title: Phase I study of oral azacitidine in myelodysplastic syndromes, chronic myelomonocytic leukemia, and acute myeloid leukemia.
abstract: OBJECTIVE
  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).
  
  
  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.
  
  
  CONCLUSIONS
  Oral azacitidine was bioavailable and demonstrated biologic and clinical activity in patients with MDSs and CMML.
authors.affiliation: University of Texas, MD Anderson Cancer Center, Box 428, 1515 Holcombe Blvd, Houston, TX 77025, USA. ggarciam@mdanderson.org
authors.forename: Guillermo
authors.initials: G
authors.lastname: Garcia-Manero
authors.forename: Steven D
authors.initials: SD
authors.lastname: Gore
authors.forename: Christopher
authors.initials: C
authors.lastname: Cogle
authors.forename: Renee
authors.initials: R
authors.lastname: Ward
authors.forename: Tao
authors.initials: T
authors.lastname: Shi
authors.forename: Kyle J
authors.initials: KJ
authors.lastname: Macbeth
authors.forename: Eric
authors.initials: E
authors.lastname: Laille
authors.forename: Heidi
authors.initials: H
authors.lastname: Giordano
authors.forename: Sarah
authors.initials: S
authors.lastname: Sakoian
authors.forename: Elias
authors.initials: E
authors.lastname: Jabbour
authors.forename: Hagop
authors.initials: H
authors.lastname: Kantarjian
authors.forename: Barry
authors.initials: B
authors.lastname: Skikne
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000963:Antimetabolites / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D000964:Antimetabolites, Antineoplastic / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D001374:Azacitidine / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001682:Biological Availability; D019175:DNA Methylation / Q000187:drug effects; D005221:Fatigue / Q000139:chemically induced; D005260:Female; D005767:Gastrointestinal Diseases / Q000139:chemically induced; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy*; D015477:Leukemia, Myelomonocytic, Chronic / Q000188:drug therapy*; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009190:Myelodysplastic Syndromes / Q000188:drug therapy*; D009503:Neutropenia / Q000139:chemically induced
chemical_list: D000963:Antimetabolites; D000964:Antimetabolites, Antineoplastic; D001374:Azacitidine