Investigate Safety, Pharmacokinetics and Pharmacodynamics of GSK2118436 & GSK1120212

Inclusion Criteria:

• Capable of given written informed consent, which includes compliance with the requirements and restrictions listed in the consent form.
• Male or female age 18 years or greater; able to swallow and retain oral medication.
• BRAF mutation positive melanoma or colorectal cancer; other BRAF mutation positive tumor types may be considered.
• Measurable disease according to RECIST version 1.1.
• Eastern Cooperative Oncology Group Performance Status of 0 or 1 for Parts A and B. Subjects with Eastern Cooperative Oncology Group Performance Status of 2 or less may be entered into Part C with approval of medical monitor.
• Agree to contraception requirements.
• Calcium phosphorus product less than 4.0mmol2/L2.
• Adequate organ system function.

Exclusion Criteria:

• Currently receiving cancer therapy (chemotherapy, radiation therapy, immunotherapy, or biologic therapy).
• Part A and Part B: Prior exposure to BRAF or MEK inhibitors unless approved by the GSK Medical Monitor.
• Part C: Prior exposure to BRAF or MEK inhibitors. Prior anti-cancer therapy in the metastatic setting, with the exception of up to one regimen of chemotherapy and/or interleukin-2 (IL-2).
• Part D: Prior exposure to BRAF inhibitors. A washout period of 6 weeks is required for ipilimumab.
• Received an investigational anti-cancer drug within 4 weeks or 5 half-lives (whichever is shorter) of study drug administration--- at least 14 days must have passed between the last dose of prior investigational anti-cancer drug and the first dose of study drug.
• Current use of a prohibited medication or requires any of these medications during treatment with study drug.
• Current use of therapeutic warfarin.
• Any major surgery, radiotherapy, or immunotherapy within the last 4 weeks. Limited radiotherapy within the last 2 weeks.
• Chemotherapy regimens with delayed toxicity within the last 4 weeks. Chemotherapy regimens given continuously or on a weekly basis with limited potential for delayed toxicity within the last 2 weeks.
• Unresolved toxicity greater than National Cancer Institute-Common Terminology Criteria for Adverse Events version 4 Grade 1 from previous anti-cancer therapy except alopecia.
• History of retinal vein occlusion, central serous retinopathy or glaucoma.
• Predisposing factors to retinal vein occlusion including uncontrolled hypertension, uncontrolled diabetes, uncontrolled hyperlipidemia, and coagulopathy.
• Visible retinal pathology as assessed by ophthalmologic exam that is considered a risk factor for retinal vein occlusion or central serous retinopathy.
• Intraocular pressure greater than 21mm Hg as measured by tonography.
• Glaucoma diagnosed within one month prior to study Day 1.
• Presence of active gastrointestinal disease or other condition that will interfere significantly with the absorption, distribution, metabolism or excretion of drugs.
• Known human immunodeficiency virus, Hepatitis B or Hepatitis C infection.
• Primary malignancy of the central nervous system.
• Untreated or symptomatic brain metastasis, leptomeningeal disease or spinal cord compression. Subjects who are on a stable dose of corticosteroids for more than 1 month or off corticosteroids for 2 weeks can be enrolled with approval of medical monitor. Subjects are not permitted to receive enzyme-inducing anti-epileptic drugs.

• Subjects with brain metastases are excluded, unless

  a. All known lesions must be previously treated with surgery or stereotactic radiosurgery, and- b. Brain lesion(s), if still present, must be confirmed stable (i.e. no increase in lesion size) for ≥90 days prior to first dose on study (must be documented with two consecutive MRI or CT scans using contrast), and c. Asymptomatic with no corticosteroids requirement for ≥ 30 days prior to first dose on study, and d. No enzyme-inducing anticonvulsants for ≥ 30 days prior to first dose on study.

• History of alcohol or drug abuse within 6 months prior to screening.
• Psychological, familial, sociological or geographical conditions that do not permit compliance with the protocol.
• QTc interval greater than or equal to 480msecs.
• History of acute coronary syndromes (including unstable angina), coronary angioplasty, or stenting within the past 24 weeks.
• Class II, III, or IV heart failure as defined by the New York Heart Association functional classification system.
• Abnormal cardiac valve morphology (subjects with minimal abnormalities can be entered on study with approval from the medical monitor.
• 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
• Patients with intra-cardiac defibrillators or permanent pacemakers.
• Cardiac metastases
• Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to the study drugs or excipients.
• Pregnant or lactating female.
• Unwillingness or inability to follow the procedures required in the protocol.
• Uncontrolled diabetes, hypertension or other medical conditions that may interfere with assessment of toxicity.
• Subjects with known glucose 6 phosphate dehydrogenase deficiency.