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    Clinical Trial Results:
    Open-label, Single-arm Trial to Evaluate Antitumor Activity, Safety, and Pharmacokinetics of Isatuximab Used in Combination With Chemotherapy in Pediatric Patients From 28 Days to Less Than 18 Years of Age With Relapsed/Refractory B or T Acute Lymphoblastic Leukemia or Acute Myeloid Leukemia In First or Second Relapse

    Summary
    EudraCT number
    2018-002697-45
    Trial protocol
    SE   NO   FI   DK   FR   NL   PT   BE   DE   CZ   GR   Outside EU/EEA   IT  
    Global end of trial date
    26 May 2023

    Results information
    Results version number
    v1(current)
    This version publication date
    02 Dec 2023
    First version publication date
    02 Dec 2023
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    ACT15378
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT03860844
    WHO universal trial number (UTN)
    U1111-1202-1096
    Sponsors
    Sponsor organisation name
    Sanofi aventis recherche & développement
    Sponsor organisation address
    1 avenue Pierre Brossolette, Chilly-Mazarin, France, 91380
    Public contact
    Trial Transparency Team, Sanofi aventis recherche & développement, Contact-US@sanofi.com
    Scientific contact
    Trial Transparency Team, Sanofi aventis recherche & développement, Contact-US@sanofi.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    EMEA-002205-PIP01-17
    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
    26 May 2023
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    26 May 2023
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the anti-leukemic activity of isatuximab in combination with chemotherapies in pediatric participants of 28 days to less than 18 years of age with Relapsed/Refractory (R/R) Acute Lymphoblastic Leukemia (ALL) or Acute Myeloid Leukemia (AML).
    Protection of trial subjects
    The study was conducted by investigators experienced in the treatment of pediatric participants. The parent (s) or guardian (s) as well as children were fully informed of all pertinent aspects of the clinical trial as well as the possibility to discontinue at any time. In addition to the consent form for the parent(s)/guardian(s), an assent form in child-appropriate language was provided and explained to the child. Repeated invasive procedures were minimized. The number of blood samples as well as the amount of blood drawn were adjusted according to age and weight. A topical anesthesia may have been used to minimize distress and discomfort.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    06 Aug 2019
    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
    Argentina: 7
    Country: Number of subjects enrolled
    Brazil: 12
    Country: Number of subjects enrolled
    Peru: 2
    Country: Number of subjects enrolled
    United States: 2
    Country: Number of subjects enrolled
    Netherlands: 1
    Country: Number of subjects enrolled
    Norway: 3
    Country: Number of subjects enrolled
    Portugal: 4
    Country: Number of subjects enrolled
    Sweden: 2
    Country: Number of subjects enrolled
    Denmark: 4
    Country: Number of subjects enrolled
    France: 10
    Country: Number of subjects enrolled
    Germany: 2
    Country: Number of subjects enrolled
    Greece: 2
    Country: Number of subjects enrolled
    Hungary: 1
    Country: Number of subjects enrolled
    Italy: 7
    Country: Number of subjects enrolled
    Korea, Republic of: 5
    Country: Number of subjects enrolled
    Mexico: 3
    Worldwide total number of subjects
    67
    EEA total number of subjects
    36
    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)
    18
    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
    This Phase II, open-label, single-arm study was conducted in 3 separate cohorts at 41 investigational sites in 16 countries. A total of 67 participants were enrolled between 06 Aug 2019 and 08 Jun 2022.

    Pre-assignment
    Screening details
    The study consisted of a screening period (up to 3 weeks prior to the first study treatment administration), treatment period (Day 1 to Day 57 for ALL; Day 1 to Day 22 for AML), a period of aplasia followed by recovery period; an end of treatment (EOT) visit within 30 days after hematological recovery and follow-up period.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    B-cell Acute Lymphoblastic Leukemia (B-ALL)
    Arm description
    Participants with B-ALL received isatuximab 20 milligram per kilogram (mg/kg) intravenous (IV) infusion once every week (QW) for 4 weeks during the induction period (i.e., on Days 1, 8, 15, and 22) and every 2 weeks (Q2W) during the consolidation period (i.e., on Days 29, 43, and 57). Participants received recommended isatuximab premedication as per protocol. Starting on Day 8, combination chemotherapies were added. Participants without documented disease progression at EOT visit who had not started treatment with another anticancer therapy received follow-up visits every 2 months until initiation of another anticancer therapy, disease progression, death, or final analysis cut-off date, whichever occurred first. Participants with documented disease progression/initiation of new anticancer treatment were followed for survival every 4 months until death or final analysis cut-off date, whichever occurred first.
    Arm type
    Experimental

    Investigational medicinal product name
    Isatuximab
    Investigational medicinal product code
    SAR650984
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Isatuximab was administered as 20 mg/kg weekly on Days 1, 8, 15, 22, 29, 43, and 57.

    Investigational medicinal product name
    Dexamethasone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection, Tablet
    Routes of administration
    Intravenous use, Oral use
    Dosage and administration details
    Dexamethasone was administered before each administration of isatuximab, at least 15 to 30 minutes (but no longer than 60 minutes) prior to infusion as premedication for prevention of infusion associated reactions consisting of dexamethasone 10 mg/meter square (m^2) (maximum 20 mg) IV or orally (PO) on Days -3, -2, and -1 before isatuximab administration, Days 1, 8, 15 to 19, 22, and 29 to 33 during the induction period, and on Days 43 to 47 and 57 during the consolidation period.

    Investigational medicinal product name
    Mitoxantrone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Mitoxantrone was administered as 10 mg/m^2 IV over 15 minutes on Days 8 and 9 of the induction period.

    Investigational medicinal product name
    Doxorubicin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Doxorubicin was administered as 25 mg/m^2 IV over 15 minutes on Days 10, 17, 24, and 31 of the induction period.

    Investigational medicinal product name
    Vincristine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Vincristine was administered as 1.5 mg/m^2 IV on Days 10, 17, 24, and 31 during the induction period (not exceeding 2 mg per infusion in any participant) and on Day 38 during the consolidation period.

    Investigational medicinal product name
    Pegaspargase
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intramuscular use, Intravenous use
    Dosage and administration details
    Pegaspargase was administered as 1000 International units (IU)/m^2 on Days 10 and 24 during the induction period and Day 44 during the consolidation period.

    Investigational medicinal product name
    L-asparaginase
    Investigational medicinal product code
    Other name
    Erwinase
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intramuscular use, Intravenous use
    Dosage and administration details
    L-asparaginase was administered as 25000 IU/m^2 on Days 8, 10, 12, 15, 17, 19, 22, 24, 26, 29, 31, 33 during induction and days 43, 45, 47, 50, 52, 54 during consolidation, only in case of confirmed hypersensitivity reaction to pegaspargase prior or during the study or loss of asparaginase activity and/or country availability and regulations.

    Investigational medicinal product name
    Cyclophosphamide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Cyclophosphamide 440 mg/m^2 was administered as a 1-hour infusion on Days 50 to 54 (inclusive) during the consolidation period.

    Investigational medicinal product name
    Etoposide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Etoposide 100 mg/m^2 was administered as a 2-hour infusion on Days 50 to 54 (inclusive) during the consolidation period.

    Investigational medicinal product name
    Methotrexate
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Methotrexate 1000 mg/m^2 was infused over 36 hours and calcium folinate rescue started 48 hours from start of infusion on Day 43 during the consolidation period.

    Arm title
    T-cell Acute Lymphoblastic Leukemia (T-ALL)
    Arm description
    Participants with T-ALL received isatuximab 20 mg/kg IV infusion QW for 4 weeks during the induction period (i.e., on Days 1, 8, 15, and 22) and Q2W during the consolidation period (i.e., on Days 29, 43, and 57. Participants received recommended isatuximab premedication as per protocol. Starting on Day 8, combination chemotherapies were added. Participants without documented disease progression at EOT visit who had not started treatment with another anticancer therapy received follow-up visits every 2 months until initiation of another anticancer therapy, disease progression, death, or final analysis cut-off date, whichever occurred first. Participants with documented disease progression/initiation of new anticancer treatment were followed for survival every 4 months until death or final analysis cut-off date, whichever occurred first.
    Arm type
    Experimental

    Investigational medicinal product name
    Isatuximab
    Investigational medicinal product code
    SAR650984
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Isatuximab was administered as 20 mg/kg weekly on Days 1, 8, 15, 22, 29, 43, and 57.

    Investigational medicinal product name
    Dexamethasone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection, Tablet
    Routes of administration
    Intravenous use, Oral use
    Dosage and administration details
    Dexamethasone was administered before each administration of isatuximab, at least 15 to 30 minutes (but no longer than 60 minutes) prior to infusion as premedication for prevention of infusion associated reactions consisting of dexamethasone 10 mg/m^2 (maximum 20 mg) IV or PO on Days -3, -2, and -1 before isatuximab administration, Days 1, 8, 15 to 19, 22, and 29 to 33 during the induction period, and on Days 43 to 47 and 57 during the consolidation period.

    Investigational medicinal product name
    Mitoxantrone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Mitoxantrone was administered as 10 mg/m^2 IV over 15 minutes on Days 8 and 9 of the induction period.

    Investigational medicinal product name
    Doxorubicin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Doxorubicin was administered as 25 mg/m^2 IV over 15 minutes on Days 10, 17, 24, and 31 of the induction period.

    Investigational medicinal product name
    Vincristine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Vincristine was administered as 1.5 mg/m^2 IV on Days 10, 17, 24, and 31 during the induction period (not exceeding 2 mg per infusion in any participant) and on Day 38 during the consolidation period.

    Investigational medicinal product name
    Pegaspargase
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intramuscular use, Intravenous use
    Dosage and administration details
    Pegaspargase was administered as 1000 IU/m^2 on Days 10 and 24 during the induction period and Day 44 during the consolidation period.

    Investigational medicinal product name
    L-asparaginase
    Investigational medicinal product code
    Other name
    Erwinase
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intramuscular use, Intravenous use
    Dosage and administration details
    L-asparaginase was administered as 25000 IU/m^2 on Days 8, 10, 12, 15, 17, 19, 22, 24, 26, 29, 31, 33 during induction and days 43, 45, 47, 50, 52, 54 during consolidation, only in case of confirmed hypersensitivity reaction to pegaspargase prior or during the study or loss of asparaginase activity and/or country availability and regulations.

    Investigational medicinal product name
    Cyclophosphamide
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Cyclophosphamide 440 mg/m^2 was administered as a 1-hour infusion on Days 50 to 54 (inclusive) during the consolidation period.

    Investigational medicinal product name
    Methotrexate
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Methotrexate 1000 mg/m^2 was infused over 36 hours and calcium folinate rescue started 48 hours from start of infusion on Day 43 during the consolidation period.

    Arm title
    Acute Myeloid Leukemia (AML)
    Arm description
    Participants with AML received isatuximab 20 mg/kg IV infusion on Days 1, 8, and 15 of each Cycle (up to 2 treatment cycles, each cycle 28 days). Participants received recommended isatuximab premedication as per protocol. Starting on Day 8, combination chemotherapies were added. Participants without documented disease progression at EOT visit who had not started treatment with another anticancer therapy received follow-up visits every 2 months until initiation of another anticancer therapy, disease progression, death, or final analysis cut-off date, whichever occurred first. Participants with documented disease progression/initiation of new anticancer treatment were followed for survival every 4 months until death or final analysis cut-off date, whichever occurred first.
    Arm type
    Experimental

    Investigational medicinal product name
    Isatuximab
    Investigational medicinal product code
    SAR650984
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Isatuximab was administered as 20 mg/kg weekly on Days 1, 8, 15 (mandatory for Cycles 1 and 2).

    Investigational medicinal product name
    Dexamethasone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet, Solution for injection
    Routes of administration
    Oral use, Intravenous use
    Dosage and administration details
    Dexamethasone was administered as a premedication for prevention of infusion associated reactions before each administration of isatuximab, at least 15 to 30 minutes (but no longer than 60 minutes) prior to infusion consisting of dexamethasone 10 mg/m^2 (maximum 20 mg) IV or PO on Days 1, 8, and 15 during the induction period (mandatory for Cycle 1 and before first isatuximab infusion Cycle 2). It was optionally used for rapid control of tumor burden on Days -3, -2 and -1. When dexamethasone was administered at 10 mg/m^2 orally, it could have been divided in 2 daily doses.

    Investigational medicinal product name
    Fludarabine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Fludarabine 30 mg/m^2 IV was administered as 30-minute infusion after granulocyte colony-stimulating factor (G-CSF) administration, if any on Days 8 to 12 (inclusive) (mandatory for Cycles 1 and 2).

    Investigational medicinal product name
    Cytarabine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Cytarabine 2 gram (g)/m^2 was administered as a 4-hour infusion, beginning 4 hours after start of fludarabine on Days 8 to 12 (inclusive) (mandatory for Cycles 1 and 2)

    Investigational medicinal product name
    Anthracycline
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Anthracycline (a choice of liposomal daunorubicin 60 mg/m^2, non-liposomal daunorubicin 60 mg/m^2, or idarubicin 10 mg/m^2) was given after administration of fludarabine. Anthracycline administration on Day 8 in Cycle 1 was mandatory. Administrations on Cycle 1 Days 10 and 12 and on Cycle 2 were at the Investigator’s discretion.

    Investigational medicinal product name
    Filgrastim
    Investigational medicinal product code
    Other name
    Granulocyte colony-stimulating factor
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use, Subcutaneous use
    Dosage and administration details
    Filgrastim (optional for Cycles 1 and 2) was administered as 200 microgram/m^2/day on Days 7 to 12 (inclusive) and was continued until neutrophil recovery.

    Number of subjects in period 1
    B-cell Acute Lymphoblastic Leukemia (B-ALL) T-cell Acute Lymphoblastic Leukemia (T-ALL) Acute Myeloid Leukemia (AML)
    Started
    27
    13
    27
    Completed
    19
    7
    20
    Not completed
    8
    6
    7
         Other, Not related to COVID-19
    -
    1
    -
         Adverse event, unrelated to Coronavirus Disease-19
    3
    2
    3
         Progressive disease
    5
    3
    4

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    B-cell Acute Lymphoblastic Leukemia (B-ALL)
    Reporting group description
    Participants with B-ALL received isatuximab 20 milligram per kilogram (mg/kg) intravenous (IV) infusion once every week (QW) for 4 weeks during the induction period (i.e., on Days 1, 8, 15, and 22) and every 2 weeks (Q2W) during the consolidation period (i.e., on Days 29, 43, and 57). Participants received recommended isatuximab premedication as per protocol. Starting on Day 8, combination chemotherapies were added. Participants without documented disease progression at EOT visit who had not started treatment with another anticancer therapy received follow-up visits every 2 months until initiation of another anticancer therapy, disease progression, death, or final analysis cut-off date, whichever occurred first. Participants with documented disease progression/initiation of new anticancer treatment were followed for survival every 4 months until death or final analysis cut-off date, whichever occurred first.

    Reporting group title
    T-cell Acute Lymphoblastic Leukemia (T-ALL)
    Reporting group description
    Participants with T-ALL received isatuximab 20 mg/kg IV infusion QW for 4 weeks during the induction period (i.e., on Days 1, 8, 15, and 22) and Q2W during the consolidation period (i.e., on Days 29, 43, and 57. Participants received recommended isatuximab premedication as per protocol. Starting on Day 8, combination chemotherapies were added. Participants without documented disease progression at EOT visit who had not started treatment with another anticancer therapy received follow-up visits every 2 months until initiation of another anticancer therapy, disease progression, death, or final analysis cut-off date, whichever occurred first. Participants with documented disease progression/initiation of new anticancer treatment were followed for survival every 4 months until death or final analysis cut-off date, whichever occurred first.

    Reporting group title
    Acute Myeloid Leukemia (AML)
    Reporting group description
    Participants with AML received isatuximab 20 mg/kg IV infusion on Days 1, 8, and 15 of each Cycle (up to 2 treatment cycles, each cycle 28 days). Participants received recommended isatuximab premedication as per protocol. Starting on Day 8, combination chemotherapies were added. Participants without documented disease progression at EOT visit who had not started treatment with another anticancer therapy received follow-up visits every 2 months until initiation of another anticancer therapy, disease progression, death, or final analysis cut-off date, whichever occurred first. Participants with documented disease progression/initiation of new anticancer treatment were followed for survival every 4 months until death or final analysis cut-off date, whichever occurred first.

    Reporting group values
    B-cell Acute Lymphoblastic Leukemia (B-ALL) T-cell Acute Lymphoblastic Leukemia (T-ALL) Acute Myeloid Leukemia (AML) Total
    Number of subjects
    27 13 27 67
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    8.22 ( 3.92 ) 8.72 ( 4.15 ) 9.04 ( 5.41 ) -
    Gender categorical
    Units: Subjects
        Female
    10 4 12 26
        Male
    17 9 15 41
    Race
    Units: Subjects
        American Indian or Alaska Native
    3 0 0 3
        Asian
    1 1 4 6
        Native Hawaiian or Other Pacific Islander
    0 0 0 0
        Black or African American
    1 1 2 4
        White
    17 7 15 39
        More than one race
    1 0 0 1
        Unknown or Not Reported
    4 4 6 14

    End points

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    End points reporting groups
    Reporting group title
    B-cell Acute Lymphoblastic Leukemia (B-ALL)
    Reporting group description
    Participants with B-ALL received isatuximab 20 milligram per kilogram (mg/kg) intravenous (IV) infusion once every week (QW) for 4 weeks during the induction period (i.e., on Days 1, 8, 15, and 22) and every 2 weeks (Q2W) during the consolidation period (i.e., on Days 29, 43, and 57). Participants received recommended isatuximab premedication as per protocol. Starting on Day 8, combination chemotherapies were added. Participants without documented disease progression at EOT visit who had not started treatment with another anticancer therapy received follow-up visits every 2 months until initiation of another anticancer therapy, disease progression, death, or final analysis cut-off date, whichever occurred first. Participants with documented disease progression/initiation of new anticancer treatment were followed for survival every 4 months until death or final analysis cut-off date, whichever occurred first.

