A phase I trial of 14-day continuous intravenous infusion mitoxantrone

Abstract

Based on clinical evidence that prolonged exposure to anti-neoptastic 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 Ill or IV leukopenla (mean WBC nadir 1900/μl, range, 800–3600/μl). Other toxiclties 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 compllcations 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 μg h/l. No responses were observed, although no patients with mitoxantrone-sensitive tumors were treated. We recommend proceeding with phase II trials in clinically responsive tumors using a 14-day continuous intravenous infusion with a starting dose of 1.5 mg/m²/day.