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

Sponsor

Groupe Francophone des Myelodysplasies (Other)

Overall Status

Completed

CT.gov ID

NCT02214407

Collaborator

Janssen-Cilag Ltd. (Industry)

170

Enrollment

Locations

Arms

82.1

Actual Duration (Months)

3.8

Patients Per Site

Patients Per Site Per Month

Study Details

Study Description

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)

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 Design

Study Type:

Interventional

Actual Enrollment :

170 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 :

Oct 14, 2014

Actual Primary Completion Date :

Jul 5, 2021

Actual Study Completion Date :

Aug 16, 2021

Arms and Interventions

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 Names: 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.

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 Names:

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.

Outcome Measures

Primary Outcome Measures

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

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

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	CHU La Réunion - Site nord	Saint-Denis	La Réunion	France	97400
2	CHU La Réunion-Site Sud	Saint-Pierre	La Réunion	France	97410
3	Chu Amiens	Amiens		France	80054
4	CHU d'Angers	Angers		France	49 000
5	CH Victor Dupouy	Argenteuil		France	95107
6	Ch Avignon	Avignon		France	84000
7	Centre Hospitalier de La Cote Basque	Bayonne		France	64100
8	Hôpital Nord Franche-Comté	Belfort		France	90015
9	Hôpital Avicenne	Bobigny		France	93009
10	CHU de Brest - Hôpital Morvan	Brest		France	29609
11	CHU Côte de Nacre	Caen		France	14033
12	Hôpital privé Sévigné	Cesson-Sévigné		France	35510
13	CHU Estaing	Clermont-Ferrand		France	63058
14	CH de Compiègne	Compiègne		France	60321
15	Centre Hospitalier Sud-Francilien	Corbeil-Essonnes		France	91106
16	Centre Henri Mondor	Créteil		France	94010
17	CHU Albert Michallon	Grenoble		France	38043
18	CH Le Mans	Le Mans		France	72000
19	Clinique Victor Hugo	Le Mans		France	72000
20	Hôpital Saint Vincent de Paul	Lille		France	59020
21	CHRU de Limoges	Limoges		France	87046
22	Centre Hospitalier Lyon Sud	Lyon		France	69495
23	Institut Paoli-Calmette	Marseille		France	13009
24	Centre Hospitalier de Meaux	Meaux		France	77100
25	Clinique Beausoleil	Montpellier		France	34000
26	Hôpital Saint Eloi	Montpellier		France	34295
27	Hopital de l'Hotel Dieu	Nantes		France	44093
28	Hopital Archet I	Nice		France	06202
29	CHU de Nîmes	Nîmes		France	30029
30	CHR d'Orléans	Orléans		France	45067
31	Hopital St Louis T4	Paris		France	75475
32	Centre Hospitalier Joffre	Perpignan		France	66046
33	CHU de Haut-Lévèque	Pessac		France	33604
34	CHU Poitiers	Poitiers		France	86021
35	CH René Dubos	Pontoise		France	95000
36	CH Annecy Genevois	Pringy		France	74374
37	CHU de Reims	Reims		France	51092
38	CHU Pontchaillou	Rennes		France	35033
39	Centre Henri Bequerel	Rouen		France	76038
40	Hôpital Hautepierre	Strasbourg		France	67098
41	IUCT Oncopole - Département d'hématologie	Toulouse		France	31059
42	Iuct Oncopole	Toulouse		France	31059
43	CH Valence	Valence		France	26953
44	CHU Brabois	Vandœuvre-lès-Nancy		France	54511
45	Institut gustave Roussy	Villejuif		France	94805

Sponsors and Collaborators

Groupe Francophone des Myelodysplasies
Janssen-Cilag Ltd.

Investigators

Principal Investigator: ITZYKSON Raphael, PHD, Hopital Saint-Louis, Service hematologie Senior

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

Responsible Party:

Groupe Francophone des Myelodysplasies

ClinicalTrials.gov Identifier:

NCT02214407

Other Study ID Numbers:

GFM-DAC-CMML

First Posted:

Aug 12, 2014

Last Update Posted:

Nov 19, 2021

Last Verified:

Nov 1, 2021

Additional relevant MeSH terms:

Decitabine

Hydroxyurea

Study Results

No Results Posted as of Nov 19, 2021