Trial Outcomes & Findings for Tepotinib Drug-Drug Interaction Study With Itraconazole in Healthy Participants (NCT NCT05203822)

NCT ID: NCT05203822

Last Updated: 2024-02-20

Results Overview

The AUC from time zero (= dosing time) extrapolated to infinity, based on the predicted value for the concentration at tlast, as estimated using the linear regression from lambda (λ)z determination.

Recruitment status

COMPLETED

Study phase

PHASE1

Target enrollment

18 participants

Primary outcome timeframe

Predose up to 168 hours post dose

Results posted on

2024-02-20

Participant Flow

A total of 44 participants were screened, out of which 18 participants received the study drug.

Participant milestones

Participant milestones
Measure	Tepotinib and Itraconazole Participants received a single oral dose of Tepotinib 500 milligrams (mg) on Day 1 and Day 12 under fed condition followed by single oral dose of itraconazole 200 mg on Days 8 to 11 and Days 13 to 18. On Day 12, participants received a single dose of 200 mg itraconazole simultaneously with a single dose of 500 mg tepotinib.
Overall Study STARTED	18
Overall Study COMPLETED	16
Overall Study NOT COMPLETED	2

Reasons for withdrawal

Reasons for withdrawal
Measure	Tepotinib and Itraconazole Participants received a single oral dose of Tepotinib 500 milligrams (mg) on Day 1 and Day 12 under fed condition followed by single oral dose of itraconazole 200 mg on Days 8 to 11 and Days 13 to 18. On Day 12, participants received a single dose of 200 mg itraconazole simultaneously with a single dose of 500 mg tepotinib.
Overall Study Adverse Event	1
Overall Study Withdrawal by Subject	1

Baseline Characteristics

Tepotinib Drug-Drug Interaction Study With Itraconazole in Healthy Participants

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Tepotinib and Itraconazole n=18 Participants Participants received a single oral dose of Tepotinib 500 milligrams (mg) on Day 1 and Day 12 under fed condition followed by single oral dose of itraconazole 200 mg on Days 8 to 11 and Days 13 to 18. On Day 12, participants received a single dose of 200 mg itraconazole simultaneously with a single dose of 500 mg tepotinib.
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	1 Participants n=5 Participants
Race (NIH/OMB) White	17 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
Age, Continuous	43 Years STANDARD_DEVIATION 10 • n=5 Participants
Sex: Female, Male Female	4 Participants n=5 Participants
Sex: Female, Male Male	14 Participants n=5 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	0 Participants n=5 Participants

PRIMARY outcome

Timeframe: Predose up to 168 hours post dose

Population: Pharmacokinetic (PK) analysis set included all participants who were administered any dose of any study intervention and completed the study without any relevant protocol deviations and factors likely to affect the comparability of PK results.

The AUC from time zero (= dosing time) extrapolated to infinity, based on the predicted value for the concentration at tlast, as estimated using the linear regression from lambda (λ)z determination.

Outcome measures

Outcome measures
Measure	Tepotinib n=17 Participants Participants received a single oral dose of Tepotinib 500 milligrams (mg) on Day 1.	Tepotinib and Itraconazole n=17 Participants Participants received 200 mg itraconazole with food once daily in the morning from Day 12 to Day 18 along with a single oral dose of Tepotinib 500 mg on Day 12.
Area Under the Plasma Concentration-Time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of Tepotinib	18927 hours* nanograms per milliliter(h*ng/mL) Geometric Coefficient of Variation 28.2	23158 hours* nanograms per milliliter(h*ng/mL) Geometric Coefficient of Variation 29.9

PRIMARY outcome

Timeframe: Predose up to 168 hours post dose

Population: PK analysis set included all participants who were administered any dose of any study intervention and completed the study without any relevant protocol deviations and factors likely to affect the comparability of PK results.

The AUC from time zero (= dosing time) to time of the last quantifiable concentration (tlast). Calculated using the mixed log-linear trapezoidal rule (linear up, log down).

Outcome measures

Outcome measures
Measure	Tepotinib n=17 Participants Participants received a single oral dose of Tepotinib 500 milligrams (mg) on Day 1.	Tepotinib and Itraconazole n=17 Participants Participants received 200 mg itraconazole with food once daily in the morning from Day 12 to Day 18 along with a single oral dose of Tepotinib 500 mg on Day 12.
Area Under the Plasma Concentration-Time Curve (AUC) From Time Zero to Time of Last Measurable Concentration (AUC0-tlast) of Tepotinib	18300 h*ng/mL Geometric Coefficient of Variation 27.9	21391 h*ng/mL Geometric Coefficient of Variation 30.2

PRIMARY outcome

Timeframe: Predose up to 168 hours post dose

Cmax was obtained directly from the concentration versus time curve.

Outcome measures

Outcome measures
Measure	Tepotinib n=17 Participants Participants received a single oral dose of Tepotinib 500 milligrams (mg) on Day 1.	Tepotinib and Itraconazole n=17 Participants Participants received 200 mg itraconazole with food once daily in the morning from Day 12 to Day 18 along with a single oral dose of Tepotinib 500 mg on Day 12.
Maximum Observed Plasma Concentration (Cmax) of Tepotinib and Metabolite	308 nanogram per mililiter (ng/mL) Geometric Coefficient of Variation 24.8	313 nanogram per mililiter (ng/mL) Geometric Coefficient of Variation 28.2

SECONDARY outcome

Timeframe: Baseline (Day 1) up to follow up (assessed up to Day 20)

Population: The Safety Analysis Set (SAF) included all participants, who were administered any dose of any study intervention.

An adverse event (AE) was defined as any untoward medical occurrence in a participant. An AE was any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with use of a study intervention. A serious adverse event (SAE) was any untoward medical occurrence 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. TEAE's were those events with onset dates on or after the first administration of study intervention. Severity of abnormalities were evaluated using the Common Terminology Criteria for Adverse Events (CTCAE) version \[24.1\]. grade 1 : mild grade 2 : moderate grade 3 : severe or medically significant but not immediately life-threatening grade 4 : life threatening or disabling grade 5 : death related to AE

Outcome measures

Outcome measures
Measure	Tepotinib n=18 Participants Participants received a single oral dose of Tepotinib 500 milligrams (mg) on Day 1.	Tepotinib and Itraconazole Participants received 200 mg itraconazole with food once daily in the morning from Day 12 to Day 18 along with a single oral dose of Tepotinib 500 mg on Day 12.
Number of Participants With Treatment-emergent Adverse Events (TEAEs), Serious TEAEs, TEAES With Severity of Grade Greater or Equal to 3 Any TEAE	14 Participants	—
Number of Participants With Treatment-emergent Adverse Events (TEAEs), Serious TEAEs, TEAES With Severity of Grade Greater or Equal to 3 Any serious TEAE	0 Participants	—
Number of Participants With Treatment-emergent Adverse Events (TEAEs), Serious TEAEs, TEAES With Severity of Grade Greater or Equal to 3 Any TEAE of Grade ≥ 3 (severe)	0 Participants	—

SECONDARY outcome

Timeframe: Baseline (Day 1) up to follow up (assessed up to Day 20)

Population: SAF included all participants, who were administered any dose of any study intervention.

Laboratory investigation included hematology, biochemistry and urinalysis. Clinically meaningful was decided by the investigator. Number of participants with clinically meaningful change from baseline in laboratory values were reported.

Outcome measures

Outcome measures
Measure	Tepotinib n=18 Participants Participants received a single oral dose of Tepotinib 500 milligrams (mg) on Day 1.	Tepotinib and Itraconazole Participants received 200 mg itraconazole with food once daily in the morning from Day 12 to Day 18 along with a single oral dose of Tepotinib 500 mg on Day 12.
Number of Participants With Clinically Meaningful Change From Baseline in Laboratory Values Hematology	0 Participants	—
Number of Participants With Clinically Meaningful Change From Baseline in Laboratory Values Biochemistry	0 Participants	—
Number of Participants With Clinically Meaningful Change From Baseline in Laboratory Values Urinalysis	0 Participants	—

SECONDARY outcome

Timeframe: Baseline (Day 1) up to follow up (assessed up to Day 20)

Population: SAF included all participants, who were administered any dose of any study intervention.

The 12-lead ECGs were recorded after the participants have rested for at least 5 minutes in supine position. The parameters included heart rate (HR), Respiratory Rate, Pulse Rate, QRS, QT and QTcB calculated by the Bazett formula. Clinical Significance was decided by the investigator. Number of participants with clinically meaningful change from baseline in ECG parameters were reported.

Outcome measures

Outcome measures
Measure	Tepotinib n=18 Participants Participants received a single oral dose of Tepotinib 500 milligrams (mg) on Day 1.	Tepotinib and Itraconazole Participants received 200 mg itraconazole with food once daily in the morning from Day 12 to Day 18 along with a single oral dose of Tepotinib 500 mg on Day 12.
Number of Participants With Clinically Meaningful Change From Baseline in Electrocardiogram (ECG)	0 Participants	—

SECONDARY outcome

Timeframe: Baseline (Day 1) up to follow up (assessed up to Day 20)

Population: SAF included all participants, who were administered any dose of any study intervention.

