Melanoma and Brain MetastasesPhase 2Break MBNCT01266967
A Study of GSK2118436 in BRAF Mutant Metastatic Melanoma to the Brain
A Phase 2 study testing GSK2118436 in people with Melanoma and Brain Metastases, run by GlaxoSmithKline at 24 sites in 6 countries.
Trial summary
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. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Melanoma and Brain Metastases
- What is being tested?
- GSK2118436
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 172 participants
- Where
- 24 sitesin 6 countries
- Study dates
- Feb 2011to Nov 2012
- Phase
- Phase 2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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.
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- 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.
Who cannot join
- 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.
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- 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.
Trial locations and contacts
24 sites in 6 countries.
24 sites in 6 countries
United States9 sites
GSK Investigational Site
Ann Arbor, Michigan, 48019
GSK Investigational Site
Houston, Texas, 77030
GSK Investigational Site
Los Angeles, California, 90095
GSK Investigational Site
Nashville, Tennessee, 37232
GSK Investigational Site
New York, New York, 10065
GSK Investigational Site
Pittsburgh, Pennsylvania, 15232
GSK Investigational Site
San Francisco, California, 94115
GSK Investigational Site
San Francisco, California, 94143
GSK Investigational Site
Seattle, Washington, 98109
France4 sites
GSK Investigational Site
Boulogne-Billancourt, 92100
GSK Investigational Site
Lille, 59037
GSK Investigational Site
Marseille, 13385
GSK Investigational Site
Villejuif, 94805
Australia3 sites
GSK Investigational Site
Nedlands, Western Australia, 6009
GSK Investigational Site
Waratah, New South Wales, 2300
GSK Investigational Site
Westmead, New South Wales, 2145
Canada3 sites
GSK Investigational Site
Edmonton, Alberta, T6G 1Z2
GSK Investigational Site
Montreal, Quebec, H3T 1E2
GSK Investigational Site
Toronto, Ontario, M5G 2M9
Germany3 sites
GSK Investigational Site
Berlin, State of Berlin, 10117
GSK Investigational Site
Essen, North Rhine-Westphalia, 45122
GSK Investigational Site
Kiel, Schleswig-Holstein, 24105
Italy2 sites
GSK Investigational Site
Naples, Campania, 80131
GSK Investigational Site
Padova, Veneto, 35128
About this study
Official title: 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.
- Conditions
- Melanoma and Brain Metastases
- Being tested
- GSK2118436
- Keywords
- GSK2118436, Metastatic melanoma to the brain, Brain metastases, Braf mutation, Brain neoplasm, BRAF inhibitor
- Medical subject headings
- Melanoma, Brain Neoplasms
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
GSK2118436Drug
Also called Dabrafenib
Subjects in this study receive 150 mg of GSK2118436 twice daily and continue on treatment until disease progression, death, or unacceptable adverse event.
| Study group | Role | What they receive |
|---|---|---|
| Single Arm | Experimental | Single arm with 2 cohorts; Cohort A no previous brain therapy and Cohort B previous brain therapy Receives: Drug: GSK2118436 |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: From the time of the Baseline assessment until disease progression or end of study treatment (average of 18.3 weeks)
Secondary outcomes (21)
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.
Measured: 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.
Measured: 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.
Measured: 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).
Measured: 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).
Measured: 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).
Measured: 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).
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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.
Measured: 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).
Measured: 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.
Measured: 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.
Measured: 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.
Measured: Screening
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted24 Dec 2010 (estimated)
- Study startFeb 2011
- Primary completionNov 2011
- Study completionNov 2012
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (3)Papers the sponsor has linked to this study.
- Other trials for Melanoma and Brain MetastasesStudies of the same condition, open and under way.
- More trials run by GlaxoSmithKlineThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 172 participants (actual)
Sponsor and investigators
- Lead sponsor
- GlaxoSmithKline
- Sponsor type
- Industry (pharma, biotech, devices)
- Responsible party
- Sponsor
- Investigators
- GSK Clinical Trials, Study director, GlaxoSmithKline
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT01266967
- Sponsor's protocol ID
- 113929
- Acronym
- Break MB
- Status last verified
- Mar 2014
- First submitted
- 2 Dec 2010
- Last updated
- 8 May 2014
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
Publications
Long GV, Trefzer U, Davies MA, Kefford RF, Ascierto PA, Chapman PB, Puzanov I, Hauschild A, Robert C, Algazi A, Mortier L, Tawbi H, Wilhelm T, Zimmer L, Switzky J, Swann S, Martin AM, Guckert M, Goodman V, Streit M, Kirkwood JM, Schadendorf D. Dabrafenib in patients with Val600Glu or Val600Lys BRAF-mutant melanoma metastatic to the brain (BREAK-MB): a multicentre, open-label, phase 2 trial. Lancet Oncol. 2012 Nov;13(11):1087-95. doi: 10.1016/S1470-2045(12)70431-X. Epub 2012 Oct 8.
PubMed 23051966Santiago-Walker A, Gagnon R, Mazumdar J, Casey M, Long GV, Schadendorf D, Flaherty K, Kefford R, Hauschild A, Hwu P, Haney P, O'Hagan A, Carver J, Goodman V, Legos J, Martin AM. Correlation of BRAF Mutation Status in Circulating-Free DNA and Tumor and Association with Clinical Outcome across Four BRAFi and MEKi Clinical Trials. Clin Cancer Res. 2016 Feb 1;22(3):567-74. doi: 10.1158/1078-0432.CCR-15-0321. Epub 2015 Oct 7.
PubMed 26446943Ouellet D, Gibiansky E, Leonowens C, O'Hagan A, Haney P, Switzky J, Goodman VL. Population pharmacokinetics of dabrafenib, a BRAF inhibitor: effect of dose, time, covariates, and relationship with its metabolites. J Clin Pharmacol. 2014 Jun;54(6):696-706. doi: 10.1002/jcph.263. Epub 2014 Jan 17.
PubMed 24408395
Study at a glance
From the registry record, last updated by the sponsor on 8 May 2014. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- 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
- ClinicalTrials.gov ID
- NCT01266967
- Acronym / sponsor ID
- Break MB / 113929
- Conditions
- Melanoma and Brain Metastases
- Keywords
- GSK2118436, Metastatic melanoma to the brain, Brain metastases, Braf mutation, Brain neoplasm, BRAF inhibitor
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 172 participants (actual)
- Lead sponsor
- GlaxoSmithKlineIndustry (pharma, biotech, devices)
- Study start
- Feb 2011
- Primary completion
- Nov 2011 (actual)
- Study completion
- Nov 2012 (actual)
- First posted
- 24 Dec 2010 (estimated)
- Results
- Posted 5 Mar 2014
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Single Arm | Experimental | Drug: GSK2118436Single arm with 2 cohorts; Cohort A no previous brain therapy and Cohort B previous brain therapy |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (27 listed)
- 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:
Key exclusion criteria (12 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| GSK2118436Also: DabrafenibSubjects in this study receive 150 mg of GSK2118436 twice daily and continue on treatment until disease progression, death, or unacceptable adverse event. | Drug | Single Arm |
Primary outcome
Number of Participants With BRAF V600E Mutation-positive Melanoma With Overall Intracranial Response (OIR), as Assessed by the Investigator
Time frame: From the time of the Baseline assessment until disease progression or end of study treatment (average of 18.3 weeks)
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.
21 secondary outcomes
Number of Participants With V600E Mutation-positive Melanoma With a Best Overall Response (OR) of CR or PR, as Assessed by the Investigator
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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
Time frame: 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)
Time frame: 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
Time frame: From Screening until the conclusion of the study (up to 103 weeks)
Number of Participants With the Indicated Hepatobiliary Laboratory Abnormalities
Time frame: 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
Time frame: 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
Time frame: 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)
Time frame: Baseline; Weeks 4, 12, 20, 28, 40, 52, and 64
Number of Participants With Abnormal Echocardiograms (ECHO) at Weeks 4 and 12
Time frame: Weeks (W) 4 and 12
Median Concentrations of GSK2118436 and Its Metabolites Including GSK2285403, GSK2298683, and GSK2167542
Time frame: 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
Time frame: 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
Time frame: Screening
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 8 May 2014.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Background: PubMed 23051966Long GV, Trefzer U, Davies MA, Kefford RF, Ascierto PA, Chapman PB, Puzanov I, Hauschild A, Robert C, Algazi A, Mortier L, Tawbi H, Wilhelm T, Zimmer L, Switzky J, Swann S, Martin AM, Guckert M, Goodman V, Streit M, Kirkwood JM, Schadendorf D. Dabrafenib in patients with Val600Glu or Val600Lys BRAF-mutant melanoma metastatic to the brain (BREAK-MB): a multicentre, open-label, phase 2 trial. Lancet Oncol. 2012 Nov;13(11):1087-95. doi: 10.1016/S1470-2045(12)70431-X. Epub 2012 Oct 8.
- Derived from this study: PubMed 26446943Santiago-Walker A, Gagnon R, Mazumdar J, Casey M, Long GV, Schadendorf D, Flaherty K, Kefford R, Hauschild A, Hwu P, Haney P, O'Hagan A, Carver J, Goodman V, Legos J, Martin AM. Correlation of BRAF Mutation Status in Circulating-Free DNA and Tumor and Association with Clinical Outcome across Four BRAFi and MEKi Clinical Trials. Clin Cancer Res. 2016 Feb 1;22(3):567-74. doi: 10.1158/1078-0432.CCR-15-0321. Epub 2015 Oct 7.
- Derived from this study: PubMed 24408395Ouellet D, Gibiansky E, Leonowens C, O'Hagan A, Haney P, Switzky J, Goodman VL. Population pharmacokinetics of dabrafenib, a BRAF inhibitor: effect of dose, time, covariates, and relationship with its metabolites. J Clin Pharmacol. 2014 Jun;54(6):696-706. doi: 10.1002/jcph.263. Epub 2014 Jan 17.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
GSK Clinical Trials study director
GlaxoSmithKline
24 sites in 6 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing GSK2118436 in people with Melanoma and Brain Metastases, run by GlaxoSmithKline at 24 sites in 6 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 27 inclusion and 12 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 8 May 2014. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 24 sites in United States, France, Australia, Canada, Germany and 1 more country. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 5 Mar 2014). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Number of Participants With BRAF V600E Mutation-positive Melanoma With Overall Intracranial Response (OIR), as Assessed by the Investigator (time frame: From the time of the Baseline assessment until disease progression or end of study treatment (average of 18.3 weeks)). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT01266967, which also lists 3 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 8 May 2014.