Conditions: Malignant Melanoma
Keywords: dabrafenib trametinib adjuvant Stage III melanoma combination treatment pyrexia
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 552
Healthy volunteers: no

Brief summary:
The main purpose of this study was to evaluate the impact on pyrexia-related outcomes of an adapted pyrexia adverse event (AE)-management algorithm, as well as safety, efficacy and health-related outcomes.

Detailed description:
This was an open-label Phase IIIb study of dabrafenib in combination with trametinib in the adjuvant treatment of melanoma after complete resection. Patients with completely resected, histologically confirmed, BRAF V600E/K mutation-positive, high-risk cutaneous melanoma were screened for eligibility.

This study consisted of two periods:

1. Treatment Period - patients received up to 12 months of dabrafenib (150 mg twice daily) and trametinib (2 mg once daily). In the adapted pyrexia management algorithm, dabrafenib and trametinib were interrupted promptly at the onset of pyrexia (≥38°C) and were restarted upon the improvement of symptoms at the same dose if patients remained symptom free (temperature \<38°C) for at least 24 hours. In addition, dabrafenib and trametinib could be interrupted in the presence of pyrexia syndrome (i.e. chills, rigours, night sweats, or influenza-like symptoms) without documented temperature ≥38°C for cases of suspected recurrent pyrexia, at the investigators' discretion.
2. Follow-up Period - patients were followed for disease relapse through 24 months from first dose date. Moreover, patients were followed for overall survival through withdrawal, lost to follow-up, death, or the end of study, whichever occurs first. The follow-up period started once treatment was completed or treatment was prematurely discontinued.

Arms:
arm 1: Subjects received dabrafenib (150 mg twice daily) and trametinib (2 mg once daily) orally for up to 12 months.

Interventions: intervention 1: Dabrafenib intervention 2: Trametinib
Intervention descriptions: intervention 1: Supplied as dabrafenib 50 mg and 75 mg capsules for oral administration intervention 2: Supplied as trametinib 0.5mg, and 2.0mg tablets for oral administration

Protocol document:
Prot_000.pdf: 
Novartis Research and Development 
DRB436/dabrafenib and TMT212/trametinib 
Clinical Trial Protocol CDRB436F2410 / NCT03551626
COMBI-APlus: Open-label, phase IIIb study of dabrafenib in 
COMBInation with trametinib in the Adjuvant treatment of 
stage III BRAF V600 mutation-positive melanoma after 
complete resection to evaluate the impact on pyrexia 
related outcomes of an adapted pyrexia AE-management 
algorithm (Plus) 
Document type: 
Amended Protocol Version 
EUDRACT number: 
2018-000168-27 
Version number: 
02 (Clean) 
Clinical Trial Phase: 
IIIb 
Release date: 
09-May-2019
Property of Novartis 
Confidential 
May not be used, divulged, published, or otherwise disclosed 
without the consent of Novartis 
Clinical Trial Protocol Template Version 1.0 (13-Dec-2017) 


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Table of contents 
Table of contents ................................................................................................................. 2 
List of tables ........................................................................................................................ 6 
List of figures ...................................................................................................................... 7 
List of abbreviations ............................................................................................................ 8 
Glossary of terms ............................................................................................................... 10 
Protocol summary .............................................................................................................. 11 
Amendment 2 (12-Mar-2019) ........................................................................................... 14 
Amendment 1 (03-Dec-2018) ............................................................................................ 17 
1 
Introduction ....................................................................................................................... 21 
1.1 
Background ............................................................................................................ 21 
1.1.1 
Clinical Experience ............................................................................... 24 
1.2 
Purpose .................................................................................................................. 29 
2 
Objectives and endpoints ................................................................................................... 30 
3 
Study design ...................................................................................................................... 31 
4 
Rationale ............................................................................................................................ 32 
4.1 
Rationale for study design ..................................................................................... 32 
4.2 
Rationale for dose/regimen and duration of treatment .......................................... 33 
4.3 
Rationale for choice of control drugs (comparator/placebo) or combination 
drugs ...................................................................................................................... 33 
4.4 
Purpose and timing of interim analyses/design adaptations .................................. 34 
4.5 
Risks and benefits .................................................................................................. 34 
5 
Population .......................................................................................................................... 36 
5.1 
Inclusion criteria .................................................................................................... 36 
5.2 
Exclusion criteria ................................................................................................... 37 
6 
Treatment ........................................................................................................................... 39 
6.1 
Study treatment ...................................................................................................... 39 
6.1.1 
Investigational and control drugs .......................................................... 39 
6.1.2 
Additional study treatments .................................................................. 39 
6.1.3 
Treatment arms/group ........................................................................... 39 
6.1.4 
Guidelines for continuation of treatment .............................................. 40 
6.1.5 
Treatment duration ................................................................................ 40 
6.2 
Other treatment(s) .................................................................................................. 40 
6.2.1 
Concomitant therapy ............................................................................. 41 
6.2.2 
Prohibited medication ........................................................................... 44 
6.3 
Subject numbering, treatment assignment, randomization .................................... 44 
6.3.1 
Subject numbering ................................................................................ 44 
6.3.2 
Treatment assignment, randomization .................................................. 44 
6.4 
Treatment blinding ................................................................................................ 44 


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6.5 
Dose modification .................................................................................................. 44 
6.5.1 
Dose modifications ................................................................................ 44 
6.5.2 
Follow-up for toxicities ......................................................................... 67 
6.6 
Additional treatment guidance ............................................................................... 68 
6.6.1 
Treatment compliance ........................................................................... 68 
6.7 
Preparation and dispensation ................................................................................. 68 
6.7.1 
Handling of study treatment and additional treatment .......................... 69 
6.7.2 
Instruction for prescribing and taking study treatment ......................... 69 
7 
Informed consent procedures ............................................................................................ 71 
8 
Visit schedule and assessments ......................................................................................... 71 
8.1 
Screening ............................................................................................................... 78 
8.1.1 
BRAF V600E/K pre-screening ............................................................. 78 
8.1.2 
Eligibility screening .............................................................................. 79 
8.1.3 
Information to be collected on pre-screening failures ........................... 79 
8.1.4 
Information to be collected on screening failures ................................. 79 
8.2 
Subject demographics/other baseline characteristics............................................. 79 
8.3 
Efficacy .................................................................................................................. 80 
8.3.1 
Efficacy Assessments ............................................................................ 80 
8.4 
Safety ..................................................................................................................... 83 
8.4.1 
Performance status ................................................................................ 85 
8.4.2 
Physical Exam ....................................................................................... 85 
8.4.3 
Vital Signs ............................................................................................. 85 
8.4.4 
Height and Weight ................................................................................ 85 
8.4.5 
Ophthalmic examination ....................................................................... 85 
8.4.6 
Dermatologic Examination ................................................................... 86 
8.4.7 
Laboratory evaluations .......................................................................... 86 
8.4.8 
Cardiac Assessments ............................................................................. 87 
8.4.9 
Cardiac imaging – ECHO or MUGA scan ............................................ 88 
8.4.10 
Pregnancy and assessments of fertility ................................................. 88 
8.5 
Additional Assessments ......................................................................................... 89 
8.5.1 
Patient Reported Outcomes ................................................................... 89 
9 
Study discontinuation and completion .............................................................................. 90 
9.1 
Discontinuation ...................................................................................................... 90 
9.1.1 
Discontinuation of study treatment ....................................................... 90 
9.1.2 
Withdrawal of informed consent ........................................................... 91 
9.1.3 
Lost to follow-up ................................................................................... 91 
9.1.4 
Early study termination by the sponsor ................................................. 91 
9.2 
Study completion and post-study treatment .......................................................... 92 
10 Safety monitoring and reporting ........................................................................................ 92 


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10.1 
Definition of adverse events and reporting requirements ...................................... 92 
10.1.1 
Adverse events ...................................................................................... 92 
10.1.2 
Serious adverse events .......................................................................... 95 
10.1.3 
SAE reporting........................................................................................ 96 
10.1.4 
Pregnancy reporting .............................................................................. 97 
10.1.5 
Reporting of study treatment errors including misuse/abuse ................ 98 
10.2 
Additional Safety Monitoring ................................................................................ 98 
10.2.1 
Liver safety monitoring ......................................................................... 98 
10.2.2 
Renal safety monitoring ........................................................................ 98 
10.2.3 
Data Monitoring Committee ................................................................. 98 
10.2.4 
Steering Committee ............................................................................... 99 
11 Data Collection and Database Management ...................................................................... 99 
11.1 
Data collection ....................................................................................................... 99 
11.2 
Database management and quality control ............................................................ 99 
11.3 
Site monitoring .................................................................................................... 100 
12 Data analysis and statistical methods .............................................................................. 101 
12.1 
Analysis sets ........................................................................................................ 101 
12.2 
Subject demographics and other baseline characteristics .................................... 101 
12.3 
Treatments ........................................................................................................... 101 
12.4 
Analysis of the primary endpoint(s) .................................................................... 102 
12.4.1 
Definition of primary endpoint(s) ....................................................... 102 
12.4.2 
Statistical model, hypothesis, and method of analysis ........................ 102 
12.4.3 
Handling of missing values/censoring/discontinuations ..................... 103 
12.5 
Analysis of secondary endpoints ......................................................................... 103 
12.5.1 
Efficacy endpoints ............................................................................... 104 
12.5.2 
Safety endpoints .................................................................................. 104 
12.5.3 
Patient reported outcomes ................................................................... 105 
12.6 
Analysis of exploratory endpoints ....................................................................... 105 
12.7 
Interim analyses ................................................................................................... 106 
12.8 
Sample size calculation........................................................................................ 108 
13 Ethical considerations and administrative procedures .................................................... 109 
13.1 
Regulatory and ethical compliance ...................................................................... 109 
13.2 
Responsibilities of the investigator and IRB/IEC ................................................ 109 
13.3 
Publication of study protocol and results............................................................. 109 
13.4 
Quality Control and Quality Assurance ............................................................... 109 
14 Protocol adherence .......................................................................................................... 110 
14.1 
Protocol Amendments ......................................................................................... 110 
15 References ....................................................................................................................... 110 
16 Appendices ...................................................................................................................... 114 


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16.1 
Appendix 1:  AJCC Melanoma Staging Eight Edition ........................................ 114 
 


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List of tables 
Table 2-1 
Objectives and related endpoints .......................................................... 30 
Table 6-1 
Investigational drug ............................................................................... 39 
Table 6-2 
Prohibited Medications ......................................................................... 42 
Table 6-3 
Medication to be used with Caution ...................................................... 42 
Table 6-4 
Mandatory dose modification and recommended clinical 
management for pyrexia suspected to be related to dabrafenib 
and/or trametinib treatment ................................................................... 46 
Table 6-5 
Dose modification steps for dabrafenib and trametinib ........................ 47 
Table 6-6 
Reference of AEs and toxicity management guidelines ....................... 48 
Table 6-7 
Mandatory dose modifications and recommended clinical 
management guidelines for abnormal liver enzyme test ....................... 49 
Table 6-8 
Mandatory dose modifications and recommended clinical 
management guidelines for renal function alterations .......................... 50 
Table 6-9 
Mandatory dose modifications and recommended clinical 
management guidelines for rash............................................................ 52 
Table 6-10 
Mandatory dose modifications and recommended clinical 
management guidelines for pneumonitis .............................................. 53 
Table 6-11 
General guidelines for dose modification for adverse events 
suspected to be related to dabrafenib and/or trametinib treatment ....... 55 
Table 6-12 
Mandatory dose modifications and recommended clinical 
management guidelines for hand foot skin reaction (palmar-plantar 
erythrodysesthesia) ................................................................................ 57 
Table 6-13 
Mandatory dose modifications and recommended clinical 
management guidelines for hematological adverse events ................... 58 
Table 6-14 
Mandatory dose modifications and recommended clinical 
management guidelines for non-hematological adverse events ............ 60 
Table 6-15 
Mandatory dose modification and recommended clinical 
management for changes in LVEF suspected to be related to 
dabrafenib and/or trametinib treatment ................................................. 61 
Table 6-16 
Mandatory dose modification and recommended clinical 
management for hypertension suspected to be related to dabrafenib 
and/or trametinib treatment ................................................................... 62 
Table 6-17 
Mandatory dose modifications and recommended clinical 
management guidelines for diarrhea/colitis .......................................... 63 
Table 6-18 
Mandatory dose modification and recommended clinical 
management for visual changes and/or ophthalmic examination 
findings suspected to be related to dabrafenib and/or trametinib 
treatment ................................................................................................ 66 
Table 6-19 
Mandatory dose modification and recommended clinical 
management for retinal pigment epithelial detachments (RPED) 
suspected to be related to trametinib treatment ..................................... 66 
Table 6-20 
Dose treatment and schedule ................................................................. 71 


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Table 8-1 
Treatment Visit and Assessment Schedule ........................................... 73 
Table 8-2 
Follow-up (Pre-Relapse) Assessment Schedule .................................... 77 
Table 8-3 
Follow-up (Post-Relapse) Assessment Schedule .................................. 78 
Table 8-4 
Imaging assessments ............................................................................. 80 
Table 8-5 
Assessments & Specifications............................................................... 84 
Table 8-6 
ECOG performance status scale ............................................................ 85 
Table 8-7 
Clinical laboratory parameters collection plan ..................................... 87 
Table 8-8 
ECG collection plan for Treatment Period ............................................ 87 
Table 10-1 
Adverse events of special interest by study treatment .......................... 95 
Table 10-2 
Guidance for capturing the study treatment errors including 
misuse/abuse ......................................................................................... 98 
Table 12-1 
Exact 95% CI for different observed event rates at primary analysis . 103 
Table 12-2 
Posterior probability for a positive effect at primary analysis ............ 103 
Table 12-3 
Predictive probability of observing composite pyrexia event rate 
greater or equal 20% (n=200) in the safety set at primary analysis 
(600 subjects) under different interim results ..................................... 107 
Table 12-4 
Predictive probability of observing RFS rate greater or equal 61% 
(n=200) at the secondary analysis (600 subjects) ............................... 107 
Table 12-5 
Operating Characteristics .................................................................... 108 
Table 16-1 
Melanoma Stage III Subgroups Based on Primary Tumor (T) and 
Regional Lymph Nodes (N ) categories .............................................. 114 
Table 16-2 
Definition of Regional Lymph Node (N) ............................................ 115 
 
List of figures 
Figure 3-1 
Study design .......................................................................................... 32 
 


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List of abbreviations 
AE 
Adverse Event 
AESI 
Adverse Event of Special Interest 
AJCC 
American Joint Committee on Cancer 
ALP 
Alkaline Phosphatase 
ALT 
Alanine Aminotransferase 
AST 
Aspartate Aminotransferase 
BID 
bis in diem/twice a day 
BUN 
Blood Urea Nitrogen 
CD-
ROM 
Compact Disc - Read Only Memory 
CFR 
Code of Federal Regulation 
CI 
Confidence Interval 
CLDN 
Complete Lymph Node Dissection 
CRF 
Case Report/Record Form ( electronic) 
CRO 
Contract Research Organization 
CRP 
C-reactive protein 
CTC 
Common Toxicity Criteria 
cuSCC 
Cutaneous Squamous Cell Carcinoma 
DAR 
Dose Administration Record 
DBP 
Diastolic Blood Pressure 
DDI 
Drug-drug Interaction 
DILI 
Drug-Induced Liver Injury 
DMC 
Data Monitoring Committee 
DMFS 
Distant Metastasis-Free Survival  
DMSO 
Dimethyl Sulfoxide  
DOR 
Duration of response 
DVT 
Deep Vein Thrombosis  
ECG 
Electrocardiogram 
ECHO 
Echocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
EDC 
Electronic Data Capture 
EoT 
End of Treatment  
EoS 
End of Study  
FACT-G 
Functional Assessment of Cancer Therapy-General  
FACT-M 
Functional Assessment of Cancer Therapy–Melanoma  
FDA 
Food and Drug Administration 
FFR 
Freedom From Relapse 
GCP 
Good Clinical Practice 
HBV 
Hepatitis B Virus 
HCV 
Hepatitis C Virus 
HIV 
Human Immunodeficiency Virus 
HR 
Hazard Ratio 
HRQOL 
Health-Related Quality Of Life 
IA 
Interim Analysis 
IB 
Investigator Brochure 
ICH 
International Conference on Harmonization of Technical Requirements for Registration of 
Pharmaceuticals for Human Use 
IEC 
Independent Ethics Committee 
IFNα 
Interferon alfa 
IRB 
Institutional Review Board 


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IRT 
Interactive Response Technology 
LFT 
Liver Function Test 
LLN 
Lower Limit of Normal 
LPFV 
Last Patient First Visit 
LVEF 
Left Ventricular Ejection Fraction  
MedDRA 
Medical dictionary for regulatory activities 
MUGA 
Multigated acquisition scan 
NSAID 
Non-Steroidal Anti-Inflammatory Drugs 
ORR 
Overall response rate 
OS 
Overall Survival 
PE 
Pulmonary Embolism 
PFS 
Progression-free Survival 
PHI 
Protect Health Information 
PP 
Predictive Probability 
PPES 
Palmar-Plantar Erythrodysesthesia 
PRO 
Patient Reported Outcome 
PS 
Performance Status 
QD/q.d. 
quauque die/once daily 
RPED 
Retinal Pigment Epithelial Detachment  
RFS 
Relapse-free Survival 
RVO 
Retinal Vein Occlusion  
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SBP 
Systolic Blood Pressure 
SLNB 
Sentinel Lymph Node Biopsy 
SOP 
Standard Operating Procedure 
SUSAR 
Suspected Unexpected Serious Adverse Reactions 
TBIL 
Total Bilirubin 
TLND 
Full therapeutic lymph node dissection 
ULN 
Upper Limit of Normal 
US 
United States 
WHO 
World Health Organization 


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Glossary of terms 
Assessment 
A procedure used to generate data required by the study 
Biologic 
specimen 
A biological specimen including, for example, blood (plasma, serum), saliva, tissue, urine, 
stool, etc. taken from a study patient 
Dosage 
Dose of the study treatment given to the subject in a time unit (e.g., 100 mg once a day, 
75 mg twice a day) 
Enrollment 
Point/time of subject entry into the study; the point at which informed consent must be 
obtained (i.e., prior to starting any of the procedures described in the protocol). 
Investigational 
drug 
The study drug whose properties are being tested in the study; this definition is consistent 
with US CFR 21 Section 312.3 and Directive 2001/20/EC and is synonymous with 
“investigational new drug”.  
Investigational 
treatment 
All investigational drug(s) whose properties are being tested in the study. This includes 
approved drugs used outside of their indication/approved dosage or tested in a fixed 
combination. Investigational treatment does not include other treatments administered as 
concomitant background therapy required or allowed by the protocol when used within 
approved indication/dosage.  Investigational treatment is synonymous with study 
treatment. 
Medication 
number 
A unique identifier on the label of each study drug package in studies that dispense study 
drug using an IRT system. 
Patient 
An individual with the condition of interest for the study 
Personal Data 
Subject information collected by the Investigator that is transferred to Novartis for the 
purpose of the clinical trial. This data includes subject identifier information, study 
information and biological samples. 
Subject number  
A unique identifying number assigned to each patient who is consented in the study.   
Relapse 
Used interchangeably with recurrence to indicate the return of disease after treatment 
Report and 
Analysis Plan 
A regulatory document which provides evidence of preplanned analyses 
Screen Failure 
A subject who is screened but is not treated or randomized 
Stage-related to 
study timeline 
A major subdivision of the study timeline; begins and ends with major study milestones 
such as enrollment, completion of treatment, etc. 
Stop study 
participation 
Point/time at which the subject came in for a final evaluation visit or when study treatment 
was discontinued whichever is later 
Study completion 
Point/time at which the subject came in for a final evaluation visit or when study drug was 
discontinued whichever is later. 
Study treatment 
discontinuation 
Point/time when subject permanently stops taking study treatment for any reason.  
Study 
drug/treatment 
Any drug (or combination of drugs) administered to the subject as part of the required 
study procedures; includes investigational drug, active drug run-ins. 
In specific examples, it is important to judge investigational treatment component 
relationship relative to a study treatment combination; study treatment, in this case, refers 
to the investigational treatment. 
Subject 
An individual who has consented to participate in this study. 
Subject number 
A unique number assigned to each subject upon signing the informed consent. This 
number is the definitive, unique identifier for the subject and should be used to identify the 
subject throughout the study for all data collected, sample labels, etc. 
Variable 
Information used in the data analysis; derived directly or indirectly from data collected 
using specified assessments at specified time points. 
Withdrawal of 
study consent  
Withdrawal of consent from the study occurs only when a subject does not want to 
participate in the study any longer, and does not allow any further collection of personal 
data 
 


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Protocol summary 
Protocol 
number 
CDRB436F2410 
Full Title 
COMBI-APlus: Open-label, phase IIIb study of dabrafenib in COMBInation with 
trametinib in the Adjuvant treatment of stage III BRAF V600 mutation-positive melanoma 
after complete resection to evaluate the impact on pyrexia related outcomes of an 
adapted pyrexia AE-management algorithm (Plus) 
Brief title 
Phase IIIb study for the effectiveness of an adapted pyrexia AE-management algorithm 
with dabrafenib in combination with trametinib in stage III BRAF V600 mutation-positive 
melanoma after complete resection 
Sponsor and 
Clinical Phase 
Novartis Pharma AG 
Phase IIIb 
Investigation 
type 
Drug 
Study type 
Interventional 
Purpose and 
rationale 
The COMBI-AD study experienced a higher percentage of AEs leading to permanent 
study drug discontinuation than what has been historically seen in the previously pivotal 
studies of unresectable or metastatic melanoma. Pyrexia is the most frequently 
observed adverse event with dabrafenib and trametinib therapy. Pyrexia (Grade 3/4) led 
to hospitalization (11%) and permanent treatment discontinuation (9%) in the adjuvant 
COMBI-AD study. 
In the COMBI-APlus study, optimal management of pyrexia will be assessed to reduce 
adverse outcomes in pyrexia (Grade 3/4 pyrexia, hospitalization due to pyrexia, and 
permanent treatment discontinuation due to pyrexia). In fact, a recently published clinical 
guideline suggests that an improved algorithm for pyrexia management, which focuses 
on early detection of pyrexia, early interruption of dabrafenib and trametinib treatment, 
and recommended use of anti-inflammatory medications to prevent and treat pyrexia 
may reduce adverse outcomes in the management of dabrafenib and/or trametinib-
induced pyrexia.  
The goal of this phase III study is to reduce the incidence of grade 3/4 pyrexia, 
hospitalization due to pyrexia, or permanent treatment discontinuation due to pyrexia 
compared to historical control from COMBI-AD study. 
Primary 
Objective(s)  
The primary objective of this study is to assess whether an adapted AE- management 
algorithm for pyrexia will reduce the incidence of grade 3/4 pyrexia, hospitalization due 
to pyrexia, or permanent treatment discontinuation due to pyrexia compared to historical 
control 
Secondary 
Objectives 
• 
Evaluate the Relapse-free survival (RFS) rate at 12 and 24 months  
• 
Evaluate the Overall survival (OS) rate at 12 and 24 months  
• 
Evaluation of pyrexia  
• 
Evaluate safety (AEs and SAEs) and tolerability: the overall AE rate leading to 
permanent treatment discontinuation by 12 months  
• 
Assess quality of life  
Study design 
This is an open-label Phase IIIb study of dabrafenib in combination with trametinib in the 
adjuvant treatment of melanoma after complete resection. Approximately 600 subjects 
will be enrolled to receive dabrafenib (150 mg BID) and trametinib (2 mg once daily) 
combination therapy for 12 months. At Day 1, subjects will be instructed on the pyrexia 
management algorithm. Doses of study treatment may be modified and/or interrupted for 
management of toxicities associated with study treatment.  There will be an Interim 
Analysis (IA) of the primary endpoint and secondary efficacy endpoint RFS when 
approximately the first 200 subjects dosed have been followed for 6 months (either 
completed 6 months of treatment or discontinued treatment earlier).  
For this study, one study month is equal to 4 weeks or 28 days. 
This study consists of two Periods for Enrolled subjects: 
• 
Treatment Period - subjects will receive up to 12 months of treatment. 
• Follow-up Period - subjects will be followed through 24 months from their first dose 
date for relapse, and through end of study for overall survival. Follow-up will start 
once treatment is complete or is prematurely discontinued and continue through the 
end of the study, regardless of disease recurrence. Follow-up contact prior to 
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be limited to: Patient Reported Outcome information (through 24 months), new anti-
cancer therapy initiated after treatment completion, and survival data. 
Population 
Approximately 600 subjects with completely resected, histologically confirmed, BRAF 
V600 E/K mutation-positive, high-risk [AJCC ed. 8 Stage IIIA (lymph node metastasis >1 
mm), IIIB, IIIC or IIID] cutaneous melanoma, over 18 years old, are expected to be 
enrolled in this study. 
Key Inclusion 
criteria 
The inclusion criteria are as follows: 
• 
 ≥18 years of age 
• 
Signed informed consent must be obtained prior to participation in the study. 
• 
Completely resected histologically confirmed cutaneous melanoma stage IIIA (LN 
metastasis >1 mm), IIIB, IIIC, IIID [AJCC (ed 8)] no more than 12 weeks, from last 
surgery, before Day 1 
• 
V600E/K mutation positive using a validated local test  
• 
Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-1  
• 
Subject has adequate bone marrow and organ function as defined by the following 
laboratory values without continuous supportive treatment (such as blood 
transfusion, coagulation factors and/or platelet infusion, or red/white blood cell 
growth factor administration) as assessed by laboratory for eligibility: 
• 
Hematological 
• 
Coagulation 
• 
Renal 
• 
Hepatic 
• 
 Left ventricular ejection fraction (LVEF) ≥ lower limit of institutional normal (LLN) as 
assessed by echocardiogram (ECHO) or multigated acquisition (MUGA) scan 
• 
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 
Key Exclusion 
criteria 
The exclusion criteria are as follows: 
• 
Uveal or mucosal melanoma  
• 
Evidence of metastatic disease including unresectable in-transit metastasis  
• 
Received any prior adjuvant treatment, including but not limited to chemotherapy, 
checkpoint inhibitors, targeted therapy [e.g., BRAF and/or MEK inhibitors], biologic 
therapy, vaccine therapy, investigational treatment, or radiotherapy for melanoma 
• 
Taken an investigational drug within 28 days or 5 half-lives, whichever is longer, prior 
to Day 1. 
• 
Current or expected use of a prohibited medications (other anticancer therapies, 
other investigational drugs, antiretroviral drugs, herbal remedies, and drugs that are 
strong inhibitors or inducers of CYP3A and CYP2C8). 
• 
Non-melanoma related major surgery or significant traumatic injury ≤ 2 weeks prior to 
start of study treatment. Minor surgical procedures should be completed 7 days 
prior to start of study treatment 
• 
Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs 
chemically related to the study treatments, their excipients, and/or dimethyl 
sulfoxide (DMSO)  
• 
Subjects with known history for testing positive for Human Immunodeficiency Virus 
(HIV) 
• 
Malignant disease, other than that being treated in this study. Exceptions to this 
exclusion include the following: malignancies that were treated curatively and have 
not recurred within 2 years prior to study treatment; completely resected basal cell 
and squamous cell skin cancers and any completely resected carcinoma in situ 
• 
Cardiac or cardiac repolarization abnormality 
• 
A history or current evidence/risk of retinal vein occlusion (RVO) or central serous 
retinopathy 
• 
History of clinically significant or active interstitial lung disease or pneumonitis  
• 
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  


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• 
Women of child-bearing potential, defined as all women physiologically capable of 
becoming pregnant, must use highly effective methods of contraception during 
dosing and for 16 weeks after stopping treatment with trametinib or 2 weeks after 
stopping treatment with dabrafenib whichever is longer. 
• 
Women who are nursing during dosing and for 16 weeks after stopping study 
treatment 
• Male subjects (including those that have had a vasectomy) taking study treatment 
must use a condom during intercourse, and for 16 weeks after stopping treatment, 
and should not father a child during these periods 
Study 
treatment 
The combination of dabrafenib 150 mg twice a day and trametinib 2 mg once a day 
Efficacy 
assessments 
Tumor assessment by investigator’s assessment measured at Month 3, 6, 12, 15, 18 
and 24 
Key safety 
assessments 
• 
Physical examination 
• 
ECOG PS 
• 
Weight and vital signs 
• 
Ophthalmic examination 
• 
12-lead ECGs 
• 
ECHO/MUGA 
• 
Laboratory assessments, including hematology, chemistry, and coagulation 
• 
Monthly pregnancy testing for women of child-bearing potential. 
• Adverse events (AEs), the severity, the relationship to study treatment and the 
seriousness 
Other 
assessments 
• 
Patient reported outcome assessment by Melanoma Subscale of the FACT M 
Data analysis 
• 
The data will be summarized with respect to demographic, baseline characteristics, 
safety observations and efficacy measurements. Categorical data will be presented 
as frequencies and percentages. For continuous data, mean, standard deviation, 
median, minimum, and maximum will be presented.  
• 
The primary analysis will be based on the calculation of the observed pyrexia event 
rate (composite rate of grade 3/4 pyrexia, hospitalization due to pyrexia or 
permanent treatment discontinuation due to pyrexia)  and its 95% two-sided exact 
confidence interval (Clopper and Pearson 1934) up to 12 months of therapy. 
• 
The study will meet its primary objective if the upper bound of the two-sided 95% CI 
is less than 20%. 
• 
The secondary endpoints RFS and OS distribution will be estimated by using Kaplan-
Meier approach. 
• 
One IA for futility of the primary endpoint and the secondary endpoint RFS is planned 
for the study when approximately the first 200 subjects dosed have been followed 
for 6 months (either completed 6 months of treatment or discontinued treatment 
earlier.) 
• The sample size of 600 subjects has been chosen so that the study operating 
characteristics comply with the requirement to have a high probability (> 95%) to 
declare futility at IA if the true 12-month pyrexia event rate is ≥ 20%. 
Key words 
dabrafenib, trametinib, adjuvant, melanoma, combination treatment, pyrexia 


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Amendment 2 (12-Mar-2019) 
As of 12-Mar-2019, 86 sites have been initiated, 311 subjects have enrolled into the study, and 
234 subjects have started treatment in the study. 
Amendment rationale 
The primary purpose of this protocol amendment is to implement clinically relevant feedback 
received from the Health Authorities and participating center’s Ethics Committees upon review 
of the protocol. In addition, study population inclusion criteria was expanded, clarifications and 
corrections are made throughout the protocol, as well as editorial change to improve flow and 
consistency. 
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 
• Protocol Summary Section updated to match the body of the protocol 
• List of Abbreviations was updated  
• Section 3 -  Study Design: Treatment Period was clarified: 
• One study month is equal to 4 weeks or 28 days.  
• Section 5.1 - Inclusion Criteria 
• Removed criteria that patients with unknown primary melanoma are not eligible 
• Section 5.2 – Exclusion Criteria 
• Updated that women of child-bearing potential must use highly effective methods of 
contraception during dosing and for 2 weeks after stopping treatment with dabrafenib 
instead of 4 
• Section 6.5.1.2 Other dose modifications and reductions 
• Added that for study treatment interruptions due to adverse events unrelated to 
dabrafenib and/or trametinib, approval from Novartis Medical Monitor is required to 
restart study treatments after ≥28 days interruption 
• Table 6-7  Mandatory dose modifications and recommended clinical management 
guidelines for abnormal liver enzyme test 
• Updated Grade 3 and 4 mandatory dose modifications to indicate dabrafenib and 
trametinib must be interrupted until recovery to ≤ Grade 1 or baseline and if no 
recovery to ≤ Grade 1 within 4 weeks, permanently discontinue dabrafenib and 
trametinib. 
• Removed following footnote as patients with metastatic disease are not eligible for study: 
For subjects with liver metastasis who begin treatment with Grade 2 AST or ALT, if AST 
or ALT increase by ≥ 50% relative to baseline and last for at least 1 week then the subject 
should be discontinue 
• Table 6-8 Mandatory dose modifications and recommended clinical management 
guidelines for renal function alterations: 
• Updated recommended management guidelines for Grade 1 creatinine level increase 
to repeat serum creatinine within 24 hours for any increase in serum creatinine.  If the 
increase in creatinine is confirmed, assess fluid status and consider fluid bolus and 


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monitor serum creatinine at least every 2 days until back to baseline.  Mandatory 
treatment interruption   
• Updated recommended management guidelines for Grade 2 creatinine level to closely 
monitor serum creatinine   
• Table 6-9 Mandatory dose modifications and recommended clinical management 
guidelines for rash 
• Guidelines updated for Grade 2 and Grade 3: AE resolution to ≤ Grade 1 or baseline 
must occur within a period of 4 weeks since a Grade 2 event has been identified 
• Table 6-10  Mandatory dose modifications and recommended clinical management 
guidelines for pneumonitis 
• Guidelines updated for Grade 2: AE resolution to ≤ Grade 1 or baseline must occur 
within a period of 4 weeks since a Grade 2 event has been identified 
• Table 6-11 General guidelines for dose modification for adverse events suspected to be 
related to dabrafenib and/or trametinib treatment 
• Dose modification language for Grade 4 updated to include restart with dabrafenib 
and trametinib reduced by one dose level per table 6-5 once toxicity resolved to ≤ 
Grade 1 or baseline or permanently discontinue dabrafenib and trametinib at the 
discretion of the investigator.  
• Table 6-17 Mandatory dose modifications and recommended clinical management 
guidelines for diarrhea/colitis 
• Guidelines updated for Grade 3: AE resolution to ≤ Grade 1 or baseline must occur 
within a period of 4 weeks since a Grade 3 event has been identified 
• Table 6-19 Mandatory dose modification and recommended clinical management for 
retinal pigment epithelial detachments (RPED) suspected to be related to trametinib 
treatment 
• Clarified for Grade 2-3 RPED, trametinib should only be restarted at a lower dose if 
improved to ≤ grade 1.  If there is no improvement within 3 weeks, trametinib should 
be permanently discontinued. 
• Table 8.1 Treatment Visit and Assessment Schedule 
• Added “X” for pre-screening visit to include molecular consent and demographic 
information collection 
• Added ECHO/MUGA scan at Month 9 visit 
• Added footnote to indicate Screening and Day 1 Hematology and Clinical Chemistry 
do not need to be repeated if screening labs are drawn within 3 days of Day 1   
• Section 8.1.3 added  Information to be collected on pre-screening failures 
Subjects who signed a Molecular Pre-screening Informed Consent Form but are not BRAF 
V600E/K mutation positive will be considered a pre-screen failure.  
The following eCRFs should be completed for pre-screen failures: 
• Demography 
• Molecular Informed Consent 
• Disposition, including reason for pre-screen failure 
• Biomarker Assessment - BRAF V600 Mutation Result 


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No other data will be entered into the clinical database for subjects who are pre-screen failures, 
unless the subject experienced a Serious Adverse Event during Pre-Screening (see Section 10 
for SAE reporting details)  
• Table 8-3  Follow-up (Post-Relapse) Assessment Schedule 
• Clarified post relapse data collection of disease information will be collected  
• Section 10.1.4 Pregnancy Reporting 
• Corrected  to reflect this study enrolls women who are considered to be of child-
bearing potential using highly effective methods of contraception  
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. 


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Amendment 1 (03-Dec-2018) 
As of  30-Nov-2018, 47 sites have been initiated, 58 subjects have enrolled into the study, and 
37 subjects have started treatment in the study. 
Amendment rationale 
The primary purpose of this protocol amendment is to implement clinically relevant feedback 
received from the Health Authorities and participating center’s Ethics Committees upon review 
of the protocol. In addition, clarifications and corrections are made throughout the protocol as 
well as editorial change to improve flow and consistency. 
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. 
• Protocol Summary Section updated to match the body of the protocol 
• List of Abbreviations was updated  
• Glossary of terms: Patient, Personal Data and Withdrawal of study consent definitions 
updated to align with Novartis template language 
• Table 2-1 Objectives and related endpoints, Section 3 Study Design, Section 4.1 Rationale 
for study design, Section 4.4 Purpose and timing of interim analyses/design adaptations, 
Section 4.5 Risks and benefits, Section 8.3.1 Efficacy Assessments, Section 10.3.1  Data 
Monitoring Committee and Section 12.5.1 Efficacy endpoints removed reference to “key” 
from secondary endpoints 
• Section 3 Study Design, Section 4.4 Purpose and timing of interim analyses/design 
adaptions, Section 4.5 Risks and benefits, Section 10.2.3 Data Monitoring Committee, 
Section 12.5 Data analysis and statistical methods, and Section 12.7 Interim analyses: 
language regarding timing of interim analysis has been updated for consistency and 
clarification  
• Section 3 Study Design, Section 5.1 Inclusion criteria number 3, Table 8-1 and Section 8.3  
Efficacy, section 8.4.7 Laboratory evaluations: updated the term “enrollment” to “Day 1”  
or “First dose of study medication” for clarification at which timepoint specific 
accessments or procedure need to be completed  
• Section 4.1 Rationale for study design and Section 6.5.1.1: replaced the term “treatment-
related” pyrexia with pyrexia “occurring while on study treatment” 
• Section 4.1 Rationale for study design and Section 12.4.1 Definition of Primary Endpoints 
added clarification detailing how the composite endpoint is calculated 
• Section 5.1 Inclusion Criteria:  
• Inclusion Criteria 3: removed “(R0)”; updated to clarify the 12 week window is time 
from last surgery to Day 1; Patients who have previously had Stage III melanoma are 
not eligible; Complete nodal resection is not mandatory for microscopic (SNB) 
disease; Full therapeutic lymph node dissection (TLND) is required for macroscopic 
disease, as per established treatment guidelines. 
• removed hepatic laboratory requirements for patients with liver metastasis; patients 
with liver metastasis are not eligible 
• Section 5.2 Exclusion Criteria:    
• Updated to exclude patients that have received prior neoadjuvant treatment 


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• Updated the timeframe for which females must use highly effective methods of 
contraction after treatment discontinuation 
• For clarity, rephrased the sentence “Male sterilization (at least 6 months prior to 
screening). The vasectomized male partner should be the sole partner for that 
subject.” to  read “Sterilization (at least 6 months prior to screening) for male 
partners. The vasectomized male partner should be the sole partner for that subject”  
• Added hormonal intrauterine device as part of highly effective contraception methods 
allowed  
• Added “and/or trametinib” to the note on Hormonal-based methods  
• Removed the sentence “No additional exclusions may be applied by the investigator, 
in order to ensure that the study population will be representative of all eligible 
subjects” to algin with Novartis template language 
• Section 6.2.1.1 Permitted concomitant therapy requiring caution and/or action:  
• Added  “Moderate inhibitors or inducers of CYP3A and CYP2C8 are to be used with 
caution”  
• Clarified that strong inhibitors or inducers of CYP2C8 or CYP3A4 should be avoided 
and may only be used under special circumstances 
• Added list of the prohibited medications and of medications to be used with caution 
for reference 
• Section 6.5.1 1 Mandatory dose modification and recommended clinical management for 
pyrexia suspected to be related to dabrafenib and/or trametinib treatment and Table 6-4 
Mandatory dose modification and recommended clinical management for pyrexia 
suspected to be related to dabrafenib and/or trametinib treatment: 
• Added definition of pyrexia syndrome “defined as one or more of the following 
symptoms: chills/rigors/night sweats; flu-like symptoms” and it’s distinction  from 
pyrexia 
• Added “In a minority of cases the pyrexia was accompanied by symptoms such as 
severe rigors/chills, dehydration, hypotension, dizziness or weakness and required 
hospitalization” 
• Added “Subjects should be instructed to take non-steroidal anti-inflammatory drugs 
(NSAID) and/or paracetamol and/or metamizole, as appropriate, to control pyrexia 
syndrome (i.e. symptoms without documented temperature ≥ 38°C degrees)” 
• Added the use of oral corticosteroids should be considered to manage acute pyrexia 
refractory to dose interruption and anti-pyretics and to prevent further episodes of 
pyrexia in those with recurrent pyrexia events  
• Added “subjects experiencing pyrexia higher than 40°C (104°F), and/or pyrexia 
associated with rigors, severe chills, dehydration or hypotension, serum creatinine and 
other evidence of renal function should be monitored frequently. The frequency of 
monitoring must be adapted based on the individual clinical presentation.” 
• Added dabrafeinib and trametinib can be interrupted in the presence of the pyrexia 
syndrome at investigators discretion for recurrent pyrexia and should be restarted 
upon improvement of symptoms at the same dose if symptom free for at least 24 
hours. 
• Added for recurrent pyrexia that cannot be managed with dabrafeinib and trametinib 
interruption or prophylactic steroids, dose reductions are required 


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• Added metamizole as a possible anti-pyretic treatment to be given to patients 
• Table 6-8 Mandatory dose modifications and recommended clinical management 
guidelines for renal function alterations: 
• Updated to reflect NCI-CTCAE v4.03 for acute kidney injury  
• Remove language regarding initiation of steroid treatment from the recommended 
management guidelines for all grades 
• Added “hospitalization is indicated with frequent creatinine monitoring” for Grade 3 
creatinine 
• Section 6.5.1.3.14 Mandatory dose modification and management guideline for new 
malignancies suspected to be related to dabrafenib and/or trametinib treatment: Updated to 
say “Monitoring should follow institiuional guidelines and/or as clinically indicated” 
• Section 6.5.1.3.15 Mandatory dose modification and management guideline for visual 
changes suspected to be related to dabrafenib and/or trametinib treatment, and Table 6-18: 
Added recommendation that an ophthalmological evaluation be performed within 24 
hours for cases of patient-reported loss of vision or other visual disturbances 
• Table 6-19 Mandatory dose modification and recommended clinical management for 
retinal pigment epithelial detachments (RPED) suspected to be related to trametinib 
treatment: updated mandatory dose modification requirements for Grade 2-3 RPED 
• Tabe 8-1 Treatment Visit and Assessment Schedule: 
• Removed “enrollment” as an assessment from the table 
• Added one additional ECHO/MUGA assessment within eight weeks of initiating 
treatment (either at Month 1 or at Month 2), to align with product information for 
LVEF monitoring. Added footnote to clarify hepatitis screening is applicable only for 
subjects with a history of chronic HBV and/or HCV 
• Added footnote for ophthalmic examinations with reference to section 8.4.5 for 
details of ophthalmic exams needed and to Table 6-18 for management and dose 
guidelines  
• Table 8-1 Treatment Visit and Assessment Schedule, Table 8-2 Follow-up (Pre-Relapse) 
Assessment Schedule and Table 8-4 Imaging assessments: Added footnote “CT contrast of 
the chest, with contrast-enhanced MRI of the abdomen and pelvis should be substituted 
for full CT scan if the CT frequency defined here is not permitted per country or ethics 
requirements or if CT contrast is contraindicated” 
• Section 8.1.1 BRAF V600E/K pre-screening, removed “Verification of locally 
documented BRAF V600 mutation result must be completed prior to enrollment.”  
• Table 8-4 Imaging assessments and Section 8.3.1.1 Assessment Guideline: deleted “(only 
if MRI contraindicated or unavailable)” 
• Table 8-5 Assessments and Specifications: updated title of table and vitals signs 
specifications to align with Novartis template language  
• Table 8-7 Clinical laboratory parameters collection plan: added footnote making Bands 
optional test for hematology  
• Section 8.4.8.1 Electrocardiogram (ECG) and Table 8-8 ECG collection plan for 
Treatment Period: removed requirement to collect ECGs in triplicates at Screening, Month 
6 and Month 12 
• Section 9.1.2 Withdrawal of informed consent: updated language to align with Novartis 
template language 


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• Section 10.1.3 SAE reporting: deleted the following sentence “complete the SAE Report 
Form in English, and submit the completed, signed form within 24 hours to the oncology 
Novartis Drug Safety and Epidemiology (DS&E) department” this study uses electronic 
SAE submission  
• Section 12.1 Analysis sets, updated to clarify “the Full Analysis Set (FAS) and Safety Set 
are defined in the same way and comprise all subjects who received at least one dose of 
study treatment” 
• Section 12.4.2 Statistical model, hypothesis, and method of analysis:  
• Revised the analysis of the primary endpoint will be based on the upper limit of the 
two-sided exact 95% confidence interval (Clopper and Pearson  1934) 
• Added Table 12-1 Exact 95% CI for different observed event rates at primary analysis 
• Table 12-4 Operating Characteristics: added footnote clarifying that probabilities are 
calculated based on the exact binomial distribution 
• Term “patient” was updated with “subject” when referring study participants to align with 
Novartis template language  
• Added Appendix 16.1 with AJCC Melanoma Staging Eight Edition 
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. 


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1 
Introduction 
1.1 
Background  
Cutaneous melanoma is the most aggressive form of all skin cancers and has the highest rate of 
increasing incidence worldwide. The World Health Organization (WHO) estimated that 
132,000 melanoma skin cancers occur globally each year (WHO 2017). In the United States 
(US), it was estimated that there would be 87,110 new cases of melanoma of the skin and an 
estimated 9,730 people would die of this disease in 2017 (SEER 2017). Surgical excision is the 
treatment of choice for early cutaneous melanoma and is curative in most cases. However, some 
patients will subsequently relapse with disseminated disease. High-risk features in the primary 
tumor (e.g., tumor thickness, ulceration, mitotic rate) and regional lymph node metastasis define 
patient subsets that are at increased risk for recurrent disease (Balch et al., 2009). Patients with 
positive Sentinel Lymph Node Biopsy (SLNB) are at higher risk of recurrence, and might be 
candidates for Complete Lymph Node Dissection (CLND) and/or adjuvant systemic therapy 
(NCCN V1, 2018). In addition to the recent results with drug therapies, it has been demonstrated 
by the DeCOG-SLT and the MSLT-2 trials CLND does not improve melanoma-specific 
survival (Leiter et al., 2016, Faries et al. 2017). It is anticipated that these findings will reduce 
the number of CLNDs in the management of melanoma (Eggermont et al., 2017). 
The overall 5-year relapse-free survival (RFS) rates observed for Stage IIIA, IIIB, and IIIC 
patients were 63%, 32%, and 11%, respectively. The estimated 5-year survival rates for Stages 
IIIA, IIIB, and IIIC from the time of the first relapse were 20%, 20%, and 11%, respectively 
(Romano et al., 2010). According to a multivariate analysis, systemic relapse has been 
associated with shorter survival than regional relapse, particularly for older patients and patients 
experiencing a symptomatic relapse. Of note, more than 40% of patients with Stage III 
melanoma will present with systemic disease at first relapse (observed in 40%, 51%, and 61% 
of patients with Stage IIIA, IIIB, and IIIC disease, respectively) (Romano et al., 2010). 
For patients with completely resected Stage III Melanoma, additional postoperative 
management options may include high-dose or pegylated IFN, High-dose Ipilimumab, 
Nivolumab or Dabrafenib/Trametinib for patients with BRAF V600 activating mutation. 
Selection of active adjuvant treatment in these patients depends on many factors, including 
patients preference, patient age and comorbidities, and risk of recurrence. (NCCN, V1, 2018) 
Prior to the development of checkpoint inhibitor and BRAFV600 targeted therapies, high-dose 
interferon alfa (IFNα) was the only option for adjuvant treatment of high-risk melanoma that 
had demonstrated an improvement in overall survival (OS). The use of high-dose IFNα was 
supported by the results of the Eastern Cooperative Oncology Group (ECOG) 1684 and 
Intergroup E1694 trials (Kirkwood et al, 1996, Kirkwood et al, 2001, respectively) as well as a 
meta-analysis that included results from trials with various schedules and doses of IFNα 
(Kirkwood et al, 2013). Administration of adjuvant high-dose IFNα was associated with 
numerous serious side effects, including acute constitutional symptoms, chronic fatigue, 
myelosuppression, hepatotoxicity, and neurologic and psychologic effects, which were 
experienced to some degree by the majority of patients (Eggermont 2016). IFNα no longer has 
a well-defined role in the adjuvant setting for cutaneous melanoma. The use of high-dose IFNα 
for the high-risk node-negative disease may occasionally be an alternative, but its use should 
be discouraged in favor of clinical trial participation or observation. 
Melanoma is a highly immunogenic tumor, initially suggested by observations of spontaneous 
remissions and identification of lymphocytic responses to primary melanoma (Kirkwood et al., 


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2013). With the availability of new therapies (including immune checkpoint inhibitors, agents 
targeting the BRAF V600 activating mutation and MAPK pathway), significant progress has 
been made for the treatment of metastatic melanoma, translating into improved progression-
free survival (PFS) and OS outcomes (Hodi et al, 2010; Larkin et al, 2015; Larkin et al, 2017; 
Robert et al, 2015; Long et al, 2015; Robert et al, 2016). 
Adjuvant checkpoint inhibitors 
Ipilimumab, an immune checkpoint inhibitor targeting CTLA-4, used at a dosage of 10 mg/kg, 
has shown significant RFS improvement in high-risk Stage III melanoma after complete 
resection [Hazard Ratio (HR)=0.76, 95% confidence interval (CI): 0.64, 0.89] which later 
translated into a survival benefit (HR=0.72, 95% CI: 0.58, 0.88) after a median follow-up of 5.3 
years (Eggermont et al, 2015; Eggermont et al, 2016). Ipilimumab at a dosage of 10 mg/kg was 
approved in the adjuvant setting in the US in October 2015. Nivolumab versus ipilimumab have 
been assessed as adjuvant treatment in resected Stage IIIB, IIIC, or IV melanoma (Weber et al., 
2017). The primary endpoint of RFS was met; showing a HR for disease recurrence or death of 
0.65 (95 % CI, 0.51 to 0.83; P<0.001) favoring the nivolumab arm. The OS data is not yet 
mature. Nivolumab at a dosage of 240 mg every 2 weeks in the adjuvant setting was approved 
in the US in December 2017. 
Adjuvant Targeted therapy 
In the BRIM8 study, vemurafenib was evaluated as adjuvant treatment in patients with resected 
BRAF V600 mutant melanoma in two separate cohorts, Stage IIC-IIIB and Stage IIIC. The 
primary DFS endpoint in the Stage IIIC cohort was not met (HR=0.80; 95% CI 0.54-1.18; 
p=0.25); the DFS results in the Stage IIC-IIIB cohort showed clinical benefit (HR=0.54; 95%CI 
0.37-0.78 p=0.001), although no formal testing was performed. The OS data was not yet mature 
(Lewis et al., 2017). 
The COMBI-AD Study (Study BRF115532, Novartis code: DRB436F2301) evaluated the 
combination of dabrafenib and trametinib versus two placebos in the adjuvant treatment of 
advanced melanoma after complete resection. The study enrolled patients with completely 
resected, histologically confirmed, BRAF V600E/K mutation-positive, high-risk (Stage IIIA, 
IIIB or IIIC) cutaneous melanoma. 
The primary endpoint was RFS, and secondary endpoints included OS, distant metastasis-free 
survival (DMFS), freedom from relapse (FFR), and safety.  The primary endpoint was met, with 
a 53% decrease in the relative risk of disease relapse or death observed with dabrafenib plus 
trametinib vs placebo (HR=0.47 [95% CI, 0.39-0.58]; P<0.001; median RFS, not reached in the 
dabrafenib+trametinib arm vs. 16.6 months in the placebo arm, respectively). RFS benefit with 
the combination treatment was observed across all patient subgroups analyzed, including BRAF 
mutation status, sex, age, disease stage, the presence of micro- or macrometastases and/or 
ulceration, and the number of nodal metastases. The OS results at the first interim analysis 
showed a favorable trend towards survival benefit in the dabrafenib + trametinib arm. Although 
the OS data was not mature, results favored the dabrafenib + trametinib arm, (HR, 0.57 [95% 
CI, 0.42-0.79]; P=0.0006); despite this low P value, the interim statistical significance threshold 
of P=1.9 × 10-5 was not reached. The combination treatment also resulted in DMFS and FFR 
improvements (49% and 53%, respectively) consistent with the RFS improvement observed 
(Long, 2017). In addition, the safety profile of the dabrafenib + trametinib combination in the 
COMBI-AD study was comparable to that observed in other approved indications, including 
unresectable/metastatic melanoma where it has been well characterized with consistent results 


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across two randomized Phase III studies. The AEs were manageable, and no new safety risks 
were identified. 
In unresectable or metastatic melanoma, pyrexia is the most frequently observed adverse event 
with dabrafenib and trametinib therapy (63% in the COMBI-AD study and 54% in the COMBI-
D [MEK115306] and COMBI-V [MEK116513] pooled metastatic melanoma data); the 
majority of the pyrexia events were of grade 1-2, with the same proportion of grade 3/4 (5%) 
in both settings. Pyrexia led to hospitalization in 11% of the patients in the adjuvant setting, and 
a similar proportion of hospitalization is observed in the metastatic setting (12% and 11% in the 
COMBI-D and COMBI-V, respectively). Pyrexia led to permanent treatment discontinuation 
in 9% of patients in the adjuvant setting while a lower proportion is observed in the metastatic 
setting (2% and 3% in the COMBI-D and COMBI-V, respectively). In the adjuvant COMBI-
AD study, 87 of 435 patients (20%) in treatment arm experienced at least one of the following 
adverse outcomes of pyrexia (Grade 3/4 pyrexia, hospitalization due to pyrexia and permanent 
treatment discontinuation due to pyrexia). 
The primary objective of this study is to assess whether an adapted AE-management algorithm 
for pyrexia will reduce the incidence of grade 3/4 pyrexia, hospitalization due to pyrexia, or 
permanent treatment discontinuation due to pyrexia compared to historical control from 
COMBI-AD study. 
Introduction to study treatments 
Dabrafenib (Tafinlar®) is an orally bioavailable, potent and selective RAF kinase inhibitor of 
human wild-type (WT) BRAF and CRAF enzymes as well as the mutant forms of the BRAF 
enzyme: BRAF V600E, V600K, and V600D. The mechanism of action of dabrafenib is 
consistent with competitive inhibition of ATP binding. 
Dabrafenib was first approved by the FDA in 2013 as a single-agent oral treatment for 
unresectable or metastatic melanoma in adult patients with the BRAF V600E mutation. 
Dabrafenib is currently also approved in the EU, Switzerland, Canada, Australia and multiple 
other countries for the treatment of adult patients with unresectable or metastatic melanoma 
with a BRAF V600 mutation. Prior to initiation of dabrafenib, patients must have confirmation 
of tumor BRAF V600 mutation. These approvals include the following limitation of use: 
dabrafenib is not indicated for the treatment of wild-type BRAF melanoma. The recommended 
dose of dabrafenib is 150 mg (two 75 mg capsules) twice daily (BID) (corresponding to a total 
daily dose of 300 mg). 
Trametinib (Mekinist®) is a reversible and highly selective allosteric inhibitor of MEK1 and 
MEK2. MEK proteins are critical components of the MAPK pathway which is commonly 
hyperactivated in tumor cells. Oncogenic mutations in both BRAF and RAS signals through 
MEK1 or MEK2 proteins. Trametinib was first approved by the FDA in 2013 as a single-agent 
oral treatment for unresectable or metastatic melanoma in adult patients with BRAF V600 
mutations. Trametinib is currently also approved in the EU, Canada, and Australia and multiple 
other countries for the treatment of adult patients with unresectable or metastatic melanoma. 
The recommended dose of trametinib is 2 mg once daily (QD). 
Dabrafenib in combination with trametinib was first approved by the FDA in 2014 to treat 
unresectable or metastatic melanoma in adult patients with BRAF V600 mutations. Dabrafenib 
and trametinib are currently approved in more than 60 countries worldwide as monotherapies 
and in combination for the treatment of patients with unresectable or metastatic melanoma with 
a BRAF V600E/K mutation. More recently, the combination was approved in the EU, the US, 


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and Switzerland for the treatment advanced non-small cell lung cancer with a BRAF V600 
mutation, and applications for this indication are currently under review in other countries. 
Based on the positive results of the COMBI-AD study, applications for the adjuvant treatment 
of patients with Stage III melanoma with a BRAF V600 mutation, following complete resection, 
are also being submitted worldwide, and are already under review by a number of health 
authorities. 
Please refer to the local product information for details on the exact indications approved in a 
given country. 
1.1.1 
Clinical Experience 
The below sections provide an overview on the clinical experience with dabrafenib and 
trametinib to date. For more details, please refer to the most current dabrafenib and trametinib 
Investigator’s Brochures (IB). 
1.1.1.1 
Human Pharmacokinetics 
Dabrafenib is absorbed orally with a median time to achieve tmax of 2 hours post-dose. Mean 
absolute bioavailability of oral dabrafenib is 94.5% (90% CI: 81 to 110%). Dabrafenib exposure 
(Cmax and AUC) increased in a dose-proportional manner between 12 and 300 mg following 
single-dose administration, but the increase was less than dose-proportional after repeat BID 
dosing. There was a decrease in exposure observed with repeat dosing, likely due to induction 
of its metabolism. Mean accumulation AUC Day 18/Day 1 ratios was 0.73. Dabrafenib binds 
to human plasma protein and is 99.7% bound. The metabolism of dabrafenib is primarily 
mediated by cytochromes P450 (CYP) 2C8 and CYP3A4 to form hydroxy-dabrafenib, which 
is further oxidized via CYP3A4 to form carboxy-dabrafenib. Carboxy-dabrafenib can be 
decarboxylated via a non-enzymatic process to form desmethyl-dabrafenib. Mean metabolite to 
parent AUC ratios following repeat dose administration were 0.9, 11 and 0.7 for hydroxy-, 
carboxy-, and desmethyl-dabrafenib, respectively. Based on exposure, relative potency, and 
pharmacokinetic properties, both hydroxy- and desmethyl-dabrafenib are likely to contribute to 
the clinical activity of dabrafenib; while the activity of carboxy-dabrafenib is not likely to be 
significant. Dabrafenib terminal half-life is 8 hours. Faecal excretion is the major route of 
elimination after oral dosing, accounting for 71% of a radioactive dose while urinary excretion 
accounted for 23% of radioactivity. 
Trametinib is absorbed orally with a median time to achieve peak concentrations (tmax) of 1.5 
hours post-dose. The mean absolute bioavailability of a single 2 mg tablet dose is 72%. The 
increase in exposure (Cmax and AUC) was dose-proportional following repeat dosing. 
Trametinib accumulates with repeat daily dosing with a mean accumulation ratio of 6.0 
following a 2 mg once daily dose. Mean terminal half-life is 127 hours (5.3 days) after single 
oral dose administration. Steady-state was achieved by Day 15. In vitro and in vivo studies 
demonstrated that trametinib is metabolized predominantly via deacetylation alone or in 
combination with mono-oxygenation. The deacetylated metabolite was further metabolized by 
glucuronidation. The deacetylation is mediated by the carboxyl-esterases 1b, 1c and 2, with 
possible contributions by other hydrolytic enzymes. The drug-related material was excreted 
predominantly in the feces (≥ 81% of recovered radioactivity) and to a small extent in urine 
(≤20%). Less than 0.1% of the excreted dose was recovered as parent in urine. 
Repeated co-administration of dabrafenib 150 mg twice daily and trametinib 2 mg once daily 
resulted in a 16% increase in dabrafenib Cmax and a 23% increase in dabrafenib AUC. A small 


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decrease in trametinib bioavailability, corresponding to a decrease in AUC of 12%, was 
estimated when dabrafenib is administered in combination with trametinib using a population 
pharmacokinetic analysis. These changes in dabrafenib or trametinib Cmax and AUC are 
considered not clinically relevant. 
1.1.1.2 
Drug-drug interaction 
Effects of Other Drugs on Dabrafenib: 
Dabrafenib is primarily metabolized by CYP2C8 and CYP3A4. Strong inhibitors of CYP3A4 
or CYP2C8 may increase concentrations of dabrafenib. Substitution of strong inhibitors of 
CYP3A4 or CYP2C8 is recommended during treatment with dabrafenib. If concomitant use of 
strong inhibitors (e.g., ketoconazole, nefazodone, clarithromycin, gemfibrozil) of CYP3A4 or 
CYP2C8 is unavoidable, patients should be closely monitored for adverse reactions when taking 
strong inhibitors. 
Effects of Dabrafenib on Other Drugs: 
Dabrafenib induces CYP3A4 and CYP2C9. Dabrafenib decreased the systemic exposures of 
midazolam (a CYP3A4 substrate), S-warfarin (a CYP2C9 substrate), and R-warfarin (a 
CYP3A4/CYP1A2 substrate). International normalized ratio (INR) levels should be monitored 
more frequently in patients receiving warfarin during initiation or discontinuation of dabrafenib. 
Coadministration of dabrafenib with other substrates of these enzymes, including 
dexamethasone or hormonal contraceptives, can result in decreased concentrations and loss of 
efficacy. It is recommended to substitute for these medications or monitor patients for loss of 
efficacy if the use of these medications is unavoidable. 
Trametinib is an inducer of CYP3A4 in vitro. However, trametinib’s efficacious dose of 2 mg 
once daily results in a low systemic maximal concentration (22.2 ng/mL or 0.036 μM), relative 
to its in vitro inhibition potency of CYP enzymes and transporters, rendering the risk of an 
inhibitory effect of trametinib on the PK of co-administered CYP or transporter substrates low. 
Trametinib is eliminated primarily via deacetylation and possibly other hydrolases. There is 
little evidence from clinical studies for drug interactions mediated by carboxylesterases. 
Trametinib is also a substrate of P-gp and BSEP. However, due to its high passive permeability, 
these active transport processes are likely of limited relevance. Therefore, a clinically relevant 
effect of a co-administered P-gp or BSEP inhibitor on the PK of trametinib is unlikely. 
No clinically relevant drug-drug interaction (DDI) was observed after repeat dosing dabrafenib 
150 mg twice daily and trametinib 2 mg once daily. 
1.1.1.3 
Clinical safety in unresectable or metastatic melanoma 
Safety data pooled from the dabrafenib and trametinib combination arms of 2 completed phase 
III studies in subjects (N=559) with melanoma [COMBI-D and COMBI-V] based on a cut-off 
date of 13-Mar-2015 are provided below. Data are in comparison to the dabrafenib monotherapy 
arm (N=211) of the COMBI-D and the vemurafenib monotherapy arm (N=349) of the COMBI-
V study. The safety population consists of all subjects who received at least 1 dose of study 
treatment. 
The median duration of follow-up, defined as the time from study start to last contact or death, 
was 19 months for the combination therapy group, 15 months for the vemurafenib group, and 
16 months for the dabrafenib group. 


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The incidences of subjects with any on-therapy AE, study treatment-related AE, all SAEs, and 
study treatment-related SAE were similar between the treatment arms. The incidence of AEs 
leading to study treatment discontinuation, dose reductions, or dose interruptions was similar 
in the combination therapy group and the vemurafenib arm, and higher than in the dabrafenib 
monotherapy arm. The rate of fatal SAEs was higher in the combination therapy group 
compared to the two monotherapy groups. However, no subjects in the combination therapy 
group had fatal SAEs considered related to study treatment by the investigator. 
Common Adverse Events [COMBI-D and COMBI-V studies] 
The most commonly occurring AEs (>20%) in subjects treated with dabrafenib in combination 
with trametinib) were pyrexia, nausea, rash diarrhea, chills, headache, vomiting, hypertension, 
arthralgia, peripheral edema and cough and the most common Grade 3 or 4 AEs (>5%) 
occurring in patients treated with the combination were hypertension and pyrexia. 
The most common AEs leading to discontinuation (>1% of subjects) were pyrexia (2% and 3% 
in the COMBI-D and COMBI-V studies, respectively) and ejection fraction decreased in the 
combination therapy group. 
Adverse events leading to dose reduction or interruption of study treatment [COMBI-D 
and COMBI-V studies] 
In this pooled analysis, 55% of the patients had an AE leading to dose interruption, and 31% of 
the patients had an AE leading to dose reduction. The most common AEs leading to dose 
reduction (>3% of subjects) were pyrexia, and ejection fraction decreased in the combination 
therapy group. Of the most common events, dose reductions due to pyrexia were more common 
in the combination therapy group compared with each monotherapy arm. 
Of the most common AEs leading to dose interruption, dose interruptions due to pyrexia were 
more common in the combination therapy group compared with either monotherapy arm. 
The incidences of pyrexia and neutropenia were higher (>10% difference) in the combination 
therapy group compared with either monotherapy arm. In addition, the incidences of diarrhea, 
hepatic events, hypertension, and edema were higher (>10% difference) in the combination 
therapy group compared with the dabrafenib monotherapy arm only, but similar to vemurafenib, 
and the incidence of bleeding events was higher in the combination therapy group compared 
with the vemurafenib monotherapy arm. 
Skin Toxicities [COMBI-D and COMBI-V studies] 
Skin adverse effects were less frequent in the combination therapy group, especially the events 
linked to a paradoxical activation of the MAPK pathway, including both benign and malignant 
skin tumors. This finding is in accordance with preclinical models showing that the addition of 
MEK inhibitors may down regulate the BRAF inhibitor-induced paradoxical activation of the 
MAPK pathway. Thus, secondary resistance and paradoxical activation of the MAPK pathway 
that occurr with BRAF inhibitor monotherapy, which translate into rapid tumor relapses and 
the emergence of skin cancers, respectively, are both improved by the combination therapy. 
For more details, please refer to the most current dabrafenib and trametinib IBs and the 
approved product information. 


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1.1.1.4 
Clinical efficacy in unresectable or metastatic melanoma 
Both dabrafenib and trametinib have proven anti-tumor activity as monotherapy in BRAF V600 
mutant metastatic melanoma (BREAK 3 and METRIC trials respectively) (Hauschild A, 2012; 
Schadendorf D, 2017). 
The efficacy of dabrafenib and trametinib combination therapy vs. dabrafenib was initially 
assessed in a randomized Phase II study (BRF113220, Cohort C) (Flaherty et al., 2012). The 
combination therapy with dabrafenib (150 mg twice daily) plus trametinib (2 mg once daily 
demonstrated superior PFS over dabrafenib monotherapy. The median PFS in the combination 
group was 9.4 months as compared with 5.8 months in the monotherapy group (HR=0.39; 95% 
CI: 0.25 - 0.62; P<0.001). The overall response rate (ORR) with combination therapy was 76%, 
as compared with 54% in the monotherapy group (P=0.03). At the updated 5-year OS analysis, 
28% of patients treated with dabrafenib plus trametinib monotherapy and 13% of patients 
treated with dabrafenib monotherapy were alive (Long et al., 2017). 
Two randomized Phase III trials confirmed the above results and showed that the combination 
of dabrafenib and trametinib improved OS, PFS, ORR, and duration of response (DOR) versus 
BRAF monotherapy (either dabrafenib or vemurafenib) in unresectable or metastatic melanoma 
(Long et al., 2014; Robert et al., 2015; Long et al., 2017). 
The COMBI-D study assessed dabrafenib and trametinib versus dabrafenib in patients with 
untreated metastatic BRAF V600 mutated melanoma and demonstrated a 29% reduction in the 
risk of death for the combination therapy compared with dabrafenib monotherapy (HR=0.71, 
95% CI: 0.55, 0.92; p=0.011) with a median OS of 25.1 months (95% CI: 19.2–not reached) in 
the combination arm versus 18.7 months (range: 15.2 to 23.7) in the dabrafenib arm. Clinical 
benefit was observed across all other efficacy parameters and sub-groups analyzed (Long et al., 
2017). Additionally, the COMBI-V demonstrated a 31% reduction in the risk of death for the 
combination therapy compared with vemurafenib (HR=0.69, 95% CI: 0.53, 0.89; p=0.005). The 
median OS at the time of the analysis was not reached for the combination therapy arm relative 
to 17.2 months for the vemurafenib monotherapy arm and, as in COMBI-D, clinical benefit was 
observed across all efficacy parameters and subgroups analyzed (Robert et al, 2015). An 
updated 3-year efficacy and safety analysis has confirmed a superior efficacy and good 
tolerability profile supporting the long-term use of the combination across both of these trials 
(Robert et al, 2016).  
1.1.1.5 
Clinical efficacy in adjuvant melanoma 
The COMBI-AD Study evaluated the combination of dabrafenib and trametinib versus two 
placebos in the adjuvant treatment of advanced melanoma after complete resection. The study 
enrolled patients with completely resected, histologically confirmed, BRAF V600E/K 
mutation-positive, high-risk (Stage IIIA, IIIB or IIIC) cutaneous melanoma. 
Please refer to Section 1.1 for details of efficacy study results. 
1.1.1.6 
Clinical safety in adjuvant melanoma 
The safety profile of dabrafenib plus trametinib in the COMBI-AD study is in line with that 
reported in key trials of the combination in patients with BRAF V600E/K–mutant Stage IIIC 
unresectable or Stage IV metastatic melanoma (Flaherty et al., 2012; Long, 2017). 
A total of 435 patients in dabrafenib+trametinib group and 432 patients in the placebo group 
were included in the safety analysis. The median daily dose received by the patients was close 
to the planned dose, indicative of high treatment compliance. The median duration of exposure 


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in the dabrafenib+trametinib arm was 11 months as compared to 10 months for placebo. 
Treatment interruptions and reductions were more frequent in the dabrafenib and trametinib 
arm compared to the placebo arm. Of the AEs that occurred in more than 10% of patients in the 
combination therapy group as compared to the placebo group, the most frequent were pyrexia 
(63% vs. 11%), fatigue (47% vs. 28%), nausea (40% vs. 20%), headache (39% vs. 24%), chills 
(37% vs. 4%) and diarrhea (33% vs. 15%). The percentage of patients with AEs suspected to 
be related to study treatment were higher in the dabrafenib+trametinib arm (91%) compared to 
the placebo arm (63%). Most of the AEs suspected to be related to study treatment were grade 
1 or 2 in severity. 
Grade 3/4 AEs were reported in 41% patients in the dabrafenib+trametinib treatment group and 
14% in placebo group; the most frequently reported AEs in the dabrafenib+trametinib arm were 
hypertension (6%), pyrexia (5%), fatigue (4%), and elevated ALT (4%). Grade 3/4 AEs were 
not frequently reported in the placebo arm. 
While SAEs were reported in both study arms, there was no particular AE that indicated a new 
safety signal. Pyrexia, chills, and decreased ejection fraction were the most common SAEs, 
reported in the dabrafenib+trametinib arm. Additionally, 1 patient had a fatal SAE of 
pneumonia; which was not suspected to be related to study drug. 
Most of the deaths occurring during the study were due to disease progression: 90% (54/60) of 
all deaths in the dabrafenib + trametinib arm and 83% (77/93) in the placebo arm. On-treatment 
deaths occurred in 4 patients (<1%) in the dabrafenib+trametinib arm and 1 patient (<1%) in 
the placebo arm. In the dabrafenib+trametinib arm, 1 patient died due to pneumonia (fatal SAE), 
the 3 remaining deaths were due to disease progression. 
Most patients in the combination arm completed the scheduled treatment duration (63% 
completed all scheduled dabrafenib treatment, and 64% completed all scheduled trametinib 
treatment); 26% of patients permanently discontinued treatment in the dabrafenib and 
trametinib arm vs. 3% in the placebo arm. The most common AEs leading to discontinuation 
common were pyrexia (9%), chills (4%), ALT increase (2%), and headache (2%) of patients. 
The observed overall treatment discontinuation rate (26%) is higher than that observed with 
dabrafenib and trametinib combination in unresectable or metastatic melanoma (13% and 11% 
in the COMBI-D and COMBI-V studies, respectively) (Robert et al., 2015; Long et al., 2014). 
This increased discontinuation rate may be explained by a different threshold in patients’ 
tolerability to side effects in the adjuvant setting. While in an adjuvant setting patients are 
considered cured, in the metastatic setting, the disease is active, and patients may experience 
symptoms; clinical deterioration is present with a shorter life expectancy. Similar observations 
have been made between other adjuvant and metastatic trials in melanoma and other tumor 
types (Hodi et al., 2010, Eggermont et al., 2015, Cuzick et al., 2014, Mehta et al., 2012, Yu et 
al., 2015, Slamon et al., 2001, Lewis et al. 2017). 
Pyrexia-related events were the most frequently observed Adverse Events of Special Interest 
(AESIs); 67% patients in the dabrafenib and trametinib arm and 15% patients in the placebo 
arm, and were mostly grade 1 or 2 in severity. Events were managed by a combination of dose 
modifications and antipyretics, including corticosteroids. 
Hepatic disorder-related AESIs were reported in 21% of patients in the dabrafenib and 
trametinib arm and 3% of patients in the placebo arm; events were primarily grade 1 or 2 
increases in transaminases; AST or ALT increases of >5×ULN were reported in 7% of patients 
and >8×ULN in 2% of patients. Eight patients (2%) met protocol stopping criteria due to liver 
enzyme abnormalities. Three patients treated in the dabrafenib and trametinib arm had a 


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concomitant increase of ALT >3×ULN and bilirubin ≥2×ULN; however, confounding factors 
(including pre-existing liver conditions, high alcohol consumption, reactivation of EBV 
infection during treatment, and other concomitant medications) excluded these from meeting 
the criteria for drug-induced liver injury. 
The AESI of treatment-emergent malignancies were infrequently reported in the dabrafenib and 
trametinib group. These comprised cutaneous squamous cell carcinoma (cuSCC) (including 
keratoacanthoma), non-cutaneous treatment-emergent malignancies, and new primary 
melanomas. cuSCC was reported in the same proportion in both arms (6 patients, 1%, in the 
dabrafenib and trametinib arm, and 5 patients, 1% in the placebo arm). Non-cutaneous 
malignancies were observed in 5 patients (1%) in the dabrafenib+trametinib group and 3 
patients (<1%) in the placebo group. New primary melanomas were reported in 1 patient (<1%) 
in the dabrafenib+trametinib group compared to 6 patients (1%) in the placebo group. The 
incidence of treatment emergent malignancies was consistent with observations from other 
melanoma studies using the BRAF and MEK inhibitor combination therapy (Long et al., 2017; 
Robert et al., 2015). 
No new safety signals emerged in the COMBI-AD study; the safety profile was comparable to 
that observed in other approved indications, with manageable AEs. This consistent safety 
profile further supports the use of this drug combination, as a more tolerable therapy is desirable 
in the adjuvant setting, and many healthcare providers are already experienced with the 
management of therapy-related AEs associated with dabrafenib and trametinib in the metastatic 
setting (Long, 2017). 
The discontinuation rate observed in the COMBI-AD compares favorably to other published 
adjuvant studies where the discontinuation rates due to AEs were higher (PEGinterferon 37%; 
IFNα 37%, ipilimumab 52% (Eggermont et al., 2012; Kirkwood et al., 1996; Eggermont et al, 
2015) 
1.2 
Purpose 
In the dabrafenib plus trametinib arm of the COMBI-AD study (n=435), 114 patients (26.2%) 
experienced AEs leading to permanent study drug discontinuation, a higher percentage than 
what is historically seen in the pivotal studies in unresectable or metastatic melanoma studies 
(13% and 11% in the COMBI-D and COMBI-V studies, respectively (Robert et al., 2015; Long 
et al., 2014). In the COMBI-AD study, 289 patients (66%) had AEs leading to dose interruption, 
and 167 patients (38%) had AEs leading to dose reduction. A similar proportion of dose 
modifications were observed in the metastatic setting (55% for dose interruption and 31% for 
dose reductions). The most common AEs leading to treatment discontinuation in the dabrafenib 
and trametinib arm were pyrexia (9%), chills (4%), ALT increase (2%), and headache (2%). 
In unresectable or metastatic melanoma, pyrexia is the most frequently observed adverse event 
with dabrafenib and trametinib therapy (63% in the COMBI-AD study and 54% in the COMBI-
D and COMBI-V pooled metastatic melanoma data); the majority of the pyrexia events were of 
grade 1-2, with the same proportion of grade 3/4 (5%) in both settings. Pyrexia led to 
hospitalization in 11% of the patients in the adjuvant setting and a similar proportion of 
hospitalization is observed in the metastatic setting (12% and 11% in the COMBI-D and 
COMBI-V, respectively). Pyrexia led to permanent treatment discontinuation in 9% of patients 
in the adjuvant setting while a lower proportion is observed in metastatic setting (2% and 3% 
in the COMBI-D and COMBI-V, respectively). In the adjuvant COMBI-AD study 87 of 435 
patients (20%) in treatment arm experienced at least one of the following adverse outcomes of 


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pyrexia (Grade 3/4 pyrexia, hospitalization due to pyrexia and permanent treatment 
discontinuation due to pyrexia). 
Whilst a number of potential hypothesis for the increased permanent treatment discontinuation 
rates due to pyrexia in the adjuvant setting can be postulated (reduced tolerability threshold for 
AEs in the adjuvant setting vs metastatic; limited pyrexia AE-management experience at the 
time of the study conduct), the optimal management of pyrexia has also been the subject of 
expert discussion. In fact, a recently published clinical guideline suggests that an improved 
algorithm for pyrexia management, which focuses on early detection of pyrexia, early 
interruption of dabrafenib and trametinib treatment, and recommended use of anti-inflammatory 
medications to prevent and treat pyrexia may reduce adverse outcomes in the management of 
dabrafenib and/or trametinib-induced pyrexia (Atkinson 2016). However, this clinical 
guideline, including the effectiveness of anti-inflammatory medications to prevent and treat 
pyrexia, has not yet been prospectively studied. 
The objective of this study is to assess whether an adapted AE-management algorithm for 
pyrexia (Fever > 38 °C), will reduce adverse outcomes in pyrexia (Grade 3/4 pyrexia, 
hospitalization due to pyrexia, and permanent treatment discontinuation due to pyrexia). The 
targeted patient population for this study overlaps with the one enrolled in the COMBI-AD 
study and is defined by patients with high-risk [AJCC ed. 8 Stage IIIA (lymph node 
metastasis >1 mm), IIIB, IIIC or IIID] BRAF V600E/K mutation-positive melanoma after 
complete resection. 
2 
Objectives and endpoints 
Objectives and related endpoints are described in Table 2-1 below. 
Table 2-1 
Objectives and related endpoints 
Objective(s) 
Endpoint(s) 
Primary objective(s) 
Endpoint(s) for primary objective(s) 
To assess whether an adapted AE- management algorithm 
for pyrexia will reduce the incidence of grade 3/4 pyrexia, 
hospitalization due to pyrexia, or permanent treatment 
discontinuation due to pyrexia compared to historical control 
The composite rate of grade 3/4 pyrexia, 
hospitalization due to pyrexia, or permanent 
treatment discontinuation due to pyrexia by 12 
months in overall treated subjects 
Secondary objective(s) 
Endpoint(s) for secondary objective(s) 
 
Secondary Objectives 
RFS rate at 12 and 24 months  
 
 
RFS is defined as the time from the first dose 
of the study medication to disease recurrence 
or death from any cause at 12 and 24 months 
OS rate at 12 and 24 months 
OS is defined as the time from the first dose of 
study medication to date of death due to any 
cause at 12 and 24 months 
Other Secondary Objectives 
To evaluate the life quality: Health-Related Quality Of Life 
(HRQOL) measures assessed using FACT-M 
 
Changes in the HRQOL from baseline will be 
assessed using by FACT-M questionnaire 
To evaluate the overall AE rate leading to permanent 
treatment discontinuation by 12 months 
The proportion of subjects in the study who 
permanently discontinued treatment due to any 
Adverse event by 12 months 
To evaluate pyrexia 
Frequency, number of episodes, duration, AE 
management (including concomitant 
medications and study treatment modifications) 
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Objective(s) 
Endpoint(s) 
To evaluate safety (AEs and SAEs)  
Safety will be assessed by the frequency and 
severity of adverse events (AEs), serious AEs 
(SAEs) and laboratory abnormalities 
3 
Study design 
This is an open-label Phase IIIb study of dabrafenib in combination with trametinib in the 
adjuvant treatment of melanoma after complete resection. Patients with completely resected, 
histologically confirmed, BRAF V600E/K mutation-positive, high-risk [AJCC ed. 8 Stage IIIA 
(lymph node metastasis >1 mm), IIIB, IIIC or IIID] cutaneous melanoma will be screened for 
eligibility. 
The main purpose of the study is to assess whether an adapted AE-management algorithm for 
pyrexia (Fever (> 38 °C), Section 6.5.1.1), will reduce the incidence of Grade 3/4 pyrexia, 
hospitalization due to pyrexia and permanent treatment discontinuation due to pyrexia. The 
effectiveness of dabrafenib and trametinib therapy in this setting will also be assessed based on 
RFS and OS. 
Approximately 600 subjects will be enrolled to receive dabrafenib (150 mg BID) and trametinib 
(2 mg once daily) combination therapy for 12 months. At Day 1, subjects will be instructed on 
the pyrexia management algorithm (refer to Section 6.5.1.1). Doses of study treatment may be 
modified and/or interrupted for management of toxicities associated with study treatment 
(Section 6.5.1.1). There will be an IA of the primary endpoint and secondary efficacy endpoint 
RFS when approximately the first 200 subjects dosed have been followed for 6 months  (either 
completed 6 months of treatment or discontinued treatment earlier (see Section 4.4). 
For this study, one study month is equal to 4 weeks or 28 days. 
This study consists of two Periods for Enrolled subjects: 
• Treatment Period – subjects will receive up to 12 months of treatment (refer to the 
schedule as noted in Table 8-1). 
• Follow-up Period – subjects will be followed from treatment discontinuation through 24 
months from their first dose date for relapse; and will be followed for overall survival 
through withdrawal, lost to follow-up, death, or the end of study (see definition in Section 
9.2), whichever occurs first.  Follow-up will start once: 1) treatment is completed; or 2) is 
prematurely discontinued and continue until withdrawal, lost to follow-up, death, or the 
end of study even if disease recurs. Follow-up contact prior to disease recurrence and 
through the 24 month assessment will include clinic visits (refer to the schedule as noted 
in Table 8-2). Follow-up after disease recurrence and until EoS should follow the schedule 
as noted in Table 8-3. 


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Figure 3-1 
Study design 
 
4 
Rationale   
4.1 
Rationale for study design 
The COMBI-AD study demonstrated significant improvements with dabrafenib and trametinib 
in the adjuvant treatment of stage III BRAF V600E/K mutation-positive melanoma and this 
combination is already recommended in treatment guidelines as a new standard of care (NCCN 
2017).  
Considering that pyrexia is a common and well-characterized adverse event, it is observed early 
in the course of dabrafenib and trametinib treatment and presenting multiple occurrences in 
some patients. Therefore, an adapted pyrexia AE-management algorithm will be prospectively 
implemented in this single-arm, multicenter, phase IIIb study in order to evaluate the reduction 
of adverse outcomes of pyrexia (grade 3/4 pyrexia, hospitalization due to pyrexia, and 
permanent treatment discontinuation due to pyrexia).  
This single-arm study does not have a control population. The COMBI-AD study will serve as 
a benchmark for the incidence of pyrexia over 12 months of treatment, an endpoint that is valid 
because most events were observed within this period. A phase IIIb, single-arm, non-
randomized trial design for this study was chosen over a controlled study to compare AE 
management algorithms because of logistical issues, as it cannot be predicted which subjects 
will develop pyrexia while on study treatment. Also, unblinded randomization of different AE 
management algorithms in a controlled study would be subject to selection bias, and the 
COMBI-AD study provides a benchmark for historical comparison. 
This study will consist of two periods for enrolled subjects: the Treatment period and the 
Follow-up period. The Treatment Period will enroll approximately 600 subjects with high-risk 
stage III BRAF V600E/K mutation-positive melanoma after complete resection. Subjects 
fulfilling the eligibility criteria will be enrolled to receive dabrafenib and trametinib for up to 
12 months. The Follow-up Period will include all subjects from study treatment discontinuation 
through EoS, death, withdrawal of consent, or lost to follow-up, whichever occurs first.  
The primary endpoint in the Treatment Period is the composite rate of grade 3/4 pyrexia, 
hospitalization due to pyrexia, or permanent treatment discontinuation due to pyrexia among 
all treated subjects for up to twelve months of therapy.  
The rate of the composite primary endpoint is defined as the total number of subjects 
experiencing at least one of the three components of the composite endpoint (i.e., Grade 3/4 
pyrexia, hospitalization due to pyrexia, or permanent treatment discontinuation due to pyrexia), 
divided by the total number of subjects treated in the study. In the COMBI-AD study, 23 (5%) 


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subjects had grade 3/4 pyrexia, 46 (11%) subjects were hospitalized due to pyrexia and 38 (9%) 
subjects permanently discontinued due to pyrexia. In total, in COMBI-AD, 87 out of 435 
subjects in the treatment arm (20%) developed either grade 3/4 pyrexia or hospitalization due 
to pyrexia or discontinued due to pyrexia. This rate of 20% will be used as the historical control 
rate for the assessment of pyrexia management algorithm in this study. 
In the absence of control arm in the study, the composite rate due to adverse outcomes of pyrexia 
in the study will be compared with the 20% historical rate observed in COMBI-AD study. 
As this is the first trial to prospectively test the algorithm, an IA of the primary endpoint and 
secondary efficacy endpoint RFS at 6 months is planned which will allow assessing the futility 
of the adapted algorithm. Please refer to Section 4.4.  
The secondary endpoints of RFS and OS (12 and 24 months) will be assessed across both 
periods in the study based on efficacy assessment guidelines in the COMBI-AD study. Subjects 
will be followed up to EoS, death, withdrawal of consent, or lost to follow-up, whichever occurs 
first, but will only have on-study tumor assessments through 24 months after first dose of study 
treatment. Other secondary endpoints include the evaluation of the overall adverse events rate 
leading to permanent treatment discontinuation at 12 months, overall safety and tolerability, as 
well as patient-reported outcomes (FACT-M) through 24 months. 
4.2 
Rationale for dose/regimen and duration of treatment 
Rationale for dabrafenib dose 
The dabrafenib dose is 150 mg BID (corresponding to a total daily dose of 300 mg) which is 
the approved dose for patients with unresectable or metastatic melanoma with BRAF V600E or 
V600K mutations and the dose, which was tested in the adjuvant phase III study COMBI-AD. 
Rationale for trametinib dose 
Trametinib will be administered as 2 mg QD, which is the approved dose for patients with 
unresectable or metastatic melanoma with BRAF V600E or V600K mutations and the dose 
which was tested in the adjuvant phase III study COMBI-AD. 
Rationale for combination dose 
The active biological dose range of trametinib and dabrafenib was established based on 
pharmacodynamics parameters, assessing dose-dependent tumor changes in phosphorylated 
ERK, Ki67, and p27 consistent with enzymatic pathway inhibition (Infante et al., 2012; 
Falchook et al., 2014). The randomized, Phase II doses of trametinib and dabrafenib as single 
agents were determined to be 2 mg once daily and dabrafenib 150 mg BID, respectively. 
According to pharmacodynamic models, these doses have shown near to maximum predicted 
target inhibition. The same doses were confirmed in the COMBI-D study for the trametinib 
+dabrafenib combination and implemented in pivotal studies in metastatic melanoma (Flaherty 
et al., 2012; Long et al., 2014; Robert et al., 2015). 
The approved doses of dabrafenib 150 mg BID and trametinib 2 mg QD will be used in the 
Treatment Period of this study, and is aligned with the doses and treatment duration as used in 
the COMBI-AD trial. 
4.3 
Rationale for choice of control drugs (comparator/placebo) or 
combination drugs 
Not applicable 


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4.4 
Purpose and timing of interim analyses/design adaptations 
One IA of the primary endpoint and secondary efficacy endpoint RFS is planned for the study 
when approximately the first 200 subjects dosed have been followed for 6 months  (either 
completed 6 months of treatment or discontinued treatment earlier.) This analysis will allow 
assessing the effect of an adapted pyrexia treatment algorithm on the primary endpoint and RFS 
at 6 months.  As this is the first trial to prospectively test the algorithm, the IA will allow for 
the assessment of futility of the adapted algorithm. Please refer to Sections 10.2.3 and 12.7. 
4.5 
Risks and benefits  
The risk associated with participation in this study can be modeled after the results of the 
COMBI-AD study. In this study, a total of 435 patients in dabrafenib and trametinib group and 
432 patients in the placebo group were included in the safety analysis. For details on the adverse 
events observed in the COMBI-AD study, refer to Section 1.1.1.5. For details of efficacy 
benefits observed, refer to Section 1.1.1.6. 
Of the AEs that occurred in more than 10% of patients in the combination therapy group as 
compared to the placebo group, the most frequent were pyrexia (63% vs. 11%), fatigue (47% 
vs. 28%), nausea (40% vs. 20%), headache (39% vs. 24%), chills (37% vs. 4%) and diarrhea 
(33% vs. 15%). The percentage of patients with AEs suspected to be related to study treatment 
were higher in the dabrafenib and trametinib arm (91%) compared to the placebo arm (63%). 
Most of the AEs suspected to be related to study treatment were grade 1 or 2 in severity. 
Grade 3/4 AEs were reported in 41% patients in the dabrafenib and trametinib treatment group 
and 14% in placebo group; the most frequently reported AEs in the dabrafenib and trametinib 
arm were hypertension (6%), pyrexia (5%), fatigue (4%), and elevated ALT (4%). Grade 3/4 
AEs were not frequently reported in the placebo arm. 
While SAEs were reported in both study arms, there was no particular AE that indicated a new 
safety signal. Pyrexia, chills, and decreased ejection fraction were the most common SAEs, 
reported in the dabrafenib and trametinib arm. Additionally, 1 patient had a fatal SAE of 
pneumonia; which was not suspected to be related to study drug. 
In unresectable or metastatic melanoma, pyrexia is the most frequently observed adverse event 
with dabrafenib and trametinib therapy (63% in the COMBI-AD study and 54% in the COMBI-
D and COMBI-V pooled metastatic melanoma data); the majority of the pyrexia events were of 
grade 1-2, with the same proportion of grade 3-4 (5%) in both settings. Pyrexia led to 
hospitalization in 11% of the patients in the adjuvant setting, and a similar proportion of 
hospitalization is observed in the metastatic setting (12% and 11% in the COMBI-D and 
COMBI-V, respectively). Pyrexia led to permanent treatment discontinuation in 9% of patients 
in the adjuvant setting while a lower proportion is observed in the metastatic setting (2% and 
3% in the COMBI-D and COMBI-V, respectively). In the adjuvant COMBI-AD study 87 of 
435 patients (20%) in treatment arm experienced at least one of the following adverse outcomes 
of pyrexia (Grade 3/4 pyrexia, hospitalization due to pyrexia and permanent treatment 
discontinuation due to pyrexia). 
Besides the already demonstrated efficacy benefit of the adjuvant treatment with the 
combination of dabrafenib and trametinib, an additional potential benefit for the subjects 
participating in this study is that they will follow a recently published algorithm for pyrexia 
management, which may reduce adverse outcomes of dabrafenib and/or trametinib-induced 
pyrexia (Atkinson 2016). These potential benefits may lead to improved quality of life and may 
prevent subjects from prematurely discontinuing an efficacious treatment with a potential 


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negative impact on clinical outcome. Although this adapted algorithm has not been 
prospectively tested before, the algorithm is not anticipated to adversely impact patient 
outcomes. 
This study incorporates routine safety monitoring and regularly scheduled safety assessments 
to identify and report any potential safety issues. All subjects must have routine safety 
evaluations through permanent discontinuation of study drug (See Table 8-1). Comprehensive 
dose modification, stopping rules and toxicity management plan for drug-related adverse events 
are provided in Section 6.5.1. Appropriate eligibility criteria as well as specific dose 
modification and stopping rules along with adverse event management guidelines Section 
6.5.1.2, are included in this protocol. Recommended guidelines for prophylactic or supportive 
treatment for expected toxicities, including management of study-drug induced adverse events, 
i.e., skin toxicity and diarrhea are provided in Section 6.5.1. 
The risk to subjects in this trial is further minimized by compliance with the eligibility criteria, 
study procedures, and close clinical monitoring. In summary, the data from phase I-III studies 
on the combination of dabrafenib and trametinib indicate that the majority of adverse events in 
patients receiving dabrafenib and trametinib combination have been manageable. In addition, 
prior to enrollment, this protocol will undergo appropriate review by local and regional 
governance bodies including ethics committees and drug regulatory bodies. 
As the adverse event management algorithm for pyrexia is being tested prospectively for the 
first time in this study, an IA for futility has been included after the first 200 subjects dosed 
have been followed for 6 months (either completed 6 months of treatment or discontinued 
treatment earlier.) At the time of IA, if futility for the primary endpoint or secondary endpoint 
of RFS is reached, the independent Data Monitoring Committee (DMC) will recommend 
whether to continue, modify or terminate the trial.  In the event the study is terminated due to 
futility, study subjects currently on treatment who are still deriving clinical benefit will be 
eligible to receive medication through a locally established Novartis program. 
The safety profile of the combination of dabrafenib and trametinib reflects the safety profiles 
of the individual agents, with adverse events that are manageable with appropriate intervention, 
as described in the product labeling. No new safety signals were emerged in in the COMBI-AD 
study; the safety profile was comparable to that observed in other approved indications, with 
manageable AEs. As observed previously in the melanoma setting, pyrexia remains the most 
common AE and requires appropriate clinical management. 
Taken together, the results of pivotal studies with dabrafenib and trametinib in the metastatic 
and adjuvant melanoma settings demonstrate the treatment benefit of the combination therapy 
with an acceptable safety profile with manageable AEs. Thus, the benefit-risk assessment 
remains positive. 
Women of childbearing potential and sexually active males must be informed that taking the 
study treatment may involve unknown risks to the fetus if pregnancy were to occur during the 
study, and agree that in order to participate in the study they must adhere to the contraception 
requirements outlined in the exclusion criteria. If there is any question that the subject will not 
reliably comply, they should not be entered or continue in the study. 


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5 
Population 
Approximately 600 subjects with completely resected, histologically confirmed, BRAF 
V600E/K mutation-positive, high-risk [AJCC ed. 8 Stage IIIA (lymph node metastasis >1 mm), 
IIIB, IIIC or IIID] cutaneous melanoma, over 18 years old, are expected to be enrolled in this 
study. BRAF V600E/K mutation status will be determined locally with validated diagnostic 
kits.  Subjects enrolled in this study are not permitted to participate in additional parallel 
investigational drug or device studies. 
The investigator or designee must ensure that only subject who meet all of the inclusion and 
none of the exclusion criteria are entered into this protocol. Deviation from any entry criterion 
excludes a subject from enrollment into the study. Subjects will not be permitted to re-screen 
once they are deemed a screen failure. Subjects who discontinue the study will not be replaced. 
5.1 
Inclusion criteria 
Subjects eligible for inclusion in this study must meet all of the following criteria: 
1.  ≥18 years of age 
2. Signed informed consent must be obtained prior to participation in the study. 
3. Completely resected histologically confirmed cutaneous melanoma stage IIIA (LN 
metastasis >1 mm), IIIB, IIIC, IIID [AJCC (ed 8) see appendix 16.1] no more than 12 
weeks, from last surgery, before Day 1 
a. Subjects presenting with initial resectable lymph node recurrence after a diagnosis of 
Stage I or II melanoma are eligible. 
b. Patients who have previously had Stage III melanoma at any time are not eligible  
c. Recovered from definitive surgery (e.g. no uncontrolled wound infections or 
indwelling drains).  
d. Complete nodal resection is not mandatory for microscopic (SNB) disease  
e. Full therapeutic lymph node dissection (TLND) is required for macroscopic disease, 
as per established treatment guidelines. 
4. V600E/K mutation positive using a validated local test  
5. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-1  
6. Subject has adequate bone marrow and organ function as defined by the following 
laboratory values without continuous supportive treatment (such as blood transfusion, 
coagulation factors and/or platelet infusion, or red/white blood cell growth factor 
administration) as assessed by laboratory for eligibility: 
• Hematological 
• Absolute neutrophil count ≥ 1.5 × 109/L 
• Platelet count ≥ 100 × 109/L 
• Hemoglobin ≥ 9 g/dL 
• Coagulation 
• PT/INR and PTT ≤ 1.5 x ULN. Subjects receiving anticoagulation treatment may 
be allowed to participate with INR established within the therapeutic range prior 
to Day 1 
• Renal 
• Serum creatinine < 1.5 mg/dL 
• Hepatic 


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• Total bilirubin ≤ 1.5 x ULN except for subjects with Gilbert’s syndrome who 
may only be included if the total bilirubin is ≤ 3.0 × ULN or direct bilirubin ≤ 1.5 
× ULN 
• Aspartate transaminase (AST) < 2.5 × ULN 
• Alanine transaminase (ALT) < 2.5 × ULN 
• Albumin ≥ 2.5 g/dL 
7. Left ventricular ejection fraction (LVEF) ≥ lower limit of institutional normal (LLN) as 
assessed by ECHO or MUGA scan 
8. 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 
5.2 
Exclusion criteria 
Subjects meeting any of the following criteria are not eligible for inclusion in this study. 
1. Uveal or mucosal melanoma  
2. Evidence of metastatic disease including unresectable in-transit metastasis  
3. Received any prior adjuvant or neoadjuvant treatment, including but not limited to 
chemotherapy, checkpoint inhibitors, targeted therapy [e.g., BRAF and/or MEK 
inhibitors], biologic therapy, vaccine therapy, investigational treatment, or radiotherapy 
for melanoma 
4. Taken an investigational drug within 28 days or 5 half-lives, whichever is longer, prior to 
Day 1. 
5. Current or expected use of prohibited medications (other anticancer therapies, other 
investigational drugs, antiretroviral drugs, herbal remedies, and drugs that are strong 
inhibitors or inducers of CYP3A and CYP2C8). 
6. Non-melanoma related major surgery or significant traumatic injury ≤ 2 weeks prior to the 
start of study treatment. Minor surgical procedures should be completed 7 days prior to 
start of study treatment 
7. Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs 
chemically related to the study treatments, their excipients, and/or dimethyl sulfoxide 
(DMSO)  
8. Subjects with known history for testing positive for Human Immunodeficiency Virus 
(HIV) 
9. Malignant disease, other than that being treated in this study. Exceptions to this exclusion 
include the following: malignancies that were treated curatively and have not recurred 
within 2 years prior to study treatment; completely resected basal cell and squamous cell 
skin cancers and any completely resected carcinoma in situ 
10. Cardiac or cardiac repolarization abnormality, including any of the following: 
• History or current diagnosis of cardiac disease indicating a significant risk of safety 
for subjects participating in the study such as uncontrolled or significant cardiac 
disease, including any of the following: 
• Recent (within last 6 months) myocardial infarction  
• Unstable angina (within last 6 months), 
• Uncontrolled congestive heart failure  


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• Clinically significant (symptomatic) cardiac arrhythmias (e.g., sustained ventricular 
tachycardia, and clinically significant second or third-degree atrioventricular block 
without a pacemaker) 
11. A history or current evidence/risk of retinal vein occlusion (RVO) or central serous 
retinopathy including: 
• Presence of predisposing factors to RVO or central serous retinopathy (e.g., 
uncontrolled glaucoma or ocular hypertension, uncontrolled hypertension, 
uncontrolled diabetes mellitus, or a history of hyperviscosity or hypercoagulability 
syndromes); or 
• Visible retinal pathology as assessed by ophthalmic examination that is considered a 
risk factor for RVO or central serous retinopathy such as: 
• Evidence of new optic disc cupping; 
• Evidence of new visual field defects on automated perimetry; 
• Intraocular pressure >21 mmHg as measured by tonometry. 
12. History of clinically significant or active interstitial lung disease or pneumonitis  
13. 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  
14. Pregnant or nursing (lactating) women confirmed by a positive hCG laboratory test within 
72 hours prior to initiating study treatment.  
15. Women of child-bearing potential, defined as all women physiologically capable of 
becoming pregnant, must use highly effective methods of contraception during dosing and 
for 16 weeks after stopping treatment with trametinib or 2 weeks after stopping treatment 
with dabrafenib whichever is longer. Highly effective contraception methods include: 
a. Total abstinence (when this is 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. 
b. Female sterilization (have had surgical bilateral oophorectomy with or without 
hysterectomy), total hysterectomy, or tubal ligation at least six weeks before 
taking study treatment. In case of oophorectomy alone, only when the 
reproductive status of the woman has been confirmed by follow up hormone 
level assessment. 
c. Sterilization (at least 6 months prior to screening) for male partners. The 
vasectomized male partner should be the sole partner for that subject. 
d. Placement of a hormonal or non-hormonal intrauterine device (IUD) or 
intrauterine system (IUS) with a documented failure rate of less than 1% per 
year.  
NOTES:  
• Double-barrier contraception: condom and occlusive cap (diaphragm or 
cervical/vault caps) with a vaginal spermicidal agent 
(foam/gel/cream/suppository) are not considered highly effective methods of 
contraception. 


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• Hormonal-based methods (e.g., oral contraceptives) are not considered as highly 
effective methods of contraception due to potential drug-drug interactions with 
dabrafenib and/or trametinib. 
• Women are considered post-menopausal and not of child bearing potential if they 
have had 12 months of natural (spontaneous) amenorrhea with an appropriate 
clinical profile (i.e. age appropriate, history of vasomotor symptoms) or have had 
surgical bilateral oophorectomy (with or without hysterectomy), total 
hysterectomy, or tubal ligation at least six weeks ago. In the case of 
oophorectomy alone, only when the reproductive status of the woman has been 
confirmed by follow up hormone level assessment is she considered not of child 
bearing potential. 
16. Male subjects (including those that have had a vasectomy) taking study treatment must use 
a condom during intercourse, and for 16 weeks after stopping treatment, and should not father 
a child during these periods or donate sperm. 
6 
Treatment 
6.1 
Study treatment 
The term ‘study treatment’ is used throughout the protocol to describe the combination of 
dabrafenib 150 mg BID and trametinib 2 mg QD. Study treatment may, therefore, refer to the 
individual study treatments or the combination of those study treatments. 
6.1.1 
Investigational and control drugs 
Dabrafenib and trametinib will either be sourced as local commercial or provided as global 
clinical open-label supply. Global clinical open-label supply will be provided in bottles. 
Trametinib will be provided as 0.5 mg and 2 mg tablets, and dabrafenib as 50 mg and 75 mg 
capsules for oral administration.  
All dosages prescribed and dispensed to subjects and all dose changes during the study must be 
recorded on the Dosage Administration Record (DAR) eCRF. 
Table 6-1 
Investigational drug 
Investigational 
(Name and Strength) 
Pharmaceutical 
Dosage Form 
Route of 
Administration 
Supply type 
Sponsor 
(global or 
local) 
dabrafenib 50 mg, 75 mg 
Capsules 
Oral use 
Open-label subject 
packs; bottles 
Novartis or 
locally 
trametinib 0.5 mg, 2 mg 
Tablets 
Oral use 
Open-label subject 
packs; bottles 
Novartis or 
locally  
6.1.2 
Additional study treatments  
No additional treatment beyond study treatment are included in this trial. 
6.1.3 
Treatment arms/group  
There will be only one treatment arm in the study - dabrafenib 150mg BID (300mg/day) with 
trametinib 2mg QD. Subjects will be assigned treatment at Day 1. 


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6.1.4 
Guidelines for continuation of treatment  
Guidelines on management of common dabrafenib or trametinib associated toxicities and dose 
modification instructions are provided in Section 6.5.1. 
6.1.5 
Treatment duration 
Subjects will receive study treatment for twelve months  or until the subject experiences one of 
the following: disease recurrence by investigator’s assessment, unacceptable toxicity, treatment 
is discontinued at the discretion of the investigator or the subject, start of a new anti-neoplastic 
therapy, withdrawal of consent, lost to follow-up, pregnancy, death, or study is terminated by 
the sponsor. 
6.1.5.1 
Treatment beyond disease relapse 
Post relapse therapy will be permitted during the study in the Follow-up Period per Investigator 
discretion, but not provided or administered as study treatment. 
6.2 
Other treatment(s)  
During study treatment and until disease relapse, subjects must not receive other additional 
investigational drugs, devices, chemotherapy, or any other therapies that may be active against 
cancer. 


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6.2.1 
Concomitant therapy 
The investigator must instruct the subject to notify the study site of any new medication(s) 
he/she takes after start of study participation. All prescription medications, OTC drugs and 
significant non-drug therapies (including physical therapy, herbal/natural medications and 
blood transfusions) taken within 28 days or 5 half-lives, whichever is shorter, including 
vitamins taken within one week prior to dosing must be recorded on the ‘Concomitant 
Medications’ or ‘Prior or Concomitant non-drug therapies/procedures’ eCRF. Prior 
antineoplastic surgery(ies) are to be recorded on the separate ‘Prior Antineoplastic Surgery’ 
eCRF page during screening. Medication entries must be specific to trade name, dose and units, 
frequency and route of administration, start and discontinuation dates, and reason for therapy. 
For medications administered one time, the frequency column may reflect “once”. 
Administration of certain concomitant medications may lead to the requirement for subject to 
be discontinued. Discussions regarding discontinuation of subjects requiring concomitant 
medication will be discussed with Novartis on a case-by-case basis. 
In general, concomitant medications and therapies deemed necessary for the supportive care 
(e.g., such as anti-emetics, anti-diarrhea) and safety of the subject are allowed except those 
prohibited in Section 6.2.2. Please refer to Section 6.5.1.1 for details of supportive care for 
pyrexia management. 
Subjects are permitted to use the following medications during study treatment: 
• Antivirus medications to manage HBV or HCV infection and/or prevent reactivation (e.g., 
tenofovir); supportive care. 
• Medications to prevent or treat nausea or vomiting. 
• Anti-diarrheal medications (e.g., loperamide) for subjects who develop diarrhea. 
• Pain medication to allow the subject to be as comfortable as possible. 
• Nutritional support or appetite stimulants (e.g., megestrol). 
• Oxygen therapy and blood products or transfusions. 
• Inactivated vaccines. 
• The subject must be told to notify the investigational site about any new medications 
he/she takes after the start of the study drug.  
All medications (other than study drug) and significant non-drug therapies (including physical 
therapy, herbal/natural medications and blood transfusions) administered after the subject 
signed consent and through 30 days after the last dose of study treatment must be listed on the 
Concomitant Medications or the Procedures and Surgical and Medical Procedures eCRF. 
Any anti-neoplastic therapy (including surgery, radiotherapy, medications) administered in the 
Follow-up Period after discontinuation of study treatment must be listed on Antineoplastic 
Medication Since Discontinuation eCRF pages including best response to therapy, if available. 
6.2.1.1 
Permitted concomitant therapy requiring caution and/or action 


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6.2.1.1.1 Dabrafenib 
Effect of other drugs on dabrafenib 
Based on in vitro studies, dabrafenib was shown to be primarily metabolized by CYP2C8 and 
CYP3A4. Medicinal products that are strong inhibitors or inducers of CYP2C8 or CYP3A4 are 
likely to increase or decrease, respectively, dabrafenib concentrations. Alternative agents 
should be considered during administration with dabrafenib when possible. Moderate inhibitors  
or inducers of CYP3A and CYP2C8 are to be used with caution. See Table 6-3. Drugs that are 
strong inhibitors  or inducers  of CYP2C8 or CYP3A4 should be avoided and 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. See Table 6-2.  
Effect of dabrafenib on other drugs 
Dabrafenib induces CYP3A4- and CYP2C9- mediated metabolism and may induce other 
enzymes including CYP2B6, CYP2C8, CYP2C19 and UDP glucuronosyltransferases (UGT). 
Dabrafenib may also induce transporters (e.g., P-glycoprotein (P-gp)). Co-administration of 
dabrafenib and medicinal products which are affected by the induction of CYP3A4 or CYP2C9 
such as hormonal contraceptives, warfarin or dexamethasone may result in decreased 
concentrations and loss of efficacy. If co-administration of these medications is necessary, 
monitor subjects for loss of efficacy or consider substitutions of these medicinal products. Use 
caution if co-administration of CYP2C or CYP3A4 substrates with the narrow therapeutic index 
is required. Refer to the Tafinlar label for further information. 
A partial list of the prohibited medications and of medications to be used with caution is 
provided in Table 6-2 and Table 6-3 respectively. The list may be modified based on emerging 
data. 
Table 6-2 
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  
Table 6-3 
Medication 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 


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USE WITH CAUTION: Moderate  inhibitors of CYP3A, or CYP2C8 since concentrations of dabrafenib 
may be increased 
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 
Selective Aldosterone Blockers 
Eplerenone 
6.2.1.1.2 Trametinib 
Based on in vitro and in vivo data, trametinib is unlikely to significantly affect the 
pharmacokinetics of other medicinal products via interactions with CYP enzymes or 
transporters. 


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6.2.2 
Prohibited medication 
The following medications or non-drug therapies are prohibited while on treatment in this study: 
• Other anti-cancer therapies 
• Other investigational drugs 
Although not contraindicated/prohibited, certain medications drugs should be used with caution 
due to potential drug-drug interactions (see Section 6.2.1.1.1). 
6.3 
Subject numbering, treatment assignment, randomization  
6.3.1 
Subject numbering 
Each subject is identified in the study by a Subject Number (Subject No.), that is assigned when 
the subjects is first enrolled for screening and is retained as the primary identifier for the subject 
throughout his/her entire participation in the trial. The Subject No. consists of the Center 
Number (Center No.) (as assigned by Novartis to the investigative site) with a sequential subject 
number suffixed to it, so that each subject is numbered uniquely across the entire database. 
Upon signing the informed consent form, the subject is assigned to the next sequential Subject 
No. available. 
6.3.2 
Treatment assignment, randomization 
No randomization will be performed in this study. The assignment of a subject to enter the study 
will be coordinated by the sponsor. 
6.4 
Treatment blinding  
Not applicable 
6.5 
Dose modification 
Guidelines on management of common dabrafenib or trametinib associated toxicities and dose 
modification instructions are provided in Section 6.5.1. 
6.5.1 
Dose modifications 
The starting dose for subjects enrolled in the trial is set at 150 mg dabrafenib BID and 2 mg 
trametinib QD. Please refer to Section 4.2 for more details on the dose rationale. 
6.5.1.1 
Mandatory dose modification and recommended clinical management 
for pyrexia suspected to be related to dabrafenib and/or trametinib 
treatment 
For the purpose of this study, pyrexia is defined as fever occurring while on study treatment (≥ 
38°C) and pyrexia syndrome is defined as one or more of the following symptoms: 
chills/rigors/night sweats; flu-like symptoms. The incidence and severity of pyrexia are 
increased when dabrafenib is used in combination with trametinib compared to dabrafenib 
monotherapy. In a minority of cases the pyrexia was accompanied by symptoms such as severe 
rigors/chills, dehydration, hypotension, dizziness or weakness and required hospitalization. 
Dabrafenib and trametinib must be interrupted promptly at the onset of pyrexia and should be 
restarted upon the improvement of symptoms at the same dose if symptom-free (temperature < 
38°C) for at least 24 hours. 


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If a subject’s dose of dabrafenib and trametinib has been reduced as per the dose modification 
guideline, re-escalation of the subject’s dose is recommended provided the following criteria 
are met: 
• a period of 4 weeks of treatment has elapsed since treatment is restarted at the lower 
dose level and there is no recurrence of the AE 
• the subject is deriving clinical benefit 
Subjects should be comprehensively educated and receive written guidance regarding 
febrile episodes before starting study drug treatment and also be instructed on the 
importance of immediately reporting febrile episodes or pyrexia syndrome.  
Subjects should be instructed to take non-steroidal anti-inflammatory drugs (NSAID) and/or 
paracetamol and/or metamizole, as appropriate, to control pyrexia syndrome (i.e. symptoms 
without documented temperature ≥ 38°C degrees) 
In the event of a fever (≥ 38°C). 
• The subject should immediately stop both dabrafenib and trametinib 
• The subject should be instructed to take non-steroidal anti-pyretics, as appropriate, to 
control fever. 
• The use of oral corticosteroids should be considered to:  
• manage acute pyrexia refractory to dose interruption and anti-pyretics (paracetamol, 
NSAIDs) 
• prevent further episodes of pyrexia in those with recurrent pyrexia events i.e. 
prophylaxis 
• In subjects experiencing pyrexia higher than 40°C (104°F), and/or pyrexia associated   
with rigors, severe chills, dehydration or hypotension, serum creatinine and other 
evidence of renal function should be monitored frequently. The frequency of 
monitoring must be adapted based on the individual clinical presentation.   
• Clinical evaluation for infection and hypersensitivity is recommended for subjects 
experiencing pyrexia not resolving within 24 hours 
Dabrafeinib and trametinib can be interrupted in the presence of the pyrexia syndrome (i.e. 
chills or rigors or night sweats or flu-like symptoms without documented temperature ≥ 38°C 
degrees) at investigators discretion for recurrent pyrexia and should be restarted upon 
improvement of symptoms at the same dose if symptom free for at least 24 hours. 
If recurrent pyrexia cannot be managed with dabrafeinib and trametinib interruption or 
prophylactic steroids, dose reduce as per Table 6-5. 
Pyrexia accompanied by hypotension, dehydration requiring intravenous fluids, renal 
insufficiency and/or severe (≥ Grade 3) rigors/chills in the absence of an obvious infectious 
cause should be reported as a SAE. 
Guidelines for dose modification and management for pyrexia considered to be related to 
dabrafenib and/or trametinib are provided in Table 6-4. 


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Table 6-4 
Mandatory dose modification and recommended clinical management 
for pyrexia suspected to be related to dabrafenib and/or trametinib 
treatment 
Pyrexia  
(≥ 38°C) 
 
 
Occurrence 
Recommended adverse event management 
guidelines 
Mandatory dose modification 
requirements 
1st occurrence and 
subsequent 
occurrences 
• 
Educate subject about pyrexia and its 
associated syndrome (chills or rigors or night 
sweats or flue like symptoms) to ensure prompt 
recognition and reporting 
• 
Clinical evaluation for infection and 
hypersensitivity b 
• 
Laboratory work-up b 
• 
Prompt administration of anti-pyretic treatment 
with non-steroidal anti-inflammatory drugs 
(NSAID) and/or paracetamol and/or 
metamizole at the onset of pyrexia a   or of 
pyrexia syndrome 
• 
Recommend oral corticosteroids (i.e., 
prednisone 10 mg/d) for at least 5 days or as 
clinically indicatedc 
• 
Optimize oral corticosteroid dose as clinically 
indicated for pyrexia that cannot be managed 
with dose interruptionsc 
• 
Oral hydration should be encouraged in 
subjects without evidence of dehydration. 
Intravenous hydration is recommended in 
subjects experiencing pyrexia complicated by 
dehydration/hypotension. 
• 
Dabrafenib and trametinib must be 
interrupted promptly at the very 
first observation of pyrexia and 
should be restarted upon 
resolution of pyrexia (temperature 
< 38°C) at the same dose if 
pyrexia free at least 24 hours*. 
• 
If recurrent pyrexia cannot be 
managed with interruption or 
prophylactic steroids, dose reduce 
as per Table 6-5. Re-escalation of 
the subject’s dose is 
recommended if criteria in Section 
6.5.1.2 are met. 
• 
Note: proactive intermittent dosing 
is not allowed. 
 
* Dabrafenib and Trametinib can be interrupted in the presence of  pyrexia syndrome (i.e. symptoms without 
documented temperature ≥ 38°C degrees) at investigator discretion for recurrent pyrexia. 
a. Anti-pyretic treatment should be started immediately at the onset of pyrexia or pyrexia syndrome, and 
prophylactic anti-pyretic treatment is recommended. Anti-pyretic treatment may include acetaminophen, 
ibuprofen, metamizole, or suitable anti-pyretic medication according to institutional standards. Prophylactic anti-
pyretic treatment is recommended to be discontinued after three days in the absence of pyrexia.  
b. For subjects experiencing pyrexia not resolving within 24 hours, if clinically indicated by the treating physician, a 
clinical evaluation and laboratory work-up, thorough clinical examination for signs and symptoms of infection or 
hypersensitivity may be performed. Laboratory work-up may include full-blood-count, electrolytes, creatinine, 
blood urea nitrogen (BUN), C-reactive protein (CRP), liver-function tests, blood culture, and urine culture. 
c. Corticosteroids are recommended for recurrent pyrexia that cannot be managed with dose interruptions and 
anti-pyretic treatments and for pyrexia associated with complications. This recommendation may be superseded 
by local institutional guidelines where available, or the investigator’s discretion on how to best manage a given 
subject. 
6.5.1.2 
Other dose modifications and reductions 
The following sections address the specific instructions for mandatory dose modifications and 
recommended management for AEs considered suspected to be related to study treatment. For 
subjects who do not tolerate the protocol-specified dosing schedule, dose interruptions or 
modifications are mandated in order to allow subjects to continue study treatment. 
 
Three dose reductions for dabrafenib and two dose reductions for trametinib are permitted. If 
more dose reductions of dabrafenib and trametinib are required, the subject must be 
permanently discontinued from that specific study treatment. Dose modification steps for 
dabrafenib and trametinib in  Table 6-5 must be followed for the AEs presented in Section 6.5.1. 


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Table 6-6 provides sections where detailed dose modification and management requirements 
for relevant AEs can be found. All AEs are to be graded according to NCI-CTCAE v4.03, unless 
otherwise specified. Investigators should refer to the current dabrafenib and trametinib local 
prescribing information for additional information regarding the background of each drug and 
the management of other AEs or potential safety-related issues not specifically mentioned in 
this protocol. 
If treatment-related toxicities occur that are specific to combination treatment of dabrafenib and 
trametinib, then both treatments should be simultaneously dose reduced, interrupted or 
discontinued with the exceptions shown below: 
Exception where dose modification is necessary for only dabrafenib: 
• Uveitis (Table 6-18) 
Exception where dose modifications are necessary for only trametinib: 
• RVO (Table 6-18) and retinal pigment epithelial detachment (RPED) (Table 6-19) 
• Left ventricular ejection fraction (LVEF) reduction (Table 6-15) 
If a subject’s dose of dabrafenib and trametinib has been reduced per the dose modification 
instructions, re-escalation of the subject’s dose is recommended provided the following criteria 
are met: 
• a period of 4 weeks of treatment has passed since restarting dosing at the lower dose level 
and there is no recurrence of the AE 
• the subject is deriving clinical benefit 
For dabrafenib and/or trametinib related adverse events: if following an interruption of 
dabrafenib and trametinib, an AE doesn’t recover to ≤ Grade 1 or baseline within 4 weeks, 
dabrafenib and trametinib must be discontinued. 
For study treatment interruptions due to adverse events unrelated to dabrafenib and/or 
trametinib, approval from Novartis Medical Monitor is required to restart study treatment after 
≥28 days interruption. 
Table 6-5 
Dose modification steps for dabrafenib and trametinib 
Dose reduction for dabrafenib a, b 
 
Starting dose level 
Dose level - 1 
Dose level - 2 
Dose level – 3 
Dabrafenib 
150 mg BID (300 
mg/day) 
100 mg BID (200 
mg/day) 
75 mg BID (150 
mg/day) 
50 mg BID (100 
mg/day) 
Dose reduction for trametinib a, b 
 
Starting dose level 
Dose level - 1 
Dose level - 2 
Dose level – 3 
Trametinib 
2 mg QD 
1.5 mg QD 
1.0 mg QD 
- 
BID: twice daily; QD: once daily  
a. Dose modification should be based on the worst toxicity demonstrated at the last dose.  
b. Dose reduction below 50 mg BID for dabrafenib and 1.0 mg QD for trametinib are not allowed. 
6.5.1.3 
Dose modification and management guideline for adverse events 
common to dabrafenib and trametinib 
Adverse events that have been reported with dabrafenib in combination with trametinib in the 
adjuvant melanoma setting include, but are not limited to pyrexia, fatigue, nausea, headache, 
chills, diarrhea, vomiting, arthralgia, and rash. The most common adverse events for dabrafenib 


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and trametinib combination therapy include pyrexia, fatigue, nausea, headache, chills, diarrhea, 
rash, arthralgia, hypertension, vomiting, and cough. 
Table 6-6 
Reference of AEs and toxicity management guidelines  
Adverse Events 
dabrafenib 
trametinib 
Guideline 
Pyrexia  
X 
X 
Section 6.5.1.1 
Table 6-4 
Abnormal liver enzyme 
test 
X 
X 
Section 6.5.1.3.2  
Table 6-7 
Renal Function 
Alterations 
X 
X 
Section 6.5.1.3.3  
Table 6-8 
Skin rash 
X 
X 
Section 6.5.1.3.4 
 Table 6-9 
Serious skin reaction 
X 
X 
Section 6.5.1.3.5 
Pneumonitis 
X 
X 
Section 6.5.1.3.6 
 Table 6-10 
Hand foot skin reaction 
X 
X 
Section 6.5.1.3.8  
 Table 6-12 
Hematologic adverse 
events 
X 
X 
Section 6.5.1.3.9 
 Table 6-13 
Non-hematologic adverse 
events 
X 
X 
Section 6.5.1.3.10 
 Table 6-14 
LVEF 
X 
X 
Section 6.5.1.3.11 
 Table 6-15 
Hypertension 
X 
X 
Section 6.5.1.3.12 
 Table 6-16 
Diarrhea/colitis 
X 
X 
Section 6.5.1.3.13  
 Table 6-17 
New malignancies 
X 
X 
Section 6.5.1.3.14 
Visual changes 
X (Uveitis) 
X (RVO) 
Section 6.5.1.3.15 
 Table 6-18,  Table 6-19 
RPED 
 
X 
Section 6.5.1.3.15 
 Table 6-19 
Hyperglycemia 
X 
 
Section 6.5.1.3.16 
Hemorrhage 
X 
X 
Section 6.5.1.3.17 
Thromboembolic events 
 
X 
Section 6.5.1.3.18 
General 
X 
X 
Section 6.5.1.3.7 
 Table 6-11 
“X” indicates study treatment (s) that may need to be modified 
 
6.5.1.3.1 Guidance for corticosteroids tapering for management of adverse events 
common to dabrafenib and trametinib 
Reduce prednisone dose by 2.5 to 5.0 mg decrements every 3–7 days until physiologic dose (5 
to 7.5 mg of prednisone per day) is reached. Consider completing tapering over a period of at 
least 4 weeks. Slower tapering of corticosteroids therapy may be recommended if the adverse 
event is not showing improvement. 


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6.5.1.3.2 Mandatory dose modifications and recommended clinical management 
guidelines for abnormal liver enzyme test 
Guidelines for dose modification and management of abnormal liver enzyme functions 
considered to be related to study treatment by the investigator are provided in Table 6-7. 
In addition to the instructions below, subjects with normal baseline transaminases and bilirubin 
who experience sudden elevations even within Grade 1, should be monitored more closely. 
Table 6-7 
Mandatory dose modifications and recommended clinical 
management guidelines for abnormal liver enzyme test 
Abnormal liver enzyme tests/hepatitis 
Grade 
Recommended adverse event 
management guidelines 
Mandatory dose modification 
requirements 
Grade 2: AST or ALT >3× 
ULN to ≤ 5× ULN and/or 
bilirubin > 1.5× ULN to ≤ 3× 
ULN 
• 
Monitor hepatic laboratory tests 
more frequently(every 2-3 days) 
until returned to baseline values 
• 
Interrupt, dabrafenib and 
trametinib until ≤ Grade 1, and 
then reinstate, dabrafenib and 
trametinib at the same dose level. 
Grade 3 or 4: AST or ALT > 
5× ULN and/or bilirubin > 3× 
ULN 
• 
Monitor hepatic laboratory tests 
more frequently (every 2-3 days) 
until return to baseline values. 
• 
Consider appropriate consultation* 
with hepatologist and liver biopsy 
to establish etiology of hepatic 
injury, if necessary 
• 
If after 2-3 days new liver 
assessment shows worsening of 
laboratory test consider to initiate 
treatment with high dose steroids 
(1 to 2 mg/kg/day prednisone or 
equivalents) 
• 
Add prophylactic antibiotics for 
opportunistic infections 
• 
Start steroid taper as outlined in 
Section 6.5.1.3.1 if symptoms 
improve to Grade ≤1 
• 
If serum transaminase levels do 
not decrease 48 hours after 
initiation of systemic steroids, oral 
mycophenolate mofetil 500 mg 
every 12 hours may be given. 
• 
Infliximab is not recommended due 
to its potential for hepatotoxicity 
1st occurrence 
• 
Interrupt dabrafenib and trametinib 
until recovery to ≤ Grade 1 or 
baseline 
• 
Reduce dabrafenib and 
trametinib to the next 
lower dose level per 
Table 6-5. Re-escalation 
of the subject’s dose is 
recommended if criteria in 
Section 6.5.1.2 are met  
• 
If no recovery to ≤ Grade 
1 within 4 weeks, 
permanently discontinue 
dabrafenib and 
trametinib. 
2nd occurrence 
• 
Interrupt dabrafenib and trametinib 
until ≤ Grade 1. 
• 
Reduce dabrafenib and 
trametinib to the next lower 
dose level per Table 6-5. Re-
escalation of the subject’s 
dose is recommended if 
criteria in Section 6.5.1.2 are 
met dose  
3rd occurrence 
• 
Permanently discontinue 
dabrafenib and trametinib 
*Rule out viral hepatitis and other potential causes of liver injury 
Note: For additional information on follow-up of potential drug induced liver injury cases, refer to Section 6.5.2. 
6.5.1.3.3 Mandatory dose modifications and recommended clinical management 
guidelines for renal function alterations 
Cases of renal insufficiency have occurred in adult patients receiving dabrafenib and the 
combination of dabrafenib and trametinib. Prior to start of study treatment, concomitant 
medications must be reviewed for the potential risk of inducing nephrotoxicity and 
concomitant medications may be modified if clinically possible. 


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Guidelines regarding management and dose reduction for renal insufficiency considered to be 
related to study treatment by the investigator are provided in Table 6-8. 
Table 6-8 
Mandatory dose modifications and recommended clinical 
management guidelines for renal function alterations 
NCI-CTCAE v4.03 for acute kidney injury 
Grade 
Recommended adverse event 
management guidelines 
Mandatory dose modification 
requirements 
Grade 1 (Creatinine level 
increase of >0.3 mg/dL; 
creatinine 1.5 - 2.0 x above 
baseline) 
Repeat serum creatinine within 24 
hours for any increase in serum 
creatinine >0.5 mg/dl 
• If the increase in creatinine is 
confirmed: 
a) 
Assess fluid status and 
consider fluid bolus 
b) 
Monitor serum creatinine at 
least every 2 days until 
back to baseline 
• If creatinine returns to baseline:  
a) 
resume routine creatinine 
monitoring per protocol  
 
• Promote hydration and cessation 
of nephrotoxic drugs. 
 
 
 
• If the increase in creatinine is 
confirmed: 
a) 
Interrupt treatment 
 
 
 
• If creatinine returns to baseline:  
a) 
Continue dabrafenib and 
trametinib at the same dose. 
Grade 2: (Creatinine 2 - 3 x 
above baseline)  
• Closely monitor creatinine  
• Consult with specialist and 
consider renal biopsy 
• Promote hydration and cessation 
of nephrotoxic drugs. 
1st occurrence: 
• Interrupt dabrafenib and trametinib until 
≤ Grade 1 or baseline and then 
reinstate dabrafenib and trametinib at 
the same dose. 
2nd occurrence: 
• Interrupt dabrafenib and trametinib until 
≤ Grade 1 or baseline. Once 
recovered, reduce dabrafenib and 
trametinib to the next dose level. Re-
escalation of the subject’s dose is 
recommended if criteria in Section 
6.5.1.2 are met. 
3rd occurrence: 
• Interrupt dabrafenib and trametinib until 
≤ Grade 1 or baseline. Once 
recovered, reduce dabrafenib and 
trametinib to the next dose level. Re-
escalation of the subject’s dose is 
recommended if criteria in Section 
6.5.1.2 are met. 
4th occurrence 
• Permanently discontinue dabrafenib 
and trametinib. 


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NCI-CTCAE v4.03 for acute kidney injury 
Grade 
Recommended adverse event 
management guidelines 
Mandatory dose modification 
requirements 
Grade 3 (Creatinine > 3.0 x 
baseline or >4.0 mg/dL; 
hospitalization indicated) 
• Hospitalization is indicated with 
frequent creatinine monitoring 
• Consult with nephrologist. 
• Promote hydration and cessation 
of nephrotoxic drugs. 
1st occurrence: 
• Interrupt dabrafenib and trametinib until 
≤ Grade 1 or baseline and then 
reduce dabrafenib and trametinib to 
the next lower dose. Re-escalation of 
the subject’s dose is recommended if 
criteria in Section 6.5.1.2 are met. 
2nd occurrence: 
• Interrupt dabrafenib and trametinib until 
≤ Grade 1 or baseline and then 
reduce dabrafenib and trametinib to 
the next lower dose. Re-escalation of 
the subject’s dose is recommended if 
criteria in Section 6.5.1.2 are met. 
3rd occurrence: 
• Interrupt dabrafenib and trametinib until 
≤ Grade 1 or baseline and then 
reduce dabrafenib and trametinib to 
the next lower dose, if available as 
dose level -2. If already at dose level-
2 at time of occurrence, permanently 
discontinue dabrafenib and 
trametinib. Re-escalation of the 
subject’s dose is recommended if 
criteria in Section 6.5.1.2 are met. 
4th occurrence: 
Permanently discontinue dabrafenib and 
trametinib 
Grade 4: Life-threatening 
consequences; dialysis 
indicated 
• Consult with specialist and 
recommend renal biopsy. 
• Promote hydration and cessation 
of nephrotoxic drugs. 
• Permanently discontinue dabrafenib 
and trametinib. 
 
6.5.1.3.4 Mandatory dose modifications and recommended clinical management 
guidelines for skin rash 
Guidelines for dose modification and management of skin rash considered to be related to study 
treatment by the investigator are provided in Table 6-9. 


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Table 6-9 
Mandatory dose modifications and recommended clinical 
management guidelines for rash 
Rash Events (NCI-CTCAE v4.03) 
Grade 
Recommended adverse event 
management guidelines 
Mandatory dose modification 
requirements 
Grade 1: Rash covering 
< 10% body surface area 
• Initiate prophylactic and symptomatic 
treatment measures. 
• Consider use of topical corticosteroids 
or urea containing creams in 
combination with oral antipruritics or 
moderate strength topical steroid 
(hydrocortisone 2.5% cream or 
fluticasone propionate 0.5% cream) 
• Reassess after 2 weeks 
• Continue, dabrafenib and 
trametinib at the same dose. 
Grade 2: 10-30% of body 
surface area 
• If tolerable, as per Grade 1 
• If intolerable, initiate systemic steroids 
(0.5 to 1 mg/kg/day prednisone or 
equivalents) 
• If symptoms persist or recur consider 
skin biopsy. 
• If tolerable, continue dabrafenib 
and trametinib at the same dose. 
• If intolerable: 
1st occurrence 
• Interrupt, dabrafenib and trametinib 
until ≤ Grade 1, and then 
reinstate reduce dabrafenib and 
trametinib to the next dose level 
per Table 6-5. Re-escalation of 
the subject’s dose is 
recommended if criteria in 
Section 6.5.1.2 are met  
• AE resolution to ≤ Grade 1 or 
baseline must occur within a 
period of 4 weeks since a Grade 
2 event has been identified  
Grade 3: More than 30% 
of body surface area 
Obtain a skin biopsy and dermatology 
consult. 
Initiate therapy with high dose steroids (1 to 
2 mg/kg/d prednisone or equivalents) 
1st occurrence 
• Interrupt dabrafenib and trametinib 
until ≤ Grade 1, and reduce 
dabrafenib and trametinib to the 
next dose level per Table 6-5. 
Re-escalation of the subject’s 
dose is recommended if criteria 
in Section 6.5.1.2 are met 
• AE resolution to ≤ Grade 1 or 
baseline must occur within a 
period of 4 weeks since a grade 
3 event has been identified 
2nd occurrence 
• Interrupt dabrafenib and trametinib 
until ≤ Grade 1 or baseline. Once 
recovered, reduce dabrafenib 
and trametinib to the next dose 
level per Table 6-5. Re-
escalation of the subject’s dose 
is recommended if criteria in 
Section 6.5.1.2 are met 
3rd occurrence 
• Interrupt dabrafenib and trametinib 
until ≤ Grade 1 or baseline. Once 
recovered, reduce dabrafenib 
and trametinib to the next dose 
level per Table 6-5. Re-
escalation of the subject’s dose 
is recommended if criteria in 
Section 6.5.1.2 are met 


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Rash Events (NCI-CTCAE v4.03) 
Grade 
Recommended adverse event 
management guidelines 
Mandatory dose modification 
requirements 
4th occurrence 
• Permanently discontinue 
dabrafenib and trametinib. 
Grade 4: Life-threatening 
Same as Grade 3 
Permanently discontinue dabrafenib 
and trametinib. 
6.5.1.3.5 Mandatory dose modifications and recommended clinical management of 
serious skin reactions 
Withhold trametinib for intolerable or severe skin toxicity. Resume trametinib at reduced doses 
in subjects with improvement or recovery from skin toxicity within 3 weeks. In cases of 
Stevens-Johnson syndrome and toxic epidermal necrolysis, permanently discontinue dabrafenib 
and trametinib and institute supportive care as per institutional guidelines. 
6.5.1.3.6 Mandatory dose modifications and recommended clinical management 
guidelines for pneumonitis 
Guidelines for dose modification and management of pneumonitis considered to be related to 
study treatment by the investigator are provided in Table 6-10. 
Table 6-10 
Mandatory dose modifications and recommended clinical 
management guidelines for pneumonitis 
Pneumonitis (NCI-CTCAE v4.03) 
Grade 
Recommended adverse event 
management guidelines 
Mandatory dose modification 
requirements 
Grade 1: Radiographic 
changes only- 
Asymptomatic 
• CT scan (high-resolution with lung 
windows) recommended, with 
serial imaging to monitor for 
resolution or progression- re-
image at least every 3 weeks 
• Monitor for symptoms every 2-3 
days - Clinical evaluation and 
laboratory work-up for infection 
• Monitoring of oxygenation via 
pulse oximetry recommended 
• Consultation of pulmonologist 
recommended. 
• Continue dabrafenib and trametinib at 
the same dose. 
 
Grade 2: Symptomatic-
medical intervention 
indicated; limits 
instrumental ADLs 
• CT scan (high-resolution with lung 
windows) 
• Monitor symptoms daily, consider 
hospitalization 
• Clinical evaluation and laboratory 
work up for infection 
• Consult pulmonologist 
• Pulmonary function tests - if 
normal at baseline, repeat every 
8 weeks 
• Bronchoscopy with biopsy and/or 
BAL recommended 
• Interrupt trametinib until recovery to ≤ 
Grade 1 or baseline. Dabrafenib 
may continue at the same dose. 
• Once recovered, reduce trametinib to 
the next lower dose per Table 6-5. 
Re-escalation of the subject’s dose 
is recommended if criteria in Section 
6.5.1.2 are met. 
• If no recovery to ≤ Grade 1 within 4 
weeks, permanently discontinue 
trametinib. Dabrafenib may 
continue. 
• AE resolution to ≤ Grade 1 or baseline 
must occur within a period of 4 


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Pneumonitis (NCI-CTCAE v4.03) 
Grade 
Recommended adverse event 
management guidelines 
Mandatory dose modification 
requirements 
• Symptomatic therapy including 
corticosteroids if clinically 
indicated (systemic 
corticosteroids at a dose of 1 to 
2 mg/kg/day prednisone or 
equivalent as clinically 
indicated). 
weeks since Grade 2 event has 
been identified. 
 
Grade 3: Severe 
symptoms; limits self-care 
ADLs; oxygen indicated 
• CT scan (high-resolution with lung 
windows) 
• Clinical evaluation and laboratory 
work-up for infection 
• Consult pulmonologist 
• Pulmonary function tests-if < 
normal, repeat every 8 weeks 
until ≥ normal 
• Bronchoscopy with biopsy and/or 
BAL if possible 
• Treat with intravenous steroids 
(methylprednisolone 125 mg) as 
indicated. When symptoms 
improve to ≤ Grade 1, a high 
dose oral steroid (prednisone 1 
to 2 mg/kg once per day or 
dexamethasone 4 mg every 4 
hours). 
• If IV steroids followed by high 
dose oral steroids does not 
reduce initial symptoms within 
48 to 72 hours, consider non-
corticosteroid 
immunosuppressive medication 
(e.g., infliximab, 
cyclophosphamide, IVIG or 
mycophenolate mofetil). 
• Interrupt trametinib until recovery to 
Grade ≤1 or baseline. Dabrafenib 
may continue. 
• Once recovered, trametinib may be 
restarted at the next lower dose per 
Table 6-5. Re-escalation of the 
subject’s dose is recommended if 
criteria in Section 6.5.1.2 are met  
• If no recovery to Grade ≤ 1 or baseline 
within 4 weeks, permanently 
discontinue trametinib. Dabrafenib 
may continue. 
Grade 4: Life-threatening 
respiratory compromise 
Same as Grade 3 
Same as Grade 3 


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6.5.1.3.7 Dose modification and management guideline for adverse events suspected 
to be related to dabrafenib and/or trametinib (other than Pyrexia) 
For adverse events of special interest reported only for dabrafenib and/or trametinib, general 
guidelines for dose modification in Table 6-11 should be followed for dabrafenib and 
trametinib. 
In general, if an AE resolves to Grade 1 or baseline at the reduced dose level, and no additional 
toxicities are seen after 4 weeks of study treatment at the reduced dose, the dose may be 
increased to the previous dose level. 
A dose reduction below 50 mg BID for dabrafenib or below 1 mg QD for trametinib is not 
allowed. If a dose reduction below 50 mg BID for dabrafenib is required, dabrafenib will be 
permanently discontinued but these subjects will be allowed to continue trametinib. If a dose 
reduction below 1.0 mg QD for trametinib is required, then trametinib will be permanently 
discontinued, but these subjects will be allowed to continue dabrafenib. 
Table 6-11 
General guidelines for dose modification for adverse events 
suspected to be related to dabrafenib and/or trametinib treatment 
Grade 
Recommended adverse event 
management guidelines 
Mandatory dose modification 
requirements 
Grade 1 or Grade 2 tolerable 
• Monitor closely. 
• Provide supportive care according 
to institutional standards. 
• Continue dabrafenib and 
trametinib at the same dose 
level. 
Grade 2 (intolerable) or 
Grade 3 
• Monitor closely. 
• Provide supportive care according 
to institutional standards. 
• Interrupt dabrafenib and trametinib 
(except for cuSCC, 
keratoacanthoma, new primary 
melanoma, and basal cell 
carcinoma) 
• When toxicity resolves to ≤ Grade 
1 or baseline, restart dabrafenib 
and trametinib reduced by one 
dose level per Table 6-5. Re-
escalation of the subject’s dose 
is recommended if criteria in 
Section 6.5.1.2 are met 
• If the Grade 2 (intolerable) or 
Grade 3 toxicity recurs, interrupt 
dabrafenib and trametinib. 
• When toxicity resolves to Grade 1 
or baseline, restart dabrafenib 
and trametinib reduced by 
another dose level per Table 6-
5. Re-escalation of the subject’s 
dose is recommended if criteria 
in Section 6.5.1.2 are met 


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Grade 
Recommended adverse event 
management guidelines 
Mandatory dose modification 
requirements 
Grade 4 
• Monitor closely. 
• Provide supportive care according 
to institutional standards. 
• Interrupt dabrafenib and 
trametinib. 
• Restart with dabrafenib and 
trametinib reduced by one dose 
level per Table 6-5 once toxicity 
resolves to ≤ Grade 1 or 
baseline or permanently 
discontinue dabrafenib and 
trametinib at the discretion of the 
investigator. Re-escalation of the 
subject’s dose is recommended 
if criteria in Section 6.5.1.2 are 
met 
6.5.1.3.8 Mandatory dose modifications and recommended clinical management 
guidelines for hand-foot reaction (palmar-plantar erythrodysesthesia) 
In general, management of hand-foot skin reactions 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 
• Infected lesions: topical or systemic antibiotics 
• 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. 
Guidelines for dose modification for hand-foot skin reaction considered to be related to study 
treatment by the investigator are provided in Table 6-12. 


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Table 6-12 
Mandatory dose modifications and recommended clinical 
management guidelines for hand foot skin reaction (palmar-plantar 
erythrodysesthesia) 
Hand foot skin reaction 
Grade 
Recommended adverse 
event management 
guidelines 
Mandatory dose modification requirements 
Grade 1: Numbness, 
dysesthesia, paresthesia, 
tingling, painless swelling, 
erythema or discomfort of 
the hands or feet which 
does not disrupt the 
subject’s normal activities 
• 
Recommend topical 
therapy for symptomatic 
relief. 
• 
Continue dabrafenib and trametinib at the 
same dose. 
Grade 2: Painful erythema 
and swelling of the hands 
or feet and/or discomfort 
affecting the subject’s 
normal activities 
• 
Recommend topical 
therapy for symptomatic 
relief 
• 
Continue treatment and if no improvement 
within 7 days, see below. 
• 
No improvement within 7 days or 2nd or 3rd 
occurrence: 
• 
Interrupt dabrafenib and trametinib until 
toxicity resolves to ≤ Grade 1 or baseline. 
• 
Reduce dabrafenib and trametinib at the 
next lower dose per Table 6-5. Re-
escalation of the subject’s dose is 
recommended if criteria in Section 6.5.1.2 
are met 
4th occurrence: 
• Discontinue dabrafenib and trametinib. 
Grade 3: Moist 
desquamation, ulceration, 
blistering or severe pain of 
the hands or feet, or severe 
discomfort that causes the 
subject to be unable to 
work or perform activities of 
daily living 
• 
Recommend topical 
therapy for symptomatic 
relief 
1stoccurrence: 
• 
Interrupt dabrafenib and trametinib until 
toxicity resolves to ≤ Grade 1 or baseline. 
• 
Once recovered, reduce dabrafenib and 
trametinib to the next dose level per Table 6-
5. Re-escalation of the subject’s dose is 
recommended if criteria in Section 6.5.1.2 
are met 
2nd occurrence: 
• 
Interrupt dabrafenib and trametinib until 
toxicity recovers to ≤ Grade 1 or baseline. 
• 
Once recovered, reduce dabrafenib and 
trametinib to the next dose level per Table 6-
5. Re-escalation of the subject’s dose is 
recommended if criteria in Section 6.5.1.2 
are met 
3rd occurrence: 
• Discontinue dabrafenib and trametinib. 
6.5.1.3.9 Mandatory dose modifications and recommended clinical management 
guidelines for hematological adverse events 
Guidelines for dose modification for hematologic adverse events suspected to be related to 
study treatment by the investigator are provided in Table 6-13. 


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Table 6-13 
Mandatory dose modifications and recommended clinical 
management guidelines for hematological adverse events 
Hematologic suspected AEs (NCI-CTCAE v4.03) 
Grade 
Recommended adverse event 
management guidelines 
Mandatory dose modification 
requirements 
Neutropenia 
Grade 1, 2 
NA 
• 
Continue dabrafenib and trametinib 
at the same dose. 
Grade 3, 4 
• 
Monitor blood test more frequently 
(every 7 days for Grade 3, and 3-5 
days for Grade 4). 
1st occurrence: 
• 
Interrupt dabrafenib and trametinib 
until toxicity recovers to ≤ Grade 2 
or baseline. 
• 
Reduce dabrafenib and trametinib 
to the next dose level per Table 6-
5. Re-escalation of the subject’s 
dose is recommended if criteria in 
Section 6.5.1.2 are met 
2nd occurrence: 
• 
Interrupt dabrafenib and trametinib 
until toxicity recovers to ≤ Grade 2 
or baseline. 
• 
Reduce dabrafenib and trametinib 
at the next dose level per Table 6-
5. Re-escalation of the subject ’s 
dose is recommended if criteria in 
Section 6.5.1.2 are met 
3rd occurrence: 
• 
Interrupt dabrafenib and trametinib 
until toxicity recovers to ≤ Grade 2 
or baseline. 
• 
Once recovered, reduce dabrafenib 
and trametinib to the next dose 
level per Table 6-5. Re-escalation 
of the subject’s dose is 
recommended if criteria in Section 
6.5.1.2 are met 
4th occurrence: 
• 
Permanently discontinue 
dabrafenib and trametinib 
Febrile Neutropenia 
• 
Apply Institutional guidelines 
• 
Follow modification guide for 
neutropenia Grade 4 (above). 
Thrombocytopenia 
Grade 1, 2, 3 without 
clinically significant bleeding 
• 
Grade 3: monitor blood test more 
frequently (every 7 days) 
• 
Continue dabrafenib and trametinib 
at the same dose. 


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Hematologic suspected AEs (NCI-CTCAE v4.03) 
Grade 
Recommended adverse event 
management guidelines 
Mandatory dose modification 
requirements 
Grade 3 with clinically 
significant bleeding 
Grade 4 
• 
Grade 3: monitoring blood test 
more frequently (every 3-5 days) 
1st occurrence: 
• 
Interrupt dabrafenib and trametinib 
until toxicity resolves to ≤ Grade 2 
or baseline. 
• 
Restart dabrafenib and trametinib 
at same dose. 
2nd occurrence: 
• 
Interrupt dabrafenib and trametinib 
until toxicity resolves to ≤ Grade 2 
or baseline. 
• 
Restart dabrafenib and trametinib 
at the next lower dose per Table 6-
5.  Re-escalation of the subject’s 
dose is recommended if criteria in 
Section 6.5.1.2 are met 
3rd occurrence: 
• 
Interrupt dabrafenib and trametinib 
until toxicity resolves to ≤ Grade 2 
or baseline. 
• 
Restart dabrafenib and trametinib 
at another lower dose per Table 6-
5. Re-escalation of the subject’s 
dose is recommended if criteria in 
Section 6.5.1.2 are met 
4th occurrence: 
• 
Interrupt dabrafenib and trametinib 
until toxicity resolves to ≤ Grade 2 
or baseline. 
• 
Permanently discontinue 
dabrafenib and trametinib. 
6.5.1.3.10 Mandatory dose modifications and recommended clinical management 
guidelines for non-hematological adverse events 
Guidelines for dose modification for non-hematologic adverse events suspected to be related to 
study treatment by the investigator are provided in Table 6-14. 


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Table 6-14 
Mandatory dose modifications and recommended clinical 
management guidelines for non-hematological adverse events 
Non-Hematologic AEs (except Grade 2 alopecia, Grade 2 fatigue) (NCI-CTCAE v4.03) 
Grade 
• 
Recommended adverse event 
management guidelines 
• 
Mandatory dose modification requirements 
Grade 1-2 tolerable 
• 
Monitor closely. 
• 
Provide supportive care 
according to institutional 
standards. 
• 
Continue, dabrafenib and trametinib at the 
same dose. 
Grade 2 intolerable or 
Grade 3 
• 
Monitor closely 
• 
Provide supportive care 
according to institutional 
standards 
1st or 2nd occurrence: 
• 
Interrupt dabrafenib and trametinib until 
toxicity recovers to ≤ Grade 1 or baseline. 
• 
Restart dabrafenib and trametinib at the 
same dose. 
3rd occurrence:  
• 
Restart dabrafenib and trametinib at the 
next lower dose per Table 6-5. Re-
escalation of the subject’s dose is 
recommended if criteria in Section 6.5.1.2 
are met 
4th occurrence: 
• 
Permanently discontinue dabrafenib and 
trametinib. 
Grade 4 
Monitor closely 
Provide supportive care according 
to institutional standards 
1st occurrence: 
• 
Interrupt dabrafenib and trametinib. 
• 
Dabrafenib and trametinib may be 
reinitiated at the next lower dose per 
Table 6-5. Re-escalation of the subject’s 
dose is recommended if criteria in 
Section 6.5.1.2 are met 
2nd occurrence: 
• 
Permanently discontinue dabrafenib and 
trametinib. 
6.5.1.3.11 Mandatory dose modification and management guideline for changes in 
LVEF suspected to be related to dabrafenib and/or trametinib treatment 
Decreases of left-ventricular-ejection-fraction (LVEF) have been observed in patients receiving 
trametinib in combination with dabrafenib. Therefore, ECHOs must be performed to assess 
cardiac ejection fraction in regular intervals as outlined in the Visit Evaluation Schedule (Table 
8-1). Dose modification guidance and stopping criteria for LVEF decrease are provided in Table 
6-15. 


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Table 6-15 
Mandatory dose modification and recommended clinical management 
for changes in LVEF suspected to be related to dabrafenib and/or 
trametinib treatment  
Left Ventricular Ejection Fraction decrease (NCI-CTCAE v4.03) 
LVEF-drop (%) & 
clinical symptoms 
Recommended adverse event 
management guidelines 
Mandatory dose modification 
requirements 
Asymptomatic: 
Absolute decrease of >10% in 
LVEF compared to baseline 
and ejection fraction below the 
institution’s LLN 
• 
Report as SAE. 
• 
Closely monitoring LVEF via 
ECHO, repeat ECHO within 2 
weeks*. 
• If the LVEF recovers within 4 weeks 
(defined as LVEF ≥LLN and 
absolute decrease ≤10% 
compared to baseline) 
• 
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 
• 
Repeat ECHO after 2, 4, 8, 
12, and 16 weeks or until 
resolution 
• 
Interrupt trametinib. 
• 
If the LVEF recovers, restart 
trametinib reduced by one dose 
level per Table 6-5.  
• 
More than two occurrence, 
permanently discontinue 
trametinib. 
 
 
 
• Permanently discontinue 
trametinib if repeat LVEF does 
not recover within 4 weeks. 
Symptomatic: 
Resting LVEF 39-20% 
or >20% absolute reduction 
from baseline 
resting LVEF <20% 
• 
Report as SAE. 
• 
Consult with cardiologist. 
• 
Repeat ECHO after 2, 4, 8, 12, and 
16 weeks or until resolution. 
• 
Permanently discontinue 
trametinib. 
• 
Interrupt dabrafenib 
• 
Restart dabrafenib if LVEF 
recovers including resolution of 
symptoms. 
* If ECHO does not show LVEF recovery after 2 weeks, repeat ECHO 2 weeks later. 
6.5.1.3.12 Mandatory dose modification and management guideline for hypertension 
suspected to be related to dabrafenib and/or trametinib treatment 
Increases in blood pressure have been observed in patients receiving trametinib. For adequate 
monitoring and management of hypertension, all blood pressure assessments should be 
performed under the following optimal conditions: 
• the subject has been seated with back support, ensuring that legs are uncrossed and flat on 
the floor 
• the subject is relaxed comfortably for at least 5 minutes 
• restrictive clothing has been removed from the cuff area and the right cuff size has been 
selected 
• the subject’s arm is supported so that the middle of the cuff is at heart level 
• the subject remains quiet during the measurement. 
In subjects with an initial blood pressure reading within the hypertensive range, a second 
reading should be taken at least 1 minute later, with the 2 readings averaged to obtain a final 
blood pressure measurement. The averaged value should be recorded in the eCRF. 
Persistent hypertension is defined as an increase of systolic blood pressure (SBP) > 140 mm Hg 
and/or diastolic blood pressure (DBP) > 90 mm Hg in three consecutive visits with blood 
pressure assessments from two readings collected as described above. Visits to monitor 


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increased blood pressure can be scheduled independently from the per- protocol visits outlined 
in the Visit Evaluation Schedule (Table 8-1). Ideally, subsequent blood pressure assessments 
should be performed within one week. 
Asymptomatic hypertension is defined as an increase of SBP >140 mm Hg and/or DBP >90 
mmHg in the absence of headache, light-headedness, vertigo, tinnitus, episodes of fainting or 
other symptoms indicative of hypertension. 
For subjects experiencing an increase in systolic and/or diastolic blood pressure that is persistent 
and may be associated with the study treatment, recommendations for dose modifications and 
management of hypertension are described below in Table 6-16. 
Table 6-16 
Mandatory dose modification and recommended clinical management 
for hypertension suspected to be related to dabrafenib and/or 
trametinib treatment 
Hypertension (NCI-CTCAE 4.03) 
Severity 
Recommended adverse event 
management guidelines 
Mandatory dose modification 
requirements 
(Scenario A) 
Asymptomatic and persistent a 
SBP of >140 and <160 
mmHg, or DBP >90 and <100 
mmHg, or 
Clinically significant increase 
in DBP of 20 mmHg (but still 
below 100 mmHg). 
• 
Adjust current or initiate new 
antihypertensive medication. 
• 
Titrate antihypertensive 
medication(s) during the next 2 
weeks as indicated to achieve well-
controlled BPb 
• 
If BP is not well controlled within 2 
weeks, recommended to refer to a 
specialist and go to scenario (B). 
Continue dabrafenib and trametinib at 
the same dose. 
(Scenario B) 
Asymptomatic SBP ≥160 
mmHg, or DBP ≥100 mmHg, 
or 
Failure to achieve well-
controlled BP within 2 weeks 
in Scenario A 
• 
Adjust current or initiate new 
antihypertensive medication(s). 
• 
Titrate antihypertensive 
medication(s) during the next 2 
weeks as indicated to achieve well-
controlled BP. 
• 
Interrupt dabrafenib and 
trametinib if clinically indicated. 
• 
Once BP is well controlled, restart 
dabrafenib and trametinib 
reduced by one dose level per 
Table 6-5.  
Symptomatic c hypertension or 
Persistent SBP ≥160 mmHg, 
or DBP ≥100 mmHg, despite 
antihypertensive medication 
and dose reduction of study 
treatment. 
• 
Adjust current or initiate new 
antihypertensive medication(s) 
• 
Titrate antihypertensive medication 
during the next 2 weeks as 
indicated to achieve well-controlled 
BP. 
• 
Referral to a specialist for further 
evaluation and follow-up is 
recommended 
• 
Interrupt dabrafenib and 
trametinib. 
• 
Once BP is well controlled, restart 
dabrafenib and trametinib 
reduced by one dose level per 
Table 6-5.  
Refractory hypertension 
unresponsive to above 
interventions or hypertensive 
crisis. 
• 
Continue follow-up per protocol. 
• 
Permanently discontinue 
dabrafenib and trametinib. 
a. Hypertension detected in two separate readings during up to three consecutive visits. 
b. Well-controlled blood pressure defined as SBP ≤140 mm Hg and DBP ≤90 mm Hg in two separate readings 
during up to three consecutive visits. 
c. Symptomatic hypertension defined as hypertension aggravated by symptoms (e.g., headache, light-
headedness, vertigo, tinnitus, episodes of fainting) that resolve after the blood pressure is controlled within 
the normal range. 


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6.5.1.3.13 Mandatory dose modifications and recommended clinical management 
guidelines for diarrhea/colitis 
Guidelines for dose modification and management for diarrhea considered to be related to study 
treatment by the investigator are provided in Table 6-17. 
Table 6-17 
Mandatory dose modifications and recommended clinical 
management guidelines for diarrhea/colitis 
CTCAE v4.03 
Recommended adverse event 
management guidelines 
Mandatory dose modification 
requirements 
Grade 1 diarrhea (increase of 
<4 stools per day over 
baseline; mild increase in 
ostomy output compared to 
baseline) 
OR 
Grade 2 diarrhea (increase of 
4 - 6 stools per day over 
baseline; moderate 
increase in ostomy output 
compared to baseline) 
 
• 
Diet: stop all lactose containing 
products; eat small meals, BRAT 
diet (banana, rice, apples, toast) 
• 
Hydration: 8-10 large glasses of 
clear liquids per day (e.g., 
Gatorade or broth) 
• 
Loperamide: initially 4 mg, followed 
by 2 mg every four hours or after 
every unformed stool; maximum 
16 mg/day. Continue until 
diarrhea free for 12 hours; 
• 
Diarrhea > 24hr: loperamide 2 mg 
every two hours; maximum 16 
mg/day. Consider adding oral 
antibiotics. 
• 
Diarrhea > 48hr: loperamide 2 mg 
every two hours; maximum 16 
mg/day. Consider other second-
line therapies for diarrhea (e.g., 
octreotide, oral diphenoxylate, 
and oral antibiotics) 
• 
If Grade 2 and no improvement in 
5 days consider oral steroids 
• 
If Grade 2 diarrhea persists >1 
week consider gastroenterologist 
consultation and endoscopy to 
evaluate for colitis 
• 
If Grade 2 persists for 5 days and 
worsening of symptoms or diffuse 
ulcerations and bleeding seen on 
endoscopy, commence oral 
steroids at a dose 0.5 to 1 
mg/kg/day prednisone equivalents 
and continue until symptoms 
improve to Grade 1. If no 
improvement occurs, manage as 
per Grade 3.  
• 
Lower GI endoscopy and biopsy 
should be considered and may 
assist in determining the duration 
of steroid taper based on the 
evidence of macroscopic and 
microscopic inflammation. 
• 
Continue dabrafenib and trametinib 
at the same dose level. 
 
• 
If diarrhea is Grade 2, despite 
loperamide at 2 mg every two 
hours for > 48hr: 
• 
Interrupt dabrafenib and 
trametinib until ≤ Grade 1, 
and then reinstate, 
dabrafenib and trametinib at 
the same dose level. 
Grade 3 diarrhea (increase of 
≥7 stools per day over 
baseline; incontinence; 
hospitalization indicated; 
severe increase in ostomy 
output compared to baseline; 
limiting self-care ADL) 
• 
Clinical evaluation and 
hospitalization mandatory; rule out 
bowel perforation and intravenous 
hydration. 
• 
Consider consultation with 
gastroenterologist and 
1st occurrence 
• 
Interrupt, dabrafenib and trametinib 
until ≤ Grade 1, and then reinstate 
treatment (after appropriate 
steroid tapering) and reduce 
dabrafenib and trametinib to the 
next lower dose level per Table 6-


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CTCAE v4.03 
Recommended adverse event 
management guidelines 
Mandatory dose modification 
requirements 
 
confirmation biopsy with lower GI 
endoscopy. 
• 
In addition to symptomatic 
treatment (diet, hydration, 
loperamide, antibiotics if 
indicated); initiate immediate 
treatment with intravenous 
steroids (methylprednisolone 
1mg/kg/day) followed by high 
dose oral steroids (1 to 2 
mg/kg/day prednisone 
equivalents) 
• 
When symptoms improve to ≤ 
Grade 1, steroid taper should be 
started and continued over no 
less than 4 weeks as per Section 
6.5.1.3.1. 
• 
Taper over 6 to 8 weeks in 
subjects with diffuse and severe 
ulceration and/or bleeding. 
• 
If no improvement in 2-3 days: 
consider initiating infliximab 5 
mg/kg and continue steroids. 
(Infliximab is contraindicated in 
subjects with sepsis or a 
perforation). Upon symptomatic 
relief initiate a prolonged steroid 
taper over 45 to 60 days. 
• 
If symptoms worsen during steroid 
reduction, initiate a re-tapering of 
steroids starting at a higher dose 
followed by a more prolonged 
taper and administer infliximab. 
• 
If symptoms persist despite the 
above treatment, a surgical 
consult should be obtained. 
5 Re-escalation of the subject’s 
dose is recommended if criteria in 
Section 6.5.1.2 are met. 
• 
AE resolution to ≤ Grade 1 or 
baseline must occur within a 
period of 4weeks since a grade 3 
event has been identified 
2nd occurrence 
• 
Interrupt dabrafenib and trametinib 
until ≤ Grade 1, and then reduce 
dabrafenib and trametinib to the 
next lower dose per Table 6-5. 
Re-escalation of the subject’s 
dose is recommended if criteria in 
Section 6.5.1.2 are met. 
 3rd occurrence 
• 
Permanently discontinue 
dabrafenib and trametinib. 
Grade 4: Life-threatening 
consequences; urgent 
intervention indicated 
Same as Grade 3 
Permanently discontinue, dabrafenib 
and trametinib. 
6.5.1.3.14 Mandatory dose modification and management guideline for new 
malignancies suspected to be related to dabrafenib and/or trametinib 
treatment 
New cutaneous malignancies: 
Cutaneous squamous cell carcinoma (CuSCC), keratoacanthomas (KA) and new primary 
melanomas have been observed in patients treated with dabrafenib and dabrafenib/trametinib 
combination therapy. These treatment-related lesions should be surgically removed according 
to institutional practices. Dose modification or interruption of study treatment is not required 
for cuSCC, KA, or new primary melanoma. However, cuSCC and new primary melanoma 
should be reported as a SAE. In addition, a biopsy of the lesion should be taken, where possible, 
and submitted for further analyses and a summary of the results submitted to Novartis. 
Subjects should be instructed to immediately inform their physician if new lesions develop. 
Skin examination should be performed prior to initiation of study treatment and throughout 
therapy as detailed in the Visit Evaluation Schedule. Monitoring should follow institutional 


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guidelines and/or as clinically indicated following discontinuation of dabrafenib or until 
initiation of another anti-neoplastic therapy. 
New non-cutaneous malignancies: 
In vitro experiments have demonstrated paradoxical activation of MAP-kinase signaling in 
BRAF wild-type cells with RAS mutations when exposed to BRAF inhibitors, which may lead 
to increased risk of non-cutaneous malignancies in patients treated with dabrafenib. Cases of 
RAS-driven malignancies have been seen with BRAF inhibitors, including dabrafenib. Subjects 
should be monitored as clinically appropriate. Consider the benefits and risks before continuing 
treatment with dabrafenib in subjects with a non-cutaneous malignancy harboring a RAS 
mutation. No dose modification of trametinib is required when taken in combination with 
dabrafenib. 
Following discontinuation of dabrafenib, monitoring for non-cutaneous secondary/recurrent 
malignancies should continue for up to 6 months or until initiation of another anti-neoplastic 
therapy. 
New cutaneous and non-cutaneous malignancies that are reported to the Investigator should be 
reported as an SAE. A biopsy of the new malignancy should be taken, where possible, and 
submitted for further analyses including RAS mutation status. Testing of these biopsies may 
include analysis of genomic alterations, which include but not limited to DNA, RNA and protein 
analysis of these biopsy specimens, and would analyze the biological pathways known to be 
associated with, and relevant to, BRAF-mutant tumor activation. 
6.5.1.3.15 Mandatory dose modification and management guideline for visual 
changes suspected to be related to dabrafenib and/or trametinib 
treatment 
Episodes of visual changes have been observed in patients receiving trametinib, dabrafenib or 
the combination of dabrafenib/trametinib. An ophthalmologist should be consulted if changes 
in vision develop. If a subject reports loss of vision or other visual disturbancies, an urgent 
ophthalmological evaluation (within 24 hours) is recommended to detect potential retinal vein 
occlusion (RVO). However, if the visual changes are clearly unrelated to study treatment (e.g., 
allergic conjunctivitis), then monitor closely as it may be reasonable to defer ophthalmic 
examination. 
Treatment with dabrafenib has been associated with the development of uveitis, including iritis. 
Monitor subjects for visual signs and symptoms (such as, change in vision, photophobia and 
eye pain) during therapy. Permanently discontinue dabrafenib for persistent ≥ Grade 2 uveitis 
(including iritis and iridocyclitis) of > 6 weeks duration. No dose modification of trametinib is 
required when taken in combination with dabrafenib. 
In subjects treated with trametinib, special attention should be given to retinal findings (e.g., 
RPED) or retinovascular abnormalities (i.e., branch or central RVO). Treatment-emergent cases 
of RVO and RPED should be reported as SAEs. 
Guidelines for dose modification and management for visual changes and/or ophthalmic 
examination findings considered to be related to dabrafenib and/or trametinib are provided in 
Table 6-18 and Table 6-19. 


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Table 6-18 
Mandatory dose modification and recommended clinical management 
for visual changes and/or ophthalmic examination findings suspected 
to be related to dabrafenib and/or trametinib treatment 
Visual changes (Eye disorders – Other, CTCAE Version 4.03) 
Grade 
Recommended adverse event 
management guidelines 
Mandatory dose modification requirements 
Grade 1 a 
• 
Consult ophthalmologist within 7 
days of onset 
• 
If dilated fundus examination cannot be 
performed within 7 days of onset, interrupt 
trametinib until RPED and RVO can be 
excluded by retina 
specialist/ophthalmologist. Continue 
dabrafenib. 
• 
If RPED and RVO excluded, continue (or 
restart) trametinib at the same dose level. 
• 
If RPED suspected or diagnosed: see 
RPED dose modification in Table 6-19; 
report as SAE if diagnosed. 
• 
If RVO diagnosed: Permanently discontinue 
trametinib and report as SAE. 
Grade 2 and 
Grade 3 
• 
Consult ophthalmologist 
immediately, perform 
ophthalmological evaluation within 
24 hours. 
• 
Interrupt trametinib. Dabrafenib may be 
continued at the same dose b. If RPED and 
RVO excluded, restart trametinib at the 
same dose level. 
• 
If RPED diagnosed, see RPED dose 
modification in Table 6-19; report as SAE. 
• If RVO diagnosed: Permanently 
discontinue trametinib and report as 
SAE. 
Grade 4 
• 
Consult ophthalmologist 
immediately, perform 
ophthalmological evaluation within 
24 hours. 
• 
Interrupt trametinib. Dabrafenib may be 
continued at the same dose b. If RPED and 
RVO excluded, should consider restarting 
trametinib at same or reduced dose after 
discussion with study medical monitor. 
• 
If RVO or RPED diagnosed, permanently 
discontinue trametinib and report as SAE. 
a. If visual changes are clearly unrelated to study treatment (e.g., allergic conjunctivitis), monitor closely but 
ophthalmic examination is not required. 
b. Permanently discontinue dabrafenib for ≥ Grade 2 uveitis (including iritis and iridocyclitis) of > 6 weeks duration. 
Table 6-19 
Mandatory dose modification and recommended clinical management 
for retinal pigment epithelial detachments (RPED) suspected to be 
related to trametinib treatment 
Retinal pigment epithelial detachments (RPED) CTCAE Version 4.03 
Grade 
Recommended adverse event 
management guidelines 
Mandatory dose modification 
requirements 
• 
Grade 1 (Asymptomatic; 
clinical or diagnostic 
observations only) 
• 
If RPED worsens follow 
instructions below. 
• 
Continue treatment with retinal 
evaluation monthly until 
resolution. 
• 
Grade 2-3 RPED 
(Symptomatic with mild to 
moderate decrease in 
visual acuity). 
• 
Retinal evaluation monthly. 
• 
Interrupt trametinib for up to 3 
weeks. 
• 
If improved to ≤ Grade 1, restart 
trametinib at a lower dose per 
Table 6-5.  
• 
If not improved to ≤ Grade 1 within 
3 weeks, permanently discontinue 
trametinib  


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6.5.1.3.16 Monitoring guideline for hyperglycemia suspected to be related to 
dabrafenib treatment 
Hyperglycemia requiring an increase in the dose of, or initiation of insulin or oral therapy can 
occur with dabrafenib. Monitor serum glucose levels as clinically appropriate during treatment 
with dabrafenib in subjects with pre-existing diabetes or hyperglycemia. 
Advise subjects to report symptoms of severe hyperglycemia such as excessive thirst or any 
increase in the volume or frequency of urination. 
6.5.1.3.17 Mandatory dose modification and management guideline for hemorrhage 
Hemorrhage, including major hemorrhage defined as symptomatic bleeding in a critical area or 
organ, can occur when dabrafenib is administered with trametinib. Permanently discontinue 
dabrafenib and trametinib for all Grade 4 hemorrhagic events and for any persistent Grade 3 
hemorrhagic events. Withhold dabrafenib and trametinib for Grade 3 hemorrhagic events; if 
improved, resume at the next lower dose level. 
6.5.1.3.18 Mandatory dose modification and management guideline thromboembolic 
events 
Advise subjects to immediately seek medical care if they develop symptoms of deep vein 
thrombosis (DVT) or pulmonary embolism (PE), such as shortness of breath, chest pain, or arm 
or leg swelling. If any signs or symptoms of venous thromboembolism are present, the subject 
will undergo specific laboratory and medical imaging studies to confirm it. The medical 
imaging study or studies selected will depend on the anatomic site or organ of involvement 
(e.g., Doppler ultrasound, venography, ventilation-perfusion lung scan, angiography, MRI). If 
the diagnosis is confirmed, appropriate medical care according to standard local clinical practice 
should be initiated immediately. 
Permanently discontinue trametinib for life-threatening PE. Withhold trametinib for 
uncomplicated venous thromboembolism for up to 3 weeks; if improved, trametinib may be 
resumed at a lower dose level. 
6.5.2 
Follow-up for toxicities 
6.5.2.1 
Follow up on potential drug-induced liver injury (DILI) cases 
Subjects with transaminase increase combined with total bilirubin (TBIL) increase may be 
indicative of potential DILI, and should be considered as clinically important events. 
The threshold for potential DILI may depend on the subject’s baseline AST/ALT and TBIL 
value; subjects meeting any of the following criteria will require further follow-up as outlined 
below: 
• For subjects with normal ALT and AST and TBIL value at baseline: AST or ALT > 3.0 x 
ULN combined with TBIL > 2.0 x ULN 
• For subjects with elevated AST or ALT or TBIL value at baseline: [AST or ALT > 2 x 
baseline AND > 3.0 x ULN] OR [AST or ALT > 8.0 x ULN], combined with [TBIL > 2 x 
baseline AND > 2.0 x ULN] 
Medical review needs to ensure that liver test elevations are not caused by cholestasis, defined 
as ALP elevation > 2.0 x ULN with R value < 2 in subjects without bone metastasis, or elevation 
of ALP liver fraction in subjects with bone metastasis. 


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Note: (The R value is calculated by dividing the ALT by the ALP, using multiples of the ULN 
for both values. It denotes whether the relative pattern of ALT and/or ALP elevation is due to 
cholestatic (R ≤ 2), hepatocellular (R ≥ 5), or mixed (R >2 and < 5) liver injury). 
In the absence of cholestasis, these subjects should be immediately discontinued from study 
drug treatment, and repeat LFT testing as soon as possible, preferably within 48 hours from the 
awareness of the abnormal results. The evaluation should include laboratory tests, detailed 
history, physical assessment and the possibility of liver metastasis or new liver lesions, 
obstructions/compressions, etc. 
1. Laboratory tests should include ALT, AST, albumin, creatine kinase, total bilirubin, direct 
and indirect bilirubin, GGT, prothrombin time (PT)/INR and alkaline phosphatase. 
2. A detailed history, including relevant information, such as review of ethanol, concomitant 
medications, herbal remedies, supplement consumption, history of any pre-existing liver 
conditions or risk factors, should be collected. 
3. Further testing for acute hepatitis A, B, C or E infection and liver imaging (e.g., biliary 
tract) may be warranted. 
4. Additional testing for other hepatotropic viral infection (e.g., CMV, EBV, Adenovirus, 
HSV, HHV6, HIV), autoimmune hepatitis or liver biopsy may be considered as clinically 
indicated or after consultation with specialist/hepatologist. 
All cases confirmed on repeat testing meeting the laboratory criteria defined above, with no 
other alternative cause for LFT abnormalities identified should be considered as “medically 
significant”, thus, met the definition of SAE (Section 10.1.2) and reported as SAE using the 
term “potential drug-induced liver injury”.  All events should be followed up with the outcome 
clearly documented. 
6.6 
Additional treatment guidance 
6.6.1 
Treatment compliance 
The investigator must promote compliance by instructing the subject to take the study treatment 
exactly as prescribed and by stating that compliance is necessary for the subject’s safety and 
the validity of the study. The subject must also be instructed to contact the investigator if he/she 
is unable for any reason to take the study treatment as prescribed. Compliance will be assessed 
by the investigator and/or study personnel at each visit using tablet/capsule counts and 
information provided by the subject.   This information should be captured in the source 
document at each visit.  All study treatment dispensed and returned must be recorded in the 
Drug Accountability Log. 
Subjects should record treatment compliance and pyrexia events on paper diaries, which should 
be verified at each monthly Treatment visit. These data should correspond to the information 
recorded on the eCRFs 
6.7 
Preparation and dispensation 
No special preparation of the study treatments is required. 
Dabrafenib and trametinib will be either sourced as local commercial supply or provided as 
global clinical open-label supply. Global clinical open-label supply will be provided in bottles. 
A unique medication number is printed on the study medication label. 


