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.
Name: Trametinib 0.5 mg
Name: Trametinib 2 mg
Name: ORTHO-NOVUM® tablet 1/35
Name: Placebo
Description: 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)
Measure: Composite of steady state PK parameters of NE and EE Time: Day 11 and Day 12 of both the treatment periodsDescription: Steady state PK parameters will include AUC(0-tau), Cmax, C0 and Tmax
Measure: Composite of steady state PK parameters of NE and EE in combination with trametinib Time: Day 11 and Day 12 of both the treatment periodsDescription: Steady-state PK parameters will include AUC(0-tau), Cmax, C0, Tmax, and metabolite/parent AUC ratio
Measure: Composite of steady state PK parameters of Plasma trametinib and M5 Time: Day 11 and Day 12 of treatment period 2Description: Vital signs will include measurement of blood pressure, temperature and pulse rate
Measure: Safety and tolerability as assessed by measuring vital signs Time: Up to 107 daysDescription: 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.
Measure: Safety and tolerability as assessed by measuring electrocardiogram (ECGs) Time: Up to 107 daysDescription: The evaluation of the echocardiographer will include an evaluation for Left ventricular ejection fraction (LVEF) and both right and left-sided valvular lesions
Measure: Safety and tolerability by assessing ECHOs Time: Up to 107 daysDescription: Clinical laboratory tests will include hematology, clinical chemistry, urinalysis and additional parameters
Measure: Safety and tolerability by assessing clinical laboratory tests Time: Up to 107 daysDescription: AEs will be collected throughout the treatment periods up to follow up
Measure: Safety and tolerability by assessing adverse events (AEs) Time: Up to 107 daysAllocation: N/A
Single Group Assignment
There is one SNP
ALT with documented liver metastases or tumor infiltration; >2.5xULN but <=5xULN) ; Renal (Creatinine or <=1.5 ULN; Calculated creatinine clearance [calculated by the Cockcroft-Gault formula] >=50 milliliters/minute [mL/min]) ; Cardiac (left ventricular ejection fraction [LVEF] >= lower limit of normal [LLN] by echocardiogram [ECHO] or Multigated acquisition scan [MUGA]) Exclusion Criteria: A subject will not be eligible for inclusion in this study if any of the following criteria apply: - Had prior exposure to a MEK inhibitor - Has one of the following excluded tumor types as trametinib therapy has been shown to have minimal benefit in these populations: BRAF V600E mutant melanoma and failed prior BRAF inhibitor therapy; Metastatic pancreatic cancer - Has had any major surgery extensive radiotherapy, or anti-cancer therapy (e.g., chemotherapy with delayed toxicity, biologic therapy, or immunotherapy) within 21 days prior to enrollment and/or daily or weekly chemotherapy without the potential for delayed toxicity within 14 days prior to enrollment. --- V600E ---