Trial Outcomes & Findings for c-Met Second-Line Hepatocellular Carcinoma (NCT NCT02115373)

Last Updated: 2022-08-24

Results Overview

DLT: defined using NCI-CTCAE for AEs Version 4.0, as any of following toxicities: Grade 4 neutropenia for more than 7 days; greater than or equal to (\>=) Grade 3 febrile neutropenia for more than 1 day; Grade 4 or Grade 3 thrombocytopenia with nontraumatic bleeding; \>=Grade 3 uncontrolled nausea/vomiting and/or diarrhoea despite adequate treatment for more than 3 days; \>=Grade 3 any non-hematological AE. (DLT defined specifically for following cases: \>=Grade 3 liver AE requiring recovery period of more than 7 days or to Grade 1 or less or Grade 2 with liver metastases ; \>=Grade 3 lipase and/or amylase elevation with confirmation of pancreatitis. An isolated lipase and/or amylase elevation of \>=Grade 3 without clinical/radiological evidence of pancreatitis was not classified as DLT); and AEs assessed by investigators to be exclusively related to the participant's underlying disease or medical condition/concomitant treatment are not considered as DLTs.

Recruitment status

COMPLETED

Study phase

PHASE1/PHASE2

Target enrollment

66 participants

Primary outcome timeframe

Day 1 to Day 21 of Cycle 1 (each cycle was 21 days)

Results posted on

2022-08-24

Participant Flow

First participant signed informed consent:18 May 2014, Last participant last visit: 14th Feb 2018

In Phase 1b, 24 participants were screened of which, 17 started the treatment. In Phase 2 ,155 participants were screened, of which 49 participants started the treatment.

Participant milestones

Participant milestones
Measure	Phase 1b: Tepotinib 300 mg Participants received a single oral dose of Tepotinib 300 milligram (mg) daily in each 21 days treatment cycle until progressive disease, intolerable toxicity, death, or withdrawal from treatment.	Phase 1b: Tepotinib 500 mg Participants received a single oral dose of Tepotinib 500 mg daily in each 21 days treatment cycle until progressive disease, intolerable toxicity, death, or withdrawal from treatment.	Phase 2: Tepotinib 500 mg Participants received a single oral dose of Tepotinib 500 mg daily in each 21 days treatment cycle until progressive disease, intolerable toxicity, death, or withdrawal from treatment.
Overall Study STARTED	4	13	49
Overall Study COMPLETED	4	13	49
Overall Study NOT COMPLETED	0	0	0

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

c-Met Second-Line Hepatocellular Carcinoma

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Phase 1b: Tepotinib 300 mg n=4 Participants Participants received a single oral dose of Tepotinib 300mg daily in each 21 days treatment cycle until progressive disease, intolerable toxicity, death, or withdrawal from treatment.	Phase 1b: Tepotinib 500 mg n=13 Participants Participants received a single oral dose of Tepotinib 500mg daily in each 21 days treatment cycle until progressive disease, intolerable toxicity, death, or withdrawal from treatment.	Phase 2: Tepotinib 500 mg n=49 Participants Participants received a single oral dose of Tepotinib 500 mg daily in each 21 days treatment cycle until progressive disease, intolerable toxicity, death, or withdrawal from treatment.	Total n=66 Participants Total of all reporting groups
Age, Categorical <=18 years	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Age, Categorical Between 18 and 65 years	1 Participants n=5 Participants	3 Participants n=7 Participants	21 Participants n=5 Participants	25 Participants n=4 Participants
Age, Categorical >=65 years	3 Participants n=5 Participants	10 Participants n=7 Participants	28 Participants n=5 Participants	41 Participants n=4 Participants
Sex: Female, Male Female	2 Participants n=5 Participants	2 Participants n=7 Participants	8 Participants n=5 Participants	12 Participants n=4 Participants
Sex: Female, Male Male	2 Participants n=5 Participants	11 Participants n=7 Participants	41 Participants n=5 Participants	54 Participants n=4 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Race (NIH/OMB) Asian	0 Participants n=5 Participants	0 Participants n=7 Participants	2 Participants n=5 Participants	2 Participants n=4 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Race (NIH/OMB) Black or African American	0 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants	1 Participants n=4 Participants
Race (NIH/OMB) White	1 Participants n=5 Participants	8 Participants n=7 Participants	26 Participants n=5 Participants	35 Participants n=4 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	1 Participants n=7 Participants	0 Participants n=5 Participants	1 Participants n=4 Participants
Race (NIH/OMB) Unknown or Not Reported	3 Participants n=5 Participants	4 Participants n=7 Participants	20 Participants n=5 Participants	27 Participants n=4 Participants

PRIMARY outcome

Timeframe: Day 1 to Day 21 of Cycle 1 (each cycle was 21 days)

Population: DLT analysis set included all participants who completed Cycle 1 and who received 80 percent (%) or more of the planned cumulative dose of Tepotinib (MSC2156119J) in Cycle 1, and participants who experienced a DLT during Cycle 1.

Outcome measures

Outcome measures
Measure	Phase 2: Tepotinib 500 mg Participants received a single oral dose of Tepotinib 500 mg daily in each 21 days treatment cycle until progressive disease, intolerable toxicity, death, or withdrawal from treatment.	Phase 1b: Tepotinib 300 mg n=3 Participants Participants received a single oral dose of Tepotinib 300mg daily in each 21 days treatment cycle until progressive disease, intolerable toxicity, death, or withdrawal from treatment.	Phase 1b: Tepotinib 500 mg n=11 Participants Participants received a single oral dose of Tepotinib 500mg daily in each 21 days treatment cycle until progressive disease, intolerable toxicity, death, or withdrawal from treatment.
Phase 1b: Number of Participants Experiencing Dose Limiting Toxicity (DLT) According to National Cancer Institute Common Toxicity Criteria (NCI-CTCAE) for Adverse Events (AEs) Version 4.0	—	0 Participants	0 Participants

PRIMARY outcome

Timeframe: At 12 weeks post first-dose in Phase 2

Population: Intent to Treat (ITT) set included all participants who had been administered at least one dose of Tepotinib (MSC2156119J). The outcome measure was planned to be analyzed for Phase 2 only.

PFS status was evaluated by the number of participants who were progression-free at 12 weeks according to RECIST Version 1.1. Participants were considered to be progression-free if the participant had a tumor assessment of Complete Response (CR) defined as disappearance of all target and non-target lesions and any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \< 10 millimeter (mm). Partial response (PR) defined as at least a 30% decrease in the sum of diameters of target lesions taking as reference the baseline sum diameters, or Stable Disease (SD) defined as any cases that do not qualify for either partial response or progressive disease (an increase of at least 20% in the sum of the diameters of target lesions, taking as reference the smallest sum of the diameters of target lesions recorded since treatment started)12 weeks after start of treatment or later.

