Trial Outcomes & Findings for A Study Comparing GSK2118436 to Dacarbazine (DTIC) in Previously Untreated Subjects With BRAF Mutation Positive Advanced (Stage III) or Metastatic (Stage IV) Melanoma (NCT NCT01227889)

Last Updated: 2017-10-04

Results Overview

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.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

251 participants

Primary outcome timeframe

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)

Results posted on

2017-10-04

Participant Flow

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.

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

Participant milestones

Participant milestones
Measure	GSK2118436 150 mg BID 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.	DTIC 1000 mg/m^2 in RP; GSK2118436 in Crossover Phase 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.
Randomized Phase (RP) STARTED	187	63
Randomized Phase (RP) COMPLETED	0	0
Randomized Phase (RP) NOT COMPLETED	187	63
Crossover Phase STARTED	0	37
Crossover Phase COMPLETED	0	0
Crossover Phase NOT COMPLETED	0	37

Reasons for withdrawal

Reasons for withdrawal
Measure	GSK2118436 150 mg BID 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.	DTIC 1000 mg/m^2 in RP; GSK2118436 in Crossover Phase 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.
Randomized Phase (RP) Adverse Event	13	0
Randomized Phase (RP) Physician Decision	13	5
Randomized Phase (RP) Progressive Disease	135	52
Randomized Phase (RP) Study terminated by sponsor	10	0
Randomized Phase (RP) Missing	1	3
Randomized Phase (RP) Withdrawal by Subject	15	3
Crossover Phase Adverse Event	0	1
Crossover Phase Physician Decision	0	3
Crossover Phase Progressive Disease	0	31
Crossover Phase Study Terminated By Sponsor	0	1
Crossover Phase Withdrawal by Subject	0	1

Baseline Characteristics

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

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	GSK2118436 150 mg BID n=187 Participants 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.	DTIC 1000 mg/m^2 in RP; GSK2118436 in Crossover Phase n=63 Participants 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 n=250 Participants Total of all reporting groups
Age, Continuous	53.5 Years STANDARD_DEVIATION 13.76 • n=5 Participants	51.6 Years STANDARD_DEVIATION 14.22 • n=7 Participants	53.0 Years STANDARD_DEVIATION 13.87 • n=5 Participants
Sex: Female, Male Female	75 Participants n=5 Participants	26 Participants n=7 Participants	101 Participants n=5 Participants
Sex: Female, Male Male	112 Participants n=5 Participants	37 Participants n=7 Participants	149 Participants n=5 Participants
Race/Ethnicity, Customized White	186 participants n=5 Participants	63 participants n=7 Participants	249 participants n=5 Participants
Race/Ethnicity, Customized Missing	1 participants n=5 Participants	0 participants n=7 Participants	1 participants n=5 Participants

PRIMARY outcome

Timeframe: 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)

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

Outcome measures

Outcome measures
Measure	GSK25118436 in Crossover Phase n=187 Participants 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.	DTIC 1000 mg/m^2 in RP n=63 Participants 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.
Progression-free Survival (PFS) as Assessed by the Investigator	6.9 Months Interval 5.5 to 9.0	2.7 Months Interval 1.4 to 3.2

PRIMARY outcome

Timeframe: 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)

Population: ITT Population

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.

Outcome measures

Outcome measures
Measure	GSK25118436 in Crossover Phase n=187 Participants 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.	DTIC 1000 mg/m^2 in RP n=63 Participants 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.
Progression-free Survival (PFS) as Assessed by an Independent Radiologist: Randomized Phase	6.7 Months Interval 5.0 to 6.9	2.9 Months Interval 1.7 to 4.9

SECONDARY outcome

Timeframe: Time interval between the date of randomization and the date of death due to any cause (up to 22.1 months)

Population: ITT Population

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.

Outcome measures

Outcome measures
Measure	GSK25118436 in Crossover Phase n=187 Participants 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.	DTIC 1000 mg/m^2 in RP n=63 Participants 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 Survival	20.0 Months Interval 16.7 to 24.2	15.6 Months Interval 11.9 to 21.2

SECONDARY outcome

Timeframe: From randomization until the first documented evidence of a confirmed complete response or partial response (median of 6.6 weeks)

Population: ITT Population

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.

Outcome measures

Outcome measures
Measure	GSK25118436 in Crossover Phase n=187 Participants 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.	DTIC 1000 mg/m^2 in RP n=63 Participants 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.
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 PR	86 participants	11 participants
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 CR	26 participants	4 participants

SECONDARY outcome

Timeframe: From randomization until the first documented evidence of a confirmed complete response or partial response (median of 12.0 weeks)

Population: ITT Population

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.

