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    Clinical Trial Results:
    A multicentre, open, randomized, Phase 2/3 study, evaluating efficacy and safety of red blood cells (RBC) encapsulating L-Asparaginase (GRASPA®) versus reference L-asparaginase treatment in combination with standard polychemotherapy in patients with first recurrence of Philadelphia chromosome negative Acute Lymphoblastic Leukemia (ALL Ph-)

    Summary
    EudraCT number
    		 2009-012584-34
    Trial protocol
    		 BE   ES  
    Global end of trial date
    06 Sep 2016

    Results information
    Results version number
    		 v1(current)
    This version publication date
    21 Mar 2020
    First version publication date
    21 Mar 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    GRASPALL2009-06
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01518517
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Erytech Pharma
    Sponsor organisation address
    60 Avenue Rockefeller, LYON, France,
    Public contact
    Jean-baptiste Bertrand, ERYTECH Pharma, 33 78781586, jb.bertrand@erytech.com
    Scientific contact
    Jason Cain, ERYTECH Pharma, +1 857 285 24 15, jason.cain@erytech.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-000341-PIP02-09
    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
    06 Oct 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    06 Sep 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    06 Sep 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study was to determine the efficacy and safety of GRASPA at a dose equivalent to 150 U/kg of L-asparaginase (ASNase) combined with standard polychemotherapy in several populations of patients with first recurrence of Ph- ALL, i.e., children from 1 to <18 years old and adults from 18 to 55 years old, with or without known hypersensitivity to ASNase.
    Protection of trial subjects
    An independent DSMB reviewed the interim results from the study as well as safety and futility on a regular basis. The DSMB had the potential to stop the study for overwhelming evidence of benefit or futility.
    Background therapy
    		 All patients were to receive the recommended standard polychemotherapy, i.e., the COOPRALL protocol, which consisted of successive blocks of chemotherapy of 14 to 21 days each (F1: Days 1-14; F2: Days 15-28; R2: Days 1-14; R1: Days 1-14; then subsequent R2 and R1 blocks every 3 weeks, alternately).
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Dec 2009
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Efficacy
    Long term follow-up duration
    		 36 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Belgium: 3
    Country: Number of subjects enrolled
    France: 82
    Worldwide total number of subjects
    85
    EEA total number of subjects
    85
    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)
    48
    Adolescents (12-17 years)
    12
    Adults (18-64 years)
    24
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Recruitment completed. 85 patients were enrolled and 80 received treatment and were included in the Full Analysis Set.

    Pre-assignment
    Screening details
    		 Inclusion Criteria: •Pts from 1 to 55 years old (Children and adolescents from 1 to <18 years/ Adults from 18 to 55 years) •Pts with 1st ALL relapse, which could be either isolated bone marrow relapse, or combined (medullary and extra-medullary) relapse, or extra-medullary isolated relapse; or lymphoblastic lymphoma (excepted Burkitt lymphoma)

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 GRASPA-non allergic population
    Arm description
    		 Each patient randomized in GRASPA® group is to receive at least 2 and up to 10 administration of GRASPA® 150IU/kg, in combination with standard chemotherapy (COOPRALL). GRASPA® administration takes place as below: ◦for induction phase: at Day 4 and D18 (F1-F2 induction ) or at D6 if Vanda induction applies (according disease severity) ◦for consolidation phase: at Day 6 of R2 / R1 blocks, each time block of chemotherapy is given (up to 8 cycles)
    Arm type
    		 Experimental

    Investigational medicinal product name
    GRASPA
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Dispersion for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Each patient randomized in GRASPA® group is to receive at least 2 and up to 10 administration of GRASPA® 150 IU/kg, in combination with standard chemotherapy (COOPRALL). GRASPA® administration takes place as below: ◦for induction phase: at Day 4 and D18 (F1-F2 induction ) or at D6 if Vanda induction applies (according disease severity) ◦for consolidation phase: at Day 6 of R2 / R1 blocks, each time block of chemotherapy is given (up to 8 cycles)

