Biomarkers of Response and Resistance to Sequential B-RAF and MEK Targeted Therapy in a Pre-Surgical Model of Advanced, Operable Melanoma

Inclusion Criteria:

- Signed written informed consent

- Patients with locally-or regionally advanced melanoma being considered for resection
of the lesion(s) for local-regional control and potential cure

- Patients with limited, resectable metastatic disease (three or fewer lesions)
are eligible if surgical resection is considered to be the best therapeutic
option

- Patients with AJCC clinical stage IIb-IV disease at initial diagnosis, or
patients with melanoma of any stage with advanced local or regional recurrence,
with or without limited resectable metastatic disease, would be eligible

- B-RAF V-600 mutation positive by snapshot molecular analysis

- Individuals with B-RAF V-600 mutations other than V600E are eligible

- Measurable disease, i.e. presenting with at least one measurable lesion per Response
Evaluation Criteria in Solid tumors (RECIST) 1.1

- All prior treatment related toxicities must be Common Terminology Criteria for
Adverse Events (CTCAE) (Version 4.0) =< Grade 1 at the time of enrollment

- Adequate baseline organ function defined by the criteria below:

- Absolute Neutrophil Count (ANC) >= 1.5 X 10^9/L

- Platelet Count >= 60 X 10^9/L

- Hemoglobin >= 9 g/dl

- Creatinine =< 2 mg/dl

- Aspartate aminotransferase (AST) =< 100 U/L

- Alanine aminotransferase (ALT) =< 100 U/L

- Alkaline Phosphatase =< 380 U/L

- Total Bilirubin =< 2.0 mg/dl

- Women of childbearing potential must have a negative serum pregnancy test within 14
days of first dose of study treatment and agree to use effective contraception during
the study and for 7 days following the last dose of study treatment

- Men with a female partner of childbearing potential must have either had a prior
vasectomy or agree to use effective contraception from 1 day prior to administration
of the first dose of study treatment until 7 days after the last dose of study
treatment

Exclusion Criteria:

- ECOG Performance Status > 2

- Lactating female

- 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

- Any serious medical condition that would render the patient unable to undergo
surgical resection or would limit life expectancy to less than 1 year

- Any prohibited medication

- Administration of an investigational drug within 30 days or 5 half-lives, whichever
is longer, preceding the first dose of study treatment

- A known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs
chemically related to GSK-2118436 (dabrafenib) or GSK-1120212 (trametinib) or
excipient that contraindicates their participation

- Patients with a history of severe cardiovascular disease as defined:

- Symptomatic or uncontrolled cardiac arrhythmias

- Treatment refractory hypertension, defined as a systolic blood pressure > 160mm
Hg and/or diastolic > 100 mmHg which cannot be controlled by antihypertensive
therapy.

- Current ≥ NYHA Class II congestive heart failure

- History of myocardial infarction or unstable angina within 6 months prior to
study entry.

- History of stroke or TIA within 6 months prior to study entry

- QTc ≥ 480 msec

- Cardiac valvular disease ≥ grade 2

- Patients with a known history of glucose-6-phosphate dehydrogenase (G6PD) deficiency.

- Patients with a history of interstitial lung disease or interstitial pneumonitis