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

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ClinicalTrials.gov Identifier: NCT02214407
Recruitment Status : Recruiting
First Posted : August 12, 2014
Last Update Posted : December 6, 2018
Sponsor:
Collaborator:
Janssen-Cilag Ltd.
Information provided by (Responsible Party):
Groupe Francophone des Myelodysplasies

Brief Summary:

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


Condition or disease Intervention/treatment Phase
MDS Drug: Decitabine Drug: HYDROXYUREA Phase 3

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.


Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 168 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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)
Actual Study Start Date : October 31, 2014
Estimated Primary Completion Date : December 2019
Estimated Study Completion Date : December 2020


Arm Intervention/treatment
Experimental: ARM A: DECITABINE (DACOGEN)

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.

Drug: Decitabine

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.

Other Name: DACOGEN

Experimental: ARM B: HYDROXYUREA

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.

Drug: HYDROXYUREA

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.





Primary Outcome Measures :
  1. compare between the two arms Event-free Survival (EFS) [ Time Frame: 3 months ]

    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 :
  1. Overall Survival (OS) [ Time Frame: 7 month ]
    Overall survival compared between both Arm of treatment (decitabine and hydroxyurea)

  2. Cumulative incidence of AML [ Time Frame: 7 month ]
    Comparaison of Cumulative incidence of AML between both arm of treatment (decitabine and hydroxyurea)

  3. 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

  4. 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)

  5. Toxicity [ Time Frame: 1 month ]
    hematological and non hematological

  6. Prognostic factors [ Time Frame: 3 month ]
    Prognostic factors of Event Free Survival with decitabine and hydroxyurea



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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)

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02214407


Contacts
Contact: Fatiha Chermat +33171207059 fatiha.chermat-ext@aphp.fr
Contact: Pierre Fenaux pierre.fenaux@aphp.fr

