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    Clinical Trial Results:
    Efficacy and safety of recombinant asparaginase in infants (< 1 year) with previously untreated acute lymphoblastic leukaemia - Phase II Clinical Trial -

    Summary
    EudraCT number
    		 2008-006300-27
    Trial protocol
    		 NL   DE  
    Global end of trial date
    14 Sep 2010

    Results information
    Results version number
    		 v1(current)
    This version publication date
    23 Sep 2016
    First version publication date
    23 Sep 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    MC-ASP.6/INF
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    medac Gesellschaft für klinische Spezialpräparate mbH
    Sponsor organisation address
    Theaterstraße 6, Wedel, Germany, 22880
    Public contact
    Clinical Trial Disclosure Desk, medac GmbH Theaterstraße 6 22880 Wedel Germany, 0049 04103 8006 0, eudract@medac.de
    Scientific contact
    Medical Expert, medac GmbH Theaterstraße 6 22880 Wedel Germany, 0049 04103 8006 0, med-wiss@medac.de
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-000013-PIP01-07
    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
    31 Oct 2011
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    14 Sep 2010
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To determine the number of patients with hypersensitivity reactions to rASNase.
    Protection of trial subjects
    Only pseudonymous collection and storage of patient`s data
    Background therapy
    		 ALL type chemotherapy
    Evidence for comparator
    		 Not applicable
    Actual start date of recruitment
    12 Aug 2009
    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
    Netherlands: 4
    Country: Number of subjects enrolled
    Germany: 8
    Worldwide total number of subjects
    12
    EEA total number of subjects
    12
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    1
    Infants and toddlers (28 days-23 months)
    11
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    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
    		 Included in the study only if "Inclusion Criteria" applied and "Exclusion criteria" did not applied Included in Interfant 06 Protocol

    Pre-assignment
    Screening details
    		 Demographic data, Laboratory, Results of bone marrow biopsy and/or Peripheral blood sample, Risk group stratification

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

    Arms
    Arm title
    		 rASNase
    Arm description
    		 (Days 15, 18, 22, 25, 29, 33 of the INTERFANT-06 induction phase) Infusion (depend on BSA) on these days; blood samples immediately before ASNase infusions; controlling of allergic reactions; day 33 assessment of complete remission and MRD status
    Arm type
    		 Experimental

    Investigational medicinal product name
    r-L-asparaginase
    Investigational medicinal product code
    CAS number: 9015-68-3 (MC0707)
    Other name
    recombinant L-Asparaginase, L-Asparaginase aminohydrolase,
    Pharmaceutical forms
    Powder for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    10,000 U/m²; adjusted to the current age of the patient at the time of administration; over 1+- 0.5 hours, on day 15, 18, 22, 25, 29 and 33 (6 doses).

    Number of subjects in period 1
    		rASNase
    Started
    12
    Completed
    8
    Not completed
    4
         Relapse
    4

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Induction phase
    Reporting group description
    		 We have only 12 Subjects in this study. See listed before.

    Reporting group values
    		 Induction phase Total
    Number of subjects
    		 12 12
    Age categorical
    Units: Subjects
        In utero
    		 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0
        Newborns (0-27 days)
    		 1 1
        Infants and toddlers (28 days-23 months)
    		 11 11
        Children (2-11 years)
    		 0 0
        Adolescents (12-17 years)
    		 0 0
        Adults (18-64 years)
    		 0 0
        From 65-84 years
    		 0 0
        85 years and over
    		 0 0
    Age continuous
    Units: months
        median (full range (min-max))
    		 6 (0.5 to 12.2) -
    Gender categorical
    Units: Subjects
        Female
    		 5 5
        Male
    		 7 7
    Immunophenotype
    Units: Subjects
        Pro-B-ALL
    		 9 9
        Common ALL
    		 1 1
        Pre-B-ALL
    		 2 2
    Genetics
    Units: Subjects
        MLL-AF4
    		 5 5
        MLL-AF9
    		 1 1
        MLL-ENL
    		 2 2
        t(1,14)
    		 1 1
        No aberration
    		 3 3
    Risk group stratification
    Units: Subjects
        Low Risk
    		 4 4
        Medium Risk
    		 4 4
        High Risk
    		 4 4
    Height
    Units: cm
        median (full range (min-max))
    		 65.5 (46 to 79) -
    Weight
    Units: Gramm
        median (full range (min-max))
    		 6982.5 (3100 to 9870) -
    BodySurfaceArea
    Units: m²
        median (full range (min-max))
    		 0.36 (0.19 to 0.45) -
    Subject analysis sets

