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    Clinical Trial Results:
    A multicentre, roll-over study to provide continued treatment with lyophilized pegaspargase (S95014) in Pediatric Patients with Acute Lymphoblastic Leukemia (ALL)

    Summary
    EudraCT number
    2020-004895-17
    Trial protocol
    Outside EU/EEA  
    Global end of trial date
    23 Jan 2023

    Results information
    Results version number
    v1(current)
    This version publication date
    26 Jul 2023
    First version publication date
    26 Jul 2023
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CL2-95014-003
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT04956666
    WHO universal trial number (UTN)
    -
    Other trial identifiers
    Investigational New Drug Application No.: 152743
    Sponsors
    Sponsor organisation name
    Institut de Recherches Internationales Servier and Les Laboratoires Servier (L.L.S.)
    Sponsor organisation address
    50 rue Carnot, Suresnes Cedex, France, 92284
    Public contact
    Clinical Studies Department, Institut de Recherches Internationales Servier, +33 155724366, clinicaltrials@servier.com
    Scientific contact
    Clinical Studies Department, Institut de Recherches Internationales Servier, +33 155724366, clinicaltrials@servier.com
    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?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    18 Apr 2023
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    23 Jan 2023
    Global end of trial reached?
    Yes
    Global end of trial date
    23 Jan 2023
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To provide treatment with lyophilized S95014 in pediatric patients with ALL who completed the CL2-95014-002 study during the induction phase.
    Protection of trial subjects
    The study was performed in accordance with the ethical principles stated in the Declaration of Helsinki 1964, as revised in Fortaleza, 2013 with the good clinical practice (GCP) and with the applicable regulatory requirements. Each patient, in the presence of their parent(s) / legal guardians, was informed by the investigator (or their delegate) to the fullest extent possible about the details of the study in language and terms they could understand. The patients were also informed that they had the possibility not to participate in the study and that they were free to reconsider their assent at any time.
    Background therapy
    The following treatments were to be used with caution during the whole treatment phase: - Coumarin/warfarin and heparin, dipyridamole, acetylsalicylic acid or non-steroidal anti-inflammatory medicines (e.g. ibuprofen, naproxen) - Prednisone, methotrexate, vincristine, cytarabine. The main pharmacological classes of concomitant treatments, listed by decreasing frequency of use, were: - 70% or more patients: antiemetics and antinauseants, antibacterials for systemic use, blood substitutes and perfusion solutions. - 60% to 70% of patients: corticosteroids for systemic use, antihistamines for systemic use, antithrombotic agents. - 40% to 60% of patients: drugs for acid related disorders, mineral supplements, bile and liver therapy, antimycotics for systemic use, antianemic preparations. - 20% to 40% of patients: antivirals for systemic use, analgesics, digestives, incl. enzymes, antihemorrhagics, psychoanaleptics, immunostimulants, other alimentary tract and metabolism products. - 10% to 20% of patients: cardiac therapy, drugs for constipation, drugs for functional gastrointestinal disorders, psycholeptics, stomatological preparations, vitamins, and anti-inflammatory and antirheumatic products, other nervous system drugs, immune sera and immunoglobulins.
    Evidence for comparator
    Not applicable
    Actual start date of recruitment
    15 May 2021
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Safety
    Long term follow-up duration
    1 Months
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Russian Federation: 74
    Worldwide total number of subjects
    74
    EEA total number of subjects
    0
    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)
    66
    Adolescents (12-17 years)
    7
    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
    All investigators were oncologists.

    Pre-assignment
    Screening details
    Patients who completed the CL2-95014-002 study and received clinical benefit from previous treatment with S95014 as per investigator’s judgment, were included in the current CL2-95014-003 study. Other main criteria for inclusion in the study were signed informed consent and assent (where appropriate) and highly effective contraception method.

    Period 1
    Period 1 title
    Treatment period (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Non-randomised - controlled
    Blinding used
    Not blinded
    Blinding implementation details
    This was a non-randomized, open-label, roll-over study of S95014 lyophilizate during the consolidation phase of pediatric patients with ALL.

    Arms
    Arm title
    Consolidation phase
    Arm description
    In this study, patients were treated for the consolidation phase and received the backbone chemotherapy agents outlined in the ALL-MB 2015 protocol. The patients were assigned to receive lyophilized pegaspargase (S95014) which was administered on 9 occasions, at weeks 7, 9, 11, 15, 17, 19, 23, 25 and 27 (3 phases S1, S2 and S3) over 1-hour IV infusion, at a dose of 1000 U/m².
    Arm type
    Experimental

    Investigational medicinal product name
    Pegaspargase
    Investigational medicinal product code
    S95014
    Other name
    Oncaspar®
    Pharmaceutical forms
    Powder for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    S95014 lyophilizate was reconstituted with sterile water for intravenous (IV) administration and was administered every two weeks during the consolidation phase for a total of 9 infusions, at weeks 7, 9, 11, 15, 17, 19, 23, 25 and 27, at a dose of 1000 U/m².