Outcome measures

Outcome measures
Measure	Phase 2: Tepotinib 500 mg Participants received a single oral dose of Tepotinib 500 mg daily in each 21 days treatment cycle until progressive disease, intolerable toxicity, death, or withdrawal from treatment.	Phase 1b: Tepotinib 300 mg n=49 Participants Participants received a single oral dose of Tepotinib 300mg daily in each 21 days treatment cycle until progressive disease, intolerable toxicity, death, or withdrawal from treatment.	Phase 1b: Tepotinib 500 mg Participants received a single oral dose of Tepotinib 500mg daily in each 21 days treatment cycle until progressive disease, intolerable toxicity, death, or withdrawal from treatment.
Phase 2: Number of Participants Who Were Progression-free at 12 Weeks (PFS Status) as Assessed by the Investigator According to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1	—	31 Participants	—

SECONDARY outcome

Timeframe: Time from first study drug administration to the date of first occurrence of radiological progressive disease (PD), assessed up to 12 months after last participant's first dose (assessed maximum up to 1369 days)

Population: ITT set included all participants who had been administered at least one dose of Tepotinib (MSC2156119J).

TTP was the time (in months) from the date of first study drug administration to the date of radiological confirmation of PD performed according to RECIST Version 1.1. PD was defined as an increase of at least 20% in the sum of the diameters of target lesions, taking as reference the smallest sum of the diameters of target lesions recorded since treatment started. The descriptive data represents the number of participants with progression.

Outcome measures

Outcome measures
Measure	Phase 2: Tepotinib 500 mg n=49 Participants Participants received a single oral dose of Tepotinib 500 mg daily in each 21 days treatment cycle until progressive disease, intolerable toxicity, death, or withdrawal from treatment.	Phase 1b: Tepotinib 300 mg n=4 Participants Participants received a single oral dose of Tepotinib 300mg daily in each 21 days treatment cycle until progressive disease, intolerable toxicity, death, or withdrawal from treatment.	Phase 1b: Tepotinib 500 mg n=13 Participants Participants received a single oral dose of Tepotinib 500mg daily in each 21 days treatment cycle until progressive disease, intolerable toxicity, death, or withdrawal from treatment.
Phase 1b and Phase 2: Time to Progression According to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1	36 Participants	3 Participants	9 Participants

SECONDARY outcome

Timeframe: From randomization up to first observation of PD or death, assessed maximum up to 1369 days

Population: ITT analysis set included all participants who had been administered at least one dose of Tepotinib (MSC2156119J).

PFS time was defined as the time from date of randomization until date of the first observation of progressive disease (PD) or death due to any cause within 12 weeks of the last tumor assessment in the absence of documented PD, whichever occurs first. PFS was assessed as per RECIST v1.1 as adjudicated by independent endpoint review committee (IERC). PD was defined as an increase of at least 20% in the sum of the diameters of target lesions, taking as reference the smallest sum of the diameters of target lesions recorded since treatment started. The descriptive data represents number of participants with death or progressive disease.

Outcome measures

Outcome measures
Measure	Phase 2: Tepotinib 500 mg n=49 Participants Participants received a single oral dose of Tepotinib 500 mg daily in each 21 days treatment cycle until progressive disease, intolerable toxicity, death, or withdrawal from treatment.	Phase 1b: Tepotinib 300 mg n=4 Participants Participants received a single oral dose of Tepotinib 300mg daily in each 21 days treatment cycle until progressive disease, intolerable toxicity, death, or withdrawal from treatment.	Phase 1b: Tepotinib 500 mg n=13 Participants Participants received a single oral dose of Tepotinib 500mg daily in each 21 days treatment cycle until progressive disease, intolerable toxicity, death, or withdrawal from treatment.
Phase 1b and Phase 2: Progression-free Survival (PFS) Time According to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1	38 Participants	4 Participants	12 Participants

SECONDARY outcome

Timeframe: From randomization up to first observation of PD or death, assessed maximum up to 1369 days

Population: ITT analysis set included all participants who had been administered at least one dose of Tepotinib (MSC2156119J).

PFS time was defined as the time from date of randomization until date of the first observation of progressive disease (PD) or death due to any cause within 12 weeks of the last tumor assessment in the absence of documented PD, whichever occurs first. PFS was assessed as per mRECIST for HCC as adjudicated by independent endpoint review committee (IERC). PD was defined as an increase of at least 20% in the sum of the diameters of viable (enhancing) target lesions, taking as reference the smallest sum of the diameters of target lesions recorded since treatment started. The descriptive data represents number of participants with death or progressive disease.

Outcome measures

Outcome measures
Measure	Phase 2: Tepotinib 500 mg n=49 Participants Participants received a single oral dose of Tepotinib 500 mg daily in each 21 days treatment cycle until progressive disease, intolerable toxicity, death, or withdrawal from treatment.	Phase 1b: Tepotinib 300 mg n=4 Participants Participants received a single oral dose of Tepotinib 300mg daily in each 21 days treatment cycle until progressive disease, intolerable toxicity, death, or withdrawal from treatment.	Phase 1b: Tepotinib 500 mg n=13 Participants Participants received a single oral dose of Tepotinib 500mg daily in each 21 days treatment cycle until progressive disease, intolerable toxicity, death, or withdrawal from treatment.
Phase 1b and Phase 2: Progression-free Survival (PFS) Time According to Modified Response Evaluation Criteria in Solid Tumors (mRECIST) for Hepatocellular Carcinoma (HCC)	37 Participants	4 Participants	9 Participants

SECONDARY outcome

Timeframe: From date of randomization up to 1369 days

Population: ITT analysis set included all participants who had been administered at least one dose of Tepotinib (MSC2156119J). Here, Overall number of participants analyzed signified those participants who had symptomatic progression. As per planned analysis, data for this outcome was analyzed for Phase 2 only.

Time-to-symptomatic progression was defined as time (in months) from first study drug administration to the date of deterioration of symptoms assessed by Functional Assessment of Cancer Therapy Hepatobiliary Symptom Index 8 (FHSI-8) (defined as at least a 4-point increase, i.e., higher score, compared with baseline value), or deterioration to Eastern Cooperative Oncology Group (ECOG) performance score 4, or death. FHSI-8 assesses hepatobiliary cancer symptoms with total score ranges from 0 to 32 (0 = the best quality of life; 32 = the worst quality of life with severe symptoms). ECOG assess participant's performance status on a scale of 0 to 5, where 0=fully active and 5=dead.

Outcome measures

Outcome measures
Measure	Phase 2: Tepotinib 500 mg Participants received a single oral dose of Tepotinib 500 mg daily in each 21 days treatment cycle until progressive disease, intolerable toxicity, death, or withdrawal from treatment.	Phase 1b: Tepotinib 300 mg n=41 Participants Participants received a single oral dose of Tepotinib 300mg daily in each 21 days treatment cycle until progressive disease, intolerable toxicity, death, or withdrawal from treatment.	Phase 1b: Tepotinib 500 mg Participants received a single oral dose of Tepotinib 500mg daily in each 21 days treatment cycle until progressive disease, intolerable toxicity, death, or withdrawal from treatment.
Phase 2: Time-to-symptomatic Progression (TTSP)	—	4.86 months Interval 0.03 to 17.97	—

SECONDARY outcome

Timeframe: From date of randomization up to the date of death, assessed maximum up to 1369 days

Population: ITT analysis set included all participants who had been administered at least one dose of Tepotinib (MSC2156119J).

The OS time was defined as the time from randomization to the date of death. The participants who were still alive at the time of data analysis or who were lost to follow-up OS time was censored at the last recorded date that the participant was known to be alive before the data cutoff date. The descriptive data represents number of participants who had an event of death.