    Subject analysis set title
    Full Analysis Set
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All patients who received all six rASNase infusions and for whom ASN-levels were available from at least 2 of the 3 sceduled time points (measured directly before rASNase infusion 2, 4 and 6)

    Subject analysis sets values
    		 Full Analysis Set
    Number of subjects
    12
    Age categorical
    Units: Subjects
        In utero
    0
        Preterm newborn infants (gestational age < 37 wks)
    0
        Newborns (0-27 days)
    1
        Infants and toddlers (28 days-23 months)
    11
        Children (2-11 years)
    0
        Adolescents (12-17 years)
    0
        Adults (18-64 years)
    0
        From 65-84 years
    0
        85 years and over
    0
    Age continuous
    Units: months
        median (full range (min-max))
    6 (0.5 to 12.2)
    Gender categorical
    Units: Subjects
        Female
    5
        Male
    7
    Immunophenotype
    Units: Subjects
        Pro-B-ALL
    9
        Common ALL
    1
        Pre-B-ALL
    2
    Genetics
    Units: Subjects
        MLL-AF4
    5
        MLL-AF9
    1
        MLL-ENL
    2
        t(1,14)
    1
        No aberration
    3
    Risk group stratification
    Units: Subjects
        Low Risk
    4
        Medium Risk
    4
        High Risk
    4
    Height
    Units: cm
        median (full range (min-max))
    65.5 (46 to 79)
    Weight
    Units: Gramm
        median (full range (min-max))
    6982.5 (3100 to 9870)
    BodySurfaceArea
    Units: m²
        median (full range (min-max))
    0.36 (0.19 to 0.45)

    End points

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    End points reporting groups
    Reporting group title
    rASNase
    Reporting group description
    		 (Days 15, 18, 22, 25, 29, 33 of the INTERFANT-06 induction phase) Infusion (depend on BSA) on these days; blood samples immediately before ASNase infusions; controlling of allergic reactions; day 33 assessment of complete remission and MRD status

    Subject analysis set title
    Full Analysis Set
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All patients who received all six rASNase infusions and for whom ASN-levels were available from at least 2 of the 3 sceduled time points (measured directly before rASNase infusion 2, 4 and 6)

    Primary: Hypersensitivity Reactions

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    End point title
    		 Hypersensitivity Reactions [1]
    End point description
    Hypersensitivity reactions were defined as: - Any allergic reaction occurring during or up to 12 hours after rASNase infusion (e.g. rash, urticaria, oedema/angiooedema, symptomatic bronchospasm, anaphylaxis) - Silent inactivation of ASNase activity, defined as ASNase trough serum activity < 20 U/L (directly before rASNase administration numbers 2, 4, and 6).
    End point type
    Primary
    End point timeframe
    - allergic reaction occurring during or up to 12 hours after rASNase infusion - silent inactivation directly before rASNase administration numbers 2, 4, 6
    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 for comparison has been performed because this trial consists only of one treatment arm.
    End point values
    		 rASNase Full Analysis Set
    Number of subjects analysed
    12
    12
    Units: Number
        Patients with hypersensitivity reactions
    4
    4
    No statistical analyses for this end point

    Secondary: ASNase activity in serum Day 15

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    End point title
    		 ASNase activity in serum Day 15
    End point description
    ASNase activity in serum directly before ASNase infusion 1 during induction treatment
    End point type
    Secondary
    End point timeframe
    Day 15
    End point values
    		 rASNase Full Analysis Set
    Number of subjects analysed
    12
    12
    Units: U/L
        geometric mean (standard deviation)
    1 ( 1 )
    1 ( 1 )
    No statistical analyses for this end point

    Secondary: ASNase activity in serum Day 18

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    End point title
    		 ASNase activity in serum Day 18
    End point description
    ASNase activity in serum directly before ASNase infusion 2 during induction treatment
    End point type
    Secondary
    End point timeframe
    Day 18
    End point values
    		 rASNase Full Analysis Set
    Number of subjects analysed
    11
    11
    Units: U/L
        geometric mean (standard deviation)
    177.122 ( 2.007 )
    177.122 ( 2.007 )
    No statistical analyses for this end point

