<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT03836690</url>
  </required_header>
  <id_info>
    <org_study_id>UCL/13/0372</org_study_id>
    <secondary_id>MR/R025436/1</secondary_id>
    <nct_id>NCT03836690</nct_id>
  </id_info>
  <brief_title>Transfer of Effector Memory T Cells (Tem) Following Allogeneic Stem Cell Transplantation</brief_title>
  <acronym>ToTem</acronym>
  <official_title>Phase I Study of Transfer of Effector Memory T Cells (Tem) Following Allogeneic Stem Cell Transplantation</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University College, London</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Medical Research Council</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>University College, London</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      RATIONALE: Following stem cell transplantation, a major risk is graft-versus-host disease&#xD;
      (GVHD). This occurs when donor immune cells that have been infused recognise the host's cells&#xD;
      as 'foreign' and attack these cells. Prevention of GVHD relies upon depletion of donor immune&#xD;
      T cells or drugs that block T cell function. However, these methods also increase the risk of&#xD;
      life threatening infection. There is an important unmet need for better means of accelerating&#xD;
      immune recovery following stem cell transplantation while avoiding GVHD.&#xD;
&#xD;
      Pre-clinical studies have shown that infusion of donor CD62L- effector memory T cells (Tem)&#xD;
      into the host improve immune recovery after allo-Stem Cell Transplant but do not cause GVHD.&#xD;
&#xD;
      PURPOSE: This phase I dose escalation trial aims to determine the feasibility and safety of&#xD;
      transfer of donor Tem following allogeneic stem cell transplantation.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Phase I study using a Bayesian Time-to-Event Continual Reassessment Method (CRM) to determine&#xD;
      safety and maximum tolerated dose (MTD) of CD62L- Tem.&#xD;
&#xD;
      Eligible patients and HLA-identical sibling donors will be registered prior to stem cell&#xD;
      transplant (SCT). Donors will undergo an additional steady state apheresis for the collection&#xD;
      of T cells between day -14 and day +24 of the allo-SCT according to logistics. Selection of&#xD;
      Tem at the required dose will be performed at UCL Centre for Cell, Gene and Tissue&#xD;
      Therapeutics (CCGTT) before distribution of the cryopreserved cells to the trial centre.&#xD;
      Doses of Tem selected and infused will be: 1x10^5, 3x10^5, 1x10^6 or 3x10^6.&#xD;
&#xD;
      Donor Tem will be infused on day 24-32 following allo-SCT. Patients will be followed-up for&#xD;
      12 months with specific evaluation points just prior to Tem infusion and at 3, 6, 9 and 12&#xD;
      months following allo-SCT.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Recruiting</last_known_status>
  <start_date type="Actual">October 21, 2019</start_date>
  <completion_date type="Anticipated">April 1, 2023</completion_date>
  <primary_completion_date type="Anticipated">July 1, 2022</primary_completion_date>
  <phase>Phase 1</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Occurrence of dose limiting toxicity (DLT)</measure>
    <time_frame>up to 72 days after Tem infusion</time_frame>
    <description>Occurrence of dose limiting toxicity (DLT) (defined as acute-pattern GvHD grade II-IV)</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Incidence and severity of acute GvHD</measure>
    <time_frame>From date of infusion of Tem until 100 days post stem cell transplant</time_frame>
    <description>Incidence and severity of acute GvHD (whether dose limiting or not)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Incidence and severity of chronic GvHD</measure>
    <time_frame>From date of infusion of Tem up to 1 year post stem cell transplant</time_frame>
    <description>Incidence and severity of chronic GvHD</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Non-relapse mortality</measure>
    <time_frame>From date of patient registration up to 1 year post stem cell transplant</time_frame>
    <description>Death without reoccurrence of cancer</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall survival</measure>
    <time_frame>From date of patient registration up to 1 year post stem cell transplant</time_frame>
    <description>Death</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Progression-free survival</measure>
    <time_frame>From date of patient registration up to 1 year post stem cell transplant</time_frame>
    <description>Disease progression or death</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Incidence/type of infection requiring inpatient admission</measure>
    <time_frame>From date of infusion of Tem up to 1 year post stem cell transplant</time_frame>
    <description>Any infection that has required an inpatient admission, incidence and type of infection</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Total Number of inpatient days</measure>
    <time_frame>From date of infusion of Tem up to 1 year post stem cell transplant</time_frame>
