Dabrafenib/Trametinib, BRAF or BRAF AND MEK Pre-op With BRAF and MEK Post-op, Phase IIB, Melanoma With Brain Mets,Biomarkers and Metabolites

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