COMBI-AD: A Phase III Randomized Double Blind Study of Dabrafenib (GSK2118436) in COMBInation With Trametinib (GSK1120212) Versus Two Placebos in the ADjuvant Treatment of High-risk BRAF V600 Mutation-positive Melanoma After Surgical Resection
Phase: PHASE3
Conditions: Melanoma
Sponsor: Novartis Pharmaceuticals

Clinical Development
DRB436 (GSK2118436) +TMT212 (GSK1120212)
Protocol BRF115532 / NCT01682083
COMBI-AD: A phase III randomized double blind study of 
dabrafenib (GSK2118436) in COMBInation with 
trametinib (GSK1120212) versus two placebos in the 
ADjuvant treatment of high-risk BRAF V600 
mutation-positive melanoma after surgical resection
Document type
Amended Protocol Version (Clean)
EUDRACT number
2012-001266-15
Version number
10 
Clinical Trial phase
III
Document status
FINAL
Release date
08-Feb-2023
Novartis internal 
reference number
CDRB436F2301
Property of Novartis
Confidential
May not be used, divulged, published, or otherwise disclosed
without the consent of Novartis

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Table of contents
Table of contents .......................................................................................................2
List of tables ..............................................................................................................5
List of figures ............................................................................................................5
List of Abbreviations.................................................................................................7
Amendment rationale ..............................................................................................10
Amendment 10 (08-Feb-2023)................................................................................10
Amendment 9 (05-Nov-2021).................................................................................12
Amendment 8 (21-Dec-2018) .................................................................................13
Amendment 07 (31-May-2017)...............................................................................14
PROTOCOL SUMMARY ......................................................................................19
1
INTRODUCTION...................................................................................................21
1.1
Background.....................................................................................................21
1.1.1
The BRAF Inhibitor Dabrafenib as Monotherapy .............................22
1.1.2
The MEK Inhibitor Trametinib as Monotherapy ...............................23
1.1.3
BRAF and MEK Inhibitors as Combination Therapy........................23
1.2
Study Rationale...............................................................................................25
2
OBJECTIVES AND ENDPOINTS.........................................................................26
3
STUDY DESIGN....................................................................................................27
3.1
Discussion of Design ......................................................................................29
3.1.1
Dose Rationale ...................................................................................29
3.2
Rationale for Public Health Emergency mitigation procedures......................30
4
SUBJECT SELECTION AND DISCONTINUATION/ COMPLETION 
CRITERIA...............................................................................................................30
4.1
Subject Selection Criteria................................................................................30
4.1.1
Number of Subjects............................................................................30
4.1.2
Inclusion Criteria................................................................................31
4.1.3
Exclusion Criteria...............................................................................32
4.2
Permanent Discontinuation from Study Treatment and Subject Completion 
Criteria............................................................................................................34
4.2.1
Subject Completion............................................................................35
5
STUDY TREATMENT ..........................................................................................35
5.1
Investigational Products..................................................................................35
5.1.1
Dabrafenib..........................................................................................35
5.1.2
Trametinib ..........................................................................................35
5.1.3
Placebos..............................................................................................36
5.2
Dosage and Administration.............................................................................36
5.3
Handling and Storage of Study Treatment......................................................36

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5.4
Treatment Assignment....................................................................................37
5.5
Blinding...........................................................................................................37
5.6
Product Accountability ...................................................................................38
5.7
Treatment Compliance....................................................................................38
5.8
Dose Modification Guidelines ........................................................................38
5.8.1
General supportive guidelines............................................................38
5.8.2
Dose Modification for General Toxicities..........................................39
5.8.3
Dose Modification Guidelines - Adverse Events of Special Interest.41
5.9
Monitoring, Interruption, and Stopping Criteria for Hepatobiliary Events ....46
5.9.1
Liver chemistry stopping criteria .......................................................46
6
CONCOMITANT MEDICATIONS AND NON-DRUG THERAPIES ................50
6.1
Permitted Medications and Non-Drug Therapies ...........................................50
6.2
Prohibited Medications and Non-Drug Therapies ..........................................50
6.3
Medications to be Used with Caution.............................................................51
6.4
Treatment after Discontinuation of Study Treatment or Withdrawal 
from/Completion of Study..............................................................................53
6.5
Treatment of Study Treatment Overdose........................................................53
7
STUDY ASSESSMENTS AND PROCEDURES ..................................................54
7.1
Critical Baseline Assessments ........................................................................66
7.1.1
Baseline Confirmation of BRAF Mutation-positive Melanoma........66
7.2
Efficacy...........................................................................................................66
7.2.1
Efficacy Endpoints .............................................................................66
7.3
Safety ..............................................................................................................69
7.3.1
Safety Endpoints.................................................................................69
7.3.2
Adverse Events...................................................................................69
7.3.3
Pregnancy Testing, Prevention and Reporting...................................74
7.3.4
Laboratory Assessments.....................................................................75
7.3.5
Ophthalmic Examination....................................................................76
7.3.6
Vital Signs ..........................................................................................77
7.3.7
Physical Examinations .......................................................................77
7.3.8
Dermatologic Examination.................................................................77
7.3.9
Electrocardiograms (ECG).................................................................78
7.3.10 Echocardiograms (ECHO) .................................................................78
78
78
78
79
79

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79
79
79
79
7.7
Translational Research....................................................................................80
7.7.1
BRAF mutation assay.........................................................................80
80
81
81
81
8
DATA MANAGEMENT........................................................................................82
9
DATA ANALYSIS AND STATISTICAL CONSIDERATIONS .........................82
9.1
Hypotheses......................................................................................................82
9.2
Study Design Considerations..........................................................................83
9.2.1
Sample Size Assumptions ..................................................................83
9.2.2
Sample Size Sensitivity......................................................................85
9.2.3
Sample Size Re-estimation.................................................................86
9.3
Data Analysis Considerations.........................................................................86
9.3.1
Analysis Populations ..........................................................................86
9.3.2
Analysis Data Sets..............................................................................86
9.3.3
Treatment Comparisons .....................................................................86
9.3.4
Interim Analysis & IDMC..................................................................87
9.3.5
Key Elements of Analysis Plan..........................................................87
10
STUDY CONDUCT CONSIDERATIONS............................................................91
10.1 Posting of Information on Publicly Available Clinical Trial Registers..........91
10.2 Regulatory and Ethical Considerations, Including the Informed Consent 
Process............................................................................................................91
10.3 Quality Control (Study Monitoring) ...............................................................92
10.4 Quality Assurance...........................................................................................92
10.5 Study and Site Closure....................................................................................93
10.6 Records Retention...........................................................................................93
10.7 Provision of Study Results to Investigators, Posting of Information on 
Publicly Available Clinical Trials Registers and Publication ........................94
10.8 Independent Data Monitoring Committee ......................................................94
11
REFERENCES........................................................................................................95
12
APPENDICES.........................................................................................................98
12.1 Appendix 1: Melanoma of the Skin Staging...................................................98
12.2 Appendix 2: Surgical Guidelines....................................................................99

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12.3 Appendix 3: Eastern Cooperative Oncology Group (ECOG) Performance 
Status ............................................................................................................100
12.4 Appendix 4: Cockcroft-Gault Formula.........................................................100
12.5 Appendix 5: QT interval on electrocardiogram corrected using the Bazett’s 
formula (QTcB)............................................................................................101
12.6 Appendix 6: New York Heart Association (NYHA) Guidelines..................101
12.7 Appendix 7: Liver Chemistry Monitoring, Interruption Stopping and Follow-
up Criteria.....................................................................................................102
103
105
12.10 Appendix 10: Country Specific Requirements..........................................110
12.11 Appendix 11: Protocol Changes................................................................110
List of tables
Table 1
Definitions for Adequate Baseline Organ Function...............31
Table 2
Dose Levels ............................................................................40
Table 3
Dose Modification Guidelines - General................................40
Table 4
Management and Dose Modification Guidelines for 
Pyrexiaa,b.................................................................................41
Table 5
Management and Dose Modification Guidelines for Visual 
Changes ..................................................................................43
Table 6
Dose Modification Guidelines and Stopping Criteria for LVEF 
Decrease .................................................................................44
Table 7
Withholding and Stopping Criteria for QTc-Prolongation.....45
Table 8
Prohibited Medications...........................................................51
Table 9
Medications to be used with Caution .....................................52
Table 10
Time and Events Table – Screening and Treatment...............55
Table 11
Time and Events Table – Follow-Up Assessments................61
Table 12
Time Frames for Reporting SAEs and Other Events .............72
Table 13
Clinical Chemistry and Hematology Parameters ...................76
Table 14
Statistical Power Scenario for RFS Analysis .........................85
Table 15
Statistical Power Scenario for OS Analysis ...........................85
List of figures
24
Figure 2
BRF115532 Study Design Schema (N=852) .................................28

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SPONSOR INFORMATION PAGE
Clinical Study Identifier BRF115532
Sponsor Contact Address
Novartis Pharmaceuticals Corporation
In some countries, the clinical trial sponsor may be the local Novartis and its authorized 
agents. Where applicable, the details of the Sponsor and contact person will be provided to 
the relevant regulatory authority as part of the clinical trial submission.
Sponsor Serious Adverse Events (SAE) Contact Information: 
Please refer to the study procedures manual. 
For study conduct questions not related to patient safety, the first line of contact should be 
with the designated local country company contact. In the event that the designated 
company contact is not available please contact the Medical Lead.
If you have any questions regarding the protocol, please contact your local Novartis office.
Regulatory Agency Identifying Number(s): 
Investigational New Drug (IND) Number
113,557
European Drug Regulatory Authorities Clinical Trials (EudraCT) Number 
2012-001266-15
Universal Trial Number (UTN)
U1111-1148-3778

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List of Abbreviations
AE
Adverse Event
ALT
Alanine Aminotransferase
ANC
Absolute neutrophil count
AST
Aspartate Aminotransferase
ATP
Adenosine triphosphate
BCC
Basal cell carcinoma
BID
Twice daily
bMX
bioMerieux
BRAF
Protein with an important role in cell signalling
BUN
Blood Urea Nitrogen
CI
Confidence Interval
CL/F
Apparent clearance following oral dosing
CPK
Serum creatine phosphokinase
CR
Complete Response
CRO
Clinical Research Organization
CRAF
protein functioning in the MAPK/ERK signal transduction pathway as part of a 
protein kinase cascade
CRP
C-reactive protein
CSR
Central serous retinopathy
CT
Computed tomography
CTCAE
Common terminology criteria for adverse events
cuSCC
Cutaneous squamous cell carcinoma
DBP
Diastolic blood pressure
DMFS
Distant metastasis-free survival
DMSO
Dimethyl sulfoxide
DTIC
Dacarbazine
ECG
Electrocardiogram
ECHO
Echocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
Electronic case report form
EDTA
Ethylenediaminetetraacetic acid
ERK
Extracellular signalling-regulated kinase
FDA
United States Food and Drug Administration
FDG-PET
Fluorodeoxyglucose positron emission tomography
FFR
Freedom From Relapse
GCP
Good Clinical Practice
GCPH
Global Clinical Program Head
GLP
Good Laboratory Practice
GSK
GlaxoSmithKline
HA
Health Authority
Hg
Mercury
HPLC
High Performance Liquid Chromatography
HPMC
Hydroxypropylmethylcellulose

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HR
Hazard ratio
ICH
International Conference on Harmonisation
IDMC
Independent Data Monitoring Committee 
IEC
Independent Ethics Committee
INR
International normalized ratio
IP
Investigational product
IRB
Institutional Review Board
ITT
Intent to Treat
IUO
Investigational Use Only
IVRS
Interactive Voice Response System
KA
Keratoacanthoma
KRAS
KRAS gene makes KRAS protein which is involved in cell signaling pathways, cell 
growth and apoptosis. When mutated the KRAS gene may cause cancer.
LDH
Lactate dehydrogenase
LLN
Lower limit of normal
LN
Lymph node
LVEF
Left ventricular ejection fraction
MAPK
Mitogen-activated protein kinase
MedDRA
Medical Dictionary for Regulatory Activities
MEK1 and MEK2
Mitogen-activated extracellular signal-related kinases 1 and 2
mm
Millimeter
MRI
Magnetic resonance imaging
msec
milliseconds
NCCN
National Comprehensive Cancer Network
NCI
National Cancer Institute
NR
Not Reached
NRAS
NRAS gene makes NRAS protein which is involved in regulating cell division
NYHA
New York Heart Association
ORR
Overall response rate
OS
Overall survival
PCR
Polymerase chain reaction
PD
Progressive Disease
PFS
Progression-free survival
PK
Pharmacokinetic
PPES
Palmar-Plantar Erythrodysesthaesia Syndrome
PR
Partial Response
PT
Prothrombin time
PTT
Partial thromboplastin time
QT
Electrocardiogram interval from onset of the QRS complex to the end of the T wave 
representing duration of repolarisation
QTcB
QT duration corrected for heart rate by Bazett’s formula
RAF
Serine threonine-protein kinase activating downstream effectors involved in 
tumorigenesis
RAP
Reporting and Analysis Plan

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RAS
Protein activating signaling cascades (promoting cell proliferation, neoplastic 
transformation and oncogenesis)
RECIST
Response Evaluation Criteria in Solid Tumours
RFS
Relapse Free Survival
RR
Response Rate
RVO
Retinal vein occlusion
SAE
Serious adverse event(s)
SBP
Systolic blood pressure
SCC
Squamous cell carcinoma
SD
Stable Disease
SGOT
Serum glutamic oxaloacetic transaminase
SGPT
Serum glutamic pyruvic transaminase
SPM
Study Procedures Manual
ULN
Upper limit of normal
US/USA
United States
V/F
Volume of distribution 
WBC
White blood cell

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Amendment rationale
Amendment 10 (08-Feb-2023)
First Patient First Visit in this study occurred on 31-Jan-2013, Last Patient Last Treatment 
occurred on 01-Dec-2015 which at the time, all patients were off study treatment. As of 
03-Jan-2023, 446 patients are still in follow-up. The patients and investigators are still 
blinded to the treatment assignments. The original protocol planned an interim OS analysis 
at 153 events (26%) and a final OS analysis at 597 events. Due to an unexpectedly slow 
event accrual rate, this was revised with Amendment 8 to perform a final OS analysis at 
299 events. As the event rate has slowed even more (to less than 2 events per month), the 
analysis plan has been amended to perform a final OS analysis when 260 events occur (or 
by the end of Jul-2023, whichever comes first). This change is applied in the interest of 
bringing the study conclusions to the medical community in a timely manner. The 
anticipated impact of this change in event number from 299 to approximately 260 on the 
power of the final analysis is expected to be minimal (see Section 9). 
Changes to the protocol
Changes to specific sections of the protocol are shown in the track changes version of the
protocol using strike through red font for deletions and red underline for insertions.
Section
Brief description of the change and/or new text 
Amendment Rationale
Moved to after glossary.
Medical Lead Information page
Removed as no longer applicable.
Section 1.2 Study Rationale
Changed from “side” to “adverse” effect. 
Section 3 Study Design
Section 4.2 Permanent Discontinuation 
from Study Treatment and Subject 
Completion Criteria 
Section 9.3.2 Analysis Data Sets
Section 9.3.4 Interim Analysis & IDMC
Updated the Final OS analysis to occur when 260 events occur 
(or by the end of Jul-2023, whichever comes first).
Section 9.2 Study Design Considerations Updated the Final OS analysis to occur when 260 events occur 
(or by the end of Jul-2023, whichever comes first).
Added the following: All remaining alpha will be spent for this final 
OS analysis by taking into account alpha spent at the first interim 
analysis corresponding to the information fraction of 25.6%.
Section 9.2.2 Sample Size Sensitivity
Table 15: Updated number of OS events and updated the 
percentage (%) of statistical power for 255, 260 and 299 events.
Additional text regarding statistical power added.
Section 10.5 Study and Site Closure
Updated percentage (%) and number of OS events for study 
completion 
Appendix 11
Appendix 11removed as it is not applicable, available in prior 
amendments 

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IRBs/IECs
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities.
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation. The changes herein do not affect the Informed Consent. 

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Amendment 9 (05-Nov-2021)
Amendment rationale 
As of 01-Dec-2015, all subjects have discontinued from study treatment and are in follow 
up. As of 20-Oct-2021, 287 subjects remain in follow-up for recurrence and 184 subjects 
remain in the follow-up for survival. 
The main purpose of this protocol amendment is to:
1. Cease central imaging collection.
2. Include disruption proof language in the event of a public health emergency.
3. Make clarifications, editorial and typographic changes.
Rationale for stopping central imaging collection:
The primary and secondary endpoints are based on investigator’s assessment of CT/MRI 
scans. The primary endpoint was reached for Relapse Free Survival (RFS), and now the 
patients are only being followed for long term RFS/Overall Survival (OS) milestones.
There were no central assessments done in the study and no plans to perform in the future, 
therefore central imaging collection will cease, as the vendor function was only to collect 
and hold the CT/MRI scans. Tumor response will continue to be assessed locally as per 
investigator’s assessment and imaging data will continue to be collected in EDC and 
archived locally. 
Additional summary of changes:
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underline for insertions.
Section
Brief description of the change and/or new text 
Sponsor Signatory page
Removed as per Novartis SOPs
Sponsor Information page
Medical lead and Study lead contact details have been updated
Investigator Agreement page
Removed as per Novartis SOPs 
3 Study Design
Annual visit calculation has been clarified.
3.2 Rational for Public Health 
Emergency mitigation 
procedures.
7 Study assessments and 
procedures.
7.2.1.4 Assessment Guidelines.
7.3.2.7 Regulatory reporting 
requirements for SAEs.
7.3.3.2 Pregnancy reporting.
7.3.4 Laboratory Assessments.
7.4.2 Health Outcomes 
Assessments
Disruption proof language has been added in the event of a public health 
emergency how the site should proceed if the subject cannot attend study 
visits at site
5.8.3.2 Visual Changes
Clarification provided, PK samples for ocular events are no longer required 
for subjects that have discontinued study treatment.
Table 11 Time and Events Table 
– Follow-Up Assessments
Footnote has been updated to clarify:
 

Annual visit calculation

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Section
Brief description of the change and/or new text 

Chemistry and hematology sample collection after month 60 and upon 
disease recurrence

Typo regarding non-contrast CT has been corrected

QoL collection after month 60 only required for subjects before 
recurrence
7.2.1.3 
Efficacy 
Assessment 
7.2.1.4 Assessment Guidelines
Typo regarding non-contrast CT has been corrected. Reference to SPM 
has been removed as central imaging scan collection will cease and sites 
to continue to follow standard of care for performing imaging scan 
collection.
7.3.2.6 Prompt reporting of SAEs 
and other events for Novartis
This has been updated based on feedback from the Federal Institute for 
Drugs and Medical Devices (BfArM) in Germany to require prompt SAE 
follow up reporting. 
7.3.8 Dermatologic Exam
Clarified Table 11. Dermatologic examination is not required for subjects 
that have had disease recurrence and are in follow up after Month 60 visit
9.3.4 Interim analysis & IDMC
As per Protocol Amendment 8 the final OS analysis will be conducted at 
299 events. Corrected the typo of 597 events.
10.5 Study and Site Closure
As per Protocol Amendment 8 summary of changes the study will be 
considered complete when approximately 50 percent of the initially 
planned target number of randomized subjects have died or are otherwise 
lost to follow-up (approximately 299), at which time final OS analysis will 
be performed. The previous protocol V8.0 did not update section 10.5 to 
reflect this change, and this has now been corrected.
IRBs/IECs
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities. The changes 
described in this amended protocol are non-substantial and do not require IRB/IEC 
approval prior to implementation.
Amendment 8 (21-Dec-2018) 
Amendment rationale 
Primary analysis was conducted on the data cut-off of 30-June-2017. At the time there were 
410 recurrence events and 153 deaths were reported. These results were presented to health 
authorities in support of the marketing authorization application for dabrafenib and 
trametinib in the adjuvant treatment of melanoma. 
Based on a Health Authority request, the RFS analysis was updated on the basis of extended 
study follow-up with an additional 10 months of data (cut-off date 30-April-2018) and a 
cure-rate model analysis was presented to estimate the fraction of patients expected to 
remain relapse free long term. As of 30-Apr-2018, 355 patients remained in the follow-up 
for recurrence and 577 patients remained in the follow-up for survival. This additional 
assessment evidenced a continuation of the slower than anticipated trend for recurrence 
and death events. As a result, the final analysis of OS is being changed from 597 events to 
approximately 299 death events with this amendment. This represents approximately 50% 
information fraction of the original target which was communicated to FDA and EMA to 
be an adequate milestone for final assessment given the event predictions and maturity of 
data at that time point.

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Furthermore, the follow-up assessment schedule has been updated to extend the time 
between clinic visits to annually after patients have been on study beyond Month 60 
(~5 years from randomization). 
Changes to the protocol
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underline for insertions.

Updated the Final OS analysis to occur after 50% of OS events rather than at 70% and 
addressed statistical considerations in the relevant sections 

Section 9: Statistical assumptions and Table 15 updated for Statistical Power Scenarios 
for Overall Survival: 

Additional analyses added for 5-year and study completion RFS rates 

Additional descriptive analysis added for post-recurrence antineoplastic treatment.

Section 7 and Table 11: Updates made to the Time and events Schedule to reduce the 
number of assessments for both pre-and post-recurrence after patients have been on 
study for more than 60 months.

Formatting changes and updated Sponsor Contact information
IRBs/IECs
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities.
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation. 
The changes herein affect the Informed Consent. Sites are required to update and submit 
for approval a revised Informed Consent that takes into account the changes described in 
this protocol amendment.
Amendment 07 (31-May-2017)
Amendment rationale

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The purpose of this protocol Amendment 07 is:

Perform the primary analysis of RFS using a data cut-off at approximately 2.5 years 
after Last patient First Dose which also corresponds to a projected median follow up of 
3.3 years for all subjects.

Add an additional interim OS analysis when approximately 299 death events have 
occurred, i.e. at 50% information fraction of originally targeted 597 OS events. 

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Changes to the protocol
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underline for insertions.

Updated Sponsor Contact information

Section 9.1.: Added language to state the primary analysis of RFS can be performed 
using a data cut-off at approximately 2.5 years after Last patient First Dose. Updated 
data-cut-off date for final RFS analysis and provided related updated statistical 
assumptions.

Section 9.2.1: Clarified that the primary analysis for RFS will be a first interim analysis 
for Overall Survival and added a second interim analysis for survival after 
approximately 299 events. Statistical rationale and updated assumptions were also 
added. 

