Clinical Trials /

Randomized Phase III Study of Decitabine +/- Hydroxyurea (HY) Versus HY in Advanced Proliferative CMML

NCT02214407

Description:

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

Related Conditions:
  • Chronic Myelomonocytic Leukemia
Recruiting Status:

Recruiting

Phase:

Phase 3

Trial Eligibility

Document

Title

  • Brief Title: Randomized Phase III Study of Decitabine +/- Hydroxyurea (HY) Versus HY in Advanced Proliferative CMML
  • 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)

Clinical Trial IDs

  • ORG STUDY ID: GFM-DAC-CMML
  • NCT ID: NCT02214407

Conditions

  • MDS

Interventions

DrugSynonymsArms
DecitabineDACOGENARM A: DECITABINE (DACOGEN)
HYDROXYUREAARM B: HYDROXYUREA

Purpose

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

Detailed Description

      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.
    

Trial Arms

NameTypeDescriptionInterventions
ARM A: DECITABINE (DACOGEN)ExperimentalDecitabine (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.
  • Decitabine
ARM B: HYDROXYUREAExperimentalHydroxyurea (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.
  • HYDROXYUREA

Eligibility Criteria

        Inclusion Criteria:

          -  Age ≥ 18

          -  CMML diagnosis according to WHO criteria Stable excess in blood monocytes, > 1 G/L
             Lack of bcr-abl rearrangement (or Philadelphia chromosome) Bone marrow blast cells <
             20% Dysplasia of at least one lineage or clonality marker or blood monocytosis during
             more than 3 months w/o other explanation Blood and marrow smears will be reviewed at
             each country's level, but morphologist meetings at the 3 country level are planned for
             better harmonization and review of difficult cases

          -  WBC ≥ 13 G/L Measured on two successive CBC at least two weeks apart, outside of a
             context of infection.

          -  Either D1 or D2

        D1: At least two of the following criteria, reviewed at each country's level: (modified
        from Wattel et al. Blood 1996) Marrow blasts >= 5 % Clonal cytogenetic abnormality (other
        than t(5;12) (q33; p13) and isolated loss of Y chromosome ) Anemia (Hb < 10 g/dL) ANC > 16
        G/l (in absence of infection) Thrombocytopenia (platelet count < 100 G/L) Splenomegaly > 5
        cm below costal margin (spleen size should also be measured by an imaging technique)

        Or:

        D2: Extramedullary involvement: Including documented cutaneous, pleural or pericardial
        effusion.

          -  No prior treatment (except supportive care, or ESA, or short term (< 6 weeks) HY in
             patients presenting with high WBC counts)

          -  Performance status 0-2 on the Eastern Cooperative Oncology Group (ECOG) Scale.

          -  Adequate organ function including the following Hepatic : total bilirubin < 1.5 times
             upper limit of normal (ULN) (except moderate unconjugated hyperbilirubinemia due to
             intra medullary hemolysis or Gilbert syndrome) , alanine transaminase (ALT) and
             aspartate transaminase (AST) < 3xULN Renal : serum creatinine < 2 x ULN

          -  Signed Informed consent

          -  Negative pregnancy and adequate contraception (including in male patients wishing to
             father) if relevant.

        Exclusion Criteria:

          -  Myeloproliferative / myelodysplastic syndrome other than CMML

          -  CMML with t(5 ;12) or PDGFBR rearrangement that may receive imatinib

          -  Patients eligible for allogeneic bone marrow transplantation with an identified donor

          -  Pregnant or breastfeeding

          -  Performance status > 2 on the ECOG Scale.

          -  Serious concomitant systemic disorder, including active bacterial, fungal or viral
             infection that in the opinion of the investigator would compromise the safety of the
             patient and/or his/her ability to complete the study

          -  Prior malignancy (except in situ cervix carcinoma, limited basal cell carcinoma, or
             other tumors if not active during the last 3 years)
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:compare between the two arms Event-free Survival (EFS)
Time Frame:3 months
Safety Issue:
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.

Secondary Outcome Measures

Measure:Overall Survival (OS)
Time Frame:7 month
Safety Issue:
Description:Overall survival compared between both Arm of treatment (decitabine and hydroxyurea)
Measure:Cumulative incidence of AML
Time Frame:7 month
Safety Issue:
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
Safety Issue:
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
Safety Issue:
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
Safety Issue:
Description:hematological and non hematological
Measure:Prognostic factors
Time Frame:3 month
Safety Issue:
Description:Prognostic factors of Event Free Survival with decitabine and hydroxyurea

Details

Phase:Phase 3
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Groupe Francophone des Myelodysplasies

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