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    Clinical Trial Results:
    A phase 1, open label, non-comparative, study to evaluate the safety and the ability of UCART19 to induce molecular remission in paediatric patients with relapsed /refractory B-cell acute lymphoblastic leukaemia

    Summary
    EudraCT number
    2015-004293-15
    Trial protocol
    GB   BE   FR   ES  
    Global end of trial date
    04 Nov 2020

    Results information
    Results version number
    v1(current)
    This version publication date
    19 May 2021
    First version publication date
    19 May 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    UCART19_02 (CL1-68587-001)
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02808442
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Institut de Recherches Internationales Servier
    Sponsor organisation address
    50 rue Carnot, Suresnes, France, 92284
    Public contact
    Therapeutic Area in Oncology, Institut de Recherches Internationales Servier, +33 1 55 72 43 66, clinicaltrials@servier.com
    Scientific contact
    Therapeutic Area in Oncology, Institut de Recherches Internationales Servier, +33 1 55 72 43 66, clinicaltrials@servier.com
    Sponsor organisation name
    Servier R&D Ltd
    Sponsor organisation address
    Sefton House, Sefton Park, Bell Hill, Stoke Poges, Slough, Berkshire, United Kingdom, SL2 4JS
    Public contact
    Therapeutic Area in Oncology, Institut de Recherches Internationales Servier, +33 1 55 72 43 66, clinicaltrials@servier.com
    Scientific contact
    Therapeutic Area in Oncology, Institut de Recherches Internationales Servier, +33 1 55 72 43 66, clinicaltrials@servier.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    17 Sep 2020
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    17 Sep 2020
    Global end of trial reached?
    Yes
    Global end of trial date
    04 Nov 2020
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    To evaluate the safety of UCART19 in paediatric patients with relapsed or refractory (R/R) B-ALL.
    Protection of trial subjects
    This study was conducted in accordance with Good Clinical Practice standards, ethical principles stated in the Declaration of Helsinki and applicable regulatory requirements. After the subject has ended his/her participation in the trial, the investigator provided appropriate medication and/or arranged access to appropriate care for the patient.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    03 Jun 2016
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Safety
    Long term follow-up duration
    15 Years
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 6
    Country: Number of subjects enrolled
    United States: 5
    Country: Number of subjects enrolled
    France: 2
    Worldwide total number of subjects
    13
    EEA total number of subjects
    2
    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)
    3
    Children (2-11 years)
    5
    Adolescents (12-17 years)
    5
    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
    -

    Pre-assignment
    Screening details
    Male or female patients aged < 18 years, with R/R CD19-positive B-ALL, as per National Comprehensive Cancer Network guidelines, 2020: Morphologically confirmed with ≥ 5% leukemic blasts in the bone marrow or presenting a quantifiable Minimal Residual Disease (MRD) load of 1x10-3 and/or quantitative polymerase chain reaction (qPCR).

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

    Arms
    Arm title
    UCART19
    Arm description
    At D-4 , a LymphoDepletion (LD) was initiated. The LD regimen was modified by amendments (see below). The final combination was fludarabine 30 mg/m2/day IV over 15/30 minutes from D-4 to D-2 (90 mg/m² total dose), cyclophosphamide 800 mg/m²/day over 1 hour from D-3 to D-2 (1600 mg/m² total dose) and alemtuzumab 0.3 mg/kg at D-4, 0.3 mg/kg at D-3 and 0.4 mg/kg at D-2 [1mg/kg capped at 40 mg (total dose)]. The treatment period started at time of UCART19 administration at D0 up to D84. UCART19 is a frozen suspension of allogeneic genetically modified T-cells expressing a CD19 CAR, cryopreserved in an infusible grade cryomedium. UCART19 is an allogeneic engineered 19CAR/RQR8+_TCRαβ–_T-cells. Follow-up period (FU): D85 to M12. At FU end, 7 patients entered a separate LTFU study to be followed for 15 years and 6 patients did not : 5 for death and 1 for investigator decision. At cut-off in the LTFU, 1 patient withdrew due to progressive disease, 3 due to death. 3 patients are ongoing.
    Arm type
    Experimental

    Investigational medicinal product name
    UCART19
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Delivery of UCART19 was performed at D0 by intravenous infusion over approximately 5 minutes, following cell thawing in a 37°C bath. All patients received a dose of 1 to 3x106/kg CD19CAR/RQR8+_TCRαβ-_T-cells.

    Number of subjects in period 1
    UCART19
    Started
    13
    Completed
    2
    Not completed
    11
         Progressive disease
    5
         Death
    3
         Physician decision
    3

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall study period
    Reporting group description
    -

    Reporting group values
    Overall study period Total
    Number of subjects
    13 13
    Age categorical
    Units: Subjects
        Infants and toddlers (28 days-23 months)
    3 3
        Children (2-11 years)
    5 5
        Adolescents (12-17 years)
    5 5
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    7.39 ± 6.44 -
    Gender categorical
    Units: Subjects
        Female
    6 6
        Male
    7 7

    End points

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    End points reporting groups
    Reporting group title
    UCART19
    Reporting group description
    At D-4 , a LymphoDepletion (LD) was initiated. The LD regimen was modified by amendments (see below). The final combination was fludarabine 30 mg/m2/day IV over 15/30 minutes from D-4 to D-2 (90 mg/m² total dose), cyclophosphamide 800 mg/m²/day over 1 hour from D-3 to D-2 (1600 mg/m² total dose) and alemtuzumab 0.3 mg/kg at D-4, 0.3 mg/kg at D-3 and 0.4 mg/kg at D-2 [1mg/kg capped at 40 mg (total dose)]. The treatment period started at time of UCART19 administration at D0 up to D84. UCART19 is a frozen suspension of allogeneic genetically modified T-cells expressing a CD19 CAR, cryopreserved in an infusible grade cryomedium. UCART19 is an allogeneic engineered 19CAR/RQR8+_TCRαβ–_T-cells. Follow-up period (FU): D85 to M12. At FU end, 7 patients entered a separate LTFU study to be followed for 15 years and 6 patients did not : 5 for death and 1 for investigator decision. At cut-off in the LTFU, 1 patient withdrew due to progressive disease, 3 due to death. 3 patients are ongoing.

    Primary: Incidence and Severity of Adverse Events

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    End point title
    Incidence and Severity of Adverse Events [1]
    End point description
    Adverse events assessed according to NCI-CTCAE v5.0 criteria (See Adverse Events Section)
    End point type
    Primary
    End point timeframe
    From inclusion to Month 12
    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 one group of treatment.
    End point values
    UCART19
    Number of subjects analysed
    13
    Units: no unit
    13
    No statistical analyses for this end point

    Secondary: Molecular Remission Rate

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    End point title
    Molecular Remission Rate
    End point description
    Proportion of patients in whom a molecular Complete Remission (CR) or a Complete Remission with incomplete blood recovery (CRi) is observed (i.e. a CR or CRi combined to a Minimal residual disease <10-4).
    End point type
    Secondary
    End point timeframe
    At Day 28 after the first UCART19 infusion
    End point values
    UCART19
    Number of subjects analysed
    13
    Units: no unit
    5
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Emergent adverse events during treatment period were defined as adverse events that occurred or worsened (in terms of severity) or became serious between the first IMP intake date and the last IMP intake + 30 days.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    23.0
    Reporting groups
    Reporting group title
    UCART19
    Reporting group description
    -

    Serious adverse events
    UCART19
    Total subjects affected by serious adverse events
         subjects affected / exposed
    13 / 13 (100.00%)
         number of deaths (all causes)
    5
         number of deaths resulting from adverse events
    0
    Vascular disorders
    Hypertension
         subjects affected / exposed
    2 / 13 (15.38%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Acute lymphocytic leukaemia recurrent
         subjects affected / exposed
    3 / 13 (23.08%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 2
    Leukaemic infiltration extramedullary
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Malignant neoplasm progression
         subjects affected / exposed
    2 / 13 (15.38%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    Immune system disorders
    Acute graft versus host disease in intestine
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Acute graft versus host disease in skin
         subjects affected / exposed
    2 / 13 (15.38%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Cytokine release syndrome
         subjects affected / exposed
    10 / 13 (76.92%)
         occurrences causally related to treatment / all
    10 / 10
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    Physical deconditioning
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Psychiatric disorders
    Disorganised speech
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Hallucination
         subjects affected / exposed
    2 / 13 (15.38%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Irritability
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Major depression
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Reproductive system and breast disorders
    Penile erythema
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Penile swelling
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Injury, poisoning and procedural complications
    Airway complication of anaesthesia
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infusion related reaction
         subjects affected / exposed
    4 / 13 (30.77%)
         occurrences causally related to treatment / all
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    Investigations
    Activated partial thromboplastin time prolonged
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Blood fibrinogen decreased
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    International normalised ratio increased
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    JC polyomavirus test positive
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Neutrophil count decreased
         subjects affected / exposed
    2 / 13 (15.38%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Platelet count decreased
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    White blood cell count decreased
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiac disorders
    Cardiac arrest
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Sinus bradycardia
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pulmonary hypertension
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cytopenia
         subjects affected / exposed
    4 / 13 (30.77%)
         occurrences causally related to treatment / all
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    2 / 13 (15.38%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Neutropenia
         subjects affected / exposed
    5 / 13 (38.46%)
         occurrences causally related to treatment / all
    1 / 5
         deaths causally related to treatment / all
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    2 / 13 (15.38%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Thrombotic microangiopathy
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Nervous system disorders
    Cerebral haemorrhage
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Chorea
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Dysarthria
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Dyskinesia
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Encephalopathy
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Intraventricular haemorrhage
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Lethargy
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Neurotoxicity
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Posterior reversible encephalopathy syndrome
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Seizure
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Constipation
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Mouth haemorrhage
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cystitis haemorrhagic
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Renal haematoma
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Urethral obstruction
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hepatobiliary disorders
    Gallbladder oedema
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Periportal oedema
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Skin and subcutaneous tissue disorders
    Ecchymosis
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Petechiae
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Musculoskeletal and connective tissue disorders
    Muscle twitching
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Metabolism and nutrition disorders
    Fluid overload
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hypoalbuminaemia
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Hypocalcaemia
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    3 / 13 (23.08%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Hypophosphataemia
         subjects affected / exposed
    2 / 13 (15.38%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Tumour lysis syndrome
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Adenoviral upper respiratory infection
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Adenovirus infection
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Appendicitis
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    BK virus infection
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Bacterial sepsis
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cystitis viral
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cytomegalovirus infection
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Cytomegalovirus infection reactivation
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Fungal infection
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Metapneumovirus infection
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pneumonia bacterial
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pulmonary mucormycosis
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Streptococcal sepsis
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Viral haemorrhagic cystitis
         subjects affected / exposed
    2 / 13 (15.38%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    UCART19
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    12 / 13 (92.31%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Hypotension
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Immune system disorders
    Acute graft versus host disease in skin
         subjects affected / exposed
    3 / 13 (23.08%)
         occurrences all number
    3
    Cytokine release syndrome
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Hypogammaglobulinaemia
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    General disorders and administration site conditions
    Face oedema
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Pyrexia
         subjects affected / exposed
    2 / 13 (15.38%)
         occurrences all number
    4
    Psychiatric disorders
    Confusional state
         subjects affected / exposed
    3 / 13 (23.08%)
         occurrences all number
    3
    Delirium
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Depression
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Disorientation
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Reproductive system and breast disorders
    Acquired phimosis
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Infusion related reaction
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Skin wound
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Investigations
    Activated partial thromboplastin time prolonged
         subjects affected / exposed
    2 / 13 (15.38%)
         occurrences all number
    2
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Aspartate aminotransferase increased
         subjects affected / exposed
    2 / 13 (15.38%)
         occurrences all number
    2
    Blood bilirubin increased
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Blood creatinine increased
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    International normalised ratio increased
         subjects affected / exposed
    3 / 13 (23.08%)
         occurrences all number
    4
    Neutrophil count decreased
         subjects affected / exposed
    2 / 13 (15.38%)
         occurrences all number
    2
    Lymphocyte count decreased
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Platelet count decreased
         subjects affected / exposed
    2 / 13 (15.38%)
         occurrences all number
    2
    Prothrombin time prolonged
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Serum ferritin increased
         subjects affected / exposed
    3 / 13 (23.08%)
         occurrences all number
    3
    White blood cell count decreased
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Weight increased
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Cardiac disorders
    Sinus tachycardia
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    5 / 13 (38.46%)
         occurrences all number
    6
    Thrombocytopenia
         subjects affected / exposed
    3 / 13 (23.08%)
         occurrences all number
    3
    Splenomegaly
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Respiratory, thoracic and mediastinal disorders
    Epistaxis
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Hypoxia
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Pleural effusion
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Pulmonary oedema
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Tachypnoea
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Nervous system disorders
    Ataxia
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Aphasia
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Headache
         subjects affected / exposed
    2 / 13 (15.38%)
         occurrences all number
    2
    Lethargy
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Neuropathy peripheral
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Neurotoxicity
         subjects affected / exposed
    2 / 13 (15.38%)
         occurrences all number
    2
    Speech disorder
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    2 / 13 (15.38%)
         occurrences all number
    2
    Gastrointestinal inflammation
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Haematemesis
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Gastrooesophageal reflux disease
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Mouth haemorrhage
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Nausea
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Stomatitis
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Urinary ascites
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Vomiting
         subjects affected / exposed
    2 / 13 (15.38%)
         occurrences all number
    4
    Skin and subcutaneous tissue disorders
    Rash macular
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Rash maculo-papular
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Musculoskeletal and connective tissue disorders
    Muscular weakness
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Myalgia
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Metabolism and nutrition disorders
    Hyperkalaemia
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Decreased appetite
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Hypocalcaemia
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Hypokalaemia
         subjects affected / exposed
    6 / 13 (46.15%)
         occurrences all number
    8
    Hypophosphataemia
         subjects affected / exposed
    2 / 13 (15.38%)
         occurrences all number
    2
    Infections and infestations
    Coronavirus infection
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    BK virus infection
         subjects affected / exposed
    2 / 13 (15.38%)
         occurrences all number
    2
    Cytomegalovirus infection reactivation
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Oral herpes
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1
    Viral haemorrhagic cystitis
         subjects affected / exposed
    1 / 13 (7.69%)
         occurrences all number
    1

