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.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
50
Each capsule contains 75 mg of GSK2118436A as the mesylate salt, micronized particles as active equivalents.
Matching placebo capsules will be administered in Part 2 of the study.
GSK Investigational Site
Scottsdale, Arizona, United States
GSK Investigational Site
Memphis, Tennessee, United States
GSK Investigational Site
Nashville, Tennessee, United States
GSK Investigational Site
San Antonio, Texas, United States
GSK Investigational Site
Salt Lake City, Utah, United States
GSK Investigational Site
Heidelberg, Victoria, Australia
GSK Investigational Site
Melbourne, Victoria, Australia
GSK Investigational Site
London, United Kingdom
Part 1: Safety and tolerability of GSK2118436 as assessed by changes in physical examination findings
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.
Time frame: Screening, Day 1 and Week 6.
Part 1: Safety and tolerability of GSK2118436 as assessed by changes in vital signs measurements
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.
Time frame: Screening, pre-dose and 8 hours post-dose on Study Day 1, 8, 15, and Week 6.
Part 1: Safety and tolerability of GSK2118436 as assessed by changes in ECG readings
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.
Time frame: Screening, Day 1, 8 Day 15 and Week 6. On study days 1 and 8, ECG will be obtained at 30 minutes pre-dose and 2-hours (hrs) post-dose administration.
Part 1: Safety and tolerability of GSK2118436 as assessed by changes in clinical laboratory assessments
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.
Time frame: Day 1, 8, 15 and and Week 6.
Part 2: Change from Baseline in QTcF interval at each time point for GSK2118436
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.
Time frame: Baseline (Study Day -1)/pre-dose (Study Days 1 and 8) (within 30 minutes prior to administration of study treatment) and 1, 1.5, 2, 3, 4, 6, 8, 10 and 24-hrs post-dose. Day 2 and 9, 24 hr post dose Holter ECG.
Part 1: Plasma concentration of GSK2118436 and its metabolites
Plasma concentrations of GSK2118436 and its metabolites GSK2285403, GSK2298683 and GSK2167542 will be recorded.
Time frame: On Day 1 and Day 8 at pre-dose (30 minutes (mins) prior to the administration of study treatment) and 1, 1.5, 2, 3, 4, 6, 8, and 10-hours post-dose.
Part 1: The AUC(0-t)) of GSK2118436 and its metabolites
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.
Time frame: On Day 1 and Day 8 at pre-dose (30 mins prior to the administration of study treatment) and 1, 1.5, 2, 3, 4, 6, 8, and 10-hours post-dose.
Part 1: The Cmax of GSK2118436 and its metabolites
Pharmacokinetic data will include maximum plasma concentration (Cmax) of GSK2118436 and its metabolites GSK2285403, GSK2298683 and GSK2167542.
Time frame: Part 1: Day 1 and Day 8 pre-dose (30 mins prior to the administration of study treatment) and 1, 1.5, 2, 3, 4, 6, 8, and 10-hours post-dose.
The Ctrough of GSK2118436 and its metabolites
Pharmacokinetic data will include predose concentration (Ctrough) of GSK2118436 and its metabolites GSK2285403, GSK2298683 and GSK2167542.
Time frame: Part 1: Day 8 pre-dose (30 mins prior to the administration of study treatment) and 1, 1.5, 2, 3, 4, 6, 8, and 10-hours post-dose.
The tmax of GSK2118436 and its metabolites
Pharmacokinetic data will include time of occurrence of Cmax (tmax) of GSK2118436 and its metabolites GSK2285403, GSK2298683 and GSK2167542.
Time frame: Part 1: Day 1 and Day 8 pre-dose (30 mins prior to the administration of study treatment) and 1, 1.5, 2, 3, 4, 6, 8, and 10-hours post-dose.
Part 2: Change from Baseline in slope of the relationships between the baseline-adjusted, placebo-corrected change in QTc interval and the plasma concentrations of GSK2118436 or its metabolites and predicted change in QTc
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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.
Time frame: Part 2: Baseline (pre-dose study Days 1 and 8 within 30 minutes prior to administration of study treatment) and 1, 1.5, 2, 3, 4, 6, 8, 10 and 24-hrs post-dose (Day 1 and 8). On Day 2 and 9, 24-hr post-dose PK sample and Holter ECG.
