Phase I trial and pharmacokinetic evaluation of fazarabine in children.
A phase I trial of fazarabine (1-beta-D-arabinofuranosyl-5-azacytosine, NSC 281272) administered as a 24-h continuous infusion was performed in 16 children with refractory malignancies. Dose-limiting toxicity consisting of reversible granulocytopenia and thrombocytopenia was observed in 4 of 4 solid tumor patients treated at the starting dose of 20 mg/m2/h. Subsequent patients were treated at a dose of 15 mg/m2/h which was determined to be the maximum tolerated dose. Moderate nausea and vomiting were the only other toxicities observed. Plasma steady-state concentrations of fazarabine were attained by 2-4 h in all patients and were 1.8 and 2.5 microM at the 15- and 20-mg/m2/h doses, respectively. The total body clearance of fazarabine was 571 and 550 ml/min/m2 at the 15- and 20-mg/m2/h doses, respectively. In three of four patients evaluated, fazarabine was detectable in the cerebrospinal fluid (CSF). Steady-state CSF concentrations ranged from 0.29 to 0.74 microM in these three individuals and the steady-state CSF:plasma ratios ranged from 0.22-0.25. Both the plasma and CSF steady-state concentrations were within the 0.1 to 1 microM range reported to be cytotoxic in vitro against the Molt-4 human T-lymphoblastic leukemia cell line. Based on the above, the optimal dose for phase II trials of fazarabine administered as a 24-h infusion is 15 mg/m2/h (360 mg/m2/day).
Heideman
R L
RL
Pediatric Branch, National Cancer Institute, Bethesda, Maryland 20892.
Gillespie
A
A
Ford
H
H
Reaman
G H
GH
Balis
F M
FM
Tan
C
C
Sato
J
J
Ettinger
L J
LJ
Packer
R J
RJ
Poplack
D G
DG
D000964:Antimetabolites, Antineoplastic / Q000009:adverse effects*; D001374:Azacitidine / Q000009:adverse effects* / Q000493:pharmacokinetics / Q000627:therapeutic use / Q000031:analogs & derivatives; D002648:Child; D004341:Drug Evaluation; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008657:Metabolic Clearance Rate; D009369:Neoplasms / Q000188:drug therapy
D000964:Antimetabolites, Antineoplastic; C022121:fazarabine; D001374:Azacitidine