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)

NCT ID: NCT01015352

Last Updated: 2014-03-19

Study Results

Results pending

The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.

Basic Information

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Recruitment Status

COMPLETED

Clinical Phase

PHASE2

Total Enrollment

98 participants

Study Classification

INTERVENTIONAL

Study Start Date

2009-02-28

Study Completion Date

2014-03-31

Brief Summary

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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

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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.

Conditions

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Myelodysplastic Syndromes

Study Design

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Allocation Method

RANDOMIZED

Intervention Model

PARALLEL

Primary Study Purpose

TREATMENT

Blinding Strategy

NONE

Study Groups

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Arm A

Azacitidine 75mg/sqm SQ per day for 5 days every 28 days for 6 courses and 12 additional maintenance courses in responders.

Group Type ACTIVE_COMPARATOR

Azacitidine

Intervention Type DRUG

Azacitidine 75mg/sqm SQ per day for 5 days every 28 days

Arm B

Azacitidine: 75mg/sqm SQ per day for 5 days every 28 days for 6 courses AND

Epoetin beta : 60000U weekly SQ injections (to be adapted according to Hb as described above)

12 additional maintenance courses are planned in responders

Group Type ACTIVE_COMPARATOR

Azacitidine

Intervention Type DRUG

Azacitidine 75mg/sqm SQ per day for 5 days every 28 days

Epoetin beta

Intervention Type DRUG

Epoetin beta : 60000U weekly SQ injections

NeoRecormon®

Interventions

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Azacitidine

Azacitidine 75mg/sqm SQ per day for 5 days every 28 days

Intervention Type DRUG

Epoetin beta

Epoetin beta : 60000U weekly SQ injections

NeoRecormon®

Intervention Type DRUG

Other Intervention Names

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Vidaza® Epoetin beta : 60000U weekly SQ injections

Eligibility Criteria

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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
Minimum Eligible Age

18 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

No

Sponsors

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Celgene Corporation

INDUSTRY

Sponsor Role collaborator

Roche Pharma AG

INDUSTRY

Sponsor Role collaborator

Groupe Francophone des Myelodysplasies

OTHER

Sponsor Role lead

Responsible Party

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Responsibility Role SPONSOR

Principal Investigators

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Simone Boehrer, MD

Role: PRINCIPAL_INVESTIGATOR

Groupe Francophone des Myélodysplasies

Claude Gardin, MD

Role: PRINCIPAL_INVESTIGATOR

Groupe Francophone des Myélodysplasies

Locations

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CHU d'Amiens

Amiens, , France

Site Status

Hôpital Angers

Angers, , France

Site Status

Hôpital Avignon

Avignon, , France

Site Status

Hôpital de la Côte Basque

Bayonne, , France

Site Status

Hopital Avicenne

Bobigny, , France

Site Status

Hôpital Boulogne Sur Mer

Boulogne-sur-Mer, , France

Site Status

Hopital Clémenceau

Caen, , France

Site Status

Hôpital le Bocage

Dijon, , France

Site Status

Hôpital Versailles

Le Chesnay, , France

Site Status

Hôpital kremlin Bicêtre

Le Kremlin-Bicêtre, , France

Site Status

Hôpital Saint Vincent

Lille, , France

Site Status

Hôpital Huriez

Lille, , France

Site Status

Hôpital Limoges

Limoges, , France

Site Status

Hôpital Edouard Herriot

Lyon, , France

Site Status

Hôpital Paoli-Calmettes

Marseille, , France

Site Status

Hôpital Brabois

Nancy, , France

Site Status

Hôpital Hôtel Dieu

Nantes, , France

Site Status

Hôpital Archet1

Nice, , France

Site Status

Hôpital La Source

Orléans, , France

Site Status

Hôpital Lariboisière

Paris, , France

Site Status

Hôpital Saint Louis

Paris, , France

Site Status

Hôpital Saint Antoine

Paris, , France

Site Status

Hôpital Cochin

Paris, , France

Site Status

Hôpital Maréchal Joffre

Perpignan, , France

Site Status

Hôpital Jean-Bernard

Poitiers, , France

Site Status

Hôpital Reims

Reims, , France

Site Status

Hôpital Henri Becquerel

Rouen, , France

Site Status

Hôpital Hautepierre

Strasbourg, , France

Site Status

Hôpital Purpan

Toulouse, , France

Site Status

Countries

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France

References

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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.

Reference Type DERIVED
PMID: 27229713 (View on PubMed)

Related Links

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http://www.gfmgroup.org

(Website of the french group of MDS)

Other Identifiers

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GFM-Aza-Epo-2008-01

Identifier Type: -

Identifier Source: org_study_id

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