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    Clinical Trial Results:
    Phase I/II open label, dose escalation trial to determine the MTD, safety, PK and efficacy of afatinib monotherapy in children aged ≥1 year to <18 years with recurrent/refractory neuroectodermal tumours, rhabdomyosarcoma and/or other solid tumours with known ErbB pathway deregulation regardless of tumour histology

    Summary
    EudraCT number
    2014-002123-10
    Trial protocol
    ES   DE   GB   AT   FR   DK   IT   NL   IE  
    Global end of trial date
    05 Aug 2020

    Results information
    Results version number
    v2(current)
    This version publication date
    14 Nov 2021
    First version publication date
    22 Feb 2021
    Other versions
    v1
    Version creation reason

    Trial information

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    Trial identification
    Sponsor protocol code
    1200.120
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02372006
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Boehringer Ingelheim
    Sponsor organisation address
    Binger Str. 173, Ingelheim am Rhein, Germany, 55216
    Public contact
    Boehringer Ingelheim, Call Center, Boehringer Ingelheim, 001 8002430127, clintriage.rdg@boehringer-ingelheim.com
    Scientific contact
    Boehringer Ingelheim, Call Center, Boehringer Ingelheim, 001 8002430127, clintriage.rdg@boehringer-ingelheim.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    EMEA-001596-PIP02-17
    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 Oct 2020
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    05 Aug 2020
    Global end of trial reached?
    Yes
    Global end of trial date
    05 Aug 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The objective of the Phase I dose finding part was to determine the maximum tolerated dose (MTD), safety, and pharmacokinetics of afatinib in paediatric patients across all applicable tumour entities. The objective of the MTD expansion cohorts/Phase II part was to assess anti-tumour activity, safety, and pharmacokinetics of afatinib in a larger number of patients.
    Protection of trial subjects
    Prior to the initiation of any trial-related procedure, all patients´ parents/legally accepted representatives were informed about the trial verbally and in writing by the investigator. The parents/legally accepted representatives were allowed sufficient time to consider participation in the trial and to ask questions concerning the details of the trial. Because a high rate of screening failures was expected for the MTD expansion cohorts/Phase II part, a pre-screening informed consent was allowed to be used to enable collection and testing of tumour tissue for ErbB deregulations. Upon confirmation of positivity for selection biomarkers and before proceeding with trial procedures, the informed consent/assent for trial entry had to be signed. The patient’s parents/legally accepted representatives and (where applicable) the patient were informed that they were free to withdraw their consent at any time during the trial without penalty or prejudice. They were informed that the patient’s personal trial-related data would be considered confidential and used by BI in accordance with the local data protection laws. The level of disclosure was explained to the parents/legally accepted representatives. The 397 enrolled participants in age category of "In Utero" was actually with age missing.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    22 May 2015
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Australia: 6
    Country: Number of subjects enrolled
    Austria: 12
    Country: Number of subjects enrolled
    Canada: 33
    Country: Number of subjects enrolled
    Denmark: 39
    Country: Number of subjects enrolled
    France: 102
    Country: Number of subjects enrolled
    Germany: 8
    Country: Number of subjects enrolled
    Italy: 71
    Country: Number of subjects enrolled
    Netherlands: 4
    Country: Number of subjects enrolled
    Spain: 44
    Country: Number of subjects enrolled
    United States: 51
    Country: Number of subjects enrolled
    United Kingdom: 193
    Worldwide total number of subjects
    563
    EEA total number of subjects
    280
    Number of subjects enrolled per age group
    In utero
    397
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    96
    Adolescents (12-17 years)
    68
    Adults (18-64 years)
    2
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Phase I/II open label, dose escalation trial to determine the MTD, safety, PK and efficacy of afatinib monotherapy in children aged ≥1 year to <18 years with recurrent/refractory neuroectodermal tumours, rhabdomyosarcoma and/or other solid tumours with known ErbB pathway deregulation regardless of tumour histology.

    Pre-assignment
    Screening details
    Only subjects that met all the study inclusion and none of the exclusion criteria were to be entered in the study. All subjects were free to withdraw from the clinical trial at any time for any reason given. Close monitoring of all subjects was adhered to throughout the trial conduct. Rescue medication was allowed for all patients as required.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Not blinded
    Blinding implementation details
    This study is open label

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Dose finding - level 0
    Arm description
    Afatinib, dose level 0. (Once daily at 80% of the recommended adult dose per m2 body surface area using allometric scaling): Oral solid single-unit film-coated tablets for pediatric patients who are able to swallow them. Oral liquid formulation for patients who cannot swallow the film-coated tablets, or for doses which cannot be achieved by the film-coated tablets, or for pediatric patients who did not accept the film-coated tablets. Therapy with afatinib continued as long as the individual patient benefited from the therapy, did not develop secondary malignancy, and did not meet one of the criteria requiring withdrawal from treatment. Afatinib in film-coated tablet form can be given in tablets of 20, 30, 40 and 50 milligram (mg). The tablet dose is related to the free base equivalent to afatinib. The dose of afatinib as capsule and solvent for oral solution is given as a 200 mg capsule to be dissolved in aqueous solvent (2 capsules per 100 milliliter (ml) solvent) i.e. 4 mg per ml.
    Arm type
    Experimental

    Investigational medicinal product name
    Afatinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet, Capsule, Powder and solvent for oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    Once daily at 80% of the recommended adult dose per m2 body surface area [BSA] using allometric scaling: Oral solid single-unit film-coated tablets for pediatric patients who are able to swallow them. Oral liquid formulation for patients who cannot swallow the film-coated tablets, or for doses which cannot be achieved by the film-coated tablets, or for pediatric patients who did not accept the film-coated tablets. Therapy continued as long as the individual patient benefited from the therapy, did not develop secondary malignancy, and did not meet one of the criteria requiring withdrawal from treatment. Afatinib in film-coated tablet from can be given in tablets of 20, 30, 40 and 50 mg. The dose in film-coated tablets is related to the free base equivalent to afatinib. The dose of afatinib as capsule and solvent for oral solution is given as a 200 mg capsule to be dissolved in aqueous solvent (2 capsules per 100 milliliter solvent) i.e. 4 milligram per milliliter.

    Arm title
    Dose finding - level 1
    Arm description
    Afatinib, dose level 1. (Once daily at 100% of the recommended adult dose per m2 body surface area using allometric scaling): Oral solid single-unit film-coated tablets for pediatric patients who are able to swallow them. Oral liquid formulation for patients who cannot swallow the film-coated tablets, or for doses which cannot be achieved by the film-coated tablets, or for pediatric patients who did not accept the film-coated tablets. Therapy with afatinib continued as long as the individual patient benefited from the therapy, did not develop secondary malignancy, and did not meet one of the criteria requiring withdrawal from treatment. Afatinib in film-coated tablet form can be given in tablets of 20, 30, 40 and 50 milligram (mg). The tablet dose is related to the free base equivalent to afatinib. The dose of afatinib as capsule and solvent for oral solution is given as a 200 mg capsule to be dissolved in aqueous solvent (2 capsules per 100 milliliter (ml) solvent) i.e. 4 mg per ml.
    Arm type
    Experimental

    Investigational medicinal product name
    Afatinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet, Capsule, Powder and solvent for oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    Once daily at 100% of the recommended adult dose per m2 body surface area [BSA] using allometric scaling: Oral solid single-unit film-coated tablets for pediatric patients who are able to swallow them. Oral liquid formulation for patients who cannot swallow the film-coated tablets, or for doses which cannot be achieved by the film-coated tablets, or for pediatric patients who did not accept the film-coated tablets. Therapy continued as long as the individual patient benefited from the therapy, did not develop secondary malignancy, and did not meet one of the criteria requiring withdrawal from treatment. Afatinib in film-coated tablet from can be given in tablets of 20, 30, 40 and 50 mg. The dose in film-coated tablets is related to the free base equivalent to afatinib. The dose of afatinib as capsule and solvent for oral solution is given as a 200 mg capsule to be dissolved in aqueous solvent (2 capsules per 100 milliliter solvent) i.e. 4 milligram per milliliter.

    Arm title
    Maximum tolerated dose (MTD) expansion cohort - level 0
    Arm description
    Afatinib, dose level 0. (Once daily at 80% of the recommended adult dose per m2 body surface area using allometric scaling): Oral solid single-unit film-coated tablets for pediatric patients who are able to swallow them. Oral liquid formulation for patients who cannot swallow the film-coated tablets, or for doses which cannot be achieved by the film-coated tablets, or for pediatric patients who did not accept the film-coated tablets. Therapy with afatinib continued as long as the individual patient benefited from the therapy, did not develop secondary malignancy, and did not meet one of the criteria requiring withdrawal from treatment. Afatinib in film-coated tablet form can be given in tablets of 20, 30, 40 and 50 milligram (mg). The tablet dose is related to the free base equivalent to afatinib. The dose of afatinib as capsule and solvent for oral solution is given as a 200 mg capsule to be dissolved in aqueous solvent (2 capsules per 100 milliliter (ml) solvent) i.e. 4 mg per ml.
    Arm type
    Experimental

    Investigational medicinal product name
    Afatinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet, Capsule, Powder and solvent for oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    Once daily at 80% of the recommended adult dose per m2 body surface area [BSA] using allometric scaling: Oral solid single-unit film-coated tablets for pediatric patients who are able to swallow them. Oral liquid formulation for patients who cannot swallow the film-coated tablets, or for doses which cannot be achieved by the film-coated tablets, or for pediatric patients who did not accept the film-coated tablets. Therapy continued as long as the individual patient benefited from the therapy, did not develop secondary malignancy, and did not meet one of the criteria requiring withdrawal from treatment. Afatinib in film-coated tablet from can be given in tablets of 20, 30, 40 and 50 mg. The dose in film-coated tablets is related to the free base equivalent to afatinib. The dose of afatinib as capsule and solvent for oral solution is given as a 200 mg capsule to be dissolved in aqueous solvent (2 capsules per 100 milliliter solvent) i.e. 4 milligram per milliliter.

    Number of subjects in period 1 [1]
    Dose finding - level 0 Dose finding - level 1 Maximum tolerated dose (MTD) expansion cohort - level 0
    Started
    8
    9
    39
    Completed
    0
    0
    0
    Not completed
    8
    9
    39
         Progressive disease
    8
    7
    34
         Other reason for not completing
    -
    -
    1
         Adverse event, non-fatal
    -
    -
    3
         Consent withdrawn by subject
    -
    1
    1
         Drug limiting toxicity
    -
    1
    -
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: Baseline characteristics are based on patients who were randomised after successfully completing the screening period and received at least one dose of the trial medication.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Dose finding - level 0
    Reporting group description
    Afatinib, dose level 0. (Once daily at 80% of the recommended adult dose per m2 body surface area using allometric scaling): Oral solid single-unit film-coated tablets for pediatric patients who are able to swallow them. Oral liquid formulation for patients who cannot swallow the film-coated tablets, or for doses which cannot be achieved by the film-coated tablets, or for pediatric patients who did not accept the film-coated tablets. Therapy with afatinib continued as long as the individual patient benefited from the therapy, did not develop secondary malignancy, and did not meet one of the criteria requiring withdrawal from treatment. Afatinib in film-coated tablet form can be given in tablets of 20, 30, 40 and 50 milligram (mg). The tablet dose is related to the free base equivalent to afatinib. The dose of afatinib as capsule and solvent for oral solution is given as a 200 mg capsule to be dissolved in aqueous solvent (2 capsules per 100 milliliter (ml) solvent) i.e. 4 mg per ml.

    Reporting group title
    Dose finding - level 1
    Reporting group description
    Afatinib, dose level 1. (Once daily at 100% of the recommended adult dose per m2 body surface area using allometric scaling): Oral solid single-unit film-coated tablets for pediatric patients who are able to swallow them. Oral liquid formulation for patients who cannot swallow the film-coated tablets, or for doses which cannot be achieved by the film-coated tablets, or for pediatric patients who did not accept the film-coated tablets. Therapy with afatinib continued as long as the individual patient benefited from the therapy, did not develop secondary malignancy, and did not meet one of the criteria requiring withdrawal from treatment. Afatinib in film-coated tablet form can be given in tablets of 20, 30, 40 and 50 milligram (mg). The tablet dose is related to the free base equivalent to afatinib. The dose of afatinib as capsule and solvent for oral solution is given as a 200 mg capsule to be dissolved in aqueous solvent (2 capsules per 100 milliliter (ml) solvent) i.e. 4 mg per ml.

    Reporting group title
    Maximum tolerated dose (MTD) expansion cohort - level 0
    Reporting group description
    Afatinib, dose level 0. (Once daily at 80% of the recommended adult dose per m2 body surface area using allometric scaling): Oral solid single-unit film-coated tablets for pediatric patients who are able to swallow them. Oral liquid formulation for patients who cannot swallow the film-coated tablets, or for doses which cannot be achieved by the film-coated tablets, or for pediatric patients who did not accept the film-coated tablets. Therapy with afatinib continued as long as the individual patient benefited from the therapy, did not develop secondary malignancy, and did not meet one of the criteria requiring withdrawal from treatment. Afatinib in film-coated tablet form can be given in tablets of 20, 30, 40 and 50 milligram (mg). The tablet dose is related to the free base equivalent to afatinib. The dose of afatinib as capsule and solvent for oral solution is given as a 200 mg capsule to be dissolved in aqueous solvent (2 capsules per 100 milliliter (ml) solvent) i.e. 4 mg per ml.

    Reporting group values
    Dose finding - level 0 Dose finding - level 1 Maximum tolerated dose (MTD) expansion cohort - level 0 Total
    Number of subjects
    8 9 39 56
    Age categorical
    Treated set (TS) This patient set included all patients enrolled in the trial who were documented to have taken at least one dose of study medication.
    Units: Years
        In utero
    0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0 0 0
        Newborns (0-27 days)
    0 0 0 0
        Infants and toddlers (28 days-23 months)
    0 0 0 0
        Children (2-11 years)
    4 4 20 28
        Adolescents (12-17 years)
    4 5 18 27
        Adults (18-64 years)
    0 0 1 1
        From 65-84 years
    0 0 0 0
        85 years and over
    0 0 0 0
    Age Continuous
    Treated set (TS) This patient set included all patients enrolled in the trial who were documented to have taken at least one dose of study medication.
    Units: years
        arithmetic mean (standard deviation)
    9.75 ± 4.83 10.44 ± 5.29 10.92 ± 4.44 -
    Sex: Female, Male
    Treated set (TS) This patient set included all patients enrolled in the trial who were documented to have taken at least one dose of study medication.
    Units: Participants
        Female
    4 4 16 24
        Male
    4 5 23 32
    Ethnicity (NIH/OMB)
    Treated set (TS) This patient set included all patients enrolled in the trial who were documented to have taken at least one dose of study medication.
    Units: Subjects
        Hispanic or Latino
    0 0 0 0
        Not Hispanic or Latino
    4 5 37 46
        Unknown or Not Reported
    4 4 2 10
    Race (NIH/OMB)
    Treated set (TS) This patient set included all patients enrolled in the trial who were documented to have taken at least one dose of study medication.
    Units: Subjects
        American Indian or Alaska Native
    0 0 0 0
        Asian
    0 0 1 1
        Native Hawaiian or Other Pacific Islander
    0 0 0 0
        Black or African American
    0 0 2 2
        White
    3 4 29 36
        More than one race
    1 0 0 1
        Unknown or Not Reported
    4 5 7 16

