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    Clinical Trial Results:
    Protocol ALL-11: Treatment study protocol of the Dutch Childhood Oncology Group for children and adolescents (1-19 year) with newly diagnosed acute lymphoblastic leukemia

    Summary
    EudraCT number
    		 2012-000067-25
    Trial protocol
    		 NL  
    Global end of trial date
    30 May 2023

    Results information
    Results version number
    		 v1(current)
    This version publication date
    08 Aug 2024
    First version publication date
    08 Aug 2024
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    ALL11
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 OMON register: NL-OMON29675
    Sponsors
    Sponsor organisation name
    Princess Máxima Center for pediatric oncology
    Sponsor organisation address
    Heidelberglaan 25, Utrecht, Netherlands, 3584 CS
    Public contact
    Trial and Data Center, Princess Máxima Center for pediatric oncology, 0031 889727272, trialmanagement@prinsesmaximacentrum.nl
    Scientific contact
    Trial and Data Center, Princess Máxima Center for pediatric oncology, 0031 889727272, trialmanagement@prinsesmaximacentrum.nl
    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
    15 Nov 2023
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    30 May 2023
    Global end of trial reached?
    Yes
    Global end of trial date
    30 May 2023
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To treat children with ALL with the best available treatment as possible, based upon the risk factors of the patient at diagnosis.
    Protection of trial subjects
    Patient data are pseudonymised by applying a subject study code.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Apr 2012
    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
    Netherlands: 819
    Worldwide total number of subjects
    819
    EEA total number of subjects
    819
    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)
    55
    Children (2-11 years)
    600
    Adolescents (12-17 years)
    163
    Adults (18-64 years)
    1
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 risk classification

    Period 1
    Period 1 title
    ASP randomisation
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded
    Blinding implementation details
    No blinding

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 ASP continu
    Arm description
    		 arm B
    Arm type
    		 Experimental

    Investigational medicinal product name
    Oncospar
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate and solvent for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    17 international units per day

    Arm title
    		 ASP interrupted
    Arm description
    		 arm A
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Oncospar
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate and solvent for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    17 international units per day

    Number of subjects in period 1 [1]
    		ASP continu ASP interrupted
    Started
    155
    157
    Completed
    151
    155
    Not completed
    4
    2
         Adverse event, serious fatal
    3
    1
         Lack of efficacy
    1
    1
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: The ALL11 protocol is the standard of care therapy for children with ALL. Only the randomizations are reported here.
    Period 2
    Period 2 title
    IVIG randomisation
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 IVIG profylaxis
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Nanogam
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    0,7 g/kg

    Arm title
    		 IVIG control
    Arm description
    		 -
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 2 [2]
    		IVIG profylaxis IVIG control
    Started
    130
    131
    Completed
    91
    86
    Not completed
    39
    45
         Adverse event, serious fatal
    1
    2
         Consent withdrawn by subject
    3
    -
         Adverse event, non-fatal
    1
    1
         stratified to SR/HR - predefined not eligible
    34
    42
    Notes
    [2] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: The ALL11 protocol is the standard of care therapy for children with ALL. Only the randomizations are reported here.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    ASP randomisation
    Reporting group description
    		 -

    Reporting group values
    		 ASP randomisation Total
    Number of subjects
    		 312 312
    Age categorical
    Units: Subjects
        Infants and toddlers (28 days-23 months)
    		 27 27
        Children (2-11 years)
    		 226 226
        Adolescents (12-17 years)
    		 58 58
        Adults (18-64 years)
    		 1 1
    Gender categorical
    Units: Subjects
        Female
    		 120 120
        Male
    		 192 192
    Subject analysis sets

    Subject analysis set title
    IVIG cohort
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Treatment completed for at least 1 year

    Subject analysis set title
    ASP cohort
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Intention to treat according to randomization

    Subject analysis sets values
    		 IVIG cohort ASP cohort
    Number of subjects
    177
    312
    Age categorical
    Units: Subjects
        Infants and toddlers (28 days-23 months)
    11
    27
        Children (2-11 years)
    132
    226
        Adolescents (12-17 years)
    34
    58
        Adults (18-64 years)
    0
    1
    Age continuous
    Units:
        
    ( )
    ( )
    Gender categorical
    Units: Subjects
        Female
    72
    120
        Male
    105
    192

    End points

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    End points reporting groups
    Reporting group title
    ASP continu
    Reporting group description
    		 arm B

    Reporting group title
    ASP interrupted
    Reporting group description
    		 arm A
    Reporting group title
    IVIG profylaxis
    Reporting group description
    		 -

    Reporting group title
    IVIG control
    Reporting group description
    		 -

    Subject analysis set title
    IVIG cohort
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Treatment completed for at least 1 year

    Subject analysis set title
    ASP cohort
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Intention to treat according to randomization

    Primary: Hospital admissions

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    End point title
    		 Hospital admissions [1]
    End point description
    per protocol
    End point type
    Primary
    End point timeframe
    1 year
    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: Documentation has been uploaded in Section "Chart"
    End point values
    		 IVIG cohort
    Number of subjects analysed
    177
    Units: admissions
    463
    Attachments
    		 ALL11_IVIG_stat-analysis2024
    No statistical analyses for this end point

    Primary: Incidence of hypersensitivity

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    End point title
    		 Incidence of hypersensitivity [2]
    End point description
    End point type
    Primary
    End point timeframe
    1 year of treatment
    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: Documentation has been uploaded in Section "Chart"
    End point values
    		 ASP continu ASP interrupted ASP cohort
    Number of subjects analysed
    155
    157
    312
    Units: reactions
    4
    17
    21
    Attachments
    		 Untitled (Filename: ALL 11_Publication JCO 2024_vd Sluis et al_Aspa.pdf)
    No statistical analyses for this end point

    Secondary: Disease free survival

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    End point title
    		 Disease free survival
    End point description
    End point type
    Secondary
    End point timeframe
    5 years
    End point values
    		 ASP continu ASP interrupted IVIG cohort ASP cohort
    Number of subjects analysed
    155
    157
    177
    312
    Units: % of patients
        number (not applicable)
    91.9
    95.3
    92.1
    93.6
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Max 2 year
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 CTCAE
    Dictionary version
    4.03
    Reporting groups
    Reporting group title
    IVIG cohort
    Reporting group description
    		 Patients randomized for IVIG randomisation

    Reporting group title
    ASP cohort
    Reporting group description
    		 All patients randomized according to ASP randomisation

    Serious adverse events
    		 IVIG cohort ASP cohort
    Total subjects affected by serious adverse events
         subjects affected / exposed
    71 / 177 (40.11%)
    54 / 312 (17.31%)
         number of deaths (all causes)
    1
    4
         number of deaths resulting from adverse events
    0
    4
    Vascular disorders
    thrombosis
    Additional description: Includes cerebral and peripheral thrombosis
         subjects affected / exposed
    16 / 177 (9.04%)
    12 / 312 (3.85%)
         occurrences causally related to treatment / all
    0 / 16
    3 / 12
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    2 / 177 (1.13%)
    1 / 312 (0.32%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Neurotoxicity
    Additional description: Includes Central neurotoxicity convulsion, Central neurotoxicity encephalopathy, Central neurotoxicity other and Peripheral neurotoxicity
         subjects affected / exposed
    17 / 177 (9.60%)
    19 / 312 (6.09%)
         occurrences causally related to treatment / all
    0 / 22
    0 / 24
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    bleeding
         subjects affected / exposed
    1 / 177 (0.56%)
    1 / 312 (0.32%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Electrolyte disorder
         subjects affected / exposed
    2 / 177 (1.13%)
    3 / 312 (0.96%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoglycemia
         subjects affected / exposed
    3 / 177 (1.69%)
    5 / 312 (1.60%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    other
    Additional description: not specified
         subjects affected / exposed
    5 / 177 (2.82%)
    11 / 312 (3.53%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 13
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Allergic reaction
    Additional description: incl anaphylaxis
         subjects affected / exposed
    3 / 177 (1.69%)
    3 / 312 (0.96%)
         occurrences causally related to treatment / all
    1 / 3
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    gastrointestinal disorders
    Additional description: Includes GI bleeding, GI colitis, GI constipation, GI diabetes,GI pancreatitis, GI perforation and other gastrointestinal events Liver failure Veno-occlusive disease
         subjects affected / exposed
    29 / 177 (16.38%)
    32 / 312 (10.26%)
         occurrences causally related to treatment / all
    0 / 29
    8 / 37
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Respiratory, thoracic and mediastinal disorders
    Pneumothorax
         subjects affected / exposed
    1 / 177 (0.56%)
    1 / 312 (0.32%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    kidney failure
         subjects affected / exposed
    1 / 177 (0.56%)
    4 / 312 (1.28%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Infections
    Additional description: Includes bacterial, fungal, viral and pneumocystis jerovecii (carini) infections and infections of unknown origin
         subjects affected / exposed
    25 / 177 (14.12%)
    30 / 312 (9.62%)
         occurrences causally related to treatment / all
    0 / 30
    0 / 34
         deaths causally related to treatment / all
    0 / 0
    0 / 3
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 IVIG cohort ASP cohort
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    160 / 177 (90.40%)
    286 / 312 (91.67%)
    Vascular disorders
    Thrombosis
         subjects affected / exposed
    29 / 177 (16.38%)
    42 / 312 (13.46%)
         occurrences all number
    62
    91
    Gastrointestinal disorders
    Pancreatitis
         subjects affected / exposed
    14 / 177 (7.91%)
    18 / 312 (5.77%)
         occurrences all number
    16
    21
    Musculoskeletal and connective tissue disorders
    avascular necrosis
         subjects affected / exposed
    2 / 177 (1.13%)
    2 / 312 (0.64%)
         occurrences all number
    5
    5
    Infections and infestations
    Febrile neutropenia
         subjects affected / exposed
    138 / 177 (77.97%)
    255 / 312 (81.73%)
         occurrences all number
    285
    531
    Infection
    Additional description: all types of infections
         subjects affected / exposed
    107 / 177 (60.45%)
    210 / 312 (67.31%)
         occurrences all number
    204
    402

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    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

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/37459571
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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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