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