    End points

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    End points reporting groups
    Reporting group title
    Dose finding - level 0
    Reporting group description
    Afatinib, dose level 0. (Once daily at 80% of the recommended adult dose per m2 body surface area using allometric scaling): Oral solid single-unit film-coated tablets for pediatric patients who are able to swallow them. Oral liquid formulation for patients who cannot swallow the film-coated tablets, or for doses which cannot be achieved by the film-coated tablets, or for pediatric patients who did not accept the film-coated tablets. Therapy with afatinib continued as long as the individual patient benefited from the therapy, did not develop secondary malignancy, and did not meet one of the criteria requiring withdrawal from treatment. Afatinib in film-coated tablet form can be given in tablets of 20, 30, 40 and 50 milligram (mg). The tablet dose is related to the free base equivalent to afatinib. The dose of afatinib as capsule and solvent for oral solution is given as a 200 mg capsule to be dissolved in aqueous solvent (2 capsules per 100 milliliter (ml) solvent) i.e. 4 mg per ml.

    Reporting group title
    Dose finding - level 1
    Reporting group description
    Afatinib, dose level 1. (Once daily at 100% of the recommended adult dose per m2 body surface area using allometric scaling): Oral solid single-unit film-coated tablets for pediatric patients who are able to swallow them. Oral liquid formulation for patients who cannot swallow the film-coated tablets, or for doses which cannot be achieved by the film-coated tablets, or for pediatric patients who did not accept the film-coated tablets. Therapy with afatinib continued as long as the individual patient benefited from the therapy, did not develop secondary malignancy, and did not meet one of the criteria requiring withdrawal from treatment. Afatinib in film-coated tablet form can be given in tablets of 20, 30, 40 and 50 milligram (mg). The tablet dose is related to the free base equivalent to afatinib. The dose of afatinib as capsule and solvent for oral solution is given as a 200 mg capsule to be dissolved in aqueous solvent (2 capsules per 100 milliliter (ml) solvent) i.e. 4 mg per ml.

    Reporting group title
    Maximum tolerated dose (MTD) expansion cohort - level 0
    Reporting group description
    Afatinib, dose level 0. (Once daily at 80% of the recommended adult dose per m2 body surface area using allometric scaling): Oral solid single-unit film-coated tablets for pediatric patients who are able to swallow them. Oral liquid formulation for patients who cannot swallow the film-coated tablets, or for doses which cannot be achieved by the film-coated tablets, or for pediatric patients who did not accept the film-coated tablets. Therapy with afatinib continued as long as the individual patient benefited from the therapy, did not develop secondary malignancy, and did not meet one of the criteria requiring withdrawal from treatment. Afatinib in film-coated tablet form can be given in tablets of 20, 30, 40 and 50 milligram (mg). The tablet dose is related to the free base equivalent to afatinib. The dose of afatinib as capsule and solvent for oral solution is given as a 200 mg capsule to be dissolved in aqueous solvent (2 capsules per 100 milliliter (ml) solvent) i.e. 4 mg per ml.

    Primary: Area under the curve over dosing interval τ at steady state (AUCτ, ss) - Dose finding part

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    End point title
    Area under the curve over dosing interval τ at steady state (AUCτ, ss) - Dose finding part [1] [2]
    End point description
    Area under the curve over dosing interval τ at steady state (AUCτ,ss) was reported. Pharmacokinetics (PK) analysis set (PKS): This patient set included all patients in the TS who provided at least one PK endpoint that was not excluded due to a protocol deviation relevant to the evaluation of PK or due to PK non-evaluability.
    End point type
    Primary
    End point timeframe
    Pre-dose before afatinib administration then 1 hour (h), 2 h, 3 h, 4 h, 5 h, 6 h, 8 h and 24 h after administration at steady state on Day 8.
    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: This endpoint was evaluated only descriptively. Thus, no statistical hypothesis were tested.
    [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: Only those arms for which the comparisons are presented in the clinical trial report thus, those that would yield meaningful results were reported.
    End point values
    Dose finding - level 0 Dose finding - level 1
    Number of subjects analysed
    7
    6
    Units: hours times nanogram per milliliter
        geometric mean (geometric coefficient of variation)
    681 ± 43.8
    1380 ± 29.0
    No statistical analyses for this end point

    Primary: Maximum measured concentration of the analyte in plasma at steady state (Cmax,ss) - Dose finding part

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    End point title
    Maximum measured concentration of the analyte in plasma at steady state (Cmax,ss) - Dose finding part [3] [4]
    End point description
    Maximum measured concentration of the analyte in plasma at steady state (Cmax,ss) - Dose finding part was reported. Pharmacokinetics (PK) analysis set (PKS): This patient set included all patients in the TS who provided at least one PK endpoint that was not excluded due to a protocol deviation relevant to the evaluation of PK or due to PK non-evaluability. Only participants with non-missing results were included in the analysis.
    End point type
    Primary
    End point timeframe
    Pre-dose before afatinib administration then 1 hour (h), 2 h, 3 h, 4 h, 5 h, 6 h, 8 h and 24 h after administration at steady state on Day 8.
    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: This endpoint was evaluated only descriptively. Thus, no statistical hypothesis were tested.
    [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: Only those arms for which the comparisons are presented in the clinical trial report thus, those that would yield meaningful results were reported.
    End point values
    Dose finding - level 0 Dose finding - level 1
    Number of subjects analysed
    7
    6
    Units: nanogram per mililiter
        geometric mean (geometric coefficient of variation)
    53.0 ± 48.8
    115 ± 39.3
    No statistical analyses for this end point

    Primary: Number of participants with objective response - maximum tolerated dose (MTD) expansion cohort

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    End point title
    Number of participants with objective response - maximum tolerated dose (MTD) expansion cohort [5] [6]
    End point description
    Number of participants with objective response in maximum tolerated dose (MTD) expansion cohort was reported. The objective response was defined as a best overall response of complete response or partial response based on investigator’s assessment according to the institutional response evaluation criteria for the given tumour type, assessed every 8 weeks until progression. Treated set (TS): This patient set included all patients enrolled in the trial who were documented to have taken at least one dose of study medication.
    End point type
    Primary
    End point timeframe
    Assessed every 8 weeks until progression of disease, up to 336 days.
    Notes
    [5] - 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: This endpoint was evaluated only descriptively. Thus, no statistical hypothesis were tested.
    [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: Only those arms for which the comparisons are presented in the clinical trial report thus, those that would yield meaningful results were reported.
    End point values
    Maximum tolerated dose (MTD) expansion cohort - level 0
    Number of subjects analysed
    39
    Units: Participants
    3
    No statistical analyses for this end point

    Primary: Number of participants with Dose Limiting Toxicity adverse events - Dose finding part

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    End point title
    Number of participants with Dose Limiting Toxicity adverse events - Dose finding part [7] [8]
    End point description
    Number of participants with Dose Limiting Toxicity adverse events in Dose finding part was reported. Treated set (TS) This patient set included all patients enrolled in the trial who were documented to have taken at least one dose of study medication.
    End point type
    Primary
    End point timeframe
    During the first course (28 days) of treatment.
    Notes
    [7] - 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: This endpoint was evaluated only descriptively. Thus, no statistical hypothesis were tested.
    [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: Only those arms for which the comparisons are presented in the clinical trial report thus, those that would yield meaningful results were reported.
    End point values
    Dose finding - level 0 Dose finding - level 1
    Number of subjects analysed
    8
    9
    Units: Participants
    1
    2
    No statistical analyses for this end point

    Secondary: Number of participants with objective response - Dose finding part

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    End point title
    Number of participants with objective response - Dose finding part [9]
    End point description
    Number of participants with objective response in Dose finding part was reported. The objective response was defined as a best overall response of complete response or partial response based on investigator’s assessment according to the institutional response evaluation criteria for the given tumour type, assessed every 8 weeks until progression. Treated set (TS): This patient set included all patients enrolled in the trial who were documented to have taken at least one dose of study medication.
    End point type
    Secondary
    End point timeframe
    Assessed every 8 weeks until progression of disease, up to 336 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: Only those arms for which the comparisons are presented in the clinical trial report thus, those that would yield meaningful results were reported.
    End point values
    Dose finding - level 0 Dose finding - level 1
    Number of subjects analysed
    8
    9
    Units: Participants
    0
    0
    No statistical analyses for this end point

    Secondary: Area under the concentration-time curve of the analyte in plasma over the time interval from 0 to 24 hours (AUC0-24) - Dose finding part

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    End point title
    Area under the concentration-time curve of the analyte in plasma over the time interval from 0 to 24 hours (AUC0-24) - Dose finding part [10]
    End point description
    Area under the concentration-time curve of the analyte in plasma over the time interval from 0 to 24 hours (AUC0-24) for Dose finding part was reported. Pharmacokinetics (PK) analysis set (PKS): This patient set included all patients in the TS who provided at least one PK endpoint that was not excluded due to a protocol deviation relevant to the evaluation of PK or due to PK non-evaluability. Only participants with non-missing results were included in the analysis.
    End point type
    Secondary
    End point timeframe
    Pre-dose before afatinib administration then 1 hour (h), 2 h, 3 h, 4 h, 5 h, 6 h, 8 h and 24 h after administration on Day 1.
    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: Only those arms for which the comparisons are presented in the clinical trial report thus, those that would yield meaningful results were reported.
    End point values
    Dose finding - level 0 Dose finding - level 1
    Number of subjects analysed
    8
    8
    Units: hours times nanogram per mililiter
        geometric mean (geometric coefficient of variation)
    383 ± 46.4
    512 ± 40.6
    No statistical analyses for this end point

    Secondary: Maximum measured concentration (Cmax) - Dose finding part/maximum tolerated dose (MTD) expansion cohort

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    End point title
    Maximum measured concentration (Cmax) - Dose finding part/maximum tolerated dose (MTD) expansion cohort
    End point description
    Maximum measured concentration (Cmax) for Dose finding part/maximum tolerated dose expansion cohort was reported. Pharmacokinetics (PK) analysis set (PKS): This patient set included all patients in the TS who provided at least one PK endpoint that was not excluded due to a protocol deviation relevant to the evaluation of PK or due to PK non-evaluability. Only participants with non-missing results were included in the analysis.
    End point type
    Secondary
    End point timeframe
    Pre-dose before afatinib administration then 1 hour (h), 2 h, 3 h, 4 h, 5 h, 6 h, 8 h and 24 h after administration on Day 1.
    End point values
    Dose finding - level 0 Dose finding - level 1 Maximum tolerated dose (MTD) expansion cohort - level 0
    Number of subjects analysed
    8
    8
    36
    Units: nanogram per mililiter
        geometric mean (geometric coefficient of variation)
    36.4 ± 55.9
    43.8 ± 61.2
    30.5 ± 90.3
    No statistical analyses for this end point

    Secondary: Time from (last) dosing to the maximum measured concentration (tmax) - Dose finding part/maximum tolerated dose (MTD) expansion cohort

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    End point title
    Time from (last) dosing to the maximum measured concentration (tmax) - Dose finding part/maximum tolerated dose (MTD) expansion cohort
    End point description
    Times from (last) dosing to the maximum measured concentration (tmax) for Dose finding oart/maximum tolerated dose (MTD) expansion cohort was reported. Pharmacokinetics (PK) analysis set (PKS): This patient set included all patients in the TS who provided at least one PK endpoint that was not excluded due to a protocol deviation relevant to the evaluation of PK or due to PK non-evaluability. Only participants with non-missing results were included in the analysis.
    End point type
    Secondary
    End point timeframe
    Pre-dose before afatinib administration then 1 hour (h), 2 h, 3 h, 4 h, 5 h, 6 h, 8 h and 24 h after administration on Day 1.
    End point values
    Dose finding - level 0 Dose finding - level 1 Maximum tolerated dose (MTD) expansion cohort - level 0
    Number of subjects analysed
    8
    8
    36
    Units: Hours
        median (full range (min-max))
    3.02 (2.00 to 6.00)
    3.43 (2.00 to 6.02)
    3.98 (1.00 to 8.00)
    No statistical analyses for this end point

    Secondary: Time from (last) dosing to the maximum measured concentration at steady state (tmax,ss) - Dose finding part/maximum tolerated dose (MTD) expansion cohort

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    End point title
    Time from (last) dosing to the maximum measured concentration at steady state (tmax,ss) - Dose finding part/maximum tolerated dose (MTD) expansion cohort
    End point description
    Time from (last) dosing to the maximum measured concentration at steady state (tmax,ss) for Dose finding part/maximum tolerated dose (MTD) expansion cohort was reported. Pharmacokinetics (PK) analysis set (PKS): This patient set included all patients in the TS who provided at least one PK endpoint that was not excluded due to a protocol deviation relevant to the evaluation of PK or due to PK non-evaluability. Only participants with non-missing results were included in the analysis.
    End point type
    Secondary
    End point timeframe
    Pre-dose before afatinib administration then 1 hour (h), 2 h, 3 h, 4 h, 5 h, 6 h, 8 h and 24 h after administration at steady state on Day 8.
    End point values
    Dose finding - level 0 Dose finding - level 1 Maximum tolerated dose (MTD) expansion cohort - level 0
    Number of subjects analysed
    7
    6
    25
    Units: Hours
        median (full range (min-max))
    3.00 (2.00 to 6.00)
    2.75 (2.00 to 5.05)
    4.17 (2.00 to 8.00)
    No statistical analyses for this end point

    Secondary: Progression free survival - maximum tolerated dose (MTD) expansion cohort

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    End point title
    Progression free survival - maximum tolerated dose (MTD) expansion cohort [11]
    End point description
    Progression free survival for maximum tolerated dose (MTD) expansion cohort was reported. Progression free survival (PFS) was defined as the duration from the date of first treatment until the date of the first documented progression or death due to any cause. If a patient did not have an event, PFS was censored at the date of last adequate tumour assessment. Median PFS was estimated by Kaplan-Meier. Treated set (TS) This patient set included all patients enrolled in the trial who were documented to have taken at least one dose of study medication.
    End point type
    Secondary
    End point timeframe
    From the first treatment until date of first progression or death, up to 336 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: Only those arms for which the comparisons are presented in the clinical trial report thus, those that would yield meaningful results were reported.
    End point values
    Maximum tolerated dose (MTD) expansion cohort - level 0
    Number of subjects analysed
    39
    Units: Months
        median (confidence interval 95%)
    8.0 (6.4 to 8.29)
    No statistical analyses for this end point

    Secondary: Accumulation (or effective) half-life - Dose finding part/maximum tolerated dose (MTD) expansion cohort

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    End point title
    Accumulation (or effective) half-life - Dose finding part/maximum tolerated dose (MTD) expansion cohort
    End point description
    Accumulation (or effective) half-life for Dose finding part/maximum tolerated dose (MTD) expansion cohort was reported. Pharmacokinetics (PK) analysis set (PKS): This patient set included all patients in the TS who provided at least one PK endpoint that was not excluded due to a protocol deviation relevant to the evaluation of PK or due to PK non-evaluability. Only participants with non-missing results were included in the analysis.
    End point type
    Secondary
    End point timeframe
    Pre-dose before afatinib administration then 1 hour (h), 2 h, 3 h, 4 h, 5 h, 6 h, 8 h and 24 h after administration at steady state on Day 8.
    End point values
    Dose finding - level 0 Dose finding - level 1 Maximum tolerated dose (MTD) expansion cohort - level 0
    Number of subjects analysed
    7
    6
    24
    Units: hours
        geometric mean (geometric coefficient of variation)
    18.7 ± 44.3
    31.0 ± 56.7
    30.3 ± 83.6
    No statistical analyses for this end point

    Secondary: Duration of objective response - maximum tolerated dose (MTD) expansion cohort

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    End point title
    Duration of objective response - maximum tolerated dose (MTD) expansion cohort [12]
    End point description
    Duration of objective response for maximum tolerated dose (MTD) expansion cohort was reported. Treated set (TS) This patient set included all patients enrolled in the trial who were documented to have taken at least one dose of study medication.
    End point type
    Secondary
    End point timeframe
    From first documented response until the earliest of disease progression or death, up to 336 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: Only those arms for which the comparisons are presented in the clinical trial report thus, those that would yield meaningful results were reported.
    End point values
    Maximum tolerated dose (MTD) expansion cohort - level 0
    Number of subjects analysed
    39
    Units: Days
        median (full range (min-max))
    62 (57 to 170)
    No statistical analyses for this end point

    Secondary: Area under the curve over dosing interval τ at steady state (AUCτ, ss) - maximum tolerated dose (MTD) expansion cohort

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    End point title
    Area under the curve over dosing interval τ at steady state (AUCτ, ss) - maximum tolerated dose (MTD) expansion cohort [13]
    End point description
    Area under the curve over dosing interval τ at steady state (AUCτ, ss) for maximum tolerated dose (MTD) expansion cohort was reported. Pharmacokinetics (PK) analysis set (PKS): This patient set included all patients in the TS who provided at least one PK endpoint that was not excluded due to a protocol deviation relevant to the evaluation of PK or due to PK non-evaluability. Only participants with non-missing results were included in the analysis.
    End point type
    Secondary
    End point timeframe
    Pre-dose before afatinib administration then 1 hour (h), 2 h, 3 h, 4 h, 5 h, 6 h, 8 h and 24 h after administration at steady state on Day 8.
    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: Only those arms for which the comparisons are presented in the clinical trial report thus, those that would yield meaningful results were reported.
    End point values
    Maximum tolerated dose (MTD) expansion cohort - level 0
    Number of subjects analysed
    25
    Units: hours times nanogram per milliliter
        geometric mean (geometric coefficient of variation)
    780 ± 60.7
    No statistical analyses for this end point

    Secondary: Maximum measured concentration of the analyte in plasma at steady state (Cmax,ss) - maximum tolerated dose (MTD) expansion cohort

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    End point title
    Maximum measured concentration of the analyte in plasma at steady state (Cmax,ss) - maximum tolerated dose (MTD) expansion cohort [14]
    End point description
    Maximum measured concentration of the analyte in plasma at steady state (Cmax,ss) for maximum tolerated dose (MTD) expansion cohort was reported. Pharmacokinetics (PK) analysis set (PKS): This patient set included all patients in the TS who provided at least one PK endpoint that was not excluded due to a protocol deviation relevant to the evaluation of PK or due to PK non-evaluability. Only participants with non-missing results were included in the analysis.
    End point type
    Secondary
    End point timeframe
    Pre-dose before afatinib administration then 1 hour (h), 2 h, 3 h, 4 h, 5 h, 6 h, 8 h and 24 h after administration at steady state on Day 8.
    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: Only those arms for which the comparisons are presented in the clinical trial report thus, those that would yield meaningful results were reported.
    End point values
    Maximum tolerated dose (MTD) expansion cohort - level 0
    Number of subjects analysed
    25
    Units: nanogram per mililiter
        geometric mean (geometric coefficient of variation)
    52.5 ± 61.0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From the first drug administration until end of study period, up to 336 days.
    Adverse event reporting additional description
    Treated set (TS) This patient set included all patients enrolled in the trial who were documented to have taken at least one dose of study medication.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    23.0
    Reporting groups
    Reporting group title
    Dose finding Level 0
    Reporting group description
    Afatinib, dose level 0. (Once daily at 80% of the recommended adult dose per m2 body surface area using allometric scaling): Oral solid single-unit film-coated tablets for pediatric patients who are able to swallow them. Oral liquid formulation for patients who cannot swallow the film-coated tablets, or for doses which cannot be achieved by the film-coated tablets, or for pediatric patients who did not accept the film-coated tablets. Therapy with afatinib continued as long as the individual patient benefited from the therapy, did not develop secondary malignancy, and did not meet one of the criteria requiring withdrawal from treatment. Afatinib in film-coated tablet form can be given in tablets of 20, 30, 40 and 50 milligram (mg). The tablet dose is related to the free base equivalent to afatinib. The dose of afatinib as capsule and solvent for oral solution is given as a 200 mg capsule to be dissolved in aqueous solvent (2 capsules per 100 milliliter (ml) solvent) i.e. 4 mg per ml.

    Reporting group title
    Maximum tolerated dose (MTD) expansion - Level 0
    Reporting group description
    Afatinib, dose level 0. (Once daily at 80% of the recommended adult dose per m2 body surface area using allometric scaling): Oral solid single-unit film-coated tablets for pediatric patients who are able to swallow them. Oral liquid formulation for patients who cannot swallow the film-coated tablets, or for doses which cannot be achieved by the film-coated tablets, or for pediatric patients who did not accept the film-coated tablets. Therapy with afatinib continued as long as the individual patient benefited from the therapy, did not develop secondary malignancy, and did not meet one of the criteria requiring withdrawal from treatment. Afatinib in film-coated tablet form can be given in tablets of 20, 30, 40 and 50 milligram (mg). The tablet dose is related to the free base equivalent to afatinib. The dose of afatinib as capsule and solvent for oral solution is given as a 200 mg capsule to be dissolved in aqueous solvent (2 capsules per 100 milliliter (ml) solvent) i.e. 4 mg per ml.

