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    Clinical Trial Results:
    Phase 2, Safety and Efficacy Study of Isatuximab, an Anti-CD38 Monoclonal Antibody, Administered by Intravenous (IV) Infusion in Patients with Relapsed or Refractory T-acute Lymphoblastic Leukemia (T-ALL) or T-lymphoblastic Lymphoma (T-LBL)

    Summary
    EudraCT number
    2016-002739-14
    Trial protocol
    LT   HU   FI  
    Global end of trial date
    14 Nov 2017

    Results information
    Results version number
    v1(current)
    This version publication date
    22 Nov 2018
    First version publication date
    22 Nov 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    ACT14596
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02999633
    WHO universal trial number (UTN)
    U1111-1179-5294
    Sponsors
    Sponsor organisation name
    Sanofi aventis recherche & développement
    Sponsor organisation address
    1 avenue Pierre Brossolette, Chilly- Mazarin, France,
    Public contact
    Sanofi aventis recherche & développement, Trial Transparency Team, US@sanofi.com
    Scientific contact
    Sanofi aventis recherche & développement, Trial Transparency Team, US@sanofi.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    05 Feb 2018
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    14 Nov 2017
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    To evaluate the efficacy of isatuximab in subjects with relapsed or refractory T-ALL or T-LBL as measured by overall response rate (ORR) (as per National Comprehensive Cancer Network [NCCN] guidelines).
    Protection of trial subjects
    Subjects were fully informed of all pertinent aspects of the clinical trial as well as the possibility to discontinue at any time in language and terms appropriate for the subject and considering the local culture. During the course of the trial, subjects were provided with individual subject cards indicating the nature of the trial the subject is participating, contact details and any information needed in the event of a medical emergency. Collected personal data and human biological samples were processed in compliance with the Sanofi-Aventis Group Personal Data Protection Charter ensuring that the Group abides by the laws governing personal data protection in force in all countries in which it operates.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    14 Mar 2017
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Finland: 1
    Country: Number of subjects enrolled
    France: 6
    Country: Number of subjects enrolled
    Lithuania: 1
    Country: Number of subjects enrolled
    Italy: 2
    Country: Number of subjects enrolled
    Russian Federation: 3
    Country: Number of subjects enrolled
    United States: 1
    Worldwide total number of subjects
    14
    EEA total number of subjects
    10
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    1
    Adults (18-64 years)
    10
    From 65 to 84 years
    3
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    The study was conducted in 6 countries. A total of 16 subjects were screened of those 2 subjects failed screening: 1 subject for evidence of ongoing infection and 1 subject for not meeting the criterion for relapsed or refractory T-acute lymphoblastic leukemia (ALL)/T-lymphoblastic lymphoma (LBL).

    Pre-assignment
    Screening details
    The first subject was enrolled on 14 March 2017. A total of 14 subjects were enrolled to receive isatuximab. The study was early terminated on 08 Nov 2017.

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

    Arms
    Arm title
    Isatuximab
    Arm description
    Subjects received intravenous administration of isatuximab at a dose of 20 mg/kg at Day 1, 8, 15 and 22 of each Cycle (up to 2 treatment cycles, each cycle 28 days).
    Arm type
    Experimental

    Investigational medicinal product name
    Isatuximab
    Investigational medicinal product code
    SAR650984
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects received intravenous administration of isatuximab at a dose of 20 milligram/kilogram (mg/kg).

    Number of subjects in period 1
    Isatuximab
    Started
    14
    Completed
    0
    Not completed
    14
         Progressive disease
    12
         Adverse Event
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Isatuximab
    Reporting group description
    Subjects received intravenous administration of isatuximab at a dose of 20 mg/kg at Day 1, 8, 15 and 22 of each Cycle (up to 2 treatment cycles, each cycle 28 days).

    Reporting group values
    Isatuximab Total
    Number of subjects
    14 14
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    41.36 ± 19.30 -
    Gender categorical
    Units: Subjects
        Female
    2 2
        Male
    12 12

    End points

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    End points reporting groups
    Reporting group title
    Isatuximab
    Reporting group description
    Subjects received intravenous administration of isatuximab at a dose of 20 mg/kg at Day 1, 8, 15 and 22 of each Cycle (up to 2 treatment cycles, each cycle 28 days).

    Primary: Percentage of Subjects With Objective Response

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    End point title
    Percentage of Subjects With Objective Response [1]
    End point description
    Objective response was defined as percentage of subjects with complete response or with complete response with incomplete peripheral recovery as per National Comprehensive Cancer Network (NCCN) guidelines. Complete response was defined as no circulating blasts or extramedullary disease, no lymphadenopathy, splenomegaly, skin/gum infiltration/testicular mass/central nervous system involvement, trilineage hematopoiesis and less than 5 percentage blasts, absolute neutrophil count (ANC) greater than 1000 per micro liter, platelets less than 100 000 per micro liter, no recurrence for 4 weeks. Complete response with incomplete blood count recovery (Cri) meet all criteria for complete response except platelet count and/or ANC. Safety analysis set included all subjects who received at least 1 dose of isatuximab.
    End point type
    Primary
    End point timeframe
    Baseline until disease progression or death (maximum duration: 12.1 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: Only descriptive data was planned to be analysed for this study.
    End point values
    Isatuximab
    Number of subjects analysed
    14
    Units: percentage of subjects
        number (confidence interval 95%)
    0 (0 to 23.2)
    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
    DOR defined as time (in days) from date of first response until date of first documented progressive disease (PD) or death (from any cause), whichever came first. Progressive disease as per NCCN guidelines was defined as increase of at least 25% in the absolute number of circulating or bone marrow blasts or development of extramedullary disease. The endpoint was not analyzed due to lack of objective response. There was no specific additional data collected for the analysis of DOR as this endpoint was to be derived using time point responses and death information that were collected and analyzed as part of primary endpoint and safety endpoints, respectively.
    End point type
    Secondary
    End point timeframe
    Baseline until disease progression or death (maximum duration: 12.1 weeks)
    End point values
    Isatuximab
    Number of subjects analysed
    0 [2]
    Units: days
        number (not applicable)
    Notes
    [2] - The endpoint was not analyzed due to lack of objective response.
    No statistical analyses for this end point

    Secondary: Progression Free Survival (PFS)

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    End point title
    Progression Free Survival (PFS)
    End point description
    PFS was defined as the time interval (in days) from the date of first study drug administration to the date of first observation of PD or death due to any cause, whichever came first. PD as per NCCN guidelines was defined as increase of at least 25% in the absolute number of circulating or bone marrow blasts or development of extramedullary disease. The endpoint was not analyzed due to lack of objective response. There was no specific additional data collected for the analysis of PFS as this endpoint was to be derived using time point responses and death information that were collected and analyzed as part of primary endpoint and safety endpoints, respectively.
    End point type
    Secondary
    End point timeframe
    Baseline until disease progression or death (maximum duration: 12.1 weeks)
    End point values
    Isatuximab
    Number of subjects analysed
    0 [3]
    Units: days
        number (not applicable)
    Notes
    [3] - The endpoint was not analyzed due to lack of objective response.
    No statistical analyses for this end point

    Secondary: Overall Survival

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    End point title
    Overall Survival
    End point description
    OS was defined as the time interval from the date of first study drug administration to the date of death due to any cause. The endpoint was not analyzed due to lack of objective response. There was no specific additional data collected for the analysis of OS as this endpoint was to be derived using time point responses and death information that were collected and analyzed as part of primary endpoint and safety endpoints, respectively.
    End point type
    Secondary
    End point timeframe
    Baseline until disease progression or death (maximum duration: 12.1 weeks)
    End point values
    Isatuximab
    Number of subjects analysed
    0 [4]
    Units: days
        number (not applicable)
    Notes
    [4] - The endpoint was not analyzed due to lack of objective response.
    No statistical analyses for this end point

    Secondary: Number of Subjects With Minimal Residual Disease (MRD)

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    End point title
    Number of Subjects With Minimal Residual Disease (MRD)
    End point description
    Presence of MRD was measured by sequencing and/or flow cytometry in subjects achieving CR and CRi. Complete response was defined as no circulating blasts or extramedullary disease, no lymphadenopathy, splenomegaly, skin/gum infiltration/testicular mass/central nervous system involvement, trilineage hematopoiesis and less than 5 percentage blasts, absolute neutrophil count (ANC) greater than 1000 per micro liter, platelets less than 100 000 per micro liter, no recurrence for 4 weeks. Complete response with incomplete blood count recovery (Cri) meet all criteria for complete response except platelet count and/or ANC. The endpoint was not analyzed because no subject achieved CR or CRi.
    End point type
    Secondary
    End point timeframe
    Baseline until disease progression or death (maximum duration: 12.1 weeks)
    End point values
    Isatuximab
    Number of subjects analysed
    0 [5]
    Units: subjects
    Notes
    [5] - The endpoint was not analyzed because no subject achieved CR or CRi.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Baseline up to 30 days after last dose of study drug administration (up to maximum of 12.1 weeks)
    Adverse event reporting additional description
    Reported Adverse events(AEs) are treatment emergent adverse events that is AEs that developed/worsened during the ‘on treatment period’ (from first study treatment administration until 30 days after the last administration of study treatment). Safety analysis set included all subjects who received at least 1 dose of isatuximab.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    20.1
    Reporting groups
    Reporting group title
    Isatuximab
    Reporting group description
    Subjects received intravenous administration of isatuximab at a dose of 20 mg/kg at Day 1, 8, 15 and 22 of each Cycle (up to 2 treatment cycles, each cycle 28 days).

