A Study Comparing GSK2118436 to Dacarbazine (DTIC) in Previously Untreated Subjects With BRAF Mutation Positive Advanced (Stage III) or Metastatic (Stage IV) Melanoma

• ClinicalTrials.gov Identifier: NCT01227889
• Recruitment Status: Completed
• First Posted: October 25, 2010
• Results First Posted: May 16, 2014
• Last Update Posted: October 4, 2017
• Sponsor: GlaxoSmithKline
• Information provided by (Responsible Party): GlaxoSmithKline

• Study Type: Interventional
• Study Design: Allocation: Randomized; Intervention Model: Crossover Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Cancer
• Interventions: Drug: GSK2118436; Drug: Dacarbazine (DTIC)
• Enrollment: 251

Participant Flow

Recruitment Details	This was a Phase III randomized, open-label study to compare GSK2118436 to Dacarbazine (DTIC) in previously untreated participants (par.) with BRAF mutation positive advanced (Stage III) or metastatic (Stage IV) melanoma. This study was conducted at 70 centers in 12 countries.
Pre-assignment Details	The study has 2 phases: Randomized and Crossover Phase. In Randomized Phase, a total of 250 par. were randomized in 3:1 to receive either oral dabrafenib 150 mg twice daily (BID) or intravenous DTIC 1000 milligram/meter square. Par. in DTIC arm with disease progression were considered for crossover to dabrafenib arm in Crossover Phase

Arm/Group Title	GSK2118436 150 mg BID	DTIC 1000 mg/m^2 in RP; GSK2118436 in Crossover Phase
Arm/Group Description	Participants (par.) were randomly assigned to receive oral GSK2118436 150 milligrams (mg) twice a day (BID). Dose reductions were permitted based on the severity of the hematological toxicity. Stopping recommendations for study treatment were also provided for cases of reoccurring skin toxicity, cardiovascular complication or abnormalities, and liver abnormalities. Participants continued on treatment until disease progression (DP), death, the occurrence of an unacceptable adverse event (AE), or withdrawal from the study. Participants who experienced investigator-reported DP but were benefitting from study treatment were permitted to continue GSK2118436 treatment upon approval of the GlaxoSmithKline Medical Monitor.	In the RP, par. received intravenous (IV) Dacarbazine (DTIC) 1000 mg per meters squared (mg/m^2) every 3 weeks. Dose reductions were permitted based on the severity of the hematological toxicity. Stopping recommendations for study treatment were also provided for cases of reoccurring skin toxicity, cardiovascular complication or abnormalities, and liver abnormalities. Par. continued on treatment until DP, death, the occurrence of an unacceptable AE, or withdrawal from the study. Par. who received DTIC in the RP and experienced DP had the option, at the discretion of the Investigator, of receiving GSK2118436 150 mg BID in the Crossover Phase. Par. who permanently discontinued DTIC treatment due to an AE, withdrawal of consent, or for any reason other than DP were not eligible for crossover to GSK2118436. Crossover par. continued on GSK2118436 until further DP was noted. After DP on GSK2118436, par. were followed for response, progression, survival, and further anti-cancer therapy.
Period Title: Randomized Phase (RP)
Started	187	63
Completed	0	0
Not Completed	187	63
Reason Not Completed
Adverse Event	13	0
Physician Decision	13	5
Progressive Disease	135	52
Study terminated by sponsor	10	0
Missing	1	3
Withdrawal by Subject	15	3
Period Title: Crossover Phase
Started	0	37 [1]
Completed	0	0
Not Completed	0	37
Reason Not Completed
Adverse Event	0	1
Physician Decision	0	3
Progressive Disease	0	31
Study Terminated By Sponsor	0	1
Withdrawal by Subject	0	1
[1] As of the data cut on December 18, 2012, 36 of 63 participants crossed over from DTIC to GSK2118436.

Baseline Characteristics

Arm/Group Title		GSK2118436 150 mg BID	DTIC 1000 mg/m^2 in RP; GSK2118436 in Crossover Phase	Total
Arm/Group Description		Participants were randomly assigned to receive oral GSK2118436 150 mg BID. Dose reductions were permitted based on the severity of the hematological toxicity. Stopping recommendations for study treatment were also provided for cases of reoccurring skin toxicity, cardiovascular complication or abnormalities, and liver abnormalities. Participants continued on treatment until DP, death, the occurrence of an unacceptable AE, or withdrawal from the study. Participants who experienced investigator-reported DP but were benefitting from study treatment were permitted to continue GSK2118436 treatment upon approval of the GlaxoSmithKline Medical Monitor.	In the RP, par. received IV DTIC 1000 mg/m^2 every 3 weeks. Dose reductions were permitted based on the severity of the hematological toxicity. Stopping recommendations for study treatment were also provided for cases of reoccurring skin toxicity, cardiovascular complication or abnormalities, and liver abnormalities. Par. continued on treatment until DP, death, the occurrence of an unacceptable AE, or withdrawal from the study. Par. who received DTIC in the RP and experienced DP had the option, at the discretion of the Investigator, of receiving GSK2118436 150 mg BID in the Crossover Phase. Par. who permanently discontinued DTIC treatment due to an AE, withdrawal of consent, or for any reason other than DP were not eligible for crossover to GSK2118436. Crossover par. continued on GSK2118436 until further DP was noted. After DP on GSK2118436, par. were followed for response, progression, survival, and further anti-cancer therapy.	Total of all reporting groups
Overall Number of Baseline Participants		187	63	250
Baseline Analysis Population Description		[Not Specified]
Age, Continuous; Mean (Standard Deviation); Unit of measure: Years
	Number Analyzed	187 participants	63 participants	250 participants
		53.5 (13.76)	51.6 (14.22)	53.0 (13.87)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	187 participants	63 participants	250 participants
	Female	75 40.1%	26 41.3%	101 40.4%
	Male	112 59.9%	37 58.7%	149 59.6%
Race/Ethnicity, Customized; Measure Type: Number; Unit of measure: Participants	Number Analyzed	187 participants	63 participants	250 participants
White		186	63	249
Missing		1	0	1

Outcome Measures

1. Primary Outcome

Title	Progression-free Survival (PFS) as Assessed by the Investigator
Description	PFS is defined as the interval of time between the date of randomization and the earlier of the date of disease progression or the date of death due to any cause. Disease progression was based on radiographic or photographic evidence, and assessments were made by the investigator according to Response Evaluation Criteria in Solid Tumors (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 (e.g., percent change from nadir, where nadir is defined as the smallest sum of diameters recorded since treatment start). In addition, the sum must have an absolute increase from nadir of 5 millimeters (mm). For participants who did not progress or die, PFS was censored at the date of last contact. Data are presented as median and 96% confidence interval.
Time Frame	Time interval between the date of randomization and the earlier of the date of disease progression or the date of death due to any cause (up to 9.9 months)

Outcome Measure Data

Analysis Population Description

Intent-to-Treat (ITT) Population: all randomized participants regardless of whether or not treatment was administered