    Arm title
    		 L-asparaginase-non allergic population
    Arm description
    		 For patient randomized in control group, reference L-asparaginase 10,000 IU/m² will be administered every 3 days intravenously, in combination with standard chemotherapy (COOPRALL).
    Arm type
    		 Active comparator

    Investigational medicinal product name
    L-asparaginase
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    For patient randomized in control group, reference L-asparaginase 10,000 IU/m² was administered every 3 days intravenously, in combination with standard chemotherapy (COOPRALL). •for induction phase:at Day 4 , D7, D10, D13 (F1 block ) then at Day 18, D21, D24, D27 (of F2 Blocks). NB: administrations take place at D6, D9, D12 and D15 in case of F1-F2 Induction is replaced by VANDA (according disease severity) •for consolidation phase: at D6, D9, D12 ofR2/R1 blocks, each time block of chemotherapy is given (up to 8 cycles).

    Arm title
    		 GRASPA Allergic population
    Arm description
    		 GRASPA was administered at a dose of 150 U/kg of ASNase on Day 4 of F1 block and Day 18 of F2 block (or Day 6 of VANDA), and on Day 6 of R2 and R1 blocks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    GRASPA
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Dispersion for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Each patient randomized in GRASPA® group was to receive at least 2 and up to 10 administration of GRASPA® 150 IU/kg, in combination with standard chemotherapy (COOPRALL). GRASPA® administration takes place as below: ◦for induction phase: at Day 4 and D18 (F1-F2 induction ) or at D6 if Vanda induction applies (according disease severity) ◦for consolidation phase: at Day 6 of R2 / R1 blocks, each time block of chemotherapy is given (up to 8 cycles)

    Number of subjects in period 1
    		GRASPA-non allergic population L-asparaginase-non allergic population GRASPA Allergic population
    Started
    29
    30
    26
    Receiving study treatment
    26
    28
    26
    Completed
    1
    3
    0
    Not completed
    28
    27
    26
         Adverse event, serious fatal
    -
    -
    1
         Consent withdrawn by subject
    1
    2
    -
         other termination prior consolidation
    2
    -
    -
         Adverse event, non-fatal
    1
    15
    1
         progressive disease
    -
    5
    2
         other term prior to consolidation
    -
    -
    3
         allograft
    7
    3
    5
         treatment not received
    3
    2
    -
         Lack of efficacy
    12
    -
    14
         ASN depletion target not reached
    2
    -
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    GRASPA-non allergic population
    Reporting group description
    		 Each patient randomized in GRASPA® group is to receive at least 2 and up to 10 administration of GRASPA® 150IU/kg, in combination with standard chemotherapy (COOPRALL). GRASPA® administration takes place as below: ◦for induction phase: at Day 4 and D18 (F1-F2 induction ) or at D6 if Vanda induction applies (according disease severity) ◦for consolidation phase: at Day 6 of R2 / R1 blocks, each time block of chemotherapy is given (up to 8 cycles)

    Reporting group title
    L-asparaginase-non allergic population
    Reporting group description
    		 For patient randomized in control group, reference L-asparaginase 10,000 IU/m² will be administered every 3 days intravenously, in combination with standard chemotherapy (COOPRALL).

    Reporting group title
    GRASPA Allergic population
    Reporting group description
    		 GRASPA was administered at a dose of 150 U/kg of ASNase on Day 4 of F1 block and Day 18 of F2 block (or Day 6 of VANDA), and on Day 6 of R2 and R1 blocks.

    Reporting group values
    		 GRASPA-non allergic population L-asparaginase-non allergic population GRASPA Allergic population Total
    Number of subjects
    		 29 30 26 85
    Age categorical
    number of subject in the age category
    Units: Subjects
        In utero
    		 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0
        Adults (18-64 years)
    		 0 0 0 0
        From 65-84 years
    		 0 0 0 0
        85 years and over
    		 0 0 0 0
        children: from 1 to <18 years old
    		 23 23 15 61
        Adults from 18 to 55 years
    		 6 7 11 24
    Gender categorical
    Units: Subjects
        Female
    		 11 10 8 29
        Male
    		 18 20 18 56
    Subject analysis sets

