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    Clinical Trial Results:
    Phase II trial of Tisagenlecleucel in Elderly Patients with First-Relapsed or Primary Refractory Agressive B-cell Non-Hodgkin Lymphoma

    Summary
    EudraCT number
    		 2019-002930-35
    Trial protocol
    		 DE  
    Global end of trial date
    24 Feb 2023

    Results information
    Results version number
    		 v1(current)
    This version publication date
    20 Jul 2023
    First version publication date
    20 Jul 2023
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    Uni-Koeln-3903
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT04161118
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 ClinicalTrials.gov: NCT04161118
    Sponsors
    Sponsor organisation name
    University of Cologne
    Sponsor organisation address
    Albertus-Magnus-Platz, Köln, Germany, 50923
    Public contact
    Cologne Lymphoma Working Group (C-LWG), University Hospital Cologne, 0049 22147896533, TIGER-CTL019-Studienteam@uk-koeln.de
    Scientific contact
    Cologne Lymphoma Working Group (C-LWG), University Hospital Cologne, 0049 22147896533, TIGER-CTL019-Studienteam@uk-koeln.de
    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
    19 Jun 2023
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    24 Feb 2023
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The primary objective was to estimate efficacy of treatment with tisagenlecleucel in elderly patients with relapsed or refractory aggressive B-cell non-Hodgkin lymphoma (r/r aNHL).
    Protection of trial subjects
    Written informed consent before study entry, central response evaluation
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    02 Aug 2021
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Germany: 3
    Worldwide total number of subjects
    3
    EEA total number of subjects
    3
    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)
    0
    From 65 to 84 years
    3
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 We enrolled 3 participants from 3 trial sites between 02 Aug 2021 and 28 Oct 2021.

    Pre-assignment
    Screening details
    		 Main entry criteria were histologically confirmed first relapse of aNHL within 365 days after rituximab- and anthracycline-containing first-line immunochemotherapy or refractory to respective 1st-line therapy, ineligibility for either autologous or allogeneic SCT, age <= 80 years

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

    Arms
    Arm title
    		 TIGER-CTL019
    Arm description
    		 Patients received a single tisagenlecleucel infusion in a range of 0.6 – 6.0 x 108 CAR-positive viable T cells.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Tisagenlecleucel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Dispersion for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    The recommended dose consists of a single IV infusion of 0.6 – 6.0 x 10^8 CAR-positive viable T cells. The viability of the entire cells has to be not less than 70%. Tisagenlecleucel infusion was to start 2 - 8 days after completion of LD chemotherapy. Vital signs were monitored before, during, and following tisagenlecleucel infusion.

    Number of subjects in period 1
    		TIGER-CTL019
    Started
    3
    Completed
    3

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Enrollment
    Reporting group description
    		 -

    Reporting group values
    		 Enrollment Total
    Number of subjects
    		 3 3
    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)
    		 0 0
        Adolescents (12-17 years)
    		 0 0
        Adults (18-64 years)
    		 0 0
        From 65-84 years
    		 3 3
        85 years and over
    		 0 0
    Gender categorical
    Units: Subjects
        Female
    		 2 2
        Male
    		 1 1

    End points

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    End points reporting groups
    Reporting group title
    TIGER-CTL019
    Reporting group description
    		 Patients received a single tisagenlecleucel infusion in a range of 0.6 – 6.0 x 108 CAR-positive viable T cells.

    Primary: Complete metabolic response rate

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    End point title
    		 Complete metabolic response rate [1]
    End point description
    The following special cases should be considered: • If in the restaging after 4 weeks a PET/CT is performed and a CMR is reached according to central review, the patient will count as responder for the primary endpoint irrespective of their response after 12 weeks. • If in the restaging after 4 weeks no PET/CT is performed, images are not available for central review, or no CMR has been reached according to central review, the response in the restaging after 12 weeks is used for determination of the primary endpoint. • If the restaging after 12 weeks is not performed or images are not available for panel review and the patient did not already reach a CMR by central review in the restaging after 4 weeks, the patient will count as failure for the primary endpoint. Patients will be excluded from analysis of the primary endpoint if their diagnosis of r/r aNHL is disconfirmed or if they did not receive any investigational drug for any reasons.
    End point type
    Primary
    End point timeframe
    Efficacy will be determined using the complete metabolic response (CMR) rate, which is the proportion of patients with a Deauville score of 1–3 according to central review up until the restaging 12 weeks after treatment with tisagenlecleucel.
    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: The TIGER-CTL019 trial was prematurely closed on 24 Feb 2023 with a total of 3 patients enrolled. Therefore, the statistical analyses planned in the trial protocol were not done, as stated in the statistical analysis plan.
    End point values
    		 TIGER-CTL019
    Number of subjects analysed
    3
    Units: subjects
        CMR
    2
        Non-CMR
    1
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All AEs that occured from the time of signing the ICF up to the end of the trial had to be reported.
    Adverse event reporting additional description
    AEs were assessed on the regular trial CRFs. SAEs were additionally assessed on specific forms. SAEs may thus be reported twice; non-serious AEs might contain SAEs; non-serious and SAEs might not add up to a total number of AEs. All AEs of CTCAE grade >=1 will be reported.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    10.1
    Reporting groups
    Reporting group title
    TIGER-CTL019
    Reporting group description
    		 Patients received a single tisagenlecleucel infusion in a range of 0.6 – 6.0 x 108 CAR-positive viable T cells.

    Serious adverse events
    		 TIGER-CTL019
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 3 (100.00%)
         number of deaths (all causes)
    2
         number of deaths resulting from adverse events
    1
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Disease progression
         subjects affected / exposed
    1 / 3 (33.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiac disorders
    Tachyarrhythmia
         subjects affected / exposed
    1 / 3 (33.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 3 (33.33%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Surgical and medical procedures
    Pituitary tumour removal
         subjects affected / exposed
    1 / 3 (33.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Nervous system disorders
    Neurotoxicity
         subjects affected / exposed
    1 / 3 (33.33%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    1 / 3 (33.33%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Musculoskeletal and connective tissue disorders
    Muscular weakness
         subjects affected / exposed
    1 / 3 (33.33%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Sepsis
         subjects affected / exposed
    1 / 3 (33.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Cytokine release syndrome
         subjects affected / exposed
    1 / 3 (33.33%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    1 / 3 (33.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 1%
    Non-serious adverse events
    		 TIGER-CTL019
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    3 / 3 (100.00%)
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    2 / 3 (66.67%)
         occurrences all number
    4
    Other general disorders and administration site conditions
         subjects affected / exposed
    1 / 3 (33.33%)
         occurrences all number
    2
    Immune system disorders
    Cytokine release syndrome
         subjects affected / exposed
    2 / 3 (66.67%)
         occurrences all number
    2
    Immune effector cell-associated neurotoxicity syndrome
         subjects affected / exposed
    2 / 3 (66.67%)
         occurrences all number
    3
    Respiratory, thoracic and mediastinal disorders
    Respiratory, thoracic and mediastinal disorders
         subjects affected / exposed
    1 / 3 (33.33%)
         occurrences all number
    1
    Psychiatric disorders
    Psychiatric disorders
         subjects affected / exposed
    1 / 3 (33.33%)
         occurrences all number
    1
    Cardiac disorders
    Cardiac disorders
         subjects affected / exposed
    1 / 3 (33.33%)
         occurrences all number
    1
    Nervous system disorders
    Nervous system disorders
         subjects affected / exposed
    1 / 3 (33.33%)
         occurrences all number
    3
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    3 / 3 (100.00%)
         occurrences all number
    16
    Thrombocytopenia
         subjects affected / exposed
    3 / 3 (100.00%)
         occurrences all number
    15
    Leukopenia
         subjects affected / exposed
    3 / 3 (100.00%)
         occurrences all number
    18
    Other blood and lymphatic system disorders
         subjects affected / exposed
    2 / 3 (66.67%)
         occurrences all number
    3
    Eye disorders
    Eye disorders
         subjects affected / exposed
    1 / 3 (33.33%)
         occurrences all number
    3
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    2 / 3 (66.67%)
         occurrences all number
    2
    Nausea
         subjects affected / exposed
    1 / 3 (33.33%)
         occurrences all number
    2
    Other gastrointestinal disorders
         subjects affected / exposed
    3 / 3 (100.00%)
         occurrences all number
    6
    Skin and subcutaneous tissue disorders
    Skin and subcutaneous tissue disorders
         subjects affected / exposed
    1 / 3 (33.33%)
         occurrences all number
    1
    Renal and urinary disorders
    Renal and urinary disorders
         subjects affected / exposed
    1 / 3 (33.33%)
         occurrences all number
    2
    Endocrine disorders
    Hypothyroidism
         subjects affected / exposed
    1 / 3 (33.33%)
         occurrences all number
    1
    Other endocrine disorders
         subjects affected / exposed
    1 / 3 (33.33%)
         occurrences all number
    1
    Musculoskeletal and connective tissue disorders
    Musculoskeletal and connective tissue disorders
         subjects affected / exposed
    1 / 3 (33.33%)
         occurrences all number
    1
    Infections and infestations
    Infections and infestations
         subjects affected / exposed
    1 / 3 (33.33%)
         occurrences all number
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    24 Feb 2023
    Premature termination of the trial
    -

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    The trial was prematurely closed with 3 patients enrolled. Therefore, the statistical analyses planned in the trial protocol were not done, as stated in the SAP V1.0.
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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