Clinical trial NCT00398047: Azacitidine, Darbepoetin Alfa, and Erythropoietin and Filgastrim (G-CSF) in Treating Patients With Myelodysplastic Syndromes
Official title: Combination of Azacitadine and Hematopoietic Growth Factors for Myelodysplastic Syndrome
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Leukemia
Myelodysplastic Syndromes
Keywords: de novo myelodysplastic syndromes
refractory anemia with ringed sideroblasts
refractory anemia with excess blasts
refractory anemia
refractory cytopenia with multilineage dysplasia
chronic myelomonocytic leukemia
secondary myelodysplastic syndromes
childhood myelodysplastic syndromes
Lead sponsor: Wake Forest University Health Sciences
Sponsor class: OTHER
Collaborators: name: National Cancer Institute (NCI)
First posted: 2006-11-10
Enrollment: 3
Sex: ALL
Maximum age (years): 120
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: 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.

Detailed description: 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.

Eligibility criteria: DISEASE CHARACTERISTICS:

* Diagnosis of myelodysplastic syndromes (MDS)

  * Bone marrow aspirate and biopsy with karyotyping performed within the past 8 weeks
* Patients with chronic myelomonocytic leukemia (CMML), refractory anemia (RA), or refractory anemia with ringed sideroblasts (RARS) according to FAB classification OR RA, RARS, refractory anemia with multilineage dysplasia, or RARS with multilineage dysplasia according to WHO classification must meet ≥ 1 of the following criteria:

  * Symptomatic anemia requiring RBC transfusion for ≥ 3 months before study entry
  * Thrombocytopenia with ≥ 2 platelet counts \< 50,000/mm³ OR a significant hemorrhage requiring platelet transfusion
  * Neutropenia with an absolute neutrophil count \< 1,000/mm³ and an infection requiring IV antibiotics
* No refractory anemia with excess blasts in transformation
* No history of leukemia
* No known primary or metastatic hepatic tumor

PATIENT CHARACTERISTICS:

* ECOG performance status 0-2
* Life expectancy \> 2 months
* AST and ALT ≤ 2 times upper limit of normal
* Creatinine \< 2.0 mg/dL
* Serum vitamin B12 normal
* Serum and/or red cell folate levels normal
* Ferritin ≥ 50 ng/mL
* Copper \> 40 µg/dL
* Not pregnant or nursing
* Fertile patients must use effective contraception
* Negative pregnancy test

PRIOR CONCURRENT THERAPY:

* No prior azacitidine or decitabine
* No prior therapy for MDS

  * Supportive therapy within the past 28 days allowed
* No other concurrent treatment for MDS (i.e., thalidomide, arsenic trioxide, cyclosporine, or melphalan)
* No other concurrent hematopoietic growth factors, including epoetin alfa, filgrastim (G-CSF), sargramostim (GM-CSF), or interleukin-11 (oprelvekin)

Primary outcomes:
measure: Number of Participants With Complete Response
timeFrame: Approximately 112 days
measure: Rate of Major Hematological Improvement
timeFrame: Approximately 112 days
Secondary outcomes:
measure: Minor Hematological Improvements
timeFrame: Approximately 112 days
measure: Time to Progression to Acute Myeloid Leukemia (Blast ≥ 20%) or Death
timeFrame: Approximately 12 months
measure: Overall Survival
timeFrame: Approximately 12 months
measure: Change in Bone Marrow Apoptosis
timeFrame: Baseline and approximately 12 months
measure: Expression of p53 and p21
timeFrame: Approximately 12 months
Other outcomes:
Locations:
city: Winston-Salem
country: United States
facility: Wake Forest University Comprehensive Cancer Center
state: North Carolina
Study officials:
affiliation: Wake Forest University Health Sciences
name: Bayard L. Powell, MD
role: PRINCIPAL_INVESTIGATOR
References: