A Pharmacokinetics (PK) and Safety Study to Determine the Effect of Repeat Dosing of Trametinib on Combined Oral Contraceptive (Norethindrone Plus Ethinyl Estradiol) in Female Subjects With Solid Tumors

NCT02292732 | Withdrawn Phase 1

• 1 other identifier: 113707
• Study Type: interventional
• Target: N/A
• Locations: 0 countries
• Sites: N/A

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.

Conditions

Cancer

Keywords

Pharmacokinetics; Solid Tumors; Safety; Trametinib; MEK Inhibitor; Combined Oral Contraceptive; Trametinib's Metabolite M5; Norethindrone; Ethinyl Estradiol

Outcome Measures

Primary Outcomes (2)

• 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)

  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

  Day 11 and Day 12 of both the treatment periods

Secondary Outcomes (6)

• 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

Study Arms (1)

Trametinib/ ORTHO-NOVUM® tablet

EXPERIMENTAL

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).

Drug: Trametinib 0.5 mg; Drug: Trametinib 2 mg; Drug: ORTHO-NOVUM® tablet 1/35; Drug: Placebo

Interventions

Trametinib 0.5 mg DRUG

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

Trametinib/ ORTHO-NOVUM® tablet

Trametinib 2 mg DRUG

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.

Trametinib/ ORTHO-NOVUM® tablet

ORTHO-NOVUM® tablet 1/35 DRUG

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

Trametinib/ ORTHO-NOVUM® tablet

Placebo DRUG

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

Trametinib/ ORTHO-NOVUM® tablet

Eligibility Criteria

• Age: 18 Years - 58 Years
• Sex: female
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• Is a female subject \>=18 years but \<59 years of age at the time of signing the informed consent.

You may not qualify if:

• 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 \[MUGA\])
• 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 life expectancy of \<3 months

Sponsors & Collaborators

• GlaxoSmithKline: lead

MeSH Terms

Conditions

Neoplasms

Interventions

trametinib

Study Officials

• GSK Clinical Trials

  GlaxoSmithKline

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 13, 2014
• First Posted: November 17, 2014
• Study Start: February 1, 2016
• Primary Completion: May 1, 2017
• Study Completion: May 1, 2017
• Last Updated: January 26, 2016

Record last verified: 2016-01