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Combination of Azacitadine andHematopoietic Growth Factors

Combination of Azacitadine and Hematopoietic Growth Factors

Azacitadine and Hematopoietic Growth Factors

Bayard L. Powell, MD

RATIONALE: Drugs used in chemotherapy, such as azacitidine, work in different ways to stop the growth of abnormal cells, either by killing the cells or by stopping them from dividing. Colony-stimulating factors, such as darbepoetin alfa and G-CSF, may increase the number of red blood cells and white blood cells found in bone marrow or peripheral blood and may help the immune system recover from the side effects of chemotherapy. Giving azacitidine together with darbepoetin alfa and G-CSF may be an effective treatment for myelodysplastic syndromes.

PURPOSE: This clinical trial is studying how well giving azacitidine together with darbepoetin alfa and G-CSF works in treating patients with myelodysplastic syndromes.

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.

Azacitidine, Darbepoetin Alfa, and Erythropoietin and Filgastrim (G-CSF) in Treating Patients With Myelodysplastic Syndromes

Combination of Azacitadine and Hematopoietic Growth Factors for Myelodysplastic Syndrome

Complete response is normalization of abnormal blood counts, and disappearance of signs of morphological changes in the bone marrow. If the previously present cytogenetic abnormalities are absent then it is referred also as a cytogenetic complete remission.

For patients with pretreatment hemoglobin less than 11 g/dL, greater than 2 g/dL increase in hemoglobin; for red cell transfusion-dependent patients, transfusion independence.

For patients with pretreatment platelet count less than 100,000/mm3, a 50% or more increase in platelet count with a net increase greater than 10,000/mm3 but less than 30,000/mm3

Death during treatment or disease progression characterized by worsening of cytopenias, increase in the percentage of the blasts, reduction of hemoglobin concentration by at least 2 g/dl or transfusion dependence in the absence of another explanation, such as acute infection, gastrointestinal bleeding, hemolysis.

National Cancer Institute (NCI)

Wake Forest University Health Sciences

Azacitidine and Darbopoietin and G-CSF

Age, Categorical

Age, Continuous

Sex: Female, Male

United States

Region of Enrollment

Ralph D'Agostino Jr., Ph.D.

There were a total of 3 patients accrued on this trial. All were eligible and evaluable for response and evaluable for toxicity, as per protocol.

Number of Participants With Complete Response

azacitidine 100 miligrams/meter squares subcutaneous for 5 days every 28 day cycle,o If the patient had a major hematological improvement; or the patient had grade 3 or 4 hematological toxicities during the first two cycles, and/or there is \>=50% reduction in bone marrow cellularity compared to the baseline bone marrow, filgastrim will be administered at dose of 300 µg (if weight is less then 100 kilogram) or 450 µg (if weight is ≥100 kilogram) subcutaneous three times a week on week 2, 3, 4 along with darbopoietin 500 µg subcutaneous on day 8. Patients not meeting the above criteria will have a dose escalation of azacitidine to 125 miligrams/meter subcutaneous for 5 days, beginning on day 57 with growth factor support and filgastrim will be administered at dose of 300 µg (if weight is less then 100 kilogram) or 450 µg (if weight is ≥100 kilogra,) sq three times a week on week 2, 3, 4 along with darbopoietin 500 µg subcutaneous on day 8).

Because no patients completed therapy, no analysis was possible

Rate of Major Hematological Improvement

Minor Hematological Improvements

Time to Progression to Acute Myeloid Leukemia (Blast ≥ 20%) or Death

Because no patients completed therapy, and the protocol was closed early, analysis was not performed

Spots Global Cancer Trial Database for azacitadine and hematopoietic growth factors