<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/NCT03035422</url>
  </required_header>
  <id_info>
    <org_study_id>2016-A00862-49</org_study_id>
    <nct_id>NCT03035422</nct_id>
  </id_info>
  <brief_title>Sequential Conditioning in Haploidentical Transplantation for Refractory Acute Myeloid Leukemia</brief_title>
  <acronym>SET-HAPLO</acronym>
  <official_title>Sequential Chemotherapy Prior to Reduced Intensity Conditioning: Interventional Study in Haploidentical Hematopoietic Stem Cells Transplantation for Patients With Refractory Acute Myeloid Leukemia</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Association for Training, Education, and Research in Hematology, Immunology, and Transplantation</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Association for Training, Education, and Research in Hematology, Immunology, and Transplantation</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>
      Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the only treatment option&#xD;
      with a significant chance of healing in acute myeloid leukemia (AML) or refractory multiple&#xD;
      relapses after chemotherapy. However, all patients with an indication of allo-HSC can not&#xD;
      benefit because of two limitations: the toxicity of the treatment and graft shortage&#xD;
      available.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      The goal is to evaluate the efficacy and safety of the combination of an SET followed by&#xD;
      haploidentical transplant with post-transplant immune modulation by prophylactic DLI in&#xD;
      patients with refractory acute myeloid leukemia or relapsed. The main objective is to assess&#xD;
      overall survival at 2 years in these patients.&#xD;
&#xD;
      Secondary objectives:&#xD;
&#xD;
        1. To evaluate the efficacy of this therapeutic strategy in terms of remission of disease,&#xD;
           incidence of relapse and relapse-free survival&#xD;
&#xD;
        2. To evaluate the non-relapse mortality&#xD;
&#xD;
        3. To evaluate the incidence of acute and chronic graft against host disease (GVHD)&#xD;
&#xD;
        4. To assess the feasibility of prophylactic injections of donor lymphocytes (pDLI)&#xD;
&#xD;
        5. To analyze the post-transplant immune reconstitution&#xD;
&#xD;
      Secondary endpoints:&#xD;
&#xD;
        1. partial or complete remission rate by standard criteria at 90 days and then 6, 12 and 24&#xD;
           months after transplantation.&#xD;
&#xD;
           Relapse incidence and death related to the disease 90 days 6, 12 and 24 months after&#xD;
           transplantation Leukemia-free survival at 1 year and 2 years after transplantation&#xD;
&#xD;
        2. Cumulative incidence of death not related to relapse at 90 days, 1 year and 2 years&#xD;
           after transplantation&#xD;
&#xD;
        3. Cumulative incidence of acute and chronic graft against host disease (GVHD)&#xD;
&#xD;
        4. Number of patients for whom pDLI was possible and number of pDLI / patient; incidence,&#xD;
           severity and treatment of possible secondary GVHD in these patients&#xD;
&#xD;
        5. Study of immune reconstitution post-transplant in the peripheral blood 30, 90 and 180&#xD;
           days after transplantation (CD4 lymphocyte levels, CD8, T regulators, Natural Killer&#xD;
           cells and B cells)&#xD;
&#xD;
      Methodology, experimental design:&#xD;
&#xD;
      Multicenter study in routine care, prospective&#xD;
&#xD;
      All patients will receive, as part of the marketing authorization of the products used, the&#xD;
      following regimen:&#xD;
&#xD;
      1- sequential Packaging (SET):&#xD;
&#xD;
        1. sequential chemotherapy:&#xD;
&#xD;
             -  Thiotepa 5 mg / kg / day for 1 day (D-13)&#xD;
&#xD;
             -  Cyclophosphamide 400 mg / m² / day for 4 days (J-12 to J-9)&#xD;
&#xD;
             -  Etoposide 100 mg / m² / day for 4 days (J-12 to J-9)&#xD;
&#xD;
        2. Rest days J-8 and J-6&#xD;
&#xD;
        3. Reduced-intensity conditioning (RIC)&#xD;
&#xD;
             -  Fludarabine 30 mg / m² / day for 5 days (J-5 to D-1)&#xD;
&#xD;
             -  Busulfan IV 3.2 mg / kg / day for 2 days (J-5 and J-4)&#xD;
&#xD;
             -  Anti-lymphocyte serum (Thymoglobuline) 2.5 mg / kg / day for 2 days (J-3 and J-2)&#xD;
&#xD;
                2 Graft transfusion: the day D0. A graft of peripheral stem cells is preferred.&#xD;
&#xD;
                3- Prevention of GVHD:&#xD;
&#xD;
             -  Cyclophosphamide 50mg / kg / day on days D + 3 and D + 5&#xD;
&#xD;
             -  Cyclosporine A (CSA; 3 mg / kg / day IV from D + 6)&#xD;
&#xD;
             -  Mycophenolate mofetil (MMF; 30 mg / kg / day, maximum x2 1g / day from day J + 6)&#xD;
&#xD;
                4- Care supports: according to the protocols of each center&#xD;
&#xD;
                5- lymphocyte injection of prophylactic donor (pDLI): according to the protocols of&#xD;
                each center. The following scheme is proposed:&#xD;
&#xD;
             -  In the absence of clinical contraindication(GVHD), tapering MMF between days D + 35&#xD;
                and D + 56, then tapering CSA between D + 62 and D + 90&#xD;
&#xD;
             -  pDLI: 3 injections from the D + 120 in patients who discontinued immunosuppressive&#xD;
                therapy for ≥ 1 month and having no active GVHD or history of acute GVHD grade&gt; II.&#xD;
&#xD;
                6. Feedback: at baseline and 1, 3, 6, 12 and 24 months after transplant&#xD;
                (engraftment, disease response, immune reconstitution, chimerism, GVHD, infection,&#xD;
                quality of life).&#xD;
&#xD;
      The treatments evaluated in this strategy are all used in the usual care of patients and&#xD;
      follow-up will not be changed.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">January 15, 2018</start_date>
  <completion_date type="Actual">December 18, 2021</completion_date>
  <primary_completion_date type="Actual">December 18, 2021</primary_completion_date>
  <phase>N/A</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>Other</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Overall survival (OS)</measure>
    <time_frame>2 years after transplantation</time_frame>
    <description>The aim is to describe the efficacy of the combination of a SET followed by haploidentical transplant with post-transplant immune modulation by pDLI in patients with AML.&#xD;
The main objective is to assess overall survival at 2 years in these patients.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Partial or complete remission rate by standard criteria Relapse incidence and death related to the disease</measure>
    <time_frame>90 days and then 6, 12 and 24 months after transplantation</time_frame>
    <description>To evaluate the efficacy of this therapeutic strategy in terms of remission of disease, incidence of relapse</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Cumulative incidence of death not related to relapse</measure>
    <time_frame>90 days and then 12 and 24 months after transplantation</time_frame>
    <description>Assess not related to relapse mortality</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Cumulative incidence of acute and chronic graft against host disease (GVHD)</measure>
    <time_frame>100 days and then 12 and 24 months after transplantation</time_frame>
    <description>To evaluate the incidence of acute and chronic graft against host disease (GVHD)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of patients for whom pDLI was possible.</measure>
    <time_frame>2 years after transplantation</time_frame>
    <description>Assess the feasibility of prophylactic injections of donor lymphocytes (pDLI)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Study of immune reconstitution post-transplant in the peripheral blood will be used:CD4 lymphocyte levels, CD8, T regulators, Natural Killer cells and B cells</measure>
    <time_frame>90 days and then 6, 12 and 24 months after transplantation</time_frame>
    <description>Study the post-transplant immune reconstitution</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Leukemia free survival</measure>
    <time_frame>90 days and then 6, 12 and 24 months after transplantation</time_frame>
    <description>Relapse-free survival</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of pDLI / patient; incidence, severity and treatment of possible secondary GVHD in these patients</measure>
    <time_frame>90 days and then 6, 12 and 24 months after transplantation</time_frame>
    <description>Assess the feasibility of prophylactic injections of donor lymphocytes (pDLI)</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">24</enrollment>
  <condition>Refractory Acute Myeloid Leukemia</condition>
  <arm_group>
    <arm_group_label>Patients with primary refractory acute myeloid leukemia</arm_group_label>
    <arm_group_type>Other</arm_group_type>
    <description>Patients with primary refractory acute myeloid leukemia</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Sequential Packaging (SET)</intervention_name>
    <description>Sequential chemotherapy:&#xD;
Thiotepa 5 mg / kg / day for 1 day (D-13)&#xD;
Cyclophosphamide 400 mg / m² / day for 4 days (J-12 to J-9)&#xD;
Etoposide 100 mg / m² / day for 4 days (J-12 to J-9) Repos days J-8 and J-6 Reduced-intensity conditioning (RIC)&#xD;
Fludarabine 30 mg / m² / day for 5 days (J-5 to D-1)&#xD;
Busulfan IV 3.2 mg / kg / day for 2 days (J-5 and J-4)&#xD;
Anti-lymphocyte serum (Thymoglobuline) 2.5 mg / kg / day for 2 days (J-3 and J-2)</description>
    <arm_group_label>Patients with primary refractory acute myeloid leukemia</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Transfusion graft</intervention_name>
    <description>Graft of peripheral stem cells is preferred at D0</description>
    <arm_group_label>Patients with primary refractory acute myeloid leukemia</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Prevention of GVHD</intervention_name>
    <description>Cyclophosphamide 50mg / kg / day on days D + 3 and D + 5&#xD;
Cyclosporine A (CSA; 3 mg / kg / day IV from D + 6)&#xD;
Mycophenolate mofetil (MMF; 30 mg / kg / day, maximum x2 1g / day from day J + 6)</description>
    <arm_group_label>Patients with primary refractory acute myeloid leukemia</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Care supports</intervention_name>
    <description>According to the protocols of each center</description>
    <arm_group_label>Patients with primary refractory acute myeloid leukemia</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Lymphocyte injection of prophylactic donor (PDLI)</intervention_name>
    <description>According to the protocols of each center. In the absence of clinical indication against-disease (GVHD), phasing MMF between days D + 35 and D + 56, then phasing APF between D + 62 and D + 90&#xD;
- PDLI: 3 injections from the D + 120 patients who discontinued immunosuppressive therapy for ≥ 1 month and having no active GVHD or history of acute GVHD grade&gt; II</description>
    <arm_group_label>Patients with primary refractory acute myeloid leukemia</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Patients with a confirmed diagnosis of acute myeloid leukemia after primary induction&#xD;
             treatment failure (persistent leukemia after 2 cycles of induction chemotherapy)&#xD;
&#xD;
          -  Patient age ≥ 18 to &lt;60 years&#xD;
&#xD;
          -  Cardiac ejection fraction of the left ventricle ≥ 45%&#xD;
&#xD;
          -  Lung function - free diffusion capacity for carbon monoxide ≥ 50% of predicted value&#xD;
&#xD;
          -  Creatinine clearance ≥ 50 ml / min depending on the CKD-EPI formula&#xD;
&#xD;
          -  Availability of an HLA haploidentical donor in the family&#xD;
&#xD;
          -  Collection of non-opposition&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Uncontrolled invasion of CNS&#xD;
&#xD;
          -  Availability of an HLA identical family donor who agreed to donate hematopoietic stem&#xD;
             cells OR non-related donor HLA-compatible 10/10 on HLA-A alleles, B, C, and DRB1 DQB1&#xD;
             available and ready to give in 4 weeks to make a decision allograft&#xD;
&#xD;
          -  Presence in the patient HLA-specific antibodies directed against an antigen HLA&#xD;
             haploidentical donor family&#xD;
&#xD;
          -  Karnofsky score &lt;70%&#xD;
&#xD;
          -  Patient HIV positive&#xD;
&#xD;
          -  Hepatitis B or C or chronic active&#xD;
&#xD;
          -  Uncontrolled infection at the time of start packing&#xD;
&#xD;
          -  Contraindication to the use of treatments provided by the Protocol&#xD;
&#xD;
          -  Previous history of allo-HSC&#xD;
&#xD;
          -  No beneficiary of a social security scheme.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>60 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <location>
    <facility>
      <name>Service d'hématologie Clinique Hôpital Saint Antoine</name>
      <address>
        <city>Paris</city>
        <zip>75012</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>France</country>
  </location_countries>
  <verification_date>July 2022</verification_date>
  <study_first_submitted>November 24, 2016</study_first_submitted>
  <study_first_submitted_qc>January 27, 2017</study_first_submitted_qc>
  <study_first_posted type="Estimate">January 30, 2017</study_first_posted>
  <last_update_submitted>July 22, 2022</last_update_submitted>
  <last_update_submitted_qc>July 22, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">July 25, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Allogenic cell stem transplant, Sequential chemotherapy Haploidentical transplant</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Leukemia</mesh_term>
    <mesh_term>Leukemia, Myeloid</mesh_term>
    <mesh_term>Leukemia, Myeloid, Acute</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/NCT03035422
org study id: 2016-A00862-49
nct id: NCT03035422
lead sponsor: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the only treatment option
      with a significant chance of healing in acute myeloid leukemia (AML) or refractory multiple
      relapses after chemotherapy. However, all patients with an indication of allo-HSC can not
      benefit because of two limitations: the toxicity of the treatment and graft shortage
      available.
The goal is to evaluate the efficacy and safety of the combination of an SET followed by
      haploidentical transplant with post-transplant immune modulation by prophylactic DLI in
      patients with refractory acute myeloid leukemia or relapsed. The main objective is to assess
      overall survival at 2 years in these patients.

      Secondary objectives:

        1. To evaluate the efficacy of this therapeutic strategy in terms of remission of disease,
           incidence of relapse and relapse-free survival

        2. To evaluate the non-relapse mortality

        3. To evaluate the incidence of acute and chronic graft against host disease (GVHD)

        4. To assess the feasibility of prophylactic injections of donor lymphocytes (pDLI)

        5. To analyze the post-transplant immune reconstitution

      Secondary endpoints:

        1. partial or complete remission rate by standard criteria at 90 days and then 6, 12 and 24
           months after transplantation.

           Relapse incidence and death related to the disease 90 days 6, 12 and 24 months after
           transplantation Leukemia-free survival at 1 year and 2 years after transplantation

        2. Cumulative incidence of death not related to relapse at 90 days, 1 year and 2 years
           after transplantation

        3. Cumulative incidence of acute and chronic graft against host disease (GVHD)

        4. Number of patients for whom pDLI was possible and number of pDLI / patient; incidence,
           severity and treatment of possible secondary GVHD in these patients

        5. Study of immune reconstitution post-transplant in the peripheral blood 30, 90 and 180
           days after transplantation (CD4 lymphocyte levels, CD8, T regulators, Natural Killer
           cells and B cells)

      Methodology, experimental design:

      Multicenter study in routine care, prospective

      All patients will receive, as part of the marketing authorization of the products used, the
      following regimen:

      1- sequential Packaging (SET):

        1. sequential chemotherapy:

             -  Thiotepa 5 mg / kg / day for 1 day (D-13)

             -  Cyclophosphamide 400 mg / m² / day for 4 days (J-12 to J-9)

             -  Etoposide 100 mg / m² / day for 4 days (J-12 to J-9)

        2. Rest days J-8 and J-6

        3. Reduced-intensity conditioning (RIC)

             -  Fludarabine 30 mg / m² / day for 5 days (J-5 to D-1)

             -  Busulfan IV 3.2 mg / kg / day for 2 days (J-5 and J-4)

             -  Anti-lymphocyte serum (Thymoglobuline) 2.5 mg / kg / day for 2 days (J-3 and J-2)

                2 Graft transfusion: the day D0. A graft of peripheral stem cells is preferred.

                3- Prevention of GVHD:

             -  Cyclophosphamide 50mg / kg / day on days D + 3 and D + 5

             -  Cyclosporine A (CSA; 3 mg / kg / day IV from D + 6)

             -  Mycophenolate mofetil (MMF; 30 mg / kg / day, maximum x2 1g / day from day J + 6)

                4- Care supports: according to the protocols of each center

                5- lymphocyte injection of prophylactic donor (pDLI): according to the protocols of
                each center. The following scheme is proposed:

             -  In the absence of clinical contraindication(GVHD), tapering MMF between days D + 35
                and D + 56, then tapering CSA between D + 62 and D + 90

             -  pDLI: 3 injections from the D + 120 in patients who discontinued immunosuppressive
                therapy for ≥ 1 month and having no active GVHD or history of acute GVHD grade> II.

                6. Feedback: at baseline and 1, 3, 6, 12 and 24 months after transplant
                (engraftment, disease response, immune reconstitution, chimerism, GVHD, infection,
                quality of life).

