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Transfer of Effector Memory T Cells (Tem) Following Allogeneic Stem Cell Transplantation (ToTem)
RATIONALE: Following stem cell transplantation, a major risk is graft-versus-host disease (GVHD). This occurs when donor immune cells that have been infused recognise the host's cells as 'foreign' and attack these cells. Prevention of GVHD relies upon depletion of donor immune T cells or drugs that block T cell function. However, these methods also increase the risk of life threatening infection. There is an important unmet need for better means of accelerating immune recovery following stem cell transplantation while avoiding GVHD.
Pre-clinical studies have shown that infusion of donor CD62L- effector memory T cells (Tem) into the host improve immune recovery after allo-Stem Cell Transplant but do not cause GVHD.
PURPOSE: This phase I dose escalation trial aims to determine the feasibility and safety of transfer of donor Tem following allogeneic stem cell transplantation.
| Condition or disease | Intervention/treatment | Phase |
|---|---|---|
| Lymphoma Leukemia Myeloma Myelodysplastic Syndromes Severe Aplastic Anemia Primary Immune Deficiency Graft Vs Host Disease | Biological: CD62L- Tem | Phase 1 |
Phase I study using a Bayesian Time-to-Event Continual Reassessment Method (CRM) to determine safety and maximum tolerated dose (MTD) of CD62L- Tem.
Eligible patients and HLA-identical sibling donors will be registered prior to stem cell transplant (SCT). Donors will undergo an additional steady state apheresis for the collection of T cells between day -14 and day +24 of the allo-SCT according to logistics. Selection of Tem at the required dose will be performed at UCL Centre for Cell, Gene and Tissue Therapeutics (CCGTT) before distribution of the cryopreserved cells to the trial centre. Doses of Tem selected and infused will be: 1x10^5, 3x10^5, 1x10^6 or 3x10^6.
Donor Tem will be infused on day 24-32 following allo-SCT. Patients will be followed-up for 12 months with specific evaluation points just prior to Tem infusion and at 3, 6, 9 and 12 months following allo-SCT.
| Study Type : | Interventional (Clinical Trial) |
| Estimated Enrollment : | 18 participants |
| Allocation: | N/A |
| Intervention Model: | Single Group Assignment |
| Masking: | None (Open Label) |
| Primary Purpose: | Treatment |
| Official Title: | Phase I Study of Transfer of Effector Memory T Cells (Tem) Following Allogeneic Stem Cell Transplantation |
| Actual Study Start Date : | October 21, 2019 |
| Estimated Primary Completion Date : | July 1, 2022 |
| Estimated Study Completion Date : | April 1, 2023 |
| Arm | Intervention/treatment |
|---|---|
|
Experimental: Donor T cells depleted of CD62L+ cells (CD62L- Tem)
Donors will undergo a steady state apheresis for the collection of T cells. Selection of CD62L- Tem at the required dose will be performed at UCL Centre for Cell, Gene and Tissue Therapeutics (CCGTT). Donor Tem will be infused into patients on day 24-32 following allo-Stem Cell Transplant.
|
Biological: CD62L- Tem
Donor memory T cells that have been depleted of CD62L+
|
- Occurrence of dose limiting toxicity (DLT) [ Time Frame: up to 72 days after Tem infusion ]Occurrence of dose limiting toxicity (DLT) (defined as acute-pattern GvHD grade II-IV)
- Incidence and severity of acute GvHD [ Time Frame: From date of infusion of Tem until 100 days post stem cell transplant ]Incidence and severity of acute GvHD (whether dose limiting or not)
- Incidence and severity of chronic GvHD [ Time Frame: From date of infusion of Tem up to 1 year post stem cell transplant ]Incidence and severity of chronic GvHD
- Non-relapse mortality [ Time Frame: From date of patient registration up to 1 year post stem cell transplant ]Death without reoccurrence of cancer
- Overall survival [ Time Frame: From date of patient registration up to 1 year post stem cell transplant ]Death
- Progression-free survival [ Time Frame: From date of patient registration up to 1 year post stem cell transplant ]Disease progression or death
- Incidence/type of infection requiring inpatient admission [ Time Frame: From date of infusion of Tem up to 1 year post stem cell transplant ]Any infection that has required an inpatient admission, incidence and type of infection
- Total Number of inpatient days [ Time Frame: From date of infusion of Tem up to 1 year post stem cell transplant ]Total Number of inpatient days for any reason
- TCR repertoire analysis by deep CDR3 sequencing [ Time Frame: Day -14 to -7 (day of cell processing) and day 100 and 360 post stem cell transplant ]
- Chimerism of immune subsets (analysing the genetic profiles of recipient and donor at baseline and following stem cell transplant) [ Time Frame: Pre-Registration and Day 100, 180, 270, 360 post stem cell transplant ]Identifying the genetic profiles of the recipient and of the donor at baseline, evaluating changes in this following stem cell transplant
- Assessing the reconstitution level of virus- and bacterial-specific immunity (by measuring the levels of immune cells involved in virus- and bacterial immunity post Tem Infusion) [ Time Frame: Day 100, 180, 270, 360 post stem cell transplant ]Measuring the levels of immune cells at specific points in follow up to determine how virus- and bacterial-specific immunity recovers in patients following a stem cell transplant and Tem infusion
- Difference between donor immune profile with number of CD62L- Tem selected [ Time Frame: Day -14 to -7 (day of cell processing) ]Analysing the donors immune profile pre and post CD62L- Tem selection (cell processing), against the cohort the patient is in (which dose of CD62L- Tem they will receive).
- Alemtuzumab levels on the day of CD62L- Tem infusion [ Time Frame: Day 28 post stem cell transplant ]
| Ages Eligible for Study: | 16 Years to 70 Years (Child, Adult, Older Adult) |
| Sexes Eligible for Study: | All |
| Accepts Healthy Volunteers: | Yes |
Patient Registration Inclusion Criteria:
- Severe aplastic anaemia or
- Primary immune deficiency or
-
Haematological cancer which can be ONE OF the following:
- Non-Hodgkin's lymphoma (NHL) in CR or PR;
- Hodgkin's lymphoma (HL) in CR or PR;
- Chronic (Pro-)lymphocytic leukaemia (CLL or PLL) in CR or PR
- Plasma cell myeloma (PCM) in CR, VGPR or PR;
- Acute myeloid leukaemia (AML) in CR;
- Acute lymphoblastic leukaemia (ALL) in CR;
- Myelodysplastic syndrome (MDS) < 10 % blasts in bone marrow;
- Chronic myelomonocytic leukaemia (CMML) < 10% blasts in bone marrow
- Suitable for HLA-identical sibling transplant using a standard alemtuzumab-based conditioning regimen with calcineurin-inhibitor based immunoprophylaxis
- Aged ≥ 16 years, <70 years
- Written informed consent
Patient Registration Exclusion Criteria:
- Women who are pregnant or breast-feeding
- Life expectancy of < 8 weeks
- Currently taking part in any other interventional clinical research study (involving any IMP, ATMP or cellular therapy)
- Proposed use of any other method of GVHD prophylaxis other than alemtuzumab and calcineurin inhibitor
-
Organ dysfunction:
- LVEF<45%
- Creatinine >200 µmol/lglomerular filtration rate (corrected) <50ml/min
- Bilirubin > 50 µmol/l
- AST or ALT >3x 2.5 x ULN (NB: If both are performed then both must be ≤3 2.5 x ULN)
Patient Trial Treatment Exclusion criteria:
- Prior or active acute pattern GvHD of any grade
- Relapse or progression
- Primary or secondary graft failure
- Has received other cellular therapies
Donor inclusion criteria:
- Aged ≥ 16 years
- HLA-identical sibling
- Have met transplant centre criteria regarding suitability for cell therapy donation
- Negative for HIV 1 and 2, hepatitis B, hepatitis C, HTLV-1 and 2, syphilis serology (to be confirmed before both registration and before trial treatmentat time of or up to 7 days following donation)
- Written informed consent
Donor exclusion criteria:
- Pregnant/lactating women
| Contact: Toyin Adedayo | 0207 679 9867 | ctc.totem@ucl.ac.uk | |
| Contact: Nadjet El-Mehidi | 0207 679 9283 | ctc.totem@ucl.ac.uk |
| United Kingdom | |
| UCLH | Recruiting |
| London, United Kingdom | |
| Contact: Ron Chakraverty, Prof | |
| Tracking Information | |||||||||
|---|---|---|---|---|---|---|---|---|---|
| First Submitted Date ICMJE | January 10, 2019 | ||||||||
| First Posted Date ICMJE | February 11, 2019 | ||||||||
| Last Update Posted Date | October 25, 2019 | ||||||||
| Actual Study Start Date ICMJE | October 21, 2019 | ||||||||
| Estimated Primary Completion Date | July 1, 2022 (Final data collection date for primary outcome measure) | ||||||||
| Current Primary Outcome Measures ICMJE |
Occurrence of dose limiting toxicity (DLT) [ Time Frame: up to 72 days after Tem infusion ] Occurrence of dose limiting toxicity (DLT) (defined as acute-pattern GvHD grade II-IV)
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| Original Primary Outcome Measures ICMJE | Same as current | ||||||||
| Change History | |||||||||
| Current Secondary Outcome Measures ICMJE |
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| Original Secondary Outcome Measures ICMJE | Same as current | ||||||||
| Current Other Pre-specified Outcome Measures |
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| Original Other Pre-specified Outcome Measures | Same as current | ||||||||
| Descriptive Information | |||||||||
| Brief Title ICMJE | Transfer of Effector Memory T Cells (Tem) Following Allogeneic Stem Cell Transplantation | ||||||||
| Official Title ICMJE | Phase I Study of Transfer of Effector Memory T Cells (Tem) Following Allogeneic Stem Cell Transplantation | ||||||||
| Brief Summary |
RATIONALE: Following stem cell transplantation, a major risk is graft-versus-host disease (GVHD). This occurs when donor immune cells that have been infused recognise the host's cells as 'foreign' and attack these cells. Prevention of GVHD relies upon depletion of donor immune T cells or drugs that block T cell function. However, these methods also increase the risk of life threatening infection. There is an important unmet need for better means of accelerating immune recovery following stem cell transplantation while avoiding GVHD. Pre-clinical studies have shown that infusion of donor CD62L- effector memory T cells (Tem) into the host improve immune recovery after allo-Stem Cell Transplant but do not cause GVHD. PURPOSE: This phase I dose escalation trial aims to determine the feasibility and safety of transfer of donor Tem following allogeneic stem cell transplantation. |
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| Detailed Description |
Phase I study using a Bayesian Time-to-Event Continual Reassessment Method (CRM) to determine safety and maximum tolerated dose (MTD) of CD62L- Tem. Eligible patients and HLA-identical sibling donors will be registered prior to stem cell transplant (SCT). Donors will undergo an additional steady state apheresis for the collection of T cells between day -14 and day +24 of the allo-SCT according to logistics. Selection of Tem at the required dose will be performed at UCL Centre for Cell, Gene and Tissue Therapeutics (CCGTT) before distribution of the cryopreserved cells to the trial centre. Doses of Tem selected and infused will be: 1x10^5, 3x10^5, 1x10^6 or 3x10^6. Donor Tem will be infused on day 24-32 following allo-SCT. Patients will be followed-up for 12 months with specific evaluation points just prior to Tem infusion and at 3, 6, 9 and 12 months following allo-SCT. |
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| Study Type ICMJE | Interventional | ||||||||
| Study Phase ICMJE | Phase 1 | ||||||||
| Study Design ICMJE | Allocation: N/A Intervention Model: Single Group Assignment Masking: None (Open Label) Primary Purpose: Treatment |
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| Condition ICMJE |
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| Intervention ICMJE | Biological: CD62L- Tem
Donor memory T cells that have been depleted of CD62L+
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| Study Arms ICMJE | Experimental: Donor T cells depleted of CD62L+ cells (CD62L- Tem)
Donors will undergo a steady state apheresis for the collection of T cells. Selection of CD62L- Tem at the required dose will be performed at UCL Centre for Cell, Gene and Tissue Therapeutics (CCGTT). Donor Tem will be infused into patients on day 24-32 following allo-Stem Cell Transplant.
Intervention: Biological: CD62L- Tem
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| Publications * | Not Provided | ||||||||
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* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline. |
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| Recruitment Information | |||||||||
| Recruitment Status ICMJE | Recruiting | ||||||||
| Estimated Enrollment ICMJE |
18 | ||||||||
| Original Estimated Enrollment ICMJE | Same as current | ||||||||
| Estimated Study Completion Date ICMJE | April 1, 2023 | ||||||||
| Estimated Primary Completion Date | July 1, 2022 (Final data collection date for primary outcome measure) | ||||||||
| Eligibility Criteria ICMJE |
Patient Registration Inclusion Criteria:
Patient Registration Exclusion Criteria:
Patient Trial Treatment Exclusion criteria:
Donor inclusion criteria:
Donor exclusion criteria: - Pregnant/lactating women |
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| Sex/Gender ICMJE |
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| Ages ICMJE | 16 Years to 70 Years (Child, Adult, Older Adult) | ||||||||
| Accepts Healthy Volunteers ICMJE | Yes | ||||||||
| Contacts ICMJE |
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| Listed Location Countries ICMJE | United Kingdom | ||||||||
| Removed Location Countries | |||||||||
| Administrative Information | |||||||||
| NCT Number ICMJE | NCT03836690 | ||||||||
| Other Study ID Numbers ICMJE | UCL/13/0372 MR/R025436/1 ( Other Grant/Funding Number: Medical Research Council ) |
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| Has Data Monitoring Committee | Yes | ||||||||
| U.S. FDA-regulated Product |
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| IPD Sharing Statement ICMJE |
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| Responsible Party | University College, London | ||||||||
| Study Sponsor ICMJE | University College, London | ||||||||
| Collaborators ICMJE | Medical Research Council | ||||||||
| Investigators ICMJE | Not Provided | ||||||||
| PRS Account | University College, London | ||||||||
| Verification Date | October 2019 | ||||||||
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ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP |
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