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    17 Nov 2016
    Amendment N°1, applicable in all countries, mainly concerned: - Modification of the definitions of “Criteria for defining toxicity”. - Removal of inclusion criterion n°8 requesting the patients to consent in the same time to their participation to the parent study and to the LTFU study and addition of an exclusion criterion (criterion n°34) for patients who were unable or unwilling to undergo a safety follow-up for 15 years. - Clarification regarding the maximum amount of blood to be taken from participants. Reduction in time interval between inclusion of the 3rd and the 4th patient and thereafter between inclusion of 2 consecutive patients within a group of 3 patients. - Addition of a communication plan between sponsor and sites. - Addition of exclusion criteria n° 33 (patients tested positive for HIV). - Clarification regarding exclusion criteria n°11 (reduction of the washout period required after the use of previous treatment). - Addition of reporting of CD52 expression data on leukemic cells as exploratory objective.
    24 Feb 2017
    Amendment N°2, applicable in all countries, mainly concerned: - Clarification of AEs to be reported during the FU period and deletion of Appendix 2. - Several modifications to be consistent with the safety changes implemented in the CALM protocol following Food and Drug Administration request and NIH recombinant DNA advisory Committee: * Modification of the definitions of “Criteria for defining toxicity”. * Use of the grading of Harris (Harris et al, 2016) for grading scale for GvHD. * Update on the management of safety risks and supportive care measures; addition of appendices “CRS management” and “neurotoxicity management”. * Addition of ineligibility criteria for using alemtuzumab in LD regimen. * Addition of discontinuation criteria for using alemtuzumab in LD regimen. * Recommendation for antimicrobial surveillance/prophylaxis for opportunistic infections (viral, fungal, bacterial) until blood count recovery for patients receiving alemtuzumab. * Addition of one blood sample for potential retrospective genomic analysis in case of T-cell transformation, at D0, D84, M6 and M12. * Addition of immunogenicity assays (human anti-UCART19 antibodies) at D0, D28, D84 and M12. - Rewording of exclusion criteria n° 24 to define more specifically an active infection. - Addition of eligibility criteria before UCART19 administration in the study plan. - Modification of the exclusion criteria n°33 with the exclusion of patients tested positive for HTLV at inclusion. - Addition of IL4 in the list of parameters to be dosed among the cytokines. - Reporting in the eCRF of data on CD52 expression on leukemic blasts (on blood or bone marrow if assessments were performed locally).
    23 Nov 2017
    Amendment N°3, applicable in all countries, mainly concerned: - To discontinue the use of alemtuzumab following DSMB recommendation. - To modify the doses of fludarabine-cyclophosphamide used as part of LD regimen. - To implement the request received from the ANSM after the submission of PALL and CALM protocols: - Addition of the inclusion criterion n°35 (list of biological parameters and clinical parameters with limit values to be checked). - Deletion of the exclusion criterion n°23 (“Unstable cardiovascular disease”, replaced by clinical parameters of cardiac function as part of the inclusion criterion n°35). - Addition of the exclusion criterion n°36 (“Any known contraindication to any of the drugs that will be used for the lymphodepletion (fludarabine, cyclophosphamide) or other drugs proposed for safety issues (including tocilizumab, rituximab)”). - Addition of a neurological consultation (mandatory for France and according to local practices for other countries) during the screening period. - Addition of cytoreduction decision criteria. - Addition of an immunoglobulin assay at D14 (if required). - Update of paragraph on neurotoxicities and its corresponding appendix. - Update of appendix “CRS mitigation and management”.
    28 Feb 2018
    Amendment N°4, applicable in all countries, mainly concerned: - To remove the planned allo-HSCT from the study protocol, with update of study objectives. - To add the possibility of an optional UCART19 re-dosing after the initial UCART19 infusion. - To modify the study duration from 15 months to 12 months and to modify the study plan with the definition of treatment and follow-up periods. - To add 8 participants (up to 18 participants) and consequently to modify the stopping rules and to define the enrolment strategy from the 10th patient. - To clarify the safety risks (CRS, neurologic toxicity and genotoxicity and tumorigenicity). - To add a new safety identified risk, prolonged cytopenia. - To add “prolonged cytopenia” as new AESI to be considered during the treatment period. - Addition of an eligibility criterion n°44 “Availability of a donor for potential allo-HSCT in the event of persistent marrow aplasia without evidence of residual leukaemia”.
    17 Aug 2018
    Amendment N°6, applicable in all countries. The main objective of this amendment was to re-introduce the use of alemtuzumab in the lymphodepletion regimen following DSMB recommendation. Accordingly, the following changes were applied: - Re-introduction of ineligibility criteria and stopping rules for alemtuzumab administration. - Modification of the doses of fludarabine and cyclophosphamide when administered in combination with alemtuzumab. - Modification of exclusion criteria n°36 to include alemtuzumab. - Modification of treatment authorized to include methylprednisolone and surveillance/prophylaxis measures in case of alemtuzumab use. - Modification of safety risks and supportive care measures for infection in case of alemtuzumab use. - Update of assessment of safety to include the addition of surveillance/prophylaxis measures in case of alemtuzumab use in viral/bacterial/protozoal work-up.
    26 Mar 2019
    Amendment N°8, applicable in all countries. The main objectives of this substantial amendment were: - To modify some inclusion and exclusion criteria in order to address a high unmet medical need for some categories of patients: - Update of inclusion criterion n°2 with the inclusion of patients from birth. - Addition of inclusion criterion n°60 (no detectable anti-CD19 CAR transgene copies in blood, by qPCR, in patients previously treated with CAR T cell therapy). - Update of exclusion criterion n°10 (with the addition of the exception “autologous CAR-T cell therapy”). - Addition of exclusion criterion n°61 (known history of CRS grade 4 related to previous CAR T cell therapy). - Removal of exclusion criterion n°14 (weight below 8.8 kg). - Update of exclusion criterion n°16a (with exclusion of patients with allogeneic HSCT within 3 months prior to screening instead of 6 months). - Update of exclusion criterion n°29 (which became “known history of irreversible severe neurological toxicity related to previous antileukemic treatment leading to organic central nervous system lesions”). - To update the dose of CD19CAR/RQR8+_TCRαβ-_T-cells/kg resulting from the weight band dosing calculation.
    23 Jan 2020
    Amendment N°9, applicable in all countries. The main objectives were: - To modify LD regimen schedule: start lymphodepletion at D-4 and modifications of doses of cyclophosphamide and alemtuzumab. - To modify some exclusion/inclusion criteria: update of inclusion criteria 35a, 38a, 53a with serum ALT/ AST ≤ 5 times ULN instead of 3 times ULN; update of inclusion criterion n°60 with the addition of B cells recovery as surrogate demonstrating the loss of CAR T cells persistence and update of exclusion criterion n°59 to allow use of corticosteroids in combination with alemtuzumab at D-4 and D-3. - To modify eligibility criteria for UCART19 (re)-administration: deletion of criteria 41a and 56 concerning disease progression after lymphodepletion. - To clarify the use of alemtuzumab: update of the use of alemtuzumab as non-optional, update of the stopping rules for the use of alemtuzumab and addition of exclusion criteria related to use of alemtuzumab (criterion n°62). - To allow re-dosing possibility from D14 instead of D28 (update of criteria n°46 and 47). - And to update AESI immediate reporting rules (only severe and/ or serious events to be notified immediately).

    Interruptions (globally)

    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    04 Nov 2020
    The study was terminated as sponsor reviewed its development strategy and decided to stop the development of S68587 in the indication of R/R B ALL. This decision was not due to safety concerns.
    -

    Limitations and caveats

    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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