Arm/Group Title	GSK2118436 150 mg BID	DTIC 1000 mg/m^2 in RP
Arm/Group Description:	Participants were randomly assigned to receive oral GSK2118436 150 milligrams (mg) twice a day (BID). Dose reductions were permitted based on the severity of the hematological toxicity. Stopping recommendations for study treatment were also provided for cases of reoccurring skin toxicity, cardiovascular complication or abnormalities, and liver abnormalities. Participants continued on treatment until disease progression (DP), death, the occurrence of an unacceptable adverse event (AE), or withdrawal from the study. Participants who experienced investigator-reported DP but were benefitting from study treatment were permitted to continue GSK2118436 treatment upon approval of the GlaxoSmithKline Medical Monitor.	In the RP, participants received intravenous (IV) Dacarbazine (DTIC) 1000 milligrams per meters squared (mg/m^2) every 3 weeks. Dose reductions were permitted based on the severity of the hematological toxicity. Stopping recommendations for study treatment were also provided for cases of reoccurring skin toxicity, cardiovascular complication or abnormalities, and liver abnormalities. Participants continued on treatment until DP, death, the occurrence of an unacceptable AE, or withdrawal from the study.
Overall Number of Participants Analyzed	187	63
Median (95% Confidence Interval); Unit of Measure: Months
	6.9; (5.5 to 9.0)	2.7; (1.4 to 3.2)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	GSK2118436 150 mg BID, DTIC 1000 mg/m^2 in RP
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Statistical Test of Hypothesis	P-Value	<0.0001
	Comments	The p value from a stratified log-rank test was adjusted for disease stage at screening.
	Method	Log Rank
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.40
	Confidence Interval	(2-Sided) 95%; 0.26 to 0.60
	Estimation Comments	HRs were estimated using a Pike estimator. HR from a stratified log-rank test was adjusted for disease stage at screening.

2. Primary Outcome

Title	Progression-free Survival (PFS) as Assessed by an Independent Radiologist: Randomized Phase
Description	PFS is defined as the interval of time between the date of randomization and the earlier of the date of disease progression or the date of death due to any cause. Disease progression was based on radiographic or photographic evidence, and assessments were made by an independent radiologist 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 (e.g., percent change from nadir, where nadir is defined as the smallest sum of diameters recorded since treatment start). In addition, the sum must have an absolute increase from nadir of 5 mm. For participants who did not progress or die, PFS was censored at the date of last contact.
Time Frame	Time interval between the date of randomization and the earlier of the date of disease progression or the date of death due to any cause (up to 9.9 months)

Outcome Measure Data

Analysis Population Description

ITT Population

Arm/Group Title	GSK2118436 150 mg BID	DTIC 1000 mg/m^2 in RP
Arm/Group Description:	Participants were randomly assigned to receive oral GSK2118436 150 mg BID. Dose reductions were permitted based on the severity of the hematological toxicity. Stopping recommendations for study treatment were also provided for cases of reoccurring skin toxicity, cardiovascular complication or abnormalities, and liver abnormalities. Participants continued on treatment until DP, death, the occurrence of an unacceptable AE, or withdrawal from the study. Participants who experienced investigator-reported DP but were benefitting from study treatment were permitted to continue GSK2118436 treatment upon approval of the GlaxoSmithKline Medical Monitor.	In the RP, participants received IV DTIC 1000 mg/m^2 every 3 weeks. Dose reductions were permitted based on the severity of the hematological toxicity. Stopping recommendations for study treatment were also provided for cases of reoccurring skin toxicity, cardiovascular complication or abnormalities, and liver abnormalities. Participants continued on treatment until DP, death, the occurrence of an unacceptable AE, or withdrawal from the study.
Overall Number of Participants Analyzed	187	63
Median (95% Confidence Interval); Unit of Measure: Months
	6.7; (5.0 to 6.9)	2.9; (1.7 to 4.9)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	GSK2118436 150 mg BID, DTIC 1000 mg/m^2 in RP
	Comments	[Not Specified]
	Type of Statistical Test	Superiority or Other
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.35
	Confidence Interval	(2-Sided) 95%; 0.20 to 0.61
	Estimation Comments	HRs were estimated using a Pike estimator. HR was adjusted for disease stage at screening.

3. Secondary Outcome

Title	Overall Survival
Description	Overall survival is defined as the interval of time between the date of randomization and the date of death due to any cause. For participants who did not die, overall survival was censored at the date of last contact.
Time Frame	Time interval between the date of randomization and the date of death due to any cause (up to 22.1 months)

Outcome Measure Data

Analysis Population Description

ITT Population

Arm/Group Title	GSK2118436 150 mg BID	DTIC 1000 mg/m^2 in RP
Arm/Group Description:	Participants were randomly assigned to receive oral GSK2118436 150 mg BID. Dose reductions were permitted based on the severity of the hematological toxicity. Stopping recommendations for study treatment were also provided for cases of reoccurring skin toxicity, cardiovascular complication or abnormalities, and liver abnormalities. Participants continued on treatment until DP, death, the occurrence of an unacceptable AE, or withdrawal from the study. Participants who experienced investigator-reported DP but were benefitting from study treatment were permitted to continue GSK2118436 treatment upon approval of the GlaxoSmithKline Medical Monitor.	In the RP, participants received IV DTIC 1000 mg/m^2 every 3 weeks. Dose reductions were permitted based on the severity of the hematological toxicity. Stopping recommendations for study treatment were also provided for cases of reoccurring skin toxicity, cardiovascular complication or abnormalities, and liver abnormalities. Participants. continued on treatment until DP, death, the occurrence of an unacceptable AE, or withdrawal from the study.
Overall Number of Participants Analyzed	187	63
Median (95% Confidence Interval); Unit of Measure: Months
	20.0; (16.7 to 24.2)	15.6; (11.9 to 21.2)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	GSK2118436 150 mg BID, DTIC 1000 mg/m^2 in RP
	Comments	[Not Specified]
	Type of Statistical Test	Other
	Comments	[Not Specified]
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.82
	Confidence Interval	(2-Sided) 95%; 0.57 to 1.18
	Estimation Comments	HRs were estimated using a Pike estimator. HR was adjusted for disease stage at screening.

4. Secondary Outcome

Title	Number of Participants With a Best Overall Response of Confirmed Complete Response (CR) or Confirmed Partial Response (PR) as Assessed by the Investigator: Randomized Phase
Description	A participant was defined as a responder if he/she achieved either a CR (the disappearance of all target lesions. Any pathological lymph nodes must be <10 mm in the short axis.) or PR (at least a 30% decrease in the sum of the diameters of target lesions, taking as a reference, the Baseline sum of the diameters [e.g., percent change from Baseline]). Response was evaluated by an investigator per RECIST, version 1.1. A participant without a post-Baseline assessment of response was considered a non-responder. Confirmation, per RECIST version 1.1, requires a confimatory disease assessment of CR or PR at least 28 days after the initial disease assessment of CR or PR.
Time Frame	From randomization until the first documented evidence of a confirmed complete response or partial response (median of 6.6 weeks)

Outcome Measure Data

Analysis Population Description

ITT Population

Arm/Group Title	GSK2118436 150 mg BID	DTIC 1000 mg/m^2 in RP
Arm/Group Description:	Participants were randomly assigned to receive oral GSK2118436 150 mg BID. Dose reductions were permitted based on the severity of the hematological toxicity. Stopping recommendations for study treatment were also provided for cases of reoccurring skin toxicity, cardiovascular complication or abnormalities, and liver abnormalities. Participants continued on treatment until disease DP, death, the occurrence of an unacceptable adverse AE, or withdrawal from the study. Participants who experienced investigator-reported DP but were benefitting from study treatment were permitted to continue GSK2118436 treatment upon approval of the GlaxoSmithKline Medical Monitor.	In the RP, participants received IV DTIC 1000 mg/m^2 every 3 weeks. Dose reductions were permitted based on the severity of the hematological toxicity. Stopping recommendations for study treatment were also provided for cases of reoccurring skin toxicity, cardiovascular complication or abnormalities, and liver abnormalities. Participants continued on treatment until DP, death, the occurrence of an unacceptable AE, or withdrawal from the study.
Overall Number of Participants Analyzed	187	63
Measure Type: Number; Unit of Measure: participants
CR	26	4
PR	86	11