    Reporting group title
    T-cell Acute Lymphoblastic Leukemia (T-ALL)
    Reporting group description
    Participants with T-ALL received isatuximab 20 mg/kg IV infusion QW for 4 weeks during the induction period (i.e., on Days 1, 8, 15, and 22) and Q2W during the consolidation period (i.e., on Days 29, 43, and 57. Participants received recommended isatuximab premedication as per protocol. Starting on Day 8, combination chemotherapies were added. Participants without documented disease progression at EOT visit who had not started treatment with another anticancer therapy received follow-up visits every 2 months until initiation of another anticancer therapy, disease progression, death, or final analysis cut-off date, whichever occurred first. Participants with documented disease progression/initiation of new anticancer treatment were followed for survival every 4 months until death or final analysis cut-off date, whichever occurred first.

    Reporting group title
    Acute Myeloid Leukemia (AML)
    Reporting group description
    Participants with AML received isatuximab 20 mg/kg IV infusion on Days 1, 8, and 15 of each Cycle (up to 2 treatment cycles, each cycle 28 days). Participants received recommended isatuximab premedication as per protocol. Starting on Day 8, combination chemotherapies were added. Participants without documented disease progression at EOT visit who had not started treatment with another anticancer therapy received follow-up visits every 2 months until initiation of another anticancer therapy, disease progression, death, or final analysis cut-off date, whichever occurred first. Participants with documented disease progression/initiation of new anticancer treatment were followed for survival every 4 months until death or final analysis cut-off date, whichever occurred first.

    Primary: Percentage of Participants With Complete Response (CR) Rate

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    End point title
    Percentage of Participants With Complete Response (CR) Rate [1]
    End point description
    The CR rate (CR+CRi [CR with incomplete peripheral recovery]): % of participants achieving CR assessed by investigator per National Comprehensive Cancer Network (NCCN) guidelines version 1.2018 criteria. CR:<5% blasts in bone marrow aspirate (BMA)with spicules;no circulating blasts(ALL)/no blasts with Auer rods(AML)or extramedullary disease,no lymphadenopathy, splenomegaly,skin/gum infiltration/testicular mass/central nervous system involvement(ALL),trilineage hematopoiesis(ALL);Absolute neutrophil count(ANC)>=1000/microliter (mcL);platelets >100000/mcL;red blood cell transfusion independence.If physician documented transfusion dependency related to study treatment;not participant’s underlying disease, CRi was reported.CRi=CR, except neutrophils (<1000/mcL) and/or platelets recovery(<100000/mcL). Evaluable population(EP):Evaluable participants from All-treated (AT) population who received atleast 1 full dose of isatuximab in Cycle 1 and who had atleast 1 valid response value evaluable
    End point type
    Primary
    End point timeframe
    From enrollment until the primary analysis completion date of 12 Sep 2022; the median duration of exposure was approximately 7 weeks
    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: As the endpoint is descriptive in nature, no statistical analysis is provided.
    End point values
    B-cell Acute Lymphoblastic Leukemia (B-ALL) T-cell Acute Lymphoblastic Leukemia (T-ALL) Acute Myeloid Leukemia (AML)
    Number of subjects analysed
    25
    11
    23
    Units: percentage of participants
        number (not applicable)
    52.0
    45.5
    60.9
    No statistical analyses for this end point

    Secondary: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Emergent Serious Adverse Events (TESAEs)

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    End point title
    Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Treatment-Emergent Serious Adverse Events (TESAEs)
    End point description
    An AE was defined as any untoward medical occurrence in a participant temporally associated with the use of study treatment, whether or not considered related to the study treatment. SAEs were any untoward medical occurrence that at any dose: resulted in death, was life-threatening, required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, was a congenital anomaly/birth defect, was a medically important event. TEAEs were defined as an AE which occurred after the first dose of study treatment administration until the last dose plus 30 days, or until the start of hematological recovery period or a new anti-leukemia/lymphoma therapy, whichever occurred first. The AT population consisted of all participants who received at least 1 dose (even incomplete) of study treatment.
    End point type
    Secondary
    End point timeframe
    From the time of the first treatment administration (Day 1) up to 30 days after the last treatment (maximum duration of exposure of 13.1 weeks for B-ALL cohort, 10.7 weeks for T-ALL cohort and 7.1 weeks for AML cohort)
    End point values
    B-cell Acute Lymphoblastic Leukemia (B-ALL) T-cell Acute Lymphoblastic Leukemia (T-ALL) Acute Myeloid Leukemia (AML)
    Number of subjects analysed
    27
    13
    27
    Units: participants
    number (not applicable)
        Any TEAEs
    27
    13
    26
        Any TESAEs
    19
    12
    17
    No statistical analyses for this end point

    Secondary: Number of Participants With Infusion Reactions (IRs)

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    End point title
    Number of Participants With Infusion Reactions (IRs)
    End point description
    An IR was an AE related to isatuximab typically with onset within 24 hours from the start of the isatuximab infusion and was reported by the investigator. The AT population consisted of all participants who received at least 1 dose (even incomplete) of study treatment.
    End point type
    Secondary
    End point timeframe
    From the time of the first treatment administration (Day 1) up to 30 days after the last treatment (maximum duration of exposure of 13.1 weeks for B-ALL cohort, 10.7 weeks for T-ALL cohort and 7.1 weeks for AML cohort)
    End point values
    B-cell Acute Lymphoblastic Leukemia (B-ALL) T-cell Acute Lymphoblastic Leukemia (T-ALL) Acute Myeloid Leukemia (AML)
    Number of subjects analysed
    27
    13
    27
    Units: participants
        number (not applicable)
    9
    5
    15
    No statistical analyses for this end point

    Secondary: B-ALL and T-ALL: Area Under the Concentration Time Curve (AUC) of Isatuximab

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    End point title
    B-ALL and T-ALL: Area Under the Concentration Time Curve (AUC) of Isatuximab [2]
    End point description
    Plasma samples were collected at specified timepoints to determine the AUC of isatuximab. The Pharmacokinetic (PK) population consisted of all participants from the AT population with at least 1 PK parameter available (isatuximab concentration). Only those participants with data available at specified timepoints were analyzed.
    End point type
    Secondary
    End point timeframe
    From Week 0 to Week 1, Week 0 to Week 5, and Week 0 to Week 10
    Notes
    [2] - 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 participants from B-ALL and T-ALL cohort were included in this endpoint.
    End point values
    B-cell Acute Lymphoblastic Leukemia (B-ALL) T-cell Acute Lymphoblastic Leukemia (T-ALL)
    Number of subjects analysed
    27
    12
    Units: mg*hour (h)/Liter (L)
    arithmetic mean (standard deviation)
        Week 0 to Week 1
    31703 ( 10048 )
    29057 ( 8294 )
        Week 0 to Week 5
    299071 ( 127581 )
    289167 ( 93095 )
        Week 0 to Week 10
    582686 ( 316749 )
    540375 ( 233411 )
    No statistical analyses for this end point

    Secondary: AML: AUC of Isatuximab

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    End point title
    AML: AUC of Isatuximab [3]
    End point description
    Plasma samples were collected at specified timepoints to determine the AUC of isatuximab. The PK population consisted of all participants from the AT population with at least 1 PK parameter available (isatuximab concentration). Only those participants with data available at specified timepoints were analyzed.
    End point type
    Secondary
    End point timeframe
    From Week 0 to Week 1, Week 0 to Week 3, and Week 0 to Week 8
    Notes
    [3] - 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 participants from AML cohort were included in this endpoint.
    End point values
    Acute Myeloid Leukemia (AML)
    Number of subjects analysed
    26
    Units: mg*h/L
    arithmetic mean (standard deviation)
        Week 0 to Week 1
    28592 ( 6858 )
        Week 0 to Week 3
    130862 ( 40827 )
        Week 0 to Week 8
    291962 ( 112222 )
    No statistical analyses for this end point

    Secondary: B-ALL and T-ALL: Plasma Concentration Reached by Isatuximab Before Next Dose Administration (Ctrough)

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    End point title
    B-ALL and T-ALL: Plasma Concentration Reached by Isatuximab Before Next Dose Administration (Ctrough) [4]
    End point description
    Plasma samples were collected at specified timepoints to determine the Ctrough of isatuximab. The PK population consisted of all participants from the AT population with at least 1 PK parameter available (isatuximab concentration). Only those participants with data available at specified timepoints were analyzed and are denoted by 'n' in the categories. 99999= Standard deviation (SD) could not be derived for a single participant.
    End point type
    Secondary
    End point timeframe
    Cycle 1 Day 8, Cycle 1 Day 15, Cycle 1 Day 22, Cycle 1 Day 29, Cycle 2 Day 43, Cycle 2 Day 57
    Notes
    [4] - 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 participants from B-ALL and T-ALL cohort were included in this endpoint.
    End point values
    B-cell Acute Lymphoblastic Leukemia (B-ALL) T-cell Acute Lymphoblastic Leukemia (T-ALL)
    Number of subjects analysed
    27
    13
    Units: microgram/milliliter (mcg/mL)
    arithmetic mean (standard deviation)
        Cycle 1: Day 8 (n=25, 11)
    114 ( 45.7 )
    127 ( 49.9 )
        Cycle 1: Day 15 (n=23, 11)
    272 ( 118 )
    263 ( 103 )
        Cycle 1: Day 22 (n=15, 8)
    388 ( 163 )
    323 ( 206 )
        Cycle 1: Day 29 (n=18, 9)
    475 ( 174 )
    426 ( 209 )
        Cycle 2: Day 43 (n=5, 1)
    504 ( 296 )
    357 ( 99999 )
        Cycle 2: Day 57 (n=8, 2)
    531 ( 224 )
    478 ( 261 )
    No statistical analyses for this end point

    Secondary: AML: Plasma Concentration Reached by Isatuximab Before Next Dose Administration (Ctrough)

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    End point title
    AML: Plasma Concentration Reached by Isatuximab Before Next Dose Administration (Ctrough) [5]
    End point description
    Plasma samples were collected at specified timepoints to determine the Ctrough of isatuximab. The PK population consisted of all participants from the AT population with at least 1 PK parameter available (isatuximab concentration). Only those participants with data available at specified timepoints were analyzed and are denoted by 'n' in the categories.
    End point type
    Secondary
    End point timeframe
    Cycle 1 Day 8, Cycle 1 Day 15, Cycle 2 Day 1 and Cycle 2 Day 15
    Notes
    [5] - 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 participants from AML cohort were included in this endpoint.
    End point values
    Acute Myeloid Leukemia (AML)
    Number of subjects analysed
    27
    Units: mcg/mL
    arithmetic mean (standard deviation)
        Cycle 1: Day 8 (n=19)
    126 ( 41.0 )
        Cycle 1: Day 15 (n=24)
    217 ( 60.6 )
        Cycle 2: Day 1 (n=10)
    115 ( 94.2 )
        Cycle 2: Day 15 (n=8)
    420 ( 205 )
    No statistical analyses for this end point

    Secondary: B-ALL and T-ALL: Concentrations at the End of Infusion (Ceoi) of Isatuximab

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    End point title
    B-ALL and T-ALL: Concentrations at the End of Infusion (Ceoi) of Isatuximab [6]
    End point description
    Ceoi is the plasma concentration observed at the end of intravenous infusion of isatuximab. The PK population consisted of all participants from the AT population with at least 1 PK parameter available (isatuximab concentration). Only those participants with data available at specified timepoints were analyzed and are denoted by 'n' in the categories.
    End point type
    Secondary
    End point timeframe
    At end of infusion on Cycle 1 Days 1 and 29
    Notes
    [6] - 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 participants from B-ALL and T-ALL cohort were included in this endpoint.
    End point values
    B-cell Acute Lymphoblastic Leukemia (B-ALL) T-cell Acute Lymphoblastic Leukemia (T-ALL)
    Number of subjects analysed
    27
    13
    Units: mcg/mL
    arithmetic mean (standard deviation)
        Cycle 1: Day 1 (n=21, 8)
    452 ( 344 )
    259 ( 120 )
        Cycle 1: Day 29 (n=19, 7)
    835 ( 366 )
    745 ( 330 )
    No statistical analyses for this end point

    Secondary: AML: Ceoi of Isatuximab

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    End point title
    AML: Ceoi of Isatuximab [7]
    End point description
    Ceoi is the plasma concentration observed at the end of intravenous infusion of isatuximab. The PK population consisted of all participants from the AT population with at least 1 PK parameter available (isatuximab concentration). Only those participants with data available at specified timepoints were analyzed and are denoted by 'n' in the categories.
    End point type
    Secondary
    End point timeframe
    At end of infusion on Cycle 1 Days 1 and 15
    Notes
    [7] - 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 participants from AML cohort were included in this endpoint.
    End point values
    Acute Myeloid Leukemia (AML)
    Number of subjects analysed
    27
    Units: mcg/mL
    arithmetic mean (standard deviation)
        Cycle 1: Day 1 (n=19)
    363 ( 110 )
        Cycle 1: Day 15 (n=20)
    562 ( 176 )
    No statistical analyses for this end point

    Secondary: Number of Participants With Negative Minimal Residual Disease (MRD)

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    End point title
    Number of Participants With Negative Minimal Residual Disease (MRD)
    End point description
    The MRD assessment was performed by next generation sequencing using clonoSEQ and T-cell receptor assays for B-ALL and T-ALL cohorts respectively. It was performed by flow cytometry for AML cohort. Number of participants with CR or CRi who achieved negative MRD in bone marrow and blood were analyzed. The EP consisted of evaluable participants from the AT population who received at least 1 full dose of isatuximab in Cycle 1 and who had at least 1 valid response value that was evaluable. Only those participants who achieved CR/CRi were analyzed. 9999 = In AML indication, peripheral blood tissue is not representative of the tumor burden and cannot be used to assess MRD.
    End point type
    Secondary
    End point timeframe
    From screening until the study end date, approximately 45 months
    End point values
    B-cell Acute Lymphoblastic Leukemia (B-ALL) T-cell Acute Lymphoblastic Leukemia (T-ALL) Acute Myeloid Leukemia (AML)
    Number of subjects analysed
    13
    5
    14
    Units: participants
    number (not applicable)
        Blood, 1 in 10^6
    3
    1
    9999
        Bone marrow, 1 in 10^6
    0
    2
    0
    No statistical analyses for this end point

    Secondary: Overall Response Rate (ORR)

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    End point title
    Overall Response Rate (ORR)
    End point description
    ORR:Percentage of participants with CR/CRi or partial response for blood and bone marrow disease based on NCCN guideline. CR: <5% blasts in BMA with spicules; no circulating blasts (ALL)/no blasts with Auer rods (AML) or extramedullary disease, no lymphadenopathy, splenomegaly, skin/gum infiltration/testicular mass/central nervous system involvement (ALL), trilineage hematopoiesis (ALL);ANC >=1000/mcL; platelets >100000/mcL; RBC transfusion independence. If physician documented transfusion dependency related to study treatment;not to participant’s underlying disease, CRi was reported. CRi met the same criteria as CR, except neutrophils and/or platelets recovery (ANC <1000/mcL or platelets <100000/mcL). PR: >50% decrease in the sum of the product of the greatest perpendicular diameters of the mediastinal enlargement. For participants with a previous positive positron emission tomography (PET) scan, a post-treatment PET was to be positive in at least 1 previously involved site. The EP.
    End point type
    Secondary
    End point timeframe
    From enrollment until the primary analysis completion date of 12 Sep 2022; the median duration of exposure was approximately 7 weeks
    End point values
    B-cell Acute Lymphoblastic Leukemia (B-ALL) T-cell Acute Lymphoblastic Leukemia (T-ALL) Acute Myeloid Leukemia (AML)
    Number of subjects analysed
    25
    11
    23
    Units: percentage of participants
        number (confidence interval 80%)
    52.0 (37.5 to 66.2)
    54.5 (31.8 to 75.9)
    65.2 (49.7 to 78.6)
    No statistical analyses for this end point

    Secondary: Overall Survival (OS)

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    End point title
    Overall Survival (OS)
    End point description
    Overall survival was defined as the time interval from the date of first study treatment administration to death from any cause. It was estimated using the Kaplan-Meier method. Confidence interval (CI) for Kaplan-Meier estimates were calculated with log-log transformation of survival function and methods of Brookmeyer and Crowley. The EP consisted of evaluable participants from the AT population who received at least 1 full dose of isatuximab in Cycle 1 and who had at least 1 valid response value that was evaluable. 99999 = Upper limit of CI was not estimable due to insufficient number of participants with events at study closure.
    End point type
    Secondary
    End point timeframe
    From first study treatment administration up to death due to any cause, a maximum of 45 months
    End point values
    B-cell Acute Lymphoblastic Leukemia (B-ALL) T-cell Acute Lymphoblastic Leukemia (T-ALL) Acute Myeloid Leukemia (AML)
    Number of subjects analysed
    25
    11
    23
    Units: months
        median (confidence interval 95%)
    12.09 (3.975 to 99999)
    6.85 (2.201 to 99999)
    9.40 (5.947 to 99999)
    No statistical analyses for this end point

    Secondary: Event-Free Survival (EFS)

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    End point title
    Event-Free Survival (EFS)
    End point description
    The EFS was defined as the time interval from the date of first study treatment administration to the date of the first of: completion or going off protocol induction/consolidation therapy without CR, relapse from CR, or death due to any cause, whichever occurred first. It was estimated using the Kaplan-Meier method. CI for Kaplan-Meier estimates are calculated with log-log transformation of survival function and methods of Brookmeyer and Crowley. The EP consisted of evaluable participants from the AT population who received at least 1 full dose of isatuximab in Cycle 1 and who had at least 1 valid response value that was evaluable. 99999 = Upper limit of CI was not estimable due to insufficient number of participants with events at study closure.
    End point type
    Secondary
    End point timeframe
    From study treatment administration up to the date of first documented disease progression or death due to any cause, a maximum of 45 months
    End point values
    B-cell Acute Lymphoblastic Leukemia (B-ALL) T-cell Acute Lymphoblastic Leukemia (T-ALL) Acute Myeloid Leukemia (AML)
    Number of subjects analysed
    25
    11
    23
    Units: months
        median (confidence interval 95%)
    2.23 (1.413 to 99999)
    2.14 (1.347 to 99999)
    5.65 (1.347 to 99999)
    No statistical analyses for this end point

    Secondary: Duration of Response (DoR)

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    End point title
    Duration of Response (DoR)
    End point description
    The DoR was defined as the time from the date of the first complete response to the event date of first disease progression or death from any cause, whichever happened first. It was estimated using the Kaplan-Meier method. CI for Kaplan-Meier estimates are calculated with log-log transformation of survival function and methods of Brookmeyer and Crowley. The EP consisted of evaluable participants from the AT population who received at least 1 full dose of isatuximab in Cycle 1 and who had at least 1 valid response value that was evaluable. Only responders were included in this analysis. -99999= Lower limit of CI not estimable due to insufficient number of participants with events at study closure. 99999= Upper limit of CI was not estimable due to insufficient number of participants with events at study closure.
    End point type
    Secondary
    End point timeframe
    From first documented response up to the date of first documented disease progression or death due to any cause, a maximum of 45 months
    End point values
    B-cell Acute Lymphoblastic Leukemia (B-ALL) T-cell Acute Lymphoblastic Leukemia (T-ALL) Acute Myeloid Leukemia (AML)
    Number of subjects analysed
    13
    5
    14
    Units: months
        median (confidence interval 95%)
    7.26 (-99999 to 99999)
    1.18 (0.887 to 99999)
    4.40 (-99999 to 99999)
    No statistical analyses for this end point

    Secondary: Cluster of Differentiation (CD)38 Receptor Density

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    End point title
    Cluster of Differentiation (CD)38 Receptor Density
    End point description
    Blood samples were collected to assess CD38 receptor density as a predictive biomarker. It was assessed across complete responders and non-complete responders. The Antibody Binding Capacity (ABC) was calculated using the following equation: ABC = 10^(Logarithm(Mean Fluorescence Intensity)*a+b) where “a” was the slope and “b” was the Y-intercept of the calibration curve equation. Specific and absolute quantitative values (specific antibody-binding capacity [sABC]) of binding of the selected antibodies were calculated after subtraction of the negative isotypic immunoglobulin G (IgG) control. The EP consisted of evaluable participants from the AT population who received at least 1 full dose of isatuximab in Cycle 1 and who had at least 1 valid response value that was evaluable. Only those participants with data available at specified timepoints were analyzed and denoted by 'n' in the categories . 99999 = SD cannot be derived for a single participant. NK=Natural killer cells.
    End point type
    Secondary
    End point timeframe
    Pre-dose on Day 1
    End point values
    B-cell Acute Lymphoblastic Leukemia (B-ALL) T-cell Acute Lymphoblastic Leukemia (T-ALL) Acute Myeloid Leukemia (AML)
    Number of subjects analysed
    25
    11
    23
    Units: specific antibody-binding capacity
    arithmetic mean (standard deviation)
        Blood blast cells: CR/CRi (n=5,2,3)
    20345.6 ( 23439.7 )
    12780.0 ( 15559.2 )
    19502.0 ( 20919.7 )
        Blood blast cells: Non CR/CRi (n=2,1,2)
    31080.0 ( 2397.1 )
    22952.0 ( 99999 )
    9815.0 ( 4203.0 )
        Blood immune cells (NK cells): CR/CRi (n=5,2,3)
    13506.2 ( 3018.6 )
    22639.0 ( 1796.1 )
    11220.3 ( 3764.6 )
        Blood immune cells (NK cells):Non CR/CRi (n=2,1,2)
    16650.0 ( 851.4 )
    33859.0 ( 99999 )
    22530.0 ( 685.9 )
    No statistical analyses for this end point

    Secondary: CD38 Receptor Occupancy

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    End point title
    CD38 Receptor Occupancy
    End point description
    Blood samples were collected to assess CD38 receptor occupancy as a pharmacodynamics marker. It was assessed across complete responders and non-complete responders. Multicolor flow cytometry assay was validated for CD38 receptor occupancy (CD38RO) quantification, based on the use of 2 murine monoclonal antibodies (MAbs), one competing with SAR650984 to determine number of free CD38 receptors (MAb1) and one recognizing a different binding epitope on CD38 to measure total number of receptors (MAb2) at cell surface of the cancer cells. Cells were tagged with either MAb1 (Tube #1) or MAb2 (Tube #2). The percentage RO was calculated using following equation: % CD38RO = [(sABC MAb2 - sABC MAb1)/sABC MAb2] X 100. The EP consisted of evaluable participants from AT population who received at least 1 full dose of isatuximab in Cycle 1 and who had at least 1 valid response value that was evaluable. Only those participants with data available at specified timepoints were analyzed; denoted by 'n'.
    End point type
    Secondary
    End point timeframe
    Pre-dose on Day 15
    End point values
    B-cell Acute Lymphoblastic Leukemia (B-ALL) T-cell Acute Lymphoblastic Leukemia (T-ALL) Acute Myeloid Leukemia (AML)
    Number of subjects analysed
    25
    11
    23
    Units: percent receptor occupancy
    arithmetic mean (standard deviation)
        Blood plasma cells: CR/CRi (n=0,2,0)
    9999 ( 9999 )
    40.5 ( 30.4 )
    9999 ( 9999 )
        Blood plasma cells: Non CR/CRi (n=1,1,0)
    44.0 ( 99999 )
    55.0 ( 99999 )
    9999 ( 9999 )
        Blood NK cells: CR/CRi (n=5,3,0)
    55.6 ( 6.9 )
    66.7 ( 2.1 )
    9999 ( 9999 )
        Blood NK cells: Non CR/CRi (n=3,1,0)
    61.3 ( 3.5 )
    70.0 ( 99999 )
    9999 ( 9999 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From the time of the first treatment administration (Day 1) up to 30 days after the last treatment (maximum duration of exposure of 13.1 weeks for B-ALL cohort, 10.7 weeks for T-ALL cohort and 7.1 weeks for AML cohort)
    Adverse event reporting additional description
    Analysis was performed on the AT population.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    26.0
    Reporting groups
    Reporting group title
    B-cell Acute Lymphoblastic Leukemia (B-ALL)
    Reporting group description
    Participants with B-ALL received isatuximab 20 mg/kg IV infusion QW for 4 weeks during the induction period (i.e., on Days 1, 8, 15, and 22) and Q2W during the consolidation period (i.e., on Days 29, 43, and 57. Participants received recommended isatuximab premedication as per protocol. Starting on Day 8, combination chemotherapies were added. Participants without documented disease progression at EOT visit who had not started treatment with another anticancer therapy received follow-up visits every 2 months until initiation of another anticancer therapy, disease progression, death, or final analysis cut-off date, whichever occurred first. Participants with documented disease progression/initiation of new anticancer treatment were followed for survival every 4 months until death or final analysis cut-off date, whichever occurred first.

    Reporting group title
    All Participants
    Reporting group description
    All participants in the study were included in this cohort.

    Reporting group title
    Acute Myeloid Leukemia (AML)
    Reporting group description
    Participants with AML received isatuximab 20 mg/kg IV infusion on Days 1, 8, and 15 of each Cycle (up to 2 treatment cycles, each cycle 28 days). Participants received recommended isatuximab premedication as per protocol. Starting on Day 8, combination chemotherapies were added. Participants without documented disease progression at EOT visit who had not started treatment with another anticancer therapy received follow-up visits every 2 months until initiation of another anticancer therapy, disease progression, death, or final analysis cut-off date, whichever occurred first. Participants with documented disease progression/initiation of new anticancer treatment were followed for survival every 4 months until death or final analysis cut-off date, whichever occurred first.

