Pharmacokinetic study of cystemustine, administered on a weekly schedule in cancer patients

Background: Cystemustine is a chloroethylnitrosourea mostly active in human,., against glioma and melanoma. The present report describes the results of a new phase I trial with cystemustine administered on a weekly schedule, The pharmacokinetic and pharmacodynamic properties of cystemustine were investigated, Patients and methods: Forty-three patients entered this study. Cystemustine was administered at dose levels ranging from 30 to 60 mg/m(2). The drug was given on days 1, 8, 15 and 22, followed by a 4-week rest period, Results: Thrombocytopenia was the dose-limiting toxicity and appeared to be reversible. but probably cumulative. This toxicity appeared dose-related, both in frequency and severity. The maximum tolerated dose was 60 mg/m(2). Nonhematological toxicity was generally mild. Three partial responses were observed at dose levels of 50 and 60 mg/m(2). Pharmacokinetics analysis showed mono- or biphasic cystemustine blood disposition with a mean a half-life of 4 min and mean terminal half-life of 49 min. Conclusions: There was a clear linear relationship between the area under tire blood drug concentration-time curve (AUC) and the dose of cystemustine (P <0.001). There was also a significant relationship between the AUC and the toxic effects of cystemustine on platelets, granulocytes and leukocytes (P <0.001). A reasonable starting dose for phase II studies is 40 mg/m(2), with dose escalation based on blood cell counts.