Section 11 References: Section updated to include additional reference noted in the 
rationale for this amendment. 
IRBs/IECs
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities.
The changes described in this amended protocol do not change any study procedures or the 
safety management of the on-going patients, and therefore, do not require IRB/IEC 
approval prior to implementation.

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Summary of previous amendments 
Revision Chronology:
2012N135295_00
2012-JUL-05
Original
2012N135295_01
2012-OCT-10
Amendment No. 1
Amendment No. 1:
1. Updated RFS and OS analysis and study completion definitions.
2. Deleted the formal interim efficacy analysis.
3. Added details of randomization capping and interim analysis for OS at the time of the RFS analysis.
4. Updated male contraception requirements to align with current standard for dabrafenib and trametinib.
5. Updated dosage and administration guidelines for grapefruit and grapefruit juice, Seville oranges, or 
pommelos consumption before randomization from 7 days to 24 hours.
6. Updated Table 3 Dose Modification Guidelines for General Toxicity and corresponding text.
7. Revised Dose Modification Guidelines for:

Pyrexia

Visual Changes

LVEF
8. Changes to the Time and Events Tables including modification to 
 
, addition of PK sample at Month 1, update 
to instruction for MRI substitution of CT, correction of typographical errors, modification of visit window 
during the treatment period, clarification of central lab schedule during follow-up and removal of Month 
21 CT scan.
9. Added table showing statistical power scenario for OS analysis.
10.Minor changes for clarification and consistency throughout the protocol including:

Patients that present with initial resectable lymph node recurrence after a diagnosis of Stage I or 
II melanoma are eligible.

Patients with history of another malignancy including melanoma or concurrent malignancy are not 
eligible.

Clinical examination and biopsy of recurrence are considered efficacy assessments.

Ophthalmic examination must be performed by an ophthalmologist.

Added text referring to information and requirements for head and neck examinations and 
dermatologic examinations provided in the SPM.
11.Minor administrative changes, and correction to typographical errors throughout the document
2012N135295_02
2012-NOV-12
Amendment No. 2
Amendment No. 2:
 
2012N135295_03
2012-DEC-13
Amendment No. 3: 
Amendment No. 3: 
1.
Added CT/MRI assessment at Month 21.
2.
Included 80% power calculation for OS.
3.
Provide the rationale for use of the Pike estimator of the treatment hazard ratio.
4.
Updated male and female contraception requirements.
5.
Clarified exclusion #12.
6.
Added reference.
2012N135295_04
2013-JAN-17
Amendment 
No. 
04: 
 
 
 
 
Amendment No. 04: 
 
2012N135295_05
2013-OCT-24
Amendment No. 05

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Revision Chronology:
Amendment No. 05:
1. Clarifications and updates to eligibility criteria.
2. Deleted exclusion for glucose-6-phosphate dehydrogenase (G6PD) deficiency.
3. Clarified follow-up assessments required for subjects that discontinue treatment prior to Month 12 
without evidence of disease recurrence.
4. Updated dosing instructions.
5. Updated dose modification guidelines for visual changes.
6. Updated guidance for symptomatic decreased left ventricular ejection fraction (LVEF). 
7. Updated guidelines for QTc prolongation.
8. Updated prohibited and cautionary medications.
9. Clarifications and updates to the Time and Events tables including:

Addition of dermatologic skin assessments at Months 8 and 10. 

Deletion of dermatologic skin assessment at Month 9.

Addition of column and footnotes to describe follow up assessments for subjects that discontinue 
treatment prior to Month 12 without evidence of disease recurrence.

Clarification of PK, 
. 
10.Clarified imaging requirements for efficacy assessments.
11.Added collection of new malignancy information.
12.
 
13. Minor administrative changes, clarifications and corrections to typographical errors throughout the 
document.
2012N135295_06
2016-Oct-05
Amendment No. 6: 
Amendment No. 6: 

Delete or replace references to GSK or its staff with that of Novartis/Novartis and its authorized agents.

Make administrative changes to align with Novartis processes and procedures.

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PROTOCOL SUMMARY
Rationale
Cutaneous melanoma is the most aggressive form of all skin cancers. Although it represents 
only 4% of all cancers, its incidence is continuing to rise in the world at a rate exceeding 
all other cancers (Jemal, 2007). Worldwide it is expected that approximately 132,000 
people will be diagnosed with melanoma each year and approximately 37,000 people are 
expected to die of the disease annually (WHO, 2012).
Surgical resection is the treatment of choice for localized melanoma and frequently results 
in cures for early stage (I and II) disease, with a 90% long term (10-year) survival rate for 
stage I disease (Balch, 2009). However, patients with lymph node involvement ≥1mm, 
including those detected only by sentinel lymph node biopsy, are at high risk of both local 
and distant relapse after definitive surgery due to the frequent presence of distant 
micrometastatic disease at presentation (Kirkwood, 2001; Van Akkooi, 2009). 
Approximately half of these patients will ultimately die of metastatic disease 
(Markovic, 2007), and the morbidity from uncontrolled relapses is also considerable. Thus 
there is a need for effective adjuvant therapy for high-risk patients to prevent disease 
relapse after surgical resection of the primary tumor.
Although significant progress has been made recently with new treatments for metastatic 
melanoma, therapeutic options in the adjuvant setting remain limited. Many agents have 
been evaluated as potential therapies for the adjuvant treatment of melanoma however 
almost all have demonstrated little or no benefit (Schuchter, 2004). The National 
Comprehensive Cancer Network (NCCN) treatment guidelines for melanoma recommend 
clinical trials, observation and interferon as the three therapy options for the adjuvant 
treatment of melanoma with clinical trials as the preference (NCCN, 2012). Although high-
dose interferon is currently the only approved therapy for the adjuvant treatment of 
melanoma it is not widely accepted as the standard of care. Increasing evidence 
surrounding a questionable survival benefit, a high incidence of serious toxicities, and 
negligible benefit for patients with bulkier disease makes it an unattractive therapy for most 
patients and clinicians (Schuchter, 2004). Thus there is a need for more effective therapies 
with an acceptable safety profile in the adjuvant setting.
The RAS/RAF/MEK/ERK pathway (i.e., the MAP kinase pathway) is a critical 
proliferation pathway in many human cancers, including melanoma. Oncogenic mutations 
in BRAF signal through MEK1 and MEK2, and occurrence of this is an early event. This 
study will evaluate the combination of two small-molecule, oral agents, dabrafenib and 
trametinib. Dabrafenib is a potent and selective RAF kinase inhibitor of human wild type 
BRAF and CRAF enzymes as well as the mutant forms BRAFV600E, BRAFV600K and 
BRAFV600D. The mode of action of dabrafenib is consistent with competitive inhibition 
of adenosine triphosphate (ATP) binding. By contrast, trametinib is a reversible, highly 
selective, allosteric inhibitor of MEK1 and MEK2. Trametinib is non-competitive towards 
ATP and inhibits both MEK activation and kinase activity. Because BRAF and MEK are 
in the same pathway, and because MEK is a substrate of activated BRAF, inhibiting both 
proteins simultaneously rather than individually could provide more effective pathway 
inhibition and also decrease the likelihood of developing resistance. Preliminary clinical 
experience, along with data generated in cell line, mouse xenograft, and rat safety models 
with BRAF and MEK inhibitor combinations suggest enhanced effects on efficacy and less 

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potential for proliferative skin lesions or stimulation of dormant tumors containing RAS 
mutations compared to treatment with a BRAF inhibitor alone. 
Objective(s)
Primary Objective
The primary objective for this study is to evaluate the efficacy of dabrafenib and trametinib 
combination therapy compared to two placebos with respect to relapse-free survival (RFS) 
in patients with completely resected, histologically confirmed, BRAF V600E/K high-risk, 
stage III cutaneous melanoma.
Secondary Objectives
1. To evaluate the overall survival (OS) of dabrafenib and trametinib combination therapy
compared to placebo
2. To assess distant metastasis-free survival (DMFS)
3. To assess freedom from relapse (FFR)
4. To evaluate the safety of dabrafenib and trametinib in combination 
Study Design
This is a two-arm, randomized, double-blind Phase III study of dabrafenib (BRAF inhibitor) 
in combination with trametinib (MEK inhibitor) versus two placebos in the adjuvant 
treatment of melanoma after surgical resection. Patients with completely resected, 
histologically confirmed, BRAF V600E/K mutation-positive, high-risk [Stage IIIa 
(maximum diameter of the largest lymph node (LN) metastasis >1 mm), IIIb or IIIc] 
cutaneous melanoma will be screened for eligibility. Approximately 852 subjects will be 
randomized in a 1:1 ratio to receive either dabrafenib [150 mg, twice daily (BID)] and 
trametinib [2 mg, once daily] combination therapy or two placebos for each for 12 months. 
Subjects will be stratified by BRAF mutation status (V600E, V600K) and stage of disease 
(IIIa, IIIb, IIIc).
Doses of study treatment may be modified and/or interrupted for management of toxicities 
associated with study treatment (Section 5.8). 
Study Assessments
The RFS, DMFS and FFR endpoints will be determined by investigator assessment of 
disease recurrence. Subjects will be assessed with computed tomography (CT) or magnetic 
resonance imaging (MRI) at Screening and during treatment and the post-treatment follow-
up period (refer to the Time and Events Schedule in Section 7 for scanning frequency). 
Subjects will also be followed for survival. Safety will be evaluated by clinical assessments 
including vital signs and complete physical examinations, eye exams, 12-lead 
electrocardiograms (ECG), and echocardiograms (ECHO), chemistry and hematology 
laboratory values and adverse events (AEs).

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1
INTRODUCTION
1.1
Background
Cutaneous melanoma is the most aggressive form of all skin cancers. Although it represents 
only 4% of all cancers, its incidence is continuing to rise in the world at a rate exceeding 
all other cancers (Jemal, 2007). Worldwide it is expected that approximately 132,000 
people will be diagnosed with melanoma each year and approximately 37,000 people are 
expected to die of the disease annually (WHO, 2012).
Surgical resection is the treatment of choice for localized melanoma and frequently results 
in cures for early stage (I and II) disease, with a 90% long term (10-year) survival rate for 
stage I disease (Balch, 2009). However, patients with lymph node involvement ≥1mm, 
including those detected only by sentinel lymph node biopsy, are at high risk of both local 
and distant relapse after definitive surgery due to the frequent presence of distant 
micrometastatic disease at presentation (Kirkwood, 2001; Van Akkooi, 2009). 
Approximately half of these patients will ultimately die of metastatic disease 
(Markovic, 2007), and the morbidity from uncontrolled relapses is also considerable. Thus 
there is a need for effective adjuvant therapy for high-risk patients to prevent disease 
relapse after surgical resection of the primary tumor.
Although significant progress has been made recently with new treatments for metastatic 
melanoma, therapeutic options in the adjuvant setting remain limited. Many agents have 
been evaluated as potential therapies for the adjuvant treatment of melanoma however 
almost all have demonstrated little or no benefit (Schuchter, 2004). The National 
Comprehensive Cancer Network (NCCN) treatment guidelines for melanoma recommend 
clinical trials, observation and interferon as the three therapy options for the adjuvant 
treatment of melanoma with clinical trials as the preference (NCCN, 2012). Although high-
dose interferon is currently the only approved therapy for the adjuvant treatment of
melanoma it is not widely accepted as the standard of care. Increasing evidence 
surrounding a questionable survival benefit, a high incidence of serious toxicities, and 
negligible benefit for patients with bulkier disease makes it an unattractive therapy for most 
patients and clinicians (Schuchter, 2004). Thus, there is a need for more effective therapies 
with an acceptable safety profile in the adjuvant setting.
The RAS/RAF/MEK/ERK pathway (i.e., the MAP kinase pathway) is a critical 
proliferation pathway in many human cancers, including melanoma. Over 80% of 
cutaneous melanomas harbor activating mutations of either BRAF or NRAS 
(Nikolaev, 2011). Oncogenic mutations in BRAF signal through MEK1 and MEK2 and 
this is an early event. This study will evaluate the combination of two, small-molecule, oral 
agents, dabrafenib and trametinib. Dabrafenib is a potent and selective RAF kinase 
inhibitor of human wild type BRAF and CRAF enzymes as well as the mutant forms 
BRAFV600E, BRAFV600K and BRAFV600D. The mode of action of dabrafenib is 
consistent with competitive inhibition of ATP binding. By contrast, trametinib is a 
reversible, highly selective, allosteric inhibitor of MEK1 and MEK2. Trametinib is non-
competitive towards ATP and inhibits both MEK activation and kinase activity. Because 
BRAF and MEK are in the same pathway, and because MEK is a substrate of activated 
BRAF, inhibiting both proteins simultaneously rather than individually could provide more 
effective pathway inhibition and also decrease the likelihood of developing resistance. Data 

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generated in cell line, mouse xenograft, and rat safety models with BRAF and MEK 
inhibitor combinations suggest enhanced effects on efficacy and less potential for 
proliferative skin lesions or stimulation of dormant tumors containing RAS mutations 
compared to treatment with a BRAF inhibitor alone. 
Based on the demonstrated efficacy of both dabrafenib and trametinib as monotherapies 
along with preliminary clinical data suggesting that the combination may prevent resistance 
and improve efficacy, phase III clinical studies of the dabrafenib/trametinib combination 
are being initiated in advanced melanoma and as adjuvant therapy for high-risk Stage III 
disease. 
1.1.1
The BRAF Inhibitor Dabrafenib as Monotherapy
Dabrafenib, a selective BRAF inhibitor, has shown activity with a manageable safety 
profile in phase 1 and 2 studies in patients with BRAF V600E/K-mutation positive 
metastatic melanoma. The BREAK-3 (BRF113683) global phase III trial was conducted 
in patients with BRAF V600E mutation-positive advanced or metastatic melanoma 
randomized (3:1) to receive treatment with either dabrafenib [150 mg, twice daily (BID)] 
or dacarbazine (DTIC). Subjects were randomized by disease stage (unresectable Stage III, 
IVM1a and IVM1b versus IVM1c). Subjects randomized to the DTIC arm were allowed 
to crossover to receive dabrafenib after confirmation of progressive disease (PD). The 
primary endpoint was progression free survival (PFS) based on investigator assessment in 
the intent-to-treat (ITT) population comprised of all randomized subjects, regardless of 
whether or not treatment was administered. Secondary endpoints were overall survival 
(OS), overall response rate (ORR) in both groups and after crossover, PFS for subjects 
randomized to the DTIC treatment groups after crossover, duration of response, 
safety/tolerability and BRAF mutation assay validation.
Two hundred and fifty subjects were enrolled; including 187 that were randomized to 
dabrafenib and 63 to DTIC. At the time of data cut-off for the primary analysis, 141
subjects were on study treatment (dabrafenib n=127; DTIC n=14) including 21/28 DTIC 
subjects that crossed over to dabrafenib. Median age was 52 years; 31% had an Eastern 
Cooperative Oncology Group (ECOG) performance status 1, 66% were M1c, and 33% 
lactate dehydrogenase (LDH) greater than the upper limit of normal (>ULN) 
(Hauschild, 2012). 
At the time of the primary analysis, there were 118 events (77 dabrafenib and 41 DTIC). 
The hazard ratio (HR) for PFS was 0.30 (95% CI: 0.18-0.53; p<0.0001). Median PFS was 
5.1 months for dabrafenib and 2.7 months for DTIC by investigator assessment. OS data 
were immature. Confirmed response rate (RR) was 53% for dabrafenib and 19% for DTIC. 
Benefits in PFS and RR were observed in all subgroups evaluated. 
The most frequent adverse events (20%) in the dabrafenib arm were hyperkeratosis (37%), 
headache (32%), pyrexia (28%), arthralgia (27%), skin papillomas (24%), alopecia (22%), 
palmar-plantar erythrodysaesthesia syndrome (2%). Serious adverse events (SAEs) (>1%) 
on the dabrafenib arm included pyrexia (4%), squamous cell carcinomas (6%), and new 
primary melanomas (2%).
Further evidence for the safety and efficacy of dabrafenib has been established in a large 
(N=172) study of patients (BREAK-MB) with both controlled and uncontrolled brain 
metastases (Kirkwood, 2012). Activity in subjects with the V600K mutation was also seen.

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1.1.2
The MEK Inhibitor Trametinib as Monotherapy
Trametinib is a reversible, highly selective allosteric inhibitor of MEK1/2 activation and 
kinase activity. A Phase 3 trial, METRIC (MEK114267), was conducted in patients with 
BRAF V600E/K mutation positive advanced or metastatic melanoma. Subjects were 
randomized 2:1 to trametinib (2 mg once daily) or chemotherapy (DTIC or paclitaxel). 
Subjects were stratified by baseline LDH level and prior chemotherapy; subjects in the 
chemotherapy arm were allowed to crossover to receive trametinib after confirmation of 
PD. The primary endpoint was PFS in subjects with BRAF V600E mutation-positive 
metastatic melanoma and no prior brain metastases; PFS was also evaluated in the ITT 
population. Secondary endpoints were OS, ORR in the primary and ITT population and 
safety in the safety population.
Three hundred and twenty-two subjects were randomized to trametinib (n=214) or 
chemotherapy (n=108); 273 subjects were BRAF V600E mutation-positive with no prior 
brain metastases. Median age was 54 years; all had an ECOG performance status of 0 (64%) 
or 1 (36%), and 65% were M1c (Flaherty, 2012).
The HR for the primary population for PFS by investigator was 0.44 (95% CI 0.31–0.64; 
p<0.0001) in favor of trametinib with a median PFS of 4.8 months vs. 1.4 months with 
chemotherapy. The confirmed ORR was 24% with trametinib and 7% with chemotherapy. 
HR for interim OS was 0.53 (95% CI 0.30–0.94; p=0.0181), in favor of trametinib. 
The most frequent AEs (20%) with trametinib were skin rash (57%), diarrhea (43%), 
fatigue (26%), and edema (26%). Known MEK inhibitor class effects were observed in this 
study including chorioretinopathy (<1%) and decreased ejection fraction (7%).
1.1.3
BRAF and MEK Inhibitors as Combination Therapy
1.1.3.1
Nonclinical Biology 
In vitro and in vivo preclinical data provide evidence to support the potential benefit of 
combining BRAF and MEK inhibitors. In cell culture, the combination of dabrafenib and 
trametinib is significantly more effective than the single agents in inhibiting the growth of 
BRAF-mutant, dabrafenib-resistant cell lines. This combination has also demonstrated 
enhanced activity against parental (non-drug-resistant) BRAF-mutant cells, suggesting that 
potential benefits of the combination may result from overall improved activity relative to 
single agents. This cell-line data generated by GlaxoSmithKline (GSK) using GSK BRAF 
and MEK inhibitors is similar to in vitro results of other BRAF and MEK inhibitor 
combinations (Corcoran, 2010; Emery, 2009). The combination of dabrafenib and 
trametinib also has greater activity in mouse xenografts than either single agent alone, 
supporting the in vitro observations. Furthermore, in skin toxicity studies performed in rats, 
the addition of a MEK inhibitor to a BRAF inhibitor prevented the development of 
proliferative skin lesions observed following treatment with a BRAF inhibitor alone. This 
result suggests that the addition of a MEK inhibitor to a BRAF inhibitor may suppress pro-
proliferative effects, including cutaneous squamous cell carcinoma (cuSCC), which have 
been observed in the clinic following BRAF monotherapy (Flaherty, 2010; 
Chapman, 2011). Similar results have been published with another combination of BRAF 
and MEK inhibitors (Carnahan, 2010). 

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1.1.3.2
Clinical
 
 
 

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1.2
Study Rationale
Although the role of the MAP kinase pathway has not yet been studied in early melanoma, 
there is adequate scientific rationale and data to expect that the combination of dabrafenib 
and trametinib will provide similar responses on V600 mutant cells in the adjuvant setting 
as for more advanced disease. BRAF mutations are present in primary lesions, and are 
preserved in corresponding metastatic lesions indicating a common clonal origin (Nissan, 
2011). Based on early and continued involvement of V600 mutation throughout melanoma 
disease progression, MAP kinase inhibition would be expected to provide similar responses 
regardless of disease stage. 
The combination of dabrafenib with trametinib in the adjuvant setting is further supported 
by in vitro and in vivo preclinical data which has demonstrated that the combination can 
enhance the levels of apoptosis, abrogate the onset of resistance, and prevent the 
development of proliferative skin lesions compared to BRAF monotherapy. This 
combination has demonstrated enhanced activity against parental (non-drug-resistant) as 
well as dabrafenib-resistant cell lines, suggesting that potential benefits of combination 
may result from overall improved activity relative to single agents as well as an attenuation 
of tumor growth resulting from acquired resistance. Although the mechanisms of resistance 
to BRAF treatment are not completely understood, emerging data have demonstrated MEK 
activation at the time of relapse, thus the addition of a MEK inhibitor to dabrafenib 

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represents an attractive therapeutic strategy (Goetz, 2012). Cell line data generated by GSK 
are similar to in vitro data with other BRAF/MEK inhibitor combinations (Corcoran, 2010; 
Emery, 2009). Similar to cell line data, in mouse xenograft studies with A375 cells which 
harbor a BRAFV600E mutation, the combination of dabrafenib and trametinib was 
significantly better than either agent alone.
The combination in the adjuvant setting also prevents MEK activation in normal tissues, a 
mechanistic adverse effect of BRAF monotherapy, which can lead to development of low-
grade squamous-cell carcinomas. The combination of BRAF/MEK inhibitors prevented 
the development of proliferative skin lesions (epithelial hyperplasia and hyperkeratosis of 
the skin, nonglandular stomach and/or footpads) observed in rats following treatment with 
a BRAF inhibitor alone, suggesting that the addition of MEK to BRAF may potentially 
mitigate the risk of developing epithelial proliferative effects (i.e., cutaneous squamous cell 
carcinoma) as observed in the clinic. Observations on proliferative skin effects are similar 
to those published with another BRAF/MEK inhibitor combination (Carnahan, 2010). 
More importantly, emergence of clinically-significant RAS-driven tumors is far less likely 
to occur when there is combined BRAF/MEK inhibition than with BRAF alone
(Lacouture, 2012). Together the preclinical studies and clinical data support further clinical 
evaluation of dabrafenib and trametinib combination therapy in subjects with BRAF-
V600E/K mutation-positive melanoma in the adjuvant setting. 
2
OBJECTIVES AND ENDPOINTS
Objectives
Endpoints
Primary
To evaluate the efficacy of dabrafenib and trametinib 
combination therapy compared to two placebos with 
respect to relapse-free survival (RFS) in patients with 
completely resected, histologically confirmed, BRAF 
V600E/K high-risk, stage III cutaneous melanoma
Relapse Free Survival (RFS), defined as the time 
from randomization to disease recurrence or 
death from any cause. Recurrence of or death 
from the same cancer and all deaths from other 
causes 
are 
events. 
Treatment 
emergent 
malignancy(ies) other than second melanomas 
will not be considered as events, and loss to 
follow-up is censored. Patients without RFS 
events will be censored at the last adequate 
assessment.
Secondary
To compare overall survival (OS) of dabrafenib and 
trametinib as a combination therapy versus two 
placebos.
To compare distant metastasis-free survival (DMFS) of 
dabrafenib and trametinib as a combination therapy 
versus two placebos.
To compare freedom from relapse (FFR) of dabrafenib 
and trametinib as a combination therapy versus two 
placebos.
OS defined as the interval from randomization 
to the date of death, irrespective of the cause of 
death; patients still alive will be censored at the 
date of the last contact.
DMFS defined as the interval from 
randomization to the date of first distant 
metastasis or date of death, whichever occurs 
first. Patients alive and without distant 
metastasis are censored at the date of last 
assessment.
FFR defined as interval from randomization to 
local or distant recurrence with censoring of 
patients dying from causes other than melanoma 
or treatment-related toxicity at the date of death. 
Patients alive without recurrence or with second 
primary cancer will be censored at the date of 
last assessment.

