Clinical trial NCT02705963: A Drug-Drug Interaction Study to Assess the Effect of Trametinib on the Pharmacokinetics of an Oral Contraceptive in Female Patients With Solid Tumors
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Solid Tumors
Lead sponsor: Novartis
Sponsor class: INDUSTRY
First posted: 2016-03-11
Enrollment: 19
Sex: FEMALE
Minimum age (years): 18
Maximum age (years): 59
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: 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.


Eligibility criteria: 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.

Primary outcomes:
measure: Pharmacokinetics parameter: AUCtau of NE and EE alone and in combination with trametinib
timeFrame: Day 5 and 6 and 21 and 22
measure: Pharmacokinetics parameter: AUClast of NE and EE alone and in combination with trametinib
timeFrame: Day 5 and 6 and 21 and 22
measure: Pharmacokinetics parameter: Cmax of NE and EE alone and in combination with trametinib
timeFrame: Day 5 and 6 and 21 and 22
measure: Pharmacokinetics parameter: Tmax of NE and EE alone and incombination with trametinib
timeFrame: Days 5 and 6 and 21 and 22
Secondary outcomes:
measure: Pharmacokinetics parameter: AUClast of M5
timeFrame: Day 21 and 22
measure: Pharmacokinetics parameter: AUCtau of M5
timeFrame: Day 21 and 22
measure: Pharmacokinetics parameter: Cmax of M5
timeFrame: Day 21 and 22
measure: Pharmacokinetics parameter: Tmax of M5
timeFrame: Day 21 and 22
Other outcomes:
Locations:
city: Detroit
country: United States
facility: Karmanos Cancer Institute Karmanos Cancer Institute
state: Michigan
city: Oklahoma City
country: United States
facility: University of Oklahoma
state: Oklahoma
city: Edegem
country: Belgium
facility: Novartis Investigative Site
city: Namur
country: Belgium
facility: Novartis Investigative Site
city: Maastricht
country: Netherlands
facility: Novartis Investigative Site
city: Malaga
country: Spain
facility: Novartis Investigative Site
city: London
country: United Kingdom
facility: Novartis Investigative Site
Study officials:
affiliation: Novartis Pharmaceuticals
name: Novartis Pharmaceuticals
role: STUDY_DIRECTOR
References: