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    Clinical Trial Results:
    A Phase III Open-label, Multicenter Trial of Avelumab (MSB0010718C) as a Third-line Treatment of Unresectable, Recurrent, or Metastatic Gastric or Gastroesophageal Junction Adenocarcinoma

    Summary
    EudraCT number
    2015-003301-42
    Trial protocol
    DE   BE   ES   CZ   FR   PL   IT  
    Global end of trial date
    13 Nov 2019

    Results information
    Results version number
    v1(current)
    This version publication date
    22 Nov 2020
    First version publication date
    22 Nov 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    EMR100070-008
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02625623
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Merck KGaA, Darmstadt, Germany
    Sponsor organisation address
    Frankfurter Strasse 250,, Darmstadt, Germany, 64293
    Public contact
    Communication Centre, Merck KGaA, Darmstadt, Germany, +49 6151 72 5200, service@merckgroup.com
    Scientific contact
    Communication Centre, Merck KGaA, Darmstadt, Germany, +49 6151 72 5200, service@merckgroup.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    13 Nov 2019
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    13 Nov 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective was to demonstrate superiority with regard to Overall Survival (OS) of avelumab plus best supportive care (BSC) versus physician’s choice (chosen from a pre-specified list of therapeutic options) plus BSC.
    Protection of trial subjects
    Subject protection was ensured by following high medical and ethical standards in accordance with the principles laid down in the Declaration of Helsinki, and that are consistent with Good Clinical Practice and applicable regulations.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    28 Dec 2015
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Australia: 8
    Country: Number of subjects enrolled
    Belgium: 43
    Country: Number of subjects enrolled
    Chile: 20
    Country: Number of subjects enrolled
    Czechia: 8
    Country: Number of subjects enrolled
    France: 38
    Country: Number of subjects enrolled
    Germany: 28
    Country: Number of subjects enrolled
    Italy: 28
    Country: Number of subjects enrolled
    Japan: 37
    Country: Number of subjects enrolled
    Korea, Republic of: 56
    Country: Number of subjects enrolled
    Poland: 12
    Country: Number of subjects enrolled
    Romania: 19
    Country: Number of subjects enrolled
    Russian Federation: 28
    Country: Number of subjects enrolled
    Spain: 21
    Country: Number of subjects enrolled
    United States: 25
    Worldwide total number of subjects
    371
    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)
    230
    From 65 to 84 years
    140
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    First subject (informed consent): 28 December 2015 and Last subject last visit: 13 November 2019.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Physician choice chemotherapy + Best Supportive Care (BSC)
    Arm description
    Subjects received BSC plus physician’s choice chemotherapy. Chemotherapy comprised of one of the following: intravenous (IV) infusion of paclitaxel at a dose of 80 milligrams per meter square (mg/m^2) on Days 1, 8 and 15 of a 4-week treatment cycle until progressive disease or unacceptable toxicity OR irinotecan at a dose of 150 mg/m^2 on Days 1 and 15 of a 4-week treatment cycle until progressive disease or unacceptable toxicity. Subjects who were not deemed eligible to receive paclitaxel or irinotecan at the dose and schedule specified above received BSC alone once every 3 weeks. BSC was defined as treatment administered with the intent to maximize quality of life without a specific antineoplastic regimen and was based on investigator's discretion.
    Arm type
    Experimental

    Investigational medicinal product name
    Irinotecan
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Irinotecan was administered intravenously at a dose of 150 milligrams per square meter (mg/m^2) on Days 1 and 15 of a 4-week treatment cycle until disease progression or unacceptable toxicities along with best supportive care (BSC).

    Investigational medicinal product name
    Paclitaxel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Paclitaxel was administered intravenously at a dose of 80 mg/m^2 on Days 1, 8 and 15 of a 4-week treatment cycle until disease progression or unacceptable toxicities along with BSC.

    Arm title
    Avelumab + BSC
    Arm description
    Subjects received avelumab as a 1-hour intravenous (IV) infusion at 10 milligrams per kilogram (mg/kg) once every 2-week treatment cycle until progressive disease or unacceptable toxicity along with BSC. BSC was defined as treatment administered with the intent to maximize quality of life without a specific antineoplastic regimen and was based on investigator's discretion.
    Arm type
    Active comparator

    Investigational medicinal product name
    Avelumab
    Investigational medicinal product code
    Other name
    MSB0010718C Anti PD-L1
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Avelumab was administered as a 1-hour intravenous infusion at 10 milligrams per kilogram (mg/kg) once every 2-week treatment cycle until confirmed progressive disease or unacceptable toxicity along with best supportive care (BSC).