    Reporting group title
    T-cell Acute Lymphoblastic Leukemia (T-ALL)
    Reporting group description
    Participants with T-ALL received isatuximab 20 mg/kg IV infusion QW for 4 weeks during the induction period (i.e., on Days 1, 8, 15, and 22) and Q2W during the consolidation period (i.e., on Days 29, 43, and 57. Participants received recommended isatuximab premedication as per protocol. Starting on Day 8, combination chemotherapies were added. Participants without documented disease progression at EOT visit who had not started treatment with another anticancer therapy received follow-up visits every 2 months until initiation of another anticancer therapy, disease progression, death, or final analysis cut-off date, whichever occurred first. Participants with documented disease progression/initiation of new anticancer treatment were followed for survival every 4 months until death or final analysis cut-off date, whichever occurred first.

    Serious adverse events
    B-cell Acute Lymphoblastic Leukemia (B-ALL) All Participants Acute Myeloid Leukemia (AML) T-cell Acute Lymphoblastic Leukemia (T-ALL)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    19 / 27 (70.37%)
    48 / 67 (71.64%)
    17 / 27 (62.96%)
    12 / 13 (92.31%)
         number of deaths (all causes)
    17
    43
    18
    8
         number of deaths resulting from adverse events
    3
    5
    2
    0
    Injury, poisoning and procedural complications
    Infusion Related Reaction
         subjects affected / exposed
    1 / 27 (3.70%)
    3 / 67 (4.48%)
    1 / 27 (3.70%)
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    1 / 1
    3 / 3
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Aortic Aneurysm
         subjects affected / exposed
    1 / 27 (3.70%)
    1 / 67 (1.49%)
    0 / 27 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    0 / 27 (0.00%)
    2 / 67 (2.99%)
    1 / 27 (3.70%)
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Cardiac Failure
         subjects affected / exposed
    1 / 27 (3.70%)
    1 / 67 (1.49%)
    0 / 27 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    Nervous system disorders
    Seizure
         subjects affected / exposed
    1 / 27 (3.70%)
    1 / 67 (1.49%)
    0 / 27 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    1 / 27 (3.70%)
    1 / 67 (1.49%)
    0 / 27 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Generalised Tonic-Clonic Seizure
         subjects affected / exposed
    1 / 27 (3.70%)
    1 / 67 (1.49%)
    0 / 27 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Leukoencephalopathy
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 67 (1.49%)
    0 / 27 (0.00%)
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Febrile Bone Marrow Aplasia
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 67 (1.49%)
    1 / 27 (3.70%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Febrile Neutropenia
         subjects affected / exposed
    10 / 27 (37.04%)
    22 / 67 (32.84%)
    7 / 27 (25.93%)
    5 / 13 (38.46%)
         occurrences causally related to treatment / all
    11 / 12
    26 / 29
    9 / 11
    6 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    1 / 27 (3.70%)
    1 / 67 (1.49%)
    0 / 27 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancytopenia
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 67 (1.49%)
    1 / 27 (3.70%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    2 / 27 (7.41%)
    4 / 67 (5.97%)
    1 / 27 (3.70%)
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 4
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Haemophagocytic Lymphohistiocytosis
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 67 (1.49%)
    1 / 27 (3.70%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Anaphylactic Shock
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 67 (1.49%)
    0 / 27 (0.00%)
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cytokine Release Syndrome
         subjects affected / exposed
    0 / 27 (0.00%)
    2 / 67 (2.99%)
    2 / 27 (7.41%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    Gastrointestinal disorders
    Neutropenic Colitis
         subjects affected / exposed
    1 / 27 (3.70%)
    2 / 67 (2.99%)
    0 / 27 (0.00%)
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis Acute
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 67 (1.49%)
    0 / 27 (0.00%)
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Stomatitis
         subjects affected / exposed
    2 / 27 (7.41%)
    2 / 67 (2.99%)
    0 / 27 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Mouth Haemorrhage
         subjects affected / exposed
    1 / 27 (3.70%)
    1 / 67 (1.49%)
    0 / 27 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Anal Fissure
         subjects affected / exposed
    1 / 27 (3.70%)
    1 / 67 (1.49%)
    0 / 27 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Epistaxis
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 67 (1.49%)
    0 / 27 (0.00%)
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hepatic Failure
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 67 (1.49%)
    0 / 27 (0.00%)
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Bone Pain
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 67 (1.49%)
    0 / 27 (0.00%)
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    1 / 27 (3.70%)
    1 / 67 (1.49%)
    0 / 27 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Encephalitis
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 67 (1.49%)
    1 / 27 (3.70%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Disseminated Aspergillosis
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 67 (1.49%)
    0 / 27 (0.00%)
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Device Related Infection
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 67 (1.49%)
    0 / 27 (0.00%)
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 67 (1.49%)
    1 / 27 (3.70%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    Catheter Site Infection
         subjects affected / exposed
    1 / 27 (3.70%)
    1 / 67 (1.49%)
    0 / 27 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bacterial Sepsis
         subjects affected / exposed
    1 / 27 (3.70%)
    1 / 67 (1.49%)
    0 / 27 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Escherichia Sepsis
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 67 (1.49%)
    0 / 27 (0.00%)
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Genital Herpes Zoster
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 67 (1.49%)
    1 / 27 (3.70%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fungal Sepsis
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 67 (1.49%)
    1 / 27 (3.70%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    Fungal Infection
         subjects affected / exposed
    1 / 27 (3.70%)
    2 / 67 (2.99%)
    0 / 27 (0.00%)
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fournier's Gangrene
         subjects affected / exposed
    1 / 27 (3.70%)
    1 / 67 (1.49%)
    0 / 27 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    Neutropenic Sepsis
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 67 (1.49%)
    0 / 27 (0.00%)
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Otitis Externa
         subjects affected / exposed
    1 / 27 (3.70%)
    1 / 67 (1.49%)
    0 / 27 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Staphylococcal Bacteraemia
         subjects affected / exposed
    0 / 27 (0.00%)
    2 / 67 (2.99%)
    1 / 27 (3.70%)
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sinusitis Fungal
         subjects affected / exposed
    1 / 27 (3.70%)
    1 / 67 (1.49%)
    0 / 27 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Septic Shock
         subjects affected / exposed
    3 / 27 (11.11%)
    8 / 67 (11.94%)
    3 / 27 (11.11%)
    2 / 13 (15.38%)
         occurrences causally related to treatment / all
    2 / 3
    6 / 8
    3 / 3
    1 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 27 (3.70%)
    4 / 67 (5.97%)
    1 / 27 (3.70%)
    2 / 13 (15.38%)
         occurrences causally related to treatment / all
    0 / 1
    2 / 4
    1 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    Rhinovirus Infection
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 67 (1.49%)
    0 / 27 (0.00%)
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pseudomonal Sepsis
         subjects affected / exposed
    1 / 27 (3.70%)
    1 / 67 (1.49%)
    0 / 27 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 27 (3.70%)
    3 / 67 (4.48%)
    2 / 27 (7.41%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    2 / 3
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumocystis Jirovecii Pneumonia
         subjects affected / exposed
    1 / 27 (3.70%)
    1 / 67 (1.49%)
    0 / 27 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peritonitis
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 67 (1.49%)
    0 / 27 (0.00%)
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Staphylococcal Infection
         subjects affected / exposed
    1 / 27 (3.70%)
    1 / 67 (1.49%)
    0 / 27 (0.00%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    B-cell Acute Lymphoblastic Leukemia (B-ALL) All Participants Acute Myeloid Leukemia (AML) T-cell Acute Lymphoblastic Leukemia (T-ALL)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    26 / 27 (96.30%)
    62 / 67 (92.54%)
    24 / 27 (88.89%)
    12 / 13 (92.31%)
    Vascular disorders
    Hypotension
         subjects affected / exposed
    1 / 27 (3.70%)
    3 / 67 (4.48%)
    2 / 27 (7.41%)
    0 / 13 (0.00%)
         occurrences all number
    1
    3
    2
    0
    Hypertension
         subjects affected / exposed
    0 / 27 (0.00%)
    8 / 67 (11.94%)
    3 / 27 (11.11%)
    5 / 13 (38.46%)
         occurrences all number
    0
    10
    3
    7
    Flushing
         subjects affected / exposed
    1 / 27 (3.70%)
    3 / 67 (4.48%)
    1 / 27 (3.70%)
    1 / 13 (7.69%)
         occurrences all number
    1
    3
    1
    1
    General disorders and administration site conditions
    Face Oedema
         subjects affected / exposed
    2 / 27 (7.41%)
    3 / 67 (4.48%)
    0 / 27 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    2
    3
    0
    1
    Chills
         subjects affected / exposed
    0 / 27 (0.00%)
    2 / 67 (2.99%)
    1 / 27 (3.70%)
    1 / 13 (7.69%)
         occurrences all number
    0
    2
    1
    1
    Catheter Site Pain
         subjects affected / exposed
    0 / 27 (0.00%)
    2 / 67 (2.99%)
    1 / 27 (3.70%)
    1 / 13 (7.69%)
         occurrences all number
    0
    3
    2
    1
    Oedema Peripheral
         subjects affected / exposed
    0 / 27 (0.00%)
    2 / 67 (2.99%)
    2 / 27 (7.41%)
    0 / 13 (0.00%)
         occurrences all number
    0
    2
    2
    0
    Pyrexia
         subjects affected / exposed
    10 / 27 (37.04%)
    26 / 67 (38.81%)
    12 / 27 (44.44%)
    4 / 13 (30.77%)
         occurrences all number
    14
    43
    23
    6
    Fatigue
         subjects affected / exposed
    2 / 27 (7.41%)
    6 / 67 (8.96%)
    3 / 27 (11.11%)
    1 / 13 (7.69%)
         occurrences all number
    2
    8
    5
    1
    Immune system disorders
    Drug Hypersensitivity
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 67 (1.49%)
    0 / 27 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    0
    1
    Food Allergy
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 67 (1.49%)
    0 / 27 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Rhinorrhoea
         subjects affected / exposed
    2 / 27 (7.41%)
    2 / 67 (2.99%)
    0 / 27 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    2
    2
    0
    0
    Oropharyngeal Pain
         subjects affected / exposed
    2 / 27 (7.41%)
    5 / 67 (7.46%)
    2 / 27 (7.41%)
    1 / 13 (7.69%)
         occurrences all number
    2