    Reporting group title
    Dose finding Level 1
    Reporting group description
    Afatinib, dose level 1. (Once daily at 100% of the recommended adult dose per m2 body surface area using allometric scaling): Oral solid single-unit film-coated tablets for pediatric patients who are able to swallow them. Oral liquid formulation for patients who cannot swallow the film-coated tablets, or for doses which cannot be achieved by the film-coated tablets, or for pediatric patients who did not accept the film-coated tablets. Therapy with afatinib continued as long as the individual patient benefited from the therapy, did not develop secondary malignancy, and did not meet one of the criteria requiring withdrawal from treatment. Afatinib in film-coated tablet form can be given in tablets of 20, 30, 40 and 50 milligram (mg). The tablet dose is related to the free base equivalent to afatinib. The dose of afatinib as capsule and solvent for oral solution is given as a 200 mg capsule to be dissolved in aqueous solvent (2 capsules per 100 milliliter (ml) solvent) i.e. 4 mg per ml.

    Serious adverse events
    Dose finding Level 0 Maximum tolerated dose (MTD) expansion - Level 0 Dose finding Level 1
    Total subjects affected by serious adverse events
         subjects affected / exposed
    7 / 8 (87.50%)
    20 / 39 (51.28%)
    6 / 9 (66.67%)
         number of deaths (all causes)
    8
    29
    9
         number of deaths resulting from adverse events
    0
    3
    0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 39 (2.56%)
    1 / 9 (11.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    0 / 8 (0.00%)
    2 / 39 (5.13%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Oropharyngeal pain
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 39 (0.00%)
    1 / 9 (11.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 39 (2.56%)
    0 / 9 (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 arrest
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 39 (2.56%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Respiratory distress
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 39 (2.56%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Blood and lymphatic system disorders
    Lymphopenia
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 39 (2.56%)
    0 / 9 (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
    Altered state of consciousness
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 39 (2.56%)
    0 / 9 (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
    Aphasia
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 39 (2.56%)
    0 / 9 (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
    Encephalopathy
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 39 (2.56%)
    0 / 9 (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
    Generalised tonic-clonic seizure
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 39 (2.56%)
    0 / 9 (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
    Haemorrhage intracranial
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 39 (2.56%)
    0 / 9 (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
    Headache
         subjects affected / exposed
    3 / 8 (37.50%)
    0 / 39 (0.00%)
    1 / 9 (11.11%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hemiparesis
         subjects affected / exposed
    1 / 8 (12.50%)
    1 / 39 (2.56%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hydrocephalus
         subjects affected / exposed
    0 / 8 (0.00%)
    2 / 39 (5.13%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Intracranial pressure increased
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 39 (2.56%)
    0 / 9 (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
    Somnolence
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 39 (0.00%)
    0 / 9 (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
    Status epilepticus
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 39 (0.00%)
    1 / 9 (11.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Blindness
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 39 (0.00%)
    0 / 9 (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
    General disorders and administration site conditions
    General physical health deterioration
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 39 (0.00%)
    0 / 9 (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
    Pyrexia
         subjects affected / exposed
    1 / 8 (12.50%)
    2 / 39 (5.13%)
    1 / 9 (11.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 39 (2.56%)
    0 / 9 (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 / 8 (12.50%)
    0 / 39 (0.00%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ascites
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 39 (2.56%)
    0 / 9 (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
    Diarrhoea
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 39 (0.00%)
    3 / 9 (33.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Stomatitis
         subjects affected / exposed
    0 / 8 (0.00%)
    2 / 39 (5.13%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    3 / 8 (37.50%)
    2 / 39 (5.13%)
    2 / 9 (22.22%)
         occurrences causally related to treatment / all
    1 / 4
    1 / 2
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Urinary tract disorder
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 39 (2.56%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Dermatitis acneiform
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 39 (2.56%)
    0 / 9 (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
    Skin ulcer
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 39 (2.56%)
    0 / 9 (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
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 39 (0.00%)
    2 / 9 (22.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 39 (0.00%)
    1 / 9 (11.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypernatraemia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 39 (0.00%)
    1 / 9 (11.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 39 (2.56%)
    0 / 9 (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
    Hypokalaemia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 39 (0.00%)
    1 / 9 (11.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 39 (2.56%)
    0 / 9 (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
    Infections and infestations
    Gastroenteritis viral
         subjects affected / exposed
    1 / 8 (12.50%)
    1 / 39 (2.56%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Paronychia
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 39 (2.56%)
    0 / 9 (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
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 39 (2.56%)
    0 / 9 (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
    Viral infection
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 39 (2.56%)
    0 / 9 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Dose finding Level 0 Maximum tolerated dose (MTD) expansion - Level 0 Dose finding Level 1
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    8 / 8 (100.00%)
    38 / 39 (97.44%)
    9 / 9 (100.00%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    0 / 8 (0.00%)
    3 / 39 (7.69%)
    0 / 9 (0.00%)
         occurrences all number
    0
    3
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Tumour pain
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 39 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    1 / 8 (12.50%)
    2 / 39 (5.13%)
    0 / 9 (0.00%)
         occurrences all number
    1
    2
    0
    Disease progression
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 39 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    0
    Mucosal inflammation
         subjects affected / exposed
    0 / 8 (0.00%)
    7 / 39 (17.95%)
    1 / 9 (11.11%)
         occurrences all number
    0
    7
    1
    Fatigue
         subjects affected / exposed
    4 / 8 (50.00%)
    10 / 39 (25.64%)
    1 / 9 (11.11%)
         occurrences all number
    4
    11
    1
    Pyrexia
         subjects affected / exposed
    1 / 8 (12.50%)
    5 / 39 (12.82%)
    2 / 9 (22.22%)
         occurrences all number
    1
    5
    2
    Pain
         subjects affected / exposed
    1 / 8 (12.50%)
    1 / 39 (2.56%)
    0 / 9 (0.00%)
         occurrences all number
    1
    1
    0
    Xerosis
         subjects affected / exposed
    0 / 8 (0.00%)
    2 / 39 (5.13%)
    1 / 9 (11.11%)
         occurrences all number
    0
    2
    1
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 39 (2.56%)
    1 / 9 (11.11%)
         occurrences all number
    0
    1
    1
    Insomnia
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 39 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    0
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 39 (2.56%)
    1 / 9 (11.11%)
         occurrences all number
    0
    1
    1
    Upper limb fracture
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 39 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    1
