Clinical trial NCT02083354
Conditions: Cancer Melanoma
Keywords: melanoma dabrafenib trametinib malignant skin cancer skin cancer BRAF V600 Mutation-Positive Melanoma
Sponsor: Novartis Pharmaceuticals
Start date: 2014-03-18; Completion date: 2021-04-19
Enrollment: 77 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This was a single-arm, open-label, multi-center, Phase II study to evaluate dabrafenib and trametinib combination therapy in subjects with BRAF V600 mutation-positive, unresectable or metastatic Acral lentiginous or cutaneous melanoma. This study evaluated the objective response rate (ORR), progression free survival (PFS), duration of response, overall survival (OS), safety and efficacy, to assess steady state (all subjects) exposure to dabrafenib, dabrafenib metabolites, and trametinib and characterize the population pharmacokinetics (PK) and pharmacodynamics (PD) of dabrafenib and trametinib. Enrolled subjects were administered dabrafenib 150 milligram (mg) orally twice daily and trametinib 2 mg orally once daily. Treatment continued until disease progression, death, unacceptable toxicity, or withdrawal of consent, or study closure. After treatment discontinuation, subjects were followed for survival and disease progression as applicable.

Detailed description:
This was an open-label, single arm, Phase IIA, multi-center study to evaluate the Objective response rate (ORR) of dabrafenib and trametinib combination therapy in East Asian subjects that have BRAF V600 mutationpositive Stage IIIC (unresectable) or Stage IV (metastatic) acral lentiginous melanoma (ALM) or cutaneous melanoma.

All subjects enrolled received oral dabrafenib 150 mg bid in combination with oral trametinib 2 mg once daily. A primary analysis presented the efficacy, safety and pharmacokinetics (PK) data up to the data cut-off date of 23-Feb-2018. Based on these results, dabrafenib and trametinib combination was approved in the People's Republic of China (PRC) for the treatment of BRAF-mutation positive unresectable or metastatic melanoma. Data from Mainland Chinese subjects from 01-Jul-2019 onwards are not included due to local regulations in China.

Subjects continued study treatment until disease progression, death, unacceptable toxicity, withdrawal of consent, or study completion. After treatment discontinuation, subjects went into follow-up for survival and disease progression as applicable. Subjects could continue study treatment after disease progression if they achieved clinical response per Response Evaluation Criteria In Solid Tumors (RECIST) 1.1 or stable disease with tumour reduction; had no overt signs of toxicity; had Eastern Cooperative Oncology Group (ECOG) performance status of ≤1 and did not require immediate surgical or radiological intervention.

Arms: arm 1: All subjects will receive the combination of dabrafenib (150 mg) and trametinib (2 mg) in the morning at approximately the same time every day. The second dose of dabrafenib (150 mg) alone will be administered approximately 12 hours after the morning dose. Subjects will continue study treatment until disease progression, death, unacceptable toxicity, withdrawal of consent, or study closure
Interventions: intervention 1: Dabrafenib intervention 2: Trametinib
Intervention descriptions: intervention 1: Dabrafenib will be provided as 50 mg and 75 mg capsules. Each capsule will contain 50 mg or 75 mg of free base (present as the mesylate salt) intervention 2: Trametinib study medication will be provided as 0.5 mg and 2.0 mg tablets. Each tablet will contain 0.5 mg or 2.0 mg of trametinib parent (present as the DMSO solvate)

Protocol documents:
SAP_002.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)
11-
Aug-
2016
Prior 
to 
DB lock
Creation of first version
First 
version
NA
06-
Apr-
2018
Prior 
to 
DB lock
Creation of amendment 1

Addition of PK samples for
subjects with Day 1 or Day 15 
samples

Revision 
of 
secondary 
objectives and endpoints in 
relation with the updated PK
schedule

Update the RAP in line with 
Novartis RAP template 
Second 
version
2.9
2.10
05-
May-
2021
Prior 
to 
Final DB 
lock
Creation of final version for study 
closeout

Specification of data included 
in the final analysis, remove the 
Pharmacokinetic analysis set 
(PAS) which will not be used 
for the final analysis

Remove 
details 
of 
Demographics, 
baseline 
characteristics, medical history, 
prior 
anti-cancer 
therapy, 
Pharmacokinetic endpoint ，
PD and PK/PD analyses, which 
will not change from the 
primary analysis

Remove the deails of overall 
compliance, 
Biomarkers 
analyses, since these analyses 
will not be included in the fianl 
CSR.

Simplify the sentences and 
remove 
some 
unplanned 
Final 
version
(for study 
closeout)
2.1
2.2
2.3
2.4
2.8
2.9
2.10
2.12


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Date
Time point
Reason for update
Outcome 
for 
update
Section and 
title impacted 
(Current)
analysis in Safety analyses 
section


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Table of contents
Table of contents .................................................................................................................4
List of abbreviations............................................................................................................6
1
Introduction .........................................................................................................................7
1.1
Study design.............................................................................................................7
1.2
Study objectives and endpoints ...............................................................................8
2
Statistical methods.............................................................................................................10
2.1
Data analysis general information .........................................................................10
2.1.1
Data included in the analysis.................................................................10
2.1.2
General analysis conventions................................................................11
2.1.3
General definitions................................................................................11
2.2
Analysis sets ..........................................................................................................13
2.2.1
Analysis Populations.............................................................................13
2.2.2
Withdrawal of Informed Consent..........................................................13
2.2.3
Subgroup of interest ..............................................................................13
2.3
Patient disposition, demographics and other baseline characteristics ...................14
2.3.1
Patient disposition.................................................................................14
2.3.2
Protocol deviations................................................................................14
2.3.3
Analysis sets..........................................................................................14
2.4
Treatments (study treatment, rescue medication, concomitant therapies, 
compliance)............................................................................................................15
2.4.1
Study treatment / compliance................................................................15
2.4.2
Prior, concomitant and post therapies...................................................18
2.5
Analysis of the primary objective..........................................................................18
2.5.1
Primary endpoint...................................................................................19
2.5.2
Statistical hypothesis, model, and method of analysis..........................19
2.5.3
Handling of missing values/censoring/discontinuations.......................19
2.5.4
Supportive analyses...............................................................................20
2.6
Analysis of the key secondary objective ...............................................................20
2.7
Analysis of secondary efficacy objective(s)..........................................................20
2.7.1
Secondary endpoints .............................................................................20
2.7.2
Statistical hypothesis, model, and method of analysis..........................21
2.7.3
Handling of missing values/censoring/discontinuations.......................21
2.8
Safety analyses.......................................................................................................23
2.8.1
Adverse events (AEs)............................................................................23
2.8.2
Deaths....................................................................................................25
2.8.3
Laboratory data .....................................................................................26


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2.8.4
Other safety data ...................................................................................28
2.9
Pharmacokinetic endpoints....................................................................................31
2.10
PD and PK/PD analyses.........................................................................................31
2.11
Patient-reported outcomes .....................................................................................31
2.12
Biomarkers.............................................................................................................31
31
2.14
Interim analysis......................................................................................................31
3
Sample size calculation .....................................................................................................31
3.1
Primary analysis.....................................................................................................31
3.2
Power for analysis of key secondary variables......................................................31
4
Change to protocol specified analyses ..............................................................................32
5
Appendix ...........................................................................................................................33
5.1
Imputation rules.....................................................................................................33
5.1.1
Study drug.............................................................................................33
5.1.2
AE, ConMeds and safety assessment date imputation..........................34
5.1.3
Other imputations..................................................................................35
5.2
AEs coding/grading ...............................................................................................36
5.3
Laboratory parameters derivations ........................................................................36
5.4
Statistical models...................................................................................................37
5.4.1
Primary endpoint analysis.....................................................................37
5.4.2
Secondary endpoint analysis.................................................................38
5.5
Rule of exclusion criteria of analysis sets..............................................................38
6
Reference...........................................................................................................................38


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List of abbreviations
AE
Adverse event
ATC
Anatomical Therapeutic Classification
AUC
Area Under the Curve
bid
bis in diem/twice a day
CR
Complete Response
CSR
Clinical Study report
CTC
Common Toxicity Criteria
CTCAE
Common Terminology Criteria for Adverse Events
DMC
Data Monitoring Committee 
DOR
Duration of Response
eCRF
Electronic Case Report Form
EOT
End of Treatment
FAS
HGRAC
Full Analysis Set
Human Genetic Resource Administration of China
IVR
Interactive Voice Response
IWR
Interactive Web Response
MedDRA
Medical Dictionary for Drug Regulatory Activities
NCI
National Cancer Institute
o.d.
Once Daily
ORR
Objective Response Rate
OS
Overall Survival
PAS
Pharmacokinetic Analysis Set
PD
Progression Disease
PFS
Progression-Free Survival
PK
Pharmacokinetics
PPS
Per-Protocol Set
PR
Partial Response
PRO
Patient-reported Outcomes
qd
Qua’que di’e / once a day
QoL
Quality of Life
RECIST
Response Evaluation Criteria in Solid Tumors 
SAP
Statistical Analysis Plan
SD
Stable Disease
SOC
System Organ Class
TFLs
Tables, Figures, Listings
WHO
World Health Organization


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1
Introduction
This statistical analysis plan (SAP) describes all planned analyses for the final Clinical Study 
Report (CSR) of study 200104 (DRB436B2205), a phase IIA, open label, multi-center study 
to investigate the objective response rate of Dabrafenib in combination with Trametinib in 
subjects with BRAF V600 mutation-positive melanoma.
The previous SAP for primary analysis was finalized on 06-Apr-2018, which described all 
planned analyses for the primary CSR. Based on the results in the primary CSR, dabrafenib 
and trametinib combination was approved in People’s Republic of China (PRC). 
This SAP is for the final analysis, i.e., the study closeout SAP. The content of this SAP is based 
on protocol DRB436B2205 Amendment v08. All decisions regarding final analysis, as defined 
in the SAP document, have been made prior to database lock of the study data.
1.1
Study design
This is a single-arm, Phase IIA, open-label, multi-center study evaluating safety and efficacy of  
dabrafenib and trametinib combination therapy in BRAF V600 mutant-positive melanoma. 
Approximately 65 subjects were enrolled in the study.
Overall response rate (ORR), as assessed by local investigators review of tumor response and 
using RECIST 1.1 criteria, is the primary endpoint in this study.
The primary analysis was performed after all subjects had been followed for at least 16 weeks 
or had at least 2 tumor assessments or had discontinued study, with a data cut-off on 23-Feb-
2018. 
Treatment will continue until disease progression, death, unacceptable toxicity, or withdrawal 
of consent, or study completion. After treatment discontinuation, subjects will be followed for 
survival and disease progression as applicable.
Survival and new anti-cancer therapy follow-up will continue until study completion. The study 
completion is defined as:

In case all subjects stop study treatment within 48 weeks after Last Subject First Visit 
(LSFV): the study is completed once the last subject has completed the 48 weeks survival 
follow-up or all subjects die or loss to follow-up, whichever comes first. 

In case some subjects are still on study treatment 48 weeks after LSFV: the study is 
completed once all subjects stop study medication, or all subjects who are still on study 
medication can have access to alternative supply of MEK/BRAF inhibitors, whichever 
comes first.  
Doses of study treatment may be modified and/or interrupted for management of toxicities 
associated with study treatment.
No formal interim efficacy analysis is planned for this study.


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1.2
Study objectives and endpoints
Table 1-1
Study Objectives and Endpoints
Objectives
Endpoints
Primary

To determine the objective response rate 
(ORR) of dabrafenib in combination with 
trametinib in subjects with BRAF V600 
mutation-positive, unresectable or metastatic 
acral lentiginous or cutaneous melanoma   
ORR is defined as the percentage of 
subjects with evidence of a confirmed 
complete response (CR) or partial 
response (PR) as per RECIST v1.1 
[Eisenhauer, 2009].
Secondary

To further evaluate the antitumor activity 
(progression-free survival (PFS), duration of 
response (DOR), and overall survival (OS))
PFS is defined as the time from first dose 
of study treatment until the first date of 
either objective disease progression or 
death due to any cause.
Duration of response is defined as the 
time from first documented evidence of 
CR or PR until the earliest date of 
documented radiological progression or 
death due to any cause among subjects 
who achieved a confirmed CR or PR. 
OS is defined as the interval from first 
dose of study treatment to the date of 
death, irrespective of the cause of death; 
subjects still alive will be censored at the 
date of the last contact.






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2.1.2
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 subjects enrolled at centers, no center effect will 
be assessed. 
Qualitative data (e.g., gender, race, etc.) will be summarized by means of contingency tables
by Mainland Chinese and all subjects; a missing category will be included as applicable. 
Percentages will be calculated using the number of subjects in the relevant population or 
subgroup as the denominator.
Quantitative data (e.g., age, body weight, etc.) will be summarized by appropriate descriptive 
statistics (i.e. mean, standard deviation, median, minimum, and maximum) by Mainland 
Chinese and all subjects.
Mainland Chinese population means the subjects enrolled from mainland China. All subjects
means all subjects enrolled to the study.
2.1.3
General definitions
2.1.3.1
Study drug and study treatment
Study drug and study treatment both refer to Dabrafenib in Combination with Trametinib.
2.1.3.2
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 is administered and recorded on the exposure form. For the sake of simplicity, the 
date of first administration of study drug will also be referred as start date of study drug.
The date of last administration of study drug is defined as the last date when a non-zero dose of 
study drug is administered and recorded on the exposure form. This date is also referred as last 
date of study drug.
2.1.3.3
Study day 
The study day for all assessments (e.g. tumor assessment, death, disease progression, tumor
response, performance status, adverse event onset, laboratory abnormality occurrence, vital sign 
measurement, dose interruption) will be calculated using the start date of study drug as the 
origin. For assessments occurring after or on the start date of study drug, study day will be
calculated as:
Study Day = Event date - start date of study drug + 1.
The first day of study drug is therefore study day 1.
For any assessment or events such as baseline disease characteristics or medical history (e.g.,
time since diagnosis of disease) occurring prior to the start of the study drug, study day will be
negative and will be calculated as:
Study Day = Event date - start date of study drug.
The study day will be displayed in the data listings.


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2.1.3.4
Time unit
A year length is defined as 365.25 days. A month length is 30.4375 days (365.25/12). If duration 
is reported in months, duration in days will be divided by 30.4375. If duration is reported in 
years, duration in days will be divided by 365.25.
2.1.3.5
Baseline
Baseline will be defined as the most recent non-missing value prior to the first dose of study 
treatment.  For laboratory data, baseline will be defined as the most recent non-missing value 
from a laboratory prior to the first dose of study treatment.
If subjects have no value as defined above, the baseline results will be considered missing.
2.1.3.6
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 subject’s 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 (including start and stop date)
3. post-treatment period: starting at day 31 after last administration of study treatment.
2.1.3.7
Last contact date
The last contact date will be derived for subjects not known to have died at the analysis cut-off 
using the last complete date among the following:
Table 2-1
Last contact date data sources
Source data
Conditions
Last contact date/last date subject was known to 
be alive from Survival Follow-up page 
Subject status is reported to be alive
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 (RECIST) assessment date
Evaluation is marked as ‘done’.
Laboratory/PK collection dates
Sample collection marked as ‘done’. 
Vital signs date
At least one non-missing parameter value
Performance Status date
Non-missing performance status


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Source data
Conditions
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 subject 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 subjects in the analysis of overall survival.
2.2
Analysis sets
2.2.1
Analysis Populations
Full Analysis Set
The Full Analysis Set (FAS) comprises all subjects to whom study treatment has been assigned 
and who received one dose of study treatment. 
Safety Set
The Safety Set includes all subjects who received any study treatment (i.e. at least one dose of 
any component of the study treatment). 
FAS and Safety set are the same in this study.
2.2.2
Withdrawal of Informed Consent
Any data collected in the clinical database after a subject withdraws informed consent from all 
further participation in the trial, will not be included in the analysis. The date on which a subject
withdraws full consent is recorded in the eCRF. 
Death events may be used in the analysis if captured from public records (registers), local law 
and subject informed consent permiting.
Additional data for which there is a separate informed consent, e.g. PK, biomarker etc., 
collected in the clinical database without having obtained that consent will not be included in 
the analysis. 
2.2.3
Subgroup of interest
Not applicable


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2.3
Patient disposition, demographics and other baseline 
characteristics
All demographic, other baseline disease characteristics and medical history data were
summarized and listed during primary analysis, and therefore will not be summarized in the 
final analysis. 
2.3.1
Patient disposition
Subject disposition information will be listed and summarized based on FAS. The number (%) 
of treated subjects included in the FAS will be presented. The number (%) of subjects in the 
FAS who discontinued the study and the reason for discontinuation will be presented by 
mainland Chinese and all subjects.
The following summaries will be provided (with % based on the total number of FAS subjects):

Number (%) of subjects who are still on-treatment (based on the both dabrafenib and 
trametinib ‘Study Treatment Discontinuation’ pages not completed) 

Number (%) of subjects who discontinued the study treatment phase (based on both 
dabrafenib and trametinib ‘Study Treatment Discontinuation’ pages) 

Primary reason for study treatment phase discontinuation (based on dabrafenib or
trametinib ‘Study Treatment Discontinuation’ pages)
In addition, the number (%) of subjects who have discontinued from the post-treatment follow-
up and the reasons for discontinuation from the post-treatment follow-up will be provided.
2.3.2
Protocol deviations
The number (%) of subjects in the FAS with protocol deviation will be tabulated by deviation 
category (as specified in the Protocol Deviation Management Plan) overall for the FAS. Major 
protocol deviations leading to exclusion from analysis sets will be tabulated separately by 
Mainland Chinese and all subjects. All the protocol deviations including the description will be 
listed.
The ongoing coronavirus disease 2019 (COVID-19) caused by severe acute respiratory 
syndrome coronavirus 2 (SARS-CoV-2) was first identified by the World Health Organization 
in Dec 2019. Since Mainland Chinese patients’ data from 01-Jul-2019 onwards are not included 
in the final analysis due to local regulations in China, and there were no COVID-19 related PDs 
for other patients, thus COVID-19 related PDs are not considered.
2.3.3
Analysis sets
The number (%) of subjects in each analysis set (defined in Section 2.2.1) will be summarized.


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2.4
Treatments (study treatment, rescue medication, concomitant 
therapies, compliance)
2.4.1
Study treatment / compliance
2.4.1.1
Duration of study drug/treatment exposure
Extent of exposure to dabrafenib and trametinib will be summarized separately (see the details 
of duration of exposure below).
The duration of exposure to study treatment in months (from first day to last day of treatment) 
will be summarized. Descriptive statistics including mean, median, standard deviation, 
minimum, and maximum will be calculated for duration of exposure to study treatment. 
Moreover, duration of exposure to study treatment will be categorized in different time period:  
< 3 months, 3 months to 6 months, >6 months to 12 months, >12 months to 24 months, >24 
months to 36 months and >36 months. 
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 last dates of exposure to investigational drug.
Duration of exposure by person time will be summarized by trametinib and dabrafenib. Person 
time of a specified group is defined as the total exposure time experienced by all subjects 
belonging to that specified group.
2.4.1.2
Cumulative dose
Cumulative dose for any component of study treatment (dabrafenib or trametinib) is defined as 
the total dose given during the study treatment exposure. 
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 investigational drug administration. 
The planned cumulative dose is not summarized/listed. It is 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 subjects who did not take any drug the cumulative dose is by definition equal to zero.
The subject daily dose, defined as the cumulative dose divided by the duration of exposure for 
each subject will be summarized. 
Subject 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. 
2.4.1.3
Dose intensity and relative dose intensity
The dose intensity (DI) and the relative dose intensity (RDI) for each study drug component
(dabrafenib or trametinib) will be summarized by descriptive statistics. In addition, categorical 


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summary of RDI for each study drug component will be presented: <=75%, >75-90%, >90-
110%, >110%.
Dose intensity (DI) for each study drug component in subjects with non-zero duration of 
exposure is defined as follows: 
DI (dosing unit / day) = Actual Cumulative dose (dosing unit) / Duration of exposure to study 
treatment (day).
DI (mg/day) = Actual Cumulative dose (mg) / Duration of exposure (day)
For subjects who did not take any drug the DI is by definition equal to zero. 
Planned dose intensity (PDI) is defined as follows:
PDI (dosing unit / day) = Planned Cumulative dose (dosing unit) / Duration of exposure (day).
Relative dose intensity (RDI) is defined as follows:
RDI = DI (dosing unit / day)  / PDI (dosing unit / day).  
DI and RDI will be summarized for each of the study treatment components.
The following tables provide the examples for the calculations, however, the final numbers 
should be based on the actual data, not from the following tables.
Table 2-2
Examples of dabrafenib dose administration and exposure
DAR 
record 
number
Start/End 
Date
Dose 
Prescribed 
(mg), 
frequency
Dose 
Administere
d (mg) 
[total daily]
Dose 
Changes, 
Dose 
Interruption
Dose 
Permanently 
Discontinued
Reason
1
01Jan2016 / 
05Jan2016
150 mg BID
300
No
No
2
06Jan2016 / 
03Feb2016
150 mg BID
200
Yes
No
AE
3
04Feb2016 / 
25Feb2016
150 mg BID
300
No
No
Duration of exposure (days) = 25Feb2016 – 01Jan2016 + 1 = 56 days
Planned cumulative dose (for 56 days) = 300*56 = 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) = 0.83


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Table 2-3
Examples of trametinib dose administration and exposure
DAR 
record 
number
Start/End 
Date
Dose 
Prescribed 
(mg), 
frequency
Dose 
Administere
d (mg) 
[total daily]
Dose 
Changes, 
Dose 
Interruption
Dose 
Permanently 
Discontinued
Reason
1
01Jan2016 / 
10Jan2016
2 QD
2
No
No
2
11Jan2016 / 
15Jan2016
2 QD
0
Yes
No
AE
3
16Jan2016 / 
25Feb2016
1 QD
1
No
No
AE
Duration of exposure = 25Feb2016 – 01Jan2016 + 1 = 56 days
Planned cumulative dose (for 56 days) = 2*56 = 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) = 0.54
2.4.1.4
Dose reductions, interruptions or permanent discontinuations
The number of subjects 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 Study Treatment 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: 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.
A listing of actual treatments will be produced.


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In addition, summaries of study treatment exposure and dose modifications (e.g. number of 
dose reductions, number of dose interruptions) will further characterize compliance. These 
analyses are described in Section 2.4.1
2.4.2
Prior, concomitant and post therapies
2.4.2.1
Prior anti-cancer therapy
The number and percentage of subjects who received any prior anti-neoplastic medications, 
prior anti-neoplastic radiotherapy or prior anti-neoplastic surgery was summarized in primary 
analysis and therefore will not be summarized in the final analysis. 
2.4.2.2
Post treatment anti-cancer therapy
Anti-neoplastic therapies since discontinuation of study treatment will be listed and summarized 
by ATC class, preferred term, overall and by means of frequency counts and percentages using 
FAS.
2.4.2.3
Concomitant medications
Concomitant therapy is defined as all interventions (therapeutic treatments and procedures) 
other than the study treatment administered to a subject 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 summarized. 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 included. The safety set will be used for all concomitant medication tables and 
listings.
2.5
Analysis of the primary objective
The primary objective is to demonstrate the antitumor activity of dabrafenib in combination 
with trametinib as measured by ORR 
in subjects with BRAF V600 mutation-positive 
melanoma.


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2.5.1
Primary endpoint
The primary endpoint, ORR is defined as the percentage of subjects, who have a confirmed 
complete response or a partial response based on RECIST 1.1 (Eisenhauer, 2009) and are 
evaluated by the investigtor, among all subjects who have been enrolled and received at least 
one dose of investigational product. Tumor assessments performed before the start of any 
further antineoplastic therapy (i.e. any additional secondary antineoplastic therapy or surgery) 
will be considered in the assessment of overall response. Confirmation assessments must be 
performed no less than four weeks (28 days) after the criteria for response have initially been 
met and may be performed at the next protocol scheduled assessment. If a confirmation 
assessment is performed prior to the next protocol schedule assessment, the next protocol 
scheduled evaluation is still required.
ORR is defined as the proportion of subjects with confirm response of complete response (CR) 
or partial response (PR) according to RECIST 1.1. ORR will be calculated based on the FAS 
using local investigators review of tumor assessment data. Subjects with only non-measurable 
disease at baseline will be part of the analysis and will be included in the numerator only if a 
complete response was observed.
2.5.2
Statistical hypothesis, model, and method of analysis
The study will pursue an estimation strategy rather than formal hypothesis testing. This is 
reasonable given the proven performance of the combination therapy and the desire to estimate 
the effect in the Asian population. Since estimation is the goal, there are no formal hypotheses 
to be tested. 95% confidence limits for objective response rate (ORR) will be calculated. The 
minimal effect to be excluded from the lower end of the confidence interval for ORR will be 
25%.
The primary objective was supported by the calculation of objective response rate using the 
FAS population.  The primary analysis of ORR was performed after all enrolled subjects have 
completed 16 weeks of treatment or have at least 2 tumor assessments or have otherwise 
discontinued study treatment. The final analysis of ORR will be performed after LPLV.
The final efficacy analysis ORR will be summarized using descriptive statistics (N, %) along 
with 2-sided exact 95% confidence interval (CI) [Clopper and Pearson 1934].
2.5.3
Handling of missing values/censoring/discontinuations
Subjects with unknown or missing response will be treated as non-responders, i.e. they will be 
included in the denominator when calculating the percentage. No imputation will be performed 
for missing lesion assessments or tumor response data.
Subjects with unknown or missing best overall response (BOR) will be counted as failures. If 
there is no baseline tumor assessment, all post-baseline overall lesion responses are expected 
to be ‘Unknown’. If no valid post-baseline tumor assessments are available, the best overall 
response must be “Unknown” unless progression is reported. For the computation of ORR, 
these subjects will be included in the FAS and will be counted as ‘failures’.


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2.5.4
Supportive analyses
Not applicable
2.6
Analysis of the key secondary objective
There is no key secondary objective in this study.
2.7
Analysis of secondary efficacy objective(s)
The other secondary efficacy objectives are to describe PFS, OS, and DOR.
2.7.1
Secondary endpoints
Progression-Free Survival (PFS)
PFS is defined as the time from the date of the first dose to the date of the first documented 
progression or death due to any cause. PFS will be based on local investigators review of tumor 
assessments and using RECIST 1.1 criteria. The analysis will be based on FAS and will include 
all data observed up-to the cut-off date. 
In the final analysis, PFS will be censored at the date of the last adequate tumor assessment if 
no PFS event is observed prior to the analysis cut-off date or before the start of the new 
anticancer therapy date or loss to follow up, whichever is earlier. (See Section 2.7.3 for 
additional details regarding censoring rules and determination of date of last adequate tumor 
assessment).  Discontinuation due to disease progression (collected on the ‘End of treatment’ 
and ‘End of post treatment follow up’ disposition pages) without supporting objective evidence 
satisfying progression criteria per RECIST 1.1 will not be considered disease progression for 
PFS derivation. Clinical deterioration will not be considered as a qualifying event for 
progression for the final analysis.
Overall Survival (OS)
Overall Survival (OS) is defined as the time from date of first dose to date of death due to any 
cause. A cut-off date will be established for each analysis of OS. All deaths occurring on or 
before the cut-off date in the FAS will be used in the OS analysis. 
If a subject is not known to have died at the time of analysis cut-off, OS will be censored at the
date of last contact (See Section 2.1.1.7 for additional details). The survival distribution of OS 
distribution will be estimated using the Kaplan-Meier method, and Kaplan-Meier curves, 
medians and 95% confidence intervals of the medians intervals.
Duration of Response (DOR)
Duration of response (DOR) only applies to subjects whose confirmed overall response is 
complete response (CR) or partial response (PR) according to RECIST 1.1 based on local 
investigators review of tumor assessment data. The start date is the date of first documented 
response of CR or PR (i.e., the start date of response, not the date when response was confirmed), 
and the end date is defined as the date of the first documented progression or death. Subjects 
continuing without progression or death due to underlying cancer will be censored at the date 
of their last adequate tumor assessment using the censoring rule described for PFS analysis (See 
Section 2.7.3 for additional details). 


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2.7.2
Statistical hypothesis, model, and method of analysis
Similar to the analysis of primary endpoint, there is no formal hypothesis testing. PFS, OS and 
DOR will be summarized descriptively using Kaplan-Meier medians and quartiles.  
Since there is a single primary endpoint (ORR), supported by secondary endpoints, the nominal 
level of significance for the primary analysis will not be affected by multiplicity.
PFS based on local investigators review of tumor assessments and using RECIST 1.1 criteria is 
a secondary endpoint in this trial and will be analyzed using the same conventions as that of the 
primary efficacy analysis. The distribution of PFS will be estimated using the Kaplan-Meier 
method. The median PFS along with 95% confidence intervals will be presented.
The survival distribution of OS distribution will be estimated using the Kaplan-Meier method, 
and Kaplan-Meier curves, medians and 95% confidence intervals[Brookmeyer and Crowley 
1982] of the medians intervals.
DOR will be listed and summarized for all subjects in the FAS with confirmed CR or PR. The 
distribution of duration of response will be estimated using the Kaplan-Meier method and the 
median duration of response will be presented along with 95% confidence interval only if a 
sufficient number of responses is observed.
2.7.3
Handling of missing values/censoring/discontinuations
For subjects who have not progressed or died at the time of the PFS or DOR analysis, censoring 
will be performed using the rules described in Table 2-4 or first dose for subjects without any 
adequate post baseline assessments. 
PFS will be censored at the last adequate tumor assessment if one of the following occurs: 
absence of event; the event occurred after two or more missing tumor assessments. The term 
“missing adequate tumor assessment” is defined as a tumor assessment (TA) not performed or 
tumor assessment with overall lesion response of “UNK”. The rule to determine number of 
missing TAs is based on the time interval between the date of last adequate tumor assessment 
and the date of an event. If the interval is greater than twice the protocol-specified interval 
between the TAs and 2 times the protocol-allowed time window around assessments, then the 
number of missing assessments will be 2 or more.
If there is no adequate baseline assessment, the subject will be censored at their date of the first 
dose. Subjects without any adequate post baseline tumor assessments will be censored at the 
date of the first dose. Subjects who progressed or died after an extended period without adequate 
assessment will be censored at their date of last adequate assessment prior to progression or 
death even if subsequent information is available regarding progression or death.  An adequate 
assessment is defined as an assessment where the investigator determined response is CR, PR, 
or SD.  The date of response at that assessment will be used for censoring. As the assessment 
schedule changes through the course of the protocol (i.e. every 8 weeks until week 56 and then 
every 12 weeks thereafter), the following rules will be used for identifying extended loss to 
follow up or extended time without an adequate assessment(i.e. two or more missed 
assessments) .

If death or PD  is on or prior to day 399 (week 56 + 7 day window), then a subject will be 
identified as an extended loss to follow up if the subject did not have an adequate 


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assessment during the time period of 119 days (16 weeks + 7 day window) prior to death 
or PD;

Else if death or PD is after day 399 (week 56 + 7 day window) and prior to day 567 (week 
80 + 7 day window), then a subject will be identified as an extended loss to follow up if 
the subject did not have an adequate assessment during the time period of 147 days (8 
weeks + 12 weeks + 7 day window) prior to death or PD.

Else if death or PD  is after day 567 (week 80 + 7 day window), then a subject will be 
identified as an extended loss to follow up if the subject did not have an adequate 
assessment during the time period of 175 days (24 weeks + 7 day window) prior to death 
or PD.
For subjects who receive subsequent anti-cancer therapy the following rules will apply:

If the start date of the anti-cancer therapy is partial (i.e. either missing the day but has the 
month and year available or missing both day and month), the imputation rules described 
in Section 5.1 will be applied. No imputation will be made for completely missing dates.

If anti-cancer therapy is started without documented disease progression or is started prior 
to documented disease progression, then PFS will be censored at the date of the last 
adequate assessment that is no later than the date of initiation of anti-cancer

therapy (i.e. if an assessment occurs on the same day as the start of new anti-cancer 
therapy the assessment will be used - as it will be assumed the assessment occurred prior 
to the administration of new anti-cancer therapy).  The date of response at the last 
adequate assessment will be used as the censoring date.

If a subject has only a baseline visit or does not have an adequate assessment that is no 
later than the date of initiation of anti-cancer therapy, PFS will be censored at the date of 
the first dose.
Refer to Table 2-4 for censoring and event date options and outcomes for PFS.
Table 2-3
Outcome and event/censor dates for PFS analysis
Situation
Date
Outcome
No baseline assessment
Date of the first dose
Censored
Progression or death at or 
before next scheduled 
Assessment
Date of progression (or 
death)
Progressed
Progression or death after 
exactly one missing assessment
Date of progression (or 
death)
Progressed
Progression or death after two or 
more missing assessments
Date of last adequate 
assessment prior to 
missed assessment 
Censored
No progression (or death)
Date of last adequate 
assessment 
Censored
Treatment discontinuation due to 
‘Disease progression’ without 
documented progression, i.e. 
Date of last adequate 
assessment 
Censored


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Situation
Date
Outcome
clinical progression based on 
investigator claim
New anticancer therapy given 
prior to protocol defined 
progression
Date of last adequate 
assessment on or prior to 
starting new anti-cancer 
therapy (or crossover 
treatment)
Censored
Death before first PD 
assessment (including death
at baseline or prior to any
adequate assessments)
Date of death
Progressed
Overall survival (OS)
If a subject 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 subject was alive, i.e., last contact date (see Table 2-1).
2.8
Safety analyses
All safety analyses will be based on the safety set. 
2.8.1
Adverse events (AEs)
An overview summary of AEs, including counts and percentages of subjects with any AE, AEs 
related to study treatment, AEs leading to permanent discontinuation of study treatment, AEs 
leading to dose reductions, AEs leading to dose interruptions, AEs requiring additional therapy, 
SAEs, SAEs related to study treatment, fatal SAEs, and fatal SAEs related to study treatment 
will be produced.
A summary of non-serious AEs that occurred in strictly 5% of the subjects or above will be 
provided (no rounding for the percentage will be used in terms of 5% threshold, e.g. event with 
4.9% incidence rate should not be included in this table). The summary will be displayed by 
SOC and PT. (for clinicaltrials.gov purpose)
AEs will be graded according to the CTCAE v4.0. Adverse events will be coded to the preferred 
term (PT) level using the Medical Dictionary for Regulatory Activities (MedDRA dictionary)
(MedDRA 23.0).
A summary of number and percentage of subjects with any AE by maximum grade will be 
produced. AEs will be sorted by Preferred term (PT) in descending order of incidence. The 
summary will use the following algorithms for counting the subject:

Preferred term row: Subjects experiencing the same AE preferred term several times 
with different grades will only be counted once with the maximum grade.

Any event row: Each subject with at least one adverse event will be counted only once at 
the maximum grade no matter how many events they have.
In addition, the number and percentage of AEs (all grades) will be summarized and displayed 
in two ways: 1) in descending order of incidence by PT only and 2) in descending order of 


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incidence by System Organ Classes (SOC) and PT. In the SOC row, the number of subjects 
with multiple events under the same system organ class will be counted once.  
A separate summary will be provided for study treatment-related AEs. A study treatment-
related AE is defined as an AE for which the investigator classifies the relationship to study 
treatment as “Yes”.  A worst case scenario approach will be taken to handle missing relatedness 
data, i.e. the summary table will include events with the relationship to study treatment as ‘Yes’ 
or missing. The summary table will be displayed in descending order of incidence by PT only.
All AEs will be listed.  Additionally, a listing of subject IDs for each individual AE will be 
produced.  
All SAEs will be tabulated based on the number and percentage of subjects who experienced 
the event.  A summary will also be provided for study treatment-related SAEs. The summary 
tables will be displayed in descending order of incidence by PT only.
A study treatment-related SAE is defined as an SAE for which the investigator classifies the 
relationship to study treatment as “Yes”.  A worst case scenario approach will be taken to handle 
missing data, i.e. the summary table will include events with the relationship to study treatment 
as ‘Yes’ or missing.  
SAEs are included in the listing of all adverse events. Separate supportive listings with subject-
level details will be generated for all SAEs and Fatal SAEs.
AE summaries will include all AEs occurring during on-treatment period. All AEs collected in 
the AE (e)CRF page will be listed along with the information collected on those AEs e.g. AE 
relationship to study drug, AE outcome etc. AEs with start date outside of on-treatment period 
will be flagged in the listings. 
AEs will be summarized by number and percentage of subjects having at least one AE, having 
at least one AE in each primary system organ class (SOC) and for each preferred term (PT)
using MedDRA coding. A subject with multiple occurrences of an AE will be counted only 
once in the respective AE category. A subject with multiple CTCAE grades for the same 
preferred term will be summarized under the maximum CTCAE grade recorded for the event.
AE with missing CTCAE grade will be included in the ‘All grades’ column of the summary 
tables.
In AE summaries, the primary system organ class 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 number of deaths resulting from SAEs suspected to be related to study treatment and SAEs 
irrespective of study treatment relationship will be provided by SOC and PT.
If the same subject has more than one AE (irrespective of study treatment causality, seriousness 
and severity) with the same SOC and PT:

a single occurrence will be counted if there is ≤ 1 day gap between the end date of the 
preceding AE and the start date of the consecutive AE

more than one occurrence will be counted if there is > 1 day gap between the end date of 
the preceding AE and the start date of the consecutive AE


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For legal requirements of clinicaltrials.gov (there is no requirement for EudraCT), the following 
two tables will be provided by system organ class and preferred term on the safety set population:

On-treatment adverse events which are not SAEs with an incidence greater than and equal 
to 5% 

On-treatment deaths and SAEs suspected to be related to study treatment 
2.8.1.1
Adverse events of special interest / grouping of AEs
An adverse event of special interest is a grouping of adverse events that are of scientific and 
medical concern specific to 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. 
A comprehensive list of MedDRA terms based on clinical review will be used to identify each 
type of events. 
All AE groupings for a clinical program are stored in the Compound Case Retrieval Strategy 
sheet (CRS) with clear versioning and reference to the MedDRA version used.
The events of special interest will be analysed using the most updated asset specific AESI 
(Adeverse Event of Special Interest) at the time of analaysis. 
For each specified AESI, number and percentage of subjects with at least one event of the AESI 
occurring during on treatment period will be summarized.
Summaries of these AESIs will be provided, (specifying grade, SAE, relationship, leading to 
treatment discontinuation, leading to dose adjustment/interruption, hospitalization, death, etc.).
If sufficient number of events occurred, analysis of time to first occurrence will be applied.
A listing of all grouping levels down to the MedDRA preferred terms used to define each AESI 
will be generated. 
2.8.2
Deaths
In the event that a subject has withdrawn consent, no data after the withdrawal of consent date 
from this subject including death is supposed to appear in the database, which should be part of 
the data cleaning process. 
All deaths occurring any time from the time of informed consent to the clinical cut-off date will 
be summarized based on the number and percentage of subjects. This summary will classify 
subjects by time of death relative to the last dose of medication (> 30 days or 30 days) and 
primary cause of death (disease under study, SAE related to study treatment, or other). A 
supportive listing will be generated to provide subject-specific details on subjects who died. 
Separate summaries for on-treatment and all deaths (including post-treatment death) will be 
produced by system organ class and preferred term. 
All deaths and deaths prior to starting treatment will be listed.


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2.8.3
Laboratory data
The assessment of laboratory toxicities will examine the following laboratory tests:
Hematology: Hemoglobin (HGB), White Blood Cell (WBC) count, Total Neutrophils, 
Lymphocyte, Monocyte, Basophil and Eosinophil counts, and Platelet count. Basophils, 
Eosinophils and Monocytes are not gradable by CTCAE v4.0.
Clinical Chemistry: Sodium, Potassium, Calcium, Glucose, Blood Urea Nitrogen (BUN), 
Creatinine, Estimated Creatinine Clearance, Albumin, Lactate Dehydrogenase (LDH), and 
phosphate. BUN, LDH and Estimated Creatinine Clearance are not gradable by CTCAE v4.0. 
For Sodium, Potassium, Calcium, Phosphate, Lymphocyte and Glucose two bi-directional 
parameters (hyper and hypo), the tests will be graded by CTCAE v4.0 in both directions. 
Liver Function Tests: Aspartate amino transferase (AST), Alanine amino transferase (ALT), 
Alkaline phosphatase, Total bilirubin (total) and Direct bilirubin. All these tests are gradable by 
CTCAE v4.0.
Coagulation Tests: Prothrombin time (PT) or International Normalized Ratio (INR), and 
partial thromboplastin time (PTT). These tests are collected only at baseline. Therefore these 
tests will not appear in any summaries of changes from baseline.
Summaries of worst case grade increase from baseline grade will be provided for all the lab 
tests that are gradable by CTCAE v4.0. These summaries will display the number and 
percentage of subjects with a maximum on-therapy grade increasing from their baseline grade. 
Any increase in grade from baseline will be summarized along with any increase to a maximum 
grade of 3 and any increase to a maximum grade of 4.  Missing baseline grade will be assumed 
as grade 0. In addition, the summary will include grade increase from baseline by scheduled 
visits. For laboratory tests that are graded for both low and high values, summaries will be done 
separately and labeled by direction, e.g., sodium will be summarized as hyponatremia and 
hypernatremia.
For lab tests that are not gradable by CTCAE v4.0, summaries of worst case changes from 
baseline with respect to normal range will be generated. Decreases to low, changes to normal 
or no changes from baseline, and increases to high will be summarized at each scheduled visit 
as well as for the worst case post baseline.  If a subject has a decrease to low and an increase to 
high during the same time interval, then the subject is counted in both the “Decrease to Low”
categories and the “Increase to High” categories. Flag the earliest worst-case normal range 
values per time point. The worst-case for normal range values is bi-directional (either High or 
Low or both). If subject has both High and Low values in same time point, then flag both the 
earliest High record and the earliest Low record. If subject does not have a High or a Low value 
during the time point, then flag the subject's earliest in-range value. For visit 
timepoints: Baseline records are always flagged. Pre-therapy records, imputed records, and 
unscheduled records are not eligible for flagging.
Separate summary tables for (hematology, chemistry and liver function) laboratory tests will be 
produced.
Unless otherwise specified, the denominator in percentage calculation at each scheduled visit 
will be based on the number of subjects with non-missing value at each particular visit. For 


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subjects with a history of chronic Hepatitis B and/or Hepatitis C, the following tests will be 
performed at Screening:

Viral hepatitis serology (HBs Antigen, HBc Antibody, HBs Antibody, HCV Antibody);

Hepatitis BDNA; and/or 

Hepatitis C RNA.
As it is anticipated that the number of subjects with a history of chronic Hepatitis B and/or 
Hepatitis C will be small these data will only be listed and not summarized.
Summaries of hepatobiliary laboratory events including possible hy’s law cases will be 
provided in addition to what has been described above.   
On analyzing laboratory, data from all sources central and local laboratories 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):

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.
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 function parameters 
Liver function parameters of interest are total bilirubin (TBL), ALT, AST and alkaline 
phosphatase (ALP). The number (%) of subjects 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

ALT or AST > 10xULN

ALT or AST > 20xULN

TBL > 2xULN

TBL > 3xULN

ALT or AST > 3xULN & TBL > 2xULN


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ALT or AST > 3xULN & TBL > 2xULN & ALP < 2xULN  (potential Hy’s law)   
Potential Hy’s Law events are defined as those subjects with concurrent occurrence of AST or 
ALT > 3xULN and TBL > 2xULN and ALP < 2xULN  in the same assessment sample during 
the on-treatment period. Further medical review has to be conducted to assess potential 
confounding factor such as, liver metastates, liver function at baseline etc.
2.8.4
Other safety data
2.8.4.1
ECG and cardiac imaging data
A summary of the number and percentage of subjects who had normal and abnormal (clinically 
significant and not clinically significant) ECG findings will be displayed by scheduled visits. 
The QT and QTcB values based on Bazett formula will be rounded to the integer and the values 
will be categorized into the following ranges: Grade 0 (≤450), Grade 1 (>450 and ≤480), Grade 
2 (>480 and ≤500), and Grade 3 (>500).  Summaries of grade increase will be provided.  These
summaries will display the number and percentage of subjects with any grade increase, increase 
to grade 2 and increase to grade 3  at each scheduled in the worst case post baseline only. 
The changes in QT and QTcB values will be categorized into the clinical concern ranges which 
are specific to changes in QT and QTcB: (>30 and ≤60) and (> 60) msec.  A summary of change 
in QTcB value will display the number and percentage of subjects with a change within each 
range at each scheduled assessment time and in the worst case post baseline. Worst case post 
baseline will include both scheduled and unscheduled visits. Subjects with missing baseline 
values will be excluded from this summary.
The summaries for the QTcB will use the collected value based on Bazett formula. In addition, 
ECG interval values will be also be summarized.  
Listings of abnormal ECG findings and a listing of ECG values will be provided.
LVEF Absolute change from baseline in LVEF will be summarized at each scheduled 
assessment time and in the worst case post baseline.  Only the post baseline assessments that 
used the same method (ECHO or MUGA) as the baseline assessments will be used to derive 
the change from baseline. The change from baseline will be categorized as follows:

Any increase

No change

Any decrease

>0 - < 10 Decrease

10 - 19 Decrease

>= 20 Decrease

≥10 decrease and ≥LLN

≥10 decrease and <LLN

≥20 decrease and ≥LLN

≥20 decrease and <LLN
LVEF results will also be listed with subject level details including absolute change from 
baseline.


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Note: If there is any change in the methodology used throughout the study compared to 
baseline, the post-baseline values for which the methodology differs from baseline will be 
discarded in the tables presenting comparisons to baseline.
Data handling
In case the study requires ECG replicates at any assessment, the average of the ECG parameters 
at that assessment should be used in the analyses.
Data analysis
12-lead ECGs including QT, QTcB, and RR intervals will be obtained local for each subject 
during the study. ECG data will be read and interpreted locally 
The number and percentage of subjects with notable ECG values will be presented. 

