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    Clinical Trial Results:
    LUX-Bladder 1: Phase II open label single arm exploratory trial of oral afatinib monotherapy following platinum failure for patients with advanced/metastatic urothelial tract carcinoma with genetic alterations in ERBB receptors.

    Summary
    EudraCT number
    		 2015-005427-10
    Trial protocol
    		 ES   FR  
    Global end of trial date
    24 Sep 2018

    Results information
    Results version number
    		 v4(current)
    This version publication date
    14 Nov 2021
    First version publication date
    18 Sep 2020
    Other versions
    		 v1 , v2 , v3
    Version creation reason

    Trial information

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    Trial identification
    Sponsor protocol code
    1200.261
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02780687
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Boehringer Ingelheim
    Sponsor organisation address
    Binger Strasse 173, Ingelheim am Rhein, Germany,
    Public contact
    Boehringer Ingelheim, Call Center, Boehringer Ingelheim, 001 18002430127, clintriage.rdg@boehringer-ingelheim.com
    Scientific contact
    Boehringer Ingelheim, Call Center, Boehringer Ingelheim, 001 18002430127, clintriage.rdg@boehringer-ingelheim.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    02 Oct 2019
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    24 Sep 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess the anti-tumour activity and safety of afatinib monotherapy in patients with urothelial tract carcinoma who show mutations in ERBB2 or ERBB3 or amplification in ERBB2 (Cohort A), or EGFR amplification (Cohort B), progressing despite previous platinum-based chemotherapy.
    Protection of trial subjects
    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. If a subject continued to take trial medication, close monitoring was adhered to and all adverse events recorded. Rules were implemented in all trials whereby doses would be reduced if required. Thereafter, if further events were reported, the subject would be withdrawn from the trial. Symptomatic treatment of tumour associated symptoms were allowed throughout.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    20 Nov 2015
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Spain: 48
    Country: Number of subjects enrolled
    France: 7
    Country: Number of subjects enrolled
    Italy: 1
    Worldwide total number of subjects
    56
    EEA total number of subjects
    56
    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)
    17
    From 65 to 84 years
    39
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 This study was a Phase II open label single arm exploratory trial of oral afatinib monotherapy following platinum failure for patients with advanced/metastatic urothelial tract carcinoma with genetic alterations in ERBB receptors.

    Pre-assignment
    Screening details
    		 All subjects were screened for eligibility prior to participation in the trial. Subjects attended a specialist site which ensured that they (the subjects) strictly met all inclusion and none of the exclusion criteria. Subjects were not to be allocated to a treatment group if any of the entry criteria were violated.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded
    Blinding implementation details
    The trial is an open label single arm exploratory Trial.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Cohort A
    Arm description
    		 Afatinib monotherapy in patients with urothelial tract carcinoma who progressed after first line of platinum-based chemotherapy and who show mutations in ERBB2 or ERBB3 or amplification in ERBB2 (Erythroblastic leukaemia viral oncogene homolog of the human epidermal growth factor family of receptors). Therapy consists of 40 mg film-coated tablets taken orally once a day continuously. The dose could be reduced to 30 mg or, in a second step, to 20 mg once daily. No dose increase was allowed after a dose reduction.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Afatinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Afatinib monotherapy consists of 40 mg film-coated tablets taken orally once a day continuously. The dose could be reduced to 30 mg or, in a second step, to 20 mg once daily. No dose increase was allowed after a dose reduction.

    Arm title
    		 Cohort B
    Arm description
    		 Afatinib monotherapy in patients with urothelial tract carcinoma who progressed after first line of platinum-based chemotherapy and who show EGFR (Epidermal Growth Factor Receptor) amplification. Therapy consists of 40 mg film-coated tablets taken orally once a day continuously. The dose could be reduced to 30 mg or, in a second step, to 20 mg once daily. No dose increase was allowed after a dose reduction.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Afatinib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Afatinib monotherapy consists of 40 mg film-coated tablets taken orally once a day continuously. The dose could be reduced to 30 mg or, in a second step, to 20 mg once daily. No dose increase was allowed after a dose reduction.

