A Study of GSK2118436 in BRAF Mutant Metastatic Melanoma... | NCT01266967

Label	Type	Description	Intervention Names
Single Arm	Experimental	Single arm with 2 cohorts; Cohort A no previous brain therapy and Cohort B previous brain therapy	Drug: GSK2118436

Name	Type	Description	Arm Group Labels	Other Names
GSK2118436	Drug	Subjects in this study receive 150 mg of GSK2118436 twice daily and continue on treatment until disease progression, death, or unacceptable adverse event.	Single Arm

Measure	Description	Time Frame
Number of Participants With BRAF V600E Mutation-positive Melanoma With Overall Intracranial Response (OIR), as Assessed by the Investigator	OIR is defined as the number of participants whose intracranial response was a confirmed complete response (CR) or partial response (PR) assessed by investigators using modified Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1. CR is defined as disappearance of all lesions. PR is defined as 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). For the primary analysis, OIR was measured when all participants in both treatment arms had two post-Baseline disease assessments. Participants who had an intracranial response of not evaluable or a missing response were treated as non-responders. Confirmation assessments were to be performed no less than 4 weeks after the criteria for response were initially met and may have been performed at the next protocol scheduled assessment.	From the time of the Baseline assessment until disease progression or end of study treatment (average of 18.3 weeks)

Measure	Description	Time Frame
Number of Participants With V600E Mutation-positive Melanoma With a Best Overall Response (OR) of CR or PR, as Assessed by the Investigator	OR is defined as the number of participants achieving either a CR (the disappearance of all target lesions) 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]) per modified RECIST, version 1.1. To determine the OR, the extracranial response was combined with the intracranial response. Confirmation assessments were to be performed no less than 4 weeks after the criteria for response were initially met and may have been performed at the next protocol-scheduled assessment. Participants who had an overall response of not evaluable or a missing response were treated as non-responders.

Name	Affiliation	Role
GSK Clinical Trials	GlaxoSmithKline	Study Director

Facility	Status	City	State	ZIP	Country	Contacts
GSK Investigational Site		Los Angeles	California	90095	United States
GSK Investigational Site

PubMed Identifier	Type	Citation	Retractions
23051966	Background	Long GV, Trefzer U, Davies MA, Kefford RF, Ascierto PA, Chapman PB, Puzanov I, Hauschild A, Robert C, Algazi A, Mortier L, Tawbi H, Wilhelm T, Zimmer L, Switzky J, Swann S, Martin AM, Guckert M, Goodman V, Streit M, Kirkwood JM, Schadendorf D. Dabrafenib in patients with Val600Glu or Val600Lys BRAF-mutant melanoma metastatic to the brain (BREAK-MB): a multicentre, open-label, phase 2 trial. Lancet Oncol. 2012 Nov;13(11):1087-95. doi: 10.1016/S1470-2045(12)70431-X. Epub 2012 Oct 8.
26446943

ID	Title	Description
FG000	GSK2118436 150 mg: No Prior Local Therapy	Participants who received no prior local therapy for brain metastasis received GSK2118436 150 milligram (mg) capsules either one hour before or 2 hours after a meal twice daily until evidence of disease progression, death, or unacceptable adverse events.
FG001

Type

Title

Description

Population Description

Reporting Status

Anticipated Posting Date

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Time Frame

Units Analyzed

Denominator Units Selected

Arm/Group Information

Denominators

Classes

Analyses

Primary

Number of Participants With BRAF V600E Mutation-positive Melanoma With Overall Intracranial Response (OIR), as Assessed by the Investigator

OIR is defined as the number of participants whose intracranial response was a confirmed complete response (CR) or partial response (PR) assessed by investigators using modified Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1. CR is defined as disappearance of all lesions. PR is defined as 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). For the primary analysis, OIR was measured when all participants in both treatment arms had two post-Baseline disease assessments. Participants who had an intracranial response of not evaluable or a missing response were treated as non-responders. Confirmation assessments were to be performed no less than 4 weeks after the criteria for response were initially met and may have been performed at the next protocol scheduled assessment.

V600E Population: all participants with BRAF V600E mutation-positive melanoma who received at least one dose of study treatment

Posted

Number

participants

From the time of the Baseline assessment until disease progression or end of study treatment (average of 18.3 weeks)

ID	Title	Description
OG000	GSK2118436 150 mg: No Prior Local Therapy	Participants who received no prior local therapy for brain metastasis received GSK2118436 150 mg capsules either one hour before or 2 hours after a meal twice daily until evidence of disease progression, death, or unacceptable adverse events.
OG001	GSK2118436 150 mg: Prior Local Therapy	Participants who received prior local therapy for brain metastasis received GSK2118436 150 mg capsules either one hour before or 2 hours after a meal twice daily until evidence of disease progression, death, or unacceptable adverse events.

Units	Counts
Participants	OG00074 OG00165

Title

Denominators

Categories

Title	Measurements
	OG0004 OG0011

Title	Measurements
	OG000

Group IDs	Group Description	Statistical Method	Statistical Comment	P-Value	P-Value Comment	Parameter Type	Parameter Value	Dispersion Type	Dispersion Value	Confidence Interval Sides	Confidence Interval %	CI Lower Limit	CI Upper Limit	CI Lower Limit Comment	CI Upper Limit Comment	Estimate Comment	Tested Non-Inferiority	Non-Inferiority Type	Non-Inferiority Comment	Other Analysis Description
OG000		Exact Test		<0.0001		percentage of participants	41			2-Sided	95	29.3	52.6			The estimated value represents the percentage of participants with OIR.	No	Superiority or Other
OG001		Exact Test

Secondary

Number of Participants With V600E Mutation-positive Melanoma With a Best Overall Response (OR) of CR or PR, as Assessed by the Investigator

OR is defined as the number of participants achieving either a CR (the disappearance of all target lesions) 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]) per modified RECIST, version 1.1. To determine the OR, the extracranial response was combined with the intracranial response. Confirmation assessments were to be performed no less than 4 weeks after the criteria for response were initially met and may have been performed at the next protocol-scheduled assessment. Participants who had an overall response of not evaluable or a missing response were treated as non-responders.

V600E Population

Posted

Number

participants

From the time of the Baseline assessment until disease progression or end of study treatment (average of 24 weeks)

ID	Title	Description
OG000	GSK2118436 150 mg: No Prior Local Therapy	Participants who received no prior local therapy for brain metastasis received GSK2118436 150 mg capsules either one hour before or 2 hours after a meal twice daily until evidence of disease progression, death, or unacceptable adverse events.
OG001	GSK2118436 150 mg: Prior Local Therapy	Participants who received prior local therapy for brain metastasis received GSK2118436 150 mg capsules either one hour before or 2 hours after a meal twice daily until evidence of disease progression, death, or unacceptable adverse events.

Secondary

Number of Participants With V600K Mutation-positive Melanoma With a Best Overall Response (OR) of CR or PR, as Assessed by the Investigator

V600K Population: all participants with BRAF V600K mutation-positive melanoma who received at least one dose of study treatment

Posted

Number

participants

From the time of the Baseline assessment until disease progression or end of study treatment (average of 17 weeks)

ID	Title	Description
OG000	GSK2118436 150 mg: No Prior Local Therapy	Participants who received no prior local therapy for brain metastasis received GSK2118436 150 mg capsules either one hour before or 2 hours after a meal twice daily until evidence of disease progression, death, or unacceptable adverse events.
OG001	GSK2118436 150 mg: Prior Local Therapy

Secondary

Number of Participants With V600K Mutation-positive Melanoma With OIR, as Assessed by the Investigator

OIR is defined as the number of participants whose intracranial response was a confirmed complete response (CR) or partial response (PF) assessed by investigators using modified Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1. CR is defined as disappearance of all target lesions. PR is defined as 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). For the primary analysis, OIR was measured when all participants in both treatment arms had two post-Baseline disease assessments. Participants who had an intracranial response of not evaluable or a missing response were treated as non-responders. Confirmation assessments were to be performed no less than 4 weeks after the criteria for response were initially met and may have been performed at the next protocol scheduled assessment.

V600K Population

Posted

Number

participants

From the time of the Baseline assessment until disease progression or end of study treatment (average of 16 weeks)

ID	Title	Description
OG000	GSK2118436 150 mg: No Prior Local Therapy	Participants who received no prior local therapy for brain metastasis received GSK2118436 150 mg capsules either one hour before or 2 hours after a meal twice daily until evidence of disease progression, death, or unacceptable adverse events.
OG001	GSK2118436 150 mg: Prior Local Therapy

Secondary

Duration of Intracranial Response for the Subset of V600E Mutation-positive Participants

Duration of Intracranial Response is defined as the time from the first documented evidence of intracranial CR (disappearance of all target lesions) 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]) until the time of the first documented intracranial 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, 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).

V600E Population. Only the subset of participants who had a complete or partial intracranial response was included in this analysis.

