Trial Outcomes & Findings for Bioequivalence of 5 Tablets of 100 mg Versus 2 Tablets of 250 mg TF3 of Tepotinib (NCT NCT04204902)

NCT ID: NCT04204902

Last Updated: 2023-11-08

Results Overview

Area under the plasma concentration-time curve (AUC) from time zero (= dosing time) to the last sampling time (tlast) at which the concentration is at or above the lower limit of quantification (LLOQ), calculated using the mixed log linear trapezoidal rule (linear up/log down).

• Recruitment status: COMPLETED
• Study phase: PHASE1
• Target enrollment: 18 participants
• Primary outcome timeframe: Pre-dose, 0.25, 0.50, 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
• Results posted on: 2023-11-08

Participant Flow

Overall 42 participants were screened of which 18 participants were randomized in the study.

Participant milestones

Measure	First Tepotinib Test, Then Tepotinib Reference Participants received a single oral dose of test treatment of tepotinib TF3 (5 \* 100 mg) in treatment period 1 followed by a single oral dose of reference treatment of tepotinib TF3 (2 \* 250 mg) in treatment period 2. The treatment periods were separated by 21 day washout period.	First Tepotinib Reference, Then Tepotinib Test Participants received a single oral dose of reference treatment of tepotinib TF3 (2 \* 250 mg) in treatment period 1 followed by a single oral dose of test treatment of tepotinib TF3 (5 \* 100 mg) in treatment period 2. The treatment periods were separated by 21 day washout period.
Treatment Period 1 (Day 1) STARTED	9	9
Treatment Period 1 (Day 1) COMPLETED	9	9
Treatment Period 1 (Day 1) NOT COMPLETED	0	0
Washout Period (21 Days) STARTED	9	9
Washout Period (21 Days) COMPLETED	9	9
Washout Period (21 Days) NOT COMPLETED	0	0
Treatment Period 2 (Day 22) STARTED	9	9
Treatment Period 2 (Day 22) COMPLETED	9	8
Treatment Period 2 (Day 22) NOT COMPLETED	0	1

Reasons for withdrawal

Measure	First Tepotinib Test, Then Tepotinib Reference Participants received a single oral dose of test treatment of tepotinib TF3 (5 \* 100 mg) in treatment period 1 followed by a single oral dose of reference treatment of tepotinib TF3 (2 \* 250 mg) in treatment period 2. The treatment periods were separated by 21 day washout period.	First Tepotinib Reference, Then Tepotinib Test Participants received a single oral dose of reference treatment of tepotinib TF3 (2 \* 250 mg) in treatment period 1 followed by a single oral dose of test treatment of tepotinib TF3 (5 \* 100 mg) in treatment period 2. The treatment periods were separated by 21 day washout period.
Treatment Period 2 (Day 22) Withdrawal by Subject	0	1

Baseline Characteristics

Bioequivalence of 5 Tablets of 100 mg Versus 2 Tablets of 250 mg TF3 of Tepotinib

Baseline characteristics by cohort

Measure	Entire Study Population n=18 Participants Participants received a single oral dose of test treatment of tepotinib TF3 (5 \* 100 mg) or single oral dose of reference treatment of tepotinib TF3 (2 \* 250 mg) in treatment period 1 or 2. The treatment periods were separated by 21 days of washout period.
Age, Continuous	43 Years STANDARD_DEVIATION 8.8 • n=5 Participants
Sex: Female, Male Female	1 Participants n=5 Participants
Sex: Female, Male Male	17 Participants n=5 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	0 Participants n=5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	18 Participants n=5 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants
Race (NIH/OMB) Asian	0 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants
Race (NIH/OMB) Black or African American	0 Participants n=5 Participants
Race (NIH/OMB) White	18 Participants n=5 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants

PRIMARY outcome

Timeframe: Pre-dose, 0.25, 0.50, 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

Population: Pharmacokinetic(PK) Analysis set included all participants without any relevant protocol deviations with respect to PK and absence of factors likely to affect the comparability of PK results. Here 'Number of Participants Analyzed' =number of participants evaluable for this outcome measure.

Area under the plasma concentration-time curve (AUC) from time zero (= dosing time) to the last sampling time (tlast) at which the concentration is at or above the lower limit of quantification (LLOQ), calculated using the mixed log linear trapezoidal rule (linear up/log down).

