Trial Information

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

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.