QT, QTcF, or QTcB

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 ≤ 60 =ms

Increase from Baseline of > 60 ms

RR

value < 600 ms

value  >= 600 ms
A listing of all ECG assessments will be produced and notable values will be flagged. A separate 
listing of only the subjects with notable ECG values may also be produced. In the listing, the 
assessments collected during the post-treatment period will be flagged.
2.8.4.2
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 2-5
below.


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Table 2-5
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.         
A listing of all vital sign assessments will be produced and notable values will be flagged. A 
separate listing of only the subjects with notable vital sign values may also be produced. In the 
listing, the assessments collected outside of on-treatment period will be flagged. 
2.8.4.3
Ophthalmic Examination
The ophthalmic examinations of tonometry will be listed.
2.8.4.4
Echocardiograms (ECHO)
Descriptive statistics of the left ventricular ejection fraction (LVEF) change and percent 
change from baseline to worst post-baseline value will be provided.
2.8.4.5
ECOG performance status
The ECOG PS scale (Table 2-6 will be used to assess physical health of subjects, ranging from 
0 (most active) to 5 (least active):
Table 2-4
ECOG Performance Scale
Score
Description
0
Fully active, able to carry on all pre-disease performance without restriction
1
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature, e.g., light house work, office work
2
Ambulatory and capable of all self-care but unable to carry out any work 
activities. Up and about more than  50% of waking hours
3
Capable of only limited self-care, confined to bed or chair more than 50% of 
waking hours




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4
Change to protocol specified analyses
Replace All Treated Subjects (ATS) to Full Analysis Set (FAS).
Mainland Chinese patients data from 01-Jul-2019 onwards are not included due to local 
regulations in China (lack of HGRAC approval).


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5
Appendix
5.1
Imputation rules
In general imputed partial dates will not be used to derive study day, duration (e.g. duration of 
adverse events), or relapse time variables. In addition, imputed dates are not used for deriving 
the last contact date in overall survival analysis dataset.
5.1.1
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 subject is considered as on-going:
The subject should be treated as on-going and the cut-off date should be used as the dose end
date. 
Scenario 2: If the dose end date is completely or partially missing and the EOT page is 
available:
Case 1: The dose end date is completely missing, and the EOT completion date is complete, 
then this latter date should be used.  
Case 2: Only Year(yyyy) of the dose end date is available and yyyy < the year of EOT date:  
Use Dec31yyyy
Case 3: Only Year(yyyy) of the dose end date is available and yyyy = the year of EOT date:
Use EOT date
Case 4: Both Year(yyyy) and Month (mm) are available for dose end date, and yyyy = the 
year of EOT date and mm < the month of  EOT date: 
Use last day of the Month (mm)
Case 5: 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 EOT date
For subject with missing exposure end dates at the time of data cutoff, the exposure end date 
will be imputed to the earliest of: the date of the data cutoff, the date of withdrawal from the 
study, or the death date. 
The imputed exposure end date will be used to calculate cumulative dose and exposure duration. 
The imputed exposure end date will be stored in the exposure analysis dataset and an exposure 
end date imputation flag variable will be derived indicating which exposure end date records 
are imputed. Imputed exposure end dates will also be stored on the study treatment end date 
variable.
For subjects who have missing end dates in their last exposure record because they are still on 
study treatment, the on-therapy indicator variables (time in relation to study treatment) are 
assigned to on-therapy for all records where the 'dataset'.'date' is after or on the study treatment 
start date. Missing exposure end date imputation will be applied to both study treatments
(dabrafenib and trametinib). The study treatment end date variable will hold the last date of 
exposure across both study treatments.


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All other cases should be considered as a data issue and the statistician should contact the data 
manager of the study.
After imputation, compare the imputed date with start date of treatment, if the imputed date is 
< start date of treatment:
Use the treatment start date
Subjects with missing start dates are to be considered missing for all study treatment component 
related calculations 
5.1.2
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
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  
Table 5-2
Imputation of end dates (AE, CM) 
Missing 
Element
Rule
(*=last treatment date plus 30 days provided it is 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* 

For post treatment period, no imputation will be done for completely 
missing dates
day, month

If partial end date contains year only, set end date = earliest of 
31DecYYYY or end date of the on-treatment period * 




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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.
5.2
AEs coding/grading
AEs will be graded according to the CTCAE v4.0. Adverse events will be coded to the preferred 
term (PT) level using the Medical Dictionary for Regulatory Activities (MedDRA 
dictionary)( MedDRA 23.0).
5.3
Laboratory parameters derivations
Grade categorization of lab values will be assigned programmatically as per NCI Common 
Terminology Criteria for Adverse Events (CTCAE) version 4.0. 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 4.0 at the time of analysis will be used. For laboratory 
tests where grades are not defined by CTCAE v4.0, results will be graded by the 
low/normal/high (or other project-specific ranges, if more suitable) 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]
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.


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CTC grades for the derived absolute WBC differential counts (neutrophils, lymphocytes) and 
corrected calcium will be assigned as described above for grading
5.4
Statistical models
5.4.1
Primary endpoint analysis
Overall response rate 
Responses will be summarized in terms of percentage rates with 95% CIs. An exact binomial 
confidence interval (implemented using SAS procedure FREQ with EXACT statement) will be 
calculated [Clopper and Pearson 1934] 
SAS procedure FREQ will be used to estimate the proportion of responders (binary outcome = 
1 or “Yes”), along with the associated 95% (=100 × (1 – two-sided alpha level)) two-sided 
Pearson-Clopper CI.
Overall response will be determined using only target, non-target, and new lesions, using the 
criteria specified in the protocol. 
Table 5-3
Evaluation of Overall Response for Subjects
Target
Lesions
Non-Target Lesions
New Lesions
Overall Response
CR
CR or NA
No
CR
CR
Non-CR/Non-PD or NE
No
PR
PR
Non-PD or NA or NE
No
PR
SD
Non-PD or NA or NE
No
SD
NE
Non-PD or NA or NE
No
NE
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD
Any
Any
Yes
PD
CR=complete response, PR = partial response, SD=stable disease, PD=progressive disease, NA= Not
applicable, and NE=Not Evaluable
Evaluation of Best Overall Response
The best overall response is the best response recorded from the start of the treatment until 
disease progression, death, or withdrawal of consent, whichever occurs first. Best overall 
response will be determined programmatically based on the investigator’s assessment of 
response at each time point.

To be assigned a status of SD, follow-up disease assessment must have met the SD criteria 
at least once after enrollment for a minimum of 49 days.

If the minimum time for SD is not met, best response will depend on the subsequent 
assessments. For example, if an assessment of PD follows the assessment of SD and SD 
does not meet the minimum time requirement, the best response will be PD. Alternatively, 
subjects lost to follow-up after an SD assessment not meeting the minimum time criteria 
will be considered NE.
Confirmation Criteria:


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
To be assigned a status of PR or CR, a confirmatory disease assessment should be 
performed no less than 4 weeks (28 days) after the criteria for response are first met.

Confirmed best overall response will be determined programmatically based on RECIST 
1.1.
5.4.2
Secondary endpoint analysis
Kaplan-Meier estimates
An estimate of the survival function in each drug combination 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 for each treatment drug combination 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.
Progression free survival will be using ONCTTE dataset and overall survival will be using 
ONCSURV dataset respectively.
5.5
Rule of exclusion criteria of analysis sets 
Not applicable
6
Reference
Eisenhauer EA, Therasse P, Bogaert J, et al. New response evaluation criteria in solid tumors: 
revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45(2):228-247.
Stein W, Yang J, Bates SE, Fojo T. Bevacizumab reduces growth rate constants of renal 
carcinomas: a novel algorithm suggests early discontinuation of bevacizumab resulted in a lack 
of survival advantage. Oncologist. 2008;13:1055-1062.
Wang Y, Sung, C, Dartois C, Ramchandani R, Booth BP, Rock E, et al. Elucidation of 
relationship between tumor size and survival in non-small cell lung cancer patients can aid early 
decision making in clinical drug development. Clin Pharmacol Ther. 2009;86:167-174.
Claret L, Girard P, Hoff PM, Van Cutsem E, Zuideveld KP, Jorga K, et al. Model-based 
prediction of phase III overall survival in colorectal cancer on the basis of phase II tumor 
dynamics. J Clin Oncol. 2009;27:4103-4108.
GlaxoSmithKline Document Number 2012N144949_00 Study ID BRF113220. Population 
Pharmacokinetics and Exposure-Response Analysis of Dabrafenib and Trametinib in 
Combination. Report Date 17-Dec-2012.
Clopper CJ and Pearson PS, The Use of Confidence or Fiducial Limits Illustrated in the Case 
of the Binomial, Biometrika, 1934, Vol. 26 (4) pp. 404-413


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Brookmeyer R and Crowley J (1982). A Confidence Interval for the Median Survival Time. 
Biometrics, 38, 29 - 41.

Prot_001.pdf: 
Clinical Development
GSK1120212+GSK2118436
Protocol 200104 / NCT02083354
An Open-Label, Multi-Center Study to Investigate the 
Objective Response Rate of Dabrafenib in Combination 
with Trametinib in Subjects with BRAF V600 Mutation-
Positive Melanoma
Document type
Amended Protocol Version
EUDRACT number
Not applicable
Version number
08 (Clean)
Development phase
IIA
Document status
Final
Release date
27-Nov-2019
Novartis internal 
reference number
CDRB436B2205
Property of Novartis
Confidential
May not be used, divulged, published, or otherwise disclosed
without the consent of Novartis


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Amended Protocol Version 08 (Clean)
Protocol No. CDRB436B2205/200104
Amendment 08 (27-Nov-2019)
Amendment rationale 
The primary purpose of this amendment is to align the dose modification section of the protocol
related to severe cutaneous adverse reaction(s) (SCAR(s)), as updated in the dabrafenib and 
trametinib Investigator’s Brochure (IB) Edition 11.
Change to the protocol
Please refer to section 12.8: Appendix 8: Protocol Amendment Changes.
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. 
Revision Chronology
GlaxoSmithKline
Document Number
Date
Version
2013N167722_00
2013-JUL-08
Original
2013N167722_01
2015-MAR-27
Amendment No. 1
Eligibility criterion was changed to permit both cutaneous melanoma and acral 
melanoma that is BRAF v600E/K mutation positive.  Additional updates to sections 
to align with current dose modification guidelines.
2013N167722_02
2015-SEP-17
Amendment No. 2
This is a country specific protocol amendment to specify the exclusion criteria xiii to 
reflect the comments from Korea regulatory authority to change “history of RVO” to 
“history and current RVO” in exclusion criteria xiii.
2013N167722_03
2016-MAR-04
Amendment No. 3
1. The study sample size is increased. 
2. Remove the two-stage Green-Dahlberg design and related interim analysis.
3. Addition of medical knowledge in melanoma.
4. Revision of some inclusion and exclusion criteria. 
5. Change in tumor biopsy schedule for 
purpose.
2013N167722_04
2016-OCT-25
Amendment No. 4
1. Addition of PK samples in Chinese patients only 
2. Revision of secondary objectives and endpoints in relation with the updated PK 
schedule


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Protocol No. CDRB436B2205/200104
3. Clarify the requirements for enrolment of patients with a history of Hepatitis B 
Virus (HBV), or Hepatitis C Virus (HCV) infection (exclusion criterion #  6 and 
Table 22).
4. Addition of the optional non-melanoma skin biopsy in Table 20.
5. Addition of contraception requirements in male participants.
2013N167722_05
2016-DEC-16
Amendment No. 5
1. Delete or replace references to GSK or its staff with that of Novartis/Novartis and 
its authorized agents.
2. Make administrative changes to align with Novartis processes and procedures.
This amendment is not applicable for China as sponsorship will not change in 
China until the end of the study.
2013N167722_06
2018-MAR-22
Amendment No.6
1. Revise contact details 
2. Remove duplicate sentence regarding population PK parameters in study 
endpoint section.
3. Correct a typo and a discrepancy in the Dose Modification Guidelines for 
Pyrexia.  
4. Clarify that the liver PK samples will stop being collected 8 weeks after last 
patient first treatment.
5. Change the required duration of contraception for male subjects.
6. A new reference added in sample size assumption.
7. Correct the typo in creatinine clearance calculation formula.
2013N167722_07
2019-FEB-15
Amendment No.7
1. Update the contraception method for female subjects.
2. Update the contraception duration after dabrafenib discontinuation
2013N167722_08
2019-NOV-27
Amendment No.8
1. Replace “vials” wording by “bottles” as study treatments are supplied in 
bottles, and not in vials. 
2. Align the dose modification section of the protocol related to severe 
cutaneous adverse reaction(s) (SCAR(s)), as updated in the dabrafenib and 
trametinib Investigator’s Brochure (IB) Edition 11.


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Amended Protocol Version 08 (Clean)
Protocol No. CDRB436B2205/200104
SPONSOR SIGNATORY
, 
Novartis Pharmaceuticals Corporation


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Amended Protocol Version 08 (Clean)
Protocol No. CDRB436B2205/200104
SPONSOR INFORMATION PAGE
Clinical Study Identifier:  Protocol 200104
Sponsor Contact Information:
Novartis Pharmaceuticals Corporation
In some countries, the clinical trial sponsor may be the local Novartis and its authorized 
agents. Where applicable, the details of the Sponsor and contact person will be provided to the 
relevant regulatory authority as part of the clinical trial submission.
Contact Information: 
PhD
Novartis Pharmaceuticals Corporation
 
USA
Telephone Number: 
Email: 
Contact Information:
Novartis Pharma AG
Switzerland
Telephone Number: 
Email:
If you have any questions regarding the protocol, please contact your local Novartis office.
Regulatory Agency Identifying Number(s):
Investigational New Drug (IND) Number


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Amended Protocol Version 08 (Clean)
Protocol No. CDRB436B2205/200104
Investigator PROTOCOL Agreement Page
For protocol number 200104
I confirm agreement to conduct the study in compliance with the protocol, as amended by this 
protocol amendment.
I acknowledge that I am responsible for overall study conduct. I agree to personally conduct 
or supervise the described study.
I agree to ensure that all associates, colleagues and employees assisting in the conduct of the 
study are informed about their obligations. Mechanisms are in place to ensure that site staff 
receives the appropriate information throughout the study. 
Investigator Name:  _____________________________
Investigator Signature
Date


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Protocol No. CDRB436B2205/200104
TABLE OF CONTENTS
Page
LIST OF ABBREVIATIONS ..................................................................................................12
PROTOCOL SUMMARY .......................................................................................................16
1
Introduction .......................................................................................................................20
1.1
Background............................................................................................................20
1.2
Current treatment options for melanoma...............................................................20
1.2.1
Dabrafenib.............................................................................................22
1.2.2
Trametinib.............................................................................................23
1.2.3
BRAF and MEK Inhibitors as Combination Therapy...........................24
1.2.3.1
Dabrafenib and Trametinib in Acral Lentiginous Melanoma...............26
1.3
Rationale................................................................................................................27
1.4
Benefit: Risk Assessment ......................................................................................27
1.4.1
Benefit Assessment ...............................................................................32
1.4.2
Overall Benefit: Risk Conclusion .........................................................32
2
OBJECTIVE(S) and endpoints..........................................................................................33
3
Study design ......................................................................................................................35
3.1
Study Design..........................................................................................................35
4
Subject selection and discontinuation/completion criteria................................................35
4.1
Subject Selection Criteria ......................................................................................35
4.1.1
Number of Subjects...............................................................................35
4.1.2
Inclusion Criteria...................................................................................35
4.1.3
Exclusion Criteria..................................................................................37
4.2
Permanent Discontinuation from Study Treatment and Study Completion 
Criteria...................................................................................................................39
4.2.1
Permanent Discontinuation from Study Treatment...............................39
4.2.2
Continuation of Study Treatment after Disease Progression ................40
4.2.3
Subject Completion Criteria..................................................................40
5
Study treatments ................................................................................................................41
5.1
Investigational Product and Other Study Treatment .............................................41
5.1.1
Dabrafenib (GSK2118436)...................................................................41
5.1.2
Trametinib (GSK1120212) ...................................................................41
5.2
Dosage and Administration ...................................................................................41
5.3
Handling and Storage of Study Treatments...........................................................42
5.4
Treatment Assignment...........................................................................................42
5.5
Blinding .................................................................................................................42
5.6
Product Accountability..........................................................................................42


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Protocol No. CDRB436B2205/200104
5.7
Treatment Compliance...........................................................................................42
5.8
Dose Modification Guidelines...............................................................................43
5.8.1
Dose Levels of dabrafenib and trametinib ............................................44
5.8.2
General Guidelines for Clinically Significant Toxicities......................45
5.8.3
Guidelines for Cardiovascular Adverse Events ....................................45
5.8.3.1
Left Ventricular Ejection Fraction (LVEF)...........................................45
5.8.3.2
Hypertension .........................................................................................46
5.8.3.2.1
Monitoring of Hypertension..................................................................47
5.8.3.2.2
Management of Hypertension...............................................................47
5.8.3.3
QT Prolongation....................................................................................48
5.8.4
Guidelines for Skin-related Adverse Events.........................................49
5.8.4.1
Rash.......................................................................................................49
5.8.4.2
Severe Cutaneous Adverse Reactions (SCARs) ...................................51
5.8.4.3
Guidelines for Hand-foot Skin Reactions (HFSR)................................52
5.8.4.4
Guidelines for cuSCC ...........................................................................53
5.8.5
Guidelines for Other Adverse Events of Special Interest .....................53
5.8.5.1
Guidelines for Pyrexia...........................................................................53
5.8.5.2
Guidelines for Diarrhea.........................................................................55
5.8.5.3
Guidelines for Renal Insufficiency .......................................................57
5.8.5.4
Guidelines for Visual Changes or Specified Ophthalmic Examination 
Findings
58
5.8.5.5
Guidelines for Pneumonitis...................................................................60
5.9
Monitoring, Interruption and Stopping Criteria for Hepatobiliary Events............62
5.9.1
Liver Chemistry Stopping Criteria........................................................62
5.9.1.1
Liver Event Follow-up Assessments.....................................................64
5.9.1.2
Liver Chemistry Monitoring Criteria....................................................65
5.9.1.3
Drug Restart/Rechallenge Following Liver Events that are Possibly 
Related to Study Treatment ..........................................................................................65
6
Concomitant Medications and Non-Drug Therapies.........................................................66
6.1
Permitted Medications and Non-drug Therapies...................................................66
6.2
Medications to be Used with Caution....................................................................67
6.3
Treatment after Discontinuation from both Study Treatments or Withdrawal 
from/Completion of the Study...............................................................................70
6.4
Treatment of Study Treatment Overdose ..............................................................70
7
Study Assessments and Procedures...................................................................................70
7.1
Critical Baseline Assessments...............................................................................77
7.1.1
Baseline Confirmation of BRAF V600 Mutation-positive 
Melanoma..............................................................................................77
7.1.2
Baseline Documentation of Target and Non-target Lesions.................77


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7.2
Efficacy..................................................................................................................78
7.2.1
Efficacy Endpoints................................................................................78
7.2.1.1
Primary Efficacy Endpoint....................................................................78
7.2.1.2
Secondary Efficacy Endpoints..............................................................78
7.2.2
Efficacy Assessments............................................................................78
7.2.2.1
Assessment Guidelines..........................................................................79
7.2.2.2
Follow-up Assessments for Subjects Permanently Discontinued from 
both Study Treatments..................................................................................................80
7.2.2.3
Assessment at Subject Completion.......................................................80
7.2.3
Guidelines for Evaluation of Disease....................................................81
7.2.3.1
Measurable and Non-measurable Definitions.......................................81
7.2.4
Response Criteria ..................................................................................81
7.2.4.1
Evaluation of Target Lesions ................................................................81
7.2.4.2
Evaluation of Non-target Lesions .........................................................82
7.2.4.3
New Lesions..........................................................................................83
7.2.4.4
Evaluation of Overall Response............................................................83
7.2.4.5
Evaluation of Best Overall Response....................................................84
7.3
Safety.....................................................................................................................84
7.3.1
Safety Endpoints ...................................................................................84
7.3.2
Adverse Events......................................................................................84
7.3.2.1
Definition of an AE...............................................................................84
7.3.2.2
Definition of an SAE.............................................................................85
7.3.3
Laboratory and Other Safety Assessment Abnormalities Reported 
as AEs and SAEs...................................................................................87
7.3.4
Cardiovascular Events...........................................................................87
7.3.5
Death Events .........................................................................................87
7.3.6
Disease-Related Events and/or Disease-Related Outcomes Not 
Qualifying as SAEs...............................................................................88
7.3.7
Pregnancy Testing, Prevention and Reporting......................................88
7.3.7.1
Pregnancy Testing and Prevention........................................................88
7.3.7.2
Pregnancy Reporting.............................................................................89
7.3.8
Time Period and Frequency of Detecting AEs and SAEs.....................90
7.3.9
Method of Detecting AEs and SAEs.....................................................91
7.3.10
Prompt Reporting of Serious Adverse Events and Other Events to 
Novartis.................................................................................................91
7.3.10.1
Regulatory Reporting Requirements for SAEs.....................................92
7.3.11
Other Safety Outcomes .........................................................................93
7.3.12
Ophthalmic Examination ......................................................................94
7.3.13
Vital Signs.............................................................................................95


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7.3.14
Physical Examinations ..........................................................................95
7.3.14.1
Dermatological Exams..........................................................................95
7.3.15
Electrocardiograms (ECG)....................................................................95
7.3.16
Echocardiograms (ECHO) ....................................................................96
96
96
96
96
96
97
7.5
Pharmacokinetics...................................................................................................97
7.5.1
Blood Sample Collection ......................................................................97
7.5.2
Sample Analysis....................................................................................97
8
Data management ..............................................................................................................98
9
Data Analysis and Statistical Considerations....................................................................98
9.1
Hypotheses.............................................................................................................98
9.2
Study Design Considerations.................................................................................98
9.2.1
Sample Size Assumptions.....................................................................98
9.2.2
Sample Size Sensitivity.........................................................................98
9.2.3
Sample Size Re-estimation ...................................................................98
9.3
Data Analysis Considerations................................................................................98
9.3.1
Analysis Populations.............................................................................99
9.3.2
Analysis Data Sets.................................................................................99
9.3.3
Treatment Comparisons ........................................................................99
9.3.3.1
Primary Comparisons of Interest ..........................................................99
9.3.3.2
Other Comparisons of Interest ..............................................................99
9.3.4
Interim Analysis....................................................................................99
9.3.5
Key Elements of Analysis Plan.............................................................99
9.3.5.1
Efficacy Analyses................................................................................100
9.3.5.1.1
Primary Efficacy Analyses..................................................................100
9.3.5.1.2
Secondary Efficacy Analyses..............................................................100
9.3.5.2
Safety Analyses...................................................................................101
9.3.5.2.1
Extent of Exposure..............................................................................101
9.3.5.2.2
Adverse Events....................................................................................101
9.3.5.2.3
Clinical Laboratory Evaluations .........................................................101
9.3.5.2.4
Other Safety Measures ........................................................................101
9.3.5.3
Pharmacokinetic Analyses ..................................................................102


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9.3.5.4
Pharmacokinetic/Pharmacodynamic Analysis....................................102
103
103
10 Study CONDUCT CONSIDERATIONS........................................................................103
10.1
Posting of Information on Publicly Available Clinical Trial Registers...............103
10.2
Regulatory and Ethical Considerations, Including the Informed Consent 
Process .................................................................................................................103
10.3
Quality Control (Study Monitoring)....................................................................104
10.4
Quality Assurance................................................................................................104
10.5
Study and Site Closure.........................................................................................104
10.6
Records Retention................................................................................................106
10.7
Provision of Study Results to Investigators, Posting of Information on 
Publicly Available Clinical Trials Registers and Publication..............................106
11 References .......................................................................................................................107
12 Appendices ......................................................................................................................111
.111
12.2
Appendix 2: Cockcroft-Gault ..............................................................................116
12.3
Appendix 3: QT interval on electrocardiogram corrected using the 
Bazett’s formula (QTcB)...................................................................................117
12.4
Appendix 4: New York Heart Association (NYHA) Guidelines ........................118
12.5
Appendix 5: Country Specific Requirements......................................................119
12.6
Appendix 6: Liver Chemistry Monitoring, Interruption, Stopping and Follow-
up Criteria............................................................................................................120
12.7
Appendix 7: Liver Safety Drug Restart or Rechallenge Guidelines....................121
12.8
Appendix 8: Protocol Amendment Changes .......................................................126


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LIST OF ABBREVIATIONS
150/2
Dabrafenib 150 mg BID + trametinib 2 mg QD
ADME
Absorption, Distribution, Metabolism and Excretion
AE
Adverse event(s)
ALT
Alanine transaminase (SGPT)
ALM
Acral lentiginous melanoma
ANC
Absolute neutrophil count
AST
Aspartate aminotransferase (SGOT)
ATP
Adenosine triphosphate
ATS
All treated subjects
AUC
Area under the concentration-time curve
AUC (0-t)
Area under the concentration-time curve from time zero (pre-dose) 
to last time of quantifiable concentration within a subject across all 
treatments
BAL
Bronchoalveolar lavage
BCC
Basal Cell Carcinoma
BID
Twice daily
BP
Blood pressure
BRAT
Banana, rice, apples, toast
BUN
Blood urea nitrogen
CDK
Cyclin dependent kinase
CHF
Congestive heart failure
CI
Confidence interval
CL/F
Clearance following oral dosing
Cmax
Maximum peak concentration
CNS
Central nervous system
CPK
Creatine phosphokinase
CPMS
Clinical Pharmacology Modeling & Simulation
CR
Complete response
CrCl
Creatinine clearance
CRO
Clinical Research Organisation
CRP
C-reactive protein
CSR
Central serous retinopathy
CT
Computed tomography
Ctrough
Trough concentration
CTCAE
Common Terminology Criteria for Adverse Events 
CTLA
Cytotoxic T-lymphocyte antigen
cuSCC
Cutaneous Squamous Cell Carcinoma
CYP
Cytochrome P450
DBP
Diastolic blood pressure
DMSO
Dimethyl sulfoxide


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DNA
Deoxyribonucleic acid
DRESS
Drug Reaction with Eosinophilia and Systemic Symptoms
DTIC
Dacarbazine
ECG
Electrocardiogram
ECHO
Echocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
Electronic case report form
EDTA
Ethylenediaminetetraacetic acid
FDA
Food and Drug Administration
FDG-PET
Fluorodeoxyglucose positron emission tomography
FFPE
Formalin-fixed, paraffin-embedded
EGFR
Epidermal growth factor receptor
FSH
Follicle-stimulating hormone
GCP
Good Clinical Practice
GGT
Gamma-glutamyl transpeptidase
GI
Gastro-intestinal
GSK
GlaxoSmithKline
G6PD
Glucose-6-phosphate dehydrogenase
HBV
Hepatitis B virus
HCG
Human chorionic gonadotropin
HCV
Hepatitis C virus
HFSR
Hand-foot skin reaction
Hg
Mercury
HGF
Hepatocyte growth factor
HIV
Human immunodeficiency virus
HLA
Human leukocyte antigen
HMG-CoA 
3-hydroxy-3-methylglutaryl-coenzyme A
HPMC
Hydroxypropyl methylcellulose
HR
Hazard ratio
HRT
Hormone-replacement therapy
IB
Investigator’s Brochure
ICH
International Council for Harmonization
IDSL
International data standards library
IEC
Independent Ethics Committee
IL2
Interleukin-2
IND
Investigational New Drug
INR
International normalized ratio
IRB
Institutional Review Board
IRC
Independent review committee
IUO
Investigational use only 
LDH
Lactate dehydrogenase
LLN
Lower limit of normal


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LSLV
Last subject’s last visit
LVEF
Left ventricular ejection fraction
MAP
My Access Program
MAPK
Mitogen-activated protein kinases
MedDRA
Medical Dictionary for Regulatory Activities
mm
Millimeter(s)
MRI
Magnetic resonance imaging
MSDS
Material Safety Data Sheet
NA
Not applicable
NCI
National Cancer Institute 
NE
Not evaluable
NED
No evidence of disease
NSAIDS
Non-steroidal anti-inflammatory drugs
NYHA
New York Heart Association
ORR
Objective response rate
OS
Overall survival
PCR
Polymerase chain reaction
PD
Progressive disease
PFS
Progression-free survival
PK
Pharmacokinetics
PPES
Palmar-plantar erythrodysesthesia
PR
Partial response
PT
Prothrombin time
PTS
Platform technology and science
PTT
Partial thromboplastin time
QTc
Corrected QT interval on electrocardiogram
QTcB
QT interval on electrocardiogram corrected using Bazett’s formula
QTcF
QT interval on electrocardiogram corrected using Fridericia’s 
formula
SCARs
Severe Cutaneous Adverse Reactions
SAP
Statistical Analysis Plan
RECIST
Response Evaluation Criteria In Solid Tumors
RNA
Ribonucleic acid
RPED
Retinal pigment epithelial detachment
RVO
Retinal vein occlusion
SAE
Serious adverse event(s)
SBP
Systolic blood pressure
SCC
Squamous cell carcinoma
SD
Stable disease
SGOT
Serum glutamic oxaloacetic transaminase (AST)
SGPT
Serum glutamic pyruvic transaminase (ALT)


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SLD
Sum of longest diameters
SNPs
Single nucleotide polymorphisms 
SPD
Sum of the products of the two largest perpendicular diameters
SPF
Skin protection factor
SPM
Study Procedures Manual
tmax
Time to Cmax
ULN
Upper limit of normal
UP
Upper Providence
US/USA
United States
V/F
Volume of distribution
WBC
White blood cell
XRT
Radiation therapy 


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PROTOCOL SUMMARY
Rationale
Cutaneous melanoma is the most aggressive form of all skin cancers. Historically, the median 
survival time for subjects with Stage IV melanoma has been approximately 6 months and a 
median time to progression-free survival (PFS) at 1.7 months [Korn EL, 2008].  
Dependence on MAPK signaling is a key feature of BRAF V600 mutant melanoma, as 
demonstrated by the clinical efficacy of vemurafenib, dabrafenib, and trametinib Phase III 
results [Chapman PB, 2011; Hauschild A 2012; Flaherty KT, 2012b].  While monotherapy 
with MAPK inhibitors represents a significant advance in the treatment of BRAF V600 
mutation-positive, unresectable or metastatic melanoma, approximately half of patients treated 
with a BRAF or MEK inhibitor as monotherapy will develop resistance and progress within 5 
to 7 months of starting treatment [Sosman JA, 2012; Hauschild A, 2012; Flaherty KT, 2012a]. 
Concomitant inhibition of BRAF and MEK may lead to greater response rates, provide more 
durable responses, and increase progression free survival and overall survival.  Furthermore, 
hyperproliferative skin lesions, including cuSCC and keratoacanthoma, have been associated 
with paradoxical activation of the MAPK pathway by BRAF inhibition.  
Much has changed in the treatment landscape of melanoma since the past 5 years.  The 
immunotherapy as anti-cancer treatment in melanoma has significantly advanced. Ipilimumab, 
a monoclonal antibody that blocks cytotoxic T-lymphocyte antigen or CTLA-4, was approved 
by the US-Food and Drug Administration (FDA) for unresectable or metastatic melanoma in 
2011.  2 immune check-point therapy, Programmed Death (PD) receptor-1 antibody 
(pembrolizumab and nivolumab) were also approved in 2014 for the treatment of metastatic 
melanoma following the standard treatment.  The combination of ipilumumab and nivolumab 
also received FDA approval as first line treatment for metastatic melanoma in September, 
2015 for BRAF wild-type patients, and extended to BRAF mutation patients in January2016. 
However these medicines are not readily accessible in some countries, such as China.
The selective small molecule BRAF kinase inhibitor demonstrated significant clinical benefit 
as monotherapy in metastatic melanoma patients with V600 mutation. However the efficacy 
of BRAF inhibitor was not durable. In addition, BRAF-inhibitor induced paradoxical 
activation of the MAPK pathway which is associated to proliferative reaction of cells with 
wild type BRAF. Clinically this was reflected as increase hyperproliferative skin lesions 
including cutaneous squamous cancer. 
Single agent MEK inhibitor trametinib has proved to improve survival in metastatic 
melanoma with BRAF mutation and not associated with paradoxical activation of MAPK
pathway [Flaherty KT, 2012b July].
Combination of MEK and BRAF inhibitor was tolerable and delayed the emergence of 
resistance and decreased the incidence of cutaneous hyperproliferation. This was initially 
observed in a phase I/II study (BRF113220, Flaherty KT 2012a ) and later confirmed by 3 
randomized phase III studies. Long and colleagues reported the result of COMBI-D study. In 
this study, combination treatment of MEK and BRAF inhibitor (dabrafenib and trametinib) 
compared with BRAF inhibitor (dabrafenib) alone, significantly improved progression free 
survival in previously untreated patients who had metastatic melanoma with BRAF V600E or 


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V600 K mutations [Long GV 2014]. Another phase III study in the similar population 
reported same result using a different combination of MEK and BRAF inhibitor (cobimetinib 
and vermurafenib) [Larkin J,2014]. Additionally, a third phase III study was published, which 
demonstrated the combination of trametinib and dabrafenib significantly improved overall 
survival compared with vemurafenib in metastatic melanoma with BRAF V600 mutation 
[Robert C 2015]. 
In United States, Australia, Canada and most other countries, dabrafenib in combination with 
trametinib has been approved to treat metastatic melanoma with BRAF V600 mutation and 
had become a standard treatment for these patients. The above mentioned randomize phase III 
studies were mainly conducted in Caucasian population. The efficacy and safety of trametinib 
plus dabrafenib need to be evaluated in Asian melanoma patients. Patients in countries where 
this combination is not yet approved, such as China, are still in urgent unmet medical need for 
the new treatment. 
Acral lentiginous melanoma (ALM) is one of 4 major histological subtypes of cutaneous 
melanoma.  It is characterized by lesions presenting on non-hair bearing skin including the 
palm, soles, and nail beds. Although ALM accounts for only 2% to 3% of all melanomas, 
ALM makes up a much higher proportion (40-50%) of cutaneous malignant melanomas in 
darker-skinned individuals (i.e., blacks, Asians, and Hispanics) [Bradford PT 2009]. BRAF 
V600 mutations are less frequent (25 – 30%) in acral melanoma not associated with chronic 
sun-damage.  In contrast, c-Kit mutations are more common in mucosal (39%) and acral 
melanomas (36%), which can also be accompanied by an increase in c-Kit copy numbers 
[Curtin JA 2006]. Very few patients with ALM have been treated with dabrafenib and 
trametinib combination since the vast majority subjects enrolled were Caucasians. 
The original objective of the study was to evaluate the effect of dabrafenib and trametinib in 
patients with ALM in Asian countries.  In light of the most recent advances in the treatment of 
BRAF mutation cutaneous melanoma, the study aims to evaluate the efficacy and safety of 
dabrafenib and trametinib in Asian subjects with either acral lentiginous or cutaneous 
melanoma pathology subtypes who have BRAF V600 mutation. This study will provide 
important scientific information to help to address the unmet medical needs in Asian 
melanoma patients.  
Objective(s)
Primary Objective

To determine the objective response rate (ORR) of dabrafenib and trametinib combination 
in subjects with BRAF V600 mutation-positive, unresectable or metastatic acral 
lentiginous or cutaneous melanoma.  
Secondary Objectives

To further evaluate the antitumor activity [progression free survival (PFS), duration of 
response, and overall survival (OS)] 

To assess exposure to dabrafenib, dabrafenib metabolites, and trametinib after a single 
dose (Chinese patients) and at steady-state and characterize the population 
pharmacokinetics (PK) and pharmacodynamics (PD) of dabrafenib and trametinib


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
To evaluate the safety and tolerability of dabrafenib and trametinib combination therapy.
Study Design
This is a single-arm, open-label, multi-center, Phase II study to evaluate dabrafenib and 
trametinib combination therapy in BRAF V600 mutant unresectable or metastatic ALM or 
cutaneous melanoma. Subjects with histologically confirmed acral lentiginous or cutaneous 
melanoma that is either Stage IIIC (unresectable) or Stage IV will be screened for eligibility. 
Screening will include central testing of BRAF V600 mutation status. Eligible subjects must 
be BRAF V600 mutation positive.  Subjects may have had prior systemic anti-cancer 
treatment in the adjuvant or metastatic setting, but should not have been exposed to MEK or 
BRAF inhibitor.  Objective response rate will be assessed based on RECIST 1.1.  
Approximately 65 subjects will be enrolled and will receive dabrafenib 150 mg orally twice 
daily and trametinib 2 mg orally once daily. 
Treatment will continue until disease progression, death, unacceptable toxicity, or withdrawal 
of consent, or study completion. After treatment discontinuation, subjects will be followed for 
survival and disease progression as applicable.
Survival and new anti-cancer therapy follow-up will continue until study completion. The 
study completion is defined as:

In case all subjects stop study treatment within 48 weeks after Last Subject First 
Visit(LSFV): the study is completed once the last subject has completed the 48 weeks 
survival follow-up or all subjects die or loss to follow-up, whichever comes first. 

In case some subjects are still on study treatment 48 weeks after LSFV: the study is 
completed once all subjects stop study medication, or all subjects who are still on study 
medication can have access to alternative supply of MEK/BRAF inhibitors, whichever 
comes first.  
Doses of study treatment may be modified and/or interrupted for management of toxicities 
associated with study treatment.


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Study Endpoints/Assessments
The primary endpoint for the study is ORR as determined by investigator assessment as 
evaluated by the Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1. 
Duration of response, PFS, and OS endpoints will also be determined based on the 
investigator’s assessment.  
Safety Endpoints
Safety will be evaluated by clinical assessments including vital signs and physical 
examinations, 12-lead electrocardiograms (ECG), echocardiograms (ECHO), eye exams, 
chemistry and hematology laboratory values, and adverse events (AEs).
Pharmacokinetic Endpoints
Noncompartmental PK parameters will include:  
Trametinib, dabrafenib and dabrafenib metabolites Cmax, tmax, Ctrough, AUC(0-t), and 
AUC(0-8); AUC(0-12) (dabrafenib and dabrafenib metabolites only), AUC (0-24) (trametinib 
only) and the dabrafenib metabolite to dabrafenib ratio of AUC(0-12). For Chinese patients, 
the accumulation ratio will be calculated by using the pharmacokinetic parameters from Day 1 
and Day 15. Population PK parameters will include: apparent clearance following oral dosing 
(CL/F), volume of distribution (V/F), and absorption rate constant (Ka) for dabrafenib and 
trametinib.
 
 
 
 


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1
Introduction
1.1
Background
The RAS/RAF/MEK/ERK pathway (i.e., the MAP kinase pathway, Figure 1) is a critical 
proliferation pathway in many human cancers, including melanoma.  Oncogenic mutations in 
both RAS and BRAF signal through MEK1 and MEK2 and this is an early event.  Enzymes in 
this pathway, particularly BRAF and MEK, are therefore attractive anti-cancer targets.  BRAF 
mutations have been identified at a high frequency in specific cancers, including 
approximately 40% to 60% of melanoma [Davies H, 2002].  Cutaneous melanoma is the most 
aggressive form of all skin cancers, with approximately 232,000 new cases and approximately 
55,000 disease-related deaths worldwide each year [GLOBOCAN, 2012]. This study will 
evaluate the combination of two, small-molecule, oral agents, dabrafenib and trametinib in 
ALM or cutaneous melanoma.
Figure 1
The RAS/RAF/MAP (Erk1/2) Signal Transduction Pathway
1.2
Current treatment options for melanoma
Due to early detection, a majority of melanoma patients with early-stage localized disease are 
cured with surgery alone. In contrast, those with unresectable or metastatic melanoma have a 
poor prognosis.  Historically, the median survival time for subjects with Stage IV melanoma 
has been approximately 6 months with 26% of subjects alive at 1-year, and a median time to 
progression-free survival (PFS) at 1.7 months with 14.5% of subjects progression-free at 
6 months [Korn EL, 2008].  With a median age at first diagnosis of 59 years, advanced and 
metastatic melanoma ranks second only to acute leukemia in terms of loss of years of 
potential life per death [NCCN, 2014].. Although, combination therapies of chemotherapeutic 
agents and cytokines such as interferon-alpha and interleukin-2 have resulted in an increase of 
Dabra
Trame


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response rates, the overall survival (OS) of patients with unresectable melanoma has so far not 
been improved [Hodi FS 2010]. 
Since 2010, the therapeutic landscape of melanoma has rapidly changed with the regulatory 
approval of 3 targeted, small molecules (vemurafenib, dabrafenib, and trametinib), and 3 
immunomodulators (ipilimumab, pembrolizumab, and nivolumab).
Dependence on MAPK signaling is a key feature of BRAF V600 mutant melanoma, as 
demonstrated by the clinical efficacy of vemurafenib, dabrafenib, and trametinib Phase III 
results [Chapman PB, 2011; Hauschild A 2012; Flaherty KT, 2012a].  While monotherapy 
with MAPK inhibitors represents a significant advance in the treatment of BRAF V600 
mutation-positive, unresectable or metastatic melanoma, approximately half of patients treated 
with a BRAF or MEK inhibitor as monotherapy will develop resistance and progress within 5 
to 7 months of starting treatment [Sosman JA, 2012; Hauschild A, 2012; Flaherty KT, 2012b], 
therefore there is an unmet medical need for  treatments that overcome or delay resistance and 
that improve survival. 
Since both BRAF and MEK are in the MAPK pathway, and MEK is a substrate of activated 
BRAF, greater inhibition of the MAPK pathway may be achieved with the combination of 
BRAF and MEK inhibitors.  Concomitant inhibition of BRAF and MEK may lead to greater 
response rates, provide more durable responses, and increase progression free survival and 
overall survival.  Furthermore, hyperproliferative skin lesions, including cuSCC and 
keratoacanthoma, have been associated with paradoxical activation of the MAPK pathway by 
BRAF inhibition.  Combining a MEK and BRAF inhibitor may attenuate these BRAF 
inhibitor-mediated hyperproliferative skin toxicities, thereby enhancing the benefit:risk ratio 
for the combination compared to BRAF inhibitor monotherapy.
The rationale to combine a MEK and BRAF inhibitor is supported by non-clinical and clinical 
data as outlined below:
Enhanced inhibition of the MAPK pathway can be achieved by the combination of 
dabrafenib and trametinib, which predicts a greater response to therapy.  In vitro data 
demonstrate that the combination of dabrafenib and trametinib is either additive or synergistic 
in 15 BRAF inhibitor-sensitive cell lines [GlaxoSmithKline Document Number 
2011N116395_00].  
Concomitant inhibition of BRAF and MEK may prevent or delay resistance that arises 
through reactivation of the MAPK pathway.  MAPK reactivation, or MAPK-dependent 
resistance, is the most common type of BRAF-inhibitor resistance. Importantly, MAPK 
reactivation predicts sensitivity to MEK inhibition Several mechanisms mediating resistance 
to BRAF inhibitors through MAPK pathway reactivation have been described, including the 
up-regulation of bypass pathways mediated by cancer Osaka thyroid (COT)-kinases 
[Johannessen CM, 2010], development of de novo NRAS or MEK mutations [Nazarian R
2010; Emery CM, 2009; Greger JG, 2012; Shi H, 2012 (b)], amplification of BRAF V600 
[Shi H, 2012 (a)], and dimerization of variant splicing of mutant BRAF V600 [Poulikakos PI, 
2011].  In preclinical studies, combining a BRAF inhibitor and a MEK inhibitor blocked the 
rebound pERK signaling in BRAF mutant melanoma cells and enhanced cell death [Paraiso 
KH, 2010]. Non-clinical data have also shown that the combination is more effective in 
BRAF inhibitor-sensitive BRAF mutant melanoma cell lines than in BRAF mutant melanoma 
cell lines that had acquired resistance to dabrafenib [GlaxoSmithKline Document Number 


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2011N116395_00].  Finally, the combination of dabrafenib and trametinib demonstrated 
prolonged tumor growth inhibition and delayed tumor outgrowth when compared to treatment 
with the single agents in mouse melanoma xenograft studies.  
The addition of a MEK inhibitor to BRAF inhibitor therapy may decrease the frequency 
of secondary cuSCC and other hyperproliferative skin lesions caused by BRAF 
monotherapy.  Hyperproliferative skin lesions, including cuSCC, have been associated with 
paradoxical activation of the MAPK pathway in BRAF wild type cells with pre-existing RAS 
mutations in the presence of a BRAF inhibitor. The addition of a MEK inhibitor could 
potentially block the paradoxical activation, thereby attenuating the frequency of 
hyperproliferative skin lesions. [Su F, 2012].  
Overall, these data demonstrate that concomitant and more complete inhibition of the MAPK 
pathway at the level of the BRAF- and MEK -kinases could provide greater anti-tumor effect 
than administration of either monotherapy alone.
Based on the aforementioned hypothesis, the combination of BRAF and MEK inhibition, as 
compared with single-agent BRAF inhibition, was tested and demonstrated a delay of the 
emergence of resistance and decreased the incidence of cutaneous hyperproliferation.  Long 
and colleagues reported the result of a randomized double blind phase III study which 
compared trametinib plus dabrafenib versus dabrafenib alone in metastatic melanoma patient 
who had BRAF V600 E or K mutation. The combined treatment significantly improved PFS 
(mPFS: 9.3 vs 8.8 months, HR=0.75, p=0.03), response rate (67% vs 51%, p=0.0002). At 6 
months, the interim survival analysis also showed a improvement of survival (HR=0.63, 
p=0.02). The patients who received combined treatment experienced more frequent pyrexia, 
chill, diarrhea, hypertension, vomiting, peripheral edema, elevated liver enzyme, decreased 
left ventricular ejection fraction (LVEF), dermatitis acneiform,  but less frequent cutaneous 
squamous-cell carcinoma, hyperkeratosis, skin papilloma, hand-foot syndrome, dry skin, 
pruritus and alopecia.[Long GV 2014] Similar efficacy results were confirmed by 2 
independent randomized studies using trametinib plus dabrafenib versus vemurafenib [Robert 
C 2015] and  cobimetinib plus vemurafenib versus vemurafenib [Larkin J 2014].  
The AE profile of dabrafenib and trametinib given in combination was acceptable and was 
manageable with dose modifications and supportive care.
As of March, 2015, in United States, Australia, Canada and a few other countries, dabrafenib 
in combination with trametinib has been approved to treat metastatic melanoma with BRAF 
V600 mutation. 
1.2.1
Dabrafenib
Dabrafenib (GSK2118436), a 4-(3-aminosulfonylphenyl)-5-(pyrimidin-3-yl) thiazole, is a 
potent and selective inhibitor of B-RAF kinase activity with a mode of action consistent with 
adenosine triphosphate (ATP)-competitive inhibition. Dabrafenib has already demonstrated 
substantial clinical activity with an acceptable safety profile in Phase I, II and III studies  and 
was approved in May 2013 by the US FDA in patients with unresectable or metastatic 
melanoma in adult patients with the BRAF V600E mutation. In the pivotal Phase III trial 
BRF113683 (BREAK-3), 250 subjects were randomly assigned to receive either dabrafenib 
(187 subjects) or dacarbazine (63 subjects). Median PFS was 5.1 months for dabrafenib and 
2.7 months for dacarbazine, with a hazard ratio (HR) of 0.30 (95% CI 0.18-0.51; p<0·0001). 


