terms of efficacy and/or safety and tolerability). Some reported examples of 
PGx associations with safety/adverse events include:
Drug
Disease
Gene Variant
Outcome
Abacavir
HIV
[Hetherington, 
2002; Mallal, 
2002; Mallal, 
2008]
HLA-B* 5701
Carriage of the HLA-B*5701 variant has been 
shown to increase a patient's risk for 
experiencing hypersensitivity to abacavir.  
Prospective HLA-B*5701 screening and 
exclusion of HLA-B*5701 positive patients 
from abacavir treatment significantly 
decreased the incidence of abacavir 
hypersensitivity.  Treatment guidelines and 
abacavir product labeling in the United States 
and Europe now recommend (US) or require 
(EU) prospective HLA-B*5701 screening prior 
to initiation of abacavir to reduce the incidence 
of abacavir hypersensitivity.  HLA-B*5701 
screening should supplement but must never 
replace clinical risk management strategies for 
abacavir hypersensitivity.
Carbamaze
pine
Seizure, Bipolar 
disorders &
Analgesia 
[Chung, 2010; 
Ferrell, 2008]
HLA-B*1502
Independent studies indicated that patients 
carrying HLA-B*1502 are at higher risk of 
Stevens-Johnson Syndrome and toxic 
epidermal necrolysis and that this marker is 
prevalent in some populations, particularly 
with Asian ancestry.  Regulators, including the 
US FDA and the Taiwanese TFDA, have 
updated the carbamazepine drug label to 
indicate that patients with ancestry in 
genetically at risk populations should be 
screened for the presence of HLA-B*1502 
prior to initiating treatment with 
carbamazepine.


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Drug
Disease
Gene Variant
Outcome
Irinotecan
Cancer 
[Innocenti, 2004; 
Liu, 2008; 
Schulz, 2009]
UGT1A1*28
Variations in the UGT1A1 gene can influence 
a patient’s ability to break down irinotecan, 
which can lead to increased blood levels of the 
drug and a higher risk of side effects. A dose 
of irinotecan that is safe for one patient with a 
particular UGT1A1 gene variation might be too 
high for another patient without this variation, 
raising the risk of certain side-effects, that 
include neutropenia following initiation of 
Irinotecan treatment.  The irinotecan drug 
label indicates that individuals who have two 
copies of the UGT1A1*28 variant are at 
increased risk of neutropenia.  A genetic blood 
test is available that can detect variations in 
the gene.    
A key component to successful PGx research is the collection of samples during the 
conduct of clinical studies.
Collection of whole blood/saliva samples, even when no a priori hypothesis has been 
identified, may enable PGx analysis to be conducted if at any time it appears that there is 
a potential unexpected or unexplained variation in response to treatment.
Pharmacogenetic Research Objectives
The objective of the PGx research (if there is a potential unexpected or unexplained 
variation) is to investigate a relationship between genetic factors and response to 
treatment.  If at any time it appears there is potential variability in response in this clinical 
study or in a series of clinical studies that may be attributable to genetic variations of 
subjects, the following objectives may be investigated:

Pharmacokinetics and/or pharmacodynamics of study treatment

Safety and/or tolerability 

Efficacy
Study Population
Any subject who is enrolled in the clinical study can participate in PGx research. Any 
subject who has received an allogeneic bone marrow transplant must be excluded from 
the PGx research.
Subject participation in the PGx research is voluntary and refusal to participate will not 
indicate withdrawal from the clinical study or result in any penalty or loss of benefits to 
which the subject would otherwise be entitled


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


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Screen and Baseline Failures
If a blood sample for PGx research has been collected and it is determined that the 
subject does not meet the entry criteria for participation in the clinical study, then the 
investigator should instruct the participant that their PGx sample will be destroyed. No 
forms are required to complete this process as it will be completed as part of the consent 
and sample reconciliation process.  In this instance a sample destruction form will not be 
available to include in the site files.
Pharmacogenetics Analyses
Specific genes may be studied that encode the drug targets, or drug mechanism of action 
pathways, drug metabolizing enzymes, drug transporters, or which may underpin adverse 
events, disease risk or drug response. These candidate genes may include a common set 
of ADME (Absorption, Distribution, Metabolism and Excretion) genes that are studied to 
determine the relationship between gene variants or treatment response and/or tolerance. 
In addition, continuing research may identify other enzymes, transporters, proteins or 
receptors that may be involved in response to treatment.  The genes that may code for 
these proteins may also be studied.
Genome-wide scans involving a large number of polymorphic markers (e.g., single 
nucleotide polymorphisms) at defined locations in the genome, often correlated with a 
candidate gene, may be studied to determine the relationship between genetic variants 
and treatment response or tolerance. This approach is often employed when a definitive 
candidate gene(s) does not exist and/or the potential genetic effects are not well 
understood.
If applicable and PGx research is conducted, appropriate statistical analysis methods will 
be used to evaluate pharmacogenetic data in the context of the other clinical data. Results 
of PGx investigations will be reported either as part of the main clinical study report or as 
a separate report. Endpoints of interest from all comparisons will be descriptively and/or 
graphically summarized as appropriate to the data.  A detailed description of the analysis 
to be performed will be documented in the study reporting and analysis plan (RAP) 
analysis plan or in a separate pharmacogenetics RAP, as appropriate.
Informed Consent
Subjects who do not wish to participate in the PGx research may still participate in the 
clinical study. PGx informed consent must be obtained prior to any blood/saliva being 
taken for PGx research.
Provision of Study Results and Confidentiality of Subject’s PGx Data
GSK may summarize the PGx research results in the clinical study report, or separately, 
or may publish the results in scientific journals. 


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GSK does not inform the investigator, subject, or anyone else (e.g., family members, 
study investigators, primary care physicians, insurers, or employers) of individual 
genotyping results that are not known to be relevant to the subject’s medical care at the 
time of the study, unless required by law. This is due to the fact that the information 
generated from PGx studies is generally preliminary in nature, and therefore the 
significance and scientific validity of the results are undetermined.
References
Chung WH, Hung SL, Chen YT. Genetic predisposition of life-threatening antiepileptic-
induced skin reactions.  Expert Opin. Drug Saf. 2010; 9: 15-21.
Ferrell PB, McLeod HL.  Carbamazepine, HLA-B*1502 and risk of Stevens-Johnson 
syndrome and toxic epidermal necrolysis: US FDA recommendations.  
Pharmacogenomics. 2008; 9: 1543-46.
Hetherington S, Hughes AR, Mosteller M, Shortino D, Baker KL, Spreen W, Lai E, 
Davies K, Handley A, Dow DJ, Fling ME, Stocum M, Bowman C, Thurmond LM, Roses 
AD. Genetic variations in HLA-B region and hypersensitivity reactions to abacavir. 
Lancet. 2002; 359:1121-2.
Innocenti F, Undevia SD, Iyer L, Chen PX, Das S, Kocherginsky M, Karrison T, Janisch 
L, Ramirez J, Rudin CM, Vokes EE, Ratain MJ.  Genetic variants in the UDP-
glucuronosyltransferase 1A1 gene predict the risk of severe neutropenia of irinotecan. J 
Clin Oncol 2004; 22: 1382-1388.
Liu CY, Chen PM, Chiou TJ, Liu JH, Lin JK, Lin TC, Chen WS, Jiang JK, Wang HS, 
Wang WS.  UGT1A1*28 polymorphism predicts irinotecan-induced severe toxicities 
without affecting treatment outcome and survival in patients with metastatic colorectal 
carcinoma.  Cancer. 2008; 112: 1932-40.
Mallal S, Nolan D, Witt C, Masel G, Martin AM, Moore C, Sayer D, Castley A, Mamotte 
C, Maxwell D, James I.  Association between presence of HLA-B*5701, HLA-DR7, and 
HLA-DQ3 and hypersensitivity to HIV-1 reverse-transcriptase inhibitor abacavir.  
Lancet. 2002; 359:727-32.
Mallal S, Phillips E, Carosi G, Molina JM, Workman C, Tomazic J, Jägel-Guedes E, 
Rugina S, Kozyrev O, Cid JF, Hay P, Nolan D, Hughes S, Hughes A, Ryan S, Fitch N, 
Thorborn D, Benbow A; PREDICT-1 Study Team.  HLA-B*5701 screening for 
hypersensitivity to abacavir. N Engl J Med. 2008; 358; 568-78
Schulz C, Heinemann V, Schalhorn A, Moosmann N, Zwingers T, Boeck S, Giessen C, 
Stemmler HJ. UGT1A1 gene polymorphism: Impact on toxicity and efficacy of 
irinotecan-based regimens in metastatic colorectal cancer.  World J. Gastroenterol. 2009; 
15: 5058-66.


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Appendix 2: Cockcroft-Gault Formula
CLcr(mL/min) =  
Q x (140-age[yr]) x ideal body wt [kg]*
72 x serum creatinine [mg/dL]
Q = 0.85 for females
Q = 1.0 for males
OR
CLcr(mL/min) =  
K x (140-age[yr]) x ideal body wt [kg]*
Serum creatinine [umol/L]
K = 1.0 for females  
K = 1.23 for males
*Calculation of Ideal Body Weight Using the Devine Formula [Devine, 1974]
Ideal body weight
Males = 
50.0 kg + (2.3 kg x each inch over 5 feet) or 50.0 kg + (0.906 kg x each 
cm over 152.4 cm)
Females = 
45.5 kg + (2.3 kg x each inch over 5 feet) or 45.5 kg + (0.906 kg x each 
cm over 152.4 cm)
Example 1:
Male, actual body weight = 90.0 kg, height = 68 inches.
Ideal body weight = 50.0 + (2.3) (68-60) = 68.4 kg.
This subject’s actual body weight is > 30% over ideal body weight.  Therefore, in this 
case, the subject’s ideal body weight of 68.4 kg should be used in calculating estimated 
creatinine clearance.
References
Devine, BJ. Gentamicin therapy. Drug Intell Clin Pharm. 1974; 8: 650-5.


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Appendix 3: 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


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Appendix 4: Country Specific Requirements
No country-specific requirements exist.


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Appendix 5: Collection of CSF
Cerebrospinal fluid may be collected as an optional procedure on the same day as the 
resection of the melanoma brain metastasis(es).  Signed, informed consent must be 
obtained prior to the surgical procedure.  At the time of surgery, up to 3 mL of CSF can 
be collected only if the neurosurgeon attests that there are not any signs of intracranial 
hypertension (e.g. bulging of brain tissue through the craniotomy site due to recent 
intratumoral hemorrhage). Any of the four ways described below can be followed to 
collect CSF
1.
In select cases after the dura is opened, the neurosurgeon will determine if there 
is a sulcus that is large enough to permit puncture with a 25 gauge butterfly 
needle attached to a 1 mL tuberculin syringe such that CSF can be slowly 
withdrawn (see figure on the following page).
2.
If the operative exposure permits the surgeon will access one the basal cisterns, 
in a similar manner as above, CSF will be withdrawn after puncture with a 25 
gauge butterfly.
3.
Depending on the craniotomy exposure, an image-guided trajectory to the lateral 
ventricles may be possible.  In these cases, if there is no access using the above 
methods, the pia/arachnoid will be coagulated with bipolar cautery and image 
guidance will determine a trajectory to allow ventricular puncture with a 
ventricular catheter and CSF will be withdrawn.  The trajectory may be through 
the cortical surface or after the resection, through the tumor cavity into the 
ventricle.
If the above methods are not possible, a lumbar puncture will be performed while still 
under general anesthesia following the completion of the craniotomy and resection of the 
CNS tumor.  The patient will thus be placed in lateral position on the operating table and 
standard sterile technique for lumbar puncture will be done to withdraw up to 3 mL of 
CSF.


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Appendix 6: Summary of Protocol Amendment Changes
AMENDMENT 2
Summary of Amendment Changes
Updated medical monitor and sponsor contact information; revised IND number to reflect 
submission to dabrafenib + trametinib IND; added ophthalmic examinations to be 
performed at the Screening Visit, Week 4 Visit, and as clinically indicated; updated dose 
modification guidelines for QTc prolongation; removed collection of alcohol information 
at baseline; updated guidelines for missed doses of trametinib
List of Specific Changes
Sponsor Information Page
Previous text
IND 105,032
Revised text
IND 113357
Rationale for Change
Inclusion of combination arm warranted submission to combination IND. 
Section 5.1.3
Previous Text
If a subject misses a dose, the subject should not double the next regularly scheduled 
dose.  However, the subject can take the missed dose immediately if the next scheduled 
dose is at least 6 hrs later.  The subject should take the next dose at the usual time.  
Revised text
If a subject misses a dose of dabrafenib, the subject should not double the next regularly 
scheduled dose.  However, the subject can take the missed dose immediately if the next 
scheduled dose is at least 6 hrs later.  The subject should take the next dose at the usual 
time.  
If a subject misses a dose of trametinib, the subject should not double the next regularly 
scheduled dose.  However, the subject can take the missed dose immediately if the next 
scheduled dose is at least 12 hrs later.  The subject should take the next dose at the usual 
time.
Rationale for Change
Clarification and updates to recommendations for missed trametinib doses.  


