Bioequivalence of TF3 and TF2 and Effect of Food on the PK of Tepotinib

Phase 1, Open-label, 3-Parts Study With Crossover Design in Each Part to Investigate the Bioequivalence of the Tablet Formulation of TF3 Compared to TF2 (Part A), and to Investigate the Influence of Food on the PK of Each TF2 (Part B) and TF3 (Part C) of Tepotinib in Healthy Subjects

The main purpose of the study was to demonstrate bioequivalence between the new tablet formulation (TF3, test treatment) and the tablet formulation used in clinical studies (TF2, reference treatment) and to investigate effect of food on pharmacokinetics (PK) of tepotinib.

Study Overview

• Status: Completed
• Conditions: Healthy
• Intervention / Treatment: Drug: Tepotinib TF2; Drug: Tepotinib TF3

• Study Type: Interventional
• Enrollment (Actual): 66
• Phase: Phase 1

Contacts and Locations

Study Locations

• Germany
  • Neu-Ulm, Germany, 89231
    • Nuvisan GmBH

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 55 years (Adult)
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

• Healthy participants of non-child bearing potential
• Body weight between 50 to 100 kilogram (kg)
• Body mass index (BMI) between 18.5 and 29.9 kilogram per meter square (kg/m^2)
• Other protocol defined inclusion criteria could apply

Exclusion Criteria:

• Participation in a clinical study within 60 days prior to first drug administration
• Whole blood donation or loss of greater than 450 milliliter (mL) within 60 days prior to first drug administration
• Any surgical or medical condition, or any other significant disease that could interfere with the study objectives, conduct, or evaluation
• Other protocol defined exclusion criteria could apply

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: None (Open Label)

Number of Arms

6

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Part A: First Tepotinib TF2 then TF3; Participants received a single oral dose of 500 milligrams (mg) Tepotinib tablet formulation 2 (TF2, reference treatment) on Day 1 of treatment period 1 followed by a single oral dose of 500 mg (2 x 250 mg) Tepotinib tablet formulation 3 (TF3, test treatment) on Day 1 of treatment period 2 under fasting conditions. The washout period was 21 days between Day 1 of each period.	Drug: Tepotinib TF2; Participants received a single oral dose of 500 mg Tepotinib TF2 under fasting or fed conditions in treatment period 1 or 2.; Drug: Tepotinib TF3; Participants received single oral dose of 500 mg (2 x 250 mg)Tepotinib TF3 under fasting or fed conditions in treatment period 1 or 2.
Experimental: Part A: First Tepotinib TF3 then TF2; Participants received a single oral dose of 500 mg (2 x 250 mg) Tepotinib TF3 (test treatment) on Day 1 of treatment period 1 followed by a single oral dose of 500 mg Tepotinib TF2 (reference treatment) on Day 1 of treatment period 2 under fasting conditions. The washout period was 21 days between Day 1 of each period.	Drug: Tepotinib TF2; Participants received a single oral dose of 500 mg Tepotinib TF2 under fasting or fed conditions in treatment period 1 or 2.; Drug: Tepotinib TF3; Participants received single oral dose of 500 mg (2 x 250 mg)Tepotinib TF3 under fasting or fed conditions in treatment period 1 or 2.
Experimental: Part B: First Tepotinib TF2 Fasted then TF2 Fed; Participants received a single oral dose of 500 mg Tepotinib TF2 (reference treatment) on Day 1 of treatment period 1 under fasting conditions followed by a single oral dose of 500 mg Tepotinib TF2 (reference treatment) on Day 1 of treatment period 2 under fed conditions. The washout period was 21 days between Day 1 of each period.	Drug: Tepotinib TF2; Participants received a single oral dose of 500 mg Tepotinib TF2 under fasting or fed conditions in treatment period 1 or 2.
Experimental: Part B: First Tepotinib TF2 Fed then TF2 Fasted; Participants received a single oral dose of 500 mg Tepotinib TF2 (reference treatment) on Day 1 of treatment period 1 under fed conditions followed by a single oral dose of 500 mg Tepotinib TF2 (reference treatment) on Day 1 of treatment period 2 under fasting conditions. The washout period was 21 days between Day 1 of each period.	Drug: Tepotinib TF2; Participants received a single oral dose of 500 mg Tepotinib TF2 under fasting or fed conditions in treatment period 1 or 2.
Experimental: Part C: First Tepotinib TF3 Fasted then TF3 Fed; Participants received a single oral dose of 500 mg (2 x 250 mg) Tepotinib TF3 (test treatment) on Day 1 of treatment period 1 under fasting conditions followed by a single oral dose of 500 mg (2 x 250 mg) Tepotinib TF3 (test treatment) on Day 1 of treatment period 2 under fed conditions. The washout period was 21 days between Day 1 of each period.	Drug: Tepotinib TF3; Participants received single oral dose of 500 mg (2 x 250 mg)Tepotinib TF3 under fasting or fed conditions in treatment period 1 or 2.
Experimental: Part C: First Tepotinib TF3 Fed then TF3 Fasted; Participants received a single oral dose of 500 mg (2 x 250 mg) Tepotinib TF3 (test treatment) on Day 1 of treatment period 1 under fed conditions followed by a single oral dose of 500 mg (2 x 250 mg) Tepotinib TF3 (test treatment) on Day 1 of treatment period 2 under fasting conditions. The washout period was 21 days between Day 1 of each period.	Drug: Tepotinib TF3; Participants received single oral dose of 500 mg (2 x 250 mg)Tepotinib TF3 under fasting or fed conditions in treatment period 1 or 2.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Part A, B and C: Area Under the Plasma Concentration-Time Curve From Time Zero to the Last Quantifiable Concentration (AUC 0-t) of Tepotinib	Area under the plasma concentration versus time curve from time zero to the last sampling time t at which the concentration was at or above the lower limit of quantification (LLOQ). AUC0-t was to be calculated according to the mixed log-linear trapezoidal rule.	Pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 60, 72, 96, 120, 144 and 168 hours post-dose on Day 1 of each treatment period
Part A, B and C: Area Under the Plasma Concentration-Time Curve From Time Zero Extrapolated to Infinity (AUC 0-inf) of Tepotinib	AUC0-inf was calculated by combining AUC0-t and AUCextra. AUC extra represents an extrapolated value obtained by Clast/ lambda z, where Clast is the calculated plasma concentration at the last sampling time point at which the measured plasma concentration is at or above the Lower Limit of quantification (LLOQ) and lambda z is the apparent terminal rate constant determined by log-linear regression analysis of the measured plasma concentrations of the terminal log-linear phase.	Pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 60, 72, 96, 120, 144 and 168 hours post-dose on Day 1 of each treatment period
Part A, B and C: Maximum Observed Plasma Concentration (Cmax) of Tepotinib	Cmax was obtained directly from the concentration versus time curve.	Pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 60, 72, 96, 120, 144 and 168 hours post-dose on Day 1 of each treatment period

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Part A, B and C: 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, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 60, 72, 96, 120, 144 and 168 hours post-dose on Day 1 of each treatment period
Part A, B and C: Terminal Half-Life (t1/2) of Tepotinib	Terminal half-life is the time measured for the concentration to decrease by one half. Terminal half-life calculated by natural log 2 divided by lambda z. Lambda z is the terminal rate constant 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, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 60, 72, 96, 120, 144 and 168 hours post-dose on Day 1 of each treatment period
Part A, B and C: Apparent Total Body Clearance of Tepotinib From Plasma Following Oral Administration (CL/f)	Clearance of a drug was a measure of the rate at which a drug is metabolized or eliminated by normal biological processes.	Pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 60, 72, 96, 120, 144 and 168 hours post-dose on Day 1 of each treatment period
Part A, B and C: Apparent Volume of Distribution of Tepotinib During the Terminal Phase Following Extravascular Administration (Vz/f)	Vz/f was 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. Apparent volume of distribution after oral dose (Vz/f) is influenced by the fraction absorbed and was 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 after oral dose is influenced by the fraction absorbed.	Pre-dose, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12, 16, 24, 36, 48, 60, 72, 96, 120, 144 and 168 hours post-dose on Day 1 of each treatment period
Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious TEAEs	An Adverse event (AE) was defined as any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease associated with the use of study drug, whether or not considered related to the study drug or worsening of pre-existing medical condition, whether or not related to study drug. 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. An AE was considered as 'treatment emergent' if it occurred after the first drug administration of each period or if it was present prior to drug administration but exacerbated after the drug administration. TEAEs included both serious TEAEs and non-serious TEAEs.	Time from date of informed consent signature up to end of study (assessed up to 7 weeks)
Number of Participants With Clinically Significant Abnormalities in Laboratory Values	The laboratory measurements included hematology, blood chemistry and urinalysis. Number of participants with clinically significant abnormalities in laboratory values were reported. Clinically Significance was decided by investigator.	Time from date of informed consent signature up to end of study (assessed up to 7 weeks)
Number of Participants With Clinically Significant Abnormalities in 12-lead Electrocardiogram (ECG) Findings	The 12-lead ECG recordings were obtained after 5 minutes of rest in a semi-supine position. ECG recordings included rhythm, ventricular rate, PR interval, QRS duration, QT and QTc intervals. Number of participants with clinically significant abnormalities in 12-lead ECG findings were reported. Clinically significance was decided by investigator.	Time from date of informed consent signature up to end of study (assessed up to 7 weeks)
Number of Participants With Clinically Significant Abnormalities in Vital Signs	Vital sign assessment included blood pressure, pulse rate and body temperature. Number of participants with clinically significant abnormalities in vital signs were reported. Clinically significance was decided by investigator.	Time from date of informed consent signature up to end of study (assessed up to 7 weeks)

Collaborators and Investigators

• Sponsor: Merck KGaA, Darmstadt, Germany
• Investigators: Study Director: Medical Responsible, 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)
• Trial Awareness and Transparency website

Study record dates

Study Major Dates

• Study Start (Actual): August 23, 2018
• Primary Completion (Actual): January 25, 2019
• Study Completion (Actual): January 25, 2019

Study Registration Dates

• First Submitted: August 9, 2018
• First Submitted That Met QC Criteria: August 9, 2018
• First Posted (Actual): August 14, 2018

Study Record Updates

• Last Update Posted (Estimated): October 9, 2023
• Last Update Submitted That Met QC Criteria: October 6, 2023
• Last Verified: October 1, 2023

More Information

Terms related to this study

• Keywords: Pharmacokinetics; Bioequivalence; Tepotinib
• Additional Relevant MeSH Terms: Antineoplastic Agents; Tepotinib
• Other Study ID Numbers: MS200095_0044; 2017-005056-29 (EudraCT Number)

Drug and device information, study documents

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