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    Clinical Trial Results:
    A Phase II, single arm, multicenter study to determine the efficacy and safety of CTL019 in pediatric subjects with relapsed and refractory B cell acute lymphoblastic leukemia. Due to EudraCT system limitations, which EMA is aware of, data using 999 as data points in this record are not an accurate representation of the clinical trial results. Please use https://www.novctrd.com/CtrdWeb/home.nov for complete trial results.

    Summary
    EudraCT number
    2015-003736-13
    Trial protocol
    Outside EU/EEA  
    Global end of trial date
    24 May 2019

    Results information
    Results version number
    v1(current)
    This version publication date
    18 Dec 2019
    First version publication date
    18 Dec 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CCTL019B2205J
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02228096
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Novartis Pharma, AG
    Sponsor organisation address
    CH-4002, Basel, Switzerland,
    Public contact
    Clinical Disclosure Ofice, Novartis Pharma, AG, +41 613241111, novartis.email@novartis.com
    Scientific contact
    Clinical Disclosure Ofice, Novartis Pharma, AG, +41 613241111, novartis.email@novartis.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    EMEA-001654-PIP01-14
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    24 May 2019
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    24 May 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the efficacy of tisagenlecleucel therapy as measured by ORR within 6 months after tisagenlecleucel administration, which includes CR and CRi as determined by IRC assessment for B cell ALL subjects.
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and the International Conference on Harmonization (ICH) Good Clinical Practice (GCP) guidelines. All the local regulatory requirements pertinent to safety of trial subjects were also followed during the conduct of the trial.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    14 Aug 2014
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United States: 64
    Worldwide total number of subjects
    64
    EEA total number of subjects
    0
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    28
    Adolescents (12-17 years)
    26
    Adults (18-64 years)
    10
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    The data reported is based on the final CSR of 2019. The study enrolled 75 participants but only 64 were infused as 11 discontinued prior to tisagenlecleucel (CTL019) infusion.

    Pre-assignment
    Screening details
    The study enrolled 75 participants but only 64 were infused as 11 discontinued prior to tisagenlecleucel (CTL019) infusion.

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

    Arms
    Arm title
    tisagenlecleucel (CTL019) - All participants
    Arm description
    Pediatric participants with r/r B-cell ALL
    Arm type
    Experimental

    Investigational medicinal product name
    CTL019
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Dispersion for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    A target per-protocol dose of tisagenlecleucel transduced cells for pediatric subjects consisted of a single infusion of 2.0 to 5.0×106 tisagenlecleucel transduced cells per kg body weight (for subjects ≤ 50 kg) and 1.0 to 2.5×108 tisagenlecleucel transduced viable T cells (for subjects >50 kg).

    Number of subjects in period 1
    tisagenlecleucel (CTL019) - All participants
    Started
    64
    Enrolled into long-term f/u protocol
    31
    Completed
    4
    Not completed
    60
         Physician decision
    3
         New therapy for study indication
    1
         Lack of efficacy
    18
         Adverse event, serious fatal
    12
         Study terminated by Sponsor
    24
         Subject/guardian decision
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    tisagenlecleucel (CTL019) - All participants
    Reporting group description
    Pediatric participants with r/r B-cell ALL

    Reporting group values
    tisagenlecleucel (CTL019) - All participants Total
    Number of subjects
    64 64
    Age categorical
    Units: Subjects
        In utero
    0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0
        Newborns (0-27 days)
    0 0
        Infants and toddlers (28 days-23 months)
    0 0
        Children (2-11 years)
    28 28
        Adolescents (12-17 years)
    26 26
        Adults (18-64 years)
    10 10
        From 65-84 years
    0 0
        85 years and over
    0 0
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    12.4 ± 5.16 -
    Sex: Female, Male
    Units:
        Female
    34 34
        Male
    30 30
    Karnofsky/Lansky performance status
    Units: Subjects
        KL PS 100
    18 18
        KL PS 90
    28 28
        KL PS 80
    13 13
        KL PS 70
    2 2
        KL PS 60
    1 1
        KL PS 50
    2 2
        KL PS less than 50
    0 0
    Race/Ethnicity, Customized
    Units: Subjects
        White
    52 52
        Asian
    5 5
        Other
    7 7
    Weight
    Units: kg
        arithmetic mean (standard deviation)
    43.7 ± 20.10 -

    End points

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    End points reporting groups
    Reporting group title
    tisagenlecleucel (CTL019) - All participants
    Reporting group description
    Pediatric participants with r/r B-cell ALL

    Subject analysis set title
    tisagenlecleucel (CTL019) - IRC assessment
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Pediatric participants with r/r B-cell ALL

    Subject analysis set title
    tisagenlecleucel (CTL019) - per IRC assessment
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Pediatric participants with r/r B-cell ALL

    Subject analysis set title
    tisagenlecleucel (CTL019) - Local assessment
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Pediatric participants with r/r B-cell ALL

    Subject analysis set title
    CR/CRi
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Participants had Complete remission (CR)/Complete remission with incomplete blood count recovery (CRi)

    Subject analysis set title
    No Response (NR)
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    No response was defined as failure to attain the criteria needed for any response categories or relapse

    Subject analysis set title
    Unknown
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    unknown was assigned in case the baseline assessment or the response assessment was not done, incomplete, indeterminate or not performed within the respective time frame.

    Subject analysis set title
    CR/CRi
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Participants had Complete remission (CR)/Complete remission with incomplete blood count recovery (CRi)

    Subject analysis set title
    No Response
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    No response was defined as failure to attain the criteria needed for any response categories or relapse

    Subject analysis set title
    Unknown
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    unknown was assigned in case the baseline assessment or the response assessment was not done, incomplete, indeterminate or not performed within the respective time frame.

    Subject analysis set title
    tisagenlecleucel (CTL019) - Local assessment
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Pediatric participants with r/r B-cell ALL

    Subject analysis set title
    tisagenlecleucel (CTL019) - IRC assessment
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Pediatric participants with r/r B-cell ALL

    Subject analysis set title
    No response
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    No response was defined as failure to attain the criteria needed for any response categories or relapse

    Subject analysis set title
    NO CRS
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    No cytokine release syndrome

    Subject analysis set title
    Grade 1/2
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Grade 1 and 2 of cytokine release syndrome post tisagenlecleucel infusion

    Subject analysis set title
    Grade 3
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Grade 3 of cytokine release syndrome post tisagenlecleucel infusion

    Subject analysis set title
    Grade 4
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Grade 4 of cytokine release syndrome post tisagenlecleucel infusion

    Subject analysis set title
    All Participants
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    All participants with & without CRS

    Primary: Overall Remission Rate (ORR) per Independent Review Committee (IRC) (for ALL participants)

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    End point title
    Overall Remission Rate (ORR) per Independent Review Committee (IRC) (for ALL participants) [1]
    End point description
    ORR is defined as the percentage of participants with a best overall disease response of complete remission (CR) or Complete remission with incomplete blood count recovery (CRi), where the best overall disease response is defined as the best disease response recorded from CTL019 infusion until the start of new anticancer therapy. Best response was assigned in the following order: CR, CRi, CR or CRi with residual mediastinal disease, No response and Unknown.
    End point type
    Primary
    End point timeframe
    within 6 months after CTL019 infusion
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was planned for this endpoint
    End point values
    tisagenlecleucel (CTL019) - IRC assessment
    Number of subjects analysed
    64
    Units: Percentage of participants
        number (confidence interval 95%)
    70.3 (57.6 to 81.1)
    No statistical analyses for this end point

    Secondary: Percentage of participants with clinical response without stem cell transplantation (SCT) at month 6

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    End point title
    Percentage of participants with clinical response without stem cell transplantation (SCT) at month 6
    End point description
    Evaluate the percentage of participants who achieved CR or CRi at Month 6 without SCT between tisagenlecleucel infusion and Month 6 response assessment.
    End point type
    Secondary
    End point timeframe
    Month 6
    End point values
    tisagenlecleucel (CTL019) - IRC assessment
    Number of subjects analysed
    64
    Units: Percentage of participants
        number (confidence interval 95%)
    53.1 (40.2 to 65.7)
    No statistical analyses for this end point

    Secondary: Percentage of subjects who achieved CR or CRi and then proceeded to SCT while in remission prior to Month 6 response assessment

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    End point title
    Percentage of subjects who achieved CR or CRi and then proceeded to SCT while in remission prior to Month 6 response assessment
    End point description
    Evaluate the percentage of subjects who achieved CR or CRi and then proceeded to SCT while in remission prior to Month 6 response assessment.
    End point type
    Secondary
    End point timeframe
    prior to Month 6
    End point values
    tisagenlecleucel (CTL019) - per IRC assessment
    Number of subjects analysed
    64
    Units: Percentage of participants
        number (confidence interval 95%)
    7.8 (2.6 to 17.3)
    No statistical analyses for this end point