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Section 5.7.3.3
Previous Text
QTc-Prolongationa
Action and Dose Modification

QTcB ≥501 msec, OR

uncorrected QT>600 msec, OR

QTcB>530 msec for subjects with 
bundle branch block

Interrupt study treatment until QTcB prolongation 
resolves to grade 1 or baseline

If event resolves, restart study treatment at current 
dose levelb

If event does not resolve, permanently discontinue 
study treatment

If event recurs, permanently discontinue study 
treatment
1.
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 subject may resume study treatment if the investigator 
and GSK medical monitor agree that the subject will benefit from further treatment.
Revised Text
QTc-Prolongationa
Action and Dose Modification

QTcB ≥501 msec, OR

uncorrected QT>600 msec, OR

QTcB>530 msec for subjects with 
bundle branch block

Interrupt study treatment until QTcB prolongation 
resolves to grade 1 or baseline

Test serum potassium, calcium, phosphorus and 
magnesium. If <LLN correct with supplements to within 
normal limits.

Review concomitant medication usage for a prolonged 
QTc.

Restart at current dose level b

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 subject may resume study treatment if the investigator 
and GSK medical monitor agree that the subject will benefit from further treatment.
Rationale for Change
Text has been revised across all protocols to reflect additional monitoring requirements.


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Table 19
Previous Text
Alcohol consumption data were collected at baseline
Ophthalmic exams were not included in the table.
Revised Text
Alcohol consumption data are no longer being collected at baseline.
Ophthalmic exams are included as a required assessment during Screening and at Week 
4.
Rationale for Change
Alcohol consumption data are not longer required for collection.
Ophthalmic exams were included per recent FDA guidance and subsequent revision of 
standard assessments.  
Section 7.3.11
Previous Text
N/A; new section
Revised Text
Ophthalmic Examination
Subjects are required to have a standard ophthalmic examination performed by an 
ophthalmologist at baseline, at week 4, and as clinically warranted per guidance for 
visual changes (Section 5.8.5.4). The exam will include indirect 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.  Direct fundoscopy may be performed but is not required. In subjects with clinical 
suspicion of RVO or CSR, flourescein angiography and/or optical coherence tomography 
are highly recommended.
Rationale for Change
New section added per FDA recommendations. 

SAP_001.pdf: 
Clinical Development
DRB436 (GSK2118436) /Dabrafenib
CDRB436B2202 (BRV116521)
An Open-label, Multicenter, Corollary Study of Pre-
Operative Therapy with Dabrafenib and the Combination of
Dabrafenib with Trametinib in Subjects with BRAF 
Mutation-Positive Metastatic Melanoma to the Brain
Statistical Analysis Plan (SAP)
Author:
Trial Statistician, 
 Lead Statistician, 
 
 CP Statistician, 
Document type:
SAP Documentation
Document status:
Final 1.0
Release date:
08-Apr-2017
Number of pages:
20
Property of Novartis
Confidential
May not be used, divulged, published or otherwise disclosed
without the consent of Novartis
PPD
PPD
PPD
PPD


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


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Table of contents
Table of contents .................................................................................................................3
1
Introduction .........................................................................................................................6
1.1
Study design.............................................................................................................6
1.2
Study objectives and endpoints ...............................................................................6
2
Statistical methods...............................................................................................................8
2.1
Data analysis general information ...........................................................................8
2.1.1
General definitions..................................................................................9
2.2
Analysis sets ..........................................................................................................11
2.3
Patient disposition, demographics and other baseline characteristics ...................11
Patient disposition..................................................................................................12
2.4
Treatments (study treatment, rescue medication, concomitant therapies, 
compliance)............................................................................................................12
2.4.1
Study treatment / compliance................................................................12
2.4.2
Prior, concomitant and post therapies ...................................................13
2.5
Analysis of the primary objective..........................................................................13
2.5.1
Primary endpoint...................................................................................13
2.5.2
Statistical hypothesis, model, and method of analysis..........................13
2.5.3
Handling of missing values/discontinuations........................................13
2.6
Analysis of the key secondary objective ...............................................................13
2.7
Analysis of secondary objective(s)........................................................................14
As a short close-out CSR will be produced, analyses will not be performed 
for secondary endpoints. .......................................................................14
2.8
Safety analyses.......................................................................................................14
2.8.1
Adverse events (AEs)............................................................................14
2.8.2
Deaths....................................................................................................15
2.8.3
Laboratory data .....................................................................................15
2.8.4
Other safety data ...................................................................................15
2.9
Pharmacokinetic endpoints....................................................................................15
2.10
PD and PK/PD analyses.........................................................................................15
2.11
Patient-reported outcomes .....................................................................................15
2.12
Biomarkers.............................................................................................................16
2.13
Other Exploratory analyses....................................................................................16
2.14
Interim analysis......................................................................................................16
3
Sample size calculation .....................................................................................................16
3.1
Primary analysis.....................................................................................................16


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3.2
Power for analysis of key secondary variables......................................................16
4
Change to protocol specified analyses ..............................................................................16
5
Appendix ...........................................................................................................................16
5.1
Imputation rules.....................................................................................................17
5.1.1
Study drug .............................................................................................17
5.1.2
AE date imputation ...............................................................................17
5.1.3
Concomitant medication date imputation .............................................19
5.2
AEs coding/grading ...............................................................................................20
5.3
Laboratory parameters derivations ........................................................................20
5.4
Statistical models...................................................................................................20
6
Reference...........................................................................................................................20


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List of abbreviations
AE 
Adverse event
AESI
Adverse event of special interest
ALT 
Alanine aminotransferase (SGPT)
AST 
Aspartate aminotransferase (SGOT)
CRF 
Case Report Form
CSF 
Cerebrospinal fluid
CSR 
Central serous retinopathy
CTCAE v4.0 
v4.0 Common Terminology Criteria for Adverse Events, version 4.0
DNA 
Deoxyribonucleic acid
ECG 
Electrocardiogram
ECHO 
Echocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF 
Electronic Case Report Form
LDH 
Lactate dehydrogenase
LLN 
Lower limit of normal
LVEF 
Left ventricular ejection fraction
MedDRA 
Medical Dictionary for Regulatory Activities
RAP 
Reporting and Analysis Plan
RECIST 
Response Evaluation Criteria In Solid Tumours
SAE 
Serious adverse event(s)
ULN
Upper limit of normal
US/USA 
United States


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Introduction
This statistical analysis plan (SAP) describes all planned analyses for the clinical study report 
(CSR) of study CDRB436B2202 (BRV116521), a phase IIB, open-label, multicenter, 
corollary study of pre-operative therapy with dabrafenib and the combination of dabrafenib 
with trametinib in subjects with BRAF mutation-positive metastatic melanoma to the brain.
This SAP will also be used for the final analysis.
The content of this SAP is based on protocol CDRB436B2202 (BRV116521) Amendment 
version 03. All decisions regarding interim, primary and final analyses, as defined in the SAP 
document, have been made prior to database lock.
1.1
Study design
This is a global, multi-center, open-label study that will be conducted in up to 30 evaluable 
subjects with resectable, BRAF V600E or V600K mutation-positive metastatic melanoma to 
the brain. Subjects in Cohort A will receive dabrafenib orally 150 mg twice daily (BID) for 7 
to 14 days prior to surgery (Cohort A); Subjects in Cohort B (the second cohort of 2 cohorts) 
will receive the combination of dabrafenib 150 mg BID and trametinib 2 mg once daily for 7 
to 14 days prior to surgery (Cohort B).
The primary endpoints in this study are concentrations and distribution of dabrafenib, its 
metabolites hydroxyl-, carboxy- and desmethyl-dabrafenib and trametinib (Cohort B only) in 
parenchymal brain metastases, peripheral blood (plasma) and, when possible, in extracranial 
metastases. The secondary endpoints include concentrations of dabrafenib and its metabolites 
in cerebrospinal fluid (CSF) samples, changes in MAPK pathway markers and changes in the 
radiographic characteristics of the tumors. The efficacy endpoints are changes from baseline 
to pre-surgery in the sum of the longest diameters of intracranial target lesions, maximum 
change from baseline in the sum of longest diameters of unresected intracranial target lesions, 
overall extracranial response rate in unresected lesions and overall survival.
1.2
Study objectives and endpoints
Objective
Endpoint
Primary
To determine levels and tissue distribution of 
dabrafenib, its metabolites and trametinib in 
parenchymal brain metastases peripheral blood 
(plasma) and, when possible, in extracranial 
metastases within two cohorts of subjects with 
BRAF V600E/K mutation-positive metastatic 
melanoma to the brain following pre-operative 
treatment.
Concentrations and tissue distribution of 
dabrafenib, its metabolites hydroxy-, carboxy- and 
desmethyl-dabrafenib and trametinib (Cohort B 
only) in parenchymal brain metastases, peripheral 
blood (plasma) and, when possible, in 
extracranial metastases.
Secondary
Determine the levels of dabrafenib, its 
Concentrations of dabrafenib, its metabolites 


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Endpoint
metabolites and trametinib in the CSF in subjects 
who undergo resection of BRAF V600E/K 
mutation-positive metastatic melanoma to the
brain following pre-operative treatment
hydroxy-, carboxy- and desmethyl-dabrafenib) 
and trametinib (Cohort B only) in CSF samples.
Determine the activation status of the MAPK 
pathway following pre-operative treatment in 
resected brain and, when available, extracranial 
metastases. Activation of the MAPK kinase 
pathway will also be determined in samples of 
readily accessible extracranial metastases 
obtained prior to starting treatment.
Changes in MAPK pathway markers in paired 
extracranial biopsies taken pre-treatment, during 
craniotomy, and at disease progression, and 
changes in markers between post-operative 
intracranial and extracranial biopsies, when data 
is available.
Comparison of pharmacokinetics and 
pharmacodynamics to tumor response.
Changes in the radiographic characteristics of the 
tumors will be compared to (1) levels of 
dabrafenib, its metabolites and trametinib (where 
appropriate) in the brain metastases, plasma, and 
CSF, and (2) MAPK pathway activation status in 
tumors at the time of surgery. When available, 
results will also be compared to the analysis of 
early clinical responses in extracranial 
metastases, as determined by the PET-CT 
imaging.
To evaluate efficacy of study treatment in
resected and unresected lesions.

change from baseline to pre-surgery in 
the sum of the longest diameters of 
intracranial target lesions,

maximum change from baseline to pre-
surgery in the sum of longest diameters 
of unresected intracranial target lesions,

overall extracranial response rate in 
unresected lesions, and

overall survival
To characterize the safety profile of study 
treatment in subjects with melanoma brain 
metastases.
Safety as measured by clinical assessments 
including vital signs and physical examinations, 
12-lead electrocardiograms (ECG), 
echocardiogram (ECHO), chemistry and 
hematology laboratory values, and adverse 
events (AEs).
Exploratory
To characterize the prevalence of BRAF and other 
mutations in melanoma brain metastases and 
extracranial metastases when available.
Quantitative analysis of DNA from the brain and 
extracranial metastases to determine the degree of 
concordance of BRAF mutations between the two 
samples. Additional mutations found in the analysis of 
tumor samples will be summarized.
To evaluate the baseline and changes in the expression
and activation of proteins and transcriptional cell 
signaling networks, including the MAPK kinase 
pathway, in readily accessible extracranial metastases 
when available in patients treated with dabrafenib and 
dabrafenib plus trametinib and compare changes where 
appropriate.
The expression and activation of protein signaling 
pathways and transcriptional networks, including the 
MAPK pathway, will be evaluated when available in 
extracranial biopsies taken pre-treatment, at/near the 
time of craniotomy, and at disease progression to 
understand changes induced by the given treatments 
and their correlation with other molecular features (i.e. 
mutations) and treatment outcomes.
Compare the status of protein and transcriptional 
signaling pathways, including the the MAPK kinase
The expression and activation of protein signaling 
pathways and transcriptional networks, including the 


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Objective
Endpoint
pathway, in the brain metastases and readily accessible 
extracranial metastases when available.
MAPK pathway, in intracranial and, when available, 
extracranial biopsies collected at/near the time of 
craniotomy, and/or at disease progression, will be 
compared to identify differential molecular features 
and treatment effects.
Results will also be compared to the analysis of early 
clinical responses in extracranial metastases, as 
determined by the PET-CT imaging, and drug levels in 
blood and tissue samples.
Since study is terminated with 6 enrolled patients, a short close-out CSR will be produced.
The planned objectives and  endpoints will not be fully analyzed.
2
Statistical methods
2.1
Data analysis general information
The tables, figures and listings will be generated by Novartis or designated CRO. SAS version 
9.4 or later software will be used to perform all data analyses and to generate tables, figures 
and listings.
Data included in the analysis
All statistical analyses will be performed using all data collected in the database up to the data
cut-off date. All data with an assessment date or event start date (e.g. vital sign assessment
date or start date of an adverse event) prior to or on the cut-off date will be included in the
analysis. Any data collected beyond the cut-off date will not be included in the analysis and 
will not be used for any derivations.
All events with start date before or on the cut-off date and end date after the cut-off date will 
be reported as ‘continuing at the cut-off date’. The same rule will be applied to events starting 
before or on the cut-off date and not having documented end date. This approach applies, in 
particular, to adverse event and concomitant medication reports. For these events, the end date 
will not be imputed and therefore will not appear in the listings.
The analysis cut-off date for the final analysis of study data will be established at the end of 
the study when all patients have been followed for survival and new anti-cancer therapy for 2 
years from permanently discontinuing study treatment until death or the consent is withdrawn.
General analysis conventions
Pooling of center: Unless specified otherwise, data from all study centers will be pooled for 
the analysis. Due to expected small size of centers, no center effect will be assessed. 
Qualitative data (e.g. gender, race, etc.) will be summarized by means of contingency tables
by treatment group; a missing category will be included as applicable. Percentages will be
calculated using the number of patients in the relevant population or subgroup as the
denominator.


