Phase I study of oral azacitidine in myelodysplastic syndromes, chronic myelomonocytic leukemia, and acute myeloid leukemia

Abstract

Purpose: To determine the maximum-tolerated dose (MTD), safety, pharmacokinetic and pharmacodynamic profiles, and clinical activity of an oral formulation of azacitidine in patients with myelodysplastic syndromes (MDSs), chronic myelomonocytic leukemia (CMML), or acute myeloid leukemia (AML).

Patients and methods: Patients received 1 cycle of subcutaneous (SC) azacitidine (75 mg/m2) on the first 7 days of cycle 1, followed by oral azacitidine daily (120 to 600 mg) on the first 7 days of each additional 28-day cycle. Pharmacokinetic and pharmacodynamic profiles were evaluated during cycles 1 and 2. Adverse events and hematologic responses were recorded. Cross-over to SC azacitidine was permitted for nonresponders who received ≥ 6 cycles of oral azacitidine.

Results: Overall, 41 patients received SC and oral azacitidine (MDSs, n = 29; CMML, n = 4; AML, n = 8). Dose-limiting toxicity (grade 3/4 diarrhea) occurred at the 600-mg dose and MTD was 480 mg. Most common grade 3/4 adverse events were diarrhea (12.2%), nausea (7.3%), vomiting (7.3%), febrile neutropenia (19.5%), and fatigue (9.8%). Azacitidine exposure increased with escalating oral doses. Mean relative oral bioavailability ranged from 6.3% to 20%. Oral and SC azacitidine decreased DNA methylation in blood, with maximum effect at day 15 of each cycle. Hematologic responses occurred in patients with MDSs and CMML. Overall response rate (i.e., complete remission, hematologic improvement, or RBC or platelet transfusion independence) was 35% in previously treated patients and 73% in previously untreated patients.

Conclusion: Oral azacitidine was bioavailable and demonstrated biologic and clinical activity in patients with MDSs and CMML.

Conflict of interest statement

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

Figures

Fig 1.

(A) Mean azacitidine (AZA) plasma concentration versus time profiles following single subcutaneous (SC) or oral administration (linear scale). (B) Pharmacodynamics as measured by plotting the numbers of highly methylated loci (beta ≥ 0.7; ± 95% CI) for 10 patients with DNA methylation data in cycles 1 and 2 (gold lines represent individual patients, blue line represents the average). (C) Change in methylation level during treatment with SC or oral AZA for 5,232 loci highly methylated at baseline (blue box represents the 25th to 75th percentile, horizontal band represents the median, vertical line with bars represents minimum and maximum values). (D) Number of significantly differentially methylated loci on day 15 of cycle 1 (SC azacitidine) and on day 15 of cycle 2 (oral azacitidine). Upward arrows denote hypermethylated loci and downward arrows denote hypomethylated loci.

Fig 2.

Treatment duration for the 41 patients treated with oral azacitidine (AZA). AML, acute myeloid leukemia; CMML, chronic myelomonocytic leukemia; MDSs-U, myelodysplastic syndromes-unclassified; RA, refractory anemia; RCMD, refractory cytopenias with multilineage dysplasia; RAEB, RA with excess blasts; SC, subcutaneous.