    Number of subjects in period 1 [1]
    		Cohort A Cohort B
    Started
    34
    8
    Completed
    0
    0
    Not completed
    34
    8
         Consent withdrawn by subject
    2
    1
         Adverse event, non-fatal
    1
    1
         Switched to commercial program (in CTP)
    2
    -
         Progressive disease
    29
    6
    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: Not all enrolled subjects were randomized.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Cohort A
    Reporting group description
    		 Afatinib monotherapy in patients with urothelial tract carcinoma who progressed after first line of platinum-based chemotherapy and who show mutations in ERBB2 or ERBB3 or amplification in ERBB2 (Erythroblastic leukaemia viral oncogene homolog of the human epidermal growth factor family of receptors). Therapy consists of 40 mg film-coated tablets taken orally once a day continuously. The dose could be reduced to 30 mg or, in a second step, to 20 mg once daily. No dose increase was allowed after a dose reduction.

    Reporting group title
    Cohort B
    Reporting group description
    		 Afatinib monotherapy in patients with urothelial tract carcinoma who progressed after first line of platinum-based chemotherapy and who show EGFR (Epidermal Growth Factor Receptor) amplification. Therapy consists of 40 mg film-coated tablets taken orally once a day continuously. The dose could be reduced to 30 mg or, in a second step, to 20 mg once daily. No dose increase was allowed after a dose reduction.

    Reporting group values
    		 Cohort A Cohort B Total
    Number of subjects
    		 34 8 42
    Age categorical
    The treated set (TS) included all patients who took at least 1 afatinib dose.
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 10 2 12
        From 65-84 years
    		 24 6 30
        85 years and over
    		 0 0 0
    Age Continuous
    The treated set (TS) included all patients who took at least 1 afatinib dose.
    Units: years
        arithmetic mean (standard deviation)
    		 66.4 ± 10.3 70.0 ± 6.9 -
    Sex: Female, Male
    The treated set (TS) included all patients who took at least 1 afatinib dose.
    Units: Participants
        Female
    		 4 2 6
        Male
    		 30 6 36
    Race (NIH/OMB)
    The treated set (TS) included all patients who took at least 1 afatinib dose.
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 0
        Asian
    		 0 0 0
        Native Hawaiian or Other Pacific Islander
    		 0 0 0
        Black or African American
    		 0 0 0
        White
    		 34 8 42
        More than one race
    		 0 0 0
        Unknown or Not Reported
    		 0 0 0
    Biomarker status - ERBB2 mutation
    The treated set (TS) included all patients who took at least 1 afatinib dose.
    Units: Subjects
        with ERBB2 mutation
    		 8 0 8
        without ERBB2 mutation
    		 26 8 34
    Biomarker status - ERBB3 mutation
    The treated set (TS) included all patients who took at least 1 afatinib dose.
    Units: Subjects
        with ERBB3 mutation
    		 11 0 11
        without ERBB3 mutation
    		 23 8 31
    Biomarker status - ERBB2 amplification
    The treated set (TS) included all patients who took at least 1 afatinib dose.
    Units: Subjects
        with ERBB2 amplification
    		 20 0 20
        without ERBB2 amplification
    		 14 8 22
    Biomarker status - EGFR amplification
    The treated set (TS) included all patients who took at least 1 afatinib dose.
    Units: Subjects
        with EGFR amplification
    		 3 8 11
        without EGFR amplification
    		 31 0 31

    End points

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    End points reporting groups
    Reporting group title
    Cohort A
    Reporting group description
    		 Afatinib monotherapy in patients with urothelial tract carcinoma who progressed after first line of platinum-based chemotherapy and who show mutations in ERBB2 or ERBB3 or amplification in ERBB2 (Erythroblastic leukaemia viral oncogene homolog of the human epidermal growth factor family of receptors). Therapy consists of 40 mg film-coated tablets taken orally once a day continuously. The dose could be reduced to 30 mg or, in a second step, to 20 mg once daily. No dose increase was allowed after a dose reduction.

    Reporting group title
    Cohort B
    Reporting group description
    		 Afatinib monotherapy in patients with urothelial tract carcinoma who progressed after first line of platinum-based chemotherapy and who show EGFR (Epidermal Growth Factor Receptor) amplification. Therapy consists of 40 mg film-coated tablets taken orally once a day continuously. The dose could be reduced to 30 mg or, in a second step, to 20 mg once daily. No dose increase was allowed after a dose reduction.

    Primary: Progression-free survival rate at 6 months (PFS6) in Cohort A

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    End point title
    		 Progression-free survival rate at 6 months (PFS6) in Cohort A [1] [2]
    End point description
    Progression-free survival rate at 6 months for Cohort A defined as the number of patients who were alive and without disease progression at 24-week tumour assessment. Tumour response was assessed based on local radiological image (Computerised tomography (CT) or Magnetic resonance imaging (MRI)) evaluation by the investigators according to Response Evaluation Criteria In Solid Tumours (RECIST) version 1.1. Baseline imaging was to be performed within 28 days before afatinib treatment start, if the patient already had a tumour assessment within this timeframe, this test was not repeated. Progression is defined as at least a 20% increase in sum of longest diameter (LD) of target lesions taking as reference the smallest sum LD since the treatment started, together with an absolute increase in the sum of LD of at least 5 millimeter OR The appearance of one or more new lesions.
    End point type
    Primary
    End point timeframe
    From start of treatment till assesment at week 24.
    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: Endpoint was only planned to be analyzed descriptively.
    [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: Endpoint only applies to Cohort A
    End point values
    		 Cohort A
    Number of subjects analysed
    34 [3]
    Units: Participants
        Without progression/death at 24th week
    4
    Notes
    [3] - all patients who took at least 1 afatinib dose and with ERBB-deregulated tumours (cohort A).
    No statistical analyses for this end point

    Secondary: Confirmed objective response rate (ORR) in Cohort A

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    End point title
    		 Confirmed objective response rate (ORR) in Cohort A [4]
    End point description
    Confirmed objective response rate by investigator review for Cohort A was defined as the number of patients with confirmed complete response (CR, disappearance of all target lesions) or confirmed partial response (PR, at least a 30% decrease in sum of longest diameter (LD) of target lesions, reference is baseline sum LD). Tumour response was assessed based on local radiological image (Computerised tomography (CT) or Magnetic resonance imaging (MRI)) evaluation by the investigators according to Response Evaluation Criteria In Solid Tumours (RECIST) version 1.1. Baseline imaging was to be performed within 28 days before afatinib treatment start, if the patient already had a tumour assessment within this timeframe, this test was not repeated.
    End point type
    Secondary
    End point timeframe
    Scans every 8 (±1) weeks from start till end of treatment. Afterwards, if discontinuation was not for progression: every 8 (±1) weeks until month 6, every 12 (±2) weeks thereafter. Until documented disease progression, i.e., up to ~ 20 Months.
    Notes
    [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: Endpoint only applies to Cohort A
    End point values
    		 Cohort A
    Number of subjects analysed
    34 [5]
    Units: Participants
        Objective response
    2
    Notes
    [5] - all patients who took at least 1 afatinib dose and with ERBB-deregulated tumours (cohort A).
    No statistical analyses for this end point