Locations
France
CHU La Réunion - Site nord Not yet recruiting
Saint-Denis, La Réunion, France, 97400
Contact: Tahar Touahri, MD       tahar.touahri@chu-reunion.fr   
Principal Investigator: Tahar Touahri, MD         
CHU La Réunion-Site Sud Not yet recruiting
Saint-Pierre, La Réunion, France, 97410
Contact: Patricia Zunic, MD       patricia.zunic@chu-reunion.fr   
Principal Investigator: Patricia Zunic, MD         
Chu Amiens Recruiting
Amiens, France, 80054
Contact: Lavinia Merlusca, MD    0322455915    merlusca.lavinia@chu-amiens.fr   
Principal Investigator: Lavinia Merlusca, MD         
CHU d'Angers Recruiting
Angers, France, 49 000
Contact: Mathilde Hunault    +33 2 41 35 44 75    MaHunault@chu-angers.fr   
Principal Investigator: Mathilde Hunault, Professor         
CH Victor Dupouy Not yet recruiting
Argenteuil, France, 95107
Contact: Ahmad Al Jijakli, MD    +33134232339    ahmad.aljijakli@ch-argenteuil.fr   
Principal Investigator: Ahmad Al Jijakli, MD         
Ch Avignon Recruiting
Avignon, France, 84000
Contact: Bohrane Slama, MD    0432753132    bslama@ch-avignon.fr   
Principal Investigator: Bohrane Slama, MD         
Centre Hospitalier de La Cote Basque Not yet recruiting
Bayonne, France, 64100
Contact: Anne Banos, MD    033559443832    abanos@ch-cotebasque.fr   
Principal Investigator: Anne Banos, MD         
Hôpital Nord Franche-Comté Not yet recruiting
Belfort, France, 90015
Contact: Marius Moldovan, MD    +33 3 84 98 23 17    marius.moldovan@hnfc.fr   
Principal Investigator: Marius Moldovan, MD         
Hôpital Avicenne Recruiting
Bobigny, France, 93009
Contact: Thorsten Braun, MD    (0) 33 1 48 95 70 51    thorsten.braun@avc.aphp.fr   
Principal Investigator: Thorsten Braun, MD         
CHU de Brest - Hôpital Morvan Not yet recruiting
Brest, France, 29609
Contact: Jean-Richard Eveillard, MD    33 2 98 22 33 33    jean-richard.eveillard@chu-brest.fr   
Principal Investigator: Jean-Richard Eveillard, MD         
CHU Côte de Nacre Recruiting
Caen, France, 14033
Contact: Stéphane CHEZE, MD    0033231272360    cheze-s@chu-caen.fr   
Principal Investigator: Stéphane CHEZE, MD         
Hôpital privé Sévigné Recruiting
Cesson-Sévigné, France, 35510
Contact: Benoît Bareau, MD    +33 2 23 21 05 50    benoit.bareau@gmail.com   
Principal Investigator: Benoît Bareau, MD         
CHU Estaing Recruiting
Clermont-Ferrand, France, 63058
Contact: Benoit De RENZIS, MD    0334 73 75 00 65    bderenzis@chu-clermontferrand.fr   
Principal Investigator: Benoit De RENZIS, MD         
CH de Compiègne Not yet recruiting
Compiègne, France, 60321
Contact: Sophie Dennetière, MD    +33 3 44 23 63 47    s.dennetiere@ch-compiegnenoyon.fr   
Principal Investigator: Sophie Dennetière, MD         
Centre Hospitalier Sud-Francilien Not yet recruiting
Corbeil-Essonnes, France, 91106
Contact: Célia Salanoubat, MD    +33 1 60 90 31 78    celia.salanoubat@ch-sud-francilien.fr   
Principal Investigator: Célia Salanoubat, MD         
Centre Henri Mondor Recruiting
Créteil, France, 94010
Contact: Andrea Toma, MD    0033149812057    andrea.toma@hmn.aphp.fr   
Principal Investigator: Andrea Toma, MD         
CHU Albert Michallon Recruiting
Grenoble, France, 38043
Contact: Stéphane COURBY, MD    033 4 76 76 57 12    SCourby@chu-grenoble.fr   
Principal Investigator: Stéphane COURBY, MD         
Principal Investigator: Sophie Park, PHD         
CH Le Mans Recruiting
Le Mans, France, 72000
Contact: Kamel Laribi, MD    0243434361    klaribi@ch-lemans.fr   
Principal Investigator: Kamel Laribi, MD         
Clinique Victor Hugo Not yet recruiting
Le Mans, France, 72000
Contact: Anne Parcelier, MD    +33 2 43 47 94 93    a.parcelier@i-l-c.fr   
Principal Investigator: Anne Parcelier, MD         
Hôpital Saint Vincent de Paul Not yet recruiting
Lille, France, 59020
Contact: Laurent Pascal, MD, PHD    +33320874532    pascal.laurent@ghicl.net   
Principal Investigator: Laurent Pascal, MD, PHD         
CHRU de Limoges Recruiting
Limoges, France, 87046
Contact: Marie-Pierre Gourin, MD    0033555056651    marie-pierre.gourin@chu-limoges.fr   
Principal Investigator: Marie Pierre Gourin, MD         
Centre Hospitalier Lyon Sud Recruiting
Lyon, France, 69495
Contact: Eric WATTEL, PHD,MD    033 4 72 11 74 01    eric.wattel@chu-lyon.fr   
Principal Investigator: Eric WATTEL, PHD,MD         
Institut Paoli-Calmette Recruiting
Marseille, France, 13009
Contact: Norbert VEY, PHD,MD    033 4 91 22 37 54    veyn@marseille.fnclcc.fr   
Principal Investigator: Norbert VEY, PHD,MD         
Centre Hospitalier de Meaux Not yet recruiting
Meaux, France, 77100
Contact: Loïc Fouillard, MD    033164653876    l-fouillard@ch-meaux.fr   
Principal Investigator: Loïc Fouillard, MD         
Clinique Beausoleil Not yet recruiting
Montpellier, France, 34000
Contact: Sophie Auger-Quittet, MD    +33467759999    s.auger-quittet@languedoc-mutualite.fr   
Principal Investigator: Sophie Auger-Quittet, MD         
Hôpital Saint Eloi Recruiting
Montpellier, France, 34295