Posted

Median

95% Confidence Interval

weeks

Time from the first documented evidence of intracranial CR or PR until the time of the first documented intracranial disease progression or death due to any cause (average of 27 weeks)

ID	Title	Description
OG000	GSK2118436 150 mg: No Prior Local Therapy	Participants who received no prior local therapy for brain metastasis received GSK2118436 150 mg capsules either one hour before or 2 hours after a meal twice daily until evidence of disease progression, death, or unacceptable adverse events.
OG001

Secondary

Duration of Intracranial Response for the Subset of V600K Mutation-positive Participants

V600K Population. Only the subset of participants who had a complete or partial intracranial response was included in this analysis.

Posted

Median

95% Confidence Interval

weeks

Time from the first documented evidence of intracranial CR or PR until the time of the first documented intracranial disease progression or death due to any cause (average of 31 weeks)

ID	Title	Description
OG000	GSK2118436 150 mg: No Prior Local Therapy	Participants who received no prior local therapy for brain metastasis received GSK2118436 150 mg capsules either one hour before or 2 hours after a meal twice daily until evidence of disease progression, death, or unacceptable adverse events.
OG001

Secondary

Duration of Overall Response for the Subset of V600E Mutation-positive Participants

Duration of Overall Response is defined as the time from the first documented evidence of overall CR (disappearance of all target lesions) 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]) until the time of the first documented 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, 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).

V600E Population. Only the subset of participants who had a complete or partial response was included in this analysis.

Posted

Median

95% Confidence Interval

weeks

Time from the first documented evidence of CR or PR until the time of the first documented disease progression or death due to any cause (average of 28 weeks)

ID	Title	Description
OG000	GSK2118436 150 mg: No Prior Local Therapy	Participants who received no prior local therapy for brain metastasis received GSK2118436 150 mg capsules either one hour before or 2 hours after a meal twice daily until evidence of disease progression, death, or unacceptable adverse events.
OG001	GSK2118436 150 mg: Prior Local Therapy

Secondary

Duration of Overall Response for the Subset of V600K Mutation-positive Participants

V600K Population. Only the subset of participants who had a complete or partial response was included in this analysis.

Posted

Median

95% Confidence Interval

weeks

Time from the first documented evidence of CR or PR until the time of the first documented disease progression or death due to any cause (average of 31 weeks)

ID	Title	Description
OG000	GSK2118436 150 mg: No Prior Local Therapy	Participants who received no prior local therapy for brain metastasis received GSK2118436 150 mg capsules either one hour before or 2 hours after a meal twice daily until evidence of disease progression, death, or unacceptable adverse events.
OG001	GSK2118436 150 mg: Prior Local Therapy

Secondary

Progression-free Survival in V600E Mutation-positive Participants

PFS is defined as the time from the first dose of study medication to the earliest of death or progression (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). If a participant received subsequent anti-cancer therapy prior to the date of documented PD/death, the participant was censored at the last adequate assessment and the visit level response was CR (disappearance of all target lesions), 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]), or stable disease (SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD.

V600E Population

Posted

Median

95% Confidence Interval

weeks

Time from the first dose of study medication to the earliest of death or progression (average of 23 weeks)

ID	Title	Description
OG000	GSK2118436 150 mg: No Prior Local Therapy	Participants who received no prior local therapy for brain metastasis received GSK2118436 150 mg capsules either one hour before or 2 hours after a meal twice daily until evidence of disease progression, death, or unacceptable adverse events.
OG001	GSK2118436 150 mg: Prior Local Therapy

Secondary

Progression-free Survival in V600K Mutation-positive Participants

V600K Population

Posted

Median

95% Confidence Interval

weeks

Time from the first dose of study medication to the earliest of death or progression (average of 17 weeks)

ID	Title	Description
OG000	GSK2118436 150 mg: No Prior Local Therapy	Participants who received no prior local therapy for brain metastasis received GSK2118436 150 mg capsules either one hour before or 2 hours after a meal twice daily until evidence of disease progression, death, or unacceptable adverse events.
OG001	GSK2118436 150 mg: Prior Local Therapy

Secondary

Overall Survival of V600E Mutation-positive Participants

Overall survival (OS) is defined as the time from the first dose of study medication until death due to any cause. OS was censored using the date of last known contact for those participants who were alive at the time of analysis.

V600E Population

Posted

Median

95% Confidence Interval

months

Time from the first dose of study medication until death due to any cause (average of 35 weeks)

ID	Title	Description
OG000	GSK2118436 150 mg: No Prior Local Therapy	Participants who received no prior local therapy for brain metastasis received GSK2118436 150 mg capsules either one hour before or 2 hours after a meal twice daily until evidence of disease progression, death, or unacceptable adverse events.
OG001	GSK2118436 150 mg: Prior Local Therapy	Participants who received prior local therapy for brain metastasis received GSK2118436 150 mg capsules either one hour before or 2 hours after a meal twice daily until evidence of disease progression, death, or unacceptable adverse events.

Units	Counts
Participants

Secondary

Overall Survival in V600K Mutation-positive Participants

V600K Population

Posted

Median

95% Confidence Interval

months

Time from the first dose of study medication until death due to any cause (average of 26 weeks)

ID	Title	Description
OG000	GSK2118436 150 mg: No Prior Local Therapy	Participants who received no prior local therapy for brain metastasis received GSK2118436 150 mg capsules either one hour before or 2 hours after a meal twice daily until evidence of disease progression, death, or unacceptable adverse events.
OG001	GSK2118436 150 mg: Prior Local Therapy	Participants who received prior local therapy for brain metastasis received GSK2118436 150 mg capsules either one hour before or 2 hours after a meal twice daily until evidence of disease progression, death, or unacceptable adverse events.

Units	Counts
Participants

Secondary

Number of Participants With Any Adverse Event (AE) or Serious Adverse Event (SAE)

An AE is any untoward medical occurrence in a participant or clinical investigation participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product. An SAE is any untoward medical occurrence that, at any dose, results in death, is life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, is a congenital anomaly/birth defect, or is an event of possible drug-induced liver injury.

All Treated Subjects (ATS) Population: all participants who received at least one dose of study treatment

Posted

Number

participants

From Screening until the conclusion of the study (up to 103 weeks)

ID	Title	Description
OG000	GSK2118436 150 mg: No Prior Local Therapy	Participants who received no prior local therapy for brain metastasis received GSK2118436 150 mg capsules either one hour before or 2 hours after a meal twice daily until evidence of disease progression, death, or unacceptable adverse events.
OG001	GSK2118436 150 mg: Prior Local Therapy	Participants who received prior local therapy for brain metastasis received GSK2118436 150 mg capsules either one hour before or 2 hours after a meal twice daily until evidence of disease progression, death, or unacceptable adverse events.

Secondary

Number of Participants With a Worst-case on Therapy Change to Grade 3 and Grade 4, or With Any Grade Increase (AGI), From Baseline Grade for Clinical Chemistry Parameters

Clinical chemistry data were summarized at each scheduled assessment according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE, version 4.0). Grade refers to the severity of the toxicity. The CTCAE displays Grades 1 through 5 with unique clinical descriptions of severity for each toxicity based on this general guideline: Grade (G) 1, mild; Grade 2, moderate; Grade 3, severe; Grade 4, life threatening; Grade 5, death related to toxicity. Blood sample was collected for the assessment of glucose, potassium, magnesium, sodium, phosphorus, potassium. aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), creatinine, total bilirubin, albumin, amylase, cholesterol, creatine kinase, gamma glutamyl transferase (GGT), lipase, blood pH, and triglycerides.

ATS Population. Only those participants with data available for the indicated parameters were analyzed.

Posted

Number

participants

From Screening until the conclusion of the study (up to 103 weeks)

ID	Title	Description
OG000	GSK2118436 150 mg	Participants with or without prior local therapy for brain metastasis received GSK2118436 50 mg and 75 mg capsules either one hour before or 2 hours after a meal twice daily.

Units	Counts

Secondary

Number of Participants With the Indicated Hepatobiliary Laboratory Abnormalities

Blood samples were collected for the assessment of hepatobiliary parameters. ALT=alanine aminotranserase; AST=aspartate aminotransferase; ALP=alkaline phosphatase; BIL=total bilirubin; INR=international normalized ratio; ULN=upper limit of normal. Hepato-cellular injury is defined as (ALT/ULN)/(ALP/ULN) >=5.

ATS Population

Posted

Number

participants

From Screening until the conclusion of the study (up to 103 weeks)

ID	Title	Description
OG000	GSK2118436 150 mg: No Prior Local Therapy	Participants who received no prior local therapy for brain metastasis received GSK2118436 150 mg capsules either one hour before or 2 hours after a meal twice daily until evidence of disease progression, death, or unacceptable adverse events.
OG001	GSK2118436 150 mg: Prior Local Therapy	Participants who received prior local therapy for brain metastasis received GSK2118436 150 mg capsules either one hour before or 2 hours after a meal twice daily until evidence of disease progression, death, or unacceptable adverse events.

Units	Counts

Secondary

Number of Participants With a Worst-case on Therapy Change to Grade 3 and Grade 4, or With Any Grade Increase (AGI), From Baseline Grade for Hematology Parameters

Hematology data were summarized at each scheduled assessment according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE, version 4.0). Grade refers to the severity of the toxicity. The CTCAE displays Grades 1 through 5 with unique clinical descriptions of severity for each toxicity based on this general guideline: Grade 1, mild; Grade 2, moderate; Grade 3, severe, Grade 4, life threatening, Grade 5, death related to toxicity. Blood sample was collected for the assessment of hemoglobin, white blood cells, and platelet count.

ATS Population. Only those participants with data available for the indicated parameters were analyzed.

Posted

Number

participants

From Screening until the conclusion of the study (up to 103 weeks)

ID	Title	Description
OG000	GSK2118436 150 mg: No Prior Local Therapy	Participants who received no prior local therapy for brain metastasis received GSK2118436 150 mg capsules either one hour before or 2 hours after a meal twice daily until evidence of disease progression, death, or unacceptable adverse events.
OG001	GSK2118436 150 mg: Prior Local Therapy	Participants who received prior local therapy for brain metastasis received GSK2118436 150 mg capsules either one hour before or 2 hours after a meal twice daily until evidence of disease progression, death, or unacceptable adverse events.

Secondary

Mean Blood Pressure at Baseline and Weeks 4, 8, 12, 16, 20, 24, 28, 32, and 36

Systolic and diastolic blood pressure were measured for all treated participants.

ATS Population. Only those participants with data available at the indicated time points were analyzed.

Posted

Mean

Standard Deviation

millimeters of mercury (mmHg)

Baseline; Weeks 4, 8, 12, 16, 20, 24, 28, 32, and 36

ID	Title	Description
OG000	GSK2118436 150 mg: No Prior Local Therapy	Participants who received no prior local therapy for brain metastasis received GSK2118436 150 mg capsules either one hour before or 2 hours after a meal twice daily until evidence of disease progression, death, or unacceptable adverse events.
OG001	GSK2118436 150 mg: Prior Local Therapy	Participants who received prior local therapy for brain metastasis received GSK2118436 150 mg capsules either one hour before or 2 hours after a meal twice daily until evidence of disease progression, death, or unacceptable adverse events.

Units	Counts
Participants

Secondary

Number of Participants With a Worst-case On-therapy Increase From Baseline in Bazett's QTc Reading in the 12-lead Electrocardiogram (ECG)

An increase in the QTc interval corrected using Bazett's formula (Bazett's QTc) was recorded for all treated participants. Grade 1 (450-480 milliseconds [msec]), Grade 2 (481-500 msec), Grade 3/4 (>=501 msec). An increase is defined as an increase in CTCAE grade relative to Baseline grade.

ATS Population. Only those participants with data available at the indicated time points were analyzed.

Posted

Number

participants

Baseline; Weeks 4, 12, 20, 28, 40, 52, and 64

ID	Title	Description
OG000	GSK2118436 150 mg: No Prior Local Therapy	Participants who received no prior local therapy for brain metastasis received GSK2118436 150 mg capsules either one hour before or 2 hours after a meal twice daily until evidence of disease progression, death, or unacceptable adverse events.
OG001	GSK2118436 150 mg: Prior Local Therapy	Participants who received prior local therapy for brain metastasis received GSK2118436 150 mg capsules either one hour before or 2 hours after a meal twice daily until evidence of disease progression, death, or unacceptable adverse events.

Secondary

Number of Participants With Abnormal Echocardiograms (ECHO) at Weeks 4 and 12

Echocardiograms (ECHO) were measured for all treated participants. An echocardiogram test gives information about the structure and function of the heart. LLN=lower limit of normal (determined by the institution).

ATS Population

Posted

Number

participants

Weeks (W) 4 and 12

ID	Title	Description
OG000	GSK2118436 150 mg: No Prior Local Therapy	Participants who received no prior local therapy for brain metastasis received GSK2118436 150 mg capsules either one hour before or 2 hours after a meal twice daily until evidence of disease progression, death, or unacceptable adverse events.
OG001	GSK2118436 150 mg: Prior Local Therapy	Participants who received prior local therapy for brain metastasis received GSK2118436 150 mg capsules either one hour before or 2 hours after a meal twice daily until evidence of disease progression, death, or unacceptable adverse events.

Units	Counts
Participants

Secondary

Median Concentrations of GSK2118436 and Its Metabolites Including GSK2285403, GSK2298683, and GSK2167542

Summary statistics were calculated for each time point by cohort. The population pharmacokinetics were determined using a non-linear mixed effects modeling approach after pooling the data with other studies. These results are reported separately.

PK Population: participants in the ATS population for whom a PK sample was obtained and analyzed. Only those participants whose samples were available at the indicated time points were analyzed.

