<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/NCT02214407</url>
  </required_header>
  <id_info>
    <org_study_id>GFM-DAC-CMML</org_study_id>
    <nct_id>NCT02214407</nct_id>
  </id_info>
  <brief_title>Randomized Phase III Study of Decitabine +/- Hydroxyurea (HY) Versus HY in Advanced Proliferative CMML</brief_title>
  <acronym>GFM-DAC-CMML</acronym>
  <official_title>A Randomized Phase III Study of Decitabine (DAC) With or Without Hydroxyurea (HY) Versus HY in Patients With Advanced Proliferative Chronic Myelomonocytic Leukemia (CMML)</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Groupe Francophone des Myelodysplasies</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Janssen-Cilag Ltd.</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>Groupe Francophone des Myelodysplasies</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      This is a phase III, two-arm, randomized, stratified, multicenter, open-label study with&#xD;
      individual therapeutic benefit aim:&#xD;
&#xD;
      Decitabine (DAC) with or without Hydroxyurea (HY) versus HY in patients with advanced&#xD;
      proliferative Chronic Myelomonocytic Leukemia (CMML)&#xD;
&#xD;
      The primary objective of the study is to compare between the two arms Event-free Survival&#xD;
      (EFS).&#xD;
&#xD;
      Secondary objectives are to compare between both arms:&#xD;
&#xD;
      Overall Survival (OS) Cumulative incidence of AML Overall and Complete Response Rates at 3&#xD;
      and 6 cycles according to IWG 2006 criteria modified for CMML Response duration Toxicity&#xD;
      (hematological and non hematological) Prognostic factors&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      ARM A: DECITABINE (DAC)&#xD;
&#xD;
      Decitabine (DAC) will be administered at 20 mg/m2 intravenously daily for 5 days every 28&#xD;
      days.&#xD;
&#xD;
      Treatment will be delayed at the discretion of the investigator (up to D56) for febrile&#xD;
      neutropenia (≥ 38.5°C; absolute neutrophil count [ANC], &lt; 1,000/μL), clinical and/or&#xD;
      microbiologic infection with grade 3 to 4 neutropenia (ANC &lt; 1,000/μL), or hemorrhage with&#xD;
      grade 4 thrombocytopenia (&lt; 25,000 platelets/μL). If renal or hepatic dysfunction occurs,&#xD;
      treatment will be stopped until resolution or withheld if dysfunction persists more than 4&#xD;
      days. Persistent grade 4 thrombocytopenia or neutropenia beyond D49 will mandate bone marrow&#xD;
      evaluation.&#xD;
&#xD;
      Treatment will be continued until an event is reached. Events and thus study exit will be&#xD;
      acknowledged only after agreement between the investigator and a Trial Committee.&#xD;
&#xD;
      Allopurinol, 300mg/d, will be started at the time of inclusion; hydration during treatment&#xD;
      will be administered to all patients. In (the rare) case of necessity, prophylactic&#xD;
      anti-emetics could be given.&#xD;
&#xD;
      Hydroxyurea may be added during the first 3 cycles if WBC counts &gt; 30 G/L, and mandatory if&#xD;
      WBC &gt; 50 G/L. The daily dose will be adapted to maintain WBC below 15 to 20 G/L.&#xD;
&#xD;
      ARM B: HYDROXYUREA (HY)&#xD;
&#xD;
      Hydroxyurea (HY) 1g/d once daily, with dose adjustments (up to 4g/d) to maintain a WBC count&#xD;
      between 5 and 10 G/L. Allopurinol, 300mg/d started at the time of inclusion will be&#xD;
      administered to all patients.&#xD;
&#xD;
      Treatment will be continued until an event is reached. Events and thus study exit will be&#xD;
      acknowledged only after agreement between the investigator and a Trial Committee. This is&#xD;
      intended to prevent early dropout, notably in the HY arm.&#xD;
&#xD;
      Dose escalation will be performed by steps of 0.5 g/d, up to 4 g/d, if the WBC has been&#xD;
      reduced by less than 20% and remains &gt; 15 G/L. HY will then be adapted to maintain a WBC&#xD;
      count between 5 and 10 G/L. HY will be lowered if platelets decrease by &gt; 30 X 109/L (if&#xD;
      initially below 100 X 109L). HY will be discontinued in cases of grade 4 thrombocytopenia or&#xD;
      neutropenia, and reintroduced at a lower dose after recovery to grade ≤ 3. Persistent grade 4&#xD;
      thrombocytopenia or neutropenia after a 4 week discontinuation will mandate bone marrow&#xD;
      evaluation.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">October 14, 2014</start_date>
  <completion_date type="Actual">August 16, 2021</completion_date>
  <primary_completion_date type="Actual">July 5, 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>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>compare between the two arms Event-free Survival (EFS)</measure>
    <time_frame>3 months</time_frame>
    <description>Comparison of Event-free Survival between both arms. Events will include&#xD;
Death from any cause&#xD;
Disease Progression, defined as one of the following: (i) at any time point: transformation to AML according to WHO criteria ; (ii) after at least 6 cycles of treatment: doubling of bone marrow blasts to &gt; 10%, and worsening of cytopenias lasting for &gt; 4 weeks ; (iii) after at least 3 cycles of treatment: Progression of myeloproliferation (despite maximal HY or DAC dosing; in the absence of concomitant infection) defined as: ≥ 50% increase in spleen size as determined by an imaging technique or doubling in WBC or occurrence of a previously undiagnosed extramedullary localization of the disease.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Overall Survival (OS)</measure>
    <time_frame>7 month</time_frame>
    <description>Overall survival compared between both Arm of treatment (decitabine and hydroxyurea)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Cumulative incidence of AML</measure>
    <time_frame>7 month</time_frame>
    <description>Comparaison of Cumulative incidence of AML between both arm of treatment (decitabine and hydroxyurea)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Overall and Complete Response Rates</measure>
    <time_frame>3 month</time_frame>
    <description>Overall and Complete Response Rates at 3 and 6 cycles according to IWG 2006 criteria modified for CMML</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Response duration</measure>
    <time_frame>3 month</time_frame>
    <description>Comparison of response duration after 3 month and 6 month of treatment between both arm of treatment (decitabine and hydroxyurea)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Toxicity</measure>
    <time_frame>1 month</time_frame>
    <description>hematological and non hematological</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Prognostic factors</measure>
    <time_frame>3 month</time_frame>
    <description>Prognostic factors of Event Free Survival with decitabine and hydroxyurea</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">170</enrollment>
  <condition>MDS</condition>
  <arm_group>
    <arm_group_label>ARM A: DECITABINE (DACOGEN)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Decitabine (DAC) will be administered at 20 mg/m2 intravenously daily for 5 days every 28 days.&#xD;
Allopurinol, 300mg/d, will be started at the time of inclusion; hydration during treatment will be administered to all patients. In (the rare) case of necessity, prophylactic anti-emetics could be given.&#xD;
Hydroxyurea may be added during the first 3 cycles if WBC counts &gt; 30 G/L, and mandatory if WBC &gt; 50 G/L. The daily dose will be adapted to maintain WBC below 15 to 20 G/L.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>ARM B: HYDROXYUREA</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Hydroxyurea (HY) 1g/d once daily, with dose adjustments (up to 4g/d) to maintain a WBC count between 5 and 10 G/L. Allopurinol, 300mg/d started at the time of inclusion will be administered to all patients.&#xD;
Dose escalation will be performed by steps of 0.5 g/d, up to 4 g/d, if the WBC has been reduced by less than 20% and remains &gt; 15 G/L. HY will then be adapted to maintain a WBC count between 5 and 10 G/L. HY will be lowered if platelets decrease by &gt; 30 X 109/L (if initially below 100 X 109L). HY will be discontinued in cases of grade 4 thrombocytopenia or neutropenia, and reintroduced at a lower dose after recovery to grade ≤ 3. Persistent grade 4 thrombocytopenia or neutropenia after a 4 week discontinuation will mandate bone marrow evaluation.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Decitabine</intervention_name>
    <description>Decitabine (DAC) will be administered at 20 mg/m2 intravenously daily for 5 days every 28 days. Hydroxyurea may be added during the first 3 cycles if WBC counts &gt; 30 G/L, and mandatory if WBC &gt; 50 G/L. The daily dose will be adapted to maintain WBC below 15 to 20 G/L.&#xD;
Treatment will be continued until an event is reached. Events and thus study exit will be acknowledged only after agreement between the investigator and a Trial Committee.</description>
    <arm_group_label>ARM A: DECITABINE (DACOGEN)</arm_group_label>
    <other_name>DACOGEN</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>HYDROXYUREA</intervention_name>
    <description>Hydroxyurea (HY) 1g/d once daily, with dose adjustments (up to 4g/d) to maintain a WBC count between 5 and 10 G/L. Allopurinol, 300mg/d started at the time of inclusion will be administered to all patients.&#xD;
Treatment will be continued until an event is reached. Events and thus study exit will be acknowledged only after agreement between the investigator and a Trial Committee.</description>
    <arm_group_label>ARM B: HYDROXYUREA</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Age ≥ 18&#xD;
&#xD;
          -  CMML diagnosis according to WHO criteria Stable excess in blood monocytes, &gt; 1 G/L&#xD;
             Lack of bcr-abl rearrangement (or Philadelphia chromosome) Bone marrow blast cells &lt;&#xD;
             20% Dysplasia of at least one lineage or clonality marker or blood monocytosis during&#xD;
             more than 3 months w/o other explanation Blood and marrow smears will be reviewed at&#xD;
             each country's level, but morphologist meetings at the 3 country level are planned for&#xD;
             better harmonization and review of difficult cases&#xD;
&#xD;
          -  WBC ≥ 13 G/L Measured on two successive CBC at least two weeks apart, outside of a&#xD;
             context of infection.&#xD;
&#xD;
          -  Either D1 or D2&#xD;
&#xD;
        D1: At least two of the following criteria, reviewed at each country's level: (modified&#xD;
        from Wattel et al. Blood 1996) Marrow blasts &gt;= 5 % Clonal cytogenetic abnormality (other&#xD;
        than t(5;12) (q33; p13) and isolated loss of Y chromosome ) Anemia (Hb &lt; 10 g/dL) ANC &gt; 16&#xD;
        G/l (in absence of infection) Thrombocytopenia (platelet count &lt; 100 G/L) Splenomegaly &gt; 5&#xD;
        cm below costal margin (spleen size should also be measured by an imaging technique)&#xD;
&#xD;
        Or:&#xD;
&#xD;
        D2: Extramedullary involvement: Including documented cutaneous, pleural or pericardial&#xD;
        effusion.&#xD;
&#xD;
          -  No prior treatment (except supportive care, or ESA, or short term (&lt; 6 weeks) HY in&#xD;
             patients presenting with high WBC counts)&#xD;
&#xD;
          -  Performance status 0-2 on the Eastern Cooperative Oncology Group (ECOG) Scale.&#xD;
&#xD;
          -  Adequate organ function including the following Hepatic : total bilirubin &lt; 1.5 times&#xD;
             upper limit of normal (ULN) (except moderate unconjugated hyperbilirubinemia due to&#xD;
             intra medullary hemolysis or Gilbert syndrome) , alanine transaminase (ALT) and&#xD;
             aspartate transaminase (AST) &lt; 3xULN Renal : serum creatinine &lt; 2 x ULN&#xD;
&#xD;
          -  Signed Informed consent&#xD;
&#xD;
          -  Negative pregnancy and adequate contraception (including in male patients wishing to&#xD;
             father) if relevant.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Myeloproliferative / myelodysplastic syndrome other than CMML&#xD;
&#xD;
          -  CMML with t(5 ;12) or PDGFBR rearrangement that may receive imatinib&#xD;
&#xD;
          -  Patients eligible for allogeneic bone marrow transplantation with an identified donor&#xD;
&#xD;
          -  Pregnant or breastfeeding&#xD;
&#xD;
          -  Performance status &gt; 2 on the ECOG Scale.&#xD;
&#xD;
          -  Serious concomitant systemic disorder, including active bacterial, fungal or viral&#xD;
             infection that in the opinion of the investigator would compromise the safety of the&#xD;
             patient and/or his/her ability to complete the study&#xD;
&#xD;
          -  Prior malignancy (except in situ cervix carcinoma, limited basal cell carcinoma, or&#xD;
             other tumors if not active during the last 3 years)&#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>ITZYKSON Raphael, PHD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Hopital Saint-Louis, Service hematologie Senior</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>CHU La Réunion - Site nord</name>
      <address>
        <city>Saint-Denis</city>
        <state>La Réunion</state>
        <zip>97400</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>CHU La Réunion-Site Sud</name>
      <address>
        <city>Saint-Pierre</city>
        <state>La Réunion</state>
        <zip>97410</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Chu Amiens</name>
      <address>
        <city>Amiens</city>
        <zip>80054</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>CHU d'Angers</name>
      <address>
        <city>Angers</city>
        <zip>49 000</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>CH Victor Dupouy</name>
      <address>
        <city>Argenteuil</city>
        <zip>95107</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Ch Avignon</name>
      <address>
        <city>Avignon</city>
        <zip>84000</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Centre Hospitalier de La Cote Basque</name>
      <address>
        <city>Bayonne</city>
        <zip>64100</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hôpital Nord Franche-Comté</name>
      <address>
        <city>Belfort</city>
        <zip>90015</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hôpital Avicenne</name>
      <address>
        <city>Bobigny</city>
        <zip>93009</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>CHU de Brest - Hôpital Morvan</name>
      <address>
        <city>Brest</city>
        <zip>29609</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>CHU Côte de Nacre</name>
      <address>
        <city>Caen</city>
        <zip>14033</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hôpital privé Sévigné</name>
      <address>
        <city>Cesson-Sévigné</city>
        <zip>35510</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>CHU Estaing</name>
      <address>
        <city>Clermont-Ferrand</city>
        <zip>63058</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>CH de Compiègne</name>
      <address>
        <city>Compiègne</city>
        <zip>60321</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Centre Hospitalier Sud-Francilien</name>
      <address>
        <city>Corbeil-Essonnes</city>
        <zip>91106</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Centre Henri Mondor</name>
      <address>
        <city>Créteil</city>
        <zip>94010</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>CHU Albert Michallon</name>
      <address>
        <city>Grenoble</city>
        <zip>38043</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>CH Le Mans</name>
      <address>
        <city>Le Mans</city>
        <zip>72000</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Clinique Victor Hugo</name>
      <address>
        <city>Le Mans</city>
        <zip>72000</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hôpital Saint Vincent de Paul</name>
      <address>
        <city>Lille</city>
        <zip>59020</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>CHRU de Limoges</name>
      <address>
        <city>Limoges</city>
        <zip>87046</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Centre Hospitalier Lyon Sud</name>
      <address>
        <city>Lyon</city>
        <zip>69495</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Institut Paoli-Calmette</name>
      <address>
        <city>Marseille</city>
        <zip>13009</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Centre Hospitalier de Meaux</name>
      <address>
        <city>Meaux</city>
        <zip>77100</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Clinique Beausoleil</name>
      <address>
        <city>Montpellier</city>
        <zip>34000</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hôpital Saint Eloi</name>
      <address>
        <city>Montpellier</city>
        <zip>34295</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hopital de l'Hotel Dieu</name>
      <address>
        <city>Nantes</city>
        <zip>44093</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hopital Archet I</name>
      <address>
        <city>Nice</city>
        <zip>06202</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>CHU de Nîmes</name>
      <address>
        <city>Nîmes</city>
        <zip>30029</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>CHR d'Orléans</name>
      <address>
        <city>Orléans</city>
        <zip>45067</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hopital St Louis T4</name>
      <address>
        <city>Paris</city>
        <zip>75475</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Centre Hospitalier Joffre</name>
      <address>
        <city>Perpignan</city>
        <zip>66046</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>CHU de Haut-Lévèque</name>
      <address>
        <city>Pessac</city>
        <zip>33604</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>CHU Poitiers</name>
      <address>
        <city>Poitiers</city>
        <zip>86021</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>CH René Dubos</name>
      <address>
        <city>Pontoise</city>
        <zip>95000</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>CH Annecy Genevois</name>
      <address>
        <city>Pringy</city>
        <zip>74374</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>CHU de Reims</name>
      <address>
        <city>Reims</city>
        <zip>51092</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>CHU Pontchaillou</name>
      <address>
        <city>Rennes</city>
        <zip>35033</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Centre Henri Bequerel</name>
      <address>
        <city>Rouen</city>
        <zip>76038</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hôpital Hautepierre</name>
      <address>
        <city>Strasbourg</city>
        <zip>67098</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>IUCT Oncopole - Département d'hématologie</name>
      <address>
        <city>Toulouse</city>
        <zip>31059</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Iuct Oncopole</name>
      <address>
        <city>Toulouse</city>
        <zip>31059</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>CH Valence</name>
      <address>
        <city>Valence</city>
        <zip>26953</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>CHU Brabois</name>
      <address>
        <city>Vandœuvre-lès-Nancy</city>
        <zip>54511</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Institut gustave Roussy</name>
      <address>
        <city>Villejuif</city>
        <zip>94805</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>France</country>
  </location_countries>
  <verification_date>November 2021</verification_date>
  <study_first_submitted>July 30, 2014</study_first_submitted>
  <study_first_submitted_qc>August 8, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">August 12, 2014</study_first_posted>
  <last_update_submitted>November 17, 2021</last_update_submitted>
  <last_update_submitted_qc>November 17, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">November 19, 2021</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Decitabine</mesh_term>
    <mesh_term>Hydroxyurea</mesh_term>
  </intervention_browse>
  <!-- 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/NCT02214407
org study id: GFM-DAC-CMML
nct id: NCT02214407
lead sponsor: 
collaborator: 
has dmc: Yes
This is a phase III, two-arm, randomized, stratified, multicenter, open-label study with
      individual therapeutic benefit aim:

      Decitabine (DAC) with or without Hydroxyurea (HY) versus HY in patients with advanced
      proliferative Chronic Myelomonocytic Leukemia (CMML)

      The primary objective of the study is to compare between the two arms Event-free Survival
      (EFS).

      Secondary objectives are to compare between both arms:

      Overall Survival (OS) Cumulative incidence of AML Overall and Complete Response Rates at 3
      and 6 cycles according to IWG 2006 criteria modified for CMML Response duration Toxicity
      (hematological and non hematological) Prognostic factors
ARM A: DECITABINE (DAC)

      Decitabine (DAC) will be administered at 20 mg/m2 intravenously daily for 5 days every 28
      days.

      Treatment will be delayed at the discretion of the investigator (up to D56) for febrile
      neutropenia (≥ 38.5°C; absolute neutrophil count [ANC], < 1,000/μL), clinical and/or
      microbiologic infection with grade 3 to 4 neutropenia (ANC < 1,000/μL), or hemorrhage with
      grade 4 thrombocytopenia (< 25,000 platelets/μL). If renal or hepatic dysfunction occurs,
      treatment will be stopped until resolution or withheld if dysfunction persists more than 4
      days. Persistent grade 4 thrombocytopenia or neutropenia beyond D49 will mandate bone marrow
      evaluation.

      Treatment will be continued until an event is reached. Events and thus study exit will be
      acknowledged only after agreement between the investigator and a Trial Committee.

      Allopurinol, 300mg/d, will be started at the time of inclusion; hydration during treatment
      will be administered to all patients. In (the rare) case of necessity, prophylactic
      anti-emetics could be given.

      Hydroxyurea may be added during the first 3 cycles if WBC counts > 30 G/L, and mandatory if
      WBC > 50 G/L. The daily dose will be adapted to maintain WBC below 15 to 20 G/L.

      ARM B: HYDROXYUREA (HY)

      Hydroxyurea (HY) 1g/d once daily, with dose adjustments (up to 4g/d) to maintain a WBC count
      between 5 and 10 G/L. Allopurinol, 300mg/d started at the time of inclusion will be
      administered to all patients.

      Treatment will be continued until an event is reached. Events and thus study exit will be
      acknowledged only after agreement between the investigator and a Trial Committee. This is
      intended to prevent early dropout, notably in the HY arm.

      Dose escalation will be performed by steps of 0.5 g/d, up to 4 g/d, if the WBC has been
      reduced by less than 20% and remains > 15 G/L. HY will then be adapted to maintain a WBC
      count between 5 and 10 G/L. HY will be lowered if platelets decrease by > 30 X 109/L (if
      initially below 100 X 109L). HY will be discontinued in cases of grade 4 thrombocytopenia or
      neutropenia, and reintroduced at a lower dose after recovery to grade ≤ 3. Persistent grade 4
      thrombocytopenia or neutropenia after a 4 week discontinuation will mandate bone marrow
      evaluation.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: compare between the two arms Event-free Survival (EFS)
time frame: 3 months
description: Comparison of Event-free Survival between both arms. Events will include
Death from any cause
Disease Progression, defined as one of the following: (i) at any time point: transformation to AML according to WHO criteria ; (ii) after at least 6 cycles of treatment: doubling of bone marrow blasts to > 10%, and worsening of cytopenias lasting for > 4 weeks ; (iii) after at least 3 cycles of treatment: Progression of myeloproliferation (despite maximal HY or DAC dosing; in the absence of concomitant infection) defined as: ≥ 50% increase in spleen size as determined by an imaging technique or doubling in WBC or occurrence of a previously undiagnosed extramedullary localization of the disease.
measure: Overall Survival (OS)
time frame: 7 month
description: Overall survival compared between both Arm of treatment (decitabine and hydroxyurea)
measure: Cumulative incidence of AML
time frame: 7 month
description: Comparaison of Cumulative incidence of AML between both arm of treatment (decitabine and hydroxyurea)
measure: Overall and Complete Response Rates
time frame: 3 month
description: Overall and Complete Response Rates at 3 and 6 cycles according to IWG 2006 criteria modified for CMML
measure: Response duration
time frame: 3 month
description: Comparison of response duration after 3 month and 6 month of treatment between both arm of treatment (decitabine and hydroxyurea)
measure: Toxicity
time frame: 1 month
description: hematological and non hematological
measure: Prognostic factors
time frame: 3 month
description: Prognostic factors of Event Free Survival with decitabine and hydroxyurea
arm group label: ARM A: DECITABINE (DACOGEN)
arm group type: Experimental
description: Decitabine (DAC) will be administered at 20 mg/m2 intravenously daily for 5 days every 28 days.
Allopurinol, 300mg/d, will be started at the time of inclusion; hydration during treatment will be administered to all patients. In (the rare) case of necessity, prophylactic anti-emetics could be given.
Hydroxyurea may be added during the first 3 cycles if WBC counts > 30 G/L, and mandatory if WBC > 50 G/L. The daily dose will be adapted to maintain WBC below 15 to 20 G/L.
arm group label: ARM B: HYDROXYUREA
arm group type: Experimental
description: Hydroxyurea (HY) 1g/d once daily, with dose adjustments (up to 4g/d) to maintain a WBC count between 5 and 10 G/L. Allopurinol, 300mg/d started at the time of inclusion will be administered to all patients.
Dose escalation will be performed by steps of 0.5 g/d, up to 4 g/d, if the WBC has been reduced by less than 20% and remains > 15 G/L. HY will then be adapted to maintain a WBC count between 5 and 10 G/L. HY will be lowered if platelets decrease by > 30 X 109/L (if initially below 100 X 109L). HY will be discontinued in cases of grade 4 thrombocytopenia or neutropenia, and reintroduced at a lower dose after recovery to grade ≤ 3. Persistent grade 4 thrombocytopenia or neutropenia after a 4 week discontinuation will mandate bone marrow evaluation.
intervention type: Drug
intervention name: Decitabine
description: Decitabine (DAC) will be administered at 20 mg/m2 intravenously daily for 5 days every 28 days. Hydroxyurea may be added during the first 3 cycles if WBC counts > 30 G/L, and mandatory if WBC > 50 G/L. The daily dose will be adapted to maintain WBC below 15 to 20 G/L.
Treatment will be continued until an event is reached. Events and thus study exit will be acknowledged only after agreement between the investigator and a Trial Committee.
arm group label: ARM A: DECITABINE (DACOGEN)
other name: DACOGEN
intervention type: Drug
intervention name: HYDROXYUREA
description: Hydroxyurea (HY) 1g/d once daily, with dose adjustments (up to 4g/d) to maintain a WBC count between 5 and 10 G/L. Allopurinol, 300mg/d started at the time of inclusion will be administered to all patients.
Treatment will be continued until an event is reached. Events and thus study exit will be acknowledged only after agreement between the investigator and a Trial Committee.
arm group label: ARM B: HYDROXYUREA
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: ITZYKSON Raphael, PHD
role: Principal Investigator
affiliation: Hopital Saint-Louis, Service hematologie Senior
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country: France
responsible party type: Sponsor
mesh term: Decitabine
mesh term: Hydroxyurea