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

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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Melanoma and Brain Metastases

Intervention / Treatment
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* Drug: GSK2118436


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Cohort A: No prior local therapy for brain metastases. Subjects who are receiving concomitant corticosteroids must be on a stable or decreasing dose for at least 3 weeks prior to first dose of study treatment. No prophylactic or preventive anti-epileptic therapy. Exception: anti-epileptic therapy indicated in order to prevent neurologic symptoms caused by a pre-existing condition and not related to brain metastasis is allowed. Cohort B: Subjects must have received at least one local therapy for brain metastases including but not restricted to brain surgery, Whole Brain Radiotherapy or Stereotactic Radiosurgery (e.g. gamma knife, linear-accelerated-based radiosurgery, charged particles, and CyberKnife). Multiple local therapies or combinations of local therapies are allowed. For subjects receiving local therapy to all brain lesions (including WBRT), progression of pre-existing lesions based on RECIST 1.1 (> 20% increase in longest diameter on baseline scan) or new measurable lesions are required. For subjects receiving local therapy for some but not all lesions, disease progression based on RECIST 1.1 is not required as long as there are remaining brain lesions that are measurable and not previously treated. Subjects who are receiving concomitant corticosteroids must be on a stable or decreasing dose for at least 2 weeks prior to first dose of study treatment. Prophylactic or preventive anti-epileptic therapy is allowed. General: Must sign written informed consent. Must be at least 18 years of age. Histologically confirmed metastatic melanoma (Stage IV), carrying BRAF V600E- or V600K-mutation. Up to two previous treatment regimens for extracranial metastatic melanoma including chemo-, cytokine-, immuno-, biological- and vaccine-therapy. At least one measurable intracranial target lesion for which all of the following criteria have to be met: previously untreated or progressive according to RECIST 1.1 (greater than or equal to 20% increase in longest diameter on baseline scan) after previous local therapy immediate local therapy clinically not indicated or patient is not a suitable candidate to receive immediate local therapy largest diameter of greater than or equal to 0.5cm but less than or equal to 4 cm as determined by contrast-enhanced MRI for target lesions (for definition see Section 6.1.1) with diameter of greater than 0.5 cm but less than or equal to 1 cm documented measurement by a neuroradiologist is required. for all lesions with diameter of greater than or equal to 3 cm but less than or equal to 4 cm documented measurement by a neuroradiologist is required. Time interval between last day of previous anti-tumour systemic treatment and first dose of GSK2118436: 14 days elapsed from last treatment with surgery, SRS or gamma knife 28 days elapsed from last treatment with WBRT Greater than or equal to 28 days or five half-lives (whichever is longer) have elapsed from last dose of approved or investigational chemo-, cytokine-, immune-, biological-, or vaccine-therapy. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-1. Adequate organ function. Women with child-bearing potential and men with reproductive potential must be willing to practice acceptable methods of birth control during the study. Women of childbearing potential must have a negative serum pregnancy test within 14 days prior to the first dose of study treatment. Exclusion Criteria: Neurological symptoms related to brain metastasis. Previous treatment with a BRAF or MEK inhibitor. Current or expected use of a prohibited medication during treatment with GSK2118436. Presence of leptomeningeal disease or primary dural metastases. Known allergies against contrast agents required for magnetic resonance imaging (MRI) of intracranial lesions. Current use of therapeutic warfarin. NOTE: Low molecular weight heparin and prophylactic low-dose warfarin are permitted. Unresolved toxicity of National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0 (NCI v4.0) Grade 2 or higher from previous anti-cancer therapy, except alopecia. Presence of active gastrointestinal disease or other condition that will interfere significantly with the absorption of drugs. A history of known Human Immunodeficiency Virus (HIV), Hepatitis B Virus (HBV), or Hepatitis C Virus (HCV) infection. Acute infection requiring intravenous antibiotics History of another malignancy. Exception: (a) Subjects who have been disease-free for 5 years, (b) a history of completely resected non-melanoma skin cancer, (c) successfully treated in situ carcinoma, (d) CLL in stable remission, or (e) indolent prostate cancer requiring no or only anti-hormonal therapy with histologically confirmed tumour lesions that can be clearly differentiated from melanoma target and non-target lesions are eligible. Certain cardiac abnormalities.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Single Arm<br>Single arm with 2 cohorts; Cohort A no previous brain therapy and Cohort B previous brain therapy | Drug: GSK2118436<br>* Subjects in this study receive 150 mg of GSK2118436 twice daily and continue on treatment until disease progression, death, or unacceptable adverse event.<br>* Other names: Dabrafenib;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | 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) | 

Secondary Outcome Measures

| Outcome Measure | 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. | From the time of the Baseline assessment until disease progression or end of study treatment (average of 24 weeks) | 
| Number of Participants With V600K 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. | From the time of the Baseline assessment until disease progression or end of study treatment (average of 17 weeks) | 
| 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. | From the time of the Baseline assessment until disease progression or end of study treatment (average of 16 weeks) | 
| 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). | 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) | 
| Duration of Intracranial Response for the Subset of V600K 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). | 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) | 
| 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). | 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) | 
| Duration of Overall Response for the Subset of V600K 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). | 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) | 
| 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. | Time from the first dose of study medication to the earliest of death or progression (average of 23 weeks) | 
| Progression-free Survival in V600K 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. | Time from the first dose of study medication to the earliest of death or progression (average of 17 weeks) | 
| 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. | Time from the first dose of study medication until death due to any cause (average of 35 weeks) | 
| Overall Survival in V600K 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. | Time from the first dose of study medication until death due to any cause (average of 26 weeks) | 
| 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. | From Screening until the conclusion of the study (up to 103 weeks) | 
| 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. | From Screening until the conclusion of the study (up to 103 weeks) | 
| 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. | From Screening until the conclusion of the study (up to 103 weeks) | 
| 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. | From Screening until the conclusion of the study (up to 103 weeks) | 
| 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. | Baseline; Weeks 4, 8, 12, 16, 20, 24, 28, 32, and 36 | 
| 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. | Baseline; Weeks 4, 12, 20, 28, 40, 52, and 64 | 
| 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). | Weeks (W) 4 and 12 | 
| 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. | 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) | 
| 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. | Day 15 | 
| 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. | Screening | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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GSK2118436, Metastatic melanoma to the brain, Brain metastases, Braf mutation, Brain neoplasm, BRAF inhibitor