Clinical trial NCT01266967: A Study of GSK2118436 in BRAF Mutant Metastatic Melanoma to the Brain
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Melanoma and Brain Metastases
Keywords: GSK2118436
Metastatic melanoma to the brain
Brain metastases
Braf mutation
Brain neoplasm
BRAF inhibitor
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
First posted: 2010-12-24
Enrollment: 172
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief 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. 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.


Eligibility criteria: 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.

Primary outcomes:
measure: Number of Participants With BRAF V600E Mutation-positive Melanoma With Overall Intracranial Response (OIR), as Assessed by the Investigator
timeFrame: From the time of the Baseline assessment until disease progression or end of study treatment (average of 18.3 weeks)
Secondary outcomes:
measure: Number of Participants With V600E Mutation-positive Melanoma With a Best Overall Response (OR) of CR or PR, as Assessed by the Investigator
timeFrame: From the time of the Baseline assessment until disease progression or end of study treatment (average of 24 weeks)
measure: Number of Participants With V600K Mutation-positive Melanoma With a Best Overall Response (OR) of CR or PR, as Assessed by the Investigator
timeFrame: From the time of the Baseline assessment until disease progression or end of study treatment (average of 17 weeks)
measure: Number of Participants With V600K Mutation-positive Melanoma With OIR, as Assessed by the Investigator
timeFrame: From the time of the Baseline assessment until disease progression or end of study treatment (average of 16 weeks)
measure: Duration of Intracranial Response for the Subset of V600E Mutation-positive Participants
timeFrame: 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)
measure: Duration of Intracranial Response for the Subset of V600K Mutation-positive Participants
timeFrame: 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)
measure: Duration of Overall Response for the Subset of V600E Mutation-positive Participants
timeFrame: 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)
measure: Duration of Overall Response for the Subset of V600K Mutation-positive Participants
timeFrame: 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)
measure: Progression-free Survival in V600E Mutation-positive Participants
timeFrame: Time from the first dose of study medication to the earliest of death or progression (average of 23 weeks)
measure: Progression-free Survival in V600K Mutation-positive Participants
timeFrame: Time from the first dose of study medication to the earliest of death or progression (average of 17 weeks)
measure: Overall Survival of V600E Mutation-positive Participants
timeFrame: Time from the first dose of study medication until death due to any cause (average of 35 weeks)
measure: Overall Survival in V600K Mutation-positive Participants
timeFrame: Time from the first dose of study medication until death due to any cause (average of 26 weeks)
measure: Number of Participants With Any Adverse Event (AE) or Serious Adverse Event (SAE)
timeFrame: From Screening until the conclusion of the study (up to 103 weeks)
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
timeFrame: From Screening until the conclusion of the study (up to 103 weeks)
measure: Number of Participants With the Indicated Hepatobiliary Laboratory Abnormalities
timeFrame: From Screening until the conclusion of the study (up to 103 weeks)
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
timeFrame: From Screening until the conclusion of the study (up to 103 weeks)
measure: Mean Blood Pressure at Baseline and Weeks 4, 8, 12, 16, 20, 24, 28, 32, and 36
timeFrame: Baseline; Weeks 4, 8, 12, 16, 20, 24, 28, 32, and 36
measure: Number of Participants With a Worst-case On-therapy Increase From Baseline in Bazett's QTc Reading in the 12-lead Electrocardiogram (ECG)
timeFrame: Baseline; Weeks 4, 12, 20, 28, 40, 52, and 64
measure: Number of Participants With Abnormal Echocardiograms (ECHO) at Weeks 4 and 12
timeFrame: Weeks (W) 4 and 12
measure: Median Concentrations of GSK2118436 and Its Metabolites Including GSK2285403, GSK2298683, and GSK2167542
timeFrame: 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)
measure: Composite of Pharmacokinetic Parameters of GSK2118436 in a Subset of Participants Receiving Dexamethasone
timeFrame: Day 15
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
timeFrame: Screening
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: GSK Investigational Site
state: California
city: San Francisco
country: United States
facility: GSK Investigational Site
state: California
city: San Francisco
country: United States
facility: GSK Investigational Site
state: California
city: Ann Arbor
country: United States
facility: GSK Investigational Site
state: Michigan
city: New York
country: United States
facility: GSK Investigational Site
state: New York
city: Pittsburgh
country: United States
facility: GSK Investigational Site
state: Pennsylvania
city: Nashville
country: United States
facility: GSK Investigational Site
state: Tennessee
city: Houston
country: United States
facility: GSK Investigational Site
state: Texas
city: Seattle
country: United States
facility: GSK Investigational Site
state: Washington
city: Waratah
country: Australia
facility: GSK Investigational Site
state: New South Wales
city: Westmead
country: Australia
facility: GSK Investigational Site
state: New South Wales
city: Nedlands
country: Australia
facility: GSK Investigational Site
state: Western Australia
city: Edmonton
country: Canada
facility: GSK Investigational Site
state: Alberta
city: Toronto
country: Canada
facility: GSK Investigational Site
state: Ontario
city: Montreal
country: Canada
facility: GSK Investigational Site
state: Quebec
city: Boulogne-Billancourt
country: France
facility: GSK Investigational Site
city: Lille
country: France
facility: GSK Investigational Site
city: Marseille Cedex 5
country: France
facility: GSK Investigational Site
city: Villejuif
country: France
facility: GSK Investigational Site
city: Essen
country: Germany
facility: GSK Investigational Site
state: Nordrhein-Westfalen
city: Kiel
country: Germany
facility: GSK Investigational Site
state: Schleswig-Holstein
city: Berlin
country: Germany
facility: GSK Investigational Site
city: Napoli
country: Italy
facility: GSK Investigational Site
state: Campania
city: Padova
country: Italy
facility: GSK Investigational Site
state: Veneto
Study officials:
affiliation: GlaxoSmithKline
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References:
citation: 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.
citation: Santiago-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.
citation: Ouellet 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.