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When clinical supply is utilized, Investigator staff will identify the study medication kits to 
dispense to the subject by contacting the IRT and obtaining the medication number(s). The 
study medication has a 2-part label (base plus tear-off label), immediately before dispensing the 
medication kit to the subject, site personnel will detach the outer part of the label from the 
packaging and affix it to the source document. 
6.7.1 
Handling of study treatment and additional treatment  
6.7.1.1 
Handling of study treatment  
Study treatment must be received by a designated person at the study site, handled and stored 
safely and properly and kept in a secured location to which only the investigator and designated 
site personnel have access. Upon receipt, all study treatment must be stored according to the 
instructions specified on the labels and in the IBs. Clinical supplies are to be dispensed only in 
accordance with the protocol. Technical complaints are to be reported to the respective Novartis 
CPO Quality Assurance. 
Medication labels will be in the local language and comply with the legal requirements of each 
country. They will include storage conditions for the study treatment but no information about 
the subject except for the medication number. 
The investigator must maintain an accurate record of the shipment and dispensing of study 
treatment in a drug accountability log. Monitoring of drug accountability will be performed by 
monitors during site visits or remotely and at the completion of the trial. Subjects will be asked 
to return all unused study treatment and packaging at the end of the study or at the time of 
discontinuation of study treatment. 
At the conclusion of the study, and as appropriate during the course of the study, the investigator 
will return all unused study treatment, packaging, drug labels, and a copy of the completed drug 
accountability log to the Novartis monitor or to the Novartis address provided in the investigator 
folder at each site. 
6.7.2 
Instruction for prescribing and taking study treatment 
Dabrafenib and trametinib should be taken as follows: 
• Dabrafenib will be administered orally twice daily (BID) during the treatment period. 
• Trametinib will be administered orally once daily (QD) during the treatment period. 
• Subjects should be instructed to take the dabrafenib and trametinib concurrently in the 
morning, at approximately the same time every day. The second (evening) dose of 
dabrafenib (150 mg) should be administered approximately 12 (± 4) hours apart from the 
first dose (morning) of dabrafenib. 
• Dabrafenib and trametinib should be taken with approximately 120-240 mL of water 
under fasting conditions, at least 1 hour before or 2 hours after a meal. 
• Subjects should be instructed to swallow whole capsules of dabrafenib and not chew or 
open them. 
• If a subject vomits after taking study drug, the subject should be instructed not to retake 
the dose and wait for the next scheduled dose. The occurrence and frequency of any 
vomiting during treatment must be noted in the AE section of the eCRF. 
• If a subject misses a scheduled dose not due interruption for any AE, he/she should be 
instructed not to double the next regularly scheduled dose. However, subject may take the 
missed dose immediately if the next scheduled dose is at least 6 hours later for dabrafenib 


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and 12 hours later for trametinib. Subject may then take the next dose at the scheduled 
time. 
• Global clinical open-label supply kits of study treatment assigned by the IRT will be 
recorded in the IRT system.  


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Table 6-20 
Dose treatment and schedule 
Study 
treatments 
Pharmaceutical form and 
route of administration 
Strength 
Frequency and/or 
Regimen 
Dose 
Dabrafenib 
Capsules for oral use 
50 mg, 75 mg 
BID 
150 mg BID (300 
mg/day) 
Trametinib 
Tablets for oral use 
0.5 mg, 2 mg 
QD 
2 mg/day 
7 
Informed consent procedures 
Eligible subjects may only be included in the study after providing (witnessed, where required 
by law or regulation), IRB/IEC-approved informed consent. 
If applicable, in cases where the subject's representative(s) gives consent (if allowed according 
to local requirements), the subject must be informed about the study to the extent possible given 
his/her understanding. If the subject is capable of doing so, he/she must indicate agreement by 
personally signing and dating the written informed consent document. 
Informed consent must be obtained before conducting any study-specific procedures (e.g. all of 
the procedures described in the protocol). The process of obtaining informed consent must be 
documented in the subject source documents. 
Novartis will provide to investigators in a separate document a proposed informed consent form 
that complies with the ICH GCP guidelines and regulatory requirements and is considered 
appropriate for this study. Any changes to the proposed consent form suggested by the 
investigator must be agreed by Novartis before submission to the IRB/IEC. 
Information about common side effects already known about the investigational drug can be 
found in the IB. This information will be included in the subject informed consent and should 
be discussed with the subject during the study as needed. Any new information regarding the 
safety profile of the investigational drug that is identified between IB updates will be 
communicated as appropriate, for example, via an investigator notification or an aggregate 
safety finding. New information might require an update to the informed consent and then must 
be discussed with the subject. 
Women of child bearing potential must be informed that taking the study treatment may involve 
unknown risks to the fetus if pregnancy were to occur during the study and agree that in order 
to participate in the study they must adhere to the contraception requirements. Male subjects 
must be informed that if a female partner becomes pregnant while he is enrolled in the study, 
contact with the female partner will be attempted to request her consent to collect pregnancy 
outcome information. Subjects must be informed of the contraception requirements outlined in 
the Inclusion/Exclusion Criteria (Section 5). 
A copy of the approved version of all consent forms must be provided to Novartis after IRB/IEC 
approval. 
8 
Visit schedule and assessments 
Assessment schedule lists all of the assessments and indicates with an “X”, the visits when they 
are performed. All data obtained from these assessments must be supported in the subject’s 
source documentation. 
Subjects should be seen for all visits/assessments as outlined in the assessment schedule or as 
close to the designated day/time as possible. Missed or rescheduled visits should not lead to 


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automatic discontinuation. Subjects who prematurely discontinue the study for any reason 
should be scheduled for a visit as soon as possible, at which time all of the assessments listed 
for the final visit will be performed. At this final visit, all dispensed investigational product 
should be reconciled, and the adverse event and concomitant medications recorded on the CRF. 
Subjects will receive study treatment for twelve months or until disease recurrence or early 
discontinuation of treatment.  Subjects who discontinue study treatment prior to 12 months 
should complete an EoT visit.   Subjects who complete 12 months of treatment and do not 
relapse will continue into the Follow-up Phase and follow assessments in Table 8-2 (i.e. 
beginning at the Month 15 assessment). In addition, subjects who permanently discontinue 
study treatment prior to 12 months without evidence of disease recurrence will complete an 
EoT visit and then will be followed for disease recurrence according to Table 8-2 until 
withdrawal of consent, lost to follow-up, death, or study completion (as defined in Section 9.2).  
Subjects will return for Follow-up visits starting at the next regularly scheduled disease 
assessment visit (i.e. Month 3, 6, or 12) and continue thereafter according to Table 8-2.  
If a subject experiences disease recurrence, Follow-up visits should be conducted according to 
Table 8-3.  Such follow-up assessments should start at the next scheduled assessment visit and 
continue thereafter according to Table 8-3.  For example, if disease recurrence is observed at 
Month 6, the subject would complete the EoT visit, and then begin Follow-up assessments at 
Month 12 and continue according to the visit schedule in Table 8-3. 
Follow-up for survival, new anti-cancer therapy (including radiotherapy) and response to new 
anti-cancer therapy will continue for all subjects beyond the 24 month assessment according to 
the schedule in Table 8-2 and Table 8-3 until the study is considered to be complete after which 
all protocol-required assessments and procedures will be discontinued.  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.).  


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Table 8-1 
Treatment Visit and Assessment Schedule 
Period 
Pre-
Screening 
Screening 
Treatment Visits & Assessment Schedule1 
Visit Name 
Pre-
screening Screening 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  
End of Treatment (EoT) 
2 
Informed consent 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Disposition 
Assessment (at 
the end of each 
study period) 
 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Demography 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion / 
Exclusion criteria 
 
X4 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical 
history/current 
medical conditions 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Disease Medical 
History 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Diagnosis and 
extent of cancer 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior 
Antineoplastic 
therapy 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
IRT Registration 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
IRT enrollment 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Ophthalmic 
Examination11 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
BRAF V600E/K 
mutation testing 
X3 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Period 
Pre-
Screening 
Screening 
Treatment Visits & Assessment Schedule1 
Visit Name 
Pre-
screening Screening 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  
End of Treatment (EoT) 
2 
Concomitant 
medications7 
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Hematology 
  
X 
X12 X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X  
Clinical Chemistry   
X 
X12 X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 X 
Physical 
Examination 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ECOG 
Performance 
Status 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Body Height 
  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Body Weight 
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 X 
Vital Signs 
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 X 
Coagulation Panel   
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Hepatitis screen8 
  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Pregnancy Test 
(serum) 5 
  
X 
  
  
  
  
  
  
  
  
  
  
  
  
X  
X 
Pregnancy 
(Urine)5 
  
  
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Chest, abdomen 
& pelvic CT 
Scans9 
 
X 
 
 
 
X 
 
 
X 
 
 
 
 
 
X 
X 
Brain CT/MRI 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dermatological 
Assessment 
  
X 
  
  
  
 X 
  
  
X  
  
  
  
  
  
X  
X  
Electrocardiogram 
(ECG) 
  
X 
  
  
  
  
  
  
X 
  
  
  
  
  
X 
X 


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Period 
Pre-
Screening 
Screening 
Treatment Visits & Assessment Schedule1 
Visit Name 
Pre-
screening Screening 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  
End of Treatment (EoT) 
2 
ECHO/MUGA10 
  
X 
  
  
 X10 
  
  
  
X 
  
  
 X 
  
  
X 
X 
Patient reported 
outcomes 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Study drug 
dispensed6 
  
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
  
Study drug 
accountability6 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Events 
  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
1 All assessments mandated throughout the study must be performed on a calendar schedule; delays in treatment administration will not delay performance of 
assessments. Screening procedures may be performed up to 28 days prior to start of study treatment (Day1). 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 Section 8.3.1.1. 
 
2 If treatment is discontinued prior to Month 12, the treatment discontinuation visit (EoT) 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 Table 8-2 unless the subject withdraws from the study. 
 
3 A BRAF V600E/K mutation positive result must be confirmed via a validated local test prior to enrollment. Refer to Section 8.1.1. 
 
4 Complete resection of Stage III cutaneous melanoma must have occurred within 12 weeks of first dose (Day 1). 
 
5 For all women of childbearing potential, a serum pregnancy test will be required within 72 hours prior to start of study treatment (Day1). Subsequent tests may be urine 
tests, and should be performed monthly or at EoT 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. 
 
6 Dosing instructions must be provided to the subject. Subjects should start treatment as soon as possible but no later than 72 hours after drug being dispensed. Study 
treatment will be dispensed at Day 1 and monthly. Site must call IRT to register Enrollment. Treatment compliance will be assessed at all visits after Day 1 . To assess 


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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. 
 
7All medications taken by the subject during the study from the time of Informed Consent 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 Tables 8-2 and 8-3. 
 
8Hepatitis screening only for subjects with a history of chronic HBV and/or HCV 
 
 9CT contrast of the chest, with contrast-enhanced MRI of the abdomen and pelvis should be substituted for full CT scan if the CT frequency defined here is not permitted 
per country or ethics requirements or if CT contrast is contraindicated. 
 
10LVEF will be evaluated prior to initiation of study treatment, within eight weeks of initiating treatment (either at Month 1 or at Month 2), at Month 6, Month 9, Month 12, 
EoT and as clinically appropriate.  
 
11Refer to section 8.4.5 for details of ophthalmic exams needed and to Table 6-18 for management and dose modification guidelines. 
 
 
12Screening and Day 1 Hematology and Clinical Chemistry do not need to be repeated if screening labs are drawn within 3 days of Day 1   
 


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If early treatment discontinuation occurs due to reason other than disease relapse or a subject 
has completed treatment and has not relapsed, refer to Table 8-2. 
Table 8-2 
Follow-up (Pre-Relapse) Assessment Schedule 
 
Pre-Relapse Visit & Assessment Schedule1 
Visit Name 
Month 3  
Month 6  Month 12  Month 15  Month 18  Month 24  
Survival 
Contact 
(every 3 
mo)2 
End of 
Study 
(EoS)3 
Physical 
Examination 
X 
X 
X 
X 
X 
X 
 
X3 
ECOG 
Performance 
Status 
X 
X 
X 
X 
X 
X 
 
X3 
Chest, abdomen 
and pelvic CT 
scans4 
X 
X 
X 
X 
X 
X 
 
X3 
Dermatologic 
Assessment 
X 
X 
X 
X 
X 
X 
 
X3 
Patient reported 
outcomes 
X 
X 
X 
X 
X 
X 
 
X3 
Any anti-
neoplastic 
therapy 
(including 
surgery, 
radiotherapy, 
medications) 
since 
discontinuation 
of study 
treatment 
including Best 
Response 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
Survival Follow 
Up 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
Disposition 
Assessment (at 
the end of each 
study period) 
 
 
 
 
 
 
 
X 
1 Follow-up will start once treatment is completed or discontinued and should continue through EoS Visit, 
withdrawal or death, even if disease recurs. Follow-up visits prior to disease recurrence should follow Table 8-2, 
and should be clinic visits through the Month 24 Assessment. Follow-up visits after the Month 24 Assessment are 
not required to be clinic visits and the information collected will be limited to the following: any radiotherapy; 
surgical procedure or new anti-cancer therapy initiated until EoS visit, withdrawal or death; best response to any 
follow-up treatment; and survival data.  For example, if a subject discontinues treatment at Month 2 for reason 
other than disease relapse, the EoT should be performed according to Table 8-1 and the follow-up assessments 
would start at Month 3 according to Table 8-2 until EoS, withdrawal or death.  Follow-up after disease relapse 
should follow the schedule in Table 8-3.  
2 Survival follow-up after the Month 24 assessment should be conducted every 3 months until withdrawal, death, 
or study end (whichever occurs first), and can be done via phone contact. 
3The EoS visit should be completed at withdrawal, lost to follow-up, death, or at the end of study (see definition in 
Section 9.2), whichever occurs first.  If the EoS visit occurs after the Month 24 visit, a clinic visit is not required 
and the information collected will be limited to the following: anti-cancer therapy, best response to any follow-up 
treatment, and survival data 


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4CT contrast of the chest, with contrast-enhanced MRI of the abdomen and pelvis should be substituted for full CT 
scan if the CT frequency defined here is not permitted per country or ethics requirements or if CT contrast is 
contraindicated. 
If relapse occurs, refer to Table 8-3. 
Table 8-3 
Follow-up (Post-Relapse) Assessment Schedule 
 
Post-Relapse Visit & Assessment Schedule1 
Visit Name 
Month 
3  
Month 6  Month 12  
Month 15  
Month 18   Month 24  
Survival 
Contact 
(every 3 
mo)2 
End of 
Study 
(EoS)3 
Patient reported 
outcomes 
X 
X 
X 
X 
X 
X 
 
X3 
Any anti-neoplastic 
therapy (including 
surgery, 
radiotherapy, 
medications) and 
disease information 
since 
discontinuation of 
study treatment 
including Best 
Response 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Survival Follow Up  
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
Disposition 
Assessment (at the 
end of each study 
period) 
 
 
 
 
 
 
 
X 
1 Follow-up will start once treatment is completed or discontinued and should continue through EoS Visit, 
withdrawal or death, even if disease recurs. Follow-up visits prior to disease recurrence should follow Table 8-2. 
Follow-up after disease relapse should follow the schedule in Table 8-3. For example, if a subject discontinues 
treatment at Month 2 due to disease relapse, the EoT should be performed according to Table 8-1 and the follow-
up assessments would start at Month 3 according to Table 8-3 until EoS, withdrawal, lost to follow-up, or death.   
2 Survival follow-up after the Month 24 assessment should be conducted every 3 months until withdrawal, death, 
or study end (whichever occurs first), and can be done via phone contact. 
3The EoS visit should be completed at withdrawal, lost to follow-up, death, or at the end of study (see definition in 
Section 9.2), whichever occurs first.  If the EoS visit occurs after the Month 24 visit, a clinic visit is not required 
and the information collected will be limited to the following: anti-cancer therapy, best response to any follow-up 
treatment, and survival data 
8.1 
Screening 
8.1.1 
 BRAF V600E/K pre-screening 
Subjects will be enrolled based on local BRAF V600E/K mutation result as part of study 
inclusion criteria (Section 5). The BRAF V600 mutation will be assessed via a local institutional 
assay using a validated tissue-based molecular test for BRAF V600 mutations. 
Immunohistochemistry is not an accepted method and liquid biopsy based BRAF V600 results 
cannot be used to enroll subjects. If BRAF mutation results are not part of the patient’s Medical 
History and must be completed as a study procedure to qualify for the study, the subject should 
first complete the Informed Consent. 


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The eCRF page for methods of local BRAF mutation testing must be completed.  
8.1.2 
Eligibility screening 
Subject re-screening will not be permitted. Subjects should be registered in the Rave eCRF 
system for screening and subject eligibility will be checked once all screening procedures are 
completed. The eligibility check will be embedded in the eCRF system. Please refer and comply 
with detailed guidelines in the CCG. 
8.1.3 
Information to be collected on pre-screening failures 
Subjects who signed a Molecular Pre-screening Informed Consent Form but are not BRAF 
V600E/K mutation positive will be considered a pre-screen failure.  
The following eCRFs should be completed for pre-screen failures: 
• Demography 
• Molecular Informed Consent 
• Disposition, including reason for pre-screen failure 
• Biomarker Assessment - BRAF V600 Mutation Result 
No other data will be entered into the clinical database for subjects who are pre-screen failures, 
unless the subject experienced a Serious Adverse Event during Pre-Screening (see Section 10 
for SAE reporting details) 
8.1.4 
Information to be collected on screening failures 
Subjects who signed an Informed Consent Form but failed to be started on treatment for any 
reason will be considered a screen failure. Subjects who are found not eligible after signing the 
Informed Consent Form will be considered as screening failures. 
The following eCRFs should be completed for screen failures: 
• Demography 
• Informed Consent 
• Disposition, including reason for screen failure 
• Inclusion/Exclusion Criteria 
• Biomarker Assessment - BRAF V600 Mutation Local Result 
No other data will be entered into the clinical database for subjects who are screen failures, 
unless the subject experienced a Serious Adverse Event during Screening (see Section 10 for 
SAE reporting details) 
8.2 
Subject demographics/other baseline characteristics 
Country specific regulations should be considered for the collection of demographic and 
baseline characteristics in alignment with CRF. 
The data to be collected on subject characteristics at screening includes: 
• Demography (age, gender, childbearing potential, race and ethnicity, or as allowed by 
local regulations) 


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• Past and current medical conditions including cardiovascular medical history and risk 
factors 
• Diagnosis and extent of cancer using AJCC edition 8 
• Prior antineoplastic surgery(ies) 
• Prior and current concomitant medications, surgical and medical procedures and 
significant non-drug therapies 
Note: All other medications taken within 28 days or 5 half-lives, whichever is shorter before 
the first dose of study treatment is administered must be recorded on the Prior and current 
concomitant medication eCRF page and updated on an ongoing basis if there is new change to 
the medication. 
Assessments to be performed at screening/baseline include; 
• Physical examination (e.g. performance status (ECOG), height, weight, vital signs, 
ophthalmic and skin examination) 
• Cardiovascular assessments (e.g., ECG, ECHO or MUGA) 
• Laboratory assessments (e.g., hematology, chemistry, coagulation, serum pregnancy test, 
hepatitis test, if applicable) 
• Imaging assessments (e.g., CT and MRI) 
• Patient reported  outcomes (FACT-M) 
8.3 
Efficacy 
8.3.1 
Efficacy Assessments 
The secondary efficacy endpoints of this study are: 
• RFS defined as the time from first dose of study medication to disease recurrence or death 
from any cause.  
• OS defined as the interval from first dose of study medication to the date of death, 
irrespective of the cause of death; subjects still alive will be censored at the date of the last 
contact. 
Tumor response will be assessed locally. The imaging assessment collection plan is presented 
in Table 8-4. The local investigator’s assessment will be used for the primary Interim and 
endpoint RFS analysis and for treatment decision making, as well as the final OS analysis. 
For subjects who continue on study without documented disease relapse, death, lost to follow-
up, or withdrawal of consent, tumor assessments must continue to be performed according to 
the schedule in Table 8-1, Table 8-2 and Table 8-4 (i.e. to Month 24 assessments) until 
documented disease relapse, death, lost to follow-up, withdrawal of consent, or EoS, whichever 
occurs first. 
Table 8-4 
Imaging assessments 
Procedure 
Screening  Treatment Period and Follow up Period 
Chest, abdomen and pelvis CT 
or MRI (with contrast 
enhancement)* 
Mandated 
• 
Months 3, 6, 12, 15, 18, 24, regardless of whether subject 
is on treatment or not, until disease recurrence or start of 
new anti-cancer therapy. 


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• 
EoT: if a scan was not conducted within 30 days prior to 
end of study treatment or when subject discontinues 
treatment. 
• 
EoS: if a scan was not conducted within 30 days prior to 
end of study for subjects who have not had disease 
recurrence or started other anti-cancer therapy. 
Brain imaging (CT or MRI) 
Mandated  
Baseline MRI (preferred) or CT  of the brain must be 
performed on all subjects. Post-baseline scans should be 
performed as clinically indicated. 
*CT contrast of the chest, with contrast-enhanced MRI of the abdomen and pelvis should be substituted for full CT scan if the 
CT frequency defined here is not permitted per country or ethics requirements or if CT contrast is contraindicated 
8.3.1.1 
Assessment Guideline 
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/EoT 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 Table 8-1, Table 8-2, and 
Table 8-4. Intravenous contrast should be used for the CT scans preferably with oral 
contrast as well. CT contrast of the chest, with contrast-enhanced MRI of the abdomen and 
pelvis should be substituted for full CT scanning if the CT frequency prescribed in Table 
8-1, Table 8-2, and Table 8-4 is not permitted per country or ethics requirements or if CT 
contrast is contraindicated. The method of imaging, including use of contrast, should be 
consistent throughout the study (i.e. if CT is done at screening, CT will be done at all 
future timepoints), where not contraindicated. 
• A baseline MRI of the brain is required for all subjects. CT may be performed. Subsequent 
brain scans should only be performed as clinically indicated (e.g. symptoms suggestive of 
CNS recurrence). Contrast enhanced brain MRI is preferred, however, if MRI contrast is 
contraindicated, then MRI without contrast or CT with/without contrast is acceptable. 
• Biopsy of suspected recurrences is strongly recommended to confirm the diagnosis. 
• 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. 
• If clinically indicated, CT or MRI of other areas (e.g., neck) of disease as appropriate 
should be performed. 
• 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. 
• 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 


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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 8.3.1), 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 should be used. 
Brain Scan: For the baseline brain scan and any post-baseline brain scans, contrast enhanced 
MRI is preferable to contrast enhanced CT. 
8.3.1.2 
Baseline imaging assessments 
Imaging assessments will be performed at screening/baseline within 28 days of start of 
treatment (Day -28 to Day -1 prior to Day 1). 
Any imaging assessments already completed during the regular work-up of the subject within 
28 days prior to start of treatment, including before signing the main study ICF, can be 
considered as the baseline images for this study. Any imaging assessments obtained after Day 
1 cannot be considered baseline images. The following assessments are required at 
screening/baseline: 
• Chest, abdomen and pelvis CT or MRI 
• Brain CT or MRI  
8.3.1.3 
Post-baseline imaging assessments 
Imaging assessments as described in Table 8-1, Table 8-2, and Table 8-4 should be performed 
using the same imaging modality used at baseline, irrespective of study treatment interruption 
or actual dosing. Imaging assessments for response evaluation will be performed according to 
Table 8-1, Table 8-2, and Table 8-4 until disease relapse, death, lost to follow-up, withdrawal 
of consent or the 24 month/ EoS assessment. Imaging assessments should be scheduled using 
Day 1 as the reference date (not the date of the previous tumor assessment), and should be 
respected regardless of whether treatment with study treatment is temporarily withheld, 
permanently discontinued, or unscheduled assessments performed. 
Tumor assessments after start of new anti-neoplastic therapy post-relapse are recommended 
however not required.  Best response to anti-neoplastic therapy after relapse will be collected 
on the eCRF. 
Additional imaging assessments may be performed at any time during the study at the 
investigator’s discretion to support the efficacy evaluations for a subject, as necessary. Clinical 
suspicion of disease relapse at any time requires a physical examination and imaging 
assessments to be performed promptly rather than waiting for the next scheduled imaging 
assessment. 


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Combined PET/CT may be used only if the CT is of similar diagnostic quality as a CT 
performed without PET, including the utilization of IV contrast media. At the discretion of the 
Investigators, FDG-PET scans may be performed to document relapse. 
8.3.1.4 
Study Completion Assessments 
Prior to disease recurrence, if a subject withdraws from the study Day 1 through Month 24 
and the last radiographic assessment was more than 3 months prior to withdrawal from study, 
a disease assessment should be obtained at the time of withdrawal from study. 
8.4 
Safety 
Safety assessments are specified below with the assessment schedule detailing when each 
assessment is to be performed. 
Significant findings that were present prior to the signing of informed consent must be included 
in the ‘Relevant Medical History/Current Medical Conditions’ page on the subject’s CRF. 
Significant new findings that begin or worsen after informed consent must be recorded on the 
Adverse Event page of the subject’s CRF. 
For details on AE collection and reporting, refer to Section 10. 


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Table 8-5 
Assessments & Specifications 
Assessment 
Specification 
Physical 
examination 
• 
A complete physical examination will include the examination of general appearance, skin, neck (including thyroid), eyes, ears, nose, throat, 
lungs, heart, abdomen, back, lymph nodes, extremities, vascular, and neurological. If indicated based on medical history and/or symptoms, 
rectal, external genitalia, breast, and pelvic exams will be performed. 
• 
A short physical exam will include the examination of general appearance and vital signs (blood pressure [SBP and DBP] and pulse). A short 
physical exam will be at all visits starting from Day 1, except for Month 12 or EoT, where a full physical exam is required.  
• 
Information for all physical examinations must be included in the source documentation at the study site. Clinically relevant findings that are 
present prior to signing informed consent must be recorded on the Relevant Medical History/Current Medical Conditions CRF. Significant 
findings made that begin or worsen after signing informed consent which meet the definition of an Adverse Event must be recorded on the 
Adverse Event CRF. 
Vital sign 
• 
Vital signs include blood pressure (supine position preferred when ECG is collected), pulse measurement, and body temperature. 
Height and 
weight 
• 
Height in centimeters (cm) at screening only and body weight (to the nearest 0.1 kilogram (kg) in indoor clothing, but without shoes) will be 
measured at screening and subsequent time points as specified in Table 8-1 


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8.4.1 
Performance status 
Performance status will be assessed as described in Table 8-1 and Table 8-2. More frequent 
examinations may be performed at the investigator’s discretion, if medically indicated. ECOG 
Performance status scale will be used as described in the Table 8-6 below: 
Table 8-6 
ECOG performance status scale 
Score 
Performance Status 
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 housework, 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 
8.4.2 
Physical Exam 
A complete physical examination will be performed at screening, Month 12 or EoT, and later 
as clinically indicated and will include the examination of general appearance, skin, neck 
(including thyroid), eyes, ears, nose, throat, lungs, heart, abdomen, back, lymph nodes, 
extremities, vascular, and neurological assessments. If indicated based on medical history 
and/or symptoms, rectal, external genitalia, breast, and pelvic exams will be performed. 
A short physical exam will be performed beginning at Day 1 as per schedule in Table 8-1 and 
will include the examination of general appearance, skin (including Dermatologic Exam), and 
vital signs (blood pressure and pulse). 
8.4.3 
Vital Signs 
Vital signs include blood pressure (supine position preferred when ECG is collected), pulse 
measurement, and body temperature and will be measured at screening and at subsequent time 
points as specified in Table 8-1. 
8.4.4 
Height and Weight 
Height will be measured at screening. 
Body weight (in indoor clothing, but without shoes) will be measured at screening and at 
subsequent time points as specified in Table 8-1. 
8.4.5 
Ophthalmic examination 
A standard ophthalmic examination by an ophthalmologist will be performed as per schedule 
in Table 8-1. The exam will include best corrected visual acuity, tonometry, slit lamp 
biomicroscopic examination, visual field examination, and dilated indirect fundoscopy with 
special attention to retinal abnormalities (dilation only required if clinically indicated). Optical 
coherence tomography is recommended at scheduled visits, and mandated if retinal 


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abnormalities are suspected. Other types of ancillary testing including color fundus 
photography and fluorescein angiography are also recommended if clinically indicated. 
More frequent examinations may be performed at the investigator’s discretion, if medically 
indicated. 
8.4.6 
Dermatologic Examination 
Dermatologic exams are required as per schedule in Table 8-1 and Table 8-2 through Month 24 
or disease relapse. Exams may be performed by the investigator as part of the Physical Exam 
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. 
8.4.7 
Laboratory evaluations 
Local laboratories will be used for routine safety assessments as outlined in Table 8-7 and the 
results will be recorded in the eCRF.  
Novartis must be provided with a copy of the local laboratory’s certification, and a tabulation 
of the normal ranges and units of each parameter collected for entry into the eCRF. Any changes 
regarding normal ranges and units for laboratory values assessed during the study must be 
reported via an updated tabulation indicating the new effective date. Additionally, if at any time 
a subject has laboratory parameters obtained from a different (outside) laboratory, Novartis 
must be provided with a copy of the certification and a tabulation of the normal ranges and units 
for this laboratory as well. The Investigator is responsible for reviewing all laboratory reports 
for subjects in the study and evaluating any abnormalities for clinical significance. 
In the case where a laboratory assessment that is listed in the inclusion/exclusion criteria is 
outside of a protocol-specified lab normal range at screening and/or at baseline, the 
assessment may be repeated to rule out laboratory error. If the repeat value remains outside of 
protocol-specified ranges during screening procedures, the subject must be excluded from the 
study. 
In the case where a laboratory range is not specified by the protocol, but is outside the normal 
range for the center at screening and/or baseline, a decision regarding whether the result is of 
clinical significance or not must be made by the Investigator and should be based, in part, upon 
the nature and degree of the observed abnormality. The assessment may be repeated as soon as 
possible, and in any case, prior to Day 1, to rule out laboratory error. 
In all cases, the Investigator must document in the source documents, the clinical considerations 
(i.e. result was/was not clinically significant and/or medically relevant) in allowing or 
disallowing the subject to continue in the study. 
Clinically relevant deviations of laboratory test results occurring during or at completion of the 
study must be reported and discussed with Novartis personnel. The results must be evaluated 
for criteria defining an adverse event and reported as such if the criteria are met. Repeated 
evaluations are mandatory until normalization of the result(s) or until the change is no longer 
clinically relevant. In case of doubt, Novartis personnel should be contacted. 


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Table 8-7 
Clinical laboratory parameters collection plan 
Test Category 
Test Name 
Hematology 
Hemoglobin, Platelets, White blood cells, Differential (Basophils, Eosinophils, 
Lymphocytes, Monocytes, Neutrophils, Bands*, Other) 
Chemistry 
Albumin, Alkaline phosphatase, ALT, AST, Calcium, Magnesium, Phosphorus, 
Sodium, Potassium, Chloride, Creatinine, Creatine kinase, Direct Bilirubin, Total 
Bilirubin, Total Cholesterol, Blood Urea Nitrogen (BUN) or Urea, Uric Acid, 
Amylase, Lipase, Glucose (fasting or non-fasting) 
Coagulation 
International normalized ratio (INR), Activated partial thromboplastin time (APTT) 
Pregnancy Test 
A serum pregnancy test must be performed at screening (at the local laboratory) 
≤ 72 hours before first dose of study treatment, and at treatment discontinuation 
(Month 12 or EoT) 
A local laboratory urine pregnancy test must be performed at day 1 and at 
Monthly visits during the treatment period. 
Hepatitis markers (for 
subjects with a history of 
chronic HBV and/or HCV) 
HBV-DNA, HbsAg, HbsAb, HbcAb, HCV RNA-PCR 
*optional  
 
8.4.8 
Cardiac Assessments 
8.4.8.1 
Electrocardiogram (ECG) 
A standard 12 lead ECG will be performed according to Table 8-1 and Table 8-8. 
Standard 12 lead ECG will be performed after the subject has been resting for approximately 
10 min prior to each ECG collection. Additional, unscheduled, ECGs may be performed at the 
discretion of the investigator at any time during the study as clinically indicated.  
For any ECGs with subject safety concerns, two additional ECGs must be performed to confirm 
the safety finding. A monitoring or review process should be in place for clinically significant 
ECG findings throughout the study and especially at baseline before administration of study 
treatment. All ECGs need to be collected and copies kept in the medical record for central 
review, if requested by the sponsor. 
Any identifier details must be redacted (e.g. subject initials, date of birth). 
Table 8-8 
ECG collection plan for Treatment Period 
Visit 
Time 
ECG Type 
Number of ECG 
Screening 
Anytime 
12 Lead 
1 
Month 6 
Anytime 
12 Lead 
1 
Month 12 
Anytime 
12 Lead 
1 
EoT 
Anytime 
12 Lead 
1 
Unscheduled 
Anytime 
12 Lead 
1 
Twelve (12)-lead ECGs will be obtained using an ECG machine that automatically calculates 
heart rate and measures RR, PR, QRS, QT, and QTcF intervals. All ECG assessments will be 
performed in the supine position. ECG data will be read and interpreted locally. 


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Interpretation of the tracing must be made by a qualified physician and documented on the ECG 
eCRF page. Each ECG tracing should be labeled with the study number, subject initials (where 
regulations permit), subject number, date, and kept in the source documents at the study site. 
Clinically significant abnormalities present when the subject signed informed consent should 
be reported on the Medical History eCRF page. Clinically significant findings must be 
discussed with Novartis prior to enrolling the subject in the study. New or worsened clinically 
significant findings occurring after informed consent must be recorded on the Adverse Events 
eCRF page. 
8.4.9 
Cardiac imaging – ECHO or MUGA scan 
Decreases of the LVEF have been observed in subjects receiving trametinib. Therefore, ECHO 
or MUGAs must be performed to assess cardiac ejection fraction in regular intervals according 
to the relevant schedule (see Table 8-1). 
The same procedure (either ECHO or MUGA, although ECHO is preferred) should be 
performed at baseline and at follow-up visit(s). Dose modification guidance and stopping 
criteria for LVEF decrease are provided in Table 6-15. 
8.4.10 
Pregnancy and assessments of fertility 
All pre-menopausal women who are not surgically sterile will have pregnancy testing. 
Additional pregnancy testing might be performed if requested by local requirements. Women 
of child-bearing potential will have serum pregnancy tests within 72 hours prior to the first dose 
of study treatment and at the Month 12 or the EoT visit. Monthly urine pregnancy tests will 
then be required to be performed beginning at Month 1 through Month 11.  See Table 8-1 for 
timing of the protocol required pregnancy testing; additional pregnancy testing may be 
performed to meet local requirements.  
Male subjects (including those that have had a vasectomy) taking study treatment must use a 
condom during intercourse from Day 1 through 16 weeks after stopping treatment, and should 
not father a child during these periods. In addition, male participants should not donate sperm 
from Day 1 to 16 weeks after last dose.  
Refer to Section 5.2 for contraception requirements. 
Women of child-bearing potential will be instructed to contact the site immediately at any time 
during the study and for 16 weeks after stopping treatment should they have a positive 
pregnancy test.  
Refer to Section 10.1.4 for details on Pregnancy Reporting. 
 
 
 
Assessments of Fertility 


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Medical documentation of oophorectomy, hysterectomy, or tubal ligation must be retained as 
source documents. Subsequent hormone level assessment to confirm the woman is not of child 
bearing potential must also be available as source documentation in the following cases: 
1. surgical bilateral oophorectomy without a hysterectomy 
2. reported 12 months of natural (spontaneous) amenorrhea with an appropriate clinical 
profile. 
In the absence of the above medical documentation, FSH testing is required of any female 
subject, regardless of reported reproductive/menopausal status at screening/baseline. 
8.5 
Additional Assessments 
8.5.1 
Patient Reported Outcomes 
The patient-reported outcomes (PRO) data will be collected using an electronic tablet device.  
All PRO assessments should be administered in the subjects’ local language according to the 
Visit Evaluation Schedule in Table 8-1, Table 8-2, and Table 8-3, prior to any tests, treatments 
or receipt of results from any test to avoid biasing the subject’s perspective.  
Subjects should be given sufficient space and time to complete all study questionnaires and all 
administered questionnaires should be reviewed for completeness. If missing responses are 
noted, subjects should be encouraged to complete any missing responses. Attempts should be 
made to collect responses to all questionnaires for all subjects, including from those who 
discontinue prior to the study evaluation completion visit, however, if subjects refuse to 
complete questionnaires, this should be documented in study source records. Subject’s refusal 
to complete study questionnaires are not protocol deviations. 
Completed questionnaires, including both responses to the questions and any unsolicited 
comments written by the subject, must be reviewed and assessed by the investigator before the 
clinical examination for responses which may indicate potential AEs or SAEs. This review 
should be documented in study source records. 
If an AE or SAE is confirmed then the physician should record the event as instructed in Section 
10 of this protocol. Investigators should not encourage the subjects to change responses reported 
in questionnaires. 
8.5.1.1 
Functional Assessment of Cancer Therapy-Melanoma (FACT-M) 
The Melanoma Subscale of the Functional Assessment of Cancer Therapy-Melanoma (FACT-
M) will be used to evaluate patient-reported outcome measures of health-related quality-of-life, 
functioning, disease symptoms, treatment-related side effects, and global health status. The 
Melanoma Subscale of the FACT-M are recognized as reliable and valid measures (Cormier 
2008) frequently used in clinical trials of patients with advanced or metastatic cancer. 
The FACT-M quality of life questionnaire consists of the FACT-General (FACT-G) plus the 
Melanoma Subscale and the Melanoma Surgery Subscale, which complement the general scale 
with items specific to HRQOL in melanoma. Higher scores on all the FACT-M scales indicate 
a higher quality of life. In psychometric testing FACT-M questionnaire has been shown to be a 
reliable and valid instrument for subjects with melanoma that can be used for the assessment of 


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HRQOL in clinical trials (Cormier 2008). For the purpose of this study the 16 items that 
comprise the Melanoma Subscale of the FACT-M are used.  
9 
Study discontinuation and completion 
9.1 
Discontinuation 
9.1.1 
Discontinuation of study treatment  
Discontinuation of study treatment for a subject occurs when study treatment is stopped earlier 
than the protocol planned duration, and can be initiated by either the subject or the investigator. 
The investigator must discontinue study treatment for a given subject if, he/she believes that 
continuation would negatively impact the subject's well-being. 
Study treatment must be discontinued under the following circumstances: 
• Disease relapse 
• Unacceptable adverse event, including meeting stopping criteria as described in Sections 
6.5.1 and 6.5.2. 
• Subject/guardian decision 
• Pregnancy 
• Use of prohibited treatment as per recommendations in Section 6.2.2 
• Any situation in which study participation might result in a safety risk to the subject.  
If discontinuation of study treatment occurs, the investigator should make a reasonable effort 
to understand the primary reason for the subject’s premature discontinuation of study treatment 
and record this information. 
Subjects who discontinue study treatment or who decide they do not wish to participate in the 
study further should NOT be considered withdrawn from the study UNLESS they withdraw 
their consent (see Section 9.1.2). Where possible, they should return for the assessments 
indicated in the assessment schedule. If they fail to return for these assessments for unknown 
reasons, every effort (e.g. telephone, e-mail, letter) should be made to contact the subject/pre-
designated contact as specified in the lost to follow-up section (see Section 9.1.3). This contact 
should preferably be done according to the study visit schedule. 
If the subject cannot or is unwilling to attend any visit(s), the site staff should maintain regular 
telephone contact with the subject, or with a person pre-designated by the subject. This 
telephone contact should preferably be done according to the study visit schedule. 
After study treatment discontinuation, at a minimum, in abbreviated visits, the following data 
should be collected at clinic visits or via telephone/email contact (per assessment schedule in 
Table 8-2 or Table 8-3): 
• new / concomitant treatments including any radiotherapy, surgical procedure or new anti-
cancer therapy 
• adverse events/Serious Adverse Events 
• survival status 


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The investigator must also contact the IRT to register the subject’s discontinuation from study 
treatment. 
9.1.1.1 
Replacement policy 
Not applicable. Subjects will not be replaced on study. 
9.1.2 
Withdrawal of informed consent  
Subjects may voluntarily withdraw consent to participate in the study for any reason at any 
time. Withdrawal of consent occurs only when a subject: 
• Does not want to participate in the study anymore, and 
• Does not allow further collection of personal data 
In this situation, the investigator should make a reasonable effort (e.g. telephone, e-mail, letter) 
to understand the primary reason for the subject’s decision to withdraw his/her consent and 
record this information. 
Study treatment must be discontinued and no further assessments conducted, and the data that 
would have been collected at subsequent visits will be considered missing.   
Further attempts to contact the subject are not allowed unless safety findings require 
communicating or follow-up. 
All efforts should be made to complete the assessments prior to study withdrawal. A final 
evaluation at the time of the subject’s study withdrawal should be made as detailed in the 
assessment table. 
Novartis will continue to keep and use collected study information according to applicable law.  
9.1.3 
Lost to follow-up  
For subjects whose status is unclear because they fail to appear for study visits without stating 
an intention to discontinue or withdraw, the investigator must show "due diligence" by 
documenting in the source documents steps taken to contact the subject, e.g. dates of telephone 
calls, registered letters, etc. A subject should not be considered as lost to follow-up until due 
diligence has been completed or until the end of the study. 
9.1.4 
Early study termination by the sponsor  
The study can be terminated by Novartis at any time for any reason. This may include reasons 
related to the benefit/ risk assessment of participating in the study, practical reasons (including 
slow enrollment), or for regulatory or medical reasons. In taking the decision to terminate, 
Novartis will always consider the subject welfare and safety. Should early termination be 
necessary, subjects must be seen as soon as possible (provide instruction for contacting the 
subject, when the subject should stop taking drug, when the subject should come for a final 
visit) and treated as a prematurely withdrawn subject (see also Section 9.2). The investigator 
may be informed of additional procedures to be followed in order to ensure that adequate 
consideration is given to the protection of the subject’s interests. The investigator or sponsor 
depending on the local regulation will be responsible for informing IRBs/IECs of the early 
termination of the trial. 


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9.2 
Study completion and post-study treatment  
Following twelve months of treatment or early treatment discontinuation, no further study 
treatment will be made available to a subject. All treated subjects should have a safety follow-
up call conducted 30 days after last administration of study treatment. The information collected 
is kept as source documentation. All SAEs reported during this time period must be reported as 
described in Section 10.1.3. Documentation of attempts to contact the subject should be 
recorded in the source documentation. 
Study completion is defined as 24 months after the first dose (Day 1) of the last subject enrolled, 
and any repeat assessments associated with this visit have been documented and followed-up 
appropriately by the Investigator, or in the event of an early study termination decision, the date 
of that decision. 
Subjects will be followed on the study per the schedule of assessments (refer to Table 8-1, Table 
8-2, Table 8-3). Each subject will complete their EoS visit 24 months after Day 1 of the last 
subject enrolled or at early withdrawal from the study, death, withdrawal of consent, or lost to 
follow-up.  
Post relapse therapy will be permitted during the study in the Follow-up Period per Investigator 
discretion, but not provided or administered as study treatment. 
The final OS analysis will be performed when the last subject completes their EoS visit (i.e. 24 
months after LPFV). All available data from all subjects up to this cut-off date will be analyzed. 
The study will be closed when all subjects have either died, withdrawn consent, are lost to 
follow-up, 24 months after Day 1 of last subject enrolled, or when the last EoS visit is 
completed, whichever occurs first. 
In the event the study is terminated due to futility, study subjects currently on study treatment 
in the Treatment Phase and who are still deriving clinical benefit will be eligible to continue 
their adjuvant treatment (i.e. up to 12 months dabrafenib in combination with trametinib) 
through a locally established Novartis program. 
10 
Safety monitoring and reporting  
10.1 
Definition of adverse events and reporting requirements 
10.1.1 
Adverse events  
An adverse event (AE) is any untoward medical occurrence (e.g., any unfavorable and 
unintended sign, symptom or disease) in a subject or clinical investigation subject after 
providing written informed consent for participation in the study. Therefore, an AE may or may 
not be temporally or causally associated with the use of a medicinal (investigational) product. 
Abnormal laboratory values or test results occurring after informed consent constitute adverse 
events only if they induce clinical signs or symptoms, are considered clinically significant, 
require therapy (e.g., hematologic abnormality that requires transfusion or hematological stem 
cell support), or require changes in study medication(s). 


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The investigator has the responsibility for managing the safety of individual subject and 
identifying adverse events. 
Novartis qualified medical personnel will be readily available to advise on trial related medical 
questions or problems 
Adverse events that begin or worsen after informed consent must be recorded in the Adverse 
Events CRF. Conditions that were already present at the time of informed consent must be 
recorded in the Medical History page of the subject’s CRF. Adverse event monitoring must be 
continued for at least 30 days (or 5 half-lives, whichever is longer) following the last dose of 
study treatment. Adverse events (including lab abnormalities that constitute AEs) must be 
described using a diagnosis whenever possible, rather than individual underlying signs and 
symptoms. When a clear diagnosis cannot be identified, each sign or symptom must be reported 
as a separate Adverse Event. 
Adverse events will be assessed according to the Common Terminology Criteria for Adverse 
Events (CTCAE) version 4.03. 
If CTCAE grading does not exist for an adverse event, the severity of mild, moderate, severe, 
and life-threatening, death related to the AE corresponding respectively to Grades 1 - 5, will be 
used. Information about any deaths (related to an Adverse Event or not) will also be collected 
though a Death form. 
The occurrence of adverse events should be sought by non-directive questioning of the subject 
during the screening process after signing informed consent and at each visit during the study. 
Adverse events also may be detected when they are volunteered by the subject during the 
screening process or between visits, or through physical examination, laboratory test, or other 
assessments. As far as possible, each adverse event should be evaluated to determine: 
1. The severity grade (CTCAE v4.03 Grade 1-5) 
2. its relationship to the study treatment. If the event is due to lack of efficacy or progression 
of underlying illness (i.e. progression of the study indication) the assessment of causality 
will usually be ‘Not suspected’. The rationale for this guidance is that the symptoms of a 
lack of efficacy or progression of underlying illness are not caused by the trial drug, they 
happen in spite of its administration and/or both lack of efficacy and progression of 
underlying disease can only be evaluated meaningfully by an analysis of cohorts, not on a 
single subject 
3. its duration (start and end dates) or if the event is ongoing, an outcome of not 
recovered/not resolved must be reported. 
4. whether it constitutes a SAE (see Section 10.1.2 for definition of SAE) and which 
seriousness criteria have been met 
5. action taken regarding with study treatment. 
6. All adverse events must be treated appropriately. Treatment may include one or more of 
the following: 
• Dose not changed 
• Dose Reduced/increased 
• Drug interrupted/withdrawn 
7. its outcome i.e., its recovery status or whether it was fatal 


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If the event worsened the event should be reported a second time in the CRF noting the start 
date when the even worsens in toxicity. For Grade 3 and 4 adverse events only, if improvement 
to a lower grade is determined a new entry for this event should be reported in the CRF noting 
the start date when the event improved from having been Grade 3 or Grade 4. 
Conditions that were already present at the time of informed consent should be recorded in 
medical history of the subject. 
Adverse events (including lab abnormalities that constitute AEs) should be described using a 
diagnosis whenever possible, rather than individual underlying signs and symptoms. 
Adverse event monitoring should be continued for at least 30 days following the last dose of 
study treatment. 
All adverse events must be treated appropriately. If a concomitant medication or non-drug 
therapy is given, this action must be recorded on the Adverse Event CRF. 
Once an adverse event is detected, it must be followed until its resolution or until it is judged to 
be permanent, and assessment must be made at each visit (or more frequently, if necessary) of 
any changes in severity, the suspected relationship to the study treatment, the interventions 
required to treat it, and the outcome. 
Relapse or progression of malignancy (including fatal outcomes), confirmed via Investigator 
assessment, should not be reported as a serious adverse event. 
Adverse events separate from the relapse or progression of malignancy (example, deep vein 
thrombosis at the time of progression or hemoptysis concurrent with finding of disease 
progression) will be reported as per usual guidelines used for such events with proper attribution 
regarding relatedness to the drug. 
Information about adverse drug reactions for the investigational drug can be found in the IB. 
Abnormal laboratory values or test results constitute adverse events only if they fulfill at least 
one of the following criteria: 
• they induce clinical signs or symptoms 
• they are considered clinically significant 
• they require therapy 
Clinically significant abnormal laboratory values or test results must be identified through a 
review of values outside of normal ranges/clinically notable ranges, significant changes from 
baseline or the previous visit, or values which are considered to be non-typical in subjects with 
the underlying disease.  
Adverse events of special interest 
Adverse events of special interest (AESI) are defined as events (serious or non-serious) which 
are ones of scientific and medical concern specific to the Sponsor’s product or program, for 
which ongoing monitoring and rapid communication by the Investigator to the Sponsor may be 
appropriate. Such events may require further investigation in order to characterize and 
understand them. 


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AESIs are defined on the basis of an ongoing review of the safety data. AESIs are discussed in 
detail in the IB and a list of Medical Dictionary for Regulatory Activities (MedDRA) preferred 
terms to flag as AESI’s will be included in the SAP. 
AESI for the study drug include: 
Table 10-1 
Adverse events of special interest by study treatment 
 
trametinib 
dabrafenib 
dabrafenib and 
trametinib 
combination 
Hepatic disorders 
x 
 
x 
Pneumonitis/Interstitial lung disease 
x 
 
x 
Skin toxicities (e.g., rash, dermatitis acneiform) 
x 
 
x 
Bleeding events 
x 
 
x 
Hypersensitivity 
x 
x 
x 
Pancreatitis 
 
x 
x 
Neutropenia 
 
 
x 
Pulmonary embolism, deep vein thrombosis 
x 
 
x 
Pre-renal and intrinsic renal failure 
 
x 
x 
New primary melanoma 
 
x 
x 
Non-Cutaneous Treatment-Emergent Malignancies 
 
x 
x 
Hyperglycemia 
 
x 
x 
Cardiac related events 
x 
 
x 
Complicated pyrexia and/or Grade 3 and Grade 4 
pyrexia 
 
x 
x 
Uveitis 
 
x 
x 
Ocular events (e.g., retinal vein occlusion, retinal 
pigment epithelial detachment and uveitis) 
x 
 
x 
Cutaneous squamous cell carcinoma including 
keratocanthoma 
 
x 
x 
Hypertension 
x 
 
x 
10.1.2 
Serious adverse events  
An SAE is defined as any adverse event [appearance of (or worsening of any pre-existing)] 
undesirable sign(s), symptom(s) or medical conditions(s)) which meets any one of the following 
criteria: 
• fatal 
• life-threatening 
Life-threatening in the context of a SAE refers to a reaction in which the subject was at risk of 
death at the time of the reaction; it does not refer to a reaction that hypothetically might have 
caused death if it were more severe (please refer to the ICH-E2D Guidelines). 
• results in persistent or significant disability/incapacity 
• constitutes a congenital anomaly/birth defect 
• requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is for:  


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• routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition  
• elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since signing the informed consent 
• social reasons and respite care in the absence of any deterioration in the subject’s 
general condition 
treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of a SAE given above and not resulting in hospital admission is medically 
significant, e.g. defined as an event that jeopardizes the subject or may require 
medical or surgical intervention to prevent one of the outcomes listed above 
Medical and scientific judgment should be exercised in deciding whether other situations should 
be considered serious reactions, such as important medical events that might not be immediately 
life threatening or result in death or hospitalization but might jeopardize the subject or might 
require intervention to prevent one of the other outcomes listed above. Such events should be 
considered as “medically significant”. Examples of such events are 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 dependency or abuse.  
All malignant neoplasms will be assessed as serious under “medically significant” if other 
seriousness criteria are not met and the malignant neoplasm is not a disease relapse of the study 
indication. Relapse of malignancy (including fatal outcomes), confirmed via Investigator 
assessment, should not be reported as a serious adverse event. 
Any suspected transmission via a medicinal product of an infectious agent is also considered a 
serious adverse reaction. 
All reports of intentional misuse and abuse of the product are also considered serious adverse 
event irrespective if a clinical event has occurred.  
10.1.3 
SAE reporting 
To ensure subject safety, every SAE, regardless of suspected causality, occurring after the 
subject has provided informed consent and until at least 30 days after the subject has stopped 
study treatment must be reported to Novartis within 24 hours of learning of its occurrence. 
Detailed instructions regarding the submission process and requirements are to be found in the 
investigator folder provided to each site. 
Any additional information for the SAE including complications, progression of the initial SAE, 
and recurrent episodes must be reported as follow-up to the original episode within 24 hours of 
the investigator receiving the follow-up information. 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. 
Any SAEs experienced after the 30 day safety evaluation follow-up period (or 5 half-lives, 
whichever is longer) must only be reported to Novartis if the investigator suspects a causal 
relationship to the study treatment. 
Information about all SAEs is collected and recorded on the Serious Adverse Event Report 
Form; all applicable sections of the form must be completed in order to provide a clinically 


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thorough report. The investigator must assess and record the relationship of each SAE to each 
specific study treatment (if there is more than one study treatment). Instructions regarding the 
SAE submission process and requirements for signatures are to be found in the investigator 
folder provided to each site. 
Follow-up information is submitted in the same way as the original SAE Report. Each re-
occurrence, complication, or progression of the original event must be reported as a follow-up 
to that event regardless of when it occurs. The follow-up information must describe whether the 
event has resolved or continues, if and how it was treated, whether the blind was broken or not, 
and whether the subject continued or withdrew from study participation. 
If the SAE is not previously documented in the IB or Package Insert (new occurrence) and is 
thought to be related to the study treatment, an oncology Novartis Drug Safety and 
Epidemiology (DS&E) department associate may urgently require further information from the 
investigator for Health Authority reporting. Novartis may need to issue an Investigator 
Notification (IN), to inform all investigators involved in any study with the same drug that this 
SAE has been reported. Suspected Unexpected Serious Adverse Reactions (SUSARs) will be 
collected and reported to the competent authorities and relevant ethics committees in 
accordance with EU Guidance 2011/C 172/01 or as per national regulatory requirements in 
participating countries. 
10.1.4 
Pregnancy reporting  
Reproductive toxicity and teratogenicity data are not available for the investigational drug at 
this time, therefore no guidelines on therapeutic recommendations in case of pregnancy are 
available. This study enrolls women who are considered to be of child-bearing potential using 
highly effective methods of contraception. In the case that a pregnancy in a female study 
participant should occur, please follow the below reporting guidelines. 
To ensure subject safety, each pregnancy occurring after signing the informed consent must be 
reported to Novartis within 24 hours of learning of its occurrence. The pregnancy should be 
followed up to determine outcome, including spontaneous or voluntary termination, details of 
the birth, and the presence or absence of any birth defects, congenital abnormalities, or maternal 
and/or newborn complications. 
Pregnancy must be recorded on the Pharmacovigilance Pregnancy Form and reported by the 
investigator to the local Novartis Chief Medical Office and Patient Safety (CMO& PS) 
Department. Pregnancy follow-up should be recorded on the same form and should include an 
assessment of the possible relationship to the study treatment. 
Any SAE experienced during the pregnancy and unrelated to the pregnancy must be reported 
on a SAE form. 
The study drug must be discontinued, though the subject may stay in the study, if she wishes to 
do so. All assessments that are considered as a risk during pregnancy must not be performed. 
The subject may continue all other protocol assessments. 
Pregnancy outcomes should be collected for the female partners of any males who took study 
treatment in this study. Consent to report information regarding these pregnancy outcomes 
should be obtained from the mother. 


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10.1.5 
Reporting of study treatment errors including misuse/abuse  
Medication errors are unintentional errors in the prescribing, dispensing, administration or 
monitoring of a medicine while under the control of a healthcare professional, subject or 
consumer (EMA definition). 
Misuse refers to situations where the medicinal product is intentionally and inappropriately used 
not in accordance with the protocol. 
Abuse corresponds to the persistent or sporadic, intentional excessive use of a medicinal 
product, which is accompanied by harmful physical or psychological effects. 
Study treatment errors and uses outside of what is foreseen in the protocol will be collected in 
the DAR eCRF irrespective of whether or not associated with an AE/SAE and reported to Safety 
only if associated with an SAE. Misuse or abuse will be collected and reported in the safety 
database irrespective of it being associated with an AE/SAE within 24 hours of Investigator’s 
awareness. 
Table 10-2 
Guidance for capturing the study treatment errors including 
misuse/abuse 
Treatment error type 
Document in Dose 
Administration (DAR) eCRF 
(Yes/No) 
Document in AE 
eCRF 
Complete SAE form 
Unintentional study 
treatment error 
Yes 
Only if associated 
with an AE 
Only if associated with 
an SAE 
Misuse/Abuse 
Yes 
Yes 
Yes, even if not 
associated with a SAE 
For more information on AE and SAE definition and reporting requirements, please see the, 
respective sections. 
10.2 
Additional Safety Monitoring 
Not applicable 
10.2.1 
Liver safety monitoring  
Please, refer to Section 6.5.1.3.2. 
All follow-up information, and the procedures performed must be recorded as appropriate in 
the CRF. 
10.2.2 
Renal safety monitoring  
Please refer to Section 6.5.1.3.3. 
All follow-up information, and the procedures performed must be recorded as appropriate in 
the CRF. 
10.2.3 
Data Monitoring Committee 
This study will include a DMC that will function independently of all other individuals 
associated with the conduct of this clinical trial, including the site investigators participating in 


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the study. The DMC will assess at defined intervals the progress of the clinical trial, safety data, 
and critical efficacy variables and recommend whether to continue, modify or terminate the 
trial. The DMC will be informed and convened quickly in the event of unexpected results that 
raise concerns to permit DMC evaluation and input.  An IA for futility of the primary endpoint 
will be conducted when the first 200 subjects dosed have been followed for 6 months (either 
completed 6 months of treatment or discontinued treatment earlier) (see Section 12.7 and the 
DMC charter for details).  At the time of this IA, the futility of a secondary efficacy endpoint 
RFS will also be assessed. 
Responsibilities of the DMC and communication flow between the DMC and Novartis will be 
described in the DMC charter document.  It is expected that the DMC will consist at a minimum 
of two physicians with appropriate disease area qualifications and one statistician.  
10.2.4 
Steering Committee  
The steering committee will be established comprising investigators participating in the trial, 
i.e. not being members of the DMC and Novartis representatives from the Clinical Trial Team. 
The SC will ensure transparent management of the study according to the protocol through 
recommending and approving modifications as circumstances require. The SC will review 
protocol amendments as appropriate. Together with the clinical trial team, the SC will also 
develop recommendations for publications of study results including authorship rules. The 
details of the membership and role of the Steering Committee will be defined in a Steering 
Committee charter. 
11 
Data Collection and Database Management  
11.1 
Data collection  
The designated investigator staff will enter the data required by the protocol into the Electronic 
Case Report Forms (eCRF). The eCRFs have been built using fully validated secure web-
enabled software that conforms to 21 CFR Part 11 requirements, Investigator site staff will not 
be given access to the EDC system until they have been trained. Automatic validation programs 
check for data discrepancies in the eCRFs, allow modification and/or verification of the entered 
data by the investigator staff. 
The Principal investigator is responsible for assuring that the data (recorded on CRFs) (entered 
into eCRF) is complete, accurate, and that entry and updates are performed in a timely manner. 
The Investigator must certify that the data entered are complete and accurate. 
After final database lock, the investigator will receive copies of the subject data for archiving 
at the investigational site. 
All data should be recorded, handled and stored in a way that allows its accurate reporting, 
interpretation and verification. 
11.2 
Database management and quality control  
Novartis personnel (or designated CRO) will review the data entered by investigational staff 
for completeness and accuracy. Electronic data queries stating the nature of the problem and 


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requesting clarification will be created for discrepancies and missing values and sent to the 
investigational site via the EDC system. Designated investigator site staff are required to 
respond promptly to queries and to make any necessary changes to the data. 
Concomitant treatments and prior medications entered into the database will be coded using the 
WHO Drug Reference List, which employs the Anatomical Therapeutic Chemical classification 
system. Medical history/current medical conditions and adverse events will be coded using the 
Medical dictionary for regulatory activities (MedDRA) terminology. 
Data about all study treatment (s) dispensed to the subject and all dosage changes will be tracked 
using an Interactive Response Technology (IRT) for clinically supplied drug.  The system will 
be supplied by a vendor, who will also manage the database. The data will be sent electronically 
to Novartis (or a designated CRO) at specific timelines. IRT will not be utilized to track study 
drug that is sourced as local commercial supply; this information will be recorded on local study 
drug accountability logs. 
Once all the necessary actions have been completed and the database has been declared to be 
complete and accurate, it will be locked. Any changes to the database after that time can only 
be made after written agreement by Novartis development management. 
After database lock, the investigator will receive a CD-ROM or paper copies of the subject data 
for archiving at the investigational site. 
11.3 
Site monitoring  
Before study initiation, at a site initiation visit or at an investigator’s meeting, a Novartis 
representative will review the protocol and data capture requirements (eCRFs) with the 
investigators and their staff. During the study, Novartis employs several methods of ensuring 
protocol and GCP compliance and the quality/integrity of the sites’ data. The field monitor will 
visit the site to check the completeness of subject records, the accuracy of data capture / data 
entry, the adherence to the protocol and to Good Clinical Practice, the progress of enrollment, 
and to ensure that study treatment is being stored, dispensed, and accounted for according to 
specifications. Key study personnel must be available to assist the field monitor during these 
visits. Continuous remote monitoring of each site’s data may be performed by a centralized 
Novartis. Additionally, a central analytics organization may analyze data & identify risks & 
trends for site operational parameters, and provide reports to Novartis clinical teams to assist 
with trial oversight. 
The investigator must maintain source documents for each subject in the study, consisting of 
case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, electrocardiograms, and the results of any other tests or 
assessments. All information on CRFs must be traceable to these source documents in the 
subject’s file. The investigator must also keep the original informed consent form signed by the 
subject (a signed copy is given to the subject). 
The investigator must give the monitor access to all relevant source documents to confirm their 
consistency with the data capture and/or data entry. Novartis monitoring standards require full 
verification for the presence of informed consent, adherence to the inclusion/exclusion criteria, 
documentation of SAEs, and of data that will be used for all primary variables. Additional 
checks of the consistency of the source data with the CRFs are performed according to the 


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study-specific monitoring plan. No information in source documents about the identity of the 
subjects will be disclosed. 
12 
Data analysis and statistical methods  
One IA for futility is planned for the study when approximately the first 200 subjects dosed 
have been followed for 6 months (either completed 6 months of treatment or discontinued 
treatment earlier.)  Primary statistical analysis will be performed 12 months after LPFV. Final 
analysis of the study will be performed at the end of the study defined as 24 months after LPFV. 
The data will be summarized with respect to demographic and baseline characteristics, and 
safety observations and efficacy measurements. Categorical data will be presented as 
frequencies and percentages. For continuous data, mean, standard deviation, median, minimum, 
and maximum will be presented. 
12.1 
Analysis sets 
The Full Analysis Set (FAS) and Safety Set are defined in the same way and comprise all 
subjects who received at least one dose of study treatment. 
The Safety Set includes all subjects who received at least one dose of study treatment.  
12.2 
Subject demographics and other baseline characteristics  
Summary statistics of subject demographics and baseline characteristics will be provided 
using FAS. Categorical data will be presented as frequencies and percentages. For continuous 
data, mean, standard deviation, median, minimum, and maximum will be presented. 
Relevant medical histories and current medical at baseline will be summarized by system 
organ class and preferred term. 
12.3 
Treatments  
The safety set will be used for the analyses below. Categorical data will be summarized as 
frequencies and percentages. For continuous data, mean, standard deviation, median, 25th and 
75th percentiles, minimum, and maximum will be presented. 
The duration of exposure in dabrafenib and trametinib and their dose intensity (computed as the 
ratio of actual cumulative dose received and actual duration of exposure) will be summarized 
by means of descriptive statistics using the safety set. 
The number of subjects with dose adjustments (reductions, interruption, or permanent 
discontinuation) and the reasons will be summarized and all dosing data will be listed. 
Concomitant medications and significant non-drug therapies prior to and after the start of the 
study treatment will be listed and summarized according to the Anatomical Therapeutic 
Chemical (ATC) classification system. 


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12.4 
Analysis of the primary endpoint(s) 
To assess whether an adapted AE-management algorithm for pyrexia will reduce the incidence 
of grade 3/4 pyrexia, hospitalization due to pyrexia, or permanent treatment discontinuation due 
to pyrexia compared to historical control. 
12.4.1 
Definition of primary endpoint(s) 
The primary endpoint is defined as the composite rate of grade 3/4 pyrexia, hospitalization due 
to pyrexia or permanent treatment discontinuation due to pyrexia up to 12 months of therapy 
among overall treated subjects. 
The rate of this composite endpoint is calculated as the total number of subjects experiencing 
at least one of the three components of the composite endpoint (i.e., grade 3/4 pyrexia, 
hospitalization due to pyrexia, or permanent treatment discontinuation due to pyrexia), divided 
by the total number of subjects in the FAS. The composite endpoint is assessed over a treatment 
period of 12 months. 
12.4.2 
Statistical model, hypothesis, and method of analysis 
The primary analysis will be based on the calculation of the observed pyrexia event rate up to 
12 months of therapy (primary endpoint) using the FAS. The observed pyrexia event rate will 
be summarized using descriptive statistics (N, %) along with its two-sided exact 95% 
confidence interval (Clopper and Pearson 1934). 
In the COMBI-AD study, 87 out of 435 subjects in the treatment arm (20%) developed either 
grade 3/4 pyrexia or hospitalization due to pyrexia or discontinued due to pyrexia. This rate of 
20% will be used as the historical control rate for the assessment of pyrexia management 
algorithm in this study. 
Evidence of treatment effect (improvement in pyrexia event rate using the AE-management 
algorithm) will be concluded, if the upper bound of the two-sided 95% confidence interval is 
less than 20%. 
The exact 95% confidence intervals for various observed event rates at the primary analysis are 
shown in Table 12-1. If 100 (16.7%) out of 600 subjects are observed with pyrexia event,  then 
the upper bound of the 95% confidence interval will be less than 20%. 


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 Table 12-1 
Exact 95% CI for different observed event rates at primary analysis 
N 
r 
Pyrexia event rate (%) 
95% exact CI (%)* 
600 
100 
16.7 
13.8 – 19.9 
600 
101 
16.8 
13.9 – 20.1 
600 
102 
17.0 
14.1 – 20.2 
600 
103 
17.2 
14.2 – 20.4 
600 
104 
17.3 
14.4 – 20.6 
600 
105 
17.5 
14.5 – 20.8 
N: Total numbers of subjects; 
r: Number of subjects with pyrexia events at primary analysis 
* Clopper and Pearson (1934) 
In addition, the probability that the pyrexia even rate is below the threshold of 20% will be 
calculated from the posterior distribution. For illustration, as shown in Table 12-2, if 104 out of 
600 subjects are observed with pyrexia events at primary analysis, then the posterior probability 
of observing an event rate of < 20% is 0.954 (probability ≥ 0.95).   
Table 12-2 
Posterior probability for a positive effect at primary analysis 
N 
r 
Pyrexia event rate (%) 
Posterior* 
Pr (event rate<20%|data) 
600 
100 
16.7 
0.983 
600 
101 
16.8 
0.977 
600 
102 
17.0 
0.971 
600 
103 
17.2 
0.963 
600 
104 
17.3 
0.954 
600 
105 
17.5 
0.943 
600 
110 
18.3 
0.854 
600 
115 
19.2 
0.703 
600 
120 
20.0 
0.508 
600 
125 
20.8 
0.313 
600 
130 
21.7 
0.161 
600 
135 
22.5 
0.068 
N: Total numbers of subjects; 
r: Number of subjects with pyrexia events at primary analysis 
* A diffuse (highly non-informative) prior distribution of the composite rate with a skeptical expectation of 20%, 
namely Beta (0.25, 1) is assumed. 
12.4.3 
Handling of missing values/censoring/discontinuations 
No missing data imputation rule will be applied to the primary analysis. For the primary 
endpoint, subjects who discontinued prematurely prior to 12 months without pyrexia will be 
counted as no event. 
12.5 
Analysis of secondary endpoints  


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12.5.1 
Efficacy endpoints 
The secondary endpoints are the RFS and OS rates at 12 and 24 months. 
RFS is defined as the time from the date of first dose of the study medication to the date of 
disease recurrence or death due to any cause. Treatment emergent malignancies other than 
second melanomas will not be considered as events. RFS will be censored if no RFS event is 
observed before the first to occur between: (i) the analysis cut-off date, and (ii) the date when a 
new anti-cancer therapy is started. The censoring date will be the date of the last adequate tumor 
assessment prior to cut-off/start of new anti-cancer therapy. 
OS is defined as the time from date of the first dose of study medication to date of death due to 
any cause. If a subject is not known to have died, then OS will be censored at the latest date the 
subject was known to be alive (on or before the cut-off date).  
RFS and OS will be analyzed descriptively in the FAS population. The RFS and OS distribution 
will be estimated using the Kaplan-Meier method, and the Kaplan-Meier curves, medians and 
95% confidence intervals of the medians will be presented. 
12.5.2 
Safety endpoints 
Other secondary objectives related to safety include: 
• To evaluate overall AE rate leading to permanent treatment discontinuation by 12 months 
• Frequency, number of episodes, duration, AE management (including concomitant 
medications and study treatment modifications) due to pyrexia 
• To evaluate overall safety (AEs and SAEs) 
For all safety analyses, the safety set will be used.  
The overall observation period will be divided into three mutually exclusive segments: 
1. pre-treatment period: from day of subject’s informed consent to the day before first dose 
of study medication 
2. on-treatment period: from day of first dose of study medication to 30 days after last dose 
of study medication 
3. post-treatment period: starting at day 30+1 after last dose of study medication. 
Adverse events 
Summary tables for adverse events (AEs) will include only AEs that started or worsened during 
the on-treatment period, the treatment-emergent AEs. 
The incidence of treatment-emergent adverse events (new or worsening from baseline) will be 
summarized by system organ class and or preferred term, severity (based on CTCAE grades), 
type of adverse event, relation to study treatment. 
Serious adverse events, non-serious adverse events and adverse events of special interest (AESI) 
during the on-treatment period will be tabulated. 
All deaths (on-treatment and post-treatment) will be summarized. 


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All AEs, deaths and serious adverse events (including those from the pre and post-treatment 
periods) will be listed and those collected during the pre-treatment and post-treatment period 
will be flagged. 
The proportion of subjects in the study, who have permanently discontinued treatment due to 
any AE, will be estimated, along with 95% confidence intervals using Clopper Pearson exact 
method.  
Vital signs 
All vital signs data will be listed by treatment group, subject, and visit/time and if ranges are 
available, abnormalities will be flagged. Summary statistics will be provided by treatment and 
visit/time. 
Clinical laboratory evaluations 
Grading of laboratory values will be assigned programmatically as per NCI Common 
Terminology Criteria for Adverse Events (CTCAE) version 4.03. The calculation of CTCAE 
grades will be based on the observed laboratory values only, clinical assessments will not be 
taken into account. 
CTCAE Grade 0 will be assigned for all non-missing values not graded as 1 or higher. Grade 5 
will not be used. 
For laboratory tests where grades are not defined by CTCAE v 4.03, results will be categorized 
as low/normal/high based on laboratory normal ranges. 
The following summaries will be generated separately for hematology, and biochemistry tests: 
• Listing of all laboratory data with values flagged to show the corresponding CTCAE 
v4.03 grades if applicable and the classifications relative to the laboratory normal ranges 
For laboratory tests where grades are defined by CTCAE v4.03 
• Worst post-baseline CTCAE grade (regardless of the baseline status). Each subject will be 
counted only once for the worst grade observed post-baseline. 
• Shift tables using CTCAE v4.03 grades to compare baseline to the worst on-treatment 
value 
For laboratory tests where grades are not defined by CTCAE v4.03, 
• Shift tables using the low/normal/high/ (low and high) classification to compare baseline 
to the worst on-treatment value. 
12.5.3 
Patient reported outcomes 
Changes in HRQOL from baseline will be assessed using the FACT-M questionnaire. The 
summary table of change in HRQOL from baseline will be presented by using the FAS. 
12.6 
Analysis of exploratory endpoints 
Not applicable 


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12.7 
Interim analyses 
One IA for futility of the primary endpoint is planned for the study when approximately the first 
200 subjects dosed have been followed for 6 months (either completed 6 months of treatment 
or discontinued treatment earlier.) At the time of this IA, the futility of a secondary efficacy 
endpoint RFS will also be assessed. This analysis will allow assessing the impact of the adapted 
pyrexia AE-management algorithm on both the pyrexia event rate and the RFS rate at 6 months. 
The DMC will review the IA results and make a recommendation using the scenarios provided 
below. Any decision to stop or continue the pyrexia management algorithm will be made based 
on all data available at the IA cut-off taking the futility analysis into account. 
From the COMBI-AD study that used the approved pyrexia management algorithm, the pyrexia 
event rate (composite rate of grade 3/4 pyrexia, hospitalization due to pyrexia, or permanent 
treatment discontinuation due to pyrexia) at 12 month observed for dabrafenib + trametinib 
(N=435) was: 20% with 95% CI (16%, 24%). Under the new pyrexia treatment algorithm, an 
observed primary endpoint rate of at least 20% may indicate lack of improvement of the new 
algorithm. Assessment of futility for primary endpoint will be based on the calculated Bayesian 
predictive probabilities of the event that observed pyrexia event rate will be 20% or more in the 
FAS, if the study is continued beyond the interim (i.e. till the primary analysis). 
The pyrexia event rate is assumed to be binary and the number of subjects with pyrexia events 
is assumed to follow a binomial distribution. Suppose the prior belief regarding the probability 
of event rate (π) is that it has a beta distribution with parameters 𝑎𝑎0 and 𝑏𝑏0. If there are x events 
out of n subjects, then the posterior distribution for π is beta with parameters 𝑎𝑎1 = a0 + x and 
𝑏𝑏1 = 𝑏𝑏0 + n - x. Now let Y represent the number of subjects with pyrexia events from m future 
observations, then the (posterior) predictive distribution of Y conditional on the observed data 
at the interim (x events out of n subjects) is a beta-binomial distribution described by 
 
where B(a, b) is the beta function. 
A diffuse (highly non-informative) prior distribution of the composite rate with a skeptical 
expectation of 20%, namely Beta (0.25, 1) is assumed. 
Under these assumptions, the DMC will be provided the predictive probability of observing 
pyrexia event rate of ≥ 20%, a criterion that may trigger consideration for stopping the study 
taking account of all available data and not just the pyrexia event rate data required for 
determination of futility. 
Table 12-3 shows the predictive probabilities of observing pyrexia event rate ≥ 20% (n=200) 
under different interim results. For illustration, with 200 subjects at IA, if the observed pyrexia 
event rate is 22%, the probability of observing the pyrexia event rate ≥ 20% at primary analysis 
is > 80%. The DMC might interpret this scenario as an outcome where stopping the study for 
futility may be a sensible option. If the observed pyrexia event rate is 18% at IA, the probability 
of observing the pyrexia event rate ≥ 20% at primary analysis is < 20%. 


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Table 12-3 
Predictive probability of observing composite pyrexia event rate 
greater or equal 20% (n=200) in the safety set at primary analysis (600 
subjects) under different interim results 
Observed rate at IA (n=200) 
Predictive probability of observing 
pyrexia event rate ≥ 20% at primary 
analysis* 
# of subjects with 
pyrexia events 
% 
30 
15 
0.0135 
32 
16 
0.0392 
34 
17 
0.0943 
36 
18 
0.1913 
38 
19 
0.3318 
40 
20 
0.5000 
42 
21 
0.6673 
44 
22 
0.8058 
46 
23 
0.9015 
48 
24 
0.9569 
50 
25 
0.9838 
52 
26 
0.9948 
54 
27 
0.9986 
56 
28 
0.9997 
58 
29 
0.9999 
60 
30 
1.0000 
*prior distribution Beta (0.25, 1) is assumed. 
At the time of this IA, the DMC will also be provided with interim results for the secondary 
endpoint RFS.  Similar to the futility analysis for the primary endpoint, Bayesian predictive 
probabilities of the RFS rate will be provided. 
From the COMBI-AD study, the Kaplan-Meier estimated RFS rate at 12 month for control 
group and treatment group were: 56% with 95% CI (51%, 61%) and 88% with 95% CI (85%, 
91%), respectively. We consider the futility threshold of 12-month RFS rate of 61%, which is 
the upper bound 95% CI of control group, and calculate the predictive probability (PP) as 
follows: 
PP = Prob. [Observed 12 month RFS rate ≥ 61% | x, n; x successes among n subjects] 
The DMC will be provided the predictive probability of observing RFS of ≥ 61%, a criterion 
that may trigger consideration for stopping the study taking account of all available data and 
not just the RFS data required for determination of futility. 
Table 12-4 shows the predictive probabilities of observing RFS rate ≥ 61% (n=200) under 
different interim results. For illustration, with 200 subjects at IA, if the observed RFS rate at 6-
month is 65%, the probability of observing the RFS rate ≥ 61% at the primary analysis at 12 
months is > 90%. If the observed RFS rate is 57%, the probability of observing the RFS rate ≥ 
61% at the primary analysis is < 10%. 
Table 12-4 
Predictive probability of observing RFS rate greater or equal 61% 
(n=200) at the secondary analysis (600 subjects) 
Observed rate at IA (n=200) 


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# of relapse free 
% 
Predictive probability of 
observing RFS rate ≥ 61% at 
secondary analysis* 
110 
55 
0.0163 
112 
56 
0.0371 
114 
57 
0.0760 
116 
58 
0.1403 
120 
60 
0.3550 
122 
61 
0.4930 
124 
62 
0.6321 
128 
64 
0.8529 
130 
65 
0.9201 
*prior distribution Beta (0.37, 1) is assumed. 
Subject enrollment will not be stopped for the IA.  According to enrollment expectation, 
approximately 570 subjects are planned to be included in the study at the time of the IA cutoff. 
12.8 
Sample size calculation 
The sample size calculation is based on the primary variable. The sample size of 600 has been 
chosen so that the study operating characteristics comply with the requirement to have a high 
probability (e.g. > 95%) for futility at IA if the true 12-month pyrexia event rate is > 20%, e.g., 
when the true pyrexia event rate is 27%, the probability is 95.5% for futility. 
Operating characteristics are described below (see Table 12-5). For illustration, if the true 12-
months pyrexia event rate is 30%, then there is a high chance (99.6%) of futility at the time of 
the IA, and the probability to continue the study and conclude success is lower than 0.001. 
If the true pyrexia event rate is 20%, then the probability of observing a pyrexia event rate < 
20% (i.e., study success for primary analysis) is 43.4%. If the true pyrexia event rate is lower 
(for example 18%), then there is 83.9% probability of declaring study success for primary 
analysis. 
Table 12-5 
Operating Characteristics 
True 6 -month 
event rate 
Probability to stop the 
study at IA 
Probability of success at primary analysis 
(i.e., not stop at the IA and observe event 
rate < 20% at primary analysis) 
16% 
0.016 
0.980 
17% 
0.040 
0.939 
18% 
0.086 
0.839 
19% 
0.161 
0.661 
20% 
0.265 
0.434 
21% 
0.391 
0.228 
22% 
0.528 
0.094 
25% 
0.856 
0.001 
26% 
0.917 
<0.001 
27% 
0.955 
<0.001 
28% 
0.978 
<0.001 


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True 6 -month 
event rate 
Probability to stop the 
study at IA 
Probability of success at primary analysis 
(i.e., not stop at the IA and observe event 
rate < 20% at primary analysis) 
30% 
0.996 
<0.001 
Probabilities are calculated based on the exact binomial distribution. 
13 
Ethical considerations and administrative procedures  
13.1 
Regulatory and ethical compliance 
This clinical study was designed and shall be implemented, executed and reported in accordance 
with the ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with applicable 
local regulations (including European Directive 2001/20/EC, US CFR 21), and with the ethical 
principles laid down in the Declaration of Helsinki. 
13.2 
Responsibilities of the investigator and IRB/IEC 
Before initiating a trial, the investigator/institution must obtain approval/favorable opinion from 
the Institutional Review Board/Independent Ethics Committee (IRB/IEC) for the trial protocol, 
written informed consent form, consent form updates, subject recruitment procedures (e.g., 
advertisements) and any other written information to be provided to subjects. Prior to study 
start, the investigator is required to sign a protocol signature page confirming his/her agreement 
to conduct the study in accordance with these documents and all of the instructions and 
procedures found in this protocol and to give access to all relevant data and records to Novartis 
monitors, auditors, Novartis Quality Assurance representatives, designated agents of Novartis, 
IRBs/IECs, and regulatory authorities as required. If an inspection of the clinical site is 
requested by a regulatory authority, the investigator must inform Novartis immediately that this 
request has been made. 
13.3 
Publication of study protocol and results 
The protocol will be registered in a publicly accessible database such as clinicaltrials.gov and 
as required in EudraCT. In addition, after study completion (defined as last patient last visit) 
and finalization of the study report the results of this trial will be submitted for publication and 
posted in a publicly accessible database of clinical trial results, such as the Novartis clinical trial 
results website and all required Health Authority websites (e.g. Clinicaltrials.gov, EudraCT 
etc.) . 
For details on the Novartis publication policy including authorship criteria, please refer to the 
Novartis publication policy training materials that were provided to you at the trial investigator 
meetings 
13.4 
Quality Control and Quality Assurance 
Novartis maintains a robust Quality Management System (QMS) that includes all activities 
involved in quality assurance and quality control, to ensure compliance with written Standard 
Operating Procedures as well as applicable global/local GCP regulations and ICH Guidelines. 


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Audits of investigator sites, vendors, and Novartis systems are performed by auditors, 
independent from those involved in conducting, monitoring or performing quality control of the 
clinical trial. The clinical audit process uses a knowledge/risk based approach. 
Audits are conducted to assess GCP compliance with global and local regulatory requirements, 
protocols and internal SOPs, and are performed according to written Novartis processes 
14 
Protocol adherence  
This protocol defines the study objectives, the study procedures and the data to be collected on 
study participants. Additional assessments required to ensure safety of subjects should be 
administered as deemed necessary on a case-by-case basis. Under no circumstances including 
incidental collection is an investigator allowed to collect additional data or conduct any 
additional procedures for any purpose involving any investigational drugs under the protocol, 
other than the purpose of the study. If despite this interdiction prohibition, data, information, 
observation would be incidentally collected, the investigator shall immediately disclose it to 
Novartis and not use it for any purpose other than the study, except for the appropriate 
monitoring on study participants. 
Investigators ascertain they will apply due diligence to avoid protocol deviations. If an 
investigator feels a protocol deviation would improve the conduct of the study this must be 
considered a protocol amendment, and unless such an amendment is agreed upon by Novartis 
and approved by the IRB/IEC and health authorities, where required, it cannot be implemented. 
14.1 
Protocol Amendments 
Any change or addition to the protocol can only be made in a written protocol amendment that 
must be approved by Novartis, health authorities where required, and the IRB/IEC prior to 
implementation. 
Only amendments that are required for subject safety may be implemented immediately 
provided the health authorities are subsequently notified by protocol amendment and the 
reviewing IRB/IEC is notified. 
Notwithstanding the need for approval of formal protocol amendments, the investigator is 
expected to take any immediate action required for the safety of any subject included in this 
study, even if this action represents a deviation from the protocol. In such cases, Novartis should 
be notified of this action and the IRB/IEC at the study site should be informed according to 
local regulations. 
15 
References 
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in Patients With Resected Stage IIB-III Melanoma: Results of Intergroup Trial 
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randomised controlled trial. Lancet; 386: 444-51 
Long GV, Eroglu Z, Infante J, et al (2017) Long-Term Outcomes in Patients With BRAF 
V600–Mutant Metastatic Melanoma Receiving Dabrafenib Combined With Trametinib. J 
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Metastatic Breast Cancer. N Engl J Med; 367:435-44. 
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with Combined Dabrafenib and Trametinib. N Engl J Med; 372:30-9. 
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Romano E, Scordo M, Dusza SW,et al (2010). Site and timing of first relapse in stage III 
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Schadendorf D, Amonkar MM, Milhem M et al (2014) Functional and symptom impact of 
trametinib versus chemotherapy in BRAF V600E advanced or metastatic melanoma: quality-
of-life analyses of the METRIC study. Ann Oncol. Mar;25(3):700-6. 


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SEER (2017). https://www.cancer.org/content/dam/cancer-org/research/cancer-facts-
andstatistics/annual-cancer-facts-and-figures/2017/cancer-facts-and-figures-2017.pdf. 
Slamon D, Leyland-Jones B, Shak S, et al (2001) Use of Chemotherapy plus a Monoclonal 
Antibody against HER2 for Metastatic Breast Cancer That Overexpresses HER2. N Engl J 
Med; 344:783-92. 
Weber J, Mandala, M, Del Vecchio M, et al (2017) Adjuvant Nivolumab versus Ipilimumab 
in Resected Stage III or IV Melanoma, N Engl J Med. 2017 Nov 9;377(19):1824-1835 
WHO (2017). Skin Cancer http://www.who.int/uv/faq/skincancer/en/index1.html accessed 11-
Aug-2017. 
Yu A, Yadav N, Lung B (2015) Trastuzumab interruption and treatment-induced 
cardiotoxicity in early HER2-positive breast cancer. Breast Cancer Res Treat; 149: 489-95. 


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16 
Appendices 
16.1 
Appendix 1:  AJCC Melanoma Staging Eight Edition  
Table 16-1 
Melanoma Stage III Subgroups Based on Primary Tumor (T) and 
Regional Lymph Nodes (N ) categories  
 
 
 
 
 
 
 
 
 
 
 


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Table 16-2 
Definition of Regional Lymph Node (N) 
 
Reproduced from Amin MB, Edge SB, Greene FL, et al, eds. AJCC Cancer Staging 
Manual. 8th ed. New York: Springer; 2017. 
 