    Secondary: Duration of remission (DOR) per Local and IRC assessment

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    End point title
    Duration of remission (DOR) per Local and IRC assessment
    End point description
    DOR is the time from achievement of CR or CRi, whichever occurs first, to relapse or death due to ALL
    End point type
    Secondary
    End point timeframe
    From CR or CRi to relapse or death up to 60 months
    End point values
    tisagenlecleucel (CTL019) - IRC assessment tisagenlecleucel (CTL019) - Local assessment
    Number of subjects analysed
    64
    64
    Units: months
        median (confidence interval 95%)
    999 (13.6 to 999)
    999 (13.6 to 999)
    No statistical analyses for this end point

    Secondary: Percentage of participants with Bone marrow minimum residual disease (MRD) status by flow cytometry within 6 months post CTL019 infusion by Local & IRC assessment

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    End point title
    Percentage of participants with Bone marrow minimum residual disease (MRD) status by flow cytometry within 6 months post CTL019 infusion by Local & IRC assessment
    End point description
    Evaluate the quality of response by assessing BOR of CR or CRi with MRD negative bone marrow 6 months after CTL019 infusion.
    End point type
    Secondary
    End point timeframe
    within 6 months
    End point values
    tisagenlecleucel (CTL019) - IRC assessment tisagenlecleucel (CTL019) - Local assessment
    Number of subjects analysed
    64
    64
    Units: Percentage of participants
    number (confidence interval 95%)
        With BM MRD-ve ( MRD% < 0.01%) (n = 27, 27)
    67.2 (54.3 to 78.4)
    67.2 (54.3 to 78.4)
        With BM 0.01% <= MRD% <5% (n=2, 2)
    3.1 (0 to 999)
    3.1 (0 to 999)
    No statistical analyses for this end point

    Secondary: Relapse-free survival (RFS) for responders per Local and IRC and assessment

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    End point title
    Relapse-free survival (RFS) for responders per Local and IRC and assessment
    End point description
    RFS is the time from achievement of CR or CRi whichever occurs first to relapse or death due to any cause during CR or CRi.
    End point type
    Secondary
    End point timeframe
    60 Months
    End point values
    tisagenlecleucel (CTL019) - IRC assessment tisagenlecleucel (CTL019) - Local assessment
    Number of subjects analysed
    64
    64
    Units: months
        median (confidence interval 95%)
    999 (13.6 to 999)
    999 (13.6 to 999)
    No statistical analyses for this end point

    Secondary: Event-free survival (EFS) per Local and IRC assessment

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    End point title
    Event-free survival (EFS) per Local and IRC assessment
    End point description
    EFS is the time from date of CTL019 infusion to the earliest of death, relapse or treatment failure
    End point type
    Secondary
    End point timeframe
    60 Months
    End point values
    tisagenlecleucel (CTL019) - IRC assessment tisagenlecleucel (CTL019) - Local assessment
    Number of subjects analysed
    64
    64
    Units: months
        median (confidence interval 95%)
    15.6 (6.4 to 999)
    15.6 (6.4 to 999)
    No statistical analyses for this end point

    Secondary: Overall survival (OS)

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    End point title
    Overall survival (OS)
    End point description
    OS is the time from date of CTL019 infusion to the date of death due to any reason
    End point type
    Secondary
    End point timeframe
    60 Months
    End point values
    tisagenlecleucel (CTL019) - All participants
    Number of subjects analysed
    64
    Units: months
        median (confidence interval 95%)
    29.9 (15.1 to 42.4)
    No statistical analyses for this end point

    Secondary: Percentage of subjects attaining CR or CRi and bone marrow MRD status by flow cytometry based on Local and IRC assessment

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    End point title
    Percentage of subjects attaining CR or CRi and bone marrow MRD status by flow cytometry based on Local and IRC assessment
    End point description
    Evaluate the response subjects attaining CR or CRi and bone marrow MRD status at Day 28 +/- 4 days
    End point type
    Secondary
    End point timeframe
    Day 28
    End point values
    tisagenlecleucel (CTL019) - IRC assessment tisagenlecleucel (CTL019) - Local assessment
    Number of subjects analysed
    64
    64
    Units: Percentage of participants
    number (confidence interval 95%)
        With BM MRD -ve: i.e. MRD% < 0.01% (n=46,46)
    71.9 (59.2 to 82.4)
    71.9 (59.2 to 82.4)
        With BM 0.01% <= MRD% < 5%: (n=1,1)
    1.6 (0 to 999)
    1.6 (0 to 999)
        With BM MRD% >= 5%(n = 1, 1)
    1.6 (0 to 999)
    1.6 (0 to 999)
        BM MRD not available (n = 4, 4)
    6.3 (0 to 999)
    6.3 (0 to 999)
    No statistical analyses for this end point

    Secondary: CTL019 transgene levels by qPCR CTL019 cells by in qPCR blood and bone marrow

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    End point title
    CTL019 transgene levels by qPCR CTL019 cells by in qPCR blood and bone marrow
    End point description
    Characterize the in vivo cellular pharmacokinetic (PK) profile (levels,persistence, trafficking) of CTL019 cells in target tissues
    End point type
    Secondary
    End point timeframe
    Enrollment; D1; D4; D7; D11; D14; D21; D28; M3; M6; M9, M12; M18; M24, M30, M42, M48 for transgene levels in blood; Screening, D28, M3, M6 for transgene levels in bone marrow
    End point values
    CR/CRi No Response (NR) Unknown
    Number of subjects analysed
    52
    6
    6
    Units: copies/ug DNA
    geometric mean (geometric coefficient of variation)
        Enrollment blood (n=49,6,5)
    999 ± 999
    999 ± 999
    999 ± 999
        Day 1 (D1): blood (n= 41, 4, 6)
    3680 ± 344.3
    3190 ± 348.6
    2440 ± 220.6
        D4: blood (n= 48, 6, 6)
    234 ± 197.8
    48.8 ± 282.4
    88.0 ± 71.0
        D7: blood (n= 51, 6, 6)
    4460 ± 616.2
    231 ± 499.1
    402 ± 114.7
        D11: blood (n= 34, 4, 4)
    21200 ± 262.3
    423 ± 52.7
    1920 ± 8318.1
        D14: blood (n= 49, 6, 5)
    12500 ± 292.1
    1600 ± 337.1
    42835.8 ± 9060
        D21: blood (n= 49, 6, 5)
    3720 ± 480.5
    7750 ± 334.5
    1050 ± 220743.9
        D28: blood (n= 52, 6, 3)
    1360 ± 650.3
    2770 ± 684.8
    515 ± 244650713.9
        Month 3 (M3): blood (n=49, 2, 2)
    220 ± 224.3
    690 ± 999
    564 ± 999
        Month M6: blood (n=40, 1, 1)
    146 ± 157.5
    999 ± 999
    127 ± 999
        Month M9: blood (n=30, 0, 0)
    117 ± 179.3
    999 ± 999
    999 ± 999
        Month M12: blood (n=30, 0, 0)
    113 ± 312.4
    999 ± 999
    999 ± 999
        Month M18: blood (n=18, 0, 0)
    87.2 ± 200.3
    999 ± 999
    999 ± 999
        Month M24: blood (n=15, 0, 0)
    92.7 ± 160.5
    999 ± 999
    999 ± 999
        Month M30: blood (n=5, 0, 0)
    59.9 ± 150.0
    999 ± 999
    999 ± 999
        Month M36: blood (n=3, 0, 0)
    10.7 ± 19.9
    999 ± 999
    999 ± 999
        Month M42: blood (n=2, 0, 0)
    35.3 ± 999
    999 ± 999
    999 ± 999
        Month M48: blood (n=1, 0, 0)
    999 ± 999
    999 ± 999
    999 ± 999
        Screening: Bone marrow (BM) (n=47, 6, 6)
    999 ± 999
    999 ± 999
    999 ± 999
        D28 BM (n=50,4, 4)
    646 ± 1009.7
    969 ± 166.8
    615 ± 4763885.9
        M3 BM (n = 40, 0, 2)
    179 ± 182.5
    999 ± 999
    542 ± 999
        M6 BM (n = 32, 1, 0)
    133 ± 121.7
    35.3 ± 999
    999 ± 999
    No statistical analyses for this end point

    Secondary: Humoral immunogenicity interpretation by day 28 disease response per IRC (Anti-CTL019 antibodies)

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    End point title
    Humoral immunogenicity interpretation by day 28 disease response per IRC (Anti-CTL019 antibodies)
    End point description
    Humary immunogenicity was measured by anti-CTL019 antibodies in human serum using a flow cytometry method. (Prevalence and incidence of immunogenicity to CTL019)
    End point type
    Secondary
    End point timeframe
    Baseline; Day 14; Day 28; Month 3; Month 6; Month 12; Month 24
    End point values
    CR/CRi No Response Unknown
    Number of subjects analysed
    43
    6
    9
    Units: Percentage of participants
    number (not applicable)
        Baseline: Negative
    23.3
    33.3
    33.3
        Baseline: Positive
    69.8
    66.7
    66.7
        Day 14: Negative
    37.2
    0
    33.3
        Day 14: Positive
    88.4
    100.0
    66.7
        Day 28: Negative
    14.0
    0
    0
        Day 28: Positive
    86.0
    100.0
    22.2
        Month 3: Negative
    7.0
    0
    0
        Month 3: Positive
    67.4
    16.7
    11.1
        Month 6: Negative
    7.0
    0
    0
        Month 6: Positive
    51.2
    16.7
    11.1
        Month 12: Negative
    0
    0
    0
        Month 12: Positive
    23.3
    0
    0
        Month 24: Negative
    2.3
    0
    0
        Month 24: Positive
    7.0
    0
    0
    No statistical analyses for this end point

    Secondary: Response as a function of baseline (BL) tumor burden: ORR within 6 months post CTL019 infusion by local investigator & IRC assessment

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    End point title
    Response as a function of baseline (BL) tumor burden: ORR within 6 months post CTL019 infusion by local investigator & IRC assessment
    End point description
    ORR within 6 months after infusion per IRC and local assessment by baseline marrow tumor burden; ORR within 6 months after infusion per IRC and local assessment by baseline extramedullary disease presence.
    End point type
    Secondary
    End point timeframe
    Within 6 months
    End point values
    tisagenlecleucel (CTL019) - Local assessment tisagenlecleucel (CTL019) - IRC assessment
    Number of subjects analysed
    42
    42
    Units: percentage of participants
    number (confidence interval 95%)
        BL bone marrow tumor burden: Low (<50%) (n=10,10)
    83.3 (51.6 to 97.9)
    83.3 (51.6 to 97.9)
        BL BM tumor burden: High (>=50%) (n=19,19)
    63.3 (43.9 to 80.1)
    63.3 (43.9 to 80.1)
        BL extramedullary disease presence:Yes (n=2,2)
    100 (0 to 999)
    100 (0 to 999)
        BL extramedullary disease presence:No (n=27, 27)
    67.5 (50.9 to 81.4)
    67.5 (50.9 to 81.4)
    No statistical analyses for this end point

    Secondary: Response as a function of baseline tumor burden: Bone marrow (BM) minimum residual disease (MRD) status by flow cytometry within 6 months post CTL019 infusion by local investigator and IRC assessment, by baseline bone marrow tumor burden

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    End point title
    Response as a function of baseline tumor burden: Bone marrow (BM) minimum residual disease (MRD) status by flow cytometry within 6 months post CTL019 infusion by local investigator and IRC assessment, by baseline bone marrow tumor burden
    End point description
    MRD status within 6 months after infusion by baseline bone marrow tumor burden( BMTB); MRD status within 6 months after infusion by baseline extramedullary disease presence (EDP).
    End point type
    Secondary
    End point timeframe
    Within 6 months
    End point values
    tisagenlecleucel (CTL019) - Local assessment tisagenlecleucel (CTL019) - IRC assessment
    Number of subjects analysed
    42
    42
    Units: percentage of participants
    number (confidence interval 95%)
        BL BMTB with BM MRD -ve (MRD% < 0.01%: High
    56.7 (37.4 to 74.5)
    56.7 (37.4 to 74.5)
        BL BMTB with BM 0.01% <= MRD% < 5%: High
    6.7 (0 to 999)
    6.7 (0 to 999)
        BL BMTB with BM MRD -ve (MRD% < 0.01%: Low
    83.3 (51.6 to 97.9)
    83.3 (51.6 to 97.9)
    No statistical analyses for this end point

    Secondary: Response as a function of baseline tumor burden: Bone marrow (BM) minimum residual disease (MRD) status by flow cytometry within 6 months post CTL019 infusion by local investigator and IRC assessment, by baseline extramedullary disease presence

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    End point title
    Response as a function of baseline tumor burden: Bone marrow (BM) minimum residual disease (MRD) status by flow cytometry within 6 months post CTL019 infusion by local investigator and IRC assessment, by baseline extramedullary disease presence
    End point description
    MRD status within 6 months after infusion by baseline bone marrow tumor burden( BMTB); MRD status within 6 months after infusion by baseline extramedullary disease presence (EDP).
    End point type
    Secondary
    End point timeframe
    Within 6 months
    End point values
    tisagenlecleucel (CTL019) - Local assessment tisagenlecleucel (CTL019) - IRC assessment
    Number of subjects analysed
    42
    42
    Units: percentage of participants
    number (confidence interval 95%)
        BL EDP with BM MRD -ve (MRD% < 0.01%: Yes (n=2,2)
    100 (15.8 to 100)
    100 (15.8 to 100)
        BL EDP with BM MRD -ve (MRD% < 0.01%: No(n=25,25)
    62.5 (45.8 to 77.3)
    62.5 (45.8 to 77.3)
        BL EDP with BM 0.01% <= MRD% < 5%: No (n=2, 2)
    5.0 (0 to 999)
    5.0 (0 to 999)
    No statistical analyses for this end point

    Secondary: Response as a function of baseline (BL) tumor burden: duration of remission (DOR) censoring HSCT by local investigator & IRC assessment, by baseline bone marrow tumor burden

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    End point title
    Response as a function of baseline (BL) tumor burden: duration of remission (DOR) censoring HSCT by local investigator & IRC assessment, by baseline bone marrow tumor burden
    End point description
    DOR per IRC and local assessment by baseline marrow tumor burden; DOR per IRC and local assessment by baseline extramedullary disease presence.
    End point type
    Secondary
    End point timeframe
    from FPFV to LPLV
    End point values
    tisagenlecleucel (CTL019) - Local assessment tisagenlecleucel (CTL019) - IRC assessment
    Number of subjects analysed
    42
    42
    Units: months
    median (confidence interval 95%)
        BL bone marrow tumor burden: Low (<50%)
    999 (5.4 to 999)
    999 (5.4 to 999)
        BL bone marrow tumor burden: High (>=50%)
    999 (5.3 to 999)
    999 (5.3 to 999)
        BL extramedullary disease presence:Yes
    999 (3.4 to 999)
    999 (3.4 to 999)
        BL extramedullary disease presence:No
    999 (5.9 to 999)
    999 (5.9 to 999)
    No statistical analyses for this end point

    Secondary: Participants achieving cellular immunogenicity net response by day 28 response per IRC

