A Study Comparing Trametinib and Dabrafenib Combination Therapy to Dabrafenib Monotherapy in Subjects With BRAF-mutant Melanoma

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ClinicalTrials.gov Identifier: NCT01584648

Recruitment Status : Completed

First Posted : April 25, 2012

Results First Posted : August 15, 2014

Last Update Posted : February 17, 2021

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Sponsor:

Information provided by (Responsible Party):

Novartis ( Novartis Pharmaceuticals )

Study Type	Interventional
Study Design	Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment
Condition	Melanoma
Interventions	Drug: Dabrafenib Drug: Trametinib Drug: Trametinib placebo
Enrollment	423

Participant Flow

Recruitment Details	This study was conducted in 103 centers in 14 countries worldwide: Argentina (1), Australia (6), Canada (5), France (8), Germany (25), Greece (3), Italy (8), Netherlands (3), Russia (4), Spain (7), Sweden (4), Ukraine (7), United Kingdom (10), and USA (12).
Pre-assignment Details	Approximately, 340 subjects were planned to be randomized in a 1:1 ratio (170 subjects each in combination therapy and monotherapy). A total of 423 subjects with unresectable or metastatic, BRAF V600E or V600K mutation-positive melanoma were randomized to dabrafenib and trametinib (n=211) or dabrafenib and placebo (n=212).


Arm/Group Title	Dabrafenib + Trametinib	Dabrafenib + Placebo
Arm/Group Description	Participants received dabrafenib 15...	Participants received dabrafenib 15...
Arm/Group Description	Participants received dabrafenib 150 milligram (mg) HPMC capsules orally twice daily (BID), once in the morning and a second dose approximately 12 hours after the morning dose, and trametinib 2 mg once daily in the morning. Treatment was continued until disease progression, death, unacceptable toxicity, or withdrawal of consent.	Participants received dabrafenib 150 mg HPMC capsules orally BID, once in the morning and a second dose approximately 12 hours after the morning dose, and trametinib placebo once daily in the morning. Treatment was continued until disease progression, death, unacceptable toxicity, or withdrawal of consent. Crossover to the combination therapy arm was allowed for subjects still receiving study treatment on the dabrafenib monotherapy arm after the positive result for the final OS analysis.
Period Title: Overall Study
Started ^[1]	211	212
Safety Set ^[2]	209	211
Crossover Population ^[3]	0	28
Completed	0	0
Not Completed	211	212
Reason Not Completed
Death	136	146
Lost to Follow-up	9	9
Investigator discretion	3	2
Withdrew consent	13	4
Study closed/terminated	50	23
Crossover to Dabrafenib + Trametinib	0	28
[1] All randomized patients included into Intent-to-Treat (ITT) population. [2] All patients who received at least one dose of study treatment [3] All monotherapy randomized patients who crossed over to combination therapy

Baseline Characteristics

Arm/Group Title		Dabrafenib + Trametinib	Dabrafenib + Placebo	Total
Arm/Group Description		Participants received dabrafenib 15...	Participants received dabrafenib 15...	Total of all reporting groups
Arm/Group Description		Participants received dabrafenib 150 milligram (mg) HPMC capsules orally twice daily (BID), once in the morning and a second dose approximately 12 hours after the morning dose, and trametinib 2 mg once daily in the morning. Treatment was continued until disease progression, death, unacceptable toxicity, or withdrawal of consent.	Participants received dabrafenib 150 mg HPMC capsules orally BID, once in the morning and a second dose approximately 12 hours after the morning dose, and trametinib placebo once daily in the morning. Treatment was continued until disease progression, death, unacceptable toxicity, or withdrawal of consent. Crossover to the combination therapy arm was allowed for subjects still receiving study treatment on the dabrafenib monotherapy arm after the positive result for the final OS analysis.	Total of all reporting groups
Overall Number of Baseline Participants		211	212	423
Baseline Analysis Population Description		[Not Specified]
Baseline Analysis Population Description		[Not Specified]
Age, Continuous Mean (Standard Deviation) Unit of measure: Years
	Number Analyzed	211 participants	212 participants	423 participants
		55.1 (13.33)	55.3 (13.75)	55.2 (13.52)
Sex: Female, Male Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	211 participants	212 participants	423 participants
	Female	100 47.4%	98 46.2%	198 46.8%
	Male	111 52.6%	114 53.8%	225 53.2%
Race/Ethnicity, Customized Measure Type: Number Unit of measure: Participants	Number Analyzed	211 participants	212 participants	423 participants
African American/African Heritage		0	1	1
White - White/Caucasian/European Heritage		211	211	422

Outcome Measures

1.Primary Outcome


Title	Progression-Free Survival (PFS) as Assessed by the Investigator
Description	PFS is defined as the interval between the date of randomization and t...
Description	PFS is defined as the interval between the date of randomization and the earliest date of PD or death due to any cause. PD was based on radiographic or photographic evidence, and assessments were made by the investigator according to RECIST, version 1.1. PD is defined as 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. In addition, the sum must have an absolute increase from nadir of 5 mm. The appearance of one or more new lesions, or the worsening of non-target lesions significant enough to require study treatment discontinuation, was also included as PD. Participants who received anti-cancer therapy prior to the date of documented events, were censored at the last adequate assessment prior to the initiation of therapy. If the participant did not have documented progression or death, PFS was censored at the date of the last adequate assessment.
Time Frame	From randomization until the earliest date of disease progression (PD) or death due to any cause (up to approximately 6 years)

Outcome Measure Data

Analysis Population Description

Intent-to-Treat (ITT) Population was considered.


Arm/Group Title	Dabrafenib + Trametinib	Dabrafenib + Placebo
Arm/Group Description:	Participants received dabrafenib 15...	Participants received dabrafenib 15...
Arm/Group Description:	Participants received dabrafenib 150 milligram (mg) HPMC capsules orally twice daily (BID), once in the morning and a second dose approximately 12 hours after the morning dose, and trametinib 2 mg once daily in the morning. Treatment was continued until disease progression, death, unacceptable toxicity, or withdrawal of consent.	Participants received dabrafenib 150 mg HPMC capsules orally BID, once in the morning and a second dose approximately 12 hours after the morning dose, and trametinib placebo once daily in the morning. Treatment was continued until disease progression, death, unacceptable toxicity, or withdrawal of consent. Crossover to the combination therapy arm was allowed for subjects still receiving study treatment on the dabrafenib monotherapy arm after the positive result for the final OS analysis.
Overall Number of Participants Analyzed	211	212
Median (95% Confidence Interval) Unit of Measure: Months
	10.2 (8.1 to 12.8)	8.8 (5.9 to 9.3)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Dabrafenib + Trametinib, Dabrafenib + Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.73
	Confidence Interval	(2-Sided) 95% 0.59 to 0.91
	Estimation Comments	Hazard ratios (HRs) were estimated using a Pike estimator.

2.Secondary Outcome


Title	Overall Survival (OS)
Description	OS is defined as the interval of time between the date of randomizatio...
Description	OS is defined as the interval of time between the date of randomization and the date of death due to any cause. For the participants who did not die, overall survival was censored at the date of last contact.
Time Frame	From the date of randomization until date of death due to any cause (up to approximately 6 years)

Outcome Measure Data

Analysis Population Description

Intent-to-Treat (ITT) Population was considered.


Arm/Group Title	Dabrafenib + Trametinib	Dabrafenib + Placebo
Arm/Group Description:	Participants received dabrafenib 15...	Participants received dabrafenib 15...
Arm/Group Description:	Participants received dabrafenib 150 milligram (mg) HPMC capsules orally twice daily (BID), once in the morning and a second dose approximately 12 hours after the morning dose, and trametinib 2 mg once daily in the morning. Treatment was continued until disease progression, death, unacceptable toxicity, or withdrawal of consent.	Participants received dabrafenib 150 mg HPMC capsules orally BID, once in the morning and a second dose approximately 12 hours after the morning dose, and trametinib placebo once daily in the morning. Treatment was continued until disease progression, death, unacceptable toxicity, or withdrawal of consent. Crossover to the combination therapy arm was allowed for subjects still receiving study treatment on the dabrafenib monotherapy arm after the positive result for the final OS analysis.
Overall Number of Participants Analyzed	211	212
Median (95% Confidence Interval) Unit of Measure: Months
	25.8 (19.2 to 38.2)	18.7 (15.2 to 23.1)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Dabrafenib + Trametinib, Dabrafenib + Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other (legacy)
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.81
	Confidence Interval	(2-Sided) 95% 0.64 to 1.02
	Estimation Comments	Hazard ratios (HRs) were estimated using a Pike estimator.

3.Secondary Outcome


Title	Objective Response Rate (ORR) as Assessed by the Investigator
Description	ORR is defined as the percentage of participants with a confirmed comp...
Description	ORR is defined as the percentage of participants with a confirmed complete response (CR) or partial response (PR). A participant was defined as a responder if he/she sustained a complete response (CR: the disappearance of all target lesions and any pathological lymph nodes must have a short axis of <10 mm and the disappearance of all non-target lesions) or 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 or the persistence of 1 or more non-target lesions or lymph nodes identified as a site of disease at Baseline with a short axis of ≥10mm). Only descriptive analysis performed.
Time Frame	From randomization until the first documented complete response or partial response (up to approximately 6 years)

Outcome Measure Data

Analysis Population Description

Intent-to-Treat (ITT) Population was considered. Only participants with measurable disease at Baseline per RECIST were analyzed.


Arm/Group Title	Dabrafenib + Trametinib	Dabrafenib + Placebo
Arm/Group Description:	Participants received dabrafenib 15...	Participants received dabrafenib 15...
Arm/Group Description:	Participants received dabrafenib 150 milligram (mg) HPMC capsules orally twice daily (BID), once in the morning and a second dose approximately 12 hours after the morning dose, and trametinib 2 mg once daily in the morning. Treatment was continued until disease progression, death, unacceptable toxicity, or withdrawal of consent.	Participants received dabrafenib 150 mg HPMC capsules orally BID, once in the morning and a second dose approximately 12 hours after the morning dose, and trametinib placebo once daily in the morning. Treatment was continued until disease progression, death, unacceptable toxicity, or withdrawal of consent. Crossover to the combination therapy arm was allowed for subjects still receiving study treatment on the dabrafenib monotherapy arm after the positive result for the final OS analysis.
Overall Number of Participants Analyzed	210	210
Measure Type: Count of Participants Unit of Measure: Participants
	146 69.5%	113 53.8%

4.Secondary Outcome


Title	Duration of Response (DoR)
Description	Duration of response is defined as the time from the first documented ...
Description	Duration of response is defined as the time from the first documented complete response (CR: the disappearance of all target lesions and any pathological lymph nodes must have a short axis of <10 mm and the disappearance of all non-target lesions) or 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 or the persistence of 1 or more non-target lesions or lymph nodes identified as a site of disease at Baseline with a short axis of ≥10mm) until disease progression (PD) or death due to any cause. PD is defined as at least a 20% increase in the sum of the diameters of target lesions with an absolute increase of at least 5mm or the appearance of one or more new lesions, or the worsening of non target lesions significant enough to require study treatment discontinuation. PD was based on the radiological evidence by investigator. Only descriptive analysis performed.
Time Frame	From the time of the first documented response (CR or PR) until disease progression (up to approximately 6 years)

Outcome Measure Data

Analysis Population Description

ITT population. Only those participants with a confirmed CR or PR were analyzed (with or without measurabe disease at Baseline).


Arm/Group Title	Dabrafenib + Trametinib	Dabrafenib + Placebo
Arm/Group Description:	Participants received dabrafenib 15...	Participants received dabrafenib 15...
Arm/Group Description:	Participants received dabrafenib 150 milligram (mg) HPMC capsules orally twice daily (BID), once in the morning and a second dose approximately 12 hours after the morning dose, and trametinib 2 mg once daily in the morning. Treatment was continued until disease progression, death, unacceptable toxicity, or withdrawal of consent.	Participants received dabrafenib 150 mg HPMC capsules orally BID, once in the morning and a second dose approximately 12 hours after the morning dose, and trametinib placebo once daily in the morning. Treatment was continued until disease progression, death, unacceptable toxicity, or withdrawal of consent. Crossover to the combination therapy arm was allowed for subjects still receiving study treatment on the dabrafenib monotherapy arm after the positive result for the final OS analysis.
Overall Number of Participants Analyzed	146	114
Median (95% Confidence Interval) Unit of Measure: Months
	12.9 (9.3 to 18.4)	10.2 (8.3 to 13.8)

5.Secondary Outcome


Title	Trametinib Pharmacokinetic Concentrations
Description	Blood samples were collected for Pharmacokinetic (PK) analysis in all ...
Description	Blood samples were collected for Pharmacokinetic (PK) analysis in all participants. Three blood samples were collected at Week 8: pre-dose, 1-3 hours post dose, and 4-6 hours post dose. One pre-dose blood sample was obtained at Weeks 16 and 24. Only descriptive analysis performed.
Time Frame	Week 8 (0, 1-3, 4-6 hours post dose), Weeks 16 and 24 (0 hour pre-dose)

Outcome Measure Data

Analysis Population Description

Pharmacokinetic (PK) Population: all participants included in the safety population for whom a PK sample was obtained and analyzed. Only participants with data available at the specified time points were analyzed.


Arm/Group Title		Dabrafenib + Trametinib	Dabrafenib + Placebo
Arm/Group Description:		Participants received dabrafenib 15...	Participants received dabrafenib 15...
Arm/Group Description:		Participants received dabrafenib 150 milligram (mg) HPMC capsules orally twice daily (BID), once in the morning and a second dose approximately 12 hours after the morning dose, and trametinib 2 mg once daily in the morning. Treatment was continued until disease progression, death, unacceptable toxicity, or withdrawal of consent.	Participants received dabrafenib 150 mg HPMC capsules orally BID, once in the morning and a second dose approximately 12 hours after the morning dose, and trametinib placebo once daily in the morning. Treatment was continued until disease progression, death, unacceptable toxicity, or withdrawal of consent. Crossover to the combination therapy arm was allowed for subjects still receiving study treatment on the dabrafenib monotherapy arm after the positive result for the final OS analysis.
Overall Number of Participants Analyzed		203	194
Mean (Standard Deviation) Unit of Measure: Nanogram per Milliliter (ng/mL)
Week 8, pre-dose	Number Analyzed	176 participants	170 participants
Week 8, pre-dose		9.9209 (3.86587)	0.0000 (0.00000)
Week 8, 1-3 hours	Number Analyzed	176 participants	176 participants
Week 8, 1-3 hours		19.0382 (6.86542)	0.0261 (0.34598)
Week 8, 4-6 hours	Number Analyzed	174 participants	171 participants
Week 8, 4-6 hours		16.7496 (5.64363)	0.0000 (0.00000)
Week 16 pre-dose	Number Analyzed	179 participants	162 participants
Week 16 pre-dose		11.0385 (4.79185)	0.0039 (0.03548)
Week 24 pre-dose	Number Analyzed	157 participants	130 participants
Week 24 pre-dose		11.5167 (5.19171)	0.0548 (0.62447)

6.Secondary Outcome


Title	Dabrafenib and Dabrafenib Metabolites (Hydroxy-, Carboxy- and Desmethyl-Dabrafenib) Concentrations
Description	Blood samples were collected for PK analysis in all participants. Thre...
Description	Blood samples were collected for PK analysis in all participants. Three blood samples were collected at Week 8: pre-dose, 1-3 hours post dose, and 4-6 hours post dose. One pre-dose blood sample was obtained at Weeks 16 and 24. Plasma concentrations of Dabrafenib (GSK2118436) and its metabolites (Hydroxy-Dabrafenib (GSK2285403), Carboxy-Dabrafenib (GSK2298683), and Desmethyl-Dabrafenib (GSK2167542)) were determined using the currently approved analytical methodology. Only descriptive analysis performed.
Time Frame	Week 8 (0, 1-3, 4-6 hours post dose), Weeks 16 and 24 (0 hour pre-dose)

Outcome Measure Data

Analysis Population Description

PK Population.