5. Secondary Outcome

Title	Number of Participants With a Best Overall Response of Confirmed CR or PR as Assessed by an Independent Radiologist: Randomized Phase
Description	A participant was defined as a responder if he/she achieved either a CR (the disappearance of all target lesions. Any pathological lymph nodes must be <10 mm in the short axis.) or PR (at least a 30% decrease in the sum of the diameters of target lesions, taking as a reference, the Baseline sum of the diameters [e.g., percent change from Baseline]). Response was evaluated by an independent radiologist per RECIST, version 1.1. A participant without a post-Baseline assessment of response was considered a non-responder. Confirmation, per RECIST version 1.1, requires a confimatory disease assessment of CR or PR at least 28 days after the initial disease assessment of CR or PR.
Time Frame	From randomization until the first documented evidence of a confirmed complete response or partial response (median of 12.0 weeks)

Outcome Measure Data

Analysis Population Description

ITT Population

Arm/Group Title	GSK2118436 150 mg BID	DTIC 1000 mg/m^2 in RP
Arm/Group Description:	Participants were randomly assigned to receive oral GSK2118436 150 mg BID. Dose reductions were permitted based on the severity of the hematological toxicity. Stopping recommendations for study treatment were also provided for cases of reoccurring skin toxicity, cardiovascular complication or abnormalities, and liver abnormalities. Participants continued on treatment until disease DP, death, the occurrence of an unacceptable AE, or withdrawal from the study. Participants who experienced investigator-reported DP but were benefitting from study treatment were permitted to continue GSK2118436 treatment upon approval of the GlaxoSmithKline Medical Monitor.	In the RP, participants received IV DTIC 1000 mg/m^2 every 3 weeks. Dose reductions were permitted based on the severity of the hematological toxicity. Stopping recommendations for study treatment were also provided for cases of reoccurring skin toxicity, cardiovascular complication or abnormalities, and liver abnormalities. Participants continued on treatment until DP, death, the occurrence of an unacceptable AE, or withdrawal from the study.
Overall Number of Participants Analyzed	187	63
Measure Type: Number; Unit of Measure: participants
CR	6	1
PR	87	3

6. Secondary Outcome

Title	Duration of Response as Assessed by the Investigator: Randomized Phase
Description	Duration of response for participants with either a CR (the disappearance of all target lesions. Any pathological lymph nodes must be <10 mm in the short axis.) or PR (at least a 30% decrease in the sum of the diameters of target lesions, taking as a reference, the Baseline sum of the diameters [e.g., percent change from Baseline]) was defined as the time from the first documented evidence of a PR or CR until the first documented sign of 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, taking as a reference, the smallest sum of diameters recorded since the treatment started (e.g., percent change from nadir, where nadir is defined as the smallest sum of diameters recorded since treatment start). In addition, the sum must have an absolute increase from nadir of 5 mm.
Time Frame	Time from the first documented evidence of PR or CR until the first documented sign of disease progression or death due to any cause (up to 65.6 weeks)

Outcome Measure Data

Analysis Population Description

ITT Population. Only participants with a confirmed CR or PR were assessed for duration of response.

Arm/Group Title	GSK2118436 150 mg BID	DTIC 1000 mg/m^2 in RP
Arm/Group Description:	Participants were randomly assigned to receive oral GSK2118436 150 mg BID. Dose reductions were permitted based on the severity of the hematological toxicity. Stopping recommendations for study treatment were also provided for cases of reoccurring skin toxicity, cardiovascular complication or abnormalities, and liver abnormalities. Participants continued on treatment until DP, death, the occurrence of an unacceptable AE, or withdrawal from the study. Participants who experienced investigator-reported DP but were benefitting from study treatment were permitted to continue GSK2118436 treatment upon approval of the GlaxoSmithKline Medical Monitor.	In the RP, participants received IV DTIC 1000 mg/m^2 every 3 weeks. Dose reductions were permitted based on the severity of the hematological toxicity. Stopping recommendations for study treatment were also provided for cases of reoccurring skin toxicity, cardiovascular complication or abnormalities, and liver abnormalities. Participants continued on treatment until DP, death, the occurrence of an unacceptable AE, or withdrawal from the study.
Overall Number of Participants Analyzed	112	15
Median (95% Confidence Interval); Unit of Measure: Months
	9.2; (7.4 to 11.9)	8.2; (3.5 to 18.3)

7. Secondary Outcome

Title	Duration of Response as Assessed by an Independent Radiologist: Randomized Phase
Description	Duration of response for participants with either a CR (the disappearance of all target lesions. Any pathological lymph nodes must be <10 mm in the short axis.) or PR (at least a 30% decrease in the sum of the diameters of target lesions, taking as a reference, the Baseline sum of the diameters [e.g., percent change from Baseline]) was defined as the time from the first documented evidence of a PR or CR until the first documented sign of 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, taking as a reference, the smallest sum of diameters recorded since the treatment started (e.g., percent change from nadir, where nadir is defined as the smallest sum of diameters recorded since treatment start). In addition, the sum must have an absolute increase from nadir of 5 mm. NA indicates that data is not available.
Time Frame	Time from the first documented evidence of PR or CR until the first documented sign of disease progression or death due to any cause (up to 7.4 months)

Outcome Measure Data

Analysis Population Description

ITT Population. Only participants with a confirmed CR or PR were assessed for duration of response.

Arm/Group Title	GSK2118436 150 mg BID	DTIC 1000 mg/m^2 in RP
Arm/Group Description:	Participants were randomly assigned to receive oral GSK2118436 150 mg BID. Dose reductions were permitted based on the severity of the hematological toxicity. Stopping recommendations for study treatment were also provided for cases of reoccurring skin toxicity, cardiovascular complication or abnormalities, and liver abnormalities. Participants continued on treatment until DP, death, the occurrence of an unacceptable AE, or withdrawal from the study. Participants who experienced investigator-reported DP but were benefitting from study treatment were permitted to continue GSK2118436 treatment upon approval of the GlaxoSmithKline Medical Monitor.	In the RP, participants received IV DTIC 1000 mg/m^2 every 3 weeks. Dose reductions were permitted based on the severity of the hematological toxicity. Stopping recommendations for study treatment were also provided for cases of reoccurring skin toxicity, cardiovascular complication or abnormalities, and liver abnormalities. Participants continued on treatment until DP, death, the occurrence of an unacceptable AE, or withdrawal from the study.
Overall Number of Participants Analyzed	93	4
Median (95% Confidence Interval); Unit of Measure: Months
	5.5; (5.0 to 6.7)	NA [1]; (NA to NA)

[1]

Median duration of response could not be calculated because there were not enough participants with a CR or PR.

8. Secondary Outcome

Title	Progression-free Survival (PFS2) as Assessed by the Investigator: Crossover Phase
Description	PFS2 is defined as the time from the first dose of GSK2118436, in participants randomized to DTIC who crossed over to GSK2118436 after initial progression, to the earliest date of radiographic or photographic disease progression or death due to any cause. Disease progression 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 (e.g., percent change from nadir, where nadir is defined as the smallest sum of diameters recorded since treatment start). In addition, the sum must have an absolute increase from nadir of 5 mm. For participants who did not progress or die, PFS was censored at the date of last contact.
Time Frame	Time from first dose of GSK2118436 in participants who crossover after initial progression to the earliest date of radiographical or photographical PD or death due to any cause (up to 6.4 months)

Outcome Measure Data

Analysis Population Description

Crossover Treatment Population: the subset of participants who were randomized to the DTIC arm, and who elected at the point of disease progression to receive GSK2118436. Only participants who received at least one dose of GSK2118436 were included in the Crossover Treatment Population.

