Trial document





This study has been imported from ClinicalTrials.gov without additional data checks.
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  DRKS00007641

Trial Description

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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)

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Trial Acronym

GFM-DAC-CMML

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URL of the Trial

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Brief Summary in Lay Language

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

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Brief Summary in Scientific Language

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 D49) 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 3 week discontinuation will mandate bone marrow
evaluation.

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Organizational Data

  •   DRKS00007641
  •   2015/01/21
  •   2014/07/30
  •   yes
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Secondary IDs

  •   NCT02214407  (ClinicalTrials.gov)
  •   GFM-DAC-CMML  (Groupe Francophone des Myelodysplasies)
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Health Condition or Problem studied

  •   MDS
  •   D46 -  Myelodysplastic syndromes
  •   D47.1 -  Chronic myeloproliferative disease
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Interventions/Observational Groups

  •   Drug: Decitabine
  •   Drug: HYDROXYUREA
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Characteristics

  •   Interventional
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  •   Randomized controlled trial
  •   Open (masking not used)
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  •   Treatment
  •   Parallel
  •   III
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Primary Outcome

- compare between the two arms Event-free Survival (EFS); time frame: 3 month; Events will include
Death from any cause
Transformation to AML according to WHO criteria (≥20% circulating blasts, or ≥20% marrow blasts and with an increase ≥ 50% from baseline)
Progression of myeloproliferation defined as (i) ≥ 50% increase in spleen size as determined by an imaging technique or doubling in WBC (despite maximal HY or DAC dosing; in the absence of concomitant infection) or the occurrence of a previously undiagnosed extramedullary localization of the disease.
(ii) Disease occuring or persisting after at least 3 cycles of DAC or HY

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Secondary Outcome

- Overall Survival (OS); time frame: 7 month; Overall survival compared between both Arm of treatment (decitabine and hydroxyurea)
- Cumulative incidence of AML; time frame: 7 month; Comparaison of Cumulative incidence of AML between both arm of treatment (decitabine and hydroxyurea)
- Overall and Complete Response Rates; time frame: 3 month; Overall and Complete Response Rates at 3 and 6 cycles according to IWG 2006 criteria modified for CMML
- Response duration; time frame: 3 month; Comparison of response duration after 3 month and 6 month of treatment between both arm of treatment (decitabine and hydroxyurea)
- Toxicity; time frame: 1 month; hematological and non hematological
- Prognostic factors; time frame: 3 month; Prognostic factors of Event Free Survival with decitabine and hydroxyurea

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Countries of Recruitment

  •   France
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Locations of Recruitment

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Recruitment

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  •   2014/08/31
  •   168
  •   Multicenter trial
  •   International
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Inclusion Criteria

  •   Both, male and female
  •   18   Years
  •   no maximum age
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Additional Inclusion Criteria

- Age ≥ 18

- CMML diagnosis according to WHO criteria Stable excess in blood monocytes, > 1 G/L
and accounting for > 10% WBC 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.

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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)

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Addresses

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    • Groupe Francophone des Myelodysplasies
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    • Janssen-Cilag Ltd.
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    • Hopital Saint-Louis, Service hematologie Senior
    • ITZYKSON Raphael, PHD 
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    • Fatiha Chermat 
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Sources of Monetary or Material Support

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    • Bitte wenden Sie sich an den Sponsor / Please refer to primary sponsor
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Status

  •   Recruiting planned
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Trial Publications, Results and other Documents

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The parameters in ClinicalTrials.gov and DRKS are not identical. Therefore the data import from ClinicalTrials.gov required adjustments. For full details please see the DRKS FAQs .
  •   3
  •   2014/12/17
* This entry means the parameter is not applicable or has not been set.