PHASE-I TRIAL OF SPIROMUSTINE (NSC-172112) AND EVALUATION OF TOXICITY AND SCHEDULE IN A MURINE MODEL

  • 1 August 1987
    • journal article
    • research article
    • Vol. 47  (15) , 4213-4217
Abstract
Phase I evaluation of spiromustine was performed using an every-3-week schedule and a weekly .times. 3 schedule. Neurotoxicity was the dose-limiting toxicity presenting as alterations in cortical integrative functions (orientation, language, coordination), leading to a decrease in the level of consciousness. Traditional criteria for grading neurotoxicity poorly characterized these toxicities. The maximum tolerated dose was 6 mg/m2 every 3 weeks and 3 mg/m2 weekly .times. 3. Concurrent murine studies confirmed spiromustine as a schedule independnet drug with toxicity correlating with peak plasma levels. Physostigmine had little effect on decreasing neurotoxicity in the murine model. The solvating agent used was not responsible for the neurotoxicity. Injection of spiromustine on a split-dose schedule decreased the acute neurological toxicity in mice and allowed a larger total dosage to be delivered (compared to single bolus dosage). Based on these results a split-dose schedule is suggested for future clinical trials.