Posted

Median

Full Range

nanograms per milliliter (ng/mL)

Week 4 (pre-dose and 1-3 hours post-dose) and Weeks 8, 16, 24, and 32 (either pre-dose in the morning or in the afternoon at 4-8 hours post-dose)

ID	Title	Description
OG000	GSK2118436 150 mg: No Prior Local Therapy	Participants who received no prior local therapy for brain metastasis received GSK2118436 150 mg capsules either one hour before or 2 hours after a meal twice daily until evidence of disease progression, death, or unacceptable adverse events.
OG001	GSK2118436 150 mg: Prior Local Therapy	Participants who received prior local therapy for brain metastasis received GSK2118436 150 mg capsules either one hour before or 2 hours after a meal twice daily until evidence of disease progression, death, or unacceptable adverse events.

Secondary

Composite of Pharmacokinetic Parameters of GSK2118436 in a Subset of Participants Receiving Dexamethasone

This outcome measure could not be analyzed because too few participants participated in the dexamethasone study.

Posted

Day 15

ID	Title	Description
OG000	GSK2118436 150 mg: No Prior Local Therapy	Participants who received no prior local therapy for brain metastasis received GSK2118436 150 mg capsules either one hour before or 2 hours after a meal twice daily until evidence of disease progression, death, or unacceptable adverse events.
OG001	GSK2118436 150 mg: Prior Local Therapy	Participants who received prior local therapy for brain metastasis received GSK2118436 150 mg capsules either one hour before or 2 hours after a meal twice daily until evidence of disease progression, death, or unacceptable adverse events.

Units	Counts
Participants	OG000

Secondary

Number of Response Genetics Incorporated (RGI) Investigational Use Only (IUO) Assay Mutation Positive Participants and THxID BRAF Assay Mutation Positive Participants With the Indicated Best Intracranial Response

The BRAF screening assay determines the specific BRAF mutational status (V600 E and K) in participants with metastatic melanoma who may benefit from treatment with GSK2118436. Per RECIST, version 1.1, CR is defined as the disappearance of all lesions. PR is defined as a >=30% decrease in the sum of the diameters of target lesions, taking as a reference, the Baseline (BL) sum of the diameters (e.g., percent change from BL). Stable disease is defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD). PD is defined as 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 [smallest sum of diameters recorded since treatment start]). In addition, the sum must have an absolute increase from nadir of 5 millimeters. Not evaluable: cannot be classified by a preceding definition.

V600EK and THIDEK Population: all enrolled participants who were V600E or V600K mutation positive by the RGI IUO assay

Posted

Number

participants

Screening

ID	Title	Description
OG000	RGI IUO Mutation Positive Participants	Melanoma participants determined to be positive for the BRAF V600E and V600K mutations as determined by the RGI assay. The RGI assay is a BRAF mutation test developed by Response Genetics Incorporated, and was used to determine eligibility. It employs the allele-specific polymerase chain reaction (ASPCR) methodology, and was offered as an Investigational Use Only assay (only for pre-market investigational purposes).