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Quantitative data (e.g. age, body weight, etc.) will be summarized by appropriate
descriptive statistics (i.e. mean, standard deviation, median, minimum, and maximum) by
treatment group.
2.1.1
General definitions
Investigational drug and study treatment
The investigational drug refers to dabrafenib or trametinib. 
The study treatment refers to dabrafenib and combination of dabrafenib with trametinib.
Study treatment component refers to dabrafenib or trametinib.
Treatment
For presentation in the outputs, treatment refers to
Cohort A : Dabrafenib prior to surgery
Cohort B : Dabrafenib + Trametinib prior to surgery
Date of first administration of investigational drug
The date of first administration of investigational drug is defined as the first date when a 
nonzero dose of investigational drug is administered and recorded on the Dosage 
Administration Record (DAR) eCRF. The date of first administration of study drug will also 
be referred as start of investigational drug.
Date of last administration of investigational drug
The date of last administration of investigational drug is defined as is the last date when a 
nonzero dose of investigational drug is administered and recorded on DAR eCRF. The date of 
last administration of investigational drug will also be referred as end of investigational drug.
Study day
The study day, describes the day of the event or assessment date, relative to the reference start 
date. 
The study day is defined as:
The date of the event (visit date, onset date of an event, assessment date etc.) − 
reference start date + 1 if event is on or after the reference start date;

The date of the event (visit date, onset date of an event, assessment date etc.) − 
reference start date if event precedes the reference start date.
The reference date for all assessments (safety, efficacy, PK, QoL, etc) is the start of study 
treatment. 
The study day will be displayed in the data listings. If an event starts before the reference start 
date, the study day displayed on the listing will be negative.


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Time unit
A year length is defined as 365.25 days. A month length is 30.4375 days (365.25/12). If 
duration is reported in months, duration in days will be divided by 30.4375.  If duration is 
reported in years, duration in days will be divided by 365.25.
Baseline
Baseline is defined as the most recent non-missing value prior to the first dose of study 
treatment.
On-treatment assessment/event and observation periods
The overall observation period will be divided into three mutually exclusive segments: 
Pre-treatment period is defined as from day of patient’s informed consent to the day before 
first administration of study treatment
On-treatment period is defined as from date of first administration of study treatment to 30
days after date of last actual administration of study treatment (including start and stop date)
Post-treatment period is defined as starting at day 30+1 after last administration of study 
treatment.
Notes: if data on clock time is available in the clinical database (e.g. for time of blood/urine 
sample taken, ECG performed, etc. and first study treatment administration), a more precise 
distinction between pre-treatment and on-treatment periods is encouraged to be used. If dates 
are incomplete in a way that clear assignment to pre-, on-, post-treatment period cannot be 
made, then the respective data will be assigned to the on-treatment period.  
Safety summaries (tables, figures) include data from the pre-treatment period (to display the 
baseline status e.g. for ECG) and the on-treatment period, i.e. data from the post-treatment 
period with the exception of deaths should not be included unless requested from Health 
Authorities or external committees.
In particular, summary tables for adverse events (AEs) will summarize only on-treatment 
events, with a start date during the on-treatment period, the so-called treatment-emergent AEs.  
However, all safety data (including those from the post-treatment period) will be listed and 
those collected during the pre-treatment and post-treatment period are to be flagged.
Windows for multiple assessments
All data will be reported according to the nominal visit date for which it was reported (that is, 
no visit windows will be applied during dataset creation). 
Last contact date 
As a short close-out CSR will be produced, survival data will not be analyzed, this is not 
applicable.


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2.2
Analysis sets
Full Analysis Set
The Full Analysis Set (FAS) will include all patients who receive at least one dose of study 
treatment. The FAS will be used for summaries of baseline characteristics and all efficacy 
analyses unless otherwise specified.
Safety Set
The Safety Set includes all patients who received at least one dose of study treatment. All 
safety data will be analyzed using the Safety Set. In this study, the FAS and safety set are 
identical.
Pharmacokinetic analysis set
The Pharmacokinetic analysis set (PAS) includes all patients who provide at least one 
evaluable PK concentration. 
The PAS will be used in the analysis of PK data. Any samples missing collection date or time, 
or missing associated study drug dosing date or time will be excluded. 
Withdrawal of Informed Consent
Any data collected in the clinical database after a patient withdraws informed consent from all 
further participation in the trial will not be included in the analysis data sets. The date on 
which a patient withdraws full consent is recorded in the eCRF. 
Third party data e.g. PK, biomarker etc., collected in the clinical database without having 
obtained consent for collection will not be included in the analysis data sets. These data will 
be excluded by the presence of the appropriate protocol deviation criterion.
2.3
Patient disposition, demographics and other baseline 
characteristics
The FAS will be used for all baseline and demographic summaries and listings unless 
otherwise specified.
Basic demographic and background data
All demographic and baseline disease characteristics data will be summarized and listed by 
cohorts. Categorical data (e.g. gender, age groups >= 65, < 65, race, ethnicity, ECOG
performance status) will be summarized by frequency counts and percentages; the number and 
percentage of patients with missing data will be provided. Continuous data (e.g. age, weight, 
height, Body Mass Index (BMI)) will be summarized by descriptive statistics (N, mean, 
median, standard deviation, minimum and maximum).
BMI will be calculated using baseline height and baseline weight:
BMI (kg/m2) = weight [kg] / ((height [m])2


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All demographic data and other baseline characteristics (alcohol history, smoking history, etc.) 
will be listed by patient using FAS. 
Patient disposition
Subject disposition will be summarized using the FAS by cohorts.
A summary of patient status and reason for end of study will be provided. This display will 
show the number and percentage of patients who withdrew from the study, and primary 
reasons for study withdrawal. Reasons for study withdrawal will be presented in the order 
they are displayed in the eCRF.
A summary of study treatment status will be provided. This display will show the number and 
percentage of patients who discontinued study treatment or has treatment ongoing or
completed the study and a summary of the primary reasons for discontinuation of study 
treatment. Reasons for study treatment discontinuation will be presented in the order they are 
displayed in the eCRF. A listing of study treatment discontinuation will be generated. The 
listing will include last dose date, and reasons for study treatment discontinuation.
Analysis sets
The number and percentages (based on the total number of FAS patients) of patients in each 
analysis set (defined in Section 2.2) will be summarized.
2.4
Treatments (study treatment, rescue medication, concomitant 
therapies, compliance)
2.4.1
Study treatment / compliance
Dose administration data will be summarized by cohorts and by pre-craniotomy phase and 
post-craniotomy phase using the Safety Set.
In addition, a listing of exposure to dabrafenib, dabrafenib and trametinib will be produced.
Duration of exposure to study treatment
Duration of exposure to study treatment is considered by taking into account the duration of 
exposure to the investigational drugs:
Duration of exposure to study treatment (days) = (last date of exposure to study treatment) –
(date of first administration of study treatment) + 1.
The last date of exposure to study treatment is the latest of the last dates of exposure to 
investigational drug.
Summary of duration of exposure of study treatment in appropriate time units will include 
categorical summaries based on intervals and continuous summaries (i.e. mean, standard 
deviation etc.) using appropriate units of time.


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2.4.2
Prior, concomitant and post therapies
Not applicable.
2.5
Analysis of the primary objective
2.5.1
Primary endpoint
As a short close-out CSR will be produced, summary analyses will not be performed. The 
concentration and distribution (when applicable) of dabrafenib, dabrafenib metabolites and 
trametinib (Cohort B only) will be listed for each cohort by tissue type (i.e., parenchymal 
brain metastases, optional assessment of extracranial metastases, plasma) and by pre-
craniotomy phase and post-craniotomy phase. Both absolute concentrations and ratios relative 
to plasma will be determined for the different sample types, if data permit.
2.5.2
Statistical hypothesis, model, and method of analysis
Not applicable.
2.5.3
Handling of missing values/discontinuations
Missing values for any PK, and tissue concentrations and distribution (when applicable) will 
not be imputed and will be treated as missing. Below the limit of quantitation (BLQ) values 
(<1 ng/mL for a 50-µL aliquot of human plasma for dabrafenib, hydroxy-dabrafenib and 
desmethyl-dabrafenib and <5 ng/mL for a 25-µL aliquot of human plasma for carboxy-
dabrafenib) will be set to zero by the Bioanalyst, and will be displayed in the listings as zero 
and flagged. BLQ values (<5 ng/g for dabrafenib and hydroxy-dabrafenib and <30 ng/g for 
desmethyl-dabrafenib for a 50 µL aliquot of tissue homogenate) for tissue concentrations and 
distribution (when applicable) and trametinib (<5 ng/g for a 50 µL aliquot of tissue 
homogenate) (Cohort B only) in the measured tissues (i.e., parenchymal brain metastases, 
optional assessment of extracranial metastases) will be set to zero by the Bioanalyst.
Concentrations measured in CSF sample below the limit of quantitation (BLQ) values (<1 
ng/mL for dabrafenib, hydroxy-dabrafenib and desmethyl-dabrafenib, <5 ng/mL for carboxy-
dabrafenib and <0.250 ng/mL for trametinib) will be set to zero by the Bioanalyst, and will be 
displayed in the listings as zero.
2.6
Analysis of the key secondary objective
Not applicable.


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2.7
Analysis of secondary objective(s)
As a short close-out CSR will be produced, analyses will not be performed for secondary 
endpoints. The concentration of dabrafenib, dabrafenib metabolites and trametinib (Cohort B 
only) in CSF will be listed for each cohort by pre-craniotomy phase and post-craniotomy 
phase. Both absolute concentrations and ratios relative to plasma will be determined for the 
different sample types, if data permit.
2.8
Safety analyses
All safety analyses will be based on the safety set. Summaries will be sorted and displayed by 
cohorts.
2.8.1
Adverse events (AEs)
AE summaries will include all AEs occurring during on treatment period. All AEs collected in 
the AE (e)CRF page will be listed along with the information collected on those AEs e.g. AE 
relationship to study drug, AE outcome etc. AEs with start date outside of on-treatment period 
will be flagged in the listings. 
AEs will be summarized by number and percentage of subjects having at least one AE, having 
at least one AE in each primary system organ class (SOC) and for each preferred term (PT) 
using MedDRA coding. A subject with multiple occurrences of an AE will be counted only 
once in the respective AE category. A subject with multiple CTCAE grades for the same 
preferred term will be summarized under the maximum CTCAE grade recorded for the event.
In AE summaries, the primary system organ class (SOC) will be presented alphabetically and 
the preferred terms will be sorted within primary SOC in descending frequency. The sort 
order for the preferred term will be based on their frequency. 
The following AE summaries will be produced: AEs by SOC, PT and maximum grade, 
summarized by relationship to study drug, seriousness, leading to treatment discontinuation, 
in addition, a summary of serious adverse events with number of occurrences will be 
produced.
2.8.1.1
Adverse events of special interest / grouping of AEs
Data analysis of AESIs
Adverse events of special interest (AESIs) are defined as AEs within the following 
categories/groupings of PTs:

Cutaneous squamous cell carcinoma (including keratoacanthomas)

Treatment emergent malignancies (excluding cuSCC, basal cell carcinoma)

Pyrexia

Uveitis

Renal failure/acute renal failure

Pancreatitis


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
Hypersensitivity

Hyperglycaemia
AESIs are defined at the project level and may be updated based on emergent data to reflect
new AESIs of interest at the time of analysis.
For each specified AESI, number and percentage of subjects with at least one event of the 
AESI occurring during on treatment period will be summarized.
A listing of all grouping levels down to the MedDRA preferred terms used to define each 
AESI will be generated. 
2.8.2
Deaths
Separate summaries for on-treatment death and all deaths on-treatment and post-treatment 
will be produced by system organ class and preferred term. All deaths will be listed, post 
treatment deaths will be flagged.
Note: The death summaries cover subjects from the Safety Set. 
2.8.3
Laboratory data
As a short close-out CSR will be produced, data will not be summarized and listed.
2.8.4
Other safety data
2.8.4.1
ECG and cardiac imaging data
As a short close-out CSR will be produced, data will not be summarized and listed.
2.8.4.2
Vital signs
As a short close-out CSR will be produced, data will not be summarized and listed.
2.9
Pharmacokinetic endpoints
Please refer to Section 2.5 and Section 2.7 for primary and secondary PK-related endpoints.
2.10
PD and PK/PD analyses
Not applicable.
2.11
Patient-reported outcomes
Not applicable. 


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2.12
Biomarkers
As a short close-out CSR will be produced, biomarker data will not be summarized. The 
biomarker data will be listed, if data permit.
2.13
Other Exploratory analyses
Not applicable.
2.14
Interim analysis
No formal interim analysis is planned for this study.
3
Sample size calculation
3.1
Primary analysis
For the objective of estimating the levels of dabrafenib its metabolites, and trametinib in brain 
metastases, the average level for the parent drug and each metabolite along with the range and 
95% confidence interval for the brain metastases, extracranial metastases, and plasma will be 
reported. A sample size of 15 patients per cohort was chosen to characterize concentrations 
with reasonable precision (within 0.7 standard deviation) within each cohort. The correlation 
and corresponding 95% confidence interval between concentrations in the brain metastases 
and concentrations in the plasma, and in the optional extracranial metastases and CSF, for the 
parent drug and each metabolite will also be estimated. Additionally, the ratio between the 
concentrations in the brain metastases and in the extracranial metastases and the plasma 
concentrations within each subject for each metabolite will be estimated and summarized with 
95% CI’s.
Due to the difficulty in recruiting patients, this study was terminated early, 6 patients were 
enrolled to study at termination of study.
3.2
Power for analysis of key secondary variables
Not applicable.
4
Change to protocol specified analyses

The primary endpoints and secondary endpoints will not be analyzed as in protocol.

Clinical laboratory data, vital signs, 12-lead ECG, and ECHO/MUGA scan data will 
not be summarized and listed. 
5
Appendix
This will be used later for drafting CSR Appendix 16.1.9.


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5.1
Imputation rules
5.1.1
Study drug
The following rule should be used for the imputation of the dose end date for dabrafenib:
Scenario 1: If the dose end date is completely missing and there is no EOT page and no death 
date, the patient is considered as on-going:
The patient should be treated as on-going and the cut-off date should be used as the last 
dosing date. 
Scenario 2: If the dose end date is completely or partially missing and the EOT page is 
available:
Case 1: The dose end date is completely missing, and the EOT  completion date is complete, 
then this latter date should be used.  
Case 2: Only Year(yyyy) of the dose end date is available and yyyy < the year of EOT date:  
Use Dec31yyyy
Case 3: Only Year(yyyy) of the dose end date is available and yyyy  = the year of EOT date:
Use EOT date
Case 4: Both Year(yyyy) and Month (mm) are available for dose end date, and yyyy  = the 
year of EOT date and mm < the month of  EOT date: 
Use last day of the Month (mm)
All other cases should be considered as a data issue and the statistician should contact the data 
manager of the study.
After imputation, compare the imputed date with start date of treatment, if the imputed date is 
< start date of treatment:
Use the treatment start date
Patients with missing start dates are to be considered missing for all study treatment 
component related calculations and no imputation will be made. If start date is missing then 
end-date should not be imputed.
5.1.2
AE date imputation
The following missing dates will not be imputed

Missing AE start dates

AE start dates missing the year

Partial/missing AE end dates
For other type of missing dates, rules specified in Tables 5-1 to 5-3 will be used
Table 5-1
AE/Treatment Date Abbreviations 
Day
Month
Year
Partial Adverse Event Start Date
<not used>
AEM
AEY


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Day
Month
Year
Treatment Start Date (TRTSTD)
<not used>
TRTM
TRTY
Table 5-2 describes the possible combinations and their associated imputations. The upper 
text indicates the imputation (NC, A, B, C etc.) and the lower text the relationship of the AE 
start date to the treatment start date (TRTSTD).
Table 5-2
Imputation algorithm
AEM MISSING
AEM < TRTM
AEM = TRTM
AEM > TRTM
AEY MISSING
NC
Uncertain
NC
Uncertain
NC
Uncertain
NC
Uncertain
AEY < TRTY
( D )
Before TRTSTD
( C )
Before TRTSTD
( C )
Before TRTSTD
( C )
Before TRTSTD
AEY = TRTY
( B )
Uncertain
( C )
Before TRTSTD
( B )
Uncertain
( A )
After TRTSTD
AEY > TRTY
( E )
After TRTSTD
( A )
After TRTSTD
( A )
After TRTSTD
( A )
After TRTSTD
The legend to the above table is shown in Table 5-3.
Table 5-3
Imputation algorithm legends
Relationship
Before TRTSTD
Indicates AE start date prior to Treatment Start Date
After TRTSTD
Indicates AE start date after Treatment Start Date
Uncertain
Insufficient to determine the relationship of AE start date 
to Treatment Start Date
Imputation calculation
NC / Blank
No convention/imputation
( A )
01MONYYYY
( B )
TRTSTD+1
( C )
15MONYYYY
( D )
01JULYYYY
( E )
01JANYYYY
Few examples are shown in Table 5-4.
Table 5-4
Example scenarios
Partial
AE start date
Treatment
start date
Relationship 
with TRTSTD
Imputation 
Calculation
Imputed Date
12mmyyyy
20OCT2001
Uncertain
NC
<blank>
ddmmm2000
20OCT2001
Before
( D )
01JUL2000
ddmmm2002
20OCT2001
After
( E )
01JAN2002
ddmmm2001
20OCT2001
Uncertain
( B )
21OCT2001
ddSEP2001
20OCT2001
Before
( C )
15SEP2001
ddOCT2001
20OCT2001
Uncertain
( B )
21OCT2001


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Partial
AE start date
Treatment
start date
Relationship 
with TRTSTD
Imputation 
Calculation
Imputed Date
ddNOV2001
20OCT2001
After
( A )
01NOV2001
5.1.3
Concomitant medication date imputation
5.1.3.1
Prior therapies date imputation
Start date: The same rule which is applied to the imputation of AE/concomitant medication 
start date will be used with the exception that: for scenario (B) will be replaced to be start
date of study drug -1.
End date: 

Imputed date = min (reference end date, DEC 31), if month and day are missing.

Imputed date = min (reference end date, last day of the Month), if day is missing. 

Reference end date will be start date of study drug. 
If the end date is not missing and the imputed start date is after the end date, use t he end date 
as the imputed start date. If both the start date and the end date are imputed and if the 
imputed start date is after the imputed end date, use the imputed end date as the imputation for 
the start date
5.1.3.2
Post therapies date imputation
Start date: 

If Day is missing, then impute to the max (reference start date, first day of the month). 

Day and month are missing then impute to the max(reference start date, Jan 1) 

Reference start date will be last date of study treatment administration + 1. 
End date: No imputation
5.1.3.3
Other imputations
Incomplete date of initial diagnosis of cancer and  date of most recent 
recurrence 
Missing day is defaulted to the 15th of the month and missing month and day is defaulted to 
01-Jan. 
Incomplete assessment dates for tumor assessment
All investigation dates (e.g. MRI scan, CT scan) must be completed with day, month and year. 
If one or more assessment dates are incomplete but other investigation dates are available, 
this/these incomplete date(s) are not considered for calculation of the assessment date and 
assessment date is calculated as the latest of all investigation dates (e.g. MRI scan, CT scan) if 
the overall response at that assessment is CR/PR/SD/UNK. Otherwise – if overall response is 
progression – the assessment date is calculated as the earliest date of all investigation dates at 


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that evaluation number.  If all measurement dates have no day recorded, the 1st of the month is 
used. If the month is not completed, for any of the investigations, the respective assessment 
will be considered to be at the date which is exactly between previous and following 
assessment. If a previous and following assessment is not available, this assessment will not 
be used for any calculation.
Missing death date
All dates must be completed with day, month and year. For cases when either day is missing 
or both month and day are missing for the date of death, the following imputation rules will be 
implemented:

If only day is missing, then impute max [(1 mmm-yyyy), min(last contact date+1 , cutoff 
date)]. 

If both day and month are missing, then impute max [(1 Jan-yyyy, min (last contact date 
+1, cutoff date)].
Will the initial date of relapse, PD, or failed to respond to frontline therapy be collected on the 
“prior antineoplastic therapy” page? 
5.2
AEs coding/grading
Adverse events are coded using the Medical dictionary for regulatory activities (MedDRA) 
terminology.
AEs will be assessed according to the Common Terminology Criteria for Adverse Events 
(CTCAE) version 4.03.
The CTCAE represents a comprehensive grading system for reporting the acute and late 
effects of cancer treatments. CTCAE grading is by definition a 5-point scale generally 
corresponding to mild, moderate, severe, life threatening, and death. This grading system 
inherently places a value on the importance of an event, although there is not necessarily 
proportionality among grades (a grade 2 is not necessarily twice as bad as a grade 1). The 
CTCAE grade of 5 (death) is not used; rather, ‘fatal’ is collected as AE outcome and death 
information is also collected on a separate (e)CRF page.
5.3
Laboratory parameters derivations
Not applicable.
5.4
Statistical models
Not applicable.
6
Reference
None.


Clinical Development
DRB436(GSK2118436)/Dabrafenib
CDRB436B2202 (BRV116521)
An Open-label, Multicenter, Corollary Study of Pre-
Operative Therapy with Dabrafenib and the Combination of 
Dabrafenib with Trametinib in Subjects with BRAF 
Mutation-Positive Metastatic Melanoma to the Brain
Tables, Figures and Listings (TFL) Shells- CSR deliverables
Author(s):
 Contract Statistician; 
 Trial 
Statistician
Document type:
RAP Document: TFL shells
Document status:
Final 1.0
Release date:
17-July-2017
Number of pages:
50
Property of Novartis
For business use only
May not be used, divulged, published or otherwise disclosed
without the consent of Novartis
PPD
PPD


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Document History - Changes compared to previous version
Version
Date
Changes


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Table of contents
Table of contents .................................................................................................................3
1
General guidance.................................................................................................................4
1.1
Document headers ...................................................................................................4
1.2
Presentation of table numbering and titles within this document............................4
1.3
Treatment group labels and ordering.......................................................................4
1.4
Distribution logistics................................................................................................4
2
Overall table of contents for statistics and programming output ........................................5
3
Shells and specification .......................................................................................................7
3.1
Shells and specifications for sections 10, 11 and 12 of the CSR (Text tables 
and figures) ..............................................................................................................7
Section 10
Study Subjects.....................................................................................7
Section 11
Efficacy and/or PK/PD evaluation (also Health Economics, QoL 
etc.)..........................................................................................................8
Section 12
Safety evaluation.................................................................................9
Shells and specifications for Sections 14 and 16 of the CSR............................................15
Section 14
Tables, figures and graphs referred to but not included in the text...15
Section 16
Appendices (Safety Set and Pharmacokinetic Analysis Set)............39


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1
General guidance
1.1
Document headers
The following header will be used for all tables, listings and figures in sections 14 and 16 outlined in 
this document:  CDRB436B2202
1.2
Presentation of table numbering and titles within this document
In practice, the numbering and title for all tables and listings in sections 14 and 16 defined in this 
document will be of the following formats respectively:
Table XX.X-X.X
Title Title Title Title Title Title
Population
Listing XX.X-X.X
Title Title Title Title Title Title
Population
1.3
Treatment group labels and ordering
The following treatment labels will be used for all tables, listings and figures in the order provided 
here:

Treatment group label 1
Cohort A
Cohort B
All subjects
1.4
Distribution logistics
Details on in-text tables are added in section 3.1


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Overall table of contents for statistics and programming 
output
Table 10-1
Subject disposition (FAS) .......................................................................7
Table 10-2
Analysis set (FAS) ..................................................................................7
Table 11-1
Demographic (FAS)................................................................................8
Table 12-1
Duration of exposure to study drug (Safety Set).....................................9
Table 12-2
Overview of adverse events (Safety set)...............................................10
Table 12-3
Adverse events, regardless of study drug relationship by primary 
system organ class, maximum severity and treatment group (Safety 
Set) ........................................................................................................11
Table 12-4
Adverse events, regardless of study drug relationship by preferred 
term, maximum severity and treatment group (Safety Set) ..................12
Table 12-5
Adverse events, suspected to be study drug related by preferred 
term, maximum severity and treatment group (Safety Set) ..................12
Table 12-6
On-treatment deaths by preferred term (Safety Set) .............................12
Table 12-7
Serious adverse events, regardless of study drug relationship by 
preferred term, maximum severity and treatment group (Safety Set)...13
Table 12-8
Adverse events leading to study drug discontinuation, regardless of 
study drug relationship by preferred term, maximum severtity and 
treatment group (Safety Set) .................................................................14
Table 12-9
Non-serious adverse events (threshold = x%) by system organ class 
and preferred term (Safety Set).............................................................14
Table 14.1-1.1
Subject disposition (FAS) .....................................................................16
Table 14.1-2.1
Analysis set (FAS) ................................................................................17
Table 14.1-3.1
Demographics (FAS) ............................................................................18
Table 14.3-1.1
Duration of exposure to study treatment (Safety Set)...........................21
Table 14.3-1.2
Summary statistics of exposure of study treatment by compound 
(Safety Set)............................................................................................22
Table 14.3.1-1.1
Adverse events, regardless of study drug relationship by primary 
system organ class, preferred term, maximum severity and 
treatment group (Safety Set) .................................................................23
Table 14.3.1-1.2
Adverse events, suspected to be study drug related by primary 
system organ class, preferred term, maximum severity and 
treatment group (Safety Set) .................................................................24
Table 14.3.1-1.3
On-treatment deaths, by system organ class and preferred term 
(Safety set) ............................................................................................25
Table 14.3.1-1.4
All deaths, by system organ class and preferred term (Safety set) .......26