Arm/Group Title		Dabrafenib + Trametinib	Dabrafenib + Placebo
Arm/Group Description:		Participants received dabrafenib 15...	Participants received dabrafenib 15...
Arm/Group Description:		Participants received dabrafenib 150 milligram (mg) HPMC capsules orally twice daily (BID), once in the morning and a second dose approximately 12 hours after the morning dose, and trametinib 2 mg once daily in the morning. Treatment was continued until disease progression, death, unacceptable toxicity, or withdrawal of consent.	Participants received dabrafenib 150 mg HPMC capsules orally BID, once in the morning and a second dose approximately 12 hours after the morning dose, and trametinib placebo once daily in the morning. Treatment was continued until disease progression, death, unacceptable toxicity, or withdrawal of consent. Crossover to the combination therapy arm was allowed for subjects still receiving study treatment on the dabrafenib monotherapy arm after the positive result for the final OS analysis.
Overall Number of Participants Analyzed		203	194
Mean (Standard Deviation) Unit of Measure: Nanogram per Milliliter (ng/mL)
GSK2118436, Week 8, pre-dose	Number Analyzed	176 participants	170 participants
GSK2118436, Week 8, pre-dose		92.1 (204.85)	64.4 (96.98)
GSK2118436, Week 8, 1-3 hours	Number Analyzed	176 participants	176 participants
GSK2118436, Week 8, 1-3 hours		1309.6 (982.25)	1362.3 (992.97)
GSK2118436, Week 8, 4-6 hours	Number Analyzed	173 participants	171 participants
GSK2118436, Week 8, 4-6 hours		458.9 (318.59)	539.7 (553.09)
GSK2118436, Week 16 pre-dose	Number Analyzed	179 participants	162 participants
GSK2118436, Week 16 pre-dose		151.6 (261.31)	151.02 (381.32)
GSK2118436, Week 24 pre-dose	Number Analyzed	157 participants	130 participants
GSK2118436, Week 24 pre-dose		167.0 (346.97)	156.5 (357.50)
GSK2285403, Week 8, pre-dose	Number Analyzed	176 participants	170 participants
GSK2285403, Week 8, pre-dose		346.6 (261.73)	308.9 (224.56)
GSK2285403, Week 8, 1-3 hours	Number Analyzed	176 participants	176 participants
GSK2285403, Week 8, 1-3 hours		361.7 (245.92)	341.8 (240.96)
GSK2285403, Week 8, 4-6 hours	Number Analyzed	174 participants	171 participants
GSK2285403, Week 8, 4-6 hours		316.9 (208.51)	328.1 (234.95)
GSK2285403, Week 16 pre-dose	Number Analyzed	179 participants	162 participants
GSK2285403, Week 16 pre-dose		335.0 (228.26)	331.0 (250.04)
GSK2285403, Week 24 pre-dose	Number Analyzed	157 participants	130 participants
GSK2285403, Week 24 pre-dose		306.2 (203.77)	312.8 (250.28)
GSK2298683, Week 8, pre-dose	Number Analyzed	176 participants	172 participants
GSK2298683, Week 8, pre-dose		82.0 (123.93)	76.7 (109.09)
GSK2298683,Week 8, 1-3 hours	Number Analyzed	177 participants	179 participants
GSK2298683,Week 8, 1-3 hours		648.5 (459.01)	672.7 (519.45)
GSK2298683, Week 8, 4-6 hours	Number Analyzed	174 participants	173 participants
GSK2298683, Week 8, 4-6 hours		391.3 (206.70)	502.2 (356.72)
GSK2298683, Week 16 pre-dose	Number Analyzed	179 participants	163 participants
GSK2298683, Week 16 pre-dose		128.7 (174.26)	121.1 (195.15)
GSK2298683,Week 24 pre-dose	Number Analyzed	156 participants	130 participants
GSK2298683,Week 24 pre-dose		126.1 (219.82)	145.7 (265.57)
GSK2167542, Week 8, pre-dose	Number Analyzed	176 participants	170 participants
GSK2167542, Week 8, pre-dose		3237.2 (1694.66)	3469.4 (1854.02)
GSK2167542, Week 8, 1-3 hours	Number Analyzed	176 participants	176 participants
GSK2167542, Week 8, 1-3 hours		4286.3 (2514.50)	4456.6 (2687.32)
GSK2167542, Week 8, 4-6 hours	Number Analyzed	174 participants	171 participants
GSK2167542, Week 8, 4-6 hours		6238.3 (2716.05)	6891.6 (2739.07)
GSK2167542, Week 16 pre-dose	Number Analyzed	179 participants	162 participants
GSK2167542, Week 16 pre-dose		3842.4 (2428.74)	4114.1 (2432.72)
GSK2167542, Week 24 pre-dose	Number Analyzed	157 participants	130 participants
GSK2167542, Week 24 pre-dose		3617.9 (2645.51)	4193.2 (2730.78)

7.Secondary Outcome


Title	Number of Participants With Adverse Events and Serious Adverse Events
Description	Analysis of absolute and relative frequencies for Adverse Event (AE) a...
Description	Analysis of absolute and relative frequencies for Adverse Event (AE) and Serious Adverse Event (SAE) by primary System Organ Class (SOC) to characterize the safety of dabrafenib and trametinib combination therapy through the monitoring of relevant clinical and laboratory safety parameters. In addition, new malignancies and AEs possibly related to study treatment were collected even if they occurred more than 30 days post-treatment. Only descriptive analysis performed.
Time Frame	From the time the first dose of study treatment administered until 30 days after discontinuation of study treatment (up to approximately 6 years).

Outcome Measure Data

Analysis Population Description

Safety Population: all randomized participants who received at least one dose of study medication and were based on the actual treatment received if this differed from that to which the participant was randomized.


Arm/Group Title	Dabrafenib + Trametinib	Dabrafenib + Placebo	Crossover Dabrafenib + Trametinib
Arm/Group Description:	Participants received dabrafenib 15...	Participants received dabrafenib 15...	Crossover Dabrafenib + Trametinib
Arm/Group Description:	Participants received dabrafenib 150 milligram (mg) HPMC capsules orally twice daily (BID), once in the morning and a second dose approximately 12 hours after the morning dose, and trametinib 2 mg once daily in the morning. Treatment was continued until disease progression, death, unacceptable toxicity, or withdrawal of consent.	Participants received dabrafenib 150 mg HPMC capsules orally BID, once in the morning and a second dose approximately 12 hours after the morning dose, and trametinib placebo once daily in the morning. Treatment was continued until disease progression, death, unacceptable toxicity, or withdrawal of consent. Crossover to the combination therapy arm was allowed for subjects still receiving study treatment on the dabrafenib monotherapy arm after the positive result for the final OS analysis.	Crossover Dabrafenib + Trametinib
Overall Number of Participants Analyzed	209	211	28
Measure Type: Count of Participants Unit of Measure: Participants
Adverse Event (AEs)	203 97.1%	205 97.2%	24 85.7%
Serious Adverse Event (SAEs)	100 47.8%	80 37.9%	8 28.6%

8.Post-Hoc Outcome


Title	All Collected Deaths
Description	Pre-treatment deaths were collected from screening visit up to the fir...
Description	Pre-treatment deaths were collected from screening visit up to the first day of treatment, for a maximum duration of 28 days. Patients who died during the screening period are considered as screen failure. On treatment deaths were collected from FPFT up to 30 days after study drug discontinuation, for a maximum duration of 77.4 months (treatment duration ranged from 0.1 to 76.4 months). Deaths post treatment survival follow up were collected after the on- treatment period, up to approximately 6 years. Patients who didn't die during the on-treatment period and had not stopped study participation at the time of data cut-off (end of study) were censored.
Time Frame	up to 28 days before Day 1 (Screening), up to 77.4 months (on-treatment), up to approximately 6 years (study duration)

Outcome Measure Data

Analysis Population Description

Clinical database population; all treated patients and patients who died during screening.


Arm/Group Title	Dabrafenib + Trametinib	Dabrafenib + Placebo	Crossover Dabrafenib + Trametinib
Arm/Group Description:	Participants received dabrafenib 15...	Participants received dabrafenib 15...	Crossover Dabrafenib + Trametinib
Arm/Group Description:	Participants received dabrafenib 150 milligram (mg) HPMC capsules orally twice daily (BID), once in the morning and a second dose approximately 12 hours after the morning dose, and trametinib 2 mg once daily in the morning. Treatment was continued until disease progression, death, unacceptable toxicity, or withdrawal of consent.	Participants received dabrafenib 150 mg HPMC capsules orally BID, once in the morning and a second dose approximately 12 hours after the morning dose, and trametinib placebo once daily in the morning. Treatment was continued until disease progression, death, unacceptable toxicity, or withdrawal of consent. Crossover to the combination therapy arm was allowed for subjects still receiving study treatment on the dabrafenib monotherapy arm after the positive result for the final OS analysis.	Crossover Dabrafenib + Trametinib
Overall Number of Participants Analyzed	210	211	28
Measure Type: Count of Participants Unit of Measure: Participants
Pre-treatment deaths	1 0.5%	0 0.0%	0 0.0%
On-treatment deaths	29 13.8%	25 11.8%	0 0.0%
Post-treatment deaths	106 50.5%	121 57.3%	5 17.9%
All deaths	136 64.8%	146 69.2%	5 17.9%

Adverse Events

Time Frame	Adverse events were collected from First Patient First Treatment (FPFT) up to 30 days after study drug discontinuation, for a maximum duration of 77.4 months (treatment duration ranged from 0.1 to 76.4 months). In addition, new malignancies and AEs possibly related to study treatment were collected up to approximately 6 years
Adverse Event Reporting Description	Any clinically significant sign or symptom that occurs during the study treatment and 30 days post treatment follow up. In addition, new malignancies and AEs possibly related to study treatment were collected even if they occurred more than 30 days post-treatment.

Arm/Group Title	Dabrafenib + Trametinib	Dabrafenib + Placebo	Crossover Dabrafenib + Trametinib	All Patients
Arm/Group Description	Participants received dabrafenib 15...	Participants received dabrafenib 15...	Crossover Dabrafenib + Trametinib	All Patients
Arm/Group Description	Participants received dabrafenib 150 milligram (mg) HPMC capsules orally twice daily (BID), once in the morning and a second dose approximately 12 hours after the morning dose, and trametinib 2 mg once daily in the morning. Treatment was continued until disease progression, death, unacceptable toxicity, or withdrawal of consent.	Participants received dabrafenib 150 mg HPMC capsules orally BID, once in the morning and a second dose approximately 12 hours after the morning dose, and trametinib placebo once daily in the morning. Treatment was continued until disease progression, death, unacceptable toxicity, or withdrawal of consent. Crossover to the combination therapy arm was allowed for subjects still receiving study treatment on the dabrafenib monotherapy arm after the positive result for the final OS analysis.	Crossover Dabrafenib + Trametinib	All Patients
All-Cause Mortality
	Dabrafenib + Trametinib	Dabrafenib + Placebo	Crossover Dabrafenib + Trametinib	All Patients
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	135/209 (64.59%)	146/211 (69.19%)	5/28 (17.86%)	286/420 (68.10%)
Serious Adverse Events Serious Adverse Events
	Dabrafenib + Trametinib	Dabrafenib + Placebo	Crossover Dabrafenib + Trametinib	All Patients
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	100/209 (47.85%)	80/211 (37.91%)	8/28 (28.57%)	183/420 (43.57%)
Blood and lymphatic system disorders
Anaemia ^† 1	5/209 (2.39%)	3/211 (1.42%)	0/28 (0.00%)	8/420 (1.90%)
Febrile neutropenia ^† 1	0/209 (0.00%)	2/211 (0.95%)	0/28 (0.00%)	2/420 (0.48%)
Haemolytic uraemic syndrome ^† 1	1/209 (0.48%)	0/211 (0.00%)	0/28 (0.00%)	1/420 (0.24%)
Hypochromic anaemia ^† 1	1/209 (0.48%)	0/211 (0.00%)	0/28 (0.00%)	1/420 (0.24%)
Neutropenia ^† 1	1/209 (0.48%)	0/211 (0.00%)	0/28 (0.00%)	1/420 (0.24%)
Pancytopenia ^† 1	1/209 (0.48%)	0/211 (0.00%)	0/28 (0.00%)	1/420 (0.24%)
Thrombocytopenia ^† 1	2/209 (0.96%)	0/211 (0.00%)	0/28 (0.00%)	2/420 (0.48%)
Cardiac disorders
Acute coronary syndrome ^† 1	1/209 (0.48%)	0/211 (0.00%)	0/28 (0.00%)	1/420 (0.24%)
Atrial fibrillation ^† 1	3/209 (1.44%)	2/211 (0.95%)	0/28 (0.00%)	5/420 (1.19%)
Cardiac failure ^† 1	0/209 (0.00%)	2/211 (0.95%)	1/28 (3.57%)	3/420 (0.71%)
Cardiovascular insufficiency ^† 1	1/209 (0.48%)	0/211 (0.00%)	0/28 (0.00%)	1/420 (0.24%)
Myocardial infarction ^† 1	1/209 (0.48%)	0/211 (0.00%)	0/28 (0.00%)	1/420 (0.24%)
Supraventricular tachycardia ^† 1	1/209 (0.48%)	0/211 (0.00%)	0/28 (0.00%)	1/420 (0.24%)
Tachycardia ^† 1	0/209 (0.00%)	1/211 (0.47%)	0/28 (0.00%)	1/420 (0.24%)
Eye disorders
Chorioretinopathy ^† 1	1/209 (0.48%)	1/211 (0.47%)	0/28 (0.00%)	2/420 (0.48%)
Iridocyclitis ^† 1	1/209 (0.48%)	0/211 (0.00%)	0/28 (0.00%)	1/420 (0.24%)
Uveitis ^† 1	0/209 (0.00%)	1/211 (0.47%)	0/28 (0.00%)	1/420 (0.24%)
Visual impairment ^† 1	0/209 (0.00%)	1/211 (0.47%)	0/28 (0.00%)	1/420 (0.24%)
Gastrointestinal disorders
Abdominal pain ^† 1	4/209 (1.91%)	2/211 (0.95%)	0/28 (0.00%)	6/420 (1.43%)
Abdominal pain upper ^† 1	1/209 (0.48%)	0/211 (0.00%)	0/28 (0.00%)	1/420 (0.24%)
Acute abdomen ^† 1	1/209 (0.48%)	0/211 (0.00%)	0/28 (0.00%)	1/420 (0.24%)
Colitis ^† 1	0/209 (0.00%)	1/211 (0.47%)	0/28 (0.00%)	1/420 (0.24%)
Constipation ^† 1	1/209 (0.48%)	0/211 (0.00%)	0/28 (0.00%)	1/420 (0.24%)
Diarrhoea ^† 1	2/209 (0.96%)	0/211 (0.00%)	0/28 (0.00%)	2/420 (0.48%)
Gastrointestinal disorder ^† 1	0/209 (0.00%)	1/211 (0.47%)	0/28 (0.00%)	1/420 (0.24%)
Gastrooesophageal reflux disease ^† 1	0/209 (0.00%)	1/211 (0.47%)	0/28 (0.00%)	1/420 (0.24%)
Intestinal perforation ^† 1	1/209 (0.48%)	0/211 (0.00%)	0/28 (0.00%)	1/420 (0.24%)
Jejunal perforation ^† 1	1/209 (0.48%)	0/211 (0.00%)	0/28 (0.00%)	1/420 (0.24%)
Melaena ^† 1	1/209 (0.48%)	0/211 (0.00%)	0/28 (0.00%)	1/420 (0.24%)
Nausea ^† 1	2/209 (0.96%)	0/211 (0.00%)	0/28 (0.00%)	2/420 (0.48%)
Pancreatitis acute ^† 1	1/209 (0.48%)	0/211 (0.00%)	0/28 (0.00%)	1/420 (0.24%)
Peritoneal haemorrhage ^† 1	0/209 (0.00%)	1/211 (0.47%)	0/28 (0.00%)	1/420 (0.24%)
Rectal haemorrhage ^† 1	2/209 (0.96%)	0/211 (0.00%)	0/28 (0.00%)	2/420 (0.48%)
Small intestinal obstruction ^† 1	1/209 (0.48%)	0/211 (0.00%)	0/28 (0.00%)	1/420 (0.24%)
Upper gastrointestinal haemorrhage ^† 1	0/209 (0.00%)	1/211 (0.47%)	0/28 (0.00%)	1/420 (0.24%)
Vomiting ^† 1	3/209 (1.44%)	0/211 (0.00%)	0/28 (0.00%)	3/420 (0.71%)
General disorders
Chest pain ^† 1	0/209 (0.00%)	1/211 (0.47%)	0/28 (0.00%)	1/420 (0.24%)
Chills ^† 1	10/209 (4.78%)	3/211 (1.42%)	0/28 (0.00%)	13/420 (3.10%)
Drowning ^† 1	1/209 (0.48%)	0/211 (0.00%)	0/28 (0.00%)	1/420 (0.24%)
Fatigue ^† 1	3/209 (1.44%)	1/211 (0.47%)	0/28 (0.00%)	4/420 (0.95%)
General physical health deterioration ^† 1	3/209 (1.44%)	0/211 (0.00%)	0/28 (0.00%)	3/420 (0.71%)
Influenza like illness ^† 1	1/209 (0.48%)	0/211 (0.00%)	0/28 (0.00%)	1/420 (0.24%)
Malaise ^† 1	0/209 (0.00%)	1/211 (0.47%)	0/28 (0.00%)	1/420 (0.24%)
Pyrexia ^† 1	36/209 (17.22%)	15/211 (7.11%)	2/28 (7.14%)	51/420 (12.14%)
Hepatobiliary disorders
Cholecystitis ^† 1	1/209 (0.48%)	0/211 (0.00%)	0/28 (0.00%)	1/420 (0.24%)
Cholelithiasis ^† 1	0/209 (0.00%)	1/211 (0.47%)	0/28 (0.00%)	1/420 (0.24%)
Hepatic haematoma ^† 1	1/209 (0.48%)	0/211 (0.00%)	0/28 (0.00%)	1/420 (0.24%)
Immune system disorders
Contrast media allergy ^† 1	1/209 (0.48%)	0/211 (0.00%)	0/28 (0.00%)	1/420 (0.24%)
Infections and infestations
Bacteraemia ^† 1	1/209 (0.48%)	0/211 (0.00%)	0/28 (0.00%)	1/420 (0.24%)
Cellulitis ^† 1	2/209 (0.96%)	1/211 (0.47%)	0/28 (0.00%)	3/420 (0.71%)
Clostridium difficile colitis ^† 1	1/209 (0.48%)	0/211 (0.00%)	0/28 (0.00%)	1/420 (0.24%)
Cystitis ^† 1	1/209 (0.48%)	0/211 (0.00%)	0/28 (0.00%)	1/420 (0.24%)
Diverticulitis ^† 1	0/209 (0.00%)	1/211 (0.47%)	0/28 (0.00%)	1/420 (0.24%)
Febrile infection ^† 1	0/209 (0.00%)	0/211 (0.00%)	1/28 (3.57%)	1/420 (0.24%)
