Relative Bioavailability of Two Tepotinib Film-Coated Tablet Formulations in Healthy Volunteers

A Phase I, Open-label, Randomized, Cross-over Trial to Investigate the Relative Bioavailability of Two Tepotinib Film-Coated Tablet Formulations in Healthy Volunteers

This is a Phase I, open label, randomized, crossover trial to investigate the relative bioavailability of tepotinib in healthy volunteers. Twenty-four volunteers will be randomized to one of the two treatment sequences: Sequence A: test, reference, Sequence B: reference, test. The reference treatment refers to the current Phase II film-coated tablet (5 * 100 milligram (mg) tepotinib film-coated tablets) and the test treatment to the new Phase III film-coated tablet (1 * 500 mg film-coated tepotinib tablet).

Study Overview

• Status: Completed
• Conditions: Healthy
• Intervention / Treatment: Drug: Tepotinib test (Treatment Period 1); Drug: Tepotinib reference (Treatment Period 2); Drug: Tepotinib reference (Treatment Period 1); Drug: Tepotinib test (Treatment Period 2)

• Study Type: Interventional
• Enrollment (Actual): 24
• Phase: Phase 1

Contacts and Locations

Study Locations

• Germany
  • Darmstadt, Germany
    • For Recruiting Locations outside US, please Contact Merck KGaA Communication Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 60 years (ADULT)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Healthy male and non-fertile, healthy female volunteers, 18 to 60 years of age (both inclusive) at the time of informed consent.
• Written informed consent given before any trial related activities are performed.
• Body weight greater than 50 kg and a body mass index (BMI) above 18 kilogram per meter square (kg/m^2) and below 30 kg/m^2 (BMI = weight [kg]/height [m^2]) at screening.

• Has vital signs in the following normal range:

  • Oral body temperature: 35.5 to 37.5 degree celsius (°C)
  • Blood pressure (BP) and pulse rate after at least 5 minutes of rest, measured in the supine position: Systolic blood pressure: 90 to 150 millimeter of mercury (mm Hg); Diastolic blood pressure: 40 to 90 mm Hg
  • Pulse rate: 35 to 110 beats per minute (bpm)
• Non-smoker (= 0 cigarettes, pipes, cigars, e-cigarettes, or others) for at least 6 months prior to screening
• Women must be postmenopausal for at least 2 years, as confirmed by luteinizing hormone (LH) and follicle-stimulating hormone (FSH) assessments performed at screening, or surgically sterile (that is, hysterectomy, oophorectomy). Pregnancy assessments will also be performed on female volunteers at screening and at admission.
• Males must agree to use and to have their female partners use highly effective medically acceptable methods of contraception during the period of participation in the trial and for at least 3 months after the last treatment administration. Men must refrain from donating sperm up to 3 months after the last treatment administration.
• Ability to understand the full nature and purpose of the trial, including possible risks and adverse effects; ability to cooperate with the Investigator and to comply with the requirements of the entire trial, including dietary restrictions.

Exclusion Criteria:

• Any condition, including findings in the medical history, physical examination or in pretrial assessments that in the opinion of the Investigator, constitutes a risk or a contraindication for the participation of the volunteer in the trial or that could interfere with the trial objectives, conduct or evaluation.
• Any clinically relevant abnormality in the results of the screening safety laboratory parameters. Specifically Alanine transaminase (ALT), aspartate aminotransferase (AST), total bilirubin, Alkaline phosphatase (ALP), amylase, and lipase must not exceed the upper limit of the normal range.
• Any clinically relevant abnormality on the 12-lead electrocardiogram recording.
• Positive result from virology tests for hepatitis B surface antigen (HBsAg), hepatitis C virus antibody (anti-HCV), or human immunodeficiency virus antibody (anti-HIV 1 and 2) at screening.
• History of clinically relevant renal, cardiovascular, and pulmonary disease, or endocrinology disorder.
• History of clinically relevant gastrointestinal disease, in particular pancreatic disease, cholecystitis, liver diseases or hepatic dysfunction.
• History of psychiatric or neurological disorders (depression, epilepsy etc.).
• Known hypersensitivity to tepotinib or its excipients.
• Presence or history of any serious allergy (requiring hospitalization or prolonged systemic treatment).
• Presence of drug or alcohol abuse, confirmed by positive test results for drugs of abuse or alcohol or history of drug and alcohol abuse in the past 3 years. Volunteers who consume more than 14 (female volunteers) or 21 (male volunteers) units of alcohol a week (unit = 1 glass of wine (125 milliliter [mL]) = 1 measure of spirits = ½ pint of beer).
• Loss or donation of more than 400 mL of blood within 12 weeks prior to entry into the trial.
• Participation in another clinical trial within the past 60 days.
• Any prescription or over the counter medication intake within 2 weeks prior to the first administration of tepotinib, including multivitamins and herbal products (St. John's wort), with the exception of acetaminophen and ibuprofen.
• Consumption of enzyme inducing or inhibiting herbal drugs, fruit juices and beverages (eg, grapefruit, grapefruit juice, Seville orange, quinine [tonic water], star fruit), and consumption of poppy seed within 3 days prior to the first administration of the investigational medicinal product.
• Excessive consumption of beverages containing xanthine (more than (>) 5 cups of coffee a day or equivalent) or inability to stop caffeine consumption while resident in the trial site. Continued use of caffeine (less than or equal to (=<)3 cups/day) or caffeine containing drinks or food, eg, coffee, tea, chocolate, Red Bull, or cola (1 caffeine unit is contained in the following items: 1 [6 ounces (oz)] cup of coffee, 2 [12 oz] cans of cola, 1 [12 oz] cup of tea, ½ [4 oz] cup of energy drink [eg, Red Bull], or 3 oz of chocolate).
• Legal incapacity or limited legal capacity.
• Unlikely to comply with the protocol requirements, instructions and trial related restrictions; eg, uncooperative attitude, inability to return for follow-up visits, and improbability of completing the trial.
• Volunteer is the Investigator or Sub-Investigator, research assistant, pharmacist, trial coordinator, other staff or relative thereof directly involved in the conduct of the trial.
• Vulnerable volunteers (eg, persons kept in detention).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: CROSSOVER
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: First Tepotinib Test, Then Tepotinib Reference	Drug: Tepotinib test (Treatment Period 1); Subjects will be administered a single oral dose of test treatment of film-coated tepotinib tablet (1 * 500 mg tablet) in Treatment period 1 (Day 1); Drug: Tepotinib reference (Treatment Period 2); Followed by a 21-day washout after Treatment period 1 (Day 1), subjects will be administered a single oral dose of reference treatment of film-coated tepotinib tablet (5 * 100 mg tablet) in Treatment period 2 (Day 22)
EXPERIMENTAL: First Tepotinib Reference, Then Tepotinib Test	Drug: Tepotinib reference (Treatment Period 1); Subjects will be administered a single oral dose of reference treatment of film-coated tepotinib tablet (5 * 100 mg tablet) in Treatment period 1 (Day 1); Drug: Tepotinib test (Treatment Period 2); Followed by a 21-day washout after Treatment period 1 (Day 1), subjects will be administered a single oral dose of test treatment of film-coated tepotinib tablet (1 * 500 mg tablet) in Treatment period 2 (Day 22)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Area Under the Plasma Concentration-Time Curve From Time Zero to the Last Sampling Time (AUC0-t) at Concentration at or Above Lower Limit of Quantitation (LLOQ) of Tepotinib	AUC0-t was calculated according to the mixed log linear trapezoidal rule.	Pre-dose, 0.25, 0.50, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 10, 16, 24, 30, 36, 48, 54, 60, 72, 96, 120, 144, 168, 216, 288, 336, and 504 hours post-dose during Treatment Periods 1 and 2
Area Under the Plasma Concentration-Time Curve From Time Zero to Infinity (AUC0-inf) of Tepotinib	AUC0-inf was calculated as AUC0-t + AUCextra. AUCextra represents the extrapolated part of AUC0-inf calculated by Clastcalc/λz, where Clastcalc was the calculated plasma concentration at the last sampling time point at which the measured plasma concentration was at or above the LLOQ and λz was the apparent terminal rate constant determined from the terminal slope of the log-transformed plasma concentration curve.	Pre-dose, 0.25, 0.50, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 10, 16, 24, 30, 36, 48, 54, 60, 72, 96, 120, 144, 168, 216, 288, 336, and 504 hours post-dose during Treatment Periods 1 and 2
Maximum Plasma Concentration Observed (Cmax) of Tepotinib	Cmax was obtained directly from the concentration versus time curve.	Pre-dose, 0.25, 0.50, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 10, 16, 24, 30, 36, 48, 54, 60, 72, 96, 120, 144, 168, 216, 288, 336, and 504 hours post-dose during Treatment Periods 1 and 2
Time to Reach the Maximum Plasma Concentration (Tmax) of Tepotinib	Time to reach the maximum plasma concentration (Tmax) was obtained directly from the concentration versus time curve.	Pre-dose, 0.25, 0.50, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 10, 16, 24, 30, 36, 48, 54, 60, 72, 96, 120, 144, 168, 216, 288, 336, and 504 hours post-dose during Treatment Periods 1 and 2

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Area Under the Plasma Concentration-Time Curve From Time Zero to the Last Sampling Time (AUC0-t) of Tepotinib Metabolites (MSC2571109A and MSC2571107A)	AUC0-t at which the concentration was at or above LLOQ was calculated according to the mixed log linear trapezoidal rule.	Pre-dose, 0.25, 0.50, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 10, 16, 24, 30, 36, 48, 54, 60, 72, 96, 120, 144, 168, 216, 288, 336, and 504 hours post-dose during Treatment Periods 1 and 2
Area Under the Plasma Concentration-Time Curve From Time Zero to Infinity (AUC0-inf) of Tepotinib Metabolites (MSC2571109A and MSC2571107A)	AUC0-inf was calculated as AUC0-t + AUCextra. AUCextra represents the extrapolated part of AUC0-inf calculated by Clastcalc/λz, where Clastcalc was the calculated plasma concentration at the last sampling time point at which the measured plasma concentration was at or above the LLOQ and λz was the apparent terminal rate constant determined from the terminal slope of the log-transformed plasma concentration curve.	Pre-dose, 0.25, 0.50, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 10, 16, 24, 30, 36, 48, 54, 60, 72, 96, 120, 144, 168, 216, 288, 336, and 504 hours post-dose during Treatment Periods 1 and 2
Maximum Plasma Concentration Observed (Cmax) of Tepotinib Metabolites (MSC2571109A and MSC2571107A)	Cmax was obtained directly from the concentration versus time curve.	Pre-dose, 0.25, 0.50, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 10, 16, 24, 30, 36, 48, 54, 60, 72, 96, 120, 144, 168, 216, 288, 336, and 504 hours post-dose during Treatment Periods 1 and 2
Time to Reach the Maximum Plasma Concentration (Tmax) of Tepotinib Metabolites (MSC2571109A and MSC2571107A)	Tmax was obtained directly from the concentration versus time curve.	Pre-dose, 0.25, 0.50, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 10, 16, 24, 30, 36, 48, 54, 60, 72, 96, 120, 144, 168, 216, 288, 336, and 504 hours post-dose during Treatment Periods 1 and 2
Apparent Terminal Half-Life (t1/2) of Tepotinib and Metabolites (MSC2571109A and MSC2571107A) in Plasma	t1/2 was defined as the time taken for the plasma concentration or the amount of drug in the body to be reduced by half.	Pre-dose, 0.25, 0.50, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 10, 16, 24, 30, 36, 48, 54, 60, 72, 96, 120, 144, 168, 216, 288, 336, and 504 hours post-dose during Treatment Periods 1 and 2
Apparent Terminal Rate Constant (λz) of Tepotinib and Metabolites (MSC2571109A and MSC2571107A) in Plasma	Apparent terminal rate constant was determined from the terminal slope of the log-transformed plasma concentration curve using linear regression on terminal data points of the curve.	Pre-dose, 0.25, 0.50, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 10, 16, 24, 30, 36, 48, 54, 60, 72, 96, 120, 144, 168, 216, 288, 336, and 504 hours post-dose during Treatment Periods 1 and 2
Total Body Clearance of Drug From Plasma (CL/f) for Tepotinib	CL/f following oral administration was calculated as Dose/AUC0-inf, where AUC0-inf calculated as AUC0-t + AUCextra. AUCextra represents the extrapolated part of AUC0-inf calculated by Clastcalc/λz, where Clastcalc was the calculated plasma concentration at the last sampling time point at which the measured plasma concentration was at or above the LLOQ and λz was the apparent terminal rate constant determined from the terminal slope of the log-transformed plasma concentration curve.	Pre-dose, 0.25, 0.50, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 10, 16, 24, 30, 36, 48, 54, 60, 72, 96, 120, 144, 168, 216, 288, 336, and 504 hours post-dose during Treatment Periods 1 and 2
Apparent Volume of Distribution (Vz/f) for Tepotinib	Vz/f is defined as the theoretical volume in which the total amount of drug would need to be uniformly distributed to produce the desired plasma concentration of a drug. Vz/f during the terminal phase was reported.	Pre-dose, 0.25, 0.50, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 10, 16, 24, 30, 36, 48, 54, 60, 72, 96, 120, 144, 168, 216, 288, 336, and 504 hours post-dose during Treatment Periods 1 and 2
