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GSK2118436 (3 capsules of 75 mg) will be administered orally at the dose of 225 mg BID from Day 1 to 7 (and single dose on Day 8) under fasted conditions, either 1 hour before or 2 hours after a meal.

GSK2118436 (4 capsules of 75 mg) will be administered orally at the dose of 300 mg BID from Day 1 to 7 (and single dose on Day 8) under fasted conditions, either 1 hour before or 2 hours after a meal. If 225 mg BID is not tolerated in Part 1 /Cohort 1, then Part 1/Cohort 2 will not be initiated and 150 mg BID will be used in Part 2.

Subjects will receive a single dose of GSK2118436/placebo (4 capsules of 75 mg/highest tolerated dose) orally on the first 2 days of the study followed by 2 doses daily for 6 days and a single dose on the 9th day. There will be 1 day when a placebo will be given. All doses will be administered under fasted conditions, either 1 hour before or 2 hours after a meal.

Each capsule contains 75 mg of GSK2118436A as the mesylate salt, micronized particles as active equivalents.

GSK2118436 75 mg

Matching placebo capsules will be administered in Part 2 of the study.

Placebo

GSK Clinical Trials

This is a Phase I, multicenter, 2-part study with Part 1 designed as a safety lead-in and Part 2 designed to evaluate the effect of GSK2118436 on cardiac repolarization (corrected QT interval \[QTc\] duration) as compared with placebo in subjects with V600 BRAF mutation-positive tumors.

Each part of the study will consist of screening (14 days prior to the start of the study treatment), treatment and follow-up period (14 days).

In Part 1 in Cohort 1 six subjects will receive GSK2118436 225 mg twice a day (BID) on study days 1 to 7 and a single 225 milligram (mg) dose on morning of Day 8. Based on the safety data of subjects in Cohort 1 subjects will be enrolled in Cohort 2 and the dose of GSK2118436 will be escalated to 300 mg BID. If the 225 mg dose of GSK2118436 is not well tolerated in Cohort 1 (i.e., 2 or more dose-limiting toxicities \[DLTs\]), then Cohort 2 of Part 1 will not be initiated and a dose of 150 mg BID of GSK2118436 will be administered in Part 2 of the study. In Cohort 2 six subjects will receive GSK2118436 300 mg BID on Study Days 1 to 7 and a single 300 mg dose on the morning of Day 8. Based on the safety data of subjects in Cohort 2 subjects will be enrolled in Part 2. If the 300 mg BID dose level of GSK2118436 is not well tolerated, then the highest tolerated dose will be selected for Part 2 of the study.

In Part 1 of the study the decision to proceed to the next cohort or Part 2 of the study will be based on the safety data of at least 6 evaluable subjects (\<=1 DLTs during the 14 days following the first dose of GSK2118436).

In Part 2 of the study eligible subjects will receive a single dose of GSK2118436/placebo (4 capsules of 75 mg/highest tolerated dose) orally on the first 2 days of the study followed by 2 doses daily for 6 days and a single dose on the 9th day. There will be 1 day when a placebo will be given.

In both the parts of the study serial blood samples for pharmacokinetic (PK) analysis for GSK2118436 and its metabolites (GSK2285403, GSK2298683 and GSK2167542) will be obtained at the same time points on the first and last day of dosing (2nd day of dosing also included for Part 2). Safety electrocardiogram (ECG)s will be performed at several timepoints during the study. In Part 2 Holter ECG monitoring will be performed for 24 hours on the 1st, 2nd and 9th days of dosing.

A Study to Evaluate the Effect of Repeat Oral Dosing of GSK2118436 on Cardiac Repolarization in Subjects With V600 BRAF Mutation-Positive Tumors

A Two-Part Study to Evaluate the Effect of Repeat Oral Dosing of GSK2118436 on Cardiac Repolarization in Subjects With V600 BRAF Mutation-Positive Tumors: An Open-label, Dose-escalating Safety Lead-in Study Followed by a Single-sequence, Placebo-controlled, Single-blind Study

Safety and tolerability parameter will include a complete (head, eyes, ears, nose, throat, skin, thyroid, neurological, lungs, cardiovascular, abdomen \[liver and spleen\], lymph nodes, extremities, height and weight) and brief (skin, lungs, cardiovascular system, abdomen \[liver and spleen\] and weight) physical examination at Baseline and at the end of Part 1 of the study.

Safety and tolerability parameter will include measurement of vital signs (recording of systolic and diastolic blood pressure, temperature, and pulse rate) at Baseline and at the end of Part 1 of the study.

Safety and tolerability parameter will include ECGs readings (heart rate and measurement of RR, PR, QRS, QT, and QTc intervals) at Baseline and at the end of Part 1 of the study.

Safety and tolerability parameter will include laboratory values (hematology, clinical chemistry, coagulation, liver function tests, cardiac enzyme and beta-hCG/serum or urine pregnancy test for female subjects of childbearing potential only) at Baseline and at end of Part 1 of the study.

Change from Baseline in QTcF interval at each time point for GSK2118436 will be calculated as average of 3 Holter ECG replicates per time point minus the value at Baseline.

Plasma concentrations of GSK2118436 and its metabolites GSK2285403, GSK2298683 and GSK2167542 will be recorded.

Pharmacokinetic data will include area under the time-concentration curve from time zero (pre-dose) to last time of quantifiable concentration (AUC(0-t)) of GSK2118436 and its metabolites GSK2285403, GSK2298683 and GSK2167542.

Pharmacokinetic data will include maximum plasma concentration (Cmax) of GSK2118436 and its metabolites GSK2285403, GSK2298683 and GSK2167542.

Pharmacokinetic data will include predose concentration (Ctrough) of GSK2118436 and its metabolites GSK2285403, GSK2298683 and GSK2167542.

Pharmacokinetic data will include time of occurrence of Cmax (tmax) of GSK2118436 and its metabolites GSK2285403, GSK2298683 and GSK2167542.

The relationship between plasma concentrations of GSK2118436 and its metabolites (GSK2285403, GSK2298683 and GSK2167542) and the baseline-adjusted, placebo-corrected, time-matched change from Baseline in QTc intervals will be assessed.

ECG parameters: QT, QTcB, QTci, HR, RR interval, PR interval, QRS interval and morphology will be assessed in subjects receiving GSK2118436.

The plasma concentration of GSK2118436 and its metabolites GSK2285403, GSK2298683 and GSK2167542 will be measured.

Pharmacokinetic data will include AUC from time zero (pre-dose) to 10 hours after the last dose of study treatment (AUC(0-10)) and AUC(0 t) of GSK2118436 and its metabolites GSK2285403, GSK2298683 and GSK2167542.

Pharmacokinetic data will include AUC from time zero to infinity AUC(0-infinity) of GSK2118436 and its metabolites GSK2285403, GSK2298683 and GSK2167542 on Study Day 1, if data permit).

Pharmacokinetic data will include elimination half life (t1/2) of GSK2118436 and its metabolites GSK2285403, GSK2298683 and GSK2167542 if data permits.

Pharmacokinetic data will include C trough of GSK2118436 and its metabolites GSK2285403, GSK2298683 and GSK2167542.

Pharmacokinetic data will include Cmax of GSK2118436 and its metabolites GSK2285403, GSK2298683 and GSK2167542.

Pharmacokinetic data will include tmax of GSK2118436 and its metabolites GSK2285403, GSK2298683 and GSK2167542.

Safety parameters will include recording of AEs, in Part 2 of the study.

Safety parameters will include measurement of vital signs (recording of systolic and diastolic blood pressure, temperature, and pulse rate) at Baseline and at the end of Part 2 of the study.

Safety parameters will include ECGs readings (heart rate and measurement of RR, PR, QRS, QT, and QTc intervals) at Baseline and at the end of Part 2 of the study.

Safety parameters will include laboratory values (hematology, clinical chemistry, coagulation, liver function tests, cardiac enzyme and beta-hCG/serum or urine pregnancy test for female subjects of childbearing potential only) at Baseline and at end of Part 2 of the study.

Spots Global Cancer Trial Database for gsk2118436 75 mg