title: Phase I and pharmacological trial of fazarabine (Ara-AC) with granulocyte colony-stimulating factor.
abstract: Fazarabine (1-beta-D-arabinofuranosyl-5-aza-cytosine, or Ara-AC) is a nucleoside analogue that consists of the arabinoside ring of 1-beta-D-arabinofuranosylcytosine and the pyrimidine base of 5-azacytidine. In Phase I and Phase II trials, neutropenia was dose limiting, with minimal nonhematological toxicity. The in vitro cytotoxic concentrations of Ara-AC could not be achieved in these studies; neutropenia precluded dose escalation. The objectives of this study were: to determine either the maximum tolerated dose of Ara-AC or to safely achieve target plasma levels of 2-5 microgram/ml when Ara-AC was administered as a 24-h infusion with granulocyte colony-stimulating factor (G-CSF) to patients with advanced refractory malignancies; to characterize the pharmacokinetic behavior of Ara-AC with G-CSF; and to define the relationship of Ara-AC pharmacokinetics to toxicity. Twenty-four patients received 67 courses of Ara-AC at doses of 54-112 mg/m2/h. Dose-limiting toxicity was approached but not reached. Grade 3 or 4 neutropenia and nausea were the principle side effects. Steady-state plasma concentrations exceeded the minimum target concentration of 2 microgram/ml in all patients who received >/=78 mg/m2/h for 24 h. The maximum target concentration was approached during administration of 112 mg/m2/h for 24 h. The mean steady-state clearance was 475 +/- 103 ml/min/m2 and did not change with dose. One partial response was seen. One patient received 16 courses and another received 7 courses of therapy before progression. Ara-AC can be safely administered in doses that result in plasma concentrations of 2-5 microgram/ml, if it is given with G-CSF. Phase II trials of Ara-AC in selected malignancies are planned.
authors.affiliation: Divisions of Medical Oncology, Developmental Oncology Research, and Cancer Statistics, Mayo Clinic, Rochester, Minnesota 55905, USA.
authors.forename: R M
authors.initials: RM
authors.lastname: Goldberg
authors.forename: J M
authors.initials: JM
authors.lastname: Reid
authors.forename: M M
authors.initials: MM
authors.lastname: Ames
authors.forename: J A
authors.initials: JA
authors.lastname: Sloan
authors.forename: J
authors.initials: J
authors.lastname: Rubin
authors.forename: C
authors.initials: C
authors.lastname: Erlichman
authors.forename: M J
authors.initials: MJ
authors.lastname: Kuffel
authors.forename: T R
authors.initials: TR
authors.lastname: Fitch
mesh_terms: D000328:Adult; D000970:Antineoplastic Agents / Q000009:adverse effects* / Q000493:pharmacokinetics; D001374:Azacitidine / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D005260:Female; D016179:Granulocyte Colony-Stimulating Factor / Q000009:adverse effects* / Q000493:pharmacokinetics; D006801:Humans; D008297:Male; D008657:Metabolic Clearance Rate; D009325:Nausea / Q000139:chemically induced; D009369:Neoplasms / Q000188:drug therapy / Q000628:therapy*; D009503:Neutropenia / Q000139:chemically induced
chemical_list: D000970:Antineoplastic Agents; D016179:Granulocyte Colony-Stimulating Factor; C022121:fazarabine; D001374:Azacitidine