Trial Information

Combination of Azacitadine and Hematopoietic Growth Factors for Myelodysplastic Syndrome

OBJECTIVES:

Primary

- Determine the hematological response rate in patients with myelodysplastic syndromes
treated with azacitidine, darbepoetin alfa, and filgrastim (G-CSF).

Secondary

- Determine the time to leukemia progression, survival, and changes in apoptotic index of
bone marrow in patients treated with this regimen.

OUTLINE: This is an open-label, nonrandomized study.

- Initial therapy (courses 1 and 2): Patients receive azacitidine subcutaneously (SC) or
intra-venous (IV) on days 1-5 (week 1) and darbepoetin alfa* SC on day 8 (week 2).
Treatment repeats every 28 days for 2 courses.

Patients undergo bone marrow aspirate and biopsy to assess response. Patients with a major
hematological improvement OR with grade 3-4 hematological toxicities during the first 2
courses of therapy AND/OR ≥ 50% reduction in bone marrow cellularity compared to baseline
proceed to optimization therapy A. Patients not meeting any of the above criteria proceed to
optimization therapy B. Patients with disease progression are removed from study.

- Optimization therapy A (courses 3-8): Patients receive azacitidine SC or IV on days 1-5
(week 1), darbepoetin alfa** SC on day 8 (week 2), and filgrastim (G-CSF) SC 3 times
weekly in weeks 2-4.

- Optimization therapy B (courses 3-8): Patients receive a higher dose of azacitidine on
days 1-5 (week 1), darbepoetin alfa** SC on day 8 (week 2), and G-CSF 3 times weekly in
weeks 2-4.

In both optimization therapy A and B, treatment repeats every 28 days for 6 courses.
Patients with any degree of hematological improvement after initial therapy and optimization
therapy proceed to maintenance therapy.

- Maintenance therapy (course 9 and all subsequent courses): Patients receive azacitidine
on days 1-5 (week 1). Only patients with anemia (hemoglobin < 12 g/dL) and/or
neutropenia (absolute neutrophil count < 1,500/mm ³) at the start of any given course
during maintenance therapy receive darbepoetin alfa** SC beginning on day 8 (week 2)
and continuing once every 21 days and G-CSF SC 3 times weekly beginning in week 2.

Courses repeat every 28-56 days (determined by the treating physician) in the absence of
disease progression or unacceptable toxicity.

Bone marrow samples are obtained at baseline and after the completion of course 2 of study
treatment for apoptosis analysis, flow cytometry, and gene expression profiles of p53 and
p21 by immunohistochemistry. Peripheral blood samples are obtained periodically and analyzed
for hemoglobin F quantitation.

NOTE: *Administered only if the patient is anemic (hemoglobin < 12 g/dL).

NOTE: **Darbepoetin alfa is held if hemoglobin > 12 g/dL on day 1 of a given cycle.