Neoplasms

Skin and Connective Tissue Diseases

All Conditions

Symptoms and General Pathology

Nervous System Diseases

Rare Diseases

Melanoma

Neoplasm Metastasis

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

Channel Blockers

Trametinib

Dabrafenib

Gallopamil

Protein Kinase Inhibitors

Enzyme Inhibitors

Subjects will receive dabrafenib 150 milligram (mg) twice daily and trametinib 2 mg once daily until evidence of disease progression, death, or unacceptable toxicity.

Subjects will receive dabrafenib 150 mg twice daily and trametinib 2 mg once daily until evidence of disease progression, death, or unacceptable toxicity

Dabrafenib will be provided as 50 mg and 75 mg capsules

Trametinib will be provided as 0.5 mg and 2.0 mg tablets

Novartis Pharmaceuticals

This is a multi-cohort, open label, Phase II study with Dabrafenib (GSK2118436) and Trametinib (GSK1120212) combination therapy in subject with BRAF mutation-positive melanoma that has metastasized to the brain. This study will evaluate the safety and efficacy of 4 cohorts. Cohorts will consist of; V600 E, D, K, R mutations, metastases to the brain, symptomatic and asymptomatic, with or without prior local (brain) therapy, with or without prior local (brain) therapy, and range of ECOG scores from 0-2.

Study to Evaluate Treatment of Dabrafenib Plus Trametinib in Subjects With BRAF Mutation-Positive Melanoma That Has Metastasized to the Brain

BRF117277: A Phase II, Open-Label, Multicentre Study of Dabrafenib Plus Trametinib in Subjects With BRAF Mutation-Positive Melanoma That Has Metastasized to the Brain

The intracranial response rate is defined as the percentage of subjects achieving a confirmed intracranial CR or PR. This is based on investigator-assessed best intracranial response.

The intracranial response rate is defined as the percentage of subjects achieving a confirmed intracranial CR or PR. This is based on investigator-assessed best intracranial response. No hypothesis testing completed for cohort A, B,C and D

Disease Control rate is defined as the percentage of subjects achieving a confirmed intracranial/extracranial/overall CR or PR or SD or Non-CR/Non-PD. This is based on investigator-assessed response. No hypothesis testing completed for cohort A, B,C and D

Extracranial Response Rate was defined as the percentage of participants with Complete response (CR) or Partial response (PR) at anytime. This is based on investigator-assessed response. No hypothesis testing completed for cohort A,B,C and D

the number of subjects with a confirmed overall Complete response (CR) or Partial response (PR) by investigator assessment using the Response evaluation criteria in solid tumors (RECIST 1.1 criteria). To determine the overall response, all target and non-target lesions will be assessed using modified RECIST 1.1 criteria.

Duration of intracranial, extracranial and overall response, are defined as the time from first documented evidence of CR or PR until time of first documented intracranial, extracranial, or overall disease progression. No hypothesis testing completed for cohort A,B,C and D

PFS is defined as the interval between first dose and the earliest date of disease progression or death due to any cause. No hypothesis testing completed for cohort A,B,C and D

Overall survival (OS) is defined as the time from the first dose until death due to any cause. No hypothesis testing completed for cohort A,B,C and D

Cohort A

Cohort B

Cohort C

Cohort D

Total

Age, Continuous

Sex: Female, Male

Race (NIH/OMB)

Study Director

All Treated population - All subjects who receive at least one dose of study medication are comprised the All Treated subjects (ATS) population.

Intracranial Response (IR) Rate in Cohort A

All Treated population - All subjects who receive at least one dose of study medication are comprised the All Treated subjects (ATS) population

Intracranial Response Rate of Cohorts B, C and D

Intracranial

Extra cranial

Overall rate

Disease Control for Intracranial, Extracranial and Overall Response for Each Cohort

Extracranial Response Rate (ER) for Each Cohort

Overall Response (OR) for Each Cohort

Duration of intracranial

Duration of extracranial

Duration of Overall Response

Duration of Intracranial, Extracranial and Overall Response for Each Cohort

Progression-free Survival (PFS) for Each Cohort Based on Investigator Assessment

Overall Survival (OS) for Each Cohort

Overall Study

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.

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

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

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Study to Evaluate Treatment of Dabrafenib Plus Trametinib in Subjects With BRAF Mutation-Positive Melanoma That Has Metastasized to the Brain	NCT02039947	Melanoma and Br...	Dabrafenib Trametinib	18 Years -	Novartis
A Study of GSK2118436 in BRAF Mutant Metastatic Melanoma to the Brain	NCT01266967	Melanoma and Br...	GSK2118436	18 Years -	GlaxoSmithKline
Dabrafenib/Trametinib, BRAF or BRAF AND MEK Pre-op With BRAF and MEK Post-op, Phase IIB, Melanoma With Brain Mets,Biomarkers and Metabolites	NCT01978236	Melanoma and Br...	Dabrafenib 150 ... Trametinib 2.0 ...	18 Years -	GlaxoSmithKline
Dabrafenib/Trametinib, BRAF or BRAF AND MEK Pre-op With BRAF and MEK Post-op, Phase IIB, Melanoma With Brain Mets,Biomarkers and Metabolites	NCT01978236	Melanoma and Br...	Dabrafenib 150 ... Trametinib 2.0 ...	18 Years -	GlaxoSmithKline

Spots Global Cancer Trial Database for melanoma and brain metastases