<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/NCT03771222</url>
  </required_header>
  <id_info>
    <org_study_id>pDLI2018</org_study_id>
    <nct_id>NCT03771222</nct_id>
  </id_info>
  <brief_title>Prophylactic Donor Lymphocyte Infusion After Allo-PBSCT for Patients With Very High-risk Hematologic Malignancies</brief_title>
  <official_title>Prophylactic Donor Lymphocyte Infusion After Allo-PBSCT for Patients With Very High-risk Hematologic Malignancies</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Chinese PLA General Hospital</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Chinese PLA General Hospital</source>
  <oversight_info>
    <has_dmc>No</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>
      Unmanipulated allogenic peripheral blood stem cell transplantation (allo-PBSCT) has been an&#xD;
      established treatment to cure high-risk leukemia/lymphoma. Relapse is the main cause of&#xD;
      treatment failure for patients with relapsed/refractory disease or with very high-risk gene&#xD;
      mutations such as TP53, TET2 and DNMT3a. Donor lymphocyte infusion (DLI) is an option to&#xD;
      reduce relapse after allo-PBSCT for very high-risk disease without effective targeted&#xD;
      therapy. In this study, the investigators aimed to compare the safety and efficacy of&#xD;
      prophylactic DLI with G-CSF-primed peripheral blood progenitors for prevention of relapse&#xD;
      after allo-PBSCT in patients with very high-risk leukemia/lymphoma.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Conventional DLI has invariably been associated with high rates of severe graft-versus-host&#xD;
      disease (GVHD) and GVHD-related non-relapse mortality (NRM). Thus, in our previous studies,&#xD;
      the DLI procedure has been modified to use G-CSF-mobilized peripheral blood stem cells&#xD;
      (PBSCs) instead of steady-state lymphocytes. G-CSF mobilization results in the modulation of&#xD;
      the polarization potential of T cells from Th1 to Th2. In addition, T-cell hyporesponsiveness&#xD;
      is induced via the proliferation of dendritic cell 2 and monocytes and the down-regulation of&#xD;
      CD28/B7. Furthermore, G-CSF augments NK-T-cell-dependent CD8+ cytotoxicity. These data&#xD;
      constructed the rationale for the use of G-CSF-primed peripheral blood DLI to reduce&#xD;
      DLI-associated GVHD and enhance the GVT effect of DLI. To date, there is no effective target&#xD;
      therapy for acute leukemia with gene mutations such as DNMT3A, TET2 and TP53 and their&#xD;
      response to chemotherapy and survival even after allogenic stem cell transplantation remains&#xD;
      poor. Hypomethylating agents were reported to reverse the repression of HLA molecules and&#xD;
      cancer testis antigens on leukemia cells, rendering them more sensitive to anti-leukemic&#xD;
      activity mediated by DLI. The use of low-dose decitabine after allogenic stem cell&#xD;
      transplantation was safe for early hematopoietic reconstitution. Therefore, decitabine was&#xD;
      planned to be given prior to prophylactic DLI in the current study.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Unknown status</overall_status>
  <last_known_status>Not yet recruiting</last_known_status>
  <start_date type="Anticipated">January 2019</start_date>
  <completion_date type="Anticipated">December 2021</completion_date>
  <primary_completion_date type="Anticipated">December 2020</primary_completion_date>
  <phase>Phase 2</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>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Cumulative incidence of relapse at 1 year after randomization</measure>
    <time_frame>1 year</time_frame>
    <description>Relapse was defined as hematologic recurrence of malignancies after transplantation. Cumulative incidence of relapse was analyzed in a competing risk framework using Gray's method.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Cumulative incidence of non-relapse mortality (NRM) at 1 year after randomization</measure>
    <time_frame>1 year</time_frame>
    <description>NRM was deﬁned as death from any cause without relapse. Cumulative incidence of NRM was analyzed in a competing risk framework using Gray's method.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Relapse-free survival (RFS) at 1 year after randomization</measure>
    <time_frame>1 year</time_frame>
    <description>RFS will be evaluated in an intent-to-treat analysis by Kaplan Meier estimate and Log Rank test. Survival will be calculated from the date of randomization.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Cumulative incidence of acute GVHD at 100 days after randomization</measure>
    <time_frame>100 days</time_frame>
    <description>The cumulative incidence of acute GVHD was estimated considering the competing risks.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Cumulative incidence of chronic GVHD at 1 year after randomization</measure>
    <time_frame>1 year</time_frame>
    <description>The cumulative incidence of chronic GVHD was estimated considering the competing risks.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">40</enrollment>
  <condition>Donor Lymphocyte Infusion</condition>
  <condition>Peripheral Blood Stem Cell Transplantation</condition>
  <condition>Relapse</condition>
  <condition>Graft-versus-host Disease</condition>
  <condition>Decitabine</condition>
  <arm_group>
    <arm_group_label>Prophylactic DLI</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>The scheduled time of the first prophylactic DLI was +30 ~ +60 days after transplantation for HLA-matched sibling donors (MSD)-PBSCT recipients and +60 ~ +90 days after transplantation for HLA-haploidentical sibling donors (HID)-PBSCT recipients.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>No prophylactic DLI</arm_group_label>
    <arm_group_type>No Intervention</arm_group_type>
  </arm_group>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>Prophylactic DLI</intervention_name>
    <description>The G-CSF-mobilized PBSCs from cryopreserved cells of the graft were infused to the recipient at a dose of 2X10^7 CD3+ cells/kg recipient body weight. Decitabine (10 mg/m2, days 1 to 5) followed by prophylactic DLI would be given to those patients carrying TET2, DNMT3a or TP53 gene mutations.</description>
    <arm_group_label>Prophylactic DLI</arm_group_label>
    <other_name>Decitabine (trade name Dacogen)</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  disease in the non-remission (NR) state prior to transplantation, including primary&#xD;
             induction failure, relapse untreated or refractory to reinduction chemotherapy.&#xD;
&#xD;
          -  achieving CR1 with ≥3 cycles of induction of chemotherapy.&#xD;
&#xD;
          -  carrying TP53, DNMT3a, TET2 or FLT3-ITD gene mutation.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  early relapse, either molecular relapse or hematological relapse.&#xD;
&#xD;
          -  primary or secondary graft failure.&#xD;
&#xD;
          -  concomitant uncontrolled disease and/or organ dysfunction (infection, severe heart,&#xD;
             renal, respiratory or hepatic failure…).&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>14 Years</minimum_age>
    <maximum_age>65 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <location>
    <facility>
      <name>Chinese PLA General Hospital</name>
      <address>
        <city>Beijing</city>
        <state>Beijing</state>
        <zip>100853</zip>
        <country>China</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>China</country>
  </location_countries>
  <verification_date>December 2018</verification_date>
  <study_first_submitted>December 7, 2018</study_first_submitted>
  <study_first_submitted_qc>December 7, 2018</study_first_submitted_qc>
  <study_first_posted type="Actual">December 11, 2018</study_first_posted>
  <last_update_submitted>December 11, 2018</last_update_submitted>
  <last_update_submitted_qc>December 11, 2018</last_update_submitted_qc>
  <last_update_posted type="Actual">December 13, 2018</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Chinese PLA General Hospital</investigator_affiliation>
    <investigator_full_name>Daihong Liu</investigator_full_name>
    <investigator_title>Head of Hematology</investigator_title>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Hematologic Neoplasms</mesh_term>
    <mesh_term>Graft vs Host Disease</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Decitabine</mesh_term>
  </intervention_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/NCT03771222
org study id: pDLI2018
nct id: NCT03771222
lead sponsor: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
Unmanipulated allogenic peripheral blood stem cell transplantation (allo-PBSCT) has been an
      established treatment to cure high-risk leukemia/lymphoma. Relapse is the main cause of
      treatment failure for patients with relapsed/refractory disease or with very high-risk gene
      mutations such as TP53, TET2 and DNMT3a. Donor lymphocyte infusion (DLI) is an option to
      reduce relapse after allo-PBSCT for very high-risk disease without effective targeted
      therapy. In this study, the investigators aimed to compare the safety and efficacy of
      prophylactic DLI with G-CSF-primed peripheral blood progenitors for prevention of relapse
      after allo-PBSCT in patients with very high-risk leukemia/lymphoma.
Conventional DLI has invariably been associated with high rates of severe graft-versus-host
      disease (GVHD) and GVHD-related non-relapse mortality (NRM). Thus, in our previous studies,
      the DLI procedure has been modified to use G-CSF-mobilized peripheral blood stem cells
      (PBSCs) instead of steady-state lymphocytes. G-CSF mobilization results in the modulation of
      the polarization potential of T cells from Th1 to Th2. In addition, T-cell hyporesponsiveness
      is induced via the proliferation of dendritic cell 2 and monocytes and the down-regulation of
      CD28/B7. Furthermore, G-CSF augments NK-T-cell-dependent CD8+ cytotoxicity. These data
      constructed the rationale for the use of G-CSF-primed peripheral blood DLI to reduce
      DLI-associated GVHD and enhance the GVT effect of DLI. To date, there is no effective target
      therapy for acute leukemia with gene mutations such as DNMT3A, TET2 and TP53 and their
      response to chemotherapy and survival even after allogenic stem cell transplantation remains
      poor. Hypomethylating agents were reported to reverse the repression of HLA molecules and
      cancer testis antigens on leukemia cells, rendering them more sensitive to anti-leukemic
      activity mediated by DLI. The use of low-dose decitabine after allogenic stem cell
      transplantation was safe for early hematopoietic reconstitution. Therefore, decitabine was
      planned to be given prior to prophylactic DLI in the current study.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Cumulative incidence of relapse at 1 year after randomization
time frame: 1 year
description: Relapse was defined as hematologic recurrence of malignancies after transplantation. Cumulative incidence of relapse was analyzed in a competing risk framework using Gray's method.
measure: Cumulative incidence of non-relapse mortality (NRM) at 1 year after randomization
time frame: 1 year
description: NRM was deﬁned as death from any cause without relapse. Cumulative incidence of NRM was analyzed in a competing risk framework using Gray's method.
measure: Relapse-free survival (RFS) at 1 year after randomization
time frame: 1 year
description: RFS will be evaluated in an intent-to-treat analysis by Kaplan Meier estimate and Log Rank test. Survival will be calculated from the date of randomization.
measure: Cumulative incidence of acute GVHD at 100 days after randomization
time frame: 100 days
description: The cumulative incidence of acute GVHD was estimated considering the competing risks.
measure: Cumulative incidence of chronic GVHD at 1 year after randomization
time frame: 1 year
description: The cumulative incidence of chronic GVHD was estimated considering the competing risks.
arm group label: Prophylactic DLI
arm group type: Experimental
description: The scheduled time of the first prophylactic DLI was +30 ~ +60 days after transplantation for HLA-matched sibling donors (MSD)-PBSCT recipients and +60 ~ +90 days after transplantation for HLA-haploidentical sibling donors (HID)-PBSCT recipients.
arm group label: No prophylactic DLI
arm group type: No Intervention
intervention type: Biological
intervention name: Prophylactic DLI
description: The G-CSF-mobilized PBSCs from cryopreserved cells of the graft were infused to the recipient at a dose of 2X10^7 CD3+ cells/kg recipient body weight. Decitabine (10 mg/m2, days 1 to 5) followed by prophylactic DLI would be given to those patients carrying TET2, DNMT3a or TP53 gene mutations.
arm group label: Prophylactic DLI
other name: Decitabine (trade name Dacogen)
criteria: 
gender: All
minimum age: 14 Years
maximum age: 65 Years
healthy volunteers: No
facility: 
country: China
responsible party type: Principal Investigator
investigator affiliation: Chinese PLA General Hospital
investigator full name: Daihong Liu
investigator title: Head of Hematology
mesh term: Hematologic Neoplasms
mesh term: Graft vs Host Disease
mesh term: Decitabine
sharing ipd: No