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    Clinical Trial Results:
    WT1 TCR Gene Therapy for Leukaemia: A Phase I/II Safety and Toxicity Study

    Summary
    EudraCT number
    2006-004950-25
    Trial protocol
    GB  
    Global end of trial date
    17 Apr 2018

    Results information
    Results version number
    v1(current)
    This version publication date
    11 Mar 2020
    First version publication date
    11 Mar 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    D-00272-CT2014001
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    -
    WHO universal trial number (UTN)
    -
    Other trial identifiers
    ClinicalTrials.gov: NCT01621724
    Sponsors
    Sponsor organisation name
    Cell Medica
    Sponsor organisation address
    2617 Bissonnet St, Suite 300, Houston, United States, TX 77005
    Public contact
    Clinical Trials Information, Cell Medica, 1 7132313224, info@cellmedica.co.uk
    Scientific contact
    Clinical Trials Information, Cell Medica, 1 7132313224, info@cellmedica.co.uk
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    17 Apr 2018
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    17 Apr 2018
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    PRIMARY OBJECTIVES 1) To determine the feasibility of TCR gene transfer in a clinical setting. 2) To identify organ toxicities or other side effects related to the re-infusion of TCR-Transduced T cells. 3) Propose a safe dose of TCR-Transduced T cells for Phase II evaluation.
    Protection of trial subjects
    This study was conducted in accordance with the protocol, the International Conference on Harmonisation Guidelines on Good Clinical Practice (GCP), the Declaration of Helsinki (Edinburgh 2000) and applicable regulatory requirements. The study was conducted under a Clinical Trials Authorisation and approval from the Medicines and Healthcare products Regulatory Agency was obtained.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    08 Sep 2014
    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
    United Kingdom: 7
    Worldwide total number of subjects
    7
    EEA total number of subjects
    7
    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)
    1
    From 65 to 84 years
    6
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    This study was conducted at 2 centres in the UK.

    Pre-assignment
    Screening details
    The study aimed to enrol up to 18 HLA-A*0201 positive patients aged between 18 and 75 years with AML or CML confirmed by morphology, histology, immunophenotyping and cytogenetics. Patients were to have a life expectancy of ≥16 weeks, a World Health Organisation (WHO) performance status of 0 to 2, and a total peripheral blood lymphocyte count of >0.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Cohort 1
    Arm description
    Patients in Cohort 1 received standard conditioning [fludarabine plus methylprednisolone] and the lower dose of ≤2x10^7/kg T cells
    Arm type
    Experimental

    Investigational medicinal product name
    Gene-modified Wilms’ Tumour Antigen 1 (WT1) T cell receptor (TCR)-transduced autologous T cells
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Bulk transduced WT1 TCR T-lymphocytes were administered by iv infusion over 30 to 60 minutes through a large peripheral vein or centrally through a Hickman line at a dose of ≤2x10^7/kg after standard conditioning (fludarabine plus methylprednisolone). Patients were also administered 106 units/m2 interleukin-2 (IL-2) by subcutaneous injection immediately after T cell infusion and for the next 4 days.

    Arm title
    Cohort 2A
    Arm description
    Patients in Cohort 2A received standard conditioning [fludarabine plus methylprednisolone] and the higher dose of ≤1x10^8/kg T cells
    Arm type
    Experimental

    Investigational medicinal product name
    Gene-modified Wilms’ Tumour Antigen 1 (WT1) T cell receptor (TCR)-transduced autologous T cells
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Bulk transduced WT1 TCR T-lymphocytes were administered by iv infusion over 30 to 60 minutes through a large peripheral vein or centrally through a Hickman line at a dose of ≤1x10^8/kg after standard conditioning (fludarabine plus methylprednisolone). Patients were also administered 106 units/m2 interleukin-2 (IL-2) by subcutaneous injection immediately after T cell infusion and for the next 4 days.

    Number of subjects in period 1
    Cohort 1 Cohort 2A
    Started
    3
    4
    Completed
    2
    3
    Not completed
    1
    1
         Disease progression
    1
    -
         Other
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Cohort 1
    Reporting group description
    Patients in Cohort 1 received standard conditioning [fludarabine plus methylprednisolone] and the lower dose of ≤2x10^7/kg T cells

    Reporting group title
    Cohort 2A
    Reporting group description
    Patients in Cohort 2A received standard conditioning [fludarabine plus methylprednisolone] and the higher dose of ≤1x10^8/kg T cells

    Reporting group values
    Cohort 1 Cohort 2A Total
    Number of subjects
    3 4 7
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    1 0 1
        From 65-84 years
    2 4 6
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    69.7 ( 5.5 ) 69.5 ( 1.9 ) -
    Gender categorical
    Units: Subjects
        Female
    2 2 4
        Male
    1 2 3
    Race
    Units: Subjects
        White
    3 3 6
        Black/African American
    0 1 1

    End points

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    End points reporting groups
    Reporting group title
    Cohort 1
    Reporting group description
    Patients in Cohort 1 received standard conditioning [fludarabine plus methylprednisolone] and the lower dose of ≤2x10^7/kg T cells

    Reporting group title
    Cohort 2A
    Reporting group description
    Patients in Cohort 2A received standard conditioning [fludarabine plus methylprednisolone] and the higher dose of ≤1x10^8/kg T cells

    Primary: Dose-limiting toxicity

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    End point title
    Dose-limiting toxicity [1]
    End point description
    Dose-limiting toxicity was defined as almost certainly/probably dose-related, WT1 TCR-transduced T cell infusion related: - Grade 4 neutropenia (absolute neutrophil count <0.1x10^9/L) of five or more days duration. - Infection (documented clinically or microbiologically) with Grade 4 neutropenia (absolute neutrophil count <0.1x10^9/L). -Grade 4 thrombocytopenia for five or more days associated with active bleeding or requiring platelet transfusion. -Grade 3 or 4 non-haematologocial toxicity (excluding Grade 3 nausea and Grade 3 or 4 vomiting or diarrhoea in patients who had not received optimal treatment with anti-emetics or anti-diarrhoeal agents). -Death
    End point type
    Primary
    End point timeframe
    28 days
    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: All analyses were exploratory, with data presented using descriptive statistics for all variables.
    End point values
    Cohort 1 Cohort 2A
    Number of subjects analysed
    3
    4
    Units: Subjects
        Dose-limiting toxicity
    0
    0
        No dose-limiting toxicity
    3
    4
    No statistical analyses for this end point

    Secondary: Persistence of of TCR-transduced T cells

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    End point title
    Persistence of of TCR-transduced T cells
    End point description
    WT1-TCR expressing T cells in the peripheral blood post infusion were identified using a PCR assay. The persistence of TCR-transduced T cells was measured at various time points during the study. This primary end point refers to the persistence of TCR-transduced T cells at the end of the study.
    End point type
    Secondary
    End point timeframe
    12 months
    End point values
    Cohort 1 Cohort 2A
    Number of subjects analysed
    3
    4
    Units: Subjects
        Persistence of TCR-transduced T cells
    2
    2
        Absence of TCR-transduced T cells
    1
    2
    No statistical analyses for this end point

    Secondary: Disease response

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    End point title
    Disease response
    End point description
    Disease response to treatment from the start of the study to the end of the study. Disease response was assessed by bone marrow aspirate and trephine and/or cytogenetics and molecular studies (specific to individual cytogenetic/molecular abnormality in a given trial patient)
    End point type
    Secondary
    End point timeframe
    12 months
    End point values
    Cohort 1 Cohort 2A
    Number of subjects analysed
    3
    4
    Units: Subjects
        Complete response
    1
    3
        No response
    2
    1
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    28 days
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    17.1
    Reporting groups
    Reporting group title
    Cohort 1
    Reporting group description
    -

    Reporting group title
    Cohort 2A
    Reporting group description
    -

    Serious adverse events
    Cohort 1 Cohort 2A
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 3 (66.67%)
    0 / 4 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    Blood and lymphatic system disorders
    Febrile neutropenia
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anaemia
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 1%
    Non-serious adverse events
    Cohort 1 Cohort 2A
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    1 / 3 (33.33%)
    4 / 4 (100.00%)
    Investigations
    Platelet count decreased
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 4 (50.00%)
         occurrences all number
    0
    2
    Lymphocyte count decreased
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    Monocyte count decreased
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    Injury, poisoning and procedural complications
    Infusion related reaction
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    Vascular disorders
    Hypotension
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Hot flush
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    Nervous system disorders
    Lethargy
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 4 (0.00%)
         occurrences all number
    2
    0
    Hypersomnia
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Hypoaesthesia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    Dizziness
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    Headache
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    1 / 3 (33.33%)
    3 / 4 (75.00%)
         occurrences all number
    1
    3
    Injection site reaction
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    Fatigue
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    2
    Localised oedema
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    Eye disorders
    Dry eye
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Vomiting
         subjects affected / exposed
    1 / 3 (33.33%)
    1 / 4 (25.00%)
         occurrences all number
    2
    1
    Nausea
         subjects affected / exposed
    1 / 3 (33.33%)
    2 / 4 (50.00%)
         occurrences all number
    1
    2
    Mouth ulceration
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Dyspepsia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Epistaxis
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    Cough
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    1 / 3 (33.33%)
    1 / 4 (25.00%)
         occurrences all number
    1
    1
    Rash maculo-papular
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Pruritus
         subjects affected / exposed
    0 / 3 (0.00%)
    2 / 4 (50.00%)
         occurrences all number
    0
    2
    Skin ulcer
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    Dry skin
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    Psychiatric disorders
    Depression
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Musculoskeletal and connective tissue disorders
    Bone pain
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    2
    Myalgia
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    2
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1
    Lung infection
         subjects affected / exposed
    1 / 3 (33.33%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    Folliculitis
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    1

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    06 Jan 2008
    Protocol V1.0 to V5.0 were submitted by a different Sponsor. No subjects were enrolled until 2014.
    19 Jan 2012
    Version 5.1
    11 Feb 2014
    Version 5.2
    14 Jul 2014
    Version 6.0
    15 Jul 2015
    Version 7.0
    15 Apr 2016
    Version 7.1
    22 Sep 2017
    Version 8.0

    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 difficulties in recruitment of patients, enrolment into the study was terminated early.
    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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