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    Summary
    EudraCT Number:2008-006649-18
    Sponsor's Protocol Code Number:08/0214
    National Competent Authority:UK - MHRA
    Clinical Trial Type:EEA CTA
    Trial Status:Prematurely Ended
    Date on which this record was first entered in the EudraCT database:2011-11-22
    Trial results View results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedUK - MHRA
    A.2EudraCT number2008-006649-18
    A.3Full title of the trial
    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.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    CMV TCR Gene Therapy Trial
    A.3.2Name or abbreviated title of the trial where available
    CMV TCR Gene Therapy (CMV TCR-001)
    A.4.1Sponsor's protocol code number08/0214
    A.5.4Other Identifiers
    Name:GTACNumber:169
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorUniversity College London
    B.1.3.4CountryUnited Kingdom
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportMedical Research Council
    B.4.2CountryUnited Kingdom
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisation
    B.5.2Functional name of contact point
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameCMV TCR-transduced donor T cells
    D.3.4Pharmaceutical form Solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) Yes
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product Yes
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    CMV reactivation/infection in post allogeneic haematopoietic stem cell transplant recipients. Allo-HSCT being performed for underlying haematological malignancy (eg, AML, ALL, NHL, Hodgkin Lymphoma, etc).
    E.1.1.1Medical condition in easily understood language
    Viral infection occuring in people who's immune system has been affected by a bone marrow transplant for leukaemia or lymphoma.
    E.1.1.2Therapeutic area Diseases [C] - Virus Diseases [C02]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 19.0
    E.1.2Level LLT
    E.1.2Classification code 10067859
    E.1.2Term Allogenic stem cell transplantation
    E.1.2System Organ Class 100000004865
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main 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.

    We propose that CMV TCR-transduced T cells, generated from
    E.2.2Secondary objectives of the trial
    Secondary Objectives:
    (i) Evaluate the efficacy of CMV TCR-transduced T cells in the pre-emptive treatment of CMV reactivation;
    (ii) Evaluate the effect of CMV TCR-transduced T cells on immune reconstitution and Graft-versus Host Disease (GvHD) after Allo-HSCT;
    (iii) Determine the persistence of CMV TCR-transduced T cells in the recipients; (iv) Evaluate for long-term complications related to retroviral gene therapy, as per Gene Therapy Advisory Committee Guidelines.

    Secondary Endpoints:
    (i) Document CMV-specific immune responses of TCR-transduced T cells pre- and post-infusion using in vitro functional assays such as intracellular cytokine secretion, elispot, proliferation and cytotoxicity assays;
    (ii) Document anti-CMV responses post infusion of CMV TCR-transduced T cells using serial quantitative PCR for viral copy numbers in peripheral blood;
    (iii) Document incidence and severity of GvHD post infusion of CMV TCR-transduced T cells following Allo-HSCT using standardised inter
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Inclusion Criteria (Recipient):
    1. Age: 18-65 years (inclusive)
    2. Recipients of HLA-matched sibling Allo-HSCT for underlying haematological malignancies as per national and institutional guidelines.
    3. HLA-A*0201 positive
    4. CMV seropositive (anti-CMV IgG detectable pre-transplant)
    5. Meets all other recipient criteria for Allo-HSCT as per institutional guidelines.

    Inclusion Criteria (Donors)
    1. Pre-selected HLA-matched sibling stem cell donor (as per institutional criteria)
    2. Age: 16 years or older (inclusive)
    3. HLA-A*0201 positive
    4. CMV seronegative (no anti-CMV IgG detectable)

    For further details of inclusion and exclusion criteria please see Clinical Trial Protocol.

    Patients will be recruited to the study during their pre-transplant consultation and medical. Participants will only be eligible for the study if they are: (i) HLA-A*0201 positive (the TCR is HLA-A*0201 restricted and CMV pp65-specific) and (ii) CMV seropositive (CMV IgG detected) and their donor is: (i) an HLA-matched sibling/family member and (ii) CMV seronegative (CMV IgG not detected). All participants will be required to give signed, informed consent. A detailed explanation of the study rationale and risks will be given by the relevant PI. All patients will receive a patient information sheet and be given time to discuss the study with family and friends.
    E.4Principal exclusion criteria
    (i) Pregnant or lactating women
    (ii) Co-existing medical problems that would place the patient at significant risk of death due to GVHD or its sequelae
    (iii) HIV infection

    And to be assessed prior to CMV-specific T cell infusion (for confirmation prior to product release):
    (i) Active acute GVHD > Grade I
    (ii) Concurrent use of systemic corticosteroids
    (iii) Organ dysfunction as measured by
    ii. creatinine > 200 uM/l
    iii. bilirubin > 50 uM/l
    iv. ALT > 3x upper limit of normal
    E.5 End points
    E.5.1Primary end point(s)
    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.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Transduction effeciency and TCR expression on transduced T cells known prior to infusion.

    Safety and Toxicity assessments made at Time 0, +6hrs, +24hrs, +48hrs, +72hrs, 7d, then weekly until +6 weeks, bi-weekly until + 12 weeks, then +4m, +5m, +6m, +9m and +12m, then 6-monthly to 5 yrs.
    E.5.2Secondary end point(s)
    (i) Document CMV-specific immune responses of TCR-transduced T cells pre- and post-infusion using in vitro functional assays such as intracellular cytokine secretion, elispot, proliferation and cytotoxicity assays;
    (ii) Document anti-CMV responses post infusion of CMV TCR-transduced T cells using serial quantitative PCR for viral copy numbers in peripheral blood;
    (iii) Document incidence and severity of GvHD post infusion of CMV TCR-transduced T cells following Allo-HSCT using standardised international criteria;
    (iv) Perform immune reconstitution studies post infusion of CMV TCR-transduced T cells following Allo-HSCT;
    (v) Detect persistence of TCR-transduced T cells by Vbeta13 and tetramer staining, PCR for Vbeta13 and TCR vector fragments.
    E.5.2.1Timepoint(s) of evaluation of this end point
    (i) CMV-specific T cell function: Day -2 (baseline), +7d, +14d, +28d, +6w, +10w, +4m, +5m, +6m, +8m, +10m,+12m, then 6-monthly to 5 yrs

    (ii) Quantitative CMV PCR at Day -2 (baseline), + 48 hrs, +7d, +14d, then weekly until +6 wks, bi-weekly until + 12 weeks, then +4m, +5m, +6m, +8m, +10m,+12m, then 6-monthly to 5 yrs

    (iii) GVHD assessments at Day -2, +6hrs, 7d, then weekly until +6 weeks, bi-weekly until + 12 wks, then +4m, +5m, +6m, +8m, +10m,+12m, then 6-monthly to 5 yrs

    (iv) T cell reconstitution: Day -2 (baseline), +7d, +14d, +28d, +6w, +10w, +4m, +5m, +6m, +8m, +10m, +12m, then 6-monthly to 5 yrs

    (v) Persistence: Time 0, +6hrs, +24hrs, +48hrs, +72hrs, 7d, then weekly until +6 wks, bi-weekly until + 12 wks, then +4m, +5m, +6m, +8m, +10m, +12m, then 6-monthly to 5 yrs
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy No
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) Yes
    E.7.1.1First administration to humans Yes
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled No
    E.8.1.1Randomised No
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned4
    E.8.5The trial involves multiple Member States No
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.7Trial has a data monitoring committee Yes
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    Yearly review for 5 years after infusion of genetically modified T cells for assessment of unexpected late toxicities as requested by MHRA for gene therapy studies.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years7
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years7
    E.8.9.2In all countries concerned by the trial months0
    E.8.9.2In all countries concerned by the trial days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1Number of subjects for this age range: 0
    F.1.1.1In Utero No
    F.1.1.1.1Number of subjects for this age range: 0
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.2.1Number of subjects for this age range: 0
    F.1.1.3Newborns (0-27 days) No
    F.1.1.3.1Number of subjects for this age range: 0
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.4.1Number of subjects for this age range: 0
    F.1.1.5Children (2-11years) No
    F.1.1.5.1Number of subjects for this age range: 0
    F.1.1.6Adolescents (12-17 years) No
    F.1.1.6.1Number of subjects for this age range: 0
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 10
    F.1.3Elderly (>=65 years) No
    F.1.3.1Number of subjects for this age range: 0
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations No
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception No
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state10
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    Not applicable as trial is designed to test the safety, feasibility, toxicity and efficacy of single infusion of cellular therapy product.
    G. Investigator Networks to be involved in the Trial
    G.4 Investigator Network to be involved in the Trial: 1
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2011-11-16
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2010-11-04
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
    P.Date of the global end of the trial2018-12-11
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