A Phase II Study of Intravenous Azacitidine Alone in Patients With Myelodysplastic Syndromes

Study Overview
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Brief Summary
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The primary endpoint of this study is to estimate morphologic complete remission rate. Estimation of response rate is also a secondary objection.

Detailed Description
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Myelodysplastic syndrome (MDS) is a hematological disorder characterized by ineffective hematopoiesis. The only known curative treatment for patients with MDS is allogeneic stem cell transplantation. However, only a minority of patients are candidates for this aggressive therapy. DNA hypomethylation agents have been shown to have activity in this disorder and are postulated to work by reversing this epigenetic mechanism of gene-silencing. Recently, 5-azacitidine, administered subcutaneously for seven days, received approval by the FDA for the therapy of MDS based on a randomized trial which demonstrated a diminished risk of leukemic transformation and improved survival when compared to best supportive care. The subcutaneous route of administration can present challenges to implementing this therapy. In the CALGB studies 8921 and 9221, approximately 23% of patients had significant injection site pain. Moreover, 35 % of patients had injection site bruising which can be extensive in thrombocytopenic patients. Due to limitations on drug concentration and administration volumes for subcutaneous dosing, patients often need to have two or three injections at separate sites each day to meet target dosing. In addition, the schedule of administration is inconvenient in an outpatient setting secondary to the need to schedule administrations over weekends. Therefore, there is great interest in pursuing an abbreviated intravenous route for administration of the drug.

Official Title
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A Phase II Study of Intravenous Azacitidine Alone in Patients With Myelodysplastic Syndromes

Conditions
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Myelodysplastic Syndromes

Intervention / Treatment
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* Drug: Azacitidine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Pathological MDS either de novo or secondary, fitting any of the FAB classifications, confirmed by institutional pathologist within 2 weeks prior to start of treatment. Patients with 5% bone marrow blasts must also meet one of the following criteria: Symptomatic anemia with either hemoglobin less than 10.0 g/dL or requiring RBC transfusion Thrombocytopenia with a history of two or more platelet counts < 50,000 / µL or a significant hemorrhage requiring platelet transfusions, or Neutropenia with two or more absolute neutrophil counts less than 1,000 /µL. ECOG performance status of 0-2. Must give written informed consent indicating their awareness of the investigational nature of this study and its potential hazards. Adequate renal and hepatic function (creatinine ≤ 150% of institutional upper limit of normal, total bilirubin ≤ 150% institutional upper limit of normal, AST ≤ 200% institutional upper limit of normal). Life expectancy of at least 12 weeks. Have not received any chemotherapy within 4 weeks of study enrollment and must have recovered from any treatment-related toxicities. Women of childbearing age must have a negative serum pregnancy test prior to initiating therapy. Sexually active women of childbearing potential must use effective birth control during the trial and for an appropriate period after the trial. Men must be willing to avoid fathering a new child while receiving therapy with azacitidine. ≥18 years, no upper age limit Individuals who are candidates for hematopoietic stem cell transplantation and who meet all other study criteria may participate in the study and receive intravenous azacitidine alone as a treatment prior to transplantation. Exclusion Criteria: Known CNS leukemia. Previously received Azacitidine (Vidaza®, Pharmion Corp., Boulder CO) or decitabine (Dacogen®, MGI Pharma Inc. Bloomington, MN). Known or suspected hypersensitivity to azacitidine or mannitol. Receiving any other investigational agents within 30 days of first dose of study drug. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, congestive heart failure of NYHA class 3 or 4, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situation that would limit compliance with study requirements. Known positive serology for HIV. Had radiotherapy within 14 days prior to study enrollment. Known presence of hepatic tumors. <18 years of age Exclude women who are pregnant or breast feeding.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Azacitidine<br>Azacitidine 75 mg/m2 IV on days 1-5 of each 28 day cycle. Patients that do not respond after two cycles will have the dose increased to 100 mg/m2. Patients who achieve a CR will receive 3 additional 28 day cycles and then begin treatment on days 1-5 of a 56 day cycle. Individuals who demonstrate a loss of response will resume 28 day cycles. | Drug: Azacitidine<br> <br> * Other names: Vidaza;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of Complete Remission (CR) and Partial Remission (PR) | Defined according to the modified International Working Group (IWG) (2006) response criteria for myelodysplasia: CR=bone marrow with <5% myeloblasts and 0% peripheral blasts, hemoglobin ≥11g/dL, platelets ≥ 100 x 10^9/L, and neutrophils ≥1.0 x 10^9/L. Residual dysplasia was allowed. PR= All of the CR criteria if abnormal before treatment except: bone marrow blasts decreased by ≥50% over pretreatment but still >5%. | After 4 cycles of therapy (up to 112 days after start of treatment) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rate of Hematologic Improvement | International Working Group (IWG) for Myelodysplasia (MDS). | 4 weeks following last azacitidine dose [median number of cycles 4.5 (1-20)] | 
| Rate of Transfusion Independence |  | 4 weeks following last azacitidine dose [median number of cycles 4.5 (1-20)] | 
| Rate of Cytogenetic Response |  | 2 years after first dose of study drug or until participant is lost to follow-up or dies | 
| Rate of Overall Survival | Overall survival is defined as the date of first dose of study drug to the date of death from any cause. | 2 years after first dose of study drug or until participant is lost to follow-up or dies | 
| Rate of Relapse After Hematopoietic Stem Cell Transplant in Individuals Treated With 5-azacitidine Prior to Transplant. |  | 2 years after first dose of study drug or until participant is lost to follow-up or dies | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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MDS either de novo or secondary, fitting any of the WHO classifications.