Neoplasms

Symptoms and General Pathology

All Conditions

Skin and Connective Tissue Diseases

Nervous System Diseases

Rare Diseases

Neoplasm Metastasis

Melanoma

Brain Neoplasms

Neuroendocrine Tumors

Neuroectodermal Tumors

Neuroectodermal Tumors, Primitive

Neoplasms, Germ Cell and Embryonal

Neoplasms by Histologic Type

Neoplasms, Nerve Tissue

Nevus, Pigmented

Nevus

Nevi and Melanomas

Skin Neoplasms

Skin Diseases

Neoplastic Processes

Central Nervous System Neoplasms

Nervous System Neoplasms

Brain Diseases

Central Nervous System Diseases

Neuroendocrine Tumor

Neuroepithelioma

Antineoplastic Agents

All Drugs and Chemicals

Dabrafenib

Protein Kinase Inhibitors

Enzyme Inhibitors

Single arm with 2 cohorts; Cohort A no previous brain therapy and Cohort B previous brain therapy

Subjects in this study receive 150 mg of GSK2118436 twice daily and continue on treatment until disease progression, death, or unacceptable adverse event.

GSK2118436

GSK Clinical Trials

This study is designed to assess the efficacy, pharmacokinetics, safety, and tolerability of an oral, twice daily dose of 150 mg GSK2118436 administered to subjects with BRAF V600E or V600K mutation-positive metastatic melanoma to the brain. Subjects in Cohort A will not have received any local brain therapy, and subjects in Cohort B will have received prior local therapy for brain metastases. Subjects will continue on treatment until disease progression, death, or unacceptable adverse event.

A Study of GSK2118436 in BRAF Mutant Metastatic Melanoma to the Brain

BRF113929: An Open-Label, Two-Cohort, Multicentre Study of GSK2118436 as a Single Agent in Treatment Naïve and Previously Treated Subjects With BRAF Mutation-Positive Metastatic Melanoma to the Brain

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.

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.

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.

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).

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).

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.

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.

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.

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.

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.

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.

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

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.

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).

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.

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

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.

GlaxoSmithKline

SAEs and non-serious AEs were collected in the All Treated Subjects (ATS) Population, comprised of all participants who received at least one dose of study medication.

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.

GSK2118436 150 mg: No 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.

GSK2118436 150 mg: 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.

Total

Age, Continuous

Sex: Female, Male

White

Not reported

Race was not reported for one participant who recevied prior local therapy.

Race/Ethnicity, Customized

GSK Response Center

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

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

Number of Participants With V600E 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