Vital signs included oral body temperature, systolic blood pressure, diastolic blood pressure, and pulse rate. Clinical Significance was decided by the investigator. Number of participants with clinically significant change from baseline in vital signs.

Outcome measures

Outcome measures
Measure	Tepotinib n=18 Participants Participants received a single oral dose of Tepotinib 500 milligrams (mg) on Day 1.	Tepotinib and Itraconazole Participants received 200 mg itraconazole with food once daily in the morning from Day 12 to Day 18 along with a single oral dose of Tepotinib 500 mg on Day 12.
Number of Participants With Clinically Meaningful Change From Baseline in Vital Signs	0 Participants	—

SECONDARY outcome

Timeframe: Predose up to 168 hours post dose

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.

Outcome measures

Outcome measures
Measure	Tepotinib n=17 Participants Participants received a single oral dose of Tepotinib 500 milligrams (mg) on Day 1.	Tepotinib and Itraconazole n=17 Participants Participants received 200 mg itraconazole with food once daily in the morning from Day 12 to Day 18 along with a single oral dose of Tepotinib 500 mg on Day 12.
Total Body Clearance of Drug From Plasma (CL/f) for Tepotinib	23.8 liter/hour Geometric Coefficient of Variation 28.2	19.4 liter/hour Geometric Coefficient of Variation 29.9

SECONDARY outcome

Timeframe: Predose up to 168 hours post dose

Vz/F was defined as the apparent volume of distribution during the terminal phase following extravascular administration.

Outcome measures

Outcome measures
Measure	Tepotinib n=17 Participants Participants received a single oral dose of Tepotinib 500 milligrams (mg) on Day 1.	Tepotinib and Itraconazole n=17 Participants Participants received 200 mg itraconazole with food once daily in the morning from Day 12 to Day 18 along with a single oral dose of Tepotinib 500 mg on Day 12.
Apparent Volume of Distribution (Vz/f) for Tepotinib	1102 liters Geometric Coefficient of Variation 29.4	1148 liters Geometric Coefficient of Variation 34.3

SECONDARY outcome

Timeframe: Predose up to 168 hours post dose

The time to reach the maximum observed plasma concentration (Tmax) was obtained directly from the concentration versus time curve.

Outcome measures

Outcome measures
Measure	Tepotinib n=17 Participants Participants received a single oral dose of Tepotinib 500 milligrams (mg) on Day 1.	Tepotinib and Itraconazole n=17 Participants Participants received 200 mg itraconazole with food once daily in the morning from Day 12 to Day 18 along with a single oral dose of Tepotinib 500 mg on Day 12.
Time to Reach the Maximum Plasma Concentration (Tmax) of Tepotinib	8.00 hours Interval 6.0 to 16.0	8.00 hours Interval 6.05 to 24.0

SECONDARY outcome

Timeframe: Predose up to 168 hours post dose

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

Outcome measures
Measure	Tepotinib n=17 Participants Participants received a single oral dose of Tepotinib 500 milligrams (mg) on Day 1.	Tepotinib and Itraconazole n=17 Participants Participants received 200 mg itraconazole with food once daily in the morning from Day 12 to Day 18 along with a single oral dose of Tepotinib 500 mg on Day 12.
Apparent Terminal Half-Life (t1/2) of Tepotinib in Plasma	32.1 hours Geometric Coefficient of Variation 7.8	40.9 hours Geometric Coefficient of Variation 19.2