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    2 / 8 (25.00%)
    5 / 39 (12.82%)
    1 / 9 (11.11%)
         occurrences all number
    2
    5
    2
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 8 (0.00%)
    3 / 39 (7.69%)
    1 / 9 (11.11%)
         occurrences all number
    0
    5
    2
    Blood creatinine increased
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 39 (2.56%)
    1 / 9 (11.11%)
         occurrences all number
    0
    2
    2
    Blood lactate dehydrogenase increased
         subjects affected / exposed
    1 / 8 (12.50%)
    2 / 39 (5.13%)
    0 / 9 (0.00%)
         occurrences all number
    1
    3
    0
    Blood thyroid stimulating hormone increased
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 39 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    0
    Blood uric acid increased
         subjects affected / exposed
    0 / 8 (0.00%)
    2 / 39 (5.13%)
    0 / 9 (0.00%)
         occurrences all number
    0
    2
    0
    C-reactive protein increased
         subjects affected / exposed
    0 / 8 (0.00%)
    2 / 39 (5.13%)
    0 / 9 (0.00%)
         occurrences all number
    0
    3
    0
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    1 / 8 (12.50%)
    2 / 39 (5.13%)
    1 / 9 (11.11%)
         occurrences all number
    2
    2
    1
    Neutrophil count decreased
         subjects affected / exposed
    1 / 8 (12.50%)
    2 / 39 (5.13%)
    0 / 9 (0.00%)
         occurrences all number
    1
    2
    0
    Lymphocyte count decreased
         subjects affected / exposed
    0 / 8 (0.00%)
    4 / 39 (10.26%)
    3 / 9 (33.33%)
         occurrences all number
    0
    5
    5
    Platelet count decreased
         subjects affected / exposed
    1 / 8 (12.50%)
    1 / 39 (2.56%)
    0 / 9 (0.00%)
         occurrences all number
    1
    1
    0
    Weight decreased
         subjects affected / exposed
    1 / 8 (12.50%)
    10 / 39 (25.64%)
    3 / 9 (33.33%)
         occurrences all number
    1
    14
    3
    White blood cell count decreased
         subjects affected / exposed
    0 / 8 (0.00%)
    3 / 39 (7.69%)
    1 / 9 (11.11%)
         occurrences all number
    0
    4
    2
    Cardiac disorders
    Sinus bradycardia
         subjects affected / exposed
    0 / 8 (0.00%)
    2 / 39 (5.13%)
    0 / 9 (0.00%)
         occurrences all number
    0
    2
    0
    Sinus tachycardia
         subjects affected / exposed
    0 / 8 (0.00%)
    2 / 39 (5.13%)
    0 / 9 (0.00%)
         occurrences all number
    0
    2
    0
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 39 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    1
    Epistaxis
         subjects affected / exposed
    4 / 8 (50.00%)
    7 / 39 (17.95%)
    1 / 9 (11.11%)
         occurrences all number
    6
    9
    1
    Cough
         subjects affected / exposed
    2 / 8 (25.00%)
    5 / 39 (12.82%)
    0 / 9 (0.00%)
         occurrences all number
    2
    5
    0
    Hypoxia
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 39 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    0
    Nasal oedema
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 39 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    1
    Nasal congestion
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 39 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    0
    Nasal pruritus
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 39 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    1
    Oropharyngeal pain
         subjects affected / exposed
    0 / 8 (0.00%)
    2 / 39 (5.13%)
    0 / 9 (0.00%)
         occurrences all number
    0
    2
    0
    Tachypnoea
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 39 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    0
    Pharyngeal inflammation
         subjects affected / exposed
    1 / 8 (12.50%)
    1 / 39 (2.56%)
    0 / 9 (0.00%)
         occurrences all number
    1
    1
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    3 / 8 (37.50%)
    7 / 39 (17.95%)
    1 / 9 (11.11%)
         occurrences all number
    3
    9
    1
    Lymphopenia
         subjects affected / exposed
    0 / 8 (0.00%)
    2 / 39 (5.13%)
    1 / 9 (11.11%)
         occurrences all number
    0
    3
    1
    Leukopenia
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 39 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    2
    0
    0
    Neutropenia
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 39 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    2
    0
    0
    Nervous system disorders
    Aphasia
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 39 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    0
    Ataxia
         subjects affected / exposed
    0 / 8 (0.00%)
    2 / 39 (5.13%)
    0 / 9 (0.00%)
         occurrences all number
    0
    2
    0
    Dizziness
         subjects affected / exposed
    0 / 8 (0.00%)
    2 / 39 (5.13%)
    0 / 9 (0.00%)
         occurrences all number
    0
    2
    0
    Dysarthria
         subjects affected / exposed
    0 / 8 (0.00%)
    2 / 39 (5.13%)
    0 / 9 (0.00%)
         occurrences all number
    0
    2
    0
    Headache
         subjects affected / exposed
    3 / 8 (37.50%)
    9 / 39 (23.08%)
    3 / 9 (33.33%)
         occurrences all number
    3
    9
    3
    Lethargy
         subjects affected / exposed
    0 / 8 (0.00%)
    2 / 39 (5.13%)
    0 / 9 (0.00%)
         occurrences all number
    0
    2
    0
    Neurological decompensation
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 39 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    0
    Peripheral motor neuropathy
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 39 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    0
    Somnolence
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 39 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    0
    VIth nerve disorder
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 39 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    0
    Eye disorders
    Dry eye
         subjects affected / exposed
    3 / 8 (37.50%)
    3 / 39 (7.69%)
    0 / 9 (0.00%)
         occurrences all number
    3
    4
    0
    Eye discharge
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 39 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    1
    Eye pruritus
         subjects affected / exposed
    1 / 8 (12.50%)
    1 / 39 (2.56%)
    0 / 9 (0.00%)
         occurrences all number
    1
    1
    0
    Keratitis
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 39 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    1
    Punctate keratitis
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 39 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    0
    Vision blurred
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 39 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    2
    0
    0
    Visual acuity reduced
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 39 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    4 / 8 (50.00%)
    8 / 39 (20.51%)
    2 / 9 (22.22%)
         occurrences all number
    12
    14
    2
    Abdominal pain upper
         subjects affected / exposed
    1 / 8 (12.50%)
    1 / 39 (2.56%)
    0 / 9 (0.00%)
         occurrences all number
    1
    1
    0
    Anal haemorrhage
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 39 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    0
    Angular cheilitis
         subjects affected / exposed
    1 / 8 (12.50%)
    1 / 39 (2.56%)
    0 / 9 (0.00%)
         occurrences all number
    1
    1
    0
    Cheilitis
         subjects affected / exposed
    2 / 8 (25.00%)
    6 / 39 (15.38%)
    2 / 9 (22.22%)
         occurrences all number
    2
    6
    2
    Constipation
         subjects affected / exposed
    6 / 8 (75.00%)
    4 / 39 (10.26%)
    1 / 9 (11.11%)
         occurrences all number
    7
    4
    1
    Diarrhoea
         subjects affected / exposed
    6 / 8 (75.00%)
    30 / 39 (76.92%)
    6 / 9 (66.67%)
         occurrences all number
    21
    52
    10
    Dyschezia
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 39 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    0
    Dysphagia
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 39 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    1
    0
    1
    Glossitis
         subjects affected / exposed
    1 / 8 (12.50%)
    1 / 39 (2.56%)
    0 / 9 (0.00%)
         occurrences all number
    1
    1
    0
    Lip dry
         subjects affected / exposed
    0 / 8 (0.00%)
    5 / 39 (12.82%)
    0 / 9 (0.00%)
         occurrences all number
    0
    5
    0
    Mouth ulceration
         subjects affected / exposed
    1 / 8 (12.50%)
    1 / 39 (2.56%)
    0 / 9 (0.00%)
         occurrences all number
    1
    1
    0
    Nausea
         subjects affected / exposed
    1 / 8 (12.50%)
    15 / 39 (38.46%)
    2 / 9 (22.22%)
         occurrences all number
    1
    17
    2
    Oral pain
         subjects affected / exposed
    0 / 8 (0.00%)
    3 / 39 (7.69%)
