Phase I and pharmacological trial of fazarabine (Ara-AC) with granulocyte colony-stimulating factor

Richard M. Goldberg, Joel M. Reid, Matthew M. Ames, Jeff A. Sloan, Joseph Rubin, Charles Erlichman, Mary J. Kuffel, Thomas R. Fitch

Research output: Contribution to journalArticlepeer-review

8 Scopus citations


Fazarabine (1-β-D-arabinofuranosyl-5-aza-cytosine, or Ara-AC) is a nucleoside analogue that consists of the arabinoside ring of 1-β-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 μg/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 μg/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 μg/ml, if it is given with G-CSF. Phase II trials of Ara-AC in selected malignancies are planned.

Original languageEnglish (US)
Pages (from-to)2363-2370
Number of pages8
JournalClinical Cancer Research
Issue number12 I
StatePublished - Dec 1997

ASJC Scopus subject areas

  • Oncology
  • Cancer Research


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