<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/NCT03236129</url>
  </required_header>
  <id_info>
    <org_study_id>P140303</org_study_id>
    <secondary_id>2016-A00645-46</secondary_id>
    <nct_id>NCT03236129</nct_id>
  </id_info>
  <brief_title>Allogeneic Immunotherapy for Hematological Malignancies by Selective Depletion of Regulatory T Cells</brief_title>
  <acronym>DLI-Boost</acronym>
  <official_title>Allogeneic Immunotherapy for Hematological Malignancies by Selective Depletion of Regulatory T Cells: A Confirmatory, Randomized, Double Blinded Trial</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Assistance Publique - Hôpitaux de Paris</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Assistance Publique - Hôpitaux de Paris</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>
      The investigators have previously shown the absence of toxicity of Treg-depleted-DLI and the&#xD;
      possibility to triggering alloreactivity (GVHD/GVT) in relapsing patients dealing with&#xD;
      hematological malignancies who had never shown any signs of GVHD after transplant or after&#xD;
      one or more DLI.&#xD;
&#xD;
      The Investigators, we plan to demonstrate the benefit of Treg-depleted DLI as compared to the&#xD;
      reference treatment of relapse in hematological malignancies after allogeneic HSCT which is&#xD;
      currently based on standard DLI&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      This clinical trial is designed to demonstrate the benefit of Treg-depleted DLI as compared&#xD;
      to the reference treatment of relapse in hematological malignancies after allogeneic HSCT&#xD;
      which is currently based on standard DLI.&#xD;
&#xD;
      Patients who have never shown any signs of GVHD and for which one (or more) unmanipulated DLI&#xD;
      have been ineffective. Those patients will receive a subsequent DLI, which will be either&#xD;
      unmanipulated (control arm) or Treg depleted (experimental arm) after a randomization. In&#xD;
      both cases, the second DLI will be immediately preceded by a lymphodepleting treatment based&#xD;
      on cyclophosphamide and fludarabine association.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Recruiting</last_known_status>
  <start_date type="Actual">February 22, 2018</start_date>
  <completion_date type="Anticipated">February 2022</completion_date>
  <primary_completion_date type="Anticipated">February 2021</primary_completion_date>
  <phase>Phase 3</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Double (Participant, Investigator)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Cumulative incidence of clinical manifestations of GVHD, in the form of acute GVHD with grade ≥ 2 and/or extensive chronic. This parameter will take into account the competitive risk of death unrelated to the GVHD</measure>
    <time_frame>1 year after injection</time_frame>
  </primary_outcome>
  <secondary_outcome>
    <measure>Cumulative incidence of relapse, taking into account the competitive risk of death unrelated to relapse</measure>
    <time_frame>1 year after injection</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Relapse-free survival</measure>
    <time_frame>1 year after injection</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall survival</measure>
    <time_frame>1 year after injection</time_frame>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">52</enrollment>
  <condition>Hematological Malignancies</condition>
  <condition>Regulatory T Cell Depletion</condition>
  <condition>Relapse</condition>
  <arm_group>
    <arm_group_label>Treg depleted DLI</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Patients will receive a lymphodepleting treatment combining cyclophosphamide and fludarabine followed by Treg depleted (Donor Lymphocytes Infusion (DLI)</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Unmanipulated DLI</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Patients will receive a lymphodepleting treatment combining cyclophosphamide and fludarabine followed by a standard DLI (unmanipulated)</description>
  </arm_group>
  <intervention>
    <intervention_type>Procedure</intervention_type>
    <intervention_name>T-reg depleted DLI</intervention_name>
    <description>The patients in the experimental arm benefit of a DLI depleted from regulatory T lymphocytes</description>
    <arm_group_label>Treg depleted DLI</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Procedure</intervention_type>
    <intervention_name>Standard DLI</intervention_name>
    <description>The patients in this arm benefit of a standard DLI.</description>
    <arm_group_label>Unmanipulated DLI</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Children and adults regardless of age or weight allograft for primary or secondary&#xD;
             acute leukemia, MDS, lympho-proliferative syndrome (CLL, Myeloma, Lymphoma) or&#xD;
             myelo-proliferative syndrome.&#xD;
&#xD;
          -  Prior allogeneic HSCT (myeloablative or non-myeloablative conditioning) from a family&#xD;
             donor geno-identical HLA or a volunteer donor HLA 10/10 or 9/10.&#xD;
&#xD;
          -  Molecular, cytogenetic, cytological relapse regardless of the date after the&#xD;
             transplant.&#xD;
&#xD;
          -  Previous standard DLI should have brought a total dose of at least 5.106 CD3 + / kg&#xD;