Herpes zoster ^† 1	1/209 (0.48%)	1/211 (0.47%)	0/28 (0.00%)	2/420 (0.48%)
Kidney infection ^† 1	1/209 (0.48%)	0/211 (0.00%)	0/28 (0.00%)	1/420 (0.24%)
Laryngitis ^† 1	1/209 (0.48%)	0/211 (0.00%)	0/28 (0.00%)	1/420 (0.24%)
Neutropenic sepsis ^† 1	1/209 (0.48%)	0/211 (0.00%)	0/28 (0.00%)	1/420 (0.24%)
Peritonitis ^† 1	0/209 (0.00%)	1/211 (0.47%)	0/28 (0.00%)	1/420 (0.24%)
Pneumonia ^† 1	6/209 (2.87%)	2/211 (0.95%)	0/28 (0.00%)	8/420 (1.90%)
Pseudomonas infection ^† 1	1/209 (0.48%)	0/211 (0.00%)	0/28 (0.00%)	1/420 (0.24%)
Pyelonephritis ^† 1	1/209 (0.48%)	0/211 (0.00%)	0/28 (0.00%)	1/420 (0.24%)
Sepsis ^† 1	1/209 (0.48%)	1/211 (0.47%)	0/28 (0.00%)	2/420 (0.48%)
Septic shock ^† 1	1/209 (0.48%)	0/211 (0.00%)	0/28 (0.00%)	1/420 (0.24%)
Staphylococcal sepsis ^† 1	1/209 (0.48%)	0/211 (0.00%)	0/28 (0.00%)	1/420 (0.24%)
Superinfection ^† 1	1/209 (0.48%)	0/211 (0.00%)	0/28 (0.00%)	1/420 (0.24%)
Upper respiratory tract infection ^† 1	0/209 (0.00%)	0/211 (0.00%)	1/28 (3.57%)	1/420 (0.24%)
Urinary tract infection ^† 1	2/209 (0.96%)	1/211 (0.47%)	0/28 (0.00%)	3/420 (0.71%)
Urosepsis ^† 1	2/209 (0.96%)	0/211 (0.00%)	0/28 (0.00%)	2/420 (0.48%)
Injury, poisoning and procedural complications
Humerus fracture ^† 1	1/209 (0.48%)	0/211 (0.00%)	0/28 (0.00%)	1/420 (0.24%)
Joint dislocation ^† 1	1/209 (0.48%)	0/211 (0.00%)	0/28 (0.00%)	1/420 (0.24%)
Ligament rupture ^† 1	1/209 (0.48%)	0/211 (0.00%)	0/28 (0.00%)	1/420 (0.24%)
Ligament sprain ^† 1	1/209 (0.48%)	0/211 (0.00%)	0/28 (0.00%)	1/420 (0.24%)
Meniscus injury ^† 1	1/209 (0.48%)	0/211 (0.00%)	0/28 (0.00%)	1/420 (0.24%)
Post procedural persistent drain fluid ^† 1	1/209 (0.48%)	0/211 (0.00%)	0/28 (0.00%)	1/420 (0.24%)
Radius fracture ^† 1	1/209 (0.48%)	0/211 (0.00%)	0/28 (0.00%)	1/420 (0.24%)
Subarachnoid haemorrhage ^† 1	0/209 (0.00%)	1/211 (0.47%)	0/28 (0.00%)	1/420 (0.24%)
Upper limb fracture ^† 1	1/209 (0.48%)	0/211 (0.00%)	0/28 (0.00%)	1/420 (0.24%)
Investigations
Alanine aminotransferase increased ^† 1	3/209 (1.44%)	0/211 (0.00%)	1/28 (3.57%)	4/420 (0.95%)
Aspartate aminotransferase increased ^† 1	1/209 (0.48%)	0/211 (0.00%)	1/28 (3.57%)	2/420 (0.48%)
Blood alkaline phosphatase increased ^† 1	1/209 (0.48%)	0/211 (0.00%)	0/28 (0.00%)	1/420 (0.24%)
Ejection fraction decreased ^† 1	13/209 (6.22%)	5/211 (2.37%)	1/28 (3.57%)	19/420 (4.52%)
Forced expiratory volume decreased ^† 1	1/209 (0.48%)	0/211 (0.00%)	0/28 (0.00%)	1/420 (0.24%)
Haemoglobin decreased ^† 1	1/209 (0.48%)	0/211 (0.00%)	0/28 (0.00%)	1/420 (0.24%)
Hepatic enzyme increased ^† 1	1/209 (0.48%)	0/211 (0.00%)	0/28 (0.00%)	1/420 (0.24%)
Neutrophil count decreased ^† 1	1/209 (0.48%)	0/211 (0.00%)	0/28 (0.00%)	1/420 (0.24%)
Oxygen saturation decreased ^† 1	0/209 (0.00%)	1/211 (0.47%)	0/28 (0.00%)	1/420 (0.24%)
Renal function test abnormal ^† 1	0/209 (0.00%)	0/211 (0.00%)	1/28 (3.57%)	1/420 (0.24%)
Transaminases increased ^† 1	1/209 (0.48%)	0/211 (0.00%)	0/28 (0.00%)	1/420 (0.24%)
White blood cell count decreased ^† 1	1/209 (0.48%)	0/211 (0.00%)	0/28 (0.00%)	1/420 (0.24%)
Metabolism and nutrition disorders
Dehydration ^† 1	1/209 (0.48%)	2/211 (0.95%)	1/28 (3.57%)	4/420 (0.95%)
Hypercalcaemia ^† 1	0/209 (0.00%)	1/211 (0.47%)	0/28 (0.00%)	1/420 (0.24%)
Hyperglycaemia ^† 1	1/209 (0.48%)	0/211 (0.00%)	0/28 (0.00%)	1/420 (0.24%)
Hypoglycaemia ^† 1	2/209 (0.96%)	0/211 (0.00%)	0/28 (0.00%)	2/420 (0.48%)
Hypokalaemia ^† 1	1/209 (0.48%)	0/211 (0.00%)	0/28 (0.00%)	1/420 (0.24%)
Hyponatraemia ^† 1	0/209 (0.00%)	1/211 (0.47%)	1/28 (3.57%)	2/420 (0.48%)
Hypophosphataemia ^† 1	1/209 (0.48%)	0/211 (0.00%)	0/28 (0.00%)	1/420 (0.24%)
Type 2 diabetes mellitus ^† 1	0/209 (0.00%)	1/211 (0.47%)	0/28 (0.00%)	1/420 (0.24%)
Musculoskeletal and connective tissue disorders
Back pain ^† 1	0/209 (0.00%)	2/211 (0.95%)	0/28 (0.00%)	2/420 (0.48%)
Compartment syndrome ^† 1	0/209 (0.00%)	1/211 (0.47%)	0/28 (0.00%)	1/420 (0.24%)
Haemarthrosis ^† 1	1/209 (0.48%)	0/211 (0.00%)	0/28 (0.00%)	1/420 (0.24%)
Hypercreatinaemia ^† 1	1/209 (0.48%)	0/211 (0.00%)	0/28 (0.00%)	1/420 (0.24%)
Immunoglobulin G4 related disease ^† 1	1/209 (0.48%)	0/211 (0.00%)	0/28 (0.00%)	1/420 (0.24%)
Intervertebral disc degeneration ^† 1	1/209 (0.48%)	1/211 (0.47%)	0/28 (0.00%)	2/420 (0.48%)
Muscle haemorrhage ^† 1	1/209 (0.48%)	0/211 (0.00%)	0/28 (0.00%)	1/420 (0.24%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Adenocarcinoma gastric ^† 1	0/209 (0.00%)	1/211 (0.47%)	0/28 (0.00%)	1/420 (0.24%)
Basal cell carcinoma ^† 1	8/209 (3.83%)	14/211 (6.64%)	0/28 (0.00%)	22/420 (5.24%)
Bile duct adenocarcinoma ^† 1	0/209 (0.00%)	1/211 (0.47%)	0/28 (0.00%)	1/420 (0.24%)
Bowen's disease ^† 1	2/209 (0.96%)	2/211 (0.95%)	1/28 (3.57%)	5/420 (1.19%)
Breast cancer ^† 1	0/209 (0.00%)	1/211 (0.47%)	0/28 (0.00%)	1/420 (0.24%)
Hodgkin's disease ^† 1	0/209 (0.00%)	1/211 (0.47%)	0/28 (0.00%)	1/420 (0.24%)
Invasive ductal breast carcinoma ^† 1	0/209 (0.00%)	1/211 (0.47%)	0/28 (0.00%)	1/420 (0.24%)
Keratoacanthoma ^† 1	0/209 (0.00%)	1/211 (0.47%)	0/28 (0.00%)	1/420 (0.24%)
Lipofibroma ^† 1	0/209 (0.00%)	1/211 (0.47%)	0/28 (0.00%)	1/420 (0.24%)
Malignant melanoma ^† 1	1/209 (0.48%)	2/211 (0.95%)	0/28 (0.00%)	3/420 (0.71%)
Osteosarcoma ^† 1	1/209 (0.48%)	0/211 (0.00%)	0/28 (0.00%)	1/420 (0.24%)
Papillary thyroid cancer ^† 1	1/209 (0.48%)	0/211 (0.00%)	0/28 (0.00%)	1/420 (0.24%)
Phaeochromocytoma ^† 1	1/209 (0.48%)	0/211 (0.00%)	0/28 (0.00%)	1/420 (0.24%)
Prostate cancer ^† 1	1/209 (0.48%)	0/211 (0.00%)	0/28 (0.00%)	1/420 (0.24%)
Schwannoma ^† 1	0/209 (0.00%)	1/211 (0.47%)	0/28 (0.00%)	1/420 (0.24%)
Squamous cell carcinoma ^† 1	3/209 (1.44%)	7/211 (3.32%)	1/28 (3.57%)	11/420 (2.62%)
Squamous cell carcinoma of skin ^† 1	2/209 (0.96%)	15/211 (7.11%)	1/28 (3.57%)	18/420 (4.29%)
Superficial spreading melanoma stage unspecified ^† 1	0/209 (0.00%)	1/211 (0.47%)	0/28 (0.00%)	1/420 (0.24%)
Transitional cell carcinoma ^† 1	0/209 (0.00%)	1/211 (0.47%)	0/28 (0.00%)	1/420 (0.24%)
Tumour haemorrhage ^† 1	0/209 (0.00%)	1/211 (0.47%)	0/28 (0.00%)	1/420 (0.24%)
Nervous system disorders