Arm/Group Title	GSK25118436 in Crossover Phase
Arm/Group Description:	Participants who received DTIC in the RP and experienced DP had the option, at the discretion of the Investigator, of receiving GSK2118436 150 mg BID in the Crossover Phase. Participants who permanently discontinued DTIC treatment due to an AE, withdrawal of consent, or for any reason other than DP were not eligible for crossover to GSK2118436. Crossover participants continued on GSK2118436 until further DP was noted. After DP on GSK2118436, participants were followed for response, progression, survival, and further anti-cancer therapy.
Overall Number of Participants Analyzed	37
Median (95% Confidence Interval); Unit of Measure: Months
	4.3; (4.1 to 6.1)

9. Secondary Outcome

Title	Number of Participants With a Best Overall Response of Confirmed Complete Response (CR) or Confirmed Partial Response (PR) as Assessed by the Investigator: Crossover Phase
Description	A participant was defined as a responder if he/she achieved either a CR (the disappearance of all target lesions. Any pathological lymph nodes must be <10 mm in the short axis.) or PR (at least a 30% decrease in the sum of the diameters of target lesions, taking as a reference, the Baseline sum of the diameters [e.g., percent change from Baseline]). Response was evaluated by an investigator per RECIST, version 1.1. A participant without a post-Baseline assessment of response was considered a non-responder. Confirmation, per RECIST version 1.1, requires a confimatory disease assessment of CR or PR at least 28 days after the initial disease assessment of CR or PR.
Time Frame	From randomization until the first documented evidence of a confirmed complete response or partial response (up to 6.4 months)

Outcome Measure Data

Analysis Population Description

Crossover Treatment Population. At the time data were analyzed for overall response, only 37 participants had crossed over from DTIC treatment to GSK25118436 treatment.

Arm/Group Title	GSK25118436 in Crossover Phase
Arm/Group Description:	Participants who received DTIC in the RP and experienced DP had the option, at the discretion of the Investigator, of receiving GSK2118436 150 mg BID in the Crossover Phase. Participants who permanently discontinued DTIC treatment due to an AE, withdrawal of consent, or for any reason other than DP were not eligible for crossover to GSK2118436. Crossover participants continued on GSK2118436 until further DP was noted. After DP on GSK2118436, participants were followed for response, progression, survival, and further anti-cancer therapy.
Overall Number of Participants Analyzed	37
Measure Type: Number; Unit of Measure: participants
CR	0
PR	12

10. Secondary Outcome

Title	Duration of Response as Assessed by the Investigator: Crossover Phase
Description	Duration of response for participants with either a CR (the disappearance of all target lesions. Any pathological lymph nodes must be <10 mm in the short axis.) or PR (at least a 30% decrease in the sum of the diameters of target lesions, taking as a reference, the Baseline sum of the diameters [e.g., percent change from Baseline]) was defined as the time from the first documented evidence of a PR or CR until the first documented sign of 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, taking as a reference, the smallest sum of diameters recorded since the treatment started (e.g., percent change from nadir, where nadir is defined as the smallest sum of diameters recorded since treatment start). In addition, the sum must have an absolute increase from nadir of 5 mm.
Time Frame	Time from the first documented evidence of PR or CR until the first documented sign of disease progression or death due to any cause (up to 6.4 months)

Outcome Measure Data

Analysis Population Description

Crossover Population. Only participants with a confirmed CR or PR were assessed for duration of response.

Arm/Group Title	GSK25118436 in Crossover Phase
Arm/Group Description:	Participants who received DTIC in the RP and experienced DP had the option, at the discretion of the Investigator, of receiving GSK2118436 150 mg BID in the Crossover Phase. Participants who permanently discontinued DTIC treatment due to an AE, withdrawal of consent, or for any reason other than DP were not eligible for crossover to GSK2118436. Crossover participants continued on GSK2118436 until further DP was noted. After DP on GSK2118436, participants were followed for response, progression, survival, and further anti-cancer therapy.
Overall Number of Participants Analyzed	12
Median (95% Confidence Interval); Unit of Measure: Months
	4.4; (2.5 to 6.2)

11. Secondary Outcome

Title	Number of Participants With Non-melanoma Skin Lesions: Randomized Phase
Description	Dermatological examinations were performed by the investigator, or at the discretion of the investigator, referred to a dermatologist. The number of participants with non-melanoma skin lessions was assessed from the time of Screening until study completion or discontinuation from the study for any reason.
Time Frame	From Screening until study completion or discontinuation from the study (up to 9.9 months)

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	GSK2118436 150 mg BID	DTIC 1000 mg/m^2 in RP
Arm/Group Description:	Participants were randomly assigned to receive oral GSK2118436 150 mg BID. Dose reductions were permitted based on the severity of the hematological toxicity. Stopping recommendations for study treatment were also provided for cases of reoccurring skin toxicity, cardiovascular complication or abnormalities, and liver abnormalities. Participants continued on treatment until DP, death, the occurrence of an unacceptable AE, or withdrawal from the study. Participants who experienced investigator-reported DP but were benefitting from study treatment were permitted to continue GSK2118436 treatment upon approval of the GlaxoSmithKline Medical Monitor.	In the RP, participants received IV DTIC 1000 mg/m^2 every 3 weeks. Dose reductions were permitted based on the severity of the hematological toxicity. Stopping recommendations for study treatment were also provided for cases of reoccurring skin toxicity, cardiovascular complication or abnormalities, and liver abnormalities. Participants continued on treatment until DP, death, the occurrence of an unacceptable AE, or withdrawal from the study.
Overall Number of Participants Analyzed	187	59
Measure Type: Number; Unit of Measure: participants
Number of Subjects with Event	14	0
Number of Events	24	0

12. Secondary Outcome

Title	Agreement Rate for V600E Mutation Validation of the BRAF Mutation Assay
Description	Analytical and clinical validation of the companion diagnostic (cDx) assay was performed to determine the extent of agreement between the bioMerieux cDx assay (THxID BRAF Assay) and the Clinical Trial Assay (CTA) to detect BRAF mutations to determine participant eligibility into the study. Skin tissue samples collected at the Screening visit were used for this analysis. Multiple specimen per participant were analyzed.
Time Frame	Screening

Outcome Measure Data

Analysis Population Description

V600E positive participants screened for BREAK-3 study

Arm/Group Title	All Screened Participants
Arm/Group Description:	Specimens were tested for V600E mutations to determine trial eligibility with the CTA were retested with the THxID BRAF test. The analytical agreement between the THxID BRAF and the CTA was evaluated for both mutation positive and mutation negative specimens from all sites.
Overall Number of Participants Analyzed	734
Measure Type: Number; Number (95% Confidence Interval); Unit of Measure: Percent agreement
Agreement for V600E	96.70; (93.6 to 98.3)
Agreement for V600K	90.00; (78.6 to 95.7)
Agreement for mutation negative	95.00; (91.6 to 97.0)
Agreement for overall	94.90; (92.7 to 96.4)

Adverse Events

Time Frame	Serious adverse events (SAEs) and non-serious AEs were collected from the first dose of investigational product to the end of the study. The total duration of the study including a long-term follow-up phase was up to 5 years.
Adverse Event Reporting Description	SAEs and non-serious AEs were collected in members of the Safety Population, comprised of all randomized participants who received at least one dose of study drug, based on the actual treatment received, if this differed from that to which the participant was randomized.
Arm/Group Title	GSK2118436 150 mg BID		DTIC 1000 mg/m^2 in RP		GSK25118436 in the Crossover Phase
Arm/Group Description	Participants were randomly assigned to receive oral GSK2118436 150 mg BID. Dose reductions were permitted based on the severity of the hematological toxicity. Stopping recommendations for study treatment were also provided for cases of reoccurring skin toxicity, cardiovascular complication or abnormalities, and liver abnormalities. Participants continued on treatment until DP, death, the occurrence of an unacceptable AE, or withdrawal from the study. Participants who experienced investigator-reported DP but were benefitting from study treatment were permitted to continue GSK2118436 treatment upon approval of the GlaxoSmithKline Medical Monitor.		In the RP, participants received IV DTIC 1000 mg/m^2 every 3 weeks. Dose reductions were permitted based on the severity of the hematological toxicity. Stopping recommendations for study treatment were also provided for cases of reoccurring skin toxicity, cardiovascular complication or abnormalities, and liver abnormalities. Participants continued on treatment until DP, death, the occurrence of an unacceptable AE, or withdrawal from the study.		Participants who received DTIC in the RP and experienced DP had the option, at the discretion of the Investigator, of receiving GSK2118436 150 mg BID in the Crossover Phase. Participants who permanently discontinued DTIC treatment due to an AE, withdrawal of consent, or for any reason other than DP were not eligible for crossover to GSK2118436. Crossover participants continued on GSK2118436 until further DP was noted. After DP on GSK2118436, participants were followed for response, progression, survival, and further anti-cancer therapy.
All-Cause Mortality
	GSK2118436 150 mg BID		DTIC 1000 mg/m^2 in RP		GSK25118436 in the Crossover Phase
	Affected / at Risk (%)		Affected / at Risk (%)		Affected / at Risk (%)
Total	5/187 (2.67%)		0/59 (0.00%)		1/37 (2.70%)
Serious Adverse Events
	GSK2118436 150 mg BID		DTIC 1000 mg/m^2 in RP		GSK25118436 in the Crossover Phase
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	64/187 (34.22%)		14/59 (23.73%)		9/37 (24.32%)
Blood and lymphatic system disorders
Anaemia † 1	1/187 (0.53%)	1	1/59 (1.69%)	1	0/37 (0.00%)	0
Febrile neutropenia † 1	1/187 (0.53%)	1	1/59 (1.69%)	1	0/37 (0.00%)	0
Lymphadenopathy † 1	1/187 (0.53%)	1	0/59 (0.00%)	0	0/37 (0.00%)	0
Neutropenia † 1	0/187 (0.00%)	0	1/59 (1.69%)	1	0/37 (0.00%)	0
Cardiac disorders
Acute coronary syndrome † 1	1/187 (0.53%)	1	0/59 (0.00%)	0	0/37 (0.00%)	0
Acute myocardial infarction † 1	1/187 (0.53%)	1	0/59 (0.00%)	0	0/37 (0.00%)	0
Angina pectoris † 1	0/187 (0.00%)	0	1/59 (1.69%)	1	0/37 (0.00%)	0
Atrial fibrillation † 1	3/187 (1.60%)	3	0/59 (0.00%)	0	0/37 (0.00%)	0
Cardiac failure congestive † 1	1/187 (0.53%)	1	0/59 (0.00%)	0	0/37 (0.00%)	0
Myocardial infarction † 1	2/187 (1.07%)	2	0/59 (0.00%)	0	0/37 (0.00%)	0
Myocardial ischaemia † 1	1/187 (0.53%)	1	0/59 (0.00%)	0	0/37 (0.00%)	0
Eye disorders
Cataract † 1	1/187 (0.53%)	1	0/59 (0.00%)	0	0/37 (0.00%)	0
Eyelid oedema † 1	0/187 (0.00%)	0	1/59 (1.69%)	1	0/37 (0.00%)	0
Macular hole † 1	0/187 (0.00%)	0	0/59 (0.00%)	0	1/37 (2.70%)	1
Gastrointestinal disorders
Abdominal pain † 1	1/187 (0.53%)	1	2/59 (3.39%)	2	1/37 (2.70%)	1
Colitis † 1	1/187 (0.53%)	1	0/59 (0.00%)	0	0/37 (0.00%)	0
Constipation † 1	1/187 (0.53%)	1	1/59 (1.69%)	1	0/37 (0.00%)	0
Diarrhoea † 1	1/187 (0.53%)	1	0/59 (0.00%)	0	0/37 (0.00%)	0
Haemorrhoidal haemorrhage † 1	1/187 (0.53%)	1	0/59 (0.00%)	0	0/37 (0.00%)	0
Ileus † 1	1/187 (0.53%)	2	0/59 (0.00%)	0	0/37 (0.00%)	0
Large intestine perforation † 1	1/187 (0.53%)	1	0/59 (0.00%)	0	0/37 (0.00%)	0
Nausea † 1	1/187 (0.53%)	2	1/59 (1.69%)	1	0/37 (0.00%)	0
Pancreatic necrosis † 1	1/187 (0.53%)	1	0/59 (0.00%)	0	0/37 (0.00%)	0
Pancreatitis † 1	2/187 (1.07%)	2	0/59 (0.00%)	0	0/37 (0.00%)	0
Pancreatitis acute † 1	1/187 (0.53%)	1	0/59 (0.00%)	0	0/37 (0.00%)	0
Small intestinal perforation † 1	1/187 (0.53%)	1	0/59 (0.00%)	0	0/37 (0.00%)	0
Vomiting † 1	2/187 (1.07%)	3	1/59 (1.69%)	1	0/37 (0.00%)	0
Ascites † 1	0/187 (0.00%)	0	0/59 (0.00%)	0	1/37 (2.70%)	1
General disorders
Chills † 1	4/187 (2.14%)	4	0/59 (0.00%)	0	0/37 (0.00%)	0
Euthanasia † 1	1/187 (0.53%)	1	0/59 (0.00%)	0	0/37 (0.00%)	0
Gait disturbance † 1	1/187 (0.53%)	1	0/59 (0.00%)	0	0/37 (0.00%)	0
Influenza like illness † 1	1/187 (0.53%)	1	0/59 (0.00%)	0	0/37 (0.00%)	0
Pain † 1	0/187 (0.00%)	0	1/59 (1.69%)	1	0/37 (0.00%)	0
Pyrexia † 1	10/187 (5.35%)	13	0/59 (0.00%)	0	1/37 (2.70%)	1
Hepatobiliary disorders
Cholecystitis † 1	0/187 (0.00%)	0	1/59 (1.69%)	1	0/37 (0.00%)	0
Hepatic pain † 1	1/187 (0.53%)	1	1/59 (1.69%)	1	0/37 (0.00%)	0
Infections and infestations
Abdominal infection † 1	1/187 (0.53%)	1	0/59 (0.00%)	0	0/37 (0.00%)	0
Anal abscess † 1	1/187 (0.53%)	1	0/59 (0.00%)	0	0/37 (0.00%)	0
Cellulitis † 1	1/187 (0.53%)	2	0/59 (0.00%)	0	0/37 (0.00%)	0
Erysipelas † 1	1/187 (0.53%)	1	0/59 (0.00%)	0	0/37 (0.00%)	0
Gastrointestinal infection † 1	0/187 (0.00%)	0	1/59 (1.69%)	1	0/37 (0.00%)	0
Hepatitis E † 1	1/187 (0.53%)	1	0/59 (0.00%)	0	0/37 (0.00%)	0
Localised infection † 1	1/187 (0.53%)	1	0/59 (0.00%)	0	0/37 (0.00%)	0
