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

• Sponsor: Wake Forest University Health Sciences (Other)
• Overall Status: Terminated
• CT.gov ID: NCT00398047
• Collaborator: National Cancer Institute (NCI) (NIH)
• Enrollment: 3
• Location: 1
• Arm: 1
• Duration (Months): 36
• Patients Per Site Per Month: 0.1

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Leukemia; Myelodysplastic Syndromes	Drug: Azacitadine and Hematopoietic Growth Factors	Phase 2

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 Design

• Study Type: Interventional
• Actual Enrollment: 3 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Combination of Azacitadine and Hematopoietic Growth Factors for Myelodysplastic Syndrome
• Study Start Date: Sep 1, 2006
• Actual Primary Completion Date: Sep 1, 2009
• Actual Study Completion Date: Sep 1, 2009

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures

1. Number of Participants With Complete Response [Approximately 112 days]

   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.

2. Rate of Major Hematological Improvement [Approximately 112 days]

   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.

Secondary Outcome Measures

1. Minor Hematological Improvements [Approximately 112 days]

   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

2. Time to Progression to Acute Myeloid Leukemia (Blast ≥ 20%) or Death [Approximately 12 months]

   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.

3. Overall Survival [Approximately 12 months]

4. Change in Bone Marrow Apoptosis [Baseline and approximately 12 months]

5. Expression of p53 and p21 [Approximately 12 months]

Eligibility Criteria

Criteria

• Ages Eligible for Study: N/A to 120 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Wake Forest University Comprehensive Cancer Center	Winston-Salem	North Carolina	United States	27157-1096

Sponsors and Collaborators

• Wake Forest University Health Sciences
• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Bayard L. Powell, MD, Wake Forest University Health Sciences

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Wake Forest University Health Sciences
• ClinicalTrials.gov Identifier: NCT00398047
• Other Study ID Numbers: CDR0000515108; P30CA012197; CCCWFU-29106
• First Posted: Nov 10, 2006
• Last Update Posted: Sep 6, 2018
• Last Verified: Aug 1, 2018

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Wake Forest University Health Sciences: 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
• Additional relevant MeSH terms: Preleukemia; Myelodysplastic Syndromes; Syndrome; Mitogens

Study Results

Participant Flow

Recruitment Details	Three patients were enrolled between 09/14/06 and 01/07/2008. The study was closed for slow accrual on 09/02/2009.

Arm/Group Title	Combination of Azacitadine and Hematopoietic Growth Factors
Arm/Group Description	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).
Period Title: Overall Study
STARTED	3
COMPLETED	0
NOT COMPLETED	3

Baseline Characteristics

Arm/Group Title	Azacitidine and Darbopoietin and G-CSF
Arm/Group Description
Overall Participants	3
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	0 0%
>=65 years	3 100%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	69.407 (3.691)
Sex: Female, Male (Count of Participants)
Female	1 33.3%
Male	2 66.7%
Region of Enrollment (participants) [Number]
United States	3 100%

Outcome Measures

1. Primary Outcome

Title	Number of Participants With Complete Response
Description	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.
Time Frame	Approximately 112 days

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Azacitidine and Darbopoietin and G-CSF
Arm/Group Description
Measure Participants	3
Number [Participants]	0 0%

2. Primary Outcome

Title	Rate of Major Hematological Improvement
Description	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.
Time Frame	Approximately 112 days

Outcome Measure Data

Analysis Population Description

Because no patients completed therapy, no analysis was possible

Arm/Group Title	Azacitidine and Darbopoietin and G-CSF
Arm/Group Description	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).
Measure Participants	0

3. Secondary Outcome

Title	Minor Hematological Improvements
Description	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
Time Frame	Approximately 112 days

Outcome Measure Data

Analysis Population Description

Because no patients completed therapy, no analysis was possible

Arm/Group Title	Azacitidine and Darbopoietin and G-CSF
Arm/Group Description
Measure Participants	0

4. Secondary Outcome

Title	Time to Progression to Acute Myeloid Leukemia (Blast ≥ 20%) or Death
Description	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.
Time Frame	Approximately 12 months

Outcome Measure Data

Analysis Population Description

Because no patients completed therapy, no analysis was possible

Arm/Group Title	Azacitidine and Darbopoietin and G-CSF
Arm/Group Description
Measure Participants	0

5. Secondary Outcome

Title	Overall Survival
Time Frame	Approximately 12 months

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Azacitidine and Darbopoietin and G-CSF
Arm/Group Description
Measure Participants	0

6. Secondary Outcome

Title	Change in Bone Marrow Apoptosis
Time Frame	Baseline and approximately 12 months

Outcome Measure Data

Analysis Population Description

Because no patients completed therapy, no analysis was done

Arm/Group Title	Azacitidine and Darbopoietin and G-CSF
Arm/Group Description
Measure Participants	0

7. Secondary Outcome

Title	Expression of p53 and p21
Time Frame	Approximately 12 months

Outcome Measure Data

Analysis Population Description

Because no patients completed therapy, no analysis was possible

Arm/Group Title	Azacitidine and Darbopoietin and G-CSF
Arm/Group Description
Measure Participants	0

Adverse Events

Time Frame	Adverse event data collected for the 3 patients on study for a total of 14 months.
Arm/Group Title	Azacitidine and Darbopoietin and G-CSF
Arm/Group Description
All Cause Mortality
	Azacitidine and Darbopoietin and G-CSF
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Azacitidine and Darbopoietin and G-CSF
	Affected / at Risk (%)	# Events
Total	1/3 (33.3%)
Blood and lymphatic system disorders
Neutropenia	1/3 (33.3%)	1
Gastrointestinal disorders
GI Bleed	1/3 (33.3%)	1
Infections and infestations
Cellulitis	1/3 (33.3%)	1
Other (Not Including Serious) Adverse Events
	Azacitidine and Darbopoietin and G-CSF
	Affected / at Risk (%)	# Events
Total	3/3 (100%)
Blood and lymphatic system disorders
Platelets	3/3 (100%)	3
Hemoglobin (gender based)	3/3 (100%)	3
Neutrophils/granulocytes (ANC/AGC)	2/3 (66.7%)	2
Leukocytes (total WVC)	1/3 (33.3%)	1
Gastrointestinal disorders
Hemmorrhage, GI: Rectum	1/3 (33.3%)	1
Diarrhea	1/3 (33.3%)	1
Infections and infestations
Infection (Doc.) with Grade 3/4 ANC: Skin (cellulitis)	1/3 (33.3%)	1
Respiratory, thoracic and mediastinal disorders
Pleural effusion (non-malignant)	1/3 (33.3%)	1
Hypoxia	1/3 (33.3%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.