    5
    2
    1
    Hypoxia
         subjects affected / exposed
    0 / 27 (0.00%)
    2 / 67 (2.99%)
    2 / 27 (7.41%)
    0 / 13 (0.00%)
         occurrences all number
    0
    3
    3
    0
    Epistaxis
         subjects affected / exposed
    0 / 27 (0.00%)
    3 / 67 (4.48%)
    3 / 27 (11.11%)
    0 / 13 (0.00%)
         occurrences all number
    0
    5
    5
    0
    Cough
         subjects affected / exposed
    6 / 27 (22.22%)
    8 / 67 (11.94%)
    1 / 27 (3.70%)
    1 / 13 (7.69%)
         occurrences all number
    8
    10
    1
    1
    Dyspnoea
         subjects affected / exposed
    0 / 27 (0.00%)
    2 / 67 (2.99%)
    2 / 27 (7.41%)
    0 / 13 (0.00%)
         occurrences all number
    0
    2
    2
    0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    1 / 27 (3.70%)
    4 / 67 (5.97%)
    2 / 27 (7.41%)
    1 / 13 (7.69%)
         occurrences all number
    1
    4
    2
    1
    Depression
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 67 (1.49%)
    0 / 27 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    0
    1
    Irritability
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 67 (1.49%)
    0 / 27 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    0
    1
    Insomnia
         subjects affected / exposed
    0 / 27 (0.00%)
    2 / 67 (2.99%)
    1 / 27 (3.70%)
    1 / 13 (7.69%)
         occurrences all number
    0
    2
    1
    1
    Investigations
    Weight Decreased
         subjects affected / exposed
    2 / 27 (7.41%)
    4 / 67 (5.97%)
    1 / 27 (3.70%)
    1 / 13 (7.69%)
         occurrences all number
    2
    4
    1
    1
    Injury, poisoning and procedural complications
    Infusion Related Reaction
         subjects affected / exposed
    8 / 27 (29.63%)
    26 / 67 (38.81%)
    14 / 27 (51.85%)
    4 / 13 (30.77%)
         occurrences all number
    12
    33
    16
    5
    Contusion
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 67 (1.49%)
    0 / 27 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    0
    1
    Cardiac disorders
    Tachycardia
         subjects affected / exposed
    2 / 27 (7.41%)
    5 / 67 (7.46%)
    2 / 27 (7.41%)
    1 / 13 (7.69%)
         occurrences all number
    2
    5
    2
    1
    Nervous system disorders
    Peripheral Sensory Neuropathy
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 67 (1.49%)
    0 / 27 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    0
    1
    Seizure
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 67 (1.49%)
    0 / 27 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    0
    1
    Tremor
         subjects affected / exposed
    2 / 27 (7.41%)
    4 / 67 (5.97%)
    1 / 27 (3.70%)
    1 / 13 (7.69%)
         occurrences all number
    2
    5
    1
    2
    Headache
         subjects affected / exposed
    3 / 27 (11.11%)
    15 / 67 (22.39%)
    9 / 27 (33.33%)
    3 / 13 (23.08%)
         occurrences all number
    3
    21
    14
    4
    Facial Paralysis
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 67 (1.49%)
    0 / 27 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    0
    1
    Dysgeusia
         subjects affected / exposed
    0 / 27 (0.00%)
    2 / 67 (2.99%)
    2 / 27 (7.41%)
    0 / 13 (0.00%)
         occurrences all number
    0
    2
    2
    0
    Dizziness
         subjects affected / exposed
    1 / 27 (3.70%)
    3 / 67 (4.48%)
    1 / 27 (3.70%)
    1 / 13 (7.69%)
         occurrences all number
    1
    3
    1
    1
    Dysaesthesia
         subjects affected / exposed
    1 / 27 (3.70%)
    2 / 67 (2.99%)
    0 / 27 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    1
    2
    0
    1
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 27 (3.70%)
    3 / 67 (4.48%)
    2 / 27 (7.41%)
    0 / 13 (0.00%)
         occurrences all number
    1
    6
    5
    0
    Febrile Neutropenia
         subjects affected / exposed
    4 / 27 (14.81%)
    10 / 67 (14.93%)
    5 / 27 (18.52%)
    1 / 13 (7.69%)
         occurrences all number
    6
    12
    5
    1
    Haemolysis
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 67 (1.49%)
    0 / 27 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    0
    1
    Eye disorders
    Eyelid Oedema
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 67 (1.49%)
    0 / 27 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    2
    0
    2
    Periorbital Oedema
         subjects affected / exposed
    2 / 27 (7.41%)
    2 / 67 (2.99%)
    0 / 27 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    2
    2
    0
    0
    Gastrointestinal disorders
    Abdominal Pain
         subjects affected / exposed
    6 / 27 (22.22%)
    12 / 67 (17.91%)
    5 / 27 (18.52%)
    1 / 13 (7.69%)
         occurrences all number
    6
    17
    8
    3
    Abdominal Pain Upper
         subjects affected / exposed
    1 / 27 (3.70%)
    4 / 67 (5.97%)
    2 / 27 (7.41%)
    1 / 13 (7.69%)
         occurrences all number
    1
    4
    2
    1
    Anal Fissure
         subjects affected / exposed
    3 / 27 (11.11%)
    5 / 67 (7.46%)
    2 / 27 (7.41%)
    0 / 13 (0.00%)
         occurrences all number
    5
    7
    2
    0
    Anal Inflammation
         subjects affected / exposed
    1 / 27 (3.70%)
    3 / 67 (4.48%)
    0 / 27 (0.00%)
    2 / 13 (15.38%)
         occurrences all number
    1
    4
    0
    3
    Colitis
         subjects affected / exposed
    1 / 27 (3.70%)
    5 / 67 (7.46%)
    2 / 27 (7.41%)
    2 / 13 (15.38%)
         occurrences all number
    1
    5
    2
    2
    Constipation
         subjects affected / exposed
    3 / 27 (11.11%)
    12 / 67 (17.91%)
    7 / 27 (25.93%)
    2 / 13 (15.38%)
         occurrences all number
    3
    13
    7
    3
    Diarrhoea
         subjects affected / exposed
    4 / 27 (14.81%)
    15 / 67 (22.39%)
    8 / 27 (29.63%)
    3 / 13 (23.08%)
         occurrences all number
    5
    17
    9
    3
    Dyspepsia
         subjects affected / exposed
    0 / 27 (0.00%)
    5 / 67 (7.46%)
    4 / 27 (14.81%)
    1 / 13 (7.69%)
         occurrences all number
    0
    7
    6
    1
    Gastritis
         subjects affected / exposed
    0 / 27 (0.00%)
    2 / 67 (2.99%)
    1 / 27 (3.70%)
    1 / 13 (7.69%)
         occurrences all number
    0
    3
    2
    1
    Nausea
         subjects affected / exposed
    9 / 27 (33.33%)
    18 / 67 (26.87%)
    6 / 27 (22.22%)
    3 / 13 (23.08%)
         occurrences all number
    17
    31
    9
    5
    Oral Pain
         subjects affected / exposed
    0 / 27 (0.00%)
    2 / 67 (2.99%)
    1 / 27 (3.70%)
    1 / 13 (7.69%)
         occurrences all number
    0
    2
    1
    1
    Pancreatitis
         subjects affected / exposed
    1 / 27 (3.70%)
    2 / 67 (2.99%)
    0 / 27 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    1
    2
    0
    1
    Stomatitis
         subjects affected / exposed
    10 / 27 (37.04%)
    22 / 67 (32.84%)
    8 / 27 (29.63%)
    4 / 13 (30.77%)
         occurrences all number
    10
    23
    8
    5
    Vomiting
         subjects affected / exposed
    6 / 27 (22.22%)
    19 / 67 (28.36%)
    10 / 27 (37.04%)
    3 / 13 (23.08%)
         occurrences all number
    7
    25
    15
    3
    Hepatobiliary disorders
    Hepatic Failure
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 67 (1.49%)
    0 / 27 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    0
    1
    Hepatic Steatosis
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 67 (1.49%)
    0 / 27 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    0
    1
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    2 / 27 (7.41%)
    3 / 67 (4.48%)
    0 / 27 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    2
    3
    0
    1
    Dry Skin
         subjects affected / exposed
    0 / 27 (0.00%)
    2 / 67 (2.99%)
    2 / 27 (7.41%)
    0 / 13 (0.00%)
         occurrences all number
    0
    2
    2
    0
    Rash Maculo-Papular
         subjects affected / exposed
    1 / 27 (3.70%)
    3 / 67 (4.48%)
    2 / 27 (7.41%)
    0 / 13 (0.00%)
         occurrences all number
    1
    7
    6
    0
    Rash
         subjects affected / exposed
    0 / 27 (0.00%)
    6 / 67 (8.96%)
    6 / 27 (22.22%)
    0 / 13 (0.00%)
         occurrences all number
    0
    7
    7
    0
    Erythema
         subjects affected / exposed
    1 / 27 (3.70%)
    3 / 67 (4.48%)
    2 / 27 (7.41%)
    0 / 13 (0.00%)
         occurrences all number
    1
    4
    3
    0
    Renal and urinary disorders
    Nephropathy Toxic
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 67 (1.49%)
    0 / 27 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    0
    1
    Renal Tubular Necrosis
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 67 (1.49%)
    0 / 27 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    0
    1
    Urinary Retention
         subjects affected / exposed
    2 / 27 (7.41%)
    6 / 67 (8.96%)
    1 / 27 (3.70%)
    3 / 13 (23.08%)
         occurrences all number
    2
    7
    1
    4
    Musculoskeletal and connective tissue disorders
    Pain In Extremity
         subjects affected / exposed
    4 / 27 (14.81%)
    8 / 67 (11.94%)
    2 / 27 (7.41%)
    2 / 13 (15.38%)
         occurrences all number
    6
    13
    5
    2
    Neck Pain
         subjects affected / exposed
    0 / 27 (0.00%)
    3 / 67 (4.48%)
    3 / 27 (11.11%)
    0 / 13 (0.00%)
         occurrences all number
    0
    3
    3
    0
    Bone Pain
         subjects affected / exposed
    2 / 27 (7.41%)
    3 / 67 (4.48%)
    1 / 27 (3.70%)
    0 / 13 (0.00%)
         occurrences all number
    2
    3
    1
    0
    Back Pain
         subjects affected / exposed
    0 / 27 (0.00%)
    4 / 67 (5.97%)
    3 / 27 (11.11%)
    1 / 13 (7.69%)
         occurrences all number
    0
    4
    3
    1
    Infections and infestations
    Conjunctivitis
         subjects affected / exposed
    1 / 27 (3.70%)
    4 / 67 (5.97%)
    2 / 27 (7.41%)
    1 / 13 (7.69%)
         occurrences all number
    1
    4
    2
    1
    Respiratory Syncytial Virus Infection
         subjects affected / exposed
    2 / 27 (7.41%)
    2 / 67 (2.99%)
    0 / 27 (0.00%)
    0 / 13 (0.00%)
         occurrences all number
    2
    2
    0
    0
    Oral Herpes
         subjects affected / exposed
    1 / 27 (3.70%)
    2 / 67 (2.99%)
    0 / 27 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    1
    2
    0
    1
    Oral Candidiasis
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 67 (1.49%)
    0 / 27 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    0
    1
    Lip Infection
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 67 (1.49%)
    0 / 27 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    0
    1
    Device Related Infection
         subjects affected / exposed
    0 / 27 (0.00%)
    3 / 67 (4.48%)
    2 / 27 (7.41%)
    1 / 13 (7.69%)
         occurrences all number
    0
    3
    2
    1
    Viral Rhinitis
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 67 (1.49%)
    0 / 27 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    0
    1
    Upper Respiratory Tract Infection
         subjects affected / exposed
    0 / 27 (0.00%)
    2 / 67 (2.99%)
    2 / 27 (7.41%)
    0 / 13 (0.00%)
         occurrences all number
    0
    2
    2
    0
    Skin Infection
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 67 (1.49%)
    0 / 27 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    0
    1
    Metabolism and nutrition disorders
    Increased Appetite
         subjects affected / exposed
    0 / 27 (0.00%)
    1 / 67 (1.49%)
    0 / 27 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    0
    1
    Decreased Appetite
         subjects affected / exposed
    1 / 27 (3.70%)
    11 / 67 (16.42%)
    8 / 27 (29.63%)
    2 / 13 (15.38%)
         occurrences all number
    1
    11
    8
    2