Outcome measures

Outcome measures
Measure	Phase 2: Tepotinib 500 mg n=49 Participants Participants received a single oral dose of Tepotinib 500 mg daily in each 21 days treatment cycle until progressive disease, intolerable toxicity, death, or withdrawal from treatment.	Phase 1b: Tepotinib 300 mg n=4 Participants Participants received a single oral dose of Tepotinib 300mg daily in each 21 days treatment cycle until progressive disease, intolerable toxicity, death, or withdrawal from treatment.	Phase 1b: Tepotinib 500 mg n=13 Participants Participants received a single oral dose of Tepotinib 500mg daily in each 21 days treatment cycle until progressive disease, intolerable toxicity, death, or withdrawal from treatment.
Phase 1b and Phase 2: Overall Survival (OS) Time	40 Participants	3 Participants	11 Participants

SECONDARY outcome

Timeframe: From date of randomization up to first occurrence of PD, assessed maximum up to 1369 days

Population: ITT analysis set included all participants who had been administered at least one dose of Tepotinib (MSC2156119J).

Percentage of participants with best overall tumor assessment of (CR or PR) according to RECIST Version 1.1 was reported. CR defined as disappearance of all target and non-target lesions and any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \< 10 mm. PR defined as at least a 30% decrease in the sum of diameters of target lesions taking as reference the baseline sum diameters. PD was defined as an increase of at least 20% in the sum of the diameters of target lesions, taking as reference the smallest sum of the diameters of target lesions recorded since treatment started.

Outcome measures

Outcome measures
Measure	Phase 2: Tepotinib 500 mg n=49 Participants Participants received a single oral dose of Tepotinib 500 mg daily in each 21 days treatment cycle until progressive disease, intolerable toxicity, death, or withdrawal from treatment.	Phase 1b: Tepotinib 300 mg n=4 Participants Participants received a single oral dose of Tepotinib 300mg daily in each 21 days treatment cycle until progressive disease, intolerable toxicity, death, or withdrawal from treatment.	Phase 1b: Tepotinib 500 mg n=13 Participants Participants received a single oral dose of Tepotinib 500mg daily in each 21 days treatment cycle until progressive disease, intolerable toxicity, death, or withdrawal from treatment.
Phase 1b and Phase 2: Percentage of Participants With Best Overall Tumor Assessment of CR or PR According to RECIST v1.1	8.2 percentage of Participants Interval 2.8 to 17.7	50.0 percentage of Participants Interval 9.8 to 90.2	0.0 percentage of Participants Interval 0.0 to 20.6

SECONDARY outcome

Timeframe: From date of randomization up to first occurrence of PD, assessed maximum up to 1369 days

Population: ITT analysis set included all participants who had been administered at least one dose of Tepotinib (MSC2156119J).

Disease control was defined as CR, PR, or SD as the best overall response according to RECIST Version 1.1. Complete Response (CR) defined as disappearance of all target and non-target lesions and any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \< 10 mm. Partial response (PR) defined as at least a 30% decrease in the sum of diameters of target lesions taking as reference the baseline sum diameters, or Stable Disease (SD) defined as any cases that do not qualify for either partial response or progressive disease (an increase of at least 20% in the sum of the diameters of target lesions, taking as reference the smallest sum of the diameters of target lesions recorded since treatment started)12 weeks after start of treatment or later. Percentage of Participants With Disease Control were reported.

Outcome measures

Outcome measures
Measure	Phase 2: Tepotinib 500 mg n=49 Participants Participants received a single oral dose of Tepotinib 500 mg daily in each 21 days treatment cycle until progressive disease, intolerable toxicity, death, or withdrawal from treatment.	Phase 1b: Tepotinib 300 mg n=4 Participants Participants received a single oral dose of Tepotinib 300mg daily in each 21 days treatment cycle until progressive disease, intolerable toxicity, death, or withdrawal from treatment.	Phase 1b: Tepotinib 500 mg n=13 Participants Participants received a single oral dose of Tepotinib 500mg daily in each 21 days treatment cycle until progressive disease, intolerable toxicity, death, or withdrawal from treatment.
Phase 1b and Phase 2: Percentage of Participants With Disease Control	57.1 percentage of participants Interval 44.4 to 69.2	50.0 percentage of participants Interval 9.8 to 90.2	30.8 percentage of participants Interval 11.3 to 57.3

SECONDARY outcome

Timeframe: Baseline up to Cycle 3 (each cycle is 21 days)

Population: ITT analysis set included all participants who had been administered at least one dose of Tepotinib (MSC2156119J). Here, "Overall number of participants analyzed" signified the participants with baseline and post baseline AFP assessments.

Percentage of participants with biological response was measured by serum Alpha-Fetoprotein (AFP), defined as a greater than 20% decrease in AFP level by Cycle 3 (each cycle is of 21 days) compared with baseline.

Outcome measures

Outcome measures
Measure	Phase 2: Tepotinib 500 mg n=45 Participants Participants received a single oral dose of Tepotinib 500 mg daily in each 21 days treatment cycle until progressive disease, intolerable toxicity, death, or withdrawal from treatment.	Phase 1b: Tepotinib 300 mg n=3 Participants Participants received a single oral dose of Tepotinib 300mg daily in each 21 days treatment cycle until progressive disease, intolerable toxicity, death, or withdrawal from treatment.	Phase 1b: Tepotinib 500 mg n=11 Participants Participants received a single oral dose of Tepotinib 500mg daily in each 21 days treatment cycle until progressive disease, intolerable toxicity, death, or withdrawal from treatment.
Phase 1b and Phase 2: Percentage of Participants With Biological Response	31.1 percentage of participants Interval 19.9 to 44.3	66.7 percentage of participants Interval 13.5 to 98.3	45.5 percentage of participants Interval 20.0 to 72.9

SECONDARY outcome

Timeframe: Pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10 and 24 hours Post-dose on Day 1 and Day 15 of Treatment Cycle 1 (each cycle was 21 days)

Population: Pharmacokinetic (PK) population included all participants who have received Tepotinib (MSC2156119J) and who had at least one blood sample drawn that provided drug concentration data for PK evaluation. Here, number analyzed signified participants evaluable at specified timepoint.

Outcome measures

Outcome measures
Measure	Phase 2: Tepotinib 500 mg Participants received a single oral dose of Tepotinib 500 mg daily in each 21 days treatment cycle until progressive disease, intolerable toxicity, death, or withdrawal from treatment.	Phase 1b: Tepotinib 300 mg n=3 Participants Participants received a single oral dose of Tepotinib 300mg daily in each 21 days treatment cycle until progressive disease, intolerable toxicity, death, or withdrawal from treatment.	Phase 1b: Tepotinib 500 mg n=12 Participants Participants received a single oral dose of Tepotinib 500mg daily in each 21 days treatment cycle until progressive disease, intolerable toxicity, death, or withdrawal from treatment.
Phase 1b: Area Under the Plasma Concentration-Time Curve From Time Zero to Last Sampling Time at Which the Concentration is at or Above the Lower Limit of Quantification (AUC0-t) of Tepotinib Cycle 1 Day 1	—	4440 nanogram hour per milliliter (ng*h/mL) Geometric Coefficient of Variation 6.7	5060 nanogram hour per milliliter (ng*h/mL) Geometric Coefficient of Variation 38.9
Phase 1b: Area Under the Plasma Concentration-Time Curve From Time Zero to Last Sampling Time at Which the Concentration is at or Above the Lower Limit of Quantification (AUC0-t) of Tepotinib Cycle 1 Day 15	—	15200 nanogram hour per milliliter (ng*h/mL) Geometric Coefficient of Variation 18.2	12900 nanogram hour per milliliter (ng*h/mL) Geometric Coefficient of Variation 50.4

SECONDARY outcome

Timeframe: Pre-dose and at 0.25, 0.5, 1, 2, 4, 8, 10, and 24 hours post-dose; Day 1 and Day 15 of Cycle 1 (each Cycle is 21 days)

Population: PK population included all participants who have received Tepotinib (MSC2156119J) and who had at least one blood sample drawn that provided drug concentration data for PK evaluation. Here, number analyzed signified participants evaluable at specified timepoint.

