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    Clinical Trial Results:
    A randomized, open-label, active-controlled, Phase II study of intravenous anetumab ravtansine (BAY 94-9343) or vinorelbine in patients with advanced or metastatic malignant pleural mesothelioma overexpressing mesothelin and progressed on first line platinum/pemetrexed-based chemotherapy

    Summary
    EudraCT number
    2012-003650-88
    Trial protocol
    FI   DE   BE   GB   ES   NL   PL   FR   IT  
    Global end of trial date
    06 Sep 2019

    Results information
    Results version number
    v1(current)
    This version publication date
    11 Sep 2020
    First version publication date
    11 Sep 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    BAY94-9343/15743
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02610140
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Bayer AG
    Sponsor organisation address
    Kaiser Wilhelm Allee, Leverkusen, Germany, D-51368
    Public contact
    Therapeutic Area Head, Bayer AG, clinical-trials-contact@bayer.com
    Scientific contact
    Therapeutic Area Head, Bayer AG, clinical-trials-contact@bayer.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
    06 Sep 2019
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    06 Sep 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Superiority of anetumab ravtansine monotherapy over vinorelbine in progression-free survival (PFS)
    Protection of trial subjects
    The conduct of this clinical study met all local legal and regulatory requirements. The study was conducted in accordance with ethical principles that have their origin in the Declaration of Helsinki and the International Council for Harmonization guideline E6: Good Clinical Practice. Before entering the study, the informed consent was read by and explained to all the subjects. Participating subjects signed informed consent form and could withdraw from the study at any time without any disadvantage and without having to provide a reason for this decision. Only investigators qualified by training and experience were selected as appropriate experts to investigate the study drug.
    Background therapy
    -
    Evidence for comparator
    Vinorelbine
    Actual start date of recruitment
    13 Nov 2015
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Safety, Efficacy
    Long term follow-up duration
    24 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Australia: 14
    Country: Number of subjects enrolled
    Belgium: 21
    Country: Number of subjects enrolled
    Canada: 3
    Country: Number of subjects enrolled
    Finland: 9
    Country: Number of subjects enrolled
    France: 12
    Country: Number of subjects enrolled
    Italy: 60
    Country: Number of subjects enrolled
    Korea, Republic of: 2
    Country: Number of subjects enrolled
    Netherlands: 20
    Country: Number of subjects enrolled
    Poland: 10
    Country: Number of subjects enrolled
    Russian Federation: 1
    Country: Number of subjects enrolled
    Spain: 21
    Country: Number of subjects enrolled
    Turkey: 8
    Country: Number of subjects enrolled
    United Kingdom: 44
    Country: Number of subjects enrolled
    United States: 23
    Worldwide total number of subjects
    248
    EEA total number of subjects
    197
    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)
    103
    From 65 to 84 years
    145
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Country / Number of study centers: Australia (5), Belgium (6), Canada (4), Finland (3), France (7), Italy (7), Republic of Korea (2), Netherlands (2), Poland (4), Russian Federation (2), Spain (5), Turkey (6), United Kingdom (7), and United States (16), between 03-Dec-2015 (first patient first visit) and 02-Jul-2019 (last patient last visit).

    Pre-assignment
    Screening details
    Overall, 589 patients were enrolled for pre-screening in the study (i.e., signed informed consent for pre-screening) and 274 patients were pre-screening failures. A total of 315 patients were screened; of these, 67 patients were screening failures.

    Period 1
    Period 1 title
    Overall Period
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Anetumab Ravtansine
    Arm description
    Data cut-off date 06-APR-2018
    Arm type
    Experimental

    Investigational medicinal product name
    Anetumab ravtansine (BAY 94-9343)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    6.5 mg/kg every 3 weeks; Intravenous (IV) infusion over 1 hour

    Arm title
    Vinorelbine
    Arm description
    Data cut-off date 06-APR-2018
    Arm type
    Active comparator

    Investigational medicinal product name
    Vinorelbine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    30 mg/m^2 once weekly

    Number of subjects in period 1
    Anetumab Ravtansine Vinorelbine
    Started
    166
    82
    Entered safety follow-up
    102
    45
    Entered active follow-up
    48
    26
    Entered long-term follow-up
    123
    66
    Completed
    0
    0
    Not completed
    166
    82
         Discontinued study treatment
    154
    71
         Study drug never administered
    3
    10
         Ongoing with treatment but not completed
    9
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Anetumab Ravtansine
    Reporting group description
    Data cut-off date 06-APR-2018

    Reporting group title
    Vinorelbine
    Reporting group description
    Data cut-off date 06-APR-2018

    Reporting group values
    Anetumab Ravtansine Vinorelbine Total
    Number of subjects
    166 82 248
    Age Categorical
    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)
    66 37 103
        From 65-84 years
    100 45 145
        85 years and over
    0 0 0
    Age Continuous
    Units:
        
    66.5 ± 42.0 65.5 ± 46.0 -
    Gender Categorical
    Units: Subjects
        Female
    44 20 64
        Male
    122 62 184
    Subject analysis sets

    Subject analysis set title
    Anetumab Ravtansine
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    All randomized patients were included in the Intent-to-treat set (ITT) set. Patients in this set were reported by treatment arm as randomized.

    Subject analysis set title
    Vinorelbine
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    All randomized patients were included in the ITT set. Patients in this set were reported by treatment arm as randomized.

    Subject analysis sets values
    Anetumab Ravtansine Vinorelbine
    Number of subjects
    166
    82
    Age Categorical
    Units: Subjects
        In utero
    0
    0
        Preterm newborn infants (gestational age < 37 wks)
    0
    0
        Newborns (0-27 days)
    0
    0
        Infants and toddlers (28 days-23 months)
    0
    0
        Children (2-11 years)
    0
    0
        Adolescents (12-17 years)
    0
    0
        Adults (18-64 years)
    66
    37
        From 65-84 years
    100
    45
        85 years and over
    0
    0
    Age Continuous
    Units:
        
    66.5 ± 42.0
    65.5 ± 46.0
    Gender Categorical
    Units: Subjects
        Female
    44
    20
        Male
    122
    62

    End points

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    End points reporting groups
    Reporting group title
    Anetumab Ravtansine
    Reporting group description
    Data cut-off date 06-APR-2018

    Reporting group title
    Vinorelbine
    Reporting group description
    Data cut-off date 06-APR-2018

    Subject analysis set title
    Anetumab Ravtansine
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    All randomized patients were included in the Intent-to-treat set (ITT) set. Patients in this set were reported by treatment arm as randomized.

    Subject analysis set title
    Vinorelbine
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    All randomized patients were included in the ITT set. Patients in this set were reported by treatment arm as randomized.

    Primary: Progression-free survival (PFS)

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    End point title
    Progression-free survival (PFS)
    End point description
    Progression-free survival (PFS), defined as time from randomization until disease progression according to mRECIST (Modified Response Evaluation Criteria in Solid Tumors) for Malignant pleural mesothelioma (MPM) per blinded central radiology review, or death.
    End point type
    Primary
    End point timeframe
    From randomization till approximately approx. 30 months (data cut-off: 31-May-2017) and 40 months (data cut-off: 06-Apr-2018)
    End point values
    Anetumab Ravtansine Vinorelbine
    Number of subjects analysed
    166
    82
    Units: months
    median (confidence interval 95%)
        PFS - Data cut off: 31-May-2017 [95% CI]
    4.3 (4.1 to 5.2)
    4.5 (4.1 to 5.8)
        PFS - Data cut off: 06-Apr-2018 [95% CI]
    4.3 (4.1 to 5.5)
    4.6 (4.1 to 5.8)
        PFS - Data cut off: 31-May-2017 [97.5% CI]
    4.3 (4.1 to 5.2)
    4.5 (3.9 to 5.8)
        PFS - Data cut off: 06-Apr-2018[97.5% CI]
    4.3 (4.1 to 5.6)
    4.6 (3.9 to 5.8)
    Statistical analysis title
    PFS - Data cut off: 31-May-2017
    Statistical analysis description
    Hazard ratio (anetumab ravtansine/vinorelbine) was estimated using Cox proportional hazards models with Wald CIs, stratified by TTP on 1st line treatment.
    Comparison groups
    Anetumab Ravtansine v Vinorelbine
    Number of subjects included in analysis
    248
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    > 0.859125 [1]
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    1.215
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.85
         upper limit
    1.738
    Notes
    [1] - 1-sided p-value from log-rank test (stratified by TTP on 1st line treatment). P-value is calculated based on alpha level 0.0125.
    Statistical analysis title
    PFS - Data cut off: 06-Apr-2018
    Statistical analysis description
    Hazard ratio (anetumab ravtansine/vinorelbine) was estimated using Cox proportional hazards models with Wald CIs, stratified by TTP on 1st line treatment.
    Comparison groups
    Anetumab Ravtansine v Vinorelbine
    Number of subjects included in analysis
    248
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    Hazard ratio (HR)
    Point estimate
    1.121
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.813
         upper limit
    1.545
    Statistical analysis title
    PFS - Data cut off: 31-May-2017
    Statistical analysis description
    Hazard ratio (anetumab ravtansine/vinorelbine) was estimated using Cox proportional hazards models with Wald CIs, stratified by TTP on 1st line treatment.
    Comparison groups
    Anetumab Ravtansine v Vinorelbine
    Number of subjects included in analysis
    248
    Analysis specification
    Pre-specified
    Analysis type
    superiority [2]
    P-value
    > 0.859125 [3]
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    1.215
    Confidence interval
         level
    97.5%
         sides
    2-sided
         lower limit
    0.807
         upper limit
    1.83
    Notes
    [2] - 97.5% CIs correspond to 0.0125 one-sided alpha level.
    [3] - 1-sided p-value from log-rank test (stratified by TTP on 1st line treatment). P-value is calculated based on alpha level 0.0125.
    Statistical analysis title
    PFS - Data cut off: 06-Apr-2018
    Statistical analysis description
    Hazard ratio (anetumab ravtansine/vinorelbine) was estimated using Cox proportional hazards models with Wald CIs, stratified by TTP on 1st line treatment.
    Comparison groups
    Anetumab Ravtansine v Vinorelbine
    Number of subjects included in analysis
    248
    Analysis specification
    Pre-specified
    Analysis type
    superiority [4]
    Method
    Parameter type
    Hazard ratio (HR)
    Point estimate
    1.121
    Confidence interval
         level
    97.5%
         sides
    2-sided
         lower limit
    0.776
         upper limit
    1.618
    Notes
    [4] - 97.5% CIs correspond to 0.0125 one-sided alpha level.

    Secondary: Overall survival (OS)

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    End point title
    Overall survival (OS)
    End point description
    Overall survival (OS) was defined as time from randomization until death from any cause.
    End point type
    Secondary
    End point timeframe
    Up to approx. 30 month (data cut-off: 31-May-2017) and (40 months (data cut-off: 06-Apr-2018) - Time from randomization until death from any cause; one-sided log-rank test stratified by time to progression (TTP) on first line treatment.
    End point values
    Anetumab Ravtansine Vinorelbine
    Number of subjects analysed
    166 [5]
    82
    Units: months
    median (confidence interval 95%)
        OS - Data cut off: 31-May-2017 [95% CI]
    10.1 (7.6 to 99999.9)
    11.6 (7.7 to 12.5)
        OS - Data cut off: 06-Apr-2018 [95% CI]
    9.5 (8.3 to 12.3)
    11.6 (8.6 to 13.1)
        OS - Data cut off: 31-May-2017 [adjusted CI%]
    10.1 (7.0 to 99999.9)
    11.6 (7.1 to 12.5)
        OS - Data cut off: 06-Apr-2018 [adjusted CI%]
    9.5 (8.3 to 12.3)
    11.6 (8.6 to 13.1)
    Notes
    [5] - OS - Data cut off: 31-May-2017 [CI]: 99999.9 = cannot be estimated due to censored data.
    Statistical analysis title
    OS - Data cut off: 31-May-2017
    Statistical analysis description
    Hazard ratio (anetumab ravtansine/vinorelbine) was estimated using Cox proportional hazards models with Wald CIs, stratified by TTP on 1st line treatment.
    Comparison groups
    Anetumab Ravtansine v Vinorelbine
    Number of subjects included in analysis
    248
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    > 0.720888 [6]
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    1.147
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.724
         upper limit
    1.817
    Notes
    [6] - 1-sided p-value from log-rank test (stratified by TTP on 1st line treatment). Alpha spending/boundary for interim was 0.00245. Alpha boundary value for final analysis was 0.02421.
    Statistical analysis title
    OS - Data cut off: 06-Apr-2018
    Statistical analysis description
    Hazard ratio (anetumab ravtansine/vinorelbine) was estimated using Cox proportional hazards models with Wald CIs, stratified by TTP on 1st line treatment.
    Comparison groups
    Anetumab Ravtansine v Vinorelbine
    Number of subjects included in analysis
    248
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    > 0.655624 [7]
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    1.072
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.763
         upper limit
    1.506
    Notes
    [7] - 1-sided p-value from log-rank test (stratified by TTP on 1st line treatment). Alpha spending/boundary for interim was 0.00245. Alpha boundary value for final analysis was 0.02421.
    Statistical analysis title
    OS - Data cut off: 31-May-2017
    Statistical analysis description
    Hazard ratio (anetumab ravtansine/vinorelbine) was estimated using Cox proportional hazards models with Wald CIs, stratified by TTP on 1st line treatment.
    Comparison groups
    Anetumab Ravtansine v Vinorelbine
    Number of subjects included in analysis
    248
    Analysis specification
    Pre-specified
    Analysis type
    superiority [8]
    P-value
    > 0.720888 [9]
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    1.147
    Confidence interval
         level
    99.51%
         sides
    2-sided
         lower limit
    0.593
         upper limit
    2.221
    Notes
    [8] - Interim analysis: CI adjusted for group sequential design: alpha spending for interim was 0.00245. The 99.51% CIs are based on this adjusted alpha level. Final analysis: CI adjusted for group sequential design: Alpha spending for interim OS analysis was 0.00245. Final alpha level is 0.02421. The 95.158% CIs are based on this adjusted alpha level.
    [9] - 1-sided p-value from log-rank test (stratified by TTP on 1st line treatment). Alpha spending/boundary for interim was 0.00245. Alpha boundary value for final analysis was 0.02421.
    Statistical analysis title
    OS - Data cut off: 06-Apr-2018
    Statistical analysis description
    Hazard ratio (anetumab ravtansine/vinorelbine) was estimated using Cox proportional hazards models with Wald CIs, stratified by TTP on 1st line treatment.
    Comparison groups
    Anetumab Ravtansine v Vinorelbine
    Number of subjects included in analysis
    248
    Analysis specification
    Pre-specified
    Analysis type
    superiority [10]
    P-value
    > 0.655624 [11]
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    1.072
    Confidence interval
         level
    95.16%
         sides
    2-sided
         lower limit
    0.761
         upper limit
    1.51
    Notes
    [10] - Interim analysis: CI adjusted for group sequential design: alpha spending for interim was 0.00245. The 99.51% CIs are based on this adjusted alpha level. Final analysis: CI adjusted for group sequential design: Alpha spending for interim OS analysis was 0.00245. Final alpha level is 0.02421. The 95.158% CIs are based on this adjusted alpha level.
    [11] - 1-sided p-value from log-rank test (stratified by TTP on 1st line treatment). Alpha spending/boundary for interim was 0.00245. Alpha boundary value for final analysis was 0.02421.

    Secondary: Objective response rate (ORR)

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    End point title
    Objective response rate (ORR)
    End point description
    A patient is a responder if the patient has a confirmed best tumor response on-study of CR (Complete response) or PR (Partial response), as determined by the central radiological reviewer per mRECIST criteria. ORR in each treatment arm was defined as the number of responders divided by the number of randomized patients. A responder was a patient who had a confirmed best tumor response on-study of CR or PR, as determined by the central radiological reviewer per mRECIST criteria.
    End point type
    Secondary
    End point timeframe
    up to approx. 30 months (data cut-off: 31-May-2017) and 40 months (data cut-off: 06-Apr-2018) - Time from randomization until death from any cause.
    End point values
    Anetumab Ravtansine Vinorelbine
    Number of subjects analysed
    166
    82
    Units: Percentage
    number (confidence interval 95%)
        ORR: Data cut off 31-May-2017
    8.4 (4.7 to 13.7)
    6.1 (2.0 to 13.7)
        ORR: Data cut off 06-Apr-2018
    9.6 (5.6 to 15.2)
    7.3 (2.7 to 15.2)
    No statistical analyses for this end point

    Secondary: Disease control rate (DCR)

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    End point title
    Disease control rate (DCR)
    End point description
    A patient has disease control if the patient has a best tumor response on-study of CR, PR, or SD (Stable disease). DCR was defined as a percentage of patients achieving CR, PR, or SD per mRECIST criteria, as determined by the central radiological reviewer. DCR was calculated in each treatment arm as the number of patients with disease control (a best tumor response on-study of CR, PR, or SD) divided by the number of randomized patients.
    End point type
    Secondary
    End point timeframe
    Up to approx. 30 months (data cut-off: 31-May-2017) and 40 months (data cut-off: 06-Apr-2018) - Time from randomization until death from any cause.
    End point values
    Anetumab Ravtansine Vinorelbine
    Number of subjects analysed
    166
    82
    Units: Percentage
    number (confidence interval 95%)
        DCR - Data cut off: 31- May-2017
    73.5 (66.1 to 80.0)
    68.3 (57.1 to 78.1)
        DCR - Data cut off: 06-Apr- 2018
    73.5 (66.1 to 80.0)
    68.3 (57.1 to 78.1)
    No statistical analyses for this end point

    Secondary: Duration of response (DOR)

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    End point title
    Duration of response (DOR)
    End point description
    DOR was defined in responders as the time from central documentation of tumor response (date of first response in the confirmation sequence) to the earlier of disease progression as determined by the central radiological reviewer, or death without centrally documented progression. A responder was a patient who had a confirmed best tumor response on-study of CR or PR, as determined by the central radiological reviewer per mRECIST criteria.
    End point type
    Secondary
    End point timeframe
    Up to approx. 30 months (data cut-off: 31-May-2017) and 40 months (data cut-off: 06-Apr-2018) - Time from randomization until death from any cause.
    End point values
    Anetumab Ravtansine Vinorelbine
    Number of subjects analysed
    166 [12]
    82 [13]
    Units: months
    median (confidence interval 95%)
        DOR - Data cut off: 31- May-2017
    6.5 (4.6 to 9999.9)
    3333.3 (3.1 to 9999.9)
        DOR - Data cut off: 06-Apr- 2018
    7.4 (6.0 to 9999.9)
    6.7 (3.0 to 10.3)
    Notes
    [12] - 99999.9 = CI limit values could not be estimated due to censored data.
    [13] - 3333.3 / 99999.9 = CI limit values could not be estimated due to censored data.
    No statistical analyses for this end point

    Secondary: Durable response rate (DRR)

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    End point title
    Durable response rate (DRR)
    End point description
    A durable responder was a responder (i.e. confirmed best tumor response on study of CR or PR) with duration of response of 180 days or more.
    End point type
    Secondary
    End point timeframe
    Up to approx. 30 months (data cut-off: 31-May-2017) and 40 months (data cut-off: 06-Apr-2018) - Time from randomization until death from any cause.
    End point values
    Anetumab Ravtansine Vinorelbine
    Number of subjects analysed
    166
    82
    Units: Percentage
    number (confidence interval 95%)
        DRR: Data cut off 31- May-2017
    4.2 (1.7 to 8.5)
    1.2 (0.0 to 6.6)
        ORR: Data cut off 06- Apr-2018
    7.2 (3.8 to 12.3)
    4.9 (1.3 to 12.0)
    No statistical analyses for this end point

