Randomized Phase III Study of Decitabine +/- Hydroxyurea (HY) Versus HY in Advanced Proliferative CMML
NCT ID: NCT02214407
Last Updated: 2021-11-19
Study Results
The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.
Basic Information
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COMPLETED
PHASE3
170 participants
INTERVENTIONAL
2014-10-14
2021-08-16
Brief Summary
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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
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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.
Conditions
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Study Design
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RANDOMIZED
PARALLEL
TREATMENT
NONE
Study Groups
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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.
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.
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.
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.
Interventions
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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.
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.
Other Intervention Names
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Eligibility Criteria
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Inclusion Criteria
* 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
* 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)
18 Years
ALL
No
Sponsors
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Janssen-Cilag Ltd.
INDUSTRY
Groupe Francophone des Myelodysplasies
OTHER
Responsible Party
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Principal Investigators
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ITZYKSON Raphael, PHD
Role: PRINCIPAL_INVESTIGATOR
Hopital Saint-Louis, Service hematologie Senior
Locations
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CHU La Réunion - Site nord
Saint-Denis, La Réunion, France
CHU La Réunion-Site Sud
Saint-Pierre, La Réunion, France
Chu Amiens
Amiens, , France
CHU d'Angers
Angers, , France
CH Victor Dupouy
Argenteuil, , France
Ch Avignon
Avignon, , France
Centre Hospitalier de La Cote Basque
Bayonne, , France
Hôpital Nord Franche-Comté
Belfort, , France
Hôpital Avicenne
Bobigny, , France
CHU de Brest - Hôpital Morvan
Brest, , France
CHU Côte de Nacre
Caen, , France
Hôpital privé Sévigné
Cesson-Sévigné, , France
CHU Estaing
Clermont-Ferrand, , France
CH de Compiègne
Compiègne, , France
Centre Hospitalier Sud-Francilien
Corbeil-Essonnes, , France
Centre Henri Mondor
Créteil, , France
CHU Albert Michallon
Grenoble, , France
CH Le Mans
Le Mans, , France
Clinique Victor Hugo
Le Mans, , France
Hôpital Saint Vincent de Paul
Lille, , France
CHRU de Limoges
Limoges, , France
Centre Hospitalier Lyon Sud
Lyon, , France
Institut Paoli-Calmette
Marseille, , France
Centre Hospitalier de Meaux
Meaux, , France
Clinique Beausoleil
Montpellier, , France
Hôpital Saint Eloi
Montpellier, , France
Hopital de l'Hotel Dieu
Nantes, , France
Hopital Archet I
Nice, , France
CHU de Nîmes
Nîmes, , France
CHR d'Orléans
Orléans, , France
Hopital St Louis T4
Paris, , France
Centre Hospitalier Joffre
Perpignan, , France
CHU de Haut-Lévèque
Pessac, , France
CHU Poitiers
Poitiers, , France
CH René Dubos
Pontoise, , France
CH Annecy Genevois
Pringy, , France
CHU de Reims
Reims, , France
CHU Pontchaillou
Rennes, , France
Centre Henri Bequerel
Rouen, , France
Hôpital Hautepierre
Strasbourg, , France
IUCT Oncopole - Département d'hématologie
Toulouse, , France
Iuct Oncopole
Toulouse, , France
CH Valence
Valence, , France
CHU Brabois
Vandœuvre-lès-Nancy, , France
Institut gustave Roussy
Villejuif, , France
Countries
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References
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Itzykson R, Santini V, Thepot S, Ades L, Chaffaut C, Giagounidis A, Morabito M, Droin N, Lubbert M, Sapena R, Nimubona S, Goasguen J, Wattel E, Zini G, Torregrosa Diaz JM, Germing U, Pelizzari AM, Park S, Jaekel N, Metzgeroth G, Onida F, Navarro R, Patriarca A, Stamatoullas A, Gotze K, Puttrich M, Mossuto S, Solary E, Gloaguen S, Chevret S, Chermat F, Platzbecker U, Fenaux P. Decitabine Versus Hydroxyurea for Advanced Proliferative Chronic Myelomonocytic Leukemia: Results of a Randomized Phase III Trial Within the EMSCO Network. J Clin Oncol. 2023 Apr 1;41(10):1888-1897. doi: 10.1200/JCO.22.00437. Epub 2022 Dec 1.
Pleyer L, Leisch M, Kourakli A, Padron E, Maciejewski JP, Xicoy Cirici B, Kaivers J, Ungerstedt J, Heibl S, Patiou P, Hunter AM, Mora E, Geissler K, Dimou M, Jimenez Lorenzo MJ, Melchardt T, Egle A, Viniou AN, Patel BJ, Arnan M, Valent P, Roubakis C, Bernal Del Castillo T, Galanopoulos A, Calabuig Munoz M, Bonadies N, Medina de Almeida A, Cermak J, Jerez A, Montoro MJ, Cortes A, Avendano Pita A, Lopez Andrade B, Hellstroem-Lindberg E, Germing U, Sekeres MA, List AF, Symeonidis A, Sanz GF, Larcher-Senn J, Greil R. Outcomes of patients with chronic myelomonocytic leukaemia treated with non-curative therapies: a retrospective cohort study. Lancet Haematol. 2021 Feb;8(2):e135-e148. doi: 10.1016/S2352-3026(20)30374-4.
Other Identifiers
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GFM-DAC-CMML
Identifier Type: -
Identifier Source: org_study_id