Serious Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Pyrexia	Gastrointestinal disorders	MedDRA	Systematic Assessment	EG0004 affected89 at risk EG0019 affected83 at risk
Haemorrhage intracranial	Nervous system disorders	MedDRA	Systematic Assessment	EG0002 affected89 at risk EG0013 affected83 at risk
Squamous cell carcinoma	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA	Systematic Assessment	EG0006 affected89 at risk EG0017 affected83 at risk
Headache	Nervous system disorders	MedDRA	Systematic Assessment	EG0002 affected89 at risk EG0012 affected83 at risk
Chills	General disorders	MedDRA	Systematic Assessment	EG0001 affected89 at risk EG0012 affected83 at risk
Hypotension	Vascular disorders	MedDRA	Systematic Assessment	EG0000 affected89 at risk EG0013 affected83 at risk
Atrial fibrillation	Cardiac disorders	MedDRA	Systematic Assessment	EG0002 affected89 at risk EG0010 affected83 at risk
Ejection fraction decreased	Investigations	MedDRA	Systematic Assessment	EG0003 affected89 at risk EG0010 affected83 at risk
Fatigue	General disorders	MedDRA	Systematic Assessment	EG0000 affected89 at risk EG0012 affected83 at risk
Nausea	Gastrointestinal disorders	MedDRA	Systematic Assessment	EG0001 affected89 at risk EG0011 affected83 at risk
Neutropenia	Blood and lymphatic system disorders	MedDRA	Systematic Assessment	EG0002 affected89 at risk EG0010 affected83 at risk
Pancytopenia	Blood and lymphatic system disorders	MedDRA	Systematic Assessment	EG0000 affected89 at risk EG0012 affected83 at risk
Syncope	Nervous system disorders	MedDRA	Systematic Assessment	EG0001 affected89 at risk EG0011 affected83 at risk
Vomiting	Gastrointestinal disorders	MedDRA	Systematic Assessment	EG0000 affected89 at risk EG0012 affected83 at risk
Agranulocytosis	Blood and lymphatic system disorders	MedDRA	Systematic Assessment	EG0000 affected89 at risk EG0011 affected83 at risk
Anaemia	Blood and lymphatic system disorders	MedDRA	Systematic Assessment	EG0000 affected89 at risk EG0011 affected83 at risk
Aphasia	Nervous system disorders	MedDRA	Systematic Assessment	EG0001 affected89 at risk EG0010 affected83 at risk
Arthritis	Musculoskeletal and connective tissue disorders	MedDRA	Systematic Assessment	EG0001 affected89 at risk EG0010 affected83 at risk
Atrial flutter	Cardiac disorders	MedDRA	Systematic Assessment	EG0001 affected89 at risk EG0010 affected83 at risk
Bone pain	Musculoskeletal and connective tissue disorders	MedDRA	Systematic Assessment	EG0000 affected89 at risk EG0011 affected83 at risk
Cerebrovascular accident	Nervous system disorders	MedDRA	Systematic Assessment	EG0000 affected89 at risk EG0011 affected83 at risk
Cholecystitis	Hepatobiliary disorders	MedDRA	Systematic Assessment	EG0000 affected89 at risk EG0011 affected83 at risk
Convulsion	Nervous system disorders	MedDRA	Systematic Assessment	EG0000 affected89 at risk EG0012 affected83 at risk
Deep vein thrombosis	Vascular disorders	MedDRA	Systematic Assessment	EG0000 affected89 at risk EG0011 affected83 at risk
Depressed level of consciousness	Nervous system disorders	MedDRA	Systematic Assessment	EG0000 affected89 at risk EG0011 affected83 at risk
Disseminated intravascular coagulation	Blood and lymphatic system disorders	MedDRA	Systematic Assessment	EG0000 affected89 at risk EG0011 affected83 at risk
Dizziness	Nervous system disorders	MedDRA	Systematic Assessment	EG0000 affected89 at risk EG0011 affected83 at risk
Dyspnoea	Respiratory, thoracic and mediastinal disorders	MedDRA	Systematic Assessment	EG0000 affected89 at risk EG0011 affected83 at risk
Femoral neck fracture	Injury, poisoning and procedural complications	MedDRA	Systematic Assessment	EG0001 affected89 at risk EG0010 affected83 at risk
Hemiparesis	Nervous system disorders	MedDRA	Systematic Assessment	EG0000 affected89 at risk EG0011 affected83 at risk
Hyperglycaemia	Metabolism and nutrition disorders	MedDRA	Systematic Assessment	EG0000 affected89 at risk EG0011 affected83 at risk
Infection	Infections and infestations	MedDRA	Systematic Assessment	EG0001 affected89 at risk EG0010 affected83 at risk
Influenza like illness	General disorders	MedDRA	Systematic Assessment	EG0000 affected89 at risk EG0011 affected83 at risk
Lethargy	Nervous system disorders	MedDRA	Systematic Assessment	EG0000 affected89 at risk EG0011 affected83 at risk
Leukopenia	Blood and lymphatic system disorders	MedDRA	Systematic Assessment	EG0001 affected89 at risk EG0010 affected83 at risk
Mental status changes	Psychiatric disorders	MedDRA	Systematic Assessment	EG0000 affected89 at risk EG0011 affected83 at risk
Mobility decreased	Musculoskeletal and connective tissue disorders	MedDRA	Systematic Assessment	EG0000 affected89 at risk EG0011 affected83 at risk
Motor dysfunction	Nervous system disorders	MedDRA	Systematic Assessment	EG0001 affected89 at risk EG0010 affected83 at risk
Muscular weakness	Musculoskeletal and connective tissue disorders	MedDRA	Systematic Assessment	EG0000 affected89 at risk EG0011 affected83 at risk
Oedema peripheral	General disorders	MedDRA	Systematic Assessment	EG0001 affected89 at risk EG0010 affected83 at risk
Pain	General disorders	MedDRA	Systematic Assessment	EG0001 affected89 at risk EG0010 affected83 at risk
Pancreatitis	Gastrointestinal disorders	MedDRA	Systematic Assessment	EG0001 affected89 at risk EG0010 affected83 at risk
Paraesthesia	Nervous system disorders	MedDRA	Systematic Assessment	EG0000 affected89 at risk EG0011 affected83 at risk
Partial seizures	Nervous system disorders	MedDRA	Systematic Assessment	EG0001 affected89 at risk EG0011 affected83 at risk
Pleural effusion	Respiratory, thoracic and mediastinal disorders	MedDRA	Systematic Assessment	EG0001 affected89 at risk EG0010 affected83 at risk
Pneumonia	Infections and infestations	MedDRA	Systematic Assessment	EG0000 affected89 at risk EG0011 affected83 at risk
Pulmonary embolism	Respiratory, thoracic and mediastinal disorders	MedDRA	Systematic Assessment	EG0002 affected89 at risk EG0010 affected83 at risk
Renal failure	Renal and urinary disorders	MedDRA	Systematic Assessment	EG0001 affected89 at risk EG0010 affected83 at risk
Renal failure acute	Renal and urinary disorders	MedDRA	Systematic Assessment	EG0001 affected89 at risk EG0011 affected83 at risk
Somnolence	Nervous system disorders	MedDRA	Systematic Assessment	EG0000 affected89 at risk EG0011 affected83 at risk
Subileus	Gastrointestinal disorders	MedDRA	Systematic Assessment	EG0001 affected89 at risk EG0010 affected83 at risk
Thrombocytopenia	Blood and lymphatic system disorders	MedDRA	Systematic Assessment	EG0001 affected89 at risk EG0010 affected83 at risk
Thrombosis	Vascular disorders	MedDRA	Systematic Assessment	EG0000 affected89 at risk EG0011 affected83 at risk
Viral pericarditis	Infections and infestations	MedDRA	Systematic Assessment	EG0001 affected89 at risk EG0010 affected83 at risk
Cerebral haemorrhage	Nervous system disorders	MedDRA	Systematic Assessment	EG0002 affected89 at risk EG0011 affected83 at risk
Intracranial tumour haemorrhage	Nervous system disorders	MedDRA	Systematic Assessment	EG0001 affected89 at risk EG0011 affected83 at risk
Bowen's disease	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA	Systematic Assessment	EG0000 affected89 at risk EG0011 affected83 at risk
Cardiac arrest	Cardiac disorders	MedDRA	Systematic Assessment	EG0001 affected89 at risk EG0010 affected83 at risk
Cellulitis	Infections and infestations	MedDRA	Systematic Assessment	EG0001 affected89 at risk EG0010 affected83 at risk
Metastases to meninges	Neoplasms benign, malignant and unspecified (incl cysts and polyps)	MedDRA	Systematic Assessment	EG0001 affected89 at risk EG0010 affected83 at risk
Pain in extremity	Musculoskeletal and connective tissue disorders	MedDRA	Systematic Assessment	EG0000 affected89 at risk EG0011 affected83 at risk
Phlebitis	Vascular disorders	MedDRA	Systematic Assessment	EG0001 affected89 at risk EG0010 affected83 at risk
Urinary tract infection	Infections and infestations	MedDRA	Systematic Assessment	EG0001 affected89 at risk EG0010 affected83 at risk