Perineal abscess † 1	1/187 (0.53%)	1	0/59 (0.00%)	0	0/37 (0.00%)	0
Pleural infection † 1	1/187 (0.53%)	1	0/59 (0.00%)	0	0/37 (0.00%)	0
Pneumonia † 1	2/187 (1.07%)	2	0/59 (0.00%)	0	1/37 (2.70%)	1
Sepsis † 1	0/187 (0.00%)	0	1/59 (1.69%)	1	1/37 (2.70%)	1
Streptococcal infection † 1	0/187 (0.00%)	0	0/59 (0.00%)	0	1/37 (2.70%)	1
Injury, poisoning and procedural complications
Head injury † 1	1/187 (0.53%)	1	0/59 (0.00%)	0	0/37 (0.00%)	0
Radius fracture † 1	1/187 (0.53%)	1	0/59 (0.00%)	0	0/37 (0.00%)	0
Investigations
Blood bilirubin increased † 1	1/187 (0.53%)	1	0/59 (0.00%)	0	0/37 (0.00%)	0
Blood creatine phosphokinase increased † 1	1/187 (0.53%)	1	0/59 (0.00%)	0	0/37 (0.00%)	0
Blood creatinine increased † 1	1/187 (0.53%)	1	0/59 (0.00%)	0	0/37 (0.00%)	0
Ejection fraction decreased † 1	3/187 (1.60%)	5	0/59 (0.00%)	0	0/37 (0.00%)	0
White blood cell count decreased † 1	0/187 (0.00%)	0	1/59 (1.69%)	1	0/37 (0.00%)	0
Metabolism and nutrition disorders
Dehydration † 1	2/187 (1.07%)	2	0/59 (0.00%)	0	0/37 (0.00%)	0
Diabetes mellitus † 1	1/187 (0.53%)	1	0/59 (0.00%)	0	0/37 (0.00%)	0
Diabetes mellitus inadequate control † 1	1/187 (0.53%)	1	0/59 (0.00%)	0	0/37 (0.00%)	0
Hyperlipasaemia † 1	1/187 (0.53%)	1	0/59 (0.00%)	0	0/37 (0.00%)	0
Hyponatraemia † 1	1/187 (0.53%)	1	0/59 (0.00%)	0	1/37 (2.70%)	1
Hypophosphataemia † 1	1/187 (0.53%)	1	0/59 (0.00%)	0	0/37 (0.00%)	0
Musculoskeletal and connective tissue disorders
Arthralgia † 1	1/187 (0.53%)	1	0/59 (0.00%)	0	1/37 (2.70%)	1
Back pain † 1	1/187 (0.53%)	1	0/59 (0.00%)	0	0/37 (0.00%)	0
Joint effusion † 1	1/187 (0.53%)	1	0/59 (0.00%)	0	0/37 (0.00%)	0
Muscular weakness † 1	1/187 (0.53%)	1	0/59 (0.00%)	0	0/37 (0.00%)	0
Musculoskeletal pain † 1	1/187 (0.53%)	1	0/59 (0.00%)	0	0/37 (0.00%)	0
Osteoporotic fracture † 1	1/187 (0.53%)	1	0/59 (0.00%)	0	0/37 (0.00%)	0
Pain in extremity † 1	1/187 (0.53%)	1	0/59 (0.00%)	0	0/37 (0.00%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Acoustic neuroma † 1	1/187 (0.53%)	1	0/59 (0.00%)	0	0/37 (0.00%)	0
Adenocarcinoma of the cervix † 1	1/187 (0.53%)	1	0/59 (0.00%)	0	0/37 (0.00%)	0
Basal cell carcinoma † 1	6/187 (3.21%)	8	0/59 (0.00%)	0	0/37 (0.00%)	0
Bowen’s disease † 1	1/187 (0.53%)	1	0/59 (0.00%)	0	0/37 (0.00%)	0
Breast cancer † 1	1/187 (0.53%)	1	0/59 (0.00%)	0	0/37 (0.00%)	0
Focal nodular hyperplasia † 1	1/187 (0.53%)	1	0/59 (0.00%)	0	0/37 (0.00%)	0
Lip squamous cell carcinoma † 1	1/187 (0.53%)	1	0/59 (0.00%)	0	2/37 (5.41%)	2
Malignant melanoma † 1	3/187 (1.60%)	3	0/59 (0.00%)	0	0/37 (0.00%)	0
Malignant melanoma in situ † 1	3/187 (1.60%)	3	0/59 (0.00%)	0	0/37 (0.00%)	0
Malignant melanoma stage I † 1	0/187 (0.00%)	0	1/59 (1.69%)	1	0/37 (0.00%)	0
Papillary thyroid cancer † 1	1/187 (0.53%)	1	0/59 (0.00%)	0	0/37 (0.00%)	0
Soft tissue sarcoma † 1	1/187 (0.53%)	1	0/59 (0.00%)	0	0/37 (0.00%)	0
Squamous cell carcinoma † 1	7/187 (3.74%)	11	0/59 (0.00%)	0	2/37 (5.41%)	2
Squamous cell carcinoma of skin † 1	8/187 (4.28%)	12	0/59 (0.00%)	0	2/37 (5.41%)	3
Fibrous histiocytoma † 1	0/187 (0.00%)	0	0/59 (0.00%)	0	1/37 (2.70%)	1
Nervous system disorders
Lethargy † 1	0/187 (0.00%)	0	1/59 (1.69%)	1	0/37 (0.00%)	0
Parkinsonism † 1	1/187 (0.53%)	1	0/59 (0.00%)	0	0/37 (0.00%)	0
Presyncope † 1	1/187 (0.53%)	1	0/59 (0.00%)	0	0/37 (0.00%)	0
Syncope † 1	1/187 (0.53%)	1	0/59 (0.00%)	0	0/37 (0.00%)	0
Transient ischaemic attack † 1	1/187 (0.53%)	1	0/59 (0.00%)	0	0/37 (0.00%)	0
Psychiatric disorders
Depression † 1	0/187 (0.00%)	0	1/59 (1.69%)	1	0/37 (0.00%)	0
Psychotic disorder † 1	1/187 (0.53%)	1	0/59 (0.00%)	0	0/37 (0.00%)	0
Renal and urinary disorders
Haematuria † 1	0/187 (0.00%)	0	1/59 (1.69%)	1	0/37 (0.00%)	0
Renal failure † 1	1/187 (0.53%)	1	0/59 (0.00%)	0	0/37 (0.00%)	0
Urinary bladder polyp † 1	1/187 (0.53%)	1	0/59 (0.00%)	0	0/37 (0.00%)	0
Reproductive system and breast disorders
Ovarian cyst † 1	0/187 (0.00%)	0	0/59 (0.00%)	0	1/37 (2.70%)	1
Respiratory, thoracic and mediastinal disorders
Hypoxia † 1	1/187 (0.53%)	1	0/59 (0.00%)	0	0/37 (0.00%)	0
Pleural effusion † 1	1/187 (0.53%)	1	0/59 (0.00%)	0	0/37 (0.00%)	0
Pleuritic pain † 1	1/187 (0.53%)	1	0/59 (0.00%)	0	0/37 (0.00%)	0
Pulmonary embolism † 1	2/187 (1.07%)	2	1/59 (1.69%)	1	0/37 (0.00%)	0
Pulmonary oedema † 1	1/187 (0.53%)	1	0/59 (0.00%)	0	0/37 (0.00%)	0
Respiratory distress † 1	1/187 (0.53%)	1	0/59 (0.00%)	0	0/37 (0.00%)	0
Respiratory failure † 1	0/187 (0.00%)	0	0/59 (0.00%)	0	1/37 (2.70%)	1
Skin and subcutaneous tissue disorders
Dermal cyst † 1	1/187 (0.53%)	1	0/59 (0.00%)	0	0/37 (0.00%)	0
Hyperhidrosis † 1	0/187 (0.00%)	0	1/59 (1.69%)	1	0/37 (0.00%)	0
Vascular disorders
Haematoma † 1	1/187 (0.53%)	1	0/59 (0.00%)	0	0/37 (0.00%)	0
Haemorrhage † 1	1/187 (0.53%)	1	0/59 (0.00%)	0	0/37 (0.00%)	0
Hypotension † 1	2/187 (1.07%)	4	0/59 (0.00%)	0	1/37 (2.70%)	1
1 Term from vocabulary, 19.0; † Indicates events were collected by systematic assessment
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	5%
	GSK2118436 150 mg BID		DTIC 1000 mg/m^2 in RP		GSK25118436 in the Crossover Phase
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	181/187 (96.79%)		51/59 (86.44%)		37/37 (100.00%)
Blood and lymphatic system disorders
Anaemia † 1	10/187 (5.35%)	14	7/59 (11.86%)	9	3/37 (8.11%)	5
Leukopenia † 1	0/187 (0.00%)	0	8/59 (13.56%)	8	0/37 (0.00%)	0
Neutropenia † 1	0/187 (0.00%)	0	10/59 (16.95%)	18	0/37 (0.00%)	0
Thrombocytopenia † 1	0/187 (0.00%)	0	8/59 (13.56%)	11	0/37 (0.00%)	0
Lymphopenia † 1	0/187 (0.00%)	0	0/59 (0.00%)	0	2/37 (5.41%)	2
Gastrointestinal disorders
Abdominal pain † 1	15/187 (8.02%)	16	7/59 (11.86%)	8	8/37 (21.62%)	10
Abdominal pain upper † 1	11/187 (5.88%)	20	0/59 (0.00%)	0	3/37 (8.11%)	4
Constipation † 1	27/187 (14.44%)	32	8/59 (13.56%)	9	4/37 (10.81%)	4