Dose normalized was calculated as area under the plasma concentration versus time curve from time zero to the last sampling time t at which the concentration is at or above the lower limit of quantification (LLQ) divided by the dose.

Outcome measures

Outcome measures
Measure	Phase 2: Tepotinib 500 mg Participants received a single oral dose of Tepotinib 500 mg daily in each 21 days treatment cycle until progressive disease, intolerable toxicity, death, or withdrawal from treatment.	Phase 1b: Tepotinib 300 mg n=3 Participants Participants received a single oral dose of Tepotinib 300mg daily in each 21 days treatment cycle until progressive disease, intolerable toxicity, death, or withdrawal from treatment.	Phase 1b: Tepotinib 500 mg n=12 Participants Participants received a single oral dose of Tepotinib 500mg daily in each 21 days treatment cycle until progressive disease, intolerable toxicity, death, or withdrawal from treatment.
Phase 1b: Dose Normalized Area Under the Plasma Concentration-Time Curve From Zero to Last Sampling Time at Which the Concentration is at or Above the Lower Limit of Quantification (AUC0-t) of Tepotinib Cycle 1 Day 1	—	14.8 ng*h/mL/mg Geometric Coefficient of Variation 6.7	10.1 ng*h/mL/mg Geometric Coefficient of Variation 38.9
Phase 1b: Dose Normalized Area Under the Plasma Concentration-Time Curve From Zero to Last Sampling Time at Which the Concentration is at or Above the Lower Limit of Quantification (AUC0-t) of Tepotinib Cycle 1 Day 15	—	50.7 ng*h/mL/mg Geometric Coefficient of Variation 18.2	25.8 ng*h/mL/mg Geometric Coefficient of Variation 50.4

SECONDARY outcome

Timeframe: Pre-dose, 0.25, 0.5, 1, 2, 4, 8, 10 and 24 hours Post-dose on Day 1 and Day 15 of Treatment Cycle 1 (each cycle was 21 days)

Outcome measures

Outcome measures
Measure	Phase 2: Tepotinib 500 mg Participants received a single oral dose of Tepotinib 500 mg daily in each 21 days treatment cycle until progressive disease, intolerable toxicity, death, or withdrawal from treatment.	Phase 1b: Tepotinib 300 mg n=3 Participants Participants received a single oral dose of Tepotinib 300mg daily in each 21 days treatment cycle until progressive disease, intolerable toxicity, death, or withdrawal from treatment.	Phase 1b: Tepotinib 500 mg n=12 Participants Participants received a single oral dose of Tepotinib 500mg daily in each 21 days treatment cycle until progressive disease, intolerable toxicity, death, or withdrawal from treatment.
Phase 1b: Area Under the Plasma Concentration-Time Curve From Time Zero to Infinity (AUC0-inf) of Tepotinib Cycle 1 Day 1	—	NA nanogram hour per milliliter (ng*h/mL) Geometric Coefficient of Variation NA Dosing and sampling scheme in Phase Ib did not allow the reliable estimation of apparent terminal rate constant (λz), Therefore, AUC0-inf dependent on λz was not determined.	NA nanogram hour per milliliter (ng*h/mL) Geometric Coefficient of Variation NA Dosing and sampling scheme in Phase Ib did not allow the reliable estimation of apparent terminal rate constant (λz), Therefore, AUC0-inf dependent on λz was not determined.
Phase 1b: Area Under the Plasma Concentration-Time Curve From Time Zero to Infinity (AUC0-inf) of Tepotinib Cycle 1 Day 15	—	NA nanogram hour per milliliter (ng*h/mL) Geometric Coefficient of Variation NA Dosing and sampling scheme in Phase Ib did not allow the reliable estimation of apparent terminal rate constant (λz), Therefore, AUC0-inf dependent on λz was not determined.	NA nanogram hour per milliliter (ng*h/mL) Geometric Coefficient of Variation NA Dosing and sampling scheme in Phase Ib did not allow the reliable estimation of apparent terminal rate constant (λz), Therefore, AUC0-inf dependent on λz was not determined.

SECONDARY outcome

Timeframe: Pre-dose and at 0.25, 0.5, 1, 2, 4, 8, 10, and 24 hours post-dose; Day 1 and Day 15 of Cycle 1 (each Cycle is 21 days)

Cmax is the maximum observed plasma concentration obtained directly from the concentration versus time curve.

Outcome measures

Outcome measures
Measure	Phase 2: Tepotinib 500 mg Participants received a single oral dose of Tepotinib 500 mg daily in each 21 days treatment cycle until progressive disease, intolerable toxicity, death, or withdrawal from treatment.	Phase 1b: Tepotinib 300 mg n=3 Participants Participants received a single oral dose of Tepotinib 300mg daily in each 21 days treatment cycle until progressive disease, intolerable toxicity, death, or withdrawal from treatment.	Phase 1b: Tepotinib 500 mg n=12 Participants Participants received a single oral dose of Tepotinib 500mg daily in each 21 days treatment cycle until progressive disease, intolerable toxicity, death, or withdrawal from treatment.
Phase 1b: Maximum Observed Plasma Concentration (Cmax) of Tepotinib Cycle 1 Day 1	—	261 nanogram per milliliter (ng/mL) Geometric Coefficient of Variation 8.4	278 nanogram per milliliter (ng/mL) Geometric Coefficient of Variation 39.3
Phase 1b: Maximum Observed Plasma Concentration (Cmax) of Tepotinib Cycle 1 Day 15	—	734 nanogram per milliliter (ng/mL) Geometric Coefficient of Variation 19.6	677 nanogram per milliliter (ng/mL) Geometric Coefficient of Variation 44.6

SECONDARY outcome

Timeframe: Pre-dose and at 0.25, 0.5, 1, 2, 4, 8, 10, and 24 hours post-dose; Day 1 and Day 15 of Cycle 1 (each Cycle is 21 days)

Dose normalized was calculated as maximum observed plasma concentration obtained directly from the concentration versus time curve divided by dose.

Outcome measures

Outcome measures
Measure	Phase 2: Tepotinib 500 mg Participants received a single oral dose of Tepotinib 500 mg daily in each 21 days treatment cycle until progressive disease, intolerable toxicity, death, or withdrawal from treatment.	Phase 1b: Tepotinib 300 mg n=3 Participants Participants received a single oral dose of Tepotinib 300mg daily in each 21 days treatment cycle until progressive disease, intolerable toxicity, death, or withdrawal from treatment.	Phase 1b: Tepotinib 500 mg n=12 Participants Participants received a single oral dose of Tepotinib 500mg daily in each 21 days treatment cycle until progressive disease, intolerable toxicity, death, or withdrawal from treatment.
Phase 1b: Dose Normalized Maximum Observed Plasma Concentration (Cmax) of Tepotinib Cycle 1 Day 1	—	0.871 ng/mL/mg Geometric Coefficient of Variation 8.4	0.556 ng/mL/mg Geometric Coefficient of Variation 39.3
Phase 1b: Dose Normalized Maximum Observed Plasma Concentration (Cmax) of Tepotinib Cycle 1 Day 15	—	2.45 ng/mL/mg Geometric Coefficient of Variation 19.6	1.35 ng/mL/mg Geometric Coefficient of Variation 44.6

SECONDARY outcome

Timeframe: Pre-dose and at 0.25, 0.5, 1, 2, 4, 8, 10, and 24 hours post-dose; Day 15 of Cycle 1 (each Cycle is 21 days)

Population: PK population included all participants who have received Tepotinib (MSC2156119J) and who had at least one blood sample drawn that provided drug concentration data for PK evaluation. Here, Overall number of participants analyzed signified participants who were evaluable for this outcome measure.

Outcome measures

Outcome measures
Measure	Phase 2: Tepotinib 500 mg Participants received a single oral dose of Tepotinib 500 mg daily in each 21 days treatment cycle until progressive disease, intolerable toxicity, death, or withdrawal from treatment.	Phase 1b: Tepotinib 300 mg n=3 Participants Participants received a single oral dose of Tepotinib 300mg daily in each 21 days treatment cycle until progressive disease, intolerable toxicity, death, or withdrawal from treatment.	Phase 1b: Tepotinib 500 mg n=9 Participants Participants received a single oral dose of Tepotinib 500mg daily in each 21 days treatment cycle until progressive disease, intolerable toxicity, death, or withdrawal from treatment.
Phase 1b: Minimum Observed Plasma Concentration (Cmin) of Tepotinib	—	526 nanogram per milliliter (ng/mL) Geometric Coefficient of Variation 28.0	435 nanogram per milliliter (ng/mL) Geometric Coefficient of Variation 57.9

SECONDARY outcome

Timeframe: Pre-dose and at 0.25, 0.5, 1, 2, 4, 8, 10, and 24 hours post-dose; Day 1 and Day 15 of Cycle 1 (each Cycle is 21 days)

Outcome measures

Outcome measures
Measure	Phase 2: Tepotinib 500 mg Participants received a single oral dose of Tepotinib 500 mg daily in each 21 days treatment cycle until progressive disease, intolerable toxicity, death, or withdrawal from treatment.	Phase 1b: Tepotinib 300 mg n=3 Participants Participants received a single oral dose of Tepotinib 300mg daily in each 21 days treatment cycle until progressive disease, intolerable toxicity, death, or withdrawal from treatment.	Phase 1b: Tepotinib 500 mg n=12 Participants Participants received a single oral dose of Tepotinib 500mg daily in each 21 days treatment cycle until progressive disease, intolerable toxicity, death, or withdrawal from treatment.
Phase 1b: Time to Reach Maximum Plasma Concentration (Tmax) of Tepotinib Cycle 1 Day 1	—	10.0 hours Interval 8.0 to 24.0	8.0 hours Interval 8.0 to 10.0
Phase 1b: Time to Reach Maximum Plasma Concentration (Tmax) of Tepotinib Cycle 1 Day 15	—	8.0 hours Interval 0.48 to 8.0	6.1 hours Interval 0.0 to 23.6

SECONDARY outcome

Timeframe: Pre-dose and at 0.25, 0.5, 1, 2, 4, 8, 10, and 24 hours post-dose; Day 15 of Cycle 1 (each Cycle is 21 days)

Population: PK population included all participants who have received Tepotinib (MSC2156119J) and who had at least one blood sample drawn that provided drug concentration data for PK evaluation. Here, Overall number of participants analyzed signified participants who were evaluable for this outcome measure.

Outcome measures

Outcome measures
Measure	Phase 2: Tepotinib 500 mg Participants received a single oral dose of Tepotinib 500 mg daily in each 21 days treatment cycle until progressive disease, intolerable toxicity, death, or withdrawal from treatment.	Phase 1b: Tepotinib 300 mg n=3 Participants Participants received a single oral dose of Tepotinib 300mg daily in each 21 days treatment cycle until progressive disease, intolerable toxicity, death, or withdrawal from treatment.	Phase 1b: Tepotinib 500 mg n=9 Participants Participants received a single oral dose of Tepotinib 500mg daily in each 21 days treatment cycle until progressive disease, intolerable toxicity, death, or withdrawal from treatment.
Phase 1b: Average Plasma Concentration at Steady State (Cav) of Tepotinib	—	635 nanogram per milliliter (ng/mL) Geometric Coefficient of Variation 18.2	542 nanogram per milliliter (ng/mL) Geometric Coefficient of Variation 50.7

SECONDARY outcome

Timeframe: Pre-dose and at 0.25, 0.5, 1, 2, 4, 8, 10, and 24 hours post-dose; Day 15 of Cycle 1 (each Cycle is 21 days)

Population: PK population included all participants who have received Tepotinib (MSC2156119J) and who had at least one blood sample drawn that provided drug concentration data for PK evaluation. Here, Overall number of participants analyzed signified participants who were evaluable for this outcome measure.

Outcome measures

Outcome measures
Measure	Phase 2: Tepotinib 500 mg Participants received a single oral dose of Tepotinib 500 mg daily in each 21 days treatment cycle until progressive disease, intolerable toxicity, death, or withdrawal from treatment.	Phase 1b: Tepotinib 300 mg n=3 Participants Participants received a single oral dose of Tepotinib 300mg daily in each 21 days treatment cycle until progressive disease, intolerable toxicity, death, or withdrawal from treatment.	Phase 1b: Tepotinib 500 mg n=9 Participants Participants received a single oral dose of Tepotinib 500mg daily in each 21 days treatment cycle until progressive disease, intolerable toxicity, death, or withdrawal from treatment.
Phase 1b: Apparent Total Body Clearance From Plasma (CL/f) of Tepotinib	—	17.7 Liter per hour (L/h) Geometric Coefficient of Variation 18.2	34.9 Liter per hour (L/h) Geometric Coefficient of Variation 50.4

SECONDARY outcome

Timeframe: Pre-dose and at 0.25, 0.5, 1, 2, 4, 8, 10, and 24 hours post-dose; Day 1 and Day 15 of Cycle 1 (each Cycle is 21 days)

Population: PK population included all participants who have received Tepotinib (MSC2156119J) and who had at least one blood sample drawn that provided drug concentration data for PK evaluation.

Outcome measures

Outcome measures
Measure	Phase 2: Tepotinib 500 mg Participants received a single oral dose of Tepotinib 500 mg daily in each 21 days treatment cycle until progressive disease, intolerable toxicity, death, or withdrawal from treatment.	Phase 1b: Tepotinib 300 mg n=3 Participants Participants received a single oral dose of Tepotinib 300mg daily in each 21 days treatment cycle until progressive disease, intolerable toxicity, death, or withdrawal from treatment.	Phase 1b: Tepotinib 500 mg n=12 Participants Participants received a single oral dose of Tepotinib 500mg daily in each 21 days treatment cycle until progressive disease, intolerable toxicity, death, or withdrawal from treatment.
Phase 1b: Apparent Volume of Distribution During the Terminal Phase (Vz/f) of Tepotinib Cycle 1 Day 1	—	NA liter Geometric Coefficient of Variation NA Dosing and sampling scheme in Phase Ib did not allow the reliable estimation of apparent terminal rate constant (λz), Therefore, VZ/F dependent on λz was not determined.	NA liter Geometric Coefficient of Variation NA Dosing and sampling scheme in Phase Ib did not allow the reliable estimation of apparent terminal rate constant (λz), Therefore, VZ/F dependent on λz was not determined.
Phase 1b: Apparent Volume of Distribution During the Terminal Phase (Vz/f) of Tepotinib Cycle 1 Day 15	—	NA liter Geometric Coefficient of Variation NA Dosing and sampling scheme in Phase Ib did not allow the reliable estimation of apparent terminal rate constant (λz), Therefore, VZ/F dependent on λz was not determined.	NA liter Geometric Coefficient of Variation NA Dosing and sampling scheme in Phase Ib did not allow the reliable estimation of apparent terminal rate constant (λz), Therefore, VZ/F dependent on λz was not determined.

SECONDARY outcome

Timeframe: Pre-dose and at 0.25, 0.5, 1, 2, 4, 8, 10, and 24 hours post-dose; Day 1 and Day 15 of Cycle 1 (each Cycle is 21 days)

Population: PK population included all participants who have received Tepotinib (MSC2156119J) and who had at least one blood sample drawn that provided drug concentration data for PK evaluation.

Outcome measures

Outcome measures
Measure	Phase 2: Tepotinib 500 mg Participants received a single oral dose of Tepotinib 500 mg daily in each 21 days treatment cycle until progressive disease, intolerable toxicity, death, or withdrawal from treatment.	Phase 1b: Tepotinib 300 mg n=3 Participants Participants received a single oral dose of Tepotinib 300mg daily in each 21 days treatment cycle until progressive disease, intolerable toxicity, death, or withdrawal from treatment.	Phase 1b: Tepotinib 500 mg n=12 Participants Participants received a single oral dose of Tepotinib 500mg daily in each 21 days treatment cycle until progressive disease, intolerable toxicity, death, or withdrawal from treatment.
Phase 1b: Apparent Volume of Distribution During the Steady State (Vss/f) of Tepotinib Cycle 1 Day 1	—	NA liter Geometric Coefficient of Variation NA Dosing and sampling scheme in Phase Ib did not allow the reliable estimation of apparent terminal rate constant (λz), Therefore, VSS/F dependent on λz was not determined.	NA liter Geometric Coefficient of Variation NA Dosing and sampling scheme in Phase Ib did not allow the reliable estimation of apparent terminal rate constant (λz), Therefore, VSS/F dependent on λz was not determined.
Phase 1b: Apparent Volume of Distribution During the Steady State (Vss/f) of Tepotinib Cycle 1 Day 15	—	NA liter Geometric Coefficient of Variation NA Dosing and sampling scheme in Phase Ib did not allow the reliable estimation of apparent terminal rate constant (λz), Therefore, VSS/F dependent on λz was not determined.	NA liter Geometric Coefficient of Variation NA Dosing and sampling scheme in Phase Ib did not allow the reliable estimation of apparent terminal rate constant (λz), Therefore, VSS/F dependent on λz was not determined.

SECONDARY outcome

Timeframe: Pre-dose and at 0.25, 0.5, 1, 2, 4, 8, 10, and 24 hours post-dose; Day 1 and Day 15 of Cycle 1 (each Cycle is 21 days)

Population: PK population included all participants who have received Tepotinib (MSC2156119J) and who had at least one blood sample drawn that provided drug concentration data for PK evaluation.

Outcome measures

Outcome measures
Measure	Phase 2: Tepotinib 500 mg Participants received a single oral dose of Tepotinib 500 mg daily in each 21 days treatment cycle until progressive disease, intolerable toxicity, death, or withdrawal from treatment.	Phase 1b: Tepotinib 300 mg n=3 Participants Participants received a single oral dose of Tepotinib 300mg daily in each 21 days treatment cycle until progressive disease, intolerable toxicity, death, or withdrawal from treatment.	Phase 1b: Tepotinib 500 mg n=12 Participants Participants received a single oral dose of Tepotinib 500mg daily in each 21 days treatment cycle until progressive disease, intolerable toxicity, death, or withdrawal from treatment.
Phase 1b: Apparent Terminal Elimination Rate Constant (λz) of Tepotinib Cycle 1 Day 1	—	NA 1 per hour Geometric Coefficient of Variation NA Dosing and sampling scheme in Phase Ib did not allow the reliable estimation of apparent terminal rate constant (λz), Therefore, λz was not determined.	NA 1 per hour Geometric Coefficient of Variation NA Dosing and sampling scheme in Phase Ib did not allow the reliable estimation of apparent terminal rate constant (λz), Therefore, λz was not determined.
Phase 1b: Apparent Terminal Elimination Rate Constant (λz) of Tepotinib Cycle 1 Day 15	—	NA 1 per hour Geometric Coefficient of Variation NA Dosing and sampling scheme in Phase Ib did not allow the reliable estimation of apparent terminal rate constant (λz), Therefore, λz was not determined.	NA 1 per hour Geometric Coefficient of Variation NA Dosing and sampling scheme in Phase Ib did not allow the reliable estimation of apparent terminal rate constant (λz), Therefore, λz was not determined.

SECONDARY outcome

Timeframe: Pre-dose and at 0.25, 0.5, 1, 2, 4, 8, 10, and 24 hours post-dose; Day 1 and Day 15 of Cycle 1 (each Cycle is 21 days)

Population: PK population included all participants who have received Tepotinib (MSC2156119J) and who had at least one blood sample drawn that provided drug concentration data for PK evaluation.

Outcome measures

Outcome measures
Measure	Phase 2: Tepotinib 500 mg Participants received a single oral dose of Tepotinib 500 mg daily in each 21 days treatment cycle until progressive disease, intolerable toxicity, death, or withdrawal from treatment.	Phase 1b: Tepotinib 300 mg n=3 Participants Participants received a single oral dose of Tepotinib 300mg daily in each 21 days treatment cycle until progressive disease, intolerable toxicity, death, or withdrawal from treatment.	Phase 1b: Tepotinib 500 mg n=12 Participants Participants received a single oral dose of Tepotinib 500mg daily in each 21 days treatment cycle until progressive disease, intolerable toxicity, death, or withdrawal from treatment.
Phase 1b: Apparent Terminal Half-life (t1/2) of Tepotinib Cycle 1 Day 1	—	NA hours Dosing and sampling scheme in Phase Ib did not allow the reliable estimation of apparent terminal rate constant (λz), Therefore, t1/2 dependent on λz was not determined.	NA hours Dosing and sampling scheme in Phase Ib did not allow the reliable estimation of apparent terminal rate constant (λz), Therefore, t1/2 dependent on λz was not determined.
Phase 1b: Apparent Terminal Half-life (t1/2) of Tepotinib Cycle 1 Day 15	—	NA hours Dosing and sampling scheme in Phase Ib did not allow the reliable estimation of apparent terminal rate constant (λz), Therefore, t1/2 dependent on λz was not determined.	NA hours Dosing and sampling scheme in Phase Ib did not allow the reliable estimation of apparent terminal rate constant (λz), Therefore, t1/2 dependent on λz was not determined.

