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    Clinical Trial Results:
    A Multicenter, Single Arm, Phase Ib/II Study to Evaluate Efficacy, Safety, and PK of MSC2156119J as Monotherapy in Subjects with MET+ Advanced Hepatocellular Carcinoma with Child Pugh Class A Liver Function Who Have Failed Sorafenib Treatment

    Summary
    EudraCT number
    2013-002053-30
    Trial protocol
    DE   BE   IT   ES  
    Global end of trial date
    14 Feb 2018

    Results information
    Results version number
    v1(current)
    This version publication date
    02 Mar 2019
    First version publication date
    02 Mar 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    EMR200095_005
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02115373
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Merck KGaA
    Sponsor organisation address
    Frankfurter Strasse 250,, Darmstadt, Germany, 64293
    Public contact
    Communication Centre Merck KGaA, Merck KGaA, +49 6151725200, service@merckgroup.com
    Scientific contact
    Communication Centre Merck KGaA, Merck KGaA, +49 6151725200, service@merckgroup.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    14 Feb 2018
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    14 Feb 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The purpose of the study was to determine the required Phase 2 dose and evaluate the efficacy of of MSC2156119J with MET+ advanced Hepatocellular Carcinoma (HCC) pretreated with sorafenib and child pugh class A liver function.
    Protection of trial subjects
    Subject protection was ensured by following high medical and ethical standards in accordance with the principles laid down in the Declaration of Helsinki, and that are consistent with Good Clinical Practice and applicable regulations.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    18 May 2014
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Spain: 5
    Country: Number of subjects enrolled
    United States: 4
    Country: Number of subjects enrolled
    Belgium: 1
    Country: Number of subjects enrolled
    France: 29
    Country: Number of subjects enrolled
    Germany: 8
    Country: Number of subjects enrolled
    Italy: 19
    Worldwide total number of subjects
    66
    EEA total number of subjects
    62
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    25
    From 65 to 84 years
    41
    85 years and over
    0

    Subject disposition

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

    Pre-assignment
    Screening details
    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.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Phase 1b: Tepotinib 300 mg
    Arm description
    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.
    Arm type
    Experimental

    Investigational medicinal product name
    Tepotinib
    Investigational medicinal product code
    Other name
    MSC2156119J
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received a single oral dose of Tepotinib 300 mg daily in each 21 days treatment cycle.

    Arm title
    Phase 1b: Tepotinib 500 mg
    Arm description
    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.
    Arm type
    Experimental

    Investigational medicinal product name
    Tepotinib
    Investigational medicinal product code
    Other name
    MSC2156119J
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received a single oral dose of Tepotinib 500 mg daily in each 21 days treatment cycle.

    Arm title
    Phase 2: Tepotinib 500 mg
    Arm description
    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.
    Arm type
    Experimental

    Investigational medicinal product name
    Tepotinib
    Investigational medicinal product code
    Other name
    MSC2156119J
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received a single oral dose of Tepotinib 500 mg daily in each 21 days treatment cycle.

    Number of subjects in period 1
    Phase 1b: Tepotinib 300 mg Phase 1b: Tepotinib 500 mg Phase 2: Tepotinib 500 mg
    Started
    4
    13
    49
    Completed
    4
    13
    49

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Phase 1b: Tepotinib 300 mg
    Reporting group description
    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.

    Reporting group title
    Phase 1b: Tepotinib 500 mg
    Reporting group description
    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.

    Reporting group title
    Phase 2: Tepotinib 500 mg
    Reporting group description
    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.

    Reporting group values
    Phase 1b: Tepotinib 300 mg Phase 1b: Tepotinib 500 mg Phase 2: Tepotinib 500 mg Total
    Number of subjects
    4 13 49 66
    Age Categorical
    Units: Subjects
        <=18 years
    0 0 0 0
        Between 18 and 65 years
    1 3 21 25
        >=65 years
    3 10 28 41
    Sex: Female, Male
    Units: Subjects
        Female
    2 2 8 12
        Male
    2 11 41 54
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    0 0 0 0
        Asian
    0 0 2 2
        Native Hawaiian or Other Pacific Islander
    0 0 0 0
        Black or African American
    0 0 1 1
        White
    1 8 26 35
        More than one race
    0 1 0 1
        Unknown or Not Reported
    3 4 20 27

    End points

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    End points reporting groups
    Reporting group title
    Phase 1b: Tepotinib 300 mg
    Reporting group description
    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.

    Reporting group title
    Phase 1b: Tepotinib 500 mg
    Reporting group description
    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.

    Reporting group title
    Phase 2: Tepotinib 500 mg
    Reporting group description
    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.

    Subject analysis set title
    Phase 1b: Tepotinib
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Participants received a single oral dose of Tepotinib 300 mg or 500 mg daily in each 21 days treatment cycle until progressive disease, intolerable toxicity, death, or withdrawal from treatment.

    Primary: 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

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    End point title
    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 [1] [2]
    End point description
    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 diarrhea 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. DLT analysis set.
    End point type
    Primary
    End point timeframe
    Day 1 to Day 21 of Cycle 1 (each cycle was 21 days)
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive statistics were planned to be analysed for this endpoint.
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The endpoint was planned to be analysed for Phase 1b arm only.
    End point values
    Phase 1b: Tepotinib 300 mg Phase 1b: Tepotinib 500 mg
    Number of subjects analysed
    3
    11
    Units: participants
    0
    0
    No statistical analyses for this end point

    Primary: 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

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    End point title
    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 [3] [4]
    End point description
    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 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. Intent to Treat analysis set.
    End point type
    Primary
    End point timeframe
    At 12 weeks post first-dose in Phase 2
    Notes
    [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive statistics were planned to be analysed for this endpoint.
    [4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The endpoint was planned to be analysed for Phase 2 arm only.
    End point values
    Phase 2: Tepotinib 500 mg
    Number of subjects analysed
    49
    Units: participants
    31
    No statistical analyses for this end point

    Secondary: Phase 1b and Phase 2: Time to Progression According to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1

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    End point title
    Phase 1b and Phase 2: Time to Progression According to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 [5]
    End point description
    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. ITT 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 progression. As per planned analysis, TTP was calculated for Tepotinib 300 mg and 500 mg arm combined in Phase 1b.
    End point type
    Secondary
    End point 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)
    Notes
    [5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The endpoint was planned to be analysed for Tepotinib 300 mg and Tepotinib 500mg arm from Phase 1b together.
    End point values
    Phase 2: Tepotinib 500 mg Phase 1b: Tepotinib
    Number of subjects analysed
    36
    12
    Units: months
        median (full range (min-max))
    3.98 (0.03 to 16.53)
    2.07 (0.03 to 22.37)
    No statistical analyses for this end point

    Secondary: Phase 1b and Phase 2: Progression-free survival (PFS) Time According to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1

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    End point title
    Phase 1b and Phase 2: Progression-free survival (PFS) Time According to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 [6]
    End point description
    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. 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 progressive disease or death. As per planned analysis, PFS time was calculated for Tepotinib 300 mg and 500 mg arm combined in Phase 1b.
    End point type
    Secondary
    End point timeframe
    From randomization up to first observation of PD or death, assessed maximum up to 1369 days
    Notes
    [6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The endpoint was planned to be analysed for Tepotinib 300 mg and Tepotinib 500mg arm from Phase 1b together.
    End point values
    Phase 2: Tepotinib 500 mg Phase 1b: Tepotinib
    Number of subjects analysed
    38
    16
    Units: months
        median (full range (min-max))
    3.22 (0.03 to 16.53)
    1.51 (0.69 to 22.37)
    No statistical analyses for this end point

    Secondary: Phase 1b and Phase 2: Progression-free survival (PFS) Time According to Modified Response Evaluation Criteria in Solid Tumors (mRECIST) for Hepatocellular Carcinoma (HCC)

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    End point title
    Phase 1b and Phase 2: Progression-free survival (PFS) Time According to Modified Response Evaluation Criteria in Solid Tumors (mRECIST) for Hepatocellular Carcinoma (HCC) [7]
    End point description
    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. 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 progressive disease or death. As per planned analysis, PFS time was calculated for Tepotinib 300 mg and 500 mg arm combined in Phase 1b.
    End point type
    Secondary
    End point timeframe
    From randomization up to first observation of PD or death, assessed maximum up to 1369 days
    Notes
    [7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The endpoint was planned to be analysed for Tepotinib 300 mg and Tepotinib 500mg arm from Phase 1b together.
    End point values
    Phase 2: Tepotinib 500 mg Phase 1b: Tepotinib
    Number of subjects analysed
    37
    13
    Units: months
        median (full range (min-max))
    3.35 (0.03 to 13.83)
    1.48 (0.03 to 22.37)
    No statistical analyses for this end point

    Secondary: Phase 2: Time-to-symptomatic Progressionn (TTSP)

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    End point title
    Phase 2: Time-to-symptomatic Progressionn (TTSP) [8]
    End point description
    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. ITT analysis set included all participants who had been administered at least one dose of Tepotinib (MSC2156119J). Here, Overall number of participants analysed signified those participants who had symptomatic progression. As per planned analysis, data for this outcome was analyzed for Phase 2 only.
    End point type
    Secondary
    End point timeframe
    From date of randomization up to 1369 days
    Notes
    [8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The endpoint was planned to be analysed for Phase 2 arm only.
    End point values
    Phase 2: Tepotinib 500 mg
    Number of subjects analysed
    41
    Units: months
        median (full range (min-max))
    4.86 (0.03 to 17.97)
    No statistical analyses for this end point

    Secondary: Phase 1b and Phase 2: Overall Survival (OS) Time

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    End point title
    Phase 1b and Phase 2: Overall Survival (OS) Time [9]
    End point description
    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. OS was measured using Kaplan-Meier (KM) estimates. ITT analysis set included all participants who had been administered at least one dose of Tepotinib (MSC2156119J). Here, “number of participant analysed" signified the participants who had an event (death) . As per planned analysis, OS time was calculated for Tepotinib 300 mg and 500 mg arm combined in Phase 1b.
    End point type
    Secondary
    End point timeframe
    From date of randomization up to the date of death, assessed maximum up to 1369 days
    Notes
    [9] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The endpoint was planned to be analysed for Tepotinib 300 mg and Tepotinib 500mg arm from Phase 1b together.
    End point values
    Phase 2: Tepotinib 500 mg Phase 1b: Tepotinib
    Number of subjects analysed
    40
    14
    Units: months
        median (full range (min-max))
    5.55 (0.13 to 23.49)
    7.20 (0.69 to 22.90)
    No statistical analyses for this end point

    Secondary: Phase 1b and Phase 2: Percentage of Participants With Best Overall Tumor Assessment of CR or PR According to RECIST v1.1

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    End point title
    Phase 1b and Phase 2: Percentage of Participants With Best Overall Tumor Assessment of CR or PR According to RECIST v1.1
    End point description
    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. ITT analysis set included all participants who had been administered at least one dose of Tepotinib (MSC2156119J). ITT analysis set included all participants who had been administered at least one dose of Tepotinib (MSC2156119J).
    End point type
    Secondary
    End point timeframe
    From date of randomization up to first occurrence of PD, assessed maximum up to 1369 days
    End point values
    Phase 1b: Tepotinib 300 mg Phase 1b: Tepotinib 500 mg Phase 2: Tepotinib 500 mg
    Number of subjects analysed
    4
    13
    49
    Units: percentage of Participants
        number (confidence interval 90%)
    50.0 (9.8 to 90.2)
    0.0 (0.0 to 20.6)
    8.2 (2.8 to 17.7)
    No statistical analyses for this end point

    Secondary: Phase 1b and Phase 2: Percentage of Participants With Disease Control

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    End point title
    Phase 1b and Phase 2: Percentage of Participants With Disease Control
    End point description
    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. ITT analysis set included all participants who had been administered at least one dose of Tepotinib (MSC2156119J).
    End point type
    Secondary
    End point timeframe
    From date of randomization up to first occurrence of PD, assessed maximum up to 1369 days
    End point values
    Phase 1b: Tepotinib 300 mg Phase 1b: Tepotinib 500 mg Phase 2: Tepotinib 500 mg
    Number of subjects analysed
    4
    13
    49
    Units: percentage of participants
        number (confidence interval 90%)
    50.0 (9.8 to 90.2)
    30.8 (11.3 to 57.3)
    57.1 (44.4 to 69.2)
    No statistical analyses for this end point

    Secondary: Phase 1b and Phase 2: Percentage of Participants With Biological Response

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    End point title
    Phase 1b and Phase 2: Percentage of Participants With Biological Response
    End point description
    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. ITT analysis set included all participants who had been administered at least one dose of Tepotinib (MSC2156119J). Here, “number of subjects analysed” signified the participants with baseline and post baseline AFP assessments.
    End point type
    Secondary
    End point timeframe
    Baseline up to Cycle 3 (each cycle is 21 days)
    End point values
    Phase 1b: Tepotinib 300 mg Phase 1b: Tepotinib 500 mg Phase 2: Tepotinib 500 mg
    Number of subjects analysed
    3
    11
    45
    Units: percentage of participants
        number (confidence interval 90%)
    66.7 (13.5 to 98.3)
    45.5 (20.0 to 72.9)
    31.1 (19.9 to 44.3)
    No statistical analyses for this end point

    Secondary: 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

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    End point title
    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 [10]
    End point description
    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, "n" is number of participants evaluable at a specified time-point.
    End point type
    Secondary
    End point 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)
    Notes
    [10] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The endpoint was planned to be analysed for Phase 1b arm only.
    End point values
    Phase 1b: Tepotinib 300 mg Phase 1b: Tepotinib 500 mg
    Number of subjects analysed
    3
    12
    Units: nanogram hour per milliliter (ng*h/mL)
    geometric mean (geometric coefficient of variation)
        Cycle 1 Day 1 (n=3,12)
    4440 ± 6.7
    5060 ± 38.9
        Cycle 1 Day 15(n=3,9)
    15200 ± 18.2
    12900 ± 50.4
    No statistical analyses for this end point

    Secondary: 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

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    End point title
    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 [11]
    End point description
    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. 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, "n" is number of participants evaluable at a specified time-point.
    End point type
    Secondary
    End point 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)
    Notes
    [11] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The endpoint was planned to be analysed for Phase 1b arm only.
    End point values
    Phase 1b: Tepotinib 300 mg Phase 1b: Tepotinib 500 mg
    Number of subjects analysed
    3
    12
    Units: ng*h/mL/mg
    geometric mean (geometric coefficient of variation)
        Cycle 1 Day 1(n=3,12)
    14.8 ± 6.7
    10.1 ± 38.9
        Cycle 1 Day 15(n=3,9)
    50.7 ± 18.2
    25.8 ± 50.4
    No statistical analyses for this end point

    Secondary: Phase 1b: Area Under the Plasma Concentration-Time Curve From Time Zero to Infinity (AUC0-inf) of Tepotinib

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    End point title
    Phase 1b: Area Under the Plasma Concentration-Time Curve From Time Zero to Infinity (AUC0-inf) of Tepotinib [12]
    End point description
    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, 99999 signified not applicable as 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.
    End point type
    Secondary
    End point 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)
    Notes
    [12] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The endpoint was planned to be analysed for Phase 1b arm only.
    End point values
    Phase 1b: Tepotinib 300 mg Phase 1b: Tepotinib 500 mg
    Number of subjects analysed
    4
    13
    Units: nanogram hour per milliliter (ng*h/mL)
    geometric mean (geometric coefficient of variation)
        Cycle 1 Day 1
    99999 ± 99999
    99999 ± 99999
        Cycle 1 Day 15
    99999 ± 99999
    99999 ± 99999
    No statistical analyses for this end point

    Secondary: Phase 1b: Maximum Observed Plasma Concentration (Cmax) of Tepotinib

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    End point title
    Phase 1b: Maximum Observed Plasma Concentration (Cmax) of Tepotinib [13]
    End point description
    Cmax is the maximum observed plasma concentration obtained directly from the concentration versus time curve. 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, "n" is number of participants evaluable at a specified time-point.
    End point type
    Secondary
    End point 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)
    Notes
    [13] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The endpoint was planned to be analysed for Phase 1b arm only.
    End point values
    Phase 1b: Tepotinib 300 mg Phase 1b: Tepotinib 500 mg
    Number of subjects analysed
    3
    12
    Units: nanogram per milliliter (ng/mL)
    geometric mean (geometric coefficient of variation)
        Cycle 1 Day 1(n=3,12)
    261 ± 8.4
    278 ± 39.3
        Cycle 1 Day 15(n=3,10)
    734 ± 19.6
    677 ± 44.6
    No statistical analyses for this end point

    Secondary: Phase 1b: Dose Normalized Maximum Observed Plasma Concentration (Cmax) of Tepotinib

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    End point title
    Phase 1b: Dose Normalized Maximum Observed Plasma Concentration (Cmax) of Tepotinib [14]
    End point description
    Dose normalized was calculated as maximum observed plasma concentration obtained directly from the concentration versus time curve divided by dose. 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, "n" is number of participants evaluable at a specified time-point.
    End point type
    Secondary
    End point 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)
    Notes
    [14] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The endpoint was planned to be analysed for Phase 1b arm only.
    End point values
    Phase 1b: Tepotinib 300 mg Phase 1b: Tepotinib 500 mg
    Number of subjects analysed
    3
    12
    Units: ng/mL/mg
    geometric mean (geometric coefficient of variation)
        Cycle 1 Day 1(n=3,12)
    0.871 ± 8.4
    0.556 ± 39.3
        Cycle 1 Day 15(n=3,10)
    2.45 ± 19.6
    1.35 ± 44.6
    No statistical analyses for this end point

    Secondary: Phase 1b: Minimum Observed Plasma Concentration (Cmin) of Tepotinib

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    End point title
    Phase 1b: Minimum Observed Plasma Concentration (Cmin) of Tepotinib [15]
    End point description
    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 of subjects analyzed signified participants evaluable for the outcome measure.
    End point type
    Secondary
    End point 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)
    Notes
    [15] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The endpoint was planned to be analysed for Phase 1b arm only.
    End point values
    Phase 1b: Tepotinib 300 mg Phase 1b: Tepotinib 500 mg
    Number of subjects analysed
    3
    9
    Units: nanogram per milliliter (ng/mL)
        geometric mean (geometric coefficient of variation)
    526 ± 28.0
    435 ± 57.9
    No statistical analyses for this end point

    Secondary: Phase 1b: Time to Reach Maximum Plasma Concentration (Tmax) of Tepotinib

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    End point title
    Phase 1b: Time to Reach Maximum Plasma Concentration (Tmax) of Tepotinib [16]
    End point description
    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, "n" is number of participants evaluable at a specified time-point.
    End point type
    Secondary
    End point 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)
    Notes
    [16] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The endpoint was planned to be analysed for Phase 1b arm only.
    End point values
    Phase 1b: Tepotinib 300 mg Phase 1b: Tepotinib 500 mg
    Number of subjects analysed
    3
    12
    Units: hours
    median (full range (min-max))
        Cycle 1 Day 1(n=3,12)
    10.0 (8.0 to 24.0)
    8.0 (8.0 to 10.0)
        Cycle 1 Day 15(n=3,10)
    8.0 (0.48 to 8.0)
    6.1 (0.0 to 23.6)
    No statistical analyses for this end point

    Secondary: Phase 1b: Average Plasma Concentration at Steady State (Cav) of Tepotinib

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    End point title
    Phase 1b: Average Plasma Concentration at Steady State (Cav) of Tepotinib [17]
    End point description
    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 of subjects analyzed signified participants evaluable for the outcome measure.
    End point type
    Secondary
    End point 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)
    Notes
    [17] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The endpoint was planned to be analysed for Phase 1b arm only.
    End point values
    Phase 1b: Tepotinib 300 mg Phase 1b: Tepotinib 500 mg
    Number of subjects analysed
    3
    9
    Units: nanogram per milliliter (ng/mL)
        geometric mean (geometric coefficient of variation)
    635 ± 18.2
    542 ± 50.7
    No statistical analyses for this end point

    Secondary: Phase 1b: Apparent Total Body Clearance From Plasma (CL/f) of Tepotinib

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    End point title
    Phase 1b: Apparent Total Body Clearance From Plasma (CL/f) of Tepotinib [18]
    End point description
    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 of subjects analyzed signified participants evaluable for the outcome measure.
    End point type
    Secondary
    End point 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)
    Notes
    [18] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The endpoint was planned to be analysed for Phase 1b arm only.
    End point values
    Phase 1b: Tepotinib 300 mg Phase 1b: Tepotinib 500 mg
    Number of subjects analysed
    3
    9
    Units: nanogram per milliliter (ng/mL)
        geometric mean (geometric coefficient of variation)
    17.7 ± 18.2
    34.9 ± 50.4
    No statistical analyses for this end point

    Secondary: Phase 1b: Apparent Volume of Distribution During the Terminal Phase (Vz/f) of Tepotinib

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    End point title
    Phase 1b: Apparent Volume of Distribution During the Terminal Phase (Vz/f) of Tepotinib [19]
    End point description
    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, 99999 signified not applicable as 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.
    End point type
    Secondary
    End point 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)
    Notes
    [19] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The endpoint was planned to be analysed for Phase 1b arm only.
    End point values
    Phase 1b: Tepotinib 300 mg Phase 1b: Tepotinib 500 mg
    Number of subjects analysed
    3
    12
    Units: liter
    geometric mean (geometric coefficient of variation)
        Cycle 1 Day 1
    99999 ± 99999
    99999 ± 99999
        Cycle 1 Day 15
    99999 ± 99999
    99999 ± 99999
    No statistical analyses for this end point

    Secondary: Phase 1b: Apparent Volume of Distribution During the Steady State (Vss/f) of Tepotinib

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    End point title
    Phase 1b: Apparent Volume of Distribution During the Steady State (Vss/f) of Tepotinib [20]
    End point description
    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, 99999 signified not applicable as 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.
    End point type
    Secondary
    End point 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)
    Notes
    [20] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The endpoint was planned to be analysed for Phase 1b arm only.
    End point values
    Phase 1b: Tepotinib 300 mg Phase 1b: Tepotinib 500 mg
    Number of subjects analysed
    3
    12
    Units: liter
    geometric mean (geometric coefficient of variation)
        Cycle 1 Day 1
    99999 ± 99999
    99999 ± 99999
        Cycle 1 Day 15
    99999 ± 99999
    99999 ± 99999
    No statistical analyses for this end point

    Secondary: Phase 1b: Apparent Terminal Elimination Rate Constant (λz) of Tepotinib

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    End point title
    Phase 1b: Apparent Terminal Elimination Rate Constant (λz) of Tepotinib [21]
    End point description
    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, 99999 signified not applicable as dosing and sampling scheme in Phase Ib did not allow the reliable estimation of apparent terminal rate constant (λz), Therefore, λz was not determined.
    End point type
    Secondary
    End point 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)
    Notes
    [21] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The endpoint was planned to be analysed for Phase 1b arm only.
    End point values
    Phase 1b: Tepotinib 300 mg Phase 1b: Tepotinib 500 mg
    Number of subjects analysed
    3
    12
    Units: 1 per hour
    geometric mean (geometric coefficient of variation)
        Cycle 1 Day 1
    99999 ± 99999
    99999 ± 99999
        Cycle 1 Day 15
    99999 ± 99999
    99999 ± 99999
    No statistical analyses for this end point

    Secondary: Phase 1b: Apparent Terminal Half-life (t1/2) of Tepotinib

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    End point title
    Phase 1b: Apparent Terminal Half-life (t1/2) of Tepotinib [22]
    End point description
    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, 99999 signified not applicable as 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.
    End point type
    Secondary
    End point 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)
    Notes
    [22] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The endpoint was planned to be analysed for Phase 1b arm only.
    End point values
    Phase 1b: Tepotinib 300 mg Phase 1b: Tepotinib 500 mg
    Number of subjects analysed
    3
    12
    Units: hours
    median (full range (min-max))
        Cycle 1 Day 1
    99999 (99999 to 99999)
    99999 (99999 to 99999)
        Cycle 1 Day 15
    99999 (99999 to 99999)
    99999 (99999 to 99999)
    No statistical analyses for this end point

    Secondary: Phase 1b: Time prior to the First Quantifiable (non-zero) Concentration (tlag) of Tepotinib

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    End point title
    Phase 1b: Time prior to the First Quantifiable (non-zero) Concentration (tlag) of Tepotinib [23]
    End point description
    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 of subjects analyzed signified participants evaluable for the outcome measure.
    End point type
    Secondary
    End point 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)
    Notes
    [23] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The endpoint was planned to be analysed for Phase 1b arm only.
    End point values
    Phase 1b: Tepotinib 300 mg Phase 1b: Tepotinib 500 mg
    Number of subjects analysed
    3
    12
    Units: hours
        median (full range (min-max))
    0.53 (0.52 to 0.55)
    0.50 (0.25 to 1.0)
    No statistical analyses for this end point

    Secondary: Phase 1b: Percentage Peak-Trough Fluctuation (PTF) Post First Dose of Tepotinib

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    End point title
    Phase 1b: Percentage Peak-Trough Fluctuation (PTF) Post First Dose of Tepotinib [24]
    End point description
    The peak trough fluctuation within complete dosing interval at steady state, calculated as PTF (%) = ([Cmax - Cmin]/Cav ) multiplied by 100. 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 of subjects analyzed signified participants evaluable for the outcome measure.
    End point type
    Secondary
    End point 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)
    Notes
    [24] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The endpoint was planned to be analysed for Phase 1b arm only.
    End point values
    Phase 1b: Tepotinib 300 mg Phase 1b: Tepotinib 500 mg
    Number of subjects analysed
    3
    9
    Units: percentage fluctuation
        geometric mean (geometric coefficient of variation)
    31.5 ± 30.5
    35.9 ± 44.1
    No statistical analyses for this end point

    Secondary: Phase 1b: Accumulation Ratio of Cmax (Racc (Cmax))

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    End point title
    Phase 1b: Accumulation Ratio of Cmax (Racc (Cmax)) [25]
    End point description
    Accumulation ratio for Cmax was calculated as Cmax, after dosing on Day 15 divided by Cmax, after dosing on day 1 of cycle 1. 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 of subjects analyzed signified participants evaluable for the outcome measure.
    End point type
    Secondary
    End point 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)
    Notes
    [25] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The endpoint was planned to be analysed for Phase 1b arm only.
    End point values
    Phase 1b: Tepotinib 300 mg Phase 1b: Tepotinib 500 mg
    Number of subjects analysed
    3
    10
    Units: ratio
        geometric mean (geometric coefficient of variation)
    2.81 ± 24.1
    2.32 ± 23.0
    No statistical analyses for this end point

    Secondary: Phase 1b: Accumulation Ratio of AUC (Racc (AUC)

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    End point title
    Phase 1b: Accumulation Ratio of AUC (Racc (AUC) [26]
    End point description
    Accumulation ratio for AUC was calculated as AUC, after dosing on Day 15 divided by AUC, after dosing on day 1 of cycle 1. 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 of subjects analyzed signified participants evaluable for the outcome measure.
    End point type
    Secondary
    End point 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)
    Notes
    [26] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The endpoint was planned to be analysed for Phase 1b arm only.
    End point values
    Phase 1b: Tepotinib 300 mg Phase 1b: Tepotinib 500 mg
    Number of subjects analysed
    3
    9
    Units: ratio
        geometric mean (geometric coefficient of variation)
    3.43 ± 22.6
    2.51 ± 22.0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From date of randomization up to 1369 days
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    20.1
    Reporting groups
    Reporting group title
    Phase 1b: Tepotinib 300 mg
    Reporting group description
    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.

    Reporting group title
    Phase 2: Tepotinib 500 mg
    Reporting group description
    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.

    Reporting group title
    Phase 1b: Tepotinib 500 mg
    Reporting group description
    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.

    Serious adverse events
    Phase 1b: Tepotinib 300 mg Phase 2: Tepotinib 500 mg Phase 1b: Tepotinib 500 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 4 (50.00%)
    21 / 49 (42.86%)
    5 / 13 (38.46%)
         number of deaths (all causes)
    3
    40
    11
         number of deaths resulting from adverse events
    0
    0
    0
    Investigations
    Blood bilirubin increased
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 49 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Cancer pain
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 49 (2.04%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tumour pain
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 49 (2.04%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pneumonia aspiration
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 49 (2.04%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Coma
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 49 (0.00%)
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatic encephalopathy
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 49 (0.00%)
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cerebral thrombosis
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 49 (2.04%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypoglycaemic coma
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 49 (2.04%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Disease progression
         subjects affected / exposed
    1 / 4 (25.00%)
    7 / 49 (14.29%)
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 7
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Localised oedema
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 49 (0.00%)
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Oedema peripheral
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 49 (2.04%)
    2 / 13 (15.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Discomfort
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 49 (2.04%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 49 (2.04%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 49 (2.04%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular stent stenosis
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 49 (2.04%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 49 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ascites
         subjects affected / exposed
    0 / 4 (0.00%)
    3 / 49 (6.12%)
    2 / 13 (15.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 49 (2.04%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Prostatitis
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 49 (0.00%)
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    1 / 4 (25.00%)
    3 / 49 (6.12%)
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 3
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Chronic kidney disease
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 49 (2.04%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholangitis
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 49 (2.04%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatic failure
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 49 (2.04%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Jaundice
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 49 (2.04%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatorenal syndrome
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 49 (0.00%)
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Rhabdomyolysis
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 49 (2.04%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hypercalcaemia
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 49 (2.04%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypercreatininaemia
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 49 (2.04%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 49 (2.04%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Decreased appetite
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 49 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Device related infection
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 49 (2.04%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Peritonitis bacterial
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 49 (2.04%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 49 (2.04%)
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Peritonitis
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 49 (0.00%)
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Post procedural infection
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 49 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    Phase 1b: Tepotinib 300 mg Phase 2: Tepotinib 500 mg Phase 1b: Tepotinib 500 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    4 / 4 (100.00%)
    48 / 49 (97.96%)
    12 / 13 (92.31%)
    Vascular disorders
    Lymphoedema
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 49 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    1
    Peripheral venous disease
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 49 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    0
    Venous thrombosis
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 49 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    1
    Deep vein thrombosis
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 49 (2.04%)
    0 / 13 (0.00%)
         occurrences all number
    0
    1
    0
    Hot flush
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 49 (2.04%)
    0 / 13 (0.00%)
         occurrences all number
    0
    1
    0
    Hypertension
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 49 (2.04%)
    0 / 13 (0.00%)
         occurrences all number
    0
    1
    0
    Hypotension
         subjects affected / exposed
    0 / 4 (0.00%)
    2 / 49 (4.08%)
    0 / 13 (0.00%)
         occurrences all number
    0
    2
    0
    Hypovolaemic shock
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 49 (2.04%)
    0 / 13 (0.00%)
         occurrences all number
    0
    1
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Cancer pain
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 49 (2.04%)
    0 / 13 (0.00%)
         occurrences all number
    0
    1
    0
    Metastases to bone
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 49 (2.04%)
    0 / 13 (0.00%)
         occurrences all number
    0
    1
    0
    Tumour pain
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 49 (2.04%)
    0 / 13 (0.00%)
         occurrences all number
    0
    1
    0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 4 (0.00%)
    15 / 49 (30.61%)
    2 / 13 (15.38%)
         occurrences all number
    0
    15
    2
    Chest pain
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 49 (2.04%)
    0 / 13 (0.00%)
         occurrences all number
    0
    1
    0
    Chills
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 49 (2.04%)
    0 / 13 (0.00%)
         occurrences all number
    0
    1
    0
    Disease progression
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 49 (2.04%)
    0 / 13 (0.00%)
         occurrences all number
    0
    1
    0
    Fatigue
         subjects affected / exposed
    1 / 4 (25.00%)
    10 / 49 (20.41%)
    2 / 13 (15.38%)
         occurrences all number
    1
    10
    2
    Generalised oedema
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 49 (2.04%)
    0 / 13 (0.00%)
         occurrences all number
    0
    1
    0
    Localised oedema
         subjects affected / exposed
    0 / 4 (0.00%)
    2 / 49 (4.08%)
    1 / 13 (7.69%)
         occurrences all number
    0
    2
    1
    Oedema
         subjects affected / exposed
    0 / 4 (0.00%)
    3 / 49 (6.12%)
    0 / 13 (0.00%)
         occurrences all number
    0
    3
    0
    Oedema peripheral
         subjects affected / exposed
    3 / 4 (75.00%)
    32 / 49 (65.31%)
    10 / 13 (76.92%)
         occurrences all number
    3
    32
    10
    Pyrexia
         subjects affected / exposed
    1 / 4 (25.00%)
    4 / 49 (8.16%)
    1 / 13 (7.69%)
         occurrences all number
    1
    4
    1
    Pain
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 49 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    1
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    0 / 4 (0.00%)
    2 / 49 (4.08%)
    2 / 13 (15.38%)
         occurrences all number
    0
    2
    2
    Depressed mood
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 49 (2.04%)
    0 / 13 (0.00%)
         occurrences all number
    0
    1
    0
    Depression
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 49 (2.04%)
    0 / 13 (0.00%)
         occurrences all number
    0
    1
    0
    Insomnia
         subjects affected / exposed
    0 / 4 (0.00%)
    2 / 49 (4.08%)
    0 / 13 (0.00%)
         occurrences all number
    0
    2
    0
    Reproductive system and breast disorders
    Scrotal oedema
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 49 (2.04%)
    0 / 13 (0.00%)
         occurrences all number
    0
    1
    0
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 49 (2.04%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    1
    Overdose
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 49 (2.04%)
    0 / 13 (0.00%)
         occurrences all number
    0
    1
    0
    Wound
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 49 (2.04%)
    0 / 13 (0.00%)
         occurrences all number
    0
    1
    0
    Lumbar vertebral fracture
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 49 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    0
    Rib fracture
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 49 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    2 / 4 (50.00%)
    3 / 49 (6.12%)
    4 / 13 (30.77%)
         occurrences all number
    2
    3
    4
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 4 (25.00%)
    6 / 49 (12.24%)
    1 / 13 (7.69%)
         occurrences all number
    1
    6
    1
    Blood alkaline phosphatase increased
         subjects affected / exposed
    2 / 4 (50.00%)
    5 / 49 (10.20%)
    2 / 13 (15.38%)
         occurrences all number
    2
    5
    2
    Blood bilirubin increased
         subjects affected / exposed
    0 / 4 (0.00%)
    5 / 49 (10.20%)
    1 / 13 (7.69%)
         occurrences all number
    0
    5
    1
    Blood creatinine increased
         subjects affected / exposed
    1 / 4 (25.00%)
    7 / 49 (14.29%)
    2 / 13 (15.38%)
         occurrences all number
    1
    7
    2
    Blood thyroid stimulating hormone increased
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 49 (2.04%)
    0 / 13 (0.00%)
         occurrences all number
    0
    1
    0
    Blood urea increased
         subjects affected / exposed
    0 / 4 (0.00%)
    3 / 49 (6.12%)
    2 / 13 (15.38%)
         occurrences all number
    0
    3
    2
    International normalised ratio increased
         subjects affected / exposed
    0 / 4 (0.00%)
    2 / 49 (4.08%)
    0 / 13 (0.00%)
         occurrences all number
    0
    2
    0
    Lipase increased
         subjects affected / exposed
    1 / 4 (25.00%)
    5 / 49 (10.20%)
    1 / 13 (7.69%)
         occurrences all number
    1
    5
    1
    Prothrombin time prolonged
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 49 (2.04%)
    0 / 13 (0.00%)
         occurrences all number
    0
    1
    0
    Transaminases increased
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 49 (2.04%)
    0 / 13 (0.00%)
         occurrences all number
    0
    1
    0
    Urobilinogen urine increased
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 49 (2.04%)
    0 / 13 (0.00%)
         occurrences all number
    0
    1
    0
    Weight decreased
         subjects affected / exposed
    1 / 4 (25.00%)
    2 / 49 (4.08%)
    1 / 13 (7.69%)
         occurrences all number
    1
    2
    1
    Weight increased
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 49 (2.04%)
    0 / 13 (0.00%)
         occurrences all number
    0
    1
    0
    Amylase increased
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 49 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    0
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 49 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    1
    0
    1
    Glomerular filtration rate decreased
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 49 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    1
    Haemoglobin decreased
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 49 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    1
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 49 (2.04%)
    0 / 13 (0.00%)
         occurrences all number
    0
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Epistaxis
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 49 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    0
    Acute respiratory failure
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 49 (2.04%)
    0 / 13 (0.00%)
         occurrences all number
    0
    1
    0
    Cough
         subjects affected / exposed
    0 / 4 (0.00%)
    2 / 49 (4.08%)
    0 / 13 (0.00%)
         occurrences all number
    0
    2
    0
    Dyspnoea
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 49 (2.04%)
    0 / 13 (0.00%)
         occurrences all number
    0
    1
    0
    Dyspnoea exertional
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 49 (2.04%)
    0 / 13 (0.00%)
         occurrences all number
    0
    1
    0
    Pleural effusion
         subjects affected / exposed
    0 / 4 (0.00%)
    6 / 49 (12.24%)
    0 / 13 (0.00%)
         occurrences all number
    0
    6
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 4 (0.00%)
    7 / 49 (14.29%)
    0 / 13 (0.00%)
         occurrences all number
    0
    7
    0
    Coagulopathy
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 49 (2.04%)
    0 / 13 (0.00%)
         occurrences all number
    0
    1
    0
    Lymph node pain
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 49 (2.04%)
    0 / 13 (0.00%)
         occurrences all number
    0
    1
    0
    Thrombocytopenia
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 49 (2.04%)
    0 / 13 (0.00%)
         occurrences all number
    0
    1
    0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 49 (2.04%)
    0 / 13 (0.00%)
         occurrences all number
    0
    1
    0
    Dysgeusia
         subjects affected / exposed
    1 / 4 (25.00%)
    2 / 49 (4.08%)
    0 / 13 (0.00%)
         occurrences all number
    1
    2
    0
    Headache
         subjects affected / exposed
    0 / 4 (0.00%)
    2 / 49 (4.08%)
    0 / 13 (0.00%)
         occurrences all number
    0
    2
    0
    Hepatic encephalopathy
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 49 (2.04%)
    0 / 13 (0.00%)
         occurrences all number
    0
    1
    0
    Sciatica
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 49 (2.04%)
    0 / 13 (0.00%)
         occurrences all number
    0
    1
    0
    Migraine with aura
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 49 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    0
    Eye disorders
    Eyelid oedema
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 49 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    0
    Lacrimation increased
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 49 (2.04%)
    2 / 13 (15.38%)
         occurrences all number
    0
    1
    2
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    0 / 4 (0.00%)
    2 / 49 (4.08%)
    0 / 13 (0.00%)
         occurrences all number
    0
    2
    0
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    0 / 4 (0.00%)
    2 / 49 (4.08%)
    0 / 13 (0.00%)
         occurrences all number
    0
    2
    0
    Abdominal pain
         subjects affected / exposed
    2 / 4 (50.00%)
    8 / 49 (16.33%)
    2 / 13 (15.38%)
         occurrences all number
    2
    8
    2
    Abdominal pain upper
         subjects affected / exposed
    0 / 4 (0.00%)
    4 / 49 (8.16%)
    1 / 13 (7.69%)
         occurrences all number
    0
    4
    1
    Ascites
         subjects affected / exposed
    0 / 4 (0.00%)
    15 / 49 (30.61%)
    2 / 13 (15.38%)
         occurrences all number
    0
    15
    2
    Constipation
         subjects affected / exposed
    2 / 4 (50.00%)
    9 / 49 (18.37%)
    0 / 13 (0.00%)
         occurrences all number
    2
    9
    0
    Diarrhoea
         subjects affected / exposed
    0 / 4 (0.00%)
    16 / 49 (32.65%)
    2 / 13 (15.38%)
         occurrences all number
    0
    16
    2
    Dry mouth
         subjects affected / exposed
    1 / 4 (25.00%)
    1 / 49 (2.04%)
    0 / 13 (0.00%)
         occurrences all number
    1
    1
    0
    Dyspepsia
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 49 (2.04%)
    0 / 13 (0.00%)
         occurrences all number
    0
    1
    0
    Dysphagia
         subjects affected / exposed
    1 / 4 (25.00%)
    1 / 49 (2.04%)
    0 / 13 (0.00%)
         occurrences all number
    1
    1
    0
    Gastric varices
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 49 (2.04%)
    0 / 13 (0.00%)
         occurrences all number
    0
    1
    0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 4 (0.00%)
    2 / 49 (4.08%)
    0 / 13 (0.00%)
         occurrences all number
    0
    2
    0
    Haematemesis
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 49 (2.04%)
    0 / 13 (0.00%)
         occurrences all number
    0
    1
    0
    Inguinal hernia
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 49 (2.04%)
    0 / 13 (0.00%)
         occurrences all number
    0
    1
    0
    Nausea
         subjects affected / exposed
    1 / 4 (25.00%)
    11 / 49 (22.45%)
    2 / 13 (15.38%)
         occurrences all number
    1
    11
    2
    Odynophagia
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 49 (2.04%)
    0 / 13 (0.00%)
         occurrences all number
    0
    1
    0
    Varices oesophageal
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 49 (2.04%)
    0 / 13 (0.00%)
         occurrences all number
    0
    1
    0
    Vomiting
         subjects affected / exposed
    2 / 4 (50.00%)
    7 / 49 (14.29%)
    0 / 13 (0.00%)
         occurrences all number
    2
    7
    0
    Eructation
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 49 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    0
    Toothache
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 49 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    1
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    1 / 4 (25.00%)
    3 / 49 (6.12%)
    1 / 13 (7.69%)
         occurrences all number
    1
    3
    1
    Dysuria
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 49 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    1
    Renal impairment
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 49 (0.00%)
    2 / 13 (15.38%)
         occurrences all number
    1
    0
    2
    Glomerulonephritis membranoproliferative
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 49 (2.04%)
    0 / 13 (0.00%)
         occurrences all number
    0
    1
    0
    Ketonuria
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 49 (2.04%)
    0 / 13 (0.00%)
         occurrences all number
    0
    1
    0
    Pollakiuria
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 49 (2.04%)
    0 / 13 (0.00%)
         occurrences all number
    0
    1
    0
    Renal failure
         subjects affected / exposed
    0 / 4 (0.00%)
    2 / 49 (4.08%)
    0 / 13 (0.00%)
         occurrences all number
    0
    2
    0
    Hepatobiliary disorders
    Hepatic vein thrombosis
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 49 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    1
    Hepatic failure
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 49 (2.04%)