    <description>Total Number of inpatient days for any reason</description>
  </secondary_outcome>
  <other_outcome>
    <measure>TCR repertoire analysis by deep CDR3 sequencing</measure>
    <time_frame>Day -14 to -7 (day of cell processing) and day 100 and 360 post stem cell transplant</time_frame>
  </other_outcome>
  <other_outcome>
    <measure>Chimerism of immune subsets (analysing the genetic profiles of recipient and donor at baseline and following stem cell transplant)</measure>
    <time_frame>Pre-Registration and Day 100, 180, 270, 360 post stem cell transplant</time_frame>
    <description>Identifying the genetic profiles of the recipient and of the donor at baseline, evaluating changes in this following stem cell transplant</description>
  </other_outcome>
  <other_outcome>
    <measure>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)</measure>
    <time_frame>Day 100, 180, 270, 360 post stem cell transplant</time_frame>
    <description>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</description>
  </other_outcome>
  <other_outcome>
    <measure>Difference between donor immune profile with number of CD62L- Tem selected</measure>
    <time_frame>Day -14 to -7 (day of cell processing)</time_frame>
    <description>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).</description>
  </other_outcome>
  <other_outcome>
    <measure>Alemtuzumab levels on the day of CD62L- Tem infusion</measure>
    <time_frame>Day 28 post stem cell transplant</time_frame>
  </other_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Anticipated">18</enrollment>
  <condition>Lymphoma</condition>
  <condition>Leukemia</condition>
  <condition>Myeloma</condition>
  <condition>Myelodysplastic Syndromes</condition>
  <condition>Severe Aplastic Anemia</condition>
  <condition>Primary Immune Deficiency</condition>
  <condition>Graft Vs Host Disease</condition>
  <arm_group>
    <arm_group_label>Donor T cells depleted of CD62L+ cells (CD62L- Tem)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>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.</description>
  </arm_group>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>CD62L- Tem</intervention_name>
    <description>Donor memory T cells that have been depleted of CD62L+</description>
    <arm_group_label>Donor T cells depleted of CD62L+ cells (CD62L- Tem)</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Patient Registration Inclusion Criteria:&#xD;
&#xD;
          -  Severe aplastic anaemia or&#xD;
&#xD;
          -  Primary immune deficiency or&#xD;
&#xD;
          -  Haematological cancer which can be ONE OF the following:&#xD;
&#xD;
               -  Non-Hodgkin's lymphoma (NHL) in CR or PR;&#xD;
&#xD;
               -  Hodgkin's lymphoma (HL) in CR or PR;&#xD;
&#xD;
               -  Chronic (Pro-)lymphocytic leukaemia (CLL or PLL) in CR or PR&#xD;
&#xD;
               -  Plasma cell myeloma (PCM) in CR, VGPR or PR;&#xD;
&#xD;
               -  Acute myeloid leukaemia (AML) in CR;&#xD;
&#xD;
               -  Acute lymphoblastic leukaemia (ALL) in CR;&#xD;
&#xD;
               -  Myelodysplastic syndrome (MDS) &lt; 10 % blasts in bone marrow;&#xD;
&#xD;
               -  Chronic myelomonocytic leukaemia (CMML) &lt; 10% blasts in bone marrow&#xD;
&#xD;
          -  Suitable for HLA-identical sibling transplant using a standard alemtuzumab-based&#xD;
             conditioning regimen with calcineurin-inhibitor based immunoprophylaxis&#xD;
&#xD;
          -  Aged ≥ 16 years, &lt;70 years&#xD;
&#xD;
          -  Written informed consent&#xD;
&#xD;
        Patient Registration Exclusion Criteria:&#xD;
&#xD;
          -  Women who are pregnant or breast-feeding&#xD;
&#xD;
          -  Life expectancy of &lt; 8 weeks&#xD;
&#xD;
          -  Currently taking part in any other interventional clinical research study (involving&#xD;
             any IMP, ATMP or cellular therapy)&#xD;
&#xD;
          -  Proposed use of any other method of GVHD prophylaxis other than alemtuzumab and&#xD;
             calcineurin inhibitor&#xD;
&#xD;
          -  Organ dysfunction:&#xD;
&#xD;
               -  LVEF&lt;45%&#xD;
&#xD;
               -  Creatinine &gt;200 µmol/lglomerular filtration rate (corrected) &lt;50ml/min&#xD;
&#xD;
               -  Bilirubin &gt; 50 µmol/l&#xD;
&#xD;
               -  AST or ALT &gt;3x 2.5 x ULN (NB: If both are performed then both must be ≤3 2.5 x&#xD;
                  ULN)&#xD;
&#xD;
        Patient Trial Treatment Exclusion criteria:&#xD;
&#xD;
          -  Prior or active acute pattern GvHD of any grade&#xD;
&#xD;
          -  Relapse or progression&#xD;
&#xD;
          -  Primary or secondary graft failure&#xD;
&#xD;
          -  Has received other cellular therapies&#xD;
&#xD;
        Donor inclusion criteria:&#xD;
&#xD;
          -  Aged ≥ 16 years&#xD;
&#xD;
          -  HLA-identical sibling&#xD;
&#xD;
          -  Have met transplant centre criteria regarding suitability for cell therapy donation&#xD;
&#xD;
          -  Negative for HIV 1 and 2, hepatitis B, hepatitis C, HTLV-1 and 2, syphilis serology&#xD;
             (to be confirmed before both registration and before trial treatmentat time of or up&#xD;
             to 7 days following donation)&#xD;
&#xD;
          -  Written informed consent&#xD;
&#xD;
        Donor exclusion criteria:&#xD;
&#xD;
        - Pregnant/lactating women&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>16 Years</minimum_age>
    <maximum_age>70 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_contact>
    <last_name>Toyin Adedayo</last_name>
    <phone>0207 679 9867</phone>
    <email>ctc.totem@ucl.ac.uk</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Nadjet El-Mehidi</last_name>
    <phone>0207 679 9283</phone>
    <email>ctc.totem@ucl.ac.uk</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>UCLH</name>
      <address>
        <city>London</city>
        <country>United Kingdom</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Ron Chakraverty, Prof</last_name>
    </contact>
  </location>
  <location_countries>
    <country>United Kingdom</country>
  </location_countries>
  <verification_date>October 2019</verification_date>
  <study_first_submitted>January 10, 2019</study_first_submitted>
  <study_first_submitted_qc>February 8, 2019</study_first_submitted_qc>
  <study_first_posted type="Actual">February 11, 2019</study_first_posted>
  <last_update_submitted>October 22, 2019</last_update_submitted>
  <last_update_submitted_qc>October 22, 2019</last_update_submitted_qc>
  <last_update_posted type="Actual">October 25, 2019</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Myelodysplastic Syndromes</mesh_term>
    <mesh_term>Anemia, Aplastic</mesh_term>
    <mesh_term>Primary Immunodeficiency Diseases</mesh_term>
    <mesh_term>Immunologic Deficiency Syndromes</mesh_term>
    <mesh_term>Graft vs Host Disease</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03836690
org study id: UCL/13/0372
secondary id: MR/R025436/1
nct id: NCT03836690
lead sponsor: 
collaborator: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
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.
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.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Occurrence of dose limiting toxicity (DLT)
time frame: up to 72 days after Tem infusion
description: Occurrence of dose limiting toxicity (DLT) (defined as acute-pattern GvHD grade II-IV)
measure: Incidence and severity of acute GvHD
time frame: From date of infusion of Tem until 100 days post stem cell transplant
description: Incidence and severity of acute GvHD (whether dose limiting or not)
measure: Incidence and severity of chronic GvHD
time frame: From date of infusion of Tem up to 1 year post stem cell transplant
description: Incidence and severity of chronic GvHD
measure: Non-relapse mortality
time frame: From date of patient registration up to 1 year post stem cell transplant
description: Death without reoccurrence of cancer
measure: Overall survival
time frame: From date of patient registration up to 1 year post stem cell transplant
description: Death
measure: Progression-free survival
time frame: From date of patient registration up to 1 year post stem cell transplant
description: Disease progression or death
measure: Incidence/type of infection requiring inpatient admission
time frame: From date of infusion of Tem up to 1 year post stem cell transplant
description: Any infection that has required an inpatient admission, incidence and type of infection
measure: Total Number of inpatient days
time frame: From date of infusion of Tem up to 1 year post stem cell transplant
description: Total Number of inpatient days for any reason
measure: 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
measure: 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
description: Identifying the genetic profiles of the recipient and of the donor at baseline, evaluating changes in this following stem cell transplant
measure: 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
description: 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
measure: Difference between donor immune profile with number of CD62L- Tem selected
time frame: Day -14 to -7 (day of cell processing)
description: 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).
measure: Alemtuzumab levels on the day of CD62L- Tem infusion
time frame: Day 28 post stem cell transplant
arm group label: Donor T cells depleted of CD62L+ cells (CD62L- Tem)
arm group type: Experimental
description: 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 type: Biological
intervention name: CD62L- Tem
description: Donor memory T cells that have been depleted of CD62L+
arm group label: Donor T cells depleted of CD62L+ cells (CD62L- Tem)
criteria: 
gender: All
minimum age: 16 Years
maximum age: 70 Years
healthy volunteers: Accepts Healthy Volunteers
last name: Toyin Adedayo
phone: 0207 679 9867
email: ctc.totem@ucl.ac.uk
last name: Nadjet El-Mehidi
phone: 0207 679 9283
email: ctc.totem@ucl.ac.uk
facility: 
status: Recruiting
contact: 
country: United Kingdom
responsible party type: Sponsor
mesh term: Myelodysplastic Syndromes
mesh term: Anemia, Aplastic
mesh term: Primary Immunodeficiency Diseases
mesh term: Immunologic Deficiency Syndromes
mesh term: Graft vs Host Disease
sharing ipd: No