    Number of subjects in period 1
    Physician choice chemotherapy + Best Supportive Care (BSC) Avelumab + BSC
    Started
    186
    185
    Treated
    177
    184
    Completed
    177
    184
    Not completed
    9
    1
         Subjects randomized not treated
    9
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Physician choice chemotherapy + Best Supportive Care (BSC)
    Reporting group description
    Subjects received BSC plus physician’s choice chemotherapy. Chemotherapy comprised of one of the following: intravenous (IV) infusion of paclitaxel at a dose of 80 milligrams per meter square (mg/m^2) on Days 1, 8 and 15 of a 4-week treatment cycle until progressive disease or unacceptable toxicity OR irinotecan at a dose of 150 mg/m^2 on Days 1 and 15 of a 4-week treatment cycle until progressive disease or unacceptable toxicity. Subjects who were not deemed eligible to receive paclitaxel or irinotecan at the dose and schedule specified above received BSC alone once every 3 weeks. BSC was defined as treatment administered with the intent to maximize quality of life without a specific antineoplastic regimen and was based on investigator's discretion.

    Reporting group title
    Avelumab + BSC
    Reporting group description
    Subjects received avelumab as a 1-hour intravenous (IV) infusion at 10 milligrams per kilogram (mg/kg) once every 2-week treatment cycle until progressive disease or unacceptable toxicity along with BSC. BSC was defined as treatment administered with the intent to maximize quality of life without a specific antineoplastic regimen and was based on investigator's discretion.

    Reporting group values
    Physician choice chemotherapy + Best Supportive Care (BSC) Avelumab + BSC Total
    Number of subjects
    186 185 371
    Age Categorical
    Units:
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    60.1 ± 12.93 58.8 ± 11.66 -
    Gender Categorical
    Units: subjects
        Female
    59 45 104
        Male
    127 140 267

    End points

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    End points reporting groups
    Reporting group title
    Physician choice chemotherapy + Best Supportive Care (BSC)
    Reporting group description
    Subjects received BSC plus physician’s choice chemotherapy. Chemotherapy comprised of one of the following: intravenous (IV) infusion of paclitaxel at a dose of 80 milligrams per meter square (mg/m^2) on Days 1, 8 and 15 of a 4-week treatment cycle until progressive disease or unacceptable toxicity OR irinotecan at a dose of 150 mg/m^2 on Days 1 and 15 of a 4-week treatment cycle until progressive disease or unacceptable toxicity. Subjects who were not deemed eligible to receive paclitaxel or irinotecan at the dose and schedule specified above received BSC alone once every 3 weeks. BSC was defined as treatment administered with the intent to maximize quality of life without a specific antineoplastic regimen and was based on investigator's discretion.

    Reporting group title
    Avelumab + BSC
    Reporting group description
    Subjects received avelumab as a 1-hour intravenous (IV) infusion at 10 milligrams per kilogram (mg/kg) once every 2-week treatment cycle until progressive disease or unacceptable toxicity along with BSC. BSC was defined as treatment administered with the intent to maximize quality of life without a specific antineoplastic regimen and was based on investigator's discretion.

    Primary: Overall Survival (OS)

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    End point title
    Overall Survival (OS)
    End point description
    OS was defined as the time from randomization to the date of death due to any cause. For subjects who were still alive at the time of data analysis or who were lost to follow-up, OS time was censored at the date of last contact. OS was measured using Kaplan-Meier (KM) estimates. Full analysis set (FAS) included all subjects who were randomized to study treatment.
    End point type
    Primary
    End point timeframe
    From randomization up to 627 days
    End point values
    Physician choice chemotherapy + Best Supportive Care (BSC) Avelumab + BSC
    Number of subjects analysed
    186
    185
    Units: months
        median (confidence interval 95%)
    5.0 (4.5 to 6.3)
    4.6 (3.6 to 5.7)
    Statistical analysis title
    Treatment Comparison
    Comparison groups
    Physician choice chemotherapy + Best Supportive Care (BSC) v Avelumab + BSC
    Number of subjects included in analysis
    371
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.8078 [1]
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    1.11
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.88
         upper limit
    1.41
    Notes
    [1] - The treatment arms were compared using a stratified, 1-sided, log rank Test. The stratification factor was region (Asia versus non Asia).