    Secondary: Percentage of Participants With Confirmed Improvement of Symptoms Characteristic of Mesothelioma

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    End point title
    Percentage of Participants With Confirmed Improvement of Symptoms Characteristic of Mesothelioma
    End point description
    Improvement rate of symptoms characteristic of mesothelioma was defined as the number of patients with confirmed improvement of symptoms characteristic of mesothelioma (based on the MD Anderson Symptom Inventory-Malignant Pleural Mesothelioma, MDASI-MPM), divided by the number of patients evaluable for improvement of symptoms characteristic of mesothelioma.
    End point type
    Secondary
    End point timeframe
    up to approx. 30 months (data cut-off: 31-May-2017) and 40 months (data cut-off: 06-Apr-2018)
    End point values
    Anetumab Ravtansine Vinorelbine
    Number of subjects analysed
    166 [14]
    82 [15]
    Units: days
    median (confidence interval 95%)
        TTWS: Data cut off 31- May-2017
    3333.3 (1111.1 to 9999.9)
    3333.3 (1111.1 to 9999.9)
        TTWS: Data cut off 06- Apr-2018
    3333.3 (1111.1 to 9999.9)
    3333.3 (291.0 to 9999.9)
    Notes
    [14] - 1111.1, 3333.3, 9999.9 = CI limit values could not be estimated due to censored data.
    [15] - 1111.1, 3333.3, 9999.9 = CI limit values could not be estimated due to censored data.
    Statistical analysis title
    TTWS - Data cut off 31-May-2017
    Statistical analysis description
    Hazard ratio (anetumab ravtansine/vinorelbine) was estimated using Cox proportional hazards models with Wald CIs, stratified by TTP on 1st line treatment.
    Comparison groups
    Anetumab Ravtansine v Vinorelbine
    Number of subjects included in analysis
    248
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    > 0.313747 [16]
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.829
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.386
         upper limit
    1.779
    Notes
    [16] - 1-sided p-value from log-rank test (stratified by TTP on 1st line treatment).
    Statistical analysis title
    TTWS - Data cut off 06-Apr-2018
    Statistical analysis description
    Hazard ratio (anetumab ravtansine/vinorelbine) was estimated using Cox proportional hazards models with Wald CIs, stratified by TTP on 1st line treatment.
    Comparison groups
    Anetumab Ravtansine v Vinorelbine
    Number of subjects included in analysis
    248
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.971
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.479
         upper limit
    1.968

    Secondary: Time to worsening of pain (TTWP)

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    End point title
    Time to worsening of pain (TTWP)
    End point description
    Time to worsening of pain (TTWP) was defined in patients evaluable for assessing worsening of pain, as time from randomization until the first worsening of pain. Patients who died, were lost to follow-up, or ended (MD Anderson Symptom Inventory-Malignant Pleural Mesothelioma) MDASI-MPM assessments without confirmed worsening of pain were censored at the date of their last MDASI-MPM assessment with a non-missing pain score.
    End point type
    Secondary
    End point timeframe
    up to approx. 30 months (data cut-off: 31-May-2017) and 40 months (data cut-off: 06-Apr-2018)
    End point values
    Anetumab Ravtansine Vinorelbine
    Number of subjects analysed
    166 [17]
    82 [18]
    Units: days
    median (confidence interval 95%)
        TTWP: Data cut off 31- May-2017
    210.0 (127.0 to 9999.9)
    3333.3 (85.0 to 9999.9)
        TTWP: Data cut off 06- Apr-2018
    210.0 (127.0 to 9999.9)
    3333.3 (85.0 to 9999.9)
    Notes
    [17] - 3333.3, 9999.9 = CI limit values could not be estimated due to censored data.
    [18] - 3333.3, 9999.9 = CI limit values could not be estimated due to censored data.
    Statistical analysis title
    TTWP - Data cut off 31-May-2017
    Statistical analysis description
    Hazard ratio (anetumab ravtansine/vinorelbine) was estimated using Cox proportional hazards models with Wald CIs, stratified by TTP on 1st line treatment.
    Comparison groups
    Anetumab Ravtansine v Vinorelbine
    Number of subjects included in analysis
    248
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    > 0.378916 [19]
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.924
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.557
         upper limit
    1.533
    Notes
    [19] - 1-sided p-value from log-rank test (stratified by TTP on 1st line treatment).
    Statistical analysis title
    TTWP - Data cut off 06-Apr-2018
    Statistical analysis description
    Hazard ratio (anetumab ravtansine/vinorelbine) was estimated using Cox proportional hazards models with Wald CIs, stratified by TTP on 1st line treatment.
    Comparison groups
    Anetumab Ravtansine v Vinorelbine
    Number of subjects included in analysis
    248
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.903
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.546
         upper limit
    1.495

    Secondary: Improvement rate of symptoms characteristic of mesothelioma

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    End point title
    Improvement rate of symptoms characteristic of mesothelioma
    End point description
    Improvement rate of symptoms characteristic of mesothelioma was defined as the number of patients with confirmed improvement of symptoms characteristic of mesothelioma (based on the MDASI-MPM), divided by the number of patients evaluable for improvement of symptoms characteristic of mesothelioma. Confirmation of this endpoint required two consecutive MDASI-MPM assessments with improved symptoms, with no more than one missing CSS assessment in between.
    End point type
    Secondary
    End point timeframe
    Time from randomization until death from any cause.
    End point values
    Anetumab Ravtansine Vinorelbine
    Number of subjects analysed
    166
    82
    Units: Percentage
    number (confidence interval 95%)
        Data cut off 31-May-2017
    22.5 (15.1 to 31.4)
    17.9 (8.9 to 30.4)
        Data cut off 06-Apr-2018
    23.4 (15.9 to 32.4)
    19.6 (10.2 to 32.4)
    No statistical analyses for this end point

    Secondary: Percentage of Participants With Confirmed Improvement of Pain

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    End point title
    Percentage of Participants With Confirmed Improvement of Pain
    End point description
    Improvement rate of pain was defined as the number of patients with confirmed improvement of pain (based on the "pain at its worst" item of MDASI-MPM), divided by the number of patients evaluable for improvement of pain.
    End point type
    Secondary
    End point timeframe
    Up to approx. 30 months (data cut-off: 31-May-2017) and 40 months (data cut-off: 06-Apr-2018) - Time from randomization until death from any cause.
    End point values
    Anetumab Ravtansine Vinorelbine
    Number of subjects analysed
    166
    82
    Units: Percentage
    number (confidence interval 95%)
        Data cut off 31-May-2017
    39.4 (30.0 to 49.5)
    32.7 (19.9 to 47.5)
        Data cut off 06-Apr-2018
    40.4 (30.9 to 50.5)
    32.7 (19.9 to 47.5)
    No statistical analyses for this end point

    Secondary: Overall survival (OS) - Addendum

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    End point title
    Overall survival (OS) - Addendum
    End point description
    Overall survival (OS) was defined as time from randomization until death from any cause.
    End point type
    Secondary
    End point timeframe
    Up to approx. 55 month (data cut-off: 02-JUL-2019) - Time from randomization until death from any cause; one-sided log-rank test stratified by time to progression (TTP) on first line treatment.
    End point values
    Anetumab Ravtansine Vinorelbine
    Number of subjects analysed
    166 [20]
    82 [21]
    Units: month
    median (confidence interval 95%)
        OS (months)
    9.5 (8.3 to 12.3)
    11.6 (8.6 to 13.1)
    Notes
    [20] - Number of patients with death from any cause: 127 Number of patients with censored observation 39
    [21] - Number of patients with death from any cause: 59 Number of patients with censored observation 23
    Statistical analysis title
    OS - Data cut off: 02-Jul-2019
    Statistical analysis description
    Range (including censored values)
    Comparison groups
    Anetumab Ravtansine v Vinorelbine
    Number of subjects included in analysis
    248
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    Range (including censored values)
    Point estimate
    9.5
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.1
         upper limit
    39.3
    Statistical analysis title
    OS - Data cut off: 02-Jul-2019
    Statistical analysis description
    Range (including censored values)
    Comparison groups
    Vinorelbine v Anetumab Ravtansine
    Number of subjects included in analysis
    248
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    Range (including censored values)
    Point estimate
    11.6
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0
         upper limit
    35.9

    Secondary: Percentage of Participant With Treatment-emergent Adverse Events (TEAEs)

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    End point title
    Percentage of Participant With Treatment-emergent Adverse Events (TEAEs)
    End point description
    TEAEs = Treatment-emergent adverse events / TESAEs = Treatment-emergent serious adverse events were defined as all AEs (adverse events ) / SAEs (serious adverse events ) starting or worsening within the treatment period. The treatment period for this study extended from the initiation of study treatment until 30 days after the last administration of study treatment.
    End point type
    Secondary
    End point timeframe
    Up to approx. 30 months (data cut-off: 31-May-2017), 40 months (data cut-off: 06-Apr-2018) and 55 months (data cut-off: 02-Jul-2019)
    End point values
    Anetumab Ravtansine Vinorelbine
    Number of subjects analysed
    163
    72
    Units: Percentage
    number (not applicable)
        Data cut-off: 31-May-2017: Any TEAE
    99.4
    98.6
        Data cut-off: 31-May-2017: TESAE
    31.9
    34.7
        Data cut-off: 31-May-2017: Drug-related TEAE
    87.7
    90.3
        Data cut-off: 31-May-2017: Drug-related TESAE
    38.7
    70.8
        Data cut-off: 06-Apr-2018: Any TEAE
    99.4
    98.6
        Data cut-off: 06-Apr-2018: TESAE
    33.7
    34.7
        Data cut-off: 06-Apr-2018: Drug-related TEAE
    87.7
    90.3
        Data cut-off: 06-Apr-2018: Drug-related TESAE
    39.9
    70.8
        Data cut-off: 02-Jul-2019: Any TEAE
    99.4
    98.6
        Data cut-off: 02-Jul-2019: TESAE
    34.4
    34.7
        Data cut-off: 02-Jul-2019: Drug-related TEAE
    88.3
    90.3
        Data cut-off: 02-Jul-2019: Drug-related TESAE
    7.4
    15.3
    No statistical analyses for this end point

