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

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.

Study Overview

• Status: Terminated
• Conditions: Myelodysplastic Syndromes; Leukemia
• Intervention / Treatment: Drug: Azacitadine and Hematopoietic Growth Factors

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.

• Study Type: Interventional
• Enrollment (Actual): 3
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • North Carolina
    • Winston-Salem, North Carolina, United States, 27157-1096
      • Wake Forest University Comprehensive Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 120 years (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Azacitadine and Hematopoietic Growth Factors; Combination of Azacitadine andHematopoietic Growth Factors	Drug: Azacitadine and Hematopoietic Growth Factors; Combination of Azacitadine and Hematopoietic Growth Factors

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants With Complete Response	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.	Approximately 112 days
Rate of Major Hematological Improvement	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.	Approximately 112 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Minor Hematological Improvements	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	Approximately 112 days
Time to Progression to Acute Myeloid Leukemia (Blast ≥ 20%) or Death	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.	Approximately 12 months
Overall Survival		Approximately 12 months
Change in Bone Marrow Apoptosis		Baseline and approximately 12 months
Expression of p53 and p21		Approximately 12 months

Collaborators and Investigators

• Sponsor: Wake Forest University Health Sciences
• Collaborators: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Bayard L. Powell, MD, Wake Forest University Health Sciences

Study record dates

Study Major Dates

• Study Start: September 1, 2006
• Primary Completion (Actual): September 1, 2009
• Study Completion (Actual): September 1, 2009

Study Registration Dates

• First Submitted: November 9, 2006
• First Submitted That Met QC Criteria: November 9, 2006
• First Posted (Estimate): November 10, 2006

Study Record Updates

• Last Update Posted (Actual): September 6, 2018
• Last Update Submitted That Met QC Criteria: August 7, 2018
• Last Verified: August 1, 2018

More Information

Terms related to this study

• Keywords: refractory anemia; refractory anemia with ringed sideroblasts; refractory anemia with excess blasts; chronic myelomonocytic leukemia; de novo myelodysplastic syndromes; secondary myelodysplastic syndromes; childhood myelodysplastic syndromes; refractory cytopenia with multilineage dysplasia
• Additional Relevant MeSH Terms: Pathologic Processes; Neoplasms; Disease; Bone Marrow Diseases; Hematologic Diseases; Precancerous Conditions; Syndrome; Myelodysplastic Syndromes; Preleukemia; Molecular Mechanisms of Pharmacological Action; Mitosis Modulators; Mitogens
• Other Study ID Numbers: CDR0000515108; P30CA012197 (U.S. NIH Grant/Contract); CCCWFU-29106 (Other Identifier: Comprehensive Cancer Center of WFUHS)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No