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

MDS Clinical Trial

— GFM-DAC-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)

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02214407
• Other study ID #: GFM-DAC-CMML
• Status: Completed
• Phase: Phase 3
• Start date: October 14, 2014
• Est. completion date: August 16, 2021

Study information

• Verified date: November 2021
• Source: Groupe Francophone des Myelodysplasies
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 170
• Est. completion date: August 16, 2021
• Est. primary completion date: July 5, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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)

Related Conditions & MeSH terms

• MDS

Intervention

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.
• 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.

Locations

Country	Name	City	State
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	CHU La Réunion - Site nord	Saint-Denis	La Réunion
France	CHU La Réunion-Site Sud	Saint-Pierre	La Réunion
France	Hôpital Hautepierre	Strasbourg
France	Iuct Oncopole	Toulouse
France	IUCT Oncopole - Département d'hématologie	Toulouse
France	CH Valence	Valence
France	CHU Brabois	Vandœuvre-lès-Nancy
France	Institut gustave Roussy	Villejuif

Sponsors (2)

Lead Sponsor	Collaborator
Groupe Francophone des Myelodysplasies	Janssen-Cilag Ltd.

Country where clinical trial is conducted

France, 

Outcome

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