Results from a multi-center Phase I study that explored multiple dosing schedules of oral azacitidine in 23 patients with acute myeloid leukemia (AML), myelodysplastic syndromes or chronic myelomonocytic leukemia (CMML) who were not candidates for other therapies or who had failed previous regimens showed a potential treatment benefit. Findings from this study were presented during the 53rd Annual Meeting of the American Society of Hematologyin San Diego, CA.

Myelodysplastic syndromes (MDS) are a group of hematologic malignancies that affect approximately 300,000 people worldwide. Myelodysplastic syndromes occur when blood cells remain in an immature or ?blast? stage within the bone marrow and never develop into mature cells capable of performing their necessary functions. Eventually, the bone marrow may be filled with blast cells suppressing normal cell development. According to the American Cancer Society, 10,000 to 20,000 new cases of MDS are diagnosed each year in the United States, with median survival rates ranging from approximately six months to six years for the different classifications of MDS. MDS patients often rely on blood transfusions to manage symptoms of anemia and fatigue and may develop life-threatening iron overload and/or toxicity from frequent transfusions, thus underscoring the critical need for new therapies targeting the cause of the condition rather than simply managing its symptoms.

Acute Myeloid Leukemia
Acute myeloid leukemia (AML) is a cancer of myeloid blood cells that often transforms from MDS upon disease progression. AML is the proliferation of abnormal cells that accumulate in the bone marrow and interfere with all types of normal blood cell production (also known as multi-lineage dysplasia). AML has traditionally been treated with high intensity chemotherapy, which is poorly tolerated by the majority of the patients who are afflicted – the elderly. Many of these patients may go untreated, and because they are ineligible for curative therapy, life expectancy is short and often measured in weeks to months.

In part one of the study, patients received an initial cycle of subcutaneous azacitidine (75 mg/m2 daily for the first 7 days of a 28-day cycle). Thereafter, they were assigned to different doses of oral azacitidine (120-600 mg daily) for the first seven days of repeated 28-day schedules. In part two, patients were assigned to one of four dosing schedules of oral azacitidine: 300 mg daily or 200 mg twice per day, each for either 14 or 21 days of each 28-day cycle. Patients remained on therapy until disease progression or study withdrawal.

Prior therapy
Of the 15 patients receiving any of the part two extended dosing schedules, four (27%, 4/15 patients) achieved hematologic improvement, including patients who had complex cytogenetics and/or had failed prior therapy for AML. One of the eight patients in part one of the study treated with 7-day once daily oral azacitidine achieved a complete response with incomplete blood count recovery (CRi).

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Adverse events
Grade 3/4 adverse events occurring in at least 10% of the 23 patients enrolled in the study included febrile neutropenia (35%, 8/23), pneumonia (17%, 4/23), syncope (17%, 4/23), and nausea (13%, 3/23). Three patients died due to causes unrelated to oral azacitidine.

Oral azacitidine is an investigational agent and has not been approved for any indication.

For more information:
Clinical trials
– Safety, Pharmacokinetics, and Pharmacodynamics of Oral Azacitidine in Subjects With Myelodysplastic Syndromes, Chronic Myelomonocytic Leukemia and Acute Myelogenous Leukemia (NCT00528983)
-Safety & Pharmacokinetics Study Of Azacitidine (SC And Oral) In Subjects With MDS, CMML, AML, Lymphoma And Multiple Myeloma (RACE)(NCT00761722)
– Best Promising Drug Association With Azacitidine in Higher Risk Myelodysplastic Syndromes (AZA-PLUS)(NCT01342692)

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