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Table 14.3.1-1.5
Serious adverse events, regardless of study drug relationship by 
primary system organ class, preferred term, maximum severity and 
treatment group (Safety Set) .................................................................27
Table 14.3.1-1.6
Adverse events leading to study drug discontinuation, regardless of 
study drug relationship by primary system organ class, preferred 
term, maximum severity and treatment group (Safety Set) ..................28
Table 14.3.1-1.7
On-treatment deaths and serious adverse events by system organ 
class and preferred term (Safety Set) ....................................................29
Table 14.3.1-1.8
Non-serious adverse events (threshold = x%) by system organ class 
and preferred term (Safety Set).............................................................31
Table 14.3.1-1.9
Adverse events of special interest by system organ class, preferred 
term and maximum grade (Safety Set)..................................................33
Listing 14.3.2-1.1
All deaths (Safety Set) ..........................................................................36
Listing 14.3.2-1.2
Serious adverse events (Safety Set) ......................................................37
Listing 14.3.2-1.3
Adverse events leading to study drug discontinuation (Safety Set)......38
Listing 16.2.1-1.1
Study disposition (Full Analysis Set)....................................................40
Listing 16.2.4-1.1
Baseline demographics (Full Analysis Set) ..........................................43
Listing 16.2.5-1.1
Dose administration record by treatment <and component> (Safety 
Set) ........................................................................................................44
Listing 16.2.5-2.1
PK concentrations for dabrafenib and dabrafenib metabolites 
plasma (Pharmacokinetic Analysis Set)................................................45
Listing 16.2.5-2.2
PK concentrations for dabrafenib and dabrafenib metabolites in 
cerebrospinal fluid (Pharmacokinetic Analysis Set).............................46
Listing 16.2.5-2.3
Concentration and tissue distribution of dabrafenib and dabrafenib 
metabolites in brain metastases (Pharmacokinetic Analysis Set) .........46
Listing 16.2.7-1.1
Adverse events (Safety Set) ..................................................................49
Listing 16.2.7-1.2
Adverse events of special interest (Safety Set).....................................50


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3
Shells and specification
3.1
Shells and specifications for sections 10, 11 and 12 of the CSR (Text tables and figures)
Section 10
Study Subjects
Table 10-1
Subject disposition (FAS)
Please use the same shell as Table 14.1-1.1
Source: Table 14.1-1.1
Table 10-2
Analysis set (FAS)
Please use the same shell as Table 14.1-2.1
Source: Table 14.1-2.1


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Section 11
Efficacy and/or PK/PD evaluation (also Health Economics, QoL etc.)
Table 11-1
Demographic (FAS)   
Please use the same shell as Table 14.1-3.1
Source: Table 14.1-3.1


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Section 12
Safety evaluation
Table 12-1
Duration of exposure to study drug (Safety Set)
Please use the same shell as Table 14.3-1.1
Source: Table 14.3-1.1


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Table 12-2
Overview of adverse events (Safety set)
Category
Cohort A
N=xx
Cohort B
N=xx
All subjects
N=xx
All grades
n (%)
Grade ≥ 3
n (%)
All grades
n (%)
Grade ≥ 3
n (%)
All grades
n (%)
Grade ≥ 3
n (%)
Adverse events
xx (xx.x)
xx (xx.x)
xx (xx.x)
xx (xx.x)
xx (xx.x)
xx (xx.x)
   Treatment-related
xx (xx.x)
xx (xx.x)
xx (xx.x)
xx (xx.x)
xx (xx.x)
xx (xx.x)
SAEs
xx (xx.x)
xx (xx.x)
xx (xx.x)
xx (xx.x)
xx (xx.x)
xx (xx.x)
   Treatment-related
xx (xx.x)
xx (xx.x)
xx (xx.x)
xx (xx.x)
xx (xx.x)
xx (xx.x)
Fatal SAEs
xx (xx.x)
xx (xx.x)
xx (xx.x)
xx (xx.x)
xx (xx.x)
xx (xx.x)
   Treatment-related
xx (xx.x)
xx (xx.x)
xx (xx.x)
xx (xx.x)
xx (xx.x)
xx (xx.x)
AEs leading to discontinuation
xx (xx.x)
xx (xx.x)
xx (xx.x)
xx (xx.x)
xx (xx.x)
xx (xx.x)
  Treatment-related
xx (xx.x)
xx (xx.x)
xx (xx.x)
xx (xx.x)
xx (xx.x)
xx (xx.x)
Numbers (n) represent counts of subjects.
A subject with multiple severity grades for an AE is only counted under the maximum grade.
MedDRA version <xx.x>, CTCAE version <x.xx>.
Source: Table 14.3.1-1.11


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Table 12-3
Adverse events, regardless of study drug relationship by primary system organ class, maximum severity and 
treatment group (Safety Set)
Primary system organ class
  
Cohort A
(N=xxx)
Cohort B
(N=xxx)
All Subjects
(N=xxx)
All grades 
n (%)
Grade ≥3
n (%)
All grades 
n (%)
Grade ≥3
n (%)
All grades 
n (%)
Grade ≥3
n (%)
-Total
xx (xx.x)
xx (xx.x)
xx (xx.x)
xx (xx.x)
xx (xx.x)
xx (xx.x)
Cardiac disorders
xx (xx.x)
xx (xx.x)
xx (xx.x)
xx (xx.x)
xx (xx.x)
xx (xx.x)
xxxxxxxxxxxxxxxxxx
xx (xx.x)
xx (xx.x)
xx (xx.x)
xx (xx.x)
xx (xx.x)
xx (xx.x)
xxxxxxxxxxxxxxxxxx
xx (xx.x)
xx (xx.x)
xx (xx.x)
xx (xx.x)
xx (xx.x)
xx (xx.x)
xxxxxxxxxxxxxxxxxx
xx (xx.x)
xx (xx.x)
xx (xx.x)
xx (xx.x)
xx (xx.x)
xx (xx.x)
xxxxxxxxxxxxxxxxxx
xx (xx.x)
xx (xx.x)
xx (xx.x)
xx (xx.x)
xx (xx.x)
xx (xx.x)
xxxxxxxxxxxxxxxxxx
xx (xx.x)
xx (xx.x)
xx (xx.x)
xx (xx.x)
xx (xx.x)
xx (xx.x)
xxxxxxxxxxxxxxxxxx
xx (xx.x)
xx (xx.x)
xx (xx.x)
xx (xx.x)
xx (xx.x)
xx (xx.x)
xxxxxxxxxxxxxxxxxx
xx (xx.x)
xx (xx.x)
xx (xx.x)
xx (xx.x)
xx (xx.x)
xx (xx.x)
Source: 
Table 
14.3.1-1.1
- Primary system organ class is sorted in descending frequency, as reported in “All Subjects” and 
"All grades".
- A subject with multiple occurrences of an AE is counted only once in the AE category.              
- A subject with multiple adverse events is counted only once in the total row.
- MedDRA version <xx.x> has been used for the reporting.


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Table 12-4
Adverse events, regardless of study drug relationship by preferred term, maximum severity and treatment group
(Safety Set)
  Preferred term
Cohort A
(N=xxx)
Cohort B
(N=xxx)
All Subjects
(N=xxx)
All grades 
n (%)
Grade ≥3
n (%)
All grades 
n (%)
Grade ≥3
n (%)
All grades 
n (%)
Grade ≥3
n (%)
   -Total             xx (xx.x)
xx (xx.x)
xx (xx.x)
xx (xx.x)
xx (xx.x)
xx (xx.x)
   Angina pectoris    xx (xx.x)
xx (xx.x)
xx (xx.x)
xx (xx.x)
xx (xx.x)
xx (xx.x)
   Oedema NOS         xx (xx.x)
xx (xx.x)
xx (xx.x)
xx (xx.x)
xx (xx.x)
xx (xx.x)
   Oedema lower limb  xx (xx.x)
xx (xx.x)
xx (xx.x)
xx (xx.x)
xx (xx.x)
xx (xx.x)
   Bradycardia NOS    xx (xx.x)
xx (xx.x)
xx (xx.x)
xx (xx.x)
xx (xx.x)
xx (xx.x)
   Oedema peripheral  xx (xx.x)
xx (xx.x)
xx (xx.x)
xx (xx.x)
xx (xx.x)
xx (xx.x)
   Sinus bradycardia  xx (xx.x)
xx (xx.x)
xx (xx.x)
xx (xx.x)
xx (xx.x)
xx (xx.x)
   Tachycardia NOS    xx (xx.x)
xx (xx.x)
xx (xx.x)
xx (xx.x)
xx (xx.x)
xx (xx.x)
Preferred term is sorted in descending frequency, as reported in "All Subjects" and “All 
grades”.
- A subject with multiple occurrences of an AE is counted only once in the AE category.        
- A subject with multiple adverse events is counted only once in the total row.
- MedDRA version <xx.x> has been used for the reporting.
Source: Table 14.3.1-1.1
Table 12-5
Adverse events, suspected to be study drug related by preferred term, maximum severity and treatment group
(Safety Set)
Please use the same shell as Table 12-3
Source: Table 14.3.1-1.2
Table 12-6
On-treatment deaths by preferred term (Safety Set)
  Primary reason (preferred term)
Cohort A
N=xx
n (%)
Cohort B
N=xx
n (%)
All subjects
N=xx
n (%)
Number of subjects who died
xx (xx.x)
xx (xx.x)
xx (xx.x)


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Disease Progression
xx (xx.x)
xx (xx.x)
xx (xx.x)
Other
xx (xx.x)
xx (xx.x)
xx (xx.x)
Cardiac tamponade
xx (xx.x)
xx (xx.x)
xx (xx.x)
Breast cancer
xx (xx.x)
xx (xx.x)
xx (xx.x)
Prostate cancer
xx (xx.x)
xx (xx.x)
xx (xx.x)
MedDRA version <xx.x>.
Source: Table 14.3.1-1.3
Table 12-7
Serious adverse events, regardless of study drug relationship by preferred term, maximum severity and treatment 
group (Safety Set)
Primary system organ class
  
Cohort A
(N=xxx)
Cohort B
(N=xxx)
All Subjects
(N=xxx)
All grades 
n (%)
Grade 5
n (%)
All grades 
n (%)
Grade 5
n (%)
All grades 
n (%)
Grade 5
n (%)
-Total
xx (xx.x)
xx (xx.x)
xx (xx.x)
xx (xx.x)
xx (xx.x)
xx (xx.x)
Cardiac disorders
xx (xx.x)
xx (xx.x)
xx (xx.x)
xx (xx.x)
xx (xx.x)
xx (xx.x)
xxxxxxxxxxxxxxxxxx
xx (xx.x)
xx (xx.x)
xx (xx.x)
xx (xx.x)
xx (xx.x)
xx (xx.x)
xxxxxxxxxxxxxxxxxx
xx (xx.x)
xx (xx.x)
xx (xx.x)
xx (xx.x)
xx (xx.x)
xx (xx.x)
xxxxxxxxxxxxxxxxxx
xx (xx.x)
xx (xx.x)
xx (xx.x)
xx (xx.x)
xx (xx.x)
xx (xx.x)
xxxxxxxxxxxxxxxxxx
xx (xx.x)
xx (xx.x)
xx (xx.x)
xx (xx.x)
xx (xx.x)
xx (xx.x)
xxxxxxxxxxxxxxxxxx
xx (xx.x)
xx (xx.x)
xx (xx.x)
xx (xx.x)
xx (xx.x)
xx (xx.x)
xxxxxxxxxxxxxxxxxx
xx (xx.x)
xx (xx.x)
xx (xx.x)
xx (xx.x)
xx (xx.x)
xx (xx.x)
xxxxxxxxxxxxxxxxxx
xx (xx.x)
xx (xx.x)
xx (xx.x)
xx (xx.x)
xx (xx.x)
xx (xx.x)
Source: Table 14.3.1-1.5
- Primary system organ class is sorted in descending frequency, as reported in "All Subjects" and
"All grades".
- A subject with multiple occurrences of an AE is counted only once in the AE category.              
- A subject with multiple adverse events is counted only once in the total row.
- MedDRA version <xx.x> has been used for the reporting.


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Table 12-8
Adverse events leading to study drug discontinuation, regardless of study drug relationship by preferred term,
maximum severtity and treatment group (Safety Set)
Please use the same shell as Table 12-3
Source: Table 14.3.1-1.6
Table 12-9
Non-serious adverse events (threshold = x%) by system organ class and preferred term (Safety Set)
Please use the same shell as Table 14.3.1-1.8
Source: Table 14.3.1-1.8


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Shells and specifications for Sections 14 and 16 of the CSR
Section 14
Tables, figures and graphs referred to but not included in the text
Section 14.1 Demographic data


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Table 14.1-1.1
Subject disposition (FAS)
Cohort A
N=xx
n (%)
Cohort B
N=xx
n (%)
All subjects
N=xx
n (%)
Subject treated
xx (xx.x)
xx (xx.x)
xx (xx.x)
Completed scheduled treatment
xx (xx.x)
xx (xx.x)
xx (xx.x)
Treatment ongoing
xx (xx.x)
xx (xx.x)
xx (xx.x)
Discontinued from treatment 
xx (xx.x)
xx (xx.x)
xx (xx.x)
   Reason for discontinuation
   Reason 1
xx (xx.x)
xx (xx.x)
xx (xx.x)
   Reason 2
xx (xx.x)
xx (xx.x)
xx (xx.x)
   Reason 3
xx (xx.x)
xx (xx.x)
xx (xx.x)
Completion Status                    
Completed study
xx (xx.x)
xx (xx.x)
xx (xx.x)
Discontinued from study
xx (xx.x)
xx (xx.x)
xx (xx.x)
   Reason for discontinuation
   Reason 1
xx (xx.x)
xx (xx.x)
xx (xx.x)
   Reason 2
xx (xx.x)
xx (xx.x)
xx (xx.x)
   Reason 3
xx (xx.x)
xx (xx.x)
xx (xx.x)
    Reason 4
xx (xx.x)
xx (xx.x)
xx (xx.x)
- Percentage is based on N
- Reason for end of study is from CRF end of study page


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Table 14.1-2.1
Analysis set (FAS)
Analysis set
Cohort A
N=xx
n (%)
Cohort B
N=xx
n (%)
All subjects
N=xx
n (%)
Full analysis set (FAS)       
xx (xx.x)
xx (xx.x)
xx (xx.x)
Safety set                    
xx (xx.x)
xx (xx.x)
xx (xx.x)
Pharmacokinetic analysis set  
xx (xx.x)
xx (xx.x)
xx (xx.x)
- N is the number of subjects in FAS.
- Full analysis set includes all subjects who received at least one dose of study 
- Safety set includes all subjects who received at least one dose of study medication 
- The Pharmacokinetic analysis set includes all subjects who provide at least one evaluable 
PK concentration.