Adverse Events

Tepotinib and Itraconazole

Serious events: 0 serious events

Other events: 14 other events

Deaths: 0 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Other adverse events
Measure	Tepotinib and Itraconazole n=18 participants at risk Participants received a single oral dose of Tepotinib 500 milligrams (mg) on Day 1 and Day 12 under fed condition followed by single oral dose of itraconazole 200 mg on Days 8 to 11 and Days 13 to 18. On Day 12, participants received a single dose of 200 mg itraconazole simultaneously with a single dose of 500 mg tepotinib.
Gastrointestinal disorders Abdominal discomfort	5.6% 1/18 • Baseline (Day 1) up to follow up (assessed up to Day 20)
Gastrointestinal disorders Abdominal distension	11.1% 2/18 • Baseline (Day 1) up to follow up (assessed up to Day 20)
Gastrointestinal disorders Abdominal pain	11.1% 2/18 • Baseline (Day 1) up to follow up (assessed up to Day 20)
Gastrointestinal disorders Abdominal pain upper	11.1% 2/18 • Baseline (Day 1) up to follow up (assessed up to Day 20)
Gastrointestinal disorders Diarrhoea	11.1% 2/18 • Baseline (Day 1) up to follow up (assessed up to Day 20)
Gastrointestinal disorders Dry mouth	5.6% 1/18 • Baseline (Day 1) up to follow up (assessed up to Day 20)
Gastrointestinal disorders Dyspepsia	5.6% 1/18 • Baseline (Day 1) up to follow up (assessed up to Day 20)
Gastrointestinal disorders Epigastric discomfort	5.6% 1/18 • Baseline (Day 1) up to follow up (assessed up to Day 20)
Gastrointestinal disorders Faeces hard	5.6% 1/18 • Baseline (Day 1) up to follow up (assessed up to Day 20)
Gastrointestinal disorders Flatulence	5.6% 1/18 • Baseline (Day 1) up to follow up (assessed up to Day 20)
Gastrointestinal disorders Gastrointestinal motility disorder	5.6% 1/18 • Number of events 1 • Baseline (Day 1) up to follow up (assessed up to Day 20)
Gastrointestinal disorders Rectal tenesmus	5.6% 1/18 • Baseline (Day 1) up to follow up (assessed up to Day 20)
Gastrointestinal disorders Toothache	5.6% 1/18 • Number of events 1 • Baseline (Day 1) up to follow up (assessed up to Day 20)
Gastrointestinal disorders Vomiting	5.6% 1/18 • Baseline (Day 1) up to follow up (assessed up to Day 20)
General disorders Catheter site induration	5.6% 1/18 • Baseline (Day 1) up to follow up (assessed up to Day 20)
General disorders Chest discomfort	11.1% 2/18 • Baseline (Day 1) up to follow up (assessed up to Day 20)
General disorders Chest pain	5.6% 1/18 • Baseline (Day 1) up to follow up (assessed up to Day 20)
General disorders Fatigue	11.1% 2/18 • Baseline (Day 1) up to follow up (assessed up to Day 20)
Infections and infestations Rhinitis	5.6% 1/18 • Number of events 1 • Baseline (Day 1) up to follow up (assessed up to Day 20)
Investigations Amylase increased	5.6% 1/18 • Baseline (Day 1) up to follow up (assessed up to Day 20)
Investigations Lipase increased	5.6% 1/18 • Baseline (Day 1) up to follow up (assessed up to Day 20)
Musculoskeletal and connective tissue disorders Flank pain	5.6% 1/18 • Baseline (Day 1) up to follow up (assessed up to Day 20)
Nervous system disorders Ataxia	5.6% 1/18 • Baseline (Day 1) up to follow up (assessed up to Day 20)
Nervous system disorders Clumsiness	5.6% 1/18 • Baseline (Day 1) up to follow up (assessed up to Day 20)
Nervous system disorders Dizziness	5.6% 1/18 • Baseline (Day 1) up to follow up (assessed up to Day 20)
Nervous system disorders Headache	38.9% 7/18 • Baseline (Day 1) up to follow up (assessed up to Day 20)
Nervous system disorders Hypoaesthesia	5.6% 1/18 • Baseline (Day 1) up to follow up (assessed up to Day 20)
Nervous system disorders Somnolence	11.1% 2/18 • Baseline (Day 1) up to follow up (assessed up to Day 20)
Psychiatric disorders Abnormal dreams	5.6% 1/18 • Baseline (Day 1) up to follow up (assessed up to Day 20)
Psychiatric disorders Middle insomnia	22.2% 4/18 • Baseline (Day 1) up to follow up (assessed up to Day 20)
Renal and urinary disorders Nocturia	5.6% 1/18 • Baseline (Day 1) up to follow up (assessed up to Day 20)
Respiratory, thoracic and mediastinal disorders Cough	5.6% 1/18 • Baseline (Day 1) up to follow up (assessed up to Day 20)
Respiratory, thoracic and mediastinal disorders Oropharyngeal pain	5.6% 1/18 • Baseline (Day 1) up to follow up (assessed up to Day 20)
Skin and subcutaneous tissue disorders Hyperhidrosis	5.6% 1/18 • Baseline (Day 1) up to follow up (assessed up to Day 20)

Additional Information

Communication Center

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

Phone: +49-6151-72-5200

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place