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    Clinical Trial Results:
    Phase I, open label, dose-escalation study followed by a safety expansion part to evaluate the safety, expansion and persistence of a single dose of UCART19 (allogeneic engineered T-cells expressing anti-CD19 chimeric antigen receptor), administered intravenously in patients with relapsed or refractory CD19 positive B-cell acute lymphoblastic leukaemia (B-ALL)). CALM study (UCART19 in Advanced Lymphoid Malignancies).

    Summary
    EudraCT number
    2016-000296-24
    Trial protocol
    FR  
    Global end of trial date
    28 Jul 2020

    Results information
    Results version number
    v1(current)
    This version publication date
    21 Jul 2021
    First version publication date
    21 Jul 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CL1-68587-002
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02746952
    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
    28 Jul 2020
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    28 Jul 2020
    Global end of trial reached?
    Yes
    Global end of trial date
    28 Jul 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the safety and tolerability of ascending doses of UCART19, to determine the maximum tolerated dose (MTD), the recommended dose (RD) and the lymphodepletion (LD) regimen (dose escalation part). To assess the safety and tolerability of the RD for UCART19 during the safety dose expansion part.
    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
    10 Aug 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
    Japan: 2
    Country: Number of subjects enrolled
    United States: 6
    Country: Number of subjects enrolled
    France: 6
    Country: Number of subjects enrolled
    United Kingdom: 11
    Worldwide total number of subjects
    25
    EEA total number of subjects
    6
    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)
    0
    Adults (18-64 years)
    25
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    Patients were male or female participants aged ≥ 16 years, up to < 70 years old, with R/R CD19+ B-ALL, as per NCCN guidelines, 2019 (National Comprehensive Cancer Network, 2019).

    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
    Are arms mutually exclusive
    Yes

    Arm title
    1E5 cells/kg
    Arm description
    At D-7 , a LymphoDepletion (LD) was initiated. The LD treatment was the enhancement of homeostatic proliferation of the infused UCART19 cells by deep and prolonged depletion of host immune cells. It combined fludarabine 30 mg/m2/day IV, cyclophosphamide 500 mg/m2/day IV and alemtuzumab IV 0.2 mg/kg/day or 8 mg/day or 12 mg/day. 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 defined as allogeneic engineered 19CAR/RQR8+_TCRαβ–_Tcells. Follow-up period from D85 to M12. Then, 4 patients entered a separate LTFU study to be followed for 15 years. At cut-off, 2 patients withdrew due to progressive disease, 1 for adverse events. 1 patients is ongoing.
    Arm type
    Experimental

    Investigational medicinal product name
    UCART19
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection
    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. It is cryopreserved and supplied as a suspension for IV infusion conditioned in a primary container (1.8 mL cryovials) containing approximately 1 mL of a given dosage form of cell suspension. A flat UCART19 dose per patient per dose level was initially developed, with a first dose of 6x106 UCART19/ patient (a flat dose stands for a number of CD19CAR/RQR8+_TCRαβ-_T-cells). The flat dose was developed to be administered to all patients, independently of their weight. The corresponding dose of cells expressed in a dose per kg was based on an average patient’s weight of 60 kg. As the use of partial vials is not recommended, patients enrolled at Dose level 1 (DL1) 1x 105 cells or DL-1 (1x 104) cells/kg received a flat dose not adjusted for weight. Weight band dosing was applied for DL2 (1x 106 cells/kg) and DL3 (3x 106 cells/kg).

    Arm title
    1E6 cells/kg
    Arm description
    At D-7 , a LymphoDepletion (LD) was initiated. The LD treatment was the enhancement of homeostatic proliferation of the infused UCART19 cells by deep and prolonged depletion of host immune cells. It combined fludarabine 30 mg/m2/day IV, cyclophosphamide 500 mg/m2/day IV and alemtuzumab IV 0.2 mg/kg/day or 8 mg/day or 12 mg/day. 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 defined as allogeneic engineered 19CAR/RQR8+_TCRαβ–_Tcells. Follow-up period from D85 to M12. Then, 9 patients entered a separate LTFU study to be followed for 15 years. At cut-off, 2 patients withdrew due to death, 1 for adverse events, 6 patients are ongoing.
    Arm type
    Experimental