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Table 14.1-3.1
Demographics (FAS)
Demographic
  Variable
Cohort A
N=xx
Cohort B
N=xx
All subjects
N=xx
Age (years)               
       
        
        
   n                      
xx
xx
xx
   Mean (SD)               
xx.x(x.xx)
xx.x(x.xx)
xx.x(x.xx)
   Median                 
xx.x
xx.x
xx.x
   Min - Max          
xx.x – xx.x
xx.x – xx.x
xx.x – xx.x
Age category (years)-n (%)
       
        
        
   <65                    
xx (xx.x)
xx (xx.x)
xx (xx.x)
   >= 65                  
xx (xx.x)
xx (xx.x)
xx (xx.x)
   Missing                
xx (xx.x)
xx (xx.x)
xx (xx.x)
Sex-n (%)               
       
       
       
   Female                 
xx (xx.x)
xx (xx.x)
xx (xx.x)
   Male                   
xx (xx.x)
xx (xx.x)
xx (xx.x)
   Missing                
xx (xx.x)
xx (xx.x)
xx (xx.x)
Race-n (%) 
   African American/African    
Heritage
xx (xx.x)
xx (xx.x)
xx (xx.x)
   American Indian or Alaskan 
Native                  
xx (xx.x)
xx (xx.x)
xx (xx.x)
   Asian – Central/South Asian 
Heritage                  
xx (xx.x)
xx (xx.x)
xx (xx.x)
   East Asian Heritage
xx (xx.x)
xx (xx.x)
xx (xx.x)
   Asian – Japanese Heritage    
xx (xx.x)
xx (xx.x)
xx (xx.x)
   Asian – South East Asian 
Heritage
xx (xx.x)
xx (xx.x)
xx (xx.x)
   Native Hawaiian or Other 
Pacific Islander
xx (xx.x)
xx (xx.x)
xx (xx.x)
   White – Arabic/North 
xx (xx.x)
xx (xx.x)
xx (xx.x)


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African Heritage
   White –
White/Caucasian/European 
Heritage
xx (xx.x)
xx (xx.x)
xx (xx.x)
   Missing                
xx (xx.x)
xx (xx.x)
xx (xx.x)
Ethnicity-n (%)
   Hispanic/Latino             
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
   Not Hispanic/Latino           
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
   Missing                     
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
ECOG Performance Status-n (%)
   0
xx (xx.x)
xx (xx.x)
xx (xx.x)
   1
xx (xx.x)
xx (xx.x)
xx (xx.x)
   2
xx (xx.x)
xx (xx.x)
xx (xx.x)
   3
xx (xx.x)
xx (xx.x)
xx (xx.x)
   4
xx (xx.x)
xx (xx.x)
xx (xx.x)
Missing
xx (xx.x)
xx (xx.x)
xx (xx.x)
Weight (kg)                  
       
        
         
   n                      
xx
xx
xx
   Mean (SD)               
xx.x(x.xx)
xx.x(x.xx)
xx.x(x.xx)
   Median                 
xx.x
xx.x
xx.x
   Min - Max          
xx.x – xx.x
xx.x – xx.x
xx.x – xx.x
Height (cm)                 
       
        
         
   n                      
xx
xx
xx
   Mean (SD)               
xx.x(x.xx)
xx.x(x.xx)
xx.x(x.xx)
   Median                 
xx.x
xx.x
xx.x
   Min - Max          
xx.x – xx.x
xx.x – xx.x
xx.x – xx.x
Body Mass Index (BMI)(kg/m2)#    
       
        
         
   n                      
xx
xx
xx
   Mean (SD)               
xx.x(x.xx)
xx.x(x.xx)
xx.x(x.xx)
   Median                 
xx.x
xx.x
xx.x
   Min - Max          
xx.x – xx.x
xx.x – xx.x
xx.x – xx.x


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Section 14.2 Efficacy and other non-safety data (e.g. PK, PK/PD, Health Econ., QoL)
Section 14.3 Safety data


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Table 14.3-1.1
Duration of exposure to study treatment (Safety Set)
Cohort A
Cohort B
All Subjects
Duration of exposure categories 
(weeks)-n (%)
<  1
xx (xx.x)
xx (xx.x)
xx (xx.x)
1 - <4
xx (xx.x)
xx (xx.x)
xx (xx.x)
4 - <8
xx (xx.x)
xx (xx.x)
xx (xx.x)
8 - <12
xx (xx.x)
xx (xx.x)
xx (xx.x)
12 - <24
xx (xx.x)
xx (xx.x)
xx (xx.x)
24 - <48
xx (xx.x)
xx (xx.x)
xx (xx.x)
48 - <60
xx (xx.x)
xx (xx.x)
xx (xx.x)
>=60
xx (xx.x)
xx (xx.x)
xx (xx.x)
Duration of exposure (months)
Mean (SD)
xx.x (x.xx)
xx.x (x.xx)
xx.x (x.xx)
Median
xx.x
xx.x
xx.x
Q1-Q3
xx.x-xx.x
xx.x-xx.x
xx.x-xx.x
Min - Max
xx.x-xx.x
xx.x-xx.x
xx.x-xx.x
- A subject is counted in only one duration range.
Programming Note:
1.
Duration of exposure in days = Last dosing date – First dosing date + 1


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Table 14.3-1.2
Summary statistics of exposure of study treatment by compound (Safety Set)
Exposure variable
Dabrafenib       
N=xx
           
Trametinib
N=xx
Exposure categories (weeks) -n (%)
<  1
xx (xx.x)
xx (xx.x)
1 - <4
xx (xx.x)
xx (xx.x)
4 - <8
xx (xx.x)
xx (xx.x)
8 - <12
xx (xx.x)
xx (xx.x)
12 - <24
xx (xx.x)
xx (xx.x)
24 - <48
xx (xx.x)
xx (xx.x)
48 - <60
xx (xx.x)
xx (xx.x)
>=60
xx (xx.x)
xx (xx.x)
Duration of exposure (months)
Mean (SD)
xx.x (x.xx)
xx.x (x.xx)
Median
xx.x
xx.x
Q1-Q3
xx.x-xx.x
xx.x-xx.x
Min - Max
xx.x-xx.x
xx.x-xx.x
Cumulative dose (mg)
Mean (SD)
xx.x (x.xx)
xx.x (x.xx)
Median
xx.x
xx.x
Q1-Q3
xx.x-xx.x
xx.x-xx.x
Min - Max
xx.x-xx.x
xx.x-xx.x
Section 14.3.1
Displays of adverse events


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Table 14.3.1-1.1
Adverse events, regardless of study drug relationship by primary system organ class, preferred term,
maximum severity and treatment group (Safety Set)
Primary system organ class
  Preferred term
Cohort A
(N=xxx)
Cohort B
(N=xxx)
All Subjects
(N=xxx)
All grades 
n (%)
Grade ≥3
n (%)
All grades 
n (%)
Grade ≥3
n (%)
All grades 
n (%)
Grade ≥3
n (%)
Number of subjects with at least one event  xx (xx.x)
xx (xx.x)
xx (xx.x)
xx (xx.x)
xx (xx.x)
xx (xx.x)
                         
Cardiac disorders        
   -Total                
xx (xx.x)
xx (xx.x)
xx (xx.x)
xx (xx.x)
xx (xx.x)
xx (xx.x)
   Angina pectoris       
xx (xx.x)
xx (xx.x)
xx (xx.x)
xx (xx.x)
xx (xx.x)
xx (xx.x)
   Oedema NOS            
xx (xx.x)
xx (xx.x)
xx (xx.x)
xx (xx.x)
xx (xx.x)
xx (xx.x)
   Oedema lower limb     
xx (xx.x)
xx (xx.x)
xx (xx.x)
xx (xx.x)
xx (xx.x)
xx (xx.x)
   Bradycardia NOS       
xx (xx.x)
xx (xx.x)
xx (xx.x)
xx (xx.x)
xx (xx.x)
xx (xx.x)
   Oedema peripheral     
xx (xx.x)
xx (xx.x)
xx (xx.x)
xx (xx.x)
xx (xx.x)
xx (xx.x)
   Sinus bradycardia     
xx (xx.x)
xx (xx.x)
xx (xx.x)
xx (xx.x)
xx (xx.x)
xx (xx.x)
   Tachycardia NOS       
xx (xx.x)
xx (xx.x)
xx (xx.x)
xx (xx.x)
xx (xx.x)
xx (xx.x)
Numbers (n) represent counts of subjects.
A subject with multiple severity grades for an AE is only counted under the maximum grade.
MedDRA version <xx.x>, CTCAE version <x.xx>.
Programming Note:
Sort SOC by alphabetical order, PTs by descending frequency in Investigational drug column of highest relevance and subgroup (e.g. subgroup with highest N).


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Table 14.3.1-1.2
Adverse events, suspected to be study drug related by primary system organ class, preferred term,
maximum severity and treatment group (Safety Set)
Please use the same shell as Table 14.3.1-1.1


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Table 14.3.1-1.3
On-treatment deaths, by system organ class and preferred term (Safety set)
Primary system organ class
  Primary reason (preferred term)
Cohort A
N=xx
n (%)
Cohort B
N=xx
n (%)
All subjects
N=xx
n (%)
Number of subjects who died
xx (xx.x)
xx (xx.x)
xx (xx.x)
Disease Progression
xx (xx.x)
xx (xx.x)
xx (xx.x)
Other
xx (xx.x)
xx (xx.x)
xx (xx.x)
Cardiac disorders
xx (xx.x)
xx (xx.x)
xx (xx.x)
Cardiac tamponade
xx (xx.x)
xx (xx.x)
xx (xx.x)
Neoplasms Benign, Malignant And Unspecified (Incl Cysts And Polyps)
xx (xx.x)
xx (xx.x)
xx (xx.x)
Breast cancer
xx (xx.x)
xx (xx.x)
xx (xx.x)
Prostate cancer
xx (xx.x)
xx (xx.x)
xx (xx.x)
Respiratory, Thoracic And Mediastinal Disorders
xx (xx.x)
xx (xx.x)
xx (xx.x)
Pneumonia
xx (xx.x)
xx (xx.x)
xx (xx.x)
Pneumonia aspiration
xx (xx.x)
xx (xx.x)
xx (xx.x)
MedDRA version <xx.x>.


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Table 14.3.1-1.4
All deaths, by system organ class and preferred term (Safety set)
Primary system organ class
  Primary reason (preferred term)
Cohort A
N=xx
n (%)
Cohort B
N=xx
n (%)
All subjects
N=xx
n (%)
Number of subjects who died
xx (xx.x)
xx (xx.x)
xx (xx.x)
Disease Progression
xx (xx.x)
xx (xx.x)
xx (xx.x)
Other
xx (xx.x)
xx (xx.x)
xx (xx.x)
Cardiac disorders
xx (xx.x)
xx (xx.x)
xx (xx.x)
Cardiac tamponade
xx (xx.x)
xx (xx.x)
xx (xx.x)
Neoplasms Benign, Malignant And Unspecified (Incl Cysts And Polyps)
xx (xx.x)
xx (xx.x)
xx (xx.x)
Breast cancer
xx (xx.x)
xx (xx.x)
xx (xx.x)
Prostate cancer
xx (xx.x)
xx (xx.x)
xx (xx.x)
Respiratory, Thoracic And Mediastinal Disorders
xx (xx.x)
xx (xx.x)
xx (xx.x)
Pneumonia
xx (xx.x)
xx (xx.x)
xx (xx.x)
Pneumonia aspiration
xx (xx.x)
xx (xx.x)
xx (xx.x)
Includes both on-treatment deaths, and those that occurred more than 30 days after last treatment.
MedDRA version <xx.x>.
Programming Note:
1. Deaths recorded on EOT page or within 30 days of last study treatment.


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Table 14.3.1-1.5
Serious adverse events, regardless of study drug relationship by primary system organ class, preferred 
term, maximum severity and treatment group (Safety Set)
Primary system organ class
  Preferred term
Cohort A
(N=xxx)
Cohort B
(N=xxx)
All Subjects
(N=xxx)
All grades 
n (%)
Grade 5
n (%)
All grades 
n (%)
Grade 5
n (%)
All grades 
n (%)
Grade 5
n (%)
Number of subjects with at least one event   
xx (xx.x)
xx (xx.x)
xx (xx.x)
xx (xx.x)
xx (xx.x)
xx (xx.x)
                         
Cardiac disorders        
   -Total                
xx (xx.x)
xx (xx.x)
xx (xx.x)
xx (xx.x)
xx (xx.x)
xx (xx.x)
   Angina pectoris       
xx (xx.x)
xx (xx.x)
xx (xx.x)
xx (xx.x)
xx (xx.x)
xx (xx.x)
   Oedema NOS            
xx (xx.x)
xx (xx.x)
xx (xx.x)
xx (xx.x)
xx (xx.x)
xx (xx.x)
   Oedema lower limb     
xx (xx.x)
xx (xx.x)
xx (xx.x)
xx (xx.x)
xx (xx.x)
xx (xx.x)
   Bradycardia NOS       
xx (xx.x)
xx (xx.x)
xx (xx.x)
xx (xx.x)
xx (xx.x)
xx (xx.x)
   Oedema peripheral     
xx (xx.x)
xx (xx.x)
xx (xx.x)
xx (xx.x)
xx (xx.x)
xx (xx.x)
   Sinus bradycardia     
xx (xx.x)
xx (xx.x)
xx (xx.x)
xx (xx.x)
xx (xx.x)
xx (xx.x)
   Tachycardia NOS       
xx (xx.x)
xx (xx.x)
xx (xx.x)
xx (xx.x)
xx (xx.x)
xx (xx.x)
Numbers (n) represent counts of subjects.
A subject with multiple severity grades for an AE is only counted under the maximum grade.
MedDRA version <xx.x>, CTCAE version <x.xx>.


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Table 14.3.1-1.6
Adverse events leading to study drug discontinuation, regardless of study drug relationship by primary 
system organ class, preferred term, maximum severity and treatment group (Safety Set)
Primary system organ class
  Preferred term
Cohort A
(N=xxx)
Cohort B
(N=xxx)
All Subjects
(N=xxx)
All grades 
n (%)
Grade ≥3
n (%)
All grades 
n (%)
Grade ≥3
n (%)
All grades 
n (%)
Grade ≥3
n (%)
Number of subjects with at least one event   
xx (xx.x)
xx (xx.x)
xx (xx.x)
xx (xx.x)
xx (xx.x)
xx (xx.x)
                         
Cardiac disorders        
   -Total                
xx (xx.x)
xx (xx.x)
xx (xx.x)
xx (xx.x)
xx (xx.x)
xx (xx.x)
   Angina pectoris       
xx (xx.x)
xx (xx.x)
xx (xx.x)
xx (xx.x)
xx (xx.x)
xx (xx.x)
   Oedema NOS            
xx (xx.x)
xx (xx.x)
xx (xx.x)
xx (xx.x)
xx (xx.x)
xx (xx.x)
   Oedema lower limb     
xx (xx.x)
xx (xx.x)
xx (xx.x)
xx (xx.x)
xx (xx.x)
xx (xx.x)
   Bradycardia NOS       
xx (xx.x)
xx (xx.x)
xx (xx.x)
xx (xx.x)
xx (xx.x)
xx (xx.x)
   Oedema peripheral     
xx (xx.x)
xx (xx.x)
xx (xx.x)
xx (xx.x)
xx (xx.x)
xx (xx.x)
   Sinus bradycardia     
xx (xx.x)
xx (xx.x)
xx (xx.x)
xx (xx.x)
xx (xx.x)
xx (xx.x)
   Tachycardia NOS       
xx (xx.x)
xx (xx.x)
xx (xx.x)
xx (xx.x)
xx (xx.x)
xx (xx.x)
Numbers (n) represent counts of subjects.
A subject with multiple severity grades for an AE is only counted under the maximum grade.
MedDRA version <xx.x>, CTCAE version <x.xx>.


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Table 14.3.1-1.7
On-treatment deaths and serious adverse events by system organ class and preferred term (Safety Set)
Primary system organ class
Preferred term
Cohort A
N=xxx
n (%)
Cohort B
N=xxx
n (%)
All subjects
N=xxx
n (%)
Total number of subjects affected
Subjects affected by serious adverse events / exposed (%)
xxx/xxx (xx.xx)
xxx/xxx (xx.xx)
xxx/xxx (xx.xx)
Number of deaths (all causes)
xx
xx
xx
Number of deaths resulting from adverse events*
xx
xx
xx
Infections and infestations
Pneumonia
Subjects affected / exposed (%)
xxx/xxx (xx.xx)
xxx/xxx (xx.xx)
xxx/xxx (xx.xx)
Occurrences causally related to treatment/all
xx/xx
xx/xx
xx/xx
Deaths causally related to treatment/all
xx/xx
xx/xx
xx/xx
Sepsis
Subjects affected / exposed (%)
xxx/xxx (xx.xx)
xxx/xxx (xx.xx)
xxx/xxx (xx.xx)
Occurrences causally related to treatment/all
xx/xx
xx/xx
xx/xx
Deaths causally related to treatment/all
xx/xx
xx/xx
xx/xx
Investigations
Platelet count decreased
Subjects affected / exposed (%)
xxx/xxx (xx.xx)
xxx/xxx (xx.xx)
xxx/xxx (xx.xx)
Occurrences causally related to treatment/all
xx/xx
xx/xx
xx/xx
Deaths causally related to treatment/all
xx/xx
xx/xx
xx/xx
Weight decreased
Subjects affected / exposed (%)
xxx/xxx (xx.xx)
xxx/xxx (xx.xx)
xxx/xxx (xx.xx)
Occurrences causally related to treatment/all
xx/xx
xx/xx
xx/xx
Deaths causally related to treatment/all
xx/xx
xx/xx
xx/xx
etc.
*Number of deaths resulting from adverse events corresponds to deaths resulting from serious AE causally related to 
treatment.
Occurrences causally related to treatment/all: all occurrences are all SAEs occurrences regardless of causality to treatment.
Deaths causally related to treatment/all: all deaths are all SAEs with fatal outcome regardless of causality to treatment.
MedDRA version <xx.x>.
Programming Note:
Sort system organ classes alphabetically; preferred terms in descending frequency in Investigational drug column of highest relevance and subgroup (e.g. subgroup with highest N).
Include only on-treatment events (as defined in SAP).


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“Occurrences causally related to treatment/all”: all occurrences are all SAEs occurrences regardless of causality to treatment
“Deaths causally related to treatment/all”: all deaths are all SAEs with fatal outcome regardless of causality to treatment
Only subjects having at least one serious adverse event are considered.


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Table 14.3.1-1.8
Non-serious adverse events (threshold = x%) by system organ class and preferred term (Safety Set)
Primary system organ class
Preferred term
Cohort A
N=xxx
n (%)
Cohort B
N=xxx
n (%)
All subjects
N=xxx
n (%)
Total number of subjects affected
Subjects affected by non-serious adverse events / exposed (%)
xxx/xxx (xx.xx)
xxx/xxx (xx.xx)
xxx/xxx (xx.xx)
Blood and lymphatic system disorders
Anemia
Subjects affected / exposed (%)
xxx/xxx (xx.xx)
xxx/xxx (xx.xx)
xxx/xxx (xx.xx)
Occurrences (all)
xx
xx
xx
Thrombocytopenia
Subjects affected / exposed (%)
xxx/xxx (xx.xx)
xxx/xxx (xx.xx)
xxx/xxx (xx.xx)
Occurrences (all)
xx
xx
xx
Infections and infestations
Pneumonia
Subjects affected / exposed (%)
xxx/xxx (xx.xx)
xxx/xxx (xx.xx)
xxx/xxx (xx.xx)
Occurrences (all)
xx
xx
xx
Sepsis
Subjects affected / exposed (%)
xxx/xxx (xx.xx)
xxx/xxx (xx.xx)
xxx/xxx (xx.xx)
Occurrences (all)
xx
xx
xx
Investigations
Platelet count decreased
Subjects affected / exposed (%)
xxx/xxx (xx.xx)
xxx/xxx (xx.xx)
xxx/xxx (xx.xx)
Occurrences (all)
xx
xx
xx
Weight decreased
Subjects affected / exposed (%)
xxx/xxx (xx.xx)
xxx/xxx (xx.xx)
xxx/xxx (xx.xx)
Occurrences (all)
xx
xx
xx
etc.
Total numbers of subjects affected by non-serious AEs are those subjects who had at least one preferred term that met the 
threshold criteria.
Preferred terms with a frequency greater than 5% in any treatment arm were printed.
MedDRA version <xx.x>.
Programming Note:
Threshold defined greater than 0 and less or equal to 5% (default EUDRACT/CT.gov: 5%)
Total number of subjects affected by non-serious AE is calculated back once the threshold is applied 


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Preferred terms with a frequency greater than 5% in at least one treatment arm (including the “all subjects”) are printed for all treatment arms even if in some arms the threshold criteria 
is not met (this is different from standard AE displays).
Only subjects having at least one non-serious adverse event are considered.
Sort SOC by alphabetical order, PTs by descending frequency in Investigational drug column of highest relevance and subgroup (e.g. subgroup with highest N).
Include only on-treatment events (as defined in SAP).


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Table 14.3.1-1.9
Adverse events of special interest by system organ class, preferred term and maximum grade (Safety Set)
Primary system organ class
  Preferred term
Cohort A
(N=xxx)
Cohort B
(N=xxx)
All grades 
n (%)
Grade ≥3
n (%)
All grades 
n (%)
Grade ≥3
n (%)
-AESI group       
  -Total   
xx (xx.x)
xx (xx.x)
xx (xx.x)
xx (xx.x)
AESI group 1                
xx (xx.x)
xx (xx.x)
xx (xx.x)
xx (xx.x)
  SOC 1
   -Total                
xx (xx.x)
xx (xx.x)
xx (xx.x)
xx (xx.x)
   Angina pectoris       
xx (xx.x)
xx (xx.x)
xx (xx.x)
xx (xx.x)
   ………       
xx (xx.x)
xx (xx.x)
xx (xx.x)
xx (xx.x)
Numbers (n) represent counts of subjects.
A subject with multiple severity grades for an AE is only counted under the maximum grade.
MedDRA version <xx.x>, CTCAE version <x.xx>
Programming Note:
Please repeat for AESI categories.
The AESI are:

Cutaneous squamous cell carcinoma (including keratoacanthomas)

Treatment emergent malignancies (excluding cuSCC, basal cell carcinoma)

Pyrexia

Uveitis

Renal failure/acute renal failure

Pancreatitis

Hypersensitivity

Hyperglycaemia


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Table 14.3.1-1.10
Overview of AE types (Safety Set)
Overview of Adverse events
Cohort A
N=xx
Cohort B
N=xx
All subjects
N=xx
All grades
n (%)
Grade ≥3
n (%)
All grades
n (%)
Grade ≥3
n (%)
All grades
n (%)
Grade ≥3
n (%)
Adverse events
xx (xx.x)
xx (xx.x)
xx (xx.x)
xx (xx.x)
xx (xx.x)
xx (xx.x)
   Treatment-related
xx (xx.x)
xx (xx.x)
xx (xx.x)
xx (xx.x)
xx (xx.x)
xx (xx.x)
SAEs
xx (xx.x)
xx (xx.x)
xx (xx.x)
xx (xx.x)
xx (xx.x)
xx (xx.x)
   Treatment-related
xx (xx.x)
xx (xx.x)
xx (xx.x)
xx (xx.x)
xx (xx.x)
xx (xx.x)
Fatal SAEs
xx (xx.x)
xx (xx.x)
xx (xx.x)
xx (xx.x)
xx (xx.x)
xx (xx.x)
   Treatment-related
xx (xx.x)
xx (xx.x)
xx (xx.x)
xx (xx.x)
xx (xx.x)
xx (xx.x)
AEs leading to discontinuation
xx (xx.x)
xx (xx.x)
xx (xx.x)
xx (xx.x)
xx (xx.x)
xx (xx.x)
  Treatment-related
xx (xx.x)
xx (xx.x)
xx (xx.x)
xx (xx.x)
xx (xx.x)
xx (xx.x)
Numbers (n) represent counts of subjects.
A subject with multiple severity grades for an AE is only counted under the maximum grade.
MedDRA version <xx.x>, CTCAE version <x.xx>.


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Section 14.3.2
Listings of deaths, other serious and significant adverse events


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Listing 14.3.2-1.1
All deaths (Safety Set)
Treatment :  xxxxx
Country/
Center/ 
Subject
Age/ 
Sex/ 
Race 
Date of
last   
dose   
Study day
of last  
dose   
Date of
death  
Study 
day  
Primary cause of Death
econdary Cause of Death
USA/
/
20/M/Ca
    76
2000 
  96  Heart Failure
Heart Failure
- Study day is relative to the first day of treatment(day 1).
- Subjects who died during or within 30 days after last dose of study treatment or other deaths reported in clinical database 
are included.
PPD
PPD
PPD
PPD


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Listing 14.3.2-1.2
Serious adverse events (Safety Set)
Treatment :  xxxxx
Country/
Center/ 
subject
Age/ 
Sex/ 
Race 
Adverse event                  
(REPORTED / Preferred / 
System organ class)            
Start date/
Study day
End date/ 
Study day 
Dur. 
(days)
Grade
Relat.
  to
study 
drug  
Action
taken
BEL
55/M/Ca 
MILD DIZZINESS /               
/9 
/16 
  8  
1
Not 
susp 
None
   
        
Dizziness (exc vertigo) /
   
        
Nervous system disorders
BEL
71/F/Ca 
GASTRIC DISTRESS /             
/3 
/4  
  2  
1
Susp     None
   
        
Abdominal pain upper /
   
        
Gastrointestinal disorders
BEL
62/F/Ca 
POSITION VERTIGO /             
/1 
Continuing   
     
1
Not 
susp 
None
               
        
Vertigo positional /
               
Ear and labyrinth disorders
               
GASTRIC DISTRESS /             
/3 
11 
  9  
2
Susp     2
               
Abdominal pain upper /
               
Gastrointestinal disorders
- Relationship to study drug: Not susp=Not suspected, Susp=Suspected
- Action taken: 1 = Study treatment withdrawn, 2 = Dose reduced, 3 = Dose increased, 4 = No action, 5 = Dose 
interrupted/delayed, X = Not applicable, subject not receiving IP when event occurred.
- Study day is relative to the first day of treatment(day 1).
- MedDRA version <xx.x>, CTCAE version <x.xx>.
PPD
PPD
PPD
PPD


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Listing 14.3.2-1.3
Adverse events leading to study drug discontinuation (Safety Set)
Treatment :  xxxxx
Country/
Center/ 
subject
Age/ 
Sex/ 
Race 
SAE
Adverse event               
(REPORTED / Preferred / 
System organ class)         
Start date/
Study day 
End date/ 
Study day 
Dur. 
(days)
Grade
Relat.
  to
study 
drug  
Action
taken
BEL
55/M/Ca 
    MILD DIZZINESS /            
/9 
/16 
  8  
1
Not 
susp 
2
   
        
    
Dizziness (exc vertigo) /
   
        
    
Nervous system disorders
BEL
71/F/Ca Yes 
GASTRIC DISTRESS /          
/3 
/4  
  2  
1
Susp     2
   
        
    
Abdominal pain upper /
   
        
    
Gastrointestinal 
disorders
BEL
62/F/Ca 
    POSITION VERTIGO /          
/1 
Continuing   
     
1
Not 
susp 
2
               
        
    
Vertigo positional /
               
    
Ear and labyrinth 
disorders
               
    GASTRIC DISTRESS /          
/3 
11 
  9  
2
Susp     2
               
    
Abdominal pain upper /
               
    
Gastrointestinal 
disorders
- Relationship to study drug: Not susp=Not suspected, Susp=Suspected
- Action taken: 1 = Study treatment withdrawn, 2 = Dose reduced, 3 = Dose increased, 4 = No action, 5 = Dose 
interrupted/delayed, X = Not applicable, subject not receiving IP when event occurred.
- Study day is relative to the first day of treatment (day 1).
- MedDRA version <xx.x>, CTCAE version <x.xx>.
PPD
PPD
PPD
PPD


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Section 16
Appendices (Safety Set and Pharmacokinetic Analysis Set)
Section 16.1.7
Randomization scheme and codes (subject identification and treatment assigned)
Not applicable.
Section 16.2.1
Discontinued subjects


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Listing 16.2.1-1.1
Study disposition (Full Analysis Set)
Treatment: xxxx
Country/ 
Center/ 
Subject
Age/ 
Sex/ 
Race
Last known 
date 
on study drug/
Study day
Primary reason for
end of treatment
Comments for 
end of 
treatment
Primary reason for
end of study 
discontinuation
Comments 
for end of 
study
Did 
subject
complete 
study? 
Instructions for programmers:
Repeat listing for both treatment groups
PPD - This section has been excluded to protect patient privacy.


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Section 16.2.2
Protocol deviations
Not listed due to short closeout CSR.


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Section 16.2.3
Subjects excluded from the efficacy analysis
Not applicable.


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Section 16.2.4
Demographic data
Listing 16.2.4-1.1
Baseline demographics (Full Analysis Set)
Treatment :  xxxxx
Country/
Subject
identifier
Age/
Sex/
Race
Ethnicity
Weight
(kg)
Height
(cm)
xxx/xxxxxxx
xx/xx/xx
xxxxxxxxxxxxxxx
xxx.x
xxx
xxx/xxxxxxx
xx/xx/xx
xxxxxxxxxxxxxxx
xxx.x
xxx
xxx/xxxxxxx
xx/xx/xx
xxxxxxxxxxxxxxx
xxx.x
xxx
xxx/xxxxxxx
xx/xx/xx
xxxxxxxxxxxxxxx
xxx.x
xxx
xxx/xxxxxxx
xx/xx/xx
xxxxxxxxxxxxxxx
xxx.x
xxx
xxx/xxxxxxx
xx/xx/xx
xxxxxxxxxxxxxxx
xxx.x
xxx
Instructions for programmers:
Repeat listing for both treatment groups


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Section 16.2.5
Compliance and/or drug concentration data if available (including Bioanalytical Data Report)
Listing 16.2.5-1.1
Dose administration record by treatment <and component> (Safety Set)
Treatment :  xxxxx, <Component: component 1>
Country/
Center/ 
Subject
Age/ 
Sex/race
Scheduled 
Dose (mg)
Actual 
dose 
(mg)
Dose  
change
Dose 
change 
detail
Reason
Start date
and time/
study day
End date
and time/ 
study day
xxx/xxxx/xxxxx
xx/x/xx
Yes/No
xxxx
  x
ddmmmyyyy/x
ddmmmyyyy/x
              
        
Yes/No
xxx
  x
ddmmmyyyy/x
ddmmmyyyy/x
              
        
Yes/No
xxxx
  x
ddmmmyyyy/x
ddmmmyyyy/x
              
        
Yes/No
  x
ddmmmyyyy/x
ddmmmyyyy/x
              
        
Yes/No
  x
ddmmmyyyy/x
ddmmmyyyy/x
xxx/xxxx/xxxxx
xx/x/xx
Yes/No
Reduction
  x
ddmmmyyyy/x
ddmmmyyyy/x
Programming Note:
1.
Repeat listing for both treatment groups


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Listing 16.2.5-2.1
PK concentrations for dabrafenib and dabrafenib metabolites plasma (Pharmacokinetic Analysis Set)
Treatment:  xxxxx
Tissue Type: xxxxx
Phase: xxxxxx
Country/
Center/ 
Subject
Age/ 
Sex/Race
Analyte
Visit
Sample Colected 
Time
Assessment Date
Time
Concentration 
(ng/mL)
BLQ Yes/No 
#
xxx/xxxx/xxxxx
xx/x/xx
Dabrafenib
Day 1
Before Surgery
YYYY-MM-DD hh:mm
  xx.xx
              
        
YYYY-MM-DD hh:mm
xx.xx
              
        
YYYY-MM-DD hh:mm
xx.xx
              
        
After Surgery
YYYY-MM-DD hh:mm
xx.xx
              
        
YYYY-MM-DD hh:mm
xx.xx
xxx/xxxx/xxxxx
xx/x/xx
Day 1
Before Surgery
YYYY-MM-DD hh:mm
xx.xx
              
YYYY-MM-DD hh:mm
xx.xx
              
After Surgery
YYYY-MM-DD hh:mm
xx.xx
              
YYYY-MM-DD hh:mm
xx.xx
# Below the limit of quantitation (BLQ) values (<1 ng/mL for a 50-µL aliquot of human plasma for dabrafenib, hydroxy-
dabrafenib and desmethyl-dabrafenib and <5 ng/mL for a 25-µL aliquot of human plasma for carboxy-dabrafenib) have been set
to zero and flagged. 
BLQ values (<5 ng/g for dabrafenib and hydroxy-dabrafenib and <30 ng/g for desmethyl-dabrafenib for a 50 µL aliquot of 
tissue homogenate) for tissue concentrations in the measured tissues (i.e., parenchymal brain metastases, optional 
assessment of extracranial metastases) have been set to zero and flagged.


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Listing 16.2.5-2.2
PK concentrations for dabrafenib and dabrafenib metabolites in cerebrospinal fluid (Pharmacokinetic 
Analysis Set)
Treatment:  xxxxx
Tissue Type: xxxxx
Phase: xxxxxx
Country/
Center/ 
Subject
Age/ 
Sex/Race
Analyte
Visit
Sample Colected 
Time
Assessment Date
Time
Concentration 
(ng/mL)#
BLQ
Yes/No
xxx/xxxx/xxxxx
xx/x/xx
Dabrafenib
Day 1
Before Surgery
YYYY-MM-DD hh:mm
  xx.xx
              
        
YYYY-MM-DD hh:mm
xx.xx
              
        
YYYY-MM-DD hh:mm
xx.xx
              
        
After Surgery
YYYY-MM-DD hh:mm
xx.xx
              
        
YYYY-MM-DD hh:mm
xx.xx
xxx/xxxx/xxxxx
xx/x/xx
Trametinib
Day 1
Before Surgery
YYYY-MM-DD hh:mm
xx.xx
              
YYYY-MM-DD hh:mm
xx.xx
              
After Surgery
YYYY-MM-DD hh:mm
xx.xx
              
Sample Colected 
Time
YYYY-MM-DD hh:mm
xx.xx
# Concentrations measured in CSF sample below the limit of quantitation (BLQ) values (<1 ng/mL for dabrafenib, hydroxy-
dabrafenib and desmethyl-dabrafenib, <5 ng/mL for carboxy-dabrafenib) have been set to zero and flagged.
Listing 16.2.5-2.3
Concentration and tissue distribution of dabrafenib and dabrafenib metabolites in brain metastases
(Pharmacokinetic Analysis Set)
Treatment:  xxxxx
Phase: xxxxxx
Country/
Center/ 
Subject
Age/ 
Sex/Race
Analyte
Treatment 
description
Assessment Date 
Time
Concentration 
(ng/g)
Sample 
condition
Comment
xxx/xxxx/xxxxx
xx/x/xx
xxxxxx
YYYY-MM-DD hh:mm
              
        
xxxxxx
xxxxxx
              
        
xxxxxx
xxxxxx
xxx/xxxx/xxxxx
xx/x/xx
xxxx


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CDRB436B2202
              
        
xxxxx
xxxxx
xxxxxx
xxxx


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Section 16.2.6
Individual efficacy response data
Not applicable.
Section 16.2.7
Adverse event listings


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Listing 16.2.7-1.1
Adverse events (Safety Set)
Treatment :  xxxxx
Country/
Center/ 
Subject
Age/ 
Sex/ 
Race 
SAE
Adverse event                
(REPORTED / Preferred / 
System organ class)          
Start date/
Study day 
End date/ 
Study day 
Dur. 
(days)
Grade
Relat.
  to
study 
drug  
Action
taken
BEL/
55/M/Ca 
    MILD DIZZINESS /            
/9 
/16 
  8  
1
Not 
susp 
None
    
        
    
Dizziness (exc vertigo) /
    
        
    
Nervous system disorders
BEL/
71/F/Ca 
GASTRIC DISTRESS /          
/3 
/4  
  2  
1
Susp     None
    
        
    
Abdominal pain upper /
    
        
    
Gastrointestinal 
disorders
BEL/
62/F/Ca 
    POSITION VERTIGO /          
/1 
Continuing   
     
1
Not 
susp 
None
               
        
    
Vertigo positional /
               
    
Ear and labyrinth 
disorders
               
    GASTRIC DISTRESS /          
/3 
11 
  9  
2
Susp     2
               
    
Abdominal pain upper /
               
    
Gastrointestinal 
disorders
- Relationship to study drug: Not susp=Not suspected, Susp=Suspected
- Action taken: 1 = Study treatment withdrawn, 2 = Dose reduced, 3 = Dose increased, 4 = No action, 5 = Dose 
interrupted/delayed, X = Not applicable, subject not receiving IP when event occurred.
- Study day is relative to the first day of treatment(day 1).
- MedDRA version <xx.x>, CTCAE version <x.xx>.
Programming Note:
1. Repeat listing for both treatment groups
PPD
PPD
PPD
PPD


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Listing 16.2.7-1.2
Adverse events of special interest (Safety Set)
Treatment :  xxxxx
Country/
Center/ 
Subject
Age/ 
Sex/ 
Race 
SAE
Adverse event                
(REPORTED / Preferred / 
System organ class)          
Start date/
Study day 
End date/ 
Study day 
Dur. 
(days)
Grade
Relat.
  to
study 
drug  
Action
taken
BEL
55/M/Ca 
    MILD DIZZINESS /             
/9 
/16 
  8  
1
Not 
susp 
None
   
        
    
Dizziness (exc vertigo) /
   
        
    
Nervous system disorders
/
XXXXXXXXXXXXX
BEL
71/F/Ca 
GASTRIC DISTRESS /           
/3 
/4  
  2  
1
Susp     None
               
        
    
Abdominal pain upper /
               
        
    
Gastrointestinal 
disorders /
XXXXXXXXXXXX
- Relationship to study drug: Not susp=Not suspected, Susp=Suspected
- Action taken: 1 = Study treatment withdrawn, 2 = Dose reduced, 3 = Dose increased, 4 = No action, 5 = Dose 
interrupted/delayed, X = Not applicable, subject not receiving IP when event occurred.
- Study day is relative to the first day of treatment(day 1).
- MedDRA version <xx.x>, CTCAE version <x.xx>.
PPD
PPD
PPD