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    Clinical Trial Results:
    Multiple Ascending Dose (MAD) Phase I Study of the IGF-1R Antagonist R1507 Administered as an Intravenous Infusion in children and Adolescents with Advanced Solid Tumors

    Summary
    EudraCT number
    2016-001046-26
    Trial protocol
    Outside EU/EEA  
    Global end of trial date
    09 Dec 2011

    Results information
    Results version number
    v1(current)
    This version publication date
    17 Jun 2017
    First version publication date
    17 Jun 2017
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    NO21200
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT00560144
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    F. Hoffmann-La Roche AG
    Sponsor organisation address
    Grenzacherstrasse 124, Basel, Switzerland, CH-4070
    Public contact
    F. Hoffmann-La Roche AG, F. Hoffmann-La Roche AG, +41 616878333, global.trial_information@roche.com
    Scientific contact
    F. Hoffmann-La Roche AG, F. Hoffmann-La Roche AG, +41 616878333, global.trial_information@roche.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?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    09 Dec 2011
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    09 Dec 2011
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To determine the doses of R1507, a monoclonal antibody to the Type I Insulin-like Growth Factor Receptor (IGF-1R), that achieve serum drug exposure levels (AUCs) in children and adolescents with advanced solid tumors that are equivalent to the exposures in adults at the adult recommended doses of 9 mg/kg administered on a weekly schedule and 16 mg/kg administered every 3 weeks. To determine the maximum tolerated doses (MTD) of R1507 in children and adolescents with advanced solid tumors IF dose-limiting toxicity (DLT) is observed in 2 or more subjects at any dose level on the weekly or every 3 week schedules.
    Protection of trial subjects
    All study subjects were required to read and sign an informed consent form.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    19 Nov 2007
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United States: 34
    Worldwide total number of subjects
    34
    EEA total number of subjects
    0
    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)
    20
    Adolescents (12-17 years)
    14
    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
    -

    Pre-assignment
    Screening details
    A total of 34 subjects were enrolled across six sites in the United States.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    R1507 16 mg/kg
    Arm description
    Subjects received R1507 16 mg/kg body weight intravenously every 3 weeks until development of progressive disease or DLT that persisted or recurred after a dose reduction.
    Arm type
    Experimental

    Investigational medicinal product name
    R1507
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    R1507 16 mg/kg body weight intravenously every week.

    Arm title
    R1507 3 mg/kg
    Arm description
    Subjects received R1507 3 mg/kg body weight intravenously every week until development of progressive disease or DLT that persisted or recurred after a dose reduction.
    Arm type
    Experimental

    Investigational medicinal product name
    R1507
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    R1507 3 mg/kg body weight intravenously every week.

    Arm title
    R1507 9 mg/kg
    Arm description
    Subjects received R1507 9 mg/kg body weight intravenously every week until development of progressive disease or DLT that persisted or recurred after a dose reduction.
    Arm type
    Experimental

    Investigational medicinal product name
    R1507
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    R1507 9 mg/kg body weight intravenously every week.

    Number of subjects in period 1
    R1507 16 mg/kg R1507 3 mg/kg R1507 9 mg/kg
    Started
    12
    3
    19
    Completed
    0
    0
    0
    Not completed
    12
    3
    19
         Study Terminated by Sposor
    3
    -
    -
         Insufficient Therapeutic Response
    9
    3
    18
         Failure to Return
    -
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    R1507 16 mg/kg
    Reporting group description
    Subjects received R1507 16 mg/kg body weight intravenously every 3 weeks until development of progressive disease or DLT that persisted or recurred after a dose reduction.

    Reporting group title
    R1507 3 mg/kg
    Reporting group description
    Subjects received R1507 3 mg/kg body weight intravenously every week until development of progressive disease or DLT that persisted or recurred after a dose reduction.

    Reporting group title
    R1507 9 mg/kg
    Reporting group description
    Subjects received R1507 9 mg/kg body weight intravenously every week until development of progressive disease or DLT that persisted or recurred after a dose reduction.

    Reporting group values
    R1507 16 mg/kg R1507 3 mg/kg R1507 9 mg/kg Total
    Number of subjects
    12 3 19 34
    Age Categorical
    Units: Subjects
        Children (2-11 years)
    5 2 13 20
        Adolescents (12-17 years)
    7 1 6 14
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    12.8 ± 3.17 10 ± 5.57 9.3 ± 4.45 -
    Gender Categorical
    Units: Subjects
        Female
    3 3 10 16
        Male
    9 0 9 18

    End points

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    End points reporting groups
    Reporting group title
    R1507 16 mg/kg
    Reporting group description
    Subjects received R1507 16 mg/kg body weight intravenously every 3 weeks until development of progressive disease or DLT that persisted or recurred after a dose reduction.

    Reporting group title
    R1507 3 mg/kg
    Reporting group description
    Subjects received R1507 3 mg/kg body weight intravenously every week until development of progressive disease or DLT that persisted or recurred after a dose reduction.

    Reporting group title
    R1507 9 mg/kg
    Reporting group description
    Subjects received R1507 9 mg/kg body weight intravenously every week until development of progressive disease or DLT that persisted or recurred after a dose reduction.

    Primary: Total Number of Infusions of IGF-1R Antagonist R1507 Administered

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    End point title
    Total Number of Infusions of IGF-1R Antagonist R1507 Administered [1]
    End point description
    End point type
    Primary
    End point timeframe
    Up to 49 months
    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: No statistical analysis was performed for this end point.
    End point values
    R1507 16 mg/kg R1507 3 mg/kg R1507 9 mg/kg
    Number of subjects analysed
    12
    3
    19
    Units: number of infusions
        arithmetic mean (standard deviation)
    5.08 ± 4.1
    4.33 ± 1.53
    11.21 ± 10.16
    No statistical analyses for this end point

    Secondary: Percentage of Subjects with Adverse Events

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    End point title
    Percentage of Subjects with Adverse Events
    End point description
    An adverse event (AE) was any untoward medical occurrence in a subject who received study drug without regard to possibility of causal relationship to the study drug. An SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; Initial or prolonged inpatient hospitalization; Life-threatening experience (immediate risk of dying); Persistent or significant disability or incapacity; and congenital anomaly.
    End point type
    Secondary
    End point timeframe
    From first dose of study drug up 30 days after the last dose of study drug administration (up to 49 months)
    End point values
    R1507 16 mg/kg R1507 3 mg/kg R1507 9 mg/kg
    Number of subjects analysed
    12
    3
    19
    Units: subjects
    11
    3
    19
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From first dose of study drug up 30 days after the last dose of study drug administration (up to 49 months)
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    12.1
    Reporting groups
    Reporting group title
    R1507 16 mg/kg
    Reporting group description
    Subjects received R1507 16 mg/kg body weight intravenously every 3 weeks until development of progressive disease or DLT that persisted or recurred after a dose reduction.

    Reporting group title
    R1507 3 mg/kg
    Reporting group description
    Subjects received R1507 3 mg/kg body weight intravenously every week until development of progressive disease or DLT that persisted or recurred after a dose reduction.

    Reporting group title
    R1507 9 mg/kg
    Reporting group description
    Subjects received R1507 9 mg/kg body weight intravenously every week until development of progressive disease or DLT that persisted or recurred after a dose reduction.

    Serious adverse events
    R1507 16 mg/kg R1507 3 mg/kg R1507 9 mg/kg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 12 (16.67%)
    0 / 3 (0.00%)
    4 / 19 (21.05%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Hypoxia
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory tract haemorrhage
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 3 (0.00%)
    0 / 19 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Nephrolithiasis
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 3 (0.00%)
    0 / 19 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Pain in extremity
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 3 (0.00%)
    0 / 19 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypercalcaemia
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         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
    R1507 16 mg/kg R1507 3 mg/kg R1507 9 mg/kg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    11 / 12 (91.67%)
    3 / 3 (100.00%)
    19 / 19 (100.00%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 3 (0.00%)
    2 / 19 (10.53%)
         occurrences all number
    1
    0
    2
    Pallor
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    1
    0
    1
    Hypotension
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    General disorders and administration site conditions
    Application site rash
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 3 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    0
    Asthenia
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 3 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    0
    Catheter site erythema
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 3 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    0
    Catheter site pain
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 3 (0.00%)
    2 / 19 (10.53%)
         occurrences all number
    0
    0
    2
    Chest pain
         subjects affected / exposed
    2 / 12 (16.67%)
    1 / 3 (33.33%)
    1 / 19 (5.26%)
         occurrences all number
    2
    1
    1
    Chills
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 3 (0.00%)
    2 / 19 (10.53%)
         occurrences all number
    0
    0
    2
    Fatigue
         subjects affected / exposed
    5 / 12 (41.67%)
    1 / 3 (33.33%)
    7 / 19 (36.84%)
         occurrences all number
    10
    1
    8
    Injection site pain
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 3 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    0
    Irritability
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    1
    0
    1
    Mucosal inflammation
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    2
    Oedema peripheral
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 3 (0.00%)
    2 / 19 (10.53%)
         occurrences all number
    0
    0
    2
    Oedema
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Pain
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 3 (33.33%)
    3 / 19 (15.79%)
         occurrences all number
    0
    1
    3
    Pyrexia
         subjects affected / exposed
    1 / 12 (8.33%)
    1 / 3 (33.33%)
    5 / 19 (26.32%)
         occurrences all number
    4
    1
    6
    Psychiatric disorders
    Anger
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 3 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    0
    Aggression
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 3 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    0
    Depression
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 3 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    0
    Confusional state
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 3 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    0
    Hallucination
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 3 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    0
    Insomnia
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 3 (0.00%)
    2 / 19 (10.53%)
         occurrences all number
    1
    0
    2
    Mood altered
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 3 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    0
    Psychomotor retardation
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 3 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    0
    Anxiety
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    1
    0
    1
    Reproductive system and breast disorders
    Testicular pain
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Injury, poisoning and procedural complications
    Arthropod bite
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 3 (33.33%)
    0 / 19 (0.00%)
         occurrences all number
    0
    1
    0
    Contusion
         subjects affected / exposed
    2 / 12 (16.67%)
    0 / 3 (0.00%)
    2 / 19 (10.53%)
         occurrences all number
    4
    0
    2
    Ligament sprain
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Muscle strain
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Thermal burn
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Procedural pain
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Investigations
    Aspartate aminotransferase
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Alanine aminotransferase
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 3 (0.00%)
    2 / 19 (10.53%)
         occurrences all number
    0
    0
    2
    Blood albumin decreased
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Blood bicarbonate decreased
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Blood bilirubin
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Blood glucose increased
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 3 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    0
    Blood calcium decreased
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 3 (0.00%)
    2 / 19 (10.53%)
         occurrences all number
    0
    0
    2
    Blood lactate dehydrogenase
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Blood lactate dehydrogenase increased
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Blood phosphorus decreased
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Electrocardiogram QT prolonged
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 3 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    0
    Protein total increased
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Respiratory rate decreased
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Weight decreased
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    1
    0
    1
    Weight increased
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 3 (0.00%)
    2 / 19 (10.53%)
         occurrences all number
    0
    0
    2
    Blood chloride decreased
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Cardiac disorders
    Sinus tachycardia
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Tachycardia
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 3 (0.00%)
    2 / 19 (10.53%)
         occurrences all number
    0
    0
    2
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    2 / 12 (16.67%)
    1 / 3 (33.33%)
    6 / 19 (31.58%)
         occurrences all number
    3
    1
    7
    Dyspnoea
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    2
    Epistaxis
         subjects affected / exposed
    0 / 12 (0.00%)
    2 / 3 (66.67%)
    5 / 19 (26.32%)
         occurrences all number
    0
    2
    6
    Hiccups
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Nasal congestion
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Oropharyngeal pain
         subjects affected / exposed
    3 / 12 (25.00%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    3
    0
    1
    Pharyngeal disorder
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Pleural effusion
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 3 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    0
    Rhinitis allergic
         subjects affected / exposed
    2 / 12 (16.67%)
    0 / 3 (0.00%)
    2 / 19 (10.53%)
         occurrences all number
    2
    0
    2
    Rhinorrhoea
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 3 (33.33%)
    0 / 19 (0.00%)
         occurrences all number
    0
    1
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 3 (0.00%)
    4 / 19 (21.05%)
         occurrences all number
    0
    0
    8
    Leukopenia
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 3 (0.00%)
    2 / 19 (10.53%)
         occurrences all number
    1
    0
    11
    Neutropenia
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    1
    0
    1
    Thrombocytopenia
         subjects affected / exposed
    1 / 12 (8.33%)
    1 / 3 (33.33%)
    2 / 19 (10.53%)
         occurrences all number
    1
    1
    2
    Nervous system disorders
    Balance disorder
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Convulsion
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 3 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    0
    Dizziness
         subjects affected / exposed
    2 / 12 (16.67%)
    0 / 3 (0.00%)
    2 / 19 (10.53%)
         occurrences all number
    2
    0
    2
    Dyskinesia
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 3 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    0
    Headache
         subjects affected / exposed
    1 / 12 (8.33%)
    2 / 3 (66.67%)
    6 / 19 (31.58%)
         occurrences all number
    1
    2
    7
    Hemianopia
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 3 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    0
    Iiird nerve disorder
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    4
    Peripheral sensory neuropathy
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 3 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    0
    Somnolence
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Syncope
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 3 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    0
    Eye disorders
    Ocular surface disease
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 3 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    0
    Eye swelling
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 3 (33.33%)
    0 / 19 (0.00%)
         occurrences all number
    0
    1
    0
    Visual impairment
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Vitreous floaters
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Eyelid ptosis
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Ear and labyrinth disorders
    Cerumen impaction
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Ear pain
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    2
    Abdominal pain
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 3 (0.00%)
    3 / 19 (15.79%)
         occurrences all number
    1
    0
    5
    Abdominal pain upper
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Constipation
         subjects affected / exposed
    3 / 12 (25.00%)
    1 / 3 (33.33%)
    2 / 19 (10.53%)
         occurrences all number
    4
    1
    3
    Diarrhoea
         subjects affected / exposed
    3 / 12 (25.00%)
    0 / 3 (0.00%)
    6 / 19 (31.58%)
         occurrences all number
    4
    0
    6
    Dyspepsia
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    3
    Flatulence
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Dysphagia
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Lip blister
         subjects affected / exposed
    2 / 12 (16.67%)
    0 / 3 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    2
    0
    0
    Haematochezia
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 3 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    0
    Lip ulceration
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 3 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    0
    Periodontal disease
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Nausea
         subjects affected / exposed
    3 / 12 (25.00%)
    1 / 3 (33.33%)
    3 / 19 (15.79%)
         occurrences all number
    3
    1
    6
    Rectal lesion
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 3 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    0
    Vomiting
         subjects affected / exposed
    2 / 12 (16.67%)
    1 / 3 (33.33%)
    6 / 19 (31.58%)
         occurrences all number
    2
    1
    9
    Renal and urinary disorders
    Dysuria
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 3 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    0
    Hepatobiliary disorders
    Hepatomegaly
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Hyperbilirubinaemia
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Skin and subcutaneous tissue disorders
    Blister
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Decubitus ulcer
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    2
    Dermatitis contact
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Dry skin
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Eczema
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Erythema
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    1
    0
    1
    Pruritus
         subjects affected / exposed
    2 / 12 (16.67%)
    0 / 3 (0.00%)
    4 / 19 (21.05%)
         occurrences all number
    2
    0
    4
    Exfoliative rash
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Rash
         subjects affected / exposed
    2 / 12 (16.67%)
    0 / 3 (0.00%)
    4 / 19 (21.05%)
         occurrences all number
    4
    0
    9
    Rash maculo-papular
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Rash papular
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 3 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    0
    Skin ulcer
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Skin exfoliation
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Alopecia
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 3 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    0
    Skin hypopigmentation
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Skin disorder
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    3 / 12 (25.00%)
    0 / 3 (0.00%)
    3 / 19 (15.79%)
         occurrences all number
    4
    0
    8
    Back pain
         subjects affected / exposed
    3 / 12 (25.00%)
    0 / 3 (0.00%)
    2 / 19 (10.53%)
         occurrences all number
    3
    0
    2
    Bone pain
         subjects affected / exposed
    3 / 12 (25.00%)
    0 / 3 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    3
    0
    0
    Flank pain
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Joint stiffness
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Muscle atrophy
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 3 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    0
    Muscle contracture
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 3 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    0
    Muscle spasms
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 3 (33.33%)
    4 / 19 (21.05%)
         occurrences all number
    0
    1
    8
    Muscular weakness
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 3 (0.00%)
    2 / 19 (10.53%)
         occurrences all number
    1
    0
    2
    Musculoskeletal pain
         subjects affected / exposed
    2 / 12 (16.67%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    2
    0
    1
    Myalgia
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    2
    Neck pain
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 3 (0.00%)
    2 / 19 (10.53%)
         occurrences all number
    1
    0
    2
    Pain in extremity
         subjects affected / exposed
    3 / 12 (25.00%)
    1 / 3 (33.33%)
    1 / 19 (5.26%)
         occurrences all number
    6
    2
    2
    Pain in jaw
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 3 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    0
    Musculoskeletal chest pain
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 3 (0.00%)
    2 / 19 (10.53%)
         occurrences all number
    1
    0
    2
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    2 / 12 (16.67%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    2
    0
    1
    Hyperglycaemia
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Hyperuricaemia
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Hypoglycaemia
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    1
    0
    1
    Vitamin d deficiency
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Decreased appetite
         subjects affected / exposed
    4 / 12 (33.33%)
    0 / 3 (0.00%)
    4 / 19 (21.05%)
         occurrences all number
    4
    0
    6
    Hypokalaemia
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Infections and infestations
    Bronchitis viral
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 3 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    0
    Cellulitis
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Gastroenteritis
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 3 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    0
    Conjunctivitis infective
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Infection
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 3 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    0
    Otitis media
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    1
    0
    1
    Influenza
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    1
    0
    1
    Otitis media acute
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Paronychia
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 3 (0.00%)
    2 / 19 (10.53%)
         occurrences all number
    0
    0
    3
    Periorbital cellulitis
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Peritonsillar abscess
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 3 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    0
    Pharyngitis
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 3 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    0
    Rhinitis
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 3 (0.00%)
    0 / 19 (0.00%)
         occurrences all number
    1
    0
    0
    Respiratory tract infection
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Sinusitis
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 3 (0.00%)
    1 / 19 (5.26%)
         occurrences all number
    0
    0
    1
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 3 (0.00%)
    2 / 19 (10.53%)
         occurrences all number
    0
    0
    2

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    20 Sep 2007
    Amendment B updated the table of subject assessments, and the schedules of safety and pharmacokinetics assessments.
    15 Oct 2007
    Amendment C clarified the target population in the protocol synopsis.
    30 Jul 2008
    Amendment D clarified addition of a new dosing cohort/ schedule of 16 mg/kg every 3 weeks (q3W). Clarified which safety and routine lab assessments were to be done under each dosing schedule (once weekly [qW] or q3W). Clarified the objectives to indicate that a 16 mg/kg q3W dosing schedule would also be used in addition to the qW schedule to determine maximum tolerated dose (if dose-limiting toxicity were observed in ≥ 2 or more subjects) and also determine serum drug exposure levels in children as it was done in adults using the same schedule. Added text regarding the difference in dose reduction guidelines per each schedule (qW and q3W) for subjects who experienced dose-limiting toxicity.
    16 Sep 2008
    Amendment E included that lymphocyte phenotyping (assessments of CD3, CD4, CD8, CD19 and CD16/CD56) would be drawn at screening for all subjects.

    Interruptions (globally)

    Were there any global interruptions to the trial? No

    Limitations and caveats

    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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