Evaluation of alpha-difluoromethylornithine as a potential chemopreventive agent: tolerance to daily oral administration in humans.

An initial clinical trial of alpha-difluoromethylornithine given p.o. daily for 6 months was carried out in 27 subjects free of disease following surgery for malignancy or in a defined high-risk group for cancer. The aim was to determine the highest nontoxic dose, principal side effects, and pharmacokinetic parameters. The starting dose was 200 mg/m2/day in divided doses with escalation each month in the absence of toxicity to 6400 mg/m2/day or to the highest nontoxic dose, whichever was lower. When the highest nontoxic dose was reached, this dose was continued to complete 26 weeks of treatment. Twenty-two subjects completed 26 weeks of alpha-difluoromethylornithine treatment of whom 20 reached a nontoxic dose of at least 1600 mg/m2/day. The dose-limiting toxicity was loss of high-tone auditory acuity on an audiogram. Other side effects included diarrhea, fatigue, joint pain, insomnia, and rash. Pharmacokinetics were linear with dose. Area under the plasma concentration x time curve and maximum plasma concentration of alpha-difluoromethylornithine did not predict for development of ototoxicity. The dose for phase II chemoprevention studies should not exceed 1600 mg/m2/day.