A Drug-Drug Interaction Study to Assess the Effect of Trametinib on the Pharmacokinetics of an Oral Contraceptive in Female Patients With Solid Tumors

A Phase I, Open-Label Study to Determine the Effect of Repeat Dosing of Trametinib on the Pharmacokinetics of a Combined Oral Contraceptive (Norethindrone Plus Ethinyl Estradiol) in Female Patients With Solid Tumors

The purpose of this study is to evaluate the effect of trametinib once daily on the pharmacokinetics (PK) of a daily dosing oral contraceptives (OCs) containing norethindrone (NE) and ethinyl estradiol (EE) in female patients with solid tumors. The PK of trametinib and its metabolite M5 will also be assessed.

Study Overview

• Status: Completed
• Conditions: Solid Tumors
• Intervention / Treatment: Drug: Trametinib; Drug: Trametinib; Drug: Oral Contraceptive (1mg norethindrone, 0.035mg ethinyl estradiol)

• Study Type: Interventional
• Enrollment (Actual): 19
• Phase: Phase 1

Contacts and Locations

Study Locations

• Belgium
  • Edegem, Belgium, 2650
    • Novartis Investigative Site
  • Namur, Belgium, 5000
    • Novartis Investigative Site
• Netherlands
  • Maastricht, Netherlands, 6229 HX
    • Novartis Investigative Site
• Spain
  • Malaga, Spain, 29010
    • Novartis Investigative Site
• United Kingdom
  • London, United Kingdom, W1G 6AD
    • Novartis Investigative Site
• United States
  • Michigan
    • Detroit, Michigan, United States, 48201
      • Karmanos Cancer Institute Karmanos Cancer Institute
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73104
      • University of Oklahoma

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 59 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

Inclusion Criteria:

• Has a histologically or cytologically confirmed diagnosis of a solid tumor malignancy (except for any excluded malignancies listed in the Exclusion Criteria) that is not responsive to standard therapy(ies) or for which there is no approved therapy.
• Meets one of the following criteria: Is currently on a stable regimen of an oral contraceptive containing 1mg NE and 0.035mg EE, or Is willing to switch to a regimen of an oral contraceptive containing 1mg NE and 0.035mg EE from a stable regimen of an alternate OC, or Is willing to start a regimen of an oral contraceptive containing 1mg NE and 0.035mg EE.
• Meets one of the following criteria: Is post-menopausal, or, Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, must use highly effective methods of contraception during dosing and for four months after stopping medication.
• Has no prior treatment-related toxicities >Grade 1 (except alopecia) at the time of enrolment.
• Patient must meet the following laboratory values at the screening visit: Absolute Neutrophil Count ≥1.5 x 109/L. Platelets ≥75 x 109/L. Hemoglobin (Hgb) ≥9 g/dL. Serum creatinine <1.5 mg/dL. Total bilirubin ≤1.5 x upper limit of normal (ULN) (isolated bilirubin >1.5x ULN is acceptable if bilirubin is fractionated and direct bilirubin <35%). Aspartate transaminase (AST) ≤ 3.0 x ULN, except for patients with liver metastasis, who may only be included if AST ≤5.0 x ULN. Alanine transaminase (ALT) ≤ 3.0 x ULN, except for patients with liver metastasis or tumor infiltration, who may only be included if ALT ≤5.0 x ULN. Prothrombin time (PT)/International normalized ratio (INR) and Partial thromboplastin time (PTT) ≤1.5xULN. Note: patients receiving therapeutic anticoagulation agents prior screening are permitted. Albumin 2.5 g/dL.
• Patient has an Eastern Cooperative Oncology Group (ECOG) performance status 0-1.

Exclusion Criteria:

• History or current diagnosis of cardiac disease indicating significant risk of safety for patients participating in the study such as uncontrolled or significant cardiac disease
• 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 enrolment and/or daily or weekly chemotherapy without the potential for delayed toxicity within 14 days prior to enrolment. Prolonged immobilization must have resolved prior to enrolment.
• Has a known or suspected carcinoma that is excluded as administration of Oral Contraceptive would be contraindicated.
• Has a history of another malignancy.
• Has a history of interstitial lung disease or pneumonitis.
• Has a history of RVO.
• Has a history of any of conditions that would contraindicate administration of an OC
• Has symptomatic or untreated leptomeningeal, brain metastases, or spinal cord compression.

