Investigate Safety, Pharmacokinetics and Pharmacodynamics of GSK2118436 & GSK1120212

During Part A, a cohort of subjects will receive a single dose of GSK2118436 alone (Day 1)
and then repeat doses of GSK1120212 for (Day 2 through Day 15). The dose regimen of
GSK1120212 will be continuous dosing. A second single dose of GSK2118436 will be administered
on Day 15 concomitantly with GSK1120212. Day 16 through Day 28 will be a washout period,
during which no study medication is administered. Starting on Day 29, subjects who elect to
continue participation in the study will dose with GSK2118436. The dose of GSK2118436 after
Day 29 may be altered based on emerging data from the first-time-in human study BRF112680.
The dose may be increased to a dose level that has been completed and determined to be less
than or equal to the maximum tolerated dose in that study.

Part B of the study will enroll cohorts in escalating doses to identify a set of allowable
doses to be expanded in Part C. Subjects will enrolled in a 3+3 cohort design, with
provisional dose levels of both drugs. The decision regarding escalation to the next dose
levels of GSK1120212 and GSK2118436 will be further guided by a Bayesian logistic regression
model. The first cohort will start at low doses for both drugs. Doses up to 300 mg/day for
GSK2118436 and up to 3 mg QD for GSK1120212 have been studied to date. The starting dose may
be lowered based on emerging data from other studies and from Part A.

Expansion cohorts will be enrolled in Part C at dose levels of GSK2118436 and GSK1120212 as
defined in Part B. One of the selected doses may include GSK2118436 administered as
monotherapy at a tolerable dose (less than or equal to the maximum tolerated dose) determined
in BRF112680. Part C is a randomized open-label Phase II portion of the study, and will
consist of expansion cohorts investigating 2 to 3 dose levels of GSK2118436 and GSK1120212
dosing in combination, and GSK2118436 administered as monotherapy. Subjects will be assigned
to treatment arms in a randomized fashion to compare tolerability and safety. Population PK
parameters, clinical activity, durability of response and safety of GSK2118436 and GSK1120212
dosed orally in combination and GSK2118436 as monotherapy will be evaluated.

Part D will consist of evaluation of the pharmacokinetics of GSK2118436 HPMC capsules
administered as monotherapy and in combination with GSK1120212. Pharmacokinetics of
GSK2118436 will be assessed following a single dose on Day 1 and after repeat dosing (Day 21)
and compared between combination and monotherapy. The pharmacokinetics of GSK1120212 will
also be assessed. Safety, tolerability and clinical activity will also be evaluated in 4
dosing cohorts. These cohorts may be expanded for additional safety data. Subjects will be
randomized to different cohorts.

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.