Part 2: ECG parameters: and morphology assessments
ECG parameters: QT, QTcB, QTci, HR, RR interval, PR interval, QRS interval and morphology will be assessed in subjects receiving GSK2118436.
Time frame: Part 2: Baseline (pre-dose study Days 1 and 8 within 30 minutes prior to administration of study treatment) and 1, 1.5, 2, 3, 4, 6, 8, 10 and 24-hrs post-dose (Day 1 and 8). On Day 2 and 9, 24-hr post dose Holter ECG.
Part 2: Plasma concentrations of GSK2118436 and its metabolites
The plasma concentration of GSK2118436 and its metabolites GSK2285403, GSK2298683 and GSK2167542 will be measured.
Time frame: On Days -1, 1 and 8 at pre-dose (within 30 minutes prior to administration of study treatment) and 1, 1.5, 2, 3, 4, 6, 8, 10 and 24 hrs post-dose (Day 1 and 8). On Days 2 and 9 at 24-hr post dose PK sample.
The AUC(0-10) and AUC(0 t) of GSK2118436 and its metabolites (GSK2285403, GSK2298683 and GSK2167542)
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.
Time frame: Part 2: Days -1, 1 and 8: pre-dose (within 30 minutes prior to administration of study treatment) and 1, 1.5, 2, 3, 4, 6, 8, 10 and 24 hrs post-dose (Day 1 and 8). On Day 2 and 9, 24-hr post dose PK sample.
The AUC(0-infinity) 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).
Time frame: Part 2: Day 1: pre-dose (within 30 minutes prior to administration of study treatment) and 1, 1.5, 2, 3, 4, 6, 8, 10 and 24 hrs post-dose (Day 1).
The t½ of GSK2167542 and its metabolites
Pharmacokinetic data will include elimination half life (t1/2) of GSK2118436 and its metabolites GSK2285403, GSK2298683 and GSK2167542 if data permits.
Time frame: Part 2: Study Day 1 pre-dose (within 30 minutes prior to administration of study treatment) and 1, 1.5, 2, 3, 4, 6, 8, 10 and 24 hrs post-dose.
Part 2: The Ctrough of GSK2167542 and its metabolites
Pharmacokinetic data will include C trough of GSK2118436 and its metabolites GSK2285403, GSK2298683 and GSK2167542.
Time frame: Part 2: Study Day 8 pre-dose (within 30 minutes prior to administration of study treatment) and 1, 1.5, 2, 3, 4, 6, 8, 10 and 24 hrs post-dose.
Part 2: The Cmax, of GSK2167542 and its metabolites
Pharmacokinetic data will include Cmax of GSK2118436 and its metabolites GSK2285403, GSK2298683 and GSK2167542.
Time frame: Days -1, 1 and 8: pre-dose (within 30 minutes prior to administration of study treatment) and 1, 1.5, 2, 3, 4, 6, 8, 10 and 24 hrs post-dose (Day 1 and 8). On Day 2 and 9, 24-hr post dose PK sample.
Part 2: The tmax, of GSK2167542 and its metabolites
Pharmacokinetic data will include tmax of GSK2118436 and its metabolites GSK2285403, GSK2298683 and GSK2167542.
Time frame: Days -1, 1 and 8: pre-dose (within 30 minutes prior to administration of study treatment) and 1, 1.5, 2, 3, 4, 6, 8, 10 and 24 hrs post-dose (Day 1 and 8). On Day 2 and 9, 24-hr post dose PK sample.
Part 2: Safety of GSK2118436 as assessed by number of subjects with adverse events (AE)s
Safety parameters will include recording of AEs, in Part 2 of the study.
Time frame: Continuous throughout the study.
Part 2: Safety of GSK2118436 as assessed by changes in vital signs measurements
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.
Time frame: Screening, Day -1, Day 1, Day 8, Day 9 and Week 5.
Part 2: Safety of GSK2118436 as assessed by changes in ECG readings
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.
Time frame: Screening, Day -1, Day 1, Day 2, Day 8, Day 9 and Week 5.
Part 2: Safety of GSK2118436 as assessed by changes in clinical laboratory assessments
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.
Time frame: Screening, Day -1, Day 1, Day 8, Day 9 and Week 5.