Phase I trial of PCNU administered by 5-day courses

PCNU was selected for clinical trials based on high activity in both standard and intracisternally transplanted murine tumors. PCNU was administered of five daily to 24 patients with refractory advanced solid tumors by courses of five daily iv injections every 6 weeks. The total dose ranged from 25 to 125 mg/m2/course. The major dose-limiting toxicity was reversible thrombocytopenia, with the nadi at 28-49 days and recovery by 2 weeks later. At a dose of 125 mg/m2/course, the mean nadir platelet count was 77 X 10(3)/mm3 (range, 16-201 X 10(3)/mm3). Recovery time was prolonged with successive courses in four patients, suggesting cumulative toxicity. The mean nadir of leukopenia at this dose was 2.6 X 10(3) cells/mm3 (range, 1.2-5.0 X 10(3) cells/mm3) and tended to occur with a later median at Day 44. Nausea and vomiting were unusually mild for a nitrosourea. Sporadic transaminasemia and elevated LDH may have been related to the vehicle, N,N'-dimethylacetamide. Other major organ toxic effects were not encountered, and there were no objective responses. PCNU was found to be a base-substitution mutagen in the Salmonella typhimurium assay. A starting dose of 125 mg/m2, divided into five daily doses, is suggested for phase II trails in patients with no significant hematologic compromise from prior chemotherapy or radiation, and a dose of 75 mg/m2 is recommended for all others.