Clinical trial NCT02214407: 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)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: MDS
Lead sponsor: Groupe Francophone des Myelodysplasies
Sponsor class: OTHER
Collaborators: name: Janssen-Cilag Ltd.
First posted: 2014-08-12
Enrollment: 170
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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

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.

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)

Primary outcomes:
measure: compare between the two arms Event-free Survival (EFS)
timeFrame: 3 months
Secondary outcomes:
measure: Overall Survival (OS)
timeFrame: 7 month
measure: Cumulative incidence of AML
timeFrame: 7 month
measure: Overall and Complete Response Rates
timeFrame: 3 month
measure: Response duration
timeFrame: 3 month
measure: Toxicity
timeFrame: 1 month
measure: Prognostic factors
timeFrame: 3 month
Other outcomes:
Locations:
city: Saint-Denis
country: France
facility: CHU La Réunion - Site nord
state: La Réunion
city: Saint-Pierre
country: France
facility: CHU La Réunion-Site Sud
state: La Réunion
city: Amiens
country: France
facility: Chu Amiens
city: Angers
country: France
facility: CHU d'Angers
city: Argenteuil
country: France
facility: CH Victor Dupouy
city: Avignon
country: France
facility: Ch Avignon
city: Bayonne
country: France
facility: Centre Hospitalier de La Cote Basque
city: Belfort
country: France
facility: Hôpital Nord Franche-Comté
city: Bobigny
country: France
facility: Hôpital Avicenne
city: Brest
country: France
facility: CHU de Brest - Hôpital Morvan
city: Caen
country: France
facility: CHU Côte de Nacre
city: Cesson-Sévigné
country: France
facility: Hôpital privé Sévigné
city: Clermont-Ferrand
country: France
facility: CHU Estaing
city: Compiègne
country: France
facility: CH de Compiègne
city: Corbeil-Essonnes
country: France
facility: Centre Hospitalier Sud-Francilien
city: Créteil
country: France
facility: Centre Henri Mondor
city: Grenoble
country: France
facility: CHU Albert Michallon
city: Le Mans
country: France
facility: CH Le Mans
city: Le Mans
country: France
facility: Clinique Victor Hugo
city: Lille
country: France
facility: Hôpital Saint Vincent de Paul
city: Limoges
country: France
facility: CHRU de Limoges
city: Lyon
country: France
facility: Centre Hospitalier Lyon Sud
city: Marseille
country: France
facility: Institut Paoli-Calmette
city: Meaux
country: France
facility: Centre Hospitalier de Meaux
city: Montpellier
country: France
facility: Clinique Beausoleil
city: Montpellier
country: France
facility: Hôpital Saint Eloi
city: Nantes
country: France
facility: Hopital de l'Hotel Dieu
city: Nice
country: France
facility: Hopital Archet I
city: Nîmes
country: France
facility: CHU de Nîmes
city: Orléans
country: France
facility: CHR d'Orléans
city: Paris
country: France
facility: Hopital St Louis T4
city: Perpignan
country: France
facility: Centre Hospitalier Joffre
city: Pessac
country: France
facility: CHU de Haut-Lévèque
city: Poitiers
country: France
facility: CHU Poitiers
city: Pontoise
country: France
facility: CH René Dubos
city: Pringy
country: France
facility: CH Annecy Genevois
city: Reims
country: France
facility: CHU de Reims
city: Rennes
country: France
facility: CHU Pontchaillou
city: Rouen
country: France
facility: Centre Henri Bequerel
city: Strasbourg
country: France
facility: Hôpital Hautepierre
city: Toulouse
country: France
facility: IUCT Oncopole - Département d'hématologie
city: Toulouse
country: France
facility: Iuct Oncopole
city: Valence
country: France
facility: CH Valence
city: Vandœuvre-lès-Nancy
country: France
facility: CHU Brabois
city: Villejuif
country: France
facility: Institut gustave Roussy
Study officials:
affiliation: Hopital Saint-Louis, Service hematologie Senior
name: ITZYKSON Raphael, PHD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.