 
 
 
 
 
 
 
 
 
 


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SAP_001.pdf: 


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Document History – Changes compared to previous final version of SAP 
 
Date 
Time 
point 
Reason for 
update 
Outcome for update 
Section and 
title 
impacted 
(Current) 
 
Prior to 
database 
lock   
Incorporate 
changes 
as 
per protocol 
amendment 1 
and 2  
First version 
NA 
22 
September 
2020 
Prior to 
database 
lock of 
primary 
analysis  
Addition 
of 
analyses 
to 
describe and 
adjust 
for 
impact 
of 
COVID-19  
Additional 
outputs 
added 
for 
analysis to describe and adjust for 
impact of COVID-19 
 
22 
September 
2020 
Prior to 
database 
lock of 
primary 
analysis 
Addition 
of 
analyses 
to 
support 
the 
pyrexia label 
update  
Addition of analyses to support the 
pyrexia label update  
 
20 
July 
2021 
Prior to 
the final 
database 
lock 
Final output 
specifications 
 
 
 


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Table of contents 
Table of contents ................................................................................................................. 3 
List of abbreviations ............................................................................................................ 5 
1 
Introduction ......................................................................................................................... 6 
1.1 
Study design............................................................................................................. 8 
1.2 
Study objectives and endpoints ............................................................................... 9 
2 
Statistical methods ............................................................................................................. 10 
2.1 
Data analysis general information ......................................................................... 10 
2.1.1 
General definitions ................................................................................ 11 
2.2 
Analysis sets .......................................................................................................... 15 
2.2.1 
Subgroup of interest .............................................................................. 16 
2.3 
Patient disposition, demographics and other baseline characteristics ................... 16 
2.3.1 
Patient disposition ................................................................................. 16 
2.4 
Treatments (study treatment, concomitant therapies, compliance) ....................... 17 
2.4.1 
Study treatment/compliance .................................................................. 17 
2.4.2 
Prior, concomitant and post therapies ................................................... 21 
2.5 
Analysis of the primary objective .......................................................................... 22 
2.5.1 
Primary endpoint ................................................................................... 22 
2.5.2 
Statistical hypothesis, model and method of analysis ........................... 22 
2.5.3 
Handling of missing values/censoring/discontinuations ....................... 24 
2.5.4 
Supportive analyses ............................................................................... 24 
2.6 
Analysis of the key secondary objective ............................................................... 24 
2.7 
Analysis of the secondary objective(s) .................................................................. 24 
2.7.1 
Secondary endpoints ............................................................................. 25 
2.7.2 
Statistical hypothesis, model and method of analysis ........................... 25 
2.7.3 
Handling of missing values/censoring/discontinuations ....................... 26 
2.8 
Safety analyses ....................................................................................................... 27 
2.8.1 
Adverse events (AEs) ............................................................................ 27 
2.8.2 
Deaths .................................................................................................... 30 
2.8.3 
Laboratory data ..................................................................................... 30 
2.8.4 
Other safety data ................................................................................... 31 
2.8.5 
Additional analyses ............................................................................... 34 
2.9 
Pharmacokinetic endpoints .................................................................................... 34 
2.10 
PD and PK/PD analyses......................................................................................... 34 
2.11 
Patient reported outcomes (PRO) .......................................................................... 35 
2.11.1 
General PRO analysis ........................................................................... 35 


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2.12 
Biomarkers ............................................................................................................. 35 
2.13 
Other exploratory analysis ..................................................................................... 35 
2.14 
Interim analysis ...................................................................................................... 35 
3 
Sample size calculation ..................................................................................................... 35 
4 
Changed to protocol specified analyses ............................................................................ 37 
4.1 
Impact of COVID-19 ............................................................................................. 37 
4.2 
Analyses to support label update ........................................................................... 38 
5 
Appendix ........................................................................................................................... 40 
5.1 
Imputation rules ..................................................................................................... 40 
5.1.1 
Study drug ............................................................................................. 40 
5.1.1 
AE, ConMeds and safety assessment date imputation .......................... 41 
5.2 
AEs coding/grading ............................................................................................... 44 
5.3 
Laboratory parameters derivations ........................................................................ 44 
5.4 
Statistical models ................................................................................................... 45 
5.4.1 
Primary analysis of binary data ............................................................. 45 
5.4.2 
Secondary analysis ................................................................................ 45 
6 
Appendix for identification of corticosteroids .................................................................. 45 
7 
Reference ........................................................................................................................... 49 


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List of abbreviations 
 
 
AEs 
Adverse Events  
AESIs 
Adverse Events of Special Interest 
ATC 
AJCC 
Anatomical Therapeutic Classification 
American Joint Committee on Cancer 
BID 
CRS 
bis in diem/twice a day 
Case Retrieval Strategy 
CSR 
Clinical Study report 
CTC 
Common Toxicity Criteria 
CTCAE 
Common Terminology Criteria for Adverse Events 
DMC 
ECOG PS 
ECG 
Data Monitoring Committee  
Eastern Cooperative Oncology Group Performance Status 
Electrocardiogram 
EoT 
End of Treatment visit 
EoS 
FACT-M 
End of Study visit 
Functional Assessment of Cancer Therapy–Melanoma 
FAS 
IA 
Full Analysis Set 
Interim analysis 
eCRF 
Electronic Case Report Form 
MedDRA 
Medical Dictionary for Regulatory Activities 
NCI 
National Cancer Institute 
o.d. 
Once Daily 
OS 
Overall Survival 
RFS 
Relapse-Free Survival 
PK 
Pharmacokinetics 
PRO 
Patient-reported Outcomes 
QD 
Qua’que di’e / once a day 
QoL 
Quality of Life 
RAP 
Report and Analysis Process 
RECIST 
Response Evaluation Criteria in Solid Tumors  
SAP 
Statistical Analysis Plan 
SOC 
System Organ Class 
TFLs 
Tables, Figures, Listings 
WHO 
World Health Organization 
 
 
 


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2 
Addendum details: 
The purpose of this Statistical Analysis Plan (SAP) is to outline the statistical methods and 
document the outputs needed for the clinical study report (CSR) of the final analysis of study 
CDRB436F2410, a open-label, phase IIIb study of dabrafenib in combination with trametinib 
in the adjuvant treatment of stage III BRAF V600 mutation-positive melanoma after complete 
resection to evaluate the impact on pyrexia related outcomes of an adapted pyrexia AE-
management algorothim.  
The final analysis was planned to be performed at the end of the study defined as 24 months 
after last patient last visit.  
 
The final analysis will be a re-run of all the analyses described in the primary analysis SAP, 
dated on Nov 4, 2020 (/CREDI Projects/D/DRB436F/CREDI 
Studies/DRB436F2410/Administrative Files (study level)/RAP or RAMP Meeting - 
SAP_CDRB2410_CSR_Primary_Analysis_SAP.docx 
https://webedi02.na.novartis.net:8443/webEDI02_non_SSO/drl/objectId/090095af8e1016b1).  
All the analyses, data rules will follow the rules described in the above SAP. The final analysis 
will not include the analyses described in section 2 to support label update (Section 4.2 in the 
primary analysis SAP). The content of this SAP is based on protocol CDRB436F2410 version 
02 (Amendment 2).  
 
The tables/listings/figures will follow the shells described in COMBI_Aplus_Final reported in  
 
/CREDI Projects/D/DRB436F/CREDI Studies/DRB436F2410/Administrative Files (study 
level)/RAP or RAMP Meeting - SAP_CDRB436F2410_COMBI_Aplus_Final.docx 
https://webedi02.na.novartis.net:8443/webEDI02_non_SSO/drl/objectId/090095af8b2267b8 
For any occurrence , the following rules will be followed. 
 


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Specifically, the occurrence of AESI will follow the following rules.  
To calculate the duration of AESI, the rule will be [max(end date of all below bullets)-[min(start 
date of all below bullets]+1. 
For the first occurrence of AESI, when subsequent records AE start date is same as  first 
occurrence start date or end date is earlier than first occurrence end date  
For the first occurrence of  AESI, when subsequent records start date is after first occurrence 
start date, but is earlier than first occurrence end date  
For the first occurrence of  AESI, when subsequent records start date is after first occurrence 
start date, but is earlier than (previous latest occurrence end date+7)   
3 
The changes from primary analysis to final analysis 
 
The changes in the final analysis will be as of below: 
1)  Listing number changes  
Previous Listing Number 
Listing Name  
New Listing Number  
Listing 14.3.3-1.7 
Adverse events of special 
interest (Safety set) 
Listing 14.3.2-1.7 
 
 
2) The tables not needed  
Table Number 
Table Name   
 
Table 14.3.1-12.2 
Summary of Concomitant Oral or IV Corticosteroids 


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Table 14.3.1-12.1 
Summary 
of 
Pyrexia 
(Single 
Preferred 
Term) 
Complicated by Severe Chills, 
Hypotension, 
Dehydration, 
Syncope, 
or 
Renal 
Dysfunction 
Table 14.3.1-12.3 
Summary of Serious Pyrexia AESIs Requiring 
Hospitalization  
Table 14.3.1-12.4 
Summary of Occurrences and percentage of time for 
Pyrexia AESIs 
Table 14.3.1-12.6 
Event level Summary of Action Taken with Pyrexia 
AESI 
 
 
4 
Study design 
 
This is an open-label Phase IIIb study of dabrafenib in combination with trametinib in the 
adjuvant treatment of melanoma after complete resection. Patients with completely resected, 
histologically confirmed, BRAF V600E/K mutation-positive, high-risk [AJCC ed. 8 Stage IIIA 
(lymph node metastasis >1 mm), IIIB, IIIC or IIID] cutaneous melanoma will be screened for 
eligibility. The main purpose of the study is to assess whether an adapted AE-management 
algorithm for pyrexia (Fever (> 38 °C)), will reduce the incidence of Grade 3/4 pyrexia, 
hospitalization due to pyrexia and permanent treatment discontinuation due to pyrexia. The 
effectiveness of dabrafenib and trametinib therapy in this setting will also be assessed based on 
RFS and OS. 
As per  the protocol amendent version dated 09-May-2019, approximately 600 subjects were 
planned to be enrolled to receive dabrafenib (150 mg BID) and tramatinib (2 mg once daily) 
combination therapy for 12 months. Due to global drug supply availibility, the enrollment of 
patients was slower than anticipated,resulting in the final sample of 556 enrolled patients in the 
study by the end of anticipated recruitment period. The final sample size is reasonably close to 
the planned target. 
At enrollment, subjects will be  instructed on the pyrexia management algorithm (refer to 
protocol Section 6.5.1.1). Doses of study treatment may be modified and/or interrupted for 
management of toxicities associated with study treatment. 
Three analyses are  planned for this study.  
• The interim analysis (IA) based on primary endpoint and secondary endpoint conducted 
when 203 subjects were dosed for 6 months (either completed 6 months of treatment or 
discontinued earlier). The data cut-off date was 16 August, 2019. 
• The primary analysis is planned to be performed at 12 months after the last patient first 
visit (LPFV). The data cut-off is planned on 26th September, 2020. 


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• The final analysis will be performed at the end of the study defined as 24 months after 
LPFV.  
At the time of IA, an independent data monitoring committee (IDMC) recommended to 
continue the trial without any changes.  
 
 
 
This study consists of two Periods for Enrolled subjects: 
• Treatment Period – subjects will receive up to 12 months of treatment (refer to the 
schedule as noted in protocol Table 8-1). 
• Follow-up Period – subjects will be followed from treatment discontinuation through 24 
months from their first dose date for relapse; and will be followed for overall survival 
through withdrawal, lost to follow-up, death, or the end of study (see definition in protocol 
Section 9.2), whichever occurs first. Follow-up will start once: 1) treatment is completed; 
or 2) is prematurely discontinued and continue until withdrawal, lost to follow-up, death, 
or the end of study even if disease recurs. Follow-up contact prior to disease recurrence 
and through the 24 month assessment will include clinic visits (refer to the schedule as 
noted in protocol Table 8-2). Follow-up after disease recurrence and until EoS should 
follow the schedule as noted in protocol Table 8-3. 
 
Figure 1.1  Study design 
 
 
 
 
4.1 
Study objectives and endpoints 
Objectives and related endpoints are described in Table 1-1 below. 
Table 1-1 
Objectives and related endpoints 
Objective(s) 
Endpoint(s) 
Primary objective(s) 
Endpoint(s) for primary objective(s) 


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• To assess whether an adapted AE- 
management algorithm for pyrexia will 
reduce the incidence of grade 3/4 pyrexia, 
hospitalization due to pyrexia, or permanent 
treatment discontinuation due to pyrexia 
compared to historical control 
• The composite rate of grade 3/4 
pyrexia, hospitalization due to 
pyrexia, or permanent treatment 
discontinuation due to pyrexia by 12 
months in overall treated subjects 
 
Secondary objective(s) 
Endpoint(s) for secondary objective(s) 
 
Secondary Objectives 
• RFS rate at 12 and 24 months  
 
• RFS is defined as the time from the 
first dose of the study medication to 
disease recurrence or death from 
any cause (whichever occurs first) 
at 12 and 24 months 
• OS rate at 12 and 24 months 
• OS is defined as the time from the 
first dose of study medication to 
date of death due to any cause at 12 
and 24 months 
Other Secondary Objectives 
• To evaluate the life quality: Health-Related 
Quality Of Life (HRQOL) measures assessed 
using FACT-M 
 
• Changes in the HRQOL from 
baseline will be assessed using by 
FACT-M questionnaire 
• To evaluate the overall AE rate leading to 
permanent treatment discontinuation by 12 
months 
• The proportion of subjects in the 
study who permanently 
discontinued treatment due to any 
adverse event by 12 months 
• To evaluate pyrexia 
• Frequency, number of episodes, 
duration, AE management 
(including concomitant medications 
and study treatment modifications) 
due to pyrexia  
• To evaluate safety (AEs and SAEs)  
• Safety will be assessed by the 
frequency and severity of adverse 
events (AEs), serious AEs (SAEs) 
and laboratory abnormalities 
 
5 
Statistical methods 
5.1 
Data analysis general information 
All analysis will be performed by Novartis and/or a designated CRO.  SAS version 9.4 or later 
software will be used to perform all data analyses and to generate tables, figures and listings.  


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Data included in the analysis 
The analysis cut-off date for the primary analysis will be September 26, 2020. This date will 
be changed based on whether all enrolled 556 patients will complete 12 months of treatment 
or will discontinued from the study.  
All statistical analysis will be performed using all data collected in the database up to the data 
cut-off date. All data with an assessment date or event start date (e.g. start date of an adverse 
event) prior to or on the cut-off date will be included in the analysis. Any data collected 
beyond the cut-off date will not be included in the analysis and will not be used for any 
derivations. 
All events with start date before or on the cut-off date and end date after the cut-off date will 
be reported as ‘ongoing’. The same rule will be applied to events starting before or on the cut-
off date and not having documented end date. This approach applies, in particular, to adverse 
event and concomitant medication reports. For these events, the end date will not be imputed 
and therefore will not appear in the listings.  
The analysis cut-off date for the final analysis of study data will be established at the end of 
the study.  
General analysis conventions 
Pooling of centers: Unless specified otherwise, data from all study centers will be pooled for 
the analysis. Due to expected small number of patients enrolled at  centers, no center effect 
will be assessed.  
Qualitative data (e.g., gender, race, etc.) will be summarized by means of contingency tables; 
a missing category will be included as applicable. Percentages will be calculated using the 
number of patients in the relevant population as the denominator. 
Quantitative data (e.g., age, body weight, etc.) will be summarized by appropriate 
descriptive statistics (i.e. mean, standard deviation, median, minimum, and maximum). 
5.1.1 
General definitions  
Study treatment  
The study treatment, used throughout the protocol and SAP, will refer to the combination of 
dabrafenib 150 mg twice a day (BID) and trametinib 2 mg once a day (QD). Study drug will 
refer to the each component (either dabrafenib or trametinib) of the study treatment.  
Date of first/last administration of study drug 
The date of first administration of study drug is defined as the first date when a non-zero dose 
of study drug was administered and recorded on the Dosage Administration Record (DAR) 
eCRF. For the sake of simplicity, the date of first administration of study drug will also be 
referred to as start date of study drug. 
The date of last administration of study drug is defined as the last date when a non-zero dose of 
study drug was administered and recorded on DAR eCRF. This date will also be referred to as 
last date of study drug. 


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Date of first administration of study treatment  
The date of first administration of study treatment is derived as the first date when a nonzero 
dose of any component of study treatment was administered as per the (e)CRF. (Example: if 1st 
dose of Dabrafenib is administered on 13-Jul-2013, and 1st dose of Trametinib is administered 
on 11-Jul-2013, then the date of first administration of study treatment is on 11-Jul-2013).  The 
date of first administration of study treatment will also be referred as start of study treatment. 
Date of last administration of study treatment  
The date of last administration of study treatment is derived as the last date when a nonzero 
dose of any component of study treatment was administered as per  the (e)CRF. (Example: if 
the last dabrafenib dose is administered on 13-Jul-2014, and the last dose of trametinib is 
administered on 15-Jul-2014, then the date of last administration of study treatment is on 15-
Jul-2014).  
Study day 
The study day, describes the day of the event or assessment date, relative to the reference start 
date.  
The study day is defined as: 
• The date of the event (visit date, onset date of an event, assessment date, etc.) − 
reference start date + 1 if event is on or after the reference start date; 
• The date of the event (visit date, onset date of an event, assessment date, etc.) − 
reference start date if event precedes the reference start date. 
The reference start date for safety assessments (e.g. adverse event onset, laboratory abnormality 
occurrence, vital sign measurement, dose interruption, pk, etc.) is the start of study treatment. 
The reference start date for all other, non-safety assessments (e.g. ECOG performance status 
and patient reported outcomes (PRO)) is the start of study treatment.  
Time units 
A year length is defined as 365.25 days. A month length is 30.4375 days (365.25/12). If duration 
is reported in months, duration in days will be divided by 30.4375.  If duration is reported in 
years, duration in days will be divided by 365.25. 
Baseline 
For safety and efficacy evaluations, the last available assessment on or before the date of start 
of study treatment is defined as “baseline” assessment.  
For cases where time of assessment and time of treatment start is captured (e.g. pre-dose ECG, 
laboratory assessments), the last available assessment before the treatment start date/time is 
used for baseline.  
In rare cases where multiple measurements meet the baseline definition, with no further flag or 
label that can identify the chronological order,  then the following rule should be applied: For 
ECGs or vital signs, the last value will be considered as baseline.  


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If patients have no value defined above, the baseline result will be missing.  
On-treatment assessment/event and observation periods  
For adverse event reporting the overall observation period will be divided into three mutually 
exclusive segments:  
1. pre-treatment period: from day of patient’s sign informed consent to the day before first 
administration of study treatment. 
2. on-treatment period: from date of first administration of study treatment to 30 days after 
date of last actual administration of any study treatment: dabrafenib or trametinib  
(including start and stop date). 
3. post-treatment period: starting at day 31 after last administration of study treatment. 
 For cases where time of assessment and time of treatment start/stop is captured (e.g. ECG’s 
laboratory assessments), the last available assessment before the treatment period start/stop 
date/time will be used.  
If dates are incomplete in a way that clear assignment to pre-, on-, and post-treatment period 
cannot be made, then the respective data will be assigned to the on-treatment period. Refer to 
section 5.1.1 for imputation rules concerning AE start and stop dates.  
Safety summaries (tables, figures) include only data from the on-treatment period with the 
exception of baseline data which will also be summarized where appropriate (e.g. change from 
baseline summaries). In addition, a separate summary for death including on treatment and post 
treatment deaths will be provided.  In particular, summary tables for adverse events (AEs) will 
summarize only on-treatment events, with a start date during the on-treatment period 
(treatment-emergent AEs).   
However, all safety data (including those from the post-treatment period) will be listed and 
those collected during the pre-treatment and post-treatment period will be flagged. 
Windows for multiple assessments 
In order to summarize PRO measures, performance status (ECOG), physical exam, vital sign, 
ECG, ECHO, laboratory collected over time (including unscheduled visits), the assessments 
will be time slotted. The following general rule will be applied in creating the assessment 
windows: If more than one assessment is done within the same time window, the assessment 
performed closest to the target date will be used. If 2 assessments within a time window are 
equidistant from the target date, then the earlier of the 2  assessments  will be used. 
If multiple assessmentson the same date then the worst case result will be used. Data from all 
assessments (scheduled and unscheduled), including multiple assessments, will be listed. Data 
obtained at the end of treatment will be classified as other assessment in the corresponding time 
window. 


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Time windows for PRO, ECOG assessments 
Time window 
Planned Visit 
Timing/Target date 
Time Window Definition 
On treatment 
 
 
Baseline 
-28 
<Day 1 
Day 1 
1 
Day 1 
Month 1  
29 
Day 2 to day 42 
Month 2 ( 
57 
Day 43 to day 70 
Month 3  
85 
Day 71 to day 98 
Month 4  
113 
Day 99 to day 126 
Month k (k≥5)  
d=k*28+1 
Day d-14 to day d+13 
End of Treatment 
 
Assessment taken at the end of 
treatment visit 
Post treatment 
 
 
Follow-up Month 3  
85 
Day 2 to day 112 
Follow-up Month k  
d=k*28+1 
d±28 
Study Day 1 = drug administration date;  
 
Time windows for laboratory assessments 
Time window 
Planned Visit 
Timing/Target date 
Time Window Definition 
On treatment 
 
 
Baseline 
-28 
< Day 1 
Day 1  
1 
Day 1 
Month 1 
29 
Day 2 to day 42 
Month 2  
57 
Day 43 to day 70 
Month 3 
85 
Day 71 to day 98 
Month 4  
113 
Day 99 to day 126 
Month k (k≥5)  
d=k*28+1 
Day d-14 to day d+13 
End of Treatment 
 
Assessment taken at the end of 
treatment visit 
Post treatment 
 
 
30 day safety follow-up 
Post treatment study day 30 
Assessment taken at the 
30-day safety follow-up visit 
 
 
 
Study Day 1 = drug administration date;  
 
 
Last contact date 
The last contact date will be derived for patients not known to have died at the analysis cut-off 
using the last complete date among the following: 


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Table 2-1 
Last contact date data sources  
Source data 
Conditions 
Last contact date/last date patient was known to 
be alive from Survival Follow-up page  
 
Patient status is reported to be alive, lost to 
follow-up or unknown. 
Start/End dates from further antineoplastic 
therapy 
Non-missing medication/procedure term. 
Start/End* dates from drug administration record  
 
Non-missing dose. Doses of 0 are allowed. 
End of treatment date from end of treatment page 
 
No condition. 
Tumor (CT or MRI scan) assessment date 
Evaluation is marked as ‘done’. 
Laboratory 
 
Sample collection marked as ‘done’.  
Vital signs date 
 
At least one non-missing parameter value 
Performance Status date 
 
Non-missing performance status 
Start/End dates of AE  
Non-missing verbatim term 
The last contact date is defined as the latest complete date from the above list on or before the 
data cut-off date . The cut-off date will not be used for last contact date, unless the patient was 
seen or contacted on that date. No date post cut-off date will be used. Completely imputed 
dates (e.g. the analysis cut-off date programmatically imputed to replace the missing end date 
of a dose administration record) will not be used to derive the last contact date. Partial date 
imputation is allowed for event (death)/censoring is coming from ‘Survival information’ eCRF.  
The last contact date will be used for censoring of patients in the analysis of overall survival. 
5.2 
Analysis sets 
Full analysis set and safety set 
The full analysis set (FAS) as well as safety set includes same subjects. They comprise all 
subjecs who received at least one dose of any study treatment.  
Patient classification 
The patients who signed informed consents and received at least one dose of the study drug will 
be included in the analysis.  
Withdrawal of informed consent 
Any data collected in the clinical database after a patient withdraws informed consent from all 
further participation in the trial, will not be included in the analysis.  The date on which a patient 
withdraws full consent is recorded in the eCRF. 
 


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5.2.1 
Subgroup of interest 
Not applicable. 
 
5.3 
Patient disposition, demographics and other baseline 
characteristics 
The FAS will be used for all baseline and demographic summaries and listings unless otherwise 
specified. No inferential statistics will be provided.  
Basic demographic and background data 
All demographic and baseline disease characteristics data will summarized and listed. 
Categorical data (e.g. gender, age groups: <65 and ≥ 65 years, race, ethnicity) will be 
summarized by frequency counts and percentages; the number and percentage of patients with 
missing data will be provided. Continuous data (e.g. age, weight, height, body mass index) will 
be summarized by descriptive statistics (N, mean, median, standard deviation, 25th and 75th 
percentiles, minimum and maximum). BMI (kg/m2) will be calculated as weight[kg] / 
(height[m2]) using weight at Baseline. 
Diagnosis and extent of cancer 
Summary statistics will be tabulated for diagnosis and extent of cancer. This analysis will 
include the following: primary tumor ulceration, stage at initial diagnosis, time since initial 
diagnosis of melanoma (in months) , stage at time of study entry (AJCC version 8) etc.  
Medical history 
Medical history and ongoing conditions, including cancer-related conditions and symptoms 
entered on (e) CRF will be summarized and listed. Separate summaries will be presented for 
ongoing and historical medical conditions.  The summaries will be presented by primary system 
organ class (SOC) and preferred term (PT). Medical history and current medical conditions will 
be coded using the Medical Dictionary for Regulatory Activities (MedDRA) terminology. The 
MedDRA version 24.1.0 used for reporting will be specified in the CSR and as a footnote in the 
applicable tables/listings. 
Other 
All data collected at baseline including will be listed as appropriate. 
 
5.3.1 
Patient disposition 
Enrollment by country and center will be summarized for all screened patients. The number and 
percentage of patients included in the FAS will be presented. The number (%) of screened and 
not-treated patients and the reasons for screening failure will also be displayed. The number (%) 
of patients in the FAS who are still on treatment, who discontinued the study phases and the 
reason for discontinuation will be presented. 


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The following summaries will be provided (with % based on the total number of FAS patients): 
• Number (%) of patients who were treated (based on ‘DAR’ eCRF pages of each 
study treatment component completed with non-zero dose administered) 
• Number (%) of patients who are still on-treatment (based on the ‘Treatment 
Disposition’ page not completed);  
• Number (%) of patients who discontinued the study treatment phase (based on the 
‘Treatment Disposition’ page)  
• Primary reason for study treatment phase discontinuation (based on the ‘Treatment 
Disposition’ page) 
• Number (%) of patients who have entered the post-treatment follow-up (based on 
the ‘Treatment Disposition’ page); 
• Number (%) of patients who have discontinued from the post-treatment follow-up 
(based on ‘Subject Status’ page); 
• Reasons for discontinuation from the post-treatment follow-up (based on  ‘Subject 
Status  page); 
• Number (%) of patients who have entered the survival follow-up (based on the 
‘Subject Status’ page). 
Protocol deviations 
The number (%) of patients in the FAS with any protocol deviation will be tabulated by 
deviation category overall for the FAS. All protocol deviations will be listed.  
Analysis sets 
The number (%) of patients in each analysis set (defined in section 2.2) will be summarized.  
5.4 
Treatments (study treatment, concomitant therapies, 
compliance) 
5.4.1 
Study treatment/compliance 
Duration of exposure, actual cumulative dose, dose intensity (DI) and relative dose intensity 
(RDI) will be summarized separately for each component of study treatment (dabrafenib and 
trametinib). The duration of exposure will also be presented for the study treatment of 
dabrafenib and trametinib combination therapy. Duration of exposure will be categorized into 
time intervals; frequency counts and percentages will be presented for the number(%) of 
subjects in each interval. The number (%) of subjects who have dose reductions, escalations or 
interruptions, and the reasons, will be summarized by dabrafenib and trametinib.  
Patient level listings of all doses administered on treatment along with dose change reasons will 
be produced.  
The safety set will be used for all summaries and listings of study treatment. 


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Duration of exposure to study treatment 
Duration of exposure to study treatment is considered by taking into account the duration of 
exposure to dabrafenib and trametinib: 
Duration of exposure to study treatment (days) = (last date of exposure to study treatment) – 
(date of first administration of study treatment) + 1.  
The last date of exposure to study treatment is the latest of the last dates of exposure to 
dabrafenib or trametinib. 
Summary of duration of exposure of study treatment in appropriate time units will include 
categorical summaries and continuous summaries (i.e. mean, standard deviation etc.). 
Duration of exposure to dabrafenib and trametinib 
Duration of exposure to dabrafenib (days) = (last date of exposure to dabrafenib) – (date of first 
administration of dabrafenib) + 1. 
Duration of exposure to trametinib (days) = (last date of exposure to trametinib) – (date of first 
administration of trametinib) + 1. 
 
Table 2-2 
Definition of last date of exposure of study drug 
Scenario 
Definition of last date of exposure 
of study drug  
Example 
Daily 
administration 
of 
the study drug 
Date of last administration of a non -
zero dose of the study drug. 
Example: A patient had a 
permanent discontinuation of 
the study drug 06Jan2013 after 
being put on a temporary 
interruption since 01Jan2013. 
In this case the last date of 
exposure is- 31Dec2012.  
 
Cumulative dose 
Cumulative dose of a study treatment is defined as the total dose given during the study 
treatment exposure and will be summarized for each of the study treatment components.  
The planned cumulative dose for a study treatment component refers to the total planned dose 
as per the protocol up to the last date of study drug administration. The planned cumulative 
dose will not be summarized/listed. It will be used for relative dose intensity calculations. 
The actual cumulative dose  refers to the total actual dose administered, over the duration for 
which the subject is on the study treatment as documented in the Dose Administration eCRF.  
For patients who did not take any drug the cumulative dose is by definition equal to zero. 


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For continuous dosing, the actual cumulative dose is the sum of the non-zero doses recorded 
over the dosing period and the planned cumulative dose is the planned starting dose summed 
over the same dosing period. 
Dose intensity and relative dose intensity 
Dose intensity (DI) for patients with non-zero duration of exposure is defined as follows:  
DI (mg / day) = Actual Cumulative dose (mg) / Duration of exposure to study treatment (day). 
For patients who did not take any drug the DI is by definition equal to zero.  
Planned dose intensity (PDI) is defined as follows: 
PDI (mg / day) = Planned Cumulative dose (mg) / Duration of exposure (day). 
Relative dose intensity (RDI) is defined as follows: 
RDI = DI (mg / day)  / PDI (mg / day).   
DI and RDI will be summarized separately for each of the study treatment components, but 
using the duration of exposure of each of the components. 
Table 2-3 
Examples of dabrafenib dose administration and exposure 
DAR 
record 
number 
Start/End 
date 
Dose 
prescribed 
(mg), 
frequency 
Dose 
administered 
(mg) [ total 
daily] 
Dose 
changes, 
dose 
interruption 
Dose 
permanently 
discontinued 
Reason  
1 
01Jan2016 
/05Jan 2016 
150mg BID 
300  
No 
No 
AE 
2 
6Jan2016/03
Feb 2016 
150mg BID 
200 
Yes 
No 
3 
04Feb2016/
25Feb2016 
150mg BID 
300 
No 
No 
 
Duration of exposure (days) = 25Feb2016 – 01Jan2016 + 1 = 56 days 
Planned cumulative dose (for 56 days) = 300*56 days = 16800 mg 
Actual cumulative dose = 300*5 + 200*29 + 300*22 = 13900 mg 
Dose intensity = 13900 mg / 56 days = 248.21 mg/day 
Planned dose intensity = 16800 mg / 56 days = 300 mg/day 
Relative dose intensity = DI / PDI = (248.21 mg/day) / (300 mg/day) = 83% 
 


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Table 2-4 
Examples of trametinib dose administration and exposure 
DAR 
record 
number 
Start/End 
date 
Dose 
prescribe
d 
(mg), 
frequency 
Dose 
administered 
(mg) [ total 
daily] 
Dose 
changes, 
dose 
interruption 
Dose 
permanently 
discontinued 
Reason  
1 
01Jan2016 
/10Jan 2016 
2 QD 
2 
No 
No 
AE 
2 
11Jan2016/15
Jan 2016 
2 QD 
0 
Yes 
No 
3 
16Jan2016/25
Feb2016 
1 QD 
1 
No 
No 
Duration of exposure = 25Feb2016 – 01Jan2016 + 1 = 56 days 
Planned cumulative dose (for 56 days) = 2*56 days = 112 mg 
Actual cumulative dose = 2*10 + 0*5 + 1*41 = 61 mg 
Dose intensity = 61 mg / 56 days = 1.09 mg/day 
Planned dose intensity = 112 mg / 56 days = 2 mg/day 
Relative dose intensity = DI / PDI = (1.09 mg/day) / (2 mg/day) = 54% 
Dose reductions, interruptions or permanent discontinuation 
The number of patients who have dose reductions, permanent discontinuations or interruptions, 
and the reasons, will be summarized separately for each of the study treatment components.  
‘Dose interrupted’ and ‘Dose permanently discontinued’ fields from the Dosage Administration 
CRF pages (DAR)  will be used to determine the dose reductions, dose interruptions, and 
permanent discontinuations, respectively. 
The corresponding fields ‘Reason for dose change/dose interrupted’ and ‘Reason for permanent 
discontinuation’ will be used to summarize the reasons. 
A dose change is either ‘change in prescribed dose level’ or ‘dosing error’ where actual dose 
administered/total daily dose is different from the prescribed dose. 
For the purpose of summarizing interruptions and reasons, in case multiple entries for 
interruption that are entered on consecutive days with different reasons will be counted as 
separate interruptions. However, if the reason is the same in this mentioned multiple entries on 
consecutive days, then it will be counted as one interruption.  
Reduction is defined as a dose change where the prescribed dose level is lower than the 
previous prescribed dose level or where the actual dose administered/total daily dose is lower 
than the calculated dose amount based on the prescribed dose. Therefore any dose change to 
correct a dosing error will not be considered a dose reduction.  Only dose change is collected 
in the CRF, number of reductions will be derived programmatically  based on the change and 
the  direction of the change. 
 


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5.4.2 
Prior, concomitant and post therapies 
Prior anti-cancer therapy 
The number and percentage of patients who received any prior anti-neoplastic surgery will be 
summarized. For prior surgery, time since last surgery, procedure and residual disease of last 
therapy will be summarized.  
Separate listings will be produced for prior anti-neoplastic surgery.  
Anti-neoplastic medications will be coded using the WHO Drug Dictionary (WHO-DD); anti-
neoplastic surgery will be coded using MedDRA. Details regarding MedDRA and WHO-DD 
version will be included in the footnote in the tables/listings.  
The above analyses will be performed using the FAS. 
Post treatment anti-cancer therapy 
Anti-neoplastic therapies since discontinuation of study treatment will be listed and summarized 
by ATC class, preferred term and by means of frequency counts and percentages using FAS. 
Note that biopsies will not be regarded as an anti-neoplastic surgery for the purpose of this 
analysis. 
The number and percentage of patients who reported taking at least one anti-neoplastic therapy 
since discontinuation of study treatment by category (e.g immunotherapy, targeted therapy, 
chemotherapy, radiotherapy, etc.), the duration of treatment and the best response will be 
summarized. 
Concomitant medications 
Concomitant therapy is defined as all interventions (therapeutic treatments and procedures) 
other than the study treatment administered to a patient coinciding with the study treatment 
period. Concomitant therapy include medications (other than study drugs) starting on or after 
the start date of study treatment or medications starting prior to the start date of study treatment 
and continuing after the start date of study treatment.  
Concomitant medications will be coded using the World Health Organization (WHO) Drug 
Reference  Listing  (DRL)  dictionary  that  employs  the  WHO  Anatomical  Therapeutic 
Chemical (ATC) classification system and summarized by lowest ATC class and preferred term 
using frequency counts and percentages. Surgical and medical procedures will be coded using 
MedDRA and summarized by SOC and preferred term. These summaries will include: 
1. Medications starting on or after the start of study treatment but no later than 30 days 
after start of last dose of study treatment and 
2. Medications starting prior to start of study treatment and continuing after the start of 
study treatment. 
All concomitant therapies will be listed. Any concomitant therapies starting and ending prior 
to the start of study treatment or starting more than 30 days after the last date of study treatment 
will be flagged in the listing. The safety set will be used for all concomitant medication tables 
and listings. 


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5.5 
Analysis of the primary objective 
The primary objective of the study is to assess whether an adapted AE-management algorithm 
for pyrexia will reduce the incidence of grade 3/4 pyrexia, hospitalization due to pyrexia, or 
permanent treatment discontinuation due to pyrexia compared to historical control from 
COMBI-AD study. 
 
5.5.1 
Primary endpoint 
The primary endpoint is defined as the composite rate of grade 3/4 pyrexia (single preferred 
term), hospitalizations due to pyrexia or permanent treatment discontinuation due to pyrexia up 
to 12 months of therapy among overall treated patients. 
The rate of this composite primary endpoint is calculated as the total number of patients 
experiencing at least one of the three components of the composite endpoint (i.e., Grade 3/4 
pyrexia, hospitalization due to pyrexia, or permanent treatment discontinuation due to pyrexia), 
divided by the total number of patients in the FAS. The composite endpoint is assessed over a 
treatment period of 12 months; that is, any patient who experiences at least one of the 
components of the composite endpoint anytime within 12 month on-treatment will be included 
in the numerator for the calculation of the composite rate. 
 
5.5.2 
Statistical hypothesis, model and method of analysis 
 
The primary analysis will be based on the calculation of the observed pyrexia event rate up to12 
months of therapy (primary endpoint) using the FAS. The observed pyrexia event rate will be 
summarized using descriptive statistics (N, %) along with its two-sided exact 95% confidence 
interval (Clopper and Pearson 1934). 
 
In the COMBI-AD study, 87 out of 435 subjects in the treatment arm (20%) developed either 
grade 3/4 pyrexia or hospitalization due to pyrexia or discontinued due to pyrexia. This rate of 
20% will be used as the historical control rate for the assessment of pyrexia management 
algorithm in this study. 
 
Evidence of treatment effect (improvement in pyrexia event rate using the AE-management 
algorithm) will be concluded, if the upper bound of the two-sided 95% confidence interval is 
less than 20%. 
 
The exact 95% confidence intervals for various observed event rates at the primary analysis are 
shown in Table 2-5. This table has been updated from the protocol for the new sample size = 
556 subjects.  
 
 


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If 92 (16.5%) out of 556 subjects are observed with pyrexia event,  then the upper bound of the 
95% confidence interval will be less than 20%. 
Table 2-5 
Exact 95% CI for different observed event rates at primary analysis 
 
N 
r 
95% exact CI 
using n=600 
N 
r 
Pyrexia event 
rate (%) 
95% exact CI (%)* 
using n=556 
600 
92 
12.5 - 18.5 
556 
92 
16.5% 
13.6 - 19.9 
600 
93 
12.7 - 18.6 
556 
93 
16.7% 
13.7 - 20.1 
600 
100 
13.8 – 19.9 
556 
100 
18% 
14.9 - 21.4 
600 
101 
13.9 – 20.1 
556 
101 
18.2% 
15.0 - 21.6 
600 
102 
14.1 – 20.2 
556 
102 
18.3% 
15.2 - 21.8 
600 
103 
14.2 – 20.4 
556 
103 
18.5% 
15.4 - 22.0 
600 
104 
14.4 – 20.6 
556 
104 
18.7% 
15.5 - 22.2 
600 
105 
14.5 – 20.8 
556 
105 
18.9% 
15.7 - 22.4 
N: Total numbers of subjects; 
r: Number of subjects with pyrexia events at primary analysis 
* Clopper and Pearson (1934) 
 
In addition, the probability that the pyrexia event rate is below the threshold of 20% will be 
calculated from the posterior distribution. The pyrexia event rate will be assumed to be binary 
and the number of subjects with pyrexia events will be assumed to follow a binomial 
distribution. If Y represents the number of patients with composite pyrexia events then 
predictive distribution of Y conditional on the observed data at the primary is a beta-binomial 
distribution. A diffuse (highly non-informative) prior distribution of the composite rate with a 
skeptical expectation of 20%, namely Beta (0.25, 1) will be assumed. For illustration, as shown 
in Table 2-6, if 96 out of 556 subjects are observed with pyrexia events at primary analysis, 
then the posterior probability of observing an event rate of < 20% is 0.952 (probability ≥ 0.95).  
This table has been modified for sample size = 556 from the protocol.  
 
Table 2-6 
Posterior probability for a positive effect at primary analysis 
r 
Posterior* 
Pr (event rate<20%|data) 
N= 600 
Posterior* 
Pr (event rate<20%|data) 
N= 556 
92 
0.999 
0.982 
96 
0.994 
0.952 
100 
0.983 
0.890 
101 
0.977 
0.868 
102 
0.971 
0.843 
103 
0.963 
0.816 
104 
0.954 
0.786 
105 
0.943 
0.753 
110 
0.854 
0.559 


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r 
Posterior* 
Pr (event rate<20%|data) 
N= 600 
Posterior* 
Pr (event rate<20%|data) 
N= 556 
115 
0.703 
0.352 
120 
0.508 
0.183 
125 
0.313 
0.078 
130 
0.161 
0.027 
135 
0.068 
0.007 
N: Total numbers of subjects; 
r: Number of subjects with pyrexia events at primary analysis 
* A diffuse (highly non-informative) prior distribution of the composite rate with a skeptical expectation of 20%, 
namely Beta (0.25, 1) is assumed. 
 
 
5.5.3 
Handling of missing values/censoring/discontinuations 
 Only observed events will be summarized in the analysis; incomplete dates of events may be 
appropriately imputed. For the primary endpoint, patients who discontinued prematurely prior 
to 12 months without pyrexia will be counted as no event.  
5.5.4 
Supportive analyses 
Time to first occurrence of pyrexia will be analysed using the Kaplan-Meier (KM) method. If 
a patient has not experienced an event by the time of analysis cut-off, the time will be censored 
at the lastest date of study treatment in which the patient is known to be at risk.  
The components of the composite primary endpoint (grade ¾ pyrexia, hospitalizations due to 
pyrexia or permanent treatment discontinuation due to pyrexia) will also be analyzed 
individually by frequency counts in order to evaluate their contributions to the overall treatment 
effect.  
 
5.6 
Analysis of the key secondary objective 
Not applicable. 
5.7 
Analysis of the secondary objective(s) 
The secondary efficacy objectives are to 
• Evaluate the relapse free survival (RFS) at 12 and 24 months. 
• Evaluate overall survival (OS) rate at 12 and 24 months. 
• Evaluate patients’ quality of life with respect to patient reported outcomes (PROs) of 
functional assessment of cancer therapy–melanoma (FACT-M) melanoma subscales.  
 


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5.7.1 
Secondary endpoints 
 
Relapse free survival 
RFS is defined as the time from the date of first dose of the study treatment to the date of the 
first documented disease recurrence or death due to any cause whichever comes first. Treatment 
emergent malignancies other than second melanomas will not be considered as events. The 
analysis will be based on FAS and will include all data observed up-to the cut-off date. 
RFS will be censored if no RFS event is observed before the first to occur between: (i) the 
analysis cut-off date, and (ii) the date when a new anti-cancer therapy is started. The censoring 
date will be the date of the last adequate tumor assessment prior to data cut-off date/start of new 
anti-cancer therapy date (see Section 2.7.3 for additional details regarding censoring rules and 
determination of date of last adequate tumor assessment). 
Overall survival 
OS is defined as the time from start date of study treatment to date of death due to any cause. 
All deaths occurring on or before the cut-off date in the FAS will be used in the OS analysis. 
If a patient is not known to have died, then OS will be censored at the last contact date when 
the patient was known to be alive (on or before the cut-off date) (see Section 2.1.1 for the 
derivation of the last contact date). 
Functional assessment of cancer therapy-melanoma (FACT-M) 
FACT-M will be used to evaluate patient-reported outcome measures of health-related quality-
of-life, functioning, disease symptoms, treatment-related side effects, and global health status. 
The Melanoma Subscale of the FACT-M are recognized as reliable and valid measures 
(Cormier 2008) frequently used in clinical trials of patients with advanced or metastatic cancer. 
The FACT-M quality of life questionnaire consists of the FACT-General (FACT-G) plus the 
Melanoma Subscale and the Melanoma Surgery Subscale, which complement the general scale 
with items specific to health-related quality of life (HRQOL) in melanoma. For the purpose of 
this study the 16 items that comprise the Melanoma Subscale (MS) of the FACT-M are used. 
 
