A phase I trial of weekly lomustine in patients with advanced cancer

Lomustine is a commercially available chloroethyl nitrosourea compound whose antitumor activity in vitro and in animal tumor models exceeds its activity in humans. Part of the poor clinical performance of this drug may be explained by dose-limiting subjective toxicity observed with the standard schedule of one oral dose of approximately 130 mg/m2 every 6-8 weeks.

Twenty patients were enrolled in a Phase I clinical trial of weekly oral lomustine. The first dose level was 24 mg/m2, with subsequent dose increases in increments of 6 mg/m2. Intrapatient dose escalations were allowed if there were no toxic reactions noted after 12 weekly doses.

The dose-limiting toxic effect was the development of thrombocytopenia in 35% of patients (6 of 17) treated at 30 mg/m2 after a median of 12 weekly doses (range, 5-20 weeks), whereas in 18% of patients (3 of 17), neutropenia developed after a median of 12 weeks (range, 9-22 weeks). Grade 3 or Grade 4 hematologic toxicity developed in three of three patients whose doses were escalated to 36 mg/m2/week after showing no evidence of toxicity for 12-16 weeks at 30 mg/m2/week. Partial remission was observed in two patients with malignant melanoma, and stable disease was observed in two patients with hypernephroma. Nausea, vomiting, and malaise were not significant complications of treatment.

Lomustine can be administered at a dose of 30 mg/m2/week for 12+ weeks to patients with cancer who have received previous treatment with minimal toxicity while retaining antitumor activity.