Escalating dose regimen of intraperitoneal mitoxantrone: phase I study--clinical and pharmacokinetic evaluation

Mitoxantrone, a recent anthracenedione derivative, is a potentially useful drug for direct intraperitoneal (i.p.) application because of its high tissue binding and therapeutic index. We have carried out studies to establish maximum tolerated doses as well as pharmacokinetic studies with i.p. mitoxantrone in 21 patients (5 male, 16 female) with gastrointestinal (9), ovarian (6), unknown (2) and other (4) primary cancers and peritoneal carcinomatosis. Increasing doses (10-40 mg/m2) were given i.p. every 4 weeks. Five partial remissions (2-8+ months) and 7 stable disease courses (2-6+ months) were achieved. A reduction or disappearance of ascites was seen in an additional 3 patients. Severe toxicity (leucopenia) was observed in 4 patients only after 35 and 40 mg/m2 i.p. Pharmacokinetic analysis using high performance liquid chromatography yielded the following data: The mean ratio of area under curve peritoneal fluid to plasma was 1109. The peritoneal clearance rate was 680 ml/min and the mean disappearance half life was 13.1 h. Mean urinary excretion within 24 h was 0.42% of the i.p. dose. These data indicate that mitoxantrone is sequestered in the intraperitoneal tissue compartment and only slowly released. Based on the outcome of this phase I study we recommend phase II studies at a dose of 30 mg/m2 i.p., repeated every 3-4 weeks.