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At data cutoff, 107 (57%) subjects in the dabrafenib group and 14 (22%) in the dacarbazine 
group remained on randomized treatment. Confirmed objective responses were reported by 
the independent review committee (IRC) in 93 (50%, 95% CI 42·4–57·1) of 187 patients 
randomly assigned to dabrafenib (6 [3%] had a complete response and 87 [47%] had a partial 
response), with a median time to response of 6·3 weeks (95% CI 6·1–6.3).Treatment-related 
adverse events (grade 2 or higher) occurred in 100 (53%) of the 187 patients who received 
dabrafenib and in 26 (44%) of the 59 patients who received dacarbazine. The most common 
adverse events with dabrafenib were skin-related toxic effects, fever, fatigue, arthralgia, and 
headache. The most common adverse events with dacarbazine were nausea, vomiting, 
neutropenia, fatigue, and asthenia. Grade 3-4 adverse events were uncommon in both groups 
[Hauschild A 2012].
The experience with dabrafenib as monotherapy was generally obtained in patients with 
melanoma. Common AEs include: fatigue, gastro-intestinal (GI) effects (diarrhea), rash, 
pyrexia, arthralgias, headaches, and skin effects.  Among those common AEs, pyrexia has 
been noted in 27% of patients receiving dabrafenib. Most of these cases have been mild, self-
limited, and have responded to anti-pyretic therapy.   However, cases of complex pyrexia have 
been reported as serious adverse events (SAEs) in which patients have presented with high 
fever (up to 105 -106 degrees F), with severe rigors, and in some instances dehydration or 
hypotension.  Most cases of pyrexia have presented within the first two months of therapy and 
guidelines for supportive care and dose modifications are provided in Section 5.8.5.1. A 
variety of skin effects have been noted in BRAF inhibitor treated patients including rash, 
hyperkeratosis, actinic keratosis, seborrheic keratosis, hand-foot skin reactions (HFSR) and 
cutaneous squamous cell carcinomas (SCC), papilloma or new primary malignant melanoma.  
Squamous cell cancers related to BRAF inhibitor therapy often have characteristics of 
keratoacanthoma type of SCC, which traditionally have a relatively benign prognosis.  All 
reports of SCCs are captured as SAEs.  These lesions are treated surgically without need for 
dose modification of dabrafenib (see Section 5.8.4.44) [Hauschild A 2012].
Among the rare AEs, renal insufficiency/failure was recently identified as a potential adverse 
drug reaction associated with dabrafenib.  Most cases of renal insufficiency have been in the 
setting of dehydration and/or pyrexia; however there have been reports of acute renal failure 
suggestive of intrinsic renal disease (see Section 5.8.5.3).  Dabrafenib, like the other BRAF 
inhibitor, has been associated with reports of uveitis, the frequency of which is being currently 
determined (likely 1-2%).  The mechanism remains unclear, but may involve a possible 
immune mechanism.
1.2.2
Trametinib
Trametinib (GSK1120212), a pyrido-pyrimidine derivative, is a potent and highly selective 
allosteric i.e. non-ATP competitive inhibitor of MEK1 and MEK2 activation and kinase 
activity. Trametinib has demonstrated activity with an acceptable safety; [Gordon MS 2010; 
Kim K 2011; Kim KB 2013], and was approved in May 2013 by the US FDA in patients with 
unresectable or metastatic melanoma in adult patients with the BRAF V600E or V600K 
mutations.
In the pivotal Phase III study (NCT01245062), trametinib demonstrated significant 
improvement in both PFS and OS in subjects with advanced or metastatic BRAF V600E/K 
mutation-positive melanoma compared with chemotherapy. Median PFS was 4.8 months in 


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the trametinib group and 1.5 months in the chemotherapy group (hazard ratio for disease 
progression or death in the trametinib group, 0.45; 95% CI, 0.33 to 0.63; p<0.001). At 6 
months, the rate of overall survival was 81% in the trametinib group and 67% in the 
chemotherapy group despite crossover (hazard ratio for death, 0.54; 95% CI, 0.32 to 0.92; P = 
0.01). The confirmed response rate was 22% (95% CI, 17 to 28) in the trametinib group and 
8% (95% CI, 4 to 15) in the chemotherapy group (p=0.01). The median duration of response 
was 5.5 months (95% CI, 4.1 to 5.9) in the trametinib group (in 47 subjects) and had not been 
reached in the chemotherapy group (in 9 subjects).
Trametinib has also been evaluated, as monotherapy, in well over 500 subjects 
[GlaxoSmithKline Document Number HM2009/00151/03].  Common AEs include rash, 
peripheral edema, and GI effects (diarrhea). In addition, a decrease left-ventricular ejection 
fraction (LVEF) has been observed in approximately 10% of subjects receiving trametinib. 
Most of these cases were associated with no symptoms. Consequently, strict monitoring has 
been in place along with guidelines on management of patients with decreased LVEF (see 
Section 5.8.3.1). Emerging data on blood pressure suggests that trametinib may be associated 
with increases in blood pressure and hypertension was reported as an adverse event in 15% of 
subjects in the Phase III study. Subjects enrolled in this study are expected to have well 
controlled blood pressure at baseline and guidelines for treatment related blood pressure 
management are provided in Section 5.8.3.2. Trametinib, like other MEK inhibitors, can be 
associated with visual changes including central serous retinopathy and rarely with retinal 
vein occlusion (RVO), the latter being the more severe event.  Guidelines for the management 
of visual changes are provided in Section 5.8.5.4.
1.2.3
BRAF and MEK Inhibitors as Combination Therapy
Clinical evaluation of the dabrafenib 150 mg BID + trametinib 2 mg QD (150/2) combination 
treatment has shown efficacy in patients with V600 mutant melanoma.  The results of the 
randomized Part C of Study BRF113220 in BRAF-inhibitor naïve subjects demonstrated an 
improved efficacy profile for the 150/2 combination treatment compared to dabrafenib 
monotherapy across all efficacy parameters tested.  
BRF113220 was a Phase I/II study with 4 parts that include a randomized part (Part C) which 
investigated the clinical activity, durability of response, safety/tolerability and population PK 
parameters in the three different arms in subjects with BRAF-mutant melanoma (n=162).  In 
Part C, a statistically significant (p=0.0264) increase in the confirmed overall response rate 
was observed in the 150/2 treatment arm (76%) when compared to the dabrafenib 
monotherapy arm (54%) [Flaherty KT 2012b]. Moreover, the rate of complete responses was 
higher in the 150/2-treatment arm (9% vs 4%) while early disease progression (i.e., no best 
response of disease progression (PD) at the first timepoint assessment), was absent (0 vs 6%) 
when compared to the dabrafenib monotherapy arm. Clinically more important, the 
investigator-assessed PFS was significantly prolonged for the 150/2 combination arm relative 
to the dabrafenib monotherapy arm (HR=0.39; p<0.0001) [Flaherty KT 2012b].  This benefit 
was sustained at 12 months, with a 12-month progression-free rate of 41% in the 150/2 arm vs 
9% in the dabrafenib monotherapy arm. While a significant difference in PFS was also 
observed in the 150/1 combination therapy group compared to dabrafenib monotherapy 
(HR=0.56, p=0.0057), the benefit was lower at 12 months (12-month progression-free rate of 
26%) [Flaherty KT 2012b]. 


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Safety data reported from Part C showed that dose-limiting toxic effects were infrequently 
observed in subjects receiving combination therapy with 150 mg of dabrafenib and 2 mg of 
trametinib (combination 150/2). Cutaneous squamous-cell carcinoma was seen in 7% of 
subjects receiving combination 150/2 and in 19% receiving dabrafenib monotherapy (p = 
0.09), whereas pyrexia was more common in the combination 150/2 group than in the 
monotherapy group (71% vs. 26%) [Flaherty KT 2012b]. 
MEK115306 study is a double blind randomized phase III study that recruited 423 previously 
untreated metastatic melanoma patients who had BRF V600E or V600K mutation. Eligible 
patients were randomized to receive dabrafenib 150mg bid plus trametinib 2mg qd, or 
dabrafenib 150mg bid plus placebo. The primary endpoint was PFS. The results showed the 
combination significantly improved PFS (median PFS: 9.3 vs 8.8 months, HR=0.75, p=0.03) 
and response rate (67% vs 51%, p=0.0002) . The interim OS analysis at 6 months showed the 
survival rate was 93% and 85% in the combination arm vs dabrafenib arm (HR=0.63, p=0.02). 
However, a pre-defined specific efficacy stopping boundary of OS (two-side p=0.00028) was 
crossed. So the survival follow-up is still on-going as of December 2014. 
In this study, 9% patient from combination treatment arm and 5% from dabrafenib 
monotherapy arm permanently discontinued study medication before disease progression. In 
addition, dose reduction was required in 25% and 13% of patients receiving combination and 
dabrafenib monotherapy, respectively. 
The adverse event profile of combination treatment was different from dabrafenib 
monotherapy. The patients who received combined treatment experienced more frequent 
pyrexia(51% vs 28%), chill(30% vs 16%), diarrhea(24% vs 14%), hypertension(22% vs 14%), 
vomiting(20% vs 14%), peripheral edema(14% vs 5%), elevated ALT (11% vs 5%) or AST 
(11% vs 3%), decreased left ventricular ejection fraction(LVEF)(4% vs 2%), dermatitis 
acneiform(8% vs 3%),  but less frequent cutanenous squamous-cell carcinoma(2% vs 9%), 
hyperkeratosis(3% vs 32%), skin papilloma(1% vs 21%), hand-foot syndrome(5% vs 27%), 
dry skin(9% vs 13%), pruritus(8% vs 12%) and alopecia(7% vs 26%). [Long GV 2014]
MEK116513 study is an open label randomized phase III study that recruited 704 previously 
untreated metastatic melanoma patients who had BRF V600E or V600K mutation. Eligible 
patients were randomized to receive dabrafenib 150mg bid plus trametinib 2mg qd, or 
vemurafenib 960mg bid. The primary endpoint was overall survival. At a pre-planned interim 
analysis, this study demonstrated the combination of dabrafenib plus trametinib achieved 
significant OS improvement (12 months OS rate: 72% vs 65%, HR: 0.69, p=0.005) and this 
result crossed the pre-defined interim stopping boundary. Therefore this study was stopped 
because of the efficacy and the interim analysis was considered the final analysis. The 
combination treatment also significantly improved PFS (median PFS: 11.4 vs 7.3 months, 
HR: 0.56, p<0.001) and response rate (64% vs 51%, p<0.001). 
Rates of study-drug discontinuations were similar in the two groups(13% in combination arm 
and 12% in vemurafenib arm). Adverse events leading to dose reduction was reported in 33% 
of patients in combination arm and 39% in the vemurafenib arm. 
The most frequent adverse events in the combination-therapy group were pyrexia (53%), 
nausea (35%), diarrhea (32%), chills (31%), fatigue (29%), headache (29%), and vomiting 
(29%). In the vemurafenib group, the most frequent adverse events were arthralgia (51%), 
rash (43%), alopecia (39%), diarrhea (38%), nausea (36%), and fatigue (33%). Skin toxic 
effects were more frequent in the vemurafenib group than in the combination-therapy group, 


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in particular rash (43% vs. 22%), photosensitivity reaction (22% vs. 4%), hand–foot syndrome 
(25% vs. 4%), skin papillomas (23% vs. 2%), squamous-cell carcinomas and 
keratoacanthomas (18% vs. 1%), and hyperkeratosis (25% vs. 4%). Pyrexia was more 
frequent in the combination-therapy group than in the vemurafenib group (53% vs. 
21%).Grade 3 or 4 adverse events occurred in 52% of the patients in the combination-therapy 
group and in 63% of those in the vemurafenib group. Three fatal events occurred in each 
group; all were deemed by the investigator to be unrelated to the study drug [Robert C 2015].
1.2.3.1
Dabrafenib and Trametinib in Acral Lentiginous Melanoma
Acral lentiginous melanoma is one of 4 major histological subtypes of cutaneous melanoma.  
It is characterized by lesions presenting on non-hair bearing skin including the palm, soles, 
and nail beds. Although ALM accounts for only 2% to 3% of all melanomas in Caucasians, 
ALM makes up a much higher proportion (40-50%) of cutaneous malignant melanomas in 
darker-skinned individuals (ie, blacks, Asians, and Hispanics) [Bradford PT 2009]. The 
frequency of BRAF mutations in melanoma varies with anatomical site and sun exposure 
patterns. BRAF mutations are less frequent (25 – 30%) in acral melanoma not associated with 
chronic sun-damage [Curtin JA 2006] [Curtin JA 2006]. In contrast, c-Kit mutations are more 
common in mucosal (39%) and acral melanomas (36%), which can also be accompanied by 
an increase in c-Kit copy numbers [Curtin JA 2006]. Thus far, very few patients with ALM 
have been treated with dabrafenib and trametinib combination since the vast majority subjects 
enrolled were Caucasians. 
To date, approximately 14 subjects with acral lentiginous melanoma have been treated with 
dabrafenib or trametinib monotherapy, or combination therapy with both agents.  In the 
dabrafenib BREAK-3(BRF113683) study, 5 subjects with ALM received dabrafenib either in 
the randomized study or after crossover.  Exposure to dabrafenib ranged from 3 days (subject 
discontinued treatment due to adverse event) to 5 months.  In addition, one subject with ALM 
was enrolled into the METRIC (MEK114267) study with trametinib monotherapy and was 
treated with trametinib for over 50 weeks.  
In the BRF113220 study, 8 subjects received combination dabrafenib and trametinib therapy 
either in the randomized phase or after crossover from dabrafenib monotherapy.  Exposure 
time ranged from 3 to 18 months, including 2 subjects with a partial response who are still 
ongoing on study treatment.
In Asian population, approximately 25.5% of all melanoma patients and 15.5% of ALM have 
BRAF V600 mutation [Lu S 2011]. There are no PK data in Chinese patients. Preliminary PK 
data obtained in Japanese patients showed there no major ethnic difference in the 
pharmacokinetic profile of trametinib or dabrafenib when administered in monotherapy 
[GlaxoSmithKline Document Number 2014N196180_00 and GlaxoSmithKline Document 
Number 2012N133089_00], however, exposure to dabrafenib and trametinib tended to be 
higher when administered in combination [GlaxoSmithKline Document Number 
2014N196181_00].
Data in subjects with acral lentiginous melanoma subtype or Asian population was limited and 
further exploration in these populations is warranted. This study was originally intended to 
enroll subjects with acral lentiginous melanoma. The eligibility criterion has been amended to 
include cutaneous melanoma in light of the advance in the management of metastatic 
melanoma with BRAF V600 mutation.


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1.3
Rationale

Clinical studies for dabrafenib and trametinib monotherapies have demonstrated single-
agent clinical activity in subjects with BRAF-V600-mutant melanoma.

Preclinical studies and clinical data indicate that primary- and acquired resistance to a 
BRAF-inhibitor single-agent therapy may be addressed and potentially overcome by a 
combination of a BRAF- and MEK-inhibitor 

Data from the BRF113220 study (Part C) and 2 randomized phase III study evaluating the 
combination of dabrafenib and trametinib demonstrated promising clinical activity and an 
acceptable clinical safety profile of the dabrafenib and trametinib combination given at 
full single-agent dose 

Limited data are available in non-Caucasian populations and ALM.

Limited pharmacokinetic data are available from Asian subjects, in whom melanoma sub-
types such as ALM may be more prevalent compared to Caucasian subjects.
1.4
Benefit: Risk Assessment
Summaries of findings from both clinical and non-clinical studies conducted with dabrafenib 
and trametinib can be found in the Investigator’s Brochure [GlaxoSmithKline Document 
Number 2011N126811_02].  The following section outlines the risk assessment and 
mitigation strategy for this protocol:  


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1.4.1
Benefit Assessment
Current research suggests that combination therapies of BRAF- and MEK-targeted agents can 
further improve the effect on survival currently achieved with BRAF inhibitor monotherapy 
[Long GV 2014; Robert C 2015] in metastatic melanoma patients with BRAF V600 mutation. 
Patients treated with combination of trametinib and dabrafenib can achieve a 6 months 
survival rate of 93% [Long GV 2014] and 12 months survival rate of 72% [Robert C 2015]. 
New treatments, like CTLA-4 antibody or anti-PD-1 antibodies, are not available in countries 
like China. Dacarbazine (DTIC), considered the most active of the agents currently available, 
is approved for metastatic melanoma [Huncharek M 2001] and widely used in clinical practice 
in Asian countries. The benefit of DTIC remains small, with median progression-free survival 
lasting approximately 2 months and median overall survival of approximately 7 months.
There are no PK data in Chinese patients. Preliminary PK data obtained in Japanese patients 
showed there no major ethnic difference in the pharmacokinetic profile of trametinib or 
dabrafenib when administered in monotherapy [GlaxoSmithKline Document Number 
2014N196180_00 and GlaxoSmithKline Document Number 2012N133089_00] , however, 
exposure to dabrafenib and trametinib tended to be higher when administered in combination 
[GlaxoSmithKline Document Number 2014N196181_00]. Nevertheless, the planned dose of 
study medication is expected to be tolerable in the study population and bring clinical benefit.
Subjects enrolled into this study may benefit from receiving a combination of targeted agents 
which have demonstrated efficacy and tolerability in Caucasian populations.  
1.4.2
Overall Benefit: Risk Conclusion
To date, >3000 subjects, of predominantly Caucasian ethnicity and with majority of BRAF 
V600 mutated melanoma have received this combination regimen in 5 phase I/II studies and 3 
phase III studies. The complete list of these studies can be found in the IB. 
As both agents target the MAP-kinase (MAPK) pathway, which is constitutively activated in 
V600 BRAF-mutation positive melanoma, a concomitant combination regimen may result in 
a more pronounced and prolonged anti-tumor efficacy as experimental data strongly suggests. 
This additive or synergistic activity is the result of a near-complete MAPK-pathway inhibition 
which addresses molecular mechanisms of primary resistance and delays the onset of 
secondary resistance to monotherapy treatment. Furthermore, in a relevant pre-clinical model 
of chemically induced skin carcinogenesis, inhibition of the MAPK-pathway at the two 
separate nodes of BRAF and downstream MEK abolished the paradoxical MAPK pathway 
activation induced by the BRAF inhibitor vemurafenib and resulted in an almost complete 
inhibition of cutaneous squamous cell carcinoma (cuSCC) development which is, a known 
side effect of monotherapy BRAF inhibition.
The safety profile for the combination treatment of dabrafenib 150 mg twice daily and 
trametinib 2 mg once daily in subjects with unresectable or metastatic melanoma with a 
BRAF V600 mutation is defined by the results of the pivotal Phase III Study MEK115306 and 
MEK116513 and supported by the BRF113220 pooled combination therapy population 
[GlaxoSmithKline Document Number 2011N126811_02].


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The combination therapy has a higher rate of pyrexia, fatigue and nausea, while lower 
incidences of hyperkeratosis, alopecia and skin papilloma  were observed compared with 
dabrafenib monotherapy. Relative to trametinib monotherapy, there was a higher incidence of 
fatigue, nausea, and vomiting observed but lower incidences of rash and diarrhea with 
combination therapy.
Overall, the addition of dabrafenib to trametinib does not appear to increase the frequency or 
severity of cardiac-related AEs, hypertension, hepatic disorders, diarrhea and pneumonitis, 
which previously were observed with trametinib monotherapy.
Similarly, the addition of trametinib to dabrafenib does not appear to increase the frequency or 
severity of palmar-plantar-erythrodysaesthesia syndrome (PPES) or treatment-emergent 
malignancies previously observed with dabrafenib monotherapy.
The risk-to-benefit ratio in this patient population remains favorable.
2
OBJECTIVE(S) and endpoints
Table 1 lists the study objectives and corresponding endpoints.
Table 1
Study Objectives and Endpoints
Objectives
Endpoints
Primary

To determine the objective response rate (ORR) 
of dabrafenib in combination with trametinib in 
subjects with BRAF V600 mutation-positive, 
unresectable or metastatic acral lentiginous or 
cutaneous melanoma 
ORR defined as the percentage of subjects 
with evidence of a confirmed complete 
response (CR) or partial response (PR) as 
per RECIST v1.1 [Eisenhauer EA 2009].
Secondary

To further evaluate the antitumor activity 
(progression-free survival (PFS), duration of 
response, and overall survival (OS)
Duration of response is defined as the time 
from first documented evidence of CR or PR 
until the earliest date of documented 
radiological progression or death due to any 
cause among subjects who achieved a 
confirmed CR or PR. 
PFS defined as the time from first dose of 
study treatment until the first date of either 
objective disease progression or death due to 
any cause.
OS defined as the interval from first dose of 
study treatment to the date of death, 
irrespective of the cause of death; subjects 
still alive will be censored at the date of the 
last contact.

To assess exposures to dabrafenib, 
dabrafenib metabolites, and trametinib after a 
single dose (Chinese patients) and at steady-
Trametinib, dabrafenib and dabrafenib 
metabolites concentrations by visit.  
Noncompartmental PK parameters include 


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Objectives
Endpoints
state, and characterize the population 
pharmacokinetics and pharmacodynamics of 
dabrafenib and trametinib 
trametinib, dabrafenib and dabrafenib 
metabolites Cmax, tmax, Ctrough, AUC(0-t), 
and AUC(0-8); AUC(0-12) (dabrafenib and 
dabrafenib metabolites only), AUC (0-24) 
(trametinib only) and the dabrafenib 
metabolite to dabrafenib ratio of AUC(0-12).  
For Chinese patients, the accumulation ratio 
will be calculated by using the 
pharmacokinetic parameters from Day 1 and 
Day 15. Population PK parameters include, 
apparent clearance following oral dosing 
(CL/F), volume of distribution (V/F), and 
absorption rate constant (Ka) for dabrafenib 
and trametinib.

To evaluate the safety and tolerability of 
dabrafenib and trametinib 
Safety as measured by clinical assessments 
including vital signs and physical 
examinations, 12-lead electrocardiograms 
(ECG), echocardiogram (ECHO), eye exams, 
chemistry and hematology laboratory values, 
and adverse events (AEs).


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3
Study design
3.1
Study Design
Protocol waivers or exemptions are not allowed. Therefore, adherence to the study design 
requirements, including those specified in the Time and Events Table, are essential and 
required for study conduct. 
This is an open-label, Phase IIA, multi-center study to evaluate the objective response rate of 
dabrafenib and trametinib combination therapy in subjects that have BRAF V600 mutation-
positive ALM or cutaneous melanoma. Approximately 65 subjects will be enrolled to receive 
oral dabrafenib 150 mg twice daily in combination with oral trametinib 2 mg once daily.  
Dose modification guidelines for adverse events are provided in Section 5.8.  Other measures 
of efficacy including duration of response, PFS and OS, as well as PK and PD properties, 
safety and tolerability of dabrafenib and trametinib will also be evaluated.  Blood and tissue 
samples will be collected to determine possible mechanisms of drug response and resistance.
Subjects will continue study treatment until disease progression, death, unacceptable toxicity, 
withdrawal of consent, or study completion.  After treatment discontinuation, subjects will be 
followed for survival and disease progression as applicable. 
The study completion is defined as:

In case all subjects stop study treatment within 48 weeks after Last Subject First 
Visit(LSFV): the study is completed once the last subject has completed the 48 weeks 
survival follow-up or all subjects die or loss to follow-up, whichever comes first. 

In case some subjects are still on study treatment 48 weeks after LSFV: the study is 
completed once all subjects stop study medication, or all subjects who are still on study 
medication can have access to alternative supply of MEK/BRAF inhibitors, whichever 
comes first.
Supplementary study conduct information not mandated to be present in this protocol is 
provided in the accompanying Study Procedures Manual (SPM). The SPM will provide the 
site personnel with administrative and detailed technical information that does not impact 
subject safety.
4
Subject selection and discontinuation/completion criteria
4.1
Subject Selection Criteria
4.1.1
Number of Subjects
Approximately 65 subjects will be enrolled.  See Section 9.2.1 for sample size assumptions.
4.1.2
Inclusion Criteria
Specific information regarding warnings, precautions, contraindications, adverse events, and 
other pertinent information on the Novartis investigational product or other study treatment 
that may impact subject eligibility is provided in the trametinib  and dabrafenib and trametinib 
combination IB’s.


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Deviations from inclusion criteria are not allowed because they can potentially jeopardize the 
scientific integrity of the study, regulatory acceptability or subject safety. Therefore, 
adherence to the criteria as specified in the protocol is essential.   
Subjects eligible for enrolment in the study must meet all of the following criteria:
1. Signed written informed consent, which includes compliance with the requirements and 
restrictions listed in the consent form.
2. ≥18 years of age, 
3. Histologically confirmed acral lentiginous or cutaneous melanoma that is either Stage IIIC 
(unresectable) or Stage IV (metastatic), and determined to be BRAF V600 mutation-
positive by a central reference laboratory.  Subjects with ocular or mucosal melanoma are 
not eligible. 
4. Measurable disease (i.e., present with at least one measurable lesion) by RECIST 
version1.1 [Eisenhauer EA 2009] by investigator’s assessment.  Refer to Section 7.2.3 for 
the definition of a measurable lesion.
5. Performance status score of 0 or 1 according to the Eastern Cooperative Oncology Group 
(ECOG) scale [Oken MM 1982]. 
6. All prior anti-cancer treatment-related toxicities (except alopecia and laboratory values as 
listed on Table 2) must be ≤ Grade 1 according to the Common Terminology Criteria for 
Adverse Events version 4 (CTCAE version 4.0) at the time of enrolment [NCI 2009].
7. 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.
8. Women of child-bearing potential (see Section 7.3.7 for definitions) must have a negative 
serum pregnancy test within 14 days of first dose of study treatment and agree to use 
effective contraception, as stated in Section 7.3.7 from 14 days prior to enrolment, 
throughout the treatment period and for 4 months after the last dose of study treatment. 
9. Adequate baseline organ function as defined in Table 2.
10. Subjects with East Asian origin.
Table 2
Definitions for Adequate Baseline Organ Function
System
Laboratory Values
Hematologica
ANC
≥ 1.2 × 109/L
Hemoglobin
≥ 9 g/dL
Platelet count
≥ 100 x 109/L
PT/INRb and PTT
≤ 1.5 x ULN
Hepatic
Albumin
≥ 2.5 g/dL
Total bilirubin
≤ 1.5 x ULNc
AST and ALT
≤ 2.5 x ULN


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Renal
Calculated creatinine clearanced
≥ 50 mL/min
Cardiac
Left Ventricular Ejection Fraction (LVEF)e
≥ LLN by ECHO
ANC=absolute neutrophil count, PT=prothrombin time, INR=international normalized ratio, PTT=partial thromboplastin time, 
AST=aspartate aminotransferase, ALT=alanine aminotransferase, LLN=lower limit of normal
a. Laboratory values obtained without growth factors or transfusion support for at least 4 weeks
b.Subjects receiving anticoagulation treatment may be allowed to participate with INR established within the
therapeutic range prior to enrollment.
c. Total bilirubin < 1.5 x ULN except for patients with Gilbert’s syndrome who may only be included if total bilirubin < 3.0 x 
ULN or direct bilirubin < 1.5 x ULN.
d. Calculate creatinine clearance using standard Cockcroft-Gault formula (Appendix 2).
e. ECHO scans must be used throughout the study.
4.1.3
Exclusion Criteria
Deviations from exclusion criteria are not allowed because they can potentially jeopardise the 
scientific integrity of the study, regulatory acceptability or subject safety. Therefore, 
adherence to the criteria as specified in the protocol is essential. 
Subjects meeting any of the following criteria must not be enrolled in the study:
1. Primary mucosal or ocular melanoma.
2. Prior treatment with a BRAF inhibitor (including but not limited to dabrafenib, 
vemurafenib, LGX818, and XL281/BMS-908662) or a MEK inhibitor (including but 
not limited to trametinib, AZD6244, and RDEA119). Any major surgery, extensive 
radiotherapy, chemotherapy with delayed toxicity, biological anti-cancer therapy, or 
immunol anti-cancer therapy within 21 days prior to enrollment /or daily or weekly 
chemotherapy without the potential for delayed toxicity within 14 days prior to 
enrollment. . (Note: Ipilimumab, pembrolizumab and nivolumab treatment must have 
ended at least 8 weeks prior to enrollment).
3. Taken an investigational drug within 28 days or 5 half-lives (minimum 14 days), 
whichever is shorter, prior to enrollment(Note: in case ipilimuamb, pembrolizmab and 
nivolumab are investigational drug in the regions and countries, and in case of PD-L1 
antibody, these investigational treatment shall be ended at least 8 weeks prior to 
enrollment).
4. Current use of a prohibited medication (See Section 6.1).
5. Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs 
chemically related to the study treatments, their excipients, and/or dimethyl sulfoxide 
(DMSO).
6. A history of Hepatitis B Virus (HBV), or Hepatitis C Virus (HCV) infection (subjects 
with laboratory evidence of cleared HBV and/or HCV will be permitted, which is 
defined as HBs antigen negative and HBV DNA negative(≤1000 copies/mL) and HCV 
antibody is negative).


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7. Leptomeningeal or brain metastases or metastases causing spinal cord compression 
that are: symptomatic or untreated or not stable for 3 months (must be documented 
by imaging before inclusion and compare with the latest brain scan prior to the one for 
the inclusion) or requiring corticosteroids.  Subjects on a stable dose of 
corticosteroids >1 month, or on replacement dose only, or have been off of 
corticosteroids for at least 2 weeks can be enrolled with approval of the Novartis 
Medical Lead.  Subjects must also be off of enzyme-inducing anticonvulsants 
for >4 weeks.
8. History of malignancy other than disease under study within 3 years, of study 
enrolment with exceptions below.
Exception: Subjects with a history of completely resected non-melanoma skin cancer, 
or subjects with indolent second malignancies are eligible only after the approval of 
the sponsor’s Medical Lead.
9. History of malignancy with confirmed activating RAS mutation at any time. Note: 
Prospective RAS testing is not required. However, if the results of previous RAS 
testing are known, they must be used in assessing eligibility. 
10. Any serious or unstable pre-existing medical conditions (aside from malignancy 
exceptions specified above), psychiatric disorders, or other conditions that could 
interfere with the subject’s safety, obtaining informed consent, or compliance with 
study procedures.  
11. A history or evidence of cardiovascular risk including any of the following:
a.
Current LVEF < Institutional LLN
b. A QTc interval corrected for heart rate ≥480 msec (using Bazett’s formula; see 
Appendix 3 for correction methods)
c.
A history or evidence of current clinically significant uncontrolled arrhythmias;
Clarification: Subjects with atrial fibrillation controlled for > 30 days prior to dosing 
are eligible.
d. A history  of acute coronary syndromes (including myocardial infarction or unstable 
angina), coronary angioplasty, or stenting within 6 months prior to randomization;
e.
A history or evidence of current ≥Class II congestive heart failure as defined by the 
New York Heart Association (NYHA) guidelines (Appendix 4);
f.
Patients with intra-cardiac defibrillators;
g. Treatment refractory hypertension defined as a blood pressure of systolic> 140 mmHg 
and/or diastolic > 90 mm Hg which cannot be controlled by anti-hypertensive therapy;
h. Abnormal cardiac valve morphology (≥grade 2) documented by echocardiogram 
(subjects with grade 1 abnormalities [i.e., mild regurgitation/stenosis] can be entered 
on study). Subjects with moderate valvular thickening should not be entered on study.


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12. Uncorrectable electrolyte abnormalities (e.g. hypokalaemia, hypomagnesaemia, 
hypocalcaemia determined by blood chemistry), long QT syndrome or taking 
medicinal products known to prolong the QT interval.
13. A history or current evidence of retinal vein occlusion (RVO)
14. [Retired from protocol version 03]
15. [Retired from protocol version 03]
16. Pregnant or nursing females.
17. History of or current diagnosis of interstitial lung disease or pneumonitis.
4.2
Permanent Discontinuation from Study Treatment and Study 
Completion Criteria
4.2.1
Permanent Discontinuation from Study Treatment
Subjects will receive study treatment until disease progression, death, or unacceptable AE, 
including hematologic or other non-hematologic toxicity, and/or meeting stopping criteria for 
liver chemistry defined in Section 5.9.  Note: Subjects who are experiencing progression of 
disease (by RECIST, version 1.1) but are receiving clinical benefit based on the investigator’s 
assessment, may be allowed to continue study treatment (see Section 4.2.2) with the 
agreement of sponsor’s Medical Lead. 
In addition, study treatment may be permanently discontinued for any of the following 
reasons:
a.
deviation(s) from the protocol
b. request of the subject or his/her proxy
c.
investigator’s discretion
d. subject is lost to follow-up, (defined as no contact with the subject after  3 
telephone calls and one certified letter to the last known address, and 
documented in the patient’s chart)
e.
study is completed or terminated.
The primary reason study treatment was permanently discontinued must be documented in the 
subject’s medical records and electronic case report form (eCRF).
If the subject voluntarily discontinues from treatment due to toxicity, ‘adverse event’ will be 
recorded as the primary reason for permanent discontinuation in the eCRF.  
Note: If one study drug is permanently discontinued, administration of the other study drug 
may continue if appropriate (see Section 5.8), and subjects should be assessed as indicated in 
the Time and Events Table (see Section 7). 
All subjects who permanently discontinue all study treatment will have safety assessments at 
the time of discontinuation and during post-study treatment follow-up as specified in the Time 
and Events Table (Table 20) and Section 7.  


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All subjects who permanently discontinue all study treatment without disease progression will 
be followed for progression according to the Time and Events Table (Table 20) until disease 
progression, death, or withdrawal of consent, whichever occurs first.
In addition, all subjects who permanently discontinue all study treatment will be followed for 
survival and new anti-cancer therapy according to the Time and Events Table (Table 20).  
Follow-up contact to assess survival and new anti-cancer therapy may be made via clinic visit, 
phone, or email.
Survival and new anti-cancer therapy follow-up will continue until study completion. 
4.2.2
Continuation of Study Treatment after Disease Progression
Subjects may be eligible to continue study treatment after disease progression if they have:

Achieved an objective response (partial or complete response) according to RECIST, 
version 1.1, or have had stable disease with imaging evidence of tumor reduction 
lasting at least 8 weeks prior to disease progression while receiving study treatment

No treatment-related AEs of CTCAE grade 4 during the last four weeks of study 
treatment

No signs and symptoms of clinical disease progression that decrease ECOG 
performance status to 2

No severe clinical conditions that require immediate surgical or radiotherapeutical 
intervention. Note: subjects who require palliative radiation of bone lesions or 
limited surgical removal of isolated tumor lesions may be considered after 
completion of the procedure (radiotherapy or surgery) and review by the Novartis 
Medical Lead.
If all of the above conditions are met, the following steps must be implemented prior to 
continuation of study treatment:

The investigator must consult with and receive approval from the Novartis 
Medical Lead

The subject must sign an informed consent that specifies alternative therapies 
(e.g., FDA-approved therapies) that the subject may be foregoing by continuing 
study treatment
After a subject has been permitted to continue on study treatment:

All study procedures, including tumor assessments, must be followed as scheduled 
(Table 20)

After each tumor assessment, the investigators must confirm with the Novartis 
Medical Lead that the subject is still benefitting from study treatment and therefore 
can continue receiving study treatment.
4.2.3
Subject Completion Criteria
A subject will be considered to have completed the study if the subject dies during the study 
treatment or follow-up period. The cause of death will be documented in the eCRF. A subject 
will be considered to have withdrawn from the study if the subject has not died and is lost to 


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follow-up or has withdrawn consent, or if the study is completed. The definition of study 
completion was described in protocol Section 3.1.  
5
Study treatments
The term ‘study treatment’ is used throughout the protocol to describe any combination of 
products received by the subject as per the protocol design. Study treatment may therefore 
refer to the individual study treatments or the combination of those study treatments.
5.1
Investigational Product and Other Study Treatment
5.1.1
Dabrafenib (GSK2118436)
Dabrafenib will be provided as 50 mg and 75 mg capsules.  Each capsule will contain 50 mg 
or 75 mg of free base (present as the 
). 
Dabrafenib will be provided to sites by Novartis with the exception of sites in China where 
GSK will organize to provide supplies under GSK`s sponsorship. The contents of the label 
will be in accordance with all applicable regulatory requirements.
5.1.2
Trametinib (GSK1120212)
Trametinib study medication will be provided as 0.5 mg and 2.0 mg tablets.  Each tablet will 
contain 0.5 mg or 2.0 mg of trametinib parent (present as the 
).
Trametinib will be provided to sites by Novartis with the exception of sites in China where 
GSK will organize to provide supplies under GSK`s sponsorship. The contents of the label 
will be in accordance with all applicable regulatory requirements  
5.2
Dosage and Administration

Dabrafenib, 150 mg, BID;

Trametinib, 2.0 mg, once daily. 
When administered in combination with trametinib, take the once-daily dose of trametinib at 
approximately the same time each day with either the morning dose or the evening dose of 
dabrafenib. The second dose of dabrafenib (150 mg) should be administered approximately 12 
hours after the morning dose.  Study medication should be taken orally with approximately 
200 mL of water under fasting conditions, either 1 hour before or 2 hours after a meal.    
If a subject vomits after taking study medication, the subject should be instructed not to retake 
the dose and should take the next dose as originally scheduled.  
If administration of trametinib is interrupted or permanently discontinued, administration of 
dabrafenib may be continued.  If administration of dabrafenib is interrupted, or permanently 
discontinued, administration of trametinib may continue.
If a subject misses a dose of dabrafenib, the subject may take the dose immediately if the next 
dose is scheduled for at least 6 hours later. If the next scheduled dose of dabrafenib is due in 
less than 6 hours, the subject should skip the dose and resume of dabrafenib dosing at the next 
scheduled dose 
If a subject misses a trametinib dose, the subject may take the dose immediately if the next 
dose is scheduled for at least 12 hours later.


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5.3
Handling and Storage of Study Treatments
Dabrafenib and trametinib must be dispensed and administered in accordance with the 
protocol, and only to subjects enrolled in the study.  Dabrafenib and trametinib must be stored 
in a secure area under the appropriate physical conditions for the product.  Study medication 
is to be stored at the temperature specified on the label.  Maintenance of a temperature log 
(manual or automated) is required. Access to and administration of dabrafenib and trametinib 
will be limited to the investigator and authorized site staff.
Procedures for final disposition of unused study treatments will be provided in the SPM.
5.4
Treatment Assignment
This is a single arm, open label study. All subjects enrolled will receive the combination of 
dabrafenib and trametinib.
Subjects will be identified by a unique subject number that will remain consistent for the 
duration of the study.
All subjects will be registered into the My Access Program (MAP) system, by the investigator 
or authorized site staff.
MAP allows study sites to register subjects, and also is used in study treatment supply.
Detailed MAP user instructions, worksheets, and telephone contact numbers will be provided 
to the study site.
5.5
Blinding
This is an open-label, single-arm study.
5.6
Product Accountability
In accordance with local regulatory requirements, the investigator, designated site staff, or 
head of the medical institution (where applicable) must document the amount of 
investigational product dispensed and/or administered to study subjects, the amount returned 
by study subjects, and the amount received from and returned to Novartis, when applicable.  
Product accountability records must be maintained throughout the course of the study. Refer 
to the SPM for further detailed instructions on product accountability.
5.7
Treatment Compliance
Subjects will be instructed to return treatment bottles at each visit.  Compliance with study 
treatment will be assessed by querying the subject and thorough pill count at each visit.  
Compliance will be documented in the source documents and the eCRF.
A record of the number of dabrafenib and trametinib capsules/tablets dispensed to and taken 
by each subject must be maintained and reconciled with study treatment and compliance 
records.  Treatment start and stop dates, including dates of dose modifications and/or 
interruptions will also be recorded in the eCRF.  The investigator will make every effort to 
bring non-compliant subjects into compliance.


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5.8
Dose Modification Guidelines
The severity of adverse events will be graded utilizing the CTCAE v4.0.  Guidelines for dose 
modifications and interruptions for management of common toxicities associated with the 
study treatment are provided in this section.
Dose modifications in response to adverse events are permitted.  Dose modification guidelines 
include:

general guidelines for clinically significant toxicities related to study treatments and

specific guidelines for adverse events of special interest, which are events that have 
been observed with higher frequency or severity in subjects receiving dabrafenib, 
trametinib, or a combination of both therapies.
With the exceptions of pyrexia (likely related to dabrafenib) and LVEF (likely related to
trametinib), the guidance suggests that both therapies be reduced simultaneously in 
response to toxicities that are considered by the investigator to be treatment related.


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Table 3
Categories of Dose Modification Guidelines
5.8.1
Dose Levels of dabrafenib and trametinib
The dose levels for this study are provided in Table 4. 
Table 4
Dose Level Reduction Guidelines
Dose Level
Dabrafenib
Dose/Schedule
Trametinib 
Dose/Schedule
Starting Dose
150 mg BID
2 mg once daily
-1 (1st Dose reduction)
100 mg BID
1.5 mg once daily
-2 (2nd Dose reduction)
75 mg BID
1.0 mg once daily
Abbreviation: BID = twice daily
Re-escalation of dose levels is permitted 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. 
A dose reduction below 75 mg BID for dabrafenib or below 1 mg once daily for trametinib is 
not allowed. If a dose reduction below 75 mg BID for dabrafenib is required, dabrafenib will 
be permanently discontinued but these subjects will be allowed to continue trametinib.
If a dose reduction below1.0 mg once daily for trametinib is required, then trametinib will be 
permanently discontinued, but these subjects will be allowed to continue dabrafenib.
Note: Approval from the Novartis Medical Lead is required to restart study treatment 
after ≥21 days of interruption. Study drug must be discontinued permanently if any 
interruption goes beyond 26 weeks. 
Adverse Event
Dabrafenib
Trametinib
Section
General Guidelines for 
Clinically Significant Toxicities
X
X
5.8.2
Guidelines for Specific Adverse Events
Cardiovascular Adverse Events
LVEF
X
5.8.3.1
Hypertension 
X
X
5.8.3.2
Prolonged QTc
X
X
5.8.3.3
Skin –Related Adverse Events (Except cuSCC)a
Rash
X
X
5.8.4.1
Hand-Foot Skin Reaction
X
X
5.8.4.2
Other Adverse Events
Pyrexia
X
5.8.5.1
Diarrhea
X
X
5.8.5.2
Renal Insufficiency
X
X
5.8.5.3
Visual Changes
X
X
5.8.5.4
Pneumonitis
X
X
5.8.5.5
Liver Chemistry Stopping 
Criteria
X
X
5.9.1
a. Refer to Section 5.8.4.4 for management of cuSCC


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5.8.2
General Guidelines for Clinically Significant Toxicities
The below Table 5 presents general guidelines regarding management and dose reduction for 
adverse events that are considered by the investigator to be related to study treatment and 
which do not have specific guidelines listed in Table 3.
Table 5
General Dose Modification Guidelines for Events Considered Related to 
Study Treatment
CTCAE Grade1
Action and Dose Modification
Grade 1 

Continue study treatment at current dose level

Monitor closely 

Provide supportive care according to institutional standards
Grade 2 

Interrupt study treatment if clinically indicated

Monitor closely 

Provide supportive care according to institutional standards

When toxicity resolves to grade 1 or baseline, restart study treatment at 
current dose level
Grade 3 

Interrupt study treatment 

Monitor closely 

Provide supportive care according to institutional standards

When toxicity resolves to grade 1 or baseline, restart study treatment 
reduced by one dose level 

If the grade 3 toxicity recurs, interrupt study treatment

When toxicity resolves to grade 1 or baseline, restart study treatment 
reduced by another dose level
Grade 4 

Interrupt study treatment 

Monitor closely 

Provide supportive care according to institutional standards

Restart with study treatment reduced by one dose level once toxicity 
resolves to grade 1 or baseline

If the grade 4 toxicity recurs, either permanently discontinue study 
treatment or, if the subject is clinically benefiting, discuss continuation of 
study treatment with the Novartis Medical Lead.
1.
Adverse events assessed by clinical laboratory parameters, adverse events, cardiac parameters, and vital 
signs according to the Common Terminology Criteria for Adverse Events version 4 (CTCAE v4.0).
5.8.3
Guidelines for Cardiovascular Adverse Events
Cardiovascular adverse events have been seen in subjects receiving either dabrafenib, 
trametinib or both in combination (see the trametinib, dabrafenib and combination IBs for 
additional information).
5.8.3.1
Left Ventricular Ejection Fraction (LVEF)
Decreases of the left-ventricular-ejection-fraction (LVEF) have been observed in subjects 
receiving trametinib monotherapy and in combination with dabrafenib. Therefore, ECHOs 
must be performed to assess cardiac ejection fraction in regular intervals as outlined in the 
Time and Events Table (Table 20). All ECHOs will be collected; instructions are provided in 


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the Study Procedures Manual (SPM). Dose modification guidance and stopping criteria for 
LVEF decrease are provided in Table 6.
Table 6
Dose Modification Guidelines and Stopping Criteria for LVEF Decrease
Clinic
LVEF-drop (%) or
CTCAE grade
Action and Dose Modification
Asymptomatic
Absolute decrease of >10% in 
LVEF compared to baseline and
ejection fraction below the 
institution’s low LLN

Interrupt trametinib and repeat ECHO 
within 2 weeksa b

If the LVEF recovers within 4 weeks
(defined as LVEF ≥LLN and absolute 
decrease ≤10% compared to baseline) 
o
Consult with the Novartis Medical 
Lead and request approval for 
restart 
o
If approve, restart treatment with 
trametinib reduced by one dose 
level
o
Repeat ECHO at 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
o
Consult with cardiologist
o
Permanently discontinue 
trametinib
o
Report as SAE
o
Repeat ECHO after 2, 4, 8, 12, 
and 16 weeks or until resolution
Symptomaticc
Grade 3: resting LVEF 39-20% 
or >20% absolute reduction from 
baseline

Permanently discontinue trametinibb

Interrupt dabrafenib.d

Report as SAE

Consult with cardiologist

Repeat ECHO after 2, 4, 8, 12, and 16 
weeks or until resolutionb,d
Grade 4: resting LVEF <20%
Abbreviations: CTCAE = Common Terminology Criteria for Adverse Events; ECHO = echocardiogram; LLN = lower 
limit of normal; LVEF = left ventricular ejection fraction; 
a.
If ECHO does not show LVEF recovery after 2 weeks, repeat ECHO 2 weeks later. 
b.
If recurrent episodes of LVEF reduction occur in subjects receiving dabrafenib monotherapy, consult Novartis 
Medical Lead.
c.
Symptoms may include: dyspnea, orthopnea, and other signs and symptoms of pulmonary congestion and 
edema.
d.
Once LVEF recovers, including resolution of symptoms, restart of dabrafenib monotherapy only can be 
considered in consultation with Novartis Medical Lead.
5.8.3.2
Hypertension
Increases in blood pressure have been observed in subjects receiving trametinib. 
Recommendations for blood pressure monitoring and management are provided in Section 
5.8.3.2.1 and Section 5.8.3.2.2.