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Objectives
Endpoints
To evaluate the safety of dabrafenib and trametinib as 
a combination therapy in the overall study population 
including incidences of squamous cell carcinoma 
(SCC), new cancers in other sites, and other 
proliferative cutaneous lesions
Safety as measured by clinical assessments 
including vital signs and physical examinations, 
12-lead electrocardiograms (ECG), 
echocardiogram (ECHO), eye exams, chemistry 
and hematology laboratory values, and adverse 
events (AEs).
Refer to Section 7 for further details on endpoint definitions.
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 Tables (Section 7), are essential and required for study conduct
This is a two-arm, randomized, double-blind Phase III study of dabrafenib in combination 
with trametinib versus two placebos in the adjuvant treatment of melanoma after surgical 
resection (Figure 2). Patients with completely resected, histologically confirmed, BRAF 
V600E/K mutation-positive, high-risk [Stage IIIa (lymph node metastasis >1 mm), IIIb or 
IIIc] cutaneous melanoma will be screened for eligibility. Approximately 852 subjects will 
be randomized in a 1:1 ratio to receive either dabrafenib (150 mg BID) and trametinib (2 
mg once daily) combination therapy or two placebos for each for 12 months. Subjects will 
be stratified by BRAF mutation status (V600E, V600K) and stage of disease (Stage IIIa, 
IIIb, IIIc). 
Doses of study treatment may be modified and/or interrupted for management of toxicities 
associated with study treatment (Section 5.8). Refer to Section 5.8.3 for guidelines for 
events of special interest and Section 5.9.1 for liver stopping criteria.

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Figure 2
BRF115532 Study Design Schema (N=852)
The benefit of the dabrafenib/trametinib combination compared to placebos will be 
evaluated through the primary endpoint of investigator-assessed RFS. Crossover is not 
permitted. The treatment effect of dabrafenib and trametinib combination therapy is 
anticipated to improve RFS by 40% over placebos (median RFS of 21 months and 15 
months, respectively). See Section 9 for statistical considerations.
Subjects in both arms will receive treatment for 12 months or until disease recurrence, 
death, unacceptable toxicity, or withdrawal of consent. Subjects will be followed for 
disease recurrence and survival during and after the treatment period. Refer to the Time 
and Events Tables (Section 7) for required assessments for the following study periods:
Screening: Assessments must be completed within 28 days of randomization, unless stated 
otherwise in the Time and Events table (Table 10).
Treatment: The treatment period is 12 months. Discontinuation of study treatment may 
occur earlier than 12 months for disease recurrence, death, unacceptable toxicity or 
withdrawal of consent.
Post Treatment Follow-Up (Before Recurrence): Subjects will be followed for disease 
recurrence every 3 months after the end of treatment until Month 24, every 6 months after 
Month 24 and annually after Month 60 (365 days ±14 days from last visit, assessments to 
be completed as per Table 11).
Post Treatment Follow-Up (After Recurrence): After disease recurrence subjects will 
remain on study for follow-up assessments every three months until Month 24, every 6 
months after Month 24, and annually after Month 60 (365 days ±14 days from last visit, 
assessments to be completed as per Table 11). Follow-up assessments will include updates 
on anti-cancer treatments and responses to those treatments as well as survival and quality 
of life information. Subjects who have not died, but are no longer being followed for 
disease recurrence or survival are considered to have discontinued from the study. The 
study will be considered complete, and the final OS analysis will be conducted when 
approximately 260 OS events occur or at the data cut-off by the end of Jul-2023, whichever 
occurs first.
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 

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the site personnel with administrative and detailed technical information that does not 
impact subject safety.
3.1
Discussion of Design
The ultimate goal of adjuvant therapy is to improve the cure rate after surgery through 
eradication of occult micrometastatic disease. Notable successes have been achieved in 
oncology when highly effective therapies were available for advanced stage disease (e.g., 
breast cancer, Hodgkin’s and non-Hodgkin’s lymphoma, embryonal tumors, 
osteosarcoma). High-risk, resected BRAF V600E/K mutation positive melanoma 
represents another attractive setting for testing this paradigm since: 1) the population is at 
high risk for relapse and death without further therapy; 2) the BRAF/MEK combination is 
both highly effective and can be targeted to the population most likely to benefit, and 3) 
the combination of dabrafenib and trametinib should be at least as well tolerated as 
cytotoxic chemotherapy or high-dose interferon and thus have acceptable risk:benefit if the 
study objectives are met.
This study is designed to compare dabrafenib and trametinib in combination versus two 
placebos with regard to RFS, which is a direct measurement of anti-tumor effect. RFS was 
selected as the primary endpoint based upon historical precedent (peginterferon alfa- 2b, 
Sylatron) and because it will not be subject to confounding from subsequent therapy, as 
would OS. Since relapses are accompanied by considerable disease- and treatment-related 
morbidity, RFS is a true measure of patient benefit. 
Data from preclinical studies and clinical experience with the dabrafenib/trametinib 
combination in patients with BRAF V600E or V600K mutations suggest that efficacy may 
be observed in the adjuvant setting for either population, thus both mutation types have 
been included.
Placebo has been selected as the control arm due to the absence of an acceptable standard 
of care for the adjuvant treatment of patients with high-risk resectable melanoma. Although 
high-dose interferon is currently the only approved therapy for the adjuvant treatment of 
melanoma it is not widely accepted as the standard of care. Increasing evidence 
surrounding a questionable survival benefit, a high incidence of serious toxicities, and 
negligible benefit for patients with bulkier disease makes it an unattractive therapy for most 
patients and clinicians (Schuchter, 2004). Dabrafenib and trametinib will be administered 
at the dose recommended for further development of the combination (150 mg BID and 
2.0 mg once daily, respectively), based on the extensive monotherapy experience for both 
inhibitors along with the preliminary results of BRF113220 with combination therapy. An 
Independent Data Monitoring Committee (IDMC) will be chartered to regularly review 
safety data. 
3.1.1
Dose Rationale 
Preliminary clinical data for the proposed dabrafenib/trametinib combination are described 
in Section 1.1.3.2. Approximately 168 subjects have received combination therapy with 
dabrafenib and trametinib at the proposed study doses (150 mg BID dabrafenib and 2 mg 
once daily trametinib) with a median follow-up time of 12.8 months. n the dose-escalation 
phase (Part B), PFS was longest for the group receiving the highest doses of dabrafenib 
and trametinib with an acceptable safety profile. Based on these data the combination of 

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150 mg BID of dabrafenib and 2.0 mg once daily of trametinib has been selected for further 
development. 
Considerable experimental and clinical evidence has been amassed demonstrating the 
importance of maintaining dose intensity in the adjuvant setting. Studies of high-risk breast 
cancer patients have repeatedly demonstrated inferior outcomes, including diminished 
survival, when attenuated dose regimens were compared to standard chemotherapy (Muss, 
2009; Budman, 1998; Citron, 2003; EBCTCG, 2011). Since the dabrafenib/trametinib 
combination induces apoptosis in BRAF V600 mutation-positive melanoma cells, the same 
theoretical considerations should apply as with cytotoxic chemotherapy. Specifically, 
maximum clinical benefit should occur when the disease burden is lowest, i.e. in the 
adjuvant setting when micrometastases can be eliminated with effective therapy. Therefore, 
the adjuvant study will use the combination regimen that has already been selected as 
providing optimal efficacy for use in metastatic disease.
The duration of therapy (12 months) is based upon expert consensus and does not exceed 
that administered in other pivotal studies of adjuvant treatment in similar populations 
where treatment ranged from 12 to 60 months [EORTC18991, EORTC18071, DERMA, 
EORTC18592, ECOG1690, AVAST-M, GO27826]. In the absence of a reliable biomarker 
for minimal residual disease, empiric dosing for durations much shorter than the predicted 
median relapse free interval (median of 15 months) may increase the risk of treatment 
failure. 
 
 
 Safety of continuous dosing of dabrafenib and trametinib for over a year as 
monotherapies has been established along with preliminary safety of combination dosing 
for a similar interval. Safety precautions will include clear guidelines for management of 
toxicity, including enhanced surveillance for adverse events of special interest along with 
instructions for dose modification (Section 5.8). An IDMC will regularly review safety 
data, starting at an early timepoint (e.g. N~100). The inclusion/exclusion criteria will also 
serve to minimize participation of those at greatest risk for known or suspected toxicities 
of the combination.
3.2
Rationale for Public Health Emergency mitigation procedures 
During a Public Health emergency as declared by Local or Regional authorities i.e. 
pandemic, epidemic or natural disaster, mitigation procedures to ensure subject safety and 
trial integrity are listed in relevant sections. Notification of the Public health emergency 
should be discussed with Novartis prior to implementation of mitigation procedures and 
permitted/approved by Local or Regional Health Authorities and Ethics Committees as 
appropriate.
4
SUBJECT SELECTION AND DISCONTINUATION/ 
COMPLETION CRITERIA
4.1
Subject Selection Criteria
4.1.1
Number of Subjects
Approximately 852 subjects will be randomized, 1:1 to combination therapy (n=426) and 
to placebos (n=426). Refer to Section 9.2.1 for sample size assumptions.

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4.1.2
Inclusion Criteria
Specific information regarding warnings, precautions, contraindications, adverse events, 
and other pertinent information on dabrafenib and trametinib that may impact subject 
eligibility is provided in the Investigator’s Brochures 
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. Is ≥18 years of age.
2. Has signed written informed consent.
3. Completely resected histologically confirmed high-risk [Stage IIIa (LN metastasis >1 
mm), IIIb or IIIc; refer to Appendix 1 for Staging Guidelines] cutaneous melanoma 
determined to be V600E/K mutation positive using the bioMerieux (bMX) THxID 
BRAF Assay. The testing will be conducted by a central reference laboratory. Patients 
presenting with initial resectable lymph node recurrence after a diagnosis of Stage I or 
II melanoma are eligible. Patients with an unknown primary melanoma are not eligible.
4. Must be surgically rendered free of disease (defined as the date of the most recent 
surgery) no more than 12 weeks before randomization.
5. Recovered from definitive surgery (e.g. no uncontrolled wound infections or 
indwelling drains). For minimum surgical requirements see Appendix 2.
6. Able to swallow and retain oral medication and must not have any clinically significant 
gastrointestinal abnormalities that may alter absorption such as malabsorption 
syndrome or major resection of the stomach or bowels.
7. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-1 
(Oken, 1982) (See Appendix 3).
8. Must have adequate organ function as defined in Table 1:
Table 1
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
≤1.5 x ULN

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Hepatic
Albumin
≥2.5 g/dL
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 
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 4). Creatinine clearance must be  50 mL/min to be eligible. 
c. ECHO scans must be used throughout the study
9. Women of childbearing potential must have a negative serum pregnancy test within 7 
days of first dose of study treatment and agree to use effective contraception, as defined 
in Section 7.3.3 from 14 days prior to randomization, throughout the treatment period 
and for 4 months after the last dose of study treatment. 
10. French subjects: In France, a subject will be eligible for inclusion in this study only if 
either affiliated to or a beneficiary of a social security category.
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. Known mucosal or ocular melanoma or the presence of unresectable in-transit 
metastases.
2. Evidence of distant metastatic disease on screening evaluation.
3. Prior anti-cancer treatment (chemotherapy, immunotherapy, biologic therapy, vaccine 
therapy, or investigational treatment) including radiotherapy for melanoma. Prior 
surgery for melanoma is allowed.
4. Taken an investigational drug within 28 days or 5 half-lives, whichever is longer, prior 
to randomization.
5. Current or expected use of a prohibited medication (See Protocol Section 6.2 for a list 
of prohibited medications).
6. Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs 
chemically related to the study treatments, their excipients, and/or dimethyl sulfoxide 
(DMSO). 
7. Known Human Immunodeficiency Virus (HIV).
8. History of another malignancy including melanoma or a concurrent malignancy except 
as noted below. Patients who have previously had Stage III melanoma or any 
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Prospective RAS testing is not required. However, if the results of previous RAS testing 
are known, they must be used in assessing eligibility.
Exceptions: 

Patients with a history of any malignancy that have been disease-free for at least 5 
years are eligible except those with confirmed activating RAS mutations. 

Patients with a history of completely resected non-melanoma skin cancer (e.g. basal 
cell carcinoma, squamous cell carcinoma) are eligible irrespective of the time since the 
resection.

Patients with successfully treated in situ carcinoma are eligible.

Patients presenting with multiple primary melanomas are eligible only if the lesions are 
concurrent. Patients who have concurrent multiple primary melanomas that are 
“distant” are eligible provided each lesion is considered local disease or resectable 
regional disease. These cases should be discussed with the Medical Lead.
1. A history or evidence of cardiovascular risk including any of the following:
a.
A QT interval corrected for heart rate using the Bazett’s formula (QTcB; 
Appendix 5) 480 msec;
b.
A history or evidence of current clinically significant uncontrolled 
arrhythmias;
c.
A history of acute coronary syndromes (including myocardial infarction or 
unstable angina), coronary angioplasty, or stenting within 6 months prior to 
randomization
d.
A history or evidence of current Class II congestive heart failure as defined 
by the New York Heart Association (NYHA) guidelines (See Appendix 6)
e.
Patients with intra-cardiac defibrillators.
f.
Abnormal cardiac valve morphology (≥grade 2) documented by 
echocardiogram (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.
g.
Treatment refractory hypertension defined as a blood pressure of systolic> 
140 mm Hg and/or diastolic > 90 mm Hg which cannot be controlled by 
anti-hypertensive therapy.
2. A history or current evidence/risk of retinal vein occlusion (RVO) or central serous 
retinopathy (CSR) including: 
a.
Presence of predisposing factors to RVO or CSR (e.g., uncontrolled 
glaucoma or ocular hypertension, uncontrolled hypertension, uncontrolled 
diabetes mellitus, or a history of hyperviscosity or hypercoagulability 
syndromes); or
b.
Visible retinal pathology as assessed by ophthalmic examination that is 
considered a risk factor for RVO or CSR such as:
i. Evidence of new optic disc cupping;
ii. Evidence of new visual field defects on automated perimetry;
iii. Intraocular pressure >21 mm Hg as measured by tonography.
3. History of clinically significant or active interstitial lung disease or pneumonitis. 

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4. Any serious or unstable pre-existing medical conditions (aside from malignancy 
exceptions specified above), psychiatric disorders, or other conditions that, in the 
opinion of the investigator, could interfere with the subject’s safety, obtaining 
informed consent, or compliance with study procedures. 
5. Pregnant or nursing females.
4.2
Permanent Discontinuation from Study Treatment and 
Subject Completion Criteria
Subjects will receive study treatments for twelve months or until disease recurrence. 
During the protocol defined treatment period study treatment(s) may be permanently 
discontinued for the following reasons: 

death 

unacceptable adverse event, including meeting stopping criteria for liver chemistry 
defined in Section 5.9.1 and/or for hematologic and other non-hematologic toxicity. 

deviation(s) from the protocol

request of the subject or proxy

investigator’s discretion

subject is lost to follow-up

study is closed or terminated.
The primary reason each study treatment was permanently discontinued must be 
documented in the subject’s medical records and in the electronic case report form (eCRF). 
Refer to Section 5.2 for additional information on discontinuation of dabrafenib and/or 
trametinib.
If disease recurs prior to the completion of the 12 month treatment period, study treatment 
should be discontinued and follow-up assessments should be conducted according to the 
schedule for “Follow-up after recurrence” (Table 11). Such follow-up assessments should 
start at the next regularly scheduled disease assessment visit (i.e. Month 3, 6, 9 or 12) and 
continue thereafter according to Table 11. For example, if disease recurrence is observed 
at Month 6, the subject would complete the discontinuation visit and follow-up assessments 
after recurrence would start at Month 9, and continue according to the visit schedule in the 
Time and Events Table (Table 11). 
If the subject voluntarily discontinues from treatment due to toxicity, ‘adverse event’ will 
be recorded as the primary reason for permanently discontinuation in the eCRF.
All subjects who permanently discontinue from study treatment will have assessments at 
the time of discontinuation and during post study treatment follow-up as specified in Time 
and Events Tables (See Section 7). In addition, all subjects who permanently discontinue 
study treatment without evidence of disease recurrence will also be followed for disease 
recurrence according to the protocol schedule until:

Withdrawal of consent

Death, or

Study completion (as defined in Section 3)

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Subjects that permanently discontinue from study treatment before the end of the 12 month 
treatment period without evidence of disease recurrence will return for disease assessment 
visits starting at the next regularly scheduled disease assessment visit (i.e. Month 3, 6, 9 or 
12) and continue thereafter according to Table 11. If a subject experiences disease 
recurrence at any time subsequent follow up visits should be conducted according to the 
“After Recurrence” follow-up schedule in Table 11.
Follow-up for survival, new anti-cancer therapy (including radiotherapy) and response to 
new anti-cancer therapy will continue for all subjects including those with disease 
recurrence, according to the Time and Events Tables (Table 10 and Table 11) until the 
study is considered to be complete after which all protocol-required assessments and 
procedures will be discontinued. The study will be considered complete, and the final OS 
analysis will be conducted when approximately 260 OS events occur or at the data cut-off 
by the end of Jul-2023, whichever occurs first. Follow-up contact to assess survival and 
new anti-cancer therapy may be made via clinic visit or another form of communication 
(e.g. phone, email, mail etc.). Additional information on declaring subjects lost to follow-
up can be found in the SPM.
4.2.1
Subject Completion
A subject will be considered to have completed the study if the subject dies during the 
study treatment or follow-up period. Document the cause of death 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, at the investigator’s discretion is no longer being 
followed or if the study is closed/terminated. Subjects who are ongoing at the time the 
study is closed/terminated will be considered to have completed the study. 
5
STUDY TREATMENT
The term ‘study treatment’ is used throughout the protocol to describe the combination of 
products received by the subject as per the protocol design. Study treatment may therefore 
refer to the individual study treatments or the combination of those study treatments.
5.1
Investigational Products
No special preparation of study treatment is required. Under normal conditions of handling 
and administration, investigational product is not expected to pose significant safety risks 
to site staff. Material Safety Data Sheets (MSDS) describing the occupational hazards and 
recommended handling precautions will be provided to site staff if required by local laws 
or will otherwise be available from Novartis upon request.
5.1.1
Dabrafenib
Dabrafenib will be provided as 50 mg and 75 mg capsules to sites by Novartis. The contents 
of the label will be in accordance with all applicable regulatory requirements. Each capsule 
will contain 50 mg or 75 mg of free base (present as the mesylate salt). 
5.1.2
Trametinib
Trametinib study treatment will be provided as 0.5 mg and 2.0 mg tablets to sites by 
Novartis. The contents of the labels will be in accordance with all applicable regulatory 

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requirements. Each tablet will contain 0.5 mg or 2.0 mg of trametinib parent (present as 
the DMSO solvate). 
5.1.3
Placebos
Matching placebo capsules for dabrafenib (50 mg and 75 mg) and placebo tablets for 
trametinib (0.5 mg and 2.0 mg) will be provided to sites by Novartis. The placebo 
capsules/tablets will contain the same inactive ingredients and film coatings as the 
dabrafenib and trametinib study treatment. 
The contents of the labels will be in accordance with all applicable regulatory requirements.
5.2
Dosage and Administration

Dabrafenib, 150 mg twice daily (BID) or placebo.

Trametinib, 2.0 mg, once daily or placebo.
Both study treatments should be administered in the morning at approximately the same 
time every day. The second dose of dabrafenib (150 mg) or dabrafenib placebo should be 
administered approximately 12 hours after the morning dose. Study medication should be 
taken orally with approximately 200 mL of water under fasting conditions, either 1 hour 
before or 2 hours after a meal. If administration of trametinib or trametinib placebo is 
interrupted or permanently discontinued, administration of dabrafenib or dabrafenib 
placebo may be continued. If administration of dabrafenib or dabrafenib placebo is 
interrupted or permanently discontinued, administration of trametinib or trametinib 
placebo may continue. 
If a subject vomits after taking study treatment, the subject should be instructed not to 
retake the dose and should take the next dose as originally scheduled. 
If a subject misses a dose of dabrafenib or dabrafenib placebo, the subject may take the 
dose immediately if the next dose is scheduled for at least 6 hours later. If the next 
scheduled dose is due in less than 6 hours, the subject should skip the dose and resume 
dosing at the next scheduled dose. If a subject misses a dose of trametinib or trametinib 
placebo, the subject may take the dose immediately if the next dose is scheduled for at least 
12 hours later.
Subjects should start treatment as soon as possible after randomization and no later than 72 
hours post-randomization.
5.3
Handling and Storage of Study Treatment
Dabrafenib, dabrafenib placebo, trametinib and trametinib placebo must be stored in a 
secure area under the appropriate physical conditions for the products. Study treatments 
are to be stored at the temperature specified on the label. Maintenance of a temperature log 
(manual or automated) is required. Access to and administration of the study treatment will 
be limited to the investigator and authorized site staff. Dabrafenib, dabrafenib placebo, 
trametinib and trametinib placebo must be dispensed or administered only to subjects 
enrolled in the study and in accordance with the protocol.
Procedures for final disposition of unused study treatments will be provided in the SPM. 

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5.4
Treatment Assignment
Subjects will be identified by a unique subject number that will remain consistent for the 
duration of the study.
Upon completion of all the required screening assessments, eligible subjects will be 
registered into RAMOS (Registration and Medication Ordering System), the interactive 
voice response system (IVRS), by the investigator or authorized site staff. 
The following information for stratification must be entered into the system in order to 
obtain the blinded treatment assignment: 

Mutation type (V600E or V600K);

Disease stage (IIIa, IIIb, IIIc)
Randomization will be done centrally using a randomization schedule generated by the 
GSK Biostatistical Department, the sponsor at the time will assign subjects in a 1:1 ratio 
to:

dabrafenib and trametinib combination therapy.

dabrafenib and trametinib placebos
Once a randomization number has been assigned it must not be re-assigned even in cases 
of errors.
Detailed RAMOS user instructions, worksheets and telephone contact numbers will be 
provided to the study site at study start.
5.5
Blinding
Study treatment will be double-blinded. Novartis, the site personnel (including the 
investigator) and the subject will not know the treatment assignment. Every effort must be 
made to maintain the blind until all analyses have been performed. 
The investigator or treating physician may unblind a subject’s treatment assignment only 
in the case of an emergency, when knowledge of the study treatment is essential for the 
appropriate clinical management or welfare of the subject. Whenever possible, the 
investigator must first discuss options with the Novartis Medical Lead or appropriate 
Novartis study personnel before unblinding the subject’s treatment assignment. If this is 
impractical, the investigator must notify Novartis as soon as possible, but without revealing 
the treatment assignment of the unblinded subject, unless that information is important for 
the safety of subjects currently in the study. The date and reason for the unblinding must 
be recorded in the eCRF. A subject should remain in the study for survival follow-up even 
if the treatment code is unblinded.
Novartis' Chief Medical Office & Patient Safety (CMO&PS) Department staff may unblind 
the treatment assignment for any subject with an SAE. If the SAE requires that an expedited 
regulatory report be sent to one or more regulatory agencies, a copy of the report, 
identifying the subject’s treatment assignment, may be sent to clinical investigators in 
accordance with local regulations and/or Novartis policy.

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5.6
Product Accountability
In accordance with local regulatory requirements, the investigator, designated site staff, or 
head of the medical institution (where applicable) must document the amount of 
investigational product dispensed and/or administered to study subjects, the amount 
returned by study subjects, and the amount received from and returned to Novartis, when 
applicable. Product accountability records must be maintained throughout the course of the 
study. Reer to the SPM for further detailed instructions on product accountability.
5.7
Treatment Compliance
Subjects will be instructed to return treatment bottles at each visit. Compliance with study 
treatment will be assessed through querying the subject during the site visits and 
documented in the source documents and eCRF. 
A record of the number of study treatment capsules/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 
or dose reductions will also be recorded in the eCRF. The investigator will make every 
effort to bring non-compliant subjects in to compliance.
5.8
Dose Modification Guidelines
The severity of adverse events will be graded utilizing the National Cancer Institute (NCI) 
CTCAE, version 4.0. This section includes:

Supportive guidelines for managing common toxicities

General dose modification guidelines for toxicities related to study treatments 

Specific management guidelines for pyrexia, cardiovascular adverse events, and 
cutaneous squamous cell carcinoma/keratoacanthoma

Guidelines for management of hepatobiliary events are given separately in 
Section 5.9. Investigators should also refer to the dabrafenib and trametinib 
combination Investigator’s Brochure for the most current product safety information. 
5.8.1
General supportive guidelines
5.8.1.1
Skin Toxicity (Rash, Palmar-Plantar Erythrodysesthaesia 
syndrome)
Rash and Palmar-Plantar Erythrodysesthaesia Syndrome (PPES) are frequently observed 
in subjects receiving trametinib, dabrafenib, or the combination of both therapies. 
Guidelines for management are based on experience with other MEK inhibitors and EGFR 
inhibitors (Balagula, 2010; Lacouture, 2012) and include:

Prevention/prophylaxis: promote sunscreen use and avoidance of unnecessary sun 
exposure, use alcohol-free emollient creams, topical steroids and antibiotics as needed.

Pruritic lesions: cool compresses and oral antihistamines

Fissuring lesions: Monsel’s solution, silver nitrate or zinc oxide cream

Desquamation: thick emollients and mild soap

Paronychia: antiseptic bath, local potent corticosteroids, antibiotics, surgery as needed

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
Infected lesions: topical or systemic antibiotics
Additional measures for PPES should include:

Lifestyle modification: avoidance of hot water, traumatic activity, constrictive footwear, 
or excessive friction on the skin and the use of thick cotton socks and gloves, and shoes 
with padded insoles

Symptomatic treatments: apply moisturizing creams frequently, topical keratolytics 
(e.g. urea 20-40 % cream, salicylic acid 6%, tazarotene 0.1% cream, fluorouracil 5% 
cream), clobetasol propionate 0.05% ointment for erythematous areas, topical lidocaine 
2%, and / or systemic pain medication such as nonsteroidal anti-inflammatory drugs, 
codeine, and pregabalin for pain.
Dose modification may also be required (refer to Table 3 - General Dose Modification 
Guidelines). 
5.8.1.2
Diarrhea
Episodes of diarrhea have been reported in subjects receiving dabrafenib and trametinib 
combination therapy. Other 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 ruled out. Supportive measures should include 
the following as clinically indicated:

Dietary modifications (e.g. small, frequent meals, low fiber, and lactose-avoidance)

Maintain hydration with clear liquids or IV fluids as needed

Loperamide and/or oral antibiotics
Dose modification may also be required (refer to Table 3 – General Dose Modification 
Guidelines). 
5.8.2
Dose Modification for General Toxicities
General guidelines regarding management and dose reduction for adverse events that are 
considered by the investigator to be related to study treatment and for which specific 
guidelines do not apply are provided in Table 3. These guidelines are intended primarily 
for non-hematological toxicities not easily managed with routine supportive care. For 
example, alopecia is not an indication for dose modification, nor is grade 2 nausea and 
vomiting that can be easily managed with anti-emetics. 
These are general guidelines and investigators should use always use clinical judgment in 
determining dose adjustments for any individual patient. Some toxicities may require 
hospitalization for stabilization, additional work-up, and consultation with a specialist 
before treatment can be restarted. Specific adverse events and recommended management 
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
Renal insufficiency – close monitoring of serum creatinine, treatment of associated 
pyrexia (see Table 4 - Management and dose modification guidelines for pyrexia), and 
treatment interruption for increased serum creatinine >2 mg/dl (or >0.5 mg/dl above 
baseline). Nephrology consultation should also be obtained if no obvious cause for 
persistent creatinine elevation (e.g. volume depletion). 

Pneumonitis – initial work-up should include high-resolution CT scan, ruling out 
infection, and pulse oximetry. Pulmonary function testing, bronchoscopy and/or 
brochoalveolar lavage, and empiric steroids may be indicated for more severe cases. 
Pulmonary consultation is recommended. For Grade 2 to 3 (if no recovery to grade ≤1 
within 4 weeks) and grade 4 pneumonitis, permanently discontinue trametinib. 
Treatment with dabrafenib may continue.

Rash – For mild rash, follow Grade 1 general dose modification guidelines (Table 3). 
For moderate (Grade 2), reduction of dose is allowed by at least one dose level, 
however, dose interruption may be required until resolution to Grade 1. If toxicity 
resolves, can consider re-escalation to initial dose level. For Grade 3, if event resolves 
to Grade 1 or less, suggest to also consider restarting at a reduced dose. If Grade 2 or 3 
rash does not resolve or worsens after 2 weeks of dose modification/interruption and 
clinical treatment, discontinue trametinib. Treatment with dabrafenib may continue.

Pancreatitis – In the event of abdominal pain or suspected pancreatitis, amylase and 
lipase laboratory samples should be collected for confirmation of the diagnosis.
Investigators should always err on the side of caution in these settings if treatment-related 
toxicity is a possibility. Note that guidelines for management of hepatobiliary adverse 
events are provided separately in Section 5.9.
General dose modification guidelines are provided in Table 3 below. Dose levels referred 
to in Table 2 are as follows:
Table 2
Dose Levels
Dabrafenib/placebo
Trametinib/placebo
Starting dose
150 mg BID
2 mg once daily
L-1 (1st level dose reduction)
100 mg BID
1.5 mg once daily
L-2 (2nd level dose reduction)
75 mg BID
1 mg once daily
Table 3
Dose Modification Guidelines - General
CTCAE Grade
Action and Dose Modificationa,b,c
Grade 1 or Grade 
2 (tolerable)
Continue study treatments at same dose level (no dose modification)
Grade 2 (Intolerable)
1st or 2nd
occurrence 
Interrupt study treatments until toxicity resolves to ≤ grade 1 then restart at same 
dose level
3rd or occurrence
Interrupt study treatments until toxicity resolves to ≤ grade 1 then restart at next 
lower dose level
4th or greater 
occurrence 
Interrupt study treatments until toxicity resolves to ≤ grade 1 then restart at two 
dose levels lower than the starting dose or discontinue treatments per investigator 
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CTCAE Grade
Action and Dose Modificationa,b,c
Grade 3
1st occurrence 
Interrupt study treatments until toxicity resolves to ≤ grade 1 or baseline then restart 
at next lower dose level
2nd occurrence
Interrupt study treatments until toxicity resolves to ≤ grade 1 or baseline then restart 
at two dose levels lower than the starting dose
3rd occurrence
Discontinue treatments.
Grade 4
1st occurrence
Discontinue treatments
a. Treatments should be discontinued if more than 2 dose reductions are required
b. Approval from the Novartis Medical Lead is required to restart study treatments after ≥21 days 
interruption
c. These guidelines are intended for non-hematological toxicities not easily managed with routine 
supportive care (see above).
5.8.3
Dose Modification Guidelines - Adverse Events of Special Interest
5.8.3.1
Pyrexia
Pyrexia has been observed in subjects receiving dabrafenib, either as monotherapy or in 
combination with trametinib. In a minority of cases pyrexia was accompanied by symptoms 
such as severe chills, dehydration, hypotension, dizziness or weakness and required 
hospitalization. 
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 
(e.g. ibuprofen) as appropriate to control fever. In subjects experiencing pyrexia associated 
with rigors, severe chills, dehydration, or hypotension, renal function should be monitored 
carefully and oral corticosteroids should be started after the event resolves (see Table 4). 
Pyrexia accompanied by hypotension, dehydration requiring IV fluids, renal insufficiency, 
or severe rigors/chills in the absence of an obvious infectious cause should be reported as 
an SAE (Section 7.3.2.2).
Guidelines regarding management and dose reduction for pyrexia considered to be related 
to dabrafenib are provided in Table 4.Pyrexia is defined as a body temperature equal to or 
above 38.0 ○Celsius or 100.4○Fahrenheit. 
Trametinib dose modification is not required for pyrexia. 
Table 4
Management and Dose Modification Guidelines for Pyrexiaa,b
Occurrence
Action and Dose Modification
Any

Clinical evaluation for infection and hypersensitivityc

Laboratory work-upc

Hydration as requiredd
1st Eventb:

Administer anti-pyretic treatment if clinically indicatedf

Interrupt dabrafenib/placebo

Continue trametinib or placebo 

Once pyrexia resolves to baseline, restart dabrafenib/placebo at 
the same dose level

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Occurrence
Action and Dose Modification

If fever was associated with dehydration, hypotension, or 
renal insufficiency, reduce dabrafenib/placebo by one dose 
level and begin oral corticosteroids (prednisone 10 mg or 
equivalent) for at least 5 days or as clinically indicatedg
2nd Eventg

Same as for 1st event, and

Consider oral corticosteroids (i.e., prednisone 10 mg) for at least 
5 days or as clinically indicatedg
Subsequent Events: 

Interrupt dabrafenib/placebo

Continue trametinib or placebo 
Once 
pyrexia 
resolves 
to 
baseline, 
restart 
dabrafenib/placebo (consider dose reduction by one 
level)h 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 or escalating doses are 
required, consult Medical Lead
BUN = blood urea nitrogen; CRP = C-reactive protein
a. Pyrexia is defined as a body temperature equal to or above 38.0○Celsius or 100.4○Fahrenheit. 
b. For subjects experiencing pyrexia complicated by severe rigors/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 oral corticosteroids are recommended when restarting dabrafenib.
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.
f.
Anti-pyretic treatment may include acetaminophen (paracetamol), ibuprofen, or suitable anti-pyretic 
medication according to institutional standards. Ibuprofen is preferred and the maximum recommended 
daily dose of acetaminophen should not be exceeded to reduce risk of liver toxicity. Prophylactic anti-
pyretic treatment may be discontinued after three days in the absence of pyrexia
g. In subjects experiencing pyrexia complicated by severe rigors/chills, etc., which cannot be controlled 
with anti-pyretic medication, oral corticosteroids should be started after the 1st event and doses should 
be gradually increased for subsequent events.
h. Dabrafenib/placebo should be reduced by one dose level at discretion of the investigator if pyrexia is 
accompanied by severe recurring rigors which cannot be managed by best supportive care, including 
increasing doses of oral steroids. Re-escalation of dabrafenib is allowed if no episode of pyrexia is 
observed in the 4 weeks subsequent to dose reduction.
5.8.3.2
Visual changes
Episodes of visual changes have been observed in subjects receiving trametinib. The causal 
relationship between a change in vision and the study treatment should be carefully 
explored and an ophthalmologist should be consulted. Special attention should be given to 
retinal (e.g., CSR) or retinal vein abnormalities (e.g., RVO). For events of visual changes 
regardless of severity, a blood sample for PK analysis must be drawn as close as possible 
to the time of the event for subjects still on study treatment. 
Guidelines regarding management and dose reduction for visual changes considered to be 
related to study treatment are provided in Table 5.

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Table 5
Management and Dose Modification Guidelines for Visual Changes
CTCAE Gradea
Adverse Event Management
Action and Dose Modification
Grade 1

Consult ophthalmologist within 7 
days of onset

Exclude CSR or RVO

Consult retinal specialist if available 
in case of CSR or RVO

Continue follow up examination(s) 
(by retinal specialist if available) for 
CSR and RVO

Continue trametinib/placebo at the same 
dose level until ophthalmologic 
examination can be conductedb

If ophthalmologic examination cannot be 
performed within 7 days of onset, interrupt 
trametinib/placebo until CSR and RVO 
can be excluded and symptoms resolve

If CSR and RVO excluded restart 
trametinib/placebo at same dose level

CSR: Interrupt trametinib/placebo until 
symptoms resolve and exam (by retinal 
specialist if available) shows resolution; 
report as SAE

If CSR resolves restart with 
trametinib/placebo reduced by one dose 
level

RVO: Permanently discontinue 
trametinib/placebo and report as SAE
Grade 2 and
Grade 3
Consult ophthalmologist 
immediately 
Exclude CSR and RVO
Consult retinal specialist if 
availablein case of RVO or CSR for 
follow-up exam
Continue follow up examination(s) 
(by retinal specialist if available) for 
CSR and RVO
Interrupt trametinib/placebo until signs and 
symptoms have resolved to baseline
If CSR and RVO excluded and symptoms 
resolved to baseline restart 
trametinib/placebo reduced by one dose 
level 
CSR: Interrupt trametinib/placebo until 
symptoms resolve and exam (by retinal 
specialist if available) shows resolution; 
report as SAE
If CSR resolves restart trametinib/placebo 
reduced by one dose level
RVO: Permanently discontinue study 
treatments and report as SAE
Grade 4

Consult ophthalmologist 
immediately 

Exclude CSR and RVO

Continue follow up examination(s) 
(by retinal specialist if available) for 
CSR and RVO

Permanently discontinue 
trametinib/placebo

If CSR or RVO then report as SAE
a. Abbreviations: CSR = central serous retinopaty; CTCAE = Common Terminology Criteria for Adverse 
Events; RVO = retinal vein occlusion; SAE = serious adverse event
b. Refers to CTCAE Version 4.0 ‘Eye disorders – Other, specify
c. If visual changes are clearly unrelated to study treatment (e.g., allergic conjunctivitis), monitor closely 
but ophthalmic examination is not required.
5.8.3.3
Cardiovascular toxicity
Cardiovascular adverse events have been seen in subjects receiving trametinib and 
dabrafenib, either as monotherapy or in combination. Dose modification of either agent 
may be required for decreased LVEF, hypertension or QTc prolongation.
5.8.3.3.1 Decreased Left Ventricular Ejection Fraction (LVEF)
Decreases of the left-ventricular-ejection-fraction (LVEF) have been observed in subjects 
receiving trametinib monotherapy and with trametinib in combination with dabrafenib. 

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Therefore, ECHOs must be performed to assess cardiac ejection fraction at regular intervals 
as outlined in the Time and Events Table (Table 10). All ECHOs will be collected; 
instructions are provided in the Study Procedures Manual (SPM). 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 low LLN

Interrupt study treatments 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 Novartis Medical Lead and 
request approval for restart 

Restart with trametinib/placebo reduced by 
one dose level

Restart dabrafenib/placebo at previous dose 
level

Repeat ECHO 2 , 4 , 8 and 12 weeks after 
re-start; continue in intervals of 12 weeks 
thereafter

If repeat LVEF does not recover within 4 weeks

Consult with cardiologist

Permanently discontinue 
trametinib/placebo

Repeat ECHO after 2, 4, 8, 12, and 16 
weeks or until resolution

Consult with Novartis Medical Leadc
Symptomaticb
Grade 3: resting LVEF 39-20% 
or >20% absolute reduction from 
baseline

Permanently discontinue trametinib/placebo. 

Consult with cardiologist

Repeat ECHO after 2, 4, 8, 12, and 16 weeks or 
until resolution
Grade 4: resting LVEF <20%
Abbreviations: CTCAE = Common Terminology Criteria for Adverse Events; ECHO = echocardiogram; ; 
LLN = lower limit of normal; LVEF = left ventricular ejection fraction; 
a. If ECHO does not show LVEF recovery after 2 weeks, repeat ECHO 2 weeks later.
b. Symptoms may include: dyspnea, orthopenea, and other signs and symptoms of pulmonary congestion 
and edema.
c. Once LVEF recovers, restarting dabrafenib monotherapy can be considered in consultation with 
Novartis Medical Lead.
5.8.3.3.2 Hypertension
Any level of hypertension should be actively managed. Trametinib does not need to be 
interrupted while mild hypertension is brought under control; however treatment 
interruption and dose-reduction are recommended for more severe or symptomatic 
hypertension (e.g. persistent systolic blood pressure (SBP) ≥160 mmHg or diastolic blood 
pressure (DBP) ≥100 mmHg despite antihypertensive treatment).

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5.8.3.3.3 QTc prolongation
Guidelines for dose modification and stopping criteria due to QTc-prolongation are 
provided in Table 7 below:
Table 7
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 Novartis Medical Lead agree that the subject will benefit from further treatment.
5.8.3.3.4 Valvular Toxicity

Subjects who have an asymptomatic, moderate regurgitation or stenosis by ECHO 
(Grade 2 mitral/tricuspid/aortic valvular toxicity per NCI CTCAE v4.0) should 
temporarily discontinue dabrafenib/placebo and have a repeat evaluation by ECHO 
within 1 week. ECHO should be repeated every 1-2 weeks for 4 weeks or until valve 
recovery to baseline. 

If the valve recovers to baseline any time during the next 4 weeks, after 
consultation and approval of the Novartis Medical Lead, the subject may be 
restarted on dabrafenib/placebo at a reduced dose(s). For such subjects, monitoring 
of the valve via ECHO will then be performed 2 and 4 weeks after rechallenge, 
and every 4 weeks thereafter for 12 weeks and then per protocol.

If repeat ECHO does not reveal valve recovery to baseline within 4 weeks, then 
the subject should permanently discontinue dabrafenib/placebo. The valve should 
continue to be monitored via ECHO every 4 weeks for 16 weeks or until resolution.

Subjects with a Grade 3 or 4 (symptomatic, severe regurgitation/stenosis by imaging, 
with symptoms controlled by medical intervention) valvular toxicity must discontinue 
dabrafenib/placebo. Valvular toxicity should continue to be monitored every 4 weeks 
for 16 weeks or until resolution. If recovery occurs (return to baseline via imaging AND 
symptom resolution) within 4 weeks, the subject may restart dabrafenib/placebo at a 
reduced dose after consultation and approval of the Novartis Medical Lead. For such 
subjects, monitoring of the valve via ECHO will then be performed 2 and 4 weeks after 
rechallenge, and every 4 weeks thereafter for 12 weeks and then per protocol.
ECHO must be performed at baseline and at follow-up visit(s). Copies of all ECHO(s) and 
cardiology consultations performed on subjects who experience a valvular toxicity will be 
required by Novartis for possible review.

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5.8.3.4
Cutaneous squamous cell carcinoma (cuSCC) and 
keratoacanthoma (KA)
Both cuSCC and KA have been observed in subjects treated with dabrafenib and the 
combination of dabrafenib and trametinib [
 
. These should be surgically 
removed according to institutional practices. Dose modification or interruption of study 
treatment is not required for cuSCC or KA, however they should be reported as an SAE 
(refer to Section 7.3.2.2). In addition, a biopsy of the lesion should be taken, where possible, 
and submitted for further analyses as described in the SPM. 
5.9
Monitoring, Interruption, and Stopping Criteria for 
Hepatobiliary Events
NOTE: if serum bilirubin fractionation is not immediately available, 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.
5.9.1
Liver chemistry stopping criteria
These liver chemistry stopping and follow up criteria have been designed to assure 
subject safety and evaluate liver event etiology in alignment with the FDA Guidance for 
Industry – Drug-Induced Liver Injury: Premarketing Clinical Evaluation (July 2009, 
fda.gov). 
Liver chemistry stopping criteria 1-5 are defined as follows:
1
ALT ≥3xULN and bilirubin ≥2xULN (>35% direct bilirubin) (or ALT≥3xULN and 
INR>1.5, if INR measured)
2
NOTE: If serum bilirubin fractionation is not immediately available and if ALT ≥
3xULN and bilirubin ≥2xULN, subject should be discontinued from study 
treatments. 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.
3
ALT ≥8xULN
4
ALT ≥5xULN but <8 xULN persists for ≥2 weeks
5
ALT ≥3xULN if associated with symptoms (new or worsening) believed to be 
related to hepatitis (such as fatigue, nausea, vomiting, right upper quadrant pain or 
tenderness, or jaundice) or hypersensitivity (such as fever, rash or eosinophilia).
6
ALT ≥5xULN but <8 xULN and cannot be monitored weekly for >2 weeks.