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    11 Mar 2019
    Clarified the suspected unexpected serious adverse reactions and sponsor responsibilities to submit any change(s) considered substantial to the regulatory authorities for notification and approval. Clarified the contraception and pregnancy testing for females and males of childbearing potential, as well as the criteria for discontinuation of the study by the Sponsor. Updated the PK follow-up assessment from 60 to 90 days after last isatuximab administration to align with other isatuximab studies. Improved the feasibility of the study procedures. Clarified that administrative and editorial updates and corrections to the protocol will be performed.
    04 Dec 2019
    Clarified the definition of CR, in order to avoid participants being ‘not evaluable’ if still dependent on red blood cell transfusions. Included dexamethasone as an intervention for ALL cohort as part of study treatment. Further clarified the difference that for AML cohort dexamethasone is optional, except as premedication for isatuximab. Updated the duration for contraception. Added Montelukast as a systematic premedication, the objective being to decrease the incidence and severity of IRs; it should not be at Investigator's discretion. Added hematological criteria for ALL participants before starting the consolidation period. Simplified some procedures in order to be closer to clinical practice. Added recommendations in case of pegaspargase hypersensitivity. Added analysis of CD38 receptor density and occupancy, in order to better understand the response profile at the end of the trial. Clarified on the first interim analysis that was to be performed on first 20 participants. Clarified that administrative and editorial updates and corrections to the protocol will be performed.
    30 Jul 2020
    Protocol was amended to implement changes following health Authorities comments and to mitigate the risk of hepatitis reactivation identified in the SAR650984 Investigator’s Brochure edition 11 (30-Apr-2020).
    24 Nov 2020
    Implemented data monitoring committee (DMC) recommendations following the occurrence of first fatal case as an outcome of a Cytokine Release Syndrome (CRS) event. On 01 October 2020, due to the occurrence of first fatal CRS event, the study DMC had evaluated the safety profile of the first 9 treated participants and recommended the continuation of the study with changes to be implemented in an amendment to the protocol. The main changes were: White blood cell (WBC) counts to be below 20 x 10^9/L before isatuximab administration. Participants with high WBC counts between 20 and 50 x 10^9/L at screening and with high tumor burden in relation to extramedullary disease should receive a rescue cytoreductive therapy with a short half-life in order to potentially reach the 20 x 10^9/L WBC threshold before first isatuximab administration. As consequence, the list of cytoreductive drugs with suggested doses were proposed in this amendment in order to have less heterogeneity in the participants’ cytoreductive therapy management across participating sites. Guidance was added to clarify the CRS events with inclusion of a specific section and table describing criteria for diagnosis, grading, as well as management of these events. Prospective determinations of CRS biomarkers at different time points were included. Cytokines panel, ferritin, and C-reactive protein (CRP) were added at baseline and at different time points in order to better assess events like CRS, hemophagocytic lymphohistiocytosis (HLH), infections, etc. Moreover, specific guidance for hematology, vital signs, radiology were added in case of high tumor burden or CRS events. Anti-interleukin 6 as concomitant or rescue medication in case of CRS Grade 2 or above was added. Clarified that seizures >=Grade 3 should be reported as adverse events of special interest (AESI).
    14 Oct 2021
    Protocol was amended to allow the enrollment of children <2 years old as after PK assessment, the dose of 20 mg/kg was confirmed in this young subpopulation. The main changes were: Justification of the dose (20 mg/kg) for children <2 years old. Definition of evaluable participant update. Clarification on coagulation test frequency. Added the possibility to perform a positron emission tomography (PET)-magnetic resonance imaging instead of PET-computed tomography when needed.

    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.
    The study was prematurely stopped due to sponsor decision (stage 2 efficacy criteria not met) and not due to safety concerns.
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    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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