    Secondary: Progression Free Survival (PFS)

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    End point title
    Progression Free Survival (PFS)
    End point description
    The PFS time was defined as the time from date of randomization until date of the first documentation of progressive disease (PD) or death due to any cause (whichever occurs first). PFS was assessed as per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1). PD was defined as at least a 20 percent (%) increase in the sum of longest diameter (SLD), taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions. PFS was measured using Kaplan-Meier (KM) estimates. FAS included all subjects who were randomized to study treatment.
    End point type
    Secondary
    End point timeframe
    From randomization up to 627 days
    End point values
    Physician choice chemotherapy + Best Supportive Care (BSC) Avelumab + BSC
    Number of subjects analysed
    186
    185
    Units: months
        median (confidence interval 95%)
    2.7 (1.81 to 2.83)
    1.4 (1.38 to 1.45)
    Statistical analysis title
    Treatment Comparison
    Comparison groups
    Physician choice chemotherapy + Best Supportive Care (BSC) v Avelumab + BSC
    Number of subjects included in analysis
    371
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 1 [2]
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    1.73
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.36
         upper limit
    2.21
    Notes
    [2] - The treatment arms were compared using a stratified, 1-sided, log rank Test. The stratification factor was region (Asia versus non Asia).

    Secondary: Best Overall Response (BOR)

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    End point title
    Best Overall Response (BOR)
    End point description
    BOR was determined by RECIST v1.1 and defined as best-confirmed response of any of following: complete response (CR), partial response (PR), stable disease (SD) and PD recorded from date of randomization until disease progression or recurrence. CR:Disappearance of all evidence of target and non-target lesions. PR:At least 30% reduction from baseline in SLD of all lesions. SD=Neither sufficient increase to qualify for PD nor sufficient shrinkage to qualify for PR. PD is defined as at least a 20% increase in the SLD, taking as reference the smallest SLD recorded from baseline or appearance of 1 or more new lesions. PR or CR confirmed at a subsequent tumor assessment, not sooner than 5 weeks after initial documentation or at an assessment later than the next assessment after the initial documentation of PR or CR. SD confirmed at least 6 weeks after randomization. Confirmed PD=progression <=2 weeks after date of randomization (and not qualifying for CR, PR or SD). FAS was used.
    End point type
    Secondary
    End point timeframe
    From randomization up to 627 days
    End point values
    Physician choice chemotherapy + Best Supportive Care (BSC) Avelumab + BSC
    Number of subjects analysed
    186
    185
    Units: subjects
        Complete Response
    1
    1
        Partial response
    7
    3
        Stable disease
    62
    30
        Non-complete response/ Non-progressive disease
    12
    7
        Progressive disease
    59
    94
        Non-evaluable
    45
    50
    No statistical analyses for this end point

    Secondary: Objective Response Rate (ORR)

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    End point title
    Objective Response Rate (ORR)
    End point description
    The ORR defined as the percentage of all randomized subjects with a confirmed best overall response (BOR) of partial response (PR),or complete response (CR) according to RECIST v1.1 and as adjudicated by the Independent Review Committee (IRC). CR: Disappearance of all evidence of target and non-target lesions. PR: At least 30 percent (%) reduction from baseline in sum of longest diameter (SLD) of all lesions. FAS included all subjects who were randomized to study treatment.
    End point type
    Secondary
    End point timeframe
    From randomization up to 627 days
    End point values
    Physician choice chemotherapy + Best Supportive Care (BSC) Avelumab + BSC
    Number of subjects analysed
    186
    185
    Units: percentage of subjects
        number (confidence interval 95%)
    4.3 (1.9 to 8.3)
    2.2 (0.6 to 5.4)
    Statistical analysis title
    Treatment Comparison
    Comparison groups
    Physician choice chemotherapy + Best Supportive Care (BSC) v Avelumab + BSC
    Number of subjects included in analysis
    371
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.8764 [3]
    Method
    Cochran-Mantel-Haenszel
    Confidence interval
    Notes
    [3] - The treatment arms were compared by 1-sided CMH test. The stratification factor was region (Asia versus non Asia).

    Secondary: Change From Baseline in European Quality of Life 5-dimensions (EQ-5D-5L) Health Outcome Questionnaire Through Composite Index Score at End Of Treatment (EOT)

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    End point title
    Change From Baseline in European Quality of Life 5-dimensions (EQ-5D-5L) Health Outcome Questionnaire Through Composite Index Score at End Of Treatment (EOT)
    End point description
    EQ-5D-5L was comprised of the following 5 subject-reported dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each dimension has 5 levels: no problems, slight problems, moderate problems, severe problems, and extreme problems. The responses were used to derive overall composite health state index score, with scores ranging from -0.594 to 1. A higher score indicates better health state. Health-related quality of life (HRQoL) analysis set included a subset of the FAS and included FAS subjects who met the following criteria: had 1 Baseline HRQoL assessment, had at least 1 post-Baseline HRQoL questionnaire completed. Here, “Number of Subjects Analyzed” signifies those subjects who were evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline, EOT (up to Week 66)
    End point values
    Physician choice chemotherapy + Best Supportive Care (BSC) Avelumab + BSC
    Number of subjects analysed
    92
    74
    Units: units on a scale
        arithmetic mean (standard deviation)
    -0.103 ± 0.2113
    -0.144 ± 0.2088
    No statistical analyses for this end point

    Secondary: Change From Baseline in European Quality of Life 5-dimensions (EQ-5D-5L) Health Outcome Questionnaire Through Visual Analogue Scale (VAS) at End Of Treatment (EOT)

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    End point title
    Change From Baseline in European Quality of Life 5-dimensions (EQ-5D-5L) Health Outcome Questionnaire Through Visual Analogue Scale (VAS) at End Of Treatment (EOT)
    End point description
    EQ-5D-5L was comprised of the following 5 subject-reported dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each dimension has 5 levels: no problems, slight problems, moderate problems, severe problems, and extreme problems. The responses were used to derive overall score using a visual analog scale (VAS) that ranged from 0 to 100 millimeter (mm), where 0 is the worst health you can imagine and 100 is the best health you can imagine. HRQoL analysis set included a subset of the FAS and included FAS subjects who met the following criteria: had 1 Baseline HRQoL assessment, had at least 1 post-Baseline HRQoL questionnaire completed. Here, “Number of Subjects Analyzed” signifies those subjects who were evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline, EOT (up to Week 66)
    End point values
    Physician choice chemotherapy + Best Supportive Care (BSC) Avelumab + BSC
    Number of subjects analysed
    92
    74
    Units: millimeter (mm)
        arithmetic mean (standard deviation)
    -12.3 ± 19.22
    -13.6 ± 19.76
    No statistical analyses for this end point

    Secondary: Change From Baseline in European Organization for the Research and Treatment of Cancer Quality of Life (EORTC QLQ-C30) Global Health Status Scale at End Of Treatment (EOT)

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    End point title
    Change From Baseline in European Organization for the Research and Treatment of Cancer Quality of Life (EORTC QLQ-C30) Global Health Status Scale at End Of Treatment (EOT)
    End point description
    EORTC QLQ-C30 is a 30-question tool used to assess the overall quality of life (QoL) in cancer subjects. It consisted of 15 domains: 1 global health status (GHS) scale, 5 functional scales (Physical, role, cognitive, emotional, social), and 9 symptom scales/items (Fatigue, nausea and vomiting, pain, dyspnoea, sleep disturbance, appetite loss, constipation, diarrhea, financial impact. The EORTC QLQ-C30 GHS/QoL score ranges from 0 to 100; High score indicates better GHS/QoL. Score 0 represents: very poor physical condition and QoL. Score 100 represents: excellent overall physical condition and QoL. HRQoL analysis set included a subset of the FAS and included FAS subjects who met the following criteria: had 1 Baseline HRQoL assessment and had at least 1 post-Baseline HRQoL questionnaire completed. Here, “Number of Subjects Analyzed” signifies those subjects who were evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline, EOT (up to Week 66)
    End point values
    Physician choice chemotherapy + Best Supportive Care (BSC) Avelumab + BSC
    Number of subjects analysed
    92
    74
    Units: units on a scale
        arithmetic mean (standard deviation)
    -10.14 ± 19.914
    -15.77 ± 19.437
    No statistical analyses for this end point

    Secondary: Change From Baseline in European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire-Stomach Cancer Specific (EORTC QLQ-STO22) Questionnaire Scores at End Of Treatment (EOT)

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    End point title
    Change From Baseline in European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire-Stomach Cancer Specific (EORTC QLQ-STO22) Questionnaire Scores at End Of Treatment (EOT)
    End point description
    The EORTC QLQ-STO22 supplements the EORTC QLQ-C30 to assess symptoms and treatment-related side effects commonly reported in subjects. There are 22 questions which comprise 5 scales (dysphagia, pain, reflux symptom, dietary restrictions, and anxiety) and 4 single items (dry mouth, hair loss, taste, body image). Most questions use 4-point scale (1 ‘Not at all’ to 4 ‘Very much’; 1 question was a yes or no answer). A linear transformation was used to standardize all scores and single-items to a scale of 0 to 100; higher score=better level of functioning or greater degree of symptoms. HRQoL analysis set included a subset of the FAS and included FAS subjects who met the following criteria: had 1 Baseline HRQoL assessment and had at least 1 post-Baseline HRQoL questionnaire completed. "Number of Subjects Analyzed" signifies those subjects who were evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline, EOT (up to Week 66)
    End point values
    Physician choice chemotherapy + Best Supportive Care (BSC) Avelumab + BSC
    Number of subjects analysed
    92
    74
    Units: units on a scale
    arithmetic mean (standard deviation)
        Dysphagia
    7.25 ± 28.551
    15.32 ± 29.120
        Pain
    8.88 ± 22.402
    9.23 ± 21.527
        Reflux
    4.59 ± 20.184
    7.96 ± 18.347
        Eating Restrictions
    9.24 ± 22.661
    13.29 ± 21.276
        Anxiety
    7.49 ± 21.860
    6.61 ± 19.456
        Dry Mouth
    15.94 ± 27.725
    9.01 ± 28.827
        Tasting
    9.42 ± 25.832
    2.25 ± 35.897
        Body Image
    5.07 ± 28.787
    4.05 ± 27.561
        Hair Loss
    4.71 ± 33.546
    -13.96 ± 26.029
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From randomization up to 627 days
    Adverse event reporting additional description
    All subjects who received at least 1 dose of study drug (that is, treated subjects) were included in safety population.
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    20.0
    Reporting groups
    Reporting group title
    Physician choice chemotherapy + Best Supportive Care (BSC)
    Reporting group description
    Subjects received BSC plus physician’s choice chemotherapy. Chemotherapy comprised of one of the following: intravenous (IV) infusion of paclitaxel at a dose of 80 milligrams per meter square (mg/m^2) on Days 1, 8 and 15 of a 4-week treatment cycle until progressive disease or unacceptable toxicity OR irinotecan at a dose of 150 mg/m^2 on Days 1 and 15 of a 4-week treatment cycle until progressive disease or unacceptable toxicity. Subjects who were not deemed eligible to receive paclitaxel or irinotecan at the dose and schedule specified above received BSC alone once every 3 weeks. BSC was defined as treatment administered with the intent to maximize quality of life without a specific antineoplastic regimen and was based on investigator's discretion.

    Reporting group title
    Avelumab + BSC
    Reporting group description
    Subjects received avelumab as a 1-hour intravenous (IV) infusion at 10 milligrams per kilogram (mg/kg) once every 2-week treatment cycle until progressive disease or unacceptable toxicity along with BSC. BSC was defined as treatment administered with the intent to maximize quality of life without a specific antineoplastic regimen and was based on investigator's discretion.