    Subject analysis set title
    Full Analysis set
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All patients who received at least 1 dose of study medication and had at least 1 post-Baseline efficacy assessment performed

    Subject analysis set title
    Per Protocol analysis set
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    All patients of the full analysis set without any major protocol violations

    Subject analysis set title
    Safety population
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    All patients who received at least 1 dose of medication - coincides with the Full Analysis Set

    Subject analysis sets values
    		 Full Analysis set Per Protocol analysis set Safety population
    Number of subjects
    80
    79
    80
    Age categorical
    number of subject in the age category
    Units: Subjects
        In utero
    0
    0
    0
        Preterm newborn infants (gestational age < 37 wks)
    0
    0
    0
        Newborns (0-27 days)
    0
    0
    0
        Infants and toddlers (28 days-23 months)
    0
    0
    0
        Children (2-11 years)
    0
    0
    0
        Adolescents (12-17 years)
    0
    0
    0
        Adults (18-64 years)
    0
    0
    0
        From 65-84 years
    0
    0
    0
        85 years and over
    0
    0
    0
        children: from 1 to <18 years old
    57
    57
    57
        Adults from 18 to 55 years
    23
    22
    23
    Age continuous
    Units:
        
    ( )
    ( )
    ( )
    Gender categorical
    Units: Subjects
        Female
    28
    28
    28
        Male
    52
    51
    52

    End points

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    End points reporting groups
    Reporting group title
    GRASPA-non allergic population
    Reporting group description
    		 Each patient randomized in GRASPA® group is to receive at least 2 and up to 10 administration of GRASPA® 150IU/kg, in combination with standard chemotherapy (COOPRALL). GRASPA® administration takes place as below: ◦for induction phase: at Day 4 and D18 (F1-F2 induction ) or at D6 if Vanda induction applies (according disease severity) ◦for consolidation phase: at Day 6 of R2 / R1 blocks, each time block of chemotherapy is given (up to 8 cycles)

    Reporting group title
    L-asparaginase-non allergic population
    Reporting group description
    		 For patient randomized in control group, reference L-asparaginase 10,000 IU/m² will be administered every 3 days intravenously, in combination with standard chemotherapy (COOPRALL).

    Reporting group title
    GRASPA Allergic population
    Reporting group description
    		 GRASPA was administered at a dose of 150 U/kg of ASNase on Day 4 of F1 block and Day 18 of F2 block (or Day 6 of VANDA), and on Day 6 of R2 and R1 blocks.

    Subject analysis set title
    Full Analysis set
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All patients who received at least 1 dose of study medication and had at least 1 post-Baseline efficacy assessment performed

    Subject analysis set title
    Per Protocol analysis set
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    All patients of the full analysis set without any major protocol violations

    Subject analysis set title
    Safety population
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    All patients who received at least 1 dose of medication - coincides with the Full Analysis Set

    Primary: Duration of asparaginase activity >100 U/L during induction

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    End point title
    		 Duration of asparaginase activity >100 U/L during induction [1]
    End point description
    Co-primary efficacy endpoint: duration in days of asparaginase activity >100 U/L in whole blood during the induction treatment phase: last available date/time of activity >100 UI/L before activity drops below 100 U/L – date/time of first activity >100 UI/L. Asparaginase activity is compared for GRASPA versus native ASNase to demonstrate the non-inferiority of GRASPA.
    End point type
    Primary
    End point timeframe
    Induction treatment phase
    Notes
    [1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only non allergic population evaluated for efficacy (i.e. 2 randomized arms).
    End point values
    		 GRASPA-non allergic population L-asparaginase-non allergic population
    Number of subjects analysed
    26
    28
    Units: days
        arithmetic mean (confidence interval 95%)
    18.9 (16.7 to 21.0)
    8.5 (6.0 to 11.1)
    Statistical analysis title
    		 Non-inferiority of GRASPA for duration of activity
    Statistical analysis description
    Non-inferiority was evaluated using the ratio of the mean duration of ASNase activity (> 100 U/L) of eryaspase and native ASNase employing bootstrap sampling and constructing the 95% CI for the ratio of the means. Non-inferiority (at the one-sided 2.5% level of significance) was declared if the interval was above 0.80.
    Comparison groups
    GRASPA-non allergic population v L-asparaginase-non allergic population
    Number of subjects included in analysis
    54
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [2]
    P-value
    		 < 0.001 [3]
    Method
    		 Bootstrap
    Parameter type
    		 Ratio of means
    Point estimate
    2.27
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.57
         upper limit
    		 2.97
    Notes
    [2] - Non-inferiority
    [3] - One-sided, highly significant supporting the non-inferiority of GRASPA. Confidence interval also excludes 1 for the ratio of the means and this provides evidence supporting the superiority of GRASPA for duration of activity

