E.1 Medical condition or disease under investigation |
E.1.1 | Medical 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). |
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E.1.1.1 | Medical 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. |
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E.1.1.2 | Therapeutic area | Diseases [C] - Virus Diseases [C02] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 19.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10067859 |
E.1.2 | Term | Allogenic stem cell transplantation |
E.1.2 | System Organ Class | 100000004865 |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | 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.
We propose that CMV TCR-transduced T cells, generated from |
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E.2.2 | Secondary 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 |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal 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. |
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E.4 | Principal 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
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E.5 End points |
E.5.1 | Primary 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. |
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E.5.1.1 | Timepoint(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.
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E.5.2 | Secondary 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.
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E.5.2.1 | Timepoint(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
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | Yes |
E.7.1.1 | First administration to humans | Yes |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | 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.8.4.1 | Number of sites anticipated in Member State concerned | 4 |
E.8.5 | The trial involves multiple Member States | No |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial 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
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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. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 7 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 7 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |