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)

This study has been completed.
Sponsor:
Collaborators:
Celgene Corporation
Roche Pharma AG
Information provided by (Responsible Party):
Groupe Francophone des Myelodysplasies
ClinicalTrials.gov Identifier:
NCT01015352
First received: November 17, 2009
Last updated: March 18, 2014
Last verified: November 2009
  Purpose

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.


Condition Intervention Phase
Myelodysplastic Syndromes
Drug: Azacitidine
Drug: Epoetin beta
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
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

Resource links provided by NLM:


Further study details as provided by Groupe Francophone des Myelodysplasies:

Primary Outcome Measures:
  • To determine the major erythroid response rate after 6 courses, assessed according to IWG 2000 criteria [ Time Frame: after 6 courses of treatment in the respective treatment arm ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Degree and duration of erythroid response (including red blood cell transfusion independence),overall survival and time to progression and toxicity [ Time Frame: after 4 and 6 months of treatment until the end of study ] [ Designated as safety issue: Yes ]

Enrollment: 98
Study Start Date: February 2009
Study Completion Date: March 2014
Primary Completion Date: March 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Arm A
Azacitidine 75mg/sqm SQ per day for 5 days every 28 days for 6 courses and 12 additional maintenance courses in responders.
Drug: Azacitidine
Azacitidine 75mg/sqm SQ per day for 5 days every 28 days
Other Name: Vidaza®
Active Comparator: 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

Drug: Azacitidine
Azacitidine 75mg/sqm SQ per day for 5 days every 28 days
Other Name: Vidaza®
Drug: Epoetin beta

Epoetin beta : 60000U weekly SQ injections

NeoRecormon®

Other Name: Epoetin beta : 60000U weekly SQ injections

  Hide Detailed Description

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

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT01015352

Locations
France
CHU d'Amiens
Amiens, France, 80054
Hôpital Angers
Angers, France, 49033
Hôpital Avignon
Avignon, France, 84000
Hôpital de la Côte Basque
Bayonne, France, 64100
Hopital Avicenne
Bobigny, France, 93009
Hôpital Boulogne Sur Mer
Boulogne Sur Mer, France, 62321
Hopital Clémenceau
Caen, France, 14033
Hôpital le Bocage
Dijon, France, 21034
Hôpital kremlin Bicêtre
Kremlin Bicêtre, France, 94275
Hôpital Versailles
Le Chesnay, France, 78157
Hôpital Huriez
Lille, France, 59037
Hôpital Saint Vincent
Lille, France, 59020
Hôpital Limoges
Limoges, France, 87046
Hôpital Edouard Herriot
Lyon, France, 69437
Hôpital Paoli-Calmettes
Marseille, France, 13273
Hôpital Brabois
Nancy, France, 54511
Hôpital Hôtel Dieu
Nantes, France, 44035
Hôpital Archet1
Nice, France, 06202
Hôpital La Source
Orléans, France, 45067
Hôpital Lariboisière
Paris, France, 75475
Hôpital Saint Louis
Paris, France, 75475
Hôpital Saint Antoine
Paris, France, 75571
Hôpital Cochin
Paris, France, 75679
Hôpital Maréchal Joffre
Perpignan, France, 66046
Hôpital Jean-Bernard
Poitiers, France, 86021
Hôpital Reims
Reims, France, 51092
Hôpital Henri Becquerel
Rouen, France, 76038
Hôpital Hautepierre
Strasbourg, France, 67098
Hôpital Purpan
Toulouse, France, 31059
Sponsors and Collaborators
Groupe Francophone des Myelodysplasies
Celgene Corporation
Roche Pharma AG
Investigators
Principal Investigator: Simone Boehrer, MD Groupe Francophone des Myélodysplasies
Principal Investigator: Claude Gardin, MD Groupe Francophone des Myélodysplasies
  More Information

Additional Information:
No publications provided

Responsible Party: Groupe Francophone des Myelodysplasies
ClinicalTrials.gov Identifier: NCT01015352     History of Changes
Other Study ID Numbers: GFM-Aza-Epo-2008-01
Study First Received: November 17, 2009
Last Updated: March 18, 2014
Health Authority: France : ANSM agence nationale de sécurité du médicament et des produits de santé

Keywords provided by Groupe Francophone des Myelodysplasies:
Myelodysplastic Syndromes

Additional relevant MeSH terms:
Myelodysplastic Syndromes
Preleukemia
Bone Marrow Diseases
Hematologic Diseases
Precancerous Conditions
Neoplasms
Azacitidine
Epoetin Alfa
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Antineoplastic Agents
Therapeutic Uses
Enzyme Inhibitors
Hematinics
Hematologic Agents

ClinicalTrials.gov processed this record on April 17, 2014