Clinical trial NCT05203822: Tepotinib Drug-Drug Interaction Study With Itraconazole in Healthy Participants
Official title: Phase I, Open-label, Single-sequence, Cross-over Study of the Effect of Multiple Doses of Itraconazole on Single-dose Tepotinib Pharmacokinetics in Healthy Participants
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Healthy
Keywords: Clinical pharmacology
Metabolite
Induction of metabolism
Lead sponsor: Merck Healthcare KGaA, Darmstadt, Germany, an affiliate of Merck KGaA, Darmstadt, Germany
Sponsor class: INDUSTRY
First posted: 2022-01-24
Enrollment: 18
Sex: ALL
Minimum age (years): 18
Maximum age (years): 55
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: NA
Intervention model: SEQUENTIAL
Intervention model description: This is a single sequence cross-over trial.
Primary purpose: TREATMENT

Brief summary: The purpose of this study was to assess the effect of multiple doses of itraconazole on single dose tepotinib pharmacokinetics in healthy participants. Study details include:

Study Duration: up to 48 days Treatment Duration: single dose of tepotinib on Days 1 and 12, 11 days of treatment with itraconazole (Days 8 to 18) Visit Frequency: residence in the Clinical Research Unit from Days -1 to 4 and Days 11 to 15, ambulatory daily visits from Days 5 to 10 and 16 to 20


Eligibility criteria: Inclusion Criteria:

* Overtly healthy participants as determined by medical evaluation, including no clinically significant abnormality identified by medical history, cardiac monitoring, physical examination or laboratory evaluation and no active clinically significant disorder, condition, infection or disease that would pose a risk to participant safety or interfere with the study evaluation, procedures, or completion at Screening and Day -1
* Had a body weight within 50 and 100 kilogram (inclusive) and Body Mass Index (BMI) within the range greater than or equal (\>=) 18.5 and less than or equal to (\<=) 29.9 kilogram per meter square (inclusive) at Screening
* Male or female (not a Women of childbearing potential \[WOCBP\]). The Investigator confirms that each participant agrees to use appropriate contraception and barriers, if applicable. The contraception, barrier, and pregnancy testing requirements are below:
* Contraceptive use will be consistent with local regulations on contraception methods for those participating in clinical studies. Male Participants: Agree to the following during the study intervention period and for at least 1 week after the last dose of study intervention: Refrain from donating fresh and unwashed sperm PLUS, either: Abstain from intercourse with a WOCBP.OR Use a male condom: When having sexual intercourse with a WOCBP, who is not currently pregnant, and instruct her to use a highly effective contraceptive method with a failure rate of \< 1percent (%) per year
* Not a WOCBP, confirmed at Screening, by fulfilling at least 1 of the following criteria: Females who are postmenopausal and documentation of irreversible surgical sterilization by hysterectomy, or bilateral oophorectomy, or bilateral salpingectomy
* Capable of giving signed informed consent, which includes compliance with the requirements and restrictions listed in the ICF and this protocol
* All values for hematology, coagulation, and biochemistry tests of blood and urinalysis within the normal range (at Screening and Day -1)
* Other protocol defined inclusion criteria could apply

Exclusion Criteria:

* History or presence of clinically relevant respiratory, gastrointestinal, renal, hepatic, hematological, lymphatic, neurological, cardiovascular, psychiatric, musculoskeletal, genitourinary, immunological, dermatological, connective tissue diseases or disorders, as determined by medical evaluation
* Participants with gall bladder removal or other relevant surgery of gastrointestinal tract (appendectomy is not considered as relevant)
* History of any malignancy except for adequately treated superficial basal cell carcinoma
* History of epilepsy
* Ascertained or presumptive allergy/hypersensitivity to the active drug substance and/or excipients; history of anaphylaxis to drugs or serious allergic reactions leading to hospitalization or any other allergy reaction in general, which the Investigator considers may affect the safety of the participant and/or outcome of the study
* Any condition, including findings in the laboratory tests, medical history, or other Screening assessments, that in the opinion of the Investigator constitutes an inappropriate risk or a contraindication for participation in the study or that could interfere with the study's objectives, conduct, or evaluation
* Use of any prescribed medicine or over-the-counter drug or dietary supplement, including herbal remedies, vitamins, and minerals, antacids and dietary supplements such as fish oils within 2 weeks or 5 times the half-life of the respective drug, whichever is longer, prior to the first administration of study intervention
* Participation in the treatment phase of a clinical study within 60 days or 5 half-lives after last dosing of the previous study drug, whatever is longer, before administration of study drug
* Contraindication to itraconazole: ventricular dysfunction such as congestive heart failure or a history of congestive heart failure, drug interactions (example: co-administration of a number of CYP3A4 substrates), pregnancy, hypersensitivity to itraconazole
* Donation or loss of more than 450 milliliter (mL) of blood in the 60 days prior to Screening, donation of plasma from 2 weeks prior to Screening, or platelets from 6 weeks prior to Screening
* Consumption of alcohol from 48 hours prior to first administration of study intervention
* Smoker (cigarettes, pipes, cigars, or others) or former smoker who stopped smoking for less than 6 months before the time of the Screening visit
* Inability to communicate or cooperate with the Investigator (example: language problem, illiteracy, poor mental status) or to comply with the requirements of the entire study, including dietary restrictions
* Other factors, which in the opinion of the Investigator may interfere with study conduct
* Legal incapacity or limited legal capacity
* Other protocol defined exclusion criteria could apply

Primary outcomes:
measure: Area Under the Plasma Concentration-Time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of Tepotinib
timeFrame: Predose up to 168 hours post dose
measure: Area Under the Plasma Concentration-Time Curve (AUC) From Time Zero to Time of Last Measurable Concentration (AUC0-tlast) of Tepotinib
timeFrame: Predose up to 168 hours post dose
measure: Maximum Observed Plasma Concentration (Cmax) of Tepotinib and Metabolite
timeFrame: Predose up to 168 hours post dose
Secondary outcomes:
measure: Number of Participants With Treatment-emergent Adverse Events (TEAEs), Serious TEAEs, TEAES With Severity of Grade Greater or Equal to 3
timeFrame: Baseline (Day 1) up to follow up (assessed up to Day 20)
measure: Number of Participants With Clinically Meaningful Change From Baseline in Laboratory Values
timeFrame: Baseline (Day 1) up to follow up (assessed up to Day 20)
measure: Number of Participants With Clinically Meaningful Change From Baseline in Electrocardiogram (ECG)
timeFrame: Baseline (Day 1) up to follow up (assessed up to Day 20)
measure: Number of Participants With Clinically Meaningful Change From Baseline in Vital Signs
timeFrame: Baseline (Day 1) up to follow up (assessed up to Day 20)
measure: Total Body Clearance of Drug From Plasma (CL/f) for Tepotinib
timeFrame: Predose up to 168 hours post dose
measure: Apparent Volume of Distribution (Vz/f) for Tepotinib
timeFrame: Predose up to 168 hours post dose
measure: Time to Reach the Maximum Plasma Concentration (Tmax) of Tepotinib
timeFrame: Predose up to 168 hours post dose
measure: Apparent Terminal Half-Life (t1/2) of Tepotinib in Plasma
timeFrame: Predose up to 168 hours post dose
Other outcomes:
Locations:
city: Neu-Ulm
country: Germany
facility: Nuvisan GmbH
Study officials:
affiliation: Merck Healthcare KGaA, Darmstadt, Germany, an affiliate of Merck KGaA, Darmstadt, Germany
name: Medical Responsible
role: STUDY_DIRECTOR
References: