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    Clinical Trial Results:
    Phase 2, Parallel-Arm Study of MGCD265 in Patients with Locally Advanced or Metastatic Non-Small Cell Lung Cancer with Activating Genetic Alterations in Mesenchymal-Epithelial Transition Factor

    Summary
    EudraCT number
    		 2015-002070-21
    Trial protocol
    		 HU   GB   ES   PL   IT  
    Global end of trial date
    02 Jan 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    18 Jan 2020
    First version publication date
    18 Jan 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    265-109
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02544633
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Mirati Therapeutics, Inc.
    Sponsor organisation address
    9393 Towne Centre Drive, San Diego, United States, 92121
    Public contact
    Vanessa Tassell, Mirati Therapeutics, Inc., tassellv@mirati.com
    Scientific contact
    Dr. Hirak Der-Torossian, Mirati Therapeutics, Inc., 001 858-332-3556,
    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
    06 Sep 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    06 Sep 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    02 Jan 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To determine the tumor response to MGCD265 in patients with Locally Advanced or Metastatic Non-Small Cell Lung Cancer with Activating Genetic Alterations in Mesenchymal-Epithelial Transition Factor.
    Protection of trial subjects
    This study was conducted in accordance with International Ethical Guidelines for Biomedical Research Involving Human Patients (Council for International Organizations of Medical Sciences 2002), Guidelines for Good Clinical Practice (GCP) (International Conference on Harmonization [ICH] 1996), and concepts that have their origin in the Declaration of Helsinki (World Medical Association 1996, 2008 & 2013).
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    28 Oct 2015
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety
    Long term follow-up duration
    		 2 Months
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Korea, Republic of: 10
    Country: Number of subjects enrolled
    Hungary: 1
    Country: Number of subjects enrolled
    United States: 45
    Country: Number of subjects enrolled
    Poland: 3
    Country: Number of subjects enrolled
    Italy: 2
    Country: Number of subjects enrolled
    United Kingdom: 3
    Country: Number of subjects enrolled
    Australia: 4
    Worldwide total number of subjects
    68
    EEA total number of subjects
    9
    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)
    27
    From 65 to 84 years
    40
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Sponsor approval of each potential patient’s genetic testing following pre-screening, whether performed by the study central lab or a Sponsor-approved local lab, was filed prior to proceeding to full clinical screening. All patients considered eligible for the study following clinical screening were submitted to Sponsor for registration approval.

    Period 1
    Period 1 title
    Treatment Period
    Is this the baseline period?
    		 Yes
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 MET Activating Mutations in Tumor Tissue
    Arm description
    		 MGCD265 (750 mg twice a day (BID) spray dried dispersion tablet or 1050 mg BID soft-gel capsule) in patients with mesenchymal-epithelial transition factor (MET) activating mutations in tumor tissue.
    Arm type
    		 Experimental

    Investigational medicinal product name
    MGCD265
    Investigational medicinal product code
    Other name
    Glesatinib
    Pharmaceutical forms
    Capsule, soft, Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    MGCD265 was administered twice-daily in 21-day cycles. MGCD265 could be taken as one of two formulations; softgel capsules (1050 mg) and spray dried dispersion (750 mg).

    Arm title
    		 MET Gene Amplifications in Tumor Tissue
    Arm description
    		 MGCD265 (750 mg BID spray dried dispersion tablet or 1050 mg BID soft-gel capsule) in patients with mesenchymal-epithelial transition factor (MET) gene amplifications in tumor tissue.
    Arm type
    		 Experimental

    Investigational medicinal product name
    MGCD265
    Investigational medicinal product code
    Other name
    Glesatinib
    Pharmaceutical forms
    Capsule, soft, Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    MGCD265 was administered twice-daily in 21-day cycles. MGCD265 could be taken as one of two formulations; softgel capsules (1050 mg) and spray dried dispersion (750 mg).

    Arm title
    		 MET Activating Mutations in ctDNA
    Arm description
    		 MGCD265 (750 mg BID spray dried dispersion tablet or 1050 mg BID soft-gel capsule) in patients with mesenchymal-epithelial transition factor (MET) activating mutations in the blood (circulating tumor DNA).
    Arm type
    		 Experimental

    Investigational medicinal product name
    MGCD265
    Investigational medicinal product code
    Other name
    Glesatinib
    Pharmaceutical forms
    Tablet, Capsule, soft
    Routes of administration
    Oral use
    Dosage and administration details
    MGCD265 was administered twice-daily in 21-day cycles. MGCD265 could be taken as one of two formulations; softgel capsules (1050 mg) and spray dried dispersion (750 mg).

    Arm title
    		 MET Gene Amplifications in ctDNA
    Arm description
    		 MGCD265 (750 mg BID spray dried dispersion tablet or 1050 mg BID soft-gel capsule) in patients with mesenchymal-epithelial transition factor (MET) gene amplifications in the blood (circulating tumor DNA).
    Arm type
    		 Experimental

    Investigational medicinal product name
    MGCD265
    Investigational medicinal product code
    Other name
    Glesatinib
    Pharmaceutical forms
    Capsule, soft, Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    MGCD265 was administered twice-daily in 21-day cycles. MGCD265 could be taken as one of two formulations; softgel capsules (1050 mg) and spray dried dispersion (750 mg).

    Number of subjects in period 1
    		MET Activating Mutations in Tumor Tissue MET Gene Amplifications in Tumor Tissue MET Activating Mutations in ctDNA MET Gene Amplifications in ctDNA
    Started
    28
    20
    8
    12
    Completed
    28
    20
    8
    12
    Period 2
    Period 2 title
    Survival Follow-up Period
    Is this the baseline period?
    		 No
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 MET Activating Mutations in Tumor Tissue
    Arm description
    		 MGCD265 (750 mg BID spray dried dispersion tablet or 1050 mg BID soft-gel capsule) in patients with mesenchymal-epithelial transition factor (MET) activating mutations in tumor tissue.
    Arm type
    		 Experimental

    Investigational medicinal product name
    MGCD265
    Investigational medicinal product code
    Other name
    Glesatinib
    Pharmaceutical forms
    Capsule, soft, Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    MGCD265 was administered twice-daily in 21-day cycles. MGCD265 could be taken as one of two formulations; softgel capsules (1050 mg) and spray dried dispersion (750 mg).

    Arm title
    		 MET Gene Amplifications in Tumor Tissue
    Arm description
    		 MGCD265 (750 mg BID spray dried dispersion tablet or 1050 mg BID soft-gel capsule) in patients with mesenchymal-epithelial transition factor (MET) gene amplifications in tumor tissue.
    Arm type
    		 Experimental

    Investigational medicinal product name
    MGCD265
    Investigational medicinal product code
    Other name
    Glesatinib
    Pharmaceutical forms
    Capsule, soft, Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    MGCD265 was administered twice-daily in 21-day cycles. MGCD265 could be taken as one of two formulations; softgel capsules (1050 mg) and spray dried dispersion (750 mg).

    Arm title
    		 MET Activating Mutations in ctDNA
    Arm description
    		 MGCD265 (750 mg BID spray dried dispersion tablet or 1050 mg BID soft-gel capsule) in patients with mesenchymal-epithelial transition factor (MET) activating mutations in the blood (circulating tumor DNA).
    Arm type
    		 Experimental

    Investigational medicinal product name
    MGCD265
    Investigational medicinal product code
    Other name
    Glesatinib
    Pharmaceutical forms
    Capsule, soft, Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    MGCD265 was administered twice-daily in 21-day cycles. MGCD265 could be taken as one of two formulations; softgel capsules (1050 mg) and spray dried dispersion (750 mg).

    Arm title
    		 MET Gene Amplifications in ctDNA
    Arm description
    		 MGCD265 (750 mg BID spray dried dispersion tablet or 1050 mg BID soft-gel capsule) in patients with mesenchymal-epithelial transition factor (MET) gene amplifications in the blood (circulating tumor DNA).
    Arm type
    		 Experimental

    Investigational medicinal product name
    MGCD265
    Investigational medicinal product code
    Other name
    Glesatinib
    Pharmaceutical forms
    Capsule, soft, Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    MGCD265 was administered twice-daily in 21-day cycles. MGCD265 could be taken as one of two formulations; softgel capsules (1050 mg) and spray dried dispersion (750 mg).

    Number of subjects in period 2 [1]
    		MET Activating Mutations in Tumor Tissue MET Gene Amplifications in Tumor Tissue MET Activating Mutations in ctDNA MET Gene Amplifications in ctDNA
    Started
    28
    19
    7
    12
    Completed
    0
    0
    0
    0
    Not completed
    28
    19
    7
    12
         Death
    12
    14
    3
    9
         Other
    1
    -
    -
    -
         Withdrawal by Subject
    4
    -
    1
    -
         Study Terminated by Sponsor
    11
    4
    2
    3
         Lost to follow-up
    -
    1
    1
    -
    Notes
    [1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: Not all subjects entered follow-up period.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    MET Activating Mutations in Tumor Tissue
    Reporting group description
    		 MGCD265 (750 mg twice a day (BID) spray dried dispersion tablet or 1050 mg BID soft-gel capsule) in patients with mesenchymal-epithelial transition factor (MET) activating mutations in tumor tissue.

    Reporting group title
    MET Gene Amplifications in Tumor Tissue
    Reporting group description
    		 MGCD265 (750 mg BID spray dried dispersion tablet or 1050 mg BID soft-gel capsule) in patients with mesenchymal-epithelial transition factor (MET) gene amplifications in tumor tissue.

    Reporting group title
    MET Activating Mutations in ctDNA
    Reporting group description
    		 MGCD265 (750 mg BID spray dried dispersion tablet or 1050 mg BID soft-gel capsule) in patients with mesenchymal-epithelial transition factor (MET) activating mutations in the blood (circulating tumor DNA).

    Reporting group title
    MET Gene Amplifications in ctDNA
    Reporting group description
    		 MGCD265 (750 mg BID spray dried dispersion tablet or 1050 mg BID soft-gel capsule) in patients with mesenchymal-epithelial transition factor (MET) gene amplifications in the blood (circulating tumor DNA).

    Reporting group values
    		 MET Activating Mutations in Tumor Tissue MET Gene Amplifications in Tumor Tissue MET Activating Mutations in ctDNA MET Gene Amplifications in ctDNA Total
    Number of subjects
    		 28 20 8 12 68
    Age categorical
    Units: Subjects
        In utero
    		 0
        Preterm newborn infants (gestational age < 37 wks)
    		 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)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 70.7 ± 6.02 61.8 ± 13.17 59.1 ± 7.70 64.8 ± 11.09 -
    Gender categorical
    Units: Subjects
        Female
    		 16 4 6 6 32
        Male
    		 12 16 2 6 36
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 0 0 1 0 1
        Not Hispanic or Latino
    		 28 20 7 12 67
    Race
    Units: Subjects
        Asian
    		 4 6 2 2 14
        Black or African American
    		 2 1 0 0 3
        White
    		 21 13 6 10 50
        Unknown or Not Reported
    		 1 0 0 0 1
    ECOG Performance Status
    0 - Fully active, able to carry on all pre-disease performance without restriction 1 - Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g., light house work, office work 2 - Ambulatory and capable of all self care but unable to carry out any work activities. Up and about more than 50% of waking hours 3 - Capable of only limited self care, confined to bed or chair more than 50% of waking hours 4 - Completely disabled. Cannot carry on any self care. Totally confined to bed or chair 5 - Dead
    Units: Subjects
        ECOG Performance Status - 0
    		 10 6 2 2 20
        ECOG Performance Status - 1
    		 16 12 6 6 40
        ECOG Performance Status - 2
    		 2 2 0 4 8
        ECOG Performance Status - 3
    		 0 0 0 0 0
        ECOG Performance Status - 4
    		 0 0 0 0 0
    Primary Disease Histology
    Units: Subjects
        Adenocarcinoma
    		 22 18 7 6 53
        Squamous Cell Carcinoma
    		 3 2 1 2 8
        Large Cell Carcinoma
    		 0 0 0 2 2
        Other
    		 3 0 0 2 5
    Current Stage
    Units: Subjects
        Locally Advanced
    		 1 1 0 1 3
        Metastatic
    		 27 19 8 11 65
    Smoking History
    Units: Subjects
        Lifetime Non-Smoker
    		 10 2 3 2 17
        Current Smoker
    		 0 4 1 3 8
        Past Smoker
    		 18 14 4 7 43
    Height
    Some patients did not have their height recorded at baseline.
    Units: cm
        arithmetic mean (standard deviation)
    		 168.63 ± 9.74 173.18 ± 8.77 161.11 ± 8.10 167.70 ± 8.98 -
    Body Mass Index
    BMI unable to be calculated in patients with no height recorded at baseline.
    Units: Kg/m^2
        arithmetic mean (standard deviation)
    		 25.16 ± 4.58 24.92 ± 4.46 22.24 ± 2.34 21.80 ± 4.18 -
    Weight
    Units: Kg
        arithmetic mean (standard deviation)
    		 70.85 ± 17.64 75.33 ± 17.77 60.97 ± 8.68 61.58 ± 13.56 -

    End points

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    End points reporting groups
    Reporting group title
    MET Activating Mutations in Tumor Tissue
    Reporting group description
    		 MGCD265 (750 mg twice a day (BID) spray dried dispersion tablet or 1050 mg BID soft-gel capsule) in patients with mesenchymal-epithelial transition factor (MET) activating mutations in tumor tissue.

    Reporting group title
    MET Gene Amplifications in Tumor Tissue
    Reporting group description
    		 MGCD265 (750 mg BID spray dried dispersion tablet or 1050 mg BID soft-gel capsule) in patients with mesenchymal-epithelial transition factor (MET) gene amplifications in tumor tissue.

    Reporting group title
    MET Activating Mutations in ctDNA
    Reporting group description
    		 MGCD265 (750 mg BID spray dried dispersion tablet or 1050 mg BID soft-gel capsule) in patients with mesenchymal-epithelial transition factor (MET) activating mutations in the blood (circulating tumor DNA).

    Reporting group title
    MET Gene Amplifications in ctDNA
    Reporting group description
    		 MGCD265 (750 mg BID spray dried dispersion tablet or 1050 mg BID soft-gel capsule) in patients with mesenchymal-epithelial transition factor (MET) gene amplifications in the blood (circulating tumor DNA).
    Reporting group title
    MET Activating Mutations in Tumor Tissue
    Reporting group description
    		 MGCD265 (750 mg BID spray dried dispersion tablet or 1050 mg BID soft-gel capsule) in patients with mesenchymal-epithelial transition factor (MET) activating mutations in tumor tissue.

    Reporting group title
    MET Gene Amplifications in Tumor Tissue
    Reporting group description
    		 MGCD265 (750 mg BID spray dried dispersion tablet or 1050 mg BID soft-gel capsule) in patients with mesenchymal-epithelial transition factor (MET) gene amplifications in tumor tissue.