    Serious adverse events
    Physician choice chemotherapy + Best Supportive Care (BSC) Avelumab + BSC
    Total subjects affected by serious adverse events
         subjects affected / exposed
    81 / 177 (45.76%)
    90 / 184 (48.91%)
         number of deaths (all causes)
    131
    142
         number of deaths resulting from adverse events
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 184 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Shock symptom
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 184 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Lymphangiosis carcinomatosa
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 184 (0.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malignant ascites
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 184 (0.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malignant neoplasm progression
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 184 (0.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Metastases to central nervous system
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 184 (0.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastases to spine
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 184 (0.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neoplasm swelling
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 184 (0.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pericarditis malignant
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 184 (0.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tumour associated fever
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 184 (0.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tumour pain
         subjects affected / exposed
    2 / 177 (1.13%)
    1 / 184 (0.54%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neoplasm progression
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 184 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Disease progression
         subjects affected / exposed
    30 / 177 (16.95%)
    39 / 184 (21.20%)
         occurrences causally related to treatment / all
    0 / 30
    1 / 39
         deaths causally related to treatment / all
    0 / 24
    0 / 35
    General physical health deterioration
         subjects affected / exposed
    3 / 177 (1.69%)
    11 / 184 (5.98%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 11
         deaths causally related to treatment / all
    0 / 0
    0 / 5
    Asthenia
         subjects affected / exposed
    2 / 177 (1.13%)
    3 / 184 (1.63%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 184 (0.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    1 / 177 (0.56%)
    1 / 184 (0.54%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chills
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 184 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Condition aggravated
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 184 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 184 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multiple organ dysfunction syndrome
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 184 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Oedema peripheral
         subjects affected / exposed
    2 / 177 (1.13%)
    0 / 184 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sudden death
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 184 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Injury, poisoning and procedural complications
    Hip fracture
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 184 (0.54%)
         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 / 177 (0.00%)
    1 / 184 (0.54%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anastomotic stenosis
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 184 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 177 (0.56%)
    1 / 184 (0.54%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 177 (0.56%)
    1 / 184 (0.54%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Liver function test increased
         subjects affected / exposed
    1 / 177 (0.56%)
    1 / 184 (0.54%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Platelet count decreased
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 184 (0.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Cardio-respiratory arrest
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 184 (0.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pericardial effusion
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 184 (0.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 184 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Tachycardia
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 184 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    3 / 177 (1.69%)
    5 / 184 (2.72%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    3 / 177 (1.69%)
    0 / 184 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Disseminated intravascular coagulation
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 184 (0.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Lymphadenopathy mediastinal
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 184 (0.54%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    4 / 177 (2.26%)
    2 / 184 (1.09%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    1 / 177 (0.56%)
    2 / 184 (1.09%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary oedema
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 184 (0.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    1 / 177 (0.56%)
    1 / 184 (0.54%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Pleural effusion
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 184 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    2 / 177 (1.13%)
    0 / 184 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory distress
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 184 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    0 / 177 (0.00%)
    2 / 184 (1.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 177 (0.56%)
    6 / 184 (3.26%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 177 (0.56%)
    5 / 184 (2.72%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    1 / 177 (0.56%)
    4 / 184 (2.17%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Ascites
         subjects affected / exposed
    1 / 177 (0.56%)
    3 / 184 (1.63%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dysphagia
         subjects affected / exposed
    1 / 177 (0.56%)
    3 / 184 (1.63%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Ileus
         subjects affected / exposed
    4 / 177 (2.26%)
    2 / 184 (1.09%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subileus
         subjects affected / exposed
    3 / 177 (1.69%)
    1 / 184 (0.54%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    3 / 177 (1.69%)
    0 / 184 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    0 / 177 (0.00%)
    2 / 184 (1.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 184 (0.54%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    1 / 177 (0.56%)
    1 / 184 (0.54%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Duodenal obstruction
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 184 (0.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal perforation
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 184 (0.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Nausea
         subjects affected / exposed
    2 / 177 (1.13%)
    1 / 184 (0.54%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    1 / 177 (0.56%)
    1 / 184 (0.54%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric stenosis
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 184 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematemesis
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 184 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhagic ascites
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 184 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Melaena
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 184 (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
    Hydronephrosis
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 184 (0.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute kidney injury
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 184 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 184 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Hepatobiliary disorders
    Autoimmune hepatitis
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 184 (0.54%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bile duct obstruction
