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.
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Summary
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EudraCT number |
2008-006649-18 |
Trial protocol |
GB |
Global end of trial date |
11 Dec 2018
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Results information
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Results version number |
v1(current) |
This version publication date |
22 Aug 2020
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First version publication date |
22 Aug 2020
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Other versions |
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Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
08/0214
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Additional study identifiers
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ISRCTN number |
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US NCT number |
NCT02988258 | ||
WHO universal trial number (UTN) |
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Other trial identifiers |
GTAC: 169 | ||
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Sponsors
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Sponsor organisation name |
University College London
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Sponsor organisation address |
Gower Street, London, United Kingdom, W1T 7DN
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Public contact |
Professor Emma Morris, University College London, 44 (0)20 7794 0500, e.morris@ucl.ac.uk
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Scientific contact |
Professor Emma Morris, University College London, 44 (0)20 7794 0500, e.morris@ucl.ac.uk
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
22 Jan 2020
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Is this the analysis of the primary completion data? |
No
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Global end of trial reached? |
Yes
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Global end of trial date |
11 Dec 2018
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Was the trial ended prematurely? |
Yes
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General information about the trial
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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.
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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.
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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
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
Yes
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
United Kingdom: 3
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Worldwide total number of subjects |
3
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EEA total number of subjects |
3
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
3
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From 65 to 84 years |
0
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85 years and over |
0
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Recruitment
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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. | ||||||||||||||
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Pre-assignment
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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. | ||||||||||||||
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Period 1
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Period 1 title |
Overall trial (overall period)
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Is this the baseline period? |
Yes | ||||||||||||||
Allocation method |
Not applicable
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Blinding used |
Not blinded | ||||||||||||||
Blinding implementation details |
Not applicable
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Arms
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Arm title
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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
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Solution for infusion
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Routes of administration |
Intravenous use
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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.
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Baseline characteristics reporting groups
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Reporting group title |
Overall trial
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Reporting group description |
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Subject analysis sets
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Subject analysis set title |
Treated patients
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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.
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End points reporting groups
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Reporting group title |
Treatment arm
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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
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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.
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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.
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End point type |
Primary
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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.
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| 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. |
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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.
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End point type |
Primary
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End point timeframe |
At point of QP release of study treatment
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| 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%. |
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| Notes [3] - The value given is the average percentage for the product as released for each treated patient (n=2) |
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| No statistical analyses for this end point | |||||||
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Adverse events information
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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.
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Adverse event reporting additional description |
Participants were questioned about adverse events at each study visit.
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
23.0
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Reporting groups
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Reporting group title |
Treatment group
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Reporting group description |
This group contains all those participants who received the CMV TCR-Transduced T Cells | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Frequency threshold for reporting non-serious adverse events: 5% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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Date |
Amendment |
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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. |
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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)
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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. |
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26 Sep 2014 |
Temporary halt of trial in order to manufacture more vector. |
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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
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24 Jul 2018 |
Temporarily halt to recruitment as the original trial grant reached the end of its no cost extension. |
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Interruptions (globally) |
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| Were there any global interruptions to the trial? Yes | |||||||
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Limitations and caveats |
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| 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. | |||||||