    0 / 9 (0.00%)
         occurrences all number
    0
    3
    0
    Tongue eruption
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 39 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    0
    Stomatitis
         subjects affected / exposed
    3 / 8 (37.50%)
    9 / 39 (23.08%)
    1 / 9 (11.11%)
         occurrences all number
    3
    9
    1
    Vomiting
         subjects affected / exposed
    3 / 8 (37.50%)
    16 / 39 (41.03%)
    6 / 9 (66.67%)
         occurrences all number
    7
    25
    10
    Renal and urinary disorders
    Proteinuria
         subjects affected / exposed
    1 / 8 (12.50%)
    1 / 39 (2.56%)
    0 / 9 (0.00%)
         occurrences all number
    2
    1
    0
    Urinary retention
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 39 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    0
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 39 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    0
    Dermatitis
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 39 (2.56%)
    1 / 9 (11.11%)
         occurrences all number
    0
    1
    1
    Dermatitis acneiform
         subjects affected / exposed
    1 / 8 (12.50%)
    9 / 39 (23.08%)
    1 / 9 (11.11%)
         occurrences all number
    1
    9
    1
    Dermatitis diaper
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 39 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    1
    Dry skin
         subjects affected / exposed
    2 / 8 (25.00%)
    10 / 39 (25.64%)
    4 / 9 (44.44%)
         occurrences all number
    3
    10
    4
    Eczema
         subjects affected / exposed
    1 / 8 (12.50%)
    1 / 39 (2.56%)
    0 / 9 (0.00%)
         occurrences all number
    1
    1
    0
    Erythema
         subjects affected / exposed
    0 / 8 (0.00%)
    2 / 39 (5.13%)
    2 / 9 (22.22%)
         occurrences all number
    0
    2
    2
    Hair colour changes
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 39 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    0
    Hand dermatitis
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 39 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    1
    Hyperhidrosis
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 39 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    0
    Pruritus
         subjects affected / exposed
    2 / 8 (25.00%)
    3 / 39 (7.69%)
    0 / 9 (0.00%)
         occurrences all number
    2
    3
    0
    Rash
         subjects affected / exposed
    1 / 8 (12.50%)
    4 / 39 (10.26%)
    1 / 9 (11.11%)
         occurrences all number
    1
    8
    1
    Rash maculo-papular
         subjects affected / exposed
    0 / 8 (0.00%)
    4 / 39 (10.26%)
    1 / 9 (11.11%)
         occurrences all number
    0
    4
    1
    Rash papular
         subjects affected / exposed
    0 / 8 (0.00%)
    2 / 39 (5.13%)
    0 / 9 (0.00%)
         occurrences all number
    0
    2
    0
    Skin fissures
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 39 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    1
    0
    1
    Skin irritation
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 39 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    1
    Musculoskeletal and connective tissue disorders
    Groin pain
         subjects affected / exposed
    0 / 8 (0.00%)
    2 / 39 (5.13%)
    0 / 9 (0.00%)
         occurrences all number
    0
    2
    0
    Muscle spasms
         subjects affected / exposed
    0 / 8 (0.00%)
    2 / 39 (5.13%)
    0 / 9 (0.00%)
         occurrences all number
    0
    2
    0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    3 / 8 (37.50%)
    7 / 39 (17.95%)
    1 / 9 (11.11%)
         occurrences all number
    3
    7
    1
    Dehydration
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 39 (2.56%)
    2 / 9 (22.22%)
         occurrences all number
    0
    1
    2
    Hyperglycaemia
         subjects affected / exposed
    1 / 8 (12.50%)
    2 / 39 (5.13%)
    1 / 9 (11.11%)
         occurrences all number
    1
    2
    1
    Hyperkalaemia
         subjects affected / exposed
    1 / 8 (12.50%)
    1 / 39 (2.56%)
    0 / 9 (0.00%)
         occurrences all number
    2
    1
    0
    Hypermagnesaemia
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 39 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    0
    Hypoalbuminaemia
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 39 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    1
    0
    1
    Hypernatraemia
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 39 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    1
    0
    2
    Hypocalcaemia
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 39 (2.56%)
    1 / 9 (11.11%)
         occurrences all number
    0
    1
    2
    Hypokalaemia
         subjects affected / exposed
    0 / 8 (0.00%)
    3 / 39 (7.69%)
    1 / 9 (11.11%)
         occurrences all number
    0
    5
    4
    Hypoglycaemia
         subjects affected / exposed
    2 / 8 (25.00%)
    0 / 39 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    2
    0
    0
    Hyponatraemia
         subjects affected / exposed
    0 / 8 (0.00%)
    4 / 39 (10.26%)
    1 / 9 (11.11%)
         occurrences all number
    0
    6
    3
    Hypomagnesaemia
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 39 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    3
    Hypophosphataemia
         subjects affected / exposed
    1 / 8 (12.50%)
    3 / 39 (7.69%)
    1 / 9 (11.11%)
         occurrences all number
    2
    4
    2
    Infections and infestations
    Conjunctivitis
         subjects affected / exposed
    1 / 8 (12.50%)
    3 / 39 (7.69%)
    0 / 9 (0.00%)
         occurrences all number
    1
    3
    0
    Cystitis
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 39 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    0
    Escherichia infection
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 39 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    0
    Ear infection
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 39 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    1
    Herpes zoster
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 39 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    1
    Impetigo
         subjects affected / exposed
    1 / 8 (12.50%)
    1 / 39 (2.56%)
    0 / 9 (0.00%)
         occurrences all number
    1
    1
    0
    Infection
         subjects affected / exposed
    1 / 8 (12.50%)
    1 / 39 (2.56%)
    0 / 9 (0.00%)
         occurrences all number
    2
    1
    0
    Nasopharyngitis
         subjects affected / exposed
    0 / 8 (0.00%)
    2 / 39 (5.13%)
    1 / 9 (11.11%)
         occurrences all number
    0
    2
    1
    Paronychia
         subjects affected / exposed
    1 / 8 (12.50%)
    9 / 39 (23.08%)
    0 / 9 (0.00%)
         occurrences all number
    1
    11
    0
    Rhinitis
         subjects affected / exposed
    0 / 8 (0.00%)
    2 / 39 (5.13%)
    0 / 9 (0.00%)
         occurrences all number
    0
    2
    0
    Pharyngitis
         subjects affected / exposed
    0 / 8 (0.00%)
    0 / 39 (0.00%)
    1 / 9 (11.11%)
         occurrences all number
    0
    0
    1
    Tinea capitis
         subjects affected / exposed
    1 / 8 (12.50%)
    0 / 39 (0.00%)
    0 / 9 (0.00%)
         occurrences all number
    1
    0
    0
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 8 (12.50%)
    1 / 39 (2.56%)
    0 / 9 (0.00%)
         occurrences all number
    1
    1
    0
    Urinary tract infection
         subjects affected / exposed
    1 / 8 (12.50%)
    1 / 39 (2.56%)
    0 / 9 (0.00%)
         occurrences all number
    1
    1
    0
    Viral infection
         subjects affected / exposed
    0 / 8 (0.00%)
    1 / 39 (2.56%)
    1 / 9 (11.11%)
         occurrences all number
    0
    1
    1

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    04 May 2015
    Addition of optional cerebrospinal fluid PK sampling: Assess afatinib penetration into the cerebrospinal fluid / Implemented only after approval of the IRB/IEC/ Competent Authorities. Addition of details on handling of strong P-gp inhibitors/ inducers: Assure that MTD determination was not affected by the use of strong P-gp inhibitors or inducers / Implemented without IRB/IEC/Competent Authority approval as changes involved logistical or administrative aspects only.
    18 Aug 2016
    Clarifications, e.g. regarding the possible use of a pre-screening informed consent for the collection and testing of tumour tissue sample and collection of tumour images during the screening period.
    02 Jun 2017
    Change from Phase I trial to adaptive Phase I/II design, clarification of pre-screening informed consent use and alternative PK samplings. To comply with the Written Request received from FDA and to follow the contraception guidance per ICH M3 (R2)2 and HMA CTFG / Implemented only after approval of the IRB/IEC/ Competent Authorities

    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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