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)

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

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.

Study Overview

• Status: Completed
• Conditions: Myelodysplastic Syndromes
• Intervention / Treatment: Drug: Azacitidine; Drug: Epoetin beta

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.

• Study Type: Interventional
• Enrollment (Actual): 98
• Phase: Phase 2

Contacts and Locations

Study Locations

• France
  • Amiens, France, 80054
    • CHU d'Amiens
  • Angers, France, 49033
    • Hôpital Angers
  • Avignon, France, 84000
    • Hôpital Avignon
  • Bayonne, France, 64100
    • Hopital de la cote Basque
  • Bobigny, France, 93009
    • Hopital Avicenne
  • Boulogne Sur Mer, France, 62321
    • Hôpital Boulogne Sur Mer
  • Caen, France, 14033
    • Hôpital Clémenceau
  • Dijon, France, 21034
    • Hôpital Le Bocage
  • Kremlin Bicêtre, France, 94275
    • Hôpital Kremlin Bicêtre
  • Le Chesnay, France, 78157
    • Hôpital Versailles
  • Lille, France, 59020
    • Hopital Saint Vincent
  • Lille, France, 59037
    • Hôpital Huriez
  • Limoges, France, 87046
    • Hôpital Limoges
  • Lyon, France, 69437
    • Hôpital Edouard Herriot
  • Marseille, France, 13273
    • Hôpital Paoli-Calmettes
  • Nancy, France, 54511
    • Hôpital Brabois
  • Nantes, France, 44035
    • Hôpital Hôtel Dieu
  • Nice, France, 06202
    • Hôpital Archet1
  • Orléans, France, 45067
    • Hopital La Source
  • Paris, France, 75679
    • Hôpital Cochin
  • Paris, France, 75475
    • Hôpital Saint Louis
  • Paris, France, 75571
    • Hôpital Saint Antoine
  • Paris, France, 75475
    • Hôpital Lariboisière
  • Perpignan, France, 66046
    • Hôpital Maréchal Joffre
  • Poitiers, France, 86021
    • Hôpital Jean-Bernard
  • Reims, France, 51092
    • Hôpital Reims
  • Rouen, France, 76038
    • Hopital Henri Becquerel
  • Strasbourg, France, 67098
    • Hôpital Hautepierre
  • Toulouse, France, 31059
    • Hopital Purpan

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
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 Names: 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 Names: Vidaza®; Drug: Epoetin beta; Epoetin beta : 60000U weekly SQ injections NeoRecormon®; Other Names: Epoetin beta : 60000U weekly SQ injections

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
To determine the major erythroid response rate after 6 courses, assessed according to IWG 2000 criteria	after 6 courses of treatment in the respective treatment arm

Secondary Outcome Measures

Outcome Measure	Time Frame
Degree and duration of erythroid response (including red blood cell transfusion independence),overall survival and time to progression and toxicity	after 4 and 6 months of treatment until the end of study

Collaborators and Investigators

• Sponsor: Groupe Francophone des Myelodysplasies
• Collaborators: Roche Pharma AG; Celgene Corporation
• Investigators: Principal Investigator: Simone Boehrer, MD, Groupe Francophone des Myelodysplasies

Publications and helpful links

General Publications

• 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.

Helpful Links

• (Website of the french group of MDS)

Study record dates

Study Major Dates

• Study Start: February 1, 2009
• Primary Completion (Actual): March 1, 2014
• Study Completion (Actual): March 1, 2014

Study Registration Dates

• First Submitted: November 17, 2009
• First Submitted That Met QC Criteria: November 17, 2009
• First Posted (Estimate): November 18, 2009

Study Record Updates

• Last Update Posted (Estimate): March 19, 2014
• Last Update Submitted That Met QC Criteria: March 18, 2014
• Last Verified: November 1, 2009

More Information

Terms related to this study

• Keywords: Myelodysplastic Syndromes
• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms; Disease; Bone Marrow Diseases; Hematologic Diseases; Precancerous Conditions; Syndrome; Myelodysplastic Syndromes; Preleukemia; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Hematinics; Epoetin Alfa; Azacitidine
• Other Study ID Numbers: GFM-Aza-Epo-2008-01