<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/NCT03765541</url>
  </required_header>
  <id_info>
    <org_study_id>RC31/17/0450</org_study_id>
    <nct_id>NCT03765541</nct_id>
  </id_info>
  <brief_title>Dexamethasone in Refractory or First Relapsed Acute Myeloid Leukemia</brief_title>
  <acronym>DEXAML-03</acronym>
  <official_title>Dexamethasone Plus Salvage Chemotherapy Versus Salvage Chemotherapy Alone in Patients With First Relapsed or Refractory Acute Myeloid Leukemia: a Randomized, Controlled, Open-label, Multicenter, Phase III Study</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University Hospital, Toulouse</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>University Hospital, Toulouse</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>
      Recent preclinical and retrospective clinical data have suggested that dexamethasone might&#xD;
      sensitize leukemic cells to chemotherapy-induced cell death and thus limit the risk of&#xD;
      leukemic regrowth and relapse. Moreover, it has been experimentally shown that leukemic cells&#xD;
      in acute myeloid leukemia patients who relapse become sensitive to glucocorticoids treatment&#xD;
      highlighting a novel potential role for dexamethasone in relapsed or refractory acute myeloid&#xD;
      leukemia (R/R).&#xD;
&#xD;
      This study was designed to determine whether adding dexamethasone to standard salvage therapy&#xD;
      in the treatment of relapsed/refractory acute myeloid leukemia in adult patients (intensive&#xD;
      chemotherapy amsacrine-cytarabine or azacitidine according to investigator's willingness)&#xD;
      results in a significant improvement of the overall survival.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      The prognosis for patients with relapsed or refractory acute myeloid leukemia is poor ;&#xD;
      median survival is less than 1 year. High-dose cytarabine monotherapy or cytarabine-based&#xD;
      combination regimens are often used as salvage therapy with limited efficacy. A recent&#xD;
      retrospective study has shown that the addition of dexamethasone to intensive chemotherapy&#xD;
      was significantly associated with better disease-free and overall survival in hyperleukocytic&#xD;
      acute myeloid leukemia patients. The gene signatures of some molecular subgroups of acute&#xD;
      myeloid leukemia were highly enriched in genes responsive to dexamethasone, including acute&#xD;
      myeloid leukemia with NPM1 mutations which were particularly sensitive to the antileukemic&#xD;
      activity of dexamethasone both in vitro and in vivo. Moreover, three recent preclinical&#xD;
      studies have shown that cytarabine-resistant or RUNX1-mutated acute myeloid leukemia cells&#xD;
      acquired sensitivity to glucocorticoids. Therefore, dexamethasone might sensitize leukemic&#xD;
      stem cells to chemotherapy-induced cell death and thus limit the risk of relapse.&#xD;
&#xD;
      This study consists of a screening period, a treatment period, and a post-treatment follow-up&#xD;
      period. Adult patients with relapsed/refractory acute myeloid leukemia are randomly assigned&#xD;
      in a 1:1 ratio to receive either standard salvage therapy in combination with dexamethasone&#xD;
      or standard salvage therapy alone. Standard salvage therapy is intensive chemotherapy&#xD;
      (amsacrine-cytarabine) or azacitidine according to the investigator's willingness. For those&#xD;
      patients with intensive chemotherapy amsacrine-cytarabine, the study treatment period&#xD;
      includes 1 induction cycle and up to 3 consolidation cycles. For those patients with&#xD;
      azacitidine, the study treatment period includes 3 cycles prior to the evaluation of the&#xD;
      complete remission and thereafter lasts until progression. Of note, any patients in the study&#xD;
      can undergo allogeneic hematopoietic stem cell transplantation providing his/her disease is&#xD;
      controlled. After discontinuing the study treatment all patients must further carry out&#xD;
      post-treatment follow-up visits every 3 months during the first and second year, and every 6&#xD;
      months thereafter until death, withdrawal of consent, loss to follow-up, or the end of the&#xD;
      study, whichever occurs first. The end of the study is planned 5 years after the&#xD;
      randomization of the first patient. The primary endpoint is the overall survival.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">January 13, 2020</start_date>
  <completion_date type="Anticipated">December 2025</completion_date>
  <primary_completion_date type="Anticipated">December 2025</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>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Overall survival</measure>
    <time_frame>Up to 60 months</time_frame>
    <description>Time from the date of randomization to the date of death from any cause</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Response to therapy</measure>
    <time_frame>Up to 60 months</time_frame>
    <description>Best response of complete remission or complete remission with incomplete recovery as assessed by the investigators according to the 2010 European Leukemia Net recommendations for diagnosis and management of acute myeloid leukemia in adults</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Minimal residual disease positivity</measure>
    <time_frame>Up to 60 months</time_frame>
    <description>Quantitative assessment by either quantitative polymerase chain reaction or multiparameter flow cytometry of any tumor cells greater than pre-specified sensitivity thresholds of detection</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of patient who realize allogeneic hematopoietic stem cell transplantation</measure>
    <time_frame>Up to 60 months</time_frame>
    <description>Undergoing allogeneic hematopoietic stem cell transplantation</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Duration of remission</measure>
    <time_frame>Up to 60 months</time_frame>
    <description>Time from the date of first complete remission or complete remission with incomplete recovery to the date of relapse, where complete remission, complete remission with incomplete recovery, and relapse as assessed by the investigators according to the 2010 European Leukemia Net recommendations for diagnosis and management of acute myeloid leukemia in adults</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Relapse-free survival</measure>
    <time_frame>Up to 60 months</time_frame>
    <description>Time from the date of first complete remission or complete remission with incomplete recovery to the date of relapse or death from any cause, whichever occurs first, where complete remission, complete remission with incomplete recovery, and relapse as assessed by the investigators according to the 2010 European Leukemia Net recommendations for diagnosis and management of acute myeloid leukemia in adults</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Event-free survival</measure>
    <time_frame>Up to 60 months</time_frame>
    <description>Time from the date of randomization to the date of treatment failure, or relapse from complete remission or complete remission with incomplete recovery, or death from any cause, whichever occurs first, where treatment failure, complete remission, complete remission with incomplete recovery, and relapse as assessed by the investigators according to the 2010 European Leukemia Net recommendations for diagnosis and management of acute myeloid leukemia in adults</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Quality of life with leukemia questionnaire</measure>
    <time_frame>At baseline, through complete remission, on Day 1 before dosing of each post-remission cycle, at 60 months</time_frame>
    <description>Scoring of functional assessment of cancer therapy - Leukemia questionnaire</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Adverse events</measure>
    <time_frame>During 60 months</time_frame>
    <description>Adverse events reported according to the descriptions and grading scale found in the version 4.03 of the National Cancer Institute - Common Terminology Criteria for Adverse Events</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">142</enrollment>
  <condition>Relapsed or Refractory Acute Myeloid Leukemia</condition>
  <arm_group>
    <arm_group_label>Standard salvage therapy + dexamethasone</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Intensive chemotherapy amsacrine-cytarabine or azacitidine according to the investigator's willingness in combination with dexamethasone</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Standard salvage therapy alone</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Intensive chemotherapy amsacrine-cytarabine or azacitidine according to the investigator's willingness</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Dexamethasone</intervention_name>