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When any of the liver chemistry stopping criteria 1 - 5 is met, do the following:

Immediately discontinue subject from study treatment 

Report the event to Novartis within 24 hours of learning its occurrence

Complete the liver event eCRF and SAE data collection tool if the event also meets the 
criteria for an SAE 

All events of ALT ≥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

Complete the liver imaging and/or liver biopsy eCRFs if these tests are performed

Perform liver event follow up assessments, and monitor the subject until liver 
chemistries resolve, stabilize, or return to baseline values as described below

Withdraw the subject from the study after completion of the liver chemistry monitoring 
(unless further safety follow up is required or Novartis Medical Governance approval 
of drug restart is granted, as described in Section 5.9.1.3).

Follow-up for overall survival or disease recurrence is required following 
discontinuation from study treatment

Do not restart investigational product unless written approval is granted by Novartis 
Medical Governance (details for restarting investigational product are described in 
Section 5.9.1.3), whereupon the subject continues in the study after completion of the 
liver chemistry monitoring described in Section 5.9.1.2). 

Subjects meeting criterion 5 should be monitored as frequently as possible.
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 5.9.1.1), 
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.
For subjects meeting any of the liver stopping 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 5.9.1.1)

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.

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5.9.1.1
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 10 days of last dose. 
Record the date/time of the PK blood sample draw and the date/time of the last dose of 
study treatment prior to blood sample draw on the eCRF. If the date or time of the last 
dose is unclear, provide the subject’s best approximation. If the date/time of the last 
dose cannot be approximated OR a PK sample cannot be collected in the time period 
indicated above, do not obtain a PK sample. Instructions for sample handling and 
shipping are in the SPM. 

Serum creatinine 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 form. Please note that 
treatment with trametinib often associates with rash which is usually acneiform and 
affects the scalp, face, neck, chest, and upper back. Discuss with Novartis Medical Lead 
as needed.

Record use of concomitant medications such as acetaminophen (paracetamol), herbal 
remedies, other over the counter medications, or putative hepatotoxins, on the 
concomitant medications form.

Record alcohol use on the liver event alcohol intake form.
The following assessments are required for 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.

Serum acetaminophen adduct assay (quantifies potential acetaminophen contribution 
to liver injury, detectable by high performance liquid chromatography (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.

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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: //.ncbi.nlm.nih.gov/pmc/articles/PMC1153793/
5.9.1.2
Liver Chemistry Monitoring Criteria
For subjects with ALT 3xULN but <8xULN which exhibit a decrease to 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 Novartis Medical Lead 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 values 

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 7 for algorithm of liver chemistry monitoring, stopping and follow up 
criteria.
5.9.1.3
Restarting Investigational Product
5.9.1.3.1
Drug Restart/Rechallenge Following Liver Events that are Possibly 
Related to Study Treatment
Approval by Novartis for study treatment restart can be considered where:
The subject is receiving compelling benefit, benefit of drug restart exceeds risk, and no 
effective alternative therapy is available. Ethics Committee or Institutional Review Board 
approval of drug restart/rechallenge must be obtained, as required. 
If the restart/rechallenge is approved by Novartis in writing, the subject must be provided 
with a clear description of the possible benefits and risks of drug administration, including 
the possibility of recurrent, more severe liver injury or death. 
The subject must also provide signed informed consent specifically for the investigational 
product (IP) restart/rechallenge. Documentation of informed consent must be recorded in 
the study chart. 
Study treatment must be administered at the dose specified by Novartis.
Subjects approved by Novartis for restart/rechallenge of IP must return to the clinic twice 
a week for liver chemistry tests until stable, liver chemistries have been demonstrated and 
then laboratory monitoring may resume as per protocol. 
5.9.1.3.2 Drug Restart Following Transient Resolving Liver Events Not Related 
to Study Treatment
Approval by Novartis for drug restart can be considered where:

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
Liver chemistries have a clear underlying cause (e.g., biliary obstruction, 
hypotension and liver chemistries have improved to normal or are within 1.5 x 
baseline and ALT <3xULN). Ethics Committee or Institutional Review Board 
approval of drug restart/rechallenge must be obtained, as required.

If restart of drug is approved by Novartis in writing, the subject must be provided 
with a clear description of the possible benefits and risks of drug administration, 
including the possibility of recurrent, more severe liver injury or death. 

The subject must also provide signed informed consent specifically for the restart. 
Documentation of informed consent must be recorded in the study chart. 

Study treatment must be administered at the dose specified by Novartis.
Subjects approved by Novartis for restarting IP must return to the clinic once a week for 
liver chemistry tests until stable, liver chemistries have been demonstrated and then 
laboratory monitoring may resume as per protocol. If protocol defined stopping criteria for 
liver chemistry elevations are met, study drug must be stopped.
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. Flu shots are recommended for 
enrolled subjects.
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);

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
Dabrafenib is metabolized primarily by Cytochrome P450 (CYP) 2C8 and CYP3A4. 
Co-administration of dabrafenib with ketoconazole, a CYP3A4 inhibitor, or with 
gemfibrozil, a CYP2C8 inhibitor, resulted in increases in dabrafenib AUC of 71% and 
47%, respectively. Drugs that are strong inhibitors or inducers of CYP3A and CYP2C8 
(for examples see Table 8) 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 Novartis MedicalLead is required in these situations. A 
partial list of these medications is provided in Table 8. The list may be modified based 
on emerging data. Refer to the SPM for the most current list. 
Table 8
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
Antiretroviral
Ritonavir, saguinavir, atazanavir
Hyperlipidemia
Gemfibrozil 
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 and 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 consider substitutions of these medications. A partial 
list of these medications is provided in Table 9. The list may be modified based on 
emerging data. Refer to the SPM for the most current list.

Therapeutic level dosing of warfarin can be used with approval by the Novartis Medical 
Lead and close monitoring of PT/INR by the site. Exposure decreased by 37% due to 
enzyme induction when on treatment, thus warfarin dosing may need to be adjusted 
based upon PT/INR. Consequently, when discontinuing dabrafenib, warfarin exposure 

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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.
Table 9
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. Consider substitution 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

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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 Novartis Medical 
Lead for clarification.
6.4
Treatment after Discontinuation of Study Treatment or 
Withdrawal from/Completion of Study
The investigator is responsible for ensuring that consideration has been given for the post-
study care of the patient’s medical condition whether or not Novartis is providing specific 
post-study treatment.
Treatment after relapse or study discontinuation will not be provided as part of the protocol. 
Upon relapse or study discontinuation, subjects may receive additional (non protocol) anti-
cancer therapy at the discretion of the treating physician which may include inhibitors of 
the MAP-kinase pathway. If treatment occurs after relapse the new anti-cancer therapy and 
the subject’s best response to treatment should be documented in the eCRF. Every effort 
should be made to complete the required follow up evaluations (refer to Table 11 for 
follow-up assessments and procedures). At a minimum subjects should be followed for 
survival even if other assessments are not performed.
Refer to Section 4.2 for follow-up assessment of subjects who are to be followed up for 
disease recurrence and/or survival after permanently discontinuing from study treatment.
6.5
Treatment of Study Treatment Overdose
In the event of a dabrafenib overdose, defined as administration of more than 300 mg as a 
single dose or 600 mg per day (the highest dose tested in clinical studies to date), and/or a 
trametinib overdose, defined as administration of more than 3.0 mg once daily (the 
maximum tolerated dose defined in the MEK111054 Study), the investigator should 
contact the Novartis Medical Lead immediately and closely monitor the subject for 
AEs/SAEs and laboratory abnormalities. Novartis does not recommend specific treatment. 
The investigator will use clinical judgment to treat any overdose. 
Decisions regarding dose interruptions or modifications will be made by the investigator 
in consultation with the Novartis Medical Lead based on the clinical evaluation of the 
subject.
A plasma sample for PK analysis may be requested by the Novartis Medical Lead on a 
case-by-case basis. This plasma sample should be collected as soon as possible, but within 
10 days from the date of the last dose of on-study dosing.
Information regarding the quantity of the excess dose as well as the duration of the 
overdosing should be documented in the eCRF.

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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 Tables for the timing of all assessments (Table 10 and 
Table 11). 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., imaging, 
pelvic/rectal exam, eye exams, ECG, ECHO) 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 specified in the 
protocol. Central laboratory results for BRAF testing, coagulation, hematology, clinical 
chemistry, and serum pregnancy are required for eligibility.
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.
As per Section 3.2, during a Public Health emergency as declared by Local or Regional 
authorities i.e. pandemic, epidemic or natural disaster that limits or prevents on-site study 
visits, alternative methods of providing continuing care may be implemented by the 
investigator as the situation dictates. If allowable by a local Health Authority and 
depending on operational capabilities, phone calls or virtual contacts (e.g. tele consult) can 
replace on-site study visits for the duration of the disruption until it is safe for the subject 
to visit the site again. Refer to protocol specific sections for further details.

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Table 10
Time and Events Table – Screening and Treatment
SCREE
NING
TREATMENT
Study Assessments1
Screen
ing
Day 1
Month 
1
Month 2
Month 
3
Month 
4
Month 
5
Month 
6
Month 
7
Month 8
Month 
9
Month 
10
Month 11
Month 12
Treatment 
Discon 25
(
l
if
Unsch
Visit Window (Days)
≤28 
days 
except 
where 
noted2,
4
N/A
± 3 days
± 30 
days 
from 
last 
dose
N/A
Informed consent3
X
Tumor tissue sample for BRAF 
V600E/K mutation 
 
X
Inclusion / exclusion criteria5
X
Demographic data6
X
Pregnancy test7
X
Serum
(7 
days)
X
urine
X
urine
X
urine
X
urine
X
urine
Coagulation8
X
Central Labs9
(Hematology & Chemistry)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Disease characteristics10
X
Medical history11
X
Tobacco and alcohol consumption
X
Randomization
X
Dispense Oral study treatment and 
Assess compliance12
X
X
X
X
X
X
X
X
X
X
X
X

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SCREE
NING
TREATMENT
Study Assessments1
Screen
ing
Day 1
Month 
1
Month 2
Month 
3
Month 
4
Month 
5
Month 
6
Month 
7
Month 8
Month 
9
Month 
10
Month 11
Month 12
Treatment 
Discon 25
(
l
if
Unsch
Visit Window (Days)
≤28 
days 
except 
where 
noted2,
4
N/A
± 3 days
± 30 
days 
from 
last 
dose
N/A
Performance status (ECOG)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
ECG13
X
X±7 
days
X±7 
days
X±7 
days
X±7 
days
X±7 
days
X
ECHO14
X
X±7 
days
X±7 
days
X±7 
days
X±7 
days
X±7 
days
X
Ophthalmic examination15
X
X±7 
days
X±7 
days
X±7 
days
X±7 
days
X
Dermatologic skin assessment16
X
X±
7 
day
s
X±7 
day
s
X±7 
days
X±
7 
day
s
X±7 
day
s
X±7 
days
X
Physical examination17
X 
Comple
te
X
Bri
ef
X
Brief
X
Bri
ef
X
Brief
X
Brie
f
X
Brie
f
X
Brief
X
Brie
f
X
Bri
ef
X
Brief
X
Brie
f
X
Bri
ef
X 
Comp
lete
X 
Comp
lete
X 
Brief
Chest, abdomen and pelvic CT 
scans18
X
X±7 
days
X±7 
days
X±7 
days
X±7 
days
X
Brain CT/MRI26
X
Concomitant medications20
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Blood products and blood supportive 
care products
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Adverse events21
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X

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SCREE
NING
TREATMENT
Study Assessments1
Screen
ing
Day 1
Month 
1
Month 2
Month 
3
Month 
4
Month 
5
Month 
6
Month 
7
Month 8
Month 
9
Month 
10
Month 11
Month 12
Treatment 
Discon 25
(
l
if
Unsch
Visit Window (Days)
≤28 
days 
except 
where 
noted2,
4
N/A
± 3 days
± 30 
days 
from 
last 
dose
N/A
Tumor tissue sample for biomarker 
research28
At the time of disease recurrence only
Abbreviations: 
; 
; CT = computed tomography; ECG = electrocardiogram; ECHO = 
echocardiogram; ECOG = Eastern Cooperative Oncology Group; eCRF = electronic Case Report Form;
; LLN = lower limit of normal; LVEF = 
left ventricular ejection fraction; MRI = magnetic resonance imaging; 
; SPM = Study Procedures Manual.
1. All assessments mandated throughout the study must be performed on a calendar schedule; delays in treatment administration will not delay performance of 
assessments. For monthly visits (i.e. Month 1, 2, 3, etc.) subjects should return to the clinic approximately every 4 weeks. A post baseline study visit window of ±3 
days is allowed for visits during treatment. A window of 7 days is permitted for some post baseline assessments, where noted in Table 10.

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SCREE
NING
TREATMENT
Study Assessments1
Screen
ing
Day 1
Month 
1
Month 2
Month 
3
Month 
4
Month 
5
Month 
6
Month 
7
Month 8
Month 
9
Month 
10
Month 11
Month 12
Treatment 
Discon 25
(
l
if
Unsch
Visit Window (Days)
≤28 
days 
except 
where 
noted2,
4
N/A
± 3 days
± 30 
days 
from 
last 
dose
N/A
2. Screening procedures may be performed up to 28 days prior to randomization, unless otherwise noted in the table. Screening visits with a different window are 
noted in parentheses.
3. Informed consent may be given at any time prior to the performance of any study-related procedures. 
 
 
4. Tumor tissue must be collected to assess the BRAF V600E/K mutation status via central lab testing 
 A positive BRAF 
result from the central lab need not be repeated if randomization falls outside the 28-day screening window. 
5. Only subjects who meet all inclusion and exclusion criteria will be eligible to enter into the study.
6. Record date of birth, race, ethnicity, and gender.
7. For all women of childbearing potential a serum pregnancy test will be required within 7 days prior to randomization; preferably, as close to the first dose as possible. 
Subsequent tests may be urine tests, and should be performed at Months 3, 6, 9, and 12 or discontinuation if discontinuation occurs prior to Month 12. Additionally 
if study treatment is interrupted for more than 7 days, regardless of the reason for the disruption, a urine test must be performed to confirm the subject is not 
pregnant prior to re-starting study treatment. 
8. Coagulation sample to be obtained at screening only and analyzed by a central laboratory.
9. Analysis of clinical chemistry and hematology samples including those at screening will be performed by a central laboratory. Screening labs must be performed 
within 28 days prior to randomization.
10.Record date of diagnosis, primary tumor type, histology, stage, and other disease characteristics as indicated in the eCRF.
11.Record past and current medical conditions, surgical procedures and cardiovascular family history.
12.Dosing instructions must be provided to the subject. Subjects should start treatment as soon as possible after randomization but no later than 72 hours post-
randomization. Study treatment will be dispensed at randomization and monthly. Site must call IVRS to register each study visit. Compliance will be assessed at 
all visits after Day 1 (Randomization). To assess compliance subjects should be instructed to return study drug at each visit; compliance will be assessed by 
querying the subject and counting tablets/capsules. Dose reductions, dose interruptions/delays, and/or dose escalations must be recorded in the eCRF.
13.ECG must be performed at Screening, Months 1, 3, 6, 9, and 12 or discontinuation if discontinuation occurs prior to Month 12, unless clinically indicated sooner. 
For subjects that discontinue study treatment before Month 12 an ECG must be performed at the discontinuation visit within 30 days of the last dose. A single 12-
lead ECG will be performed by qualified site personnel after the subject has rested in a semi-recumbent or supine position for at least 5 minutes. Two copies of the 

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SCREE
NING
TREATMENT
Study Assessments1
Screen
ing
Day 1
Month 
1
Month 2
Month 
3
Month 
4
Month 
5
Month 
6
Month 
7
Month 8
Month 
9
Month 
10
Month 11
Month 12
Treatment 
Discon 25
(
l
if
Unsch
Visit Window (Days)
≤28 
days 
except 
where 
noted2,
4
N/A
± 3 days
± 30 
days 
from 
last 
dose
N/A
ECG tracing should be obtained at the time of the ECG; the first copy will be kept in the subject’s medical chart and the second copy will be kept in the study file 
for retrospective collection by the Sponsor if necessary. ECGs should be done in triplicate when the initial test is abnormal.
14.ECHO must be performed at the Screening, Months 1, 3, 6, 9, and 12 or discontinuation if discontinuation occurs prior to Month 12, unless clinically indicated 
sooner. For subjects that discontinue study treatment before Month 12 an ECHO must be performed at the discontinuation visit within 30 days of the last dose. 
While on treatment, subjects who have asymptomatic, absolute decrease in LVEF of >10% compared to screening AND whose ejection fraction is below the 
institution's LLN, must be followed according to LVEF guidelines for study drug management and requirements for subsequent ECHO.
15.An ophthalmic examination must be performed by an ophthalmologist at Screening, Months 1, 3, 6, and 12, or at discontinuation if discontinuation occurs prior to 
Month 12. Additional ophthalmic exams will be performed only as symptomatically warranted.
16.A thorough dermatologic exam should be performed by the Investigator at Screening, and Months 2, 4, 6, 8, 10, and 12 or at discontinuation if discontinuation 
occurs prior to Month 12. Refer to Table 11 for the schedule of assessments during follow-up. This 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. These visits should include periodic patient 
counseling on primary and secondary melanoma prevention measures including self-examination.
17.All physical exams will include the measurement of height (screening only) and weight using the metric scale, collection of vital signs including blood pressure, 
body temperature, pulse rate, and respirations. In addition a complete physical exam including a thorough genitourinary (pelvic) examination, 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 discontinuation if 
discontinuation occurs prior to Month 12. For female subjects the genitourinary exam must include a PAP smear. If the subject has had a genitourinary and rectal 
exam within 6 months of randomization these do not need to be repeated at screening. Brief physical examinations will be performed at all other timepoints as 
indicated. Refer to protocol Section 7.3.7 for additional detail on these examinations. 
18.Diagnostic quality, contrast enhanced CT scan of the chest, abdomen and pelvis must be performed at all visits indicated in the table. Intravenous contrast should 
be used, for the CT scans, and preferably with oral contrast as well. A non-contrast CT of the chest, with contrast-enhanced MRI of the abdomen and pelvis should 
be substituted for full CT scanning if the CT scanning frequency is not permitted per country or ethics requirements or if CT contrast is contraindicated. If MRI 
scanning is not possible, and CT intravenous contrast is contraindicated, CT without contrast is allowed, but it is the least preferable option. Method of imaging 
should be consistent throughout the study (i.e. if CT is done at screening, CT must be done at all future timepoints). For scanning during follow-up prior to disease 
recurrence refer to Table 11. 

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SCREE
NING
TREATMENT
Study Assessments1
Screen
ing
Day 1
Month 
1
Month 2
Month 
3
Month 
4
Month 
5
Month 
6
Month 
7
Month 8
Month 
9
Month 
10
Month 11
Month 12
Treatment 
Discon 25
(
l
if
Unsch
Visit Window (Days)
≤28 
days 
except 
where 
noted2,
4
N/A
± 3 days
± 30 
days 
from 
last 
dose
N/A
 
20.All medications taken by the subject during the study from the time of screening until 30 days after the last dose of study treatment will be recorded; any new anti-
cancer therapy, if taken after study treatment discontinuation will be recorded as detailed in Table 11, Footnotes 7 & 10.
21.Adverse events will be recorded from the time the first dose of study treatment is administered until 30 days after discontinuation of study treatment. Serious 
adverse events (SAEs) will be collected over the same time period as AEs except SAEs assessed as related to study participation (e.g., protocol-mandated 
procedures, invasive tests, or change in existing therapy), study treatment, concomitant medication which must be recorded from the time a subject consents to 
participate in the study up to and including any follow-up contact.
 
.
 
 
 
 
25.If treatment discontinuation occurs prior to Month 12 the treatment discontinuation visit should be performed within 30 days of the subject’s last dose. Laboratory 
assessments and other required assessments do not need to be repeated at the discontinuation visit if they were performed within 30 days of the discontinuation 
visit. Follow-up should occur until death or study completion according to the follow-up assessment schedule in the table unless the subject withdraws from the 
study.
26.Baseline MRI (preferred) or CT (only if MRI contraindicated or unavailable) of the brain must be performed on all subjects. Post-baseline scans should be performed 
as clinically indicated.
 
 

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Table 11
Time and Events Table – Follow-Up Assessments
FOLLOW-UP10
STUDY 
COMPLETI
ON12
BEFORE RECURRENCE
AFTER RECURRENCE13
CONCLUSI
ON
Study Assessments1
Unsch
Every 3 Months
(M3-M12)14
Month 15
Every 3 Months
(M18-M24)
Every 6 months
(M 24 – M60)
Every 12 Months 
After Month 60
Every 3 Months
(M3-M24)
Every 6 months
(M 24 – M60)
Every 12 Months 
after Month 60
Unsch
Conclusion
Visit Window (Days)
N/A
(± 14 
days)
(± 14 
days)
(± 14 days)
(± 14 
days)
(± 14 
days)
(± 14 
days)
(± 14 
days)
(± 14 
days)
N/A
N/A
Central Labs2
(Hematology & Chemistry)
X
Labs to be drawn at 
M18 then annually 
during follow-up up to 
M60 and at the time of 
disease recurrence
At the 
time of 
disease 
recurren
ce only.
Performance status (ECOG)
X
X
X
X
X
X
Dermatologic skin assessment3
X
X
X
X
X
X16
Physical examination4
X
(Brief)
X 
(Brief)
X 
(Brief)
X (M18 
complete; all 
others brief)
X 
(Brief)
X 
(Brief)
Chest, abdomen and pelvic CT 
scans5
X15
X
X
X
X
Concomitant medications7
X
X

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FOLLOW-UP10
STUDY 
COMPLETI
ON12
BEFORE RECURRENCE
AFTER RECURRENCE13
CONCLUSI
ON
Study Assessments1
Unsch
Every 3 Months
(M3-M12)14
Month 15
Every 3 Months
(M18-M24)
Every 6 months
(M 24 – M60)
Every 12 Months 
After Month 60
Every 3 Months
(M3-M24)
Every 6 months
(M 24 – M60)
Every 12 Months 
after Month 60
Unsch
Conclusion
Visit Window (Days)
N/A
(± 14 
days)
(± 14 
days)
(± 14 days)
(± 14 
days)
(± 14 
days)
(± 14 
days)
(± 14 
days)
(± 14 
days)
N/A
N/A
Adverse events8
X
X
Follow-up contact, anti-cancer 
therapies and best response10
X
X
X
X
X
Subject completion
X
Death record
X
Abbreviations: CT = computed tomography; ECOG = Eastern Cooperative Oncology Group; 
; MRI = magnetic resonance imaging
1.
All assessments mandated throughout the study must be performed on a calendar schedule. After month 60, the next annual visit will be 365 days from the last 
study visit. A study visit window of 14 days is allowed for all follow-up visits.
2.
Analysis of clinical chemistry and hematology samples will be performed by a central laboratory. Labs should be drawn at Month 18 then annually until month 60, 
thereafter during follow-up prior to disease recurrence and at the time of disease recurrence. After month 60, at the time of disease recurrence only, clinical 
chemistry and hematology samples will be performed by a central laboratory (Refer to protocol Section 7.3.4 for further details).

