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    Clinical Trial Results:
    Open-label, Phase I/II study to evaluate pharmacokinetics, pharmacodynamics, safety, and anticancer activity of avelumab in pediatric subjects from birth to less than 18 years of age with refractory or relapsed solid tumors and lymphoma

    Summary
    EudraCT number
    		 2017-002985-28
    Trial protocol
    		 BE   DK  
    Global end of trial date
    31 May 2021

    Results information
    Results version number
    		 v1(current)
    This version publication date
    09 Feb 2022
    First version publication date
    09 Feb 2022
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    MS100070_0306
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03451825
    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 Center, Merck KGaA, Darmstadt, Germany, +49 6151 72 5200, service@merckgroup.com
    Scientific contact
    Communication Center, Merck KGaA, Darmstadt, Germany, +49 6151725200, service@merckgroup.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-001849-PIP02-15
    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?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    27 Jul 2021
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    31 May 2021
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The purpose of this study to evaluate the dose, safety and tolerability, antitumor activity, pharmacokinetic and pharmacodynamics of avelumab in pediatric subjects 0 to less than 18 years of age with refractory or relapsed malignant solid tumors (including central nervous system tumors) and lymphoma for which no standard therapy is available or for which the subject is not eligible for the existing therapy.
    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
    07 Mar 2018
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Efficacy
    Long term follow-up duration
    		 12 Months
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Belgium: 1
    Country: Number of subjects enrolled
    Canada: 5
    Country: Number of subjects enrolled
    Korea, Republic of: 15
    Worldwide total number of subjects
    21
    EEA total number of subjects
    1
    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)
    11
    Adolescents (12-17 years)
    10
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 A total of 26 subjects were screened for participation in the Phase I part of the study, out of which 21 subjects were eligible received the study treatment.

    Pre-assignment
    Screening details
    		 The study was planned to be conducted in 2 parts: the dose-finding part (Phase I) and the tumor-specified expansion part (Phase II). However, Phase II was cancelled due to limited clinical benefit of Programmed death ligand 1 (PD-L1) monotherapy in pediatric subjects.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Avelumab 10 miligram per kilogram (mg/kg)
    Arm description
    		 Subjects received an intravenous infusion of avelumab 10mg/kg IV once every 2 weeks until confirmed progression, death, unacceptable toxicity, or any criterion for withdrawal occurred.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Avelumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects received an intravenous infusion of avelumab 10mg/kg IV once every 2 weeks until confirmed progression, death, unacceptable toxicity, or any criterion for withdrawal occurred.

    Arm title
    		 Avelumab 20 mg/kg
    Arm description
    		 Subjects received an intravenous infusion of avelumab 20 mg/kg IV once every 2 weeks until confirmed progression, death, unacceptable toxicity, or any criterion for withdrawal occurred.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Avelumab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects received an intravenous infusion of avelumab 20mg/kg IV once every 2 weeks until confirmed progression, death, unacceptable toxicity, or any criterion for withdrawal occurred.

    Number of subjects in period 1
    		Avelumab 10 miligram per kilogram (mg/kg) Avelumab 20 mg/kg
    Started
    6
    15
    Completed
    6
    15

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Avelumab 10 miligram per kilogram (mg/kg)
    Reporting group description
    		 Subjects received an intravenous infusion of avelumab 10mg/kg IV once every 2 weeks until confirmed progression, death, unacceptable toxicity, or any criterion for withdrawal occurred.

    Reporting group title
    Avelumab 20 mg/kg
    Reporting group description
    		 Subjects received an intravenous infusion of avelumab 20 mg/kg IV once every 2 weeks until confirmed progression, death, unacceptable toxicity, or any criterion for withdrawal occurred.

    Reporting group values
    		 Avelumab 10 miligram per kilogram (mg/kg) Avelumab 20 mg/kg Total
    Number of subjects
    		 6 15 21
    Age Categorical
    Units: Subjects
        Children (2-11 years)
    		 3 8 11
        Adolescents (12-17 years)
    		 3 7 10
    Gender Categorical
    Units: Subjects
        Female
    		 2 8 10
        Male
    		 4 7 11
    Race (NIH/OMB)
    Units: Subjects
        Asian
    		 6 9 15
        White
    		 0 4 4
        Not Collected at Site
    		 0 2 2

    End points

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    End points reporting groups
    Reporting group title
    Avelumab 10 miligram per kilogram (mg/kg)
    Reporting group description
    		 Subjects received an intravenous infusion of avelumab 10mg/kg IV once every 2 weeks until confirmed progression, death, unacceptable toxicity, or any criterion for withdrawal occurred.

    Reporting group title
    Avelumab 20 mg/kg
    Reporting group description
    		 Subjects received an intravenous infusion of avelumab 20 mg/kg IV once every 2 weeks until confirmed progression, death, unacceptable toxicity, or any criterion for withdrawal occurred.

    Primary: Number of Subjects With Treatment-Emergent Adverse Events (TEAEs) as per Severity With Grade 3 or Higher According to National Cancer Institute-Common Terminology Criteria for Adverse Events Version 4.03 (NCI-CTCAE v4.03)

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    End point title
    		 Number of Subjects With Treatment-Emergent Adverse Events (TEAEs) as per Severity With Grade 3 or Higher According to National Cancer Institute-Common Terminology Criteria for Adverse Events Version 4.03 (NCI-CTCAE v4.03) [1]
    End point description
    Adverse event (AE) was defined as any untoward medical occurrence in a subject, which does not necessarily have causal relationship with treatment. A serious AE was defined as an AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial or prolonged in participant hospitalization; congenital anomaly/birth defect or was otherwise considered medically important. TEAEs were those events with onset dates occurring during the on-treatment period for the first time, or if the worsening of an event was during the on-treatment period. TEAEs included both serious TEAEs and non-serious TEAEs. Severity of grade 3 or higher TEAEs were graded using NCI-CTCAE v4.03 toxicity grades, as follows: Grade 3 = Severe; Grade 4 = Life-threatening and Grade 5 = Death. Number of subjects with TEAEs as per severity with Grade 3 and higher were reported. Safety analysis set included all subjects who received any dose of avelumab.
    End point type
    Primary
    End point timeframe
    Baseline up to 1182 days
    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: Only descriptive data was planned for this endpoint.
    End point values
    		 Avelumab 10 miligram per kilogram (mg/kg) Avelumab 20 mg/kg
    Number of subjects analysed
    6
    15
    Units: Subjects
        Subjects with TEAEs - Grade 3
    4
    6
        Subjects with TEAEs - Grade 4
    0
    2
        Subjects with TEAEs - Grade 5
    1
    3
    No statistical analyses for this end point

    Primary: Number of Subjects Experiencing Dose-Limiting Toxicities (DLTs)

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    End point title
    		 Number of Subjects Experiencing Dose-Limiting Toxicities (DLTs) [2]
    End point description
    DLT was defined as severity of AEs were graded according to NCI_CTCAE version 4.03. Hematologic: Grade 4 neutropenia for more than 7 days in duration; Grade greater than or equal to (>=) 3 neutropenic infection; Grade >= 3 thrombocytopenia with bleeding; Grade 4 thrombocytopenia > 7 days and Grade 4 anemia. Nonhematologic: Any Grade >= 3 toxicity, except for any of the following: Transient (less than or equal to (<=) 72 hours; Grade 3 flu-like symptoms or fever, which was controlled with medical management; Transient (<= 72 hours) Grade 3 fatigue, local reactions, headache, nausea, or emesis that resolved to Grade <= 1 or to Baseline. Grade 3 diarrhea or Grade 3 skin toxicity that resolved to Grade <= 1 in less than 7 days after medical management (immunosuppressant treatment) had been initiated. Grade >= 3 amylase or lipase abnormality that was not associated with clinical manifestations of pancreatitis. DLTs analysis: all subjects received all study drug in DLT evaluation period.
    End point type
    Primary
    End point timeframe
    Baseline up to 28 days
    Notes
    [2] - 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: Only descriptive data was planned for this endpoint.
    End point values
    		 Avelumab 10 miligram per kilogram (mg/kg) Avelumab 20 mg/kg
    Number of subjects analysed
    6
    12
    Units: Subjects
    0
    1
    No statistical analyses for this end point

    Secondary: Number of Subjects With Confirmed Best Overall Response (BOR) as per Response Evaluation Criteria in Solid Tumors (RECIST Version 1.1) and as Adjudicated by the Investigator

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    End point title
    		 Number of Subjects With Confirmed Best Overall Response (BOR) as per Response Evaluation Criteria in Solid Tumors (RECIST Version 1.1) and as Adjudicated by the Investigator
    End point description
    Confirmed BOR was evaluated based on RECIST v1.1 and Investigator’s assessments and defined as best response of any of confirmed complete response (CR), partial response (PR), stable disease (SD) and progressive disease (PD) recorded from date of study treatment until disease progression/recurrence. CR: Disappearance of all evidence of target/non-target lesions. PR: At least 30 percent (%) reduction from baseline in sum of longest diameter (SLD) of all lesions. SD: Neither sufficient increase to qualify for PD nor sufficient shrinkage to qualify for PR. PD: at least a 20% increase in SLD, taking as reference smallest SLD recorded from baseline/appearance of 1or more new lesions and unequivocal progression of non-target lesions. Full analysis set included all subjects who received any dose of avelumab.
    End point type
    Secondary
    End point timeframe
    Baseline up to 1182 days
    End point values
    		 Avelumab 10 miligram per kilogram (mg/kg) Avelumab 20 mg/kg
    Number of subjects analysed
    6
    15
    Units: Subjects
        Complete Response (CR)
    0
    0
        Partial Response (PR)
    0
    0
        Stable Disease (SD)
    0
    4
        Non-CR/Non-PR
    0
    0
        Progressive Disease (PD)
    5
    9
        Not Evaluable
    1
    2
    No statistical analyses for this end point

    Secondary: Duration of Response (DOR) as per Response Evaluation Criteria in Solid Tumors (RECIST Version 1.1) and as Adjudicated by the Investigator

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    End point title
    		 Duration of Response (DOR) as per Response Evaluation Criteria in Solid Tumors (RECIST Version 1.1) and as Adjudicated by the Investigator
    End point description
    Duration of response was defined for subjects with confirmed objective response (OR), as the time from first documentation of objective response (Complete Response or Partial Response) to the date of first documentation of objective PD or death due to any cause, whichever occurred first. CR: Disappearance of all evidence of target and non-target lesions. PR: At least 30% reduction from baseline in the SLD of all lesions. PD: At least a 20 % increase in the SLD, taking as reference the smallest SLD recorded from baseline or the appearance of 1 or more new lesions. DOR was determined according to RECIST v1.1 and assessed by Investigator. Full analysis set included all subjects who received any dose of avelumab.
    End point type
    Secondary
    End point timeframe
    Time from first documentation of objective response up to 1182 days
    End point values
    		 Avelumab 10 miligram per kilogram (mg/kg) Avelumab 20 mg/kg
    Number of subjects analysed
    0 [3]
    0 [4]
    Units: months
        median (full range (min-max))
    ( to )
    ( to )
    Notes
    [3] - Analyses of DOR were not conducted in the absence of any responders (For CR and PR).
    [4] - Analyses of DOR were not conducted in the absence of any responders (For CR and PR).
    No statistical analyses for this end point

    Secondary: Time to Response According to Response Evaluation Criteria in Solid Tumors (RECIST Version 1.1) and as Adjudicated by the Investigator

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    End point title
    		 Time to Response According to Response Evaluation Criteria in Solid Tumors (RECIST Version 1.1) and as Adjudicated by the Investigator
    End point description
    Time to response (TTR) was defined, for subjects with an objective response, as the time from the start date of study treatment to the first documentation of OR (CR or PR) which was subsequently confirmed. Full analysis set included all subjects who received any dose of avelumab.
    End point type
    Secondary
    End point timeframe
    Time from start of study treatment up to 1182 days
    End point values
    		 Avelumab 10 miligram per kilogram (mg/kg) Avelumab 20 mg/kg
    Number of subjects analysed
    0 [5]
    0 [6]
    Units: Months
        median (full range (min-max))
    ( to )
    ( to )
    Notes
    [5] - Analyses of Time to response were not conducted in the absence of any responders (For CR and PR).
    [6] - Analyses of Time to response were not conducted in the absence of any responders (For CR and PR).
    No statistical analyses for this end point

    Secondary: Progression-Free Survival According to Response Evaluation Criteria in Solid Tumors (RECIST Version 1.1) and as Adjudicated by the Investigator

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    End point title
    		 Progression-Free Survival According to Response Evaluation Criteria in Solid Tumors (RECIST Version 1.1) and as Adjudicated by the Investigator
    End point description
    Progression-Free survival was defined as the time from first administration of study treatment until the first documentation of disease progression (PD) or death due to any cause, whichever occurred first. PD: At least a 20 % increase in the 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. Full analysis set included all subjects who received any dose of avelumab.
    End point type
    Secondary
    End point timeframe
    Time from first administration of study drug until the first documentation of PD or death, assessed up to 1182 days
    End point values
    		 Avelumab 10 miligram per kilogram (mg/kg) Avelumab 20 mg/kg
    Number of subjects analysed
    6
    15
    Units: Weeks
        median (full range (min-max))
    7.5 (6.57 to 8.14)
    7.7 (0.14 to 131.86)
    No statistical analyses for this end point

    Secondary: Overall Survival (OS)

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    End point title
    		 Overall Survival (OS)
    End point description
    Overall Survival was defined as the time from date of first dose of study drug 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 included all subjects who received any dose of avelumab.
    End point type
    Secondary
    End point timeframe
    Time from first administration of study drug up to 1182 days
    End point values
    		 Avelumab 10 miligram per kilogram (mg/kg) Avelumab 20 mg/kg
    Number of subjects analysed
    6
    15
    Units: Months
        median (full range (min-max))
    4.4 (1.51 to 14.36)
    7.0 (0.85 to 31.97)
    No statistical analyses for this end point

    Secondary: Number of Subjects With Treatment-Emergent Adverse Events, Adverse Events of Special Interest (AESI) and Treatment-related Adverse Events According to National Cancer Institute-Common Terminology Criteria for Adverse Events Version 4.03 (NCI-CTCAE v4.03)