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5.8.3.2.1 Monitoring of Hypertension
All blood pressure assessments should be performed under the following optimal conditions:

the subject has been seated with back support, ensuring that legs are uncrossed and flat on 
the floor

the subject is relaxed comfortably for at least 5 minutes

restrictive clothing has been removed from  the cuff area and the right cuff size has been 
selected

the 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 
increased blood pressure can be scheduled independently from the per-protocol visits outlined 
in the Time and Events Table (Table 20). Ideally, subsequent blood pressure assessments 
should be performed within one week.
Asymptomatic hypertension is defined as an increase of SBP >140 mm Hg and/or DBP >90 
mm Hg in the absence of headache, light-headedness, vertigo, tinnitus, episodes of fainting or 
other symptoms indicative of hypertension.
5.8.3.2.2 Management of Hypertension
For subjects experiencing an increase in systolic and/or diastolic blood pressure that is 
persistent and may be associated with the study treatment, recommendations for the clinical 
management of hypertension are described below in Table 7.


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Table 7
Management and Dose Modification Guidelines for Hypertension
Hypertension
Action and Dose Modification
(Scenario A)

Asymptomatic and persistenta SBP of ≥140 and 
<160 mmHg, or DBP ≥90 and <100 mmHg, 
or 

Clinically significant increase in DBP of 20 
mmHg (but still below 100 mmHg).

Continue study treatment at the current 
dose 

Adjust current or initiate new 
antihypertensive medication

Titrate antihypertensive medication(s) 
during the next 2 weeks as indicated to 
achieve well-controlledb BP

If BP is not well controlled within 2 weeks, 
consider referral to a specialist and go to 
scenario (B).
(Scenario B)

Asymptomatic SBP ≥160 mmHg, or DBP 
≥100 mmHg, 
or 

Failure to achieve well-controlled BP within 2 
weeks in Scenario A

Interrupt study treatment if clinically
indicated

Adjust current or initiate new 
antihypertensive medication(s)

Titrate antihypertensive medication(s) 
during the next 2 weeks as indicated to 
achieve well-controlled BP

Once BP is well controlledb, restart study 
treatment reduced by one dose level

Symptomaticc hypertension 
or 

Persistent SBP ≥160 mmHg, or DBP 
≥100 mmHg, despite antihypertensive 
medication and dose reduction of study 
treatment

Interrupt study treatment 

Adjust current or initiate new 
antihypertensive medication(s)

Titrate antihypertensive medication during 
the next 2 weeks as indicated to achieve 
well-controlled BP

Referral to a specialist for further 
evaluation and follow-up is recommended

Once BP is well controlled, restart study 
treatment reduced by one dose level
Refractory hypertension unresponsive to above 
interventions or hypertensive crisis.

Permanently discontinue study 
treatment 

Continue follow-up per protocol.
BP = blood pressure; DBP = diastolic blood pressure; mmHg = millimetres mercury; SBP = systolic blood pressure;
a.
Hypertension detected in two separate readings during up to three consecutive visits
b.
Well-controlled blood pressure defined as SBP ≤140 mm Hg and DBP ≤90 mm Hg in two separate readings during 
up to three consecutive visits.
c.
Symptomatic hypertension defined as hypertension aggravated by symptoms (e.g., headache, light-headedness, 
vertigo, tinnitus, episodes of fainting) that resolve after the blood pressure is controlled within the normal range.
5.8.3.3
QT Prolongation
Guidelines for dose modification and stopping criteria due to QTc-prolongation are provided 
in Table 8.


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Table 8
Withholding and Stopping Criteria for QTc-Prolongation
QTc-Prolongationa
Action and Dose Modification

QTc ≥501 msec 

Interrupt study treatment until QTc prolongation 
resolves to grade 1 or baseline

Test serum potassium, calcium, phosphorus and 
magnesium. If abnormal correct per routine clinical 
practice to within normal limits.

Review concomitant medication usage for agents that 
prolong QTc.

If event resolves, restart study treatment at current dose 
levelb

If event does not resolve, permanently discontinue 
study treatments.  Consider evaluation with 
cardiologist.

If event recurs, permanently discontinue study 
treatments.  Consider evaluation with 
cardiologist.
Abbreviations: msec = milliseconds; QTc = QT interval on electrocardiogram corrected 
a.
Based on average QTc value of triplicate ECGs.  For example, if an ECG demonstrates a prolonged QT interval, 
obtain two or more ECGs over a brief period, and then use the averaged QTc values of the three ECGs to determine 
if study treatments should be interrupted or discontinued.
b.
If the QTc prolongation resolves to grade 1 or baseline, the subject may resume study treatment if the investigator 
and Novartis Medical Lead agree that the subject will benefit from further treatment.
5.8.4
Guidelines for Skin-related Adverse Events
Cutaneous adverse events have been observed in subjects receiving dabrafenib, trametinib or 
both therapies in combination (see the Investigator Brochures for more information). 
Recommendations for supportive care and guidelines for dose modifications are provided 
(Section 5.8.4.1, Section 5.8.4.2, Section 5.8.4.3 and Section 5.8.4.44. The institutional 
standards for the management of skin-related AEs can differ from these guidelines. In this 
case, best clinical judgment should be applied and a consultation with the Novartis Medical 
Lead may be required. In addition, the Sponsor may require biopsies of any new skin lesions 
especially those suspicious of cuSCC for further study.  
5.8.4.1
Rash
Rash is a frequent AE observed in subjects receiving trametinib, dabrafenib, or the 
combination of both therapies. Guidelines for rash management are based on experience with 
other MEK inhibitors and EGFR inhibitors [Balagula Y 2010; Lacouture ME 2008] and are 
provided below (Table 9 and Table 10).


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Table 9
Guidelines for Supportive Care of Rash
Type of Care
Action
Prevention/Prophylaxis
Start from Day 1a

Avoid unnecessary exposure to sunlight

Apply broad-spectrum sunscreen (containing titanium dioxide or zinc 
oxide) with a skin protection factor (SPF) ≥15 at least twice daily.

Use thick, alcohol-free emollient cream (e.g., glycerine and 
cetomacrogol cream) on dry areas of the body at least twice daily. 
Prevention/Prophylaxis
Start from Day 29 and 
implement for a total of 6 
weeks

Topical steroids and antibiotics should be applied at least twice daily 
starting on Day 29 of study treatment, to body areas such as face, 
chest, and upper back.  
o
Use mild-strength topical steroid  (hydrocortisone 1% 
cream) 
or
o
topical antibiotic (e.g., clindamycin) or oral antibiotics (e.g., 
doxycycline 100 mg BID, minocycline 100 mg BID)
Symptomatic Care 

Pruritic lesions: cool compresses and oral antihistamine therapies 

Fissuring lesions: Monsel’s solution, silver nitrate, or zinc oxide 
cream 

Desquamation: thick emollients and mild soap 

Paronychia: antiseptic bath, local potent corticosteroids in addition 
to oral antibiotics; if no improvement, consult dermatologist or 
surgeon 

Infected lesions: appropriate bacterial/fungal culture-driven systemic 
or topical antibiotics 
BID = twice daily; SPF = skin protection factor
a. Subjects who develop rash/skin toxicities should be seen by a qualified physician and should receive evaluation for 
symptomatic/supportive care management 


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Guidelines for management and dose reduction for rash considered to be related to study 
treatment are provided in Table 10.
Table 10
Management and Dose Modification Guidelines for Rash
CTCAE Grade
Adverse Event Management
Action and Dose Modification
Grade 1

Initiate prophylactic and 
symptomatic treatment measures

Use moderate strength topical 
steroida 

Reassess after 2 weeks

Continue study treatment

If rash does not recover to 
baseline within 2 weeks 
despite best supportive care, 
reduce study treatment by 
one dose levelb
Grade 2

Initiate prophylactic and 
symptomatic treatment measures

Use moderate strength topical 
steroida

Reassess after 2 weeks

Reduce study treatment by 
one dose level
o
If rash recovers to 
≤grade 1 within 2 
weeks, increase 
dose to previous 
dose level
o
If no recovery to 
≤grade 1 within 2 
weeks, interrupt 
study treatment until 
recovery to ≤grade 
1

Restart study treatment at  
reduced dose levelb
Grade ≥3

Use moderate strength topical 
steroidsa PLUS oral methyl-
prednisolone dose pack

Consult dermatologist 

Interrupt study treatment until 
rash recovers to grade ≤1

Restartb with study 
treatment reduced by one 
dose levelc

If no recovery to grade ≤2 
within 4 weeks, permanently 
discontinue study 
treatment
CTCAE = Common Terminology Criteria for Adverse Events
a. Moderate-strength topical steroids: hydrocortisone 2.5% cream or fluticasone propionate 0.5% cream
b. Approval of Novartis Medical Lead is required to restart study treatment after >21 days of interruption.
c. Escalation of study treatment to previous dose level may be considered if no rash is evident 4 weeks after restarting 
study treatment
5.8.4.2
Severe Cutaneous Adverse Reactions (SCARs)
Cases of SCARs, including Stevens-Johnson syndrome, and drug reaction with eosinophilia 
and systemic symptoms (DRESS), which can be life-threatening or fatal, have been reported 
during treatment with dabrafenib in combination with trametinib. Before initiating treatment, 
patients should be advised of the signs and symptoms and monitored closely for skin reactions. 
If signs and symptoms suggestive of SCARs appear, dabrafenib and trametinib should be 
permanently discontinued.


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5.8.4.3
Guidelines for Hand-foot Skin Reactions (HFSR)
Episodes of Hand-foot Skin Reaction (HFSR) have been observed in subjects receiving 
dabrafenib. Guidelines for management of HFSR are based on experience with other kinase 
inhibitors [Lacouture ME 2008; McLellan B 2011] and are listed Table 11.
Table 11
Management and Dose modification Guidelines for Hand-Foot Skin 
Reaction (HFSR)
CTCAE Grade
Adverse Event Management
Action and Dose Modification
Grade 1a

Life style changes 
recommendedb

Initiate symptomatic 
treatmentc if clinically 
appropriate

Continue study treatment at 
current dose level
Grade 2

Life style changes 
recommendedb

Initiate symptomatic 
treatmentc

Interrupt study treatment until 
recovery to ≤grade 1d

Recovery to ≤grade 1 within 7 
days: Restart study treatment at 
previous dose level

No recovery to grade ≤1 within 7 
days or ≥ 2nd occurrence: restart 
with study treatment reduced 
by one dose levele
Grade ≥3

Life style changes 
recommendedb

Initiate symptomatic 
treatmentc

Consult dermatologist

Interrupt study treatment until 
recovery to ≤ grade 1d

Restart with study treatment 
reduced by one dose levele

If 3rd occurrence, discontinue 
study treatment permanently 
CTCAE = Common Terminology Criteria for Adverse Events
a. A full-body skin examination and a removal of pre-existing calluses and keratotic skin is recommended prior to 
initiation of study treatment
b. Life-style changes: (1)reduce exposure of hands and feet to hot water, (2) avoid traumatic activity including vigorous 
exercise especially in the first 4 weeks after start of study treatment, (3) avoid constrictive footwear, (4) avoid 
excessive friction on the skin, when applying topical treatments, (5) wear thick cotton socks and gloves, and 
shoes with padded insoles
c. Symptomatic Treatments: (1) use moisturizing creams frequently and especially on hands and feet (2) consider 
topical keratolytics: urea 20-40 % cream, or salicylic acid 6%, or tazarotene 0.1% cream, or fluorouracil 5% 
cream; (3) erythrematous areas: clobetasol propionate 0.05% ointment; (4) Pain: topical lidocaine 2%, and / or 
systemic pain medication such as nonsteroidal anti-inflammatory drugs, codeine, and pregabalin 
d.  Approval of Novartis Medical Lead is required to re-start study treatment after 21 days of interruption.
e. Escalation of study treatment to the previous dose level is allowed if no HFSR is observed in the 4 weeks 
subsequent to dose reduction. 


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5.8.4.4
Guidelines for cuSCC
Cutaneous squamous cell carcinomas have been observed in subjects treated with dabrafenib 
and the combination of dabrafenib and trametinib (see dabrafenib and trametinib combination 
IB). These treatment-related cuSCC should be surgically removed according to institutional 
practice.  Dose modifications or interruptions of the study treatment are not required for 
cuSCC.  Occurrence of cuSCC must be reported as an SAE. Submit cuSCC tumor tissue for 
analysis as directed in the SPM.
5.8.5
Guidelines for Other Adverse Events of Special Interest
5.8.5.1
Guidelines for Pyrexia
Episodes of pyrexia have been observed in subjects receiving dabrafenib monotherapy , and is 
increased in incidence and severity in subjects receiving dabrafenib in combination with 
trametinib. In a minority of cases the pyrexia was accompanied by symptoms such as severe 
chills, dehydration, hypotension, dizziness or weakness. 
Subjects should be instructed on the importance of immediately reporting febrile episodes.  In 
the event of a fever, the subject should be instructed to take non-steroidal anti-pyretics (e.g.-
ibuprofen or acetaminophen/paracetamol) as appropriate to control fever. The use of oral 
corticosteroids should be considered in those instances in which anti-pyretics are insufficient. 
Monitor serum creatinine and other evidence of renal function during and following severe 
events of pyrexia (see Section 5.8.5.3).  
Guidelines regarding management and dose reduction for pyrexia considered to be related to 
study treatment are provided in Table 12.


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


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Table 12
Management and Dose Modification Guidelines for Pyrexia (Continued)
a.
Pyrexia is defined as a body temperature equal to or above 38.5 Celsius or 101.3○Fahrenheit. 
b.
For subjects experiencing pyrexia, a clinical evaluation and laboratory work-up is mandatory for each event; anti-
pyretic treatment should be started immediately at the first occurrence and prophylactic anti-pyretic treatment is 
recommended
c.
Thorough clinical examination for signs and symptoms of infection or hypersensitivity is required; laboratory work-
up should include full-blood-count, electrolytes, creatinine, blood urea nitrogen (BUN), C-reactive protein (CRP), 
liver-function tests, blood culture, and urine culture.
d. 
Oral hydration should be encouraged in subjects without evidence of dehydration.  Intravenous hydration is 
recommended in subjects experiencing pyrexia complicated by dehydration/hypotension.
e. 
Anti-pyretic treatment may include acetaminophen, ibuprofen, or suitable anti-pyretic medication according to 
institutional standards. Prophylactic anti-pyretic treatment may be discontinued after three days in the absence of 
pyrexia
f.
In subject experiencing pyrexia complicated by rigors, severe chills, etc., which cannot be controlled with anti-
pyretic medication, oral corticosteroids should be started at the 2nd event and doses should be gradually 
increased for subsequent events.
g. 
Dabrafenib should be reduced by one dose level after three episodes of pyrexia complicated by rigors, severe 
chills, etc., which cannot be managed by best supportive care and increasing doses of oral steroids.  Escalation of 
dabrafenib is allowed if no episode of pyrexia is observed in the 4 weeks subsequent to dose reduction.
5.8.5.2
Guidelines for Diarrhea
Episodes of diarrhea have occurred in subjects receiving dabrafenib, trametinib, or both 
therapies in combination. Other, frequent causes for diarrhea including concomitant 
medications (e.g., stool softeners, laxatives, antacids, etc.), infections by C. difficile or other 
pathogens, partial bowel obstruction, etc., should be clinically excluded.
Guidelines regarding management and dose reduction for diarrhea considered to be related to 
study treatment by the investigator are provided in Table 13.


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Table 13
Management and Dose Modification Guidelines for Diarrhea
CTCAE Grade
Adverse Event Management
Action and Dose Modification
Uncomplicated 
Diarrheaa
Grade 1 or 2

Diet: stop all lactose containing 
products; eat small meals, BRAT-
diet (banana, rice, apples, toast) 
recommended

Hydration: 8-10 large glasses of 
clear liquids per day (e.g., 
Gatorade or broth)

Loperamidec: initially 4 mg, 
followed by 2 mg every four hours 
or after every unformed stool; 
maximum 16 mg/day. Continue 
until diarrhea free for 12 hours

Diarrhea  24h: loperamide 2 mg 
every two hours; maximum 16 
mg/day.  Consider adding oral 
antibiotics

Diarrhea  48h: loperamide 2 mg 
every two hours; maximum 16 
mg/day. Add budesonide or other 
second-line therapies (otreotide, or 
tincture of opium) and oral 
antibiotics

Continue study treatment

If diarrhea is grade 2 for 48h, 
interrupt study treatment
until diarrhea resolves to grade 
≤1

Restart study treatment at the 
same dose level
Uncomplicated 
Diarrheaa
Grade 3 or 4
Any Complicated 
Diarrheab

Clinical evaluation mandatory

Loperamidec: initially 4 mg, 
followed by 2 mg every four hours 
or after every unformed stool; 
maximum 16 mg/day. Continue 
until diarrhea free for 12 hours

Oral antibiotics and second-line
therapies if clinically indicated

Hydration: intravenous fluids if 
clinically indicated

Antibiotics (oral or intravenous) if 
clinically indicated

Intervention should be continued 
until the subject is diarrhea free for 
≥ 24 hours

Intervention may require 
hospitalization for subjects at risk 
of life-threatening complications

Interrupt study treatment until 
diarrhea resolves to grade  ≤1

Restart with study treatment 
reduced by one dose leveld

If 3 dose reductions of study 
treatment are clinically 
indicated, permanently 
discontinue study treatment


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Table 13
Management and Dose Modification Guidelines for Diarrhea (Continued)
CTCAE = Common Terminology Criteria for Adverse Events
a.
Uncomplicated diarrhea defined by the absence of  symptoms such as, cramping, nausea/vomiting ≥grade 2, 
decreased performance status, pyrexia, sepsis, neutropenia grade ≥3, frank bleeding, and/or dehydration 
requiring intravenous fluid substitution
b.
Complicated diarrhea defined by the presence of symptoms such as, cramping, nausea/vomiting ≥grade 2, 
decreased performance status, pyrexia, sepsis, neutropenia grade ≥3, frank bleeding, and/or dehydration 
requiring intravenous fluid substitution
c.
Loperamide should be made available prior to start of study treatment so loperamide administration can begin at 
the first signs of diarrhea
d.
Escalation of study treatment to previous dose level is allowed after consultation with the Novartis Medical Lead
and in the absence of another episode of complicated or severe diarrhea in the 4 weeks subsequent to dose 
reduction
5.8.5.3
Guidelines for Renal Insufficiency
Cases of renal insufficiency have occurred in subjects receiving dabrafenib and the 
combination of dabrafenib and trametinib. Prior to start of study treatment, concomitant 
medications should be reviewed for the potential risk of inducing nephrotoxicity and 
concomitant medications should be modified if clinically possible. 
Guidelines regarding management and dose reduction for renal insufficiency considered to be 
related to study treatment by the investigator are provided in Table 14.


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Table 14
Management and Dose Modification Guidelines for Renal Insufficiency
Serum Creatinine Level
Adverse Event Management
Action and Dose Modification
Serum creatinine increase 
>0.2 mg/dL (18 umol/L)
but 
0.5 mg/dL (44 umol/L) 
above baseline

Recheck serum creatinine 
within 1 week

Serum creatinine increase > 1 
week: contact Novartis 
Medical Lead

If pyrexia is present, treat 
pyrexia as per guidelinesa

Continue study treatment 
at the same dose level
Serum creatinine increase 
>0.5 mg/dL (44 umol/L) 
above baseline 
or 
serum creatinine 
>2 mg/dL (> 177 umol/L)

Monitor serum creatinine ≥ 2-
times per week 

Hospitalization may be 
necessary if serum creatinine 
cannot be monitored 
frequently

If pyrexia is present, treat 
pyrexia per guidelinesa

Consult nephrologist if 
clinically indicated

Perform renal biopsy if 
clinically indicated, for 
example:
o
Renal insufficiency 
persists despite 
volume repletion
o
Subject has new rash 
or signs of 
hypersensitivity (such 
as elevated 
eosinophil count)

Interrupt study treatment 
until serum creatinine 
recovers to baseline

Restart with study 
treatmentb
NSAIDS = non-steroidal anti-inflammatory drugs
a.
NSAIDs can induce renal insufficiency, especially in subjects with dehydration; encourage oral fluids or consider 
intravenous fluids as clinically indicated. See guidelines for pyrexia Section 5.8.5.1.
b.
Investigator may restart at either the same or a reduced dose level.  Escalation of study treatment to previous 
dose level is allowed if another episode of renal insufficiency does not occur after 4 weeks of dose reduction.  
Consultation with Novartis Medical Lead is required before restarting study treatment if there is evidence of 
thrombotic microangiopathy.
5.8.5.4
Guidelines for Visual Changes or Specified Ophthalmic Examination 
Findings
Episodes of visual changes have been observed in subjects receiving trametinib, dabrafenib, 
and combination therapy. An ophthalmologist should be consulted if changes in vision 
develop.  However, if the visual changes are clearly unrelated to study treatment (e.g., allergic 
conjunctivitis), then monitor closely as it may be reasonable to defer ophthalmic examination. 


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Treatment with dabrafenib has been associated with the development of uveitis, including 
iritis. Monitor patients for visual signs and symptoms (such as, change in vision, photophobia 
and eye pain) during therapy. Special attention should be given to retinal findings (e.g., retinal 
pigment epithelial detachment (RPED) or retinovascular abnormalities (i.e., branch or central 
retinal vein occlusions (RVO).  For events of visual changes (regardless of severity) for which 
an ophthalmic examination is conducted, a blood sample for PK analysis must be drawn as 
close as possible to the time of the event.
Guidelines regarding management and dose reduction for visual changes and/or ophthalmic 
examination findings considered to be related to study treatment are provided in Table 15.
Table 15
Management and Dose Modification Guidelines for Visual Changes
and/or Ophthalmic Examination Findings
CTCAE Gradea
Adverse Event Management
Action and Dose Modification
Grade 1b

Consult ophthalmologist within 7 
days of onset

If dilated fundus examination cannot be 
performed within 7 days of onset, 
interrupt trametinib until RPED and RVO 
can 
be 
excluded 
by 
retina 
specialist/ophthalmologist. 

If
subject 
is
receiving 
trametinib/dabrafenib 
combination 
therapy dabrafenib may be continued.If 
RPED and RVO excluded, continue (or 
restart) trametinib at same dose level

If RPED suspected or diagnosed: see 
RPED dose modification Table 16
below; report as SAE if diagnosed.

If RVO:  Permanently discontinue 
study treatment
Grade 2 and
Grade 3

Consult ophthalmologist 
immediately 

Interrupt trametinib.  If subject is 
receiving trametinib/dabrafenib 
combination therapy dabrafenib 
may be continued.

If RPED and RVO excluded, restart 
trametinib at same dose level. 

If RPED diagnosed, see RPED dose 
modification table below; report as 
SAE.

If RVO: Permanently discontinue 
trametinib and report as SAE.
Grade 4

Consult ophthalmologist 
immediately 

Interrupt trametinib. If subject is 
receiving trametinib/dabrafenib 
combination therapy dabrafenib 
may be continued.

If RPED and RVO excluded, may 
consider restarting trametinib at same or 
reduced dose after discussion with 
study Medical Lead

If RVO or RPED diagnosed,
permanently discontinue trametinib 
and report as SAE.
Abbreviations:  RPED = retinal pigment epithelial detachment; CTCAE = Common Terminology Criteria for Adverse 
Events; 


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RVO = retinal vein occlusion; SAE = serious adverse event
a. 
Refers to CTCAE Version 4.0 ‘Eye disorders – Other, specify’
b.
If visual changes are clearly unrelated to study treatment (e.g., allergic conjunctivitis), monitor closely but 
ophthalmic examination is not required.
Table 16
Recommended dose modifications for trametinib for retinal pigment 
epithelial detachments (RPED)a
CTCAE Grade
Action and Dose Modification
Grade 1 RPED (Asymptomatic; clinical or 
diagnostic observations only)

Continue treatment with retinal evaluation monthly 
until resolution. If RPED worsens follow 
instructions below
Grade 2-3 RPED (Symptomatic with mild to 
moderate decrease in visual acuity; limiting 
instrumental ADL)

Interrupt trametinib 

Retinal evaluation monthly 

If improved to ≤ Grade 1, restart trametinib at 
lower dose (reduced by 0.5 mg) or discontinue in 
patients taking trametinib 1 mg daily
a.
Refers to CTCAE Version 4.0 ‘Retinopathy’
Ophthalmologic Exam
At certain time points in the trial (see Table 20) and if visual changes develop (as described in 
this section below), an eye exam is indicated. The exam will include best corrected visual 
acuity, tonometry, slit lamp biomicroscopic examination, visual field examination, and dilated 
indirect fundoscopy with special attention to retinal abnormalities. Optical coherence 
tomography is strongly recommended at scheduled visits, and if retinal abnormalities are 
suspected. Other types of ancillary testing including color fundus photography and fluorescein 
angiography are also recommended if clinically indicated.
For adverse events of uveitis, no dose modifications are required as long as effective local 
therapies can control ocular inflammation. If uveitis does not respond to local ocular therapy, 
interrupt dabrafenib and hold until resolution of ocular inflammation. Then restart dabrafenib 
reduced by one dose level. 
5.8.5.5
Guidelines for Pneumonitis
Pneumonitis has been observed in subjects receiving trametinib. To reduce the risk of 
pneumonitis, subjects will be monitored closely for symptoms, evaluated with imaging and 
functional tests. Dose modification and supportive care guidelines for pneumonitis are 
described in Table 17.


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Table 17
Management and Dose Modification Guidelines for Pneumonitis
CTCAE 
Grade
Adverse Event Management
Action and Dose Modification
Grade 1

CT scan (high-resolution with lung windows) 
recommended

Clinical evaluation and laboratory work-up for 
infection

Monitoring of oxygenation via pulse-oximetry 
recommended 

Consultation of pulmonologist recommended 

Continue trametinib at current 
dose
Grade 2

CT scan (high-resolution with lung windows)

Clinical evaluation and laboratory work-up for 
infection

Consult pulmonologist

Pulmonary function tests –if < normal, repeat
every 8 weeks until ≥ normal

Bronchoscopy with biopsy and/or BAL 
recommended

Symptomatic therapy including corticosteroids 
if clinically indicated

Interrupt trametinib until recovery 
to grade ≤1

Restart with trametinib reduced 
by one dose level

Escalation to previous dose level 
after 4 weeks and consultation 
with Novartis Medical Lead
possible

If no recovery to grade ≤1 within 
4 weeks, permanently 
discontinue study treatment
Grade 3

CT scan (high-resolution with lung windows)

Clinical evaluation and laboratory work-up for 
infection

Consult pulmonologist

Pulmonary function tests-if < normal, repeat 
every 8 weeks until ≥ normal

Bronchoscopy with biopsy and/or BAL if 
possible

Symptomatic therapy including corticosteroids 
as clinically indicated

Interrupt trametinib until recovery 
to grade ≤1

After consultation with Novartis 
Medical Lead, study treatment 
may be restarted reduced by 
one dose level

If no recovery to grade ≤1 within 
4 weeks, permanently 
discontinue study treatment
Grade 4

Same as grade 3

Permanently discontinue 
study treatment or if recovers 
to grade ≤1 obtain Novartis 
Medical Lead approval if patients 
is expected to benefit from the 
study treatment

BAL= broncioalveolar lavage; CT = computed tomography; CTCAE = Common Terminology 
Criteria for Adverse Events


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5.9
Monitoring, Interruption and Stopping Criteria for Hepatobiliary 
Events
5.9.1
Liver Chemistry Stopping Criteria
These liver chemistry stopping and follow-up criteria have been designed to assure subject 
safety and evaluate liver event etiology in alignment with the FDA premarketing clinical liver 
safety guidance).  
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances
/UCM174090. 
Liver chemistry stopping criteria 1-5 are defined below and an algorithm is presented in 
Appendix 6:
1. ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin) (or ALT3xULN and 
INR>1.5, if INR measured)
NOTE: If serum bilirubin fractionation is not immediately available, study 
treatment should be discontinued if ALT 3xULN and bilirubin 2xULN. 
Serum bilirubin fractionation should be performed if testing is available.  If 
testing is unavailable, record presence of detectable urinary bilirubin on 
dipstick, indicating direct bilirubin elevations and suggesting liver injury.
2. ALT 8xULN
3. ALT 5xULN but <8xULN persists for  ≥2 weeks
4. ALT 3xULN if associated with the appearance or worsening of symptoms believed 
to be hepatitis (such as fatigue, nausea, vomiting, right upper quadrant pain or 
tenderness, or jaundice) or hypersensitivity (such as fever, rash or eosinophilia).
5. 5xULN but <8xULN and cannot be monitored weekly for >2 weeks.
When any of the liver chemistry stopping criteria 1 – 5 is met, do the following:

Immediately discontinue subject from study treatment 

Report the event to Novartis within 24 hours of learning its occurrence

Complete the liver event CRF and SAE data collection tool if the event also meets the 
criteria for an SAE  

All events of ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin) (or 
ALT3xULN and INR>1.5, if INR measured; INR measurement is not required and 
the threshold value stated will not apply to subjects receiving anticoagulants), termed 
‘Hy’s Law’, must be reported as an SAE.

NOTE: if serum bilirubin fractionation is not immediately available, study treatment 
should be discontinued if ALT 3xULN and bilirubin 2xULN. Serum bilirubin 
fractionation should be performed if testing is available. If testing is unavailable, 
record presence of detectable urinary bilirubin on dipstick, indicating direct 
bilirubin elevations and suggesting liver injury


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
Complete the liver imaging and/or liver biopsy CRFs if these tests are performed

Perform liver event follow up assessments, and monitor the subject until liver chemistries 
resolve, stabilize, or return to baseline values as described below

Withdraw the subject from the study treatment after completion of the liver chemistry 
monitoring as described below (unless further safety follow up is required or Novartis
Medical Governance approval of drug restart is granted, as described in Section 5.9.1.3.

Follow up for overall survival is required following discontinuation from study 
treatment. 

Do not rechallenge with study treatment unless written approval for drug restart is 
granted by Novartis Medical Governance (details for restarting investigational product 
are described in Section 5.9.1.3, whereupon the subject continues in the study after 
completion of the liver chemistry monitoring described in Section 5.9.1.2). 

Subjects meeting criterion 5 should be monitored as frequently as possible.
In addition, for subjects meeting liver stopping criterion 1: 

Make every reasonable attempt to have subjects return to clinic within 24 hours for 
repeat liver chemistries, liver event follow up assessments (refer to Section 5.9.1.1), and 
close monitoring

A specialist or hepatology consultation is recommended

Monitor subjects twice weekly until liver chemistries (ALT, AST, alkaline phosphatase, 
bilirubin) resolve, stabilize or return to within baseline values.
For subjects meeting any of the liver stopping criteria 2 – 5:

Make every reasonable attempt to have subjects return to clinic within 24-72 hrs for 
repeat liver chemistries and liver event follow up assessments (refer to Section 5.9.1.1)

Monitor subjects weekly until liver chemistries (ALT, AST, alkaline phosphatase, 
bilirubin) resolve, stabilize or return to within baseline values 

Subjects meeting criterion 5 should be monitored as frequently as possible.


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5.9.1.1
Liver Event Follow-up Assessments
For subjects meeting any of the liver chemistry stopping criteria 1 – 5, make every attempt to 
carry out the liver event follow up assessments described below:

Viral hepatitis serology including:
•
Hepatitis A IgM antibody
•
Hepatitis B surface antigen and Hepatitis B Core Antibody (IgM) 
•
Hepatitis C RNA 
•
Cytomegalovirus IgM antibody 
•
Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, obtain 
heterophile antibody or monospot testing)  
•
Hepatitis E IgM antibody.

Blood sample for pharmacokinetic (PK) analysis, obtained within 10 days of last dose.  
Record the date/time of the PK blood sample draw and the date/time of the last dose of 
study treatment prior to blood sample draw on the CRF.  If the date or time of the last dose 
is unclear, provide the subject’s best approximation.  If the date/time of the last dose 
cannot be approximated OR a PK sample cannot be collected in the time period indicated 
above, do not obtain a PK sample.  Instructions for sample handling and shipping are in 
the SPM. PK sampling will be discontinued 8 weeks after last patient first treatment.

Serum creatine phosphokinase (CPK) and lactate dehydrogenase (LDH).

Fractionate bilirubin, if total bilirubin 2xULN.

Obtain complete blood count with differential to assess eosinophilia.

Record the appearance or worsening of clinical symptoms of hepatitis, or 
hypersensitivity, such as fatigue, nausea, vomiting, right upper quadrant pain or 
tenderness, pyrexia, rash or eosinophilia as relevant on the AE form. Please note that 
treatment with trametinib often associates with rash which is usually acneiform and 
affects the scalp, face, neck, chest, and upper back. Discuss with Novartis Medical Lead
as needed.

Record use of concomitant medications such as acetaminophen, herbal remedies, other 
over the counter medications, or putative hepatotoxins, on the concomitant medications 
form.

Record alcohol use on the liver event alcohol intake form.
The following assessments are required for subjects with ALT 3xULN and bilirubin 
2xULN (>35% direct) but are optional for other abnormal liver chemistries:

Anti-nuclear antibody, anti-smooth muscle antibody, and Type 1 anti-liver kidney 
microsomal antibodies and quantitative total immunoglobulin G (IgG or gamma 
globulins).

Liver imaging (ultrasound, magnetic resonance, or computerized tomography) to evaluate 
liver disease.


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
Serum acetaminophen adduct assay (quantifies potential acetaminophen contribution to 
liver injury, in subjects with definite or likely acetaminophen use in the preceding week. 
NOTE: not required in China [James LP 2009].

Only in those with underlying chronic hepatitis B at study entry (identified by positive 
hepatitis B surface antigen):  quantitative hepatitis B DNA and hepatitis delta antibody.
NOTE:  if hepatitis delta antibody assay cannot be performed,, it can be replaced with a 
Polymerase chain reaction (PCR) of hepatitis D RNA virus (where needed) [Le Gal F
2005].
5.9.1.2
Liver Chemistry Monitoring Criteria
For subjects with ALT 3xULN but <8xULN which exhibit a decrease to ALT 3xULN, but 
<5xULN and bilirubin <2xULN, without hepatitis symptoms or rash, and who can be 
monitored weekly for 4 weeks, the following actions should be taken:

Notify the Novartis Medical Lead within 24 hours of learning of the abnormality to 
discuss subject safety

Continue study treatment 

Return weekly for repeat liver chemistries (ALT, AST, alkaline phosphatase, bilirubin) 
until they resolve, stabilize or return to within baseline values 

If at any time the subject meets any of the liver chemistry stopping criteria 1 – 5, proceed 
as described above

If, after 4 weeks of monitoring, ALT <3xULN and bilirubin <2xULN, monitor subjects 
twice monthly until liver chemistries normalize or return to within baseline values. 

Refer to Section 12.6 for an algorithm of liver chemistry monitoring, stopping, and 
follow-up criteria.
5.9.1.3
Drug Restart/Rechallenge Following Liver Events that are Possibly 
Related to Study Treatment
Approval by Novartis for study treatment restart can be considered where:
The subject is receiving compelling benefit, benefit of drug restart exceeds risk, and no 
effective alternative therapy is available.  Ethics Committee or Institutional Review Board 
approval of study treatment restart/rechallenge must be obtained, as required.   
If the restart/rechallenge is approved by Novartis in writing, the subject must be provided with 
a clear description of the possible benefits and risks of drug administration, including the 
possibility of recurrent, more severe liver injury or death.  
The subject must also provide signed informed consent specifically for the study treatment 
restart/rechallenge. Documentation of informed consent must be recorded in the study chart.  
Study treatment must be administered at the dose specified by Novartis.


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Subjects approved by Novartis for restart/rechallenge of study treatment must return to the 
clinic twice a week for liver chemistry tests until stable, liver chemistries have been 
demonstrated and then laboratory monitoring may resume as per protocol. 
6
Concomitant Medications and Non-Drug Therapies
6.1
Permitted Medications and Non-drug Therapies
The investigator must be informed as soon as possible about any medication taken from the 
time of screening until 30 days after the last dose of study treatment. Any concomitant 
medication(s), including dietary supplements, taken during the study will be recorded in the 
eCRF.  The minimum requirement is that drug name, dose, and the dates of administration are 
to be recorded.  Additionally, a complete list of all prior anti-cancer therapies will be recorded 
in the eCRF.  
Subjects should receive full supportive care during the study, including transfusions of blood 
and blood products, and treatment with antibiotics, anti-emetics, anti-diarrheals, and 
analgesics, and other care as deemed appropriate, and in accordance with their institutional 
guidelines.  Use of anticoagulants such as warfarin is permitted, however, caution should be 
exercised and additional International Normalized Ratio (INR) monitoring is recommended 
when dabrafenib is used concomitantly with warfarin.While patients are on study treatment, 
palliative radiation therapy is permitted for non-target lesions that are either new or present at 
baseline.
Radiation skin injury has been reported with concurrent use of dabrafenib and radiation. It is 
recommended that dabrafenib be held for seven days before and two days after radiation 
therapy (XRT)in subjects receiving dabrafenib monotherapy or in combination with 
trametinib. These recommendations can be modified based on the physician’s assessment of 
the risk of radiation skin injury.
Prohibited Medications and Non-drug Therapies
The use of certain medications and illicit drugs within 28 days or 5 half lives, whichever is 
shorter, prior to enrollment and for the duration of the study will not be allowed. The Novartis
Medical Lead can approve the use of a prohibited medication if it is required for a single use 
(such as for a procedure) while treatment with study drug is interrupted.  
The following medications or non-drug therapies are also prohibited while on treatment in this 
study:

Other anti-cancer therapies;

Other investigational drugs;

Antiretroviral drugs (Note: Subjects with known HIV are ineligible for study 
participation);

Herbal remedies (e.g., St. John’s wort);

Dabrafenib is metabolized primarily by Cytochrome P450 (CYP) 2C8 and CYP3A4.  Co-
administration of dabrafenib with ketoconazole, a CYP3A4 inhibition, or with 
gemfibrozil, a CYP2C8 inhibitor, resulted in increases in dabrafenib AUC of 71% and 


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47%, respectively.  Drugs that are strong inhibitors or inducers of CYP3A and CYP2C8
(see list in Table 18) may only be used under special circumstances (e.g. as a single use 
for a procedure) while treatment with study drug is interrupted as they may alter 
dabrafenib concentrations; consider therapeutic substitutions for these medications.  
Approval of the Novartis Medical Lead is required in these situations. The list may be 
modified based on emerging data. Refer to the SPM for the most current list. 
Subjects should not receive palliative radiotherapy prior to documented disease progression 
while on treatment in this study.
Table 18
Prohibited Medications
PROHIBITED – strong inducers of CYP3A or CYP2C8, since concentrations of dabrafenib may be 
decreased
Class/Therapeutic Area
Drugs/Agents
Antibiotics*
Rifamycin class agents (e.g.,  rifampin, rifabutin, rifapentine), 
Anticonvulsant
Carbamazepine, oxcarbazepine phenobarbital, phenytoin, s-mephenytoin 
Miscellaneous
bosentan, St-John’s wort
PROHIBITED – Strong inhibitors of CYP3A, or CYP2C8 since concentrations of dabrafenib may be 
increased
Class/Therapeutic Area
Drugs/Agents
Antibiotics*
Clarithromycin, telithromycin, troleandomycin
Antidepressant
Nefazodone
Antifungals*
Itraconazole, ketoconazole, posaconazole, voriconazole
Hyperlipidemia
Gemfibrozil
Antiretroviral
ritonavir, saquinavir, atazanavir
Miscellaneous
Conivaptan 
*: topical use is allowed if clinically indicated.
6.2
Medications to be Used with Caution
The following medications should be used with caution as their concentrations may be altered 
by dabrafenib or they may alter dabrafenib concentrations:

Drugs that are moderate inhibitors or inducers of CYP3A and CYP2C8 as they may 
alter concentrations of dabrafenib.

Dabrafenib has been shown to induce CYP3A4 and CYP2C9 in vivo using 
midazolam (CYP3A4 substrate) and S-warfarin (CYP2C9 substrate).  Dabrafenib is 
an in vitro inducer of CYP2B6 and other enzymes such as CYP2C8, CYP2C19, 
UDP-glucuronyl transferases. Transporters may also be affected.  Co-administration 
of dabrafenib and medications which are affected by the induction of these enzymes 
(including warfarin) and transporters may result in loss of efficacy.  If co-
administration of these medications is necessary, investigators should monitor 
subjects for loss of efficacy or consider substitutions of these medications. A partial 
list of these medications is provided in the SPM.


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
Therapeutic level dosing of warfarin can be used with approval by the Novartis
Medical Lead and close monitoring of PT/INR by the site. Exposure decreased by 
37% due to enzyme induction when on treatment, thus warfarin dosing may need to 
be adjusted based upon PT/INR. Consequently, when discontinuing dabrafenib, 
warfarin exposure may be increased and thus close monitoring via PT/INR and 
warfarin dose adjustments must be made as clinically appropriate. Prophylactic low 
dose warfarin may be given to maintain central catheter patency. 

Dabrafenib solubility is pH-dependent with decreased solubility at higher pH. Drugs 
such as proton pump inhibitors that inhibit gastric acid secretion to elevate gastric pH 
may decrease the solubility of dabrafenib and reduce its bioavailability. No clinical 
study has been conducted to evaluate the effect of pH on dabrafenib 
pharmacokinetics. In an ad-hoc analysis, no differences in the maximum peak 
concentration (Cmax) and AUC were noted between subjects who reported taking pH-
elevating products relative to other subjects. Due to the theoretical risk that pH-
elevating agents may decrease oral bioavailability and exposure to dabrafenib, these 
medicinal products that increase gastric pH should be used with caution when 
administered with dabrafenib.


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Table 19
Medications to be used with Caution
USE WITH CAUTION: :  Moderate  inhibitors of CYP3A, or CYP2C8 since concentrations of 
dabrafenib may be increased
Class/Therapeutic Area
Moderate CYP3A and CYP2C8 Inhibitors
Antiarrhythmics
Diltiazem, verapamil
Antibiotic
Erythromycin
Antifungal
Fluconazole
Miscellaneous
Aprepitant
USE WITH CAUTION: Co-administration of these drugs with study treatment may result in loss of 
efficacy.  Monitor subjects for loss of efficacy or substitute with another medication.
Class/Therapeutic Area
CYP3A4, CYP2B6, CYP2C8, CYP2C9, or CYP2C19 Substrates that 
May be Affected by Induction 
Analgesics
Alfentanil, buprenorphine, celecoxib, codeine, fentanyl, methadone, oxycodone
Antiarrhythmics
Disopyramide, dronedarone, mexiletine, propafenone, quinidine
Antibiotics
Chloramphenicol, doxycycline, erythromycin, moxifloxacin 
Anticoagulants/ Antiplatelets
Cilostazole, warfarin
Anticonvulsants
Divalproex, lamotrigine, valproate, zonisamide
Antidepressants and 
Antipsychotics
Aripiprazole, bupropion, buspirone, desipramine, haloperidol, mirtazapine, 
pimozide, quetiapine, trazodone
Antidiabetics
Glyburide, saxagliptin, tolbutamide
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
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
Selective Aldosterone Blockers
Eplerenone
Abbreviations: CYP = cytochrome P450; HMG-CoA = 3-hydroxy-3-methylglutaryl-coenzyme A.
Questions regarding concomitant medications should be directed to the Novartis Medical 
Lead for clarification.


