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Report for Clinical Trial NCT01266967

Developed by Shray Alag, 2020.
SNP Clinical Trial Gene

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

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.

NCT01266967 Melanoma and Brain Metastases
MeSH: Melanoma Neoplasm Metastasis
HPO: Cutaneous melanoma Melanoma

1 Interventions

Name: GSK2118436

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

Type: Drug

Single Arm


Primary Outcomes

Description: 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.

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

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

Secondary Outcomes

Description: 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.

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

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

Description: 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.

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

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

Description: 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.

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

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

Description: 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).

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

Time: 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)

Description: 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).

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

Time: 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)

Description: 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).

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

Time: 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)

Description: 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).

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

Time: 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)

Description: 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.

Measure: Progression-free Survival in V600E Mutation-positive Participants

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

Description: 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.

Measure: Progression-free Survival in V600K Mutation-positive Participants

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

Description: 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.

Measure: Overall Survival of V600E Mutation-positive Participants

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

Description: 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.

Measure: Overall Survival in V600K Mutation-positive Participants

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

Description: 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.

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

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

Description: 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.

Measure: 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

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

Description: 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.

Measure: Number of Participants With the Indicated Hepatobiliary Laboratory Abnormalities

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

Description: 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.

Measure: 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

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

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

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

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

Description: 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.

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

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

Description: 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).

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

Time: Weeks (W) 4 and 12

Description: 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.

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

Time: 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)

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

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

Time: Day 15

Description: 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.

Measure: 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

Time: Screening

Purpose: Treatment

Allocation: Non-Randomized

Single Group Assignment


There are 2 SNPs

SNPs


1 V600E

A Study of GSK2118436 in BRAF Mutant Metastatic Melanoma to the Brain 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. --- V600E ---

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

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

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 for the Subset of V600E Mutation-positive Participants. --- V600E ---

In addition, the sum must have an absolute increase from nadir of 5 millimeters (mm).. Duration of Overall Response for the Subset of V600E Mutation-positive Participants. --- V600E ---

In addition, the sum must have an absolute increase from nadir of 5 millimeters (mm).. Progression-free Survival in V600E Mutation-positive Participants. --- V600E ---

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 of V600E Mutation-positive Participants. --- V600E ---

- Histologically confirmed metastatic melanoma (Stage IV), carrying BRAF V600E- or V600K-mutation. --- V600E ---


2 V600K

A Study of GSK2118436 in BRAF Mutant Metastatic Melanoma to the Brain 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. --- V600E --- --- V600K ---

Participants who had an overall response of not evaluable or a missing response were treated as non-responders.. Number of Participants With V600K Mutation-positive Melanoma With a Best Overall Response (OR) of CR or PR, as Assessed by the Investigator. --- V600K ---

Participants who had an overall response of not evaluable or a missing response were treated as non-responders.. Number of Participants With V600K Mutation-positive Melanoma With OIR, as Assessed by the Investigator. --- V600K ---

In addition, the sum must have an absolute increase from nadir of 5 millimeters (mm).. Duration of Intracranial Response for the Subset of V600K Mutation-positive Participants. --- V600K ---

In addition, the sum must have an absolute increase from nadir of 5 millimeters (mm).. Duration of Overall Response for the Subset of V600K Mutation-positive Participants. --- V600K ---

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.. Progression-free Survival in V600K Mutation-positive Participants. --- V600K ---

OS was censored using the date of last known contact for those participants who were alive at the time of analysis.. Overall Survival in V600K Mutation-positive Participants. --- V600K ---

- Histologically confirmed metastatic melanoma (Stage IV), carrying BRAF V600E- or V600K-mutation. --- V600E --- --- V600K ---



HPO Nodes


HPO:
Cutaneous melanoma
Genes 15
HRAS MITF CDKN2A BRAF NRAS NRAS WRN CDKN2A CXCR4 BAP1 POLH CDK4 ERCC3 XPC MC1R
Melanoma
Genes 98
MGMT NRAS POT1 NRAS XPA CTSC BRCA1 SDHC ERCC4 CXCR4 RAD51C CDKN2B ERCC3 XPC PALLD ERCC2 ERCC2 CHEK2 CDKN2A RAD51D GNAQ SDHD KRAS MBTPS2 BAP1 BAP1 CYSLTR2 RNF43 BAP1 CDKN2A PTPN11 CDK4 BRCA2 ERCC3 MITF TERF2IP ERCC4 CHEK2 BRCA1 TRPV3 POT1 OCA2 TERT CDKN2A AKT1 CDKN2A SF3B1 ERCC6 ERCC5 ERCC5 MDM2 BRCA2 BAP1 GNA11 ACD BRIP1 HRAS MRE11 BRAF TYR TP53 KLLN SEC23B PTEN PIK3CA XPA PERP MITF RAF1 BRAF POLH TP53 BARD1 NRAS SMAD4 RAD50 DDB2 ERCC2 NBN TERT MC1R SLC45A2 WRN PALB2 DDB2 PALB2 CDKN2A SDHB MC1R RAD51 TP53 XPC ERCC3 PTEN CDKN2A POLH CDK4 MC1R