title: Efficacy and safety of extended dosing schedules of CC-486 (oral azacitidine) in patients with lower-risk myelodysplastic syndromes.
abstract: CC-486, the oral formulation of azacitidine (AZA), is an epigenetic modifier and DNA methyltransferase inhibitor in clinical development for treatment of hematologic malignancies. CC-486 administered for 7 days per 28-day treatment cycle was evaluated in a phase 1 dose-finding study. AZA has a short plasma half-life and DNA incorporation is S-phase-restricted; extending CC-486 exposure may increase the number of AZA-affected diseased target cells and maximize therapeutic effects. Patients with lower-risk myelodysplastic syndromes (MDS) received 300 mg CC-486 once daily for 14 days (n=28) or 21 days (n=27) of repeated 28-day cycles. Median patient age was 72 years (range 31-87) and 75% of patients had International Prognostic Scoring System Intermediate-1 risk MDS. Median number of CC-486 treatment cycles was 7 (range 2-24) for the 14-day dosing schedule and 6 (1-24) for the 21-day schedule. Overall response (complete or partial remission, red blood cell (RBC) or platelet transfusion independence (TI), or hematologic improvement) (International Working Group 2006) was attained by 36% of patients receiving 14-day dosing and 41% receiving 21-day dosing. RBC TI rates were similar with both dosing schedules (31% and 38%, respectively). CC-486 was generally well-tolerated. Extended dosing schedules of oral CC-486 may provide effective long-term treatment for patients with lower-risk MDS.
authors.affiliation: Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: G
authors.initials: G
authors.lastname: Garcia-Manero
authors.affiliation: Yale Cancer Center, New Haven, CT, USA.
authors.forename: S D
authors.initials: SD
authors.lastname: Gore
authors.affiliation: Division of Hematology/Oncology, Department of Internal Medicine, University of Kansas Medical Center, Kansas City, KS, USA.
authors.forename: S
authors.initials: S
authors.lastname: Kambhampati
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
authors.forename: B
authors.initials: B
authors.lastname: Scott
authors.affiliation: Division of Hematology, Department of Internal Medicine, Mayo Clinic, Rochester, MN, USA.
authors.forename: A
authors.initials: A
authors.lastname: Tefferi
authors.affiliation: Medicine/Hematology & Oncology, University of Florida, Gainesville, FL, USA.
authors.forename: C R
authors.initials: CR
authors.lastname: Cogle
authors.affiliation: Cancer Centers of The Carolinas, Greenville, SC, USA.
authors.forename: W J
authors.initials: WJ
authors.lastname: Edenfield
authors.affiliation: Celgene Corporation, Summit, NJ, USA.
authors.forename: J
authors.initials: J
authors.lastname: Hetzer
authors.affiliation: Celgene Corporation, Summit, NJ, USA.
authors.forename: K
authors.initials: K
authors.lastname: Kumar
authors.affiliation: Celgene Corporation, Summit, NJ, USA.
authors.forename: E
authors.initials: E
authors.lastname: Laille
authors.affiliation: Celgene Corporation, Summit, NJ, USA.
authors.forename: T
authors.initials: T
authors.lastname: Shi
authors.affiliation: Celgene Corporation, Summit, NJ, USA.
authors.forename: K J
authors.initials: KJ
authors.lastname: MacBeth
authors.affiliation: Celgene Corporation, Summit, NJ, USA.
authors.forename: B
authors.initials: B
authors.lastname: Skikne
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000964:Antimetabolites, Antineoplastic / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001374:Azacitidine / Q000493:pharmacokinetics / Q000627:therapeutic use*; D004334:Drug Administration Schedule; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D008875:Middle Aged; D009190:Myelodysplastic Syndromes / Q000188:drug therapy* / Q000473:pathology; D009367:Neoplasm Staging; D011379:Prognosis; D012307:Risk Factors; D012449:Safety; D014018:Tissue Distribution
chemical_list: D000964:Antimetabolites, Antineoplastic; D001374:Azacitidine