Outcome measures

Outcome measures
Measure	GSK25118436 in Crossover Phase n=187 Participants 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.	DTIC 1000 mg/m^2 in RP n=63 Participants 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.
Number of Participants With a Best Overall Response of Confirmed CR or PR as Assessed by an Independent Radiologist: Randomized Phase CR	6 participants	1 participants
Number of Participants With a Best Overall Response of Confirmed CR or PR as Assessed by an Independent Radiologist: Randomized Phase PR	87 participants	3 participants

SECONDARY outcome

Timeframe: 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)

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

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.

Outcome measures

Outcome measures
Measure	GSK25118436 in Crossover Phase n=112 Participants 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.	DTIC 1000 mg/m^2 in RP n=15 Participants 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.
Duration of Response as Assessed by the Investigator: Randomized Phase	9.2 Months Interval 7.4 to 11.9	8.2 Months Interval 3.5 to 18.3

SECONDARY outcome

Timeframe: 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)

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

Outcome measures

Outcome measures
Measure	GSK25118436 in Crossover Phase n=93 Participants 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.	DTIC 1000 mg/m^2 in RP n=4 Participants 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.
Duration of Response as Assessed by an Independent Radiologist: Randomized Phase	5.5 Months Interval 5.0 to 6.7	NA Months Median duration of response could not be calculated because there were not enough participants with a CR or PR.

SECONDARY outcome

Timeframe: 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)

Population: 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.

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.

Outcome measures

Outcome measures
Measure	GSK25118436 in Crossover Phase n=37 Participants 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.	DTIC 1000 mg/m^2 in RP 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.
Progression-free Survival (PFS2) as Assessed by the Investigator: Crossover Phase	4.3 Months Interval 4.1 to 6.1	—

SECONDARY outcome

Timeframe: From randomization until the first documented evidence of a confirmed complete response or partial response (up to 6.4 months)

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

Outcome measures

Outcome measures
Measure	GSK25118436 in Crossover Phase n=37 Participants 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.	DTIC 1000 mg/m^2 in RP 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.
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 CR	0 participants	—
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 PR	12 participants	—

SECONDARY outcome

Timeframe: 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)

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

Outcome measures

Outcome measures
Measure	GSK25118436 in Crossover Phase n=12 Participants 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.	DTIC 1000 mg/m^2 in RP 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.
Duration of Response as Assessed by the Investigator: Crossover Phase	4.4 Months Interval 2.5 to 6.2	—

SECONDARY outcome

Timeframe: From Screening until study completion or discontinuation from the study (up to 9.9 months)

Population: 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

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.

Outcome measures

Outcome measures
Measure	GSK25118436 in Crossover Phase n=187 Participants 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.	DTIC 1000 mg/m^2 in RP n=59 Participants 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.
Number of Participants With Non-melanoma Skin Lesions: Randomized Phase Number of Subjects with Event	14 participants	0 participants
Number of Participants With Non-melanoma Skin Lesions: Randomized Phase Number of Events	24 participants	0 participants

SECONDARY outcome

Timeframe: Screening

Population: V600E positive participants screened for BREAK-3 study

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.

Outcome measures

Outcome measures
Measure	GSK25118436 in Crossover Phase n=734 Participants 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.	DTIC 1000 mg/m^2 in RP 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.
Agreement Rate for V600E Mutation Validation of the BRAF Mutation Assay Agreement for V600E	96.70 Percent agreement Interval 93.6 to 98.3	—
Agreement Rate for V600E Mutation Validation of the BRAF Mutation Assay Agreement for V600K	90.00 Percent agreement Interval 78.6 to 95.7	—
Agreement Rate for V600E Mutation Validation of the BRAF Mutation Assay Agreement for mutation negative	95.00 Percent agreement Interval 91.6 to 97.0	—
Agreement Rate for V600E Mutation Validation of the BRAF Mutation Assay Agreement for overall	94.90 Percent agreement Interval 92.7 to 96.4	—

Adverse Events

GSK2118436 150 mg BID

Serious events: 64 serious events

Other events: 181 other events

Deaths: 5 deaths

DTIC 1000 mg/m^2 in RP

Serious events: 14 serious events

Other events: 51 other events

Deaths: 0 deaths

GSK25118436 in the Crossover Phase

Serious events: 9 serious events

Other events: 37 other events

Deaths: 1 deaths

Serious adverse events

Other adverse events

Additional Information

GSK Response Center

GlaxoSmithKline

Phone: 866-435-7343

Results disclosure agreements

Principal investigator is a sponsor employee 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.
Publication restrictions are in place

Restriction type: OTHER