    Reporting group title
    MET Activating Mutations in ctDNA
    Reporting group description
    		 MGCD265 (750 mg BID spray dried dispersion tablet or 1050 mg BID soft-gel capsule) in patients with mesenchymal-epithelial transition factor (MET) activating mutations in the blood (circulating tumor DNA).

    Reporting group title
    MET Gene Amplifications in ctDNA
    Reporting group description
    		 MGCD265 (750 mg BID spray dried dispersion tablet or 1050 mg BID soft-gel capsule) in patients with mesenchymal-epithelial transition factor (MET) gene amplifications in the blood (circulating tumor DNA).

    Subject analysis set title
    Tablet 750 mg BID
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Tablet formulation, 750 mg, BID

    Subject analysis set title
    Soft Gel 1050 mg BID
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Soft Gel formulation, 1050 mg, BID

    Primary: Objective Response Rate

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    End point title
    		 Objective Response Rate
    End point description
    Objective disease response is defined as the percent of patients documented by investigator assessment to have a confirmed Complete Response (CR) or Partial Response (PR) in accordance with the Response Evaluation Criteria in Solid Tumors (RECIST 1.1) for target and non-target lesions as assessed by CT or MRI. CR is defined as complete disappearance of all target lesions with the exception of nodal disease; PR is defined as >=30% decrease under baseline of the sum of diameters of all target measurable lesions; Stable Disease (SD) is concluded when the response does not qualify for CR, PR or Progression; Progressive Disease (PD) is defined as a 20% increase in the sum of diameters of target measurable lesions above the smallest sum observed with a minimum absolute increase of 5 mm, or unequivocal progression of pre-existing non-target lesions.
    End point type
    Primary
    End point timeframe
    Up to 3 months
    End point values
    		 MET Activating Mutations in Tumor Tissue MET Gene Amplifications in Tumor Tissue MET Activating Mutations in ctDNA MET Gene Amplifications in ctDNA
    Number of subjects analysed
    28
    20
    8
    12
    Units: Percentage of patients
        number (confidence interval 95%)
    10.7 (2.27 to 28.23)
    15.0 (3.21 to 37.89)
    25.0 (3.19 to 65.09)
    0.00 (0.00 to 26.46)
    Statistical analysis title
    		 MET Activating Mutations in Tumor Tissue
    Comparison groups
    MET Activating Mutations in Tumor Tissue v MET Gene Amplifications in Tumor Tissue v MET Activating Mutations in ctDNA v MET Gene Amplifications in ctDNA
    Number of subjects included in analysis
    68
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [1]
    P-value
    		 = 0.94
    Method
    		 Exact test
    Confidence interval
    Notes
    [1] - An exact test for single proportion (two-sided a=5%) will be performed to test H0: ORR <=20% against H1: ORR >20%.
    Statistical analysis title
    		 MET Gene Amplifications in Tumor Tissue
    Comparison groups
    MET Activating Mutations in Tumor Tissue v MET Gene Amplifications in Tumor Tissue v MET Activating Mutations in ctDNA v MET Gene Amplifications in ctDNA
    Number of subjects included in analysis
    68
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.79
    Method
    		 Exact test
    Confidence interval
    Statistical analysis title
    		 MET Activating Mutations in ctDNA
    Comparison groups
    MET Gene Amplifications in Tumor Tissue v MET Activating Mutations in Tumor Tissue v MET Activating Mutations in ctDNA v MET Gene Amplifications in ctDNA
    Number of subjects included in analysis
    68
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.47
    Method
    		 Exact test
    Confidence interval
    Statistical analysis title
    		 MET Gene Amplifications in ctDNA
    Comparison groups
    MET Activating Mutations in Tumor Tissue v MET Gene Amplifications in Tumor Tissue v MET Activating Mutations in ctDNA v MET Gene Amplifications in ctDNA
    Number of subjects included in analysis
    68
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 > 0.999
    Method
    		 Exact test
    Confidence interval

    Secondary: Duration of Response

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    End point title
    		 Duration of Response
    End point description
    Duration of Response (DR) was defined as the time from date of the first documentation of objective tumor response (CR or PR) to the first documentation of Objective Progression of Disease (PD) or to death due to any cause in the absence of documented PD.
    End point type
    Secondary
    End point timeframe
    From date of the first documentation of objective tumor response (CR or PR) to the first documentation of Objective Progression of Disease (PD) or to death due to any cause in the absence of documented PD, assessed up to 24 months.
    End point values
    		 MET Activating Mutations in Tumor Tissue MET Gene Amplifications in Tumor Tissue MET Activating Mutations in ctDNA MET Gene Amplifications in ctDNA
    Number of subjects analysed
    3
    3
    2 [2]
    0 [3]
    Units: Days
        median (confidence interval 95%)
    85 (82 to 132)
    170 (120 to 170)
    99999 (77 to 99999)
    ( to )
    Notes
    [2] - Median DR and upper bound of 95% CI for median DR are not estimable. Median not reached.
    [3] - Median DR, lower nd upper bound of 95% CI for median DR are not estimable.
    No statistical analyses for this end point

    Secondary: Progression Free Survival

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    End point title
    		 Progression Free Survival
    End point description
    Progression-free survival (PFS) was defined as the time from date of first study treatment to first PD or death due to any cause in the absence of documented PD. Per RECIST 1.1, Progressive Disease (PD) is defined as a 20% increase in the sum of diameters of target measurable lesions above the smallest sum observed (over baseline if no decrease in the sum is observed during therapy) with a minimum absolute increase of 5 mm, or unequivocal progression of pre-existing non-target lesions.
    End point type
    Secondary
    End point timeframe
    The time from date of first study treatment to first PD or death due to any cause in the absence of documented PD, up to 24 months.
    End point values
    		 MET Activating Mutations in Tumor Tissue MET Gene Amplifications in Tumor Tissue MET Activating Mutations in ctDNA MET Gene Amplifications in ctDNA
    Number of subjects analysed
    28
    20
    8 [4]
    12
    Units: Months
        median (confidence interval 95%)
    3.95 (2.11 to 4.18)
    4.84 (1.35 to 5.53)
    3.39 (1.28 to 99999)
    2.76 (1.48 to 4.01)
    Notes
    [4] - Upper bound of 95% CI for median PFS is not estimable due to small number of events.
    No statistical analyses for this end point

    Secondary: 1-Year Survival Rate

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    End point title
    		 1-Year Survival Rate
    End point description
    1-Year Survival was defined as the probability of survival at 1 year after the first dose.
    End point type
    Secondary
    End point timeframe
    From date of first study treatment to death due to any cause, assessed up to 12 months
    End point values
    		 MET Activating Mutations in Tumor Tissue MET Gene Amplifications in Tumor Tissue MET Activating Mutations in ctDNA MET Gene Amplifications in ctDNA
    Number of subjects analysed
    28
    20
    8
    12
    Units: Percentage
        number (confidence interval 95%)
    50.47 (27.49 to 69.62)
    34.92 (14.05 to 56.89)
    54.69 (13.72 to 83.24)
    13.89 (0.86 to 44.05)
    No statistical analyses for this end point

    Secondary: Overall Survival

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    End point title
    		 Overall Survival
    End point description
    Overall Survival was defined as the time from date of first study treatment to death due to any cause.
    End point type
    Secondary
    End point timeframe
    From date of first study treatment to death due to any cause, assessed up to 24 months.
    End point values
    		 MET Activating Mutations in Tumor Tissue MET Gene Amplifications in Tumor Tissue MET Activating Mutations in ctDNA MET Gene Amplifications in ctDNA
    Number of subjects analysed
    28 [5]
    20
    8 [6]
    12
    Units: Months
        median (confidence interval 95%)
    16.32 (4.01 to 99999)
    7.04 (1.84 to 14.93)
    99999 (0.89 to 99999)
    4.08 (1.22 to 11.05)
    Notes
    [5] - Upper bound of 95% CI for median OS is not estimable due to small number of events.
    [6] - Median OS and upper bound of 95% CI for median OS are not estimable. Median not reached.
    No statistical analyses for this end point

    Secondary: Number of Patients Experiencing Treatment-Emergent Adverse Events

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    End point title
    		 Number of Patients Experiencing Treatment-Emergent Adverse Events
    End point description
    End point type
    Secondary
    End point timeframe
    Date of first dose to 28 days after the last dose, up to an average of 5.1 months on treatment.
    End point values
    		 MET Activating Mutations in Tumor Tissue MET Gene Amplifications in Tumor Tissue MET Activating Mutations in ctDNA MET Gene Amplifications in ctDNA
    Number of subjects analysed
    28
    20
    8
    12
    Units: Number of Patients
    28
    20
    8
    12
    No statistical analyses for this end point

    Secondary: Blood Plasma Concentration of MGCD265

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    End point title
    		 Blood Plasma Concentration of MGCD265
    End point description
    Blood samples for PK assessment were to be taken on Cycle 1, Day 1 and Day 15 at pre-dose and at 2 hours (1-3 hours) and 6 hours (4-8 hours) post-dose. On Cycle 2, samples were collected on Day 1 and Day 15 at pre-dose and at 6 hours post-dose (4-8 hours). Note: Assessment of Cmax and Tmax are limited by the sparse blood sampling schedule post dose (i.e., only 2 blood draws post-dose in Cycle 1 and only 1 sample collected post-dose in Cycle 2). The number of patients reported for each PK parameter was dependent on the actual number of blood samples collected post-dose.
    End point type
    Secondary
    End point timeframe
    Cycle 1, Day 1 and Day 15 at pre-dose and at 2 hours (1-3 hours) and 6 hours (4-8 hours) post-dose. Cycle 2, Day 1 and Day 15 at pre-dose and at 6 hours post-dose (4-8 hours).
    End point values
    		 Tablet 750 mg BID Soft Gel 1050 mg BID
    Number of subjects analysed
    46 [7]
    17 [8]
    Units: See Parameter
    geometric mean (geometric coefficient of variation)
        AUC0-6 (h*ng/mL) C1D1
    250.8 ± 98.0
    185.5 ± 98.8
        AUC0-6 (h*ng/mL) C1D15
    1565 ± 54.0
    1837 ± 51.3
        Cmax (ng/mL) C1D1
    69.77 ± 87.1
    60.49 ± 103.9
        Cmax (ng/mL) C1D15
    279.2 ± 54.6
    328.1 ± 49.8
        Cmax (ng/mL) C2D1
    214 ± 69.4
    386 ± 13.9
        Cmax (ng/mL) C2D15
    138 ± 100
    99999 ± 99999
        Ctrough (ng/mL) C1D15
    264 ± 52.5
    337 ± 59.2
        Ctrough (ng/mL) C2D1
    203 ± 80.9
    345 ± 48.5
        Ctrough (ng/mL) C2D15
    255 ± 37.5
    99999 ± 99999
        Accumulation Ratio AUC0-6 C1D15
    6.42 ± 87.2
    9.88 ± 96.4
        Accumulation Ratio Cmax C1D15
    4.07 ± 79.7
    5.35 ± 100.9
        Peak to Trough ratio C1D15
    1.09 ± 13.4
    1.08 ± 10.4
    Notes
    [7] - PK Analysis Set consisted of all evaluabale patients who received at least one dose of study drug
    [8] - PK Analysis Set consisted of all evaluabale patients who received at least one dose of study drug
    No statistical analyses for this end point

    Secondary: Blood Plasma Concentration of MGCD265 - Tmax

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    End point title
    		 Blood Plasma Concentration of MGCD265 - Tmax
    End point description
    Blood samples for PK assessment were to be taken on Cycle 1, Day 1 and Day 15 at pre-dose and at 2 hours (1-3 hours) and 6 hours (4-8 hours) post-dose. Note: Assessment of Cmax and Tmax are limited by the sparse blood sampling schedule post dose (i.e., only 2 blood draws post-dose in Cycle 1 and only 1 sample collected post-dose in Cycle 2). The number of patients reported for each PK parameter was dependent on the actual number of blood samples collected post-dose.
    End point type
    Secondary
    End point timeframe
    Cycle 1, Day 1 and Day 15 at pre-dose and at 2 hours (1-3 hours) and 6 hours (4-8 hours) post-dose.
    End point values
    		 Tablet 750 mg BID Soft Gel 1050 mg BID
    Number of subjects analysed
    46 [9]
    17 [10]
    Units: hours
    median (full range (min-max))
        C1D1
    6 (2 to 6)
    6 (6 to 6)
        C1D15
    2 (2 to 6)
    6 (2 to 6)
    Notes
    [9] - PK Analysis Set
    [10] - PK Analysis Set
    No statistical analyses for this end point

    Secondary: Number of Patients Showing a Correlation Between Selected Tumor Gene Alterations Using Different Analytical Techniques in Tumor Tissue and Circulating Tumor Deoxyribonucleic Acid (ctDNA)

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    End point title
    		 Number of Patients Showing a Correlation Between Selected Tumor Gene Alterations Using Different Analytical Techniques in Tumor Tissue and Circulating Tumor Deoxyribonucleic Acid (ctDNA)
    End point description
    Due to early closure of the study due to sponsor portfolio prioritization and not due to any patient safety issues, data to assess correlations between selected tumor gene alterations using different analytical techniques in tumor tissue and circulating tumor deoxyribonucleic acid (ctDNA) was not completed.
    End point type
    Secondary
    End point timeframe
    At baseline
    End point values
    		 MET Activating Mutations in Tumor Tissue MET Gene Amplifications in Tumor Tissue MET Activating Mutations in ctDNA MET Gene Amplifications in ctDNA
    Number of subjects analysed
    0 [11]
    0 [12]
    0 [13]
    0 [14]
    Units: Patients
    Notes
    [11] - Study was early terminated so data collection to assess any correlations was not completed.
    [12] - Study was early terminated so data collection to assess any correlations was not completed.
    [13] - Study was early terminated so data collection to assess any correlations was not completed.
    [14] - Study was early terminated so data collection to assess any correlations was not completed.
    No statistical analyses for this end point

    Secondary: Number of Patients Showing Change in Genetic Alteration Status in ctDNA With MGCD265 Treatment Over Time

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    End point title
    		 Number of Patients Showing Change in Genetic Alteration Status in ctDNA With MGCD265 Treatment Over Time
    End point description
    Due to early closure of the study due to sponsor portfolio prioritization and not due to any patient safety issues, data to assess change in genetic alteration status in ctDNA with MGCD265 treatment over time in the selected population was not completed.
    End point type
    Secondary
    End point timeframe
    At baseline and at time of confirmation of response to treatment
    End point values
    		 MET Activating Mutations in Tumor Tissue MET Gene Amplifications in Tumor Tissue MET Activating Mutations in ctDNA MET Gene Amplifications in ctDNA
    Number of subjects analysed
    0 [15]
    0 [16]
    0 [17]
    0 [18]
    Units: Number of Patients
    Notes
    [15] - Study was early terminated so data to assess change in genetic alteration status wasn't completed.
    [16] - Study was early terminated so data to assess change in genetic alteration status wasn't completed.
    [17] - Study was early terminated so data to assess change in genetic alteration status wasn't completed.
    [18] - Study was early terminated so data to assess change in genetic alteration status wasn't completed.
    No statistical analyses for this end point

    Secondary: Blood Plasma Concentration of Soluble MET (sMET) Biomarker

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    End point title
    		 Blood Plasma Concentration of Soluble MET (sMET) Biomarker
    End point description
    MET Activating Mutations in ctDNA. Change from Baseline - Cycle 2 Day 15 - Pre-Dose Standard Deviation not evaluable. The Pharmacodynamics Evaluable Population Population defined as all patients in the mITT population for whom PD analytical results were available. Overall number of participants analyzed at baseline and post-baseline are different due to samples not being collected post-baseline for some patients
    End point type
    Secondary
    End point timeframe
    Cycle 1 and Cycle 2
    End point values
    		 MET Activating Mutations in Tumor Tissue MET Gene Amplifications in Tumor Tissue MET Activating Mutations in ctDNA MET Gene Amplifications in ctDNA
    Number of subjects analysed
    22 [19]
    17 [20]
    4 [21]
    9 [22]
    Units: pg/mL
    arithmetic mean (standard deviation)
        Baseline
    443494.7 ± 228345.48
    461985.2 ± 122069.25
    450112.5 ± 80809.29
    961383.1 ± 1665608.92
        Actual - Cycle 1 Day 15 - Pre-Dose
    577631.4 ± 221350.47
    568938.8 ± 129859.54
    594277.3 ± 49746.18
    775242.8 ± 679349.02
        Change from Baseline - Cycle 1 Day 15 - Pre-Dose
    122074.7 ± 166978.07
    94110.4 ± 87158.09
    144164.8 ± 51740.94
    -257537.5 ± 1102955.10
        Actual - Cycle 2 Day 1 - Pre-Dose
    560790.3 ± 216802.34
    582800.9 ± 140742.66
    662385.3 ± 41039.78
    742344.9 ± 620417.99
        Change from Baseline - Cycle 2 Day 15 - Pre-Dose
    96641.3 ± 144021.14
    169374.6 ± 70996.25
    44093.0 ± 99999
    184161.0 ± 161224.04
    Notes
    [19] - Pharmacodynamics Evaluable Population
    [20] - Pharmacodynamics Evaluable Population
    [21] - Pharmacodynamics Evaluable Population
    [22] - Pharmacodynamics Evaluable Population
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to 12 months
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    21.0
    Reporting groups
    Reporting group title
    MET Activating Mutations in Tumor Tissue
    Reporting group description
    		 MGCD265 (750 mg BID spray dried dispersion tablet or 1050 mg BID soft-gel capsule) in patients with mesenchymal-epithelial transition factor (MET) activating mutations in tumor tissue.

    Reporting group title
    MET Gene Amplifications in Tumor Tissue
    Reporting group description
    		 MGCD265 (750 mg BID spray dried dispersion tablet or 1050 mg BID soft-gel capsule) in patients with mesenchymal-epithelial transition factor (MET) gene amplifications in tumor tissue.

    Reporting group title
    MET Activating Mutations in ctDNA
    Reporting group description
    		 MGCD265 (750 mg BID spray dried dispersion tablet or 1050 mg BID soft-gel capsule) in patients with mesenchymal-epithelial transition factor (MET) activating mutations in the blood (circulating tumor DNA).

    Reporting group title
    MET Gene Amplifications in ctDNA
    Reporting group description
    		 MGCD265 (750 mg BID spray dried dispersion tablet or 1050 mg BID soft-gel capsule) in patients with mesenchymal-epithelial transition factor (MET) gene amplifications in the blood (circulating tumor DNA).

    Serious adverse events
    		 MET Activating Mutations in Tumor Tissue MET Gene Amplifications in Tumor Tissue MET Activating Mutations in ctDNA MET Gene Amplifications in ctDNA
    Total subjects affected by serious adverse events
         subjects affected / exposed
    12 / 28 (42.86%)
    10 / 20 (50.00%)
    4 / 8 (50.00%)
    7 / 12 (58.33%)
         number of deaths (all causes)
    12
    14
    3
    9
         number of deaths resulting from adverse events
    9
    6
    1
    5
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Malignant neoplasm progression
         subjects affected / exposed
    5 / 28 (17.86%)
    5 / 20 (25.00%)
    1 / 8 (12.50%)
    4 / 12 (33.33%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 5
    0 / 1
    0 / 5
         deaths causally related to treatment / all
    0 / 5
    0 / 5
    0 / 1
    0 / 4
    Vascular disorders
    Hypotension
         subjects affected / exposed
    0 / 28 (0.00%)
    0 / 20 (0.00%)
    0 / 8 (0.00%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thrombosis
         subjects affected / exposed
    0 / 28 (0.00%)
    0 / 20 (0.00%)
    1 / 8 (12.50%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Myocardial infarction
         subjects affected / exposed
    2 / 28 (7.14%)
    0 / 20 (0.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebrovascular accident
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 20 (0.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemorrhage intracranial
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 20 (0.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    1 / 28 (3.57%)
    1 / 20 (5.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 28 (0.00%)
    0 / 20 (0.00%)
    1 / 8 (12.50%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 20 (0.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Multiple organ dysfunction syndrome
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 20 (0.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Colitis
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 20 (0.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Enterocolitis
         subjects affected / exposed
    0 / 28 (0.00%)
    0 / 20 (0.00%)
    0 / 8 (0.00%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 20 (5.00%)
    1 / 8 (12.50%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 20 (5.00%)
    1 / 8 (12.50%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hepatic haemorrhage
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 20 (0.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory failure
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 20 (5.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchial fistula
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 20 (0.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 20 (0.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Epistaxis
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 20 (5.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    1 / 28 (3.57%)
    1 / 20 (5.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Oesophagobronchial fistula
         subjects affected / exposed
    0 / 28 (0.00%)
    0 / 20 (0.00%)
    0 / 8 (0.00%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Pleural effusion
         subjects affected / exposed
    0 / 28 (0.00%)
    0 / 20 (0.00%)
    0 / 8 (0.00%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumothorax spontaneous
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 20 (5.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    1 / 28 (3.57%)
    1 / 20 (5.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 20 (0.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Bronchopulmonary aspergillosis
         subjects affected / exposed
    0 / 28 (0.00%)
    0 / 20 (0.00%)
    0 / 8 (0.00%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Herpes zoster
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 20 (0.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 28 (0.00%)
    0 / 20 (0.00%)
    1 / 8 (12.50%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 28 (3.57%)
    3 / 20 (15.00%)
    1 / 8 (12.50%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 28 (0.00%)
    3 / 20 (15.00%)
    0 / 8 (0.00%)
    3 / 12 (25.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 3
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 MET Activating Mutations in Tumor Tissue MET Gene Amplifications in Tumor Tissue MET Activating Mutations in ctDNA MET Gene Amplifications in ctDNA
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    28 / 28 (100.00%)
    20 / 20 (100.00%)
    7 / 8 (87.50%)
    12 / 12 (100.00%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Cancer pain
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 20 (0.00%)
    0 / 8 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    1
    0
    0
    2
    Tumour pain
         subjects affected / exposed
    0 / 28 (0.00%)
    0 / 20 (0.00%)
    0 / 8 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    1
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    2 / 28 (7.14%)
    0 / 20 (0.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Embolism
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 20 (5.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Haemorrhage
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 20 (5.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Hot flush
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 20 (5.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Hypertension
         subjects affected / exposed
    1 / 28 (3.57%)
    1 / 20 (5.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    4
    5
    0
    0
    Hypotension
         subjects affected / exposed
    3 / 28 (10.71%)
    0 / 20 (0.00%)
    0 / 8 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    3
    0
    0
    1
    Superior vena cava syndrome
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 20 (5.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Thrombosis
         subjects affected / exposed
    0 / 28 (0.00%)
    0 / 20 (0.00%)
    0 / 8 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    1
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    2 / 28 (7.14%)
    3 / 20 (15.00%)
    1 / 8 (12.50%)
    1 / 12 (8.33%)
         occurrences all number
    3
    3
    1
    1
    Catheter site pain
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 20 (5.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Chest discomfort
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 20 (5.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Chest pain
         subjects affected / exposed
    2 / 28 (7.14%)
    0 / 20 (0.00%)
    0 / 8 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    2
    0
    0
    1
    Face oedema
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 20 (0.00%)
    2 / 8 (25.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    2
    0
    Fatigue
         subjects affected / exposed
    13 / 28 (46.43%)
    8 / 20 (40.00%)
    5 / 8 (62.50%)
    7 / 12 (58.33%)
         occurrences all number
    17
    8
    8
    11
    General physical health deterioration
         subjects affected / exposed
    1 / 28 (3.57%)
    1 / 20 (5.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Malaise
         subjects affected / exposed
    2 / 28 (7.14%)
    0 / 20 (0.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 20 (5.00%)
    1 / 8 (12.50%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    1
    1
    Oedema
         subjects affected / exposed
    2 / 28 (7.14%)
    0 / 20 (0.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    3
    0
    0
    0
    Oedema peripheral
         subjects affected / exposed
    8 / 28 (28.57%)
    5 / 20 (25.00%)
    3 / 8 (37.50%)
    0 / 12 (0.00%)
         occurrences all number
    12
    5
    4
    0
    Pain
         subjects affected / exposed
    1 / 28 (3.57%)
    3 / 20 (15.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    4
    0
    0
    Peripheral swelling
         subjects affected / exposed
    2 / 28 (7.14%)
    1 / 20 (5.00%)
    0 / 8 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    7
    1
    0
    1
    Pyrexia
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 20 (0.00%)
    1 / 8 (12.50%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Reproductive system and breast disorders
    Vaginal haemorrhage
         subjects affected / exposed
    0 / 28 (0.00%)
    0 / 20 (0.00%)
    1 / 8 (12.50%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    3 / 28 (10.71%)
    6 / 20 (30.00%)
    3 / 8 (37.50%)
    1 / 12 (8.33%)
         occurrences all number
    7
    7
    5
    1
    Dysphonia
         subjects affected / exposed
    1 / 28 (3.57%)
    1 / 20 (5.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Dyspnoea
         subjects affected / exposed
    6 / 28 (21.43%)
    8 / 20 (40.00%)
    2 / 8 (25.00%)
    4 / 12 (33.33%)
         occurrences all number
    7
    18
    3
    5
    Dyspnoea exertional
         subjects affected / exposed
    0 / 28 (0.00%)
    0 / 20 (0.00%)
    0 / 8 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    3
    Haemoptysis
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 20 (5.00%)
    0 / 8 (0.00%)
    3 / 12 (25.00%)
         occurrences all number
    0
    1
    0
    3
    Hypoxia
         subjects affected / exposed
    1 / 28 (3.57%)
    1 / 20 (5.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    2
    2
    0
    0
    Nasal congestion
         subjects affected / exposed
    1 / 28 (3.57%)
    1 / 20 (5.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Oropharyngeal pain
         subjects affected / exposed
    1 / 28 (3.57%)
    1 / 20 (5.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Pharyngeal erythema
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 20 (5.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Pleural effusion
         subjects affected / exposed
    1 / 28 (3.57%)
    2 / 20 (10.00%)
    2 / 8 (25.00%)
    2 / 12 (16.67%)
         occurrences all number
    1
    3
    2
    3
    Pneumonia aspiration
         subjects affected / exposed
    0 / 28 (0.00%)
    2 / 20 (10.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Pneumothorax
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 20 (5.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Productive cough
         subjects affected / exposed
    2 / 28 (7.14%)
    0 / 20 (0.00%)
    1 / 8 (12.50%)
    0 / 12 (0.00%)
         occurrences all number
    3
    0
    1
    0
    Pulmonary congestion