Diarrhoea † 1	31/187 (16.58%)	42	7/59 (11.86%)	8	4/37 (10.81%)	5
Nausea † 1	55/187 (29.41%)	69	29/59 (49.15%)	49	9/37 (24.32%)	9
Vomiting † 1	42/187 (22.46%)	55	15/59 (25.42%)	19	5/37 (13.51%)	5
Abdominal distension † 1	0/187 (0.00%)	0	0/59 (0.00%)	0	3/37 (8.11%)	3
General disorders
Asthenia † 1	37/187 (19.79%)	56	9/59 (15.25%)	11	6/37 (16.22%)	8
Chills † 1	23/187 (12.30%)	40	0/59 (0.00%)	0	4/37 (10.81%)	5
Fatigue † 1	48/187 (25.67%)	57	14/59 (23.73%)	21	6/37 (16.22%)	6
Influenza like illness † 1	14/187 (7.49%)	16	0/59 (0.00%)	0	2/37 (5.41%)	2
Oedema peripheral † 1	12/187 (6.42%)	13	5/59 (8.47%)	5	0/37 (0.00%)	0
Pyrexia † 1	61/187 (32.62%)	102	8/59 (13.56%)	8	9/37 (24.32%)	11
Non-cardiac chest pain † 1	0/187 (0.00%)	0	0/59 (0.00%)	0	2/37 (5.41%)	2
Oedema peripheral † 1	0/187 (0.00%)	0	0/59 (0.00%)	0	3/37 (8.11%)	3
Peripheral swelling † 1	0/187 (0.00%)	0	0/59 (0.00%)	0	2/37 (5.41%)	5
Infections and infestations
Folliculitis † 1	11/187 (5.88%)	13	0/59 (0.00%)	0	0/37 (0.00%)	0
Nasopharyngitis † 1	35/187 (18.72%)	57	4/59 (6.78%)	6	4/37 (10.81%)	8
Upper respiratory tract infection † 1	12/187 (6.42%)	15	0/59 (0.00%)	0	2/37 (5.41%)	2
Urinary tract infection † 1	0/187 (0.00%)	0	4/59 (6.78%)	4	0/37 (0.00%)	0
Sinusitis † 1	0/187 (0.00%)	0	0/59 (0.00%)	0	2/37 (5.41%)	2
INFLUENZA † 1	0/187 (0.00%)	0	0/59 (0.00%)	0	2/37 (5.41%)	2
Investigations
Alanine aminotransferase increased † 1	12/187 (6.42%)	13	0/59 (0.00%)	0	0/37 (0.00%)	0
Aspartate aminotransferase increased † 1	10/187 (5.35%)	10	0/59 (0.00%)	0	0/37 (0.00%)	0
Lymphocyte count decreased † 1	0/187 (0.00%)	0	3/59 (5.08%)	7	2/37 (5.41%)	3
Platelet count decreased † 1	0/187 (0.00%)	0	4/59 (6.78%)	5	0/37 (0.00%)	0
Weight decreased † 1	13/187 (6.95%)	13	0/59 (0.00%)	0	2/37 (5.41%)	2
White blood cell count decreased † 1	0/187 (0.00%)	0	3/59 (5.08%)	7	0/37 (0.00%)	0
Metabolism and nutrition disorders
Decreased appetite † 1	26/187 (13.90%)	34	6/59 (10.17%)	7	4/37 (10.81%)	5
Hyperglycaemia † 1	14/187 (7.49%)	19	3/59 (5.08%)	4	3/37 (8.11%)	4
Hypophosphataemia † 1	11/187 (5.88%)	13	0/59 (0.00%)	0	2/37 (5.41%)	2
Hypoglycaemia † 1	0/187 (0.00%)	0	0/59 (0.00%)	0	2/37 (5.41%)	2
Hypokalaemia † 1	0/187 (0.00%)	0	0/59 (0.00%)	0	2/37 (5.41%)	2
Musculoskeletal and connective tissue disorders
Arthralgia † 1	74/187 (39.57%)	111	0/59 (0.00%)	0	16/37 (43.24%)	23
Back pain † 1	41/187 (21.93%)	48	4/59 (6.78%)	4	8/37 (21.62%)	8
Musculoskeletal chest pain † 1	10/187 (5.35%)	10	0/59 (0.00%)	0	3/37 (8.11%)	3
Musculoskeletal pain † 1	18/187 (9.63%)	20	0/59 (0.00%)	0	6/37 (16.22%)	9
Myalgia † 1	32/187 (17.11%)	41	0/59 (0.00%)	0	7/37 (18.92%)	7
Pain in extremity † 1	31/187 (16.58%)	40	6/59 (10.17%)	7	6/37 (16.22%)	6
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Acrochordon † 1	11/187 (5.88%)	20	0/59 (0.00%)	0	0/37 (0.00%)	0
Melanocytic naevus † 1	11/187 (5.88%)	18	0/59 (0.00%)	0	0/37 (0.00%)	0
Papilloma † 1	15/187 (8.02%)	23	0/59 (0.00%)	0	2/37 (5.41%)	2
Seborrhoeic keratosis † 1	23/187 (12.30%)	55	0/59 (0.00%)	0	3/37 (8.11%)	3
Skin papilloma † 1	48/187 (25.67%)	85	0/59 (0.00%)	0	10/37 (27.03%)	15
Dysplastic naevus † 1	0/187 (0.00%)	0	0/59 (0.00%)	0	2/37 (5.41%)	4
Fibroma † 1	0/187 (0.00%)	0	0/59 (0.00%)	0	2/37 (5.41%)	2
Fibrous histiocytoma † 1	0/187 (0.00%)	0	0/59 (0.00%)	0	2/37 (5.41%)	2
Keratoacanthoma † 1	0/187 (0.00%)	0	0/59 (0.00%)	0	2/37 (5.41%)	5
Nervous system disorders
Dizziness † 1	15/187 (8.02%)	17	3/59 (5.08%)	3	5/37 (13.51%)	5
Headache † 1	68/187 (36.36%)	109	5/59 (8.47%)	6	6/37 (16.22%)	7
Paraesthesia † 1	12/187 (6.42%)	13	0/59 (0.00%)	0	3/37 (8.11%)	3
Hyperaesthesia † 1	0/187 (0.00%)	0	0/59 (0.00%)	0	2/37 (5.41%)	3
Sciatica † 1	0/187 (0.00%)	0	0/59 (0.00%)	0	2/37 (5.41%)	2
Psychiatric disorders
Anxiety † 1	10/187 (5.35%)	10	5/59 (8.47%)	5	3/37 (8.11%)	3
Insomnia † 1	16/187 (8.56%)	19	0/59 (0.00%)	0	0/37 (0.00%)	0
Depression † 1	0/187 (0.00%)	0	0/59 (0.00%)	0	3/37 (8.11%)	3
Renal and urinary disorders
Pollakiuria † 1	0/187 (0.00%)	0	0/59 (0.00%)	0	2/37 (5.41%)	2
Reproductive system and breast disorders
Pelvic pain † 1	0/187 (0.00%)	0	0/59 (0.00%)	0	2/37 (5.41%)	2
Respiratory, thoracic and mediastinal disorders
Cough † 1	34/187 (18.18%)	42	4/59 (6.78%)	6	2/37 (5.41%)	2
Dyspnoea † 1	22/187 (11.76%)	28	0/59 (0.00%)	0	2/37 (5.41%)	2
Dyspnoea exertional † 1	0/187 (0.00%)	0	3/59 (5.08%)	3	0/37 (0.00%)	0
Oropharyngeal pain † 1	10/187 (5.35%)	12	0/59 (0.00%)	0	3/37 (8.11%)	3
Nasal congestion † 1	0/187 (0.00%)	0	0/59 (0.00%)	0	2/37 (5.41%)	2
Skin and subcutaneous tissue disorders
Actinic keratosis † 1	22/187 (11.76%)	51	0/59 (0.00%)	0	2/37 (5.41%)	2
Alopecia † 1	54/187 (28.88%)	59	0/59 (0.00%)	0	7/37 (18.92%)	7
Dry skin † 1	28/187 (14.97%)	36	0/59 (0.00%)	0	5/37 (13.51%)	5
Eczema † 1	10/187 (5.35%)	10	0/59 (0.00%)	0	0/37 (0.00%)	0
Erythema † 1	18/187 (9.63%)	28	0/59 (0.00%)	0	0/37 (0.00%)	0
Hair texture abnormal † 1	13/187 (6.95%)	14	0/59 (0.00%)	0	0/37 (0.00%)	0
Hyperkeratosis † 1	71/187 (37.97%)	156	0/59 (0.00%)	0	11/37 (29.73%)	20
Palmar-plantar erythrodysaesthesia syndrome † 1	37/187 (19.79%)	44	0/59 (0.00%)	0	5/37 (13.51%)	5
Palmoplantar keratoderma † 1	17/187 (9.09%)	20	0/59 (0.00%)	0	2/37 (5.41%)	2
Photosensitivity reaction † 1	0/187 (0.00%)	0	4/59 (6.78%)	4	2/37 (5.41%)	2
Pruritus † 1	11/187 (5.88%)	13	0/59 (0.00%)	0	3/37 (8.11%)	3
Rash † 1	35/187 (18.72%)	45	0/59 (0.00%)	0	10/37 (27.03%)	13
Skin lesion † 1	14/187 (7.49%)	18	0/59 (0.00%)	0	2/37 (5.41%)	3
Hyperhidrosis † 1	0/187 (0.00%)	0	0/59 (0.00%)	0	3/37 (8.11%)	3
Night sweats † 1	0/187 (0.00%)	0	0/59 (0.00%)	0	4/37 (10.81%)	4
Skin exfoliation † 1	0/187 (0.00%)	0	0/59 (0.00%)	0	2/37 (5.41%)	2
Vascular disorders
Hypertension † 1	10/187 (5.35%)	16	0/59 (0.00%)	0	0/37 (0.00%)	0
1 Term from vocabulary, 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

