Rm. Goldberg et al., PHASE-I AND PHARMACOLOGICAL TRIAL OF FAZARABINE (ARA-AC) WITH GRANULOCYTE COLONY-STIMULATIAG FACTOR, Clinical cancer research, 3(12), 1997, pp. 2363-2370
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 minim
al 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 eithe
r the maximum tolerated dose of Ara-AC or to safely achieve target pla
sma levels of 2-5 mu g/ml when Ara-AC was administered as a 24-h infus
ion with granulocyte colony-stimulating factor (G-CSF) to patients wit
h advanced refractory malignancies; to characterize the pharmacokineti
c behavior of Ara-AC with G-CSF; and to define the relationship of Ara
-AC pharmacokinetics to toxicity, Twenty-four patients received 67 cou
rses of Ara-AC at doses of 54-112 mg/m(2)/h, Dose-limiting toxicity wa
s approached but not reached, Grade 3 or 4 neutropenia and nausea were
the principle side effects, Steady-state plasma concentrations exceed
ed the minimum target concentration of 2 mu g/ml in all patients who r
eceived greater than or equal to 78 mg/m(2)/h for 24 h, The maximum ta
rget concentration was approached during administration of 112 mg/m(2)
/h for 24 h, The mean steady-state clearance was 475 +/- 103 ml/min/m(
2) and did not change with dose, One partial response was seen. One pa
tient received 16 courses and another received 7 courses of therapy be
fore progression. Ara-AC can be safely administered in doses that resu
lt in plasma concentrations of 2-5 mu g/ml, if it is given with G-CSF,
Phase II trials of Ara-AC in selected malignancies are planned.