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FOLLOW-UP10
STUDY 
COMPLETI
ON12
BEFORE RECURRENCE
AFTER RECURRENCE13
CONCLUSI
ON
Study Assessments1
Unsch
Every 3 Months
(M3-M12)14
Month 15
Every 3 Months
(M18-M24)
Every 6 months
(M 24 – M60)
Every 12 Months 
After Month 60
Every 3 Months
(M3-M24)
Every 6 months
(M 24 – M60)
Every 12 Months 
after Month 60
Unsch
Conclusion
Visit Window (Days)
N/A
(± 14 
days)
(± 14 
days)
(± 14 days)
(± 14 
days)
(± 14 
days)
(± 14 
days)
(± 14 
days)
(± 14 
days)
N/A
N/A
3.
A thorough dermatologic exam should be performed every three months Month 3-24, every six months after month 24 up to month 60 and then annually thereafter 
during the follow up period prior to disease recurrence. This 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. These visits should include periodic patient counseling on primary and 
secondary melanoma prevention measures including self-examination.
4.
All physical exams will include the measurement of height (screening only) and weight using the metric scale, collection of vital signs including blood pressure, 
body temperature, pulse rate, and respirations. In addition, a complete physical exam including a thorough genitourinary (pelvic) examination, inspection of the 
head and neck region, and digital rectal examination for both male and female subjects must be performed at Month 18. For female subjects the genitourinary
exam must include a PAP smear. Brief physical examinations will be performed at all other timepoints as indicated. Refer to protocol Section 7.3.7 for additional 
detail on these examinations. 
5.
Diagnostic quality, contrast enhanced CT scan of the chest, abdomen and pelvis must be performed at all visits indicated in the table. Intravenous contrast should 
be used, for the CT scans, and preferably with oral contrast as well. A non-contrast CT of the chest, with contrast-enhanced MRI of the abdomen and pelvis should 
be substituted for full CT scanning if the CT scanning frequency is not permitted per country or ethics requirements or if CT contrast is contraindicated. If MRI 
scanning is not possible, and CT intravenous contrast is contraindicated, CT without contrast is allowed, but it is the least preferable option. Method of imaging 
should be consistent throughout the study (i.e. if CT is done at screening, CT must be done at all future timepoints). MRI (preferred) or CT (only if MRI 
contraindicated or unavailable) of the brain should be performed as clinically indicated.
 
 
7.
All medications taken by the subject during the study from the time of screening until 30 days after the last dose of study treatment will be recorded; any new anti-
cancer therapy, if taken after study treatment discontinuation will be recorded as detailed in Footnote 10.

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FOLLOW-UP10
STUDY 
COMPLETI
ON12
BEFORE RECURRENCE
AFTER RECURRENCE13
CONCLUSI
ON
Study Assessments1
Unsch
Every 3 Months
(M3-M12)14
Month 15
Every 3 Months
(M18-M24)
Every 6 months
(M 24 – M60)
Every 12 Months 
After Month 60
Every 3 Months
(M3-M24)
Every 6 months
(M 24 – M60)
Every 12 Months 
after Month 60
Unsch
Conclusion
Visit Window (Days)
N/A
(± 14 
days)
(± 14 
days)
(± 14 days)
(± 14 
days)
(± 14 
days)
(± 14 
days)
(± 14 
days)
(± 14 
days)
N/A
N/A
8.
Adverse events will be recorded from the time the first dose of study treatment is administered until 30 days after discontinuation of study treatment. Serious 
adverse events (SAEs) will be collected over the same time period as AEs except SAEs assessed as related to study participation (e.g., protocol-mandated 
procedures, invasive tests, or change in existing therapy), study treatment, concomitant medication which must be recorded from the time a subject consents to 
participate in the study up to and including any follow-up contact. 
 
10. Follow-up will start once treatment is complete and continue through the end of the study even if disease recurs. Follow-up contact prior to disease recurrence 
will include clinic visits. Follow-up after disease recurrence should follow the schedule as noted in Table 11; however the information collected will be limited to: 
quality of life information, any radiotherapy, surgical procedure or new anti-cancer therapy initiated until study completion, withdrawal or death, best response to 
any follow-up treatment, method of assessment of best response, subsequent progression dates, and survival data. Subjects beyond month 60, in follow-up period 
after recurrence, are expected for their follow up visit every 365 days +/- 14 days (365 days to be calculated from the last study visit). 

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FOLLOW-UP10
STUDY 
COMPLETI
ON12
BEFORE RECURRENCE
AFTER RECURRENCE13
CONCLUSI
ON
Study Assessments1
Unsch
Every 3 Months
(M3-M12)14
Month 15
Every 3 Months
(M18-M24)
Every 6 months
(M 24 – M60)
Every 12 Months 
After Month 60
Every 3 Months
(M3-M24)
Every 6 months
(M 24 – M60)
Every 12 Months 
after Month 60
Unsch
Conclusion
Visit Window (Days)
N/A
(± 14 
days)
(± 14 
days)
(± 14 days)
(± 14 
days)
(± 14 
days)
(± 14 
days)
(± 14 
days)
(± 14 
days)
N/A
N/A
12. To be completed if the subject permanently withdraws from the study (i.e. death, withdrawal of consent, lost to follow-up).
13. For subjects that experience disease recurrence prior to Month 12 the discontinuation visit should be performed and follow-up assessments should start at the 
next 3 month interval following the recurrence and continue according to the schedule defined in Table 11 until study completion, withdrawal or death. For example, 
if a subject experiences disease recurrence at Month 2, the discontinuation visit should be performed according to Table 10 and the follow-up assessments would 
start at Month 3 and continue thereafter according to the schedule defined in Table 11 until study completion, withdrawal or death.
14. For subjects that discontinue study treatment prior to Month 12 with no evidence of disease recurrence follow-up visits should start at the next 3 month interval 
following treatment discontinuation. For example, if a subject discontinues treatment at Month 1, the discontinuation visit should be performed according to 
Table 10 and the follow-up visits would start at Month 3 and continue thereafter according to the schedule defined in Table 11. At the time of disease recurrence 
follow-up assessments should start at the next 3 month interval after the recurrence and continue thereafter according to the schedule defined in Table 11 until 
study completion, withdrawal or death. 
15. Chest, abdomen and pelvic CT scans do not need to be repeated at the first follow-up visit if they have been performed within 6 weeks of the first follow-up visit. 
16. Subjects that discontinue study treatments due to disease recurrence should be monitored every 3 months for six months following discontinuation of the study 
treatments or until the initiation of another anti-cancer therapy. 

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7.1
Critical Baseline Assessments
Efficacy assessments conducted at baseline are described in Section 7.2, tumor tissue 
 
Safety assessments conducted at baseline and during treatment 
are described in Section 7.3. Cardiovascular medical history/risk factors will be assessed 
at baseline.
7.1.1
Baseline Confirmation of BRAF Mutation-positive Melanoma
Subjects with completely resected histologically confirmed high-risk (Stage IIIa [LN 
metastasis >1 mm], IIIb or IIIc) cutaneous melanoma will be screened for eligibility after 
signing the informed consent form. Subjects will be screened prior to treatment to 
determine whether their tumor sample has a BRAF V600E or V600K mutation, indicating 
their eligibility for the study. Tumor BRAF mutation testing will be conducted using the 
bioMerieux BRAF THxID IUO assay (IDE: G120011), and testing will be performed in a 
central reference laboratory. Details related to BRAF mutation testing are provided in 
Section 7.7.1 and in the SPM. 
7.2
Efficacy
7.2.1
Efficacy Endpoints
7.2.1.1
Primary Endpoint
The primary efficacy endpoint of this study is relapse free survival (RFS) which is defined 
as the time from randomization to disease recurrence or death from any cause. Recurrence 
of or death from the same cancer and all deaths from other causes are events. Treatment 
emergent malignancies (excluding second melanomas) will not be considered as events, 
and loss to follow-up is censored.

Types of recurrence to be considered as an event include loco-regional, distant 
metastases and second primary melanoma.

Any death occurring without prior documentation of tumor recurrence will be 
considered as an event (and will not be censored in the statistical analysis).

If no event has occurred by the time of the analysis, then the time to event will be 
censored as the date of the last adequate assessment of the patient in question.

Any new primary cancer at another site, squamous cell carcinoma, or keratoacanthoma, 
will not be considered as a recurrence and should be reported as a SAE (See 
Section 7.3.2.2). A second primary melanoma will be considered as a recurrence. 
 

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7.2.1.2
Secondary Endpoints
The secondary efficacy endpoints of this study are:

Overall Survival (OS) defined as the interval from randomization to the date of death, 
irrespective of the cause of death; patients still alive will be censored at the date of the 
last contact.

Distant metastasis-free survival (DMFS), defined as the interval from randomization to 
the date of first distant metastasis or date of death, whichever occurs first. Patients alive 
and without distant metastasis are censored at the date of last assessment.

Freedom from relapse (FFR), defined as interval from randomization to local or distant 
recurrence with censoring of patients dying from causes other than melanoma or 
treatment-related toxicity at the date of death. Incidence of non-melanoma malignancy 
will not be considered as an event. Patients alive without recurrence or with second 
primary cancers will be censored at the date of last assessment.
7.2.1.3
Efficacy Assessment
See the Time and Events Tables (Table 10, Table 11) for the schedule of efficacy 
assessments. Assessments must be performed on a calendar schedule and should not be 
affected by dose interruptions/delays. For post-baseline efficacy assessments Month 1 
through Month 12, a window of 3 days (physical exam) or 7 days (CT scans, 
dermatologic skin assessment) is permitted to allow for flexible scheduling. After Month 
12 a post-baseline assessment window of 14 days is permitted.
The following are required for efficacy assessment: 

Clinical examination

Diagnostic quality, contrast-enhanced CT scan of the chest, abdomen and pelvis should 
be performed at baseline and subsequent timepoints as indicated in the Time and Events 
Tables (Table 10 and Table 11). Intravenous contrast should be used for the CT scans 
preferably with oral contrast as well. A non-contrast CT of the chest (MRI of the chest 
will be accepted but is not recommended), with contrast-enhanced MRI of the abdomen 
and pelvis should be substituted for full CT scanning if the CT frequency prescribed in 
the Time and Events Table is not permitted per country or ethics requirements or if CT 
contrast is contraindicated. The method of imaging should be consistent throughout the 
study (i.e. if CT is done at screening, CT will be done at all future timepoints). 

A baseline MRI of the brain is required for all subjects. CT may be performed only if 
MRI contraindicated or unavailable. Subsequent brain scans should only be performed 
as clinically indicated (e.g. symptoms suggestive of CNS recurrence). 
 
7.2.1.4
Assessment Guidelines
Please note the following:

The same diagnostic method, including use of contrast, when applicable, must be used 
throughout the study. Ultrasound is not a suitable modality of disease assessment for 
distant metastases. If new lesions are identified by ultrasound, confirmation by CT or 
MRI is required.

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
Fluorodeoxyglucose positron emission tomography (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. The sites should follow their standard of care 
for subject and radiopharmaceutical preparation. The scanning protocol should be 
conducted in accordance with the local imaging facility guidance. 

If PET/CT is performed then the CT component can only be used for standard disease 
assessments if performed to diagnostic quality, which includes the required anatomical 
coverage and prescribed use of contrast. The method of assessment should be noted as 
CT on the CRF.
Clinical examination: New lesions detected by clinical examination must be biopsied, 
where possible, to confirm disease recurrence. If a biopsy cannot be obtained then CT/MRI 
must be done to confirm disease recurrence.
CT and MRI: Contrast enhanced CT with 5mm contiguous slices is recommended.
MRI is acceptable (refer to Section 7.2.1.3), but when used, the technical specification of 
the scanning sequences should be optimized for the evaluation of the type of disease. 
Whenever possible the same scanner and scanning parameters should be used for all exams 
acquired.
Brain Scan: For the baseline brain scan and any post-baseline brain scans, contrast 
enhanced MRI with 2.5 mm contiguous slices is preferable to contrast enhanced CT. 
As per Section 3.2, during a Public Health emergency as declared by Local or Regional 
authorities i.e., pandemic, epidemic, or natural disaster, that limits or prevents on-site study 
visits, the collection of images may be modified by Novartis and will be communicated to 
the investigator.
7.2.1.5
Follow-up Assessments for Subjects Permanently Discontinued 
from Study Treatment prior to protocol treatment period (12 
months)
Refer to Section 4.2 Permanent Discontinuation from Study Treatment and the Time and 
Events Schedule (Table 11) for follow-up assessment of subjects for disease recurrence 
and survival after permanently discontinuing from study treatment.
7.2.1.6
Assessment of Subject Completion
If a subject withdraws from the study during Months 1 through Month 24, the last 
radiographic assessment was more than 3 months prior to withdrawal from study and 
disease recurrence has not been documented, a disease assessment should be obtained at 
the time of withdrawal from study. 
If a subject withdraws from the study after Month 24, the last radiographic assessment was 
more than 6 months prior to withdrawal from study and disease recurrence has not been 
documented, a disease assessment should be obtained at the time of withdrawal from study. 

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7.3
Safety
7.3.1
Safety Endpoints
The secondary objectives of the study include characterizing the safety of dabrafenib and 
trametinib combination therapy. As a consequence, clinical assessments including vital 
signs and physical examinations, 12-lead ECG, ECHO, eye exams, chemistry and 
hematology laboratory values, and AEs will be monitored and evaluated.
7.3.2
Adverse Events
The investigator or site staff will be responsible for detecting, documenting and reporting 
events that meet the definition of an AE or SAE as outlined in Section 7.3.2.1and 
Section 7.3.2.2, respectively.
7.3.2.1
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 fulfill the 
definition of an AE or SAE. 
Events that do not meet the definition of an AE include:

Medical or surgical procedure (e.g., endoscopy, appendectomy); the condition that 
leads to the procedure is an AE.

Situations where an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital).

Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present 
or detected at the start of the study that do not worsen.

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
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. 
7.3.2.2
Definition of an SAE
A serious adverse event (SAE) is any untoward medical occurrence that, at any dose:
a. Results in death
b. Is life-threatening
NOTE: The term 'life-threatening' in the definition of 'serious' refers to an event in 
which the subject was at risk of death at the time of the event. It does not refer to an 
event, which hypothetically might have caused death, if it were more severe.
c. Requires hospitalization or prolongation of existing hospitalization
NOTE: In general, hospitalization signifies that the subject has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for observation 
and/or treatment that would not have been appropriate in the physician’s office or 
out-subject setting. Complications that occur during hospitalization are AEs. If a 
complication prolongs hospitalization or fulfills any other serious criteria, the event is 
serious. When in doubt as to whether “hospitalization” occurred or was necessary, the 
AE should be considered serious.
Hospitalization for elective treatment of a pre-existing condition that did not worsen 
from baseline is not considered an AE.
d. Results in disability/incapacity, or
NOTE: The term disability means a substantial disruption of a person’s ability to 
conduct normal life functions. This definition is not intended to include experiences of 
relatively minor medical significance such as uncomplicated headache, nausea, 
vomiting, diarrhea, influenza, and accidental trauma (e.g. sprained ankle) which may 
interfere or prevent everyday life functions but do not constitute a substantial disruption.
e. Is a congenital anomaly/birth defect. 
f.
Medical or scientific judgment should be exercised in deciding whether reporting is 
appropriate in other situations, such as important medical events that may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize 
the subject or may require medical or surgical intervention to prevent one of the other 
outcomes listed in the above definition. These should also be considered serious. 
Examples of such events are invasive or malignant cancers, intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse.
g. 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 patients receiving 
anticoagulants).
NOTE: bilirubin fractionation is performed if testing is available. If testing is 
unavailable, record presence of detectable urinary bilirubin on dipstick indicating 

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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.

Any new primary cancers and treatment emergent malignancies (including 
squamous cell carcinoma, keratoacanthoma and second primary melanoma) with 
the exception of basal cell carcinoma (BCC). BCC should be reported as an AE or 
SAE based on the discretion of the investigator.

Laboratory abnormalities as referenced in Section 7.3.2.3

LVEF that meets stopping criteria Section 5.8.3.3.1.

Central serous retinopathy (CSR) or retinal vein occlusion (RVO)

Pyrexia accompanied by hypotension, dehydration requiring IV fluids, renal 
insufficiency, and/or severe rigors/chills in the absence of an obvious infectious 
cause.
7.3.2.3
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. 
7.3.2.4
Disease-Related Outcomes Not Qualifying as SAEs
An event which is part of the natural course of the disease under study (i.e., disease 
recurrence or hospitalization due to disease recurrence) does not need to be reported as an 
SAE. Death due to disease under study is to be recorded on the Death CRF form. However, 
if the underlying disease (i.e., recurrence) 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 GSK1120212 and GSK2118436 or protocol design/procedures and 
the disease recurrence, then this must be reported as an SAE. 
Local or distant relapse is the primary efficacy endpoint of the study and should not be 
reported as an SAE.
7.3.2.5
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. 

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From the time a subject consents to participate in and completes the study (See 
Section 4.2.1), all SAEs assessed as related to study participation (e.g., protocol-mandated 
procedures, invasive tests, or change in existing therapy), will be reported promptly to 
Novartis, as indicated in Table 12.SAEs will be collected over the same time period as 
stated above for AEs. In addition, any new malignancy (defined in Section 7.3.2.2) or any 
SAE assessed as related to study participation (e.g., protocol-mandated procedures, 
invasive tests, or change in existing therapy), study treatment or Novartis 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 Novartis within 24 
hours, as indicated in Section 7.3.2.6. For any new malignancy, every effort should be 
made to identify the RAS mutation status; the mutation test should be performed locally 
and reported within 12 weeks of diagnosis. Additional genetic analysis may be performed 
depending on the tumor types, and the results reported at the discretion of the investigator.
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 from the last dose of study treatment the investigator may 
report any adverse event that they believe is possibly related to study treatment. Treatment 
emergent malignancies should be reported regardless of the time from treatment 
discontinuation to occurrence of the event.
7.3.2.6
Prompt Reporting of SAEs and Other Events to Novartis
SAEs, pregnancies, and liver function abnormalities meeting pre-defined criteria will be 
reported promptly by the investigator to Novartis as described in the following table once 
the investigator determines the event meets the protocol definition for that event.
Note: If more stringent, local regulations regarding reporting timelines prevail.
Table 12
Time Frames for Reporting SAEs and Other Events
Initial Reports
Follow-up Information on a Previous 
Report
Type of Event
Time Frame
Documents
Time Frame
Documents
All SAEs
24 hours
SAE data collection 
tool
24 hours4
Updated SAE data 
collection tool 
Pregnancy
24 hours
Pregnancy 
Notification Form
2 Weeks
Pregnancy Follow 
up Form
Liver chemistry abnormalities:
ALT≥3xULN PLUS
Bilirubin≥2xULN (>35% 
direct) (or ALT3xULN 
and INR>1.5, if INR 
measured) 3
24 hours1
SAE data collection 
tool.
Liver Event CRF 
and liver imaging 
and/or biopsy 
CRFs if applicable2
24 hours4
Updated SAE data 
collection tool. 
Updated Liver 
Event CRF2
ALT≥8xULN; ALT≥3xULN 
with hepatitis or rash or 
≥3xULN and <5xULN that 
persists ≥4 weeks
24 hours1
Liver event CRF2
24 hours4 
Updated Liver 
Event CRF2

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Initial Reports
Follow-up Information on a Previous 
Report
Type of Event
Time Frame
Documents
Time Frame
Documents
ALT≥5xULN plus bilirubin 
<2xULN
24 hours1
Liver event CRF 
does not need 
completing unless 
elevations persist 
for 2 weeks or 
subject cannot be 
monitored weekly 
for 2 weeks2
24 hours4
ALT≥5xULN and bilirubin 
<2xULN that persists ≥2 
weeks
24 hours1
Liver event CRF2
24 hours4
Updated liver event 
CRF2
ALT≥3xULN and <5x 
ULN 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. Novartis 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.
4. All follow-up information for the SAE including information on complications, progression of the initial 
SAE and recurrent episodes must be reported as follow-up to the original episode immediately, without 
undue delay, but under no circumstances later than within 24 hours of the investigator receiving the 
follow-up information (Note: If more stringent, local regulations regarding reporting timelines prevail). An 
SAE occurring at a different time interval or otherwise considered completely unrelated to a previously 
reported one must be reported separately as a new event.
Liver chemistry stopping, follow-up, and monitoring criteria are provided in Section 5.9.
Methods for detecting, recording, evaluating, and following up on AEs and SAEs and 
procedures for completing and transmitting SAE reports to Novartis are provided in the 
SPM. Procedures for post-study AEs and SAEs are provided in the SPM.
7.3.2.7
Regulatory reporting requirements for SAEs
Prompt notification of SAEs by the investigator to Novartis is essential so that legal 
obligations and ethical responsibilities towards the safety of subjects are met.
Novartis has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a product under clinical investigation. Novartis will 
comply with country specific regulatory requirements relating to safety reporting to the 
regulatory authority, IRB/IEC, and investigators.
Investigator safety reports are prepared for suspected unexpected serious adverse reactions 
according to local regulatory requirements and Novartis policy and are forwarded to 
investigators as necessary.
An investigator who receives an investigator safety report describing an SAE(s) or other 
specific safety information (e.g., summary or listing of SAEs) from Novartis will file it 
with the IB and will notify the IRB/IEC, if appropriate according to local requirements.