Aphasia ^† 1	1/209 (0.48%)	0/211 (0.00%)	0/28 (0.00%)	1/420 (0.24%)
Brain oedema ^† 1	1/209 (0.48%)	1/211 (0.47%)	0/28 (0.00%)	2/420 (0.48%)
Central nervous system lesion ^† 1	0/209 (0.00%)	0/211 (0.00%)	1/28 (3.57%)	1/420 (0.24%)
Cerebral haemorrhage ^† 1	2/209 (0.96%)	0/211 (0.00%)	0/28 (0.00%)	2/420 (0.48%)
Cerebral infarction ^† 1	1/209 (0.48%)	0/211 (0.00%)	0/28 (0.00%)	1/420 (0.24%)
Cerebrovascular accident ^† 1	1/209 (0.48%)	0/211 (0.00%)	0/28 (0.00%)	1/420 (0.24%)
Dizziness ^† 1	1/209 (0.48%)	0/211 (0.00%)	0/28 (0.00%)	1/420 (0.24%)
Epilepsy ^† 1	1/209 (0.48%)	1/211 (0.47%)	0/28 (0.00%)	2/420 (0.48%)
Facial paralysis ^† 1	1/209 (0.48%)	0/211 (0.00%)	0/28 (0.00%)	1/420 (0.24%)
Hemiplegia ^† 1	1/209 (0.48%)	0/211 (0.00%)	0/28 (0.00%)	1/420 (0.24%)
Nervous system disorder ^† 1	1/209 (0.48%)	0/211 (0.00%)	0/28 (0.00%)	1/420 (0.24%)
Paraesthesia ^† 1	0/209 (0.00%)	0/211 (0.00%)	1/28 (3.57%)	1/420 (0.24%)
Presyncope ^† 1	1/209 (0.48%)	0/211 (0.00%)	0/28 (0.00%)	1/420 (0.24%)
Sciatica ^† 1	1/209 (0.48%)	0/211 (0.00%)	0/28 (0.00%)	1/420 (0.24%)
Seizure ^† 1	1/209 (0.48%)	1/211 (0.47%)	0/28 (0.00%)	2/420 (0.48%)
Syncope ^† 1	4/209 (1.91%)	1/211 (0.47%)	0/28 (0.00%)	5/420 (1.19%)
Tremor ^† 1	1/209 (0.48%)	0/211 (0.00%)	0/28 (0.00%)	1/420 (0.24%)
Psychiatric disorders
Confusional state ^† 1	3/209 (1.44%)	1/211 (0.47%)	0/28 (0.00%)	4/420 (0.95%)
Delirium ^† 1	1/209 (0.48%)	0/211 (0.00%)	0/28 (0.00%)	1/420 (0.24%)
Mania ^† 1	0/209 (0.00%)	1/211 (0.47%)	0/28 (0.00%)	1/420 (0.24%)
Organic brain syndrome ^† 1	0/209 (0.00%)	1/211 (0.47%)	0/28 (0.00%)	1/420 (0.24%)
Renal and urinary disorders
Acute kidney injury ^† 1	1/209 (0.48%)	1/211 (0.47%)	0/28 (0.00%)	2/420 (0.48%)
Azotaemia ^† 1	1/209 (0.48%)	0/211 (0.00%)	0/28 (0.00%)	1/420 (0.24%)
Haematuria ^† 1	0/209 (0.00%)	1/211 (0.47%)	0/28 (0.00%)	1/420 (0.24%)
Hydronephrosis ^† 1	0/209 (0.00%)	1/211 (0.47%)	0/28 (0.00%)	1/420 (0.24%)
Nephritis ^† 1	1/209 (0.48%)	0/211 (0.00%)	0/28 (0.00%)	1/420 (0.24%)
Pelvi-ureteric obstruction ^† 1	1/209 (0.48%)	0/211 (0.00%)	0/28 (0.00%)	1/420 (0.24%)
Renal colic ^† 1	2/209 (0.96%)	0/211 (0.00%)	0/28 (0.00%)	2/420 (0.48%)
Renal failure ^† 1	0/209 (0.00%)	0/211 (0.00%)	1/28 (3.57%)	1/420 (0.24%)
Urinary retention ^† 1	1/209 (0.48%)	0/211 (0.00%)	0/28 (0.00%)	1/420 (0.24%)
Reproductive system and breast disorders
Uterine prolapse ^† 1	0/209 (0.00%)	0/211 (0.00%)	1/28 (3.57%)	1/420 (0.24%)
Respiratory, thoracic and mediastinal disorders
Chronic obstructive pulmonary disease ^† 1	0/209 (0.00%)	1/211 (0.47%)	0/28 (0.00%)	1/420 (0.24%)
Dyspnoea ^† 1	0/209 (0.00%)	1/211 (0.47%)	0/28 (0.00%)	1/420 (0.24%)
Nasal polyps ^† 1	1/209 (0.48%)	0/211 (0.00%)	0/28 (0.00%)	1/420 (0.24%)
Pleural effusion ^† 1	1/209 (0.48%)	0/211 (0.00%)	0/28 (0.00%)	1/420 (0.24%)
Pneumonitis ^† 1	1/209 (0.48%)	0/211 (0.00%)	0/28 (0.00%)	1/420 (0.24%)
Pulmonary embolism ^† 1	3/209 (1.44%)	1/211 (0.47%)	0/28 (0.00%)	4/420 (0.95%)
Respiratory depression ^† 1	0/209 (0.00%)	1/211 (0.47%)	0/28 (0.00%)	1/420 (0.24%)
Skin and subcutaneous tissue disorders
Dermatitis allergic ^† 1	1/209 (0.48%)	0/211 (0.00%)	0/28 (0.00%)	1/420 (0.24%)
Dermatosis ^† 1	1/209 (0.48%)	0/211 (0.00%)	0/28 (0.00%)	1/420 (0.24%)
Hyperhidrosis ^† 1	1/209 (0.48%)	0/211 (0.00%)	0/28 (0.00%)	1/420 (0.24%)
Hyperkeratosis ^† 1	0/209 (0.00%)	1/211 (0.47%)	0/28 (0.00%)	1/420 (0.24%)
Skin lesion ^† 1	0/209 (0.00%)	1/211 (0.47%)	0/28 (0.00%)	1/420 (0.24%)
Skin ulcer ^† 1	0/209 (0.00%)	1/211 (0.47%)	0/28 (0.00%)	1/420 (0.24%)
Vascular disorders
Deep vein thrombosis ^† 1	1/209 (0.48%)	1/211 (0.47%)	0/28 (0.00%)	2/420 (0.48%)
Hypertension ^† 1	1/209 (0.48%)	0/211 (0.00%)	0/28 (0.00%)	1/420 (0.24%)
Hypotension ^† 1	6/209 (2.87%)	2/211 (0.95%)	1/28 (3.57%)	9/420 (2.14%)
Hypovolaemic shock ^† 1	0/209 (0.00%)	1/211 (0.47%)	0/28 (0.00%)	1/420 (0.24%)
Peripheral ischaemia ^† 1	0/209 (0.00%)	1/211 (0.47%)	0/28 (0.00%)	1/420 (0.24%)
Thrombophlebitis superficial ^† 1	0/209 (0.00%)	1/211 (0.47%)	0/28 (0.00%)	1/420 (0.24%)
1 Term from vocabulary, MedDRA (19.0) † Indicates events were collected by systematic assessment
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	Dabrafenib + Trametinib	Dabrafenib + Placebo	Crossover Dabrafenib + Trametinib	All Patients
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	194/209 (92.82%)	200/211 (94.79%)	23/28 (82.14%)	394/420 (93.81%)
Blood and lymphatic system disorders
Anaemia ^† 1	16/209 (7.66%)	22/211 (10.43%)	3/28 (10.71%)	38/420 (9.05%)
Leukopenia ^† 1	7/209 (3.35%)	1/211 (0.47%)	2/28 (7.14%)	10/420 (2.38%)
Neutropenia ^† 1	20/209 (9.57%)	5/211 (2.37%)	3/28 (10.71%)	28/420 (6.67%)
Thrombocytopenia ^† 1	9/209 (4.31%)	2/211 (0.95%)	2/28 (7.14%)	13/420 (3.10%)
Cardiac disorders
Atrial fibrillation ^† 1	2/209 (0.96%)	2/211 (0.95%)	2/28 (7.14%)	6/420 (1.43%)
Tachycardia ^† 1	6/209 (2.87%)	13/211 (6.16%)	3/28 (10.71%)	21/420 (5.00%)
Ear and labyrinth disorders
Tinnitus ^† 1	5/209 (2.39%)	2/211 (0.95%)	3/28 (10.71%)	9/420 (2.14%)
Endocrine disorders
Hypothyroidism ^† 1	3/209 (1.44%)	2/211 (0.95%)	2/28 (7.14%)	7/420 (1.67%)
Eye disorders
Blepharitis ^† 1	2/209 (0.96%)	0/211 (0.00%)	2/28 (7.14%)	4/420 (0.95%)
Cataract ^† 1	2/209 (0.96%)	4/211 (1.90%)	3/28 (10.71%)	8/420 (1.90%)
Dry eye ^† 1	11/209 (5.26%)	4/211 (1.90%)	1/28 (3.57%)	15/420 (3.57%)
Vision blurred ^† 1	10/209 (4.78%)	5/211 (2.37%)	3/28 (10.71%)	18/420 (4.29%)
Gastrointestinal disorders
Abdominal pain ^† 1	29/209 (13.88%)	17/211 (8.06%)	1/28 (3.57%)	47/420 (11.19%)
Abdominal pain upper ^† 1	20/209 (9.57%)	12/211 (5.69%)	3/28 (10.71%)	35/420 (8.33%)
Constipation ^† 1	27/209 (12.92%)	22/211 (10.43%)	3/28 (10.71%)	52/420 (12.38%)
Diarrhoea ^† 1	67/209 (32.06%)	34/211 (16.11%)	9/28 (32.14%)	107/420 (25.48%)
Dry mouth ^† 1	18/209 (8.61%)	6/211 (2.84%)	1/28 (3.57%)	24/420 (5.71%)
Nausea ^† 1	79/209 (37.80%)	57/211 (27.01%)	7/28 (25.00%)	138/420 (32.86%)
Vomiting ^† 1	57/209 (27.27%)	31/211 (14.69%)	3/28 (10.71%)	89/420 (21.19%)
General disorders
Asthenia ^† 1	29/209 (13.88%)	30/211 (14.22%)	4/28 (14.29%)	60/420 (14.29%)
Chest pain ^† 1	12/209 (5.74%)	5/211 (2.37%)	0/28 (0.00%)	17/420 (4.05%)
Chills ^† 1	63/209 (30.14%)	34/211 (16.11%)	3/28 (10.71%)	98/420 (23.33%)
Fatigue ^† 1	79/209 (37.80%)	79/211 (37.44%)	7/28 (25.00%)	161/420 (38.33%)
Influenza like illness ^† 1	17/209 (8.13%)	12/211 (5.69%)	3/28 (10.71%)	31/420 (7.38%)
Oedema peripheral ^† 1	48/209 (22.97%)	17/211 (8.06%)	2/28 (7.14%)	66/420 (15.71%)
Pain ^† 1	14/209 (6.70%)	9/211 (4.27%)	1/28 (3.57%)	23/420 (5.48%)
Pyrexia ^† 1	118/209 (56.46%)	63/211 (29.86%)	10/28 (35.71%)	183/420 (43.57%)
Immune system disorders
Hypersensitivity ^† 1	1/209 (0.48%)	2/211 (0.95%)	2/28 (7.14%)	5/420 (1.19%)
Infections and infestations
Bronchitis ^† 1	12/209 (5.74%)	8/211 (3.79%)	1/28 (3.57%)	21/420 (5.00%)
Cystitis ^† 1	11/209 (5.26%)	2/211 (0.95%)	0/28 (0.00%)	13/420 (3.10%)
Folliculitis ^† 1	12/209 (5.74%)	11/211 (5.21%)	2/28 (7.14%)	25/420 (5.95%)
Influenza ^† 1	17/209 (8.13%)	7/211 (3.32%)	5/28 (17.86%)	28/420 (6.67%)
Nasopharyngitis ^† 1	28/209 (13.40%)	21/211 (9.95%)	4/28 (14.29%)	50/420 (11.90%)
Upper respiratory tract infection ^† 1	16/209 (7.66%)	7/211 (3.32%)	1/28 (3.57%)	24/420 (5.71%)
Urinary tract infection ^† 1	29/209 (13.88%)	7/211 (3.32%)	2/28 (7.14%)	38/420 (9.05%)
Injury, poisoning and procedural complications
Fall ^† 1	6/209 (2.87%)	2/211 (0.95%)	2/28 (7.14%)	10/420 (2.38%)
Tendon rupture ^† 1	0/209 (0.00%)	1/211 (0.47%)	2/28 (7.14%)	3/420 (0.71%)
Investigations
Alanine aminotransferase increased ^† 1	25/209 (11.96%)	12/211 (5.69%)	1/28 (3.57%)	38/420 (9.05%)
Aspartate aminotransferase increased ^† 1	29/209 (13.88%)	8/211 (3.79%)	0/28 (0.00%)	37/420 (8.81%)
Blood alkaline phosphatase increased ^† 1	18/209 (8.61%)	8/211 (3.79%)	3/28 (10.71%)	29/420 (6.90%)
Blood creatine phosphokinase increased ^† 1	8/209 (3.83%)	0/211 (0.00%)	2/28 (7.14%)	10/420 (2.38%)
Blood creatinine increased ^† 1	8/209 (3.83%)	2/211 (0.95%)	2/28 (7.14%)	12/420 (2.86%)
Blood lactate dehydrogenase increased ^† 1	8/209 (3.83%)	2/211 (0.95%)	2/28 (7.14%)	12/420 (2.86%)
Ejection fraction decreased ^† 1	7/209 (3.35%)	2/211 (0.95%)	3/28 (10.71%)	12/420 (2.86%)
Gamma-glutamyltransferase increased ^† 1	6/209 (2.87%)	5/211 (2.37%)	4/28 (14.29%)	14/420 (3.33%)
Neutrophil count decreased ^† 1	7/209 (3.35%)	0/211 (0.00%)	2/28 (7.14%)	9/420 (2.14%)
Weight decreased ^† 1	13/209 (6.22%)	19/211 (9.00%)	0/28 (0.00%)	32/420 (7.62%)
Metabolism and nutrition disorders
Decreased appetite ^† 1	30/209 (14.35%)	28/211 (13.27%)	5/28 (17.86%)	60/420 (14.29%)
Hyponatraemia ^† 1	5/209 (2.39%)	1/211 (0.47%)	2/28 (7.14%)	8/420 (1.90%)
Musculoskeletal and connective tissue disorders
Arthralgia ^† 1	57/209 (27.27%)	68/211 (32.23%)	6/28 (21.43%)	127/420 (30.24%)
Back pain ^† 1	30/209 (14.35%)	34/211 (16.11%)	3/28 (10.71%)	67/420 (15.95%)
Muscle spasms ^† 1	19/209 (9.09%)	7/211 (3.32%)	3/28 (10.71%)	29/420 (6.90%)
Muscular weakness ^† 1	5/209 (2.39%)	4/211 (1.90%)	2/28 (7.14%)	11/420 (2.62%)
Musculoskeletal chest pain ^† 1	14/209 (6.70%)	11/211 (5.21%)	0/28 (0.00%)	25/420 (5.95%)
Musculoskeletal pain ^† 1	12/209 (5.74%)	19/211 (9.00%)	1/28 (3.57%)	31/420 (7.38%)
Myalgia ^† 1	27/209 (12.92%)	28/211 (13.27%)	3/28 (10.71%)	56/420 (13.33%)
Pain in extremity ^† 1	34/209 (16.27%)	38/211 (18.01%)	3/28 (10.71%)	73/420 (17.38%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Melanocytic naevus ^† 1	2/209 (0.96%)	16/211 (7.58%)	0/28 (0.00%)	18/420 (4.29%)
Seborrhoeic keratosis ^† 1	12/209 (5.74%)	22/211 (10.43%)	0/28 (0.00%)	34/420 (8.10%)
Skin papilloma ^† 1	6/209 (2.87%)	46/211 (21.80%)	1/28 (3.57%)	52/420 (12.38%)
Nervous system disorders
Dizziness ^† 1	32/209 (15.31%)	15/211 (7.11%)	1/28 (3.57%)	47/420 (11.19%)
Dysgeusia ^† 1	6/209 (2.87%)	13/211 (6.16%)	2/28 (7.14%)	21/420 (5.00%)
Headache ^† 1	71/209 (33.97%)	63/211 (29.86%)	6/28 (21.43%)	138/420 (32.86%)
Paraesthesia ^† 1	9/209 (4.31%)	12/211 (5.69%)	1/28 (3.57%)	22/420 (5.24%)
Psychiatric disorders
Anxiety ^† 1	12/209 (5.74%)	6/211 (2.84%)	3/28 (10.71%)	21/420 (5.00%)
Depression ^† 1	9/209 (4.31%)	12/211 (5.69%)	1/28 (3.57%)	22/420 (5.24%)
Insomnia ^† 1	11/209 (5.26%)	18/211 (8.53%)	1/28 (3.57%)	30/420 (7.14%)
Respiratory, thoracic and mediastinal disorders
Cough ^† 1	51/209 (24.40%)	46/211 (21.80%)	3/28 (10.71%)	97/420 (23.10%)
Dyspnoea ^† 1	16/209 (7.66%)	19/211 (9.00%)	1/28 (3.57%)	36/420 (8.57%)
Epistaxis ^† 1	21/209 (10.05%)	11/211 (5.21%)	1/28 (3.57%)	33/420 (7.86%)
Oropharyngeal pain ^† 1	24/209 (11.48%)	11/211 (5.21%)	0/28 (0.00%)	35/420 (8.33%)
Skin and subcutaneous tissue disorders
Actinic keratosis ^† 1	12/209 (5.74%)	15/211 (7.11%)	1/28 (3.57%)	27/420 (6.43%)
Alopecia ^† 1	19/209 (9.09%)	61/211 (28.91%)	0/28 (0.00%)	80/420 (19.05%)
Dermatitis acneiform ^† 1	21/209 (10.05%)	8/211 (3.79%)	0/28 (0.00%)	29/420 (6.90%)
Dry skin ^† 1	30/209 (14.35%)	33/211 (15.64%)	3/28 (10.71%)	65/420 (15.48%)
Eczema ^† 1	19/209 (9.09%)	8/211 (3.79%)	2/28 (7.14%)	29/420 (6.90%)
Erythema ^† 1	24/209 (11.48%)	16/211 (7.58%)	1/28 (3.57%)	41/420 (9.76%)
Hair texture abnormal ^† 1	0/209 (0.00%)	18/211 (8.53%)	0/28 (0.00%)	18/420 (4.29%)
Hyperhidrosis ^† 1	14/209 (6.70%)	9/211 (4.27%)	1/28 (3.57%)	23/420 (5.48%)
Hyperkeratosis ^† 1	18/209 (8.61%)	79/211 (37.44%)	3/28 (10.71%)	97/420 (23.10%)
Night sweats ^† 1	12/209 (5.74%)	5/211 (2.37%)	1/28 (3.57%)	17/420 (4.05%)
Palmar-plantar erythrodysaesthesia syndrome ^† 1	11/209 (5.26%)	39/211 (18.48%)	2/28 (7.14%)	50/420 (11.90%)
Pruritus ^† 1	28/209 (13.40%)	30/211 (14.22%)	2/28 (7.14%)	59/420 (14.05%)
Rash ^† 1	62/209 (29.67%)	45/211 (21.33%)	3/28 (10.71%)	109/420 (25.95%)
Rash maculo-papular ^† 1	13/209 (6.22%)	8/211 (3.79%)	3/28 (10.71%)	24/420 (5.71%)
Skin lesion ^† 1	13/209 (6.22%)	10/211 (4.74%)	0/28 (0.00%)	23/420 (5.48%)
Vascular disorders
Hot flush ^† 1	8/209 (3.83%)	5/211 (2.37%)	2/28 (7.14%)	15/420 (3.57%)
Hypertension ^† 1	51/209 (24.40%)	33/211 (15.64%)	2/28 (7.14%)	85/420 (20.24%)
1 Term from vocabulary, MedDRA (19.0) † Indicates events were collected by systematic assessment

