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    Clinical Trial Results:
    Phase II trial of metronomic treatment in children and adolescents with recurrent or progressive neuroblastoma

    Summary
    EudraCT number
    		 2011-004593-29
    Trial protocol
    		 DE  
    Global end of trial date
    29 Jun 2023

    Results information
    Results version number
    		 v1(current)
    This version publication date
    03 Jan 2024
    First version publication date
    03 Jan 2024
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    Uni-Koeln-1495
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02641314
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    University of Cologne
    Sponsor organisation address
    Albertus-Magnus-Platz, Cologne, Germany, 50923
    Public contact
    Neuroblastomstudie, Children’s Hospital, University of Cologne, +49 2214786853, neuroblastomstudie@uk-koeln.de
    Scientific contact
    Neuroblastomstudie, Children’s Hospital, University of Cologne, +49 2214786853, neuroblastomstudie@uk-koeln.de
    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
    Interim
    Date of interim/final analysis
    10 Apr 2019
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    29 Jun 2023
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary trial objective is to demonstrate the non-inferiority of event free survival (EFS) in children and adolescents ≥ 2 and < 21 years of age with recurrent or progressive high risk neuroblastoma treated with low toxic metronomic celecoxib therapy in combination with low-dose metronomic cyclophosphamide, etoposide and vinblastine in comparison to a historical control group. Event free survival (EFS) defined as time from start of treatment up to: Progression (emerged from residual tumor, PD) or recurrence (developing from CR achieved by metronomic treatment), drop-out for unacceptable toxicity, secondary malignant neoplasm or death of any reason
    Protection of trial subjects
    No relevant toxicities. No toxic deaths related to the metronomic treatment. No change of risk-benefit balance.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Dec 2015
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Germany: 18
    Worldwide total number of subjects
    18
    EEA total number of subjects
    18
    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)
    13
    Adolescents (12-17 years)
    1
    Adults (18-64 years)
    4
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 18 of a maximum of 26 patients have been recruited in 5 of 8 national test center in Germany.

    Pre-assignment
    Screening details
    		 1 screening failure

    Period 1
    Period 1 title
    Treatment (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Metronomic treatment
    Arm description
    		 The trial schedule consists of continuously administered cycles of metronomic therapy over 364 days. Treatment consists of eight alternating 28-day cycles of PCCVE and PCCV followed by five cycles PCCV. Vinblastine will be given every second week. Etoposide is only given in cycle PCCVE (cycle 1, 3, 5, 7). The PCCVE cycle consists of propranolol, celecoxib, cyclophosphamide, vinblastine, and etoposide. On the first day of the very first PCCVE cycle, one single intravenous infusion of cyclophosphamide loading dose (500 mg/m2 i.v., duration 1 hour) is given. The PCCV cycle consists of propranolol, celecoxib, cyclophosphamide, and vinblastine.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Propranolol
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Propranolol cycle 1: 0.5 mg/kgxd p.o. day 1, 1 mg/kgxd p.o. day 2, 2 mg/kgxd p.o. day 3-28; all further cycles: 2 mg/kgxd p.o., day 1 – 28 (maximum total daily dose: 120 mg) divided in 2 doses per day

    Investigational medicinal product name
    Celecoxib
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    400 mg/m2xd p.o.; day 1-28 (maximum total daily dose: 800 mg) divided in 2 doses per day

    Investigational medicinal product name
    Cyclophosphamide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, Solution for injection/infusion
    Routes of administration
    Oral use, Infusion
    Dosage and administration details
    cycle 1, day 1: loading dose: 500 mg/m2 intravenous 1-h-infusion, single dose cycle 1, day 2-28; all further cycles day 1-28: 25 mg/m2xd p.o (maximum total daily dose: 50 mg) as single daily dose

    Investigational medicinal product name
    Etoposide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    25 mg/m2xd p.o.; day 1-21 (maximum total daily dose: 50 mg) as single daily dose

    Investigational medicinal product name
    Vinblastine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Infusion
    Dosage and administration details
    3 mg/m2xd i.v. (maximum total daily dose: 6 mg) administered day 1 and 15 (every two weeks) as single daily dose

    Number of subjects in period 1
    		Metronomic treatment
    Started
    18
    Completed
    18

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Treatment
    Reporting group description
    		 11

    Reporting group values
    		 Treatment Total
    Number of subjects
    		 18 18
    Age categorical
    Units: Subjects
        Children (2-11 years)
    		 13 13
        Adolescents (12-17 years)
    		 1 1
        Adults (18-64 years)
    		 4 4
    Gender categorical
    Units: Subjects
        Female
    		 7 7
        Male
    		 11 11

    End points

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    End points reporting groups
    Reporting group title
    Metronomic treatment
    Reporting group description
    		 The trial schedule consists of continuously administered cycles of metronomic therapy over 364 days. Treatment consists of eight alternating 28-day cycles of PCCVE and PCCV followed by five cycles PCCV. Vinblastine will be given every second week. Etoposide is only given in cycle PCCVE (cycle 1, 3, 5, 7). The PCCVE cycle consists of propranolol, celecoxib, cyclophosphamide, vinblastine, and etoposide. On the first day of the very first PCCVE cycle, one single intravenous infusion of cyclophosphamide loading dose (500 mg/m2 i.v., duration 1 hour) is given. The PCCV cycle consists of propranolol, celecoxib, cyclophosphamide, and vinblastine.

    Subject analysis set title
    Full dataset analysis
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All patients enrolled into the study.

    Subject analysis set title
    Population for sensitivity analysis
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    patients who fulfilled the inclusion and exclusion criteria, have been registered in the study, and were treated conform to the protocol.

    Subject analysis set title
    Population for safety analysis
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    All patients who entered the study and received at least the medication of the first day of the first treatment cycle.

    Primary: Events

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    End point title
    		 Events [1]
    End point description
    End point type
    Primary
    End point timeframe
    until 30 days after the last treatment of the last patient
    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: The final stastical analysis is ongoing. Values will be updated once the analysis is completed.
    End point values
    		 Metronomic treatment Full dataset analysis
    Number of subjects analysed
    18
    18
    Units: number
        number (not applicable)
    16
    16
    No statistical analyses for this end point

    Adverse events

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    Adverse events information [1]
    Timeframe for reporting adverse events
    until 30 days after the last trial medication of the last patient
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 CTCAE
    Dictionary version
    4.03
    Reporting groups
    Reporting group title
    Population for safety analysis
    Reporting group description
    		 Patients reported with serious adverse events

    Notes
    [1] - There are no non-serious adverse events recorded for these results. It is expected that there will be at least one non-serious adverse event reported.
    Justification: Final analysis of adverse events is ongoing. Values will be updated once the analysis is completed.
    Serious adverse events
    		 Population for safety analysis
    Total subjects affected by serious adverse events
         subjects affected / exposed
    4 / 17 (23.53%)
         number of deaths (all causes)
    15
         number of deaths resulting from adverse events
    0
    Blood and lymphatic system disorders
    Febrile bone marrow aplasia
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Lung infiltration
         subjects affected / exposed
    1 / 17 (5.88%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Metabolism and nutrition disorders
    Hypoglycaemia
         subjects affected / exposed
    2 / 17 (11.76%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Population for safety analysis
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    0 / 17 (0.00%)

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    28 Aug 2017
    METRO-NB2012 Trial Protocol Amendment Version 3.5.4
    09 Mar 2020
    METRO-NB2012 Trial Protocol Amendment Version 3.5.6
    05 May 2021
    METRO-NB2012 Trial Protocol Amendment 4.0

    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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    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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