Outcome measures

Measure	Tepotinib Test Treatment n=17 Participants Participants received a single oral dose of test treatment of tepotinib TF3 (5 \* 100 mg) in either treatment period 1 or 2.	Tepotinib Reference Treatment n=18 Participants Participants received a single oral dose of reference treatment of tepotinib TF3 (2 \* 250 mg) in either treatment period 1 or 2.
Area Under the Plasma Concentration-Time Curve From Time Zero to the Last Quantifiable Concentration (AUC0-t) of Tepotinib	15348 Hours*nanogram per milliliter (hr*ng/mL) Geometric Coefficient of Variation 28	16523 Hours*nanogram per milliliter (hr*ng/mL) Geometric Coefficient of Variation 37.6

PRIMARY outcome

Timeframe: Pre-dose, 0.25, 0.50, 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

Population: PK Analysis set included all participants without any relevant protocol deviations with respect to PK and absence of factors likely to affect the comparability of PK results. Here 'Number of Participants Analyzed' =number of participants evaluable for this outcome measure.

AUC0-inf was calculated as AUC0-t + AUC from time tlast extrapolated to infinity (AUCextra). AUCextra represents the extrapolated part of AUC0-inf calculated by Clastpred/lambda z, where Clastpred was the predicted plasma concentration at the last sampling time point at which the measured plasma concentration was at or above the lower limit of quantification (LLOQ) and lambda z was the apparent terminal rate constant determined from the terminal slope of the log-transformed plasma concentration curve.

Outcome measures

Measure	Tepotinib Test Treatment n=17 Participants Participants received a single oral dose of test treatment of tepotinib TF3 (5 \* 100 mg) in either treatment period 1 or 2.	Tepotinib Reference Treatment n=18 Participants Participants received a single oral dose of reference treatment of tepotinib TF3 (2 \* 250 mg) in either treatment period 1 or 2.
Area Under the Plasma Concentration-Time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of Tepotinib	15958 hr*ng/mL Geometric Coefficient of Variation 28.7	17201 hr*ng/mL Geometric Coefficient of Variation 38.5

PRIMARY outcome

Timeframe: Pre-dose, 0.25, 0.50, 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

Population: PK Analysis set included all participants without any relevant protocol deviations with respect to PK and absence of factors likely to affect the comparability of PK results.

Cmax was obtained directly from the concentration versus time curve.

Outcome measures

Measure	Tepotinib Test Treatment n=18 Participants Participants received a single oral dose of test treatment of tepotinib TF3 (5 \* 100 mg) in either treatment period 1 or 2.	Tepotinib Reference Treatment n=18 Participants Participants received a single oral dose of reference treatment of tepotinib TF3 (2 \* 250 mg) in either treatment period 1 or 2.
Maximum Observed Plasma Concentration (Cmax) of Tepotinib	252 ng/mL Geometric Coefficient of Variation 19.1	240 ng/mL Geometric Coefficient of Variation 27.4

SECONDARY outcome

Timeframe: Pre-dose, 0.25, 0.50, 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

Population: PK Analysis set included all participants without any relevant protocol deviations with respect to PK and absence of factors likely to affect the comparability of PK results.

Tmax was obtained directly from the concentration versus time curve.

Outcome measures

Measure	Tepotinib Test Treatment n=18 Participants Participants received a single oral dose of test treatment of tepotinib TF3 (5 \* 100 mg) in either treatment period 1 or 2.	Tepotinib Reference Treatment n=18 Participants Participants received a single oral dose of reference treatment of tepotinib TF3 (2 \* 250 mg) in either treatment period 1 or 2.
Time to Reach the Maximum Plasma Concentration (Tmax) of Tepotinib	12.0 Hours Interval 6.0 to 36.0	20.1 Hours Interval 6.0 to 48.0

SECONDARY outcome

Timeframe: Pre-dose, 0.25, 0.50, 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

Population: PK Analysis set included all participants without any relevant protocol deviations with respect to PK and absence of factors likely to affect the comparability of PK results. Here 'Number of Participants Analyzed' =number of participants evaluable for this outcome measure.

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.