    Secondary: Progression-free survival (PFS) in Cohort A

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    End point title
    		 Progression-free survival (PFS) in Cohort A [6]
    End point description
    Progression-free survival was defined as the time (months) from the date of the first afatinib administration to the date of disease progression or death (if the patient died without progression). The date of progression for the primary analyses was determined based on investigator assessment. Tumour response was assessed based on local radiological image (Computerised tomography (CT) or Magnetic resonance imaging (MRI)) evaluation by the investigators according to RECIST version 1.1. Baseline imaging was to be performed within 28 days before afatinib treatment start, if the patient already had a tumour assessment within this timeframe, this test was not repeated. Progression is defined as at least a 20% increase in sum of longest diameter (LD) of target lesions taking as reference the smallest sum LD since the treatment started, together with an absolute increase in the sum of LD of at least 5 millimeter OR The appearance of one or more new lesions.
    End point type
    Secondary
    End point timeframe
    Scans every 8 (±1) weeks from start till end of treatment. Afterwards, if discontinuation was not for progression: every 8 (±1) weeks until month 6, every 12 (±2) weeks thereafter. Until documented disease progression, i.e., up to ~ 20 Months.
    Notes
    [6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Endpoint only applies to Cohort A
    End point values
    		 Cohort A
    Number of subjects analysed
    34 [7]
    Units: Weeks
        median (confidence interval 95%)
    9.8 (7.9 to 16.0)
    Notes
    [7] - all patients who took at least 1 afatinib dose and with ERBB-deregulated tumours (cohort A).
    No statistical analyses for this end point

    Secondary: Overall survival (OS) in Cohort A

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    End point title
    		 Overall survival (OS) in Cohort A [8]
    End point description
    Overall survival (OS) defined as the time from start of treatment of afatinib until death from any cause.
    End point type
    Secondary
    End point timeframe
    From start of treatment of afatinib until death from any cause, i.e. up to approximately 20 Months.
    Notes
    [8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Endpoint only applies to Cohort A
    End point values
    		 Cohort A
    Number of subjects analysed
    34 [9]
    Units: Weeks
        median (confidence interval 95%)
    30.1 (17.4 to 47.0)
    Notes
    [9] - all patients who took at least 1 afatinib dose and with ERBB-deregulated tumours (cohort A).
    No statistical analyses for this end point

    Secondary: Disease control rate (DCR) in Cohort A

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    End point title
    		 Disease control rate (DCR) in Cohort A [10]
    End point description
    Disease control rate was calculated as the number of patients with complete response (CR, disappearance of all target lesions), partial response (PR, at least a 30% decrease in sum of longest diameter (LD) of target lesions, reference is baseline sum LD), or stable disease (SD, neither sufficient shrinkage to qualify for PR, taking as reference the baseline sum of diameters (SoD), nor sufficient increase to qualify for PD taking as reference the smallest SoD since the treatment started). Tumour response was assessed based on local radiological image (Computerised tomography (CT) or Magnetic resonance imaging (MRI)) evaluation by the investigators according to Response Evaluation Criteria In Solid Tumours (RECIST) version 1.1. Baseline imaging was to be performed within 28 days before afatinib treatment start, if the patient already had a tumour assessment within this timeframe, this test was not repeated.
    End point type
    Secondary
    End point timeframe
    Scans every 8 (±1) weeks from start till end of treatment. Afterwards, if discontinuation was not for progression: every 8 (±1) weeks until month 6, every 12 (±2) weeks thereafter. Until documented disease progression, i.e., up to ~ 20 Months.
    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: Endpoint only applies to Cohort A
    End point values
    		 Cohort A
    Number of subjects analysed
    34 [11]
    Units: Participants
        Yes
    17
        No
    17
    Notes
    [11] - all patients who took at least 1 afatinib dose and with ERBB-deregulated tumours (cohort A).
    No statistical analyses for this end point