    Investigational medicinal product name
    UCART19
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection
    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. It is cryopreserved and supplied as a suspension for IV infusion conditioned in a primary container (1.8 mL cryovials) containing approximately 1 mL of a given dosage form of cell suspension. A flat UCART19 dose per patient per dose level was initially developed, with a first dose of 6x106 UCART19/ patient (a flat dose stands for a number of CD19CAR/RQR8+_TCRαβ-_T-cells). The flat dose was developed to be administered to all patients, independently of their weight. The corresponding dose of cells expressed in a dose per kg was based on an average patient’s weight of 60 kg. As the use of partial vials is not recommended, patients enrolled at Dose level 1 (DL1) 1x 105 cells or DL-1 (1x 104) cells/kg received a flat dose not adjusted for weight. Weight band dosing was applied for DL2 (1x 106 cells/kg) and DL3 (3x 106 cells/kg).

    Arm title
    3E6 cells/kg
    Arm description
    At D-7 , a LymphoDepletion (LD) was initiated. The LD treatment was the enhancement of homeostatic proliferation of the infused UCART19 cells by deep and prolonged depletion of host immune cells. It combined fludarabine 30 mg/m2/day IV, cyclophosphamide 500 mg/m2/day IV and alemtuzumab IV 0.2 mg/kg/day or 8 mg/day or 12 mg/day. 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 defined as allogeneic engineered 19CAR/RQR8+_TCRαβ–_Tcells. Follow-up period from D85 to M12. Then, 4 patients entered a separate LTFU study to be followed for 15 years. At cut-off, 1 patient withdrew due to death, 1 for other reason. 2 patients are ongoing.
    Arm type
    Experimental

    Investigational medicinal product name
    UCART19
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection
    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. It is cryopreserved and supplied as a suspension for IV infusion conditioned in a primary container (1.8 mL cryovials) containing approximately 1 mL of a given dosage form of cell suspension. A flat UCART19 dose per patient per dose level was initially developed, with a first dose of 6x106 UCART19/ patient (a flat dose stands for a number of CD19CAR/RQR8+_TCRαβ-_T-cells). The flat dose was developed to be administered to all patients, independently of their weight. The corresponding dose of cells expressed in a dose per kg was based on an average patient’s weight of 60 kg. As the use of partial vials is not recommended, patients enrolled at Dose level 1 (DL1) 1x 105 cells or DL-1 (1x 104) cells/kg received a flat dose not adjusted for weight. Weight band dosing was applied for DL2 (1x 106 cells/kg) and DL3 (3x 106 cells/kg).

    Number of subjects in period 1
    1E5 cells/kg 1E6 cells/kg 3E6 cells/kg
    Started
    6
    12
    7
    Completed
    2
    1
    0
    Not completed
    4
    11
    7
         Progressive disease
    1
    4
    1
         Non-medical reason
    -
    1
    -
         Physician decision
    2
    5
    3
         Adverse event, serious fatal
    -
    -
    1
         Adverse event, non-fatal
    1
    1
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    1E5 cells/kg
    Reporting group description
    At D-7 , a LymphoDepletion (LD) was initiated. The LD treatment was the enhancement of homeostatic proliferation of the infused UCART19 cells by deep and prolonged depletion of host immune cells. It combined fludarabine 30 mg/m2/day IV, cyclophosphamide 500 mg/m2/day IV and alemtuzumab IV 0.2 mg/kg/day or 8 mg/day or 12 mg/day. 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 defined as allogeneic engineered 19CAR/RQR8+_TCRαβ–_Tcells. Follow-up period from D85 to M12. Then, 4 patients entered a separate LTFU study to be followed for 15 years. At cut-off, 2 patients withdrew due to progressive disease, 1 for adverse events. 1 patients is ongoing.

    Reporting group title
    1E6 cells/kg
    Reporting group description
    At D-7 , a LymphoDepletion (LD) was initiated. The LD treatment was the enhancement of homeostatic proliferation of the infused UCART19 cells by deep and prolonged depletion of host immune cells. It combined fludarabine 30 mg/m2/day IV, cyclophosphamide 500 mg/m2/day IV and alemtuzumab IV 0.2 mg/kg/day or 8 mg/day or 12 mg/day. 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 defined as allogeneic engineered 19CAR/RQR8+_TCRαβ–_Tcells. Follow-up period from D85 to M12. Then, 9 patients entered a separate LTFU study to be followed for 15 years. At cut-off, 2 patients withdrew due to death, 1 for adverse events, 6 patients are ongoing.

    Reporting group title
    3E6 cells/kg
    Reporting group description
    At D-7 , a LymphoDepletion (LD) was initiated. The LD treatment was the enhancement of homeostatic proliferation of the infused UCART19 cells by deep and prolonged depletion of host immune cells. It combined fludarabine 30 mg/m2/day IV, cyclophosphamide 500 mg/m2/day IV and alemtuzumab IV 0.2 mg/kg/day or 8 mg/day or 12 mg/day. 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 defined as allogeneic engineered 19CAR/RQR8+_TCRαβ–_Tcells. Follow-up period from D85 to M12. Then, 4 patients entered a separate LTFU study to be followed for 15 years. At cut-off, 1 patient withdrew due to death, 1 for other reason. 2 patients are ongoing.

    Reporting group values
    1E5 cells/kg 1E6 cells/kg 3E6 cells/kg Total
    Number of subjects
    6 12 7 25
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    6 12 7 25
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    25.50 ± 8.76 41.92 ± 11.94 42.86 ± 14.46 -
    Gender categorical
    Units: Subjects
        Female
    2 7 2 11
        Male
    4 5 5 14

    End points

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    End points reporting groups
    Reporting group title
    1E5 cells/kg
    Reporting group description
    At D-7 , a LymphoDepletion (LD) was initiated. The LD treatment was the enhancement of homeostatic proliferation of the infused UCART19 cells by deep and prolonged depletion of host immune cells. It combined fludarabine 30 mg/m2/day IV, cyclophosphamide 500 mg/m2/day IV and alemtuzumab IV 0.2 mg/kg/day or 8 mg/day or 12 mg/day. 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 defined as allogeneic engineered 19CAR/RQR8+_TCRαβ–_Tcells. Follow-up period from D85 to M12. Then, 4 patients entered a separate LTFU study to be followed for 15 years. At cut-off, 2 patients withdrew due to progressive disease, 1 for adverse events. 1 patients is ongoing.

    Reporting group title
    1E6 cells/kg
    Reporting group description
    At D-7 , a LymphoDepletion (LD) was initiated. The LD treatment was the enhancement of homeostatic proliferation of the infused UCART19 cells by deep and prolonged depletion of host immune cells. It combined fludarabine 30 mg/m2/day IV, cyclophosphamide 500 mg/m2/day IV and alemtuzumab IV 0.2 mg/kg/day or 8 mg/day or 12 mg/day. 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 defined as allogeneic engineered 19CAR/RQR8+_TCRαβ–_Tcells. Follow-up period from D85 to M12. Then, 9 patients entered a separate LTFU study to be followed for 15 years. At cut-off, 2 patients withdrew due to death, 1 for adverse events, 6 patients are ongoing.

    Reporting group title
    3E6 cells/kg
    Reporting group description
    At D-7 , a LymphoDepletion (LD) was initiated. The LD treatment was the enhancement of homeostatic proliferation of the infused UCART19 cells by deep and prolonged depletion of host immune cells. It combined fludarabine 30 mg/m2/day IV, cyclophosphamide 500 mg/m2/day IV and alemtuzumab IV 0.2 mg/kg/day or 8 mg/day or 12 mg/day. 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 defined as allogeneic engineered 19CAR/RQR8+_TCRαβ–_Tcells. Follow-up period from D85 to M12. Then, 4 patients entered a separate LTFU study to be followed for 15 years. At cut-off, 1 patient withdrew due to death, 1 for other reason. 2 patients are ongoing.

    Primary: Best Overall Response (BOR): Complete Remission (CR) MRD negative

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    End point title
    Best Overall Response (BOR): Complete Remission (CR) MRD negative [1]
    End point description
    End point type
    Primary
    End point timeframe
    At D-1, D14, D28, D56, D84, M4, M6, M9 and M12 or at the WD visit.
    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: Groups are too small
    End point values
    1E5 cells/kg 1E6 cells/kg 3E6 cells/kg
    Number of subjects analysed
    6
    12
    7
    Units: no unit
    0
    1
    1
    No statistical analyses for this end point

    Primary: BOR: Complete remission incomplete blood count recovery (CRi) MRD negative

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    End point title
    BOR: Complete remission incomplete blood count recovery (CRi) MRD negative [2]
    End point description
    End point type
    Primary
    End point timeframe
    At D-1, D14, D28, D56, D84, M4, M6, M9 and M12 or at the WD visit.
    Notes
    [2] - 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: Groups are too small
    End point values
    1E5 cells/kg 1E6 cells/kg 3E6 cells/kg
    Number of subjects analysed
    6
    12
    7
    Units: no unit
    3
    4
    0
    No statistical analyses for this end point

    Primary: BOR: Morphologic CR/CRi

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    End point title
    BOR: Morphologic CR/CRi [3]
    End point description
    End point type
    Primary
    End point timeframe
    At D-1, D14, D28, D56, D84, M4, M6, M9 and M12 or at the WD visit.
    Notes
    [3] - 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: Groups are too small
    End point values
    1E5 cells/kg 1E6 cells/kg 3E6 cells/kg
    Number of subjects analysed
    6
    12
    7
    Units: no unit
    0
    0
    2
    No statistical analyses for this end point

    Primary: Dose Limiting Toxicity (DLT) and the Maximum Tolerated Dose (MTD)

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    End point title
    Dose Limiting Toxicity (DLT) and the Maximum Tolerated Dose (MTD) [4]
    End point description
    The MTD is defined as the highest dose at which the toxicity probability is the closest to the target probability of 0.3.
    End point type
    Primary
    End point timeframe
    At D-1, D14, D28, D56, D84, M4, M6, M9 and M12 or at the WD visit.
    Notes
    [4] - 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: The MTD was defined as the DL3 (3x106 cells/kg). According to DSMB meeting conclusion, the recommended dose was defined as the DL2 (1x106 cells/kg) based on several criteria: the acceptable safety profile, the greater level of UCART19 expansion and persistence in the patients receiving lymphodepletion with FCA at this dose level compared with DL1 and DL3 and the antileukemic activity of UCART19 at this dose in patients who were older or who had more aggressive disease.
    End point values
    1E5 cells/kg 1E6 cells/kg 3E6 cells/kg
    Number of subjects analysed
    6
    12
    7
    Units: no unit
    1
    1
    1
    No statistical analyses for this end point

    Secondary: BOR: MRD indeterminate CR/CRi

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    End point title
    BOR: MRD indeterminate CR/CRi
    End point description
    End point type
    Secondary
    End point timeframe
    At D-1, D14, D28, D56, D84, M4, M6, M9 and M12 or at the WD visit.
    End point values
    1E5 cells/kg 1E6 cells/kg 3E6 cells/kg
    Number of subjects analysed
    6
    12
    7
    Units: no unit
    1
    0
    0
    No statistical analyses for this end point

    Secondary: Objective Response Rate

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    End point title
    Objective Response Rate
    End point description
    End point type
    Secondary
    End point timeframe
    At D-1, D14, D28, D56, D84, M4, M6, M9 and M12 or at the WD visit.
    End point values
    1E5 cells/kg 1E6 cells/kg 3E6 cells/kg
    Number of subjects analysed
    6
    12
    7
    Units: no unit
    4
    7
    2
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All adverse events occurring from the LymphoDepletion to the end of follow-up.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    21
    Reporting groups
    Reporting group title
    1E5 cells/kg
    Reporting group description
    -

    Reporting group title
    3E6 cells/kg
    Reporting group description
    -

    Reporting group title
    1E6 cells/kg
    Reporting group description
    -

    Serious adverse events
    1E5 cells/kg 3E6 cells/kg 1E6 cells/kg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    6 / 6 (100.00%)
    7 / 7 (100.00%)
    6 / 12 (50.00%)
         number of deaths (all causes)
    3
    3
    2
         number of deaths resulting from adverse events
    1
    1
    1
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Acute lymphocytic leukaemia recurrent
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Central nervous system leukaemia
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Leukaemic infiltration extramedullary
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Leukaemic infiltration renal
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Malignant neoplasm progression
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Immune system disorders
    Acute graft versus host disease in skin
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cytokine release syndrome
         subjects affected / exposed
    3 / 6 (50.00%)
    4 / 7 (57.14%)
    3 / 12 (25.00%)
         occurrences causally related to treatment / all
    3 / 3
    4 / 4
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Drug hypersensitivity
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haemophagocytic lymphohistiocytosis
         subjects affected / exposed
    0 / 6 (0.00%)
    2 / 7 (28.57%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypersensitivity
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypogammaglobulinaemia
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Feeling hot
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Multiple organ dysfunction syndrome
         subjects affected / exposed
    2 / 6 (33.33%)
    1 / 7 (14.29%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 2
    1 / 1
    0 / 0
    Psychiatric disorders
    Agitation
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Anxiety
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Confusional state
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychomotor retardation
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Accidental underdose
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Acute haemolytic transfusion reaction
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infusion related reaction
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Product administration error
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Investigations
    BK polyomavirus test positive
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood bilirubin increased
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood creatinine increased
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lymphocyte count decreased
         subjects affected / exposed
    2 / 6 (33.33%)
    0 / 7 (0.00%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neutrophil count decreased
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Platelet count decreased
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory distress syndrome
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lung opacity
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary haemorrhage
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    Pulmonary oedema
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Bone marrow failure
         subjects affected / exposed
    2 / 6 (33.33%)
    1 / 7 (14.29%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cytopenia
         subjects affected / exposed
    2 / 6 (33.33%)
    2 / 7 (28.57%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 2
    2 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    3 / 6 (50.00%)
    2 / 7 (28.57%)
    2 / 12 (16.67%)
         occurrences causally related to treatment / all
    1 / 4
    1 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    1 / 6 (16.67%)
    2 / 7 (28.57%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    1 / 6 (16.67%)
    2 / 7 (28.57%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Brain oedema
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neurotoxicity
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyramidal tract syndrome
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tremor
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Retinal haemorrhage
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal inflammation
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lip swelling
         subjects affected / exposed
    2 / 6 (33.33%)
    0 / 7 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Swollen tongue
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Tumour lysis syndrome
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Adenovirus infection
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 7 (14.29%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bacterial infection
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bacterial sepsis
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Candida infection
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cytomegalovirus infection
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cytomegalovirus infection reactivation
         subjects affected / exposed
    1 / 6 (16.67%)
    2 / 7 (28.57%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Enterobacter sepsis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Enterococcal infection
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Enterococcal sepsis
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lower respiratory tract infection fungal
         subjects affected / exposed
    0 / 6 (0.00%)
    2 / 7 (28.57%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neutropenic sepsis
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    Septic shock
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Staphylococcal sepsis
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Viral rash
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    1E5 cells/kg 3E6 cells/kg 1E6 cells/kg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    6 / 6 (100.00%)
    7 / 7 (100.00%)
    12 / 12 (100.00%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    1
    Hypotension
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    Raynaud's phenomenon
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    Thrombophlebitis superficial
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Malignant neoplasm progression
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    Precursor B-lymphoblastic lymphoma recurrent