Limitations and Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

GSK agreements may vary with individual investigators, but will not prohibit any investigator from publishing. GSK supports the publication of results from all centers of a multi-center trial but requests that reports based on single-site data not precede the primary publication of the entire clinical trial.

Results Point of Contact

Layout table for Results Point of Contact information

Name/Title:	Study Director
Organization:	Novartis Pharmaceuticals
Phone:	862-778-8300
EMail:	Novartis.email@novartis.com

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Schadendorf D, Robert C, Dummer R, Flaherty KT, Tawbi HA, Menzies AM, Banerjee H, Lau M, Long GV. Pyrexia in patients treated with dabrafenib plus trametinib across clinical trials in BRAF-mutant cancers. Eur J Cancer. 2021 Aug;153:234-241. doi: 10.1016/j.ejca.2021.05.005. Epub 2021 Jul 2.

Syeda MM, Wiggins JM, Corless BC, Long GV, Flaherty KT, Schadendorf D, Nathan PD, Robert C, Ribas A, Davies MA, Grob JJ, Gasal E, Squires M, Marker M, Garrett J, Brase JC, Polsky D. Circulating tumour DNA in patients with advanced melanoma treated with dabrafenib or dabrafenib plus trametinib: a clinical validation study. Lancet Oncol. 2021 Mar;22(3):370-380. doi: 10.1016/S1470-2045(20)30726-9. Epub 2021 Feb 12.

Robert C, Grob JJ, Stroyakovskiy D, Karaszewska B, Hauschild A, Levchenko E, Chiarion Sileni V, Schachter J, Garbe C, Bondarenko I, Gogas H, Mandala M, Haanen JBAG, Lebbe C, Mackiewicz A, Rutkowski P, Nathan PD, Ribas A, Davies MA, Flaherty KT, Burgess P, Tan M, Gasal E, Voi M, Schadendorf D, Long GV. Five-Year Outcomes with Dabrafenib plus Trametinib in Metastatic Melanoma. N Engl J Med. 2019 Aug 15;381(7):626-636. doi: 10.1056/NEJMoa1904059. Epub 2019 Jun 4.

Long GV, Grob JJ, Nathan P, Ribas A, Robert C, Schadendorf D, Lane SR, Mak C, Legenne P, Flaherty KT, Davies MA. Factors predictive of response, disease progression, and overall survival after dabrafenib and trametinib combination treatment: a pooled analysis of individual patient data from randomised trials. Lancet Oncol. 2016 Dec;17(12):1743-1754. doi: 10.1016/S1470-2045(16)30578-2. Epub 2016 Nov 16.

Long GV, Stroyakovskiy D, Gogas H, Levchenko E, de Braud F, Larkin J, Garbe C, Jouary T, Hauschild A, Grob JJ, Chiarion-Sileni V, Lebbe C, Mandala M, Millward M, Arance A, Bondarenko I, Haanen JB, Hansson J, Utikal J, Ferraresi V, Kovalenko N, Mohr P, Probachai V, Schadendorf D, Nathan P, Robert C, Ribas A, DeMarini DJ, Irani JG, Swann S, Legos JJ, Jin F, Mookerjee B, Flaherty K. Dabrafenib and trametinib versus dabrafenib and placebo for Val600 BRAF-mutant melanoma: a multicentre, double-blind, phase 3 randomised controlled trial. Lancet. 2015 Aug 1;386(9992):444-51. doi: 10.1016/S0140-6736(15)60898-4. Epub 2015 May 31.

Schadendorf D, Amonkar MM, Stroyakovskiy D, Levchenko E, Gogas H, de Braud F, Grob JJ, Bondarenko I, Garbe C, Lebbe C, Larkin J, Chiarion-Sileni V, Millward M, Arance A, Mandala M, Flaherty KT, Nathan P, Ribas A, Robert C, Casey M, DeMarini DJ, Irani JG, Aktan G, Long GV. Health-related quality of life impact in a randomised phase III study of the combination of dabrafenib and trametinib versus dabrafenib monotherapy in patients with BRAF V600 metastatic melanoma. Eur J Cancer. 2015 May;51(7):833-40. doi: 10.1016/j.ejca.2015.03.004. Epub 2015 Mar 17.

Menzies AM, Ashworth MT, Swann S, Kefford RF, Flaherty K, Weber J, Infante JR, Kim KB, Gonzalez R, Hamid O, Schuchter L, Cebon J, Sosman JA, Little S, Sun P, Aktan G, Ouellet D, Jin F, Long GV, Daud A. Characteristics of pyrexia in BRAFV600E/K metastatic melanoma patients treated with combined dabrafenib and trametinib in a phase I/II clinical trial. Ann Oncol. 2015 Feb;26(2):415-21. doi: 10.1093/annonc/mdu529. Epub 2014 Nov 18.

Long GV, Stroyakovskiy D, Gogas H, Levchenko E, de Braud F, Larkin J, Garbe C, Jouary T, Hauschild A, Grob JJ, Chiarion Sileni V, Lebbe C, Mandala M, Millward M, Arance A, Bondarenko I, Haanen JB, Hansson J, Utikal J, Ferraresi V, Kovalenko N, Mohr P, Probachai V, Schadendorf D, Nathan P, Robert C, Ribas A, DeMarini DJ, Irani JG, Casey M, Ouellet D, Martin AM, Le N, Patel K, Flaherty K. Combined BRAF and MEK inhibition versus BRAF inhibition alone in melanoma. N Engl J Med. 2014 Nov 13;371(20):1877-88. doi: 10.1056/NEJMoa1406037. Epub 2014 Sep 29.

Layout table for additonal information

Responsible Party:	Novartis ( Novartis Pharmaceuticals )
ClinicalTrials.gov Identifier:	NCT01584648
Other Study ID Numbers:	115306 2011-006087-49 ( EudraCT Number ) CDRB436B2301 ( Other Identifier: Novartis )
First Submitted:	April 23, 2012
First Posted:	April 25, 2012
Results First Submitted:	April 10, 2014
Results First Posted:	August 15, 2014
Last Update Posted:	February 17, 2021

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