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

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

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

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

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

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

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

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

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

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

Progression-free Survival in V600E Mutation-positive Participants

Progression-free Survival in V600K Mutation-positive Participants

Overall Survival of V600E Mutation-positive Participants

Overall Survival in V600K Mutation-positive Participants

Any AE

Any SAE

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

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

Glucose (hyperglycemia), AGI, n=165

Glucose (hyperglycemia), Increase to G 3, n=165

Glucose (hyperglycemia), Increase to G 4, n=165

Glucose (hypoglycemia), AGI, n=165

Glucose (hypoglycemia), Increase to G 3, n=165

Glucose (hypoglycemia), Increase to G 4, n=165

Magnesium (hypermagnesemia) AGI, n=165

Magnesium (hypermagnesemia), Increase to G 3,n=165

Magnesium (hypermagnesemia), Increase to G 4,n=165

Magnesium (hypomagnesemia), AGI, n=165

Magnesium (hypomagnesemia), Increase to G 3, n=165

Magnesium (hypomagnesemia), Increase to G 4, n=165

Sodium (hypernatremia), AGI, n=165

Sodium (hypernatremia), Increase to G 3, n=165

Sodium (hypernatremia), Increase to G 4, n=165

Sodium (hyponatremia), AGI, n=165

Sodium (hyponatremia), Increase to G 3, n=165

Sodium (hyponatremia), Increase to G. 4, n=165

Phosphorus inorganic, AGI, n=165

Phosphorus inorganic, Increase to G 3, n=165

Phosphorus inorganic, Increase to G 4, n=165

Potassium (hyperkalemia), AGI, n=165

Potassium (hyperkalemia), Increase to G 3, n=165

Potassium (hyperkalemia), Increase to G 4, n=165

Potassium (hypokalemia), AGI, n=165

Potassium (hypokalemia), Increase to G 3, n=165

Potassium (hypokalemia), Increase to G 4, n=165

ALP, AGI, n=165

ALP, Increase to G 3, n=165

ALP, Increase to G 4, n=165

AST, AGI, n=165

AST, Increase to G 3, n=165

AST, Increase to G 4, n=165

ALT, AGI, n=165

ALT, Increase to G 3, n=165

ALT, Increase to G 4, n=165

Creatinine, AGI, n=165

Creatinine, Increase to G 3, n=165

Creatinine, Increase to G 4, n=165

Total bilirubin, AGI, n=163

Total bilirubin, Increase to G 3 n=163

Total bilirubin, Increase to G 4 n=163

Albumin, AGI, n=27

Albumin, Increase to G 3, n=27

Albumin, Increase to G 4, n=27

Amylase, AGI, n=16

Amylase, Increase to G 3, n=16

Amylase, Increase to G 4, n=16

Cholesterol, AGI, n=2

Cholesterol, Increase to G 3, n=2

Cholesterol, Increase to G 4, n=2

Creatine kinase, AGI, n=6

Creatine kinase, Increase to G 3, n=6

Creatine kinase, Increase to G 4, n=6

GGT, AGI, n=22

GGT, Increase to G 3, n=22

GGT, Increase to G 4, n=22

Lipase, AGI, n=19

Lipase, Increase to G 3, n=19

Lipase, Increase to G 4, n=19

Blood pH, AGI, n=1

Blood pH, Increase to G 3, n=1

Blood pH, Increase to G 4, n=1

Triglycerides, AGI, n=5

Triglycerides, Increase to G 3, n=5

Triglycerides, Increase to G 4, n=5

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.

GSK2118436 150 mg

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

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

Possible HYs Law, >3x ULN ALT, >=2x ULN BIL

Possible HYs Law, >3x ULN ALT, >1.5x ULN INR

Hepato-cellular injury

Bilirubin elevations, >=2x ULN BIL

Bilirubin elevations, >=2x ULN BIL and <2x ULN BIL

ALT or AST elevations, >3x ULN ALT or AST

ALT or AST elevations, >5x ULN ALT or AST

ALT or AST elevations, >8x ULN ALT or AST

ALT or AST elevations, >20x ULN ALT or AST

ALT elevations, >3x ULN ALT

ALT elevations, >5x ULN ALT

ALT elevations, >8x ULN ALT

ALT elevations, >20x ULN ALT

ALT elevations, >3x ULN ALT, <=3x ULN ALT Baseline

ALP elevations, >=3x ULN ALP

ALP elevations, >=3x ULN ALP and <3x ULN ALP

Number of Participants With the Indicated Hepatobiliary Laboratory Abnormalities

Hemoglobin (anemia), AGI

Hemoglobin (anemia), Increase to Grade 3

Hemoglobin (anemia), Increase to Grade 4

Hemoglobin (increased), AGI

Hemoglobin (increased), Increase to Grade 3

Hemoglobin (increased), Increase to Grade 4

Lymphocyte count increased, AGI

Lymphocyte count increased, Increase to Grade 3

Lymphocyte count increased, Increase to Grade 4

Lymphocyte count decreased, AGI

Lymphocyte count decreased, Increase Grade 3

Lymphocyte count decreased, Increase Grade 4

Total neutrophils, AGI,

Total neutrophils, Increase to Grade 3

Total neutrophils, Increase to Grade 4

Platelet count, AGI

Platelet count, Increase to Grade 3

Platelet count, Increase to Grade 4

White blood cell count, AGI

White blood cell count, Increase to Grade 3

White blood cell count, Increase to Grade 4

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

Spots Global Cancer Trial Database for A Study of GSK2118436 in BRAF Mutant Metastatic Melanoma to the Brain

Trial Identification

Conditions

Interventions

Study Description

Keywords

Eligibility

Locations

Contact Details

Useful links and downloads for this trial