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)

Myelodysplastic Syndromes Clinical Trial

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01015352
• Other study ID #: GFM-Aza-Epo-2008-01
• Status: Completed
• Phase: Phase 2
• First received: November 17, 2009
• Last updated: March 18, 2014
• Start date: February 2009
• Est. completion date: March 2014

Study information

• Verified date: November 2009
• Source: Groupe Francophone des Myelodysplasies
• Contact: n/a
• Is FDA regulated: No
• Health authority: France : ANSM agence nationale de sécurité du médicament et des produits de santé
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 98
• Est. completion date: March 2014
• Est. primary completion date: March 2014
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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 Design

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

Related Conditions & MeSH terms

• Myelodysplastic Syndromes
• Preleukemia

Intervention

Drug:
• Azacitidine
Azacitidine 75mg/sqm SQ per day for 5 days every 28 days
• Epoetin beta
Epoetin beta : 60000U weekly SQ injections NeoRecormon®

Locations

Country	Name	City	State
France	CHU d'Amiens	Amiens
France	Hôpital Angers	Angers
France	Hôpital Avignon	Avignon
France	Hôpital de la Côte Basque	Bayonne
France	Hopital Avicenne	Bobigny
France	Hôpital Boulogne Sur Mer	Boulogne Sur Mer
France	Hopital Clémenceau	Caen
France	Hôpital le Bocage	Dijon
France	Hôpital kremlin Bicêtre	Kremlin Bicêtre
France	Hôpital Versailles	Le Chesnay
France	Hôpital Huriez	Lille
France	Hôpital Saint Vincent	Lille
France	Hôpital Limoges	Limoges
France	Hôpital Edouard Herriot	Lyon
France	Hôpital Paoli-Calmettes	Marseille
France	Hôpital Brabois	Nancy
France	Hôpital Hôtel Dieu	Nantes
France	Hôpital Archet1	Nice
France	Hôpital La Source	Orléans
France	Hôpital Cochin	Paris
France	Hôpital Lariboisière	Paris
France	Hôpital Saint Antoine	Paris
France	Hôpital Saint Louis	Paris
France	Hôpital Maréchal Joffre	Perpignan
France	Hôpital Jean-Bernard	Poitiers
France	Hôpital Reims	Reims
France	Hôpital Henri Becquerel	Rouen
France	Hôpital Hautepierre	Strasbourg
France	Hôpital Purpan	Toulouse

Sponsors (3)

Lead Sponsor	Collaborator
Groupe Francophone des Myelodysplasies	Celgene Corporation, Roche Pharma AG

Country where clinical trial is conducted

France, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	No
Secondary	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	Yes

External Links

•   (Website of the french group of MDS)