    Serious adverse events
    Isatuximab
    Total subjects affected by serious adverse events
         subjects affected / exposed
    10 / 14 (71.43%)
         number of deaths (all causes)
    6
         number of deaths resulting from adverse events
    0
    Vascular disorders
    Pelvic Venous Thrombosis
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Vein Collapse
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiac disorders
    Acute Myocardial Infarction
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Pericarditis Constrictive
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pleural Effusion
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Acute Respiratory Failure
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Pulmonary Oedema
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    Disease Progression
         subjects affected / exposed
    4 / 14 (28.57%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 4
    Gastrointestinal disorders
    Pancreatitis
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Fungal Infection
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Device Related Infection
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Periorbital Cellulitis
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Isatuximab
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    12 / 14 (85.71%)
    Vascular disorders
    Phlebitis
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Immune system disorders
    Cytokine Release Syndrome
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Pain
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Fatigue
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Pyrexia
         subjects affected / exposed
    5 / 14 (35.71%)
         occurrences all number
    6
    Injury, poisoning and procedural complications
    Infusion Related Reaction
         subjects affected / exposed
    8 / 14 (57.14%)
         occurrences all number
    11
    Investigations
    Body Temperature Increased
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Weight Decreased
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Cardiac disorders
    Tachycardia
         subjects affected / exposed
    2 / 14 (14.29%)
         occurrences all number
    2
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Neutropenia
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Thrombocytopenia
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    2
    Respiratory, thoracic and mediastinal disorders
    Bronchostenosis
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Bronchitis Chronic
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Cough
         subjects affected / exposed
    2 / 14 (14.29%)
         occurrences all number
    2
    Dysphonia
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Dyspnoea
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Haemoptysis
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Hypoxia
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Pharyngeal Erythema
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Pleural Effusion
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Productive Cough
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Respiratory Failure
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Wheezing
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Nervous system disorders
    Facial Paralysis
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Headache
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    2
    Sciatica
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Peripheral Motor Neuropathy
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Gastrointestinal disorders
    Abdominal Pain Upper
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Constipation
         subjects affected / exposed
    2 / 14 (14.29%)
         occurrences all number
    2
    Diarrhoea
         subjects affected / exposed
    2 / 14 (14.29%)
         occurrences all number
    2
    Nausea
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Vomiting
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Hepatobiliary disorders
    Cholangitis
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Cholecystitis
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Renal and urinary disorders
    Urinary Retention
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Musculoskeletal and connective tissue disorders
    Back Pain
         subjects affected / exposed
    2 / 14 (14.29%)
         occurrences all number
    2
    Bone Pain
         subjects affected / exposed
    2 / 14 (14.29%)
         occurrences all number
    2
    Flank Pain
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    2
    Muscle Oedema
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Musculoskeletal Pain
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Pain In Extremity
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Infections and infestations
    Device Related Infection
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Bronchiolitis
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Nasopharyngitis
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Oral Herpes
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Pyelitis
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Rhinitis
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    27 Feb 2017
    Following amendments were made: - Change contraception period from ‘2 weeks prior to screening’ into ‘2 weeks prior to the first dose of isatuximab - Added blood typing and screen at screening - Removed mandatory chest X-ray from study time points other than screening period - Clarified the definition of Pharmacokinetic (PK) population - Clarified PK/PDy sampling time window and allowances - Reduced the number of PK samplings during the study - Added immunophenotyping sample collection during the induction period - Clarified the bone marrow sample collections and change sampling timing for receptor occupancy/receptor density - Editorial changes to improve clarity (add study name, abbreviations, grammatical corrections - Update of bioanalysis methods and locations for cytokines and markers of activated complements panel - Add interleukin (IL)-4 to the cytokine panel.

    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 stopped prior to the interim analysis due to lack of efficacy of isatuximab monotherapy for this study population. Therefore, majority of efficacy evaluations originally planned were no longer considered relevant and were not performed.
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