A Phase I, Open-Label Study to Determine the Effect of Repeat Dosing of Trametinib on the Pharmacokinetics and Safety of a Combined Oral Contraceptive (Norethindrone Plus Ethinyl Estradiol) and to Characterize the Pharmacokinetics of Trametinib's Metabolite M5 in Female Subjects With Solid Tumors
Overview
- Phase
- Phase 1
- Intervention
- Trametinib 0.5 mg
- Conditions
- Cancer
- Sponsor
- GlaxoSmithKline
- Primary Endpoint
- Composite of steady state PK parameters of NE and EE
- Status
- Withdrawn
- Last Updated
- 10 years ago
Overview
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.
Investigators
Eligibility Criteria
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
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. Prolonged immobilization must have resolved prior to start of study.
- •Has a known or suspected carcinoma listed below that is excluded as administration of ORTHO-NOVUM® tablet would be contraindicated: carcinoma of the breast, or carcinoma of the endometrium, or BRCA+ ovarian cancer, or other known or suspected estrogen-dependent neoplasia, or hepatocellular carcinoma
- •Has a history of another malignancy: Exception: A subject who: has been disease-free for 3 years, or; has a history of completely resected non-melanoma skin cancer, or; has an indolent second malignancy, other than any of the excluded malignancies listed in the previous exclusion Criteria.
- •Has a life expectancy of \<3 months
- •Has a history of interstitial lung disease or pneumonitis.
- •Has a history of Retinal vein occlusion (RVO)
- •Has a history of any of the following conditions that would contraindicate administration of an Oral contraceptive (OC): Uncontrolled or treatment refractory hypertension. NOTE: Treatment-refractory hypertension is defined as a blood pressure of systolic \>140 millimeters of mercury (mmHg) and/or diastolic \>90 mmHg which cannot be controlled by anti-hypertensive therapy; Diabetes mellitus (type 1 and 2) with vascular involvement (neuropathy./retinopathy/nephropathy); Stroke; Acute or past history of venous thromboembolism or known thrombophilia including factor V Leiden mutation; prothrombin mutation; protein S, protein C, and antithrombin deficiencies; or antiphospholipid antibodies; Migraine headaches (headaches with focal neurological symptoms); Undiagnosed abnormal uterine bleeding
Arms & Interventions
Trametinib/ ORTHO-NOVUM® tablet
Subjects in treatment period 1will 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 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). Subjects in treatment period 2 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 take trametinib 2 mg (1 tablet) once daily at approximately the same time each day for 11 days (Days 1 through 11).
Intervention: Trametinib 0.5 mg
Trametinib/ ORTHO-NOVUM® tablet
Subjects in treatment period 1will 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 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). Subjects in treatment period 2 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 take trametinib 2 mg (1 tablet) once daily at approximately the same time each day for 11 days (Days 1 through 11).
Intervention: Trametinib 2 mg
Trametinib/ ORTHO-NOVUM® tablet
Subjects in treatment period 1will 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 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). Subjects in treatment period 2 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 take trametinib 2 mg (1 tablet) once daily at approximately the same time each day for 11 days (Days 1 through 11).
Intervention: ORTHO-NOVUM® tablet 1/35
Trametinib/ ORTHO-NOVUM® tablet
Subjects in treatment period 1will 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 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). Subjects in treatment period 2 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 take trametinib 2 mg (1 tablet) once daily at approximately the same time each day for 11 days (Days 1 through 11).
Intervention: Placebo
Outcomes
Primary Outcomes
Composite of steady state PK parameters of NE and EE
Time Frame: 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
Time Frame: Day 11 and Day 12 of both the treatment periods
Steady state PK parameters will include AUC(0-tau), Cmax, C0 and Tmax
Secondary Outcomes
- Safety and tolerability by assessing adverse events (AEs)(Up to 107 days)
- Composite of steady state PK parameters of Plasma trametinib and M5(Day 11 and Day 12 of treatment period 2)
- Safety and tolerability as assessed by measuring vital signs(Up to 107 days)
- Safety and tolerability as assessed by measuring electrocardiogram (ECGs)(Up to 107 days)
- Safety and tolerability by assessing ECHOs(Up to 107 days)
- Safety and tolerability by assessing clinical laboratory tests(Up to 107 days)