An Open-Label, Dose-Escalation, Phase I/II Study to Investigate the Safety, Pharmacokinetics, Pharmacodynamics and ClinicalActivity of the BRAF Inhibitor GSK2118436 in Combination With the MEK Inhibitor GSK1120212 in Subjects With BRAF Mutant Metastatic Melanoma
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.
Allocation: Non-Randomized, Endpoint Classification: Pharmacokinetics/Dynamics Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment
Single dose pharmacokinetic parameters for GSK2118436 (and its metabolite(s), including GSK2285403).
GSK Clinical Trials
United States: Food and Drug Administration
|GSK Investigational Site||Bakersfield, California 93309|
|GSK Investigational Site||Gainesville, Florida 32610|
|GSK Investigational Site||Springfield, Massachusetts 01107|
|GSK Investigational Site||Duluth, Minnesota 55805|
|GSK Investigational Site||Fort Worth, Texas 76104|
|GSK Investigational Site||Baltimore, Maryland 21201|
|GSK Investigational Site||Germantown, Tennessee 38138|
|GSK Investigational Site||Aurora, Colorado 80012|
|GSK Investigational Site||Hartford, Connecticut 06106|