    Secondary: Duration of disease control in Cohort A

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    End point title
    		 Duration of disease control in Cohort A [12]
    End point description
    For patients with disease control, duration of disease control was defined as the time from afatinib treatment start to disease progression (or death if the patient died before progression). Disease control was defined as a having a complete response (CR, disappearance of all target lesions), partial response (PR, at least a 30% decrease in sum of longest diameter (LD) of target lesions, reference is baseline sum LD), or stable disease (SD, neither sufficient shrinkage to qualify for PR, taking as reference the baseline sum of diameters (SoD), nor sufficient increase to qualify for PD taking as reference the smallest SoD since the treatment started). Tumour response was assessed based on local radiological image (CT or MRI) evaluation by the investigators according to RECIST version 1.1. Baseline imaging was to be performed within 28 days before afatinib treatment start, if the patient already had a tumour assessment within this timeframe, this test was not repeated.
    End point type
    Secondary
    End point timeframe
    Scans every 8 (±1) weeks from start till end of treatment. Afterwards, if discontinuation was not for progression: every 8 (±1) weeks until month 6, every 12 (±2) weeks thereafter. Until documented disease progression, i.e., up to ~ 20 Months.
    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: Endpoint only applies to Cohort A
    End point values
    		 Cohort A
    Number of subjects analysed
    34 [13]
    Units: Weeks
        median (confidence interval 95%)
    22.7 (15.1 to 36.1)
    Notes
    [13] - all patients who took at least 1 afatinib dose and with ERBB-deregulated tumours (cohort A).
    No statistical analyses for this end point

    Secondary: Number of patients with tumour shrinkage in Cohort A

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    End point title
    		 Number of patients with tumour shrinkage in Cohort A [14]
    End point description
    Number of patients with tumour shrinkage, tumour shrinkage from baseline was defined by the maximum percentage decrease from baseline in the sum of the longest diameters of target lesions. Tumour response was assessed based on local radiological image (Computerised tomography (CT) or Magnetic resonance imaging (MRI)) evaluation by the investigators according to Response Evaluation Criteria In Solid Tumours (RECIST) version 1.1. Baseline imaging was to be performed within 28 days before afatinib treatment start, if the patient already had a tumour assessment within this timeframe, this test was not repeated.
    End point type
    Secondary
    End point timeframe
    Scans every 8 (±1) weeks from start till end of treatment. Afterwards, if discontinuation was not for progression: every 8 (±1) weeks until month 6, every 12 (±2) weeks thereafter. Until documented disease progression, i.e., up to ~ 20 Months.
    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: Endpoint only applies to Cohort A
    End point values
    		 Cohort A
    Number of subjects analysed
    34 [15]
    Units: Participants
        Patients with Shrinkage
    9
    Notes
    [15] - all patients who took at least 1 afatinib dose and with ERBB-deregulated tumours (cohort A).
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From the time of first drug administration till the end of treatment + 30 days (REP), up to approximately 20 Months.
    Adverse event reporting additional description
    The treated set (TS) included all patients who took at least 1 afatinib dose.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    22.0
    Reporting groups
    Reporting group title
    Cohort A
    Reporting group description
    		 Afatinib monotherapy in patients with urothelial tract carcinoma who progressed after first line of platinum-based chemotherapy and who show mutations in ERBB2 or ERBB3 or amplification in ERBB2 (Erythroblastic leukaemia viral oncogene homolog of the human epidermal growth factor family of receptors). Therapy consists of 40 mg film-coated tablets taken orally once a day continuously. The dose could be reduced to 30 mg or, in a second step, to 20 mg once daily. No dose increase was allowed after a dose reduction.

    Reporting group title
    Cohort B
    Reporting group description
    		 Afatinib monotherapy in patients with urothelial tract carcinoma who progressed after first line of platinum-based chemotherapy and who show EGFR (Epidermal Growth Factor Receptor) amplification. Therapy consists of 40 mg film-coated tablets taken orally once a day continuously. The dose could be reduced to 30 mg or, in a second step, to 20 mg once daily. No dose increase was allowed after a dose reduction.