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    End point title
    Participants achieving cellular immunogenicity net response by day 28 response per IRC
    End point description
    Activation of T cells in PBMC collected from subjects in response to mCAR19 -derived peptides was used to assess the cellular immunogeinicty against tisagenlecleucel. CD4 and CD8 T cell net responses (in %) were calculated for 2 non-overlapping CTL019 peptide pools (i.e., Pool 1 and Pool 2). (Lymphocyte subsets of B and T cells and description of associated safety events)
    End point type
    Secondary
    End point timeframe
    Baseline; Day 14; Day 28; Month 3; Month 6; Month 12; Month 24
    End point values
    CR/CRi Unknown No response
    Number of subjects analysed
    43
    9
    6
    Units: Percentage of participants
    number (not applicable)
        Baseline: Pool 1 CD3+ CD4+ IFNg+ (n=38, 3, 6)
    88.4
    66.7
    50.0
        Day 14: Pool 1 CD3+ CD4+ IFNg+ (n=34, 6, 4)
    79.1
    44.4
    100
        Day 28: Pool 1 CD3+ CD4+ IFNg+ (n=41, 6, 2)
    95.3
    22.2
    100
        Month 3: Pool 1 CD3+ CD4+ IFNg+ (n=32, 1, 1)
    74.4
    11.1
    16.7
        Month 6: Pool 1 CD3+ CD4+ IFNg+ (n=23, 1, 1)
    53.4
    11.1
    16.7
        Month 12: Pool 1 CD3+ CD4+ IFNg+ (n=5,0,0)
    11.6
    999
    999
        Month 24: Pool 1 CD3+ CD4+ IFNg+ (n=5,0,0)
    11.6
    999
    999
        Baseline: Pool 2 CD3+ CD4+ IFNg+ (n=38, 3, 6)
    88.4
    66.7
    50.0
        Day 14: Pool 2 CD3+ CD4+ IFNg+ (n=34, 6, 4)
    79.1
    44.4
    100
        Day 28: Pool 2 CD3+ CD4+ IFNg+ (n=41,6,2)
    95.3
    22.2
    100
        Month 3: Pool 2 CD3+ CD4+ IFNg+ (n=32,1,1)
    74.4
    11.1
    16.7
        Month 6: Pool 2 CD3+ CD4+ IFNg+ (n=23,1,1)
    53.5
    11.1
    16.7
        Month 12: Pool 2 CD3+ CD4+ IFNg+ (n=5,0,0)
    11.6
    999
    999
        Month 24: Pool 2 CD3+ CD4+ IFNg+ (n=5,0,0)
    11.6
    999
    999
        Baseline: Pool 1 CD3+ CD8+ IFNg+ (n=38, 3, 6)
    88.4
    66.7
    50.0
        Day 14: Pool 1 CD3+ CD8+ IFNg+ (n=34, 6, 4)
    79.1
    44.4
    100
        Day 28: Pool 1 CD3+ CD8+ IFNg+ (n=41,6,2)
    95.3
    22.2
    100
        Month 3: Pool 1 CD3+ CD8+ IFNg+ (n=32,1,1)
    74.4
    11.1
    16.7
        Month 6: Pool 1 CD3+ CD8+ IFNg+ (n=23,1,1)
    53.5
    11.1
    16.7
        Month 12: Pool 1 CD3+ CD8+ IFNg+ (n=5,0,0)
    11.6
    999
    999
        Month 24: Pool 1 CD3+ CD8+ IFNg+ (n=5,0,0)
    11.6
    999
    999
        Baseline: Pool 2 CD3+ CD8+ IFNg+ (n=38, 3, 6)
    88.4
    66.7
    50.0
        Day 14: Pool 2 CD3+ CD8+ IFNg+ (n=34, 6, 4)
    79.1
    44.4
    100
        Day 28: Pool 2 CD3+ CD8+ IFNg+ (n=41, 6, 2)
    95.3
    22.2
    100
        Month 3: Pool 2 CD3+ CD8+ IFNg+ (n=32, 1, 1)
    74.4
    11.1
    16.7
        Month 6: Pool 2 CD3+ CD8+ IFNg+ (n=23, 1, 1)
    53.5
    11.1
    16.7
        Month 12: Pool 2 CD3+ CD8+ IFNg+ (n=5, 0, 0)
    11.6
    999
    999
        Month 24: Pool 2 CD3+ CD8+ IFNg+ (n=5, 0, 0)
    11.6
    999
    999
    No statistical analyses for this end point

    Secondary: Peripheral blood PK parameters for tisagenlecleucel transgene levels by qPCR, by Day 28 disease response by Local & IRC assessment: AUC0-28d, AUC0-84d

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    End point title
    Peripheral blood PK parameters for tisagenlecleucel transgene levels by qPCR, by Day 28 disease response by Local & IRC assessment: AUC0-28d, AUC0-84d
    End point description
    Characterize the in vivo cellular pharmacokinetic (PK) profile. AUC0-28d and AUC0-84d is defined as the AUC from time zero to day 28 and 84 or other disease assessment days, in peripheral blood (% or copies/μg x days).
    End point type
    Secondary
    End point timeframe
    60 Months
    End point values
    CR/CRi No Response (NR) Unknown
    Number of subjects analysed
    52
    6
    6
    Units: copies/µg*days
    geometric mean (geometric coefficient of variation)
        AUC0-28d (n= 52, 3, 1)
    261000 ± 199.8
    151000 ± 71.7
    617000 ± 999999
        AUC0-84d (n= 45, 2, 1)
    368000 ± 182.9
    443000 ± 79.9
    1340000 ± 999999
    No statistical analyses for this end point

    Secondary: Peripheral blood PK parameters for tisagenlecleucel transgene levels by qPCR, by Day 28 disease response by Local & IRC assessment: Cmax

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    End point title
    Peripheral blood PK parameters for tisagenlecleucel transgene levels by qPCR, by Day 28 disease response by Local & IRC assessment: Cmax
    End point description
    Characterize the in vivo cellular pharmacokinetic (PK) profile. Cmax is defined as the maximum (peak) observed in peripheral blood drug concentration after single dose administration (% or copies/μg).
    End point type
    Secondary
    End point timeframe
    60 Months
    End point values
    CR/CRi No Response (NR) Unknown
    Number of subjects analysed
    52
    6
    6
    Units: copies/µgys
        geometric mean (geometric coefficient of variation)
    28300 ± 197.0
    15100 ± 49.4
    52500 ± 91.1
    No statistical analyses for this end point

    Secondary: Peripheral blood PK parameters for tisagenlecleucel transgene levels by qPCR, by Day 28 disease response by Local & IRC assessment: Tmax

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    End point title
    Peripheral blood PK parameters for tisagenlecleucel transgene levels by qPCR, by Day 28 disease response by Local & IRC assessment: Tmax
    End point description
    Characterize the in vivo cellular pharmacokinetic (PK) profile. Tmax is defined as the time to reach maximum (peak) peripheral blood drug concentration after single dose administration (days)
    End point type
    Secondary
    End point timeframe
    60 Months
    End point values
    CR/CRi No Response (NR) Unknown
    Number of subjects analysed
    52
    6
    6
    Units: days
        median (full range (min-max))
    9.84 (6.74 to 54.8)
    20.0 (13.9 to 22.8)
    11.9 (11.0 to 12.9)
    No statistical analyses for this end point

    Secondary: Peripheral blood PK parameters for tisagenlecleucel transgene levels by qPCR, by Day 28 disease response by Local & IRC assessment: T1/2

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    End point title
    Peripheral blood PK parameters for tisagenlecleucel transgene levels by qPCR, by Day 28 disease response by Local & IRC assessment: T1/2
    End point description
    Characterize the in vivo cellular pharmacokinetic (PK) profile. T1/2 is defined as the half-life associated with the disposition phase slopes (alpha, beta, gamma etc.) of a semi logarithmic concentration-time curve (days) in peripheral blood
    End point type
    Secondary
    End point timeframe
    60 Months
    End point values
    CR/CRi No Response (NR) Unknown
    Number of subjects analysed
    52
    6
    6
    Units: days
        geometric mean (geometric coefficient of variation)
    31.9 ± 415.1
    4.36 ± 421.2
    42.1 ± 999
    No statistical analyses for this end point

    Secondary: Peripheral blood PK parameters for tisagenlecleucel transgene levels by qPCR, by Day 28 disease response by Local & IRC assessment: Clast

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    End point title
    Peripheral blood PK parameters for tisagenlecleucel transgene levels by qPCR, by Day 28 disease response by Local & IRC assessment: Clast
    End point description
    Characterize the in vivo cellular pharmacokinetic (PK) profile. Clast is defined as the last observed quantifiable concentration in peripheral blood (% or copies/ug)
    End point type
    Secondary
    End point timeframe
    60 Months
    End point values
    CR/CRi No Response (NR) Unknown
    Number of subjects analysed
    52
    6
    6
    Units: copies/µg
        geometric mean (geometric coefficient of variation)
    223 ± 283.4
    1980 ± 207.5
    80.3 ± 999
    No statistical analyses for this end point

    Secondary: Peripheral blood PK parameters for tisagenlecleucel transgene levels by qPCR, by Day 28 disease response by Local & IRC assessment: Tlast

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    End point title
    Peripheral blood PK parameters for tisagenlecleucel transgene levels by qPCR, by Day 28 disease response by Local & IRC assessment: Tlast
    End point description
    Characterize the in vivo cellular pharmacokinetic (PK) profile. ) Tlast is defined as the time of last observed quantifiable concentration in peripheral blood (days)"
    End point type
    Secondary
    End point timeframe
    60 Months
    End point values
    CR/CRi No Response (NR) Unknown
    Number of subjects analysed
    52
    6
    6
    Units: days
        median (full range (min-max))
    179 (17.8 to 921)
    26.9 (26.7 to 96.1)
    210 (210 to 210)
    No statistical analyses for this end point

    Secondary: CD19 status of bone marrow/blood relapse in patients who achieved CR or CRi

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    End point title
    CD19 status of bone marrow/blood relapse in patients who achieved CR or CRi
    End point description
    The CD19 status of bone marrow/blood relapse was relapse was categorized as follows: CD19 positive, CD19 dim, CD19 negative, CD19 positive/negative & unknown
    End point type
    Secondary
    End point timeframe
    At time of relapse up to 60 monnths
    End point values
    tisagenlecleucel (CTL019) - All participants
    Number of subjects analysed
    64
    Units: Percentage of participants
    number (not applicable)
        CD19 positive
    22.2
        CD19 dim
    5.6
        CD19 negative
    16.7
        CD19 positive/negative
    16.7
        Unknown
    55.6
    No statistical analyses for this end point

    Secondary: CD19 site of initial relapse in patients who achieved CR or CRi

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    End point title
    CD19 site of initial relapse in patients who achieved CR or CRi
    End point description
    The site of initial relapse was categorized as follows into 2 categories as follow: BM and/or blood relapse (with extramedullary relapse, without extramedullary relapse, unknown extramedullary disease status) and Extramedullary only (unknown).
    End point type
    Secondary
    End point timeframe
    At time of relapse up to 60 months
    End point values
    tisagenlecleucel (CTL019) - All participants
    Number of subjects analysed
    64
    Units: Percentage of participants
    number (not applicable)
        BM &/or blood relapse with extramed. relapse
    11.1
        BM &/or blood relapse without extramed. relapse
    44.4
        BM &/or blood relapse:UNK extramed. disease status
    16.7
        Extramedullary only
    27.8
        Unknown
    16.7
    No statistical analyses for this end point

    Secondary: Time to B-cell recovery in participants who achieved CR or CRi by IRC

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    End point title
    Time to B-cell recovery in participants who achieved CR or CRi by IRC
    End point description
    Time to B cell recovery was defined as the time from onset of remission to the earliest time when the percentage of CD19+ total B cell among viable WBC is ≥ 1% or among lymphocyte is at least 3%.
    End point type
    Secondary
    End point timeframe
    during the whole study, up to 60 months
    End point values
    tisagenlecleucel (CTL019) - All participants
    Number of subjects analysed
    64
    Units: Percentage of participants
        median (confidence interval 95%)
    35.5 (7.6 to 999)
    No statistical analyses for this end point

    Secondary: CD19+ B cell levels in peripheral blood by day 28 disease response by IRC assessment

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    End point title
    CD19+ B cell levels in peripheral blood by day 28 disease response by IRC assessment
    End point description
    The levels (%) of CD19+ total B cells amongst viable white blood cells (WBC) in peripheral blood
    End point type
    Secondary
    End point timeframe
    Enrollment/Pre-Chemotherapy; Pre-infusion; Baseline; Day 7; Day 14; Day 21; Day 28; Month 3; Month 6; Month 9; Month 12; Month 24; Month 36
    End point values
    CR/CRi Unknown No Response
    Number of subjects analysed
    52
    6
    6
    Units: Percentage of participants
    arithmetic mean (standard deviation)
        Enrollment/Pre-Chemotherapy (n=50, 6,6,)
    26.8 ± 28.733
    32.66 ± 28.102
    52.29 ± 36.758
        Pre-infusion (n=1,0,1)
    0.02 ± 999
    46.80 ± 999
    999 ± 999
        Baseline(n=50, 6, 6)
    25.11 ± 28.584
    29.50 ± 24.466
    52.29 ± 36.758
        Day 7 (n=45, 6, 6)
    1.06 ± 3.735
    23.18 ± 38.772
    34.40 ± 46.922
        Day 14 (n=50, 6, 5)
    0.73 ± 5.096
    3.43 ± 7.520
    33.76 ± 45.359
        Day 21 (n=46, 6, 5)
    0.01 ± 0.017
    16.13 ± 35.929
    19.67 ± 32.553
        Day 28 (n=48,6,3)
    0.02 ± 0.069
    0.02 ± 0.012
    34.97 ± 36.648
        Month 3 (n=44,1,2)
    0.79 ± 1.971
    11.26 ± 15.917
    0.57 ± 999
        Month 6 (n=37,1,1)
    1.86 ± 7.958
    0.01 ± 999
    9.70 ± 999
        Month 9 (n=27,0,0)
    0.63 ± 2.180
    999 ± 999
    999 ± 999
        Month 12 (n=27,0,0)
    0.85 ± 2.420
    999 ± 999
    999 ± 999
        Month 24 (n=14,0,0)
    1.74 ± 3.446
    999 ± 999
    999 ± 999
        Month 36 (n=6,0,0)
    1.10 ± 2.106
    999 ± 999
    999 ± 999
    No statistical analyses for this end point

    Secondary: key inflammatory markers and cytokine parameters in blood within 1 month by maximum cytokine release syndrome (CRS) grade: C Reactive Protein (CRP)

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    End point title
    key inflammatory markers and cytokine parameters in blood within 1 month by maximum cytokine release syndrome (CRS) grade: C Reactive Protein (CRP)
    End point description
    C-Reactive Protein at Pre-infusion, baseline, and change from baseline for Days 7, 14, 21, 28, Month 3
    End point type
    Secondary
    End point timeframe
    Pre-infusion, Baseline, Day 7, Day 14, Day 21, Day 28, Month 3
    End point values
    NO CRS Grade 1/2 Grade 3 Grade 4 All Participants
    Number of subjects analysed
    14
    31
    8
    11
    64
    Units: mg/L
    median (full range (min-max))
        Pre-infusion (n=14,29,8,9,60)
    9.21 (2.9 to 34.0)
    8.27 (2.0 to 1530.0)
    7.45 (0.6 to 50.0)
    9.00 (2.0 to 153.0)
    9.00 (0.6 to 1530.0)
        Baseline (BL) (n=14,30,8,9,61)
    9.21 (2.9 to 34.0)
    9.04 (2.0 to 1530.0)
    7.45 (0.6 to 50.0)
    9.00 (2.0 to 153.0)
    9.00 (0.6 to 1530.0)
        Change from BL Day7 (n=14, 30,8,9,61)
    0.00 (-15.0 to 25.0)
    15.00 (-460.0 to 215.0)
    79.55 (-2.0 to 380.0)
    108.00 (-125.0 to 255.0)
    9.10 (-460.0 to 380.0)
        Change from BL Day 14 (n=14,30,8,9,61)
    0.00 (-20.0 to 24.0)
    0.00 (-1031.0 to 215.0)
    10.50 (-42.0 to 199.0)
    15.70 (-148.0 to 100.0)
    0.00 (-1031.0 to 215.0)
        Change from BL Day 21 (n=14,28,8,7,57)
    0.00 (-14.0 to 29.5)
    -0.80 (-1460.0 to 677.0)
    2.00 (-42.0 to 37.0)
    -3.00 (-57.0 to 73.0)
    0.00 (-1460.0 to 677.0)
        Change from BL Day 28 (n=14,27,8,9,59)
    0.00 (-15.0 to 47.0)
    -0.70 (-1487.0 to 47.0)
    1.50 (-45.0 to 55.0)
    -3.00 (-151.0 to 27.0)
    0.00 (-1487.0 to 55.0)
        Change from BL Month 3 (n=11,23,5,7,46)
    0.00 (-12.1 to 101.0)
    -1.00 (-1501.0 to 7.1)
    0.00 (-3.0 to 120.5)
    -1.00 (-149.0 to 13.0)
    -0.65 (-1501.0 to 120.5)
    No statistical analyses for this end point

    Secondary: key inflammatory markers and cytokine parameters in blood within 1 month by maximum cytokine release syndrome (CRS) grade: Ferritin

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    End point title
    key inflammatory markers and cytokine parameters in blood within 1 month by maximum cytokine release syndrome (CRS) grade: Ferritin
    End point description
    Ferritin at Pre-infusion, baseline, and change from baseline for Days 7, 14, 21, 28, Month 3
    End point type
    Secondary
    End point timeframe
    Pre-infusion, Baseline, Day 7, Day 14, Day 21, Day 28, Month 3
    End point values
    NO CRS Grade 1/2 Grade 3 Grade 4 All Participants
    Number of subjects analysed
    14
    31
    8
    11
    64
    Units: ug/L
    median (full range (min-max))
        Pre-infusion (n=14,26,8,9,54)
    1865.20 (459.0 to 5015.0)
    2202.22 (230.0 to 18061.0)
    1906.95 (357.0 to 4200.0)
    2078.40 (487.0 to 13553.9)
    1983.90 (230.0 to 18061.0)
        Baseline (BL) (n=14,30,8,9,61)
    1865.20 (459.0 to 5015.0)
    2202.22 (230.0 to 18061.0)
    1906.95 (357.0 to 4200.0)
    2078.40 (487.0 to 13553.9)
    1983.90 (230.0 to 18061.0)
        Change from BL Day7 (n=14, 29,8,9,60)
    -146.50 (-721.4 to 710.0)
    377.80 (-1468.0 to 522220.0)
    22735.10 (-330.0 to 182380.0)
    23788.71 (-161.0 to 269529.0)
    358.90 (-1468.0 to 269529.0)
        Change from BL Day 14 (n=14,30,8,9,61)
    -321.30 (-2035.1 to 520.0)
    861.50 (-3483.3 to 59435.9)
    10728.40 (1262.0 to 104170.0)
    18580.01 (707.0 to 110421.6)
    973.00 (-3483.3 to 110421.6)
        Change from BL Day 21 (n=14,29,8,8,59)
    58.00 (-2302.0 to 524.0)
    331.00 (-3571.6 to 43336.0)
    3299.85 (-600.0 to 121100.0)
    3199.00 (-17.0 to 12957.4)
    490.00 (-3571.6 to 121100.0)
        Change from BL Day 28 (n=14,27,8,9,58)
    121.10 (-2952.0 to 1510.0)
    283.00 (-6443. to 9879.0)
    1104.00 (-890.0 to 331000.0)
    1211.00 (-606.0 to 12957.4)
    280.50 (-6443.7 to 33100.0)
        Change from BL Month 3 (n=11,23,5,7,46)
    -124.90 (-2418.0 to 1985.5)
    -358.00 (-5415.0 to 7050.0)
    -487.60 (-1500.0 to 8140.0)
    -377.00 (-1808.2 to 2641.6)
    -330.00 (-5415.0 to 8140.0)
    No statistical analyses for this end point

    Secondary: key inflammatory markers and cytokine parameters in blood within 1 month by maximum cytokine release syndrome (CRS) grade: INF-gamma

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    End point title
    key inflammatory markers and cytokine parameters in blood within 1 month by maximum cytokine release syndrome (CRS) grade: INF-gamma
    End point description
    INF-gamma at Pre-infusion, baseline, and change from baseline for Days 7, 14, 21, 28, Month 3
    End point type
    Secondary
    End point timeframe
    Pre-infusion, Baseline, Day 7, Day 14, Day 21, Day 28, Month 3
    End point values
    NO CRS Grade 1/2 Grade 3 Grade 4 All Participants
    Number of subjects analysed
    14
    31
    8
    11
    64
    Units: pg/mL
    median (full range (min-max))
        Pre-infusion (n=14,30,8,9,61)
    29.63 (1.0 to 283.0)
    23.39 (1.0 to 242.8)
    15.73 (6.4 to 31.5)
    5.79 (2.5 to 34.1)
    20.22 (1.0 to 283.0)
        Baseline (BL) (n=14,31,8,9,63)
    29.63 (1.0 to 283.0)
    22.51 (1.0 to 242.8)
    15.73 (6.4 to 31.5)
    4.77 (1.0 to 34.1)
    15.75 (1.0 to 283.0)
        Change from BL Day7 (n=14, 31,8,10,63)
    0.47 (-167.9 to 140.6)
    52.59 (-201.2 to 39452.4)
    3023.82 (-14.7 to 162376.0)
    1347.48 (60.2 to 89599.0)
    72.09 (-201.2 to 162376.0)
        Change from BL Day 14 (n=13,30,8,9,60)
    -5.10 (-278.3 to 39.2)
    -4.44 (-194.8 to 131.1)
    58.65 (-14.3 to 1328.7)
    102.04 (-2.2 to 8925.9)
    1.32 (-278.3 to 8925.9)
        Change from BL Day 21 (n=13,29,8,8,58)
    -4.97 (-264.0 to 58.5)
    1.06 (-219.7 to 1384.6)
    0.53 (-22.8 to 1048.7)
    5.23 (-4.0 to 167.1)
    -0.89 (-264.0 to 1384.6)
        Change from BL Day 28 (n=14,28,8,9,59)
    -6.93 (-269.9 to 60.4)
    0.20 (-223.6 to 738.8)
    -1.19 (-26.1 to 187.7)
    0.36 (-4.7 to 138.4)
    -0.62 (-269.9 to 738.8)
        Change from BL Month 3 (n=11,22,6,6,45)
    -6.08 (-278.6 to 167.5)
    -14.58 (-173.9 to 7.6)
    21.25 (-7.7 to 37.2)
    -0.67 (-4.4 to 23.1)
    -5.71 (-278.6 to 167.5)
    No statistical analyses for this end point

    Secondary: key inflammatory markers and cytokine parameters in blood within 1 month by maximum cytokine release syndrome (CRS) grade: Interleuken-6 (IL-6)

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    End point title
    key inflammatory markers and cytokine parameters in blood within 1 month by maximum cytokine release syndrome (CRS) grade: Interleuken-6 (IL-6)
    End point description
    IL-6 at Pre-infusion, baseline, and change from baseline for Days 7, 14, 21, 28, Month 3
    End point type
    Secondary
    End point timeframe
    Pre-infusion, Baseline, Day 7, Day 14, Day 21, Day 28, Month 3
    End point values
    NO CRS Grade 1/2 Grade 3 Grade 4 All Participants
    Number of subjects analysed
    14
    31
    8
    11
    64
    Units: pg/mL
    median (full range (min-max))
        Pre-infusion (n=14,30,8,9,61)
    2.42 (0.4 to 12.0)
    2.89 (0.2 to 19.6)
    1.00 (0.8 to 9.4)
    2.27 (0.4 to 6.2)
    2.27 (0.2 to 19.6)
        Baseline (BL) (n=14,31,8,10,63)
    2.42 (0.4 to 12.0)
    2.83 (0.2 to 19.6)
    1.00 (0.8 to 9.4)
    1.84 (0.2 to 6.2)
    1.99 (0.2 to 19.6)
        Change from BL Day7 (n=14,31,8,10,63)
    -0.23 (-9.6 to 4.3)
    2.64 (-13.1 to 61.3)
    52.75 (-0.6 to 7201.6)
    141.68 (1.3 to 12615.8)
    2.64 (-13.1 to 12615.8)
        Change from BL Day 14 (n=13,30,8,9,60)
    -0.36 (-2.3 to 4.1)
    -0.67 (-13.4 to 21.5)
    8.88 (-0.6 to 30.4)
    165.16 (-0.2 to 5734.8)
    -0.11 (-13.4 to 5734.8)
        Change from BL Day 21 (n=13,29,8,8,58)
    -0.97 (-5.3 to 5.3)
    -0.46 (-15.4 to 103.4)
    1.65 (-0.6 to 265.2)
    50.75 (-0.2 to 5734.8)
    -0.09 (-15.4 to 5734.8)
        Change from BL Day 28 (n=14,28,8,9,59)
    -0.98 (-7.8 to 1.9)
    -0.28 (-17.5 to 33.0)
    0.91 (-0.6 to 138.6)
    38.13 (-0.0 to 2148.4)
    -0.03 (-17.5 to 2148.4)
        Change from BL Month 3 (n=11,22,6,6,45)
    0.34 (-10.8 to 22.7)
    -0.59 (-8.9 to 1.2)
    0.56 (-0.6 to 30.3)
    0.40 (-0.9 to 3.2)
    -0.19 (-10.8 to 30.3)
    No statistical analyses for this end point

    Secondary: key inflammatory markers and cytokine parameters in blood within 1 month by maximum cytokine release syndrome (CRS) grade: Interleuken-2 (IL-2)