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    Immune system disorders
    Acute graft versus host disease in skin
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    Cytokine release syndrome
         subjects affected / exposed
    3 / 6 (50.00%)
    2 / 7 (28.57%)
    7 / 12 (58.33%)
         occurrences all number
    3
    2
    7
    Hypogammaglobulinaemia
         subjects affected / exposed
    2 / 6 (33.33%)
    0 / 7 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    2
    0
    0
    General disorders and administration site conditions
    Hypothermia
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    Malaise
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    Oedema
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    Oedema peripheral
         subjects affected / exposed
    1 / 6 (16.67%)
    3 / 7 (42.86%)
    0 / 12 (0.00%)
         occurrences all number
    1
    3
    0
    Pyrexia
         subjects affected / exposed
    2 / 6 (33.33%)
    3 / 7 (42.86%)
    5 / 12 (41.67%)
         occurrences all number
    2
    3
    7
    Swelling
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    1
    0
    1
    Confusional state
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    2 / 12 (16.67%)
         occurrences all number
    0
    0
    2
    Disorientation
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    Hallucination
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    1
    0
    1
    Insomnia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    2 / 12 (16.67%)
         occurrences all number
    0
    0
    2
    Injury, poisoning and procedural complications
    Head injury
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    Infusion related reaction
         subjects affected / exposed
    5 / 6 (83.33%)
    4 / 7 (57.14%)
    3 / 12 (25.00%)
         occurrences all number
    10
    4
    3
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    2 / 6 (33.33%)
    1 / 7 (14.29%)
    0 / 12 (0.00%)
         occurrences all number
    3
    2
    0
    Aspartate aminotransferase increased
         subjects affected / exposed
    2 / 6 (33.33%)
    1 / 7 (14.29%)
    0 / 12 (0.00%)
         occurrences all number
    3
    1
    0
    Blood bilirubin increased
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 7 (14.29%)
    2 / 12 (16.67%)
         occurrences all number
    1
    1
    2
    Blood creatinine increased
         subjects affected / exposed
    0 / 6 (0.00%)
    2 / 7 (28.57%)
    0 / 12 (0.00%)
         occurrences all number
    0
    2
    0
    Blood immunoglobulin A decreased
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    Blood immunoglobulin M decreased
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    Blood lactate dehydrogenase increased
         subjects affected / exposed
    2 / 6 (33.33%)
    0 / 7 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    2
    0
    1
    C-reactive protein increased
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    2 / 12 (16.67%)
         occurrences all number
    0
    0
    2
    Ejection fraction decreased
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    Electrocardiogram QT prolonged
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    Eosinophil count increased
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 7 (14.29%)
    1 / 12 (8.33%)
         occurrences all number
    1
    1
    1
    International normalised ratio increased
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    Liver function test abnormal
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    Neutrophil count decreased
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    1
    0
    2
    Oxygen saturation decreased
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    Platelet count decreased
         subjects affected / exposed
    2 / 6 (33.33%)
    0 / 7 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    3
    0
    1
    Serum ferritin increased
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 7 (14.29%)
    0 / 12 (0.00%)
         occurrences all number
    1
    1
    0
    Weight decreased
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 7 (14.29%)
    0 / 12 (0.00%)
         occurrences all number
    2
    1
    0
    Weight increased
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    White blood cell count decreased
         subjects affected / exposed
    2 / 6 (33.33%)
    0 / 7 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    2
    0
    0
    Cardiac disorders
    Sinus bradycardia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    Sinus tachycardia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    Ventricular tachycardia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Epistaxis
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    Hiccups
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    Hypoxia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    Productive cough
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    Upper-airway cough syndrome
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    4 / 6 (66.67%)
    4 / 7 (57.14%)
    6 / 12 (50.00%)
         occurrences all number
    4
    4
    6
    Lymphadenopathy
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    Neutropenia
         subjects affected / exposed
    2 / 6 (33.33%)
    1 / 7 (14.29%)
    0 / 12 (0.00%)
         occurrences all number
    2
    1
    0
    Thrombocytopenia
         subjects affected / exposed
    0 / 6 (0.00%)
    2 / 7 (28.57%)
    3 / 12 (25.00%)
         occurrences all number
    0
    2
    3
    Nervous system disorders
    Encephalopathy
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    Facial paralysis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    Headache
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    4 / 12 (33.33%)
         occurrences all number
    0
    1
    4
    Myoclonus
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    Neurotoxicity
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    2 / 12 (16.67%)
         occurrences all number
    0
    0
    2
    Paraesthesia
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    1
    0
    1
    Peripheral sensory neuropathy
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    Tension headache
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    Tremor
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    Eye disorders
    Visual impairment
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    Ear and labyrinth disorders
    Hypoacusis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    2 / 12 (16.67%)
         occurrences all number
    0
    0
    2
    Abdominal pain
         subjects affected / exposed
    2 / 6 (33.33%)
    1 / 7 (14.29%)
    2 / 12 (16.67%)
         occurrences all number
    2
    1
    2
    Abdominal pain lower
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    Abdominal pain upper
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 7 (14.29%)
    0 / 12 (0.00%)
         occurrences all number
    1
    1
    0
    Constipation
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    Dental caries
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    Diarrhoea
         subjects affected / exposed
    3 / 6 (50.00%)
    1 / 7 (14.29%)
    2 / 12 (16.67%)
         occurrences all number
    4
    1
    2
    Dry mouth
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    Flatulence
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    Gastrointestinal motility disorder
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    Gastrointestinal wall thickening
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    Hypoaesthesia oral
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    Nausea
         subjects affected / exposed
    3 / 6 (50.00%)
    3 / 7 (42.86%)
    5 / 12 (41.67%)
         occurrences all number
    4
    3
    6
    Parotid gland enlargement
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    Stomatitis
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    2 / 12 (16.67%)
         occurrences all number
    1
    0
    2
    Toothache
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    Vomiting
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    Haematuria
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    Proteinuria
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    Hepatobiliary disorders
    Hepatocellular injury
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    1
    Skin and subcutaneous tissue disorders
    Dermatitis contact
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    Drug eruption
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    Erythema
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    Papule
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    Petechiae
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    Pruritus
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    Rash
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 7 (14.29%)
    1 / 12 (8.33%)
         occurrences all number
    1
    1
    1
    Rash follicular
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    Rash macular
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 7 (14.29%)
    0 / 12 (0.00%)
         occurrences all number
    2
    1
    0
    Toxic skin eruption
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    Arthritis
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    Back pain
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 7 (14.29%)
    2 / 12 (16.67%)
         occurrences all number
    1
    1
    2
    Bone pain
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    Muscular weakness
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    Musculoskeletal chest pain
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    Musculoskeletal pain
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    Myalgia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    1
    Fluid overload
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    2 / 12 (16.67%)
         occurrences all number
    0
    0
    2
    Hypercalcaemia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    Hypermagnesaemia
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    Hypernatraemia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    Hyperuricaemia
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    Hypocalcaemia
         subjects affected / exposed
    1 / 6 (16.67%)
    2 / 7 (28.57%)
    0 / 12 (0.00%)
         occurrences all number
    1
    2
    0
    Hypokalaemia
         subjects affected / exposed
    2 / 6 (33.33%)
    0 / 7 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    2
    0
    1
    Hypomagnesaemia
         subjects affected / exposed
    2 / 6 (33.33%)
    1 / 7 (14.29%)
    0 / 12 (0.00%)
         occurrences all number
    4
    1
    0
    Hyponatraemia
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    Hypophosphataemia
         subjects affected / exposed
    2 / 6 (33.33%)
    1 / 7 (14.29%)
    1 / 12 (8.33%)
         occurrences all number
    3
    1
    1
    Vitamin D deficiency
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    Infections and infestations
    Adenovirus infection
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    BK virus infection
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    Cellulitis
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    Cytomegalovirus infection
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    Cytomegalovirus infection reactivation
         subjects affected / exposed
    2 / 6 (33.33%)
    2 / 7 (28.57%)
    0 / 12 (0.00%)
         occurrences all number
    2
    2
    0
    Escherichia bacteraemia
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    Herpes simplex
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    Influenza
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    Lip infection
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    Metapneumovirus infection
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    Oral herpes
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    2 / 12 (16.67%)
         occurrences all number
    1
    0
    3
    Parainfluenzae virus infection
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    Tinea versicolour
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 7 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 6 (0.00%)
    0 / 7 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    Urinary tract infection enterococcal
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 7 (14.29%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    18 Nov 2016