    Primary: Allergic reaction during induction phase

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    End point title
    		 Allergic reaction during induction phase
    End point description
    Co-primary safety endpoint: allergic reaction regardless of grade during induction phase. Only those reactions that were reported in relation to the treatment to which the patient was randomised were counted.
    End point type
    Primary
    End point timeframe
    Induction treatment period
    End point values
    		 GRASPA-non allergic population L-asparaginase-non allergic population GRASPA Allergic population Full Analysis set
    Number of subjects analysed
    26
    28
    26
    80
    Units: binary
    0
    13
    3
    16
    Statistical analysis title
    		 Superiority of GRASPA for fewer allergic reactions
    Statistical analysis description
    Evaluate superiority of GRASPA over native ASNase treatment by comparing the number of patients having at least one allergic reaction related to study treatment during the induction phase
    Comparison groups
    GRASPA-non allergic population v L-asparaginase-non allergic population
    Number of subjects included in analysis
    54
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001 [4]
    Method
    		 Fisher exact
    Parameter type
    		 Risk difference (RD)
    Point estimate
    -46.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -67.3
         upper limit
    		 -20.4
    Notes
    [4] - Highly statistically significant supporting the superiority of GRASPA in reducing the number of allergic reactions

    Secondary: Complete Remission (CR)

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    End point title
    		 Complete Remission (CR)
    End point description
    CR is defined as, no physical evidence of leukemia, normal CBC, cytologic remission: normally regenerating bone marrow, with <5% leukemic blasts and the absence of detectable CNS or extramedullary disease, evaluated with physical examination and CSF findings, at the end of induction
    End point type
    Secondary
    End point timeframe
    Induction treatment period
    End point values
    		 GRASPA-non allergic population L-asparaginase-non allergic population GRASPA Allergic population Full Analysis set
    Number of subjects analysed
    25
    28
    25
    78
    Units: binary
    19
    13
    15
    47
    Statistical analysis title
    		 Compare CR rates between GRASPA and native ASNase
    Comparison groups
    GRASPA-non allergic population v L-asparaginase-non allergic population
    Number of subjects included in analysis
    53
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.028 [5]
    Method
    		 Fisher exact
    Parameter type
    		 Risk difference (RD)
    Point estimate
    29.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 4.6
         upper limit
    		 54.5
    Notes
    [5] - Statistically significant supporting a higher rate of CR in the GRASPA group

    Secondary: Overall survival (OS)

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    End point title
    		 Overall survival (OS)
    End point description
    OS is defined as the time from randomisation or date of inclusion (allergic arm) until death due to any cause. Patients who did not die were censored at 36 months of follow-up or the date of the patient’s last visit, whichever was earlier.
    End point type
    Secondary
    End point timeframe
    Overall trial period to 36 months
    End point values
    		 GRASPA-non allergic population L-asparaginase-non allergic population GRASPA Allergic population Full Analysis set
    Number of subjects analysed
    26 [6]
    28
    26
    80
    Units: count
    9
    12
    14
    35
    Notes
    [6] - Entries given below are number of patients dying in each group
    Statistical analysis title
    		 Compare OS Kaplan-Meier curves
    Statistical analysis description
    Hazard ratio estimated using Cox regression with logrank p-value
    Comparison groups
    GRASPA-non allergic population v L-asparaginase-non allergic population
    Number of subjects included in analysis
    54
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.468 [7]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.73
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.31
         upper limit
    		 1.73
    Notes
    [7] - Not statistically significant. There is no evidence to support a treatment difference for overall survival