    Serious adverse events
    		 Cohort A Cohort B
    Total subjects affected by serious adverse events
         subjects affected / exposed
    15 / 34 (44.12%)
    6 / 8 (75.00%)
         number of deaths (all causes)
    26
    7
         number of deaths resulting from adverse events
    0
    1
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Basal cell carcinoma
         subjects affected / exposed
    1 / 34 (2.94%)
    1 / 8 (12.50%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute coronary syndrome
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 8 (12.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cardiac failure
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 8 (12.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Ischaemic stroke
         subjects affected / exposed
    1 / 34 (2.94%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sciatica
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 8 (12.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 34 (2.94%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    1 / 34 (2.94%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain
         subjects affected / exposed
    1 / 34 (2.94%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    1 / 34 (2.94%)
    1 / 8 (12.50%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    4 / 34 (11.76%)
    2 / 8 (25.00%)
         occurrences causally related to treatment / all
    5 / 5
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dysphagia
         subjects affected / exposed
    1 / 34 (2.94%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 8 (12.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    1 / 34 (2.94%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 34 (2.94%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pulmonary embolism
         subjects affected / exposed
    1 / 34 (2.94%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    1 / 34 (2.94%)
    1 / 8 (12.50%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    1 / 34 (2.94%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    1 / 34 (2.94%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fistula
         subjects affected / exposed
    1 / 34 (2.94%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Groin pain
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 8 (12.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal disorder
         subjects affected / exposed
    1 / 34 (2.94%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteonecrosis of jaw
         subjects affected / exposed
    1 / 34 (2.94%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Escherichia pyelonephritis
         subjects affected / exposed
    1 / 34 (2.94%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infected skin ulcer
         subjects affected / exposed
    1 / 34 (2.94%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    1 / 34 (2.94%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pelvic abscess
         subjects affected / exposed
    1 / 34 (2.94%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 8 (12.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    4 / 34 (11.76%)
    1 / 8 (12.50%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection bacterial
         subjects affected / exposed
    1 / 34 (2.94%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Cachexia
         subjects affected / exposed
    1 / 34 (2.94%)
    0 / 8 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Cohort A Cohort B
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    34 / 34 (100.00%)
    8 / 8 (100.00%)
    Vascular disorders
    Hypotension
         subjects affected / exposed
    2 / 34 (5.88%)
    0 / 8 (0.00%)
         occurrences all number
    2
    0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    19 / 34 (55.88%)
    3 / 8 (37.50%)
         occurrences all number
    24
    4
    Malaise
         subjects affected / exposed
    1 / 34 (2.94%)
    1 / 8 (12.50%)
         occurrences all number
    1
    1
    Mucosal inflammation
         subjects affected / exposed
    10 / 34 (29.41%)
    3 / 8 (37.50%)
         occurrences all number
    13
    3
    Oedema peripheral
         subjects affected / exposed
    2 / 34 (5.88%)
    1 / 8 (12.50%)
         occurrences all number
    3
    1
    Pain
         subjects affected / exposed
    3 / 34 (8.82%)
    1 / 8 (12.50%)
         occurrences all number
    3
    1
    Pyrexia
         subjects affected / exposed
    7 / 34 (20.59%)
    1 / 8 (12.50%)
         occurrences all number
    8
    1
    Xerosis
         subjects affected / exposed
    3 / 34 (8.82%)
    1 / 8 (12.50%)
         occurrences all number
    3
    1
    Reproductive system and breast disorders
    Pelvic pain
         subjects affected / exposed
    2 / 34 (5.88%)
    0 / 8 (0.00%)
         occurrences all number
    2
    0
    Respiratory, thoracic and mediastinal disorders
    Epistaxis
         subjects affected / exposed
    2 / 34 (5.88%)
    1 / 8 (12.50%)
         occurrences all number
    3
    1
    Haemoptysis
         subjects affected / exposed
    1 / 34 (2.94%)
    1 / 8 (12.50%)
         occurrences all number
    1
    1
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    2 / 34 (5.88%)
    1 / 8 (12.50%)
         occurrences all number
    2
    1
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 34 (0.00%)
    2 / 8 (25.00%)
         occurrences all number
    0
    2
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    1
    Blood creatine phosphokinase increased
         subjects affected / exposed
    2 / 34 (5.88%)
    0 / 8 (0.00%)
         occurrences all number
    2
    0
    Blood creatinine increased
         subjects affected / exposed
    2 / 34 (5.88%)
    1 / 8 (12.50%)
         occurrences all number
    3
    4
    Blood lactate dehydrogenase increased
         subjects affected / exposed
    1 / 34 (2.94%)
    1 / 8 (12.50%)
         occurrences all number
    1
    1
    Platelet count decreased
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    5
    Transaminases increased
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    1
    Weight decreased
         subjects affected / exposed
    1 / 34 (2.94%)
    1 / 8 (12.50%)
         occurrences all number
    1
    1
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    2 / 34 (5.88%)
    0 / 8 (0.00%)
         occurrences all number
    2
    0
    Nervous system disorders
    Dysgeusia
         subjects affected / exposed
    2 / 34 (5.88%)
    1 / 8 (12.50%)
         occurrences all number
    3
    1
    Neuropathy peripheral
         subjects affected / exposed
    2 / 34 (5.88%)
    0 / 8 (0.00%)
         occurrences all number
    2
    0
    Paraesthesia
         subjects affected / exposed
    2 / 34 (5.88%)
    0 / 8 (0.00%)
         occurrences all number
    2
    0
    Speech disorder
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    1
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    10 / 34 (29.41%)
    2 / 8 (25.00%)
         occurrences all number
    16
    5
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    2 / 34 (5.88%)
    0 / 8 (0.00%)
         occurrences all number
    3
    0
    Constipation
         subjects affected / exposed
    10 / 34 (29.41%)
    1 / 8 (12.50%)
         occurrences all number
    13
    1
    Diarrhoea
         subjects affected / exposed
    23 / 34 (67.65%)
    5 / 8 (62.50%)
         occurrences all number
    50
    6
    Dry mouth
         subjects affected / exposed
    1 / 34 (2.94%)
    1 / 8 (12.50%)
         occurrences all number
    1
    1
    Dyspepsia
         subjects affected / exposed
    3 / 34 (8.82%)
    0 / 8 (0.00%)
         occurrences all number
    3
    0
    Faeces soft
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    1
    Glossitis
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    1
    Nausea
         subjects affected / exposed
    9 / 34 (26.47%)
    1 / 8 (12.50%)
         occurrences all number
    11
    1
    Stomatitis
         subjects affected / exposed
    9 / 34 (26.47%)
    2 / 8 (25.00%)
         occurrences all number
    9
    2
    Vomiting
         subjects affected / exposed
    7 / 34 (20.59%)
    1 / 8 (12.50%)
         occurrences all number
    11
    1
    Skin and subcutaneous tissue disorders
    Dermatitis
         subjects affected / exposed
    2 / 34 (5.88%)
    1 / 8 (12.50%)
         occurrences all number
    5
    1
    Dermatitis acneiform
         subjects affected / exposed
    4 / 34 (11.76%)
    1 / 8 (12.50%)
         occurrences all number
    6
    2
    Dry skin
         subjects affected / exposed
    3 / 34 (8.82%)
    1 / 8 (12.50%)
         occurrences all number
    3
    1
    Pruritus
         subjects affected / exposed
    5 / 34 (14.71%)
    2 / 8 (25.00%)
         occurrences all number
    6
    2
    Rash
         subjects affected / exposed
    11 / 34 (32.35%)
    1 / 8 (12.50%)
         occurrences all number
    14
    1
    Skin erosion
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    1
    Skin lesion
         subjects affected / exposed
    2 / 34 (5.88%)
    1 / 8 (12.50%)
         occurrences all number
    2
    1
    Skin toxicity
         subjects affected / exposed
    4 / 34 (11.76%)
    1 / 8 (12.50%)
         occurrences all number
    4
    1
    Renal and urinary disorders
    Dysuria
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    1
    Haematuria
         subjects affected / exposed
    2 / 34 (5.88%)
    0 / 8 (0.00%)
         occurrences all number
    4
    0
    Leukocyturia
         subjects affected / exposed
    2 / 34 (5.88%)
    0 / 8 (0.00%)
         occurrences all number
    2
    0
    Oliguria
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    1
    Proteinuria
         subjects affected / exposed
    2 / 34 (5.88%)
    0 / 8 (0.00%)
         occurrences all number
    3
    0
    Renal failure
         subjects affected / exposed
    3 / 34 (8.82%)
    0 / 8 (0.00%)
         occurrences all number
    4
    0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    7 / 34 (20.59%)
    0 / 8 (0.00%)
         occurrences all number
    7
    0
    Bone pain
         subjects affected / exposed
    2 / 34 (5.88%)
    0 / 8 (0.00%)
         occurrences all number
    2
    0
    Pain in extremity
         subjects affected / exposed
    3 / 34 (8.82%)
    0 / 8 (0.00%)
         occurrences all number
    3
    0
    Infections and infestations
    Clostridium difficile infection
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    1
    Folliculitis
         subjects affected / exposed
    1 / 34 (2.94%)
    1 / 8 (12.50%)
         occurrences all number
    1
    1
    Paronychia
         subjects affected / exposed
    3 / 34 (8.82%)
    3 / 8 (37.50%)
         occurrences all number
    4
    4
    Respiratory tract infection
         subjects affected / exposed
    2 / 34 (5.88%)
    0 / 8 (0.00%)
         occurrences all number
    2
    0
    Skin candida
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    1
    Urinary tract infection
         subjects affected / exposed
    6 / 34 (17.65%)
    3 / 8 (37.50%)
         occurrences all number
    7
    4
    Metabolism and nutrition disorders
    Cachexia
         subjects affected / exposed
    2 / 34 (5.88%)
    0 / 8 (0.00%)
         occurrences all number
    2
    0
    Decreased appetite
         subjects affected / exposed
    15 / 34 (44.12%)
    2 / 8 (25.00%)
         occurrences all number
    21
    2
    Hyperkalaemia
         subjects affected / exposed
    1 / 34 (2.94%)
    1 / 8 (12.50%)
         occurrences all number
    1
    2
    Hypoalbuminaemia
         subjects affected / exposed
    0 / 34 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    1
    Hypokalaemia
         subjects affected / exposed
    2 / 34 (5.88%)
    0 / 8 (0.00%)
         occurrences all number
    2
    0
    Hypomagnesaemia
         subjects affected / exposed
    4 / 34 (11.76%)
    1 / 8 (12.50%)
         occurrences all number
    4
    1
    Hyponatraemia
         subjects affected / exposed
    2 / 34 (5.88%)
    1 / 8 (12.50%)
         occurrences all number
    2
    1
    Hypophosphataemia
         subjects affected / exposed
    2 / 34 (5.88%)
    0 / 8 (0.00%)
         occurrences all number
    2
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    13 Mar 2017
    Several minor changes throughout the CTP improved the readability and comprehensibility. Several eligibility criteria were modified. Inclusion criteria 4 and 5 were reworded, specifying ‘line of chemotherapy’ and ‘previous treatment’. Exclusion criterion 4 was reworded regarding ‘previous radiotherapy’ to align with RECIST 1.1. Exclusion criterion 8 was reworded to add incidental localised prostate cancer as allowed malignancy. Exclusion criteria 14 and 15 were reworded; the text about women of child-bearing potential was aligned with project standards and current ICH guidelines. The futility analysis criterion to assess ORR as well as PFS6 was amended. A refined statistical model and new statistical assumptions in the sample size calculations resulted in an increased number of patients to be included in Stage 2 of the trial. The afatinib treatment duration was refined as well as the criteria for treatment discontinuation. For the dose reduction scheme, it was clarified that only renal impairment related to dehydration caused by diarrhoea should lead to afatinib dose reduction. The CTCAE version was changed to version 4.03 throughout the CTP.

    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.
    Duration of confirmed objective response was not analysed because only 2 patients showed a confirmed objective response. Instead, duration of disease control was analysed.
    For support, Contact us.
    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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