Extrapolated Area Under the Plasma Concentration-Time Curve From Time t to Infinity (%AUCextra) of Tepotinib and Metabolites (MSC2571109A and MSC2571107A)	%AUCextra was defined as a percentage of AUC0-inf obtained by extrapolation: %AUCextra = (1- [AUC0-t / AUC0-inf])*100. %AUCextra was reported in terms of percentage of AUC0-inf.	Pre-dose, 0.25, 0.50, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 10, 16, 24, 30, 36, 48, 54, 60, 72, 96, 120, 144, 168, 216, 288, 336, and 504 hours post-dose during Treatment Periods 1 and 2
Ratio of Area Under the Plasma Concentration-Time Curve From Time Zero to Infinity (AUC0-inf) of Metabolite (MSC2571109A or MSC2571107A) to AUC0-inf of Tepotinib	Ratio of AUC0-inf of Metabolite (MSC2571109A or MSC2571107A) to AUC0-inf of tepotinib was reported.	Pre-dose, 0.25, 0.50, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 10, 16, 24, 30, 36, 48, 54, 60, 72, 96, 120, 144, 168, 216, 288, 336, and 504 hours post-dose during Treatment Periods 1 and 2
Ratio of Maximum Plasma Concentration Observed (Cmax) of Metabolite (MSC2571109A or MSC2571107A) to Cmax of Tepotinib	Ratio of Cmax of metabolite (MSC2571109A or MSC2571107A) to Cmax of tepotinib was reported.	Pre-dose, 0.25, 0.50, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 10, 16, 24, 30, 36, 48, 54, 60, 72, 96, 120, 144, 168, 216, 288, 336, and 504 hours post-dose during Treatment Periods 1 and 2
Number of Subjects With Treatment-emergent Adverse Events (TEAEs), Serious TEAEs, TEAEs Leading to Death, TEAEs Leading to Discontinuation	An adverse event (AE) was defined as any untoward medical occurrence in a subject which does not necessarily have a causal relationship with the treatment. An AE was any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with use of a medicinal product, whether or not considered related to the medicinal product. A serious adverse event (SAE) was an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged inpatient hospitalization; congenital anomaly/birth defect or was otherwise considered medically important. The term TEAE is defined as AEs starting or worsening after the first intake of the study drug.	Baseline up to end of trial (up to Day 43)
Number of Subjects With Clinically Significant Change From Baseline in Vital Signs, Electrocardiogram (ECG) and Laboratory Parameters	Number of subjects with clinically significant change from baseline in vital signs, ECG and laboratory parameters were reported. Clinical Significance was decided by the investigator. Vital signs included oral body temperature, systolic blood pressure, diastolic blood pressure, and pulse rate. The 12-lead ECGs were recorded after the subjects have rested for at least 5 minutes in supine position. The parameters included heart rate (HR), RR, PR, QRS, QT and QTcB calculated by the Bazett formula. Laboratory investigation included hematology, biochemistry, urinalysis, and coagulation.	Baseline up to end of trial (up to Day 43)

Collaborators and Investigators

• Sponsor: Merck KGaA, Darmstadt, Germany

Publications and helpful links

Helpful Links

• Redacted Clinical study report, redacted clinical study protocol and redacted statistical analysis plan for this study is also available at the HC-PRCI portal (Health Canada-Public release of clinical information)

Study record dates

Study Major Dates

• Study Start (ACTUAL): January 31, 2016
• Primary Completion (ACTUAL): March 31, 2016
• Study Completion (ACTUAL): March 31, 2016

Study Registration Dates

• First Submitted: January 12, 2017
• First Submitted That Met QC Criteria: January 12, 2017
• First Posted (ESTIMATE): January 16, 2017

Study Record Updates

• Last Update Posted (ACTUAL): August 24, 2022
• Last Update Submitted That Met QC Criteria: August 22, 2022
• Last Verified: August 1, 2022

More Information

Terms related to this study

• Keywords: Tepotinib; Healthy volunteer; Mesenchymal-epithelial transition factor; Translocated promoter region
• Additional Relevant MeSH Terms: Antineoplastic Agents; Tepotinib
• Other Study ID Numbers: MS200095-0012; 2015-004369-95 (EUDRACT_NUMBER)