    Secondary: Event free survival (EFS)

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    End point title
    		 Event free survival (EFS)
    End point description
    EFS is defined as the time from randomisation until the first documented sign of disease relapse or death due to any cause. In line with CHMP guidance (CHMP, 2016), patients who did not achieve CR at the end of the induction period were considered to have had an event at time 0. For the patients enrolled in the GRASPA allergic arm, EFS is defined from the date of inclusion in the study. Patients who achieved CR at the end of induction and who did not have a documented relapse or death due to any cause were censored at 36 months of follow-up or the date of the patient’s last visit, whichever was earlier.
    End point type
    Secondary
    End point timeframe
    Overall trial period to 36 months
    End point values
    		 GRASPA-non allergic population L-asparaginase-non allergic population GRASPA Allergic population Full Analysis set
    Number of subjects analysed
    26 [8]
    28
    26
    80
    Units: count
    15
    17
    19
    51
    Notes
    [8] - Entries below are the numbers of patients with events in each treatment group
    Statistical analysis title
    		 Comparison of Kaplan-Meier EFS curves
    Statistical analysis description
    Hazard ratio obtained using the Cox model with logrank p-value
    Comparison groups
    GRASPA-non allergic population v L-asparaginase-non allergic population
    Number of subjects included in analysis
    54
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.574 [9]
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.84
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.42
         upper limit
    		 1.69
    Notes
    [9] - Not statistically significant. No evidence for treatment differences for EFS

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From randomization until 4 months after last dose of study drug
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17.1
    Reporting groups
    Reporting group title
    GRASPA-non allergic population
    Reporting group description
    		 -

    Reporting group title
    GRASPA-allergic population
    Reporting group description
    		 -

    Reporting group title
    L-asparaginase-non allergic population
    Reporting group description
    		 -

    Serious adverse events
    		 GRASPA-non allergic population GRASPA-allergic population L-asparaginase-non allergic population
    Total subjects affected by serious adverse events
         subjects affected / exposed
    23 / 26 (88.46%)
    23 / 26 (88.46%)
    26 / 28 (92.86%)
         number of deaths (all causes)
    6
    13
    9
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Leukaemia recurrent
         subjects affected / exposed
    8 / 26 (30.77%)
    7 / 26 (26.92%)
    9 / 28 (32.14%)
         occurrences causally related to treatment / all
    0 / 9
    0 / 8
    0 / 9
         deaths causally related to treatment / all
    0 / 2
    0 / 2
    0 / 4
    metabolism and nutient disorder
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 26 (0.00%)
    3 / 28 (10.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebral haemorrhage
         subjects affected / exposed
    0 / 26 (0.00%)
    1 / 26 (3.85%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Blood and lymphatic system disorders
    Febrile bone marrow aplasia
         subjects affected / exposed
    11 / 26 (42.31%)
    5 / 26 (19.23%)
    7 / 28 (25.00%)
         occurrences causally related to treatment / all
    1 / 23
    1 / 7
    1 / 10
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    0 / 26 (0.00%)
    3 / 26 (11.54%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    4 / 26 (15.38%)
    4 / 26 (15.38%)
    5 / 28 (17.86%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 7
    0 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Mucosal inflammation
         subjects affected / exposed
    15 / 26 (57.69%)
    6 / 26 (23.08%)
    8 / 28 (28.57%)
         occurrences causally related to treatment / all
    0 / 15
    1 / 6
    2 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Drug hypersensitivity
         subjects affected / exposed
    3 / 26 (11.54%)
    3 / 26 (11.54%)
    7 / 28 (25.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 3
    4 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Pancreatitis
         subjects affected / exposed
    1 / 26 (3.85%)
    1 / 26 (3.85%)
    3 / 28 (10.71%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intestinal ischaemia
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 26 (0.00%)
    1 / 28 (3.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Mucosal inflammation
         subjects affected / exposed
    3 / 26 (11.54%)
    5 / 26 (19.23%)
    4 / 28 (14.29%)
         occurrences causally related to treatment / all
    0 / 3
    1 / 5
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lung disorder
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 26 (0.00%)
    2 / 28 (7.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal failure
         subjects affected / exposed
    1 / 26 (3.85%)
    0 / 26 (0.00%)
    1 / 28 (3.57%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Infections and infestations
    Sepsis
         subjects affected / exposed
    4 / 26 (15.38%)
    0 / 26 (0.00%)
    2 / 28 (7.14%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Anal abscess
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 26 (0.00%)
    2 / 28 (7.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bacteraemia
         subjects affected / exposed
    0 / 26 (0.00%)
    2 / 26 (7.69%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    3 / 26 (11.54%)
    1 / 26 (3.85%)
    1 / 28 (3.57%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Staphylococcal sepsis
         subjects affected / exposed
    3 / 26 (11.54%)
    0 / 26 (0.00%)
    1 / 28 (3.57%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Fusarium infection
         subjects affected / exposed
    0 / 26 (0.00%)
    1 / 26 (3.85%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Human herpesvirus 6 infection
         subjects affected / exposed
    0 / 26 (0.00%)
    1 / 26 (3.85%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 GRASPA-non allergic population GRASPA-allergic population L-asparaginase-non allergic population
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    26 / 26 (100.00%)
    26 / 26 (100.00%)
    28 / 28 (100.00%)
    Vascular disorders
    Haematoma
         subjects affected / exposed
    2 / 26 (7.69%)
    0 / 26 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    2
    0
    0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    2 / 26 (7.69%)
    4 / 26 (15.38%)
    0 / 28 (0.00%)
         occurrences all number
    3
    4
    0
    Asthenia
         subjects affected / exposed
    0 / 26 (0.00%)
    2 / 26 (7.69%)
    0 / 28 (0.00%)
         occurrences all number
    0
    2
    0
    Immune system disorders
    Drug hypersensitivity
         subjects affected / exposed
    7 / 26 (26.92%)
    17 / 26 (65.38%)
    18 / 28 (64.29%)
         occurrences all number
    8
    21
    21
    Graft versus host disease
         subjects affected / exposed
    2 / 26 (7.69%)
    0 / 26 (0.00%)
    2 / 28 (7.14%)
         occurrences all number
    2
    0
    2
    Psychiatric disorders
    Depression
         subjects affected / exposed
    0 / 26 (0.00%)
    1 / 26 (3.85%)
    2 / 28 (7.14%)
         occurrences all number
    0
    1
    2
    Investigations
    Transaminases increased
         subjects affected / exposed
    16 / 26 (61.54%)
    15 / 26 (57.69%)
    16 / 28 (57.14%)
         occurrences all number
    40
    21
    33
    Hypokalaemia
         subjects affected / exposed
    13 / 26 (50.00%)
    9 / 26 (34.62%)
    11 / 28 (39.29%)
         occurrences all number
    13
    12
    12
    Antithrombin III decreased
         subjects affected / exposed
    4 / 26 (15.38%)
    9 / 26 (34.62%)
    20 / 28 (71.43%)
         occurrences all number
    7
    11
    44
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    8 / 26 (30.77%)
    7 / 26 (26.92%)
    14 / 28 (50.00%)
         occurrences all number
    20
    16
    15
    Blood albumin decreased
         subjects affected / exposed
    5 / 26 (19.23%)
    6 / 26 (23.08%)
    11 / 28 (39.29%)
         occurrences all number
    5
    7
    15
    Hyponatraemia
         subjects affected / exposed
    6 / 26 (23.08%)
    7 / 26 (26.92%)
    10 / 28 (35.71%)
         occurrences all number
    6
    8
    19
    Blood bilirubin increased
         subjects affected / exposed
    4 / 26 (15.38%)
    7 / 26 (26.92%)
    9 / 28 (32.14%)
         occurrences all number
    6
    8
    11
    Hyperglycaemia
         subjects affected / exposed
    5 / 26 (19.23%)
    6 / 26 (23.08%)
    7 / 28 (25.00%)
         occurrences all number
    6
    12
    12
    Activated partial thromboplastin time prolonged
         subjects affected / exposed
    1 / 26 (3.85%)
    5 / 26 (19.23%)
    4 / 28 (14.29%)
         occurrences all number
    2
    5
    7
    Hypocalcaemia
         subjects affected / exposed
    3 / 26 (11.54%)
    1 / 26 (3.85%)
    4 / 28 (14.29%)
         occurrences all number
    3
    3
    4
    Blood triglycerides increased
         subjects affected / exposed
    2 / 26 (7.69%)
    3 / 26 (11.54%)
    3 / 28 (10.71%)
         occurrences all number
    4
    3
    4
    Prothrombin level decreased
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 26 (0.00%)
    3 / 28 (10.71%)
         occurrences all number
    0
    0
    5
    Blood lactate dehydrogenase increased
         subjects affected / exposed
    0 / 26 (0.00%)
    1 / 26 (3.85%)
    2 / 28 (7.14%)
         occurrences all number
    0
    1
    2
    Blood potassium increased
         subjects affected / exposed
    3 / 26 (11.54%)
    0 / 26 (0.00%)
    2 / 28 (7.14%)
         occurrences all number
    3
    0
    2
    C-reactive protein increased
         subjects affected / exposed
    2 / 26 (7.69%)
    0 / 26 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    3
    0
    0
    Injury, poisoning and procedural complications
    Allergic transfusion reaction
         subjects affected / exposed
    2 / 26 (7.69%)
    2 / 26 (7.69%)
    2 / 28 (7.14%)
         occurrences all number
    2
    2
    2
    Blood and lymphatic system disorders
    Leukopenia
         subjects affected / exposed
    25 / 26 (96.15%)
    26 / 26 (100.00%)
    27 / 28 (96.43%)
         occurrences all number
    76
    74
    81
    Thrombocytopenia
         subjects affected / exposed
    24 / 26 (92.31%)
    22 / 26 (84.62%)
    26 / 28 (92.86%)
         occurrences all number
    69
    71
    71
    Neutropenia
         subjects affected / exposed
    24 / 26 (92.31%)
    25 / 26 (96.15%)
    25 / 28 (89.29%)
         occurrences all number
    89
    81
    93
    Lymphopenia
         subjects affected / exposed
    21 / 26 (80.77%)
    20 / 26 (76.92%)
    23 / 28 (82.14%)
         occurrences all number
    43
    49
    43
    Febrile bone marrow aplasia
         subjects affected / exposed
    5 / 26 (19.23%)
    8 / 26 (30.77%)
    7 / 28 (25.00%)
         occurrences all number
    17
    13
    17
    Hypofibrinogenaemia
         subjects affected / exposed
    9 / 26 (34.62%)
    11 / 26 (42.31%)
    19 / 28 (67.86%)
         occurrences all number
    11
    12
    37
    Febrile neutropenia
         subjects affected / exposed
    1 / 26 (3.85%)
    3 / 26 (11.54%)
    5 / 28 (17.86%)