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6.3
Treatment after Discontinuation from both Study Treatments or 
Withdrawal from/Completion of the Study
The investigator is responsible for ensuring that consideration has been given to the post-study 
care of the subject’s medical condition whether or not Novartis is providing specific post 
study treatment.
Post-study treatment will not be provided as part of the protocol.  Upon discontinuation from 
assigned study treatment, subjects may receive additional (non-protocol) anti-cancer therapy 
at the discretion of the treating physician.  New anti-cancer therapy should be documented in 
the eCRF that includes new therapy onset and end dates if possible.  Every effort should be 
made to complete the required follow-up evaluations prior to initiating new anti-cancer 
therapy.  Subjects will be followed for survival even if other assessments are not performed.
Refer to Section 4.2 for follow-up assessment of subjects who are to be followed for survival 
and/or disease progression after permanently discontinuing both study treatments.
Upon study completion, if some subjects are still on study treatment and have not yet 
progressed, their follow-up treatment will be at the discretion of the attending physician. 
6.4
Treatment of Study Treatment Overdose
In the event of a dabrafenib overdose, defined as administration of more than 300 mg as a 
single dose or 600 mg per day (the highest dose tested in clinical studies to date), and/or a 
trametinib overdose, defined as administration of more than 3.0 mg once daily (the maximum 
tolerated dose defined in the MEK111054 Study), the investigator should contact the Novartis
Medical Lead immediately and closely monitor the subject for AEs/SAEs and laboratory 
abnormalities.  Novartis does not recommend specific treatment.  The investigator will use 
clinical judgment to treat any overdose. Haemodialysis is not expected to enhance the 
elimination of either dabrafenib or trametinib as both are highly bound to plasma proteins.
Decisions regarding dose modifications or interruptions will be made by the investigator in 
consultation with the Novartis Medical Lead based on the clinical evaluation of the subject.
A plasma sample for PK analysis may be requested by the Novartis Medical Lead on a case-
by-case basis.  This plasma sample should be collected as soon as possible, but within 10 days 
from the date of the last dose of on-study dosing.
Information regarding the quantity of the excess dose as well as the duration of the overdosing 
should be documented in the eCRF.
7
Study Assessments and Procedures
A signed, written informed consent form must be obtained from the subject prior to any study-
specific procedures or assessments.
Re-screening of patients who failed to be enrolled (for other reasons than BRAF status) will 
be allowed. BRAF assay does not need to be repeated providing a positive result from the 
central lab is available. 
Procedures conducted as part of the subject’s routine clinical management (e.g., blood counts, 
imaging) and obtained prior to signing of informed consent may be used for screening or 
baseline purposes provided the procedure meets the protocol-defined criteria and has been 
performed within the timeframe specified in the protocol. Central laboratory results for BRAF 


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testing, coagulation, hematology, clinical chemistry, and serum pregnancy are required for 
eligibility.
Refer to the Time and Events Table (Table 20) for the timing of all assessments.  Assessments 
must be performed on a calendar schedule; delays in treatment administration will not delay 
performance of assessments.  Details on efficacy and safety assessments are presented in 
Section 7.2 and Section 7.3, respectively. 
 
  Further details of study procedures and assessments can be found in the SPM.
Investigators may be requested to perform additional safety tests during the course of the 
study based on newly available data to ensure appropriate safety monitoring.  Appropriate 
local regulatory and ethical approvals should be obtained before any additional testing is 
performed.
Table 20 outlines study assessments and their timing.


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Table 20
Time and Events Table
STUDY PHASES1
SCREENING2
TREATMENT
FOLLOW-UP
Day 1
Day 15
Every 4 
Weeks
Every 8 
Weeks
Every 12 
Weeks
Treatment
Discontinuation27 Contact
Conclusion
Visit Window (Days)
(28 except 
where noted)2
(3)
(3)
(7)
(7)
(7)
(7)
N/A
CLINICAL ASSESSMENTS1
Informed consent3
X
Demographic data
X
Past and current medical conditions including 
cardiovascular medical history and risk factors
X
X4
Family history (cardiac, cancer)
X
Disease characteristics5
X
Prior anti-cancer therapies
X
Tumor tissue for BRAF V600 mutation testing 
(required for eligibility)6
X
Brain MRI/CT7
X 
X7
Lesion assessment8
X 
Week 8, and every 8 weeks through Week 56, then every 12 weeks thereafter (all ± 7 days) until disease 
progression
Performance status (ECOG)
X
X4
X
X
Enrollment
X
SAFETY ASSESSMENTS1
Physical examination9
X
(Complete)
X4
X (Brief)
X
(Complete)
Dermatological examination (including skin 
lesion photography)10
X
X
X
Ophthalmic examination11
X
X
Only at week 
4
Vital signs12
X
X
X
Adverse events13
X
X
X
X
X
X
Concomitant medications14
X
X
X
X
X


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STUDY PHASES1
SCREENING2
TREATMENT
FOLLOW-UP
Day 1
Day 15
Every 4 
Weeks
Every 8 
Weeks
Every 12 
Weeks
Treatment
Discontinuation27 Contact
Conclusion
Visit Window (Days)
(28 except 
where noted)2
(3)
(3)
(7)
(7)
(7)
(7)
N/A
ECG15
X 
(5 weeks)
X
X
(only at 
Week 4, 8 
and 12)
X
(after week 
12)
X
ECHO16
X 
(5 weeks)
X
(only at 
Week 4)
X
Optional non-melanoma skin lesion biopsy
X (anytime if cutaneous squamous cell carcinoma or basal
cell carcinoma develop during the study)
STUDY TREATMENTS
Dispensation of medication17
X
X
Assessment of compliance18
X
X
LABORATORY ASSESSMENTS1
Chemistry and Hematology19
X
X4
X
X
Serum pregnancy test20
X
(≤ 14 days)
Pharmacokinetics blood collection21
X
X


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STUDY PHASES1
SCREENING2
TREATMENT
FOLLOW-UP
Day 1
Day 15
Every 4 
Weeks
Every 8 
Weeks
Every 12 
Weeks
Treatment
Discontinuation27 Contact
Conclusion
Visit Window (Days)
(28 except 
where noted)2
(3)
(3)
(7)
(7)
(7)
(7)
N/A
END OF STUDY
Follow-up contact25
X
Follow-up anti-cancer therapy26
X
Subject completion or withdrawal
X
Abbreviations: 
; CNS = central nervous system; CT = computed tomography; ECG = electrocardiogram; ECHO = echocardiogram; ECOG = 
Eastern Cooperative Oncology Group; LDH = lactate dehydrogenase; LLN = lower limit of normal; LVEF = left ventricular ejection fraction; MRI = magnetic resonance imaging; 
 
; RECIST = Response Evaluation Criteria in Solid Tumors; SPM = study procedures manual.
1.
All assessments mandated throughout the study must be performed on a calendar schedule; delays in treatment administration will not delay performance of assessments.  
2.
Screening procedures may be performed up to 28 days prior to enrollment.  Screening procedures that have a different visit window are indicated in parentheses.  
3.
Informed consent will be obtained prior to performance of any study-related procedures. 
 
  
4.
If done within 3 days before Day 1 , this assessment does not need to be repeated on Day 1.
5.
Disease characteristics will include date of diagnosis and last recurrence, primary tumor type, histology, stage, biopsy details, and visceral/non-visceral disease.
6.
Collection of archived tumor tissue or fresh tumor biopsies for determination of the subject’s BRAF genetic status is required for enrolment (See Section 7.4.4 and SPM for 
details.); for those who consent, additional tumor genetic markers related to the activity of dabrafenib or trametinib may be analyzed. A BRAF V600 mutation test performed by
the central lab does not need to be repeated if enrolment falls outside the screening window providing that the BRAF V600 test result was positive. In case the first sample sent 
to the central laboratory for BRAF testing does not fulfil all quality requirements, the site may send an additional sample obtained from archived tumor tissue or new biopsy to 
confirm the BRAF mutation status as appropriate by clinical judgement and with the agreement from Novartis Medical Lead. 
7.
Baseline MRI (preferred) or CT (only if MRI contraindicated or unavailable) of the brain must be performed on all subjects to rule out current leptomeningeal metastases, brain 
metastases, or spinal cord compression secondary to metastasis.  Post-baseline scans should be performed in all subjects with documented CNS metastases at baseline and 
as clinically indicated (e.g., symptoms suggestive of CNS progression). 
8.
Lesion assessment must be done for chest, abdomen, pelvis, and any area of known disease. Lesion assessment by contrast CT (preferred) or MRI must be performed at the 
times indicated until disease progression, death, or withdrawal of consent, whichever occurs first. (See Section 7.2.2 for instructions regarding chest X-Rays and CT 
assessment). Target and non-target lesions must be identified at the time of screening and the same lesions must be reassessed at each time point in a consistent manner 
according to RECIST, version 1.1. Superficial skin lesions must be assessed as target/non-target lesions by digital color photography with the scale ruler. The same diagnostic 
method, including use of contrast when applicable, must be used throughout the study to evaluate each lesion. Direct lesion measurements will be taken using ruler or calipers. 
If the last assessment was >8 weeks prior to study withdrawal and disease progression had not been documented, a disease assessment should be obtained. Disease 


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assessment should continue in follow up phase for all subjects who discontinue treatment without documented RECIST 1.1 progression and for those who have consented to 
continue study treatment after documented progression. 
9.
A complete physical examination will be performed at Screening and treatment discontinuation; brief physical examinations will be performed at all other time points as indicated. 
Pelvic and rectal exams will be performed at screening and treatment discontinuation and periodically during treatment as clinically indicated; they do not need to be repeated at 
screening if they had been performed within 24 weeks of enrollment.  Refer to Section 7.3.14 for details.
10. A full skin exam will be done every 8 weeks. Photographic images are required to assess hyperproliferative skin diseases. Upon study treatment discontinuation, a final skin 
exam is required within 8 weeks of the last dose of study treatment.
11. An ophthalmic examination will be performed at Screening and week 4; after week 4, additional ophthalmic examinations will be performed only as symptomatically warranted.  
Refer to Section 7.3.12 for details.
12. Refer to Section 7.3.13 for details regarding vital sign measurements.
13. Adverse events will be recorded from the time the first dose of study treatment is administered until 30 days after discontinuation of study treatment.  Serious adverse events will 
be collected over the same time period as AEs except SAEs assessed as related to study participation (e.g., protocol-mandated procedures, invasive tests, or change in 
existing therapy), or study treatment which must be recorded from the time a subject consents to participate in the study up to and including any follow-up contact.
14. All medications the subject takes during the study from the time of screening until 30 days after the last dose of study treatment will be recorded; any new anti-cancer therapy, if 
taken after study treatment discontinuation will be recorded as detailed in footnote 27.
15. At each time point listed, a single 12-lead ECG will be performed by qualified site personnel after the subject has rested in a semi-recumbent or supine position for at least 5 
minutes.  Two copies of the ECG tracing should be obtained at the time of the ECG; the first copy will be kept in the subject’s medical chart and the second copy will be kept in 
the study file for retrospective collection by the Sponsor if necessary.
16. See Section 5.8.3.1 for LVEF guidelines for study drug management and requirements for ECHO scans.
17. A 4-week supply of study medication should be dispensed at each scheduled study visit as of Day 1; Dosing instructions must be provided.  Subjects should start treatment as 
soon as possible after enrolment but no later than 72 hours post-enrolment.
18. Subjects should be instructed to return study drug at each visit; compliance will be assessed by querying the subject and counting tablets/capsules.  Dose modifications and 
interruptions must be recorded.
19. Analysis of clinical chemistry and hematology samples will be performed by a central laboratory 
20. Serum pregnancy test is required at Screening.  Subsequent tests may be urine tests, and should be performed as clinically indicated.
21. Blood samples for PK analysis will be drawn on Day 15 at predose (within 30 minutes prior to dosing) and 1, 2, 4, 6, and 8 hours after dosing. For subjects in China, PK blood 
samples will be drawn on Day 1 at predose (within 30 minutes prior to dosing) and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10 and 24 (pre dose on Day 2) hours and on Day 15 at predose 
(within 30 minutes prior to dosing) and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10 and 24 (pre dose on Day 16) hours after dosing. Refer to section 7.5 and 5.9.1.1 for details on 
pharmacokinetics blood sampling including liver PK sampling.
22.
 
 


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25. Follow-up contact will include clinic visits, telephone contacts, and e-mail communications.  The date of contact must be recorded.  After treatment discontinuation, subjects 
should be contacted for follow-up every 12 weeks 7 days until death.
26. After treatment discontinuation, any new anti-cancer therapy initiated will be recorded until study completion/withdrawal/lost to follow-up, or death.
27. The treatment discontinuation visit should be performed within 30 days of the subject’s last dose. If a subject discontinues study treatment at a scheduled visit, the assessments 
performed at that visit can be used to fulfil the treatment discontinuation visit requirements.  Laboratory assessments and other required assessments do not need to be 
repeated at the discontinuation visit if they were performed within 14 and 30 days, respectively, of the discontinuation visit. If the last disease assessment was >8 weeks prior to 
study withdrawal and disease progression had not been documented, a disease assessment should be obtained.


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7.1
Critical Baseline Assessments
Efficacy assessments conducted at baseline are described in Section 7.2.2, and tumor tissue 
 assessments are described in Section 7.4.2.  Safety assessments conducted at 
baseline and during treatment are described in Section 7.3.  Cardiovascular medical 
history/risk factors will be assessed at baseline.
7.1.1
Baseline Confirmation of BRAF V600 Mutation-positive Melanoma
Subjects with histologically confirmed unresectable or metastatic acral lentiginous or 
cutaneous melanoma that is either Stage IIIC (unresectable) or Stage IV will be screened for
eligibility after signing the informed consent form.  Subjects will be screened prior to 
treatment to determine whether their tumor sample has a V600 mutation, indicating their 
eligibility for the study.  Formalin fixed paraffin embedded (FFPE) specimens reflective of 
the metastatic disease setting is preferred for the mutation testing.  Tumor mutation status will 
be determined in a Novartis designated central lab. Only if clinical outcome data warrants, a 
companion diagnostic assay may need to be developed for regulatory submission and 
approval. Additional BRAF mutation testing may be conducted on the screening tissue to 
support the development of the companion diagnostic assay.
Further details on tissue requirement for BRAF mutation will be provided in the SPM. 
7.1.2
Baseline Documentation of Target and Non-target Lesions
All baseline lesion assessments, including brain MRI/CT to rule out brain metastases, must be 
performed within 4 weeks prior to enrolment.

Lymph nodes that have a short axis of < 10 mm are considered non-pathological and 
should not be recorded or followed.

Pathological lymph nodes with a short axis of < 15 mm but 10 mm are considered non-
measurable.

Pathological lymph nodes with a short axis of 15 mm are considered measurable and 
can be selected as target lesions.  Lymph nodes should not be selected as target lesions 
when other suitable target lesions are available.  

Measurable lesions up to a maximum of 2 lesions per organ and 5 lesions in total, 
representative of all involved organs, should be identified as target lesions, and recorded 
and measured at baseline.  These lesions should be selected on the basis of their size (i.e., 
lesions with the longest diameter) and their suitability for accurate repeated 
measurements (i.e., either by imaging techniques or clinically).  
Note: Cystic lesions thought to represent cystic metastases should not be selected as target 
lesions when other suitable target lesions are available.
Note: Measurable lesions that have been previously irradiated and have not been shown to be 
progressing following irradiation should not be considered as target lesions.  

Lytic bone lesions or mixed lytic-blastic lesions, with identifiable soft tissue components, 
that can be evaluated by CT or MRI can be considered measurable.  Bone scans, 


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fluorodeoxyglucose positron emission tomography (FDG-PET) scans or X-rays are not 
considered adequate imaging techniques to measure bone lesions.

All other lesions (or sites of disease) should be identified as non-target and should also be 
recorded at baseline.  Non-target lesions will be grouped by organ.  Measurements of 
these lesions are not required, but the presence or absence of each should be noted 
throughout follow-up. 
7.2
Efficacy
7.2.1
Efficacy Endpoints
7.2.1.1
Primary Efficacy Endpoint
The primary endpoint for this study is objective response rate of dabrafenib in combination 
with trametinib in subjects with BRAF V600 mutation-positive, unresectable or metastatic 
acral lentiginous or cutaneous melanoma (ALM).  Objective response rate is defined as the 
percentage of subjects with evidence of confirmed complete response (CR) or partial response 
(PR) as per RECIST v1.1 [Eisenhauer EA 2009].
7.2.1.2
Secondary Efficacy Endpoints
The secondary efficacy endpoints of this study are:

Duration of response, defined as the time from first documented evidence of CR or PR 
until the earliest date of documented radiological progression or death due to any 
cause among subjects who achieve a confirmed response (i.e. confirmed CR or PR) 

PFS, defined as the time from first dose of study treatment until the first date of either 
objective disease progression or death due to any cause.

OS, defined as the interval between the treatment start date and the date of death due 
to any cause.
7.2.2
Efficacy Assessments
Disease progression and response evaluations will be determined according to the definitions 
established in RECIST, version 1.1 [Eisenhauer EA 2009].
Refer to the Time and Events Table (Table 20) for the schedule of efficacy assessments.  
Assessments must be performed on a calendar schedule and should not be affected by dose 
interruptions/delays. For post baseline assessments, a window of 7 days is permitted to allow 
for flexible scheduling. 

The following scans/assessments are required at baseline: contrast CT (preferred method) 
of chest/abdomen/pelvis or MRI of abdomen/pelvis and any area of known disease, skin 
lesion photography, and clinical disease assessment for palpable lesions.  Exception: If a 
chest CT cannot be performed, chest X-ray can be used only to document the absence of 
disease (no tumor lesions) or the presence of new lesions. If lesions are detected at 
baseline by chest X-ray, chest CT must be done to properly document these lesions at 
baseline and in follow-up tumor assessments.  At each post-baseline assessment, 
evaluations of the sites of disease identified by these scans are required.  


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
A baseline brain scan is required for all subjects.  For subjects without CNS disease at 
baseline, subsequent brain scans should only be performed as clinically indicated (e.g. 
symptoms suggestive of CNS progression).  For subjects with CNS disease at baseline, a 
brain scan is required every 8 weeks or as clinically indicated.  In addition, in order to 
confirm a CR in a subject with brain disease at baseline, a brain scan must be performed 1 
week prior to the 1st set of images showing CR to 4 weeks after the next protocol 
specified assessment.

If clinically indicated, a contrast enhanced CT or MRI scan of affected bone areas will be 
required at baseline.  Bone lesions, if present as non-target lesions, will continue to be 
followed consistently throughout the study until disease progression, death, or withdrawal 
of consent.  
Confirmation of CR and PR are required per protocol. Confirmation assessments must be 
performed no less than four weeks after the criteria for response have initially been met and 
may be performed at the next protocol scheduled assessment. If a confirmation assessment is 
performed prior to the next protocol schedule assessment, the next protocol scheduled 
evaluation is still required (e.g., evaluations must occur at each protocol scheduled time point 
regardless of unscheduled assessments).
Scans will be assessed by investigators and will be collected and stored.  Details related to 
disease assessment acquisition and image transfer to be applied to baseline and all subsequent 
imaging will be provided in the SPM.
7.2.2.1
Assessment Guidelines
Please note the following:

The same diagnostic method, including use of contrast when applicable, must be used 
throughout the study to evaluate lesions. Contrast agents must be used in accordance with 
the Image Acquisition Guidelines.

All measurements should be taken and recorded in millimeters (mm), using a ruler or 
calipers.

Ultrasound is not a suitable modality of disease assessment.  If new lesions are identified 
by ultrasound, confirmation by CT or MRI is required.

Fluorodeoxyglucose-positron emission tomography (FDG-PET) is generally not suitable 
for ongoing assessments of disease.  It can, however, be useful in confirming new sites of 
disease when a positive FDG-PET scan correlates with the new site of disease present on 
CT/MRI or when a baseline FDG-PET was previously negative for the site of the new 
lesion.  Fluorodeoxyglucose (FDG)-PET may also be used in lieu of a standard bone scan 
providing coverage allows interrogation of all likely sites of bone disease and FDG-PET 
is performed at all assessments.

If positron emission tomography/computed tomography (PET/CT) is performed then the 
CT component can only be used for standard response assessments if performed to 
diagnostic quality, which includes the required anatomical coverage and prescribed use of 
contrast.  The method of assessment should be noted as CT in the eCRF.


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Clinical Examination: Clinically detected lesions will only be considered measurable when 
they are superficial (e.g., skin nodules).  In the case of skin lesions, documentation by color 
photography, including a ruler/calipers to measure the size of the lesion, is required 
[Eisenhauer EA 2009].  See SPM for details.
CT and MRI: Contrast enhanced CT with 5 mm contiguous slices is recommended.  
Minimum size of a measurable baseline lesion should be twice the slice thickness, with a 
minimum lesion size of 10 mm when the slice thickness is 5 mm.  Magnetic resonance 
imaging (MRI) is acceptable, but when used, the technical specification of the scanning 
sequences should be optimized for the evaluation of the type and site of disease and lesions 
must be measured in the same anatomic plane by use of the same imaging examinations.  
Whenever possible, the same scanner should be used Eisenhauer EA 2009].
X-ray: In general, X-ray should not be used for target lesion measurements owing to poor 
lesion definition. Lesions on chest X-ray may be considered measurable if they are at least 20 
mm and clearly defined and surrounded by aerated lung; however chest CT is preferred over 
chest X-ray [Eisenhauer EA 2009].
Brain Scan:  Contrast enhanced MRI is preferable to contrast enhanced CT for assessment of 
brain lesion(s).  
Bone Scan (typically bone scintigraphy):  If a bone scan is performed and a new lesion(s) is 
equivocal, then correlative imaging (i.e., X-ray, CT, or MRI) is required to demonstrate 
malignant characteristics of the lesion(s).  
Note:  Positron emission tomography (PET; FDG or fluoride) may be used in lieu of a 
standard bone scan providing coverage allows interrogation of all likely sites of bone disease 
and PET is performed at all assessments.
7.2.2.2
Follow-up Assessments for Subjects Permanently Discontinued from 
both Study Treatments
Refer to Section 4.2.1 Permanent Discontinuation from Study Treatment and Time and Events 
Schedule (Table 20) for follow-up assessment of subjects who are to be followed up for  
disease progression and/or survival after permanently discontinue from study treatment.
All subjects who permanently discontinue both study treatments without disease progression 
will have radiographic disease assessments performed on the same assessment schedule noted 
in the Time and Events Table (Table 20) until disease progression, death, starting of another 
anti-cancer treatment(including radiotherapy), or withdrawal of consent, whichever is 
documented first.
In addition, all subjects who permanently discontinue both study treatments will be followed 
for survival and new anti-cancer therapy according to the Time and Events Table (Table 20).  
Follow-up contact to assess survival and new anti-cancer therapy may be made via clinic visit, 
phone, or email; follow-up will continue until study completion/withdrawal/lost to follow-up 
or death, whichever occurs first.  
7.2.2.3
Assessment at Subject Completion
If the last radiographic assessment was more than 8 weeks prior to study withdrawal and 
progressive disease had not been documented, a disease assessment should be obtained at the 
time of withdrawal.  


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7.2.3
Guidelines for Evaluation of Disease
7.2.3.1
Measurable and Non-measurable Definitions
Measurable lesion(s):
A non-nodal lesion that can be accurately measured in at least one dimension (the longest 
dimension) of:

10 mm with MRI or CT when the scan slice thickness is 5 mm.  If the slice 
thickness is >5 mm, the minimum size of a measurable lesion must be at least double 
the slice thickness (e.g., if the slice thickness is 10 mm, a measurable lesion must be 
20 mm).

10 mm caliper/ruler measurement by clinical exam or medical photography.  

20 mm by chest x-ray.
Additionally, lymph nodes can be considered pathologically enlarged and measurable if:

The short axis measures 15 mm when assessed by CT or MRI (the slice thickness 
is recommended to be 5 mm).  At baseline and follow-up, only the short axis will 
be measured [Eisenhauer EA 2009].
Non-measurable lesion(s): 
All lesions other than those considered measurable, including lesions too small to be 
considered measurable (i.e., longest diameter < 10 mm or pathological lymph nodes with a 
short axis of  10 mm but < 15 mm) as well as truly non-measurable lesions, which include: 
leptomeningeal disease, ascites, pleural or pericardial effusions, inflammatory breast disease, 
lymphangitic involvement of the skin or lung, and abdominal masses/abdominal 
organomegaly identified by physical examination that is not measurable by reproducible 
imaging techniques [Eisenhauer EA 2009].
Measurable disease: 
The presence of at least one measurable lesion.  Palpable lesions that are not measurable by 
radiologic or photographic evaluations may not be used as the only measurable lesion.
Non-measurable only disease: 
The presence of only non-measurable lesions.  Note: Non-measurable only disease is not 
allowed per protocol.
7.2.4
Response Criteria
7.2.4.1
Evaluation of Target Lesions
Definitions for assessment of response for target lesion(s) are as follows:

Complete Response (CR): Disappearance of all target lesions.  Any pathological 
lymph nodes must have a short axis of <10 mm.

Partial Response (PR): At least a 30% decrease in the sum of the diameters of target 
lesions, taking as a reference, the baseline sum of the diameters (i.e., percent change 
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
Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for progressive disease (PD).

Progressive Disease (PD): At least a 20% increase in the sum of the diameters of 
target lesions, taking as a reference, the smallest sum of diameters recorded since the 
treatment started (i.e., percent change from nadir, where nadir is defined as the 
smallest sum of diameters recorded since treatment start).  In addition, the sum must 
have an absolute increase from nadir of >5 mm.

Not Evaluable (NE): Cannot be classified by one of the 5 preceding definitions.
Note:

If lymph nodes are documented as target lesions the short axis is added into the sum of 
the diameters (i.e., sum of diameters is the sum of the longest diameters for non-nodal 
lesions and the short axis for nodal lesions).  When lymph nodes decrease to non-
pathological size (short axis < 10 mm), they should still have a measurement reported in 
order not to overstate progression.

If at a given assessment time point all target lesions identified at baseline are not
assessed, the sum of the diameters cannot be calculated for purposes of assessing CR, PR, 
or SD, or for use as the nadir for future assessments.  The sum of the diameters of the 
assessed lesions and the percent change from nadir should, nevertheless, be calculated to 
ensure that PD has not been documented.  If an assessment of PD cannot be made, the 
response assessment should be NE.

All lesions (nodal and non-nodal) should have their measurements recorded even when 
very small (e.g., 2 mm).  If lesions are present but too small to measure, 5 mm should be 
recorded and should contribute to the sum of the diameters, unless it is likely that the 
lesion has disappeared in which case 0 mm should be reported.

If a lesion disappears and reappears at a subsequent time point it should continue to be 
measured. The response at the time when the lesion reappears will depend upon the 
status of the other lesions.  For example, if the disease had reached a CR status then PD 
would be documented at the time of reappearance; if the response status was PR or SD, 
the diameter of the reappearing lesion should be added to the remaining diameters and 
response determined based on percent change from baseline and percent change from 
nadir.
7.2.4.2
Evaluation of Non-target Lesions
Definitions for assessment of response for non-target lesion(s) are as follows:

Complete Response (CR):  The disappearance of all non-target lesions.  All lymph nodes 
identified as a site of disease at baseline must be non-pathological (i.e., a short axis of 
<10 mm).

Non-CR/Non-PD:  The persistence of 1 or more non-target lesion(s) or lymph nodes 
identified as a site of disease at baseline with a short axis of 10 mm.

Progressive Disease (PD): Unequivocal progression of existing non-target lesions.  


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
Not Applicable (NA): No non-target lesions at baseline.

Not Evaluable (NE): Cannot be classified by one of the 4 preceding definitions.
Note:

In the presence of measurable disease, progression on the basis of solely non-target 
disease requires substantial worsening such that even in the presence of SD or PR in 
target disease, the overall tumor burden has increased sufficiently to merit discontinuation 
of therapy.

Sites of non-target lesions, which are not assessed at a particular time point based on the 
assessment schedule, should be excluded from the response determination (i.e., non-target 
response does not have to be NE).
7.2.4.3
New Lesions
New malignancies denoting disease progression must be unequivocal.  Lesions identified in 
follow-up in an anatomical location not scanned at baseline are considered new lesions.
Any equivocal new lesions should continue to be followed.  Treatment can continue at the 
discretion of the investigator until the next scheduled assessment.  If at the next assessment 
the new lesion is considered to be unequivocal, progression should be documented.
7.2.4.4
Evaluation of Overall Response
Table 21  presents the overall response at an individual time point for all possible 
combinations of tumor responses in target and non-target lesions with or without the 
appearance of new lesions for subjects with measurable disease at baseline.
Table 21
Evaluation of Overall Response for Subjects with Measurable Disease at 
Baseline
Target Lesions
Non-target Lesions
New Lesions
Overall Response
CR
CR or NA
No
CR
CR
Non-CR/Non-PD or NE
No
PR
PR
Non-PD or NA or NE
No
PR
SD
Non-PD or NA or NE
No
SD
NE
Non-PD or NA or NE
No
NE
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD
Any
Any
Yes
PD
Abbreviations: CR = complete response; NA = not applicable; NE = not evaluable; PD = progressive disease; PR = partial 
response; SD = stable disease.
Note:

Subjects with a global deterioration of health status requiring treatment 
discontinuation without objective evidence of disease progression at that time should 
be classified as having “symptomatic deterioration.” Objective response status is 
determined by evaluations of disease burden.  Every effort should be made to 
document the objective progression even after treatment discontinuation.  

In some circumstances, it may be difficult to distinguish residual disease from 
normal tissue.  When the evaluation of CR depends on this determination, it is 


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recommended that the residual lesion be investigated (e.g., fine needle 
aspirate/biopsy) to confirm the CR.
7.2.4.5
Evaluation of Best Overall Response
The best overall response is the best response recorded from the start of the treatment until 
disease progression, death, or withdrawal of consent, whichever occurs first.  Best overall 
response will be determined programmatically by Novartis based on the investigator’s 
assessment of response at each time point.  

To be assigned a status of SD, follow-up disease assessment must have met the SD 
criteria at least once after enrollment for a minimum of 49 days.  

If the minimum time for SD is not met, best response will depend on the subsequent 
assessments.  For example, if an assessment of PD follows the assessment of SD and 
SD does not meet the minimum time requirement, the best response will be PD.  
Alternatively, subjects lost to follow-up after an SD assessment not meeting the 
minimum time criteria will be considered NE.
Confirmation Criteria:

To be assigned a status of PR or CR, a confirmatory disease assessment should be 
performed no less than 4 weeks (28 days) after the criteria for response are first met.
7.3
Safety
7.3.1
Safety Endpoints
The secondary objectives of the study include characterizing the safety of dabrafenib and 
trametinib combination therapy.  As a consequence, clinical assessments including vital signs 
and physical examinations, 12-lead ECG, ECHO, chemistry and hematology laboratory 
values, and AEs will be monitored and evaluated.  AEs will be graded by the investigator 
according to the NCI CTCAE, version 4.0.
7.3.2
Adverse Events
The investigator or site staff will be responsible for detecting, documenting and reporting 
events that meet the definition of an AE or SAE as outlined in Section 7.3.2.1 and Section 
7.3.2.2 respectively.
7.3.2.1
Definition of an AE
Any untoward medical occurrence in a patient or clinical investigation subject, temporally 
associated with the use of a medicinal product, whether or not considered related to the 
medicinal product.
Note: An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the 
use of a medicinal product.  For marketed medicinal products, this also includes failure to 
produce expected benefits (i.e., lack of efficacy), abuse or misuse.
Events meeting the definition of an AE include:


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
Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition

New conditions detected or diagnosed after study treatment administration even though it 
may have been present prior to the start of the study

Signs, symptoms, or the clinical sequelae of a suspected interaction

Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
treatment or a concomitant medication (overdose per se will not be reported as an 
AE/SAE) unless this is an intentional overdose taken with possible suicidal/self-harming 
intent.  This should be reported regardless of sequelae.
“Lack of efficacy” or “failure of expected pharmacological action” per se is not to be 
reported as an AE or SAE. However, the signs and symptoms and/or clinical sequelae 
resulting from lack of efficacy will be reported if they fulfil the definition of an AE or SAE.  
Events that do not meet the definition of an AE include:

Medical or surgical procedure (e.g., endoscopy, appendectomy); the condition that leads 
to the procedure is an AE

Situations where an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital)

Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen

The disease/disorder being studied, or expected progression, signs, or symptoms of the 
disease/disorder being studied, unless more severe than expected for the subject’s 
condition
7.3.2.2
Definition of an SAE
A serious adverse event is any untoward medical occurrence that, at any dose:
a.
Results in death
NOTE: Death due to disease under study is to be recorded on the Death CRF form and 
does not need to be reported as an SAE
b.
Is life-threatening
NOTE:  The term 'life-threatening' in the definition of 'serious' refers to an event in which 
the subject was at risk of death at the time of the event.  It does not refer to an event, 
which hypothetically might have caused death, if it were more severe.
c.
Requires hospitalization or prolongation of existing hospitalization
NOTE:  In general, hospitalization signifies that the subject has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for observation 
and/or treatment that would not have been appropriate in the physician’s office or 


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out-patient setting.  Complications that occur during hospitalization are AEs.  If a 
complication prolongs hospitalization or fulfils any other serious criteria, the event is 
serious.  When in doubt as to whether “hospitalization” occurred or was necessary, the 
AE should be considered serious.
Hospitalization for elective treatment of a pre-existing condition that did not worsen from 
baseline is not considered an AE.
d.
Results in disability/incapacity, or
NOTE:  The term disability means a substantial disruption of a person’s ability to 
conduct normal life functions.  This definition is not intended to include experiences of 
relatively minor medical significance such as uncomplicated headache, nausea, vomiting, 
diarrhea, influenza, and accidental trauma (e.g. sprained ankle) which may interfere or 
prevent everyday life functions but do not constitute a substantial disruption.
e.
Is a congenital anomaly/birth defect
f.
Medical or scientific judgment should be exercised in deciding whether reporting is 
appropriate in other situations, such as important medical events that may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize the 
subject or may require medical or surgical intervention to prevent one of the other 
outcomes listed in the above definition.  These should also be considered serious.  
Examples of such events are invasive or malignant cancers, intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or convulsions
that do not result in hospitalization, or development of drug dependency or drug abuse.
g.
Protocol-specific SAEs:

All events of possible drug-induced liver injury with hyperbilirubinemia defined as ALT 
3xULN and bilirubin 2xULN (>35% direct) (or ALT 3xULN and INR>1.5, if INR 
measured) or termed ‘Hy’s Law’ events (INR measurement is not required and the 
threshold value stated will not apply to patients receiving anticoagulants).
Note: bilirubin fractionation is performed if testing is available. If testing is unavailable, 
record presence of detectable urinary bilirubin on dipstick indicating direct bilirubin 
elevations and suggesting liver injury. If testing is unavailable and a subject meets the 
criterion of total bilirubin 2xULN, then the event is still reported as an SAE. If INR is 
obtained, include values on the SAE form. INR elevations >1.5 suggest severe liver 
injury.

Any new primary cancers and treatment emergent malignancies (including squamous cell 
carcinoma and new primary melanoma) with the exception of basal cell carcinoma 
(BCC).  BCC should be reported as an AE or SAE based on the discretion of the 
investigator.

Symptomatic LVEF decrease that meets stopping criteria or asymptomatic LVEF 
decrease that does not recover, as outlined as LVEF guidance (Section 5.8.3.1)

Retinal pigment epithelial detachment (RPED) or retinal vein occlusion (RVO)


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7.3.3
Laboratory and Other Safety Assessment Abnormalities Reported as 
AEs and SAEs
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or other 
safety assessments (e.g., ECGs, radiological scans, vital signs measurements), including those 
that worsen from baseline, and felt to be clinically significant in the medical and scientific 
judgement of the investigator are to be recorded as AEs or SAEs in accordance with the 
definitions provided. 
In addition, an associated AE or SAE is to be recorded for any laboratory test result or other 
safety assessment that led to an intervention, including permanent discontinuation of study 
treatment, dose reduction, and/or dose interruption/delay.
Any new primary cancer must be reported as an SAE.
However, any clinically significant safety assessments that are associated with the underlying 
disease, unless judged by the investigator to be more severe than expected for the subject’s 
condition, are not to be reported as AEs or SAEs.
7.3.4
Cardiovascular Events
Investigators will be required to fill out event specific data collection tools for the following 
AEs and SAEs:  

Myocardial infarction/unstable angina

Congestive heart failure

Arrhythmias

Valvulopathy

Pulmonary hypertension

Cerebrovascular events/stroke and transient ischemic attack

Peripheral arterial thromboembolism

Deep venous thrombosis/pulmonary embolism

Revascularization
This information should be recorded in the specific cardiovascular eCRF within one week of 
when the AE/SAE(s) are first reported.
7.3.5
Death Events
In addition, all deaths that occur whether or not they are considered SAEs will require a 
specific death data collection tool to be completed.  The death data collection tool includes 
questions regarding cardiovascular (including sudden cardiac death) and noncardiovascular 
death.
This information should be recorded in the specific death eCRF within one week of when the 
death is first reported.


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7.3.6
Disease-Related Events and/or Disease-Related Outcomes Not 
Qualifying as SAEs
An event which is part of the natural course of the disease under study (i.e., disease 
progression or hospitalization due to disease progression) does not need to be reported as an 
SAE.  
Death due to disease under study is to be recorded on the Death eCRF form and does not need 
to be reported as an SAE.  
If however, the underlying disease (i.e., progression) is greater than that which would 
normally be expected for the subject, or if the investigator considers that there was a causal 
relationship between treatment with study medication(s) or protocol design/procedures and 
disease progression, then this must be reported as an SAE.  
7.3.7
Pregnancy Testing, Prevention and Reporting
7.3.7.1
Pregnancy Testing and Prevention
The need for a screening pregnancy test depends on whether a female subject is of 
childbearing potential or non-childbearing potential.
A female of non-childbearing potential (i.e., physiologically incapable of becoming 
pregnant) is defined as any female who has had a hysterectomy, bilateral oophorectomy 
(ovariectomy) or bilateral tubal ligation, or is post-menopausal.  
A practical definition accepts menopause after 1 year without menses with an appropriate 
clinical profile, e.g., age appropriate, >45 years in the absence of hormone-replacement 
therapy (HRT).  In questionable cases, the subject must have a follicle-stimulating hormone 
(FSH) value >40 mIU/mL and an estradiol value <40 pg/mL (<140 pmol/L).
A female of child-bearing potential is defined as any female who does not meet the criteria 
of non-childbearing potential as described in the previous paragraph.  
If a female subject is of childbearing potential, she must have a serum -human chorionic 
gonadotropin (HCG) pregnancy test performed within 14 days of first dose of study treatment.  
Subjects with a positive pregnancy test result must be excluded from the study.  Subjects with 
a negative pregnancy test result must agree to use an effective contraception method as 
described below throughout the treatment period and for 16 weeks after stopping treatment 
with trametinib or 2 weeks after stopping treatment with dabrafenib monotherapy, whichever 
is longer.
Novartis-acceptable contraceptive methods, when used consistently and in accordance with 
both the product label and the instructions of the physician, are as follows:

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.

Sterilization (at least 6 months prior to screening) for male partners. The vasectomized 
male partner should be the sole partner for that subject.

Total abstinence (when in line with the preferred and usual lifestyle of the subject). 
Periodic abstinence (e.g. calendar, ovulation, symptothermal, post-ovulation methods), 
and withdrawal are not acceptable methods of contraception.


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
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 levelassessment.
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.

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.
Female subjects who are lactating must discontinue nursing prior to enrollment and must 
refrain from nursing throughout the treatment period and for 30 days after the last dose of 
study treatment.
Male contraception
Dabrafenib may cause infertility in males, which may be irreversible. 
Adverse effects of trametinib on male reproductive organs have been seen in animals.  Male 
patients (including those that have had a vasectomy) taking the dabrafenib and trametinib 
combination therapy must use a condom during intercourse, and for 16 weeks after stopping 
treatment, and should not father a child during these periods. 
7.3.7.2
Pregnancy Reporting
Any pregnancy that occurs during study participation must be reported using a clinical trial 
pregnancy form.  To ensure subject safety, each pregnancy must be reported to Novartis
within 24 hours of learning of its occurrence.  The pregnancy must be followed-up to 
determine outcome (including premature termination) and status of mother and child.  
Pregnancy complications and elective terminations for medical reasons must be reported as an 
AE or SAE.  Spontaneous abortions must be reported as an SAE.
Any SAE occurring in association with a pregnancy brought to the investigator’s attention 
after the subject has completed the study and considered by the investigator as possibly 
related to study treatment, must be promptly reported to Novartis.
In addition, the investigator must attempt to collect pregnancy information on any female 
partners of male study subjects who become pregnant while the subject is enrolled in the 
study.  Pregnancy information must be reported to Novartis as described above.


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7.3.8
Time Period and Frequency of Detecting AEs and SAEs
The investigator or site staff is responsible for detecting, documenting and reporting events 
that meet the definition of an AE or SAE.
Adverse events (AEs) will be collected from the time the first dose of study treatment is 
administered until 30 days after discontinuation of study treatment regardless of initiation of a 
new anti-cancer therapy or transfer to hospice. In China, SAEs will  be recorded from the time 
the consent form is signed. For all other countries, SAEs will be collected over the same time 
period as stated above for AEs. However, any SAEs assessed as related to study participation 
(e.g., study treatment, protocol-mandated procedures, invasive tests, or change in existing 
therapy), will be recorded from the time a subject consents to participate in the study up to 
and including any follow up contact. All SAEs will be reported to Novartis within 24 hours, 
as indicated in Section 7.3.10.
After discontinuation of study treatment, the investigator will monitor all AEs/SAEs that are 
ongoing until resolution or stabilization of the event or until the subject is lost to follow-up.  
At any time after 30 days the investigator may report any adverse event that they believe 
possibly related to study treatment.


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7.3.9
Method of Detecting AEs and SAEs
Care must be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
non-leading verbal questioning of the subject is the preferred method to inquire about AE 
occurrence. Appropriate questions include:
“How are you feeling?” 
“Have you had any (other) medical problems since your last visit/contact?” 
“Have you taken any new medicines, other than those provided in this study, since your last 
visit/contact?” 
7.3.10
Prompt Reporting of Serious Adverse Events and Other Events to 
Novartis
SAEs, pregnancies, and liver function abnormalities meeting pre-defined criteria will be 
reported promptly by the investigator to Novartis as described in the following table once the 
investigator determines that the event meets the protocol definition for that event.
Initial Reports
Follow-up Information on a Previous Report
Type of Event
Time Frame
Documents
Time Frame
Documents
All SAEs
24 hours
SAE data collection 
tool
24 hours
Updated SAE data 
collection tool 
Pregnancy
24 hours
Pregnancy notification 
form
2 weeks
Pregnancy follow-up 
form
Cardiovascular or death 
event
Initial and follow 
up reports to be 
completed within 
one week of when 
the cardiovascular 
event or death is 
reported 
“CV events” and/or 
“death” data collection 
tool(s) if applicable
Initial and follow up 
reports to be 
completed within one 
week of when the 
cardiovascular event 
or death is reported
Updated “CV events” 
and/or “death” data 
collection tool(s) if 
applicable


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Initial Reports
Follow-up Information on a Previous Report
Type of Event
Time Frame
Documents
Time Frame
Documents
Liver Chemistry Abnormalities:
ALT 3 x ULN PLUS total 
bilirubin 2 x ULN (> 35% 
direct) or ALT   3 x ULN 
and INR > 1.5, if INR 
measureda
24 hoursb
SAE data collection 
tool,
liver event eCRF form, 
and liver imaging 
and/or biopsy eCRFs, 
if applicablec
24 hours
Updated SAE data 
collection tool and 
updated liver event 
eCRF formc
ALT 5 x ULN; ALT 3 x 
ULN with hepatitis or rash 
or 3 x ULN that persists 
4 weeks
24 hoursb
Liver event eCRF 
formc
24 hours 
Updated liver event 
eCRF formc
ALT 3 x ULN and < 5 x 
ULN, PLUS total bilirubin < 
2 x ULN
24 hoursb
Liver event eCRF form 
does not need 
completing unless 
elevations persist for 2 
weeks or subject 
cannot be monitored 
weekly for 2 weeksc
Abbreviations: ALT = alanine transaminase; AST = aspartate aminotransferase; eCRF = electronic case report form;
INR = international normalized ratio; SAE = serious adverse event; ULN = upper limit of normal.
a.
INR measurement is not required; if measured, the threshold value stated will not apply to subjects receiving 
anticoagulants.
b.
Novartis to be notified at onset of liver chemistry elevations to discuss subject safety.
c.
Liver Event Documents (i.e., “Liver Event CRF” and “Liver Imaging CRF” and/or “Liver Biopsy CRF”, as applicable) 
should be completed as soon as possible.
Liver chemistry stopping, follow-up, and monitoring criteria are provided in Section 5.9.  
The method of recording, evaluating and follow-up of AEs and SAEs plus procedures for 
completing and transmitting SAE reports to Novartis are provided in the SPM.  Procedures for 
post-study AEs/SAEs are provided in the SPM.
7.3.10.1 Regulatory Reporting Requirements for SAEs
Prompt notification of SAEs by the investigator to Novartis is essential so that legal 
obligations and ethical responsibilities towards the safety of subjects are met.
Novartis has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a product under clinical investigation.  Novartis will 
comply with country specific regulatory requirements relating to safety reporting to the 
regulatory authority, Institutional Review Board (IRB)/Independent Ethics Committee (IEC) 
and investigators.
Investigator safety reports are prepared for suspected unexpected serious adverse reactions 
according to local regulatory requirements and Novartis policy and are forwarded to 
investigators as necessary.
An investigator who receives an investigator safety report describing a SAE(s) or other 
specific safety information (e.g., summary or listing of SAEs) from Novartis will file it with 
the IB and will notify the IRB/IEC, if appropriate according to local requirements.