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 184 (0.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bile duct stone
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 184 (0.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Biliary dilatation
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 184 (0.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic failure
         subjects affected / exposed
    2 / 177 (1.13%)
    1 / 184 (0.54%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Hepatic function abnormal
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 184 (0.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Jaundice cholestatic
         subjects affected / exposed
    1 / 177 (0.56%)
    1 / 184 (0.54%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholangitis
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 184 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 184 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dilatation intrahepatic duct acquired
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 184 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Product issues
    Device occlusion
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 184 (0.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    0 / 177 (0.00%)
    2 / 184 (1.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Exostosis
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 184 (0.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteonecrosis
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 184 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Soft tissue disorder
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 184 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    Autoimmune hypothyroidism
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 184 (0.54%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    4 / 177 (2.26%)
    1 / 184 (0.54%)
         occurrences causally related to treatment / all
    3 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    3 / 177 (1.69%)
    1 / 184 (0.54%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    0 / 177 (0.00%)
    2 / 184 (1.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malnutrition
         subjects affected / exposed
    1 / 177 (0.56%)
    1 / 184 (0.54%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Hyperuricaemia
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 184 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    2 / 177 (1.13%)
    5 / 184 (2.72%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 5
         deaths causally related to treatment / all
    0 / 2
    0 / 1
    Sepsis
         subjects affected / exposed
    2 / 177 (1.13%)
    3 / 184 (1.63%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Device related infection
         subjects affected / exposed
    1 / 177 (0.56%)
    2 / 184 (1.09%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 184 (0.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 177 (0.00%)
    1 / 184 (0.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal infection
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 184 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device related sepsis
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 184 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Empyema
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 184 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Herpes zoster
         subjects affected / exposed
    2 / 177 (1.13%)
    0 / 184 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung infection
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 184 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary sepsis
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 184 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract infection bacterial
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 184 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    1 / 177 (0.56%)
    0 / 184 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Physician choice chemotherapy + Best Supportive Care (BSC) Avelumab + BSC
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    150 / 177 (84.75%)
    146 / 184 (79.35%)
    Injury, poisoning and procedural complications
    Infusion related reaction
         subjects affected / exposed
    3 / 177 (1.69%)
    18 / 184 (9.78%)
         occurrences all number
    3
    18
    Investigations
    Aspartate aminotransferase increased
         subjects affected / exposed
    13 / 177 (7.34%)
    16 / 184 (8.70%)
         occurrences all number
    13
    16
    Weight decreased
         subjects affected / exposed
    12 / 177 (6.78%)
    16 / 184 (8.70%)
         occurrences all number
    12
    16
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    13 / 177 (7.34%)
    15 / 184 (8.15%)
         occurrences all number
    13
    15
    Blood alkaline phosphatase increased
         subjects affected / exposed
    10 / 177 (5.65%)
    14 / 184 (7.61%)
         occurrences all number
    10
    14
    Neutrophil count decreased
         subjects affected / exposed
    16 / 177 (9.04%)
    0 / 184 (0.00%)
         occurrences all number
    16
    0
    Alanine aminotransferase increased
         subjects affected / exposed
    13 / 177 (7.34%)
    11 / 184 (5.98%)
         occurrences all number
    13
    11
    White blood cell count decreased
         subjects affected / exposed
    14 / 177 (7.91%)
    0 / 184 (0.00%)
         occurrences all number
    14
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    10 / 177 (5.65%)
    8 / 184 (4.35%)
         occurrences all number
    10
    8
    Dyspnoea
         subjects affected / exposed
    15 / 177 (8.47%)
    7 / 184 (3.80%)
         occurrences all number
    15
    7
    Blood and lymphatic system disorders
    Neutropenia
         subjects affected / exposed
    25 / 177 (14.12%)
    0 / 184 (0.00%)
         occurrences all number
    25
    0
    Anaemia
         subjects affected / exposed
    48 / 177 (27.12%)
    30 / 184 (16.30%)
         occurrences all number
    48
    30
    Nervous system disorders
    Peripheral sensory neuropathy
         subjects affected / exposed
    14 / 177 (7.91%)
    1 / 184 (0.54%)
         occurrences all number
    14
    1
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    28 / 177 (15.82%)
    28 / 184 (15.22%)
         occurrences all number
    28
    28
    Asthenia
         subjects affected / exposed
    35 / 177 (19.77%)
    26 / 184 (14.13%)
         occurrences all number
    35
    26
    Pyrexia
         subjects affected / exposed
    30 / 177 (16.95%)
    21 / 184 (11.41%)
         occurrences all number
    30
    21
    Chills
         subjects affected / exposed
    3 / 177 (1.69%)
    19 / 184 (10.33%)
         occurrences all number
    3
    19
    Oedema peripheral
         subjects affected / exposed
    16 / 177 (9.04%)
    5 / 184 (2.72%)
         occurrences all number
    16
    5
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    61 / 177 (34.46%)
    34 / 184 (18.48%)
         occurrences all number
    61
    34
    Vomiting
         subjects affected / exposed
    32 / 177 (18.08%)
    33 / 184 (17.93%)
         occurrences all number
    32
    33
    Abdominal pain
         subjects affected / exposed
    31 / 177 (17.51%)
    25 / 184 (13.59%)
         occurrences all number
    31
    25
    Diarrhoea
         subjects affected / exposed
    54 / 177 (30.51%)
    24 / 184 (13.04%)
         occurrences all number
    54
    24
    Constipation
         subjects affected / exposed
    27 / 177 (15.25%)
    18 / 184 (9.78%)
         occurrences all number
    27
    18
    Dysphagia
         subjects affected / exposed
    2 / 177 (1.13%)
    10 / 184 (5.43%)
         occurrences all number
    2
    10
    Abdominal pain upper
         subjects affected / exposed
    18 / 177 (10.17%)
    7 / 184 (3.80%)
         occurrences all number
    18
    7
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    25 / 177 (14.12%)
    0 / 184 (0.00%)
         occurrences all number
    25
    0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    6 / 177 (3.39%)
    18 / 184 (9.78%)
         occurrences all number
    6
    18
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    37 / 177 (20.90%)
    29 / 184 (15.76%)
         occurrences all number
    37
    29
    Dehydration
         subjects affected / exposed
    3 / 177 (1.69%)
    10 / 184 (5.43%)
         occurrences all number
    3
    10

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    22 Oct 2015
    Included blood draws for clinical assessments.
    06 Jan 2016
    To update the Investigation New Drug (IND) number. To change the medical responsible for the trial. To modify exclusion criteria for persisting toxicity related to prior therapy according to the National Cancer Institute-Common Terminology Criteria for Adverse Event (NCI-CTCAE) v4.03 criteria. To make minor changes to clarify the schedule of assessments and text for evaluation of radiographic scans. To clarify the role of the Independent Review Committee (IRC) and independent radiologist. To revise the protocol to include epirubicin as an acceptable regimen for the first-line treatment of metastatic, recurrent, or unresectable gastric cancer. To clarify that all prior adjuvant and neo-adjuvant treatments are allowed. To exclude subjects with active tuberculosis from the study. To modify contraceptive measures to include Clinical Trials Facilitation Group (CTFG) recommendations related to contraception and pregnancy testing in clinical trials. To correct a minor typographical error.
    29 Apr 2016
    To amend the trial schedule to have an End of Treatment Visit within 7 days of the decision to discontinue, a Safety Follow-up Visit 30 days after last treatment (±5 days), a Safety Follow-up Phone Call 90 days after last treatment (±1 week), and the Long-Term Follow-up every 12 weeks after last treatment (±2 weeks). The reporting of AEs and concomitant medications/procedures was also updated in line with the new schedule. To reduce the frequency of pregnancy testing to every 4 weeks prior to Week 13. To remove the measurement of antinuclear antibody (ANA), antineutrophil cytoplasmic antibodies (ANCA), rheumatoid factor (RF) and adrenocorticotropic hormone (ACTH) from laboratory sampling. To remove the collection of blood samples for PK determination at 2 to 8 hours post-infusion, and at the end of the infusion for both Week 13 and every 12 weeks until progression. To remove the collection of blood samples for soluble factors at 2 to 8 hours post-infusion. To remove the collection of blood samples at the End of Treatment Visit for HAHA (immunogenicity) analysis. To reduce the frequency of tumor evaluation/staging by Computed Tomography (CT) scan/Magnetic Resonance Imaging (MRI)/other established methods to every 12 weeks after the first 12 months. To add the collection of samples for soluble factors, gene expression profiling and biomarkers at Week 1 for the comparator treatment arms. To collect core serum chemistry samples rather than full serum chemistry samples during the treatment phase, and collect additional parameters for core serum chemistry (amylase, lipase, lactate dehydrogenase and creatine kinase).
    28 Dec 2016
    To add management guidelines for cardiac irAEs. To update the sponsor’s medical responsible and global program lead. To clarify the monitoring of SAEs that are ongoing at the 30-day Safety Follow-up visit. To provide the clinical trial registry number. To correct a typographical error in the Schedule of Assessments and to replace the terminology of human anti-human antibody (HAHA) with ADA. To make minor editorial corrections to abbreviations and the use of “patient” and “subject.”
    30 May 2017
    Revise the time point of the primary analysis to occur after a minimum of 6 months follow-up since the last subject randomized. Correct a discrepancy between sections in the acceptable regimens for first-line treatment. Clarify the definition of second-line therapy with the respect to another line of a platinum-based treatment or FOLFIRI. Update the requirements for premedication and mandatory discontinuation. Clarify that Pharmacokinetics (PK) and Anti-drug Antibody (ADA) samples collected at the same time point can be used interchangeably. Clarify the definition and censoring rules for duration of response. Update the background information for avelumab. Clarify the treatment of subjects who continue avelumab plus Best Supportive Care (BSC) beyond progression. Update the guidelines for management of Immune-related Adverse Event (irAEs). Update the Sponsor’s medical responsible. Clarify the monitoring of Serious Adverse Events (SAEs) that are ongoing at the 30-day Safety Follow-up visit. Update the contact information for the senior expert statistician.
    27 Mar 2018
    To change the follow-up time such that subjects who discontinue treatment will no longer be followed for disease progression of survival. Provided subjects additional treatment options.

    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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