    <description>In combination with intensive chemotherapy amsacrine-cytarabine:&#xD;
Induction (1 cycle): 10 mg/12h from Day 1 to Day 3 of cycle (2 infusions/24h, slow IV [10 minutes])&#xD;
Consolidation (3 cycles): 10 mg/12h from Day 1 to Day 3 of each cycle (2 infusions/24h, slow IV [10 minutes])&#xD;
In combination with azacitidine:&#xD;
Cycle 1: 20 mg/24h from Day 1 to Day 3 of cycle (1 infusion/24h, slow IV [10 minutes]).&#xD;
Subsequent cycles: 20 mg/24h on Day 1 of each cycle (1 infusion/24h, slow IV [10minutes]).</description>
    <arm_group_label>Standard salvage therapy + dexamethasone</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Amsacrine</intervention_name>
    <description>Induction (1 cycle): 200 mg/m2/24h from Day 1 to Day 3 of cycle (slow IV [3 hours])&#xD;
Consolidation (3 cycles): 200 mg/m2/24h on Day 1 of each cycle (slow IV [3 hours])</description>
    <arm_group_label>Standard salvage therapy + dexamethasone</arm_group_label>
    <arm_group_label>Standard salvage therapy alone</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Cytarabine</intervention_name>
    <description>Patients &lt; 60 years of age:&#xD;
Induction (1 cycle): 3 g/m2/12h from Day 1 to Day 4 of cycle (2 infusions/24h, slow IV [2 hours])&#xD;
Consolidation (3 cycles): 3 g/m2/12h from Day 1 to Day 3 of each cycle (2 infusions/24h, slow IV [2 hours]) Note: If the investigators believe that there is an undue risk for the safety of a patient under 60 years of age with comorbidity in receiving a dose level of 3 g/m2/12h, the dose may be reduced to 1 g/m2/12h</description>
    <arm_group_label>Standard salvage therapy + dexamethasone</arm_group_label>
    <arm_group_label>Standard salvage therapy alone</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Azacitidine</intervention_name>
    <description>75 mg/m2/24h from Day 1 to Day 7 of each cycle [or from Day 1 to Day 5 and from Day 8 to Day 9 of each cycle] (SC)</description>
    <arm_group_label>Standard salvage therapy + dexamethasone</arm_group_label>
    <arm_group_label>Standard salvage therapy alone</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. At least 18 years of age or older&#xD;
&#xD;
          2. Diagnosis of acute myeloid leukemia by World Health Organization classification&#xD;
&#xD;
             First relapsed or refractory acute myeloid leukemia with at least 5% blasts by bone&#xD;
             marrow biopsy or aspirate, or at least 1% blasts in peripheral blood, and meeting the&#xD;
             following criteria:&#xD;
&#xD;
             First relapsed acute myeloid leukemia :&#xD;
&#xD;
               -  First relapse occurred at least 90 days to 24 months after the first complete&#xD;
                  remission or complete remission with incomplete recovery&#xD;
&#xD;
               -  The first complete remission or complete remission with incomplete recovery had&#xD;
                  to result from no more than 2 cycles of cytotoxic chemotherapy. At least 1&#xD;
                  induction cycle must have consisted of an anthracycline and cytarabine&#xD;
                  combination with a reasonable schedule/dose of anthracycline in the judgment of&#xD;
                  the investigator.&#xD;
&#xD;
               -  The re-emergence of at least 5% leukemic blasts in bone marrow is not&#xD;
                  attributable to other causes, regardless of new or recurrent dysplastic changes&#xD;
                  or extramedullary disease, or the re-emergence of at least 1% blasts in the&#xD;
                  peripheral blood is not attributable to other causes such as regenerating marrow.&#xD;
&#xD;
             Refractory acute myeloid leukemia :&#xD;
&#xD;
               -  Persistent acute myeloid leukemia was documented by bone marrow biopsy or&#xD;
                  aspirate at least 28 days after day 1 of the first induction cycle of 1 or 2&#xD;
                  cycles of cytotoxic chemotherapy.&#xD;
&#xD;
               -  Re-emergence of at least 5% leukemic blasts in bone marrow or at least 1% blasts&#xD;
                  in peripheral blood is not attributable to other causes such as regenerating&#xD;
                  marrow, and was less than 90 days after the first complete remission or complete&#xD;
                  remission with incomplete recovery.&#xD;
&#xD;
               -  Prior induction therapy had to include no more than 2 cycles of cytotoxic&#xD;
                  chemotherapy. At least 1 induction cycle must have consisted of an anthracycline&#xD;