    0 / 13 (0.00%)
         occurrences all number
    0
    1
    0
    Hepatic pain
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 49 (2.04%)
    0 / 13 (0.00%)
         occurrences all number
    0
    1
    0
    Hepatocellular injury
         subjects affected / exposed
    0 / 4 (0.00%)
    2 / 49 (4.08%)
    0 / 13 (0.00%)
         occurrences all number
    0
    2
    0
    Hepatomegaly
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 49 (2.04%)
    0 / 13 (0.00%)
         occurrences all number
    0
    1
    0
    Hyperbilirubinaemia
         subjects affected / exposed
    0 / 4 (0.00%)
    4 / 49 (8.16%)
    0 / 13 (0.00%)
         occurrences all number
    0
    4
    0
    Hypertransaminasaemia
         subjects affected / exposed
    0 / 4 (0.00%)
    2 / 49 (4.08%)
    0 / 13 (0.00%)
         occurrences all number
    0
    2
    0
    Jaundice
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 49 (2.04%)
    0 / 13 (0.00%)
         occurrences all number
    0
    1
    0
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 49 (2.04%)
    0 / 13 (0.00%)
         occurrences all number
    0
    1
    0
    Dry skin
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 49 (2.04%)
    0 / 13 (0.00%)
         occurrences all number
    0
    1
    0
    Hyperkeratosis
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 49 (2.04%)
    0 / 13 (0.00%)
         occurrences all number
    0
    1
    0
    Nail disorder
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 49 (2.04%)
    0 / 13 (0.00%)
         occurrences all number
    0
    1
    0
    Night sweats
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 49 (2.04%)
    0 / 13 (0.00%)
         occurrences all number
    0
    1
    0
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 49 (2.04%)
    0 / 13 (0.00%)
         occurrences all number
    0
    1
    0
    Pruritus
         subjects affected / exposed
    0 / 4 (0.00%)
    5 / 49 (10.20%)
    0 / 13 (0.00%)
         occurrences all number
    0
    5
    0
    Rash
         subjects affected / exposed
    0 / 4 (0.00%)
    4 / 49 (8.16%)
    1 / 13 (7.69%)
         occurrences all number
    0
    4
    1
    Rash maculo-papular
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 49 (2.04%)
    0 / 13 (0.00%)
         occurrences all number
    0
    1
    0
    Skin lesion
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 49 (2.04%)
    0 / 13 (0.00%)
         occurrences all number
    0
    1
    0
    Papule
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 49 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 4 (0.00%)
    2 / 49 (4.08%)
    0 / 13 (0.00%)
         occurrences all number
    0
    2
    0
    Back pain
         subjects affected / exposed
    1 / 4 (25.00%)
    5 / 49 (10.20%)
    0 / 13 (0.00%)
         occurrences all number
    1
    5
    0
    Bone pain
         subjects affected / exposed
    0 / 4 (0.00%)
    4 / 49 (8.16%)
    1 / 13 (7.69%)
         occurrences all number
    0
    4
    1
    Muscle spasms
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 49 (2.04%)
    0 / 13 (0.00%)
         occurrences all number
    0
    1
    0
    Musculoskeletal chest pain
         subjects affected / exposed
    1 / 4 (25.00%)
    1 / 49 (2.04%)
    0 / 13 (0.00%)
         occurrences all number
    1
    1
    0
    Musculoskeletal pain
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 49 (2.04%)
    0 / 13 (0.00%)
         occurrences all number
    0
    1
    0
    Pain in extremity
         subjects affected / exposed
    1 / 4 (25.00%)
    1 / 49 (2.04%)
    1 / 13 (7.69%)
         occurrences all number
    1
    1
    1
    Pain in jaw
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 49 (2.04%)
    0 / 13 (0.00%)
         occurrences all number
    0
    1
    0
    Flank pain
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 49 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    0
    Osteoporosis
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 49 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    0 / 4 (0.00%)
    8 / 49 (16.33%)
    1 / 13 (7.69%)
         occurrences all number
    0
    8
    1
    Cell death
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 49 (2.04%)
    0 / 13 (0.00%)
         occurrences all number
    0
    1
    0
    Hypercreatininaemia
         subjects affected / exposed
    0 / 4 (0.00%)
    2 / 49 (4.08%)
    0 / 13 (0.00%)
         occurrences all number
    0
    2
    0
    Hyperglycaemia
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 49 (2.04%)
    0 / 13 (0.00%)
         occurrences all number
    0
    1
    0
    Hyperkalaemia
         subjects affected / exposed
    0 / 4 (0.00%)
    5 / 49 (10.20%)
    1 / 13 (7.69%)
         occurrences all number
    0
    5
    1
    Hyperlipasaemia
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 49 (2.04%)
    0 / 13 (0.00%)
         occurrences all number
    0
    1
    0
    Hypoalbuminaemia
         subjects affected / exposed
    0 / 4 (0.00%)
    13 / 49 (26.53%)
    1 / 13 (7.69%)
         occurrences all number
    0
    13
    1
    Hypocalcaemia
         subjects affected / exposed
    0 / 4 (0.00%)
    2 / 49 (4.08%)
    0 / 13 (0.00%)
         occurrences all number
    0
    2
    0
    Hypokalaemia
         subjects affected / exposed
    0 / 4 (0.00%)
    3 / 49 (6.12%)
    0 / 13 (0.00%)
         occurrences all number
    0
    3
    0
    Hypomagnesaemia
         subjects affected / exposed
    0 / 4 (0.00%)
    3 / 49 (6.12%)
    1 / 13 (7.69%)
         occurrences all number
    0
    3
    1
    Hyponatraemia
         subjects affected / exposed
    0 / 4 (0.00%)
    3 / 49 (6.12%)
    0 / 13 (0.00%)
         occurrences all number
    0
    3
    0
    Malnutrition
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 49 (2.04%)
    0 / 13 (0.00%)
         occurrences all number
    0
    1
    0
    Type 1 diabetes mellitus
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 49 (2.04%)
    0 / 13 (0.00%)
         occurrences all number
    0
    1
    0
    Infections and infestations
    Hepatitis B
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 49 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    0
    1
    Nasopharyngitis
         subjects affected / exposed
    1 / 4 (25.00%)
    1 / 49 (2.04%)
    0 / 13 (0.00%)
         occurrences all number
    1
    1
    0
    Peritonitis
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 49 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    0
    Angular cheilitis
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 49 (2.04%)
    0 / 13 (0.00%)
         occurrences all number
    0
    1
    0
    Bronchitis
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 49 (2.04%)
    0 / 13 (0.00%)
         occurrences all number
    0
    1
    0
    Clostridium difficile colitis
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 49 (2.04%)
    0 / 13 (0.00%)
         occurrences all number
    0
    1
    0
    Conjunctivitis
         subjects affected / exposed
    0 / 4 (0.00%)
    2 / 49 (4.08%)
    0 / 13 (0.00%)
         occurrences all number
    0
    2
    0
    Gastroenteritis
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 49 (2.04%)
    0 / 13 (0.00%)
         occurrences all number
    0
    1
    0
    Genital herpes
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 49 (2.04%)
    0 / 13 (0.00%)
         occurrences all number
    0
    1
    0
    Herpes zoster
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 49 (2.04%)
    0 / 13 (0.00%)
         occurrences all number
    0
    1
    0
    Infection
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 49 (2.04%)
    0 / 13 (0.00%)
         occurrences all number
    0
    1
    0
    Influenza
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 49 (2.04%)
    0 / 13 (0.00%)
         occurrences all number
    0
    1
    0
    Lung infection
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 49 (2.04%)
    0 / 13 (0.00%)
         occurrences all number
    0
    1
    0
    Paronychia
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 49 (2.04%)
    0 / 13 (0.00%)
         occurrences all number
    0
    1
    0
    Pneumonia
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 49 (2.04%)
    0 / 13 (0.00%)
         occurrences all number
    0
    1
    0
    Rash pustular
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 49 (2.04%)
    0 / 13 (0.00%)
         occurrences all number
    0
    1
    0
    Septic shock
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 49 (2.04%)
    0 / 13 (0.00%)
         occurrences all number
    0
    1
    0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 49 (2.04%)
    0 / 13 (0.00%)
         occurrences all number
    0
    1
    0
    Urinary tract infection
         subjects affected / exposed
    0 / 4 (0.00%)
    3 / 49 (6.12%)
    0 / 13 (0.00%)
         occurrences all number
    0
    3
    0

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    20 Jul 2015
    Continuation of MSC2156119J in the event of persistent Grade 3 amylase/lipase elevations without clinical or radiological evidence of pancreatitis is allowed only if there is objectiveevidence of benefit, rather than the potential for benefit. For the second dose cohort (500 mg), the SMC will decide on actions to be taken if 2 or more subjects out of the first 3 experience a DLT during the first treatment cycle. Inclusion of an exploratory PK endpoint.
    13 Jun 2016
    It was added that administrative interim analyses at time points that are not specified in the protocol may be performed for internal planning purposes.

    Interruptions (globally)

    Were there any global interruptions to the trial? No

    Limitations and caveats

    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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