A Survival Study in Patients With High Risk Myelodysplastic Syndromes Comparing Azacitidine Versus Conventional Care

A Multicenter, Randomized, Open-label, Parallel-group, Phase 3 Trial of Subcutaneous Azacitidine Plus Best Supportive Care Versus Conventional Care Regimens Plus Best Supportive Care for the Treatment of Myelodysplastic Syndromes (MDS)

The purpose of this study is to determine whether patients with high-risk myelodysplastic syndromes (MDS) treated with azacitidine have improved survival compared to conventional care treatments. The study will also assess the effect of treatments on response, duration of response, and transformation to acute myeloid leukemia (AML). The study will continue for 12 months following last patient enrolled.

See study AZA PH GL 2003 CL 001 E for information about the extension to this study.

Comparison/Control Interventions offered the physician three options:

• Best supportive care (BSC) alone,
• Low-dose cytarabine subcutaneously for 14 days every 28 to 42 days, or
• Standard chemotherapy administered for induction as a continuous intravenous infusion of cytarabine over 7 days plus an anthracycline (daunorubicin, idarubicin, or mitoxantrone) on Days 1, 2, and 3; and, for those eligible, 1 or 2 consolidation cycles administered as continuous intravenous infusions of cytarabine for 3 to 7 days with the same anthracycline that was used at induction on Days 1 and 2 (each cycle between 28 to 70 days from the start of the previous cycle).

All three options included best supportive care. Neither the experimental group (azacitidine) nor any of the comparison/control options allowed use of erythropoietin.

Duration of Intervention: Patients will be treated until death, withdrawal, unacceptable toxicity or conclusion of the study.

Inclusion Criteria:

• Have a diagnosis of refractory anemia with excess blasts or refractory anemia with excess blasts in transformation according to the French-American-British classification system for myelodysplastic syndromes (MDS) and a relatively high risk of acute myeloid leukemia (AML) transformation, with an International Prognostic Scoring System score of INT-2 or High.
• Be 18 years of age or older
• Have a life expectancy of at least 3 months
• Be unlikely to proceed to bone marrow or stem cell transplantation therapy following remission
• Have serum bilirubin levels less than or equal to 1.5 times the upper limit of normal range for the laboratory
• Have serum glutamic-oxaloacetic transaminase (aspartate aminotransferase) or serum glutamic-pyruvic transaminase (alanine aminotransferase) levels less than or equal to 2 times the upper limit of normal (unless these are considered to be related to transfusion-induced secondary hemosiderosis)
• Have serum creatinine levels less than or equal to 1.5 times the upper limit of normal

Exclusion Criteria:

• Secondary myelodysplastic syndromes (MDS)
• Prior treatment with azacitidine;
• Prior history of acute myeloid leukemia (AML);
• Malignant disease diagnosed within prior 12 months;
• Metastatic disease;
• Hepatic tumors;
• Radiation, chemotherapy, cytotoxic therapy for non-MDS conditions within prior 12 months;
• Prior transplantation or cytotoxic therapy to treat MDS;
• Serious medical illness likely to limit survival to 12 months or less;
• Treatment with erythropoietin or myeloid growth factors during prior 21 days or androgenic hormones during prior 13 days;
• Active HIV, viral hepatitis type B or C;
• Treatment with investigational drugs during prior 30 days;
• Within the 28-day screening period, documented red cell folate deficiency, as evidenced by red blood cell folate (not serum folate) or vitamin B12 deficiency