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    Clinical Trial Results:
    A Phase IIa trial of 177 Lutetium Dotatate in Children with Primary Refractory or Relapsed High-Risk Neuroblastoma

    Summary
    EudraCT number
    2012-000510-10
    Trial protocol
    GB  
    Global end of trial date
    16 Feb 2018

    Results information
    Results version number
    v1(current)
    This version publication date
    07 Oct 2018
    First version publication date
    07 Oct 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    RG_11-141
    Additional study identifiers
    ISRCTN number
    ISRCTN98918118
    US NCT number
    -
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    University of Birmingham
    Sponsor organisation address
    Edgbaston, Birmingham, Birmingham, United Kingdom, B15 2TT
    Public contact
    Emmanouela Gbandi, University of Birmingham, 0044 01214143799, ludo@trials.bham.ac.uk
    Scientific contact
    Emmanouela Gbandi, University of Birmingham, 0044 01214143799, ludo@trials.bham.ac.uk
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    17 Sep 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    16 Feb 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    16 Feb 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The trial will evaluate how effective 177Lutetium DOTATATE is in children with high-risk relapsed or refractory neuroblastoma and determine the safety and adverse events of the treatment experienced by patients on the study.
    Protection of trial subjects
    Not applicable
    Background therapy
    None mandated in the protocol
    Evidence for comparator
    Not applicable
    Actual start date of recruitment
    19 Sep 2013
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Scientific research, Efficacy
    Long term follow-up duration
    5 Years
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 21
    Worldwide total number of subjects
    21
    EEA total number of subjects
    21
    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)
    1
    Children (2-11 years)
    19
    Adolescents (12-17 years)
    1
    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
    One site was activated in the UK in March 2013 and first patient was recruited on 19 September 2013. The last patient was recruited on 28 July 2017. The trial was closed to recruitment on 16 February 2018. 21 patients in total were recruited.

    Pre-assignment
    Screening details
    No screening assessments involved. Please refer to the protocol for the eligibility criteria.

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

    Arms
    Arm title
    LuDO Treatment
    Arm description
    177 Lutetium DOTATATE
    Arm type
    Experimental

    Investigational medicinal product name
    177 Lutetium DOTATATE
    Investigational medicinal product code
    Not applicable
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    The first administered activity of 177Lutetium DOTATATE = 75MBq/kg . The administered activity for the subsequent administrations will depend on the whole body dose received and the haematological toxicity from the previous administration (detailed instructions included in the trial protocol)

    Number of subjects in period 1
    LuDO Treatment
    Started
    21
    Completed
    8
    Not completed
    13
         Progression
    10
         Death
    1
         Adverse event, non-fatal
    1
         Progression and Death
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall trial baseline
    Reporting group description
    This group contains the full number of patients that took part in stage 1 of this phase IIa study.

    Reporting group values
    Overall trial baseline Total
    Number of subjects
    21 21
    Age categorical
    Units: Subjects
        Infants and toddlers (28 days-23 months)
    1 1
        Children (2-11 years)
    19 19
        Adolescents (12-17 years)
    1 1
    Age continuous
    Units: years
        median (inter-quartile range (Q1-Q3))
    5.4 (4.4 to 8.0) -
    Gender categorical
    Units: Subjects
        Female
    11 11
        Male
    10 10
    MYCN status at diagnosis
    Units: Subjects
        Amplified
    1 1
        Not amplified
    20 20
    INSS Stage at diagnosis
    Units: Subjects
        Stage 3
    3 3
        Stage 4
    18 18
    Number of relapses prior to registration in the LuDO trial
    Units: Subjects
        Zero relapses
    6 6
        One relapse
    11 11
        Two relapses
    1 1
        Three relapses
    1 1
        Four relapses
    2 2
    Disease type
    Units: Subjects
        Not responsive
    2 2
        Persistent
    3 3
        Progressive
    1 1
        Progressive; Persistent; Not responsive
    2 2
        Relapsed
    11 11
        Relapsed; Progressive
    1 1
        Relapsed; Progressive; Persistent; Not responsive
    1 1

    End points

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    End points reporting groups
    Reporting group title
    LuDO Treatment
    Reporting group description
    177 Lutetium DOTATATE

    Subject analysis set title
    Primary endpoint population
    Subject analysis set type
    Full analysis
    Subject analysis set description
    The analysis of the primary outcome measure was carried out on an eligible and evaluable patient basis, i.e. patients who were ineligible and for whom primary outcome data was unavailable were excluded from the analysis (note: any patients who progressed or died prior to their 1 month end of treatment (EOT) assessment were treated as non responders). Patients who did not start treatment and those who died due to any cause within 3 months from registration (i.e. time between death date and registration date is less than 92 days) were excluded from this analysis.

    Primary: Response at 1 month after EOT measured by INRC

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    End point title
    Response at 1 month after EOT measured by INRC
    End point description
    • Response at 1 month after EOT measured by INRC. Complete, very good partial and partial response were count as responses for the purpose of the primary outcome. • EOT was defined as the last administration of 177Lutetium DOTATATE. Note: if there is no response assessment at 1 or 4 months post last administered course of 177Lutetium DOTATATE, the patient would be considered a non-responder.
    End point type
    Primary
    End point timeframe
    Measured at 1 month after end of treatment (EOT).
    End point values
    LuDO Treatment Primary endpoint population
    Number of subjects analysed
    21
    14
    Units: Response
        Responder
    0
    0
        Non responder
    21
    14
    Statistical analysis title
    Proportion of responders at 1 month by INRC
    Statistical analysis description
    Proportion of responders at 1 month by INRC with confidence intervals for eligible and evaluable patient population
    Comparison groups
    LuDO Treatment v Primary endpoint population
    Number of subjects included in analysis
    35
    Analysis specification
    Pre-specified
    Analysis type
    other [1]
    Method
    Parameter type
    Proportion - analysis on 14 patients
    Point estimate
    0
    Confidence interval
         level
    95%
         sides
    1-sided
         lower limit
    0
         upper limit
    -
    Notes
    [1] - Proportion of responders at 1 month with confidence intervals. Please note "Number of patients included in the analysis" is INCORRECT. Analysis performed separately on two patient groups of 21 and 14 patients respectively.

    Secondary: Progression Free Survival

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    End point title
    Progression Free Survival
    End point description
    Progression-free Survival is defined as the time from registration until objective tumour progression or death or to date of censoring for patients who do not experience the event during trial follow up.
    End point type
    Secondary
    End point timeframe
    Patients were followed up from registration until progression or death or last assessment date from patients who did not experience an event.
    End point values
    LuDO Treatment Primary endpoint population
    Number of subjects analysed
    21
    14 [2]
    Units: Months
    21
    0
    Notes
    [2] - This group was not analysed for Progression Free Survival
    Statistical analysis title
    Median Progression-free Survival (PFS)
    Comparison groups
    LuDO Treatment v Primary endpoint population
    Number of subjects included in analysis
    35
    Analysis specification
    Pre-specified
    Analysis type
    other [3]
    Method
    Parameter type
    Median PFS - analysis on 21 patients
    Point estimate
    2.96
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.71
         upper limit
    7.66
    Notes
    [3] - Median Progression-free Survival (PFS). Please note "Number of patients included in the analysis" is INCORRECT. Analysis performed on 21 patients (overall trial population patients).

    Secondary: Overall Surivival

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    End point title
    Overall Surivival
    End point description
    Overall Survival is defined as the time from registration into the trial until date of death (death from any cause) or to date of censoring for patients who do not experience the event during trial follow-up.
    End point type
    Secondary
    End point timeframe
    Patients were followed up from registration until death or last assessment date from patients who did not experience an event.
    End point values
    LuDO Treatment Primary endpoint population
    Number of subjects analysed
    21
    14 [4]
    Units: Months
    21
    0
    Notes
    [4] - This group was not analysed for Overall Survival
    Statistical analysis title
    Median Overall Survival
    Comparison groups
    LuDO Treatment v Primary endpoint population
    Number of subjects included in analysis
    35
    Analysis specification
    Pre-specified
    Analysis type
    other [5]
    Method
    Parameter type
    Median OS - analysis on 21 patients
    Point estimate
    13.04
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    2.99
         upper limit
    21.52
    Notes
    [5] - Median Overall Survival (OS). Please note "Number of patients included in the analysis" is INCORRECT. Analysis performed on 21 patients (overall trial population patients).

    Secondary: Response at 4 month after EOT measured by INRC

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    End point title
    Response at 4 month after EOT measured by INRC
    End point description
    End point type
    Secondary
    End point timeframe
    Response by International Neuroblastoma Response Criteria at 4 months after completion of therapy.
    End point values
    LuDO Treatment Primary endpoint population
    Number of subjects analysed
    21
    14 [6]
    Units: Response at 4 months
        Responder
    0
    0
        Non responder
    21
    0
    Notes
    [6] - This group was not analysed for Response at 4 months post EoT
    Statistical analysis title
    Proportion of responders at 4 months
    Statistical analysis description
    Proportion of responders at 4 months with confidence intervals
    Comparison groups
    LuDO Treatment v Primary endpoint population
    Number of subjects included in analysis
    35
    Analysis specification
    Pre-specified
    Analysis type
    other [7]
    Method
    Parameter type
    Proportion - analysis on 21 patients
    Point estimate
    0
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0
         upper limit
    0.155
    Notes
    [7] - Proportion - Please note "Number of patients included in the analysis" is INCORRECT. Analysis performed separately on 21 patients (overall trial population patients).

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse Events should be reported from the date of commencement of protocol defined treatment until 30 days after the administration of the last treatment.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    CTCAE
    Dictionary version
    4.0
    Reporting groups
    Reporting group title
    Safety population
    Reporting group description
    -

    Serious adverse events
    Safety population
    Total subjects affected by serious adverse events
         subjects affected / exposed
    6 / 20 (30.00%)
         number of deaths (all causes)
    18
         number of deaths resulting from adverse events
    0
    Injury, poisoning and procedural complications
    vascular access complication
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Investigations
    Neutrophil count decreased
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Blood and lymphatic system disorders
    Febrile neutropenia
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    Fever
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Stomach pain
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Device related infection
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Wound infection
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Other, specify: vesicular rush
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Safety population
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    16 / 20 (80.00%)
    Injury, poisoning and procedural complications
    Vascular access complication
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    2 / 20 (10.00%)
         occurrences all number
    2
    Alkaline phosphatase increased
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Blood bilirubin increased
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Lymphocyte count decreased
         subjects affected / exposed
    6 / 20 (30.00%)
         occurrences all number
    11
    Neutrophil count decreased
         subjects affected / exposed
    7 / 20 (35.00%)
         occurrences all number
    10
    Platelet count decreased
         subjects affected / exposed
    7 / 20 (35.00%)
         occurrences all number
    8
    White blood cell decreased
         subjects affected / exposed
    6 / 20 (30.00%)
         occurrences all number
    10
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    2 / 20 (10.00%)
         occurrences all number
    3
    Blood and lymphatic system disorders
    Anemia
         subjects affected / exposed
    4 / 20 (20.00%)
         occurrences all number
    6
    Febrile neutropenia
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    General disorders and administration site conditions
    Fever
         subjects affected / exposed
    6 / 20 (30.00%)
         occurrences all number
    7
    General disorders and administration site conditions - Other, specify
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Malaise
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Pain
         subjects affected / exposed
    2 / 20 (10.00%)
         occurrences all number
    2
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    2 / 20 (10.00%)
         occurrences all number
    3
    Constipation
         subjects affected / exposed
    4 / 20 (20.00%)
         occurrences all number
    4
    Diarrhea
         subjects affected / exposed
    3 / 20 (15.00%)
         occurrences all number
    3
    Enterocolitis
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Gastritis
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Gastroesophageal reflux disease
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Mucositis oral
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Nausea
         subjects affected / exposed
    2 / 20 (10.00%)
         occurrences all number
    2
    Stomach pain
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Vomiting
         subjects affected / exposed
    3 / 20 (15.00%)
         occurrences all number
    3
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Dry skin
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Periorbital edema
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Skin and subcutaneous tissue disorders - Other, specify
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    2 / 20 (10.00%)
         occurrences all number
    2
    Metabolism and nutrition disorders
    Hypoalbuminemia
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Infections and infestations
    Bronchial infection
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Device related infection
         subjects affected / exposed
    2 / 20 (10.00%)
         occurrences all number
    2
    Infections and infestations - Other, specify
         subjects affected / exposed
    2 / 20 (10.00%)
         occurrences all number
    2
    Skin infection
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Upper respiratory infection
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Urinary tract infection
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1
    Wound infection
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences all number
    1

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    13 Oct 2014
    Amendment of protocol to v 2.0 03-Sep-2014 and age adapted Patient Information Sheets v3.0 12-May-2014 Summary of changes: • Adaptation of time schedule of investigations and IMP handling instructions due to IMP supply changes • Change in SAE reporting due to new contract with manufacturer • Amendment of follow up investigations

    Interruptions (globally)

    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    01 Mar 2016
    Temporary halt due to IMP supply issues
    08 Sep 2016

    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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