      The treatments evaluated in this strategy are all used in the usual care of patients and
      follow-up will not be changed.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Other
masking: None (Open Label)
measure: Overall survival (OS)
time frame: 2 years after transplantation
description: The aim is to describe the efficacy of the combination of a SET followed by haploidentical transplant with post-transplant immune modulation by pDLI in patients with AML.
The main objective is to assess overall survival at 2 years in these patients.
measure: Partial or complete remission rate by standard criteria Relapse incidence and death related to the disease
time frame: 90 days and then 6, 12 and 24 months after transplantation
description: To evaluate the efficacy of this therapeutic strategy in terms of remission of disease, incidence of relapse
measure: Cumulative incidence of death not related to relapse
time frame: 90 days and then 12 and 24 months after transplantation
description: Assess not related to relapse mortality
measure: Cumulative incidence of acute and chronic graft against host disease (GVHD)
time frame: 100 days and then 12 and 24 months after transplantation
description: To evaluate the incidence of acute and chronic graft against host disease (GVHD)
measure: Number of patients for whom pDLI was possible.
time frame: 2 years after transplantation
description: Assess the feasibility of prophylactic injections of donor lymphocytes (pDLI)
measure: Study of immune reconstitution post-transplant in the peripheral blood will be used:CD4 lymphocyte levels, CD8, T regulators, Natural Killer cells and B cells
time frame: 90 days and then 6, 12 and 24 months after transplantation
description: Study the post-transplant immune reconstitution
measure: Leukemia free survival
time frame: 90 days and then 6, 12 and 24 months after transplantation
description: Relapse-free survival
measure: Number of pDLI / patient; incidence, severity and treatment of possible secondary GVHD in these patients
time frame: 90 days and then 6, 12 and 24 months after transplantation
description: Assess the feasibility of prophylactic injections of donor lymphocytes (pDLI)
arm group label: Patients with primary refractory acute myeloid leukemia
arm group type: Other
description: Patients with primary refractory acute myeloid leukemia
intervention type: Drug
intervention name: Sequential Packaging (SET)
description: Sequential chemotherapy:
Thiotepa 5 mg / kg / day for 1 day (D-13)
Cyclophosphamide 400 mg / m² / day for 4 days (J-12 to J-9)
Etoposide 100 mg / m² / day for 4 days (J-12 to J-9) Repos days J-8 and J-6 Reduced-intensity conditioning (RIC)
Fludarabine 30 mg / m² / day for 5 days (J-5 to D-1)
Busulfan IV 3.2 mg / kg / day for 2 days (J-5 and J-4)
Anti-lymphocyte serum (Thymoglobuline) 2.5 mg / kg / day for 2 days (J-3 and J-2)
arm group label: Patients with primary refractory acute myeloid leukemia
intervention type: Drug
intervention name: Transfusion graft
description: Graft of peripheral stem cells is preferred at D0
arm group label: Patients with primary refractory acute myeloid leukemia
intervention type: Drug
intervention name: Prevention of GVHD
description: Cyclophosphamide 50mg / kg / day on days D + 3 and D + 5
Cyclosporine A (CSA; 3 mg / kg / day IV from D + 6)
Mycophenolate mofetil (MMF; 30 mg / kg / day, maximum x2 1g / day from day J + 6)
arm group label: Patients with primary refractory acute myeloid leukemia
intervention type: Drug
intervention name: Care supports
description: According to the protocols of each center
arm group label: Patients with primary refractory acute myeloid leukemia
intervention type: Drug
intervention name: Lymphocyte injection of prophylactic donor (PDLI)
description: According to the protocols of each center. In the absence of clinical indication against-disease (GVHD), phasing MMF between days D + 35 and D + 56, then phasing APF between D + 62 and D + 90
- PDLI: 3 injections from the D + 120 patients who discontinued immunosuppressive therapy for ≥ 1 month and having no active GVHD or history of acute GVHD grade> II
arm group label: Patients with primary refractory acute myeloid leukemia
criteria: 
gender: All
minimum age: 18 Years
maximum age: 60 Years
healthy volunteers: No
facility: 
country: France
responsible party type: Sponsor
mesh term: Leukemia
mesh term: Leukemia, Myeloid
mesh term: Leukemia, Myeloid, Acute
sharing ipd: No