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As per Section 3.2, during a public health emergency as declared by Local or Regional 
authorities i.e. pandemic, epidemic or natural disaster, that limits or prevents on-site study 
visits, regular phone or virtual calls can occur for safety monitoring and discussion of the 
participant´s health status until it is safe for the participant to visit the site again.
7.3.3
Pregnancy Testing, Prevention and Reporting
7.3.3.1
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 7 days prior to randomization. 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 
months following the last dose of study treatment.
Novartis acceptable contraceptive methods, when used consistently and in accordance with 
both the product label and the instructions of the physician, are as follow:

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 months after the last dose of 
study treatment.
Note: Abstinence is acceptable only when in line with the preferred and usual lifestyle 
of the subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-
ovulation methods) and withdrawal are not acceptable methods of contraception.

Double-barrier contraception: condom and occlusive cap (diaphragm or cervical/vault 
caps) with a vaginal spermicidal agent (foam/gel/cream/suppository).
Note: Hormonal-based methods (e.g., oral contraceptives) are not recommended 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.
If a subject becomes pregnant during the treatment period of the study, the study treatments 
should be stopped immediately.

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7.3.3.2
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 Novartis 
within 24 hours 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 Novartis.
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 Novartis as described above.
As per Section 3.2, during a public health emergency as declared by Local or Regional 
authorities i.e. pandemic, epidemic or natural disaster, the mitigation procedure to ensure 
subject safety and trial integrity is listed in Section 7.3.2.7 if the investigator considers that 
the pregnancy is possibly related to study treatment.
7.3.4
Laboratory Assessments
All protocol required laboratory assessments, as defined in Table 10 and Table 11 should 
be performed by the central laboratory. Laboratory assessments must be conducted in 
accordance with the Central Laboratory Manual and Protocol Time and Events Schedule 
in Table 10 and Table 11). Laboratory requisition forms must be completed and samples 
must be clearly labeled with the subject number, protocol number, site/centre number, and 
visit date. Details for the preparation and shipment of samples will be provided by the 
central laboratory. Reference ranges for all safety parameters will be provided to the site 
by the central laboratory.
If any additional non-protocol specified laboratory assessments are performed at the 
institution’s local laboratory and result in a change in patient management or are considered 
clinical significant by the investigator (for example SAE or AE or dose modification) the 
results must be recorded in the subject’s eCRF. Refer to the SPM for appropriate processing 
and handling of samples to avoid duplication and/or additional blood draws. 
Clinical chemistry and hematology parameters to be tested are listed in Table 13. Female 
subjects will have a serum pregnancy test at Screening; urine pregnancy testing will be 
done during study treatment at the visits indicated in the Time and Events Tables (Table 10
and Table 11). Post-baseline urine pregnancy testing may be done by local laboratory. 
As per Section 3.2, if subjects cannot visit the site for safety lab collection conducted 
through central labs, local lab collection and assessments may be used during a public 
health emergency as declared by Local or Regional authorities i.e. pandemic, epidemic or 
natural disaster, that limits or prevents on-site study visits.

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Table 13
Clinical Chemistry and Hematology Parameters
Clinical Chemistry Parameters
Albumin
Alkaline Phosphatase
Alanine Transaminase (ALT) or Serum Glutamic Pyruvic Transaminase (SGPT)
Aspartate Aminotransferase (AST) or Serum Glutamic Oxaloacetic Transaminase (SGOT)
Bicarbonate
Blood Urea Nitrogen (BUN) or urea
Calcium
Chloride
Creatininec
Glucose (random)
Lactate Dehydrogenase (LDH)
Phosphate
Potassium
Sodium
Total Bilirubinb
Total Protein
Hematology Parameters
White Blood Cell (WBC) Count 
Hemoglobin
International Normalized Ratio (INR; at Screening only)a
Platelet Count
Prothrombin Time (PT; at Screening only)a
Partial Thromboplastin Time (PTT; at Screening only)a
Automated WBC Differential (expressed as %): 
Basophils 
Eosinophils
Lymphocytes
Monocytes
Neutrophils
a. Coagulation panel to be done at Screening only.
b. Bilirubin fractionation is recommended if total bilirubin is > 2 x the upper limit of normal (ULN).
c. If serum creatinine is > 1.5 mg/dL, creatinine clearance should be calculated using the standard 
Cockcroft-Gault formula (Appendix 4).
For subjects with a history of chronic HBV and/or HCV, the following tests will be 
performed at Screening:

Viral hepatitis serology.

Hepatitis B surface antigen and Hepatitis B core antibody (IgM); and/or 

Hepatitis C RNA.
7.3.5
Ophthalmic Examination
Subjects are required to have a standard ophthalmic examination performed by an 
ophthalmologist at Screening, Months 1, 3, 6, and 12 or at discontinuation if 
discontinuation occurs prior to Month 12. Additional ophthalmic exams will be performed 
only as symptomatically warranted. The exam will include a fundoscopic examination 
(direct or indirect), visual acuity (with correction), visual field examination, and tonometry 
with special attention to retinal abnormalities that are predisposing factors for RVO or CSR. 

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In subjects with clinical suspicion of RVO or CSR, flourescein angiography and/or optical 
coherence tomography are highly recommended.
7.3.6
Vital Signs
Vital sign measurements will include systolic and diastolic blood pressure, body 
temperature, pulse rate, body weight, and height (only at Screening). Body temperature, 
weight and height measurements should be recorded in the metric scale. 
All blood pressure assessments should be performed under optimal conditions i.e. after (i) 
subject has been seated with back support, ensuring that legs are uncrossed and flat on the 
floor, (ii) subject is relaxed comfortably for at least 5 minutes, (ii) preparatory steps 
including removal of any restrictive clothing over the cuff area and selection of the right 
cuff size have been ensured, (iii) the arm is supported so that the middle of the cuff is at 
the heart level, and (iv) the 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. Only the averaged value should be entered in the eCRF.
7.3.7
Physical Examinations
All physical exams (brief and complete) will include the measurement of height (screening 
only) and weight using the metric scale, collection of vital signs including blood pressure, 
body temperature, pulse rate, and respirations as well as assessments of the head, eyes, ears, 
nose, throat, skin, thyroid, neurological, lungs, cardiovascular, abdomen (liver and spleen), 
lymph nodes and extremities. A complete physical exam will also include a thorough 
genitourinary (pelvic) examination, inspection of the head and neck region, and digital 
rectal examination for both male and female subjects. For female subjects the genitourinary 
exam must include a PAP smear. Complete physical exams must be performed at Screening, 
Month 12 or discontinuation if discontinuation occurs prior to Month 12 and Month 18. If 
the subject has had a genitourinary and rectal exam within 6 months of randomization these 
do not need to be repeated at screening. Brief physical examinations will be performed at 
all other timepoints as indicated in the Time and Events Tables (Table 10 and Table 11). 
Refer to the SPM for additional detail regarding the exam requirements for the inspection 
of the head and neck region.
7.3.8
Dermatologic Examination
Dermatologic exams are required at Screening, Month 2, Month 4, Month 6, Month 8, 
Month 10 and Month 12 (or discontinuation if subject discontinues prior to Month 12), 
every three months from Month 12 until Month 24 every 6 months after Month 24 until 
Month 60 and then annually thereafter. Dermatologic examination is not required for 
subjects that have had disease recurrence and are in follow up after Month 60 visit. Exams 
may 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. Refer to the SPM for additional detail regarding 
the dermatologic examination including exam requirements and required training for 
investigators that will be performing the exam.

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7.3.9
Electrocardiograms (ECG)
Twelve (12)-lead ECGs will be obtained using an ECG machine that automatically 
calculates heart rate and measures PR, QRS, QT, RR and QTcB intervals. 
At each assessment, a single 12-lead ECG will be performed by qualified site personnel 
after the subject has rested in a semi-recumbent or supine position for at least 5 minutes. 
Two copies of the ECG tracing should be obtained at the time of the ECG; the first copy 
will be kept in the subject’s medical chart and the second copy will be kept in the study file 
for retrospective collection by the Sponsor if necessary. See Section 5.8.3.3.3 for 
instructions if QTc withholding criteria are met.
7.3.10
Echocardiograms (ECHO)
Echocardiograms (ECHO) will be performed to assess cardiac ejection fraction and cardiac 
valve morphology. The echocardiographer’s evaluation should include an evaluation for 
left ventricular ejection fraction and both right and left-sided valvular lesions. Copies of all 
ECHO scans may be collected by the sponsor for possible future central/independent 
review. Collection details and Image Acquisition Guidelines (IAG) will be provided in the 
SPM.

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7.7
Translational Research
7.7.1
BRAF mutation assay
To determine BRAF V600E/K status, tumor tissue will be assessed from all subjects at 
Screening. The tissue will be tested for the BRAFV600E or V600K mutations using the 
bioMerieux THxID BRAFassay performed in a CLIA certified central reference laboratory. 
Tissue from either the primary tumor or metastatic lymph nodes is acceptable, however the 
most recently obtained tumor tissue (either archived material or fresh biopsy) is preferred.
The tissue requirements for the BRAF mutation assay evaluating patient eligibility for the 
study are provided in the SPM. 
 

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8
DATA MANAGEMENT
For this study subject data will be entered into Novartis defined electronic case report forms 
(eCRFs), transmitted electronically to Novartis 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 Novartis 
standards and data cleaning procedures to 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 the Medical Dictionary for Regulatory Activities (MedDRA) 
andcustom drug dictionary. The eCRFs (including queries and audit trails) will be retained 
by Novartis, and copies will be sent to the investigator to maintain as the investigator copy.
9
DATA ANALYSIS AND STATISTICAL CONSIDERATIONS
9.1
Hypotheses
The primary objective of this two-arm study is to evaluate the efficacy of 
dabrafenib/trametinib combination therapy compared to placebos with respect to Relapse-
Free Survival (RFS) for subjects with Stage III, resected BRAF V600E/K mutation-
positive melanoma.
The study is designed to provide evidence with respect to RFS to either support the null 
hypothesis, H0: = 1 or reject it in favor of the alternative hypothesis, HA: ≠1, where 
is the hazard ratio (HR) of combination therapy relative to two placebos. 
As per the initial protocol design (i.e. before Amendment 7), with 467 RFS events the study 
would have 95.3% power to detect HR=0.7143 (corresponding to median RFS of 15 and 
21 months in the placebo arm and the combination therapy arm, respectively)
Final RFS analysis (as per Protocol Amendment 7):
The cutoff date for the final RFS analysis will be 30-June-2017 and the actual number of 
RFS events observed by that date will be used. At the time of Amendment 7, it is predicted 
to observe approximately 410 RFS events by the analysis cutoff date and this will provide 
more than 90% power to detect the originally targeted HR.
5-year RFS rate (as per Protocol Amendment 8):
To estimate long term relapse free survival, a RFS analysis analysis will be performed after 
all patients have completed a minimum of 5-years follow up and at the time of study 
completion.

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9.2
Study Design Considerations
9.2.1
Sample Size Assumptions
As per the initial protocol design (i.e. before Amendment 7), the following assumptions 
were made in the estimation of the required sample size:

Exponential survival distributions;

A HR of 0.7143 (median RFS times of 15 and 21 months in the placebo arm and the 
combination therapy arm, respectively);

A 1:1 randomization scheme;

An overall 5%, two-sided risk of erroneously claiming superiority of the combination 
therapy in the presence of no true underlying difference (i.e., overall Type I error);

A 95% chance of successfully claiming superiority of the combination therapy in 
the presence of a true underlying difference (i.e., power or 1-Type II error); 

An accrual rate of 42 subjects per month over 20.3 months; and

A dropout rate of 5% for the placebo group and 15% for the combination group.
To enable the observation of 467 total events, an estimated total of 852 subjects (i.e., 426 
subjects in each of the arms) would need to be enrolled, leading to implementation of final 
analyses at approximately 32 months after the start of the study.
As per Protocol Amendment 7, the final primary RFS analysis will be performed at the 
pre-defined cut-off date, by which time it is expected that approximately 410 RFS events 
will have been accrued. The study power would be approximately 92% assuming 410 RFS 
events are observed by the data-cut and assuming originally targeted treatment effect 
represented by a hazard ratio equal to 0.7143. The choice of final RFS analysis timing is 
independent of the underlying treatment effect which is unknown. With the amended 
design, the type I error in this study is therefore preserved.
Secondary Endpoint: Overall Survival
At the time of the primary analysis of RFS, all secondary endpoints will also be 
summarized. If the primary efficacy analysis of RFS is statistically significant, statistical 
analyses of secondary endpoints will be performed to supplement the primary analysis and 
facilitate a comprehensive description of the efficacy results. All statistical tests, unless 
otherwise specified, will be stratified for treatment and stratification factors. Detailed 
information on the statistical methods will be provided in the Reporting and Analysis Plan 
(RAP).
OS is identified as the key secondary endpoint. A hierarchical approach will be taken to 
control for the overall type-I error rate for testing of multiple endpoints. Therefore OS will 
be formally statistically tested only if the primary efficacy endpoint RFS is statistically 
significant. As per the initial protocol design (before Amendment 7), the first potential time 
point for OS analysis will be at the time of the RFS final analysis when 467 RFS events 
will be observed: 
1. If RFS is significant, an interim analysis for OS will be performed: 

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a. If OS is not significant at this stage, based on O’Brien-Fleming adjustments 
detailed below, the final OS analysis will be performed when 50% of the total 
number of randomized subjects have died (approximately 299 deaths). 
b. If OS is significant, no further formal analysis will be performed.
2. If RFS is not significant, OS will not be formally statistically tested.
As per the initial protocol design (before Amendment 7), the type I error rate will be 
controlled by using a group-sequential design for testing OS at multiple time points. 
Specifically, Lan-DeMets method (Lan, 1983) with O’Brien-Fleming type stopping 
boundary (as in EAST 5.3) will be used to maintain the cumulative type-I error rate at 2.5% 
(one-sided). The exact nominal p-values that will be needed to be observed to declare 
statistical significance at the time of these analyses for OS will depend on the number of 
OS events that have been observed at the time of these analyses.
Changes made in Protocol Amendment 7
Following the Protocol Amendment 7, the first OS interim analysis will be performed at 
the same time as the revised final RFS analysis; an additional 2nd OS interim analysis will 
be performed when approximately 299 OS events have occurred; the final OS analysis 
remains to be conducted at approximately 597 events. Approximately 150 OS events are 
projected to be observed by the new proposed data cut-off date of primary RFS analysis 
(~25% of the originally targeted number of OS events). The proposed additional OS interim 
analysis will be performed at approximately 299 events which represents ~50% of the 
originally targeted number. 
O’Brien-Fleming type stopping boundary will be used for all OS tests planned in the 
Amendment 7 to maintain the cumulative type-I error rate at 2.5% (one-sided). With 
O’Brien-Fleming boundaries (as in EAST 6), the interim thresholds for claiming statistical 
significance are HR=0.493 (at 1st interim analysis assuming that exactly 150 OS events) 
and HR=0.710 (at 2nd interim assuming exactly 299 OS events) and the final threshold for 
claiming statistical significance is HR=0.851 (at final OS analysis assuming exactly 597 
OS events). If any of the OS interim analyses is significant, no further formal analysis will 
be performed.
Changes made in Protocol Amendment 8
In protocol amendment 8, the group sequential scheme for OS will be modified and the 
final analysis will be conducted when approximately 299 OS events are observed. (planned 
as 2nd interim analysis for OS in amendment 7). All remaining alpha will be spent for this 
final analysis of OS by taking into account alpha spent at the first interim analysis 
corresponding to the information fraction of 25.6%
The study will be double blinded with randomization stratified for: 

Mutation type (V600E or V600K);

Disease stage (IIIa, IIIb, IIIc)
Randomization to the Stage IIIa strata will be capped at 40% of the total number of subjects. 
Randomization to the Stage IIIb and IIIc strata will not be capped. All randomized subjects 
will be included in the analyses to test the hypotheses of interest regardless of length of 

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follow-up or whether or not study treatment was administered (i.e., subjects will not be 
replaced).
Changes made in Protocol Amendment 10
In protocol amendment 10, the group sequential scheme for OS will be modified and the
final analysis will be conducted when approximately 260 OS events are observed or at the 
number of events have occurred by the end of Jul-2023, whichever comes first.
All remaining alpha will be spent for this final OS analysis by taking into account alpha 
spent at the first interim analysis corresponding to the information fraction of 25.6%.
9.2.2
Sample Size Sensitivity
As per the initial protocol design (before Amendment 7), Table 14 shows the various power 
scenarios at the time of the RFS analysis under the assumed risk reduction (29%) and for 
scenarios where percent improvement and underlying medians vary assuming 467 events 
(relapses and all-cause deaths) have accrued.
Table 14
Statistical Power Scenario for RFS Analysis
Median RFS
% Improvement
Hazard Ratio
Power
Placebos
Combination 
Therapy
14 months
20 months
42.8%
0.7
96.9%
15 months
21 months
40%
0.714
95%
16 months
21 months
31.3%
0.762
83.1%
16 months
22 months
37.5%
0.727
92.7%
The final OS analysis will be performed when approximately 260 deaths are observed. 
Table 15 shows the power to detect various treatment effects. For example with 260 deaths, 
the study would have approximately 80% power to detect a hazard ratio of 00.70. 
Conducting final analysis at 260 OS events affects the statistical power by 2%-13% 
(depending on different HR assumptions) compared to 299 OS events.
Table 15
Statistical Power Scenario for OS Analysis
Placebo
Combination 
Therapy
% 
Improvement
Hazard 
Ratio
% Power at
255 OS 
events
% Power 
at
260 OS 
events
% Power 
at
299 OS 
events
47 months
72 months
53%
0.65
93%
93%
96%
48 months
74 months
54%
0.65
93%
94%
96%
49 months
75 months
53%
0.65
92%
93%
96%
47 months
67 months
43%
0.70
81%
81%
86%
48 months
68 months
42%
0.70
79%
80%
84%
49 months
70 months
43%
0.70
81%
82%
86%
47 months
63 months
34%
0.75
65%
65%
70%
48 months
64 months
33%
0.75
63%
64%
69%
49 months
65 months
33%
0.75
62%
62%
75%
47 months
59 months
26%
0.79
44%
45%
49%
48 months
61 months
27%
0.79
48%
49%
53%
49 months
62 months
27%
0.79
47%
47%
52%

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9.2.3
Sample Size Re-estimation
There will be no sample size re-estimation. 
9.3
Data Analysis Considerations
9.3.1
Analysis Populations
The Intent-to-Treat Population (ITT) will consist of all randomized subjects whether or 
not randomized treatment was administered. This population will be based on the treatment 
to which the subject was randomized and will be the primary population for the analysis of 
efficacy data. Any subject who receives a treatment randomization number will be 
considered to have been randomized. 
The Safety Population will consist of all subjects who received at least one dose of 
randomized treatment and will be based on the actual treatment received. This population 
will be used for the analysis of clinical safety data.
 
 
9.3.2
Analysis Data Sets
The primary dataset for efficacy (RFS, OS, DMFS, FFR) will be comprised of the ITT 
population as defined in Section 9.3.1
The primary dataset for assessing safety will be the Safety Population as defined in 
Section 9.3.1. 
The primary objective will be supported by the test for superiority of combination therapy 
over placebo in relation to RFS (refer to Section 9.1) using the ITT population. The cutoff 
date for the final RFS analysis 
 the actual number of RFS events 
observed by that date will be used. Subjects will continue to be followed for OS until 
approximately 260 deaths have occurred (or by the end of Jul-2023, whichever occurs first).
Details on the handling of missing data are provided in the RAP.
9.3.3
Treatment Comparisons
9.3.3.1
Primary Comparisons of Interest
The primary treatment comparison will be between the combination therapy arm and the 
placebo arm, with respect to RFS within the ITT population.
9.3.3.2
Other Comparisons of Interest
Treatment comparisons for secondary efficacy (including subgroup analyses) and safety 
endpoints will be between the combination therapy arm and the placebo arm. 
Overall survival (OS) is a key secondary comparison of interest. At the time of the primary 
RFS analysis, OS will be estimated for each group and compared. At the end of study, OS 
will be tested provided the initial RFS analysis was statistically significant, hence the 

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testing will be treated hierarchically and no adjustments for multiplicity are planned. At 
the time of the primary RFS analysis, DMFS and FFR will be estimated for each group and 
compared.
The number and percentage of subjects that received chemotherapy, immunotherapy, 
hormonal therapy, biologic therapy, radioactive therapy, small molecule targeted therapy, 
radiotherapy and cancer-specific surgery as post study treatment anti-cancer therapy will 
be summarized along with duration of treatment and best reported response achieved.
As these are supportive analyses, no adjustments for multiplicity are planned. P-values will 
be used to provide guidance on the weight or the evidence of any observed effect.
9.3.4
Interim Analysis & IDMC
No interim analyses will be performed for efficacy or futility for the primary endpoint RFS 
unless otherwise requested by the independent data monitoring committee (IDMC).
Following the Protocol Amendment 7, the first OS interim analysis will be performed at 
the same time as the revised final RFS analysis (i.e. at the 
 cutoff date); an 
additional OS interim analysis was planned to be performed when approximately 299 OS 
events have occurred however with Amendment 10 the final OS analysis will be conducted 
at approximately 260 events or by the end of Jul-2023, whichever comes first. Interim data 
cut was performed to conduct a 5-year RFS update upon request for additional descriptive 
data for health authority information.
An IDMC will be chartered to review accumulating safety data to provide an opportunity 
to terminate the study early if there are concerns regarding safety. The IDMC will be 
convened after approximately 100 subjects have been randomized, and will review safety 
data at intervals specified in the IDMC Charter. The recommendations of the IDMC will 
be communicated to Novartis, and in the event of a recommendation to halt the trial early 
due to safety concerns to the appropriate regulatory agencies.
The IDMC responsibilities, review schedules and mechanism for communicating 
recommendations will be outlined in an IDMC charter.
9.3.5
Key Elements of Analysis Plan
Data will be listed and summarized according to the Novartis 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 accrual will be spread thinly across centers and summaries of data 
by center would be unlikely to be informative, data from all participating centers will be 
pooled prior to analysis. 
All data up to the time of study completion/withdrawal from study will be included in the 
analysis, regardless of duration of treatment. 
As the duration of treatment for a given subject will depend on efficacy and tolerability, 
the duration of follow-up will vary between subjects. Consequently, there will be no 
imputation for missing data. 
Demographic and baseline characteristics will be summarized.

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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.
As noted in Section 9.3.3.2 there will be no adjustments for multiplicity.
All significance tests, unless otherwise noted, will be stratified by mutation type (V600E 
or V600K), and disease stage (IIIa, IIIb, IIIc) for a total of 6 strata.
Additional details on efficacy analyses are provided in Section 9.3.5.1. Similarly, 
additional details on safety analyses are provided in Section 9.3.5.2.
9.3.5.1
Efficacy Analyses
9.3.5.1.1 Primary Analysis
If a subject has neither relapsed or died or started new anti-cancer therapy, then RFS will 
be censored at the date of last adequate assessment. If no post-baseline disease assessments 
exist, the subject will be censored at the date of randomization. In the primary analysis if a 
non-protocol anti-cancer therapy is started before the occurrence of a RFS event, then RFS 
will be censored at the last adequate assessment prior to the start of such therapy. Definition 
of “adequate assessment” and censoring rules will be detailed in the RAP.
RFS will be summarized using Kaplan-Meier estimates and compared between treatment 
arms using a stratified log-rank test. The Pike estimator (Bernstein, 1981, Berry, 1991) of 
the treatment hazard ratios (HR) will be provided, together with a 95% confidence interval 
(CI). The Pike estimator, which is a nonparametric estimator of the HR, has been 
specifically developed for survival data and is used as a measure of the relative survival 
experience of two groups. Within the range of values of the ratio of the hazard rates of 
interest in clinical trials, Pike estimator is more efficient in terms of mean square error than 
the Cox proportional hazard method (Bernstein, 1981). 
Median times to RFS, first and third quartiles will be presented, along with 95% CI if there 
are a sufficient number of relapses or deaths. A graph of RFS curves and a listing of RFS 
times will also be provided.
Following the final analysis of RFS, the study will remain open for further follow-up to 
collect additional survival and safety data. Updated safety and efficacy analyses may be 
performed at the close of the study.
Sensitivity Analyses for RFS:
Sensitivity analyses using the ITT population will be conducted in order to confirm the 
results of the primary analysis. Some key sensitivity analyses are provided below.
Additional sensitivity analyses will be defined in the RAP.
The following sensitivity analyses will be performed for RFS and will be detailed in the 
RAP:

RFS regardless of start of new anticancer therapy prior to documented relapse. Namely, 
all RFS events will be included regardless of whether or not subsequent anti-cancer 
therapy was initiated prior to the event.

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
Cox Regression analysis including baseline prognostic factors as covariates will be 
performed. Factors included in the model will be pre-specified in the RAP.

RFS Analysis ignoring new melanoma as an event.
9.3.5.1.2 Secondary Analyses
OS will be estimated using the Kaplan Meier method and treatment comparisons, when 
performed, will be made using a stratified log-rank test (based on the two stratification 
factors defined in Section 9.2). All cause mortality will be used and censoring will be 
performed using the date of last known contact for those who are alive at the time of 
analysis. The hazard ratio along with 95% confidence intervals will be provided. 
DMFS will be estimated using the Kaplan Meier method and treatment comparisons will 
be made using a log-rank test. The first appearance of distant metastasis or all cause 
mortality will be used as events. Censoring will be performed using the date of last 
assessment for those who are alive without distant metastasis at the time of analysis. The 
hazard ratio along with 95% confidence intervals will be provided. 
FFR will be estimated using the Kaplan Meier method and treatment comparisons will be 
made using a log-rank test. The first appearance of local/distant metastasis or mortality due 
to disease recurrence or toxicity will be used as events. Censoring will be performed using 
the date of last assessment for those who are alive without local/distant metastasis or new 
primary melanoma at the time of analysis. FFR will be censored if patients died from causes 
other than melanoma or treatment-related toxicity at the date of death. The hazard ratio 
along with 95% confidence intervals will be provided. 
Other efficacy analyses will be detailed in the RAP.
9.3.5.2
Safety Analyses
Safety endpoints are described in Section 2 and Section 7.3.
The Safety population will be used for the analysis of safety data. Complete details of the 
safety analyses will be provided in the RAP.
9.3.5.2.1 Extent of Exposure
The number of subjects administered study treatment will be summarized according to the 
duration of therapy. 
9.3.5.2.2 Adverse Events
Adverse events (AEs) will be coded using the standard Medical Dictionary for Regulatory 
Activities (MedDRA) and grouped by system organ class. AEs will be graded by the 
investigator according to the NCI-CTCAE (version 4.0). 
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.

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Characteristics (e.g. number of occurrences, action taken, grade, etc) of AEs of special 
interest (including SCC and other proliferative lesions) will be summarized separately as 
detailed in the RAP.
The incidence of deaths and the primary cause of death will be summarized.
9.3.5.2.3 Clinical Laboratory Evaluations
Hematology and clinical chemistry data will be summarized at each scheduled assessment 
according to NCI CTCAE grade (version 4.0). The proportion of values lying outside the 
reference range will also be presented for laboratory tests that are not graded because there 
are no associated NCI CTCAE criteria. Summaries will include data from scheduled 
assessments only, and all data will be reported according to the nominal visit date for which 
it was recorded (i.e. no visit windows will be applied). Unscheduled data will be included 
in “overall” and “any post-screening” summaries which will capture a worst case across 
all scheduled and unscheduled visits post first dose of study treatment. Further details will 
be provided in the RAP.
9.3.5.2.4 Other Safety Measures
The results of scheduled assessments of vital signs, ECOG performance status, 12-lead 
ECG, and ECHO 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). Unscheduled data will be included in 
‘worse case’ summaries which will capture a worst case across all scheduled and 
unscheduled visits after the first dose of study treatment. All data will be listed. Further 
details will be provided in the RAP.

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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 enrollment of subjects begins.
10.2
Regulatory and Ethical Considerations, Including the 
Informed Consent Process
Prior to initiation of a study site, the sponsor will obtain favorable 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.

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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:

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.
Novartis 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 
 
 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 Novartis procedures, Novartis 
personnel (or designated Clinical Research Organization [CRO]) will contact the site 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 Novartis requirements. When 
reviewing data collection procedures, the discussion will include identification, agreement 
and documentation of data items for which the CRF will serve as the source document.
The investigator and the head of the medical institution (where applicable) agrees to allow 
the monitor direct access to all relevant documents and to allocate their time and the time 
to their staff to monitor to discuss findings and any issues.
Monitoring visits will be conducted in a manner to ensure that the:

Data are authentic, accurate, and complete.

Safety and rights of 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, Novartis may 
conduct a quality assurance assessment and/or audit of the site records, and the regulatory 
agencies may conduct a regulatory inspection at any time during or after completion of the 
study. In the event of an assessment, audit or inspection, the investigator (and institution) 
must agree to grant the advisor(s), auditor(s) and inspector(s) direct access to all relevant 

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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 approximately 43.5 percent of the initially 
planned target number of randomized subjects have died or are otherwise lost to follow-up 
(approximately 260) or at the end of Jul-2023, whichever comes first. At which time final 
analyses will be performed.
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 Novartis Standard Operating Procedures.
Novartis 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 Novartis determines that such action is required, Novartis will discuss the reasons for 
taking such action with the investigator or head of the medical institution (where 
applicable). When feasible, Novartis 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, Novartis will promptly inform all 
investigators, heads of the medical institutions (where applicable), and/or institutions 
conducting the study. Novartis 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 Novartis 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.
Essential documents (written and electronic) should be retained for a period of not less than 
fifteen (15) years from the completion of the Clinical Trial unless the Sponsor provides 
written permission to dispose of them or, requires their retention for an additional period 
of time because of applicable laws, regulations and/or guidelines.

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The investigator must notify Novartis 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 Novartis site or other mutually-
agreeable location.
Novartis 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.
Novartis will provide the investigator with the randomization codes for their site only after 
completion of the full statistical analysis.
Novartis aims to post a results summary to the Novartis Clinical Trial Results website 
(.novartisclinicaltrials.com) and other publicly available registers no later than twelve (12) 
months after the last subject’s last visit (LSLV). In addition, upon study completion and 
finalization of study report, Novartis aims to submit results of the study for publication. 
When publication is not feasible, please refer to the Novartis Clinical Trial Results website 
(novartisclinicaltrials.com) for a summary of the trial results. 
10.8
Independent Data Monitoring Committee
An Independent Data Monitoring Committee (IDMC) will be utilized in this study to 
ensure external objective medical and/or statistical review of safety and/or efficacy issues 
in order to protect the ethical and safety interests of subjects and to protect the scientific 
validity of the study. The schedule and the analysis plan for IDMC review are described in 
the charter.

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REFERENCES
Balagula Y, Huston KB, Busam KJ, et al. Dermatologic side effects associated with the 
MEK 1/2 inhibitor selumetinib (AZD6244, ARRY-142886). Invest New Drugs 2010; 29: 
1114-1121
Balch C, Gershenwald J, Soong SJ, Thompson J, et al. Final Version of 2009 AJCC 
Melanoma Staging and Classification. J Clin Oncol. 2009; 27:6199-6206.
Bernstein L., Anderson J., Pike M.C. Estimation of the Proportional Hazard in Two-
Treatment-Group Clinical Trials. Biometrics. 1981; 37:513-519.
Berry G., Kitchin, R.M., Mock. P. A comparison of Two Simple Hazard Ratio Estimators 
Based on the Logrank Test. Statistics in Medicine. 1991:749-55.
Budman DR,et al. Dose and Dose Intensity as Determinants of Outcome in the Adjuvant 
Treatment of Breast Cancer. J Natl Cancer Inst 1998;90: 1205–11. 
Carnahan J, Beltran PJ, Babij C, Le Q, Rose MJ, et al. Selective an potent Raf inhibitors 
paradoxically stimulate normal cell proliferation and tumour growth. Mol Cancer Ther 
2010;9(8):2399-2410.
Chapman PB, et al. Improved Survival with Vemurafenib in Melanoma with BRAF 
V600E Mutation. N Engl J Med 2011;364:2507-16.
Citron ML, et al. Randomized Trial of Dose-Dense Versus Conventionally Scheduled 
and Sequential Versus Concurrent Combination Chemotherapy as Postoperative 
Adjuvant Treatment of Node- Positive Primary Breast Cancer: First Report of Intergroup 
Trial C9741/Cancer and Leukemia Group B Trial 9741. J Clin Oncol 2003;21:1431-
1439.
Clinicaltrials.gov. EORTC18991, EORTC18071, DERMA, EORTC18592, ECOG1690, 
AVAST-M, GO27826. 25 May 2012.
Corcoran RB, Dias-Santagata D, Bergethon K, Iafrate AJ, Settleman J, Engelman JA. 
BRAF gene amplification can promote acquired resistance to MEK inhibitors in cancer 
cells harboring the BRAF V600E mutation. Sci Signal. 2010 Nov 23;3(149):ra84.
Early Breast Cancer Trialists’ Collaborative Group (EBCTCG). Comparisons between 
different polychemotherapy regimens for early breast cancer: meta-analyses of long-term 
outcome in 100,000 women in 123 randomised trials. Lancet, Published Online 
December 6, 2011.
Eggermont A, Chiarion-Sileni V, Grob JJ, Dummer R, et al. Adjuvant ipilimumab versus 
placebo after complete resection of high-risk stage III melanoma (EORTC 18071): a 
randomized, double-blind, phase 3 trial. Lancet, Published Online April 1, 2015.
Eggermont A, Suciu S, Santinami M, Testori A, et al. Adjuvant therapy with pegylated 
interferon alfa-2b versus observation alone in resected stage III melanoma: final results of 
EORTC 18991, a randomised phase III trial. The Lancet. 2008; 372:117-26.
Emery C.M., Vijayendran K.G., Zipser M.C., Sawyer A.M., Niu L., Kim J.M., Hatton C, 
Chopra R., Oberholzer P.A., Karpova M.B., MacConaill L.E., Zhang J., Gray N.S., 
Sellers W.R., Dummer R., Garraway L.A. MEK1 mutations confer resistance to MEK 
and BRAF inhibition. Proceedings of the National Academy of Science. 2009; 106 
(48):20411–20416.

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Flaherty KT, Hersey RC, Garbe NP et al. Improved survival with MEK inhibition in 
BRAF-mutated melanoma. N Engl J Med 2012; [Epub ahead of print].
Flaherty KT, Puzanov I, Kim KB, et al. Inhibition of mutated, activated BRAF in 
metastatic melanoma. N Engl J Med 2010;363(9):809-819.
GlaxoSmithKline Document Number 2011N126811_00. GSK1120212 + GSK2118436 
Investigator's Brochure. Report Date 15 Feb 2012.
GlaxoSmithKline Document Number 2012N136095_00, Dabrafenib Investigator's 
Brochure. Report Date 15 May 2012.
GlaxoSmithKline Document Number HM2009/00151/02, GSK1120212 Investigator's 
Brochure. Report Date 23 June 2011.
Goetz E and Garraway L. Mechanisms of resistance to mitogen-activated protein kinase 
pathway inhibition in BRAF-mutant melanoma. American Society of Clinical Oncology 
2012.
Hauschild A, Jacques-Grob J, Demidov L et al. (2012). Dabrafenib in BRAF-mutated 
metastatic melanoma: a multicentre, open-label, phase 3 randomised controlled trial. The 
Lancet, Available online 24 June 2012, ISSN 0140-6737. doi: 10.1016/S0140-
6736(12)60868-X (httpwww.sciencedirect.com/science/article/pii/S014067361260868X).
Jemal A, Siegel R, Ward E et al. Cancer statistics, 2007. CA Cancer J Clin 2007; 57: 43-
66.
 
Kirkwood JM, Ibrahim JG, Sosman JA et al. High-dose interferon alfa-2b significantly 
prolongs relapse-free and overall survival compared with the GM2-KLH/QS-21 vaccine 
in patients with resected stage II-III melanoma: Results of Intergroup Trial 
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Kirkwood JM, Long GV, Trefzer U et al. BREAK-MB: A phase II study assessing 
overall intracranial response rate (OIRR) to dabrafenib (GSK2118436) in patients (pts) 
with BRAF V600E/K mutation-positive melanoma with brain metastases (mets). J Clin 
Oncol 2012; 30:15s (suppl abstr 8501).
Lacouture M., O’Reilly K., Rosen N., Solit D. Induction of Cutaneous Squamous Cell 
Carcinomas by RAF Inhibitors: Cause for Concern? J Clin Oncol. 2012;30(3):329-330.
Lan K.K., DeMets, D. L. Discrete Sequential Boundaries for Clinical Trials 659-663. 
Biometrika. 1983:659-63.
Markovic SN, Erickson LA, Rao RD et al. Malignant melanoma in the 21st century, part 
2: staging, prognosis and treatment. Mayo Clin. Proc. 2007; 82: 490 – 513.
Muss HB, et al. Adjuvant Chemotherapy in Older Women with Early-Stage Breast 
Cancer. N Engl J Med 2009;360:2055-65. 
National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines 
in Oncology:Melanoma. NCCN, Ft. Washington, PA; 2012.
Nikolaev SI, et al. Exome sequencing identifies recurrent somatic MAP2K1 and 
MAP2K2 mutations in melanoma. Nature Genetics (published online 25 December 
2011).

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Nissan MH, Solit DB. The “SWOT” of BRAF inhibition in melanoma: RAF inhibitors, 
MEK inhibitors, or both? Curr Oncol Rep 2011;13:479-87
Oken MM, Creech RH, Tormey DC, et al. Toxicity and response criteria of the Eastern 
Cooperative Oncology Group. Am J Clin Oncol 1982;5(6):649-655.
 
Schuchter L. Adjuvant Interferon Therapy for Melanoma: High-Dose, Low-Dose, No 
Dose, Which Dose? J Clin Oncol 2004; 22:7-10.
Van Akkooi AC, Rutkowski P, va der Ploeg M, Voit C, et al. Long-term follow-up of 
patients with minimal sentinel node tumor burden (<0.1mm) according to Rotterdam 
criteria: A study of the EORTC Melanoma Group. J Clin Oncol, 2009; 27:15s (suppl 
abstr 9005).
Weber J, Flaherty K, Infante J, et al. Updated safety and efficacy results from a phase I/II 
study of the oral BRAF inhibitor dabrafenib (GSK2118436) combined with oral MEK ½ 
inhibitor trametinib (GSK1120212) in patients with BRAFi-naive metastatic melanoma. J 
Clin Oncol 2012;30 (suppl; abstr 8510).
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APPENDICES
12.1
Appendix 1: Melanoma of the Skin Staging
Reference: American Joint Committee on Cancer. (2009). 7th Edition of AJCC Melanoma 
Staging System. Retrieved 19 April 2012 from 
wwwcancerstaging.org/staging/posters/melanoma8.5x11.pdf.

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12.2
Appendix 2: Surgical Guidelines
Management of the primary
Wide excision with a minimal 1 cm margin surrounding the primary lesion or biopsy scar 
will be required. For lesions with Breslow’s thickness >2 mm, a 2 cm margin is preferred 
only when anatomically feasible (i.e., for lesions of the trunk and proximal extremities). 
On other sites narrower margins are recommended to avoid mutilation. For subungual 
melanoma, a distal interphalangeal amputation with histologically negative margins 
constitutes an adequately wide excision. The specimen should be excised to include skin 
and all subcutaneous tissue down to the muscular fascia. Inclusion of the fascia is not 
recommended, but fascia may be included at the discretion of the operating surgeon. 
Closure of the defect may be via primary closure, split thickness skin graft, or rotation flap 
at the discretion of the surgeon.
Completion Lymph node dissection (CLND) 
Patients should have a complete lymphadenectomy with no clinical or radiographic 
evidence of regional node disease remaining.
Specific considerations apply to the following drainage areas (Garbe, 2008):
Head and Neck

Radical or modified radical neck dissection is required 

Parietal/frontal regions (excluding chin and neck) – include superficial parotoidectomy

Dorsal regions – include retroauricular and occipital lymph nodes 
Axilla

Level I and II lymph nodes

Level III lymph nodes medial to lesser pectoralis (note: muscle may need to be removed 
if lymph nodes are extensively involved)
Inguinal

Dissection should extend from femoral triangle and lower abdominal rectus from the 
pubic tubercle to the anterior iliac crest (including saphenous foramen and inguinal 
ligament and removal of saphenous vein if no contraindications)

Include iliac lymph nodes if clinically positive (including Cloquet’s node) to level of 
iliac bifurcation, along with obdurator lymph nodes
Reference:
Garbe C, et al. Evidence and interdisciplinary consensus-based German guidelines: 
surgical treatment and radiotherapy of melanoma. Melanoma Res 18:61–67 (2008).

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12.3
Appendix 3: Eastern Cooperative Oncology Group (ECOG) 
Performance Status
Activity Status
Description
0
Fully active, able to carry on all pre-disease performance without restriction.
1
Restricted in physically strenuous activity but ambulatory and able to carry 
out work of a light or sedentary nature, e.g., light house work, office work
2
Ambulatory and capable of all self-care but unable to carry out any work 
activities. Up and about more than 50% of waking hours.
3
Capable of only limited self-care, confined to bed or chair more than 50% of 
waking hours.
4
Completely disabled. Cannot carry on any self-care. Totally confined to bed 
or chair.
5
Dead.
Reference:
Oken MM, Creech RH, Tormey DC, et al. Toxicity and response criteria of the Eastern 
Cooperative Oncology Group. Am J Clin Oncol 1982; 5(6):649-655.
12.4
Appendix 4: Cockcroft-Gault Formula
To determine eligibility for the study, investigators should calculate a subject’s creatinine 
clearance by the Cockcroft-Gault formula as follows (Cockcroft , 1976):
CrCl for males (mL/min) =
(140 - age [years]) × (weight [kg])
72 × (serum creatinine [mg/dL])
CrCL for females (mL/min) =
0.85 × (140 - age [years]) × (weight [kg])
72 × (serum creatinine [mg/dL])
For SI units:
CrCl for males (mL/min) =
(140 - age [years]) × (weight [kg]) × 1.23
(serum creatinine [mol/L])
CrCL for females (mL/min) =
(140 - age [years]) × (weight [kg]) × 1.05
(serum creatinine [mol/L])
CrCl = creatinine clearance; SI = Système International d’Unités.
Reference:
Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. 
Nephron 1976; 16(1):31-41.

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12.5
Appendix 5: QT interval on electrocardiogram corrected 
using the Bazett’s formula (QTcB)
Bazett's formula used to correct QT interval for heart rate is:
where QTcB is the QT interval corrected for heart rate, RR is the interval from the onset 
of one QRS complex to the onset of the next QRS complex, measured in seconds, often 
derived from the heart rate (HR) as 60/HR, and QT is the QT interval measured in 
milliseconds. 
Reference:
Bazett HC. An analysis of the time-relations of electrocardiograms. Heart 1920; 7: 353-
370.
12.6
Appendix 6: New York Heart Association (NYHA) Guidelines
The New York Heart Association Functional Classification provides a simple way of 
classifying the extent of heart failure (The Criteria Committee of the New York Heart 
Association, 1994). It places subjects in 1 of 4 categories based on the level of limitation 
experienced during physical activity:
Functional Capacity
Objective Assessment
Class I: Subjects with cardiac disease but without resulting 
limitation of physical activity. Ordinary physical activity does not 
cause undue fatigue, palpitation, dyspnea, or anginal pain.
A: No objective evidence of 
cardiovascular disease.
Class II: Subjects with cardiac disease resulting in slight limitation 
of physical activity. They are comfortable at rest. Ordinary physical 
activity results in fatigue, palpitation, dyspnea, or anginal pain.
B: Objective evidence of minimal 
cardiovascular disease.
Class III: Subjects with cardiac disease resulting in marked 
limitation of physical activity. They are comfortable at rest. Less 
than ordinary physical activity causes fatigue, palpitation, dyspnea, 
or anginal pain.
C: Objective evidence of moderately 
severe cardiovascular disease.
Class IV: Subjects with cardiac disease resulting in inability to 
carry on any physical activity without discomfort. Symptoms of 
heart failure or the anginal syndrome may be present even at rest. 
If any physical activity is undertaken, discomfort is increased.
D: Objective evidence of severe 
cardiovascular disease.
Reference:
The Criteria Committee of the New York Heart Association. Nomenclature and criteria 
for diagnosis of diseases of the heart and great vessels. 9th ed. Boston, Mass: Little, 
Brown, & Co; 1994:253-256.
RR
QT
QTcB 

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12.7
Appendix 7: Liver Chemistry Monitoring, Interruption 
Stopping and Follow-up Criteria
IP may be re-challenged if protocol provides this option.

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12.10
Appendix 10: Country Specific Requirements
Not Applicable.
12.11
Appendix 11: Protocol Changes 
Refer to prior protocol versions for full details of amendments.