Contact: Robert Navarro, MD    +33467338362    r-navarro@chu-montpellier.fr   
Principal Investigator: Robert Navarro, MD         
Hopital de l'Hotel Dieu Recruiting
Nantes, France, 44093
Contact: Pierre Peterlin, MD    +33 2 40 08 32 71    pierre.peterlin@chu-nantes.fr   
Principal Investigator: Pierre Peterlin, MD         
Hopital Archet I Not yet recruiting
Nice, France, 06202
Contact: Laurence LEGROS, MD    00 33 4 92 03 58 44    legros.l@chu-nice.fr   
Principal Investigator: Laurence LEGROS, MD         
CHU de Nîmes Recruiting
Nîmes, France, 30029
Contact: Stefan Wickenhauser, MD    +33 4 66 68 40 33    stefan.wickenhauser@chu-nimes.fr   
Principal Investigator: Stefan Wickenhauser, MD         
CHR d'Orléans Recruiting
Orléans, France, 45067
Contact: Ali Arar, MD    +33238229546    ali.arar@chr-orleans.fr   
Principal Investigator: Ali Arar, MD         
Hopital St Louis T4 Recruiting
Paris, France, 75475
Contact: Pierre Fenaux, PHD    0171207022    pierre.fenaux@sls.aphp.fr   
Principal Investigator: Pierre Fenaux, PHD         
Principal Investigator: ITZYKSON Raphael, MD         
Centre Hospitalier Joffre Recruiting
Perpignan, France, 66046
Contact: Laurence Sanhes, MD    00 33 468616448    laurence.sanhes@ch-perpignan.fr   
Principal Investigator: Laurence Sanhes, MD         
CHU de Haut-Lévèque Not yet recruiting
Pessac, France, 33604
Contact: Sophie Dimicoli-Salazar, MD    033557656511    sophie.dimicoli-salazar@chu-bordeaux.fr   
Principal Investigator: Sophie Dimicoli-Salazar, MD         
CHU Poitiers Recruiting
Poitiers, France, 86021
Contact: Jose Miguel Torregrosa Diaz, MD    +33548444444    jose-miguel.torregrosa-diaz@chu-poitiers.fr   
Principal Investigator: Jose Miguel Torregrosa Diaz, MD         
CH René Dubos Not yet recruiting
Pontoise, France, 95000
Contact: Riad Benramdane, MD    +33156831442    benramdaner@yahoo.fr   
Principal Investigator: Riad Benramdane, MD         
CH Annecy Genevois Not yet recruiting
Pringy, France, 74374
Contact: Pascale Cony-Makhoul, MD    +33 4 50 63 64 31    pconymakhoul@ch-annecygenevois.fr   
Principal Investigator: Pascale Cony-Makhoul, MD         
CHU de Reims Not yet recruiting
Reims, France, 51092
Contact: Chantal HIMBERLIN, MD    003326783644    chimberlin@chu-reims.fr   
Principal Investigator: Chantal HIMBERLIN, MD         
CHU Pontchaillou Recruiting
Rennes, France, 35033
Contact: Stanislas Nimubona, MD    33299289521    stanislas.nimubona@chu-rennes.fr   
Principal Investigator: Stanislas Nimubona, MD         
Centre Henri Bequerel Recruiting
Rouen, France, 76038
Contact: Aspasia STAMATOULLAS, MD    00 33 2 32 08 22 88    aspasia.stamatoullas@chb.unicancer.fr   
Principal Investigator: Aspasia STAMATOULLAS, MD         
Hôpital Hautepierre Not yet recruiting
Strasbourg, France, 67098
Contact: Shanti Natarajan-Ame, MD    +33388121670    shanti.ame@chru-strasbourg.fr   
Principal Investigator: Shanti Natarajan-Ame, MD         
IUCT Oncopole - Département d'hématologie Not yet recruiting
Toulouse, France, 31059
Contact: Christian RECHER, MD, PHD    05 61 77 20 78    recher.christian@iuct-oncopole.fr   
Principal Investigator: Christian RECHER, MD         
Iuct Oncopole Recruiting
Toulouse, France, 31059
Contact: Odile BEYNE-RAUZY, MD, PHD    +33(0)5 31 15 62 64    beynerauzy.odile@iuct-oncopole.fr   
Principal Investigator: Odile Beyne-Rauzy, PHD         
CH Valence Not yet recruiting
Valence, France, 26953
Contact: Jixing Liu, MD    +33475757566    jliu@ch-valence.fr   
Principal Investigator: Jixing Liu, MD         
CHU Brabois Not yet recruiting
Vandœuvre-lès-Nancy, France, 54511
Contact: Agnès GUERCI-BRESLER, MD    0033383153281    a.guerci@chu-nancy.fr   
Principal Investigator: Agnès GUERCI-BRESLER, MD         
Institut gustave Roussy Not yet recruiting
Villejuif, France, 94805
Contact: Eric Solary, MD    +33142114507    eric.solary@igr.fr   
Principal Investigator: ERIC SOLARY, MD         
Sponsors and Collaborators
Groupe Francophone des Myelodysplasies
Janssen-Cilag Ltd.
Investigators
Principal Investigator: ITZYKSON Raphael, PHD Hopital Saint-Louis, Service hematologie Senior

Responsible Party: Groupe Francophone des Myelodysplasies
ClinicalTrials.gov Identifier: NCT02214407     History of Changes
Other Study ID Numbers: GFM-DAC-CMML
First Posted: August 12, 2014    Key Record Dates
Last Update Posted: December 6, 2018
Last Verified: December 2018

Additional relevant MeSH terms:
Leukemia, Myelomonocytic, Chronic
Leukemia, Myeloid
Leukemia
Neoplasms by Histologic Type
Neoplasms
Myelodysplastic-Myeloproliferative Diseases
Bone Marrow Diseases
Hematologic Diseases
Benzocaine
Decitabine
Azacitidine
Allopurinol
Hydroxyurea
Anesthetics, Local
Anesthetics
Central Nervous System Depressants
Physiological Effects of Drugs
Sensory System Agents
Peripheral Nervous System Agents
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Enzyme Inhibitors
Gout Suppressants
Antirheumatic Agents
Free Radical Scavengers
Antioxidants
Protective Agents
Antisickling Agents