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    End point title
    key inflammatory markers and cytokine parameters in blood within 1 month by maximum cytokine release syndrome (CRS) grade: Interleuken-2 (IL-2)
    End point description
    IL-2 at Pre-infusion, baseline, and change from baseline for Days 7, 14, 21, 28, Month 3
    End point type
    Secondary
    End point timeframe
    Pre-infusion, Baseline, Day 7, Day 14, Day 21, Day 28, Month 3
    End point values
    NO CRS Grade 1/2 Grade 3 Grade 4 All Participants
    Number of subjects analysed
    14
    31
    8
    11
    64
    Units: pg/mL
    median (full range (min-max))
        Pre-infusion (n=14,30,8,9,61)
    2.3 (2.3 to 2.3)
    2.3 (2.3 to 2.3)
    2.3 (2.3 to 2.3)
    2.3 (2.3 to 2.3)
    2.3 (2.3 to 2.3)
        Baseline (BL) (n=14,31,8,10, 63)
    2.3 (2.3 to 2.3)
    2.3 (2.3 to 2.3)
    2.3 (2.3 to 2.3)
    2.3 (2.3 to 2.3)
    2.3 (2.3 to 2.3)
        Change from BL Day7 (n=14, 31,8,10,63)
    3.33 (0.0 to 6.7)
    3.15 (0.0 to 7.0)
    13.14 (5.0 to 63.7)
    7.48 (2.9 to 12.1)
    5.16 (0.0 to 63.7)
        Change from BL Day 14 (n=13,30,8,9,60)
    999 (999 to 999)
    0.00 (0.00 to 0.00)
    999 (999 to 999)
    4.56 (4.56 to 4.6)
    0.00 (0.0 to 4.6)
        Change from BL Day 21 (n=13,29,8,8,58)
    999 (999 to 999)
    999 (999 to 999)
    999 (999 to 999)
    999 (999 to 999)
    999 (999 to 999)
        Change from BL Day 28 (n=14,28,8,9,59)
    999 (999 to 999)
    999 (999 to 999)
    999 (999 to 999)
    999 (999 to 999)
    999 (999 to 999)
        Change from BL Month 3 (n=11,22,6,6,45)
    999 (999 to 999)
    999 (999 to 999)
    999 (999 to 999)
    999 (999 to 999)
    999 (999 to 999)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse Events are collected from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV). All Adverse events are reported in this record from First Patient First Treatment until Last Patient Last Visit.
    Adverse event reporting additional description
    Consistent with EudraCT disclosure specifications, Novartis has reported under the Serious adverse events field “number of deaths resulting from adverse events” all those deaths, resulting from serious adverse events that are deemed to be causally related to treatment by the investigator.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    22.0
    Reporting groups
    Reporting group title
    tisagenlecleucel (CTL019) - All
    Reporting group description
    Pediatric participants with r/r B-cell ALL

    Serious adverse events
    tisagenlecleucel (CTL019) - All
    Total subjects affected by serious adverse events
         subjects affected / exposed
    52 / 64 (81.25%)
         number of deaths (all causes)
    30
         number of deaths resulting from adverse events
    0
    Vascular disorders
    Embolism
         subjects affected / exposed
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Hypotension
         subjects affected / exposed
    7 / 64 (10.94%)
         occurrences causally related to treatment / all
    6 / 7
         deaths causally related to treatment / all
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Glioblastoma multiforme
         subjects affected / exposed
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Myelodysplastic syndrome
         subjects affected / exposed
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Immune system disorders
    Cytokine release syndrome
         subjects affected / exposed
    41 / 64 (64.06%)
         occurrences causally related to treatment / all
    44 / 44
         deaths causally related to treatment / all
    0 / 0
    Graft versus host disease in gastrointestinal tract
         subjects affected / exposed
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    Malaise
         subjects affected / exposed
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Physical deconditioning
         subjects affected / exposed
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Pyrexia
         subjects affected / exposed
    7 / 64 (10.94%)
         occurrences causally related to treatment / all
    2 / 9
         deaths causally related to treatment / all
    0 / 0
    Psychiatric disorders
    Delirium
         subjects affected / exposed
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Reproductive system and breast disorders
    Vaginal haemorrhage
         subjects affected / exposed
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Injury, poisoning and procedural complications
    Procedural pain
         subjects affected / exposed
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Transfusion related complication
         subjects affected / exposed
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 64 (1.56%)
         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 / 64 (1.56%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiac disorders
    Atrioventricular block second degree
         subjects affected / exposed
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Ventricular tachycardia
         subjects affected / exposed
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory failure
         subjects affected / exposed
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Hypoxia
         subjects affected / exposed
    4 / 64 (6.25%)
         occurrences causally related to treatment / all
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    Pleural effusion
         subjects affected / exposed
    2 / 64 (3.13%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Pulmonary oedema
         subjects affected / exposed
    2 / 64 (3.13%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Respiratory failure
         subjects affected / exposed
    3 / 64 (4.69%)
         occurrences causally related to treatment / all
    2 / 3
         deaths causally related to treatment / all
    0 / 1
    Blood and lymphatic system disorders
    Disseminated intravascular coagulation
         subjects affected / exposed
    2 / 64 (3.13%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Eosinophilia
         subjects affected / exposed
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    23 / 64 (35.94%)
         occurrences causally related to treatment / all
    23 / 27
         deaths causally related to treatment / all
    0 / 0
    Neutropenia
         subjects affected / exposed
    3 / 64 (4.69%)
         occurrences causally related to treatment / all
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    Nervous system disorders
    Embolic stroke
         subjects affected / exposed
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 1
    Encephalopathy
         subjects affected / exposed
    4 / 64 (6.25%)
         occurrences causally related to treatment / all
    4 / 4
         deaths causally related to treatment / all
    0 / 0
    Headache
         subjects affected / exposed
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Idiopathic intracranial hypertension
         subjects affected / exposed
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Seizure
         subjects affected / exposed
    4 / 64 (6.25%)
         occurrences causally related to treatment / all
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    Eye disorders
    Papilloedema
         subjects affected / exposed
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Vision blurred
         subjects affected / exposed
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    2 / 64 (3.13%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Enterocolitis
         subjects affected / exposed
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pancreatitis
         subjects affected / exposed
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Stomatitis
         subjects affected / exposed
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    4 / 64 (6.25%)
         occurrences causally related to treatment / all
    3 / 4
         deaths causally related to treatment / all
    0 / 0
    Renal failure
         subjects affected / exposed
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Skin and subcutaneous tissue disorders
    Ecchymosis
         subjects affected / exposed
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Musculoskeletal and connective tissue disorders
    Flank pain
         subjects affected / exposed
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Osteonecrosis
         subjects affected / exposed
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pain in extremity
         subjects affected / exposed
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Metabolism and nutrition disorders
    Acidosis
         subjects affected / exposed
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Decreased appetite
         subjects affected / exposed
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Dehydration
         subjects affected / exposed
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Tumour lysis syndrome
         subjects affected / exposed
    2 / 64 (3.13%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Bacterial sepsis
         subjects affected / exposed
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Campylobacter infection
         subjects affected / exposed
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Catheter site infection
         subjects affected / exposed
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cellulitis of male external genital organ
         subjects affected / exposed
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    Cholecystitis infective
         subjects affected / exposed
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Clostridium difficile colitis
         subjects affected / exposed
    2 / 64 (3.13%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Clostridium difficile infection
         subjects affected / exposed
    3 / 64 (4.69%)
         occurrences causally related to treatment / all
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    Corona virus infection
         subjects affected / exposed
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Enterovirus infection
         subjects affected / exposed
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastroenteritis norovirus
         subjects affected / exposed
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Herpes zoster
         subjects affected / exposed
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Parainfluenzae virus infection
         subjects affected / exposed
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pneumonia
         subjects affected / exposed
    2 / 64 (3.13%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Respiratory syncytial virus infection
         subjects affected / exposed
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Respiratory tract infection viral
         subjects affected / exposed
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Rhinovirus infection
         subjects affected / exposed
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Rotavirus infection
         subjects affected / exposed
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Septic embolus
         subjects affected / exposed
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 1
    Staphylococcal infection
         subjects affected / exposed
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    2 / 64 (3.13%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Vascular device infection
         subjects affected / exposed
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Viral upper respiratory tract infection
         subjects affected / exposed
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Vulvovaginal candidiasis
         subjects affected / exposed
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    tisagenlecleucel (CTL019) - All
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    64 / 64 (100.00%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    12 / 64 (18.75%)
         occurrences all number
    14
    Hypotension
         subjects affected / exposed
    9 / 64 (14.06%)
         occurrences all number
    9
    Immune system disorders
    Cytokine release syndrome
         subjects affected / exposed
    19 / 64 (29.69%)
         occurrences all number
    19
    Hypogammaglobulinaemia
         subjects affected / exposed
    33 / 64 (51.56%)
         occurrences all number
    36
    General disorders and administration site conditions
    Catheter site pain
         subjects affected / exposed
    4 / 64 (6.25%)
         occurrences all number
    4
    Chills
         subjects affected / exposed
    10 / 64 (15.63%)
         occurrences all number
    11
    Fatigue
         subjects affected / exposed
    15 / 64 (23.44%)
         occurrences all number
    16
    Pain
         subjects affected / exposed
    4 / 64 (6.25%)
         occurrences all number
    4
    Pyrexia
         subjects affected / exposed
    21 / 64 (32.81%)
         occurrences all number
    30
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    7 / 64 (10.94%)
         occurrences all number
    7
    Confusional state
         subjects affected / exposed
    6 / 64 (9.38%)
         occurrences all number
    6
    Injury, poisoning and procedural complications
    Infusion related reaction
         subjects affected / exposed
    4 / 64 (6.25%)
         occurrences all number
    4
    Procedural pain
         subjects affected / exposed
    5 / 64 (7.81%)
         occurrences all number
    5
    Investigations
    Activated partial thromboplastin time prolonged
         subjects affected / exposed
    5 / 64 (7.81%)
         occurrences all number
    7
    Alanine aminotransferase increased
         subjects affected / exposed
    21 / 64 (32.81%)
         occurrences all number
    27
    Aspartate aminotransferase increased
         subjects affected / exposed
    20 / 64 (31.25%)
         occurrences all number
    28
    Blood bilirubin increased
         subjects affected / exposed
    8 / 64 (12.50%)
         occurrences all number
    12
    Blood creatinine increased
         subjects affected / exposed
    9 / 64 (14.06%)
         occurrences all number
    12
    Blood fibrinogen decreased
         subjects affected / exposed
    4 / 64 (6.25%)
         occurrences all number
    5
    Blood immunoglobulin M decreased
         subjects affected / exposed
    4 / 64 (6.25%)
         occurrences all number
    4
    International normalised ratio increased
         subjects affected / exposed
    9 / 64 (14.06%)
         occurrences all number
    11
    Lymphocyte count decreased
         subjects affected / exposed
    16 / 64 (25.00%)
         occurrences all number
    20
    Neutrophil count decreased
         subjects affected / exposed
    28 / 64 (43.75%)
         occurrences all number
    44
    Platelet count decreased
         subjects affected / exposed
    20 / 64 (31.25%)
         occurrences all number
    36
    Prothrombin time prolonged
         subjects affected / exposed
    9 / 64 (14.06%)
         occurrences all number
    12
    Weight decreased
         subjects affected / exposed
    4 / 64 (6.25%)
         occurrences all number
    4
    White blood cell count decreased
         subjects affected / exposed
    35 / 64 (54.69%)
         occurrences all number
    43
    Cardiac disorders
    Sinus tachycardia
         subjects affected / exposed
    6 / 64 (9.38%)
         occurrences all number
    6
    Tachycardia
         subjects affected / exposed
    15 / 64 (23.44%)
         occurrences all number
    16
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    14 / 64 (21.88%)
         occurrences all number
    19
    Epistaxis
         subjects affected / exposed
    10 / 64 (15.63%)
         occurrences all number
    12
    Hypoxia
         subjects affected / exposed
    6 / 64 (9.38%)
         occurrences all number
    7
    Nasal congestion
         subjects affected / exposed
    5 / 64 (7.81%)
         occurrences all number
    5
    Oropharyngeal pain
         subjects affected / exposed
    6 / 64 (9.38%)
         occurrences all number
    6
    Pleural effusion
         subjects affected / exposed
    6 / 64 (9.38%)
         occurrences all number
    6
    Pulmonary oedema
         subjects affected / exposed
    5 / 64 (7.81%)
         occurrences all number
    5
    Rhinitis allergic
         subjects affected / exposed
    4 / 64 (6.25%)
         occurrences all number
    5
    Rhinorrhoea
         subjects affected / exposed
    6 / 64 (9.38%)
         occurrences all number
    6
    Tachypnoea
         subjects affected / exposed
    5 / 64 (7.81%)
         occurrences all number
    5
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    27 / 64 (42.19%)
         occurrences all number
    38
    Lymphopenia
         subjects affected / exposed
    4 / 64 (6.25%)
         occurrences all number
    4
    Neutropenia
         subjects affected / exposed
    8 / 64 (12.50%)
         occurrences all number
    10
    Thrombocytopenia
         subjects affected / exposed
    10 / 64 (15.63%)
         occurrences all number
    13
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    6 / 64 (9.38%)
         occurrences all number
    8
    Headache
         subjects affected / exposed
    24 / 64 (37.50%)
         occurrences all number
    37
    Eye disorders
    Periorbital oedema
         subjects affected / exposed
    4 / 64 (6.25%)
         occurrences all number
    4
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    11 / 64 (17.19%)
         occurrences all number
    15
    Constipation
         subjects affected / exposed
    7 / 64 (10.94%)
         occurrences all number
    8
    Diarrhoea
         subjects affected / exposed
    22 / 64 (34.38%)
         occurrences all number
    26
    Nausea
         subjects affected / exposed
    25 / 64 (39.06%)
         occurrences all number
    33
    Vomiting
         subjects affected / exposed
    27 / 64 (42.19%)
         occurrences all number
    43
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    5 / 64 (7.81%)
         occurrences all number
    6
    Haematuria
         subjects affected / exposed
    5 / 64 (7.81%)
         occurrences all number
    6
    Skin and subcutaneous tissue disorders
    Dry skin
         subjects affected / exposed
    5 / 64 (7.81%)
         occurrences all number
    5
    Erythema
         subjects affected / exposed
    5 / 64 (7.81%)
         occurrences all number
    6
    Hyperhidrosis
         subjects affected / exposed
    4 / 64 (6.25%)
         occurrences all number
    5
    Petechiae
         subjects affected / exposed
    4 / 64 (6.25%)
         occurrences all number
    4
    Pruritus
         subjects affected / exposed
    4 / 64 (6.25%)
         occurrences all number
    4
    Rash
         subjects affected / exposed
    8 / 64 (12.50%)
         occurrences all number
    9
    Rash maculo-papular
         subjects affected / exposed
    5 / 64 (7.81%)
         occurrences all number
    5
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    5 / 64 (7.81%)
         occurrences all number
    6
    Myalgia
         subjects affected / exposed
    5 / 64 (7.81%)
         occurrences all number
    5
    Pain in extremity
         subjects affected / exposed
    10 / 64 (15.63%)
         occurrences all number
    11
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    21 / 64 (32.81%)
         occurrences all number
    23
    Hypernatraemia
         subjects affected / exposed
    4 / 64 (6.25%)
         occurrences all number
    6
    Hyperphosphataemia
         subjects affected / exposed
    8 / 64 (12.50%)
         occurrences all number
    12
    Hypoalbuminaemia
         subjects affected / exposed
    5 / 64 (7.81%)
         occurrences all number
    5
    Hypokalaemia
         subjects affected / exposed
    19 / 64 (29.69%)
         occurrences all number
    23
    Hypophosphataemia
         subjects affected / exposed
    10 / 64 (15.63%)
         occurrences all number
    10
    Infections and infestations
    Gastroenteritis
         subjects affected / exposed
    4 / 64 (6.25%)
         occurrences all number
    4
    Influenza
         subjects affected / exposed
    4 / 64 (6.25%)
         occurrences all number
    4
    Otitis media
         subjects affected / exposed
    4 / 64 (6.25%)
         occurrences all number
    6
    Rhinovirus infection
         subjects affected / exposed
    4 / 64 (6.25%)
         occurrences all number
    6
    Sinusitis
         subjects affected / exposed
    4 / 64 (6.25%)
         occurrences all number
    5
    Upper respiratory tract infection
         subjects affected / exposed
    8 / 64 (12.50%)
         occurrences all number
    10
    Urinary tract infection
         subjects affected / exposed
    4 / 64 (6.25%)
         occurrences all number
    6

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    14 Aug 2014
    The protocol was amended in order to include additional safety information and includes Health Authority feedback regarding reporting of SAEs including CRS and deaths, updating CTL019 dosing, staggered-enrollment design, follow-up time required after a live birth, influenza testing 10 days prior to infusion, general toxicity management, and modified Serious Adverse Event (SAE) and Adverse Event (AE) reporting.
    28 Aug 2015
    The protocol was amended to: Ensure full alignment with the agreed binding measures detailed in the Pediatric Investigation Plan (PIP) opinion of the Paediatric Committee of the European Medicines Agency, issued on 20 March 2015, including the expansion of inclusion criteria to enroll patients with relapsed or refractory B-cell lymphoblastic lymphoma; Address recommendations from EMA Scientific Advice letter on 25 April 2014; Transfer the trial sponsorship from University of Pennsylvania IND to Novartis IND. Additional PK and cytokine sample time points were added to better define cell expansion and CRS, as well as the addition of exploratory endpoints that did not impact total sample collection requirements. Testing for CMV and EBV is not required at screening per current guidelines for autologous blood product therapy. Other changes have been instituted for purposes of clarity and feasibility based on experiences from ongoing trials
    28 Apr 2016
    The protocol was amended to institute updates on safety, CTL019 target cell dose ranges, patient management, and eligibility criteria based on experiences from ongoing trials and recommendations from Health Authorities, Study Steering Committee, and Data Monitoring Committee.

    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.
    Due to EudraCT system limitations, which EMA is aware of, data using 999 as data points in this record are not an accurate representation of the clinical trial results. Please use https://www.novctrd.com/CtrdWeb/home.nov for complete trial results.
    The status of studies in GB is no longer updated from 1.1.2021
    For the UK, as from 1.1.2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI
    EU Clinical Trials Register Service Desk: https://servicedesk.ema.europa.eu
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