SECONDARY outcome

Timeframe: Pre-dose and at 0.25, 0.5, 1, 2, 4, 8, 10, and 24 hours post-dose; Day 1 Cycle 1 (each Cycle is 21 days)

Population: PK population included all participants who have received Tepotinib (MSC2156119J) and who had at least one blood sample drawn that provided drug concentration data for PK evaluation.

Outcome measures

Outcome measures
Measure	Phase 2: Tepotinib 500 mg Participants received a single oral dose of Tepotinib 500 mg daily in each 21 days treatment cycle until progressive disease, intolerable toxicity, death, or withdrawal from treatment.	Phase 1b: Tepotinib 300 mg n=3 Participants Participants received a single oral dose of Tepotinib 300mg daily in each 21 days treatment cycle until progressive disease, intolerable toxicity, death, or withdrawal from treatment.	Phase 1b: Tepotinib 500 mg n=12 Participants Participants received a single oral dose of Tepotinib 500mg daily in each 21 days treatment cycle until progressive disease, intolerable toxicity, death, or withdrawal from treatment.
Phase 1b: Time Prior to the First Quantifiable (Non-zero) Concentration (Tlag) of Tepotinib	—	0.53 hours Interval 0.52 to 0.55	0.50 hours Interval 0.25 to 1.0

SECONDARY outcome

Timeframe: Pre-dose and at 0.25, 0.5, 1, 2, 4, 8, 10, and 24 hours post-dose; Day 15 of Cycle 1 (each Cycle is 21 days)

Population: PK population included all participants who have received Tepotinib (MSC2156119J) and who had at least one blood sample drawn that provided drug concentration data for PK evaluation. Here, Overall number of participants analyzed signified participants who were evaluable for this outcome measure.

The peak trough fluctuation within complete dosing interval at steady state, calculated as PTF (%) = (\[Cmax - Cmin\]/Cav ) multiplied by 100

Outcome measures

Outcome measures
Measure	Phase 2: Tepotinib 500 mg Participants received a single oral dose of Tepotinib 500 mg daily in each 21 days treatment cycle until progressive disease, intolerable toxicity, death, or withdrawal from treatment.	Phase 1b: Tepotinib 300 mg n=3 Participants Participants received a single oral dose of Tepotinib 300mg daily in each 21 days treatment cycle until progressive disease, intolerable toxicity, death, or withdrawal from treatment.	Phase 1b: Tepotinib 500 mg n=9 Participants Participants received a single oral dose of Tepotinib 500mg daily in each 21 days treatment cycle until progressive disease, intolerable toxicity, death, or withdrawal from treatment.
Phase 1b: Percentage Peak-Trough Fluctuation (PTF) Post First Dose of Tepotinib	—	31.5 percentage fluctuation Geometric Coefficient of Variation 30.5	35.9 percentage fluctuation Geometric Coefficient of Variation 44.1

SECONDARY outcome

Timeframe: Pre-dose and at 0.25, 0.5, 1, 2, 4, 8, 10, and 24 hours post-dose; Day 1 and Day 15 of Cycle 1 (each Cycle is 21 days)

Population: PK population included all participants who have received Tepotinib (MSC2156119J) and who had at least one blood sample drawn that provided drug concentration data for PK evaluation. Here, Overall number of participants analyzed signified participants who were evaluable for this outcome measure.

Accumulation ratio for Cmax was calculated as Cmax, after dosing on Day 15 divided by Cmax, after dosing on day 1 of cycle 1.

Outcome measures

Outcome measures
Measure	Phase 2: Tepotinib 500 mg Participants received a single oral dose of Tepotinib 500 mg daily in each 21 days treatment cycle until progressive disease, intolerable toxicity, death, or withdrawal from treatment.	Phase 1b: Tepotinib 300 mg n=3 Participants Participants received a single oral dose of Tepotinib 300mg daily in each 21 days treatment cycle until progressive disease, intolerable toxicity, death, or withdrawal from treatment.	Phase 1b: Tepotinib 500 mg n=10 Participants Participants received a single oral dose of Tepotinib 500mg daily in each 21 days treatment cycle until progressive disease, intolerable toxicity, death, or withdrawal from treatment.
Phase 1b: Accumulation Ratio of Cmax (Racc (Cmax))	—	2.81 ratio Geometric Coefficient of Variation 24.1	2.32 ratio Geometric Coefficient of Variation 23.0

SECONDARY outcome

Timeframe: Pre-dose and at 0.25, 0.5, 1, 2, 4, 8, 10, and 24 hours post-dose; Day 1 and Day 15 of Cycle 1 (each Cycle is 21 days)

Population: PK population included all participants who have received Tepotinib (MSC2156119J) and who had at least one blood sample drawn that provided drug concentration data for PK evaluation. Here, Overall number of participants analyzed signified participants who were evaluable for this outcome measure.

Accumulation ratio for AUC was calculated as AUC, after dosing on Day 15 divided by AUC, after dosing on day 1 of cycle 1.

Outcome measures

Outcome measures
Measure	Phase 2: Tepotinib 500 mg Participants received a single oral dose of Tepotinib 500 mg daily in each 21 days treatment cycle until progressive disease, intolerable toxicity, death, or withdrawal from treatment.	Phase 1b: Tepotinib 300 mg n=3 Participants Participants received a single oral dose of Tepotinib 300mg daily in each 21 days treatment cycle until progressive disease, intolerable toxicity, death, or withdrawal from treatment.	Phase 1b: Tepotinib 500 mg n=9 Participants Participants received a single oral dose of Tepotinib 500mg daily in each 21 days treatment cycle until progressive disease, intolerable toxicity, death, or withdrawal from treatment.
Phase 1b: Accumulation Ratio of AUC (Racc (AUC)	—	3.43 ratio Geometric Coefficient of Variation 22.6	2.51 ratio Geometric Coefficient of Variation 22.0

Adverse Events

Phase 1b: Tepotinib 300 mg

Serious events: 2 serious events

Other events: 4 other events

Deaths: 3 deaths

Phase 1b: Tepotinib 500 mg

Serious events: 5 serious events

Other events: 12 other events

Deaths: 11 deaths

Phase 2: Tepotinib 500 mg

Serious events: 21 serious events

Other events: 48 other events

Deaths: 40 deaths

Serious adverse events

Other adverse events

Additional Information

Communication Center

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

Restriction type: OTHER

Measure	Phase 1b: Tepotinib 300 mg n=4 participants at risk Participants received a single oral dose of Tepotinib 300 milligram (mg) daily in each 21 days treatment cycle until progressive disease, intolerable toxicity, death, or withdrawal from treatment.	Phase 1b: Tepotinib 500 mg n=13 participants at risk Participants received a single oral dose of Tepotinib 500 mg daily in each 21 days treatment cycle until progressive disease, intolerable toxicity, death, or withdrawal from treatment.	Phase 2: Tepotinib 500 mg n=49 participants at risk Participants received a single oral dose of Tepotinib 500 mg daily in each 21 days treatment cycle until progressive disease, intolerable toxicity, death, or withdrawal from treatment.
Gastrointestinal disorders Abdominal pain	25.0% 1/4 • From date of randomization up to 1369 days	0.00% 0/13 • From date of randomization up to 1369 days	0.00% 0/49 • From date of randomization up to 1369 days
Gastrointestinal disorders Ascites	0.00% 0/4 • From date of randomization up to 1369 days	15.4% 2/13 • From date of randomization up to 1369 days	6.1% 3/49 • From date of randomization up to 1369 days
Gastrointestinal disorders Gastrointestinal haemorrhage	0.00% 0/4 • From date of randomization up to 1369 days	0.00% 0/13 • From date of randomization up to 1369 days	2.0% 1/49 • From date of randomization up to 1369 days
General disorders Disease progression	25.0% 1/4 • From date of randomization up to 1369 days	7.7% 1/13 • From date of randomization up to 1369 days	14.3% 7/49 • From date of randomization up to 1369 days
General disorders Localised oedema	0.00% 0/4 • From date of randomization up to 1369 days	7.7% 1/13 • From date of randomization up to 1369 days	0.00% 0/49 • From date of randomization up to 1369 days
General disorders Oedema peripheral	0.00% 0/4 • From date of randomization up to 1369 days	15.4% 2/13 • From date of randomization up to 1369 days	2.0% 1/49 • From date of randomization up to 1369 days
General disorders Discomfort	0.00% 0/4 • From date of randomization up to 1369 days	0.00% 0/13 • From date of randomization up to 1369 days	2.0% 1/49 • From date of randomization up to 1369 days
General disorders General physical health deterioration	0.00% 0/4 • From date of randomization up to 1369 days	0.00% 0/13 • From date of randomization up to 1369 days	2.0% 1/49 • From date of randomization up to 1369 days
General disorders Pyrexia	0.00% 0/4 • From date of randomization up to 1369 days	0.00% 0/13 • From date of randomization up to 1369 days	2.0% 1/49 • From date of randomization up to 1369 days
General disorders Vascular stent stenosis	0.00% 0/4 • From date of randomization up to 1369 days	0.00% 0/13 • From date of randomization up to 1369 days	2.0% 1/49 • From date of randomization up to 1369 days
Hepatobiliary disorders Cholangitis	0.00% 0/4 • From date of randomization up to 1369 days	0.00% 0/13 • From date of randomization up to 1369 days	2.0% 1/49 • From date of randomization up to 1369 days
Hepatobiliary disorders Hepatic failure	0.00% 0/4 • From date of randomization up to 1369 days	0.00% 0/13 • From date of randomization up to 1369 days	2.0% 1/49 • From date of randomization up to 1369 days
Hepatobiliary disorders Jaundice	0.00% 0/4 • From date of randomization up to 1369 days	0.00% 0/13 • From date of randomization up to 1369 days	2.0% 1/49 • From date of randomization up to 1369 days
Hepatobiliary disorders Hepatorenal syndrome	0.00% 0/4 • From date of randomization up to 1369 days	7.7% 1/13 • From date of randomization up to 1369 days	0.00% 0/49 • From date of randomization up to 1369 days
Infections and infestations Device related infection	0.00% 0/4 • From date of randomization up to 1369 days	0.00% 0/13 • From date of randomization up to 1369 days	2.0% 1/49 • From date of randomization up to 1369 days
Infections and infestations Peritonitis bacterial	0.00% 0/4 • From date of randomization up to 1369 days	0.00% 0/13 • From date of randomization up to 1369 days	2.0% 1/49 • From date of randomization up to 1369 days
Infections and infestations Sepsis	0.00% 0/4 • From date of randomization up to 1369 days	7.7% 1/13 • From date of randomization up to 1369 days	2.0% 1/49 • From date of randomization up to 1369 days
Infections and infestations Peritonitis	0.00% 0/4 • From date of randomization up to 1369 days	7.7% 1/13 • From date of randomization up to 1369 days	0.00% 0/49 • From date of randomization up to 1369 days
Infections and infestations Post procedural infection	25.0% 1/4 • From date of randomization up to 1369 days	0.00% 0/13 • From date of randomization up to 1369 days	0.00% 0/49 • From date of randomization up to 1369 days
Metabolism and nutrition disorders Hypercalcaemia	0.00% 0/4 • From date of randomization up to 1369 days	0.00% 0/13 • From date of randomization up to 1369 days	2.0% 1/49 • From date of randomization up to 1369 days
Metabolism and nutrition disorders Hypercreatininaemia	0.00% 0/4 • From date of randomization up to 1369 days	0.00% 0/13 • From date of randomization up to 1369 days	2.0% 1/49 • From date of randomization up to 1369 days
Metabolism and nutrition disorders Hyponatraemia	0.00% 0/4 • From date of randomization up to 1369 days	0.00% 0/13 • From date of randomization up to 1369 days	2.0% 1/49 • From date of randomization up to 1369 days
Metabolism and nutrition disorders Decreased appetite	25.0% 1/4 • From date of randomization up to 1369 days	0.00% 0/13 • From date of randomization up to 1369 days	0.00% 0/49 • From date of randomization up to 1369 days
Musculoskeletal and connective tissue disorders Rhabdomyolysis	0.00% 0/4 • From date of randomization up to 1369 days	0.00% 0/13 • From date of randomization up to 1369 days	2.0% 1/49 • From date of randomization up to 1369 days
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Cancer pain	0.00% 0/4 • From date of randomization up to 1369 days	0.00% 0/13 • From date of randomization up to 1369 days	2.0% 1/49 • From date of randomization up to 1369 days
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Tumour pain	0.00% 0/4 • From date of randomization up to 1369 days	0.00% 0/13 • From date of randomization up to 1369 days	2.0% 1/49 • From date of randomization up to 1369 days
Nervous system disorders Coma	0.00% 0/4 • From date of randomization up to 1369 days	7.7% 1/13 • From date of randomization up to 1369 days	0.00% 0/49 • From date of randomization up to 1369 days
Nervous system disorders Hepatic encephalopathy	0.00% 0/4 • From date of randomization up to 1369 days	7.7% 1/13 • From date of randomization up to 1369 days	0.00% 0/49 • From date of randomization up to 1369 days
Nervous system disorders Cerebral thrombosis	0.00% 0/4 • From date of randomization up to 1369 days	0.00% 0/13 • From date of randomization up to 1369 days	2.0% 1/49 • From date of randomization up to 1369 days
Nervous system disorders Hypoglycaemic coma	0.00% 0/4 • From date of randomization up to 1369 days	0.00% 0/13 • From date of randomization up to 1369 days	2.0% 1/49 • From date of randomization up to 1369 days
Renal and urinary disorders Acute kidney injury	25.0% 1/4 • From date of randomization up to 1369 days	7.7% 1/13 • From date of randomization up to 1369 days	6.1% 3/49 • From date of randomization up to 1369 days
Renal and urinary disorders Chronic kidney disease	0.00% 0/4 • From date of randomization up to 1369 days	0.00% 0/13 • From date of randomization up to 1369 days	2.0% 1/49 • From date of randomization up to 1369 days
Respiratory, thoracic and mediastinal disorders Pneumonia aspiration	0.00% 0/4 • From date of randomization up to 1369 days	0.00% 0/13 • From date of randomization up to 1369 days	2.0% 1/49 • From date of randomization up to 1369 days
Reproductive system and breast disorders Prostatitis	0.00% 0/4 • From date of randomization up to 1369 days	7.7% 1/13 • From date of randomization up to 1369 days	0.00% 0/49 • From date of randomization up to 1369 days
Investigations Blood bilirubin increased	25.0% 1/4 • From date of randomization up to 1369 days	0.00% 0/13 • From date of randomization up to 1369 days	0.00% 0/49 • From date of randomization up to 1369 days