             (donor HLA-geno idendique) or 2.106 CD3 + / kg (voluntary donor).&#xD;
&#xD;
          -  Patient corresponding to the failure criteria of a previous standard DLI, defined for&#xD;
             each type of hematological malignancies in the test model &quot;DLI-Treg-1&quot; after a delay&#xD;
             of at least 30 days in the case of a progressive disease after DLI and at least 60&#xD;
             days in the case of stable disease (due to possible delayed responses after DLI).&#xD;
&#xD;
          -  Patient consented to the study (the consent of both parents will be collected for&#xD;
             minors)&#xD;
&#xD;
          -  Patients insured by a social security system.&#xD;
&#xD;
          -  Negative pregnancy test (β-HCG hormone) within the 7 days prior to enrollment&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Presence of acute GVHD grade&gt; II or extensive chronic GVHD since the first DLI&#xD;
&#xD;
          -  Patient receiving immunosuppressive therapy for the treatment of GVHD or other reason&#xD;
&#xD;
          -  Impairment of liver function (transaminases&gt; 5 N or bilirubin&gt; 50 µM except Gilbert's&#xD;
             disease) or renal function (creatinine clearance &lt;30 ml / min)&#xD;
&#xD;
          -  OMS performance status &gt; 2&#xD;
&#xD;
          -  Non controlled severe infection&#xD;
&#xD;
          -  Patient under tutorship, curatorship or legal protection&#xD;
&#xD;
        Donor Inclusion Criteria&#xD;
&#xD;
          -  Being the initial HSC donor (HLA geno-identical family or non-family HLA 10/10 or&#xD;
             9/10)&#xD;
&#xD;
          -  Weight ≥20 kg authorizing the lymphapheresis&#xD;
&#xD;
          -  Having no contra-indications for donating blood&#xD;
&#xD;
          -  Absence of severe heart failure, unstable heart disease, uncontrolled hypertension,&#xD;
             type 1 diabetes&#xD;
&#xD;
          -  Negative serology for HIV1-2, HBV, HCV, HTLV 1 and VDRL/TPHA in the 30 days prior to&#xD;
             apheresis. Negative viral genomics diagnosis is required for HIV, HBV and HCV&#xD;
&#xD;
          -  Being informed of the study, and have given an oral non opposition&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>N/A</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Florence BEKCERICH, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Assistance Publique - Hôpitaux de Paris</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Florence BECKERICH, MD</last_name>
    <phone>(0)1 49 81 20 57</phone>
    <phone_ext>+33</phone_ext>
    <email>florence.beckerich@aphp.fr</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Sébastien MAURY, MD/ PhD</last_name>
    <phone>(0)1 49 81 20 57</phone>
    <phone_ext>+33</phone_ext>
    <email>sebastien.maury@aphp.fr</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>Henri Mondor Hospital</name>
      <address>
        <city>Creteil</city>
        <zip>94010</zip>
        <country>France</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Damien VANHOYE, PhD</last_name>
      <phone>(0)1 44 84 17 93</phone>
      <phone_ext>+33</phone_ext>
      <email>damien.vanhoye@drc.aphp.fr</email>
    </contact>
    <contact_backup>
      <last_name>Laetitia GREGOIRE, M. Sc</last_name>
      <phone>(0)1 49 81 41 64</phone>
      <phone_ext>+33</phone_ext>
      <email>Laetitia.gregoire@aphp.fr</email>
    </contact_backup>
  </location>
  <location_countries>
    <country>France</country>
  </location_countries>
  <reference>
    <citation>Maury S, Lemoine FM, Hicheri Y, Rosenzwajg M, Badoual C, Cherai M, Beaumont JL, Azar N, Dhedin N, Sirvent A, Buzyn A, Rubio MT, Vigouroux S, Montagne O, Bories D, Roudot-Thoraval F, Vernant JP, Cordonnier C, Klatzmann D, Cohen JL. CD4+CD25+ regulatory T cell depletion improves the graft-versus-tumor effect of donor lymphocytes after allogeneic hematopoietic stem cell transplantation. Sci Transl Med. 2010 Jul 21;2(41):41ra52. doi: 10.1126/scitranslmed.3001302.</citation>
    <PMID>20650872</PMID>
  </reference>
  <verification_date>November 2020</verification_date>
  <study_first_submitted>July 5, 2017</study_first_submitted>
  <study_first_submitted_qc>July 31, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">August 1, 2017</study_first_posted>
  <last_update_submitted>November 19, 2020</last_update_submitted>
  <last_update_submitted_qc>November 19, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">November 20, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>DLI</keyword>
  <keyword>Regulatory T cells depletion</keyword>
  <keyword>Hematological malignancies</keyword>
  <keyword>Relapse</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Neoplasms</mesh_term>
    <mesh_term>Hematologic Neoplasms</mesh_term>
    <mesh_term>Recurrence</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/NCT03236129
org study id: P140303
secondary id: 2016-A00645-46
nct id: NCT03236129
lead sponsor: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
The investigators have previously shown the absence of toxicity of Treg-depleted-DLI and the
      possibility to triggering alloreactivity (GVHD/GVT) in relapsing patients dealing with
      hematological malignancies who had never shown any signs of GVHD after transplant or after
      one or more DLI.

      The Investigators, we plan to demonstrate the benefit of Treg-depleted DLI as compared to the
      reference treatment of relapse in hematological malignancies after allogeneic HSCT which is
      currently based on standard DLI
This clinical trial is designed to demonstrate the benefit of Treg-depleted DLI as compared
      to the reference treatment of relapse in hematological malignancies after allogeneic HSCT
      which is currently based on standard DLI.

      Patients who have never shown any signs of GVHD and for which one (or more) unmanipulated DLI
      have been ineffective. Those patients will receive a subsequent DLI, which will be either
      unmanipulated (control arm) or Treg depleted (experimental arm) after a randomization. In
      both cases, the second DLI will be immediately preceded by a lymphodepleting treatment based
      on cyclophosphamide and fludarabine association.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Double (Participant, Investigator)
measure: Cumulative incidence of clinical manifestations of GVHD, in the form of acute GVHD with grade ≥ 2 and/or extensive chronic. This parameter will take into account the competitive risk of death unrelated to the GVHD
time frame: 1 year after injection
measure: Cumulative incidence of relapse, taking into account the competitive risk of death unrelated to relapse
time frame: 1 year after injection
measure: Relapse-free survival
time frame: 1 year after injection
measure: Overall survival
time frame: 1 year after injection
arm group label: Treg depleted DLI
arm group type: Experimental
description: Patients will receive a lymphodepleting treatment combining cyclophosphamide and fludarabine followed by Treg depleted (Donor Lymphocytes Infusion (DLI)
arm group label: Unmanipulated DLI
arm group type: Active Comparator
description: Patients will receive a lymphodepleting treatment combining cyclophosphamide and fludarabine followed by a standard DLI (unmanipulated)
intervention type: Procedure
intervention name: T-reg depleted DLI
description: The patients in the experimental arm benefit of a DLI depleted from regulatory T lymphocytes
arm group label: Treg depleted DLI
intervention type: Procedure
intervention name: Standard DLI
description: The patients in this arm benefit of a standard DLI.
arm group label: Unmanipulated DLI
criteria: 
gender: All
minimum age: N/A
maximum age: N/A
healthy volunteers: No
last name: Florence BEKCERICH, MD
role: Principal Investigator
affiliation: Assistance Publique - Hôpitaux de Paris
last name: Florence BECKERICH, MD
phone: (0)1 49 81 20 57
phone ext: +33
email: florence.beckerich@aphp.fr
last name: Sébastien MAURY, MD/ PhD
phone: (0)1 49 81 20 57
phone ext: +33
email: sebastien.maury@aphp.fr
facility: 
status: Recruiting
contact: 
contact backup: 
country: France
citation: Maury S, Lemoine FM, Hicheri Y, Rosenzwajg M, Badoual C, Cherai M, Beaumont JL, Azar N, Dhedin N, Sirvent A, Buzyn A, Rubio MT, Vigouroux S, Montagne O, Bories D, Roudot-Thoraval F, Vernant JP, Cordonnier C, Klatzmann D, Cohen JL. CD4+CD25+ regulatory T cell depletion improves the graft-versus-tumor effect of donor lymphocytes after allogeneic hematopoietic stem cell transplantation. Sci Transl Med. 2010 Jul 21;2(41):41ra52. doi: 10.1126/scitranslmed.3001302.
PMID: 20650872
responsible party type: Sponsor
mesh term: Neoplasms
mesh term: Hematologic Neoplasms
mesh term: Recurrence
sharing ipd: No