    Secondary: Number of Deaths

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    End point title
    Number of Deaths
    End point description
    TEAE(s) associated with a fatal outcome (CTCAE Grade 5); Table contains deaths only if due to a TEAE. TEAEs were defined as all AEs starting or worsening within the treatment period. The treatment period for this study, for purposes of safety analyses, extended from the initiation of study treatment until 30 days after the last administration of study treatment.
    End point type
    Secondary
    End point timeframe
    Up to approx. 30 months (data cut-off: 31-May-2017), 40 months (data cut-off: 06-Apr-2018) and 55 months (data cut-off: 02-Jul-2019) - Time from randomization until death from any cause.
    End point values
    Anetumab Ravtansine Vinorelbine
    Number of subjects analysed
    163
    72
    Units: Number
        Data cut-off: 31-May-2017
    9
    1
        Data cut-off: 06-Apr-2018
    10
    1
        Data cut-off: 02-Jul-2019
    10
    1
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    FPFV: 03-Dec-2015 until LPLV: 02-Jul-2019
    Adverse event reporting additional description
    TEAEs = Treatment-emergent adverse events were defined as all AEs starting or worsening within the treatment period. The treatment period for this study extended from the initiation of study treatment until 30 days after the last administration of study treatment.
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    22.0
    Reporting groups
    Reporting group title
    Vinorelbine
    Reporting group description
    Treatment-emergent adverse events (TEAEs): defined as all AEs starting or worsening within the treatment period.

    Reporting group title
    Anetumab ravtansine (BAY 94-9343)
    Reporting group description
    Treatment-emergent adverse events (TEAEs): defined as all AEs starting or worsening within the treatment period.

    Serious adverse events
    Vinorelbine Anetumab ravtansine (BAY 94-9343)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    25 / 72 (34.72%)
    56 / 163 (34.36%)
         number of deaths (all causes)
    55
    126
         number of deaths resulting from adverse events
    1
    10
    Vascular disorders
    Hypotension
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Embolism
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Mesothelioma
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cancer pain
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tumour compression
         subjects affected / exposed
    1 / 72 (1.39%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Anaphylactic reaction
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    0 / 72 (0.00%)
    3 / 163 (1.84%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    3 / 72 (4.17%)
    3 / 163 (1.84%)
         occurrences causally related to treatment / all
    1 / 3
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain
         subjects affected / exposed
    1 / 72 (1.39%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    1 / 72 (1.39%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Physical deconditioning
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    0 / 72 (0.00%)
    3 / 163 (1.84%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Disorientation
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mental status changes
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Scrotal mass
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Animal bite
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infusion related reaction
         subjects affected / exposed
    0 / 72 (0.00%)
    2 / 163 (1.23%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clavicle fracture
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Neutrophil count decreased
         subjects affected / exposed
    1 / 72 (1.39%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Electrocardiogram T wave inversion
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    0 / 72 (0.00%)
    3 / 163 (1.84%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Atrial flutter
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pericardial effusion
         subjects affected / exposed
    0 / 72 (0.00%)
    3 / 163 (1.84%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    2 / 72 (2.78%)
    7 / 163 (4.29%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 15
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Pleural effusion
         subjects affected / exposed
    1 / 72 (1.39%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea exertional
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleurisy
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    1 / 72 (1.39%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    0 / 72 (0.00%)
    2 / 163 (1.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    2 / 72 (2.78%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Febrile neutropenia
         subjects affected / exposed
    1 / 72 (1.39%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    3 / 72 (4.17%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    2 / 3
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Loss of consciousness
         subjects affected / exposed
    1 / 72 (1.39%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Facial paralysis
         subjects affected / exposed
    1 / 72 (1.39%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Somnolence
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Polyneuropathy
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal cord compression
         subjects affected / exposed
    0 / 72 (0.00%)
    2 / 163 (1.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Brachial plexopathy
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Balance disorder
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Ascites
         subjects affected / exposed
    1 / 72 (1.39%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    1 / 72 (1.39%)
    5 / 163 (3.07%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    1 / 72 (1.39%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    1 / 72 (1.39%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ileus paralytic
         subjects affected / exposed
    1 / 72 (1.39%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    1 / 72 (1.39%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Large intestinal obstruction
         subjects affected / exposed
    1 / 72 (1.39%)
    0 / 163 (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
    Renal failure
         subjects affected / exposed
    1 / 72 (1.39%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Acute kidney injury
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hepatic failure
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    1 / 72 (1.39%)
    0 / 163 (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
    Dehydration
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoalbuminaemia
         subjects affected / exposed
    1 / 72 (1.39%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Decreased appetite
         subjects affected / exposed
    1 / 72 (1.39%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Abscess
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    5 / 72 (6.94%)
    7 / 163 (4.29%)
         occurrences causally related to treatment / all
    3 / 6
    0 / 9
         deaths causally related to treatment / all
    0 / 1
    0 / 3
    Bronchitis
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 72 (1.39%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 72 (0.00%)
    2 / 163 (1.23%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    1 / 2
    Viral infection
         subjects affected / exposed
    1 / 72 (1.39%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abscess limb
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arthritis bacterial
         subjects affected / exposed
    1 / 72 (1.39%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung infection
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterocolitis infectious
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post procedural sepsis
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    2 / 72 (2.78%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular device infection
         subjects affected / exposed
    1 / 72 (1.39%)
    0 / 163 (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: 0%
    Non-serious adverse events
    Vinorelbine Anetumab ravtansine (BAY 94-9343)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    71 / 72 (98.61%)
    162 / 163 (99.39%)
    Vascular disorders
    Flushing
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 163 (0.61%)
         occurrences all number
    0
    1
    Haematoma
         subjects affected / exposed
    1 / 72 (1.39%)
    1 / 163 (0.61%)
         occurrences all number
    1
    1
    Hypertension
         subjects affected / exposed
    2 / 72 (2.78%)
    9 / 163 (5.52%)
         occurrences all number
    5
    13
    Hypotension
         subjects affected / exposed
    1 / 72 (1.39%)
    1 / 163 (0.61%)
         occurrences all number
    1
    2
    Jugular vein thrombosis
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 163 (0.61%)
         occurrences all number
    0
    1
    Peripheral coldness
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 163 (0.61%)
         occurrences all number
    0
    1
    Phlebitis
         subjects affected / exposed
    6 / 72 (8.33%)
    0 / 163 (0.00%)
         occurrences all number
    9
    0
    Raynaud's phenomenon
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 163 (0.61%)
         occurrences all number
    0
    1
    Deep vein thrombosis
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 163 (0.61%)
         occurrences all number
    0
    1
    Vascular pain
         subjects affected / exposed
    1 / 72 (1.39%)
    0 / 163 (0.00%)
         occurrences all number
    1
    0
    Superior vena cava occlusion
         subjects affected / exposed
    0 / 72 (0.00%)
    2 / 163 (1.23%)
         occurrences all number
    0
    2
    Hot flush
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 163 (0.61%)
         occurrences all number
    0
    1
    Embolism
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 163 (0.61%)
         occurrences all number
    0
    1
    Surgical and medical procedures
    Dermabrasion
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 163 (0.61%)
         occurrences all number
    0
    1
    Inguinal hernia repair
         subjects affected / exposed
    1 / 72 (1.39%)
    0 / 163 (0.00%)
         occurrences all number
    1
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Neoplasm skin
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 163 (0.61%)
         occurrences all number
    0
    1
    Cancer pain
         subjects affected / exposed
    1 / 72 (1.39%)
    5 / 163 (3.07%)
         occurrences all number
    1
    7
    Tumour pain
         subjects affected / exposed
    3 / 72 (4.17%)
    2 / 163 (1.23%)
         occurrences all number
    3
    2
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 163 (0.61%)
         occurrences all number
    0
    1
    Contrast media allergy
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 163 (0.61%)
         occurrences all number
    0
    1
    General disorders and administration site conditions
    Application site rash
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 163 (0.61%)
         occurrences all number
    0
    1
    Asthenia
         subjects affected / exposed
    16 / 72 (22.22%)
    32 / 163 (19.63%)
         occurrences all number
    37
    58
    Chest discomfort
         subjects affected / exposed
    3 / 72 (4.17%)
    4 / 163 (2.45%)
         occurrences all number
    3
    6
    Chest pain
         subjects affected / exposed
    13 / 72 (18.06%)
    27 / 163 (16.56%)
         occurrences all number
    21
    31
    Chills
         subjects affected / exposed
    0 / 72 (0.00%)
    2 / 163 (1.23%)
         occurrences all number
    0
    2
    Fatigue
         subjects affected / exposed
    22 / 72 (30.56%)
    60 / 163 (36.81%)
         occurrences all number
    47
    98
    Feeling cold
         subjects affected / exposed
    1 / 72 (1.39%)
    0 / 163 (0.00%)
         occurrences all number
    1
    0
    Gait disturbance
         subjects affected / exposed
    0 / 72 (0.00%)
    4 / 163 (2.45%)
         occurrences all number
    0
    4
    Hyperpyrexia
         subjects affected / exposed
    1 / 72 (1.39%)
    1 / 163 (0.61%)
         occurrences all number
    1
    2
    Influenza like illness
         subjects affected / exposed
    5 / 72 (6.94%)
    5 / 163 (3.07%)
         occurrences all number
    9
    8
    Injection site bruising
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 163 (0.61%)
         occurrences all number
    0
    1
    Malaise
         subjects affected / exposed
    5 / 72 (6.94%)
    8 / 163 (4.91%)
         occurrences all number
    5
    13
    Mass
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 163 (0.61%)
         occurrences all number
    0
    1
    Mucosal inflammation
         subjects affected / exposed
    3 / 72 (4.17%)
    2 / 163 (1.23%)
         occurrences all number
    3
    2
    Oedema
         subjects affected / exposed
    0 / 72 (0.00%)
    2 / 163 (1.23%)
         occurrences all number
    0
    2
    Oedema peripheral
         subjects affected / exposed
    3 / 72 (4.17%)
    11 / 163 (6.75%)
         occurrences all number
    4
    11
    Pyrexia
         subjects affected / exposed
    12 / 72 (16.67%)
    22 / 163 (13.50%)
         occurrences all number
    14
    25
    Pain
         subjects affected / exposed
    1 / 72 (1.39%)
    4 / 163 (2.45%)
         occurrences all number
    1
    5
    Peripheral swelling
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 163 (0.61%)
         occurrences all number
    0
    1
    General physical health deterioration
         subjects affected / exposed
    0 / 72 (0.00%)
    3 / 163 (1.84%)
         occurrences all number
    0
    4
    Infusion site pain
         subjects affected / exposed
    1 / 72 (1.39%)
    0 / 163 (0.00%)
         occurrences all number
    1
    0
    Infusion site swelling
         subjects affected / exposed
    1 / 72 (1.39%)
    0 / 163 (0.00%)
         occurrences all number
    1
    0
    Inflammation
         subjects affected / exposed
    1 / 72 (1.39%)
    0 / 163 (0.00%)
         occurrences all number
    1
    0
    Non-cardiac chest pain
         subjects affected / exposed
    3 / 72 (4.17%)
    7 / 163 (4.29%)
         occurrences all number
    3
    10
    Infusion site extravasation
         subjects affected / exposed
    1 / 72 (1.39%)
    1 / 163 (0.61%)
         occurrences all number
    1
    1
    Catheter site injury
         subjects affected / exposed
    1 / 72 (1.39%)
    0 / 163 (0.00%)
         occurrences all number
    1
    0
    Psychiatric disorders
    Agitation
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 163 (0.61%)
         occurrences all number
    0
    1
    Anxiety
         subjects affected / exposed
    3 / 72 (4.17%)
    5 / 163 (3.07%)
         occurrences all number
    3
    9
    Confusional state
         subjects affected / exposed
    0 / 72 (0.00%)
    4 / 163 (2.45%)
         occurrences all number
    0
    4
    Depression
         subjects affected / exposed
    1 / 72 (1.39%)
    2 / 163 (1.23%)
         occurrences all number
    1
    2
    Depressed mood
         subjects affected / exposed
    1 / 72 (1.39%)
    1 / 163 (0.61%)
         occurrences all number
    1
    1
    Enuresis
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 163 (0.61%)
         occurrences all number
    0
    1
    Insomnia
         subjects affected / exposed
    10 / 72 (13.89%)
    11 / 163 (6.75%)
         occurrences all number
    10
    13
    Sleep disorder
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 163 (0.61%)
         occurrences all number
    0
    1
    Reproductive system and breast disorders
    Benign prostatic hyperplasia
         subjects affected / exposed
    1 / 72 (1.39%)
    1 / 163 (0.61%)
         occurrences all number
    1
    1
    Breast pain
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 163 (0.61%)
         occurrences all number
    0
    1
    Scrotal mass
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 163 (0.61%)
         occurrences all number
    0
    1
    Penile oedema
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 163 (0.61%)
         occurrences all number
    0
    1
    Injury, poisoning and procedural complications
    Accident
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 163 (0.61%)
         occurrences all number
    0
    1
    Clavicle fracture
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 163 (0.61%)
         occurrences all number
    0
    1
    Fall
         subjects affected / exposed
    2 / 72 (2.78%)
    3 / 163 (1.84%)
         occurrences all number
    2
    3
    Ligament sprain
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 163 (0.61%)
         occurrences all number
    0
    1
    Scratch
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 163 (0.61%)
         occurrences all number
    0
    1
    Muscle strain
         subjects affected / exposed
    1 / 72 (1.39%)
    0 / 163 (0.00%)
         occurrences all number
    1
    0
    Infusion related reaction
         subjects affected / exposed
    4 / 72 (5.56%)
    16 / 163 (9.82%)
         occurrences all number
    4
    22
    Stoma site pain
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 163 (0.61%)
         occurrences all number
    0
    2
    Investigations
    Activated partial thromboplastin time prolonged
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 163 (0.61%)
         occurrences all number
    0
    1
    Alanine aminotransferase increased
         subjects affected / exposed
    6 / 72 (8.33%)
    20 / 163 (12.27%)
         occurrences all number
    10
    46
    Amylase increased
         subjects affected / exposed
    1 / 72 (1.39%)
    5 / 163 (3.07%)
         occurrences all number
    1
    11
    Aspartate aminotransferase increased
         subjects affected / exposed
    4 / 72 (5.56%)
    22 / 163 (13.50%)
         occurrences all number
    4
    43
    Bilirubin conjugated increased
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 163 (0.61%)
         occurrences all number
    0
    1
    Blood albumin decreased
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 163 (0.61%)
         occurrences all number
    0
    3
    Blood creatinine increased
         subjects affected / exposed
    1 / 72 (1.39%)
    4 / 163 (2.45%)
         occurrences all number
    1
    5
    Blood bilirubin increased
         subjects affected / exposed
    2 / 72 (2.78%)
    3 / 163 (1.84%)
         occurrences all number
    2
    5
    Blood lactic acid increased
         subjects affected / exposed
    1 / 72 (1.39%)
    0 / 163 (0.00%)
         occurrences all number
    1
    0
    C-reactive protein increased
         subjects affected / exposed
    2 / 72 (2.78%)
    3 / 163 (1.84%)
         occurrences all number
    2
    4
    Blood urea increased
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 163 (0.61%)
         occurrences all number
    0
    2
    Blood pressure increased
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 163 (0.61%)
         occurrences all number
    0
    1
    Electrocardiogram QT prolonged
         subjects affected / exposed
    2 / 72 (2.78%)
    5 / 163 (3.07%)
         occurrences all number
    3
    5
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    3 / 72 (4.17%)
    11 / 163 (6.75%)
         occurrences all number
    5
    24
    Glucose tolerance test abnormal
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 163 (0.61%)
         occurrences all number
    0
    1
    Haemoglobin decreased
         subjects affected / exposed
    3 / 72 (4.17%)
    2 / 163 (1.23%)
         occurrences all number
    5
    2
    Lipase increased
         subjects affected / exposed
    1 / 72 (1.39%)
    7 / 163 (4.29%)
         occurrences all number
    1
    17
    Lymphocyte count decreased
         subjects affected / exposed
    2 / 72 (2.78%)
    1 / 163 (0.61%)
         occurrences all number
    5
    1
    Neutrophil count decreased
         subjects affected / exposed
    17 / 72 (23.61%)
    3 / 163 (1.84%)
         occurrences all number
    41
    5
    Platelet count decreased
         subjects affected / exposed
    0 / 72 (0.00%)
    4 / 163 (2.45%)
         occurrences all number
    0
    11
    Weight decreased
         subjects affected / exposed
    8 / 72 (11.11%)
    17 / 163 (10.43%)
         occurrences all number
    12
    23
    White blood cell count decreased
         subjects affected / exposed
    9 / 72 (12.50%)
    2 / 163 (1.23%)
         occurrences all number
    25
    3
    White blood cell count increased
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 163 (0.61%)
         occurrences all number
    0
    1
    Blood phosphorus decreased
         subjects affected / exposed
    1 / 72 (1.39%)
    0 / 163 (0.00%)
         occurrences all number
    1
    0
    Blood phosphorus increased
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 163 (0.61%)
         occurrences all number
    0
    1
    Hypophonesis
         subjects affected / exposed
    1 / 72 (1.39%)
    0 / 163 (0.00%)
         occurrences all number
    1
    0
    Platelet count increased
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 163 (0.61%)
         occurrences all number
    0
    1
    Transaminases increased
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 163 (0.61%)
         occurrences all number
    0
    1
    Blood alkaline phosphatase increased
         subjects affected / exposed
    0 / 72 (0.00%)
    4 / 163 (2.45%)
         occurrences all number
    0
    4
    Klebsiella test positive
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 163 (0.61%)
         occurrences all number
    0
    1
    Blood creatine phosphokinase decreased
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 163 (0.61%)
         occurrences all number
    0
    1
    Waist circumference increased
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 163 (0.61%)
         occurrences all number
    0
    1
    Tear break up time decreased
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 163 (0.61%)
         occurrences all number
    0
    1
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    1 / 72 (1.39%)
    3 / 163 (1.84%)
         occurrences all number
    1
    3
    Atrial flutter
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 163 (0.61%)
         occurrences all number
    0
    1
    Bundle branch block left
         subjects affected / exposed
    1 / 72 (1.39%)
    0 / 163 (0.00%)
         occurrences all number
    2
    0
    Atrial tachycardia
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 163 (0.61%)
         occurrences all number
    0
    1
    Palpitations
         subjects affected / exposed
    1 / 72 (1.39%)
    3 / 163 (1.84%)
         occurrences all number
    1
    3
    Coronary artery occlusion
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 163 (0.61%)
         occurrences all number
    0
    1
    Pericardial effusion
         subjects affected / exposed
    1 / 72 (1.39%)
    2 / 163 (1.23%)
         occurrences all number
    2
    2
    Sinus tachycardia
         subjects affected / exposed
    1 / 72 (1.39%)
    5 / 163 (3.07%)
         occurrences all number
    1
    6
    Tachycardia
         subjects affected / exposed
    1 / 72 (1.39%)
    2 / 163 (1.23%)
         occurrences all number
    1
    2
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    11 / 72 (15.28%)
    22 / 163 (13.50%)
         occurrences all number
    15
    30
    Dysphonia
         subjects affected / exposed
    3 / 72 (4.17%)
    2 / 163 (1.23%)
         occurrences all number
    3
    2
    Epistaxis
         subjects affected / exposed
    1 / 72 (1.39%)
    9 / 163 (5.52%)
         occurrences all number
    1
    12
    Dyspnoea
         subjects affected / exposed
    20 / 72 (27.78%)
    30 / 163 (18.40%)
         occurrences all number
    26
    44
    Dyspnoea exertional
         subjects affected / exposed
    0 / 72 (0.00%)
    3 / 163 (1.84%)
         occurrences all number
    0
    4
    Haemoptysis
         subjects affected / exposed
    0 / 72 (0.00%)
    2 / 163 (1.23%)
         occurrences all number
    0
    2
    Hiccups
         subjects affected / exposed
    1 / 72 (1.39%)
    0 / 163 (0.00%)
         occurrences all number
    2
    0
    Nasal congestion
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 163 (0.61%)
         occurrences all number
    0
    1
    Hypoxia
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 163 (0.61%)
         occurrences all number
    0
    1
    Nasal dryness
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 163 (0.61%)
         occurrences all number
    0
    1
    Pleural effusion
         subjects affected / exposed
    1 / 72 (1.39%)
    3 / 163 (1.84%)
         occurrences all number
    1
    5
    Painful respiration
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 163 (0.61%)
         occurrences all number
    0
    1
    Pleuritic pain
         subjects affected / exposed
    1 / 72 (1.39%)
    1 / 163 (0.61%)
         occurrences all number
    1
    1
    Pneumonitis
         subjects affected / exposed
    1 / 72 (1.39%)
    0 / 163 (0.00%)
         occurrences all number
    4
    0
    Pneumothorax
         subjects affected / exposed
    1 / 72 (1.39%)
    0 / 163 (0.00%)
         occurrences all number
    1
    0
    Productive cough
         subjects affected / exposed
    1 / 72 (1.39%)
    3 / 163 (1.84%)
         occurrences all number
    1
    3
    Pulmonary embolism
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 163 (0.61%)
         occurrences all number
    0
    2
    Rhinorrhoea
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 163 (0.61%)
         occurrences all number
    0
    1
    Diaphragmalgia
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 163 (0.61%)
         occurrences all number
    0
    1
    Increased upper airway secretion
         subjects affected / exposed
    1 / 72 (1.39%)
    0 / 163 (0.00%)
         occurrences all number
    1
    0
    Increased viscosity of bronchial secretion
         subjects affected / exposed
    1 / 72 (1.39%)
    0 / 163 (0.00%)
         occurrences all number
    1
    0
    Oropharyngeal pain
         subjects affected / exposed
    3 / 72 (4.17%)
    4 / 163 (2.45%)
         occurrences all number
    3
    4
    Upper-airway cough syndrome
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 163 (0.61%)
         occurrences all number
    0
    1
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    20 / 72 (27.78%)
    15 / 163 (9.20%)
         occurrences all number
    42
    25
    Febrile neutropenia
         subjects affected / exposed
    3 / 72 (4.17%)
    0 / 163 (0.00%)
         occurrences all number
    3
    0
    Neutropenia
         subjects affected / exposed
    35 / 72 (48.61%)
    3 / 163 (1.84%)
         occurrences all number
    80
    4
    Leukopenia
         subjects affected / exposed
    5 / 72 (6.94%)
    2 / 163 (1.23%)
         occurrences all number
    12
    2
    Thrombocytosis
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 163 (0.61%)
         occurrences all number
    0
    1
    Thrombocytopenia
         subjects affected / exposed
    0 / 72 (0.00%)
    8 / 163 (4.91%)
         occurrences all number
    0
    13
    Nervous system disorders
    Asterixis
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 163 (0.61%)
         occurrences all number
    0
    1
    Ageusia
         subjects affected / exposed
    1 / 72 (1.39%)
    1 / 163 (0.61%)
         occurrences all number
    1
    1
    Dizziness
         subjects affected / exposed
    6 / 72 (8.33%)
    6 / 163 (3.68%)
         occurrences all number
    6
    6
    Burning sensation
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 163 (0.61%)
         occurrences all number
    0
    1
    Dizziness postural
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 163 (0.61%)
         occurrences all number
    0
    1
    Dysaesthesia
         subjects affected / exposed
    0 / 72 (0.00%)
    5 / 163 (3.07%)
         occurrences all number
    0
    11
    Dysgeusia
         subjects affected / exposed
    1 / 72 (1.39%)
    7 / 163 (4.29%)
         occurrences all number
    1
    9
    Dysarthria
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 163 (0.61%)
         occurrences all number
    0
    1
    Dyskinesia
         subjects affected / exposed
    0 / 72 (0.00%)
    2 / 163 (1.23%)
         occurrences all number
    0
    2
    Headache
         subjects affected / exposed
    5 / 72 (6.94%)
    15 / 163 (9.20%)
         occurrences all number
    8
    17
    Lethargy
         subjects affected / exposed
    5 / 72 (6.94%)
    4 / 163 (2.45%)
         occurrences all number
    12
    9
    Hypoaesthesia
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 163 (0.61%)
         occurrences all number
    0
    2
    Neuralgia
         subjects affected / exposed
    1 / 72 (1.39%)
    0 / 163 (0.00%)
         occurrences all number
    1
    0
    Neuropathy peripheral
         subjects affected / exposed
    5 / 72 (6.94%)
    27 / 163 (16.56%)
         occurrences all number
    6
    52
    Neurotoxicity
         subjects affected / exposed
    1 / 72 (1.39%)
    0 / 163 (0.00%)
         occurrences all number
    1
    0
    Paraesthesia
         subjects affected / exposed
    5 / 72 (6.94%)
    14 / 163 (8.59%)
         occurrences all number
    7
    44
    Peripheral motor neuropathy
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 163 (0.61%)
         occurrences all number
    0
    1
    Peripheral sensory neuropathy
         subjects affected / exposed
    0 / 72 (0.00%)
    20 / 163 (12.27%)
         occurrences all number
    0
    44
    Polyneuropathy
         subjects affected / exposed
    0 / 72 (0.00%)
    2 / 163 (1.23%)
         occurrences all number
    0
    8
    Sciatica
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 163 (0.61%)
         occurrences all number
    0
    1
    Somnolence
         subjects affected / exposed
    0 / 72 (0.00%)
    3 / 163 (1.84%)
         occurrences all number
    0
    7
    Syncope
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 163 (0.61%)
         occurrences all number
    0
    1
    Tremor
         subjects affected / exposed
    0 / 72 (0.00%)
    2 / 163 (1.23%)
         occurrences all number
    0
    2
    Balance disorder
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 163 (0.61%)
         occurrences all number
    0
    1
    Restless legs syndrome
         subjects affected / exposed
    1 / 72 (1.39%)
    0 / 163 (0.00%)
         occurrences all number
    1
    0
    Brachial plexopathy
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 163 (0.61%)
         occurrences all number
    0
    1
    Taste disorder
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 163 (0.61%)
         occurrences all number
    0
    1
    Eye disorders
    Cataract
         subjects affected / exposed
    2 / 72 (2.78%)
    9 / 163 (5.52%)
         occurrences all number
    2
    13
    Blepharitis
         subjects affected / exposed
    0 / 72 (0.00%)
    5 / 163 (3.07%)
         occurrences all number
    0
    5
    Cataract cortical
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 163 (0.61%)
         occurrences all number
    0
    1
    Corneal erosion
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 163 (0.61%)
         occurrences all number
    0
    2
    Conjunctival haemorrhage
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 163 (0.61%)
         occurrences all number
    0
    1
    Cataract nuclear
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 163 (0.61%)
         occurrences all number
    0
    1
    Diplopia
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 163 (0.61%)
         occurrences all number
    0
    1
    Dry eye
         subjects affected / exposed
    0 / 72 (0.00%)
    22 / 163 (13.50%)
         occurrences all number
    0
    26
    Eye irritation
         subjects affected / exposed
    0 / 72 (0.00%)
    2 / 163 (1.23%)
         occurrences all number
    0
    2
    Eye discharge
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 163 (0.61%)
         occurrences all number
    0
    1
    Lacrimation decreased
         subjects affected / exposed
    0 / 72 (0.00%)
    6 / 163 (3.68%)
         occurrences all number
    0
    7
    Eye pain
         subjects affected / exposed
    0 / 72 (0.00%)
    3 / 163 (1.84%)
         occurrences all number
    0
    3
    Lacrimation disorder
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 163 (0.61%)
         occurrences all number
    0
    1
    Lacrimation increased
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 163 (0.61%)
         occurrences all number
    0
    1
    Ocular hypertension
         subjects affected / exposed
    1 / 72 (1.39%)
    0 / 163 (0.00%)
         occurrences all number
    1
    0
    Photophobia
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 163 (0.61%)
         occurrences all number
    0
    1
    Pinguecula
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 163 (0.61%)
         occurrences all number
    0
    1
    Retinal haemorrhage
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 163 (0.61%)
         occurrences all number
    0
    1
    Retinal tear
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 163 (0.61%)
         occurrences all number
    0
    1
    Vision blurred
         subjects affected / exposed
    0 / 72 (0.00%)
    5 / 163 (3.07%)
         occurrences all number
    0
    6
    Retinal vascular disorder
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 163 (0.61%)
         occurrences all number
    0
    1
    Visual acuity reduced
         subjects affected / exposed
    0 / 72 (0.00%)
    6 / 163 (3.68%)
         occurrences all number
    0
    7
    Visual impairment
         subjects affected / exposed
    0 / 72 (0.00%)
    2 / 163 (1.23%)
         occurrences all number
    0
    2
    Vitreous floaters
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 163 (0.61%)
         occurrences all number
    0
    1
    Conjunctival hyperaemia
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 163 (0.61%)
         occurrences all number
    0
    1
    Eye pruritus
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 163 (0.61%)
         occurrences all number
    0
    1
    Ocular discomfort
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 163 (0.61%)
         occurrences all number
    0
    1
    Corneal disorder
         subjects affected / exposed
    0 / 72 (0.00%)
    65 / 163 (39.88%)
         occurrences all number
    0
    156
    Ear and labyrinth disorders
    Deafness
         subjects affected / exposed
    1 / 72 (1.39%)
    1 / 163 (0.61%)
         occurrences all number
    1
    1
    Vertigo
         subjects affected / exposed
    0 / 72 (0.00%)
    2 / 163 (1.23%)
         occurrences all number
    0
    2
    Hypoacusis
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 163 (0.61%)
         occurrences all number
    0
    1
    Excessive cerumen production
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 163 (0.61%)
         occurrences all number
    0
    1
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    4 / 72 (5.56%)
    4 / 163 (2.45%)
         occurrences all number
    4
    4
    Abdominal pain
         subjects affected / exposed
    10 / 72 (13.89%)
    18 / 163 (11.04%)
         occurrences all number
    13
    27
    Abdominal pain lower
         subjects affected / exposed
    0 / 72 (0.00%)
    2 / 163 (1.23%)
         occurrences all number
    0
    2
    Abdominal pain upper
         subjects affected / exposed
    5 / 72 (6.94%)
    9 / 163 (5.52%)
         occurrences all number
    5
    14
    Ascites
         subjects affected / exposed
    0 / 72 (0.00%)
    3 / 163 (1.84%)
         occurrences all number
    0
    5
    Aphthous ulcer
         subjects affected / exposed
    1 / 72 (1.39%)
    0 / 163 (0.00%)
         occurrences all number
    1
    0
    Constipation
         subjects affected / exposed
    34 / 72 (47.22%)
    29 / 163 (17.79%)
         occurrences all number
    51
    39
    Diarrhoea
         subjects affected / exposed
    15 / 72 (20.83%)
    56 / 163 (34.36%)
         occurrences all number
    22
    91
    Dry mouth
         subjects affected / exposed
    0 / 72 (0.00%)
    7 / 163 (4.29%)
         occurrences all number
    0
    8
    Dyspepsia
         subjects affected / exposed
    1 / 72 (1.39%)
    13 / 163 (7.98%)
         occurrences all number
    1
    14
    Dysphagia
         subjects affected / exposed
    1 / 72 (1.39%)
    2 / 163 (1.23%)
         occurrences all number
    1
    4
    Flatulence
         subjects affected / exposed
    1 / 72 (1.39%)
    4 / 163 (2.45%)
         occurrences all number
    1
    4
    Gastrooesophageal reflux disease
         subjects affected / exposed
    1 / 72 (1.39%)
    6 / 163 (3.68%)
         occurrences all number
    1
    7
    Gastrointestinal disorder
         subjects affected / exposed
    1 / 72 (1.39%)
    0 / 163 (0.00%)
         occurrences all number
    1
    0
    Gastrointestinal pain
         subjects affected / exposed
    0 / 72 (0.00%)
    2 / 163 (1.23%)
         occurrences all number
    0
    2
    Gingival bleeding
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 163 (0.61%)
         occurrences all number
    0
    2
    Glossitis
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 163 (0.61%)
         occurrences all number
    0
    1
    Haemorrhoids
         subjects affected / exposed
    2 / 72 (2.78%)
    1 / 163 (0.61%)
         occurrences all number
    2
    1
    Inguinal hernia
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 163 (0.61%)
         occurrences all number
    0
    1
    Lip oedema
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 163 (0.61%)
         occurrences all number
    0
    1
    Mouth ulceration
         subjects affected / exposed
    1 / 72 (1.39%)
    1 / 163 (0.61%)
         occurrences all number
    1
    1
    Nausea
         subjects affected / exposed
    24 / 72 (33.33%)
    68 / 163 (41.72%)
         occurrences all number
    38
    130
    Oral pain
         subjects affected / exposed
    3 / 72 (4.17%)
    0 / 163 (0.00%)
         occurrences all number
    3
    0
    Rectal haemorrhage
         subjects affected / exposed
    1 / 72 (1.39%)
    0 / 163 (0.00%)
         occurrences all number
    1
    0
    Toothache
         subjects affected / exposed
    1 / 72 (1.39%)
    1 / 163 (0.61%)
         occurrences all number
    1
    1
    Stomatitis
         subjects affected / exposed
    5 / 72 (6.94%)
    2 / 163 (1.23%)
         occurrences all number
    6
    2
    Vomiting
         subjects affected / exposed
    5 / 72 (6.94%)
    34 / 163 (20.86%)
         occurrences all number
    8
    62
    Aerophagia
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 163 (0.61%)
         occurrences all number
    0
    1
    Paraesthesia oral
         subjects affected / exposed
    1 / 72 (1.39%)
    0 / 163 (0.00%)
         occurrences all number
    1
    0
    Renal and urinary disorders
    Dysuria
         subjects affected / exposed
    0 / 72 (0.00%)
    2 / 163 (1.23%)
         occurrences all number
    0
    2
    Haematuria
         subjects affected / exposed
    1 / 72 (1.39%)
    2 / 163 (1.23%)
         occurrences all number
    1
    2
    Nocturia
         subjects affected / exposed
    1 / 72 (1.39%)
    1 / 163 (0.61%)
         occurrences all number
    1
    1
    Proteinuria
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 163 (0.61%)
         occurrences all number
    0
    1
    Renal failure
         subjects affected / exposed
    1 / 72 (1.39%)
    0 / 163 (0.00%)
         occurrences all number
    1
    0
    Urinary retention
         subjects affected / exposed
    0 / 72 (0.00%)
    2 / 163 (1.23%)
         occurrences all number
    0
    2
    Urinary tract pain
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 163 (0.61%)
         occurrences all number
    0
    1
    Bladder trabeculation
         subjects affected / exposed
    1 / 72 (1.39%)
    0 / 163 (0.00%)
         occurrences all number
    1
    0
    Acute kidney injury
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 163 (0.61%)
         occurrences all number
    0
    1
    Hepatobiliary disorders
    Hepatic failure
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 163 (0.61%)
         occurrences all number
    0
    1
    Hepatocellular injury
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 163 (0.61%)
         occurrences all number
    0
    1
    Jaundice cholestatic
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 163 (0.61%)
         occurrences all number
    0
    1
    Product issues
    Device malfunction
         subjects affected / exposed
    1 / 72 (1.39%)
    0 / 163 (0.00%)
         occurrences all number
    1
    0
    Device occlusion
         subjects affected / exposed
    1 / 72 (1.39%)
    0 / 163 (0.00%)
         occurrences all number
    1
    0
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    2 / 72 (2.78%)
    3 / 163 (1.84%)
         occurrences all number
    2
    3
    Dermatitis
         subjects affected / exposed
    1 / 72 (1.39%)
    0 / 163 (0.00%)
         occurrences all number
    1
    0
    Dry skin
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 163 (0.61%)
         occurrences all number
    0
    1
    Dermatitis acneiform
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 163 (0.61%)
         occurrences all number
    0
    1
    Eczema
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 163 (0.61%)
         occurrences all number
    0
    1
    Erythema
         subjects affected / exposed
    1 / 72 (1.39%)
    1 / 163 (0.61%)
         occurrences all number
    1
    4
    Erythema multiforme
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 163 (0.61%)
         occurrences all number
    0
    1
    Hyperhidrosis
         subjects affected / exposed
    1 / 72 (1.39%)
    5 / 163 (3.07%)
         occurrences all number
    1
    5
    Hyperkeratosis
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 163 (0.61%)
         occurrences all number
    0
    1
    Ingrowing nail
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 163 (0.61%)
         occurrences all number
    0
    1
    Nail disorder
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 163 (0.61%)
         occurrences all number
    0
    1
    Night sweats
         subjects affected / exposed
    2 / 72 (2.78%)
    7 / 163 (4.29%)
         occurrences all number
    2
    9
    Palmar-plantar erythrodysaesthesia syndrome
         subjects affected / exposed
    1 / 72 (1.39%)
    0 / 163 (0.00%)
         occurrences all number
    1
    0
    Photosensitivity reaction
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 163 (0.61%)
         occurrences all number
    0
    1
    Pruritus
         subjects affected / exposed
    0 / 72 (0.00%)
    3 / 163 (1.84%)
         occurrences all number
    0
    5
    Psoriasis
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 163 (0.61%)
         occurrences all number
    0
    1
    Rash
         subjects affected / exposed
    3 / 72 (4.17%)
    9 / 163 (5.52%)
         occurrences all number
    3
    12
    Rash macular
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 163 (0.61%)
         occurrences all number
    0
    1
    Rash papular
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 163 (0.61%)
         occurrences all number
    0
    1
    Rash maculo-papular
         subjects affected / exposed
    0 / 72 (0.00%)
    2 / 163 (1.23%)
         occurrences all number
    0
    4
    Rash pruritic
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 163 (0.61%)
         occurrences all number
    0
    1
    Skin irritation
         subjects affected / exposed
    1 / 72 (1.39%)
    0 / 163 (0.00%)
         occurrences all number
    1
    0
    Skin hypertrophy
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 163 (0.61%)
         occurrences all number
    0
    1
    Pruritus generalised
         subjects affected / exposed
    1 / 72 (1.39%)
    1 / 163 (0.61%)
         occurrences all number
    1
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    3 / 72 (4.17%)
    19 / 163 (11.66%)
         occurrences all number
    3
    29
    Back pain
         subjects affected / exposed
    9 / 72 (12.50%)
    11 / 163 (6.75%)
         occurrences all number
    10
    13
    Coccydynia
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 163 (0.61%)
         occurrences all number
    0
    1
    Bone pain
         subjects affected / exposed
    0 / 72 (0.00%)
    2 / 163 (1.23%)
         occurrences all number
    0
    2
    Flank pain
         subjects affected / exposed
    2 / 72 (2.78%)
    1 / 163 (0.61%)
         occurrences all number
    3
    1
    Joint swelling
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 163 (0.61%)
         occurrences all number
    0
    1
    Muscle discomfort
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 163 (0.61%)
         occurrences all number
    0
    1
    Muscle spasms
         subjects affected / exposed
    3 / 72 (4.17%)
    8 / 163 (4.91%)
         occurrences all number
    3
    8
    Muscular weakness
         subjects affected / exposed
    2 / 72 (2.78%)
    6 / 163 (3.68%)
         occurrences all number
    2
    7
    Musculoskeletal pain
         subjects affected / exposed
    3 / 72 (4.17%)
    10 / 163 (6.13%)
         occurrences all number
    3
    13
    Myalgia
         subjects affected / exposed
    5 / 72 (6.94%)
    22 / 163 (13.50%)
         occurrences all number
    7
    34
    Myopathy
         subjects affected / exposed
    1 / 72 (1.39%)
    0 / 163 (0.00%)
         occurrences all number
    1
    0
    Neck pain
         subjects affected / exposed
    0 / 72 (0.00%)
    3 / 163 (1.84%)
         occurrences all number
    0
    3
    Pain in extremity
         subjects affected / exposed
    4 / 72 (5.56%)
    10 / 163 (6.13%)
         occurrences all number
    5
    11
    Pain in jaw
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 163 (0.61%)
         occurrences all number
    0
    1
    Rotator cuff syndrome
         subjects affected / exposed
    0 / 72 (0.00%)
    2 / 163 (1.23%)
         occurrences all number
    0
    2
    Musculoskeletal chest pain
         subjects affected / exposed
    2 / 72 (2.78%)
    9 / 163 (5.52%)
         occurrences all number
    3
    13
    Musculoskeletal stiffness
         subjects affected / exposed
    0 / 72 (0.00%)
    2 / 163 (1.23%)
         occurrences all number
    0
    2
    Musculoskeletal discomfort
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 163 (0.61%)
         occurrences all number
    0
    1
    Muscle contracture
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 163 (0.61%)
         occurrences all number
    0
    2
    Tendon pain
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 163 (0.61%)
         occurrences all number
    0
    1
    Spinal pain
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 163 (0.61%)
         occurrences all number
    0
    1
    Metabolism and nutrition disorders
    Folate deficiency
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 163 (0.61%)
         occurrences all number
    0
    1
    Dehydration
         subjects affected / exposed
    0 / 72 (0.00%)
    3 / 163 (1.84%)
         occurrences all number
    0
    3
    Hyperglycaemia
         subjects affected / exposed
    1 / 72 (1.39%)
    2 / 163 (1.23%)
         occurrences all number
    2
    3
    Hyperkalaemia
         subjects affected / exposed
    1 / 72 (1.39%)
    2 / 163 (1.23%)
         occurrences all number
    1
    3
    Hypertriglyceridaemia
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 163 (0.61%)
         occurrences all number
    0
    1
    Hyperuricaemia
         subjects affected / exposed
    1 / 72 (1.39%)
    2 / 163 (1.23%)
         occurrences all number
    1
    3
    Hypoalbuminaemia
         subjects affected / exposed
    4 / 72 (5.56%)
    1 / 163 (0.61%)
         occurrences all number
    5
    1
    Hypocalcaemia
         subjects affected / exposed
    2 / 72 (2.78%)
    1 / 163 (0.61%)
         occurrences all number
    6
    1
    Hypokalaemia
         subjects affected / exposed
    2 / 72 (2.78%)
    7 / 163 (4.29%)
         occurrences all number
    9
    8
    Hyponatraemia
         subjects affected / exposed
    2 / 72 (2.78%)
    3 / 163 (1.84%)
         occurrences all number
    2
    5
    Hypomagnesaemia
         subjects affected / exposed
    2 / 72 (2.78%)
    1 / 163 (0.61%)
         occurrences all number
    2
    1
    Hypophosphataemia
         subjects affected / exposed
    3 / 72 (4.17%)
    1 / 163 (0.61%)
         occurrences all number
    5
    1
    Decreased appetite
         subjects affected / exposed
    17 / 72 (23.61%)
    58 / 163 (35.58%)
         occurrences all number
    24
    75
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    3 / 72 (4.17%)
    4 / 163 (2.45%)
         occurrences all number
    4
    5
    Cellulitis
         subjects affected / exposed
    0 / 72 (0.00%)
    3 / 163 (1.84%)
         occurrences all number
    0
    3
    Conjunctivitis
         subjects affected / exposed
    1 / 72 (1.39%)
    3 / 163 (1.84%)
         occurrences all number
    1
    4
    Cystitis
         subjects affected / exposed
    0 / 72 (0.00%)
    2 / 163 (1.23%)
         occurrences all number
    0
    2
    Eyelid infection
         subjects affected / exposed
    1 / 72 (1.39%)
    1 / 163 (0.61%)
         occurrences all number
    1
    1
    Eye infection
         subjects affected / exposed
    0 / 72 (0.00%)
    3 / 163 (1.84%)
         occurrences all number
    0
    3
    Ear infection
         subjects affected / exposed
    1 / 72 (1.39%)
    0 / 163 (0.00%)
         occurrences all number
    1
    0
    Folliculitis
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 163 (0.61%)
         occurrences all number
    0
    1
    Gastroenteritis viral
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 163 (0.61%)
         occurrences all number
    0
    1
    Gastrointestinal infection
         subjects affected / exposed
    1 / 72 (1.39%)
    0 / 163 (0.00%)
         occurrences all number
    1
    0
    Genital candidiasis
         subjects affected / exposed
    1 / 72 (1.39%)
    0 / 163 (0.00%)
         occurrences all number
    1
    0
    Herpes zoster
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 163 (0.61%)
         occurrences all number
    0
    2
    Lower respiratory tract infection
         subjects affected / exposed
    2 / 72 (2.78%)
    0 / 163 (0.00%)
         occurrences all number
    3
    0
    Nasopharyngitis
         subjects affected / exposed
    0 / 72 (0.00%)
    2 / 163 (1.23%)
         occurrences all number
    0
    2
    Oral candidiasis
         subjects affected / exposed
    4 / 72 (5.56%)
    5 / 163 (3.07%)
         occurrences all number
    4
    5
    Otitis media
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 163 (0.61%)
         occurrences all number
    0
    1
    Paronychia
         subjects affected / exposed
    1 / 72 (1.39%)
    0 / 163 (0.00%)
         occurrences all number
    1
    0
    Pyelonephritis
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 163 (0.61%)
         occurrences all number
    0
    1
    Pneumonia
         subjects affected / exposed
    3 / 72 (4.17%)
    2 / 163 (1.23%)
         occurrences all number
    3
    3
    Sinusitis
         subjects affected / exposed
    2 / 72 (2.78%)
    1 / 163 (0.61%)
         occurrences all number
    2
    1
    Tonsillitis
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 163 (0.61%)
         occurrences all number
    0
    1
    Upper respiratory tract infection
         subjects affected / exposed
    5 / 72 (6.94%)
    5 / 163 (3.07%)
         occurrences all number
    8
    7
    Urinary tract infection
         subjects affected / exposed
    0 / 72 (0.00%)
    7 / 163 (4.29%)
         occurrences all number
    0
    9
    Rectal abscess
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 163 (0.61%)
         occurrences all number
    0
    5
    Vaginal infection
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 163 (0.61%)
         occurrences all number
    0
    1
    Febrile infection
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 163 (0.61%)
         occurrences all number
    0
    1
    Lung infection
         subjects affected / exposed
    1 / 72 (1.39%)
    2 / 163 (1.23%)
         occurrences all number
    1
    2
    Oral fungal infection
         subjects affected / exposed
    0 / 72 (0.00%)
    2 / 163 (1.23%)
         occurrences all number
    0
    2
    Bronchitis bacterial
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 163 (0.61%)
         occurrences all number
    0
    1
    Penile infection
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 163 (0.61%)
         occurrences all number
    0
    1
    Respiratory tract infection
         subjects affected / exposed
    1 / 72 (1.39%)
    2 / 163 (1.23%)
         occurrences all number
    1
    2
    Lip infection
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 163 (0.61%)
         occurrences all number
    0
    1
    Mucosal infection
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 163 (0.61%)
         occurrences all number
    0
    1
    Peripheral nerve infection
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 163 (0.61%)
         occurrences all number
    0
    1
    Infectious pleural effusion
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 163 (0.61%)
         occurrences all number
    0
    3
    Candida infection
         subjects affected / exposed
    2 / 72 (2.78%)
    1 / 163 (0.61%)
         occurrences all number
    2
    1
    Tongue fungal infection
         subjects affected / exposed
    1 / 72 (1.39%)
    0 / 163 (0.00%)
         occurrences all number
    1
    0