    Amendment No. 1 applicable in all countries, mainly concerned: - Addition of information on the communication plan between Sponsor and all centres to ensure that when dose escalation or other stopping criteria were met at any site, the information was communicated to all sites immediately so that no patient received a dose that had been determined to be too toxic. - Modification of the original methodology of dose allocation into an mTPI design. - Modification of the statistical paragraph and analyses to be consistent along the protocol (response rate, duration of response, time to response, disease-specific survival and progression-free survival). - Addition of MTD to the primary objective. - Assessment of the objective response along the study (D84) was moved from the exploratory objectives to the secondary objectives; Overall response was added to the secondary objectives. - Modification of the definitions of the DLT Criteria. - Modification of the suggested lymphodepletion regimen to align with the lymphodepletion treatment suggested in the UCART19 paediatric protocol (UCART19- PALL Study). - Clarification on MRD methods of measurement: flow cytometry and/or qPCR could be used. - Modification of the adverse events definition. - Deletion of genotoxicity from the list of AESI. - Qualification of CALM study as a First-In-Human Study in adults.
    11 Jan 2017
    Amendment No. 2, applicable in all countries, to implement the recommendations received before the submission of the CALM study to the regulatory authorities in United States (US). The recommendations were mainly related to patient safety. The main changes included: - Modification of the flat dosing strategy and rationale to implement a weight-banded dosing strategy in selected cohorts (2 weight-bands). - Modification of the definitions of the DLT criteria including: * addition of any Grade ≥ 3 non-haematologic toxicity not resolving within 7 days, * down-grading of the GvHD to Grade ≥ 2 requiring oral or IV corticosteroids (> 1 mg/kg/day) and that does not resolve within 7 days, * removal of electrolyte abnormalities. - Addition of grading scale for TLS management. - Amendment of grading scale for acute GvHD to the grading of Harris. - Update on the management of safety risks and supportive care measures for CRS and neurotoxicity. - Addition of discontinuation criteria for using alemtuzumab in lymphodepletion regimen. - Addition on follow-up and management of chronic GvHD post UCART19 administration. - Surveillance/prophylaxis (viral, fungal, bacterial) was pursued for at least 1 year post UCART19 administration in patients receiving alemtuzumab. - Addition of immunogenicity assays (presence of anti-UCART19 antibodies) at D0, D28 and D84. - Modifications in the statistical paragraph, with addition of a minimum number of 3 patients to be dosed per each dose level tested in the mTPI design; addition of appendix 9. - Addition of one time point at D-7 (before the start of the lymphodepletion treatment) for UCART19 analysis by flow cytometry. - Assessment of CD52 expression on leukemic blasts (on blood/bone marrow if assessments were performed locally). - Assessment of the percentage of CD19-positive and CD19-negative leukaemia cells in bone marrow, if the assessment was performed locally.
    02 Mar 2017
    ­Amendment No. 3, applicable in all countries to implement the requests received by the US regulatory authorities (Food and Drug Administration) after the Investigational New Drug review. The recommendations were only related to patients’ safety. The main changes included: - Implementation of a dose expansion phase. - Definition of treatment pause rules. - Modification of the definition of the DLT criterion for nervous system disorders: Grade ≥ 3 lasting more than 7 days (instead of 14 days) or Grade ≥ 4. - Removal of one exploratory objective (patients planned for allo-HSCT). - Assessment of cytokines in the frame of a CRS reaction, if performed locally. - Statistics part updated with definition of treatment pause rules, addition of a dose expansion phase with 2 different lymphodepletion regimens, deletion of exploratory criteria and determination of sample size.
    22 Mar 2018
    ­Amendment No. 4, applicable in all countries. One of the main objectives of this substantial amendment was to include the possibility to re-dose the patient with UCART19. The main changes included: - Addition of a section defining criteria for an optional UCART19 re-dosing after the initial UCART19 infusion. - Extension of the study duration to 13 months and modification of the study plan (definition of treatment and follow-up periods). - Addition of a new important potential risk identified of prolonged cytopenia. - Modification of the dose of alemtuzumab in the lymphodepletion treatment. - Addition of criteria defining a patient not evaluable for DLT. - Update of the “treatments prohibited” and “treatments authorised”. - Update of safety risks: CRS, neurologic toxicity and genotoxicity. - Update of the time points of disease assessment. - Update of the safety assessments during the treatment and follow-up periods, definition of a new AESI (prolonged neutropenia), addition of a mandatory neurological consultation in France during the screening period (adapted to local practices for other countries). - Update of the exploratory analyses. - Update of the statistics part: adaptation of secondary objectives and efficacy endpoints to the extended study duration of 13 months, clarifications regarding the number of patients treated in the safety expansion part, modifications of the data analysis sets.
    25 Apr 2019
    ­Amendment No. 6, applicable in all countries. The first main objective of this substantial amendment was to assess the FCA regimen as lymphodepleting regimen prior to UCART19 infusion in the next patients included in the CALM study. Whatever the moment the patient entered in CALM (dose-escalating part or safety dose expansion part), the use of alemtuzumab at the dose of 40 mg (8 mg/kg/day for 5 days) became mandatory for all patients. The main changes concerned: - Update of study design, study plan and the safety dose expansion procedure removing the FC arm in the safety dose-expansion part. - Update of lymphodepletion regimen with possibility to increase alemtuzumab dose to 60 mg flat dose. - Modification of the total number of patients treated (from 40 patients initially to 30 patients). - Addition of the primary objective concerning the safety dose expansion part. - Removal of soluble CD52 in the exploratory endpoints. - Revision of DLT definition of nervous system disorder for UCART19. - Update of prohibited and authorized treatments. - Clarifications of the AE of special interest per study period. - Clarifications of the time frame for AE reporting. - Clarification on DSMB role at the end of the study. - Addition of checking of DSAs directed against UCART19 before any re-dosing. - Clarification on UCART19 assessment in case of neurotoxic event.

    Interruptions (globally)

    Were there any global interruptions to the trial? No

    Limitations and caveats

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