Phasee I Biological Study of IV and SQ Azacitidine (Vidaza®) to Determine the Optimal Biological Dose in Hematologic Malignancies

Abstract

Azacitidine (5-azacytidine, Vidaza) is a DNA methylation inhibitor that has been shown to have a survival benefit in patients with high-risk myelodysplastic syndrome and is under investigation in other cancers. The purpose of this study was to determine the optimal dose and route of administration for azacitidine to inhibit DNA methylation in patients with hematologic malignancies. Eligibility included patients with hematologic malignancy who provided informed consent. Enrollment criteria varied depending on the type of cancer. Patients were enrolled into 5 escalating dose levels for the first course of therapy (25mg, 50mg, 75mg, 100mg or 150mg IV per m2 per day for 5 days). On day 28 all patients received 75mg/m2/day IV for 5 days. For course 3 patients received 75mg/m2/day SQ × 5 days. Beyond course 3 patients received 75mg/m2/day either SQ or IV × 5 days every 4 weeks. Peripheral blood was collected on days 1, 3 and 5 for each course and LINE1 DNA methylation was measured using bisulfite-PCR Pyrosequencing to measure global DNA methylation changes induced by azacitidine. To date, 17 patients have been treated (3 at 25mg, 4 at 50mg, 4 at 75mg, 3 at 100mg, and 3 at 150mg/m2). Diagnosis included 6 patients with MDS, 9 patients with AML (3 untreated older patients, 6 relapsed or refractory patients), 1 patient with CML (imatinib refactory), and 1 patient with non-Hodgkin's lymphoma (relapsed disease). At the time of submission (August 2008) 12 patients were evaluable for response with 1 CR, 3 PR, 7 SD and 1 PD reported. The median number of cycles given was 2 (range 0–12+). LINE1 DNA methylation decreased by 1.4, 2.3, 4.8, 1.9 and 4.0% on day 5 for the 25mg, 50mg, 75mg, 100mg, and 150mg/m2 dose levels respectively. Mean decrease in LINE1 DNA methylation with 75mg/m2 IV was 3.7% and only 2.6% by 75mg/m2 of azacitidine SQ. There was a large amount of inter-patient variability but less intra-patient variability in DNA methylation response to azacitidine. DNA methylation and data analysis is ongoing. Azacitidine is effective at inhibiting DNA methylation at multiple dose levels for both IV and SQ routes of administration. There is a high degree of patient-to-patient variability in DNA methylation changes, but 75mg/m2 lead to the greatest mean decrease in DNA methylation by a 5 day IV regimen. Updated analysis for this study will be presented.