Outcome measures

Measure	Tepotinib Test Treatment n=17 Participants Participants received a single oral dose of test treatment of tepotinib TF3 (5 \* 100 mg) in either treatment period 1 or 2.	Tepotinib Reference Treatment n=18 Participants Participants received a single oral dose of reference treatment of tepotinib TF3 (2 \* 250 mg) in either treatment period 1 or 2.
Terminal Half-Life (t1/2) of Tepotinib	33.1 Hours Geometric Coefficient of Variation 12.6	32.1 Hours Geometric Coefficient of Variation 12.3

SECONDARY outcome

Timeframe: Pre-dose, 0.25, 0.50, 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

Population: PK Analysis set included all participants without any relevant protocol deviations with respect to PK and absence of factors likely to affect the comparability of PK results. Here 'Number of Participants Analyzed' =number of participants evaluable for this outcome measure.

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.

Outcome measures

Measure	Tepotinib Test Treatment n=17 Participants Participants received a single oral dose of test treatment of tepotinib TF3 (5 \* 100 mg) in either treatment period 1 or 2.	Tepotinib Reference Treatment n=18 Participants Participants received a single oral dose of reference treatment of tepotinib TF3 (2 \* 250 mg) in either treatment period 1 or 2.
Apparent Volume of Distribution During Terminal Phase (Vz/f) for Tepotinib	1347 Liters Geometric Coefficient of Variation 24.3	1211 Liters Geometric Coefficient of Variation 33.1

SECONDARY outcome

Timeframe: Pre-dose, 0.25, 0.50, 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

Population: PK Analysis set included all participants without any relevant protocol deviations with respect to PK and absence of factors likely to affect the comparability of PK results. Here 'Number of Participants Analyzed' =number of participants evaluable for this outcome measure.

CL/f following oral administration was calculated as Dose/AUC0-inf, where AUC0-inf calculated as AUC0-t + AUC from time tlast extrapolated to infinity (AUCextra). AUCextra represents the extrapolated part of AUC0-inf calculated by Clastpred/lambda z, where Clastpred was the predicted plasma concentration at the last sampling time point at which the measured plasma concentration was at or above the lower limit of quantification (LLOQ) and lambda z was the apparent terminal rate constant determined from the terminal slope of the log-transformed plasma concentration curve.

Outcome measures

Measure	Tepotinib Test Treatment n=17 Participants Participants received a single oral dose of test treatment of tepotinib TF3 (5 \* 100 mg) in either treatment period 1 or 2.	Tepotinib Reference Treatment n=18 Participants Participants received a single oral dose of reference treatment of tepotinib TF3 (2 \* 250 mg) in either treatment period 1 or 2.
Apparent Total Body Clearance (CL/f) of Tepotinib	28.2 Liters per hour Geometric Coefficient of Variation 28.7	26.2 Liters per hour Geometric Coefficient of Variation 38.5

SECONDARY outcome

Timeframe: Baseline up to Day 59

Population: Safety Analysis set included all participants who had received at least one dose of planned study intervention and had one subsequent safety assessment.

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. TEAEs included both Serious TEAEs and non-serious TEAEs.

Outcome measures

Measure	Tepotinib Test Treatment n=18 Participants Participants received a single oral dose of test treatment of tepotinib TF3 (5 \* 100 mg) in either treatment period 1 or 2.	Tepotinib Reference Treatment n=18 Participants Participants received a single oral dose of reference treatment of tepotinib TF3 (2 \* 250 mg) in either treatment period 1 or 2.
Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, TEAEs Leading to Death, TEAEs Leading to Discontinuation TEAEs	7 Participants	6 Participants
Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, TEAEs Leading to Death, TEAEs Leading to Discontinuation Serious TEAEs	0 Participants	0 Participants
Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, TEAEs Leading to Death, TEAEs Leading to Discontinuation TEAE leading to Discontinuation	0 Participants	0 Participants
Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious TEAEs, TEAEs Leading to Death, TEAEs Leading to Discontinuation TEAEs Leading to Death	0 Participants	0 Participants

SECONDARY outcome

Timeframe: Baseline up to Day 59

Population: Safety Analysis set included all participants who had received at least one dose of planned study intervention and had one subsequent safety assessment.

Vital signs included oral body temperature, systolic blood pressure, diastolic blood pressure, and pulse rate. The 12-lead ECGs were recorded after the participants have rested for at least 5 minutes in supine position. Laboratory parameters included hematology, biochemistry, urinalysis, and coagulation. Number of participants with clinically significant change from baseline in vital signs, ECG and laboratory parameters were reported. Clinical Significance was decided by the investigator.

Outcome measures

Measure	Tepotinib Test Treatment n=18 Participants Participants received a single oral dose of test treatment of tepotinib TF3 (5 \* 100 mg) in either treatment period 1 or 2.	Tepotinib Reference Treatment n=18 Participants Participants received a single oral dose of reference treatment of tepotinib TF3 (2 \* 250 mg) in either treatment period 1 or 2.
Number of Participants With Clinically Significant Changes From Baseline in Laboratory Parameters, 12-lead Electrocardiogram (ECG) Findings and Vital Signs Laboratory parameters	1 Participants	0 Participants
Number of Participants With Clinically Significant Changes From Baseline in Laboratory Parameters, 12-lead Electrocardiogram (ECG) Findings and Vital Signs ECG	0 Participants	0 Participants
Number of Participants With Clinically Significant Changes From Baseline in Laboratory Parameters, 12-lead Electrocardiogram (ECG) Findings and Vital Signs Vital Signs	0 Participants	0 Participants

Adverse Events

Tepotinib Test Treatment

Serious events: 0 serious events

Other events: 7 other events

Deaths: 0 deaths

Tepotinib Reference Treatment

Serious events: 0 serious events

Other events: 6 other events

Deaths: 0 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Measure	Tepotinib Test Treatment n=18 participants at risk Participants received a single oral dose of test treatment of tepotinib TF3 (5 \* 100 mg) in either treatment period 1 or 2.	Tepotinib Reference Treatment n=18 participants at risk Participants received a single oral dose of reference treatment of tepotinib TF3 (2 \* 250 mg) in either treatment period 1 or 2.
Gastrointestinal disorders Diarrhoea	16.7% 3/18 • Baseline and up to Day 59	16.7% 3/18 • Baseline and up to Day 59
Gastrointestinal disorders Faeces soft	5.6% 1/18 • Baseline and up to Day 59	5.6% 1/18 • Baseline and up to Day 59
Infections and infestations Gingivitis	0.00% 0/18 • Baseline and up to Day 59	5.6% 1/18 • Baseline and up to Day 59
Infections and infestations Nasopharyngitis	5.6% 1/18 • Baseline and up to Day 59	5.6% 1/18 • Baseline and up to Day 59
Injury, poisoning and procedural complications Burns first degree	0.00% 0/18 • Baseline and up to Day 59	5.6% 1/18 • Baseline and up to Day 59
Investigations Alanine aminotransferase increased	5.6% 1/18 • Baseline and up to Day 59	0.00% 0/18 • Baseline and up to Day 59
Metabolism and nutrition disorders Decreased appetite	5.6% 1/18 • Baseline and up to Day 59	0.00% 0/18 • Baseline and up to Day 59
Musculoskeletal and connective tissue disorders Back pain	5.6% 1/18 • Baseline and up to Day 59	5.6% 1/18 • Baseline and up to Day 59
Musculoskeletal and connective tissue disorders Spinal pain	5.6% 1/18 • Baseline and up to Day 59	0.00% 0/18 • Baseline and up to Day 59
Nervous system disorders Dizziness	0.00% 0/18 • Baseline and up to Day 59	5.6% 1/18 • Baseline and up to Day 59
Nervous system disorders Headache	0.00% 0/18 • Baseline and up to Day 59	5.6% 1/18 • Baseline and up to Day 59
Respiratory, thoracic and mediastinal disorders Throat irritation	5.6% 1/18 • Baseline and up to Day 59	5.6% 1/18 • Baseline and up to Day 59
Skin and subcutaneous tissue disorders Skin exfoliation	0.00% 0/18 • Baseline and up to Day 59	5.6% 1/18 • Baseline and up to Day 59
Vascular disorders Haematoma	0.00% 0/18 • Baseline and up to Day 59	5.6% 1/18 • Baseline and up to Day 59
Vascular disorders Hot flush	5.6% 1/18 • Baseline and up to Day 59	0.00% 0/18 • Baseline and up to Day 59

Additional Information

Communication Center

Merck Healthcare KGaA, Darmstadt, Germany, an affiliate of Merck KGaA, Darmstadt, Germany

Phone: +49-6151-72-5200

Email: service@emdgroup.com

Results disclosure agreements

• Principal investigator is a sponsor employee
• Publication restrictions are in place

Restriction type: OTHER