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Transfer of Effector Memory T Cells (Tem) Following Allogeneic Stem Cell Transplantation (ToTem)

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ClinicalTrials.gov Identifier: NCT03836690
Recruitment Status : Not yet recruiting
First Posted : February 11, 2019
Last Update Posted : February 11, 2019
Sponsor:
Collaborator:
Medical Research Council
Information provided by (Responsible Party):
University College, London

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.


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

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.


Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 18 participants
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
Estimated Study Start Date : June 1, 2019
Estimated Primary Completion Date : March 1, 2022
Estimated Study Completion Date : December 1, 2022


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+




Primary Outcome Measures :
  1. 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)


Secondary Outcome Measures :
  1. 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)

  2. 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

  3. Non-relapse mortality [ Time Frame: From date of patient registration up to 1 year post stem cell transplant ]
    Death without reoccurrence of cancer

  4. Overall survival [ Time Frame: From date of patient registration up to 1 year post stem cell transplant ]
    Death

  5. Progression-free survival [ Time Frame: From date of patient registration up to 1 year post stem cell transplant ]
    Disease progression or death

  6. 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

  7. 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


Other Outcome Measures:
  1. 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 ]
  2. 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

  3. 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

  4. 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).

  5. Alemtuzumab levels on the day of CD62L- Tem infusion [ Time Frame: Day 28 post stem cell transplant ]


Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 70 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

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
  • Have undergone disease reassessment within 8 weeks prior to registration
  • Suitable for HLA-identical sibling transplant using a standard alemtuzumab-based conditioning regimen with calcineurin-inhibitor based immunoprophylaxis
  • Aged ≥ 18 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 ≥ 18 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


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03836690


Contacts
Contact: Toyin Adedayo 0207 679 9867 ctc.port@ucl.ac.uk
Contact: Nadjet El-Mehidi 0207 679 9283 ctc.port@ucl.ac.uk

Sponsors and Collaborators
University College, London
Medical Research Council

Responsible Party: University College, London
ClinicalTrials.gov Identifier: NCT03836690     History of Changes
Other Study ID Numbers: UCL/13/0372
MR/R025436/1 ( Other Grant/Funding Number: Medical Research Council )
First Posted: February 11, 2019    Key Record Dates
Last Update Posted: February 11, 2019
Last Verified: February 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:
Myelodysplastic Syndromes
Preleukemia
Anemia, Aplastic
Immunologic Deficiency Syndromes
Graft vs Host Disease
Bone Marrow Diseases
Hematologic Diseases
Precancerous Conditions
Neoplasms
Anemia
Immune System Diseases