Clinical trial NCT01015352: Azacitidine Combined to Epoetin Beta in International Prognostic Scoring System (IPSS) Low-risk and Intermediate-1 Myelodysplastic Syndrome (MDS) Patients, Resistant to Erythropoetin-stimulating Agents (ESA)
Official title: A Phase II Study of Azacitidine (Vidaza®) Combined to Epoetin Beta (NeoRecormon®) in IPSS Low-risk and Intermediate-1 MDS Patients, Resistant to ESA
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Myelodysplastic Syndromes
Keywords: Myelodysplastic Syndromes
Lead sponsor: Groupe Francophone des Myelodysplasies
Sponsor class: OTHER
Collaborators: name: Celgene Corporation
name: Roche Pharma AG
First posted: 2009-11-18
Enrollment: 98
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: The study is aimed to treat low-risk MDS patients,who are dependent on red-blood cell transfusion due to disease-related anemia, and who have a proven resistance towards treatment with erythropoetin-stimulating agents (ESA). The study randomizes patients to receive a treatment with the demethylating agent 5-azacytidine alone or in combination with an ESA. The study thus evaluates, if efficacy of 5-azacytidine, notably on the red-blood cell transfusion-dependence is comparable/inferior to a combination treatment with azacitidine and an ESA (that is if 5-azacytidine can overcome the resistance towards ESA). Being a phase II study, the study assesses, duration of erythroid response, overall survival and time to progression as well as toxicity.

Detailed description: Phase II Study of Azacitidine (Vidaza®) Combined to Epoetin Beta (NeoRecormon®) in IPSS Low-risk and Intermediate-1 MDS Patients, Resistant to ESA

The Primary Endpoint of this study is to determine the major erythroid response rate after 6 courses, assessed according to IWG 2000 criteria.

The Secondary Endpoints are to determine the percentage of major HI-E and minor HI-E after 4 and 6 courses according to IWG 2000, the HI-E IWG 2006 criteria, the duration of erythroid response, the red blood cell transfusion independence at 4 and 6 months, the overall survival and time to IPSS progression and the toxicity (NCI-CTAE).

The trial will enroll 98 patients (49 patients per arm)

Treatment in arm A:

Azacitidine 75mg/sqm SQ per day for 5 days every 28 days for 6 courses Dosing of each subsequent course will be adapted according to extrahematological toxicity and cytopenias.

In responders after 6 courses of azacitidine according to IWG 2000 criteria (both minor and major erythroid responses of HI-E) 12 identical additional maintenance courses will be delivered every 28 days, unless relapse occurs (according to IWG 2000 criteria).

Treatment in arm B:

• Azacitidine 75mg/sqm SQ per day for 5 days every 28 days for 6 courses.

(dosing of each subsequent course will be adapted according to extra hematological toxicity and cytopenias) AND

• Epoetin beta : 60000U weekly SQ injections Dosing of epoetin beta will be adapted according to current ASH-ASCO guidelines and black box warning of epoetin beta. Epoetin beta therapy may therefore be interrupted, in case of response to azacitidine, as soon as a hemoglobin level of 12g/dl is achieved on two sequential bimonthly blood count measurements.

A 40% dose reduction of epoetin beta will be required if:

* Hb level rise of 1 g/dl is observed within two weeks
* Hb level exceeds 11g/dl

In responders after 6 courses of azacitidine + epoetin beta, according to IWG 2000 criteria (both minor and major erythroid responses of HI-E) 12 identical additional maintenance courses of azacitidine will be delivered every 28 days, unless relapse occurs (according to IWG 2000 criteria) Epoetin beta will be administered as described above.

In both arms, each subsequent course will be delivered

* In absence of persistent grade \>2 non-hematological toxicity
* In absence of rehospitalisation for severe bleeding, infection or febrile neutropenia and non-hematological toxicity following the previous course
* If neutrophil counts are \> 1G/l or \> 50% of baseline neutrophil counts
* If platelets are \> 75G/l or \> 50% of baseline platelets counts

In case of persistent cytopenia, blood counts will be at least checked every 2 weeks, and the next course delayed until resolution of cytopenia, as defined above.

In case of persistence of cytopenia beyond day 56 of the preceding course, an new evaluation of the disease, using clinical examination, blood and bone marrow examinations +/- cytogenetics will be mandatory before eventually pursuing azacitidine at lower dosing levels.

Eligibility criteria: Inclusion Criteria:

MDS defined as

* RCMD, RA with or without ring sideroblasts
* RAEB 1, or CMML 1, if WBC \< 13 G /l according to the WHO classification
* with a low or int-1 IPSS score AND
* primary or secondary resistance to epoetin alpha/ beta (\> 60000 U/w) or darbepoetin (\> 250ug/w), administered for at least 12 weeks
* requirement of RBC transfusions \> 4 U in the previous 8 weeks
* Aged 18 years or more
* Adequate contraception, if relevant
* Negative pregnancy test if relevant
* Written Informed consent
* Ability to participate to a clinical trial and adhere to study procedures
* Health insurance

Exclusion Criteria:

* Therapy-related MDS (after chemo- or radiotherapy for a previous neoplasm or immune disorder)
* Patients with a planned allogeneic bone marrow transplantation
* Creatininemia \>1.5 upper normal value or estimated Ccr less than 30ml/mn
* ALAT and ASAT \>2.5 upper normal value
* Bilirubin \>2N, except unconjugated hyperbilirubinemia due to MDS-related dyserythropoiesis
* Heart failure NYHA \> II
* Known allergy to mannitol
* Other tumor, unstable for the last three years, except in situ uterine carcinoma or basal skin tumor
* ECOG \> 2
* Life expectancy less than 3 months

Primary outcomes:
measure: To determine the major erythroid response rate after 6 courses, assessed according to IWG 2000 criteria
timeFrame: after 6 courses of treatment in the respective treatment arm
Secondary outcomes:
measure: Degree and duration of erythroid response (including red blood cell transfusion independence),overall survival and time to progression and toxicity
timeFrame: after 4 and 6 months of treatment until the end of study
Other outcomes:
Locations:
city: Amiens
country: France
facility: CHU d'Amiens
city: Angers
country: France
facility: Hôpital Angers
city: Avignon
country: France
facility: Hôpital Avignon
city: Bayonne
country: France
facility: Hôpital de la Côte Basque
city: Bobigny
country: France
facility: Hopital Avicenne
city: Boulogne Sur Mer
country: France
facility: Hôpital Boulogne Sur Mer
city: Caen
country: France
facility: Hopital Clémenceau
city: Dijon
country: France
facility: Hôpital le Bocage
city: Kremlin Bicêtre
country: France
facility: Hôpital kremlin Bicêtre
city: Le Chesnay
country: France
facility: Hôpital Versailles
city: Lille
country: France
facility: Hôpital Saint Vincent
city: Lille
country: France
facility: Hôpital Huriez
city: Limoges
country: France
facility: Hôpital Limoges
city: Lyon
country: France
facility: Hôpital Edouard Herriot
city: Marseille
country: France
facility: Hôpital Paoli-Calmettes
city: Nancy
country: France
facility: Hôpital Brabois
city: Nantes
country: France
facility: Hôpital Hôtel Dieu
city: Nice
country: France
facility: Hôpital Archet1
city: Orléans
country: France
facility: Hôpital La Source
city: Paris
country: France
facility: Hôpital Lariboisière
city: Paris
country: France
facility: Hôpital Saint Louis
city: Paris
country: France
facility: Hôpital Saint Antoine
city: Paris
country: France
facility: Hôpital Cochin
city: Perpignan
country: France
facility: Hôpital Maréchal Joffre
city: Poitiers
country: France
facility: Hôpital Jean-Bernard
city: Reims
country: France
facility: Hôpital Reims
city: Rouen
country: France
facility: Hôpital Henri Becquerel
city: Strasbourg
country: France
facility: Hôpital Hautepierre
city: Toulouse
country: France
facility: Hôpital Purpan
Study officials:
affiliation: Groupe Francophone des Myélodysplasies
name: Simone Boehrer, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Groupe Francophone des Myélodysplasies
name: Claude Gardin, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Thepot S, Ben Abdelali R, Chevret S, Renneville A, Beyne-Rauzy O, Prebet T, Park S, Stamatoullas A, Guerci-Bresler A, Cheze S, Tertian G, Choufi B, Legros L, Bastie JN, Delaunay J, Chaury MP, Sanhes L, Wattel E, Dreyfus F, Vey N, Chermat F, Preudhomme C, Fenaux P, Gardin C; Groupe Francophone des Myelodysplasies (GFM). A randomized phase II trial of azacitidine +/- epoetin-beta in lower-risk myelodysplastic syndromes resistant to erythropoietic stimulating agents. Haematologica. 2016 Aug;101(8):918-25. doi: 10.3324/haematol.2015.140988. Epub 2016 May 26.