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    09 Feb 2016
    1. The study design was changed to increase the power of the OS analysis with a corresponding increase in sample size and an increase in number of required OS events. 2. Information was updated on the estimated number of prescreened and screened patients needed to reach 210 randomized patients. The revised design also incorporated assumptions changes, including an increase in the accrual rate, more conservative PFS dropout assumptions, and a lower OS dropout assumption.
    11 Aug 2016
    1 The option for 5 drug half lives was removed from the time window for prior treatment with platinum in combination with pemetrexed before the start of study treatment. 2. Exclusion of patients having received prior device therapy. 3. Exclusion of patients with central nervous system metastasis. 4. DRR was added as a secondary variable. 5. Final analyses of DOR and DRR were specified to occur at the time of final OS analysis.
    18 Apr 2017
    1. Dextrose was added as an alternative diluent for anetumab ravtansine.
    27 Mar 2018
    1. Following OS data maturation, patients remaining on study will continue to be followed with reduced mandated assessments and data collection. in anetumab ravtansine and vinorelbine arms, respectively. 2. The sponsor will continue to assess survival data on patients after OS data maturation until 24 months after last patient’s last treatment. 3. Clarification that end of study is defined by last visit of the last patient within the 15743 study and as a whole the date when the final clean database is available. In addition the possibility that treatment or follow up of subjects could continue within a separate program was included. 4. Allow delay in administration of anetumab ravtansine for up to 12 weeks and patients should be allowed to continue as per investigator’s discretion if they are benefitting from treatment.

    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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