A phase I trial of 14-day continuous intravenous infusion mitoxantrone.
Based on clinical evidence that prolonged exposure to anti-neoplastic agents may ameliorate dose-limiting toxicity while facilitating anti-tumor activity, we conducted a phase I trial of 14-day continuous intravenous infusion mitoxantrone. Study objectives were to: (1) determine the maximally tolerated dose for phase II trials; (2) determine the incidence and severity of side effects; and (3) study the pharmacokinetics of continuous infusion mitoxantrone. Sixteen patients with drug-resistant advanced cancers were entered into the trial. Three or more patients were treated at each dose level (1.0, 1.25, and 1.5 mg/m2/day) for a total of 33 courses (mean 2.1 courses/patient, range, 1-4). Courses were repeated every 4 weeks. The maximally tolerated dose (MTD) was found to be 1.5 mg/m2/day. At this dose four of six patients had grade III or IV leukopenia (mean WBC nadir 1900/microliters, range, 800-3600/microliters). Other toxicities were grade I or II stomatitis (two patients), grade I diarrhea (one patient), and grade I nausea (one patient). Renal and hepatic toxicity were not observed. No alopecia or infectious complications occurred. Pharmacokinetic studies were performed using high-performance liquid chromatography (HPLC). Steady-state plasma levels at the 1.5 mg/m2/day dose were reached by 48 h, with a mean steady-state plasma concentration of 3.2 +/- 0.7 ng/ml, mean total body clearance of 340 +/- 79 ml/min/m2, and mean area under the plasma disappearance curve (AUC) of 955 +/- 185 micrograms h/l. No responses were observed, although no patients with mitoxantrone-sensitive tumors were treated.(ABSTRACT TRUNCATED AT 250 WORDS)
Kreisle
W H
WH
Department of Medicine, College of Pharmacy, University of Arizona.
Alberts
D S
DS
List
A F
AF
McCloskey
T
T
Plezia
P
P
Peng
Y M
YM
George
M
M
D000328:Adult; D000368:Aged; D003967:Diarrhea / Q000139:chemically induced; D004341:Drug Evaluation; D005260:Female; D005767:Gastrointestinal Diseases / Q000139:chemically induced / Q000473:pathology; D006801:Humans; D007262:Infusions, Intravenous; D007970:Leukopenia / Q000139:chemically induced; D008297:Male; D008875:Middle Aged; D008942:Mitoxantrone / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D009061:Mouth Mucosa; D009135:Muscular Diseases / Q000139:chemically induced / Q000473:pathology; D009369:Neoplasms / Q000188:drug therapy*; D013280:Stomatitis / Q000139:chemically induced; D016277:Ventricular Function, Left
D008942:Mitoxantrone