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 20 (5.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Pulmonary embolism
         subjects affected / exposed
    1 / 28 (3.57%)
    2 / 20 (10.00%)
    1 / 8 (12.50%)
    1 / 12 (8.33%)
         occurrences all number
    1
    3
    1
    1
    Pulmonary oedema
         subjects affected / exposed
    0 / 28 (0.00%)
    0 / 20 (0.00%)
    0 / 8 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    1
    Rales
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 20 (5.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Respiratory failure
         subjects affected / exposed
    0 / 28 (0.00%)
    0 / 20 (0.00%)
    0 / 8 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    1
    Rhinorrhoea
         subjects affected / exposed
    1 / 28 (3.57%)
    1 / 20 (5.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Sinus pain
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 20 (5.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Tachypnoea
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 20 (5.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Wheezing
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 20 (5.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Psychiatric disorders
    Agitation
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 20 (5.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Anxiety
         subjects affected / exposed
    2 / 28 (7.14%)
    1 / 20 (5.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    2
    1
    0
    0
    Confusional state
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 20 (5.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Dysphemia
         subjects affected / exposed
    0 / 28 (0.00%)
    0 / 20 (0.00%)
    0 / 8 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    1
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    14 / 28 (50.00%)
    8 / 20 (40.00%)
    3 / 8 (37.50%)
    5 / 12 (41.67%)
         occurrences all number
    40
    20
    3
    5
    Aspartate aminotransferase increased
         subjects affected / exposed
    12 / 28 (42.86%)
    9 / 20 (45.00%)
    3 / 8 (37.50%)
    4 / 12 (33.33%)
         occurrences all number
    40
    15
    3
    13
    Blood alkaline phosphatase increased
         subjects affected / exposed
    3 / 28 (10.71%)
    3 / 20 (15.00%)
    2 / 8 (25.00%)
    0 / 12 (0.00%)
         occurrences all number
    3
    3
    2
    0
    Blood alkaline phosphatase
         subjects affected / exposed
    0 / 28 (0.00%)
    0 / 20 (0.00%)
    0 / 8 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    1
    Blood lactate dehydrogenase increased
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 20 (5.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    3
    0
    0
    Blood magnesium decreased
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 20 (0.00%)
    1 / 8 (12.50%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Capillary nail refill test abnormal
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 20 (5.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Haemoglobin
         subjects affected / exposed
    0 / 28 (0.00%)
    0 / 20 (0.00%)
    0 / 8 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    1
    Inflammatory marker increased
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 20 (5.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    0
    International normalised ratio increased
         subjects affected / exposed
    0 / 28 (0.00%)
    0 / 20 (0.00%)
    0 / 8 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    1
    Lymphocyte count decreased
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 20 (5.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    4
    0
    0
    Neutrophil count decreased
         subjects affected / exposed
    3 / 28 (10.71%)
    1 / 20 (5.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    4
    1
    0
    0
    Platelet count decreased
         subjects affected / exposed
    3 / 28 (10.71%)
    2 / 20 (10.00%)
    0 / 8 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    3
    2
    0
    2
    Platelet count increased
         subjects affected / exposed
    0 / 28 (0.00%)
    0 / 20 (0.00%)
    1 / 8 (12.50%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Transaminases increased
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 20 (5.00%)
    0 / 8 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    0
    1
    Weight decreased
         subjects affected / exposed
    4 / 28 (14.29%)
    1 / 20 (5.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    6
    1
    0
    0
    Weight increased
         subjects affected / exposed
    1 / 28 (3.57%)
    1 / 20 (5.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    1
    0
    0
    White blood cell count decreased
         subjects affected / exposed
    2 / 28 (7.14%)
    0 / 20 (0.00%)
    1 / 8 (12.50%)
    0 / 12 (0.00%)
         occurrences all number
    2
    0
    1
    0
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 20 (0.00%)
    1 / 8 (12.50%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Fall
         subjects affected / exposed
    0 / 28 (0.00%)
    0 / 20 (0.00%)
    1 / 8 (12.50%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    1
    Joint injury
         subjects affected / exposed
    0 / 28 (0.00%)
    0 / 20 (0.00%)
    1 / 8 (12.50%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Laceration
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 20 (5.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Cardiac disorders
    Sinus tachycardia
         subjects affected / exposed
    0 / 28 (0.00%)
    0 / 20 (0.00%)
    0 / 8 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    1
    Tachycardia
         subjects affected / exposed
    1 / 28 (3.57%)
    1 / 20 (5.00%)
    1 / 8 (12.50%)
    0 / 12 (0.00%)
         occurrences all number
    1
    1
    1
    0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    4 / 28 (14.29%)
    3 / 20 (15.00%)
    3 / 8 (37.50%)
    0 / 12 (0.00%)
         occurrences all number
    10
    3
    3
    0
    Dysgeusia
         subjects affected / exposed
    2 / 28 (7.14%)
    1 / 20 (5.00%)
    2 / 8 (25.00%)
    0 / 12 (0.00%)
         occurrences all number
    2
    2
    4
    0
    Headache
         subjects affected / exposed
    4 / 28 (14.29%)
    2 / 20 (10.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    4
    2
    0
    0
    Hemiparesis
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 20 (5.00%)
    0 / 8 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    2
    0
    1
    Hypoaesthesia
         subjects affected / exposed
    1 / 28 (3.57%)
    1 / 20 (5.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Memory impairment
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 20 (5.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Neuropathy peripheral
         subjects affected / exposed
    2 / 28 (7.14%)
    0 / 20 (0.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Paraesthesia
         subjects affected / exposed
    2 / 28 (7.14%)
    0 / 20 (0.00%)
    0 / 8 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    2
    0
    0
    1
    Tremor
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 20 (5.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Insomnia
         subjects affected / exposed
    2 / 28 (7.14%)
    0 / 20 (0.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    3 / 28 (10.71%)
    1 / 20 (5.00%)
    1 / 8 (12.50%)
    1 / 12 (8.33%)
         occurrences all number
    10
    1
    1
    3
    Iron deficiency anaemia
         subjects affected / exposed
    0 / 28 (0.00%)
    0 / 20 (0.00%)
    0 / 8 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    1
    Leukocytosis
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 20 (0.00%)
    0 / 8 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    1
    0
    0
    1
    Thrombocytopenia
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 20 (0.00%)
    2 / 8 (25.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    2
    0
    Eye disorders
    Cataract
         subjects affected / exposed
    0 / 28 (0.00%)
    0 / 20 (0.00%)
    1 / 8 (12.50%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Eye discharge
         subjects affected / exposed
    0 / 28 (0.00%)
    0 / 20 (0.00%)
    1 / 8 (12.50%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Periorbital oedema
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 20 (5.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Vision blurred
         subjects affected / exposed
    0 / 28 (0.00%)
    0 / 20 (0.00%)
    1 / 8 (12.50%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Visual impairment
         subjects affected / exposed
    2 / 28 (7.14%)
    0 / 20 (0.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Gastrointestinal disorders
    Abdominal discomfort
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 20 (5.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Abdominal distension
         subjects affected / exposed
    2 / 28 (7.14%)
    1 / 20 (5.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    2
    1
    0
    0
    Abdominal pain
         subjects affected / exposed
    5 / 28 (17.86%)
    2 / 20 (10.00%)
    1 / 8 (12.50%)
    4 / 12 (33.33%)
         occurrences all number
    6
    2
    2
    4
    Abdominal pain upper 
         subjects affected / exposed
    2 / 28 (7.14%)
    1 / 20 (5.00%)
    2 / 8 (25.00%)
    0 / 12 (0.00%)
         occurrences all number
    2
    1
    2
    0
    Constipation
         subjects affected / exposed
    4 / 28 (14.29%)
    1 / 20 (5.00%)
    2 / 8 (25.00%)
    3 / 12 (25.00%)
         occurrences all number
    4
    1
    2
    4
    Diarrhoea
         subjects affected / exposed
    22 / 28 (78.57%)
    18 / 20 (90.00%)
    7 / 8 (87.50%)
    10 / 12 (83.33%)
         occurrences all number
    52
    50
    34
    20
    Dry mouth
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 20 (0.00%)
    1 / 8 (12.50%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Duodenal perforation
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 20 (5.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Dyspepsia
         subjects affected / exposed
    1 / 28 (3.57%)
    1 / 20 (5.00%)
    1 / 8 (12.50%)
    0 / 12 (0.00%)
         occurrences all number
    1
    1
    1
    0
    Dysphagia
         subjects affected / exposed
    3 / 28 (10.71%)
    1 / 20 (5.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    3
    1
    0
    0
    Flatulence
         subjects affected / exposed
    5 / 28 (17.86%)
    1 / 20 (5.00%)