5.7.2 
Statistical hypothesis, model and method of analysis 
RFS and OS will be analyzed descriptively in the FAS population. The RFS and OS distribution 
will be estimated using the Kaplan-Meier method. The Kaplan-Meier estimates will be plotted 
graphically. The median, 25th  and 75th  percentiles of RFS and OS along with 95% confidence 
intervals [Brookmeyer and Crowley 1982] will be presented.  
The survival probabilities at 12 and 24 months, and the associated 95% confidence intervals 
will be summarized. The percentage of surviving subjects who are alive and disease free 1 year 
intervals from the time of first treatment  will be estimated from the Kaplan-Meier curves for 
the RFS. The probabilities will be calculated at 1 year and at 2 years. Approximate 95% 


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confidence intervals will be calculated, based on Greenwood's formula for the standard error 
(SE) of the Kaplan-Meier estimate.  The similar analysis will be presented for the OS as well.  
 
5.7.3 
Handling of missing values/censoring/discontinuations 
Censoring of RFS 
If no event has occurred by the primary analysis cutoff, then RFS will be censored as the 
date of the last efficacy assessment (i.e. either radiological or non-radiological) prior to 
the analysis cutoff that shows no disease recurrence. Patient will be censored for RFS at 
the date of first treatment for any of the following situation: 
• The censoring algorithm calls for the patient to be censored at the date of the last adequate 
assessment meeting a certain set of criteria (e.g. prior to subsequent anticancertherapy), 
but no such assessment exists. 
RFS will be censored for extended loss to follow-up to account for missed efficacy 
assessments prior to relapse or death. Specifically, if there are two or more scheduled 
efficacy assessments which are missing during the first 12 months of the treatment period, 
two or more missing during the follow up period followed by an assessment of relapse or 
death (due to any cause), RFS will be censored at the last adequate assessment prior to 
relapse or death. If the time interval between the last adequate efficacy assessment date and 
the RFS event date is larger than the interval of 2 missing efficacy assessments (7 days for 
treatment phase and 14 days for follow-up phase, protocol-specified time window ) then the 
patient will be censored and the censoring reason will be ‘Event documented after two or 
more missing tumor assessments.  For this type of censoring, the ‘last adequate assessment’ is 
defined as the date of the last MRI or CT  assessment prior to the missing assessments that 
shows no disease recurrence.  
 
For patients who receive subsequent anti-cancer therapy the following rules will apply. 
• If such therapy is started without evidence of documented disease recurrence, then 
RFS will be censored at the date of the last efficacy ) assessment before the date of 
initiation of anti-cancer therapy. 
• If a patient has only a baseline visit or does not have an efficacy assessment before the 
date of initiation of anti-cancer therapy, RFS will be censored at the date of first treatment. 
 
Table 2-7 below further describes the algorithm to determine whether a patient should be 
classified as RFS event or censored.  
 
Table 2-7 
Outcome and event/censor dates for RFS analysis 
 
Situation 
Date 
Outcome 
 
 
 
Recurrence documented 
between scheduled visits 
Date of assessment of 
Recurrence 
Event 


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Situation 
Date 
Outcome 
No recurrence (or death) 
Date of last efficacy 
assessment 
Censored 
New anti-cancer therapy 
(including surgery for 
melanoma) started prior to 
documented disease 
recurrence* 
Date of last efficacy 
assessment on or prior 
to starting anti-cancer 
therapy 
Censored 
Death before recurrence 
assessment 
Date of death 
Event 
 
Death between adequate 
assessment visits 
Date of death 
Event 
Death or recurrence after two 
or more missed scheduled 
efficacy assessments during 
study treatment period or after 
two or more missing during 
the follow up period  
Date of last adequate 
assessment prior to 
missed assessments 
Censored 
*If relapse and new anti-cancer therapy occur on the same day then the relapse will be counted as event. If 
anticancer therapy is started prior to any adequate assessments, censoring date should be the date of first 
treatment. 
 
Censoring of OS 
If a patient is not known to have died at the time of analysis cut-off, then OS will be censored 
at the date of last known date when patient was alive, i.e., last contact date. 
5.8 
Safety analyses 
All safety analyses will be based on safety set. 
5.8.1 
Adverse events (AEs) 
Adverse events are coded using MedDRA terminology. The MedDRA 24.1 version used for 
reporting will be specified in the CSR and as a footnote in the applicable tables/listings. AEs 
will be assessed according to the Common Terminology Criteria for Adverse Events (CTCAE) 
version 4.03. 
AE summaries will include all AEs occurring during on-treatment period. All AEs collected in 
the AE (e)CRF page will be listed along with the information collected on those AEs e.g. AE 
relationship to study drug, AE outcome etc. AEs with start date outside of on-treatment period 
will be flagged in the listings.  
AEs will be summarized by number and percentage of subjects having at least one AE, having 
at least one AE in each primary system organ class (SOC) and for each preferred term (PT) 
using MedDRA coding. A patient with multiple occurrences of an AE will be counted only 


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once in the respective AE category. A subject with multiple CTCAE grades for the same 
preferred term will be summarized under the maximum CTCAE grade recorded for the event. 
AE with missing CTCAE grade will be included in the ‘All grades’ column of the summary 
tables. 
In AE summaries, the primary SOC will be presented alphabetically and the preferred terms 
will be sorted within primary SOC in descending frequency. The sort order for the preferred 
term will be based on their frequency.  
The following adverse event summaries will be produced: overview of adverse events and 
deaths, AEs by PT, SOC and PT, summarized by relationship to study treatment, seriousness, 
leading to treatment discontinuation, leading to dose interruption/adjustment, requiring 
additional therapy and leading to fatal outcome. In addition, a summary of  serious adverse 
events with number of occurrences will be produced (an occurrence is defined as >1 day 
between start and prior end date of record of same preferred term). Note that Adverse events 
leading to fatal outcomes with relationship is a EudraCT requirement. 
The proportion of subjects in the study, who have permanently discontinued treatment due to 
any AE PT, will be estimated along with 95% confidence intervals using Clopper Pearson exact 
method. 
 
5.8.1.1 
Pyrexia 
For pyrexia, other characteristics like number of episodes, duration, and AE management 
(including concomitant medications and study treatment modifications) due to pyrexia will be 
summarized.. 
The number (%) of patients who received medications for treatment of pyrexia will be 
summarized along with the type of medications. 
5.8.1.2 
Adverse events of special interest (AESI)/grouping of AEs 
All AESI definitions or AE grouping for the clinical program need to be specified in the 
Compound Case Retrieval Strategy sheet (CRS) with one exception of pyrexia AESI with clear 
versioning and reference to the MedDRA version used. The CRS version will be included in a 
footnote of the AESI tables. 
Pyrexia AESIs will be defined using the following list of PTs:   
 
Pyrexia PT 
PT Code 
Body temperature increased 
10005911 
Cytokine release syndrome 
10052015 
Hyperpyrexia 
10020741 
Hyperthermia 
10020843 
Influenza like illness 
10022004 
Pyrexia 
10037660 
Sweating fever 
10042666 
Systemic inflammatory response syndrome 
10051379 
Tumour associated fever 
10052243 


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Table 2-6 
Adverse events of special interest by study treatment 
 
trametinib 
dabrafenib 
dabrafenib and 
trametinib 
combination 
Hepatic disorders 
x 
 
x 
Pneumonitis/Interstitial lung disease 
x 
 
x 
Skin toxicities (e.g., rash, dermatitis acneiform) 
x 
 
x 
Bleeding events 
x 
 
x 
Hypersensitivity 
x 
x 
x 
Pancreatitis 
 
x 
x 
Neutropenia 
 
 
x 
Pulmonary embolism, deep vein thrombosis 
x 
 
x 
Pre-renal and intrinsic renal failure 
 
x 
x 
New primary melanoma 
 
x 
x 
Non-Cutaneous Treatment-Emergent Malignancies 
 
x 
x 
Hyperglycemia 
 
x 
x 
Cardiac related events 
x 
 
x 
Complicated pyrexia and/or Grade 3 and Grade 4 
pyrexia 
 
x 
x 
Uveitis 
 
x 
x 
Ocular events (e.g., retinal vein occlusion, retinal 
pigment epithelial detachment and uveitis) 
x 
 
x 
Cutaneous squamous cell carcinoma including 
keratocanthoma 
 
x 
x 
Hypertension 
x 
 
x 
 
Data analysis of AESIs 
An adverse event of special interest is a grouping of adverse events that are of scientific and 
medical concern specific to each components of study treatment, i.e. dabrafenib and trametinib. 
These groupings are defined using MedDRA terms, SMQs (standardized MedDRA queries), 
HGLTs (high level group terms), HLT (high level terms) and PTs (preferred terms). Customized 
SMQs (Novartis MedDRA queries, NMQ) may also be used. A NMQ is a customized group of 
search terms which defines a medical concept for which there is no official SMQ available or 
the available SMQ does not completely fit the need. It may include a combination of single 
terms and/or an existing SMQ, narrow or broad. For each specified AESI, number and 
percentage of patients with at least one event of the AESI occurring during on treatment period 
will be summarized. 
A listing of all grouping levels down to the MedDRA preferred terms used to define each AESI 
will be generated.  


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Summaries of these AESIs will be provided, (specifying PTs, grade, serious adverse event 
(SAE), 
relationship, 
leading 
to 
treatment 
discontinuation, 
leading 
to 
dose 
adjustment/interruption, hospitalization, death etc.).  
5.8.2 
Deaths  
Separate summaries for on-treatment and all deaths will be produced by SOC and PT.  
All deaths  will be listed for the Safety set, post treatment deaths will be flagged. A separate 
listing of deaths prior to starting treatment will be provided for all screened patients. 
5.8.3 
Laboratory data 
On analyzing laboratory, data from all sources will be combined. The summaries will include 
all assessments available for the lab parameter collected no later than 30 days after the last study 
treatment administration date.  
The following summaries will be produced for hematology and biochemistry laboratory data 
(by laboratory parameter and treatment): 
• Worst post-baseline CTC grade (regardless of the baseline status). Each subject will be 
counted only for the worst grade observed post-baseline. 
• Shift tables using CTC grades to compare baseline to the worst on-treatment  value  
• For laboratory tests where CTC grades are not defined, shift tables using the 
low/normal/high/(low and high) classification to compare baseline to the worst on-
treatment  value. 
• Trends of chemistry and hematology lab parameter values over time should be displayed 
via boxplots based on time windows and corresponding tables displaying the statistics 
used for the box plots by the selected time points. 
The following listings will be produced for the laboratory data: 
• Listings of all laboratory data, with CTC grades and classification relative to the 
laboratory normal range. Lab data collected during the post-treatment period will be 
flagged.   
• Listing of all CTC grade 3 or 4 laboratory toxicities. 
 
Liver parameters 
Liver parameters of interest are total bilirubin (TBL), ALT, AST and alkaline phosphatase 
(ALP). The number (%) of patients with worst post-baseline values as per Novartis Liver 
Toxicity guidelines will be summarized: 
The following summaries will be produced: 
• ALT or AST > 3xULN 
• ALT or AST > 5xULN 
• ALT or AST > 8xULN 


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• ALT or AST > 10xULN 
• ALT or AST > 20xULN 
• TBL > 2xULN 
• TBL > 3xULN 
• ALT or AST > 3xULN & TBL > 2xULN 
• ALT or AST > 3xULN & TBL > 2xULN & ALP < 2xULN (potential Hy’s law) 
Potential Hy’s Law events are defined as those patients with occurrence of AST or ALT > 
3xULN and TBL > 2xULN, and ALP < 2xULN at initial presentation during the on-treatment 
period. Note that the criteria relating to combined elevations of AST (or ALT) and TBL are 
based on the peak values at any post-baseline time for a patient. 
For patients with abnormal ALT or AST baseline values, a clinically significant liver safety 
signal corresponding to Hy’s law is defined by : [ALT or AST > 3*baseline] OR [ALT or 
AST >8*ULN], whichever is lower, combined with [TBIL >2*baseline AND >2*ULN]. 
 
5.8.4 
Other safety data 
 
5.8.4.1 
Electrocardiogram (ECG) and cardiac imaging data 
Single standard 12-lead ECGs will be obtained using an ECG machine that automatically 
calculates heart rate (HR) and measures RR, PR, QRS, QT, and QTcF intervals. All ECG 
assessments will be performed in the supine position. All ECG assessments will be read and 
interpreted locally. 
ECHO/MUGAs will be performed to assess cardiac ejection fraction. The same procedure 
(either ECHO or MUGA) should be performed at baseline and follow-up visits. All 
ECHO/MUGA assessments will be read and interpreted locally. 
Data handling 
In case of ECG replicates at any assessment, the average of the ECG parameters at that 
assessment should be used in the analyses. 
Data analysis 
The number and percentage of subjects with notable ECG values will be presented.  
• QT, QTcF 
- 
New value of > 450 and ≤ 480 ms 
- 
New value of > 480 and ≤ 500 ms 
- 
New value of > 500 ms 
- 
Increase from Baseline of > 30 ms to ≤  60ms 
- 
Increase from Baseline of > 60 ms 


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• HR 
- 
Increase from baseline >25% and to a value > 100 bpm 
- 
Decrease from baseline >25% and to a value < 50 bpm 
• PR 
- 
Increase from baseline >25% and  to a value > 200 ms 
- 
New value of > 200 ms 
• QRS 
- 
Increase from baseline >25% and  to a value > 120 ms 
- 
New values of QRS > 120 ms  
The summaries will include all ECG assessments performed no later than 30 days after the 
last study treatment date. 
A listing of all ECG assessments will be produced and notable values will be flagged. In the 
listing, the assessments collected during the post-treatment period will be flagged. 
For each of the ECG parameters, descriptive statistics at baseline, at each post-baseline time 
point and changes from baseline at each post-baseline time point will be summarized. 
Patients with notable ECG interval values will be listed and the corresponding notable values 
and abnormality findings will be included in the listings. 
Unscheduled ECG measurements will not be used in computing the descriptive statistics for 
change from baseline at each post-baseline time point. However, they will be used in the 
analysis of notable ECG values. 
For left ventricular ejection fraction (LVEF), descriptive statistics at baseline, at each 
postbaseline time point and changes from baseline at each post-baseline time point will be 
summarized. Only the post-baseline assessments that used the same method (ECHO or MUGA) 
as the baseline assessments will be used to derive the change from baseline 
To identify LVEF values of potential clinical importance, the following table will be used to 
assign categories that align with the grades for ‘Ejection fraction decreased’. 
 
LVEF Parameter Potential 
Clinical Importance (PCI) 
Range Unit 
Potential Clinical 
Importance (PCI) Range 
Unit 
Absolute change from 
baseline LVEF 
• No change or any 
increase 
• Any decrease 
• >0-<10 decrease 
• 10-19 decrease 
• >=20 decrease 
• >=10 decrease 
and >= LLN 
% 


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• >=10 decrease and < 
LLN 
• >10 decrease and < 
LLN 
• >=20 decrease 
and >= LLN 
• o >=20 decrease and 
< LLN 
 
5.8.4.2 
Vital signs 
Vital sign assessments are performed in order to characterize basic body function. The 
following parameters were collected: height (cm), weight (kg), body temperature (°C), heart 
rate (beats per minute), systolic and diastolic blood pressure (mmHg).  
Data handling 
Vital signs collected on treatment will be summarized. Values measured outside of on treatment 
period will be flagged in the listings. 
Data analysis 
For analysis of vital signs the clinically notable vital sign criteria are provided in Table 2-7 
below. 
Table 2-7 
Clinically notable changes in vital signs 
Vital sign 
(unit) 
Clinically notable criteria 
 
above normal value  
below normal value 
Weight (kg) 
increase > =10% from Baseline 
decrease  > 10% from Baseline 
Systolic blood 
pressure 
(mmHg) 
>=180 with increase from baseline 
of >=20 
<=90 with decrease from baseline 
of >=20 
 
Diastolic blood 
pressure 
(mmHg) 
>=105 with increase from baseline 
of >=15 
<=50 with decrease from baseline 
of >=15 
 
Pulse rate 
(bpm) 
>=100 with increase from baseline 
of >25% 
<=50 with decrease from baseline of  
> 25% 
 
Body 
temperature 
>= 39.1  
- 
The number and percentage of subjects with notable vital sign values (high/low) will be 
presented.  Descriptive statistics will be tabulated for baseline, at each post-baseline time point 
and changes from baseline at each post-baseline time point for each vital sign measure.         


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A listing of all vital sign assessments will be produced and notable values will be flagged. In 
the listing, the assessments collected outside of on-treatment period will be flagged.  
The ECOG performance status scale will be used to assess physical health of subjects and as 
described in Table 8-6 in the protocol. The scale ranges from 0 (fully active) to 5 (dead). 
ECOG performance status will be summarized for each assessment time. Frequency counts and 
percentages of subjects in each score category will be provided by time point based on the 
windows defined in Section 2.1.1. 
A supporting listing will also be provided. 
5.8.4.3 
Opthalmic examination 
A listing of ophthalmic examinations at screening will be produced. 
5.8.5 
Additional analyses 
Time to first occurrence 
Time to first occurrence of an event is defined as time from start of study treatment to the date 
of first occurrence of this event (or first event within an AE grouping), i.e. time in days is 
calculated as (start date of first occurrence of event ) – (start of study treatment) +1. 
 
For Kaplan-Meier analyses of time to occurrence, in the absence of an event during the on-
treatment period, the censoring date applied will be the earliest of the following dates:  
• death date 
• new anticancer antineoplastic therapy start date 
• end date of on-treatment period  
• data cut-off date 
• withdrawal of informed consent date. 
Failure curves (ascending Kaplan-Meier curves) will be constructed. Median together with 95% 
confidence interval as well as 25th percentile and 75th percentile will be presented.  
In addition, the median time to occurrence for the subset of patients who experienced the event 
of interest will be calculated. Simple descriptive statistics, median, min and max as well as 25th 
percentile and 75th percentile, will be presented. 
5.9 
Pharmacokinetic endpoints 
Not applicable. 
5.10 
PD and PK/PD analyses  
Not applicable. 


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5.11 
Patient reported outcomes (PRO) 
5.11.1 
General PRO analysis 
The FAS will be used for analyzing PRO data  
In this study, the Functional Assessment of Cancer Therapy-Melanoma (FACT-M) 
questionnaire will be used to evaluate the quality of life in patients with melanoma. This 
questionnaire consists of “physical well-being (PWB)”, “social/family well being (SWB)”, 
“emotional well-being (EWB)”, “functional well-being (FWB)”, “Melanoma subscale (MS)”.  
The total FACT-M score is calculated as PWB score+ SWB score+EWB score+FWB 
score+MS score. In this study, the 16 items that comprise MS of the FACT-M will be used.  
The variables analysed will be by the summary score. The summary score will be summarized 
descriptively in tables and graphs for baseline, post-baseline on treatment assessments 
(including the EoT assessment, if collected within 30 days of last non-zero dose intake) and 
scheduled post-treatment time points, and change from baseline to visit for total FACT-M score. 
The time windows as described in Section 2.1.1 will be used. 
The FACT-M is planned to be administered during baseline and at each scheduled post-baseline 
visit as per protocol through 24 months. The FACT-M will continue to be collected during the 
follow-up after the end of treatment. The baseline is defined as the last PRO assessment on or 
prior to first day of treatment.  
No imputation procedures will be applied for missing items or missing assessments. 
 
5.12 
Biomarkers 
Not applicable. 
5.13 
Other exploratory analysis 
Not applicable. 
5.14 
Interim analysis 
There was an interim analyses planned for this study when 203 patients completed 6 months of 
treatment or discontined earlier. The details of statistical analysis can be found in the SAP of 
interim analysis. DMC recommended to continue the trial based on interim analysis.   
 
6 
Sample size calculation 
 
As per  the protocol amendent version dated 09-May-2019, approximately 600 subjects were 
planned to be enrolled to receive dabrafenib (150 mg BID) and tramatinib (2 mg once daily) 
combination therapy for 12 months. Due to global drug supply availibility, the enrollment of 
patients was slower than anticipated,resulting in the final sample of 556 enrolled patients in the 
study by the end of anticipated recruitment period. The final sample size is reasonably close to 


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the planned target. The impact of the reduced sample size for the interim analyses has been 
discussed in detail in the Interim SAP (dated 21-Nov-2019) and DMC charter (17-Jan-2020). 
See Section 2.8 and Appendix B respectively for details.  
 
The sample size calculation was based on the primary variable. The protocol amendement dated  
provided justification for the planned sample size of 600.  However the current sample size of 
556 demonstartes that the  study operating characteristics comply with the requirement to have 
a highprobability (e.g. > 95%) for futility at IA if the true 12-month pyrexia event rate is > 20%, 
e.g., when the true pyrexia event rate is 27%, the probability is 95.5% for futility at interim 
analysis.  
 
Detailed Operating characteristics are described below (see Table 2-8). For illustration, if the 
true 12-months pyrexia event rate is 30%, then there is a high chance (99.6%) of futility at the 
time of the interim, and the probability to continue the study and conclude success is lower than 
0.001.  
 
If the true pyrexia event rate is 20%, then the probability of observing a pyrexia event rate < 
20% (i.e., study success for primary analysis) is 46.3%. If the true pyrexia event rate is lower 
(for example 18%), then there is 84.6% probability of declaring study success for primary 
analysis. 
Table 2-8 
Operating Characteristics 
True 6 -month 
event rate 
Probability to stop the 
study at IA 
Probability of success at primary analysis 
(i.e., not stop at the IA and observe event 
rate < 20% at primary analysis)* 
16% 
0.016 
0.980 
17% 
0.040 
0.940 
18% 
0.086 
 0.846 
19% 
0.161 
 0.679 
20% 
0.265 
0.463 
21% 
0.391 
0.258 
22% 
0.528 
0.115 
25% 
0.856 
0.002 
26% 
0.917 
<0.001 
27% 
0.955 
<0.001 
28% 
0.978 
<0.001 
30% 
0.996 
<0.001 
* Probabilities are calculated based on the exact binomial distribution.  
 
 


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7 
Changed to protocol specified analyses 
7.1 
Impact of COVID-19 
Due to pandemic COVID in year 2020, some extra analyses will be performed outside protocol 
specified.  
Oprational impact: Specified protocol deviation categories will be assigned to important 
deviations related to COVID-19 (e.g., missing efficacy assessments and treatment interruptions) 
and these will be summarized and listed separately. A summary table of the COVID-19 related 
deviations by relationship category will be provided.  
Safety: To help to evaluate the impact of the pandamic on safety, the incidence of COVID-19 
related adverse event preferred terms will be presented incorporating (a) COVID-19 related 
adverse events with an onset date prior to the start of the outbreak (i.e., pre-2020, please refer 
the following paragraph for the definition) and (b) all COVID-19 related adverse events 
occuring before data cut-off. A listing of all COVID-related AEs will also be provided.  
The Pre-COVID period is defined as before March 1, 2020 for Rest of the World and before 
Feb 23, 2020 for Italy patients. That means March 1 will play a data-cut off role. All the data 
before March 1 will be considered as pre-Covid period. The data from March 2, 2020 onwards 
will be considered as Post-Covid period.  
The Post-COVID period is defined as after March 1, 2020 for Rest of the World and after Feb 
23, 2020 for Italy patients. 
 
Primary endpoint:  
To help to evaluate the impact of the COVID-19 on the primary endpoint and on overall pyrexia, 
the following sensitivity analyses will be performed. The summary analyses will be performed 
if we have 10% total sample size in each of the caterogies. The KM plot will be performed only 
if we have more than 30 patients have pyrexia event in each of the categories.  
1) Composite rate of grade ¾ pyrexia, hospitalization or permanent discontinue due to 
pyrexia by 12 months for Rest of the World (Full analysis set) Pre-Covid and post-
Covid-period. 
2) Composite rate of grade ¾ pyrexia, hospitalization or permanent discontinue to pyrexia 
by 12 months for Italy (Full analysis set) with data cut-off Feb 23, 2020 vs data after 
February 23, 2020. 
3) Composite rate of grade ¾ pyrexia, hospitalization or permanent discontinue to pyrexia 
by 12 months with suspected and confirmed covid subjects using full analysis set.   
4) Summary of pyrexia – Pre and post COVID period for rest of the world 
5) Summary of pyrexia– Pre and post COVID period for Italy (Full analysis set) 
6) Summary of pyrexia – confirmed and suspected covid subjects (Full analysis set)  
7) Time to first pyrexia event - Pre and post COVID period for Rest of the World. 


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8) Time to first pyrexia event – Pre and post COVID period for Italy (Full analysis set).  
9) Time to first pyrexia event – confirmed and suspected covid subjects (Full analysis set)  
10)  Kaplan-Meier plot time to first pyrexia event - Pre and post COVID period for Rest of 
the World. 
11) Kaplan-Meier plot time to first pyrexia event – Pre and post COVID period for Italy 
(Full analysis set).  
12) Kaplan-Meier plot time to first pyrexia event – confirmed and suspected covid subjects 
(Full analysis set)  
 
7.2 
Analyses to support label update 
This section outlines additional safety analyses needed to evaluate the impact of the 
implementation of the new pyrexia management guideline used in COMBI-A+ study. 
The current dabrafenib and trametinib labels reflect the pyrexia management guidance in 
COMBI-d/v and COMBI-AD protocols; to interrupt dabrafenib if the patients temperature is 
≥38.5ºC and continue trametinib at the same dose. However, the increased incidence of pyrexia 
with combination compared to dabrafenib monotherapy, suggests that trametinib influences the 
dabrafenib -driven pyrexia process. Therefore, optimal guidance per current clinical consensus 
is to interrupt both dabrafenib + trametinib at the very first symptom of pyrexia or its associated 
prodrome (chills, rigors, night sweats or flu-like symptoms), as used in COMBI-i/COMBI-A+ 
protocols. 
With a more proactive intervention for pyrexia, it is hypothesized that a cross-study comparison 
of pyrexia-related safety outcomes (e.g. incidence of grade ≥3 pyrexia, incidence of permanent 
discontinuations) in the metastatic melanoma setting (COMBI-d/v versus COMBI-i) and the 
adjuvant setting (COMBI-AD vs COMBI-A+) may support of a change to the dose modification 
section of the dabrafenib and trametinib labels. If warranted, the safety outputs defined in this 
SAP will be used to support the label update. 
For the analyses related to complicated pyrexia and time spent in pyrexia, the following 
definitions will be used.  
Complicated pyrexia events 
Subjects who have pyrexia (single preferred term (PT)) and any of the following terms at any 
time while on-treatment will be considered as having complicated pyrexia: severe (≥ Grade 3) 
chills, hypotension, dehydration, syncope, or renal dysfunction.  
Percentage of time spent in pyrexia  
Percentage of time spent in pyrexia AESI will be calculated for each subject who experienced 
a pyrexia AESI as follows: 
Total numbers of days in pyrexia AESI/ total duration of exposure in days *100.  
The maximum duration of exposure to dabrefinb or trametinib will be used in the calculation.  


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The following tables will be required from this study. The tables generated outside protocol 
defined analyses,  are flagged with (*) in the below list. 
1) Demographics and disease characteristics 
2) Disease History 
3) Summary of exposure and dose of study drug received for dabrafenib and trametinib 
4) Dose interruptions of trametinib 
5) Dose interruptions of dabrafenib 
6) Summary of Concomitant Oral or IV Corticosteroids (*) 
7) Pyrexia AESIs leading to dose interruptions of trametinib (*) 
8) Pyrexia AESIs leading to dose interruptions of dabrafenib (*) 
9) Pyrexia AESIs leading to dose interruptions of both trametinib and dabrafenib (*) 
10) Pyrexia AESIs leading to dose reductions of trametinib (*) 
11) Pyrexia AESIs leading to dose reductions of dabrafenib (*) 
12) Pyrexia AESIs leading to dose reductions of both trametinib and dabrafenib (*) 
13) Summary of Pyrexia AESIs by maximum grade (*) 
14) Summary of Characteristics of Pyrexia AESIs (*) 
15) Time to onset and duration of first pyrexia AESI (*) 
16) AE leading to treatment discontinuation of trametinib 
17) AE leading to treatment discontinuation of dabrafenib 
18) AE leading to treatment discontinuation of both trametinib and dabrafenib 
19) Pyrexia AESI leading to treatment discontinuation of trametinib (*) 
20) Pyrexia AESI leading to treatment discontinuation of dabrafenib (*) 
21) Pyrexia AESI leading to treatment discontinuation of both dabrafenib and trametinib (*) 
22) Summary of Pyrexia (Single Preferred Term) Complicated by Severe Chills, 
Hypotension, Dehydration, Syncope, or Renal Dysfunction (*) 
23) Summary of Skin-toxicity AESIs by Maximum Grade 
24) Summary of Serious Pyrexia AESIs Requiring Hospitalization (*) 
25) Summary of Occurrences and percentage of time for Pyrexia AESIs (*) 
26) Event level Summary of Action Taken with Pyrexia AESI (*) 
27) Composite rate of grade 3/4 pyrexia, hospitalization or permanent treatment 
discontinuation due to pyrexia by 12 months 
 


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For all of the analyses mentioned in this SAP, pyrexia AESIs will be defined using the following 
list of PTs:   
 
Pyrexia PT 
PT Code 
Body temperature increased 
10005911 
Cytokine release syndrome 
10052015 
Hyperpyrexia 
10020741 
Hyperthermia 
10020843 
Influenza like illness 
10022004 
Pyrexia 
10037660 
Sweating fever 
10042666 
Systemic inflammatory response syndrome 
10051379 
Tumour associated fever 
10052243 
 
For complicated pyrexia analyses, renal dysfunction will be defined using the following list of 
PTs:  
 
Renal Dysfunction PT 
PT Code 
Prerenal failure 
10072370 
Acute kidney injury* 
10069339 
*PT Acute renal failure was replaced by Acute kidney injury in 
MedDRA 24.1  They are equivalent terms.  
 
 
 
8 
Appendix 
8.1 
Imputation rules 
8.1.1 
Study drug 
The following rule should be used for the imputation of the dose end date for a given study 
treatment component: 
Scenario 1: If the dose end date is completely missing and there is no EOT page, and no 
death date, the patient is considered as on-going:  
The patient should be treated as on-going and the cut-off date should be used as the dose end 
date. Scenario 1 should not be applicable for final CSR. All patients should have EOT page 
complete before the Database lock for Final CSR. 
 
Scenario 2: If the dose end date is completely or partially missing and theEOT page is 
available:  


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Case 1: The dose end date is completely missing, and the EOT  completion date is complete, 
then this latter date should be used.   
Case 2: Only Year(yyyy) of the dose end date is available and yyyy < the year of EOT date:   
            Use Dec31yyyy 
Case 3: Only Year(yyyy) of the dose end date is available and yyyy  = the year of EOT date:  
            Use EOT date 
Case 4: Both Year(yyyy) and Month (mm) are available for dose end date, and yyyy  = the 
year of EOT date and mm < the month of  EOT date:  
            Use last day of the Month (mm) 
All other cases should be considered as a data issue and the statistician should contact the data 
manager of the study. 
After imputation, compare the imputed date with start date of treatment, if the imputed date is 
< start date of treatment:  
Use the treatment start date 
Patients with missing start dates are to be considered missing for all study treatment component 
related calculations and no imputation will be made. If start date is missing then end-date should 
not be imputed. 
 
 
 
8.1.1 
AE, ConMeds and safety assessment date imputation 
 
Table 5-1 
Imputation of start dates (AE, CM) and assessments (LB, EG, VS) 
Missing 
Element 
Rule 
day, month, 
and year 
• No imputation will be done for completely missing dates 
day, month 
• If available year = year of study treatment start date then  
o If stop date contains a full date and stop date is earlier than 
study treatment start date then set start date = 01JanYYYY  
o Else set start date = study treatment start date.  
• If available year > year of study treatment start date then 01JanYYYY 
• If available year < year of study treatment start date then 01JulYYYY 


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Missing 
Element 
Rule 
day 
• If available month and year = month and year of study treatment start 
date then  
o If stop date contains a full date and stop date is earlier than 
study treatment start date then set start date= 01MONYYYY.  
o Else set start date = study treatment start date. 
• If available month and year > month and year of study treatment start 
date then 01MONYYYY   
• If available month and year < month year of study treatment start date 
then 15MONYYYY   


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Table 5-2 
Imputation of end dates (AE, CM)  
Missing 
Element 
Rule  
(*=last treatment date plus 30 days not > (death date, cut-off date, 
withdrawl of consent date)) 
day, month, 
and year 
• 
Completely missing end dates (incl. ongoing events) will be imputed 
by the end date of the on-treatment period*  
day, month 
• 
If partial end date contains year only, set end date = earliest of 
31DecYYYY or end date of the on-treatment period *  
day 
• 
If partial end date contains month and year, set end date = earliest of 
last day of the month or end date of the on-treatment period* 
Any AEs and ConMeds with partial/missing dates will be displayed as such in the data listings. 
Any AEs and ConMeds which are continuing as per data cut-off will be shown as ‘ongoing’ 
rather than the end date provided.  
The above imputations are only used for analyses of time to and duration of AEs and 
concomitant medications.   
8.1.1.1 
Other imputations 
Incomplete date of initial diagnosis of cancer and  date of most recent 
recurrence  
Missing day is defaulted to the 15th of the month and missing month and day is defaulted to 01-
Jan.  
Incomplete assessment dates for tumor assessment 
All investigation dates (e.g. MRI scan, CT scan) must be completed with day, month and year. 
If one or more assessment dates are incomplete but other investigation dates are available, 
this/these incomplete date(s) are not considered for calculation of the assessment date and 
assessment date is calculated as the latest of all investigation dates (e.g. MRI scan, CT scan) if 
the overall response at that assessment is CR/PR/SD/UNK. Otherwise – if overall response is 
progression – the assessment date is calculated as the earliest date of all investigation dates at 
that evaluation number.  If all measurement dates have no day recorded, the 1st of the month is 
used. If the month is not completed, for any of the investigations, the respective assessment will 
be considered to be at the date which is exactly between previous and following assessment. If 
a previous and following assessment is not available, this assessment will not be used for any 
calculation. 
Applying the cut-off to tumor assessment 
For tumor related assessments, if an evaluation has some assessments done prior to  cut-off date 
and  others after the cut-off date , then the evaluation is considered post-cut-off date and will 
be excluded from analysis. 


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8.2 
AEs coding/grading 
Adverse events are coded using the Medical dictionary for regulatory activities (MedDRA) 
terminology. The latest available MedDRA version at the time of the analyses should be used.  
AEs will be assessed according to the Common Terminology Criteria for Adverse Events 
(CTCAE) version 4.03.  
The CTCAE represents a comprehensive grading system for reporting the acute and late effects 
of cancer treatments. CTCAE grading is by definition a 5-point scale generally corresponding 
to mild, moderate, severe, life threatening, and death. This grading system inherently places a 
value on the importance of an event, although there is not necessarily proportionality among 
grades (a grade 2 is not necessarily twice as bad as a grade 1).  
 
8.3 
Laboratory parameters derivations 
Grade categorization of lab values will be assigned programmatically as per NCI Common 
Terminology Criteria for Adverse Events (CTCAE) version 4.03. The calculation of CTCAE 
grades will be based on the observed laboratory values only, clinical assessments will not be 
taken into account. The criteria to assign CTCAE grades are given in Novartis internal criteria 
for CTCAE grading of laboratory parameters. The latest available version of the document 
based on the underlying CTCAE version 4.03 at the time of analysis will be used (refer to Table 
5-3 in the Novartis internal criteria for CTC grading of laboratory parameters). For laboratory 
tests where grades are not defined by CTCAE v4.03, results will be graded by the 
low/normal/high classifications based on laboratory normal ranges. 
A severity grade of 0 will be assigned for all non-missing lab values not graded as 1 or higher. 
Grade 5 will not be used. For laboratory tests that are graded for both low and high values, 
summaries will be done separately and labelled by direction, e.g., sodium will be summarized 
as hyponatremia and hypernatremia. 
Imputation Rules   
CTC grading for blood differentials is based on absolute values. However,  this data may not 
be reported as absolute counts but rather as percentage of WBC.  
If laboratory values are provided as ‘<X’ (i.e. below limit of detection) or ‘>X’, prior to 
conversion of laboratory values to SI unit, these numeric values are set to X.   
The following rules will be applied to derive the WBC differential counts when only 
percentages are available for a xxx differential 
xxx count = (WBC count) * (xxx %value / 100) 
Further derivation of laboratory parameters might be required for CTCAE grading. For 
instance, corrected calcium can be derived using the reported total calcium value and albumin 
at the same assessment using the following formula: 
Corrected Calcium (mg/dL) = Calcium (mg/dL) – 0.8 [Albumin (g/dL)-4] 


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In order to apply the above formula, albumin values in g/L will be converted to g/dL by  
multiplying by 0.1), calcium values in mmol/L will be converted to mg/dL by dividing by 
0.2495. For calculation of laboratory CTC grades 0 and 1, the normal range for  derived 
corrected calcium is set to the same limits (in mg/dL) as for calcium. 
CTC grades for the derived absolute WBC differential counts (neutrophils, lymphocytes) and 
corrected calcium will be assigned as described above for grading 
8.4 
Statistical models 
 
8.4.1 
Primary analysis of binary data 
 
Pyrexia events will be summarized in terms of percentage rates with 95% CIs. An exact 
binomial confidence interval (implemented using SAS procedure FREQ with EXACT 
statement for one-way tables) will be calculated [Clopper and Pearson 1934]  
SAS procedure FREQ will be used to estimate the proportion of subjects with pyrexia events 
(binary outcome = 1 or “Yes”), along with the associated 95% (=100 × (1 – two-sided alpha 
level)) two-sided Pearson-Clopper CI. 
 
8.4.2 
Secondary analysis 
 
 
Kaplan-Meier estimates 
 
An estimate of the survival function will be constructed using Kaplan-Meier (product-limit) 
method as implemented in PROC LIFETEST with METHOD=KM option. The PROC 
LIFETEST statement will use the option CONFTYPE=LOGLOG. 
Median survival will be obtained along with 95% confidence intervals calculated from PROC 
LIFETEST output using the method of [Brookmeyer and Crowley 1982]. Kaplan-Meier 
estimates of the survival function with 95% confidence intervals at specific time points 
will be summarized. The standard error of the Kaplan-Meier estimate will be calculated 
using Greenwood’s formula [Collett 1994]. 
 
9 
Appendix for identification of corticosteroids 
 
 
 
CMDECOD 


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ABIRATERONE ACETATE W/PREDNISOLONE 
ADRENAL CORTICAL EXTRACT 
BECLOMETASONE 
BECLOMETASONE DIPROPIONATE 
BECLOMETASONE DIPROPIONATE MONOHYDRATE 
BETAMETHASONE 
BETAMETHASONE ACETATE 
BETAMETHASONE BENZOATE 
BETAMETHASONE DIPROPIONATE 
BETAMETHASONE PHOSPHATE 
BETAMETHASONE SODIUM PHOSPHATE 
BETAMETHASONE VALERATE 
BETAPRON 
BUDESONIDE 
CELESTONA BIFAS 
CLOPREDNOL 
CORTIPAN 
CORTISONE 
CORTISONE ACETATE 
CORTIVAZOL 
DEFLAZACORT 
DEHYDROCORTICOSTERON 
DEXAMETHASONE 
DEXAMETHASONE ACETATE 
DEXAMETHASONE ACETATE MONOHYDRATE 
DEXAMETHASONE BELOXIL 
DEXAMETHASONE DIPROPIONATE 
DEXAMETHASONE ISONICOTINATE 
DEXAMETHASONE PALMITATE 
DEXAMETHASONE PHOSPHATE 
DEXAMETHASONE SODIUM METASULFOBENZOATE 
DEXAMETHASONE SODIUM PHOSPHATE 
DEXAMETHASONE SODIUM SUCCINATE 
DEXAMETHASONE SODIUM SULFATE 
DEXAMETHASONE TEBUTATE 


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DEXAMETHASONE VALERATE 
DI-HYDROCORTISONE 
DI-HYDROCORTISONE PHOSPHATE 
DI-HYDROCORTISONE SODIUM PHOSPHATE 
DIPROSPAN                          /00582101/ 
DUO DECADRON 
EMORRIL                            /01757601/ 
FLUOCORTOLONE 
FLUOCORTOLONE CAPROATE 
FLUOCORTOLONE PIVALATE 
FLUPAMESONE 
FLUPREDNISOLONE 
FLUPREDNISOLONE ACETATE 
FLUPREDNISOLONE VALERATE 
GLUCOCORTICOIDS 
HALOPREDONE 
HALOPREDONE ACETATE 
HYDROCORTISONE 
HYDROCORTISONE ACETATE 
HYDROCORTISONE BUTYRATE 
HYDROCORTISONE CIPIONATE 
HYDROCORTISONE HYDROGEN SUCCINATE 
HYDROCORTISONE IN EURAX 
HYDROCORTISONE PROBUTAT 
HYDROCORTISONE SODIUM PHOSPHATE 
HYDROCORTISONE SODIUM SUCCINATE 
HYDROCORTISONE VALERATE 
LEDERSPAN CUM LIDOKAIN 
MAZIPREDONE 
MAZIPREDONE HYDROCHLORIDE 
MEPREDNISONE 
MEPREDNISONE SUCCINATE 
METHYLPREDNISOLONE 
METHYLPREDNISOLONE ACETATE 
METHYLPREDNISOLONE HEMISUCCINATE 


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METHYLPREDNISOLONE SODIUM SUCCINATE 
METHYLPREDNISOLONE SULEPTANATE 
PARAMETHASONE 
PARAMETHASONE ACETATE 
PARAMETHASONE DISODIUM PHOSPHATE 
PELONINE R 
PREDNISOLON STREULI                /06304501/ 
PREDNISOLONE 
PREDNISOLONE ACETATE 
PREDNISOLONE BUTYLACETATE 
PREDNISOLONE FARNESYLATE 
PREDNISOLONE HEMISUCCINATE 
PREDNISOLONE METASULFOBENZOATE SODIUM 
PREDNISOLONE PALMITATE 
PREDNISOLONE PHOSPHATE 
PREDNISOLONE PIVALATE 
PREDNISOLONE SODIUM PHOSPHATE 
PREDNISOLONE SODIUM SUCCINATE 
PREDNISOLONE SODIUM SULFATE 
PREDNISOLONE SODIUM TETRAHYDROPHTALATE 
PREDNISOLONE STEAGLATE 
PREDNISOLONE VALEROACETATE 
PREDNISONE 
PREDNISONE ACETATE 
PREDNYLIDENE 
PREGNENOLONE 
PREGNENOLONE ACETATE 
PREGNENOLONE SUCCINATE 
RIMEXOLONE 
SURELEN                            /00817601/ 
TRIAMCINOLONE 
TRIAMCINOLONE ACETONIDE 
TRIAMCINOLONE ACETONIDE DIPOTASSIUM PHOSPHATE 
TRIAMCINOLONE ACETONIDE SODIUM PHOSPHATE 
TRIAMCINOLONE DIACETATE 


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TRIAMCINOLONE HEXACETONIDE 
TRINIOL 
WACODEX 
WACOMETASONA                       /03018901/ 
BETAMETHASONE W/CHLORPHENAMINE 
 
 
10 
Reference 
1. Brookmeyer R and Crowley J (1982). A Confidence Interval for the Median Survival 
Time. Biometrics, 38, 29 - 41.    
2. Clopper CJ and Pearson ES (1934).  The use of confidence or fiducial limits illustrated in 
the case of the binomial.  Biometrical, 26, 404-413. 
3. Collet D (1994). Modelling survival data in medical research. London, Chapman & Hall. 
4. Neuenschwander B, Branson M and Gsponer T (2008). Critical aspects of the Bayesian 
approach to Phase I cancer trials. Statistics in Medicine, 27, 2420-2439