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

BACKGROUND: Cystemustine is a chloroethylnitrosourea mostly active in humans 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/m2. 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/m2. Nonhematological toxicity was generally mild. Three partial responses were observed at dose levels of 50 and 60 mg/m2. 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 the 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/m2, with dose escalation based on blood cell counts.

[Phase II trial with cystemustine (60 mg/m2) in advanced or metastatic pretreated lung carcinoma]. / Essai de phase II cystémustine (60 mg/m2) dans les cancers bronchiques avancés ou métastatiques prétraités.

From January 1990 to November 1994, 23 patients with advanced pretreated lung carcinoma were enrolled into a phase II trial to test a new nitrosourea, cystemustine, given every 2 weeks at the dose of 60 mg/m(2) in a 15-minute IV infusion. All eligible patients were considered evaluable for response and toxicity (WHO criteria).

Results of a phase II trial with cystemustine at 90 mg/m(2) as a first- or second-line treatment in advanced malignant melanoma: a trial of the EORTC Clinical Studies Group.

From May 1991 to January 1996, 54 patients with advanced malignant melanoma were enrolled into a phase II trial testing the new nitrosourea cystemustine, administrated intravenously as a 15 min infusion every 2 weeks at 90 mg/m2 for three cycles followed by 60 mg/m2. Out of the 54 enrolled patients, 10 were Ineligible, leaving 44 fully evaluable patients (World Health Organization criteria). Twenty one patients had already received first-line palliative chemotherapy and/or immunotherapy. The median age was 62 years (range 30-74 years) and the median performance status was 0 (grade 0, 19 patients; grade 1, 21 patients; grade 2, 4 patients). Five patients with partial responses (lasting 16-29 weeks, mean duration 24 weeks), nine with stable disease and 28 showing progression were observed, giving an overall response rate of 11% (confidence interval 3.8-24.6%). Toxicity was mild and consisted mainly of neutropenia (39% grade III-IV), thrombocytopenia (42% grade III-IV); febrile aplasia was rare. Cystemustine administered to this schedule appears to have limited clinical activity and acceptable toxicity in untreated or second-line advanced malignant melanoma.