Clinical trial NCT01978236: Dabrafenib/Trametinib, BRAF or BRAF AND MEK Pre-op With BRAF and MEK Post-op, Phase IIB, Melanoma With Brain Mets,Biomarkers and Metabolites
Official title: An Open-Label, Multicentre, Corollary Study of Pre-Operative Therapy With Dabrafenib and the Combination of Dabrafenib With Trametinib in Subjects With BRAF Mutation-Positive Metastatic Melanoma to the Brain
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Melanoma and Brain Metastases
Keywords: BRAF V600E mutation
brain metastases
BRAF V600K mutation
Metastatic melanoma
BRAF inhibitor
brain neoplasms
GSK2118436
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
First posted: 2013-11-07
Enrollment: 6
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: This is a global, multi-centre, open-label, study of GSK2118436 conducted in up to 30 evaluable subjects with resectable, BRAF V600E or V600K mutation-positive metastatic melanoma to the brain. All subjects in this study are required to have accessible extracranial metastases and are agreeable to undergo repetitive biopsies. The first cohort of 15 subjects will receive dabrafenib orally 150mg twice daily (BID) for 7 to 14 days prior to surgery (Cohort A); the second cohort of 15 subjects will receive the combination of dabrafenib 150 mg BID and trametinib 2 mg once daily for 7 to 14 days prior to surgery (Cohort B). The primary purpose of this study is to determine levels and distribution of dabrafenib, its metabolites, and trametinib (Cohort B only) in parenchymal brain metastases, extracranial metastases, and peripheral blood (plasma) within two cohorts of subjects with BRAF V600E/K mutation-positive melanoma that has metastasized to the brain. All subjects will be followed for survival and new anti-cancer therapy for a total of two years or until death or the subject wishes to withdraw from further follow-up.


Eligibility criteria: Inclusion Criteria:

* Signed written informed consent
* Histologically-confirmed metastatic melanoma (Stage IV), carrying BRAF V600E or V600K mutation as determined by testing certified for clinical diagnostic purposes. Previously performed certified BRAF testing is acceptable. If no prior BRAF mutation testing results are available, testing of a distant metastasis is preferred, but testing of a regional metastasis or primary tumor is also acceptable
* At least one intracranial lesion \>=1.0 cm but \<=4.0 cm that can be treated with surgical resection in the opinion of the treating physicians, and for which immediate local therapy is not clinically indicated
* At least two extracranial lesions that are easily accessible for biopsy, in the judgment of the treating physician. Easily accessible tumors may include cutaneous, subcutaneous, and superficial lymph node metastases.
* Age \>18 years of age.
* Able to swallow and retain oral medication
* Women with child-bearing 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 of first dose of study treatment.
* Must be able to understand and comply with protocol requirements and instructions
* Eastern Co-operative Oncology Group (ECOG) performance status of 0-2
* Must have adequate organ function as defined by the following screening values (Retesting of borderline screening organ function and treatment with blood transfusions, growth factors etc. will be allowed):
* Absolute neutrophil count (ANC) \>=1.2x10\^9/L
* Hemoglobin \>=9 g/dL
* Platelets \>=100x10\^9/L
* Serum bilirubin \<=1.5 x upper limit of normal (ULN)
* Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) \<=2.5xULN
* Serum creatinine \<=1.5 mg/dL (If serum creatinine is \>1.5 mg/dL, calculate creatinine clearance using standard Cockcroft and Gault Method Creatinine clearance must be \>50 mL/min)
* Prothrombin time (PT)/International normalized ratio (INR) and partial thromboplastin time (PTT) \<=1.3xULN
* Left ventricular ejection fraction (LVEF) \>= institutional lower limit of normal (LLN)

Exclusion Criteria:

* Neurological symptoms related to brain metastasis that are not controlled with a stable or decreasing dose of oral steroids for at least 7 days prior to starting GSK2118436
* Prior Central Nervous System (CNS)-directed local therapies, including surgical resection, whole brain radiation (WBRT), Stereotactic radiosurgery (SRS), or gamma knife (GK)
* Previous treatment with a BRAF or MEK inhibitor
* Cancer therapy (chemotherapy with delayed toxicity, extensive radiation therapy, immunotherapy, biologic therapy, or major surgery) or investigational anti-cancer drugs within the last 3 weeks, or chemotherapy without delayed toxicity within the last 2 weeks, preceding the first dose of study treatment.
* Current or expected use of a prohibited medication, including enzyme-inducing antiepileptic drugs (EIAEDs) during treatment with GSK2118436.
* Presence of leptomeningeal disease or dural metastases.
* History of another active malignancy within the past 5 years, or any malignancy with a confirmed activating RAS mutation. The prospective RAS mutation testing is not required, however, if results of previous RAS testing are known, they must be used in assessing eligibility. Subjects with a history of completely resected non-melanoma skin cancer are eligible.
* Known allergies against contrast agents required for magnetic resonance imaging (MRI) of intracranial lesions, or other contraindications for MRI, i.e., pacemaker
* Current use of therapeutic warfarin. 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 (CTCAE 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.
* History of a prior symptomatic stroke, dementia, or other significant central neurologic condition (i.e. multiple sclerosis)
* A history of known Human Immunodeficiency Virus (HIV), Hepatitis B Virus (HBV), or Hepatitis C Virus (HCV) infection
* Current acute infection requiring intravenous antibiotics
* A history of known glucose-6-phosphate dehydrogenase (G6PD) deficiency
* The history or evidence of following cardiac abnormalities:
* Corrected QT (QTc) interval using Bazett's Formula; (QTcB) \>= 480 msecs
* A history of acute coronary syndromes (including myocardial infarction or unstable angina), coronary angioplasty, or stenting within 6 months prior to randomization
* Coronary angioplasty or stenting within the past 12 weeks
* Class II, III, or IV heart failure as defined by the New York Heart Association (NYHA) functional classification system
* Abnormal cardiac valve morphology (\>= Grade 2) documented by echocardiogram (ECHO)
* History of or evidence of clinically significant uncontrolled cardiac arrhythmias
* Treatment refractory hypertension defined as a blood pressure of systolic \>140 mmHg and/or diastolic \>90 mm Hg which cannot be controlled by anti-hypertensive therapy
* Subjects with intra-cardiac defibrillators or permanent pacemakers
* Pregnant, lactating or breastfeeding females
* Any serious and/or unstable pre-existing medical, psychiatric disorder or other conditions that could interfere with subject's safety, obtaining informed consent or compliance to the study procedures
* Have a known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to GSK2118436 or excipients that contraindicate their participation

Primary outcomes:
measure: Concentrations of Dabrafenib, Its Metabolites Hydroxy-, Carboxy- and Desmethyl-dabrafenib in Peripheral Blood (Plasma)
timeFrame: Pre-surgery and post-surgery on Day 15
measure: Concentrations of Dabrafenib, Its Metabolites Hydroxy-, Carboxy- and Desmethyl-dabrafenib in Parenchymal Brain Metastases
timeFrame: Day 15
measure: Concentrations of Dabrafenib, Its Metabolites Hydroxy-, Carboxy- and Desmethyl-dabrafenib) and Trametinib (Cohort B Only) in CSF Samples.
timeFrame: Pre-surgery and post-surgery on Day 15
Secondary outcomes:
measure: Concentrations of Dabrafenib, Its Metabolites Hydroxy-, Carboxy- and Desmethyl-dabrafenib) in Cerebrospinal Fluid (CSF) Samples
timeFrame: Day 15
measure: Number of Participants With Changes in Mitogen-activated Protein Kinase (MAPK) Pathway Markers
timeFrame: Up to Day 15
measure: Number of Participants With Changes in Radiographic Tumors
timeFrame: Up to 2 years
measure: Percent Change From Baseline to Pre-surgery in the Sum of the Longest Diameters (SLD) of Intracranial Target Lesions
timeFrame: Up to 2 years
measure: Maximum Percent Change From Baseline in the SLD of Unresected Intracranial Target Lesions
timeFrame: Up to 2 years
measure: Percentage of Participants With Overall Extracranial Response Rate in Unresected Lesions
timeFrame: Approximately 2 years or death whichever occurs first
measure: Percentage of Participants With Overall Survival
timeFrame: Approximately 2 years or death whichever occurs first
measure: Number of Participants With Abnormal Vital Signs
timeFrame: Up to 2 years
measure: Number of Participants With Abnormal Physical Examinations
timeFrame: Up to 2 years
measure: Number of Participants With Abnormal 12-lead Electrocardiograms (ECG)
timeFrame: Screening
measure: Number of Participants With Abnormal Echocardiogram (ECHO)
timeFrame: Up to 2 years
measure: Number of Participants With Abnormal Clinical Laboratory Assessments
timeFrame: Up to 2 years
measure: Number of Participants With Adverse Events (AE) and Serious Adverse Events (SAE)
timeFrame: Up to 2 years
Other outcomes:
Locations:
city: Pittsburgh
country: United States
facility: GSK Investigational Site
state: Pennsylvania
city: Houston
country: United States
facility: GSK Investigational Site
state: Texas
city: North Sydney
country: Australia
facility: GSK Investigational Site
state: New South Wales
Study officials:
affiliation: GlaxoSmithKline
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References: