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    Clinical Trial Results:
    An open-label, Phase I/II multicenter clinical trial of VXM01 in combination with avelumab in patients with progressive glioblastoma following standard treatment with or without second surgery.

    Summary
    EudraCT number
    		 2017-003076-31
    Trial protocol
    		 DE   NL  
    Global end of trial date
    15 Aug 2022

    Results information
    Results version number
    		 v1(current)
    This version publication date
    22 Jul 2023
    First version publication date
    22 Jul 2023
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    VXM01-AVE-04-INT
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02718430
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    VAXIMM GmbH
    Sponsor organisation address
    Landteilstrasse 24, Mannheim, Germany, 68163
    Public contact
    Ralf Kubli, VAXIMM GmbH, +41 79 538 7109, ralf.kubli@vaximm.com
    Scientific contact
    Ralf Kubli, VAXIMM GmbH, +41 79 538 7109, ralf.kubli@vaximm.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
    22 Mar 2023
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    15 Aug 2022
    Global end of trial reached?
    Yes
    Global end of trial date
    15 Aug 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To examine the safety and tolerability of VXM01 in combination with avelumab
    Protection of trial subjects
    -A Data Safety Monitoring Board (DSMB) was convened to periodically assess the trial conduct and data in terms of risk-benefit balance and provide recommendations to Vaximm regarding the trial’s continuation or modification. Furthermore, the DSMB was consulted in case a treatment-limiting toxicity (TLT) was classified as possibly related to either of the IMPs. -The first 3 non-resectable patients treated with the VXM01 106 CFU/mL dose in combination with avelumab were included in a staggered fashion (1+2). For safety reasons, there was a time interval of at least 5 weeks between dosing of the first patient and the following 2 patients (TLT observation period). If no TLTs were observed, the VXM01 vaccine dose was to be increased to 107 CFU/mL, after review of the safety data by the DSMB. -Similarly, also the first 3 patients treated with the VXM01 107 CFU/mL dose in combination with avelumab were included in a staggered fashion (1+2). If the safety and tolerability were considered acceptable for the VXM01 107 CFU/mL dose in combination with avelumab, all patients treated with VXM01 106 CFU/mL dose in combination with avelumab could be treated with the higher dose (intra-dose escalation allowed) after general approval by the DSMB, at the investigator’s discretion. -Subjects were given pre-treatment with an anti-histamine and paracetamol prior to receiving the first 4 doses of Avelumab to prevent infusion-related reactions. Premedication was administered for subsequent avelumab doses based upon clinical judgment and presence/severity of prior infusion reaction.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Oct 2018
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety
    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
    France: 1
    Country: Number of subjects enrolled
    Germany: 27
    Worldwide total number of subjects
    28
    EEA total number of subjects
    28
    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)
    21
    From 65 to 84 years
    7
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The trial was conducted in 2 centers in Germany and 1 center in France. There was one site activated in The Netherlands but no patients were enrolled. The trial was terminated earlier in NL and FR at the same time. The recruitment phase was approximately 23 months (Nov18 - Nov19 and Aug20 - Jul22). First patient was included in 20Nov2018.

    Pre-assignment
    Screening details
    		 For each patient, the trial consisted of a screening period of approximately 3 weeks. Only patients meeting all inclusion and none of the exclusion criteria were included into the treatment phase. The criteria were assessed at screening and a re-check was performed at the inclusion visit (Day 0).

    Pre-assignment period milestones
    Number of subjects started
    		 32 [1]
    Intermediate milestone: Number of subjects
    INFORMED CONSENT OBTAINED: 32
    Intermediate milestone: Number of subjects
    ELIGIBILITY CRITERIA MET: 28
    Number of subjects completed
    		 28

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    		 Inclusion Criteria 5 Was Not Met: 1
    Reason: Number of subjects
    		 Exclusion Criteria 13 Was Met: 1
    Reason: Number of subjects
    		 Inclusion Criteria 7 and 13 Were Not Met: 1
    Reason: Number of subjects
    		 Inclusion Criteria 15 Was Not Met: 1
    Notes
    [1] - The number of subjects reported to have started the pre-assignment period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: 32 patients entered the pre-assignment period, however, 4 of those patients did not meet the eligibility criteria and thus were not enrolled in the trial.
    Period 1
    Period 1 title
    TREATMENT
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded
    Blinding implementation details
    This was an open-label study, blinding not applicable.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 VXM01 10^6 CFU/mL Non-resectable
    Arm description
    		 Low-dose VXM01 treatment, non-resectable patients
    Arm type
    		 Experimental

    Investigational medicinal product name
    VXM01
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral suspension
    Routes of administration
    Oral use
    Dosage and administration details
    VXM01 vaccine was administered as 4 single oral prime administrations on Day 1, 3, 5 and 7, followed by single oral boosting administrations every 4 weeks (from Week 4 to 48 in non-resectable patients). In case of patient-specific prolongation, additional 12 doses of VXM01 vaccine were given.

    Arm title
    		 VXM01 10^7 CFU/mL Non-resectable
    Arm description
    		 High dose VXM01 treatment, non-resectable patients
    Arm type
    		 Experimental

    Investigational medicinal product name
    VXM01
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral suspension
    Routes of administration
    Oral use
    Dosage and administration details
    VXM01 vaccine was administered as 4 single oral prime administrations on Day 1, 3, 5 and 7, followed by single oral boosting administrations every 4 weeks (from Week 4 to 48 in non-resectable patients). In case of patient-specific prolongation, additional 12 doses of VXM01 vaccine were given.

    Arm title
    		 VXM01 10^7 CFU/mL Resectable
    Arm description
    		 High dose VXM01 treatment, resectable patients
    Arm type
    		 Experimental

    Investigational medicinal product name
    VXM01
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral suspension
    Routes of administration
    Oral use
    Dosage and administration details
    VXM01 vaccine was administered as 4 single oral prime administrations on Day 1, 3, 5 and 7, followed by single oral boosting administrations every 4 weeks (from Week 8 to 48 in resectable patients). In case of patient-specific prolongation, additional 12 doses of VXM01 vaccine were given.

    Number of subjects in period 1
    		VXM01 10^6 CFU/mL Non-resectable VXM01 10^7 CFU/mL Non-resectable VXM01 10^7 CFU/mL Resectable
    Started
    3
    22
    3
    Tumor Resection
    0 [2]
    0 [3]
    2 [4]
    Completed
    3
    22
    3
    Notes
    [2] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: The milestone "Tumor resection" is only applicable to the Resectable arm, however, it is not possible to remove this milestone from the other arms in the EudraCT system.
    [3] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: The milestone "Tumor resection" is only applicable to the Resectable arm, however, it is not possible to remove this milestone from the other arms in the EudraCT system.
    [4] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: One patient in the Resectable arm did not under go tumor resection due to a clinical decision.
    Period 2
    Period 2 title
    FOLLOW UP
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded
    Blinding implementation details
    This was an open-label study, blinding not applicable.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 VXM01 10^6 CFU/mL Non-resectable
    Arm description
    		 Low-dose VXM01 treatment, non-resectable patients
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 VXM01 10^7 CFU/mL Non-resectable
    Arm description
    		 High dose VXM01 treatment, non-resectable patients
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 VXM01 10^7 CFU/mL Resectable
    Arm description
    		 High dose VXM01 treatment, resectable patients
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 2
    		VXM01 10^6 CFU/mL Non-resectable VXM01 10^7 CFU/mL Non-resectable VXM01 10^7 CFU/mL Resectable
    Started
    3
    22
    3
    Completed
    1
    0
    0
    Not completed
    2
    22
    3
         Death Due To Progressive Disease
    2
    20
    2
         In follow-up
    -
    2
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    TREATMENT
    Reporting group description
    		 -

    Reporting group values
    		 TREATMENT Total
    Number of subjects
    		 28 28
    Age categorical
    Adult
    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)
    		 21 21
        From 65-84 years
    		 7 7
        85 years and over
    		 0 0
    Age continuous
    Units: years
        median (standard deviation)
    		 60 ± 9.5 -
    Gender categorical
    Units: Subjects
        Female
    		 6 6
        Male
    		 22 22
    Subject analysis sets

    Subject analysis set title
    Full analysis set (FAS)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    included all patients who received any trial drug after trial entry.

    Subject analysis set title
    Per-protocol analysis set (PPS)
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    included all patients who received trial drug in compliance with the scheduled treatment regimen, underwent re-operation if in the resectable subgroup and without any major protocol deviations.

    Subject analysis set title
    Safety analysis set (SAF)
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    all patients who received at least one dose of the trial drug and for which at least one post-dose safety assessment is available.

    Subject analysis sets values
    		 Full analysis set (FAS) Per-protocol analysis set (PPS) Safety analysis set (SAF)
    Number of subjects
    28
    23
    28
    Age categorical
    Adult
    Units: Subjects
        In utero
        Preterm newborn infants (gestational age < 37 wks)
        Newborns (0-27 days)
        Infants and toddlers (28 days-23 months)
        Children (2-11 years)
        Adolescents (12-17 years)
        Adults (18-64 years)
    21
    17
    21
        From 65-84 years
    7
    6
    7
        85 years and over
    Age continuous
    Units: years
        median (standard deviation)
    58 ± 9.5
    ±
    58 ± 9.5
    Gender categorical
    Units: Subjects
        Female
    6
    6
    6
        Male
    22
    17
    22

    End points

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    End points reporting groups
    Reporting group title
    VXM01 10^6 CFU/mL Non-resectable
    Reporting group description
    		 Low-dose VXM01 treatment, non-resectable patients

    Reporting group title
    VXM01 10^7 CFU/mL Non-resectable
    Reporting group description
    		 High dose VXM01 treatment, non-resectable patients

    Reporting group title
    VXM01 10^7 CFU/mL Resectable
    Reporting group description
    		 High dose VXM01 treatment, resectable patients
    Reporting group title
    VXM01 10^6 CFU/mL Non-resectable
    Reporting group description
    		 Low-dose VXM01 treatment, non-resectable patients

    Reporting group title
    VXM01 10^7 CFU/mL Non-resectable
    Reporting group description
    		 High dose VXM01 treatment, non-resectable patients

    Reporting group title
    VXM01 10^7 CFU/mL Resectable
    Reporting group description
    		 High dose VXM01 treatment, resectable patients

    Subject analysis set title
    Full analysis set (FAS)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    included all patients who received any trial drug after trial entry.

    Subject analysis set title
    Per-protocol analysis set (PPS)
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    included all patients who received trial drug in compliance with the scheduled treatment regimen, underwent re-operation if in the resectable subgroup and without any major protocol deviations.

    Subject analysis set title
    Safety analysis set (SAF)
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    all patients who received at least one dose of the trial drug and for which at least one post-dose safety assessment is available.

    Primary: Safety and Tolerability

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    End point title
    		 Safety and Tolerability [1]
    End point description
    Safety and tolerability up to 60 weeks after first IMP administration (including end of study [EoS] visit, Week 60), incidence of AEs (number of patients with event[s])
    End point type
    Primary
    End point timeframe
    up to 60 weeks after first IMP administration (including end of study [EoS] visit, Week 60)
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Due to the early phase open-label design of this study, no statistical analysis has been performed on the primary endpoint of safety and tolerability. Results were presented in tabular summaries of incidence.
    End point values
    		 VXM01 10^6 CFU/mL Non-resectable VXM01 10^7 CFU/mL Non-resectable VXM01 10^7 CFU/mL Resectable Safety analysis set (SAF)
    Number of subjects analysed
    3
    22
    3
    28
    Units: Number of Events
        AE
    30
    218
    29
    277
        TEAE
    30
    198
    28
    256
        SAE
    0
    11
    0
    11
    No statistical analyses for this end point

    Secondary: Best Overall Response

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    End point title
    		 Best Overall Response
    End point description
    Best overall response (BOR) on MRI according to iRANO in patients with or without surgery prior to trial entry (up to re-operation), derived using iRANO 2015 guidelines.
    End point type
    Secondary
    End point timeframe
    Until progressive disease occurs, for resectable patients up to (re-)operation.
    End point values
    		 VXM01 10^6 CFU/mL Non-resectable VXM01 10^7 CFU/mL Non-resectable VXM01 10^7 CFU/mL Resectable Full analysis set (FAS) Per-protocol analysis set (PPS)
    Number of subjects analysed
    3
    22
    3
    28
    23
    Units: Best Overall Response
        Partial Response
    1
    2
    0
    3
    1
        Stable Disease
    0
    1
    2
    3
    3
        Progressive Disease
    2
    19
    1
    22
    19
    No statistical analyses for this end point

    Secondary: Duration of Response

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    End point title
    		 Duration of Response [2]
    End point description
    Duration of Response (DoR) on MRI according to iRANO in patients with or without surgery prior to trial entry (up to re-operation)
    End point type
    Secondary
    End point timeframe
    Up to end of trial
    Notes
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The Duration of Response can only be determined in patients with a partial or complete response. In the arm "10^7 CFU/mL Resectable" (Arm 3) no patients had a partial or complete response, thus duration of response could not be determined for this arm.
    End point values
    		 VXM01 10^6 CFU/mL Non-resectable VXM01 10^7 CFU/mL Non-resectable Full analysis set (FAS) Per-protocol analysis set (PPS)
    Number of subjects analysed
    1
    2
    3
    1
    Units: Months
        median (full range (min-max))
    5.6 (5.6 to 5.6)
    6.9 (2.7 to 11.1)
    5.6 (2.7 to 11.1)
    2.7 (2.7 to 2.7)
    No statistical analyses for this end point

    Secondary: Clinical Response

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    End point title
    		 Clinical Response
    End point description
    Clinical response as assessed by time-to-progression (TTP), PFS, recurrence-free survival after re-operation (RFS) and overall survival (OS) up to end of trial.
    End point type
    Secondary
    End point timeframe
    Up to end of trial
    End point values
    		 VXM01 10^6 CFU/mL Non-resectable VXM01 10^7 CFU/mL Non-resectable VXM01 10^7 CFU/mL Resectable Full analysis set (FAS) Per-protocol analysis set (PPS)
    Number of subjects analysed
    3
    22
    3
    28
    23
    Units: Months
    median (full range (min-max))
        Time-to-progression
    2.5 (1.2 to 13.8)
    2.7 (1.4 to 13.8)
    0.6 (0.3 to 22.1)
    2.7 (0.3 to 22.1)
    2.7 (0.3 to 22.1)
        Progression-free survival
    2.5 (1.2 to 13.8)
    2.7 (1.4 to 13.8)
    0.6 (0.3 to 22.1)
    2.7 (0.3 to 22.1)
    2.7 (0.3 to 22.1)
        Overall survival
    14.5 (5.6 to 38.2)
    10.8 (3.8 to 19.6)
    16.9 (2.2 to 23.1)
    11.2 (2.2 to 38.2)
    11.2 (2.2 to 23.1)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    AEs were collected as soon as the patient consented to the ICF, during each visit until 30 days after last administration of the trial medication and at day 90 after last treatment administration.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    25.1
    Reporting groups
    Reporting group title
    VXM01 10^6 CFU/mL Non-resectable
    Reporting group description
    		 Low-dose VXM01 treatment, non-resectable patients

    Reporting group title
    VXM01 10^7 CFU/mL Non-resectable
    Reporting group description
    		 High dose VXM01 treatment, non-resectable patients

    Reporting group title
    VXM01 10^7 CFU/mL Resectable
    Reporting group description
    		 High dose VXM01 treatment, resectable patients

    Serious adverse events
    		 VXM01 10^6 CFU/mL Non-resectable VXM01 10^7 CFU/mL Non-resectable VXM01 10^7 CFU/mL Resectable
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 3 (0.00%)
    7 / 22 (31.82%)
    0 / 3 (0.00%)
         number of deaths (all causes)
    2
    20
    2
         number of deaths resulting from adverse events
    0
    0
    0
    Nervous system disorders
    Brain oedema
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 22 (4.55%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Epilepsy
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 22 (4.55%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Status epilepticus
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 22 (4.55%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 22 (4.55%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 22 (4.55%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Gait disturbance
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 22 (4.55%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pulmonary embolism
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 22 (4.55%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 22 (4.55%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hyponatraemia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 22 (4.55%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 VXM01 10^6 CFU/mL Non-resectable VXM01 10^7 CFU/mL Non-resectable VXM01 10^7 CFU/mL Resectable
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    3 / 3 (100.00%)
    22 / 22 (100.00%)
    3 / 3 (100.00%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 22 (9.09%)
    0 / 3 (0.00%)
         occurrences all number
    0
    4
    0
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    1 / 3 (33.33%)
    11 / 22 (50.00%)
    2 / 3 (66.67%)
         occurrences all number
    1
    16
    2
    Influenza like illness
         subjects affected / exposed
    2 / 3 (66.67%)
    2 / 22 (9.09%)
    0 / 3 (0.00%)
         occurrences all number
    7
    4
    0
    Gait disturbance
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 22 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    0
    Malaise
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 22 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    0
    Pain
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 22 (4.55%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 22 (4.55%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    0
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 22 (9.09%)
    0 / 3 (0.00%)
         occurrences all number
    0
    4
    0
    Depression
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 22 (9.09%)
    0 / 3 (0.00%)
         occurrences all number
    0
    2
    0
    Anxiety
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 22 (4.55%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    0
    Confusional state
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 22 (4.55%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    0
    Mood swings
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 22 (4.55%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    0
    Persistent depressive disorder
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 22 (4.55%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    0
    Personality change
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 22 (4.55%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    0
    Psychomotor retardation
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 22 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    0
    1
    Investigations
    Lymphocyte count decreased
         subjects affected / exposed
    0 / 3 (0.00%)
    13 / 22 (59.09%)
    3 / 3 (100.00%)
         occurrences all number
    0
    40
    6
    White blood cell count decreased
         subjects affected / exposed
    0 / 3 (0.00%)
    6 / 22 (27.27%)
    2 / 3 (66.67%)
         occurrences all number
    0
    13
    7
    Lipase increased
         subjects affected / exposed
    0 / 3 (0.00%)
    4 / 22 (18.18%)
    1 / 3 (33.33%)
         occurrences all number
    0
    5
    1
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 3 (0.00%)
    3 / 22 (13.64%)
    1 / 3 (33.33%)
         occurrences all number
    0
    5
    1
    Blood potassium decreased
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 22 (9.09%)
    2 / 3 (66.67%)
         occurrences all number
    0
    2
    4
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    0 / 3 (0.00%)
    3 / 22 (13.64%)
    0 / 3 (0.00%)
         occurrences all number
    0
    6
    0
    Blood creatine phosphokinase increased
         subjects affected / exposed
    1 / 3 (33.33%)
    2 / 22 (9.09%)
    0 / 3 (0.00%)
         occurrences all number
    3
    2
    0
    Blood potassium increased
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 22 (4.55%)
    1 / 3 (33.33%)
         occurrences all number
    0
    2
    1
    Lymphocyte count increased
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 22 (9.09%)
    0 / 3 (0.00%)
         occurrences all number
    0
    3
    0
    Platelet count decreased
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 22 (9.09%)
    0 / 3 (0.00%)
         occurrences all number
    0
    3
    0
    Amylase increased
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 22 (4.55%)
    1 / 3 (33.33%)
         occurrences all number
    0
    1
    1
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 22 (9.09%)
    0 / 3 (0.00%)
         occurrences all number
    0
    2
    0
    Gamma-glutamyltransferase decreased
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 22 (4.55%)
    0 / 3 (0.00%)
         occurrences all number
    0
    2
    0
    Alanine aminotransferase decreased
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 22 (4.55%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    0
    Blood alkaline phosphatase increased
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 22 (4.55%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    0
    Blood bilirubin increased
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 22 (4.55%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    0
    Blood creatinine increased
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 22 (4.55%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    0
    Blood thyroid stimulating hormone increased
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 22 (4.55%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    0
    Haemoglobin decreased
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 22 (4.55%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    0
    Nervous system disorders
    Hemiparesis
         subjects affected / exposed
    2 / 3 (66.67%)
    3 / 22 (13.64%)
    1 / 3 (33.33%)
         occurrences all number
    2
    3
    1
    Aphasia
         subjects affected / exposed
    1 / 3 (33.33%)
    3 / 22 (13.64%)
    0 / 3 (0.00%)
         occurrences all number
    1
    3
    0
    Brain oedema
         subjects affected / exposed
    2 / 3 (66.67%)
    1 / 22 (4.55%)
    0 / 3 (0.00%)
         occurrences all number
    2
    1
    0
    Fine motor skill dysfunction
         subjects affected / exposed
    1 / 3 (33.33%)
    1 / 22 (4.55%)
    1 / 3 (33.33%)
         occurrences all number
    1
    1
    1
    Headache
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 22 (9.09%)
    0 / 3 (0.00%)
         occurrences all number
    0
    2
    0
    Cognitive disorder
         subjects affected / exposed
    1 / 3 (33.33%)
    1 / 22 (4.55%)
    0 / 3 (0.00%)
         occurrences all number
    2
    1
    0
    Hypoaesthesia
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 22 (9.09%)
    0 / 3 (0.00%)
         occurrences all number
    0
    2
    0
    Ataxia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 22 (4.55%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    0
    Dizziness
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 22 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    0
    Dysarthria
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 22 (4.55%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    0
    Dysdiadochokinesis
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 22 (4.55%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    0
    Dysgeusia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 22 (4.55%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    0
    Facial paralysis
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 22 (4.55%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    0
    Paraesthesia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 22 (4.55%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    0
    Paresis
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 22 (4.55%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    0
    Seizure
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 22 (4.55%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    0
    Syncope
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 22 (4.55%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    0
    Blood and lymphatic system disorders
    Lymphopenia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 22 (4.55%)
    0 / 3 (0.00%)
         occurrences all number
    0
    2
    0
    Anaemia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 22 (4.55%)
    0 / 3 (0.00%)
         occurrences all number
    0
    2
    0
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    1 / 3 (33.33%)
    4 / 22 (18.18%)
    0 / 3 (0.00%)
         occurrences all number
    1
    5
    0
    Diarrhoea
         subjects affected / exposed
    1 / 3 (33.33%)
    2 / 22 (9.09%)
    0 / 3 (0.00%)
         occurrences all number
    2
    2
    0
    Vomiting
         subjects affected / exposed
    0 / 3 (0.00%)
    3 / 22 (13.64%)
    0 / 3 (0.00%)
         occurrences all number
    0
    4
    0
    Oral dysaesthesia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 22 (4.55%)
    0 / 3 (0.00%)
         occurrences all number
    0
    2
    0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 22 (4.55%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    0
    Mouth ulceration
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 22 (4.55%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    0
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    1 / 3 (33.33%)
    1 / 22 (4.55%)
    0 / 3 (0.00%)
         occurrences all number
    2
    1
    0
    Dry skin
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 22 (4.55%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    0
    Rash
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 22 (4.55%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    0
    Endocrine disorders
    Hypothyroidism
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 22 (4.55%)
    1 / 3 (33.33%)
         occurrences all number
    0
    1
    1
    Adrenal insufficiency
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 22 (4.55%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    0
    Autoimmune thyroiditis
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 22 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    0
    1
    Musculoskeletal and connective tissue disorders
    Myalgia
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 22 (9.09%)
    0 / 3 (0.00%)
         occurrences all number
    0
    2
    0
    Back pain
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 22 (4.55%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    0
    Rheumatoid arthritis
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 22 (4.55%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    0
    Trigger finger
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 22 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    0
    Infections and infestations
    Gastroenteritis viral
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 22 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    0
    Rhinitis
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 22 (4.55%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    0
    Urinary tract infection
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 22 (4.55%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    0
    Metabolism and nutrition disorders
    Hypertriglyceridaemia
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 22 (9.09%)
    0 / 3 (0.00%)
         occurrences all number
    0
    4
    0
    Hyponatraemia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 22 (4.55%)
    0 / 3 (0.00%)
         occurrences all number
    0
    2
    0
    Decreased appetite
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 22 (0.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    0
    Hypokalaemia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 22 (4.55%)
    0 / 3 (0.00%)
         occurrences all number
    0
    1
    0

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    12 Nov 2018
    Protocol V2.0_05Sep2018 -Update and revision based on comments from Ethics Committes and Competent Authorities in France, Germany and the Netherlands Protocol V3.0_21Sep2018 -Update and revision based on comments from the ANSM in France Protocol V4.0_31Oct2018 -Update based on CCMO comments (vital sign measurements defined and added reference for immune-related cardiac events treatment guidelines) AND Record archiving period changed from 15 to 25 years. Germany -Protocol V2.0 submitted during question and answer rounds of the initial submission -Protocol V3.0 and V4.0 submitted with Substantial Amendment 01 on 12Nov2018 Netherlands -Protocol V2.0, V3.0 and V4.0 submitted in Substantial Amendment 01 on 27Feb2019 France -Protocol V2.0 and V3.0 submitted during question and answer rounds of the initial submission (Protocol V4.0 submitted with Global Substantial Amendment of protocol V5.0_11Jun2019)
    01 Jul 2019
    Global Substantial Amendments performed in Jul2019 to align protocol and introduce gut microbiome analysis Substantial Amendment (SA) in Germany: Protocol V5.0_11Jun2019 submitted on 01Jul2019 to CA and EC. SA in Netherlands: Protocol V5.0_11Jun2019 submitted on 04Jul2019 to CA and EC. SA in France: Protocol V4.0_31Oct2018 and V5.0_11Jun2019 submitted on 05Jul2019 to CA and EC.
    20 Nov 2019
    Global Substantial Amendment (SA) to: -Update of the avelumab safety information regarding pancreatitis in accordance with the current version of the Investigator’s Brochure. -Update of the approval status of avelumab -Upates of the administrative section regarding members of the study team Germany: Protocol V6.0_05Nov2019 submitted on 20Nov2019 and 21Nov2019 to CA and EC Netherlands: Protocol V6.0_05Nov2019 submitted on 21Nov2019 and 20Nov2019 to CA and EC France: Protocol V6.0_05Nov2019 submitted on 18Nov2019 to CA and EC

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    01 Nov 2019
    Patient enrolment was placed on temporary hold on 01Nov2019 due to funding issues at the sponsor. There was no effect on patients who were already enrolled in the trial; their treatment continued as per protocol. Patient enrolment was restarted on 01Aug2020 in Germany only and only at 2 German sites.
    01 Aug 2020

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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