CClinicalTrials.gg
Sign In
CompletedNCT05203822Updated Feb 20, 2024Results posted

Tepotinib Drug-Drug Interaction Study With Itraconazole in Healthy Participants

A Phase 1 interventional study of Tepotinib (HydroChloride hydrate) and Itraconazole in Healthy, sponsored by Merck Healthcare KGaA, Darmstadt, Germany, an affiliate of Merck KGaA, Darmstadt, Germany. Completed at 1 site in Germany. Open to participants aged 18 Years to 55 Years, including healthy volunteers. Per ClinicalTrials.gov, last updated 2024-02-20.

Sponsored by Merck Healthcare KGaA, Darmstadt, Germany, an affiliate of Merck KGaA, Darmstadt, Germany · Phase 1, Interventional, and Treatment

Phase
Phase 1
Study type
Interventional
Enrollment
18
Allocation
Not applicable
Ages
18 Years to 55 Years
Sex
All
01

Study 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

02

Conditions studied

  • Healthy

Keywords

  • Clinical pharmacology
  • Metabolite
  • Induction of metabolism
03

In context

Lead sponsor

Merck Healthcare KGaA, Darmstadt, Germany, an affiliate of Merck KGaA, Darmstadt, Germany is the lead sponsor of 55 studies on the registry; 5 are open to participants now.

Counted across the registry records on this site, refreshed daily.

04

Who can participate

Ages eligible
18 Years to 55 Years
Sexes eligible
All
Accepts healthy volunteers
Yes

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

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
05

Study design

Phase
Phase 1
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Sequential assignment
Masking
None (open label)
Enrollment
18 participants (actual)

Study arms

  • Experimental
    Tepotinib then Itraconazole

    Participants received a single oral dose of Tepotinib 500 milligrams (mg) on Day 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.

    Drug: Tepotinib (HydroChloride hydrate) · Drug: Itraconazole

Interventions

  • DrugTepotinib (HydroChloride hydrate)

    Participants received Tepotinib (Hydrochloride hydrate) Film-coated tablet with food on Day 1 and 12 in the morning.

  • DrugItraconazole

    Participants received Itraconazole Hard-gelatin capsule with food once daily at the same time in the morning from Day 8 to Day 18; on Day 12 itraconazole is administered concomitantly with tepotinib.

06

What researchers measure

Primary outcomes

  1. Area Under the Plasma Concentration-Time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of Tepotinib

    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.

    Time frame: Predose up to 168 hours post dose

  2. Area Under the Plasma Concentration-Time Curve (AUC) From Time Zero to Time of Last Measurable Concentration (AUC0-tlast) of Tepotinib

    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).

    Time frame: Predose up to 168 hours post dose

  3. Maximum Observed Plasma Concentration (Cmax) of Tepotinib and Metabolite

    Cmax was obtained directly from the concentration versus time curve.

    Time frame: Predose up to 168 hours post dose

Secondary outcomes

  1. Number of Participants With Treatment-emergent Adverse Events (TEAEs), Serious TEAEs, TEAES With Severity of Grade Greater or Equal to 3

    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

    Time frame: Baseline (Day 1) up to follow up (assessed up to Day 20)

  2. Number of Participants With Clinically Meaningful Change From Baseline in Laboratory Values

    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.

    Time frame: Baseline (Day 1) up to follow up (assessed up to Day 20)

  3. Number of Participants With Clinically Meaningful Change From Baseline in Electrocardiogram (ECG)

    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.

    Time frame: Baseline (Day 1) up to follow up (assessed up to Day 20)

  4. Number of Participants With Clinically Meaningful Change From Baseline in Vital Signs

    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.

    Time frame: Baseline (Day 1) up to follow up (assessed up to Day 20)

  5. 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.

    Time frame: Predose up to 168 hours post dose

  6. Apparent Volume of Distribution (Vz/f) for Tepotinib

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

    Time frame: Predose up to 168 hours post dose

  7. Time to Reach the Maximum Plasma Concentration (Tmax) of Tepotinib

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

    Time frame: Predose up to 168 hours post dose

  8. Apparent Terminal Half-Life (t1/2) of Tepotinib 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.

    Time frame: Predose up to 168 hours post dose

07

Results

Posted Feb 20, 2024

Participant flow

Participant flow — Overall Study
MilestoneTepotinib and Itraconazole
Started18
Completed16
Not completed2
Withdrew: Adverse event1
Withdrew: Withdrawal by subject1

Outcome measures

PrimaryArea Under the Plasma Concentration-Time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of Tepotinib

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.

Time frame:
Predose up to 168 hours post dose
Reported as:
Geometric mean · hours* nanograms per milliliter(h*ng/mL)
Area Under the Plasma Concentration-Time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of Tepotinib
hours* nanograms per milliliter(h*ng/mL)TepotinibTepotinib and Itraconazole
Area Under the Plasma Concentration-Time Curve From Time Zero Extrapolated to Infinity (AUC0-inf) of Tepotinib18927 ± 28.223158 ± 29.9
PrimaryArea Under the Plasma Concentration-Time Curve (AUC) From Time Zero to Time of Last Measurable Concentration (AUC0-tlast) of Tepotinib

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).

Time frame:
Predose up to 168 hours post dose
Reported as:
Geometric mean · h*ng/mL
Area Under the Plasma Concentration-Time Curve (AUC) From Time Zero to Time of Last Measurable Concentration (AUC0-tlast) of Tepotinib
h*ng/mLTepotinibTepotinib and Itraconazole
Area Under the Plasma Concentration-Time Curve (AUC) From Time Zero to Time of Last Measurable Concentration (AUC0-tlast) of Tepotinib18300 ± 27.921391 ± 30.2
PrimaryMaximum Observed Plasma Concentration (Cmax) of Tepotinib and Metabolite

Cmax was obtained directly from the concentration versus time curve.

Time frame:
Predose up to 168 hours post dose
Reported as:
Geometric mean · nanogram per mililiter (ng/mL)
Maximum Observed Plasma Concentration (Cmax) of Tepotinib and Metabolite
nanogram per mililiter (ng/mL)TepotinibTepotinib and Itraconazole
Maximum Observed Plasma Concentration (Cmax) of Tepotinib and Metabolite308 ± 24.8313 ± 28.2
SecondaryNumber of Participants With Treatment-emergent Adverse Events (TEAEs), Serious TEAEs, TEAES With Severity of Grade Greater or Equal to 3

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

Time frame:
Baseline (Day 1) up to follow up (assessed up to Day 20)
Reported as:
Count of participants · Participants
Number of Participants With Treatment-emergent Adverse Events (TEAEs), Serious TEAEs, TEAES With Severity of Grade Greater or Equal to 3
ParticipantsTepotinib and Itraconazole
Any TEAE14
Any serious TEAE0
Any TEAE of Grade ≥ 3 (severe)0
SecondaryNumber of Participants With Clinically Meaningful Change From Baseline in Laboratory Values

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.

Time frame:
Baseline (Day 1) up to follow up (assessed up to Day 20)
Reported as:
Count of participants · Participants
Number of Participants With Clinically Meaningful Change From Baseline in Laboratory Values
ParticipantsTepotinib and Itraconazole
Hematology0
Biochemistry0
Urinalysis0
SecondaryNumber of Participants With Clinically Meaningful Change From Baseline in Electrocardiogram (ECG)

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.

Time frame:
Baseline (Day 1) up to follow up (assessed up to Day 20)
Reported as:
Count of participants · Participants
Number of Participants With Clinically Meaningful Change From Baseline in Electrocardiogram (ECG)
ParticipantsTepotinib and Itraconazole
Number of Participants With Clinically Meaningful Change From Baseline in Electrocardiogram (ECG)0
SecondaryNumber of Participants With Clinically Meaningful Change From Baseline in Vital Signs

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.

Time frame:
Baseline (Day 1) up to follow up (assessed up to Day 20)
Reported as:
Count of participants · Participants
Number of Participants With Clinically Meaningful Change From Baseline in Vital Signs
ParticipantsTepotinib and Itraconazole
Number of Participants With Clinically Meaningful Change From Baseline in Vital Signs0
SecondaryTotal 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.

Time frame:
Predose up to 168 hours post dose
Reported as:
Geometric mean · liter/hour
Total Body Clearance of Drug From Plasma (CL/f) for Tepotinib
liter/hourTepotinibTepotinib and Itraconazole
Total Body Clearance of Drug From Plasma (CL/f) for Tepotinib23.8 ± 28.219.4 ± 29.9
SecondaryApparent Volume of Distribution (Vz/f) for Tepotinib

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

Time frame:
Predose up to 168 hours post dose
Reported as:
Geometric mean · liters
Apparent Volume of Distribution (Vz/f) for Tepotinib
litersTepotinibTepotinib and Itraconazole
Apparent Volume of Distribution (Vz/f) for Tepotinib1102 ± 29.41148 ± 34.3
SecondaryTime to Reach the Maximum Plasma Concentration (Tmax) of Tepotinib

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

Time frame:
Predose up to 168 hours post dose
Reported as:
Median · hours
Time to Reach the Maximum Plasma Concentration (Tmax) of Tepotinib
hoursTepotinibTepotinib and Itraconazole
Time to Reach the Maximum Plasma Concentration (Tmax) of Tepotinib8.00 (6.00 to 16.00)8.00 (6.05 to 24.00)
SecondaryApparent Terminal Half-Life (t1/2) of Tepotinib 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.