ID	Term
D018358	Neuroendocrine Tumors
D017599	Neuroectodermal Tumors
D009373	Neoplasms, Germ Cell and Embryonal
D009370	Neoplasms by Histologic Type
D009369	Neoplasms
D009380	Neoplasms, Nerve Tissue
D018326	Nevi and Melanomas
D012878	Skin Neoplasms
D009371	Neoplasms by Site
D012871	Skin Diseases
D017437	Skin and Connective Tissue Diseases
D016543	Central Nervous System Neoplasms
D009423	Nervous System Neoplasms
D001927	Brain Diseases
D002493	Central Nervous System Diseases
D009422	Nervous System Diseases

ID	Title	Description
BG000	GSK2118436 150 mg: No Prior Local Therapy	Participants who received no prior local therapy for brain metastasis received GSK2118436 150 milligram (mg) capsules either one hour before or 2 hours after a meal twice daily until evidence of disease progression, death, or unacceptable adverse events.
BG001	GSK2118436 150 mg: Prior Local Therapy	Participants who received prior local therapy for brain metastasis received GSK2118436 150 mg capsules either one hour before or 2 hours after a meal twice daily until evidence of disease progression, death, or unacceptable adverse events.
BG002	Total	Total of all reporting groups

ID	Title	Description	Deaths (Affected)	Deaths (At Risk)	Serious Events (Affected)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	GSK2118436 150 mg: No Prior Local Therapy	Participants who received no prior local therapy for brain metastasis received GSK2118436 150 mg capsules either one hour before or 2 hours after a meal twice daily until evidence of disease progression, death, or unacceptable adverse events.			26	89	79	89
EG001	GSK2118436 150 mg: Prior Local Therapy	Participants who received prior local therapy for brain metastasis received GSK2118436 150 mg capsules either one hour before or 2 hours after a meal twice daily until evidence of disease progression, death, or unacceptable adverse events.			31	83	74	83