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7.3.11
Other Safety Outcomes
Laboratory Assessments
All protocol-required laboratory assessments must be performed by the central laboratories. 
Laboratory assessments must be conducted in accordance with the Central Laboratory Manual 
and Protocol Time and Events Schedule (Table 20). 
If additional non-protocol specified laboratory assessments are performed at the institution’s 
local laboratory and they result in a change in patient management (for example SAE or AE 
or dose modification) the results must be recorded in the subject’s CRF. Refer to the SPM for 
appropriate processing and handling of sample to avoid duplicate and/or additional blood 
draws.
Laboratory requisition forms must be completed and samples must be clearly labelled with the 
subject number, protocol number, site/center number, and visit date.  Details for the 
preparation and shipment of samples, and a list of reference ranges for all safety parameters 
will be provided to the site by the central laboratory in a separate instruction manual.  
Clinical chemistry and hematology parameters to be tested are listed in Table 22. Female 
subjects will have a serum pregnancy test at Screening; urine pregnancy testing may be done 
during study treatment, if necessary.  


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Table 22
Clinical Chemistry and Hematology Parameters
Clinical Chemistry Parameters
Albumin
Alkaline Phosphatase
Alanine Transaminase (ALT) or Serum Glutamic Pyruvic Transaminase (SGPT)
Aspartate Aminotransferase (AST) or Serum Glutamic Oxaloacetic Transaminase (SGOT)
Gamma-Glutamyl Transpeptidase (GGT)
Bicarbonate
Blood Urea Nitrogen (BUN) or urea
Calcium
Chloride
Creatininec
Glucose (random)
Lactate Dehydrogenase (LDH)
Magnesium
Phosphate
Potassium
Sodium
Total Bilirubinb
Total Protein
Hematology Parameters
White Blood Cell (WBC) Count 
Hemoglobin
Hemoglobin A1C
Hematocrit
International Normalized Ratio (INR; at Screening only)a
Platelet Count
Prothrombin Time (PT; at Screening only)a
Partial Thromboplastin Time (PTT; at Screening only)a
Automated WBC Differential (expressed as Gl/L): 
Basophils 
Eosinophils
Lymphocytes
Monocytes
Neutrophils
Other tests
Amylase and lipase [monitor via local laboratory where appropriate to evaluate certain AEs (i.e., 
abdominal pain, pancreatitis, etc.)]
serum β-hCG (human chorionic gonadotrophin)
For subjects with a history of chronic HBV and/or HCV, the following tests will be performed at Screening:

Viral hepatitis serology (HBs Antigen, HBc Antibody, HBs Antibody, HCV Antibody);

HBV DNA

Hepatitis C RNA
a. Coagulation panel to be done at Screening only.
b. Bilirubin fractionation is recommended if total bilirubin is > 2 x the upper limit of normal (ULN).
c. .If serum creatinine is > 1.5 mg/dL, creatinine clearance should be calculated using the standard 
Cockcroft-Gault formula (Appendix 2).
7.3.12
Ophthalmic Examination
Subjects are required to have a standard ophthalmic examination performed by an 
ophthalmologist at baseline, at week 4 and as clinically warranted per protocol’s guidance 
(Section 5.8.5.4). The exam will include indirect fundoscopic examination, visual acuity (with 


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correction), visual field examination, and tonometry, with special attention to retinal 
abnormalities that are predisposing factors for RVO or CSR. Direct fundoscopy may be 
performed but is not required.
In subjects with clinical suspicion of RVO or CSR, flourescein angiography and/or optical 
coherence tomography are highly recommended.
7.3.13
Vital Signs
Vital sign measurements will include systolic and diastolic blood pressure, body temperature, 
pulse rate, body weight, and height (only at Screening). Body temperature, weight and height 
measurements should be recorded in the metric scale. 
See Section 5.8.3.2.1 for details on monitoring of hypertension. 
7.3.14
Physical Examinations
Complete physical examination will include assessments of eyes, neurological and 
cardiovascular systems, lungs, abdomen, and any other areas with signs and symptoms of 
disease, and of the head, neck, ears, nose, mouth, throat, thyroid, lymph nodes, extremities, 
and a full skin exam to assess cutaneous malignancies and proliferative skin diseases. 
Complete physical examinations will also include thorough genitourinary (pelvic) and rectal 
exams to assess secondary malignancies. In females the pelvic exam must visualise the cervix. 
(Pap smear and colposcopy are not required unless clinically indicated). Rectal exam must 
include digital rectal exam and visual inspection of the anus and perianal area. Brief physical 
examinations will include assessment of head, neck, eyes, neurological and cardiovascular 
systems, lungs, abdomen, and any other areas with signs and symptoms of disease.  Refer to 
the Time and Events Table (Table 20) for when to perform a complete or a brief physical 
examination.
If possible, the same physician should perform each examination for the duration of the study 
to ensure consistency between evaluations (i.e., if the subject is referred to a Dermatologist 
for the Screening examination, the Dermatologist should do all follow-up dermatologic skin 
assessments).  
7.3.14.1 Dermatological Exams
A full skin exam is required at screening and every 8 weeks to assess cutaneous malignancies 
and proliferative skin diseases.  Upon study treatment discontinuation, a final skin exam is 
required within 8 weeks of the last dose of study treatment. Medical photographs should be 
taken for patients with such skin abnormalities.
Dermatologic skin exams may be referred to a dermatologist, if needed.  If possible, the same 
physician should perform each examination for the duration of the study to ensure consistency 
between evaluations.
7.3.15
Electrocardiograms (ECG)
Twelve (12)-lead ECGs will be obtained using an ECG machine that automatically calculates 
heart rate and measures PR, QRS, QT, RR and QTcB intervals.  
At each assessment, a single 12-lead ECG will be performed by qualified site personnel after 
the subject has rested in a semi-recumbent or supine position for at least 5 minutes.  


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7.3.16
Echocardiograms (ECHO)
Echocardiograms (ECHO) will be performed to assess cardiac ejection fraction and cardiac 
valve morphology. The echocardiographer’s evaluation should include an evaluation for left 
ventricular ejection fraction and both right and left-sided valvular lesions. Copies of all ECHO 
scans will be centrally collected for review. Collection details will be provided in the SPM.


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7.5
Pharmacokinetics
7.5.1
Blood Sample Collection
Blood samples (2 mL) for pharmacokinetic analysis of dabrafenib and metabolites (hydroxy-
dabrafenib, carboxy-dabrafenib, and desmethyl-dabrafenib) and trametinib will be collected at 
the time points indicated in the Time and Events table (Table 20).  The actual date and time of 
each blood sample collection will be recorded.
7.5.2
Sample Analysis
Plasma analysis will be performed under the control of PK Sciences, the details of which will 
be included in the Study Procedures Manual.  Concentrations of carboxy-dabrafenib will be 
determined in plasma samples using a separate assay using the currently approved analytical 
methodology while the other two metabolites are quantified together with dabrafenib in one 
assay. Raw data will be stored in the Good Laboratory Practice (GLP) Archives.
Once the plasma has been analyzed for dabrafenib and its metabolites and trametinib, any 
remaining plasma may be analyzed for other compound-related metabolites and the results 
reported.


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8
Data management
Data Management will identify and implement the most effective data acquisition and 
management strategy for each clinical trial protocol and deliver datasets that support the 
protocol objectives.
For this study, subject data will be entered into Novartis-defined electronic case report forms
(eCRFs), transmitted electronically to Novartis or designee, and be combined with data from 
other sources in a validated data system.  
Clinical data management will be performed in accordance with applicable Novartis standards 
and data cleaning procedures to ensure the integrity of the data, e.g., resolving errors and 
inconsistencies in the data.  Adverse events and concomitant medications terms will be coded 
using the Medical Dictionary for Regulatory Activities (MedDRA) and a custom drug 
dictionary.  An appropriate medical dictionary that covers all approved drugs in studies where 
Japan is participating will be referenced.
The eCRFs (including queries and audit trails) will be retained by Novartis, and copies will be 
sent to the investigator to maintain as the investigator copy.
9
Data Analysis and Statistical Considerations
9.1
Hypotheses
The study will pursue an estimation strategy rather than formal hypothesis testing. This is 
reasonable given the proven performance of the combination therapy and the desire to 
estimate efficacy and safety in the Asian population. Since estimation is the goal, there are no 
formal hypotheses to be tested. The minimal effect to be excluded from the lower end of the 
confidence interval for ORR will be 25%.
9.2
Study Design Considerations
9.2.1
Sample Size Assumptions
Approximately 65 subjects will be enrolled. This sample size was deemed to be sufficient to 
assess efficacy, safety and tolerability of dabrafenib in combination with trametinib in Asian 
patients with BRAF V600 Mutation-Positive Melanoma.
9.2.2
Sample Size Sensitivity
Sample size sensitivity has been illustrated in Table 23 of Section 9.2.1. 
9.2.3
Sample Size Re-estimation
Sample size re-estimation is not planned.
9.3
Data Analysis Considerations
Data will be listed and summarized according to Novartis integrated data standards library 
(IDSL) reporting standards where applicable. Complete details will be provided in the 
Statistical Analysis Plan (SAP).


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9.3.1
Analysis Populations
The All Treated Subjects (ATS) Population will consist of all subjects that receive at least one 
dose of study treatment. Safety and efficacy data will be evaluated based on this population.
The PK Population will consist of those subjects in ATS population for whom a PK sample is 
obtained and analyzed. 
9.3.2
Analysis Data Sets
The primary dataset for efficacy and safety will be comprised of the ATS population defined 
in Section 9.3.1.
9.3.3
Treatment Comparisons
9.3.3.1
Primary Comparisons of Interest
The primary objective will be supported by the calculation of objective response rate using the 
ATS population.  The final analysis of ORR will be performed after 65 subjects have been 
treated for 16 weeks or have otherwise discontinued study treatment.
Subjects will continue to be followed for survival until death, lost to follow-up, or study 
completion. The definition of study completion is described in Section 3.1.  
9.3.3.2
Other Comparisons of Interest
Safety, PK, PD, duration of response, PFS, OS, 
 will be listed and 
summarized in tabular and graphic formats as data warrant. There are no other formal 
comparisons of interest.
Since there is a single primary endpoint (ORR), supported by secondary endpoints, the 
nominal level of significance for the primary analysis will not be affected by multiplicity.
9.3.4
Interim Analysis
Not applicable
9.3.5
Key Elements of Analysis Plan
Data will be listed and summarized according to Novartis reporting standards, where 
applicable.  Complete details will be documented in the SAP.  Any deviations from, or 
additions to, the original analysis plan described in this protocol will be documented in the 
SAP and final study report and will not require a protocol amendment.
As it is anticipated that accrual will be spread thinly across study sites, summaries of data by 
study site would not be informative.  Data from all participating study sites will therefore be 
pooled prior to analysis.
All subject data up to the time of study completion or withdrawal will be included in the 
analysis, regardless of treatment duration.
As treatment duration for a given subject will depend on efficacy and tolerability, the duration 
of follow-up will vary between subjects.  Consequently there will be no imputation for 
missing data.
Demographic and baseline characteristics will be summarized.
Details on the determination of tumor response are given in Section 7.2.4.


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Additional details on efficacy analyses (Section 9.3.5.1) and safety analyses (Section 9.3.5.2) 
are provided.
9.3.5.1
Efficacy Analyses
9.3.5.1.1 Primary Efficacy Analyses
Anti-tumor activities will be calculated based on RECIST 1.1 [Eisenhauer EA 2009]. The 
ORR is defined as the percentage of subjects among all subjects who have enrolled and 
received at least one dose of investigational product, who have a confirmed complete response 
or a partial response. Subjects with unknown or missing response will be treated as non-
responders, i.e. they will be included in the denominator when calculating the percentage.  No 
imputation will be performed for missing lesion assessments or tumor response data.
95% confidence limits for objective response rate will be calculated. . An exact binomial 
confidence interval will be calculated Clopper and Pearson 1934.
9.3.5.1.2 Secondary Efficacy Analyses
Progression-Free Survival(PFS)
PFS will be defined as the time from first dose until the first date of either objective disease 
progression or death due to any cause.  The date of objective disease progression will be 
defined as the earliest date of radiological or photographic disease progression as assessed by 
the investigator using RECIST, version 1.1.  For subjects who have not progressed or died at 
the time of the PFS analysis, censoring will be performed using the date of the last adequate 
disease assessment or first dose for subjects without any adequate post baseline assessments.  
In addition, subjects with an extended loss to follow-up or who start new anti-cancer therapy 
prior to a PFS event will be censored at the date of the last adequate disease assessment prior 
to the extended loss to follow-up or start of new anti-cancer therapy, respectively. Progression 
free survival will be summarized descriptively using Kaplan-Meier medians and quartiles.  
Further details on censoring rules will be outlined in the SAP.  
Overall Survial (OS)
OS is defined as the time from first dose until death due to any cause. For subjects who have 
not died, time to death will be censored at the last date of known contact
OS will utilize all -cause mortality and censoring will be performed using the date of last 
known contact for those who are alive at the time of analysis. OS will be summarized 
descriptively using Kaplan-Meier medians and quartiles. 
Duration of Response
If data permits (i.e. a sufficient number of subjects with confirmed CR or PR),  duration of 
response will be summarized descriptively using Kaplan-Meier medians and quartiles . 
Duration of Response for the subset of subjects with a confirmed CR or PR is defined as the 
time from first documented evidence of CR or PR until first documented disease progression 
or death due to any cause. Censoring rules for duration of response will follow the rules for 
PFS and will be outlined in detail in the SAP.


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9.3.5.2
Safety Analyses
Safety endpoints are described in Section 2 and Section 7.3.1.
The ATS population will be used for the analysis of safety data.  Complete details of the 
safety analyses will be provided in the SAP.
9.3.5.2.1 Extent of Exposure
The number of subjects administered study treatment will be summarized for subjects in the 
ATS population according to exposure and duration of therapy.
9.3.5.2.2 Adverse Events
Adverse events will be coded using the standard MedDRA and grouped by system organ 
class.  Adverse events (AEs) will be graded by the investigator according to the NCI CTCAE, 
version 4.0.
Events will be summarized by frequency and proportion of subjects, by system organ class 
and preferred term.  Separate summaries will be given for all AEs, drug-related AEs, SAEs, 
and AEs leading to treatment discontinuation.
If the AE is listed in the NCI CTCAE table, the maximum grade will be summarized.
Any AEs of special interest (including SCC and other proliferative diseases) will be 
summarized as detailed in the SAP.
The incidence of death and the primary cause of death will be summarized.
9.3.5.2.3 Clinical Laboratory Evaluations
Hematology and clinical chemistry data will be summarized at each scheduled assessment 
according to NCI CTCAE grade (v4.0).  The proportion of values lying outside the reference 
range will also be presented for laboratory tests which are not graded because there are no 
associated NCI CTCAE criteria (v4.0).  Summaries by visit will include data from scheduled 
assessments only and all data will be reported according to the nominal visit for which it was 
recorded (i.e. no visit windows will be applied).  Unscheduled data will be included in ‘worse 
case post baseline’ summaries which will be capture a worst case across all scheduled and 
unscheduled visits after the first dose of study treatment. Further details will be provided in 
the SAP.
9.3.5.2.4 Other Safety Measures
The results of scheduled assessments of vital signs, ECOG performance status, 12-lead ECG, 
and ECHO will be summarized.  Summaries by visit will include data from scheduled 
assessments only.  All data will be reported according to the nominal visit for which it was 
recorded (i.e., no visit windows will be applied).  Unscheduled data will be included in the 
‘worst case’ summaries which will capture a worst case across all scheduled and unscheduled 
visits after the first dose of study treatment.  All data will be listed.  Further details will be 
provided in the SAP.


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9.3.5.3
Pharmacokinetic Analyses
Pharmacokinetic analysis will be the responsibility of the Clinical Pharmacology Modeling & 
Simulation (CPMS) department within Novartis.  Plasma dabrafenib and metabolites 
including hydroxy- , desmethyl-, and carboxy-dabrafenib and trametinib concentration-time 
data will be analyzed by standard noncompartmental methods in subjects from whom the full 
PK blood sample scheme were collected.  Calculations will be based on the actual sampling 
times recorded during the study.  From the plasma concentration-time data, the following 
pharmacokinetic parameters will be determined for dabrafenib and metabolites and 
trametinib, as data permit: 
Steady-state (all subjects) - trough concentration at steady-state (Ctrough), Cmax, tmax, 
AUC(0-t), AUC(0-8), (AUC(0-12); dabrafenib and metabolites only), AUC (0-24) (trametinib 
only)), and apparent terminal phase half-life (t1/2) for trametinib and dabrafenib and 
metabolites.  The metabolite to parent ratio for AUC(0-12) will be calculated for each 
metabolite of dabrafenib. AUC(0-12) on Day 15 will be estimated for dabrafenib and 
metabolites by setting the plasma concentration 12 hours after dosing equal to the predose 
concentration.  The AUC(0-24) on Day 15 will be estimated for trametinib by setting the 
plasma concentration 24 hours after dosing equal to the predose concentration.
 
 
 
Noncompartmental pharmacokinetic parameters will be listed and summarized by day.  
Separate summaries will be created for parameters calculated with the dense blood sampling 
scheme and the sparse blood sampling scheme.  No formal statistical analysis of the 
pharmacokinetic parameters is planned.
9.3.5.4
Pharmacokinetic/Pharmacodynamic Analysis
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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10
Study CONDUCT CONSIDERATIONS
10.1
Posting of Information on Publicly Available Clinical Trial 
Registers
Study information from this protocol will be posted on publicly available clinical trial 
registers before enrolment of subjects begins.
10.2
Regulatory and Ethical Considerations, Including the Informed 
Consent Process
Prior to initiation of a study site, Novartis will obtain favourable opinion/approval from the 
appropriate regulatory agency to conduct the study in accordance with ICH Good Clinical 
Practice (GCP) and applicable country-specific regulatory requirements.
The study will be conducted in accordance with all applicable regulatory requirements.
The study will be conducted in accordance with ICH GCP, all applicable subject privacy 
requirements, and the ethical principles that are outlined in the Declaration of Helsinki 2008, 
including, but not limited to:

Institutional Review Board (IRB)/Independent Ethics Committee (IEC) review and 
favourable opinion/approval of study protocol and any subsequent amendments.

Subject informed consent.

Investigator reporting requirements.
Novartis will provide full details of the above procedures, either verbally, in writing, or both.
Written informed consent must be obtained from each subject prior to participation in the 
study.


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In approving the clinical protocol the IEC/IRB and, where required, the applicable regulatory 
agency are also approving the optional assessments e.g., 
 
 unless otherwise indicated.  Where permitted by regulatory authorities, approval 
of the optional assessments can occur after approval is obtained for the rest of the study.  If so, 
then the written approval will clearly indicate approval of the optional assessments is being 
deferred and the study, except for the optional assessments, can be initiated.  When the 
optional assessments are not approved, then the approval for the rest of the study will clearly 
indicate this and therefore, the optional assessments will not be conducted.
10.3
Quality Control (Study Monitoring)
In accordance with applicable regulations, GCP, and Novartis procedures, Novartis personnel 
(or designated Clinical Research Organization [CRO]) will contact the site prior to the start of 
the study to review with the site staff the protocol, study requirements, and their 
responsibilities to satisfy regulatory, ethical, and Novartis requirements.  When reviewing 
data collection procedures, the discussion will include identification, agreement and 
documentation of data items for which the CRF will serve as the source document.
The investigator and the head of the medical institution (where applicable) agrees to allow 
Novartis personnel or designated CRO direct access to all relevant documents and to allocate 
their time and the time to their staff to monitor to discuss findings and any issues.
Monitoring visits will be conducted in a manner to ensure that the:

Data are authentic, accurate, and complete.

Safety and rights of subjects are being protected.

Study is conducted in accordance with the currently approved protocol and any other 
study agreements, GCP, and all applicable regulatory requirements.
The investigator and the head of the medical institution (where applicable) agrees to allow the 
monitor direct access to all relevant documents.
10.4
Quality Assurance
To ensure compliance with GCP and all applicable regulatory requirements, Novartis may 
conduct a quality assurance assessment and/or audit of the site records, and the regulatory 
agencies may conduct a regulatory inspection at any time during or after completion of the 
study. In the event of an assessment, audit or inspection, the investigator (and institution) 
must agree to grant the advisor(s), auditor(s) and inspector(s) direct access to all relevant 
documents and to allocate their time and the time of their staff to discuss the conduct of the 
study, any findings/relevant issues and to implement any corrective and/or preventative 
actions to address any findings/issues identified.
10.5
Study and Site Closure
The study will be close when it is completed, as defined in Section 3.1.  
Upon completion or termination of the study, the Novartis personnel (or designated CRO) will 
conduct site closure activities with the investigator or site staff (as appropriate), in accordance 
with applicable regulations, GCP, and Novartis Standard Operating Procedures.


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Novartis reserves the right to temporarily suspend or terminate the study at any time for 
reasons including (but not limited to) safety issues, ethical issues, or severe non-compliance.  
If Novartis determines that such action is required, Novartis will discuss the reasons for taking 
such action with the investigator or head of the medical institution (where applicable).  When 
feasible, Novartis will provide advance notice to the investigator or head of the medical 
institution of the impending action.
If a study is suspended or terminated for safety reasons, Novartis will promptly inform all 
investigators, heads of the medical institutions (where applicable),and/or institutions 
conducting the study.  Novartis will also promptly inform the relevant regulatory authorities 
of the suspension/termination along with the reasons for such action.  Where required by 
applicable regulations, the investigator or head of the medical institution must inform the 
IRB/IEC promptly and provide the reason(s) for the suspension/termination.


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10.6
Records Retention
Following closure of the study, the investigator or head of the medical institution (where 
applicable) must maintain all site study records (except for those required by local regulations 
to be maintained elsewhere) in a safe and secure location.  The records must be easily 
accessible when needed (e.g., for a Novartis audit or regulatory inspection) and must be 
available for review in conjunction with assessment of the facility, supporting systems, and 
relevant site staff.
Where permitted by local laws/regulations or institutional policy, some or all of the records 
may be maintained in a format other than hard copy (e.g., microfiche, scanned, electronic); 
however, caution must be exercised before such action is taken.  The investigator must ensure 
that all reproductions are legible and are a true and accurate copy of the original.  In addition, 
they must meet accessibility and retrieval standards, including regeneration of a hard copy, if 
required.  The investigator must also ensure that an acceptable back-up of the reproductions 
exists and that there is an acceptable quality control procedure in place for creating the 
reproductions.
Essential documents (written and electronic) should be retained for a period of not less than 
fifteen (15) years from the completion of the Clinical Trial unless the Sponsor provides 
written permission to dispose of them or, requires their retention for an additional period of 
time because of applicable laws, regulations and/or guidelines.
The investigator must notify Novartis of any changes in the archival arrangements, including, 
but not limited to archival of records at an off-site facility or transfer of ownership of the 
records in the event that the investigator is no longer associated with the site.
10.7
Provision of Study Results to Investigators, Posting of 
Information on Publicly Available Clinical Trials Registers and 
Publication
Where required by applicable regulatory requirements, an investigator signatory will be 
identified for the approval of the clinical study report.  The investigator will be provided 
reasonable access to statistical tables, figures, and relevant reports and will have the 
opportunity to review the complete study results at a Novartis site or other mutually-agreeable 
location.
Novartis will also provide the investigator with the full summary of the study results.  The 
investigator is encouraged to share the summary results with the study subjects, as 
appropriate.
Novartis aims to post a results summary to the Novartis Clinical Trial Results website 
(www.novartisclinicaltrials.com) and other publicly available registers no later than twelve 
(12) months after the last subject’s last visit (LSLV). In addition, upon study completion and 
finalization of study report, Novartis aims to submit results of the study for publication.
When publication is not feasible, please refer to the Novartis Clinical Trial Results website 
(www.novartisclinicaltrials.com) for a summary of the trial results.


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11
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1/2 inhibitor selumetinib (AZD6244, ARRY-142886). Invest New Drugs. 2010;29:1114-1121. 
Bradford PT, Goldstein AM, McMaster ML, Tucker MA. Acral lentiginous melanoma: 
Incidence and survival patterns in the United States, 1986-2005. Archives of Dermatology. 
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Callahan MK, Rampal R, Harding JJ, et al. Progression of RAS-mutant leukemia during RAF 
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Chapman PB, Hauschild A, Robert C, et al. Improved survival with vemurafenib in melanoma 
with BRAF V600E Mutation. N Engl J Med. 2011;364:2507-16. 
Claret L, Girard P, Hoff PM, Van Cutsem E, Zuideveld KP, Jorga K, et al. Model-based 
prediction of phase III overall survival in colorectal cancer on the basis of phase II tumor 
dynamics. J Clin Oncol. 2009;27:4103-4108. 
Clopper CJ and Pearson PS, The Use of Confidence or Fiducial Limits Illustrated in the Case 
of the Binomial, Biometrika, 1934, Vol. 26 (4) pp. 404-413
Curtin JA, Busam K, Pinkel D, et al. Somatic activation of KIT in distinct subtypes of 
melanoma. J Clin Oncol. 2006;24:4340-4346. 
Daud A, Sosman J, Weber J, Kefford R, Schuchter L, Algazi A, et al. Mutation and copy 
number analysis in melanoma biopsies from Phase I/II study evaluating the combination of 
dabrafenib and trametinib. Society for Melanoma Research. 2012 Congress;Nov 8-11:poster. 
Davies H, Bignell GR, Cox C, Stephens P, Edkins S, et al. Mutations of the BRAF gene in 
human cancer Nature 2002;417:949-954
Eisenhauer EA, Therasse P, Bogaert J, et al. New response evaluation criteria in solid tumors: 
revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45(2):228-247. 
Emery CM, Vijayendran KG, Zipser MC, Sawyer AM, Niu L, et al. MEK1 mutations confer 
resistance to MEK and B-RAF inhibition. Proc Natl Acad Sci USA 2009;106:20411-6
Flaherty KT, Infante J.R., Daud A., et al. Combined BRAF and MEK inhibition in melanoma 
with BRAF V600 mutations. N Engl J Med. 2012a;367(18):1694-1703. 
Flaherty KT, Robert C, Hersey P, Nathan P, et al. Improved survival with MEK inhibition in 
BRAF-mutated melanoma. N Engl J Med. 2012b;367(2):107-114. 
GlaxoSmithKline Document Number 2011N116395_00. Cellular assays with GSK2118436A, 
GSK1120212B, and GSK2126458A as single agents and in combination with each other in 
BRAFV600E/K/D mutant melanoma cell lines. March, 2012.
GlaxoSmithKline Document Number 2011N126811_02 Study ID n/a. GSK1120212 + 
GSK2118436 Investigator's Brochure (trametinib + dabrafenib). Report Date 23-Jun-2014. 
GlaxoSmithKline Document Number 2012N133089_00 Study ID MEK114784 A phase I trial 
of GSK 1120212 and GSK11201212 in combination with gemcitabine in Japanese subjects 
with solid tumors. Report date 20-Nov-2012
GlaxoSmithKline Document Number 2012N144949_00 Study ID BRF113220. Population 
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Combination. Report Date 17-Dec-2012. 
GlaxoSmithKline Document Number 2014N196180_00 Study ID BRF116056 An open-label, 
dose escalation, phase I study to evaluate the safety, tolerability and pharmacokinetic profile 


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of GSK2118436 in Japanese subjects with BRAF V600 mutation positive solid tumors.
Report date 09-Jan-2015
GlaxoSmithKline Document Number 2014N196181_00 Study ID MEK116885 A Japanese 
open-label Phase I/II study to assess the safety, tolerability, pharmacokinetics and efficacy of 
GSK2118436 and GSK1120212 combination therapy in subjects with BRAF V600E/K 
mutation positive advanced solid tumors (Phase I part) and BRAF V600E/K mutation positive 
cutaneous melanoma (Phase II part). Report date 05-Feb-2015
GlaxoSmithKline Document Number CM2010/00010/03. Dabrafenib Investigator's Brochure. 
Report Date 3-May-2013. 
GlaxoSmithKline Document Number HM2009/00151/03. GSK1120212 (trametinib) 
Investigator’s Brochure. Report Date 5-Sep-2012. 
GLOBOCAN  http://globocan.iarc.fr/Default.aspx, 2012
Gordon MS, Infante JR, Messersmith W, et al. The oral MEK1/MEK2 inhibitor, 
GSK1120212, effectively inhibits the MAPK pathway: pharmacokinetic, pharmacodynamic, 
and clinical response relationship. 22ND EORTC-NCI-AACR Symposium. Molecular 
Targets and Cancer Therapeutics. 2010;abstract 373. 
Green S, Dahlberg S. Planned versus attained designs in phase II clinical trials. Statistics in 
Medicine. 1992;11:853-862. 
Greger JG, Eastman SD, Zhang V, Bleam MR, Hughes AM, et al. Combinations of BRAF, 
MEK and PI3K/mTOR inhibitors overcome acquired resistance to the BRAF inhibitor 
GSK2118436 dabrafenib, mediated by NRAS or MEK mutations. Mol Cancer Ther
2012;11:909-20
Hatzivassiliou G, Song K, Yen I, et al. RAF inhibitors prime wild-type RAF to activate the 
MAPK pathway and enhance growth. Nature. 2010;464:431-436
Hauschild A, Grob JJ, Demidov LV, et al. Dabrafenib in BRAF-mutated metastatic 
melanoma: a multicentre, open-label, phase 3 randomised controlled trial. Lancet. 
2012;380(9839):358-65. 
Hodi FS, O’Day SJ, McDermott DF, et al. Improved survival with Ipilimumab in patients 
with metastatic melanoma. N Engl J Med 2010; 363(8):711-723. N Engl J Med. 
2010;363(8):711-723. 
Huncharek M, Caubet JF, McGarry R. Single-agent DTIC versus combination chemotherapy 
with or without immunotherapy in metastatic melanoma: a meta-analysis of 3273 patients 
from 20 randomized trials. Melanoma Res. 2001;11(1):75-81. 
James LP, Letzig L, Simpson PM, Capparelli E, Roberts DW, Hinson JA, Davern TJ, Lee 
WM. Pharmacokinetics of Acetaminophen-Protein Adduct in Adults with  Acetaminophen 
Overdose and Acute Liver Failure. Drug Metab Dispos.2009;37(8):1779-1784. 
Johannessen CM, Boehm JS, Kim SY, Thomas SR, Wardwell L, et al. COT drives resistance 
to RAF inhibition through MAP kinase pathway reactivation. Nature 2010;468:968-72
Kim K, Lewis K, Pavlick A, et al. A phase II study of the MEK1/MEK2 inhibitor 
GKS1120212 in metastatic BRAF-V600E or K mutant cutaneous melanoma patients 
previously treated with or without a BRAF inhibitor. Pigment Cell Res. 2011;24:1021. 
Kim KB, Kefford R, Pavlick AC, Infante JR, Ribas A, Sosman JA, et al. Phase II study of the 
MEK1/MEK2 inhibitor Trametinib in patients with metastatic BRAF-mutant cutaneous 


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melanoma previously treated with or without a BRAF inhibitor. J Clin Oncol. 
2013;31(4):482-9. doi: 10.1200/JCO.2012.43.5966. Epub 2012 Dec 17. 
Korn EL, Liu PY, Lee SJ, Chapman JA, Niedzwiecki D, et al Meta-analysis of phase II 
cooperative group trials in metastatic stage IV melanoma to determine progression-free and 
overall survival benchmarks for future phase II trials. J Clin Oncol. 2008;26:527-34
Lacouture ME, Shenhong W, Robert C, et al. Evolving strategies for the management of 
hand-foot skin reaction associated with the multitargeted kinase inhibitors sorafenib and 
sunitinib. The Oncologist. 2008;13:1001-1011. 
Larkin J, Ascierto PA, Dreno B, et al. Combined vemurafenib and cobimetinib in BRAF-
mutated melanoma. N Engl J Med 2014;371:1867-76
Le Gal F, Gordien E, Affolabi D, Hanslik T, Alloui C, Deny P, Gault E. Quantification of 
Hepatitis Delta Virus RNA in Serum by Consensus Real-Time PCR Indicates Different 
Patterns of Virological Response to Interferon Therapy in Chronically Infected Patients.  J 
Clin Microbiol. 2005;43(5):2363–2369. J Clin Microbiol. 2005;43(5):2363-2369. 
Long GV, Stroyakovskiy D, Gogas H, et al. Combined BRAF and MEK inhibition versus 
BRAF inhibition alone in melanoma. N Engl J Med 2014;371:1877-88.
Lu S, Kong Y, Xu, X, et al Prevalence of BRAF V600E mutation in Chinese melanoma 
patients: large scale analysis of BRAF and NRAS mutation in a 432-case cohort. European 
Journal of Cancer 2011;48:94-100.
McLellan B, Kerr H. Cutaneous toxicities of the multikinase inhibitors sorafenib and 
sunitinib. Dermatologic Therapy. 2011;24:396-400. 
Nazarian R, Shi H, Wang Q, Kong X, Koya RC, et al. Melanomas acquire resistance to B-
RAF(V600E) inhibition by RTK or N-RAS upregulation. Nature 2010;468;973-7
NCCN. http://www.nccn.org/ ; 2014
NCI. Common Terminology Criteria for Adverse Events (CTCAE), version 4.0.  DHHS, NCI, 
NIH, Bethesda, MD; 2009. version 4.0 ed. Bethesda, MD:DHHS, NCI, NIH; 2009. 
Oken MM, Creech RH, Tormey DC, et al. Toxicity and response criteria of the Eastern 
Cooperative Oncology Group. Am J Clin Oncol. 1982;5(6):649-655. 
Paraiso KH, Fedorendko IV, Cantini LP, Munko AC, Hall M, et al. Recovery of phosphor-
ERK activity allos melanoma cell s to escape from BRAF inhibitor therapy. Br J Cancer
2010;102:1724-30
Poulikakos PI, Persaud Y, Janakiraman M, Kong X, Ng C, et al. RAF inhibitor resistance is 
mediated by dimerization of aberrantly spliced BRAF(V600E). Nature 2011;480:387-90
Robert C, Karaszewska B, Schachter J, et al. Improved overall survival in melanoma with 
combined dabrafenib and trametinib. N Engl J Med 2015;372:30-9
Shi H, Moriceau G, Kong X, Koya RC, Nazarian R, et al. Preexisting MEK1 exon 3 
mutations in V600E/KBRAF melanomas do not confer resistance to BRAF inhibitors Cancer 
Discov 2012b;2:414-24
Shi H, Moriceau G, Kong X, Lee MK, Lee H, et al. Melanoma whole-exome sequencing 
identifies (V600E) B-RAF amplification-mediated acquired B-RAF inhibitor resistance Nat 
Commun 2012a;3:724 
Sosman JA, Kim KB, Schechter L, Gonzalez R, Pavlick AC, et al. Survival in BRAF V600-
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Stein W, Yang J, Bates SE, Fojo T. Bevacizumab reduces growth rate constants of renal 
carcinomas:  a novel algorithm suggests early discontinuation of bevacizumab resulted in a 
lack of survival advantage. Oncologist. 2008;13:1055-1062. 
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2012;366;207-15
Wang Y, Sung, C, Dartois C, Ramchandani R, Booth BP, Rock E, et al. Elucidation of 
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Ther. 2009;86:167-174.


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Appendices


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12.2
Appendix 2: Cockcroft-Gault
The Cockcroft-Gault formula is a commonly-used surrogate marker for actual creatinine 
clearance and employs creatinine measurements and a subject's weight (kg) to predict the 
clearance [Cockcroft, 1976].
CrCl (mL/min)=
Q x (140-age [years]) X actual body weight (kg)a
72 X serum creatinine (mg/dL)
CrCL=creatinine clearance
Q=0.85 for females
Q=1.0 for males
OR
CrCl (mL/min)=
K x (140-age [years]) X actual body weight (kg)
serum creatinine (mol/L)
K=1.04 for females
K=1.23 for males
If the subject is obese (> 30% over ideal body weight), use ideal body weight in calculation of 
estimate CrCl.
a. Calculation of Ideal Body Weight Using the Devine Formula [Devine, 1974]
Male subjects:
50.0 kg + (2.3 kg x each inch over 5 feet)
or
50.0 kg + (0.906 kg x each cm over 152.4 cm)
Female subjects:
45.5 kg + (2.3 kg x each inch over 5 feet)
or
45.5 kg + (0.906 kg x each cm over 152.4 cm)
For example:
For a male subject with actual body weight = 90.0 kg, and height = 68 inches, the calculation 
would be as follows:
Ideal body weight= 50.0 + (2.3) (68-60) = 68.4 kg
This subject’s actual body weight is >30% over ideal body weight.  In this case, the subject’s 
ideal body weight of 68.4 kg should be used in calculating estimated creatinine clearance.
References
Cockcroft DW, Gault MH. Predication of creatinine clearance from serum creatinine. 
Nephron. 1976; 16:31-34.
Devine BJ. Case Number 25 Gentamicin Therapy: Clinical Pharmacy Case Studies. Drug 
Intelligence and Clinical Pharmacy. 1974; 8:650-655.


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12.3
Appendix 3: QT interval on electrocardiogram corrected using 
the Bazett’s formula (QTcB)
The correction method must be collected for ECG machines with a QT correction method 
programmed by the manufacturer. For purposes of data analysis, QTcB will be used.
If the ECG machine does not calculate QTc using Bazett’s formula, QTcB should be 
calculated manually and entered on the eCRF.
Bazett's formula used to correct QT interval for heart rate is:
where QTcB is the QT interval corrected for heart rate, RR is the interval from the onset of 
one QRS complex to the onset of the next QRS complex, measured in seconds, often derived 
from the heart rate (HR) as 60/HR, and QT is the QT interval measured in milliseconds.
References
Bazett HC. An analysis of the time-relations of electrocardiograms. Heart 1920; 7: 353-370.


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12.4
Appendix 4: New York Heart Association (NYHA) Guidelines
The New York Heart Association Functional Classification provides a simple way of 
classifying the extent of heart failure [The Criteria Committee of the New York Heart 
Association, 1994].  It places subjects in 1 of 4 categories based on the level of limitation 
experienced during physical activity:
Functional Capacity
Objective Assessment
Class I: Subjects with cardiac disease but without resulting 
limitation of physical activity.  Ordinary physical activity does 
not cause undue fatigue, palpitation, dyspnea, or anginal pain.
A: No objective evidence of 
cardiovascular disease.
Class II: Subjects with cardiac disease resulting in slight 
limitation of physical activity.  They are comfortable at rest.  
Ordinary physical activity results in fatigue, palpitation, 
dyspnea, or anginal pain.
B: Objective evidence of minimal 
cardiovascular disease.
Class III: Subjects with cardiac disease resulting in marked 
limitation of physical activity.  They are comfortable at rest.  
Less than ordinary physical activity causes fatigue, palpitation, 
dyspnea, or anginal pain.
C: Objective evidence of 
moderately severe cardiovascular 
disease.
Class IV: Subjects with cardiac disease resulting in inability to 
carry on any physical activity without discomfort.  Symptoms of 
heart failure or the anginal syndrome may be present even at 
rest.  If any physical activity is undertaken, discomfort is 
increased.
D: Objective evidence of severe 
cardiovascular disease.
Reference:
The Criteria Committee of the New York Heart Association.  Nomenclature and criteria for 
diagnosis of diseases of the heart and great vessels.  9th ed.  Boston, Mass: Little, Brown, & 
Co; 1994:253-256.


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Appendix 5: Country Specific Requirements
No country-specific requirements exist.


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Appendix 6: Liver Chemistry Monitoring, Interruption, Stopping 
and Follow-up Criteria


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Appendix 7: Liver Safety Drug Restart or Rechallenge Guidelines
Drug restart may be considered for a subject exhibiting compelling benefit for a critical 
medicine following drug-induced liver injury, if favorable benefit: risk and no 
alternative medicine available.  It applies to Phase I-IV studies (excluding healthy 
volunteer studies; example of phase I studies are oncology studies). 

In Phase III-IV, drug restart may be considered for liver safety events with a clear 
underlying cause (e.g. biliary, pancreatic events, hypotension, acute viral hepatitis), if not 
associated with drug-induced liver injury, alcoholic hepatitis, or hypersensitivity (fever, 
rash or eosinophilia) and drug not associated with HLA genetic marker of liver injury, 
when liver chemistries have improved to normal or are within 1.5x baseline and 
ALT<3xULN.
Liver Events Possibly Related to IP - Drug Restart/Rechallenge Following 
Possible Drug-induced Liver Injury Challenge Guidelines
Following drug-induced liver injury, drug restart or rechallenge is associated with a 13% 
mortality across all drugs in prospective studies1 Clinical outcomes vary by drug, with 
nearly 50% fatality with halothane readministered in one month of initial injury. However, 
some drugs seldom result in recurrent liver injury or fatality.  Risk factors for a fatal drug 
restart/rechallenge outcome include: hypersensitivity1 with initial liver injury (e.g. fever, rash, 
eosinophilia), jaundice or bilirubin 2xULN or INR>1.5 suggesting severe liver injury, prior 
IP-related severe or fatal drug restart/rechallenge2,3 or evidence of drug-related preclinical
liability / mitochondrial impairment3
Novartis Decision Process for Drug Restart Approval or Disapproval (also see 
Figure 2)

Principal Investigator (PI) requests consideration of drug restart for a subject receiving 
compelling benefit from a critical or life-saving drug, who exhibits liver chemistry 
elevation meeting subject stopping criteria, with no alternative treatment

Novartis Medical Lead & Clinical Safety Physician to review the subject’s restart/ 
rechallenge risk factors & complete checklist (Table 1).


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Table 1. Checklist for drug rechallenge for critical medicine (Following drug-induced 
liver injury, drug rechallenge is associated with 13% mortality across all drugs in 
prospective studies)
Yes
No
Compelling benefit of the investigational product (IP) for this subject 
and no alternative therapy.  Provide brief explanation:
Relative benefit-risk favorable for drug restart/rechallenge, after 
considering the following high risk factors:

Initial liver injury event included: 
o
fever, rash, eosinophilia, or hypersensitivity
o
or bilirubin>2xULN (direct bilirubin >35% of total)

Subject currently exhibits ALT >3xULN, bilirubin 2xULN (direct 
bilirubin >35% of total, if available), or INR 1.5

Severe or fatal restart/rechallenge has earlier been observed with IP If 
yes, please provide brief explanation:

IP associated with known preclinical hepatic liability/ injury   
*Principal Investigator (PI) Actions:

The PI must obtain Ethics Committee or Institutional Review Board review of drug 
reinitiation, as required. 

PI must discuss the possible benefits and risks of drug reinitiation with the subject.

The subject must sign informed consent with a clear description of possible benefits and 
risks of drug administration, including recurrent liver injury or death. Consent must be 
recorded in the study chart.

The drug must be reinitiated at Novartis-approved dose(s). 

Liver chemistries should be followed twice weekly until stable.

The Ethics Committee or Institutional Review Board must be informed of the subject’s 
outcome, as required.

Novartis to be notified of any adverse events, as per Section 7.3.2-Section 7.3.3. 


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Figure 2
Novartis process for drug restart after possible drug-induced liver injury
References:
1.
Andrade RJ, Robles M, Lucena MI.  Rechallenge in drug-induced liver injury: the 
attractive hazard.  Expert Opin Drug Saf. 2009;8:709-714.
2.
Papay JI, Clines D, Rafi R, Yuen N, Britt SD, Walsh JS, Hunt CM.  Drug-induced liver 
injury following positive drug rechallenge.  Regul Tox Pharm. 2009;54:84-90. 
3.
Hunt, CM.  Mitochondrial and immunoallergic injury increase risk of positive drug 
rechallenge after drug-induced liver injury: A systematic review.  Hepatol. 
2010;52:2216-2222.


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Drug Restart Guidelines
Novartis Decision Process for Drug Restart Approval or Disapproval (also see 
Figure 3)

Principal Investigator (PI) requests consideration of drug reinitiation for a subject stable 
or improving on investigational product (IP), who exhibits liver chemistry elevation 
meeting subject stopping criteria, which is transient, non-drug-related, and resolves. 

Novartis Medical Lead & Clinical Safety Physician to review the subject’s diagnosis, 
restart risk factors & complete checklist (Table 2).
Table 2. Checklist for Phase III drug restart after well-explained liver injury (e.g. 
biliary, pancreatic, hypotensive events, CHF, acute viral hepatitis), liver chemistries 
improving to normal, or 1.5x baseline and ALT<3xULN.
Yes
No
Is subject stable or improving on the investigational product 
(IP)?
Do not restart if the following risk factors at initial liver injury:

fever, rash, eosinophilia, or hypersensitivity 

drug-induced liver injury 

alcoholic hepatitis (AST>ALT, typically <10xULN)    

IP associated with liver injury and an HLA genetic marker 
(e.g. lapatinib, abacavir, amoxicillin/clavulanate)   
*Principal Investigator (PI) Actions

The PI must obtain Ethics Comm. or Institutional Review Board review of drug 
reinitiation, as required. 

PI must discuss the benefits and risks of drug reinitiation with the subject.

The subject must sign informed consent with a clear description of possible benefits and 
risks of drug administration, including recurrent liver injury or death. Consent must be 
recorded in the study chart. 

Liver chemistries should be followed weekly until stable.

The Ethics Committee or Institutional Review Board must be informed of the patient’s 
outcome, as required.

Novartis to be notified of any adverse or serious adverse events, as per Section 7.3.2-
Section 7.3.3


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Figure 3
Novartis process for drug restart approvals
References:

Andrade RJ, Robles M, Lucena MI.  Rechallenge in drug-induced liver injury: the 
attractive hazard.  Expert Opin Drug Saf. 2009;8:709-714.