Time frame:
Predose up to 168 hours post dose
Reported as:
Geometric mean · hours
Apparent Terminal Half-Life (t1/2) of Tepotinib in Plasma
hoursTepotinibTepotinib and Itraconazole
Apparent Terminal Half-Life (t1/2) of Tepotinib in Plasma32.1 ± 7.840.9 ± 19.2

Adverse events

Collected over Baseline (Day 1) up to follow up (assessed up to Day 20). Non-serious events are listed at a 5% frequency threshold.

Adverse event summary by group
GroupDeathsSeriousOther
Tepotinib and Itraconazole0/18 (0%)0/18 (0%)14/18 (77.8%)
Most frequent other events
Showing 10 of 34
Most frequent other events
EventTepotinib and Itraconazole
HeadacheNervous system disorders7/18
Middle insomniaPsychiatric disorders4/18
Abdominal distensionGastrointestinal disorders2/18
Abdominal painGastrointestinal disorders2/18
Abdominal pain upperGastrointestinal disorders2/18
DiarrhoeaGastrointestinal disorders2/18
Chest discomfortGeneral disorders2/18
FatigueGeneral disorders2/18
SomnolenceNervous system disorders2/18
Abdominal discomfortGastrointestinal disorders1/18

Baseline characteristics

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

Age, Continuous
Age, Continuous(Years)Tepotinib and Itraconazole
Mean43 ± 10
Sex: Female, Male
Sex: Female, Male(Participants)Tepotinib and Itraconazole
Female4
Male14
Ethnicity (NIH/OMB)
Ethnicity (NIH/OMB)(Participants)Tepotinib and Itraconazole
Hispanic or Latino0
Not Hispanic or Latino18
Unknown or Not Reported0
Race (NIH/OMB)
Race (NIH/OMB)(Participants)Tepotinib and Itraconazole
American Indian or Alaska Native0
Asian0
Native Hawaiian or Other Pacific Islander0
Black or African American1
White17
More than one race0
Unknown or Not Reported0
08

Study locations

1 site
  • Nuvisan GmbH
    Neu-Ulm, Germany
09

References and documents

Study documents

  • Study protocol · Sep 15, 2021
  • Statistical analysis plan · Feb 18, 2022

Documents are hosted by the registry — open the source record to download them.

Individual participant data

Plan to share: No — We are committed to enhancing public health through responsible sharing of clinical trial data. Following approval of a new product or a new indication for an approved product in both the US and the European Union, the study sponsor and/or its affiliated companies will share study protocols, anonymized patient data and study level data, and redacted clinical study reports with qualified scientific and medical researchers, upon request, as necessary for conducting legitimate research. Further information on how to request data can be found on our website bit.ly/IPD21

10

Updates

Tracking since Sep 25, 2026
No changes since tracking began. The registry record was last updated on Feb 20, 2024, before this site started recording changes on Sep 25, 2026. Its history is on ClinicalTrials.gov ↗
11

Registry details

Key details

Study ID
NCT05203822
Lead sponsor
Merck Healthcare KGaA, Darmstadt, Germany, an affiliate of Merck KGaA, Darmstadt, Germany
Responsible party
Sponsor
First posted
Jan 24, 2022
Start date
Jan 21, 2022
Primary completion
Jul 5, 2022
Completion
Jul 5, 2022
Results posted
Feb 20, 2024
Last update
Feb 20, 2024

Study contacts

Medical Responsible
study director · Merck Healthcare KGaA, Darmstadt, Germany, an affiliate of Merck KGaA, Darmstadt, Germany

Oversight

Data monitoring committee
No
FDA-regulated drug
No
FDA-regulated device
No
View the source record on ClinicalTrials.gov ↗

Not currently enrolling

This study is completed, as verified in Jun 2023. You cannot join it, but the record below documents what was studied.

Follow this study

Get an email when the registry record changes — status, dates, results — or when someone posts here.

Sign in to follow

Discussion

Questions and observations about this study, from anyone following it. Not medical advice, and not a channel to the study team — their contact details are on the registry record.

Sign in to join the discussion. Reading takes no account; posting does. You choose a display name, and a pseudonym is the default.

Nothing here yet. If you are running this trial, taking part in it, or weighing whether to, this is the place to say so.

Other studies from this sponsor

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

Start the discussion