Cancer
Conditions
Keywords
Pharmacokinetics, Solid Tumors, Safety, Trametinib, MEK Inhibitor, Combined Oral Contraceptive, Trametinib's Metabolite M5, Norethindrone, Ethinyl Estradiol
Brief summary
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.
Interventions
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
DRUGTrametinib 2 mg
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.
DRUGORTHO-NOVUM® tablet 1/35
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
DRUGPlacebo
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
Sponsors
GlaxoSmithKline
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to 58 Years
Healthy volunteers
No
Inclusion criteria
* Is a female subject \>=18 years but \<59 years of age at the time of signing the informed consent. * Has a histologically or cytologically confirmed diagnosis of a solid tumor malignancy (except for any excluded malignancies listed in
Exclusion criteria
) that is not responsive to standard therapy(ies) or for which there is no approved therapy. * Is capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the informed consent form (ICF). * Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 * Has a body mass index (BMI) within the range of 19 to 40 kilogram/squared meter (kg/m\^2) (inclusive) * Is a non-smoker or is willing to abstain from use of tobacco and/or nicotine-containing products from time of Screening until the post-treatment follow-up visit or transition to MEK rollover study (MEK114375). * Meets one of the following criteria: Is currently on a stable regimen of ORTHO-NOVUM® tablet 1/35, or Is willing to switch to a regimen of ORTHO-NOVUM® tablet 1/35 from a stable regimen of an alternate OC, or Is willing to start a regimen of ORTHO-NOVUM® tablet 1/35 * Has a negative serum beta-human chorionic gonadotropin (Beta-hCG) pregnancy test within 7 days of first dose of study treatment * Meets one of the following criteria: Is of non-childbearing potential - defined as females with a documented bilateral tubal ligation or tubal occlusion or hysterectomy without oophorectomy (at least one functioning ovary required); Is of childbearing potential and agrees to use an appropriate method of contraception in addition to the OC provided for at least 14 days prior to the first dose of study treatment until completion of the post-treatment follow-up visit or transition to the Mitogen-activated extracellular signal-regulated kinase (MEK) rollover study (MEK114375) * Has no prior treatment- related toxicities \>Grade 1 (except alopecia) at the time of enrollment * Is able to swallow and retain orally administered medication * Has adequate baseline organ function as follows: Hematologic (Absolute neutrophil count \>=1.2 × 10\^9/L; Hemoglobin \>=9 g/dL; Platelets \>=75 × 10\^9/L; prothrombin time/international normalized ratio \[PT/INR\] and partial thromboplastin time \[PTT\] \<=1.5x upper limit of normal \[ULN\]) ; Hepatic (Albumin \>=2.5 g/dL; Total bilirubin \<=1.5xULN \[isolated bilirubin \>1.5x ULN is acceptable if bilirubin is fractionated and direct bilirubin \<35%\]); alanine aminotransferase (ALT) \<=2.5xULN; 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 \[MUGA\])
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Composite of steady state PK parameters of NE and EE | Day 11 and Day 12 of both the treatment periods | 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) |
| Composite of steady state PK parameters of NE and EE in combination with trametinib | Day 11 and Day 12 of both the treatment periods | Steady state PK parameters will include AUC(0-tau), Cmax, C0 and Tmax |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Safety and tolerability as assessed by measuring electrocardiogram (ECGs) | Up to 107 days | 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. |
| Safety and tolerability by assessing ECHOs | Up to 107 days | The evaluation of the echocardiographer will include an evaluation for Left ventricular ejection fraction (LVEF) and both right and left-sided valvular lesions |
| Composite of steady state PK parameters of Plasma trametinib and M5 | Day 11 and Day 12 of treatment period 2 | Steady-state PK parameters will include AUC(0-tau), Cmax, C0, Tmax, and metabolite/parent AUC ratio |
| Safety and tolerability by assessing adverse events (AEs) | Up to 107 days | AEs will be collected throughout the treatment periods up to follow up |
| Safety and tolerability by assessing clinical laboratory tests | Up to 107 days | Clinical laboratory tests will include hematology, clinical chemistry, urinalysis and additional parameters |
| Safety and tolerability as assessed by measuring vital signs | Up to 107 days | Vital signs will include measurement of blood pressure, temperature and pulse rate |
Outcome results
None listed