    0 / 8 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    6
    1
    0
    1
    Gastrooesophageal reflux disease
         subjects affected / exposed
    3 / 28 (10.71%)
    0 / 20 (0.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    3
    0
    0
    0
    Haematochezia
         subjects affected / exposed
    0 / 28 (0.00%)
    0 / 20 (0.00%)
    1 / 8 (12.50%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Nausea
         subjects affected / exposed
    15 / 28 (53.57%)
    9 / 20 (45.00%)
    6 / 8 (75.00%)
    6 / 12 (50.00%)
         occurrences all number
    17
    12
    14
    12
    Oesophagitis
         subjects affected / exposed
    0 / 28 (0.00%)
    0 / 20 (0.00%)
    0 / 8 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    1
    Rectal haemorrhage
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 20 (5.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Small intestinal obstruction
         subjects affected / exposed
    0 / 28 (0.00%)
    0 / 20 (0.00%)
    0 / 8 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    1
    Vomiting
         subjects affected / exposed
    7 / 28 (25.00%)
    8 / 20 (40.00%)
    6 / 8 (75.00%)
    6 / 12 (50.00%)
         occurrences all number
    11
    11
    17
    33
    Hepatobiliary disorders
    Bile duct obstruction
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 20 (5.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Hepatic failure
         subjects affected / exposed
    0 / 28 (0.00%)
    0 / 20 (0.00%)
    0 / 8 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    1
    Perforation bile duct
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 20 (5.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    3 / 28 (10.71%)
    0 / 20 (0.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    3
    0
    0
    0
    Decubitus ulcer
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 20 (0.00%)
    0 / 8 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    1
    0
    0
    1
    Dry skin
         subjects affected / exposed
    0 / 28 (0.00%)
    0 / 20 (0.00%)
    2 / 8 (25.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Pruritus
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 20 (0.00%)
    1 / 8 (12.50%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    1
    0
    Pruritus generalised
         subjects affected / exposed
    0 / 28 (0.00%)
    0 / 20 (0.00%)
    1 / 8 (12.50%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Rash
         subjects affected / exposed
    4 / 28 (14.29%)
    3 / 20 (15.00%)
    0 / 8 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    6
    3
    0
    1
    Rash erythematous
         subjects affected / exposed
    1 / 28 (3.57%)
    0 / 20 (0.00%)
    0 / 8 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    1
    0
    0
    1
    Rash generalised
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 20 (5.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Rash maculo-papular
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 20 (5.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Renal and urinary disorders
    Dysuria
         subjects affected / exposed
    1 / 28 (3.57%)
    1 / 20 (5.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Haematuria
         subjects affected / exposed
    1 / 28 (3.57%)
    1 / 20 (5.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Oliguria
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 20 (5.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Urinary hesitation
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 20 (5.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Urinary tract disorder
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 20 (5.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 28 (3.57%)
    1 / 20 (5.00%)
    1 / 8 (12.50%)
    0 / 12 (0.00%)
         occurrences all number
    1
    1
    1
    0
    Back pain
         subjects affected / exposed
    3 / 28 (10.71%)
    2 / 20 (10.00%)
    2 / 8 (25.00%)
    0 / 12 (0.00%)
         occurrences all number
    3
    2
    3
    0
    Bone pain
         subjects affected / exposed
    0 / 28 (0.00%)
    0 / 20 (0.00%)
    0 / 8 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    1
    Flank pain
         subjects affected / exposed
    2 / 28 (7.14%)
    2 / 20 (10.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    2
    2
    0
    0
    Joint swelling
         subjects affected / exposed
    2 / 28 (7.14%)
    0 / 20 (0.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Muscle spasms
         subjects affected / exposed
    4 / 28 (14.29%)
    5 / 20 (25.00%)
    0 / 8 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    8
    6
    0
    1
    Muscular weakness
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 20 (5.00%)
    2 / 8 (25.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    2
    0
    Musculoskeletal pain
         subjects affected / exposed
    2 / 28 (7.14%)
    0 / 20 (0.00%)
    1 / 8 (12.50%)
    0 / 12 (0.00%)
         occurrences all number
    2
    0
    1
    0
    Neck pain
         subjects affected / exposed
    0 / 28 (0.00%)
    0 / 20 (0.00%)
    0 / 8 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    1
    Pain in extremity
         subjects affected / exposed
    1 / 28 (3.57%)
    1 / 20 (5.00%)
    2 / 8 (25.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    2
    2
    0
    Pain in jaw
         subjects affected / exposed
    1 / 28 (3.57%)
    1 / 20 (5.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Infections and infestations
    Aspergillus infection
         subjects affected / exposed
    0 / 28 (0.00%)
    0 / 20 (0.00%)
    0 / 8 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    1
    Bronchitis
         subjects affected / exposed
    0 / 28 (0.00%)
    0 / 20 (0.00%)
    1 / 8 (12.50%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Clostridium difficile infection
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 20 (5.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Conjunctivitis
         subjects affected / exposed
    0 / 28 (0.00%)
    0 / 20 (0.00%)
    1 / 8 (12.50%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Diverticulitis
         subjects affected / exposed
    0 / 28 (0.00%)
    0 / 20 (0.00%)
    1 / 8 (12.50%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Influenza
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 20 (5.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 28 (0.00%)
    0 / 20 (0.00%)
    1 / 8 (12.50%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    3
    0
    Lung infection
         subjects affected / exposed
    1 / 28 (3.57%)
    1 / 20 (5.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Mucosal infection
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 20 (5.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Oral candidiasis
         subjects affected / exposed
    1 / 28 (3.57%)
    1 / 20 (5.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Pneumonia
         subjects affected / exposed
    3 / 28 (10.71%)
    1 / 20 (5.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    4
    7
    0
    0
    Respiratory tract infection
         subjects affected / exposed
    0 / 28 (0.00%)
    0 / 20 (0.00%)
    0 / 8 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    0
    1
    Sinusitis
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 20 (5.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Urinary tract infection
         subjects affected / exposed
    2 / 28 (7.14%)
    0 / 20 (0.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    3
    0
    0
    0
    Spinal column injury
         subjects affected / exposed
    0 / 28 (0.00%)
    0 / 20 (0.00%)
    1 / 8 (12.50%)
    0 / 12 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    12 / 28 (42.86%)
    6 / 20 (30.00%)
    3 / 8 (37.50%)
    4 / 12 (33.33%)
         occurrences all number
    13
    8
    7
    4
    Dehydration
         subjects affected / exposed
    6 / 28 (21.43%)
    2 / 20 (10.00%)
    0 / 8 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    8
    5
    0
    4
    Hyperglycaemia
         subjects affected / exposed
    0 / 28 (0.00%)
    2 / 20 (10.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    4
    0
    0
    Hyperkalaemia
         subjects affected / exposed
    2 / 28 (7.14%)
    0 / 20 (0.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Hypernatraemia
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 20 (5.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Hypoalbuminaemia
         subjects affected / exposed
    4 / 28 (14.29%)
    2 / 20 (10.00%)
    1 / 8 (12.50%)
    3 / 12 (25.00%)
         occurrences all number
    8
    4
    1
    3
    Hypocalcaemia
         subjects affected / exposed
    3 / 28 (10.71%)
    1 / 20 (5.00%)
    1 / 8 (12.50%)
    2 / 12 (16.67%)
         occurrences all number
    3
    3
    1
    3
    Hypochloraemia
         subjects affected / exposed
    0 / 28 (0.00%)
    1 / 20 (5.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Hypokalaemia
         subjects affected / exposed
    5 / 28 (17.86%)
    5 / 20 (25.00%)
    1 / 8 (12.50%)
    2 / 12 (16.67%)
         occurrences all number
    5
    7
    1
    2
    Hypomagnesaemia
         subjects affected / exposed
    9 / 28 (32.14%)
    4 / 20 (20.00%)
    2 / 8 (25.00%)
    2 / 12 (16.67%)
         occurrences all number
    14
    7
    2
    3
    Hyponatraemia
         subjects affected / exposed
    2 / 28 (7.14%)
    0 / 20 (0.00%)
    0 / 8 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    4
    0
    0
    1
    Hypophosphataemia
         subjects affected / exposed
    5 / 28 (17.86%)
    2 / 20 (10.00%)
    0 / 8 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    8
    3
    0
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    17 May 2016
    Updates made to the following sections: - Background information - Study population/patient eligibility - Study objective - Region or country specific requirements - Assessments - Study treatments - Concomitant Medications - Safety Reporting - Study Analysis
    23 Mar 2017
    Updates made to the following sections: - Study summary - Schedule of Assessments - Schedule for PK, Triplicate ECG, and PD Assessments - Introduction and Rationale - Clinical Data - Study Design - Inclusion Criteria - Study Treatment - Reporting of SAEs and AEs - References

    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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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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