         occurrences all number
    4
    6
    9
    Anaemia
         subjects affected / exposed
    7 / 26 (26.92%)
    6 / 26 (23.08%)
    9 / 28 (32.14%)
         occurrences all number
    9
    6
    14
    Bone marrow failure
         subjects affected / exposed
    2 / 26 (7.69%)
    1 / 26 (3.85%)
    3 / 28 (10.71%)
         occurrences all number
    2
    1
    4
    Blood phosphorus decreased
         subjects affected / exposed
    4 / 26 (15.38%)
    3 / 26 (11.54%)
    3 / 28 (10.71%)
         occurrences all number
    5
    3
    3
    Gastrointestinal disorders
    Pancreatitis
         subjects affected / exposed
    1 / 26 (3.85%)
    0 / 26 (0.00%)
    2 / 28 (7.14%)
         occurrences all number
    1
    0
    2
    Abdominal pain
         subjects affected / exposed
    1 / 26 (3.85%)
    2 / 26 (7.69%)
    2 / 28 (7.14%)
         occurrences all number
    2
    2
    2
    Diarrhoea
         subjects affected / exposed
    3 / 26 (11.54%)
    2 / 26 (7.69%)
    2 / 28 (7.14%)
         occurrences all number
    3
    2
    3
    Rectal haemorrhage
         subjects affected / exposed
    0 / 26 (0.00%)
    0 / 26 (0.00%)
    2 / 28 (7.14%)
         occurrences all number
    0
    0
    2
    Vomiting
         subjects affected / exposed
    4 / 26 (15.38%)
    1 / 26 (3.85%)
    1 / 28 (3.57%)
         occurrences all number
    4
    1
    1
    Hepatobiliary disorders
    Hepatotoxicity
         subjects affected / exposed
    2 / 26 (7.69%)
    8 / 26 (30.77%)
    6 / 28 (21.43%)
         occurrences all number
    2
    9
    12
    Cholestasis
         subjects affected / exposed
    0 / 26 (0.00%)
    2 / 26 (7.69%)
    0 / 28 (0.00%)
         occurrences all number
    0
    2
    0
    Skin and subcutaneous tissue disorders
    Drug hypersensitivity
         subjects affected / exposed
    0 / 26 (0.00%)
    2 / 26 (7.69%)
    1 / 28 (3.57%)
         occurrences all number
    0
    2
    1
    Renal and urinary disorders
    renal failure acute
         subjects affected / exposed
    0 / 26 (0.00%)
    2 / 26 (7.69%)
    0 / 28 (0.00%)
         occurrences all number
    0
    2
    0
    Infections and infestations
    Sepsis
         subjects affected / exposed
    3 / 26 (11.54%)
    1 / 26 (3.85%)
    1 / 28 (3.57%)
         occurrences all number
    3
    1
    1
    Bronchopulmonary aspergillosis
         subjects affected / exposed
    2 / 26 (7.69%)
    0 / 26 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    2
    0
    1
    Infection
         subjects affected / exposed
    1 / 26 (3.85%)
    1 / 26 (3.85%)
    2 / 28 (7.14%)
         occurrences all number
    2
    1
    3
    Bacteraemia
         subjects affected / exposed
    1 / 26 (3.85%)
    0 / 26 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    1
    0
    2
    Candida infection
         subjects affected / exposed
    2 / 26 (7.69%)
    0 / 26 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    3
    0
    1
    Staphylococcal infection
         subjects affected / exposed
    3 / 26 (11.54%)
    4 / 26 (15.38%)
    1 / 28 (3.57%)
         occurrences all number
    7
    4
    1
    Staphylococcal sepsis
         subjects affected / exposed
    0 / 26 (0.00%)
    2 / 26 (7.69%)
    0 / 28 (0.00%)
         occurrences all number
    0
    3
    0
    Folliculitis
         subjects affected / exposed
    0 / 26 (0.00%)
    2 / 26 (7.69%)
    0 / 28 (0.00%)
         occurrences all number
    0
    2
    0
    Streptococcal infection
         subjects affected / exposed
    3 / 26 (11.54%)
    1 / 26 (3.85%)
    0 / 28 (0.00%)
         occurrences all number
    3
    1
    0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    2 / 26 (7.69%)
    0 / 26 (0.00%)
    2 / 28 (7.14%)
         occurrences all number
    2
    0
    3

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    29 Sep 2009
    Answer ANSM questions
    28 Apr 2010
    -change of inclusion criteria, to include isolated extramedullary relapse -changes for compliance to medicinal product status (regarding vigilance and traceability)
    24 Apr 2013
    - Change of the duration of the follow up and contraception (request from authorities) - Collection of survival status at 24 months (M24) and 36 months M36 (PDCO PaeDiatric COmmittee request) - French Investigators / subinvestigators list update
    02 Jul 2014
    Requested by PDCO, in accordance to CHMP (Committee for Medicinal Products for Human Use) advice, to clarify and revised one of the primary endpoint.

    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
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