This is a Phase I, open-label, non-randomized, sequential, two-period, repeat-dose study to evaluate the effect of trametinib 2 milligram (mg) once daily on the repeat-dose pharmacokinetic (PK) of an oral contraceptive (OC) containing norethindrone (NE) and ethinyl estradiol (EE) (ORTHO-NOVUM® tablets: 1 mg NE + 0.035 mg EE) in female subjects with solid tumors. The study will determine PK interaction between trametinib and the components of combination oral contraceptives that would compromise the effectiveness of the contraceptives. The study will also evaluate the repeat dose PK of trametinib and its metabolite M5 using a validated assay. The study will enroll approximately 24 subjects. Each subject will participate in the study for approximately up to 13 to 15 weeks which will consist of a 30 day screening period, followed by 2 treatment periods (Period 1: 28 days and Period 2: ranging from 12 days to up to 21 days), and a transition visit or post-treatment follow-up visit. In Period 1, subjects will take one active tablet from the ORTHO-NOVUM® tablet 1/35 dial-pack once daily at approximately the same time each day for 21 days (Days 1 through 21), followed by one inert (referred to as placebo) tablet once daily at approximately the same time each day for 7 days (Days 22 through 28). In addition, subjects will take trametinib 2 mg (1 tablet) once daily at approximately the same time each day for a total of 17 days (Days 12 through 28). In Period 2, subjects will take one active tablet from the ORTHO-NOVUM® tablet 1/35 dial-pack once daily at approximately the same time each day for 11 days (Days 1 through 11). In addition, subjects will continue taking trametinib 2 mg (1 tablet) once daily at approximately the same time each day for 11 days (Days 1 through 11). ORTHO-NOVUM® is a registered trademark of Ortho Pharmaceutical Corporation.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Each tablet will contain GSK1120212B equivalent to 0.5 mg of Trametinib. Tablets are yellow, oval, biconvex, film-coated (4.85 x 8.86 millimeter \[mm\]) to be taken orally and once daily
Each tablet will contain GSK1120212B equivalent to 2 mg Trametinib. Tablets are pink, round, biconvex and film-coated tablets (7.5 mm in diameter) to be taken orally and once daily.
Each peach tablet will contain 1 mg of NE and 0.035 mg of EE. Other inactive ingredients will include lactose, magnesium stearate and pregelatinized corn starch
Each green tablet will contain only inert ingredients: D\&C yellow No. 10 Aluminum Lake, FD\&C Blue No. 2 Aluminum Lake, lactose, magnesium stearate, microcrystalline cellulose, and pregelatinized cornstarch. The tablets are to be taken orally and once daily
Composite of steady state PK parameters of NE and EE
Steady state PK parameters will include Area under the concentration-time curve over the dosing interval (AUC\[0-tau\]), Maximum observed plasma concentration (Cmax), Pre-dose concentration (C0) and Time to Cmax (Tmax)
Time frame: Day 11 and Day 12 of both the treatment periods
Composite of steady state PK parameters of NE and EE in combination with trametinib
Steady state PK parameters will include AUC(0-tau), Cmax, C0 and Tmax
Time frame: Day 11 and Day 12 of both the treatment periods
Composite of steady state PK parameters of Plasma trametinib and M5
Steady-state PK parameters will include AUC(0-tau), Cmax, C0, Tmax, and metabolite/parent AUC ratio
Time frame: Day 11 and Day 12 of treatment period 2
Safety and tolerability as assessed by measuring vital signs
Vital signs will include measurement of blood pressure, temperature and pulse rate
Time frame: Up to 107 days
Safety and tolerability as assessed by measuring electrocardiogram (ECGs)
Single 12-lead ECGs will be obtained at each time point during the study using an ECG machine that automatically calculates the heart rate and measures PR, QRS, QT, and Corrected QT interval (QTc) intervals. Electrocardiograms (ECGs) will be performed by qualified site personnel after the subject has rested at least 5 minutes in a semi-recumbent or supine position.
Time frame: Up to 107 days
Safety and tolerability by assessing ECHOs
The evaluation of the echocardiographer will include an evaluation for Left ventricular ejection fraction (LVEF) and both right and left-sided valvular lesions
Time frame: Up to 107 days
Safety and tolerability by assessing clinical laboratory tests
Clinical laboratory tests will include hematology, clinical chemistry, urinalysis and additional parameters
Time frame: Up to 107 days
Safety and tolerability by assessing adverse events (AEs)
AEs will be collected throughout the treatment periods up to follow up
Time frame: Up to 107 days
This platform is for informational purposes only and does not constitute medical advice. Always consult a qualified healthcare professional.