Papay JI, Clines D, Rafi R, Yuen N, Britt SD, Walsh JS, Hunt CM.  Drug-induced liver 
injury following positive drug rechallenge.  Regul Tox Pharm. 2009;54:84-90. 

Hunt, CM.  Mitochondrial and immunoallergic injury increase risk of positive drug 
rechallenge after drug-induced liver injury: A systematic review.  Hepatol. 2010;52:2216-
2222.


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12.8
Appendix 8: Protocol Amendment Changes
Amendment 1 (27-Mar-2015) from the Original Protocol (08-July-2013)
This amendment applies to all investigator sites participating in this study.  The summary of 
rationale for this amendment is provided below:
Summary of Amendment Changes with Rationale

In Asian population approximately 25.5% of all melanoma patients and 15.5% of ALM 
have BRAF V600 mutation. The study was originally intended to enroll subjects with 
acral lentiginous melanoma and it was less than 5% population eligible. To explore the 
target population, it is decided to enroll subjects with BRAF V600E/K mutation positive 
melanoma, and not limited to acral lentiginous melanoma only. The changes broader data 
in Asian acral and cutaneous melanoma. 

A recently reported phase II study concluded that patients pre-treated with 1 regimen of 
chemotherapy or interleukin-2 (IL-2) in metastatic setting with BRAF V600 mutation was 
allowed to be recruited. As a result, 19% (21/162) of these patients had received prior 
chemo or IL-2 in metastatic setting. Literature also showed the efficacy of BRAF inhibitor 
was similar prior or after immunotherapy.

In approved label, it did not specify the combination of trametinib and dabrafenib 
treatment shall only be used as 1st line treatment in metastatic setting. 

There are two other China alone PK studies were approved. It is no longer needed to 
collect single dose (Chinese subjects only) PK data from this study. 
Given the clinical considerations described above, the inclusion criteria and sample collection 
time point was modified. In addition, there are some changes to meet specific country 
regulatory requirement and the safety information is updated based on most recent studies 
data.
Revised Text is captured in the format strikethrough=deleted text; 
underline=new text
12.8.1 List of Specific Changes:
Rationale for change(s): Change in Study team members
Title page
REVISED TEXT
Title:
Protocol 200104: An Open-Label, Multi-Center Study to 
Investigate the Objective Response Rate of Dabrafenib in 
Combination with Trametinib in Subjects with BRAF V600 E/K 
Mutation-Positive Acral Lentiginous Melanoma
Rationale for change(s): Change in Study team members
Revised text:
Author (s):
 


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SPONSOR SIGNATORY
, MD 
, MD PhD
Date
SPONSOR INFORMATION PAGE
Rationale for Change: The sponsor information was updated based on internal GSK team 
personnel changes.
REVISED TEXT
Sponsor Serious Adverse Events (SAE) Contact Information:
Role
Name
Day 
Time 
Phone 
Number
After-hours 
Phone/Cell/
Pager 
Number
Fax 
Number
GlaxoSmithKline (GSK) 
Address
Primary 
Medical 
Monitor
 
 MD, 
PhD
 
Cell:
GlaxoSmithKline
1250 South Collegeville 
Road 
Mailstop UP 4340
Collegeville, PA 19426, 
USA
  
GlaxoSmithKline China
No.1, 917 Long, Halei Road
Zhangjiang High Tech Park
Shanghai China 201203
Secondary 
Medical 
Monitor
 
MD 
 
 
MD, PhD
 
Cell: 
Cell:
GlaxoSmithKline
1250 South Collegeville 
Road 
Mailstop UP 4400
Collegeville, PA 19426, 
USA


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Tertiary 
Medical 
Monitor
 
 MD, 
PhD
Cell: 
GlaxoSmithKline
1250 South Collegeville 
Road
Mailstop UP 4340
Collegeville, PA 19426, 
USA
Regulatory Agency Identifying Number(s):
Investigational New Drug (IND) Number
PROTOCOL SUMMARY
Rationale for change(s): Update as per the most recent study results and clarifying the 
need for amendment.
REVISED TEXT
Paragraph 3 
However, much has changed in the treatment landscape of melanoma in 2011 withsince the 
regulatory approval of two new agents which have demonstrated a significant survival benefit 
in well-controlled Phase III trials.past 5 years.  The immunotherapy as  anti-cancer treatment 
in melanoma has significantly advanced. Ipilimumab, a monoclonal antibody that blocks 
cytotoxic T-lymphocyte antigen or CTLA-4, was approved by the US-Food and Drug 
Administration (FDA) for unresectable or metastatic melanoma based on a significant  
prolongation of OS (hazard ratio [HR] 0.68, p=0.003) compared to gp100 tumor vaccine 
[Hodi, 2010] . In addition, ipilimumab in combination with standard dacarbazine (DTIC) 
significantly improved the OS of previously untreated metastatic melanoma patients as 
compared to DTIC alone (HR 0.72, p<0.001).  While ipilimumab was approved for the 
clinical use in unselected patients,in 2011.  2 immune check-point therapy, Programmed 
Death (PD) receptor-1 antibody (pembrolizumab and nivolumab) were also approved in 2014 
for the treatment of metastatic melanoma following the standard treatment. The selective 
small molecule BRAF V600-mutant-kinase inhibitor vemurafenib received FDA-approval in 
August of 2011, demonstrated significant clinical benefit as the first molecular-targeted agent 
for unresectable or metastatic melanoma harboring BRAF V600 mutations. In the pivotal 
Phase III study BRIM-3 treatment with vemurafenib resulted in a significant improvement of 
progression-free survival (PFS) (HR 0.26, p<0.001) and overall survival (HR 0.37, p<0.001) 
in the interim data analysis compared to DTIC [Chapman, 2011].  At 6 months, overall 
survival was 84% (95% CI, 78 to 89) in the vemurafenib group and 64% (95% CI, 56 to 73) 
in the dacarbazine group.monotherapy in metastatic melanoma patients with V600 mutation. 
However the efficacy of vemurafenib. It is widely believed, that combination therapies of 
targeted agents can further improve the effect on survival currently achieved with ipilimumab-
and vemurafenib- single agent-therapies [Eggermont, 2011]. However, the recent study report 


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of hepatotoxicity highlighted the risk of concurrent administration of vemurafenib and 
ipilimumab [Ribas, 2013]. For the approximately 50% of melanoma patients whose tumor 
harbour a BRAF V600-activating mutation, a combination of a selective and potent BRAF-
and a MEK-BRAF inhibitor is favoured to address specific molecular mechanisms of intrinsic 
and acquired resistance to a was not durable In addition, BRAF-inhibitor monotherapy 
[Nissan , 2011].–induced paradoxical activation of the MAPK pathway.
In multiple dabrafenib or tramentinib trials as a monotherapy, the confirmed overall response 
rate was about 50% and 25%, respectively. Emerging data from the ongoing Phase I/II study 
BRF113220 suggest that the small-molecule BRAF V600-inhibitor dabrafenib (known as 
GSK2118436) can be safely combined with the small molecule MEK-inhibitor trametinib 
(known as GSK1120212). The rate of complete or partial response with combination 150 mg 
dabrafenib/2 mg trametinib (150/2) therapy was 76%, as compared with 54% with dabrafenib 
monotherapy (p = 0.03) [Single agent MEK inhibitor trametinib has proved to improve 
survival in metastatic melanoma with BRAF mutation and not associated with paradoxical 
activation of MAPK pathway [Flaherty, 2012].  In addition, the anti-tumor activity of the 
combination of both agents given continuously and at full-single-agent dose appears to be 
superior as compared with single-agent dabrafenib. Currently, multiple randomized phase III 
trails are ongoing with dabrafenib and trametinib combination therapy in patients with 
malignant melanoma.
July]. 
Combination of MEK and BRAF inhibitor was tolerable and delayed the emergence of 
resistance and decreased the incidence of cutaneous hyperproliferation. This was confirmed 
by 3 randomized phase III studies. In September 2014, Long and colleagues reported in New 
England Journal of Medicine the result of COMB-D study. In this study , combination 
treatment of MEK and BRAF inhibitor (dabrafenib and trametinib) compared with BRAF 
inhibitor (dabrafenib) alone, significantly improved progression free survival in previously 
untreated patients who had metastatic melanoma with BRAF V600E or V600 K 
mutations[Long, 2014]. In the same issue of New England Journal of Medicine, another phase 
III study in the similar population reported same result using a different combination of MEK 
and BRAF inhibitor (cobimetinib and vermurafenib)[Larkin, 2014]. Not long after that, also 
in New England Journal of Medicine, a third phase III study was published, which 
demonstrated the combination of trametinib and dabrafenib significantly improved overall 
survival compared with vemurafenib in metastatic melanoma with BRAF V600 mutation 
[Robert, 2014]. These 3 studied included more than 1,600 patients in total. 
In United States and Australia, dabrafenib in combination with trametinib has been approved 
to treat metastatic melanoma with BRAF V600 mutation. 
However, the above mentioned randomize phase III studies were mainly conducted in 
Caucasian population. The efficacy and safety of trametinib plus dabrafenib need to be 
evaluated in Asian melanoma patients. 
Paragraph 8
The original objective of the study was to evaluate the effect of dabrafenib and trametinib in 
patients with ALM in Asian countries.  In light of the most recent advances in the treatment of 
BRAF mutation cutaneous melanoma, the study aims to evaluate the efficacy and safety of 
dabrafenib and trametinib in Asian subjects with either acral lentiginous and  cutaneous 
melanoma pathology subtype who have BRAF V600 E/K mutation. This study will provide 


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important scientific information to help to address the unmet medical needs in Asian 
melanoma patients.  
Objective(s)
Primary Objective

To determine the objective response rate (ORR) of dabrafenib and trametinib combination 
in subjects with BRAF V600 E/K mutation-positive, unresectable or metastatic acral 
lentiginous metastaticor cutaneous melanoma.  
Secondary Objectives

To assess single-dose (Chinese subjects only) and steady state (all subjects) exposure 
to dabrafenib, dabrafenib metabolites, and trametinib and characterize the population 
pharmacokinetics (PK) and pharmacodynamics (PD) of dabrafenib and trametinib
Study Design
This is a single-arm, open-label, multi-center, Phase II study to evaluate dabrafenib and 
trametinib combination therapy in BRAF V600-E/K mutant ALM. or cutaneous melanoma.
Subjects with histologically confirmed acral lentiginous or cutaneous melanoma that is either 
Stage IIIC (unresectable) or Stage IV will be screened for eligibility. Screening will include 
central testing of BRAF V600 mutation status. Eligible subjects must be BRAF V600E/K 
mutation positive.  Subjects whomay have had prior systemic anti-cancer treatment in the 
advancedadjuvant or metastatic setting will, but should not be eligible.  Prior adjuvant 
systemic treatment is permitted.have been exposed to MEK or BRAF inhibitor.    Objective 
response rate will be assessed using a 2-stage Green-Dahlberg design.  Approximately 35 
subjects (20 subjects in stage 1 and additional 15 subjects in stage 2) will be enrolled and will 
receive dabrafenib 150 mg orally twice daily and trametinib 2 mg orally once daily. 
Treatment will continue until disease progression, death, unacceptable toxicity, or withdrawal 
of consent, or study closurecompletion. After treatment discontinuation, subjects will be 
followed for survival and disease progression as applicable.
Survival and new anti-cancer therapy follow-up will continue until 70% of the total enrolled 
population has died or been lost to follow-up. At such time the study will be closed.study 
completion. The study completion is defined as:

In case all subjects stop study treatment within 48 weeks after Last Subject First 
Visit(LSFV): the study is completed once the last subject has completed the 48 weeks 
survival follow-up or all subjects die or loss to follow-up, whichever comes first. 

In case some subjects are still on study treatment 48 weeks after LSFV: the study is 
completed once all subjects stop study medication, or all subjects who are still on study 
medication can have access to alternative supply of MEK/BRAF inhibitors, whichever 
comes first.  
Study Endpoints/Assessments
Noncompartmental PK parameters will include:  


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Single dose (Chinese subjects only) - maximum observed plasma concentration (Cmax), time 
to Cmax (tmax), area under the plasma concentration-time curve (AUC) from 0 to the time of 
the last quantifiable concentration (AUC(0-t)), AUC from 0 to 8 hours (AUC(0-8)), AUC 
from 0 to 12 hours (AUC(0-12); dabrafenib and metabolites only), AUC from 0 to 24 hours 
(AUC (0-24) :trametinib only)), AUC from 0 to infinity (AUC(0-(), and apparent terminal 
phase half-life (t1/2) for trametinib and dabrafenib and metabolites as data permit.  The 
metabolite to parent ratio for AUC(0-t) will be calculated for each metabolite of dabrafenib. 
Section 1. Introduction
Rationale for change(s): Updating as per the most recent study results and describing the 
scenario of amendment needed.
REVISED TEXT
Section 1.1. Background
The RAS/RAF/MEK/ERK pathway (i.e., the MAP kinase pathway, Figure 1) is a critical 
proliferation pathway in many human cancers, including melanoma.  Oncogenic mutations in 
both RAS and BRAF signal through MEK1 and MEK2 and this is an early event.  This study 
will evaluate the combination of two, small-molecule, oral agents, dabrafenib and trametinib 
in ALM or cutaneous melanoma.
Section 1.2. Current treatment options for melanoma
Much has changed in the treatment landscape of melanoma since the past 5 years.  The 
immunal anti-cancer treatment in melanoma had significantly advanced. Ipilimumab, a 
monoclonal antibody that blocks cytotoxic T-lymphocyte antigen or CTLA-4, was approved 
by the US-Food and Drug Administration (FDA) for unresectable or metastatic melanoma in 
2011.  2 immunal check-point therapy, Programmed Death (PD) receptor-1 antibody 
(pembrolizumab and nivolumab) were also approved in 2014 for the treatment of metastatic 
melanoma following the standard treatment. 
BRAF inhibitor demonstrated significant clinical benefit compared to chemotherapy in 
metastatic melanoma patients with V600 mutation. in the treatment landscape of melanoma in 
2011 with the regulatory approval of two new agents which have demonstrated a significant 
survival benefit in well-controlled Phase III trials. Ipilimumab, a monoclonal antibody that 
blocks cytotoxic T-lymphocyte antigen or CTLA-4, was approved by the US-Food and Drug 
Administration (FDA) for unresectable or metastatic melanoma based on a significant 
(p=0.003) improvement of OS [Hodi, 2010].  However the efficacy of BRAF inhibitor was 
not durable, as the PFS of vemurafenib or dabrafenib monotherapy was only 5.1- 5.3 
months.[Hauschild, 2012; Chapman, 2011] In addition, BRAF-inhibitor–induced paradoxical 
activation of the MAPK pathway[Hatzivassiliou, 2010] can result in secondary cancers, 


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including cutaneous squamous-cell carcinoma, and may reactivate RAS-mutant 
tumors[Callahan, 2012].
Single agent MEK inhibitor trametinib has proved to improve survival in metastatic 
melanoma with BRAF mutation and not associated with paradoxical activation of MAPK 
pathway [Flaherty, 2012]. 
Combination of MEK and BRAF inhibitor was tolerable. The combination of BRAF and 
MEK inhibition, as compared with single-agent BRAF inhibition, delayed the emergence of 
resistance and decreased the incidence of cutaneous hyperproliferation.  Long and colleagues 
reported the result of a randomized double blind phase III study which compared trametinib 
plus dabrafenib versus dabrafenib alone in metastatic melanoma patient who had BRAF V600 
E or K mutation. The combined treatment significantly improved PFS (mPFS: 9.3 vs 8.8 
months, HR=0.75, p=0.03), response rate (67% vs 51%, p=0.0002). At 6 months, the interim 
survival analysis also showed a improvement of survival (HR=0.63, p=0.02) . The patients 
who received combined treatment experienced more frequent pyrexia, chill, diarrhea, 
hypertension, vomiting, peripheral edema, elevated liver enzyme, decreased left ventricular 
ejection fraction(LVEF), dermatitis acneiform,  but less frequent cutanenous squamous-cell 
carcinoma, hyperkeratosis, skin papilloma, hand-foot syndrome, dry skin, pruritus and 
alopecia. [Long, 2014] Similar efficacy results were confirmed by 2 independent randomized 
studies using trametinib plus dabrafenib versus vemurafenib[Robert, 2015], and  cobimetinib 
plus vemurafenib versus vemurafenib [Larkin, 2014].  
In United States and Australia, dabrafenib in combination with trametinib has been approved 
to treat metastatic melanoma with BRAF V600 mutation. While ipilimumab was approved for 
the clinical use in unselected patients, the selective small molecule BRAF-inhibitor 
vemurafenib received FDA-approval in August of 2011, as the first molecular-targeted agent 
for unresectable or metastatic melanoma harbouring BRAF V600E mutations.  In the pivotal 
Phase III study BRIM-3 treatment with vemurafenib resulted in a significant improvement of 
PFS and OS  compared to DTIC [Chapman, 2011].  The BRIM-3 update on OS analysis at 
12.5 months follow-up for vemurafenib and 9.5 months follow-up for DTIC showed 
significantly longer survival with vemurafenib (13.6 months) vs DITC (9.7 months) with an 
HR of 0.70 (95% CI: 0.57 – 0.87; p < 0.001).
Despite this major initial progress in the clinical management of unresectable melanoma, 
severe immune-mediated toxicities and the lack of a validated biomarker for patient selection 
may restrict the use of ipilimumab while the onset of acquired drug resistance limits the 
efficacy of vemurafenib. It is widely believed that combination therapies of targeted agents 
can further improve the effect on survival currently achieved with ipilimumab- and 
vemurafenib- single agent-therapies [Eggermont, 2011].  However, the recent study report of 
hepatotoxicity highlighted the risk of concurrent administration of vemurafenib and 
ipilimumab [Ribas, 2013]. For the approximately 50% of melanoma patients whose tumor 
harbor a BRAF-V600-activating mutation, a combination of a selective and potent BRAF-
and a MEK-inhibitor is favoured to address specific molecular mechanisms of intrinsic and 
acquired resistance to a BRAF-inhibitor monotherapy [Nissan , 2011].


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Section 1.2.3. BRAF and MEK Inhibitors as Combination Therapy
Paragraph 4
MEK115306 study is a double blind randomized phase III study that recruited 423 previously 
untreated metastatic melanoma patients who had BRF V600E or V600K mutation. Eligible 
patients were randomized to receive dabrafenib 150mg bid plus trametinib 2mg qd, or 
dabrafenib 150mg bid plus placebo. The primary endpoint was PFS. The results showed the 
combination significantly improved PFS (median PFS: 9.3 vs 8.8 months, HR=0.75, p=0.03) 
and response rate (67% vs 51%, p=0.0002) . The interim OS analysis at 6 months showed the 
survival rate was 93% and 85% in the combination arm vs dabrafenib arm (HR=0.63, p=0.02). 
However, a pre-defined specific efficacy stopping boundary of OS (two-side p=0.00028) was 
crossed. So the survival follow-up is still on-going as of December 2014. 
In this study, 9% patient from combination treatment arm and 5% from dabrafenib 
monotherapy arm permanently discontinued study medication before disease progression. In 
addition, dose reduction was required in 25% and 13% of patients receiving combination and 
dabrafenib monotherapy, respectively. 
The adverse event profile of combination treatment was different from dabrafenib 
monotherapy. The patients who received combined treatment experienced more frequent 
pyrexia(51% vs 28%), chill(30% vs 16%), diarrhea(24% vs 14%), hypertension(22% vs 
14%), vomiting(20% vs 14%), peripheral edema(14% vs 5%), elevated ALT (11% vs 5%) or 
AST (11% vs 3%), decreased left ventricular ejection fraction(LVEF)(4% vs 2%), dermatitis 
acneiform(8% vs 3%),  but less frequent cutanenous squamous-cell carcinoma(2% vs 9%), 
hyperkeratosis(3% vs 32%), skin papilloma(1% vs 21%), hand-foot syndrome(5% vs 27%), 
dry skin(9% vs 13%), pruritus(8% vs 12%) and alopecia(7% vs 26%). [Long, 2014]
MEK116513 study is an open lable randomized phase III study that recruited 704 previously 
untreated metastatic melanoma patients who had BRF V600E or V600K mutation. Eligible 
patients were randomized to receive dabrafenib 150mg bid plus trametinib 2mg qd, or 
vemurafenib 960mg bid. The primary endpoint was overall survival. At an pre-planned 
interim analysis, this study demonstrated the combination of dabrafenib plus trametinib 
achieved significant OS improvement (12 months OS rate: 72% vs 65%, HR: 0.69, p=0.005) 
and this result crossed the pre-defined interim stopping boundary. Therefore this study was 
stopped pre-maturely because of the efficacy. The combination treatment also significantly 
improved PFS (median PFS: 11.4 vs 7.3 months, HR: 0.56, p<0.001) and response rate (64% 
vs 51%, p<0.001). 
Rates of study-drug discontinuations were similar in the two groups(13% in combination arm 
and 12% in vemurafenib arm). Adverse events leading to dose reduction was reported in 33% 
of patients in comintation arm and 39% in the vemurafenib arm. 
The most frequent adverse events in the combination-therapy group were pyrexia (53%), 
nausea (35%), diarrhea (32%), chills (31%), fatigue (29%), headache (29%), and vomiting 
(29%). In the vemurafenib group, the most frequent adverse events were arthralgia (51%), 
rash (43%), alopecia (39%), diarrhea (38%), nausea (36%), and fatigue (33%). Skin toxic 
effects were more frequent in the vemurafenib group than in the combination-therapy group, 
in particular rash (43% vs. 22%), photosensitivity reaction (22% vs. 4%), hand–foot syndrome 
(25% vs. 4%), skin papillomas (23% vs. 2%), squamous-cell carcinomas and 
keratoacanthomas (18% vs. 1%), and hyperkeratosis (25% vs. 4%). Pyrexia was more 
frequent in the combination-therapy group than in the vemurafenib group (53% vs. 


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21%).Grade 3 or 4 adverse events occurred in 52% of the patients in the combination-therapy 
group and in 63% of those in the vemurafenib group. Three fatal events occurred in each 
group; all were deemed by the investigator to be unrelated to the study drug.[Robert, 2015],
Section 1.2.3.1. Dabrafenib and Trametinib in Acral Lentiginous Melanoma
Paragraph 4
In conclusion, currently available treatments for melanoma (all types) including ipilimumab, 
pembrolizumab, nivolumab, vemurafenib, dabrafenib, and trametinib are effective 
monotherapy treatments. Combination of MEK and BRAF inhibitor has become the standard 
treatment for metastatic melanoma with BRAF V600 mutation. Combination therapy with 
ipilimumab and vemurafenib may not provide an optimal risk/benefit ratio due to potential 
hepatotoxicity.  Exploration of other combinations, such as dabrafenib and tramentinib, is 
warranted. In Part C of the BRF113220 study, statistically significant and clinically 
meaningful improvements in PFS were observed.  
In Asian population, approximately 25.5% of all melanoma patients and 15.5% of ALM have 
BRAF V600 muataion [Lu, 2011]. There are no PK data in Chinese patients. Preliminary PK 
data obtained in Japanese patients showed there no major ethnic difference in the 
pharmacokinetic profile of trametinib or dabrafenib when administered in monotherapy 
(Study BRF116056 and MEK114784), however, exposure to dabrafenib and trametinib 
tended to be higher when administered in combination [Study MEK116885 COMBO-IB]. 
Limited d Data in subjects with acral lentiginous melanoma subtype or Asian population was 
limited and further exploration in these populations is warranted. also showed promise in 
extending survival.  This study aims to further evaluate the efficacy and safety of dabrafenib 
and trametinib in acral lentiginous melanoma, which represents an unmet medical need in 
non-Caucasians.
This study was originally intended to enroll subjects with acral lentiginous melanoma. 
however based on a lower than expected BRAF v600 E/K mutation rate in this population, t
The eligibility criterion has been amended to include  cutaneous melanoma in light of the 
advance in the management of metastatic melanoma with BRAF V600 mutation.
Section 1.3 Rationale
Point no. 3 
Data from the ongoing BRF113220 study (Part C) and 2 randomized phase III study
evaluating the combination of dabrafenib and trametinib demonstrated promising clinical 
activity and an acceptable clinical safety profile of the dabrafenib and trametinib combination 
given at full single-agent dose 
Point no. 4 
Limited data are available in non-Caucasian populations where cutaneous melanoma sub-
types such as ALM may be more prevalent.


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Early safety and efficacy data, together with limited data in ALM subjects enrolled in 
dabrafenib and trametinib clinical trials, support the rationale and design of this Phase II study 
of the combination of dabrafenib and trametinib in unresectable V600E- and V600K-BRAF-
mutant acral lentiginous melanoma subjects.
Section 1.4.1. Benefit Assessment
Current research suggests that combination therapies of BRAF- and MEK-targeted agents can 
further improve the effect on survival currently achieved with BRAF inhibitor monotherapy 
[Long, 2014, Robert 2015] in metastatic melanoma patients with BRAF V600 mutation. 
Patients treated with combination of trametinib and dabrafenib can achieve a 6 months 
survival rate of 93% [Long, 2014] and 12 months survival rate of 72% [Robert, 2015]. 
ipilimumab- and vemurafenib- single agent-therapies [Eggermont, 2011]. For the 
approximately 50% of melanoma patients whose tumor harbor a BRAF V600-activating 
mutation, a combination of a selective and potent BRAF- and a MEK-inhibitor is favored to 
address specific molecular mechanisms of intrinsic and acquired resistance to a BRAF-
inhibitor monotherapy [Nissan, 2011].
Dacarbazine (DTIC), considered the most active of the agents currently available, is approved 
for metastatic melanoma and widely used in clinical practice [Huncharek, 2001] and widely 
used in clinical practice in Asian countries. The benefit of DTIC remains small, with median 
progression-free survival lasting approximately 2 months and median overall survival of 
approximately 7 months.
There are no PK data in Chinese patients. Preliminary PK data obtained in Japanese patients 
showed there no major ethnic difference in the pharmacokinetic profile of trametinib or 
dabrafenib when administered in monotherapy (Study BRF116056 and MEK114784), 
however, exposure to dabrafenib and trametinib tended to be higher when administered in 
combination (Study MEK116885).  However,  In Asian patients there was no 
pharmacokinetic difference observed with trametinib, dabrafenib or the combination, 
compared with Caucasian patients. Therefore, the planned dose of study medication is 
expected to be tolerable in the study population and bring clinical benefit.
Section 1.4.2. Overall Benefit: Risk Conclusion
Paragraph 1
To date, over 1000 subjects, of predominantly Caucasian ethnicity and with majority of
BRAF V600 mutated metastatic melanoma have received this combination regimen in 5 phase 
I/II studies and 3 phase III studies. The complete list of these studies can be found in the IB. 
the completed Phase I/II study BRF113220 and the ongoing Phase III combination clinical 
trials. The Phase I/II Study BRF113220 is a 4-part study that included a randomized Phase II 
component (Part C). Part C of this study allowed for a direct comparison of the safety profile 
of combination therapy relative to dabrafenib monotherapy in a metastatic melanoma 
population. In addition, comprehensive safety data dabrafenib or trametinib as a monotherapy 
regimen enabled a comparison between the specific safety profile of the combination regimen 
and the individual components. Dabrafenib and trametinib have independently demonstrated 


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significant clinical benefit in randomized Phase III trials extending the progression-free 
survival of subjects with metastaticV600 BRAF-mutation positive melanoma as compared to 
standard chemotherapy.
Paragraph 3
The safety profile for the combination treatment of dabrafenib 150 mg twice daily and 
trametinib 2 mg once daily in subjects with unresectable or metastatic melanoma with a 
BRAF V600 mutation is defined by the results of the pivotal Phase III Study MEK115306 and 
MEK116513 and supported by the BRF113220 pooled combination therapy population. 
Paragraph 4
The combination therapy has a higher rate of pyrexia, fatigue and nausea, while lower 
incidences of hyperkeratosis, alopecia and skin papilloma  were observed compared with 
dabrafenib monotherapy. Relative to trametinib monotherapy, there was a higher incidence of 
fatigue, nausea, and vomiting observed but lower incidences of rash and diarrhea with 
combination therapy. 
The risk-to-benefit ratio in this patient population remains favorable.
The dabrafenib/trametinib combination may decrease the frequency or severity of some 
toxicities previously observed with trametinib monotherapy such as skin-related toxicities 
(e.g., rash and dermatitis acneform). The safety profile of the combination therapy is primarily 
impacted by the emergence of a higher rate of pyrexia. While fatigue and nausea occur at a 
higher frequency relative to dabrafenib monotherapy, lower incidences of hyperkeratosis, 
alopecia, and skin papilloma are observed. Relative to trametinib monotherapy, there was a 
higher incidence of fatigue, nausea, and vomiting observed but lower incidences of rash and 
diarrhea with combination therapy. AEs resulting in dose reduction or interruption occurred 
more frequently with combination treatment. Despite this, the incidence of permanent 
discontinuation remained consistent with trametinib monotherapy suggesting that tolerability 
can be managed effectively with proper guidance to the prescribing physician. The incidence 
of serious adverse events (SAEs), which included all cases of pyrexia, was 2 to 3 fold higher 
in combination compared with either drug alone, primarily due to the inclusion of pyrexia 
cases regardless if they met the formal definition of SAE. Fatal SAEs remain infrequent with 
combination therapy. AEs of special interest were identified independently for both 
dabrafenib and trametinib based on the frequency and the potential association with the mode 
of action of BRAFand MEK- inhibitors. An extensive review of skin-related events, cardiac-
related events, hepatic events, pneumonitis, ocular events, hypertension, and diarrhea 
appeared to be consistent with the known AE profiles of either dabrafenib or trametinib. The 
incidence of treatment-emergent malignancies and new primary melanoma observed in 
melanoma subjects receiving the dabrafenib and trametinib combination therapy was 
consistent with what has been observed so far in the dabrafenib safety population. No 
additional AEs of special interests were identified for the combination regimen. The most 
notable finding in the combination study was the reduced frequency of hyperproliferative skin 
diseases including keratoacanthoma and cuSCC noted in subjects treated with the dabrafenib 
and trametinib combination regimen compared to subjects treated with dabrafenib alone. 


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Thus, the non-clinical hypothesis that addition of trametinib abrogates the paradoxical MAP-
kinase pathway excerted by BRAF-inhibitors such as dabrafenib in keratinocytes harboring 
upstream pathway activation has been substantiated. Pyrexia, a commonly noted AE 
associated with BRAF inhibition, occurred more frequently in combination compared with 
dabrafenib monotherapy. Most cases were of mild to moderate severity and occurred early 
during combination treatment. While temporary dosing modifications and supportive therapy 
led to a resolution of pyrexia, hospitalization was required in a number of cases due to 
additional complicating events including acute renal failure.
In conclusion, the combination of dabrafenib 150 mg two times a day and trametinib 2 mg 
once daily offers a unique treatment combination that has a predictable safety and tolerability 
profile that is based on the known profiles of each drug. Some commonly expected toxicities 
occur more frequently when these drugs are combined but appear to be managed clinically in 
a manner consistent with recommendations associated with monotherapy treatment. In 
addition, nonclinical and clinical data indicate that the combination also attenuates an 
important safety concern with the administration of BRAF inhibitors; namely the induction of 
hyperproliferative effects such as cutaneous squamous cell carcinoma.
Section 2. Objectives and endpoints
Rationale for change(s):
China is running the regulatory required China alone PK studies. The data from those studies 
are sufficient and it is no need to process additional single dose PK testing in this study.
REVISED TEXT
Objectives
Endpoints
Primary

To determine the objective response 
rate (ORR) of dabrafenib in 
combination with trametinib in 
subjects with BRAF V600E/K 
mutation-positive, unresectable or 
metastatic acral lentiginous or 
cutaneous melanoma (ALM)   

ORR defined as the percentage 
of subjects with evidence of a 
confirmed complete response 
(CR) or partial response (PR) as 
per RECIST v1.1 [Eisenhauer, 
2009].
Secondary
1. To assess single dose (Chinese 
subjects only) and steady state (all 
subjects) exposures to dabrafenib, 
dabrafenib metabolites, and 
trametinib, and characterize the 
population pharmacokinetics and 
pharmacodynamics of dabrafenib 
and trametinib 

Trametinib, dabrafenib and 
dabrafenib metabolites 
concentrations by visit.  
Noncompartmental PK 
parameters include trametinib, 
dabrafenib and dabrafenib 
metabolites Cmax, tmax, 
Ctrough, AUC(0-t), and AUC(0-
8); AUC(0-12) (dabrafenib and 


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Objectives
Endpoints
dabrafenib metabolites only), 
AUC (0-24) (trametinib only) 
and the dabrafenib metabolite to 
dabrafenib ratio of AUC(0-12).  
Population PK parameters 
include, apparent clearance 
following oral dosing (CL/F), 
volume of distribution (V/F), and 
absorption rate constant (Ka) for 
dabrafenib and trametinib.
Section 3 Study Design
Rationale for change(s):
To well-define the definition of study completion and avoid confusion caused. 
REVISED TEXT
Section 3.1  Study Design
Paragraph 2
This is an open-label, Phase II, multi-center study to evaluate the objective response rate of 
dabrafenib and trametinib combination therapy in subjects that have BRAF V600E/K 
mutation-positive ALM or cutaneous melanoma.
Subjects will continue study treatment until disease progression, death, unacceptable toxicity, 
withdrawal of consent, or study closure completion closure.  After treatment discontinuation, 
subjects will be followed for survival and disease progression as applicable. 
The study completion is defined as:

In case all subjects stop study treatment within 48 weeks after Last Subject First 
Visit(LSFV): the study is completed once the last subject has completed the 48 weeks 
survival follow-up or all subjects die or loss to follow-up, whichever comes first. 

In case some subjects are still on study treatment 48 weeks after LSFV: the study is 
completed once all subjects stop study medication, or all subjects who are still on 
study medication can have access to alternative supply of MEK/BRAF inhibitors, 
whichever comes first.
The study will be closed once 70% of the total enrolled study population has died or been lost 
to follow-up.  
Section 4 Subject selection and discontinuation/completion criteria


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Rationale for change(s):
1.
Changing the criteria to meet local regulatory requirement in certain country (eg. In 
certain countries, legal adult age is greater than 20 years).
2.
Specified the method of BRAF mutation testing and updating the wordings to be in 
line with asset required language. 
REVISED TEXT
Section 4.1.2 Inclusion criteria
Inclusion criteria No. 2 
≥18 years of age (or of legal adult age in countries where legal adult age is greater than 18 
years), 
Inclusion criteria No. 3 
Histologically confirmed acral lentiginous or cutaneous melanoma that is either Stage IIIC
(unresectable) or Stage IV (metastatic), and determined to be BRAF V600E/K mutation-
positive. Note: BRAF V600E/K mutation status for study eligibility should be determined 
using direct sequencing or PCR method.
 
. The testassay will be conducted at by a GSK 
designated central reference laboratory. If data warrants the development of a companion 
diagnostic assay, the screening tissue may be subject to additional testing of BRAF mutations. 
Subjects with ocular or mucosal melanoma are not eligible.
Inclusion criteria No. 8 
Women of child-bearing potential (see Section 7.3.7 for definitions) must have a negative 
serum pregnancy test within 7 14 days of first dose of study treatment and agree to use 
effective contraception, as stated in Section 7.3.7 from 14 days prior to enrollment, 
throughout the treatment period and for 4 months after the last dose of study treatment. 
Table 2
Definitions for Adequate Baseline Organ Function
System
Laboratory Values
Hematologic
Platelet count
≥ 75 100 x 109/L
b. Except subjects with known Gilbert’s syndrome.
Section 4.1.3 Exclusion criteria
Exclusion criteria No. 1 
Known non-acral lentiginous cutaneous,primary mucosal or ocular melanoma.


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Prior treatment with a BRAF inhibitor (including but not limited to dabrafenib, vemurafenib, 
LGX818, and XL281/BMS-908662) or a MEK inhibitor (including but not limited to 
trametinib, AZD6244, and RDEA119). (Note: Ipilimumab treatment must end at least 8 
weeks prior to enrollment.) Any major surgery, extensive radiotherapy, chemotherapy with 
delayed toxicity, biologicbiological anti-cancer therapy, or immunotherapyimmunol anti-
cancer therapy within 21 days prior to enrollment /or daily or weekly chemotherapy without 
the potential for delayed toxicity within 14 days prior to enrollment. . (Note: Ipilimumab, 
pembrolizumab and nivolumab treatment must ended at least 8 weeks prior to enrollment).
Exclusion criteria No. 3 (Amended)
Taken an investigational drug within 28 days or 5 half-lives (minimum 14 days), whichever is 
shorter, prior to enrollment (Note: in case ipilimuamb, pembrolizmab and nivolumab are
investigational drug in the regions and countries, and in case of PD-L1 antibody, these 
investigational treatment shall be ended at least 8 weeks prior to enrollment ).
Exclusion criteria No. 6 (Amended) 
Known Human Immunodeficiency Virus (HIV), A history of Hepatitis B Virus (HBV), or 
Hepatitis C Virus (HCV) infection (subjects with the exception laboratory evidence of chronic 
or cleared HBV and/or HCV infection which will be permitted).
Exclusion criteria No. 7 (Amended) 
Leptomeningeal or brain metastases or metastases causing spinal cord compression that are: 
symptomatic or untreated or not stable for 3 months (must be documented by imaging) or 
requiring corticosteroids.  Subjects on a stable dose of corticosteroids >1 month or who have 
been off of corticosteroids for at least 2 weeks can be enrolled with approval of the GSK 
medical monitor.  Subjects must also be off of enzyme-inducing anticonvulsants for >4 
weeks. 
Brain metastasis are excluded unless:
1.
All known lesions have been definitively treated with surgery or stereotactic 
surgery (whole-brain radiation may be given as adjuvant treatment), OR
2.
Brain lesion(s), if still present, must be confirmed stable (i.e., no increase in 
lesion size) for ≥ 12 weeks prior to enrollment (stability must be confirmed 
with two consecutive magnetic resonance image (MRI) or computed 
tomography (CT) scans with contrast, separated by >6 weeks
AND

Asymptomatic with no corticosteroid requirements for ≥ 4 weeks prior to enrollment, 
AND

No enzyme inducing anticonvulsants for ≥ 2 weeks prior to enrollment


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In addition, for subjects that had brain metastases but currently have no evidence of disease 
(NED), NED for ≥12 weeks is required and must be confirmed by two consecutive scans, 
separated by ≥6 weeks, prior to randomization.
Exclusion criteria No. 8 (Amended) 
History of another malignancy other than disease under study within 3 years, of study 
enrolment with exceptions below. Exception: Subjects who have been disease-free for 3 years, 
(i.e.with a history of completely resected non-melanoma skin cancer, or subjects with indolent 
second malignancies are eligible.
Exclusion criteria No. 9 (Amended)
History of malignancy with confirmed activating RAS mutation at any time. Note: 
Prospective RAS testing is not required. However, if the results of previous RAS testing are 
known, they must be used in assessing eligibility. 
Exclusion criteria No.10 (Amended)
Any serious or unstable pre-existing medical conditions (aside from malignancy exceptions 
specified above), psychiatric disorders, or other conditions that could interfere with the 
subject’s safety, obtaining informed consent, or compliance with study procedures.  
Exclusion criteria No.11 (Amended)
A history or evidence of cardiovascular risk including any of the following:
c. A history or evidence of current clinically significant uncontrolled arrhythmias;
Clarification Exception: Subjects with atrial fibrillation controlled for > 30 days prior to 
dosing enrollment are eligible.
d.  A history (within 6 months prior to enrollment) of acute coronary syndromes (including 
myocardial infarction or unstable angina), coronary angioplasty, or stenting within 6 months 
prior to randomization;
e. A history or evidence of current ≥Class II congestive heart failure as defined by the New 
York Heart Association (NYHA) guidelines (Appendix 3);
f. Patients with intra-cardiac defibrillators;
g. Treatment refractory hypertension defined as a blood pressure of systolic> 140 mmHg 
and/or diastolic > 90 mm Hg which cannot be controlled by anti-hypertensive therapy;
h. Subjects with intra-cardiac defibrillators or permanent pacemakers;
i. Known cardiac metastases;


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Exclusion criteria No.17 (Amended)
Interstitial lung disease or pneumonitis.
Section 4.2.1. Permanent Discontinuation from Study Treatment
Paragraph 1
Note: Subjects who are experiencing progression of disease (by RECIST, version 1.1) but are 
receiving clinical benefit based on the investigator’s assessment, may be allowed to continue 
study treatment (see Section 4.2.2).) with the agreement of sponsor’s medical monitor.
Paragraph 8
Survival and new anti-cancer therapy follow-up will continue until 70% of the total enrolled 
study population has died or been lost to follow-up.  study completion.
Section 4.2.3. Subject Completion Criteria
A subject will be considered to have completed the study if the subject dies during the study 
treatment or follow-up period. The cause of death will be documented in the eCRF. A subject 
will be considered to have withdrawn from the study if the subject has not died and is lost to 
follow-up, or has withdrawn consent, at the investigator’s discretion is no longer being 
followed or if the study is closed or terminated completed. The definition of study completion 
was described in protocol Section 3.1.  
Section 5 Study Treatments
Rationale for change(s):
1.
To further clarify how to take study treatment properly and to update wordings to be in 
line with asset required language. 
2.
Changing typo in the original protocol. 
3.
Updating dose adjustment processed based on results of recent reported studies. 
REVISED TEXT
Section 5.2. Dosage and Administration

Dabrafenib, 150 mg, BID;

Trametinib, 2.0 mg, once daily. 
Both study treatments should be When administered in the morning combination with 
trametinib, take the once-daily dose of trametinib at approximately the same time everyeach
day. with either the morning dose or the evening dose of dabrafenib. The second dose of 
dabrafenib (150 mg) should be administered approximately 12 hours after the morning dose.  
Study medication should be taken orally with approximately 200 mL of water under fasting 
conditions, either 1 hour before or 2 hours after a meal.    
Paragraph 4 


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If a subject misses a dose of dabrafenib dose, the subject may take the dose immediately if the 
next dose is scheduled for at least 6 hours later. If the next scheduled dose of dabrafenib is 
due in less than 6 hours, the subject should skip the dose and resume of dabrafenib dosing at 
the next scheduled dose 
If a subject misses a trametinib dose, the subject may take the dose immediately if the next 
dose is scheduled for at least 12 hours later. If the next scheduled dose is due in less than 12 
hours, the subject should skip the dose and resume dosing at the next scheduled dose.
Subjects should start treatment as soon as possible after enrollment but no later than 7 days 
post-enrollment.
See Section 5.8 for dose modification guidelines on dabrafenib and trametinib.
Section 5.3. Handling and Storage of Study Treatments
Under normal conditions of handling Dabrafenib and administration, investigational product 
is not expected to pose significant safety risks to site staff.  Material Safety Data Sheet 
(MSDS) describing the occupational hazards trametinib must be dispensed and recommended 
handling precautions will be provided to site staff if required by local laws or will otherwise 
be available from GSK upon request.
Investigational product administered in accordance with the protocol, and only to subjects
enrolled in the study.  Dabrafenib and trametinib must be stored in a secure area under the 
appropriate physical conditions for the product .  Study medication is to be stored at the 
temperature specified on the label.  Maintenance of a temperature log (manual or automated) 
is required. Access to and administration of the investigational productdabrafenib and 
trametinib will be limited to the investigator and authorised site staff.  Investigational product 
must be dispensed or administered only to subjects enrolled in the study and in accordance 
with the protocol. authorized site staff.
Procedures for final disposition of unused study treatments will be provided in the SPM.
Section 5.8.1. Dose Levels of dabrafenib and trametinib
Paragraph 2 
A dose reduction below 5075 mg BID for dabrafenib or below 1 mg once daily for trametinib 
is not allowed. If a dose reduction below 75 mg BID for dabrafenib is required, dabrafenib 
will be permanently discontinued but these subjects will be allowed to continue trametinib.


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Section 5.8.3.1. Left Ventricular Ejection Fraction (LVEF)
Table 6. Dose Modification Guidelines and Stopping Criteria for LVEF Decrease
Clinic
LVEF-drop (%) or
CTCAE grade
Action and Dose Modification
Asymptomatic
Absolute decrease of >10% in 
LVEF compared to baseline and
ejection fraction below the 
institution’s low LLN

Interrupt trametinibstudy treatment and 
repeat ECHO within 2 weeksa

If the LVEF recovers within 4 weeks
(defined as LVEF ≥LLN and absolute 
decrease ≤10% compared to baseline) 
o
Consult with the GSK medical 
monitor and request approval for 
restart 
o
If approve, rRestart treatment with 
trametinib reduced by one dose 
level
o
Restart dabrafenib at previous 
dose level
o
Repeat ECHO at 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
o
Consult with cardiologist
o
Permanently discontinue 
trametinib
o
Report as SAE
o
Repeat ECHO after 2, 4, 8, 12, 
and 16 weeks or until resolution
Consult with GSK medical 
monitorc
Symptomaticb
Grade 3: resting LVEF 39-20% 
or >20% absolute reduction from 
baseline

Permanently discontinue study treatment 
tramatinibb

Interrupt dabrafenib.d.  

Report as SAE

Consult with cardiologist

Repeat ECHO after 2, 4, 8, 12, and 16 
weeks or until resolutionb,d
Grade 4: resting LVEF <20%
Abbreviations: CTCAE = Common Terminology Criteria for Adverse Events; ECHO = echocardiogram; GSK = 
GlaxoSmithKline; LLN = lower limit of normal; LVEF = left ventricular ejection fraction; 
b.
If ECHO does not show LVEF recovery after 2 weeks, repeat ECHO 2 weeks later.
c.
If recurrent episodes of LVEF reduction occur in subjects receiving dabrafenib monotherapy, consult medical 
monitor.
a.
b.
Symptoms may include: dyspnea, orthopnea, and other signs and symptoms of pulmonary congestion and 
edema.
c.
Once LVEF recovers, including resolution of symptoms, restart of dabrafenib monotherapy only can be 
considered in consultation with GSK medical monitor.Once LVEF recovers, restarting dabrafenib monotherapy 
can be oonsidered in consultation with GSK medical monitor.