    Secondary: ASNase activity in serum Day 25

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    End point title
    		 ASNase activity in serum Day 25
    End point description
    ASNase activity in serum directly before ASNase infusion 4 during induction treatment
    End point type
    Secondary
    End point timeframe
    Day 25
    End point values
    		 rASNase
    Number of subjects analysed
    12
    Units: U/L
        geometric mean (standard deviation)
    102.034 ( 3.562 )
    No statistical analyses for this end point

    Secondary: ASNase activity in serum Day 33

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    End point title
    		 ASNase activity in serum Day 33
    End point description
    ASNase activity in serum directly before rASNase infusion 6 during induction treatment
    End point type
    Secondary
    End point timeframe
    Day 33
    End point values
    		 rASNase
    Number of subjects analysed
    12
    Units: U/L
        geometric mean (standard deviation)
    31.444 ( 2.83 )
    No statistical analyses for this end point

    Secondary: CR Rate

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    End point title
    		 CR Rate
    End point description
    Complete remission rate after induction
    End point type
    Secondary
    End point timeframe
    Day 33
    End point values
    		 rASNase
    Number of subjects analysed
    12
    Units: Number
        number (not applicable)
    12
    No statistical analyses for this end point

    Secondary: MRD Status

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    End point title
    		 MRD Status
    End point description
    Minimal Residual Disease Status after induction
    End point type
    Secondary
    End point timeframe
    Day 33
    End point values
    		 rASNase
    Number of subjects analysed
    12
    Units: Number
    number (not applicable)
        negative
    1
        positiv
    9
        ND
    2
    No statistical analyses for this end point

    Secondary: Level of ASN in serum Day 15

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    End point title
    		 Level of ASN in serum Day 15
    End point description
    Concentration of ASN in serum directly before rASNase infusion 1 during treatment
    End point type
    Secondary
    End point timeframe
    Day 15
    End point values
    		 rASNase
    Number of subjects analysed
    12
    Units: µmol/L
        geometric mean (standard deviation)
    45.452 ( 1.397 )
    No statistical analyses for this end point

    Secondary: Level of ASN in serum Day 18

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    End point title
    		 Level of ASN in serum Day 18
    End point description
    Concentration of ASN in serum directly before rASNase infusion 2 during treatment
    End point type
    Secondary
    End point timeframe
    Day 18
    End point values
    		 rASNase
    Number of subjects analysed
    11
    Units: µmol/L
        geometric mean (standard deviation)
    0.25 ( 1 )
    No statistical analyses for this end point

    Secondary: Level of ASN in serum Day 25

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    End point title
    		 Level of ASN in serum Day 25
    End point description
    Concentration of ASN in serum directly before rASNase infusion 4 during treatment
    End point type
    Secondary
    End point timeframe
    Day 25
    End point values
    		 rASNase
    Number of subjects analysed
    12
    Units: µmol/L
        geometric mean (standard deviation)
    0.25 ( 1 )
    No statistical analyses for this end point

    Secondary: Level of ASN in serum Day 33

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    End point title
    		 Level of ASN in serum Day 33
    End point description
    Concentration of ASN in serum directly before rASNase infusion 6 during treatment
    End point type
    Secondary
    End point timeframe
    Day 33
    End point values
    		 rASNase
    Number of subjects analysed
    12
    Units: µmol/L
        geometric mean (standard deviation)
    0.324 ( 2.464 )
    No statistical analyses for this end point

    Secondary: Level of glutamic acid in serum Day 15

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    End point title
    		 Level of glutamic acid in serum Day 15
    End point description
    Concentration of glutamic acid in serum directly before rASNase infusion 1
    End point type
    Secondary
    End point timeframe
    Day 15
    End point values
    		 rASNase
    Number of subjects analysed
    12
    Units: µmol/L
        geometric mean (standard deviation)
    78.086 ( 1.698 )
    No statistical analyses for this end point

    Secondary: Level of glutamic acid in serum Day 18

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    End point title
    		 Level of glutamic acid in serum Day 18
    End point description
    Concentration of glutamic acid in serum directly before rASNase infusion 2
    End point type
    Secondary
    End point timeframe
    Day 18
    End point values
    		 rASNase
    Number of subjects analysed
    11
    Units: µmol/L
        geometric mean (standard deviation)
    98.407 ( 1.668 )
    No statistical analyses for this end point

    Secondary: Level of glutamic acid in serum Day 25

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    End point title
    		 Level of glutamic acid in serum Day 25
    End point description
    Concentration of glutamic acid in serum directly before rASNase infusion 4
    End point type
    Secondary
    End point timeframe
    Day 25
    End point values
    		 rASNase
    Number of subjects analysed
    12
    Units: µmol/L
        geometric mean (standard deviation)
    89.268 ( 1.77 )
    No statistical analyses for this end point

    Secondary: Level of glutamic acid in serum Day 33

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    End point title
    		 Level of glutamic acid in serum Day 33
    End point description
    Concentration of glutamic acid in serum directly before rASNase infusion 6
    End point type
    Secondary
    End point timeframe
    Day 33
    End point values
    		 rASNase
    Number of subjects analysed
    12
    Units: µmol/L
        geometric mean (standard deviation)
    75.888 ( 1.667 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All AEs had to be documented and followed from Day 15 up to Day 39. Thereafter, up to Day 64, only AEs with suspected relationship to the investigational drug were reported. All SAEs were followed until resolved or stabilised.
    Adverse event reporting additional description
    Please refer to the protocol. Events coded by CTCAE V3.0, System Organ Classes mapped to CTCAE V4.0.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 CTCAE
    Dictionary version
    4.0
    Reporting groups
    Reporting group title
    Study subjects
    Reporting group description
    		 All 12 study subjects

    Serious adverse events
    		 Study subjects
    Total subjects affected by serious adverse events
         subjects affected / exposed
    4 / 12 (33.33%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Vascular disorders
    Thrombosis/thrombus/embolism
         subjects affected / exposed
    1 / 12 (8.33%)
         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 / 12 (8.33%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Edema larynx
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Infection (documented clinically)
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Study subjects
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    12 / 12 (100.00%)
    Vascular disorders
    Hematoma
         subjects affected / exposed
    2 / 12 (16.67%)
         occurrences all number
    2
    Thrombosis/thrombus/embolism
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    General disorders and administration site conditions
    Edema: head and neck
         subjects affected / exposed
    2 / 12 (16.67%)
         occurrences all number
    2
    Edema limb
         subjects affected / exposed
    2 / 12 (16.67%)
         occurrences all number
    2
    Constitutional Symptoms - other
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Edema: trunk/genital
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Fever
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Immune system disorders
    Allergic reaction
         subjects affected / exposed
    2 / 12 (16.67%)
         occurrences all number
    2
    Respiratory, thoracic and mediastinal disorders
    Hemorrhage pulmonary
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Investigations
    Weight loss
         subjects affected / exposed
    3 / 12 (25.00%)
         occurrences all number
    3
    Blood and lymphatic system disorders
    Febrile neutropenia
         subjects affected / exposed
    3 / 12 (25.00%)
         occurrences all number
    3
    Gastrointestinal disorders
    Diarrhea
         subjects affected / exposed
    5 / 12 (41.67%)
         occurrences all number
    5
    Nausea
         subjects affected / exposed
    3 / 12 (25.00%)
         occurrences all number
    3
    Mucositis (clinical exam)
         subjects affected / exposed
    2 / 12 (16.67%)
         occurrences all number
    2
    Pain [Abdomen NOS]
         subjects affected / exposed
    2 / 12 (16.67%)
         occurrences all number
    2
    Vomiting
         subjects affected / exposed
    2 / 12 (16.67%)
         occurrences all number
    2
    Skin and subcutaneous tissue disorders
    Dermatology - other
         subjects affected / exposed
    2 / 12 (16.67%)
         occurrences all number
    2
    Rash
         subjects affected / exposed
    2 / 12 (16.67%)
         occurrences all number
    2
    Decubitus
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Endocrine disorders
    Cushingoid
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Musculoskeletal and connective tissue disorders
    Musculoskeletal - other
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Pain [Bone]
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Pain [Extremity-limb]
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Infections and infestations
    Infection (documented clinically)
         subjects affected / exposed
    4 / 12 (33.33%)
         occurrences all number
    6
    Infection - other
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1
    Metabolism and nutrition disorders
    Anorexia
         subjects affected / exposed
    1 / 12 (8.33%)
         occurrences all number
    1

    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
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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