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    End point title
    		 Number of Subjects With Treatment-Emergent Adverse Events, Adverse Events of Special Interest (AESI) and Treatment-related Adverse Events According to National Cancer Institute-Common Terminology Criteria for Adverse Events Version 4.03 (NCI-CTCAE v4.03)
    End point description
    Adverse Event (AE) was defined any untoward medical occurrence in a subject administered with a study drug, which does not necessarily had a causal relationship with this treatment. Serious AE was defined AE that resulted in any of the following outcomes: death; life threatening; persistent/significant disability/incapacity; initial/prolonged inpatient hospitalization; congenital anomaly/birth defect. TEAEs: TEAEs was defined as events with onset date or worsening during the on-treatment period. TEAEs included serious AEs and non-serious AEs. Treatment-related TEAEs: reasonably related to the study intervention. AESIs included Infusion-related reactions (IRRs) and Immune-related AE (irAEs). The safety analysis set included all subjects who received any dose of avelumab.
    End point type
    Secondary
    End point timeframe
    Baseline up to 1182 days
    End point values
    		 Avelumab 10 miligram per kilogram (mg/kg) Avelumab 20 mg/kg
    Number of subjects analysed
    6
    15
    Units: Subjects
        Subject with any TEAEs
    6
    15
        Subjects with any Serious TEAEs
    4
    12
        Subjects with Treatment-emergent irAE
    0
    1
        Subjects with Treatment-emergent IRR
    2
    7
        Subjects with Study-drug related AEs
    3
    10
    No statistical analyses for this end point

    Secondary: Number of Subjects With Grade 3 or Higher Laboratory Abnormalities According to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 4.03

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    End point title
    		 Number of Subjects With Grade 3 or Higher Laboratory Abnormalities According to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) Version 4.03
    End point description
    The total number of subjects with laboratory test abnormalities were assessed. Clinical laboratory tests included hematology and biochemistry abnormalities. The on-treatment hematology and biochemistry abnormalities (by worst on-treatment NCI-CTCAE Grade 3 and Grade 4) were reported. Safety analysis set included all subjects who received any dose of avelumab.
    End point type
    Secondary
    End point timeframe
    Baseline up to 1182 days
    End point values
    		 Avelumab 10 miligram per kilogram (mg/kg) Avelumab 20 mg/kg
    Number of subjects analysed
    6
    15
    Units: Subjects
        Grade 3: Anemia:
    1
    1
        Grade 3: lymphocyte count decreased
    1
    2
        Grade 4: platelet count decreased
    0
    1
        Grade 3: hyponatremia
    1
    3
        Grade 3: hyperkalemia
    1
    0
        Grade 3: creatinine increased
    1
    0
        Grade 3: alkaline phosphatase increased
    1
    1
        Grade 3: hypokalemia
    0
    2
        Grade 3: serum amylase increased
    0
    1
        Grade 4: Hyperkalemia
    0
    1
    No statistical analyses for this end point

    Secondary: Maximum Observed Serum Concentration (Cmax) of Avelumab

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    End point title
    		 Maximum Observed Serum Concentration (Cmax) of Avelumab
    End point description
    Cmax is the maximum observed serum concentration obtained directly from the concentration versus time curve. The Pharmacokinetic (PK) analysis set included all subjects who received at least one dose of avelumab, had no important protocol deviations or important events affecting PK, and provided at least one measurable post-dose concentration.
    End point type
    Secondary
    End point timeframe
    Pre-dose, end of infusion (1 hour), 3 hours post-dose on Day 1, cycle 1 (each cycle.is for 14 days)
    End point values
    		 Avelumab 10 miligram per kilogram (mg/kg) Avelumab 20 mg/kg
    Number of subjects analysed
    6
    15
    Units: microgram per mililiter (mcg/mL)
        geometric mean (geometric coefficient of variation)
    190 ( 34.5 )
    384 ( 27.3 )
    No statistical analyses for this end point

    Secondary: Area Under the Serum Concentration-Time Curve From Time Zero to the 336 Hours Post-Dose (AUC 0-336 hours) of Avelumab

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    End point title
    		 Area Under the Serum Concentration-Time Curve From Time Zero to the 336 Hours Post-Dose (AUC 0-336 hours) of Avelumab
    End point description
    The AUC from time zero (= dosing time) to the last sampling time (tlast) at which the concentration was at or above the lower limit of quantification. Calculated using the mixed loglinear trapezoidal rule (linear up, log down). The PK analysis set included all subjects who received at least one dose of avelumab, had no important protocol deviations or important events affecting PK, and provided at least one measurable post-dose concentration.
    End point type
    Secondary
    End point timeframe
    Pre-dose, end of infusion (1 hour), 3 hours post-dose on Day 1, cycle 1 (each cycle.is for 14 days)
    End point values
    		 Avelumab 10 miligram per kilogram (mg/kg) Avelumab 20 mg/kg
    Number of subjects analysed
    6
    15
    Units: microgram*hour per mililiter (mcg•h/mL)
        geometric mean (geometric coefficient of variation)
    18800 ( 29.2 )
    43500 ( 21.5 )
    No statistical analyses for this end point

    Secondary: Apparent Terminal Half life (t1/2) of Avelumab

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    End point title
    		 Apparent Terminal Half life (t1/2) of Avelumab
    End point description
    Apparent terminal half-life was defined as the time required for the plasma concentration of drug to decrease 50 percent in the final stage of its elimination. Apparent terminal half-life. t1/2 = log (ln) 2/lambdaz (λz). PK analysis set included all subjects who received at least one dose of avelumab, had no important protocol deviations or important events affecting PK, and provided at least one measurable post-dose concentration. Here, number of subject analyzed signifies those subjects who were evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Pre-dose, end of infusion (1 hour), 3 hours post-dose on Day 1, cycle 1 (each cycle.is for 14 days)
    End point values
    		 Avelumab 10 miligram per kilogram (mg/kg) Avelumab 20 mg/kg
    Number of subjects analysed
    4
    7
    Units: hours
        geometric mean (geometric coefficient of variation)
    85.9 ( 15.1 )
    119 ( 73.7 )
    No statistical analyses for this end point

    Secondary: Minimum Serum Post-dose Trough (Ctrough) Concentration of Avelumab

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    End point title
    		 Minimum Serum Post-dose Trough (Ctrough) Concentration of Avelumab
    End point description
    The concentration observed immediately before next dosing (corresponding to predose or trough concentration for multiple dosing) was calculated. PK analysis set included all subjects who received at least one dose of avelumab, had no important protocol deviations or important events affecting PK, and provided at least one measurable post-dose concentration. Here :Number of subject analyzed" signifies those who were evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Pre-dose at Day 15
    End point values
    		 Avelumab 10 miligram per kilogram (mg/kg) Avelumab 20 mg/kg
    Number of subjects analysed
    6
    14
    Units: microgram per ml (mcg/mL)
        geometric mean (geometric coefficient of variation)
    11.2 ( 44.9 )
    34.8 ( 77.8 )
    No statistical analyses for this end point

    Secondary: Number of Subjects With Positive Treatment Emergent Anti-drug Antibodies (ADA) and Neutralizing Antibodies (Nabs)

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    End point title
    		 Number of Subjects With Positive Treatment Emergent Anti-drug Antibodies (ADA) and Neutralizing Antibodies (Nabs)
    End point description
    Serum samples were analyzed by a validated electrochemiluminesce immunoassay to detect the presence of anti-drug antibodies and neutralizing antibodies. Samples that screened positive were subsequently tested in a confirmatory assay. Those confirmed positive were titered for a quasi-quantitative result. Number of subjects with positive treatment emergent anti-drug antibodies and neutralizing antibodies were reported. Subjects not positive prior to treatment with avelumab and with at least one positive result in the human-Antihuman Antibodies assay were characterized as treatment-emergent. Immunogenicity Analysis Set included all subjects who received any dose of avelumab and have at least one valid ADA result.
    End point type
    Secondary
    End point timeframe
    Baseline up to 1182 days
    End point values
    		 Avelumab 10 miligram per kilogram (mg/kg) Avelumab 20 mg/kg
    Number of subjects analysed
    6
    15
    Units: Subjects
        Subject With Anti-drug Antibodies
    1
    0
        Subjects With Neutralizing Antibodies
    1
    0
    No statistical analyses for this end point

    Secondary: Number of Subjects With Positive Tumor Programmed death ligand 1 (PD-L1) Expression

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    End point title
    		 Number of Subjects With Positive Tumor Programmed death ligand 1 (PD-L1) Expression
    End point description
    Number of subjects with positive tumor programmed death ligand 1 (PDL-1) with cut off >=1%, >= 5%, >=25%, >=50% and >=80% expression were reported. Biomarker Analysis Set included all subjects who received any dose of avelumab and who have provided at least one blood, serum, plasma, or tumor sample for biomarker assessments.
    End point type
    Secondary
    End point timeframe
    Baseline up to end of treatment visit (27.5 weeks)
    End point values
    		 Avelumab 10 miligram per kilogram (mg/kg) Avelumab 20 mg/kg
    Number of subjects analysed
    6
    15
    Units: Subjects
        PD-L1 expression:greater than or equal to (>=)1%
    0
    5
        PD-L1 expression at cut-off of >=5%
    0
    4
        PD-L1 expression at cut-off of >=25%
    0
    3
        PD-L1 expression at cut-off of >=50%
    0
    2
        PD-L1 expression at cut-off of >=80%
    0
    2
    No statistical analyses for this end point

    Secondary: Number of Subjects With Substantial, Sustained, or Significant Changes From Baseline for Tumor-Infiltrating T-cell Levels

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    End point title
    		 Number of Subjects With Substantial, Sustained, or Significant Changes From Baseline for Tumor-Infiltrating T-cell Levels
    End point description
    Number of Subjects with substantial, sustained, or significant changes from baseline for Tumor-Infiltrating T-cell Levels were reported. We were only able to analyze tumor tissue from baseline samples. Only one subject provided post treatment tumor samples and this sample could not be analyzed, therefore this secondary variable could not be analyzed. Biomarker Analysis Set included all subjects who received any dose of avelumab and who have provided at least one blood, serum, plasma, or tumor sample for biomarker assessments. Tumor-Infiltrating T-cell Levels were observed.
    End point type
    Secondary
    End point timeframe
    Baseline up to end of treatment visit (27.5 weeks)
    End point values
    		 Avelumab 10 miligram per kilogram (mg/kg) Avelumab 20 mg/kg
    Number of subjects analysed
    0 [7]
    0 [8]
    Units: Subjects
    Notes
    [7] - This endpoint was not analyzed.
    [8] - This endpoint was not analyzed.
    No statistical analyses for this end point

    Secondary: Number of Subjects With Substantial, Sustained, or Significant Changes From Baseline for T-cell Population in Blood

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    End point title
    		 Number of Subjects With Substantial, Sustained, or Significant Changes From Baseline for T-cell Population in Blood
    End point description
    Number of subjects with substantial, sustained, or significant changes from baseline for T-cell population in blood were reported. Due to limited data (small number of subjects with baseline plus on treatment samples), no conclusions of substantial, sustained, or significant changes in blood T cells could be made. Biomarker Analysis Set included all subjects who received any dose of avelumab and who have provided at least one blood, serum, plasma, or tumor sample for biomarker assessments.
    End point type
    Secondary
    End point timeframe
    Baseline up to end of treatment visit (27.5 weeks)
    End point values
    		 Avelumab 10 miligram per kilogram (mg/kg) Avelumab 20 mg/kg
    Number of subjects analysed
    0 [9]
    0 [10]
    Units: Subjects
    Notes
    [9] - This endpoint was not analyzed..
    [10] - This endpoint was not analyzed.
    No statistical analyses for this end point

    Secondary: Number of Subjects With Substantial, Sustained, or Significant Changes From Baseline for T-cell, B-cell and NK-cell in Blood

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    End point title
    		 Number of Subjects With Substantial, Sustained, or Significant Changes From Baseline for T-cell, B-cell and NK-cell in Blood
    End point description
    Number of subjects with substantial, sustained, or significant changes from baseline for T-cell, B-cell and NK-cell in blood were reported. Due to limited data (small number of subjects with baseline plus on treatment samples), no conclusions of substantial, sustained, or significant changes in blood T, B, NK cells could be made. Biomarker Analysis Set included all subjects who received any dose of avelumab and who have provided at least one blood, serum, plasma, or tumor sample for biomarker assessments.
    End point type
    Secondary
    End point timeframe
    Baseline up to end of treatment visit (27.5 weeks)
    End point values
    		 Avelumab 10 miligram per kilogram (mg/kg) Avelumab 20 mg/kg
    Number of subjects analysed
    0 [11]
    0 [12]
    Units: Subjects
    Notes
    [11] - This endpoint was not analyzed.
    [12] - This endpoint was not analyzed.
    No statistical analyses for this end point

    Secondary: Number of Subjects With Substantial, Sustained, or Significant Changes From Baseline for Vaccination-Related Antibody Concentrations

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    End point title
    		 Number of Subjects With Substantial, Sustained, or Significant Changes From Baseline for Vaccination-Related Antibody Concentrations
    End point description
    Samples for the testing of vaccination-related antibody concentrations for diphtheria, tetanus, and pneumococcal conjugate (PCV-7) were to be collected at Cycle 1/Day 1 (pretreatment), Cycle 7/Day 85 and at the End-of-Treatment visit. Due to limited data (small # of pts with baseline + on treatment samples), no conclusions of substantial, sustained, or significant changes in vaccination related antibodies could be made. Biomarker Analysis Set included all subjects who received any dose of avelumab and who have provided at least one blood, serum, plasma, or tumor sample for biomarker assessments.
    End point type
    Secondary
    End point timeframe
    Baseline up to end of treatment visit (27.5 weeks)
    End point values
    		 Avelumab 10 miligram per kilogram (mg/kg) Avelumab 20 mg/kg
    Number of subjects analysed
    0 [13]
    0 [14]
    Units: Subjects
    Notes
    [13] - This endpoint was not analyzed.
    [14] - This endpoint was not analyzed.
    No statistical analyses for this end point

    Secondary: Number of Subjects with TEAEs Related to Vital Signs that Resulted in Treatment Discontinuation

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    End point title
    		 Number of Subjects with TEAEs Related to Vital Signs that Resulted in Treatment Discontinuation
    End point description
    Vital signs included: Heart Rate, Blood pressure, respiratory rate. Vital signs were measured in semi-supine position after 5 minutes rest for the subjects. The safety analysis set included all subjects who received any dose of avelumab.
    End point type
    Secondary
    End point timeframe
    Baseline up to 1182 days
    End point values
    		 Avelumab 10 miligram per kilogram (mg/kg) Avelumab 20 mg/kg
    Number of subjects analysed
    6
    15
    Units: Subjects
    0
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Baseline up to 1182 days
    Adverse event reporting additional description
    The safety analysis set included all subjects who received any dose of avelumab. The AEs reported under non-serious AEs are the TEAEs (including non-serious as well as serious AEs) as no separate non-serious AEs were generated per planned analysis. All fatal AEs were related to progression of disease. No treatment related death.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    24.0
    Reporting groups
    Reporting group title
    Avelumab 20 mg/kg
    Reporting group description
    		 Subjects received an intravenous infusion of avelumab 20mg/kg administered intravenously (IV) once every 2 weeks until confirmed progression, death, unacceptable toxicity, or any criterion for withdrawal occurred.

    Reporting group title
    Avelumab 10 miligram per kilogram (mg/kg)
    Reporting group description
    		 Subjects received an intravenous infusion of avelumab 10mg/kg administered intravenously (IV) once every 2 weeks until confirmed progression, death, unacceptable toxicity, or any criterion for withdrawal occurred.

    Serious adverse events
    		 Avelumab 20 mg/kg Avelumab 10 miligram per kilogram (mg/kg)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    12 / 15 (80.00%)
    4 / 6 (66.67%)
         number of deaths (all causes)
    12
    6
         number of deaths resulting from adverse events
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Malignant pleural effusion
         subjects affected / exposed
    1 / 15 (6.67%)
    1 / 6 (16.67%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tumour haemorrhage
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 6 (16.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tumour pseudoprogression
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Post procedural inflammation
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Pelvic venous thrombosis
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 6 (16.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Headache
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intracranial pressure increased
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 6 (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
    Thrombocytopaenia
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 6 (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
    Additional description: All fatal AEs were related to progression of disease.
         subjects affected / exposed
    5 / 15 (33.33%)
    1 / 6 (16.67%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 1
         deaths causally related to treatment / all
    0 / 3
    0 / 1
    Influenza like illness
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    3 / 15 (20.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal Pain
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 6 (16.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 6 (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
    1 / 15 (6.67%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hypophagia
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Avelumab 20 mg/kg Avelumab 10 miligram per kilogram (mg/kg)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    15 / 15 (100.00%)
    6 / 6 (100.00%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Lip and/or oral cavity cancer
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    Malignant pleural effusion
         subjects affected / exposed
    1 / 15 (6.67%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    Tumour haemorrhage
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    Tumour pseudoprogression
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    Vascular disorders
    Lymphoedema
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    Hypotension
         subjects affected / exposed
    3 / 15 (20.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    Hypertension
         subjects affected / exposed
    2 / 15 (13.33%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    Pelvic venous thrombosis
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    Catheter site pain
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    Chills
         subjects affected / exposed
    3 / 15 (20.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    Influenza like illness
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    Fatigue
         subjects affected / exposed
    6 / 15 (40.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    Gait disturbance
         subjects affected / exposed
    2 / 15 (13.33%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    Disease progression
         subjects affected / exposed
    5 / 15 (33.33%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    Malaise
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    Non-cardiac chest pain
         subjects affected / exposed
    2 / 15 (13.33%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    Oedema
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    Pyrexia
         subjects affected / exposed
    10 / 15 (66.67%)
    4 / 6 (66.67%)
         occurrences all number
    0
    0
    Pain
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    Peripheral swelling
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    Oedema peripheral
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    3 / 15 (20.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    Cough
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    Dyspnoea exertional
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    Rhinorrhoea
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    Pleural effusion
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    Pharyngeal inflammation
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    Oropharyngeal pain
         subjects affected / exposed
    2 / 15 (13.33%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    Increased bronchial secretion
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    Hypoxia
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    2 / 15 (13.33%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    Product issues
    Device occlusion
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    Investigations
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 15 (0.00%)
    2 / 6 (33.33%)
         occurrences all number
    0
    0
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 15 (0.00%)
    2 / 6 (33.33%)
         occurrences all number
    0
    0
    Amylase increased
         subjects affected / exposed
    1 / 15 (6.67%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    Blood alkaline phosphatase increased
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    Blood creatine phosphokinase increased
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    Blood creatinine increased
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    Lymphocyte count decreased
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    C-reactive protein increased
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    Electrocardiogram QT prolonged
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    Blood phosphorus increased
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    Platelet count decreased
         subjects affected / exposed
    2 / 15 (13.33%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    Urine output decreased
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    Weight decreased
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    Injury, poisoning and procedural complications
    Infusion related reaction
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    Ligament sprain
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    Limb injury
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    Post procedural inflammation
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    Procedural pain
         subjects affected / exposed
    3 / 15 (20.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    Cardiac disorders
    Sinus tachycardia
         subjects affected / exposed
    2 / 15 (13.33%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    Dizziness postural
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    Headache
         subjects affected / exposed
    5 / 15 (33.33%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    Hemiparesis
         subjects affected / exposed
    2 / 15 (13.33%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    Hydrocephalus
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    Hypoaesthesia
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    Intracranial pressure increased
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    Lethargy
         subjects affected / exposed
    2 / 15 (13.33%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    Memory impairment
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    Nystagmus
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    Seizure
         subjects affected / exposed
    2 / 15 (13.33%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    Paraesthesia
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    Blood and lymphatic system disorders
    Coagulopathy
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    Anaemia
         subjects affected / exposed
    5 / 15 (33.33%)
    2 / 6 (33.33%)
         occurrences all number
    0
    0
    Thrombocytopenia
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    Ear and labyrinth disorders
    Ear pain
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    Eye disorders
    Vision blurred
         subjects affected / exposed
    2 / 15 (13.33%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    Diplopia
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    Ascites
         subjects affected / exposed
    1 / 15 (6.67%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    Abdominal pain upper
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    Abdominal pain
         subjects affected / exposed
    3 / 15 (20.00%)
    2 / 6 (33.33%)
         occurrences all number
    0
    0
    Constipation
         subjects affected / exposed
    5 / 15 (33.33%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    Dental caries
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    Dyspepsia
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    Dry mouth
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    Diarrhoea
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    Dysphagia
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    Gastric haemorrhage
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    Gastrointestinal ulcer
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    Vomiting
         subjects affected / exposed
    6 / 15 (40.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    Nausea
         subjects affected / exposed
    6 / 15 (40.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    Stomatitis
         subjects affected / exposed
    2 / 15 (13.33%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    Skin and subcutaneous tissue disorders
    Blister
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    Decubitus ulcer
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    Dermatitis atopic
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    Erythema
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    Pain of skin
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    Pruritus
         subjects affected / exposed
    3 / 15 (20.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    Pruritus allergic
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    Rash
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    Rash maculo-papular
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    Urticaria
         subjects affected / exposed
    1 / 15 (6.67%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    Renal and urinary disorders
    Dysuria
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    Cystitis noninfective
         subjects affected / exposed
    2 / 15 (13.33%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    Acute kidney injury
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    Urinary retention
         subjects affected / exposed
    2 / 15 (13.33%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    Renal tubular disorder
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    Nephritis
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    Haematuria
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    Endocrine disorders
    Hypothyroidism
         subjects affected / exposed
    1 / 15 (6.67%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    Musculoskeletal and connective tissue disorders
    Musculoskeletal chest pain
         subjects affected / exposed
    1 / 15 (6.67%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    Muscular weakness
         subjects affected / exposed
    2 / 15 (13.33%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    Muscle spasms
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    Groin pain
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    Flank pain
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    Back pain
         subjects affected / exposed
    4 / 15 (26.67%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    Arthralgia
         subjects affected / exposed
    3 / 15 (20.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    Pain in extremity
         subjects affected / exposed
    4 / 15 (26.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    Infections and infestations
    Folliculitis
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    Fungal skin infection
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    Hordeolum
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    Pharyngitis
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    Oral candidiasis
         subjects affected / exposed
    2 / 15 (13.33%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    Oral herpes
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    Otitis media
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    Nasopharyngitis
         subjects affected / exposed
    3 / 15 (20.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    Pneumonia
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    Pyuria
         subjects affected / exposed
    2 / 15 (13.33%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    Rhinitis
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    Tonsillitis
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    Upper respiratory tract infection
         subjects affected / exposed
    2 / 15 (13.33%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    Skin infection
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    1 / 15 (6.67%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    Dehydration
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    Hyperkalaemia
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    Hyperuricaemia
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    Hypokalaemia
         subjects affected / exposed
    2 / 15 (13.33%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    Hypophosphataemia
         subjects affected / exposed
    0 / 15 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    Hypophagia
         subjects affected / exposed
    3 / 15 (20.00%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    Hyponatraemia
         subjects affected / exposed
    2 / 15 (13.33%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    Hypomagnesaemia
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 6 (0.00%)
         occurrences all number
    0
    0
    Hypoalbuminaemia
         subjects affected / exposed
    4 / 15 (26.67%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    15 Sep 2017
    non-substantial changes

    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.
    The study was planned to be conducted in 2 parts: the dose-finding part (Phase I) and the tumor-specified expansion part (Phase II). However, Phase II was cancelled due to limited clinical benefit of PD-L1 monotherapy in pediatric subjects.
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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