• Name/Title: GSK Response Center
• Organization: GlaxoSmithKline
• Phone: 866-435-7343

Publications:

Hauschild A, Grob JJ, Demidov LV, Jouary T, Gutzmer R, Millward M, Rutkowski P, Blank CU, Miller WH Jr, Kaempgen E, Martín-Algarra S, Karaszewska B, Mauch C, Chiarion-Sileni V, Martin AM, Swann S, Haney P, Mirakhur B, Guckert ME, Goodman V, Chapman PB. Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre, open-label, phase 3 randomised controlled trial. Lancet. 2012 Jul 28;380(9839):358-65. doi: 10.1016/S0140-6736(12)60868-X. Epub 2012 Jun 25.

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

Santiago-Walker A, Gagnon R, Mazumdar J, Casey M, Long GV, Schadendorf D, Flaherty K, Kefford R, Hauschild A, Hwu P, Haney P, O'Hagan A, Carver J, Goodman V, Legos J, Martin AM. Correlation of BRAF Mutation Status in Circulating-Free DNA and Tumor and Association with Clinical Outcome across Four BRAFi and MEKi Clinical Trials. Clin Cancer Res. 2016 Feb 1;22(3):567-74. doi: 10.1158/1078-0432.CCR-15-0321. Epub 2015 Oct 7.

Latimer NR, Abrams KR, Amonkar MM, Stapelkamp C, Swann RS. Adjusting for the Confounding Effects of Treatment Switching-The BREAK-3 Trial: Dabrafenib Versus Dacarbazine. Oncologist. 2015 Jul;20(7):798-805. doi: 10.1634/theoncologist.2014-0429. Epub 2015 Jun 3.

Grob JJ, Amonkar MM, Martin-Algarra S, Demidov LV, Goodman V, Grotzinger K, Haney P, Kämpgen E, Karaszewska B, Mauch C, Miller WH Jr, Millward M, Mirakhur B, Rutkowski P, Chiarion-Sileni V, Swann S, Hauschild A. Patient perception of the benefit of a BRAF inhibitor in metastatic melanoma: quality-of-life analyses of the BREAK-3 study comparing dabrafenib with dacarbazine. Ann Oncol. 2014 Jul;25(7):1428-36. doi: 10.1093/annonc/mdu154. Epub 2014 Apr 25.

Ouellet D, Gibiansky E, Leonowens C, O'Hagan A, Haney P, Switzky J, Goodman VL. Population pharmacokinetics of dabrafenib, a BRAF inhibitor: effect of dose, time, covariates, and relationship with its metabolites. J Clin Pharmacol. 2014 Jun;54(6):696-706. doi: 10.1002/jcph.263. Epub 2014 Jan 17.

• Responsible Party: GlaxoSmithKline
• ClinicalTrials.gov Identifier: NCT01227889 History of Changes
• Other Study ID Numbers: 113683
• First Submitted: October 21, 2010
• First Posted: October 25, 2010
• Results First Submitted: June 6, 2013
• Results First Posted: May 16, 2014
• Last Update Posted: October 4, 2017