                  and cytarabine combination with a reasonable schedule/dose of anthracycline in&#xD;
                  the judgment of the investigator.&#xD;
&#xD;
          3. Eastern Cooperative Oncology Group performance status ≤ 2.&#xD;
&#xD;
          4. Left ventricular ejection fraction ≥ 50% by echocardiogram or multi-gated acquisition&#xD;
             scan ; only applicable for patients who will receive intensive chemotherapy.&#xD;
&#xD;
          5. Serum creatinine ≤ 150 µmol/L and/or total bilirubin ≤ 1.5 × the upper limit of normal&#xD;
             and/or, aspartate aminotransferase ≤ 2.5 × the upper limit of normal, and/or alanine&#xD;
             aminotransferase ≤ 2.5 × the upper limit of normal (unless related to acute myeloid&#xD;
             leukemia)&#xD;
&#xD;
          6. Any clinically significant non-hematological toxicity after prior chemotherapy must be&#xD;
             resolved or of grade 1 as per Common Terminology Criteria for Adverse Events version&#xD;
             4.03.&#xD;
&#xD;
          7. Women must be surgically or biologically sterile, or in post-menopause (amenorrheic&#xD;
             for at least 12 months), or if of childbearing potential, must have a negative urine&#xD;
             or serum pregnancy test within 14 days prior to the randomization and agree to use a&#xD;
             highly effective method of contraception throughout the entire duration of the study&#xD;
             treatment (including dose interruptions) and until 3 months after the last study&#xD;
             treatment administration. Men must be surgically or biologically sterile, or agree to&#xD;
             use a highly effective method of contraception throughout the entire duration of the&#xD;
             study treatment (including dose interruptions) and until 6 months after the last study&#xD;
             treatment administration.&#xD;
&#xD;
          8. Registered to, or beneficiary of, social security insurance or equivalent.&#xD;
&#xD;
          9. Signed written informed consent by both the patient and the investigator prior to&#xD;
             perform any study-relayed procedure not part of normal medical care.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Acute promyelocytic leukemia (M3 subtype of acute myeloid leukemia).&#xD;
&#xD;
          2. More than 2 cycles of first line induction chemotherapy.&#xD;
&#xD;
          3. Acute myeloid leukemia with Philadelphia chromosome or BCR-ABL1 or blast crisis stage&#xD;
             of chronic myeloid leukemia.&#xD;
&#xD;
          4. Known or suspected central nervous system leukemia.&#xD;
&#xD;
          5. Undergoing allogeneic hematopoietic stem cell transplantation within 90 days prior to&#xD;
             randomization, or being on immunosuppressive therapy for prophylaxis of&#xD;
             graft-versus-host disease, or experiencing graft-versus-host disease within 2 weeks&#xD;
             prior to randomization.&#xD;
&#xD;
          6. Use of any experimental, cytotoxic, or targeted, anti-leukemic therapy within 14 days&#xD;
             prior to randomization, with the exception of hydroxyurea.&#xD;
&#xD;
          7. Formal contraindication to glucocorticoids.&#xD;
&#xD;
          8. Non-acute myeloid leukemia-associated organic or psychiatric severe disease that&#xD;
             contraindicates use of study treatment.&#xD;
&#xD;
          9. Patient who may not be followed regularly in consultation because of psychological,&#xD;
             family, social, or geographical reasons.&#xD;
&#xD;
         10. History of uncontrolled other malignancy for at least two years, with the exception of&#xD;
             basal cell carcinoma and in situ cervix carcinoma.&#xD;
&#xD;
         11. Severe uncontrolled infection at time of inclusion.&#xD;
&#xD;
         12. Positive serology for human immunodeficiency virus-1 or 2, and/or Human T-Cell&#xD;
             lymphotropic viruses-1 or 2, and/or active viral infection with hepatitis B virus&#xD;
             and/or hepatitis C virus.&#xD;
&#xD;
         13. Pregnant (beta gonadotropic chorionic hormon positive) or breastfeeding woman.&#xD;
&#xD;
         14. Incapable patient of age, under guardianship, under curators or safeguard of justice.&#xD;
&#xD;
         15. Patient under State Medical Assistance.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Christian RECHER, PhD</last_name>
    <role>Study Director</role>
    <affiliation>University Hospital, Toulouse</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Suzanne TAVITIAN, MD</last_name>
    <phone>+33 (5) 31156305</phone>
    <phone_ext>33</phone_ext>
    <email>tavitian.suzanne@iuct-oncopole.fr</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Amandine Huguet</last_name>
    <phone>+33 (5) 31156339</phone>
    <phone_ext>33</phone_ext>
    <email>huguet.amandine@iuct-oncopole.fr</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>CHU de Grenoble</name>
      <address>
        <city>Grenoble</city>
        <country>France</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Jean-Yves CAHN, PhD</last_name>
    </contact>
  </location>
  <location>
    <facility>
      <name>CHU de Limoges</name>
      <address>
        <city>Limoges</city>
        <country>France</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Arnaud JACCARD, MD</last_name>
    </contact>
  </location>
  <location>
    <facility>
      <name>Institut Paoli Calmettes</name>
      <address>
        <city>Marseille</city>
        <country>France</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Norbert VEY, PhD</last_name>
    </contact>
  </location>
  <location>
    <facility>
      <name>CHU de Montpellier</name>
      <address>
        <city>Montpellier</city>
        <country>France</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Hicheri Yosr, MD</last_name>
    </contact>
  </location>
  <location>
    <facility>
      <name>CHU de Nantes</name>
      <address>
        <city>Nantes</city>
        <country>France</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Pierre PETERLIN, MD</last_name>
    </contact>
  </location>
  <location>
    <facility>
      <name>CHU de Nîmes</name>
      <address>
        <city>Nîmes</city>
        <country>France</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Eric JOURDAN, MD</last_name>
    </contact>
  </location>
  <location>
    <facility>
      <name>CHU de Bordeaux</name>
      <address>
        <city>Pessac</city>
        <country>France</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Arnaud PIGNEUX, PhD</last_name>
    </contact>
  </location>
  <location>
    <facility>
      <name>CHU de Poitiers</name>
      <address>
        <city>Poitiers</city>
        <country>France</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Maria-Pilar GALLEGO-HERMANZ, MD</last_name>
    </contact>
  </location>
  <location_countries>
    <country>France</country>
  </location_countries>
  <verification_date>August 2022</verification_date>
  <study_first_submitted>November 19, 2018</study_first_submitted>
  <study_first_submitted_qc>December 4, 2018</study_first_submitted_qc>
  <study_first_posted type="Actual">December 5, 2018</study_first_posted>
  <last_update_submitted>August 17, 2022</last_update_submitted>
  <last_update_submitted_qc>August 17, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">August 18, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>dexamethasone</keyword>
  <keyword>acute myeloid leukemia</keyword>
  <keyword>relapse</keyword>
  <keyword>refractory</keyword>
  <keyword>azacitidine</keyword>
  <keyword>amsacrine</keyword>
  <keyword>cytarabine</keyword>
  <keyword>randomized controlled trial</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>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Cytarabine</mesh_term>
    <mesh_term>Dexamethasone</mesh_term>
    <mesh_term>Azacitidine</mesh_term>
    <mesh_term>Amsacrine</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/NCT03765541
org study id: RC31/17/0450
nct id: NCT03765541
lead sponsor: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
Recent preclinical and retrospective clinical data have suggested that dexamethasone might
      sensitize leukemic cells to chemotherapy-induced cell death and thus limit the risk of
      leukemic regrowth and relapse. Moreover, it has been experimentally shown that leukemic cells
      in acute myeloid leukemia patients who relapse become sensitive to glucocorticoids treatment
      highlighting a novel potential role for dexamethasone in relapsed or refractory acute myeloid
      leukemia (R/R).

      This study was designed to determine whether adding dexamethasone to standard salvage therapy
      in the treatment of relapsed/refractory acute myeloid leukemia in adult patients (intensive
      chemotherapy amsacrine-cytarabine or azacitidine according to investigator's willingness)
      results in a significant improvement of the overall survival.
The prognosis for patients with relapsed or refractory acute myeloid leukemia is poor ;
      median survival is less than 1 year. High-dose cytarabine monotherapy or cytarabine-based
      combination regimens are often used as salvage therapy with limited efficacy. A recent
      retrospective study has shown that the addition of dexamethasone to intensive chemotherapy
      was significantly associated with better disease-free and overall survival in hyperleukocytic
      acute myeloid leukemia patients. The gene signatures of some molecular subgroups of acute
      myeloid leukemia were highly enriched in genes responsive to dexamethasone, including acute
      myeloid leukemia with NPM1 mutations which were particularly sensitive to the antileukemic
      activity of dexamethasone both in vitro and in vivo. Moreover, three recent preclinical
      studies have shown that cytarabine-resistant or RUNX1-mutated acute myeloid leukemia cells
      acquired sensitivity to glucocorticoids. Therefore, dexamethasone might sensitize leukemic
      stem cells to chemotherapy-induced cell death and thus limit the risk of relapse.

      This study consists of a screening period, a treatment period, and a post-treatment follow-up
      period. Adult patients with relapsed/refractory acute myeloid leukemia are randomly assigned
      in a 1:1 ratio to receive either standard salvage therapy in combination with dexamethasone
      or standard salvage therapy alone. Standard salvage therapy is intensive chemotherapy
      (amsacrine-cytarabine) or azacitidine according to the investigator's willingness. For those
      patients with intensive chemotherapy amsacrine-cytarabine, the study treatment period
      includes 1 induction cycle and up to 3 consolidation cycles. For those patients with
      azacitidine, the study treatment period includes 3 cycles prior to the evaluation of the
      complete remission and thereafter lasts until progression. Of note, any patients in the study
      can undergo allogeneic hematopoietic stem cell transplantation providing his/her disease is
      controlled. After discontinuing the study treatment all patients must further carry out
      post-treatment follow-up visits every 3 months during the first and second year, and every 6
      months thereafter until death, withdrawal of consent, loss to follow-up, or the end of the
      study, whichever occurs first. The end of the study is planned 5 years after the
      randomization of the first patient. The primary endpoint is the overall survival.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Overall survival
time frame: Up to 60 months
description: Time from the date of randomization to the date of death from any cause
measure: Response to therapy
time frame: Up to 60 months
description: Best response of complete remission or complete remission with incomplete recovery as assessed by the investigators according to the 2010 European Leukemia Net recommendations for diagnosis and management of acute myeloid leukemia in adults
measure: Minimal residual disease positivity
time frame: Up to 60 months
description: Quantitative assessment by either quantitative polymerase chain reaction or multiparameter flow cytometry of any tumor cells greater than pre-specified sensitivity thresholds of detection
measure: Number of patient who realize allogeneic hematopoietic stem cell transplantation
time frame: Up to 60 months
description: Undergoing allogeneic hematopoietic stem cell transplantation
measure: Duration of remission
time frame: Up to 60 months
description: Time from the date of first complete remission or complete remission with incomplete recovery to the date of relapse, where complete remission, complete remission with incomplete recovery, and relapse as assessed by the investigators according to the 2010 European Leukemia Net recommendations for diagnosis and management of acute myeloid leukemia in adults
measure: Relapse-free survival
time frame: Up to 60 months
description: Time from the date of first complete remission or complete remission with incomplete recovery to the date of relapse or death from any cause, whichever occurs first, where complete remission, complete remission with incomplete recovery, and relapse as assessed by the investigators according to the 2010 European Leukemia Net recommendations for diagnosis and management of acute myeloid leukemia in adults
measure: Event-free survival
time frame: Up to 60 months
description: Time from the date of randomization to the date of treatment failure, or relapse from complete remission or complete remission with incomplete recovery, or death from any cause, whichever occurs first, where treatment failure, complete remission, complete remission with incomplete recovery, and relapse as assessed by the investigators according to the 2010 European Leukemia Net recommendations for diagnosis and management of acute myeloid leukemia in adults
measure: Quality of life with leukemia questionnaire
time frame: At baseline, through complete remission, on Day 1 before dosing of each post-remission cycle, at 60 months
description: Scoring of functional assessment of cancer therapy - Leukemia questionnaire
measure: Adverse events
time frame: During 60 months
description: Adverse events reported according to the descriptions and grading scale found in the version 4.03 of the National Cancer Institute - Common Terminology Criteria for Adverse Events
arm group label: Standard salvage therapy + dexamethasone
arm group type: Experimental
description: Intensive chemotherapy amsacrine-cytarabine or azacitidine according to the investigator's willingness in combination with dexamethasone
arm group label: Standard salvage therapy alone
arm group type: Active Comparator
description: Intensive chemotherapy amsacrine-cytarabine or azacitidine according to the investigator's willingness
intervention type: Drug
intervention name: Dexamethasone
description: In combination with intensive chemotherapy amsacrine-cytarabine:
Induction (1 cycle): 10 mg/12h from Day 1 to Day 3 of cycle (2 infusions/24h, slow IV [10 minutes])
Consolidation (3 cycles): 10 mg/12h from Day 1 to Day 3 of each cycle (2 infusions/24h, slow IV [10 minutes])
In combination with azacitidine:
Cycle 1: 20 mg/24h from Day 1 to Day 3 of cycle (1 infusion/24h, slow IV [10 minutes]).
Subsequent cycles: 20 mg/24h on Day 1 of each cycle (1 infusion/24h, slow IV [10minutes]).
arm group label: Standard salvage therapy + dexamethasone
intervention type: Drug
intervention name: Amsacrine
description: Induction (1 cycle): 200 mg/m2/24h from Day 1 to Day 3 of cycle (slow IV [3 hours])
Consolidation (3 cycles): 200 mg/m2/24h on Day 1 of each cycle (slow IV [3 hours])
arm group label: Standard salvage therapy + dexamethasone
arm group label: Standard salvage therapy alone
intervention type: Drug
intervention name: Cytarabine
description: Patients < 60 years of age:
Induction (1 cycle): 3 g/m2/12h from Day 1 to Day 4 of cycle (2 infusions/24h, slow IV [2 hours])
Consolidation (3 cycles): 3 g/m2/12h from Day 1 to Day 3 of each cycle (2 infusions/24h, slow IV [2 hours]) Note: If the investigators believe that there is an undue risk for the safety of a patient under 60 years of age with comorbidity in receiving a dose level of 3 g/m2/12h, the dose may be reduced to 1 g/m2/12h
arm group label: Standard salvage therapy + dexamethasone
arm group label: Standard salvage therapy alone
intervention type: Drug
intervention name: Azacitidine
description: 75 mg/m2/24h from Day 1 to Day 7 of each cycle [or from Day 1 to Day 5 and from Day 8 to Day 9 of each cycle] (SC)
arm group label: Standard salvage therapy + dexamethasone
arm group label: Standard salvage therapy alone
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Christian RECHER, PhD
role: Study Director
affiliation: University Hospital, Toulouse
last name: Suzanne TAVITIAN, MD
phone: +33 (5) 31156305
phone ext: 33
email: tavitian.suzanne@iuct-oncopole.fr
last name: Amandine Huguet
phone: +33 (5) 31156339
phone ext: 33
email: huguet.amandine@iuct-oncopole.fr
facility: 
status: Recruiting
contact: 
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status: Recruiting
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status: Recruiting
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status: Recruiting
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status: Recruiting
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status: Recruiting
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status: Recruiting
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status: Recruiting
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country: France
responsible party type: Sponsor
mesh term: Leukemia
mesh term: Leukemia, Myeloid
mesh term: Leukemia, Myeloid, Acute
mesh term: Cytarabine
mesh term: Dexamethasone
mesh term: Azacitidine
mesh term: Amsacrine
sharing ipd: No