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    Clinical Trial Results:
    CMV TCR Gene Therapy: A Phase I Safety, Toxicity and Feasibility Study of Adoptive Immunotherapy with CMV TCR-transduced Donor-derived T cells for Recipients of Allogeneic Haematopoietic Stem Cell Transplantation.

    Summary
    EudraCT number
    2008-006649-18
    Trial protocol
    GB  
    Global end of trial date
    11 Dec 2018

    Results information
    Results version number
    v1(current)
    This version publication date
    22 Aug 2020
    First version publication date
    22 Aug 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    08/0214
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02988258
    WHO universal trial number (UTN)
    -
    Other trial identifiers
    GTAC: 169
    Sponsors
    Sponsor organisation name
    University College London
    Sponsor organisation address
    Gower Street, London, United Kingdom, W1T 7DN
    Public contact
    Professor Emma Morris, University College London, 44 (0)20 7794 0500, e.morris@ucl.ac.uk
    Scientific contact
    Professor Emma Morris, University College London, 44 (0)20 7794 0500, e.morris@ucl.ac.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
    22 Jan 2020
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    11 Dec 2018
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The proposed study will test the feasibility of generating donor-derived cytomegalo virus (CMV)-specific T cells via the ex vivo introduction of a CMV-specific T cell receptor using a GMP grade retroviral vector. It will also determine the safety, toxicity (side effects) and efficacy of CMV TCR-transduced T cells used for the pre-emptive treatment of CMV reactivation following HLA-matched sibling Allo-Haematopoietic Stem Cell Transplantation. Primary Objectives: (i) Evaluate the feasibility of retroviral-mediated TCR gene transfer to generate CMV-specific T cells from CMV seronegative donors; (ii) Evaluate the safety, toxicity and side effects of pre-emptive CMV TCR-transduced donor-derived T cells for immunotherapy after Allo-HSCT, where donors are CMV seronegative. Primary Endpoints: (i) Document transduction efficiency and TCR expression on TCR-transduced T cells; (ii) Identify organ toxicities and other side effects.
    Protection of trial subjects
    Antiviral drug therapy will be initiated in the following circumstances: 1. if the CMV viral load ≥3000 copies/ml or 2. if there is evidence of CMV disease. Anti-viral therapy will be stopped when the viral load is below the level of quantification of the assay. In the event of any adverse reactions, chlorpheniramine and hydrocortisone were to be given, as well as oxygen and salbutamol in the event of respiratory distress. Nursing and medical staff experienced in the administration of cellular blood products including donor T cell infusions and CMV-specific T cells cared for the trial patients. The site followed trial-specific SOPs and local guidelines for the administration of cellular blood products.
    Background therapy
    One of the inclusion criteria is that patients were undergoing matched sibling allogeneic HSCT for an underlying haematological malignancy with a CMV seronegative donor. As part of this transplant, patients will have received conditioning treatment.
    Evidence for comparator
    Not applicable
    Actual start date of recruitment
    18 Jul 2013
    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 Kingdom: 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)
    3
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    All patients were recruited from one site. Patients who met the eligibility criteria were approached at the time or prior to commencement of their pre-transplant conditioning and the protocol was discussed with them and they were given a copy of the Patient Information Sheet. The trial was opened to recruitment on 15 Jul 2013.

    Pre-assignment
    Screening details
    Patients were screened & enrolled onto the Study prior to HSCT and the allogeneic CMV-specific T cells were to be prepared for all participants. The CMV-specific T cells were released following a single positive CMV PCR result. At this point, patients were re-evaluated for eligibility. 3 patients enrolled - 2 treated; 1 did not reactivate CMV.

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

    Arms
    Arm title
    Treatment arm
    Arm description
    Patients treated on trial with the IMP, CMV TCR-Transduced T Cells. This is a single arm non-randomised trial.
    Arm type
    Experimental

    Investigational medicinal product name
    CMV TCR-transduced Donor-derived T cells
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Each patient was planned to receive a single infusion of bulk CMV-TCR transduced donor-derived T cells on first CMV reactivation post allogeneic HSCT, at a dose of 10e4 T cells/kg recipient weight (cohort 1, n=3), 10e5 T cells/kg recipient weight (cohort 2, remaining patients if no excess toxicity, or protocol stopping rules) or at a de-escalation dose of 10e3 T cells/kg recipient weight (cohort 1a). In the trial 2 patients only were dosed, in Cohort 1 at a dose of 10e4 T cells/kg.

    Number of subjects in period 1
    Treatment arm
    Started
    3
    Completed
    0
    Not completed
    3
         Patient did not have CMV reactivation post HSCT
    1
         Lack of efficacy
    1
         Adverse event, serious fatal
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall trial
    Reporting group description
    -

    Reporting group values
    Overall trial Total
    Number of subjects
    3 3
    Age categorical
    Age ≥ 18 years and ≤ 65 years
    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)
    3 3
        From 65-84 years
    0 0
        85 years and over
    0 0
    Gender categorical
    Units: Subjects
        Female
    3 3
        Male
    0 0
    Subject analysis sets

    Subject analysis set title
    Treated patients
    Subject analysis set type
    Per protocol
    Subject analysis set description
    Patients are included in the analysis set if they reactivated for CMV and were then treated with CMV TCR-transduced Donor-derived T cells.

    Subject analysis sets values
    Treated patients
    Number of subjects
    2
    Age categorical
    Age ≥ 18 years and ≤ 65 years
    Units: Subjects
        In utero
    0
        Preterm newborn infants (gestational age < 37 wks)
    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)
    2
        From 65-84 years
    0
        85 years and over
    0
    Age continuous
    Units:
        
    ±
    Gender categorical
    Units: Subjects
        Female
    2
        Male

    End points

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    End points reporting groups
    Reporting group title
    Treatment arm
    Reporting group description
    Patients treated on trial with the IMP, CMV TCR-Transduced T Cells. This is a single arm non-randomised trial.

    Subject analysis set title
    Treated patients
    Subject analysis set type
    Per protocol
    Subject analysis set description
    Patients are included in the analysis set if they reactivated for CMV and were then treated with CMV TCR-transduced Donor-derived T cells.

    Primary: Organ toxicities and other side effects.

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    End point title
    Organ toxicities and other side effects. [1]
    End point description
    All AEs are captured in the Adverse Event Section rather than this Endpoint section - please refer to 'Adverse Event' section.
    End point type
    Primary
    End point timeframe
    AEs were recorded and reported from the day of a single positive PCR result to 12 months post T cell infusion. Adverse Reactions and/or Serious Adverse Events were recorded and reported to 5 years post T cell 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: Due to the small number of subjects treated (N=2) no statistical analyses have been done as this would not be appropriate.
    End point values
    Treated patients
    Number of subjects analysed
    Units: Number
    0
    No statistical analyses for this end point

    Primary: Transduction efficiency and TCR expression on TCR-transduced T cells

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    End point title
    Transduction efficiency and TCR expression on TCR-transduced T cells [2]
    End point description
    TCR expression of >5% and <70% of CMV-TCR+ cells within viable CD3+ cells was required in order to meet the specification defined in the IMPD. This is because sufficient numbers of CMV-specific T cells are required to be functionally effective following adoptive transfer.
    End point type
    Primary
    End point timeframe
    At point of QP release of study treatment
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was specified in the protocol for this endpoint. The protocol states that the data is to be documented. The value given (18%) is the mean value of TCR expression for the 2 patients. The individual values are 12.83% and 22.5%.
    End point values
    Treated patients
    Number of subjects analysed
    2 [3]
    Units: percentage
    18
    Notes
    [3] - The value given is the average percentage for the product as released for each treated patient (n=2)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    AEs were recorded and reported from the day of a single positive PCR result to 12 months post T cell infusion. Adverse Reactions and/or Serious Adverse Events were recorded and reported to 5 years post T cell infusion.
    Adverse event reporting additional description
    Participants were questioned about adverse events at each study visit.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    23.0
    Reporting groups
    Reporting group title
    Treatment group
    Reporting group description
    This group contains all those participants who received the CMV TCR-Transduced T Cells

    Serious adverse events
    Treatment group
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 2 (100.00%)
         number of deaths (all causes)
    1
         number of deaths resulting from adverse events
    1
    Cardiac disorders
    Right ventricular failure
         subjects affected / exposed
    1 / 2 (50.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pneumonia cytomegaloviral
         subjects affected / exposed
    1 / 2 (50.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pulmonary hypertension
         subjects affected / exposed
    1 / 2 (50.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Acute respiratory distress syndrome
         subjects affected / exposed
    1 / 2 (50.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    Multiple organ dysfunction syndrome
         subjects affected / exposed
    1 / 2 (50.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Ear and labyrinth disorders
    Hypoacusis
         subjects affected / exposed
    1 / 2 (50.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    1 / 2 (50.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Renal failure
         subjects affected / exposed
    1 / 2 (50.00%)
         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
    Treatment group
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    2 / 2 (100.00%)
    Vascular disorders
    Epistaxis
         subjects affected / exposed
    1 / 2 (50.00%)
         occurrences all number
    1
    Hypertension
         subjects affected / exposed
    1 / 2 (50.00%)
         occurrences all number
    1
    Hypotension
         subjects affected / exposed
    1 / 2 (50.00%)
         occurrences all number
    1
    General disorders and administration site conditions
    Oedema peripheral
         subjects affected / exposed
    1 / 2 (50.00%)
         occurrences all number
    1
    Fatigue
         subjects affected / exposed
    1 / 2 (50.00%)
         occurrences all number
    2
    Swelling
         subjects affected / exposed
    1 / 2 (50.00%)
         occurrences all number
    1
    Pyrexia
         subjects affected / exposed
    1 / 2 (50.00%)
         occurrences all number
    1
    Decreased appetite
         subjects affected / exposed
    1 / 2 (50.00%)
         occurrences all number
    1
    Spinal pain
         subjects affected / exposed
    1 / 2 (50.00%)
         occurrences all number
    1
    Generalised oedema
         subjects affected / exposed
    1 / 2 (50.00%)
         occurrences all number
    1
    Reproductive system and breast disorders
    Vaginal discharge
         subjects affected / exposed
    1 / 2 (50.00%)
         occurrences all number
    1
    Vulvovaginal inflammation
         subjects affected / exposed
    1 / 2 (50.00%)
         occurrences all number
    1
    Vulvovaginal swelling
         subjects affected / exposed
    1 / 2 (50.00%)
         occurrences all number
    1
    Investigations
    Human metapneumovirus test positive
         subjects affected / exposed
    1 / 2 (50.00%)
         occurrences all number
    1
    Coronavirus test positive
         subjects affected / exposed
    1 / 2 (50.00%)
         occurrences all number
    1
    BK polyomavirus test positive
         subjects affected / exposed
    1 / 2 (50.00%)
         occurrences all number
    1
    Blood urea increased
         subjects affected / exposed
    1 / 2 (50.00%)
         occurrences all number
    1
    Blood creatinine increased
         subjects affected / exposed
    1 / 2 (50.00%)
         occurrences all number
    1
    Cardiac disorders
    Tachycardia
         subjects affected / exposed
    2 / 2 (100.00%)
         occurrences all number
    2
    Pericardial effusion
         subjects affected / exposed
    1 / 2 (50.00%)
         occurrences all number
    2
    Tricuspid valve incompetence
         subjects affected / exposed
    1 / 2 (50.00%)
         occurrences all number
    1
    Right ventricular hypertrophy
         subjects affected / exposed
    1 / 2 (50.00%)
         occurrences all number
    1
    Mitral valve incompetence
         subjects affected / exposed
    1 / 2 (50.00%)
         occurrences all number
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    2 / 2 (100.00%)
         occurrences all number
    4
    Pneumonia viral
         subjects affected / exposed
    1 / 2 (50.00%)
         occurrences all number
    1
    Dyspnoea
         subjects affected / exposed
    2 / 2 (100.00%)
         occurrences all number
    2
    Lower respiratory tract infection fungal
         subjects affected / exposed
    1 / 2 (50.00%)
         occurrences all number
    1
    Oropharyngeal pain
         subjects affected / exposed
    1 / 2 (50.00%)
         occurrences all number
    1
    Pulmonary hypertension
         subjects affected / exposed
    1 / 2 (50.00%)
         occurrences all number
    1
    Hypoxia
         subjects affected / exposed
    1 / 2 (50.00%)
         occurrences all number
    1
    Blood and lymphatic system disorders
    Neutropenia
         subjects affected / exposed
    1 / 2 (50.00%)
         occurrences all number
    1
    Febrile neutropenia
         subjects affected / exposed
    1 / 2 (50.00%)
         occurrences all number
    1
    Nervous system disorders
    Headache
         subjects affected / exposed
    2 / 2 (100.00%)
         occurrences all number
    4
    Paraesthesia
         subjects affected / exposed
    2 / 2 (100.00%)
         occurrences all number
    2
    Dizziness
         subjects affected / exposed
    1 / 2 (50.00%)
         occurrences all number
    2
    Tremor
         subjects affected / exposed
    1 / 2 (50.00%)
         occurrences all number
    1
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    2 / 2 (100.00%)
         occurrences all number
    3
    Vomiting
         subjects affected / exposed
    2 / 2 (100.00%)
         occurrences all number
    5
    Diarrhoea
         subjects affected / exposed
    2 / 2 (100.00%)
         occurrences all number
    4
    Abdominal pain
         subjects affected / exposed
    1 / 2 (50.00%)
         occurrences all number
    2
    Proctalgia
         subjects affected / exposed
    1 / 2 (50.00%)
         occurrences all number
    1
    Constipation
         subjects affected / exposed
    1 / 2 (50.00%)
         occurrences all number
    3
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    1 / 2 (50.00%)
         occurrences all number
    1
    Dysuria
         subjects affected / exposed
    1 / 2 (50.00%)
         occurrences all number
    1
    Polyuria
         subjects affected / exposed
    1 / 2 (50.00%)
         occurrences all number
    1
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    2 / 2 (100.00%)
         occurrences all number
    3
    Pain of skin
         subjects affected / exposed
    1 / 2 (50.00%)
         occurrences all number
    1
    Musculoskeletal and connective tissue disorders
    Myalgia
         subjects affected / exposed
    1 / 2 (50.00%)
         occurrences all number
    3
    Pain in extremity
         subjects affected / exposed
    1 / 2 (50.00%)
         occurrences all number
    1
    Neck pain
         subjects affected / exposed
    1 / 2 (50.00%)
         occurrences all number
    1
    Infections and infestations
    Oral candidiasis
         subjects affected / exposed
    1 / 2 (50.00%)
         occurrences all number
    1
    Urinary tract infection
         subjects affected / exposed
    1 / 2 (50.00%)
         occurrences all number
    1

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    04 Dec 2012
    The Patient & Donor Information Sheets and Consent Forms were amended mainly to change the information regarding personal identifiers that will be collected from Patient/Donor.
    05 Jul 2013
    1. Addition of new Trial Site 2. An additional blood test added at multiple time-points throughout the trial for immunological evaluations. This slightly increased the amount of blood taken from the patient. 3. Modification to the T cell transduction protocol. The changes reflected an improved production procedure, to allow a more efficient CMV-specific T Cell transduction, based on scale ups at both the manufacturer’s site (GOSH) and the UCL Immunology research team. 4. New and amended product label: Different types of cryopreservation containers to be used depending on the IMP dose (cohort and weight dependent)
    18 Feb 2014
    To document a change of supplier of human albumin and that human serum (and not human serum albumin) to be used for cell culture.
    26 Sep 2014
    Temporary halt of trial in order to manufacture more vector.
    24 Nov 2016
    Amendment to: - Re-start Trial - Change IMP manufacturing site - New vector manufactured via different method - Change from human serum to Human Platelet Lysate in IMP manufacturing process - Addition of Bristol site and removal of RFH site
    24 Jul 2018
    Temporarily halt to recruitment as the original trial grant reached the end of its no cost extension.

    Interruptions (globally)

    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    30 Sep 2014
    Temporary halt of trial in order to manufacture more vector. Vector was required in order to manufacture the IMP.
    01 Dec 2017

    Limitations and caveats

    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    This trial was terminated early leading to a small number of subjects analysed. Therefore the data presented is restricted to the primary endpoints, including all AEs and SAEs. Recruitment was difficult due to strict eligibility criteria.
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