    Number of subjects in period 1
    Consolidation phase
    Started
    74
    Completed
    52
    Not completed
    22
         Physician decision
    4
         Adverse event, non-fatal
    18

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Consolidation phase
    Reporting group description
    In this study, patients were treated for the consolidation phase and received the backbone chemotherapy agents outlined in the ALL-MB 2015 protocol. The patients were assigned to receive lyophilized pegaspargase (S95014) which was administered on 9 occasions, at weeks 7, 9, 11, 15, 17, 19, 23, 25 and 27 (3 phases S1, S2 and S3) over 1-hour IV infusion, at a dose of 1000 U/m².

    Reporting group values
    Consolidation phase Total
    Number of subjects
    74 74
    Age categorical
    Units: Subjects
        Children (2-11 years)
    66 66
        Adolescents (12-17 years)
    7 7
        Adults (18-64 years)
    1 1
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    6.1 ( 3.8 ) -
    Gender categorical
    Units: Subjects
        Female
    36 36
        Male
    38 38
    Subject analysis sets

    Subject analysis set title
    Safety Analysis Set
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    The Safety Analysis Set (SAS) was defined as the set of all patients who had received at least one dose of S95014.

    Subject analysis sets values
    Safety Analysis Set
    Number of subjects
    74
    Age categorical
    Units: Subjects
        Children (2-11 years)
    66
        Adolescents (12-17 years)
    7
        Adults (18-64 years)
    1
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    6.1 ( 3.8 )
    Gender categorical
    Units: Subjects
        Female
    36
        Male
    38

    End points

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    End points reporting groups
    Reporting group title
    Consolidation phase
    Reporting group description
    In this study, patients were treated for the consolidation phase and received the backbone chemotherapy agents outlined in the ALL-MB 2015 protocol. The patients were assigned to receive lyophilized pegaspargase (S95014) which was administered on 9 occasions, at weeks 7, 9, 11, 15, 17, 19, 23, 25 and 27 (3 phases S1, S2 and S3) over 1-hour IV infusion, at a dose of 1000 U/m².

    Subject analysis set title
    Safety Analysis Set
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    The Safety Analysis Set (SAS) was defined as the set of all patients who had received at least one dose of S95014.

    Primary: Extent of exposure

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    End point title
    Extent of exposure [1]
    End point description
    All 74 patients received at least one dose of S95014 (1000 U/m²). A single dose was received by 7 patients, 2 doses only were received by 10 patients, and 3 doses only were received by 3 patients; Thus, 20/74 patients (27%) received 3 doses or less. Except for 2 patients who received 8 doses, the remaining patients (52/74 [70%]) received 9 doses, as per protocol. The number of doses administered was 7.0 Mean ± 3.23 SD (median: 9).
    End point type
    Primary
    End point timeframe
    From the Inclusion visit until the last S95014 infusion.
    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 analyses have been provided since data was summarized using descriptive statistics.
    End point values
    Consolidation phase Safety Analysis Set
    Number of subjects analysed
    74
    74
    Units: months
    arithmetic mean (standard deviation)
        Duration of treatment
    5.0 ( 2.59 )
    5.0 ( 2.59 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From the Inclusion visit up until 30 days after the last S95014 infusion or the date of withdrawal, whichever is earlier.
    Adverse event reporting additional description
    Treatment-emergent adverse event (TEAE) was defined as any untoward medical occurrence in a patient who received the IMP. The serious TEAEs include those upgraded by the Sponsor. No new safety concerns for S95014 were detected and it was well tolerated. No fatal events were reported during the study.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    25.0
    Reporting groups
    Reporting group title
    Consolidation phase
    Reporting group description
    -

    Serious adverse events
    Consolidation phase
    Total subjects affected by serious adverse events
         subjects affected / exposed
    27 / 74 (36.49%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Investigations
    Ejection fraction decreased
         subjects affected / exposed
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Neutrophil count decreased
         subjects affected / exposed
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Blood and lymphatic system disorders
    Neutropenia
         subjects affected / exposed
    5 / 74 (6.76%)
         occurrences causally related to treatment / all
    1 / 6
         deaths causally related to treatment / all
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    4 / 74 (5.41%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    Agranulocytosis
         subjects affected / exposed
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Anaemia
         subjects affected / exposed
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Leukopenia
         subjects affected / exposed
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    General physical health deterioration
         subjects affected / exposed
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    11 / 74 (14.86%)
         occurrences causally related to treatment / all
    12 / 12
         deaths causally related to treatment / all
    0 / 0
    Anaphylactic reaction
         subjects affected / exposed
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Drug hypersensitivity
         subjects affected / exposed
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Haemophagocytic lymphohistiocytosis
         subjects affected / exposed
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Enterocolitis haemorrhagic
         subjects affected / exposed
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Oedematous pancreatitis
         subjects affected / exposed
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Pancreatitis
         subjects affected / exposed
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hepatobiliary disorders
    Hepatomegaly
         subjects affected / exposed
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hepatotoxicity
         subjects affected / exposed
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    COVID-19
         subjects affected / exposed
    3 / 74 (4.05%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Bronchitis
         subjects affected / exposed
    2 / 74 (2.70%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    COVID-19 pneumonia
         subjects affected / exposed
    2 / 74 (2.70%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Sepsis
         subjects affected / exposed
    2 / 74 (2.70%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Appendicitis
         subjects affected / exposed
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cellulitis gangrenous
         subjects affected / exposed
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Device related bacteraemia
         subjects affected / exposed
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Device related infection
         subjects affected / exposed
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Laryngitis
         subjects affected / exposed
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Neutropenic sepsis
         subjects affected / exposed
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Pneumonia fungal
         subjects affected / exposed
    1 / 74 (1.35%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Consolidation phase
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    68 / 74 (91.89%)
    Investigations
    Antithrombin III decreased
         subjects affected / exposed
    53 / 74 (71.62%)
         occurrences all number
    161
    Blood fibrinogen decreased
         subjects affected / exposed
    48 / 74 (64.86%)
         occurrences all number
    118
    Alanine aminotransferase increased
         subjects affected / exposed
    35 / 74 (47.30%)
         occurrences all number
    48
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    31 / 74 (41.89%)
         occurrences all number
    31
    Aspartate aminotransferase increased
         subjects affected / exposed
    24 / 74 (32.43%)
         occurrences all number
    28
    Protein S decreased
         subjects affected / exposed
    12 / 74 (16.22%)
         occurrences all number
    17
    Blood bilirubin increased
         subjects affected / exposed
    11 / 74 (14.86%)
         occurrences all number
    11
    Neutrophil count decreased
         subjects affected / exposed
    10 / 74 (13.51%)
         occurrences all number
    16
    White blood cell count decreased
         subjects affected / exposed
    8 / 74 (10.81%)
         occurrences all number
    8
    Activated partial thromboplastin time prolonged
         subjects affected / exposed
    7 / 74 (9.46%)
         occurrences all number
    8
    Lipase increased
         subjects affected / exposed
    6 / 74 (8.11%)
         occurrences all number
    8
    Blood albumin decreased
         subjects affected / exposed
    4 / 74 (5.41%)
         occurrences all number
    5
    Haemoglobin decreased
         subjects affected / exposed
    4 / 74 (5.41%)
         occurrences all number
    4
    Nervous system disorders
    Toxic neuropathy
         subjects affected / exposed
    5 / 74 (6.76%)
         occurrences all number
    5
    Blood and lymphatic system disorders
    Neutropenia
         subjects affected / exposed
    49 / 74 (66.22%)
         occurrences all number
    105
    Anaemia
         subjects affected / exposed
    33 / 74 (44.59%)
         occurrences all number
    47
    Leukopenia
         subjects affected / exposed
    20 / 74 (27.03%)
         occurrences all number
    26
    Thrombocytopenia
         subjects affected / exposed
    11 / 74 (14.86%)
         occurrences all number
    14
    Hypofibrinogenaemia
         subjects affected / exposed
    4 / 74 (5.41%)
         occurrences all number
    6
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    7 / 74 (9.46%)
         occurrences all number
    10
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    15 / 74 (20.27%)
         occurrences all number
    20
    Drug hypersensitivity
         subjects affected / exposed
    5 / 74 (6.76%)
         occurrences all number
    6
    Infections and infestations
    COVID-19
         subjects affected / exposed
    7 / 74 (9.46%)
         occurrences all number
    7
    Upper respiratory tract infection
         subjects affected / exposed
    4 / 74 (5.41%)
         occurrences all number
    7
    Metabolism and nutrition disorders
    Hypoalbuminaemia
         subjects affected / exposed
    14 / 74 (18.92%)
         occurrences all number
    20
    Hypoglycaemia
         subjects affected / exposed
    5 / 74 (6.76%)
         occurrences all number
    7

    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.
    Not applicable
    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
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