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Section  5.8.3.3. QT Prolongation
Table 8. Withholding and Stopping Criteria for QTc-Prolongation
QTc-Prolongationa
Action and Dose Modification

QTc ≥501 msec 

Interrupt study treatment until QTc prolongation resolves 
to grade 1 or baseline

Test serum potassium, calcium, phosphorus and 
magnesium. If abnormal correct per routine clinical 
practice to within normal limits.

Review concomitant medication usage for agents that 
prolong QTc.

If event resolves, restart study treatment at current dose 
levelb

If event does not resolve, permanently discontinue study 
treatments.  Consider evaluation with cardiologist.

If event recurs, permanently discontinue study 
treatments.  Consider evaluation with cardiologist.

Restart at current dose levelb

If event recurs, permanently discontinue study treatment
Abbreviations: msec = milliseconds; QTc = QT interval on electrocardiogram corrected 
a.
Based on average QTc value of triplicate ECGs.  For example, if an ECG demonstrates a prolonged QT interval, 
obtain two or more ECGs over a brief period, and then use the averaged QTc values of the three ECGs to determine 
if study treatments should be interrupted or discontinued.
b.
If the QTc prolongation resolves to grade 1 or baseline, the subject may resume study treatment if the investigator 
and GSK medical monitor agree that the subject will benefit from further treatment.
Section 5.8.5. 1. Guidelines for Pyrexia
Episodes of pyrexia have been observed in subjects receiving dabrafenib monotherapy , and is 
increased in incidence and severity in subjects receiving dabrafenibor in combination with 
trametinib [GlaxoSmithKline Document Number CM2010/00010/03 and GlaxoSmithKline 
Document Number 2011N126811_02]. In a minority of cases the pyrexia was accompanied 
by symptoms such as severe chills, dehydration, hypotension, dizziness or weakness. 
Pyrexia accompanied by hypotension, or dehydration requiring IV fluids, or severe 
rigors/chills should be reported as an SAE as per Section 7.3.10.   
Subjects should be instructed on the importance of immediately reporting febrile episodes.  In 
the event of a fever, the subject should be instructed to take non-steroidal anti-pyretics (e.g.-
ibuprofen or acetaminophen/paracetamol) as appropriate to control fever. The use of oral 
corticosteroids should be considered in those instances in which anti-pyretics are insufficient. 
Monitor serum creatinine and other evidence of renal function during and following severe 
events of pyrexia (see Section 5.8.5.3). In subjects experiencing pyrexia associated with 


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rigors, severe chills, dehydration, hypotension, etc., renal function should be monitored 
carefully. \
Guidelines regarding management and dose reduction for pyrexia considered to be related to 
study treatment are provided in Table 12.


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Table 12  Management and Dose Modification Guidelines for Pyrexia


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Adverse 
Event
Adverse Event Management
Action and Dose Modification


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Pyrexiaa
All Events:

Clinical evaluation for infection and 
hypersensitivityc

Laboratory work-upc

Hydration as requiredd
1st Eventb:

Clinical evaluation for infection and 
hypersensitivityc 

Laboratory work-upc

Hydration as requiredd

Blood sample for cytokine analysise 

Administer anti-pyretic treatment asif
clinically indicated and initiate continue
prophylactic treatmentif associated with 
rigors, renal failure, dehydration or 
hypotensione f
2nd Eventfg

Clinical evaluation for infection and 
hypersensitivityc 

Laboratory work-upc

Hydration as requiredd

Blood sample for cytokine analysise 

Within 3 days of onset of pyrexia
o
Optimize anti-pyretic therapy
o
Consider oral corticosteroids 
(i.e., prednisone 10 mg) for at 
least 5 days or as clinically 
indicatedfg
Subsequent Events: 

Clinical evaluation for infection and 
hypersensitivityc 

Laboratory work-upc

Hydration as requiredd 

Blood sample for cytokine analysise 

Wwithin 3 days of onset of pyrexia:
o
Optimize oral corticosteroid 
dose as clinically indicated for 
recalcitrant pyrexiafg
o
If corticosteroids have been 
tapered and pyrexia recurs, 
restart steroids 
o
If corticosteroids cannot be 
tapered consult medical 
monitor
1st Event: 

Interrupt dabrafenib

Continue trametinib

Once pyrexia resolves to 
baseline, restart dabrafenib at 
the same dose level
o
If fever was associated 
with rigors, renal 
failure, dehydration or 
hypotension, reduce 
dabrafenib by one 
dose levelg
2nd Event:

Interrupt dabrafenib

Continue trametinib

Once pyrexia resolves to 
baseline, restart dabrafenib at 
the same dose level
o
If fever was associated 
with rigors, renal 
failure, dehydration or 
hypotension, reduce 
dabrafenib by one 
dose levelg
Subsequent Events:

Interrupt dabrafenib

Continue trametinib

Once pyrexia resolves to 
baseline, restart dabrafenib 
reduced by one dose levelgh

If dabrafenib must be reduced 
to <5075 mg BID, permanently  
discontinue dabrafenib. 
Trametinib may be continued


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Adverse 
Event
Adverse Event Management
Action and Dose Modification
e.
Blood sample for cytokine analysis should be taken immediately at the first occurrence of fever (i.e. when the 
subject visits the clinic) and after the fever has disappeared (i.e. during the next routine visit), samples must be 
sent to the central laboratory.
ef. Anti-pyretic treatment may include acetaminophen, ibuprofen, or suitable anti-pyretic medication according to 
institutional standards. Prophylactic anti-pyretic treatment may be discontinued after three days in the absence of 
pyrexia
fg.
In subject experiencing pyrexia complicated by rigors, severe chills, etc., which cannot be controlled with anti-
pyretic medication, oral corticosteroids should be started at the 2nd event and doses should be gradually 
increased for subsequent events.
gh. Dabrafenib should be reduced by one dose level after three episodes of pyrexia complicated by rigors, severe 
chills, etc., which cannot be managed by best supportive care and increasing doses of oral steroids.  Escalation of 
dabrafenib is allowed if no episode of pyrexia is observed in the 4 weeks subsequent to dose reduction.
Section 5.8.5.4. Guidelines for Visual Changes or Specified Ophthalmic Examination 
Findings
Episodes of visual changes have been observed in subjects receiving trametinib, dabrafenib, 
trametinib or the and combination of both therapies. The causal relationship between a change 
in vision and the study treatment should be carefully explored and therapy. An 
ophthalmologist should be consulted if changes in vision develop.  However, if the visual 
changes are clearly unrelated to study treatment (e.g., allergic conjunctivitis), then monitor 
closely as it may be reasonable to defer ophthalmic examination. 
Treatment with dabrafenib has been associated with the development of uveitis, including
iritis. Monitor patients for visual signs and symptoms (such as, change in vision, photophobia 
and eye pain) during therapy. Special attention should be given to retinal (e.g., CSR)findings 
(e.g., retinal pigment epithelial detachment (RPED) or retinovascular abnormalities (i.e., 
branch or central retinal vein abnormalities (e.g., occlusions (RVO). For events of visual 
changes (regardless of severity) for which an ophthalmic examination is conducted, a blood 
sample for PK analysis must be drawn as close as possible to the time of the event.
Guidelines regarding management and dose reduction for visual changes and/or ophthalmic 
examination findings considered to be related to study treatment are provided in Table 15.


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Table 15
Management and Dose Modification Guidelines for Visual Changes
and/or Ophthalmic Examination Findings


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CTCAE Gradea
Adverse Event Management
Action and Dose Modification
Grade 1b
1.
Consult ophthalmologist within 7 
days of onset
Exclude CSR or RVO
Consult retinal specialist in 
case of CSR or RVO
Report RVO as SAE
Continue follow up 
examination(s) by retinal 
specialist for CSR and RVO
2.
Continue study treatment  at the same 
dose level until ophthalmologic 
examination can be conductedb
3.
If ophthalmologic examination cannot be 
performed within 7 days of onset, interrupt 
study treatment until CSR and RVO can 
be excluded and symptoms resolve
4.
Restart study treatment at same dose 
level
5.
CSR: Interrupt study treatment until 
symptoms resolve and exam by retinal 
specialist shows resolution
6.
Restart with study treatment reduced by 
one dose level
7.
If dilated fundus examination cannot be 
performed within 7 days of onset, interrupt 
trametinib until RPED and RVO can be 
excluded by retina 
specialist/ophthalmologist. If subject is 
receiving trametinib/dabrafenib 
combination therapy dabrafenib may be 
continued.
8.
If RPED and RVO excluded, continue (or 
restart) trametinib at same dose level
9.
If RPED suspected or diagnosed: see 
RPED dose modification table Y below;
report as SAE if diagnosed.
10. If RVO:  Permanently discontinue study 
treatment
Grade 2 and
Grade 3
11. Consult ophthalmologist 
immediately 
1.
Interrupt trametinib.  If subject 
is receiving 
trametinib/dabrafenib 
combination therapy 
dabrafenib may be continued.
Exclude CSR and RVO
Consult retinal specialist in case of 
RVO or CSR for follow-up exam
Report RVO as SAE
Continue follow up examination(s) by 
retinal specialist for CSR and RVO
2.
Interrupt study treatment until 
signs and symptoms have 
resolved to baseline
3.
Restart with study treatment 
reduced by one dose level
4.
CSR: Interrupt study treatment 
until symptoms resolve and exam 
by retinal specialist shows 
resolution Restart study treatment 
reduced by one dose level
5.
If RPED and RVO excluded, restart 
trametinib at same dose level. 
12. If RPED diagnosed, see RPED dose
modification table below; report as SAE.
13. If RVO: Permanently discontinue study 
treatmenttrametinib and report as SAE.


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Grade 4
14. Consult ophthalmologist 
immediately 
15. Interrupt trametinib. If subject is 
receiving trametinib/dabrafenib 
combination therapy dabrafenib 
may be continued.
16. Exclude CSR and RVO
17. Report RVO as SAE
18. Continue follow up examination(s) 
by retinal specialist for CSR and 
RVO
19. If RPED and RVO excluded, may 
consider restarting trametinib at same or 
reduced dose after discussion with study 
medical monitor
20. If RVO or RPED diagnosed,
pPermanently discontinue study 
treatmenttrametinib and report as SAE.
Abbreviations:  RPED = retinal pigment epithelial detachment; CSR = central serous retinopathy; CTCAE = Common 
Terminology Criteria for Adverse Events; 
RVO = retinal vein occlusion; SAE = serious adverse event
a. 
Refers to CTCAE Version 4.0 ‘Eye disorders – Other, specify’
b.
If visual changes are clearly unrelated to study treatment (e.g., allergic conjunctivitis), monitor closely but 
ophthalmic examination is not required.
Recommended dose modifications for trametinib for retinal pigment epithelial 
detachments (RPED)a
CTCAE Grade
Action and Dose Modification
Grade 1 RPED (Asymptomatic; clinical or 
diagnostic observations only)

Continue treatment with retinal 
evaluation monthly until resolution. If 
RPED worsens follow instructions below 
Grade 2-3 RPED (Symptomatic with mild 
to moderate decrease in visual acuity; 
limiting instrumental ADL)
6.
Interrupt trametinib 
7.
Retinal evaluation monthly 
8.
If improved to ≤ Grade 1, restart 
trametinib at lower dose (reduced by 
0.5 mg) or discontinue in patients 
taking trametinib 1 mg daily
d.
Refers to CTCAE Version 4.0 ‘Retinopathy’
Ophthalmologic Exam
At certain time points in the trial and if visual changes develop, an eye exam is indicated. 
(Refer to Section 5.8.5.4 for visual changes stopping criteria). The exam will include best 
corrected visual acuity, tonometry, slit lamp biomicroscopic examination, visual field 
examination, and dilated indirect fundoscopy with special attention to retinal 
abnormalities. Optical coherence tomography is strongly recommended at scheduled visits, 
and if retinal abnormalities are suspected. Other types of ancillary testing including color 
fundus photography and fluorescein angiography are also recommended if clinically 
indicated.
Table 16
Management and Dose Modification Guidelines for Pneumonitis
In Action and Dose modification column “Study Treatment” was replaced by “Trametinib”.


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Section 6. Concomitant Medications and Non-Drug Therapies
Rationale for change(s):Update of wordings to be in line with asset required language. 
REVISED TEXT
Section 6.1. Permitted Medications and Non-drug Therapies
The investigator must be informed as soon as possible about any medication taken from the 
time of screening until 30 days after the last dose of study treatment with the exception of new 
anti-cancer therapy, if taken after study treatment discontinuation; these will be documented 
until study completion/withdrawal or death.  Any concomitant medication(s), including 
dietary supplements, taken during the study will be recorded in the eCRF.  The minimum 
requirement is that drug name, dose, and the dates of administration are to be recorded.  
Additionally, a complete list of all prior anti-cancer therapies will be recorded in the eCRF.  
Subjects should receive full supportive care during the study, including transfusions of blood 
and blood products, and treatment with antibiotics, anti-emetics, anti-diarrheals, and 
analgesics, and other care as deemed appropriate, and in accordance with their institutional 
guidelines.  Use of anticoagulants such as warfarin is permitted, however, caution should be 
exercised and additional International Normalized Ratio (INR) monitoring is recommended 
when dabrafenib is used concomitantly with warfarin.provided that INR is monitored in 
accordance with local institutional practice. 
While patients are on study treatment, palliative radiation therapy is permitted for non-target 
lesions that are either new or present at baseline.
Radiation skin injury has been reported with concurrent use of dabrafenib and radiation. It is 
recommended that dabrafenib be held for seven days before and two days after XRT in 
subjects receiving dabrafenib monotherapy or in combination with trametinib. These 
recommendations can be modified based on the physician’s assessment of the risk of radiation 
skin injury.
Section 6.3. Treatment after Discontinuation from both Study Treatments or 
Withdrawal from/Completion of the Study
Paragraph 4 
Upon study closure completion, if some subjects are still on study treatment and have not yet 
progressed, their follow-up treatment will be at the discretion of the attending physician. 
subjects who are still receiving study treatment will have the option to transition to 
BRF114144, in which they may continue to receive study treatment.


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Section 6.4. Treatment of Study Treatment Overdose
In the event of a dabrafenib overdose, defined as administration of more than 300 mg as a 
single dose or 600 mg per day (the highest dose tested in clinical studies to date), and/or a 
trametinib overdose, defined as administration of more than 3.0 mg once daily (the maximum 
tolerated dose defined in the MEK111054 Study), the investigator should contact the GSK 
Medical Monitor immediately and closely monitor the subject for AEs/SAEs and laboratory 
abnormalities.  GSK does not recommend specific treatment.  The investigator will use 
clinical judgment to treat any overdose. Haemodialysis is not expected to enhance the 
elimination of either dabrafenib or trametinib as both are highly bound to plasma proteins.
Decisions regarding dose modifications or interruptions will should be made by the 
investigator in consultation with the GSK Medical Monitor based on the clinical evaluation of 
the subject.
A plasma sample for PK analysis may be requested by the GSK Medical Monitor on a case-
by-case basis.  This plasma sample should be collected as soon as possible, but within 10 days 
from the date of the last dose of on-study dosing.


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Table 19. Time and Events Table
STUDY PHASES1
SCREENING
2
TREATMENT
FOLLOW-UP
Da
y 1
Day 
15
Every 
4 
Weeks
Every 
8 
Weeks
Every 
12 
Weeks
Treatmen
t
Discontinu
ation28
Cont
act
Conclusi
on
Visit Window (Days)
(28 
except 
where 
noted)2
(3)
(3)
(7)
(7)
(7)
(7)
N/A
SAFETY ASSESSMENTS1
Dermatological examination 
(including skin lesion 
photography)10
X
X
X
Pharmacokinetics blood 
collection21
X
X
Blood sample for cytokine 
analysis24
X
X24
Point No.10. A full skin exam will be done every 8 weeks. Photographic images are required to assess hyperproliferative 
skin diseases. Upon study treatment discontinuation, a final skin exam is required within 8 weeks of the last dose of study 
treatment.
Point No. 21. Blood samples for PK analysis will be drawn on Day 15 at predose (within 30 minutes prior to dosing) and 1, 2, 
4, 6, and 8 hours after dosing. For subjects in China, PK blood samples will be drawn at predose (within 30 minutes prior to 
dosing) and 0.5, 1, 1.5, 2, 3, 4, 6, 8, and 10 hours after dosing on Day 1 and Day 15. Refer to Section 7.5 for details on 
pharmacokinetic blood sampling.
Point No. 24. A blood sample for potential analysis of cytokines is mandatory at Screening and at week 4. Subsequent 
cytokine samples should also be collected if indicated (See Section 5.8.5.1 Management Guidelines for Pyrexia and Table 
12)..
Point No. 27. After treatment discontinuation, any new anti-cancer therapy initiated will be recorded until study 
completion/withdrawal /lost to follow-up, or death.
Section 7. Study Assessments and Procedures
Rationale for change(s):
Adding cutaneous melanoma to reflect the criteria change. Wordings are changed according to 
data and conclusion from the current reported studies. Specifying the country specific 
requiment of SAE reporting. 
REVISED TEXT
Section 7.2.1. Efficacy Endpoints
Section 7.2.1.1.  Primary Efficacy Endpoint
The primary endpoint for this study is objective response rate of dabrafenib in combination 
with trametinib in subjects with BRAF V600E/K mutation-positive, unresectable or metastatic 


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acral lentiginous or cutaneous melanoma (ALM).  Objective response rate is defined as the 
percentage of subjects with evidence of confirmed complete response (CR) or partial response 
(PR) as per RECIST v1.1 [Eisenhauer, 2009]
Section 7.2.1.2.  Secondary Efficacy Endpoints
The secondary efficacy endpoint of this study are:

Duration of response, defined as the time from first documented evidence of CR or PR 
until the earliest date of documented radiological progression or death due to any 
cause among subjects who achieve a confirmed response (i.e. confirmed CR or PR) 

PFS, defined as the time from first dose of study treatment until the first date of either 
objective disease progression or death due to any cause.

OS, defined as the interval between the treatment start date and the date of death due 
to any cause.

PFS, defined as the time from first dose of study treatment until the first date of either 
objective disease progression or death due to any cause.

OS, defined as the interval between the treatment start date and the date of death due 
to any cause.
Section 7.2.2.2.  Follow-up Assessments for Subjects Permanently Discontinued from 
both Study Treatments
Paragraph 2
All subjects who permanently discontinue both study treatments without disease progression 
will have radiographic disease assessments performed on the same assessment schedule noted 
in the Time and Events Table 19 until disease progression, death, starting of another anti-
cancer treatment(including radiotherapy),  or withdrawal of consent, whichever is documented 
first.
Section 7.2.4. Response Criteria
Section 7.2.4.1. Evaluation of Target Lesions
Point No.5 

Not Applicable (NA): No target lesions at baseline.
Section 7.3.2.2. Definition of an SAE
Point No. g. Protocol-specific SAEs:

All events of possible drug-induced liver injury with hyperbilirubinemia defined as 
ALT 3xULN and bilirubin 2xULN (>35% direct) (or ALT 3xULN and 
INR>1.5, if INR measured) or termed ‘Hy’s Law’ events (INR measurement is not 
required and the threshold value stated will not apply to patients receiving 
anticoagulants).
Note: bilirubin fractionation is performed if testing is available. If testing 
is unavailable, record presence of detectable urinary bilirubin on dipstick 
indicating direct bilirubin elevations and suggesting liver injury. If testing 
is unavailable and a subject meets the criterion of total bilirubin 2xULN, 


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then the event is still reported as an SAE. If INR is obtained, include 
values on the SAE form. INR elevations >1.5 suggest severe liver injury.   

Any new primary cancers and treatment emergent malignancies (including squamous 
cell carcinoma and new primary melanoma) with the exception of basal cell 
carcinoma (BCC).  BCC should be reported as an AE or SAE based on the discretion 
of the investigator. Any new malignancy with a histology different from the primary 
tumor, including cutaneous squamous cell carcinoma, basal cell carcinoma and new 
primary malignant melanoma.

Laboratory abnormalities as referenced in Section 7.3.3.

Symptomatic LVEF decrease that meets stopping criteria or asymptomatic LVEF 
decrease that does not recover, as outlined as LVEF guidance (Section 6.8.3.1)

LVEF that meets stopping criteria Section 5.8.3.1

Retinal pigment epithelial detachment (RPED) or retinal vein occlusion (RVO)

CSR or RVO 

Pyrexia accompanied by hypotension, or dehydration requiring IV fluids, or severe 
rigors/chills
Section 7.3.7. Pregnancy Testing, Prevention and Reporting
Section 7.3.7.1. Pregnancy Testing and Prevention
Paragraph 5
If a female subject is of childbearing potential, she must have a serum -human chorionic 
gonadotropin (HCG) pregnancy test performed within 14 days prior to enrollment7 days of 
first dose of study treatment.  Subjects with a positive pregnancy test result must be excluded 
from the study.  Subjects with a negative pregnancy test result must agree to use an effective 
contraception method as described below throughout the treatment period and until 6 months 
after the last dose of study treatment.
Section 7.3.8. Time Period and Frequency of Detecting AEs and SAEs
Paragraph 2
Adverse events (AEs) will be collected from the time the first dose of study treatment is 
administered until 30 days after discontinuation of study treatment regardless of initiation of a 
new anti-cancer therapy or transfer to hospice. In China, SAEs will  be recorded from the time 
the consent form is signed. For all other countries, SAEs will be collected over the same time 
period as stated above for AEs. However, any SAEs assessed as related to study participation 
(e.g., study treatment, protocol-mandated procedures, invasive tests, or change in existing 
therapy) or related to a GSK concomitant medication, will be recorded from the time a subject 
consents to participate in the study up to and including any follow up contact.
Section 7.3.11. Other Safety Outcomes
Table 21. Clinical Chemistry and Hematology Parameters


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Hematology Parameters
White Blood Cell (WBC) Count 
Hemoglobin
Hemoglobin A1C
Hematocrit
International Normalized Ratio (INR; at Screening only)a
Platelet Count
Prothrombin Time (PT; at Screening only)a
Partial Thromboplastin Time (PTT; at Screening only)a
Automated WBC Differential (expressed as Gl/L%): 
Basophils 
Eosinophils
Lymphocytes
Monocytes
Neutrophils
Other tests
Amylase and lipase [monitor via local laboratory where appropriate to evaluate certain AEs (i.e., 
abdominal pain, pancreatitis, etc.)]
serum β-hCG (human chorionic gonadotrophin)
For subjects with a history of chronic HBV and/or HCV, the following tests will be performed at Screening:

Viral hepatitis serology;

Hepatitis B surface antigen and Hepatitis B core antibody (IgM); and/or 

Hepatitis C RNA
a. Coagulation panel to be done at Screening only.
b. Bilirubin fractionation is recommended if total bilirubin is > 2 x the upper limit of normal (ULN).
c. .If serum creatinine is > 1.5 mg/dL, creatinine clearance should be calculated using the standard 
Cockcroft-Gault formula (Appendix 2).
Section 7.5.2. Sample Analysis
Plasma analysis will be performed under the control of GSK Platform Technology and 
Science (PTS)-Drug Metabolism and Pharmacokinetics (DMPK)/Scinovo, the details of 
which will be included in the Study Procedures Manual.  Concentrations of carboxy-
dabrafenib will be determined in plasma samples using a separate assay using the currently 
approved analytical methodology. Concentrations of dabrafenib and its metabolites (hydroxy-
and desmethyl -dabrafenib) and trametinib will be determined in plasma samples using the 
currently approved analytical methodology.  Raw data will be stored in the Good Laboratory 
Practice (GLP) Archives, GlaxoSmithKline.
Section 9. Data Analysis and Statistical Considerations
Rationale for change(s):
Even though the study target population is explored from acral melanoma to both acral or 
cutanous melanoma, the study hypothesis is remaining the same as the efficacy expected 
would remain the same. 
REVISED TEXT
Section 9.1. Hypotheses
The primary objective is to determine the objective response rate (ORR) of dabrafenib in 
combination with trametinib in BRAF V600E/K mutation-positive unresectable or metastatic 
acral lentiginous or cutaneous melanoma subjects.


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Paragraph 5
Even though, in the protocol amendment 1, the study population was extended to both acral 
and cutanenous melanoma, the hypothesis (Ho:25% & Ha: p=50%) will remain the same, 
because the expected efficacy of study medication in the new population is similar as the 
previous assumption. 
Section 9.3.3.1. Primary Comparisons of Interest
The primary objective will be supported by the calculation of objective response rate using the 
ATS population.  The final analysis of ORR will be performed after 35 subjects have been 
treated for 16 weeks or have otherwise discontinued study treatment.
Subjects will continue to be followed for survival until 70% of the total enrolled population 
has death, died or been lost to follow-up, or study completion. The definition of study 
completion is described in Section 3.1.
Section 9.3.5.1.2. Secondary Efficacy Analyses
Progression-Free Survival (PFS)
Progression free survival and overall survival will be summarized descriptively using Kaplan-
Meier medians and quartiles.  
PFS will be defined as the time from first dose until the first date of either objective disease 
progression or death due to any cause.  The date of objective disease progression will be 
defined as the earliest date of radiological or photographic disease progression as assessed by 
the investigator using RECIST, version 1.1.  For subjects who have not progressed or died at 
the time of the PFS analysis, censoring will be performed using the date of the last adequate 
disease assessment or first dose for subjects without any adequate post baseline assessments.  
In addition, subjects with an extended loss to follow-up or who start new anti-cancer therapy 
prior to a PFS event will be censored at the date of the last adequate disease assessment prior
to the extended loss to follow-up or start of new anti-cancer therapy, respectively. Progression 
free survival will be summarized descriptively using Kaplan-Meier medians and quartiles.  
Further details on censoring rules will be outlined in the RAP.  
Overall Survial (OS)
OS  is defined as the time from first dose until death due to any cause. For subjects who have 
not died, time to death will be censored at the last date of known contact
OS will utilize all cause mortality and censoring will be performed using the date of last 
known contact for those who are alive at the time of analysis. OS  will be summarized 
descriptively using Kaplan-Meier medians and quartiles.
Duration of Response
If sample size permits (i.e. a sufficient number of subjects with confirmed CR or PR)  
duration of response will be summarized descriptively using Kaplan-Meier medians and 
quartiles. Only the subset of subjects who show a confirmed complete or partial tumor 


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response will be included. Duration of Response for the subset of subjects with a confirmed 
CR or PR is defined as the time from first documented evidence of CR or PR until first 
documented disease progression or death due to any cause. Censoring rules for duration of 
response will follow the rules for PFS and will be outlined in detail in the RAP.
Section 10. Study Conduct Considerations
Rationale for change(s):
To well-define the definition of study completion and avoid confusion caused. 
REVISED TEXT
Section 10.5. Study and Site Closure
The study will close when it is completed, as defined in Section3.1 considered closed when 
70% of the total enrolled study population has died or been lost to follow-up, which is 
estimated to be approximately 3 years after the start of the study.  


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Amendment 2 (Country-Specific Amendment for the Korea)
Rationale for change(s):
According to the safety data update, it was discussed and agreed to remove ophthalmic
exclusion criteria, with the exception of the exclusion criterion for patients with a history of 
RVO, which will remain in place. 
Korean regulatory authority commented the exclusion criteria xiii has to clarify not only a 
history of retinal vein occlusion (RVO) subjects should be excluded, but subjects with 
current RVO should be excluded. 
Protocol  Change(s):
  Section 4.1.3
Exclusion Criteria Revised Text:
xiii.
A history or current evidence of retinal vein occlusion (RVO)
Amendment 3 (04 -MAR-2016) from the Amendment 02 (17-Sep-2015)
No
Proposed Change
Sections Affected
Rationale for Change
1
Refer to BRAF 
V600 mutation 
instead of BRAF 
V600 E/K 
throughout the 
protocol.
Title,           
Protocol Summary,   
Section 1.3,     
Table 1,        
Section 3.1, 
Section 4.1.2, 
Table 20,       
Section 7.1.1, 
Section 7.2.1
To be consistent will other protocols 
on the program. 
2
Update Sponsor 
Signatory
NA
Sponsor signatory changed  
3
Update Sponsor 
Serious Adverse 
Events (SAE) 
Contact 
Information
NA
Contact information changed
4
Addition of
information in 
study rationale.
Protocol Summary
More information about unmet 
medical need became available. 
5
Addition of
reference to 
protocol numbers 
and acronyms
Section 1.2.3.1 
To clarify the studies listed in the 
background and to be consistent 
throughout the protocol


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7
Increase sample 
size and remove 2 
stage study design
Section 4.1.1 
Increased sample size to fulfil the 
regulatory needs in China 
8
Remove 
GlaxoSmithKline 
reference IB 
version numbers.
Section 4.1.2, 
Section 5.8.3, 
Section 5.8.4, 
Section 5.8.5, 
Section 9.3.5.4
The most current IB versions have to 
be used. Therefore, the version 
number have been removed.
9
Broaden inclusion 
criteria 3
Section 4.1.2
Remove the requirement to use the 
 
10
Addition of 
inclusion criteria 
10: Subjects with 
East Asian origin.
Section 4.1.2
Specify the race of patients to be 
enrolled.
11
Adding the 
definition of 
Gilbert’s 
syndrome. 
Section 4.1.2, 
The change is made to further clarify 
the function limitation for subjects 
with Gilbert’s syndrome.
12
Adding definition 
of HBV/HCV 
negative in 
exclusion criteria 6. 
Section 4.1.3
The change is to indicate the 
definition of HBV/HCV negative to 
avoid confusion caused. 
13
Remove the 
duplicated
exclusion criteria
14 and 15.
Section 4.1.3
Deleting duplicated criteria to avoid 
being redundant. 
14
Clarifying the 
exclusion criteria 
13 related to retinal 
vein occlusion.
Section 4.1.3
The change in protocol amendment 2
specific to Korea is now implemented
to all countries. 
15
Clarifying all 
subjects should be 
registered in 
RAMOS regardless 
of their screening 
status. 
Section 5.4
To clarify that all subjects should be 
recorded in RAMOS, and not only 
those who complete the screening 
requirement.
16
Addition of 
instructions on how 
to handle adverse 
event of uveitis.
Section 5.8.5.4
In ophthalmologic exam, the 
instruction of handling uveitis is 
added per program updates.
17
Correcting the 
sequence number.
Section 5.9.1
The correct sequence number in the 
list of liver chemistry stopping 
criteria.  


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18
Remove the 
duplicate sentence. 
Section 5.9.1
Deleting duplicate criteria to avoid 
being redundant.
19
Allow re-screening
of patients.
Section 7
Allow patients to be re-screened and 
clarify that there is no need to repeat 
the BRAF mutation test if the positive 
results have been confirmed by the 
central lab.
20
Relevant cardiac 
and cancer family 
history should be 
recorded at 
screening.  
Table 20
Typo correction.
21
Allow sites to 
resend tumor 
sample for BRAF 
testing.
Table 20
The sites would be allowed to re-send 
the tissue sample for mutation testing
in case the samples are not fulfill 
quality requirement. 
22
Remove Day 15 
time point for 
optional tumor 
tissue sample 
collection and 
corresponding 
footnote 22 
updated.
Table 20
Based on pharmacodynamic data 
available from previous studies the 
decision to prioritize the progression 
tumor sample was taken
23
Remove details 
regarding the assay 
to be used.
Section 7.1.1
Assay detail is not required.
24
Correcting the 
duration of 
contraception after 
last dose.
Section 7.3.7.
The inconsistent information should 
be corrected.
25
Remove the 
contraception 
duration 
requirement to the 
male subjects with 
a female partner of 
childbearing 
potential.
Section 7.3.7.1
To be aligned with the asset specific 
protocol language. 
26
Remove 
pharmacodynamics 
section.
Section 7.4.3
 
 
 


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27
Update the study 
hypotheses and 
remove 2 stage
design.
Section 9.1
The study is pursuing an estimation 
strategy. 
28
Increase sample 
size.
Section 9.2
The target enrolment number is 
increased to 65 to fulfil registration 
purposes. 
29
Increase sample 
size.
Section 9.3.3.1
The final analysis of ORR will be 
performed on the increased number of 
patients.
30
Remove the need 
for an interim 
analysis
Section 9.3.4
The section is no longer applicable 
since two stages of analysis was 
removed.
Amendment 4 (25-Oct-2016) from the Amendment 03 (04-Mar-2016)
No
Proposed Change
Sections Affected
Rationale for Change
1
Revise secondary 
objectives and 
endpoints in 
relation with the 
updated PK 
schedule
Section 2 – Table 1
Addition of PK samples in Chinese 
patients only to assess PK profile after 
a single dose.
2
Clarify the 
requirements for 
enrolment of 
patients with a 
history of Hepatitis 
B Virus (HBV), or 
Hepatitis C Virus 
(HCV) infection
Section 4.1.3
Provide clarity around Exclusion 
criterion#6 and consistency with 
Table 22.
3
Addition of the 
optional non-
melanoma skin 
biopsy
Table 20
Correct the omission in previous 
protocol versions,
4
Add additional PK 
timepoints on Day 
1 and Day 15 in 
Chinese patients 
only
Table 20 – footnote 
21 
Addition of PK samples in Chinese 
patients only to assess PK profile after 
a single dose and at steady state.
5
Addition of 
contraception 
Section 7.3.7.1
New language at program level.


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requirements in 
male participants.
6
Clarify the lab 
parameters to be 
tested at screening
in patients with a 
history of Hepatitis 
B Virus (HBV), or 
Hepatitis C Virus 
(HCV) infection
Table 22
Provide clarity around the lab 
parameters to be tested at screening.
Amendment 05 (16-Dec-2016) from the Amendment 04 (25-Oct-2016)
This amendment applies to all investigator sites participating in this study except those in 
China.
Global Changes
Section(s)
Change
Rationale
Header/Footer Changed as per Novartis 
Requirements
Change in study sponsorship from GSK to 
Novartis
Title Page
Title Page replaced as 
per Novartis 
Requirements
Change in study sponsorship from GSK to 
Novartis
Sponsor 
Information 
Page 
GSK contact information 
has been replaced with 
Novartis contact details
Change in study sponsorship from GSK to 
Novartis
Sponsor 
signatory
Change of sponsor 
signatory
Change in study sponsorship from GSK to 
Novartis
Multiple
The term ‘medical 
monitor’ has been 
replaced by Medical 
Lead
Change in study sponsorship from GSK to 
Novartis
Multiple
References to GSK 
concomitant medications 
deleted
Change in study sponsorship from GSK to 
Novartis
Multiple
References to 
GlaxoSmithKline or its 
staff replaced with that 
of Novartis and its 
authorized agents
To align with the change of sponsorship 
from GSK to Novartis.


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Section(s)
Change
Rationale
Multiple
Make administrative 
changes
To align with the change of sponsorship 
from GSK to Novartis.
Appendices 
References to GSK in 
figures changed to 
Novartis
To align with the change of sponsorship 
from GSK to Novartis.
Revised Text is captured in the format strikethrough=deleted text; underlined=new text.
List of Specific Changes:
Rationale for changes: Change in study sponsorship from GSK to Novartis
List of Abbreviations
The following abbreviation was deleted:
RAMOS
Registration and Medication Ordering System
The following abbreviation has been added:
CRO
Clinical Research Organization
Section ‘Trademark Information’ has been deleted 
5.1. Investigational Product and Other Study Treatment
REVISED TEXT
5.1.1. Dabrafenib (GSK2118436)
Dabrafenib will be provided as 50 mg and 75 mg capsules.  Each capsule will contain 50 mg 
or 75 mg of free base (present as the
). 
Dabrafenib will be provided to sites by GSK Novartis, with the exception of sites in China 
where GSK will organize to provide supplies under GSK`s sponsorship. The contents of the 
label will be in accordance with all applicable regulatory requirements.
5.1.2 Trametinib (GSK1120212)
Trametinib study medication will be provided as 0.5 mg and 2.0 mg tablets.  Each tablet will 
contain 0.5 mg or 2.0 mg of trametinib parent (present as the 
).
Trametinib will be provided to sites by GSK Novartis, with the exception of sites in China 
where GSK will organize to provide supplies under GSK`s sponsorship. The contents of the 
label will be in accordance with all applicable regulatory requirements.
5.4. Treatment Assignment
REVISED TEXT
Upon completion of all the required screening assessments, eligible subjects will be registered 
into the Registration and Medication Ordering System (RAMOS), the GSK interactive voice 
response system (IVRS)My Access Program (MAP) system, by the investigator or authorized 
site staff.
RAMOS MAP allows study sites to register subjects, and also is used in study treatment 
supply.


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Detailed RAMOS MAP user instructions, worksheets, and telephone contact numbers will be 
provided to the study site in the SPM.
7.3.7.2. Pregnancy Reporting
REVISED TEXT
Any pregnancy that occurs during study participation must be reported using a clinical trial 
pregnancy form. To ensure subject safety, each pregnancy must be reported to GSK Novartis
within 2 weeks 24 hours of learning of its occurrence. The pregnancy must be followed-up to 
determine outcome (including premature termination) and status of mother and child.
7.3.10. Prompt Reporting of Serious Adverse Events and Other Events to GSK Novartis
REVISED TEXT
Initial Reports
Follow-up Information on a 
Previous Report
Type of Event
Time Frame Documents
Time Frame
Documents
All SAEs
24 hours
SAE data 
collection tool
24 hours
Updated SAE 
data collection 
tool
Pregnancy
2 weeks 24 
hours
Pregnancy 
notification form
2 weeks
Pregnancy 
follow-up form
Cardiovascular or 
death event
Initial and 
follow up 
reports to be 
completed 
within one 
week of when 
the 
cardiovascular
“CV events” 
and/or “death” 
data collection 
tool(s) if 
applicable
Initial and follow 
up reports to be 
completed within 
one week of 
when the 
cardiovascular 
event or death is 
reported
Updated “CV 
events” and/or 
“death” data 
collection tool(s) 
if applicable
8 
Data Management 
REVISED TEXT
Data Management will identify and implement the most effective data acquisition and 
management strategy for each clinical trial protocol and deliver datasets that support the 
protocol objectives.
For this study, subject data will be entered into GSK-defined the electronic case report forms
(eCRFs), transmitted electronically to GSK Novartis (or designee), and be combined with data 
from other sources in a validated data system.  
Clinical data Mmanagement of clinical data will be performed in accordance with applicable 
GSK standards and data cleaning procedures to ensure the integrity of the data, e.g., removing
resolving errors and inconsistencies in the data.  Adverse events and concomitant medications 
terms will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) and an 
internal a custom validated medication drug dictionary, GSKDrug.  An appropriate medical 


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dictionary that covers all approved drugs in studies where Japan is participating will be 
referenced.
The eCRFs (including queries and audit trails) will be retained by GSKNovartis, and copies 
will be sent to the investigator to maintain as the investigator copy.
In all cases, subject initials will not be collected or transmitted to GSK in accordance with
GSK policy.
10.3
Quality Control (Study Monitoring)
The following modifications were made:
In accordance with applicable regulations, GCP, and GSK Novartis procedures, Novartis 
personnel (or designated Clinical Research Organization [CRO]) will contact the site will be 
contacted prior to the start of the study to review with the site staff the protocol, study 
requirements, and their responsibilities to satisfy regulatory, ethical, and GSK Novartis 
requirements. 
The investigator and the head of the medical institution (where applicable) agrees to allow the 
monitor Novartis personnel (or designated CRO) direct access to all relevant documents and 
to allocate their time and the time to their staff to monitor to discuss findings and any issues.
10.5.
Study and Site Closure
REVISED TEXT
Upon completion or termination of the study, the GSK monitor Novartis personnel (or 
designated CRO) will conduct site closure activities with the investigator or site staff (as 
appropriate), in accordance with applicable regulations, GCP, and GSK Novartis Standard 
Operating Procedures.
10.6.Records Retention
The following paragraph was deleted:
GSK will inform the investigator of the time period for retaining the site records in order to 
comply with all applicable regulatory requirements.  The minimum retention time will meet 
the strictest standard applicable to a particular site, as dictated by local laws/regulations, GSK 
standard operating procedures, and/or institutional requirements.
And replaced with the following:
Essential documents (written and electronic) should be retained for a period of not less than 
fifteen (15) years from the completion of the Clinical Trial unless the Sponsor provides 
written permission to dispose of them or, requires their retention for an additional period of 
time because of applicable laws, regulations and/or guidelines.
10.7.
Provision of Study Results to Investigators, Posting of Information on Publicly 
Available Clinical Trials Registers and Publication
REVISED TEXT
The results summary will be posted to the Clinical Study Register no later than 8 months after 
the final primary completion date, the date that the final subject was examined or received an 
intervention for the purposes of final collection of data for the primary outcome. In addition, a 
manuscript will be submitted to a peer-reviewed journal for publication no later than 18 
months after the last subject’s last visit (LSLV). When manuscript publication in a peer 
reviewed journal is not feasible, a statement will be added to the register to explain the reason 
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When manuscript publication in a peer-reviewed journal is not feasible, further study
information will be posted to the GSK Clinical Study Register to supplement the results 
summary.
Novartis aims to post a results summary to the Novartis Clinical Trial Results website 
(www.novartisclinicaltrials.com) and other publicly available registers no later than twelve 
(12) months after the last subject’s last visit (LSLV). In addition, upon study completion and 
finalization of study report, Novartis aims to submit results of the study for publication.
When publication is not feasible, please refer to the Novartis Clinical Trial Results website 
(www.novartisclinicaltrials.com) for a summary of the trial results.
Amendment 6 (22-Mar-2018) from the Amendment 05 (16-Dec-2016)
No
Proposed Change
Sections Affected
Rationale for Change
1
Update Study 
Sponsor 
information
Study Sponsor 
information
Section updated following team 
member changes.
2
Remove duplicate
sentence about PK
endpoints
Protocol Summary
Remove duplicate sentence.
3
Correct the lowest 
allowed dose in 
case of pyrexia
5.8.5.1. Guidelines 
for Pyrexia
Table 12
Correct typo from previous version 
of protocol. According to general 
dose reduction guideline, a dose 
reduction below 75 mg BID for 
dabrafenib is not allowed.
4
Clarify that liver 
PK samples 
collection will be 
discontinued 8 
weeks after last 
patient first 
treatment.
5.9.1.1 Liver event 
follow up 
assessments
Clarify the liver PK samples will not 
be collected 8 weeks after last 
patient first treatment.
5
Adding ‘Refer to 
section 7.5 and 
5.9.1.1 for details 
on 
pharmacokinetics 
blood sampling 
including liver PK 
sampling.’
Table 20, footnote 
21
The liver PK sampling clarification 
is added in the assessment 
procedure.
6
Extend the 
duration of 
contraceptive for 
male participants 
from 12 weeks to 
16 weeks after 
7.3.7.1. Pregnancy 
Testing and 
Prevention
The contraception requirement for 
male participants has been increased 
from 12 to 16 weeks in the period 
following stopping of study 
treatment.  A re-evaluation of the 
existing pre-clinical data and the 


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stopping study 
treatment.
application of the Novartis 
contraception guidance for clinical 
trials resulted in this change to the 
Investigator Brochures Edition 9.0. 
7
Replace RAP by 
SAP.
All
Updated to use the Novartis 
terminology rather than the GSK 
one.
8
Remove the 
calculation of 95% 
Confidence 
Interval for vaious 
observed ORRs. 
9.2.1 Sample Size 
Assumptions
The 95% confidence interval will be 
calculated based on the actual 
treated subjects, and an exact 
binomial method will be applied to 
calculate the confidence interval.
9
Clarify that an 
exact binomial 
confidence interval
will be calculated 
[Clopper and 
Pearson 1934]
reference has been 
added.
9.3.5.1 Primary 
Efficacy Analyses
New reference is added.
10
Correct the 
constant K in the 
Crockcroft-Gault 
fomula as follows:
K=1.04 for female
K=1.23 for male
Appendix 2
The constant K in the Crockcroft-
Gault fomula was a typo. The 
correct constant is provided.
Amendment 7 (15-Feb-2019) from the Amendment 06 (22-Mar-2018)
No
Proposed Change
Sections Affected
Rationale for Change
1
Update the 
Sponsor Signatory
Sponsor Signatory 
page
 has taken the role of
from 
. 
2
Update the 
methods of 
contraception for 
female 
participants.
7.3.7.1. Pregnancy 
Testing and 
Prevention
Double barrier contraception 
methods do not fulfill the definition 
of highly effective contraception as 
per Clinical Trial Facilitation Group 
(CTFG) and Novartis internal 
guidelines.
For subjects taking trametinib, 
contraception using only oral 
contraceptives is not allowed until 


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the results from the ongoing drug 
drug interaction trial of trametinib in 
combination with oral 
contraceptives are available.
Based on clinical evidence from 
GSK studies, the contraception 
duration was decreased from 4 to 2 
weeks after dabrafenib monotherapy 
discontinuation. 
Amendment 8 (27-Nov-2019) from the Amendment 07 (15-Feb-2019)
No
Proposed Change
Sections Affected
Rationale for Change
1
Replace “vials” 
wording by 
“bottles”
5.7 Treatment 
Compliance
Study treatments are supplied in 
bottles and not in vials. 
2
Clarification on
dose modification 
instructions for 
Severe Cutaneous 
Adverse Reactions
(SCARs)
5.8.4 Guidelines 
for Skin-related 
Adverse Events 
Dose modification instructions for 
SCARs, which have been reported 
during treatment with dabrafenib in 
combination with trametinib, is now 
aligned to the most recent 
dabrafenib and trametinib 
Investigator’s Brochure edition 11.