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

NCT02214407 | Completed Phase 3 DMC

• 1 other identifier: GFM-DAC-CMML
• Study Type: interventional
• Target: 170
• Locations: 1 country
• Sites: 45

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

Conditions

MDS

Outcome Measures

Primary Outcomes (1)

• compare between the two arms Event-free Survival (EFS)

  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.

  3 months

Secondary Outcomes (6)

• Overall Survival (OS)

  7 month

• Cumulative incidence of AML

  7 month

• Overall and Complete Response Rates

  3 month

• Response duration

  3 month

• Toxicity

  1 month

Study Arms (2)

ARM A: DECITABINE (DACOGEN)

EXPERIMENTAL

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

ARM B: HYDROXYUREA

EXPERIMENTAL

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

Interventions

Decitabine DRUG

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.

Also known as: DACOGEN

ARM A: DECITABINE (DACOGEN)

HYDROXYUREA DRUG

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 B: HYDROXYUREA

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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)

Sponsors & Collaborators

• Groupe Francophone des Myelodysplasies: lead
• Janssen-Cilag Ltd.: collaborator

Study Sites (45)

CHU La Réunion - Site nord

Saint-Denis, La Réunion, 97400, France

Location

CHU La Réunion-Site Sud

Saint-Pierre, La Réunion, 97410, France

Location

Chu Amiens

Amiens, 80054, France

Location

CHU d'Angers

Angers, 49 000, France

Location

CH Victor Dupouy

Argenteuil, 95107, France

Location

Ch Avignon

Avignon, 84000, France

Location

Centre Hospitalier de La Cote Basque

Bayonne, 64100, France

Location

Hôpital Nord Franche-Comté

Belfort, 90015, France

Location

Hôpital Avicenne

Bobigny, 93009, France

Location

CHU de Brest - Hôpital Morvan

Brest, 29609, France

Location

CHU Côte de Nacre

Caen, 14033, France

Location

Hôpital privé Sévigné

Cesson-Sévigné, 35510, France

Location

CHU Estaing

Clermont-Ferrand, 63058, France

Location

CH de Compiègne

Compiègne, 60321, France

Location

Centre Hospitalier Sud-Francilien

Corbeil-Essonnes, 91106, France

Location

Centre Henri Mondor

Créteil, 94010, France

Location

CHU Albert Michallon

Grenoble, 38043, France

Location

CH Le Mans

Le Mans, 72000, France

Location

Clinique Victor Hugo

Le Mans, 72000, France

Location

Hôpital Saint Vincent de Paul

Lille, 59020, France

Location

CHRU de Limoges

Limoges, 87046, France

Location

Centre Hospitalier Lyon Sud

Lyon, 69495, France

Location

Institut Paoli-Calmette

Marseille, 13009, France

Location

Centre Hospitalier de Meaux

Meaux, 77100, France

Location

Clinique Beausoleil

Montpellier, 34000, France

Location

Hôpital Saint Eloi

Montpellier, 34295, France

Location

Hopital de l'Hotel Dieu

Nantes, 44093, France

Location

Hopital Archet I

Nice, 06202, France

Location

CHU de Nîmes

Nîmes, 30029, France

Location

CHR d'Orléans

Orléans, 45067, France

Location

Hopital St Louis T4

Paris, 75475, France

Location

Centre Hospitalier Joffre

Perpignan, 66046, France

Location

CHU de Haut-Lévèque

Pessac, 33604, France

Location

CHU Poitiers

Poitiers, 86021, France

Location

CH René Dubos

Pontoise, 95000, France

Location

CH Annecy Genevois

Pringy, 74374, France

Location

CHU de Reims

Reims, 51092, France

Location

CHU Pontchaillou

Rennes, 35033, France

Location

Centre Henri Bequerel

Rouen, 76038, France

Location

Hôpital Hautepierre

Strasbourg, 67098, France

Location

IUCT Oncopole - Département d'hématologie

Toulouse, 31059, France

Location

Iuct Oncopole

Toulouse, 31059, France

Location

CH Valence

Valence, 26953, France

Location

CHU Brabois

Vandœuvre-lès-Nancy, 54511, France

Location

Institut gustave Roussy

Villejuif, 94805, France

Location

Related Publications (2)

• 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.

  PMID: 36455187 DERIVED

• 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.

  PMID: 33513373 DERIVED

MeSH Terms

Interventions

Decitabine; Hydroxyurea

Intervention Hierarchy (Ancestors)

Azacitidine; Aza Compounds; Organic Chemicals; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Nucleosides; Nucleic Acids, Nucleotides, and Nucleosides; Ribonucleosides; Urea; Amides

Study Officials

• ITZYKSON Raphael, PHD

  Hopital Saint-Louis, Service hematologie Senior

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 30, 2014
• First Posted: August 12, 2014
• Study Start: October 14, 2014
• Primary Completion: July 5, 2021
• Study Completion: August 16, 2021
• Last Updated: November 19, 2021

Record last verified: 2021-11

Locations

FR (45)