Other protocol-defined Inclusion/Exclusion criteria may apply.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Oral Contraceptive / Trametinib; In treatment period 1 of the PK Phase patients will take the Oral Contraceptive once daily from Days 1-5. Period 2 of the PK Phase starts on Day 6 when patients take both the Oral Contraceptive and trametinib once daily from Days 6 to 21. Patients may continue dosing with trametinib only once daily from Day 22 onwards (post PK Phase).	Drug: Trametinib; Each tablet is 2mg trametinib to be taken orally once daily.; Drug: Trametinib; Each tablet is 0.5mg trametinib to be taken orally once daily. 0.5mg tablets may be used if a dose reduction is required.; Drug: Oral Contraceptive (1mg norethindrone, 0.035mg ethinyl estradiol); Combined oral contraceptive to be taken orally once daily.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pharmacokinetics parameter: AUCtau of NE and EE alone and in combination with trametinib	To evaluate the effect of multiple doses of trametinib (2 mg once daily) on the steady state pharmacokinetics of combination OC (NE and EE) in female patients with solid tumors.	Day 5 and 6 and 21 and 22
Pharmacokinetics parameter: AUClast of NE and EE alone and in combination with trametinib	To evaluate the effect of multiple doses of trametinib (2 mg once daily) on the steady state pharmacokinetics of combination OC (NE and EE) in female patients with solid tumors.	Day 5 and 6 and 21 and 22
Pharmacokinetics parameter: Cmax of NE and EE alone and in combination with trametinib	To evaluate the effect of multiple doses of trametinib (2 mg once daily) on the steady state pharmacokinetics of combination OC (NE and EE) in female patients with solid tumors.	Day 5 and 6 and 21 and 22
Pharmacokinetics parameter: Tmax of NE and EE alone and incombination with trametinib	To evaluate the effect of multiple doses of trametinib (2 mg once daily) on the steady state pharmacokinetics of combination OC (NE and EE) in female patients with solid tumors.	Days 5 and 6 and 21 and 22

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pharmacokinetics parameter: AUClast of M5	Characterize PK of metabolite M5	Day 21 and 22
Pharmacokinetics parameter: AUCtau of M5	Characterize PK of metabolite M5	Day 21 and 22
Pharmacokinetics parameter: Cmax of M5	Characterize PK of metabolite M5	Day 21 and 22
Pharmacokinetics parameter: Tmax of M5	Characterize PK of metabolite M5	Day 21 and 22

Collaborators and Investigators

• Sponsor: Novartis Pharmaceuticals

Publications and helpful links

Helpful Links

• Results for CTMT212X2102 can be found on the Novartis Clinical Trial Results Website
• A Plain Language Trial Summary is available on novartisclinicaltrials.com

Study record dates

Study Major Dates

• Study Start (Actual): October 20, 2016
• Primary Completion (Actual): August 29, 2019
• Study Completion (Actual): August 29, 2019

Study Registration Dates

• First Submitted: February 22, 2016
• First Submitted That Met QC Criteria: March 7, 2016
• First Posted (Estimate): March 11, 2016

Study Record Updates

• Last Update Posted (Actual): February 9, 2022
• Last Update Submitted That Met QC Criteria: February 7, 2022
• Last Verified: October 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Estrogens; Protein Kinase Inhibitors; Contraceptive Agents, Hormonal; Reproductive Control Agents; Contraceptive Agents, Female; Contraceptives, Oral, Synthetic; Contraceptives, Oral, Hormonal; Estradiol; Contraceptive Agents; Ethinyl Estradiol; Contraceptives, Oral; Trametinib; Norethindrone; Norethindrone Acetate
• Other Study ID Numbers: CTMT212X2102

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No