PHASE-I AND PHARMACOLOGICAL STUDIES OF PYRAZOLOACRIDINE, A NOVEL DNA INTERCALATING AGENT, ON SINGLE-DOSING AND MULTIPLE-DOSING SCHEDULES

Purpose: To determine the maximum-tolerated doses (MTDs), principal to xicities, and pharmacologic behavior of pyrazoloacridine (PZA), a nove l DNA intercalator with a unique mechanism of action, on single- and m ultiple-dosing schedules. Patients and Methods: PZA was administered o n a single-dosing schedule as a 1- to 3-hour infusion and on a multipl e-dosing schedule os a 1-hour infusion daily for 5 days to cancer pati ents at doses ranging from 400 to 935 mg/m(2) and 40 to 180 mg/m(2)/d every 3 weeks, respectively. Results: On the single-dosing 1-hour sche dule, CNS toxicity, characterized by neuropsychiatric and neuromotor e ffects, prompted prolongation of the infusion duration to 3 hours and led to a study of PZA on a multiple-dosing schedule. Both measures res ulted in lower incidence of CNS toxicity. Neutropenia was the principa l toxicity and precluded dose escalation to levels greater than 750 mg /m(2) on the single-dosing (3-hour) schedule and 150 mg/m(2)/d x 5 (to tal dose, 750 mg/m(2)) on the multiple-dosing schedule, Thrombocytopen ia, anemia, and nonhematologic effects occurred less frequently. Respo nses were observed in several patients with platinum- and toxane-refra ctory ovarian carcinoma; antitumor activity was also noted in patients with cervical and colorectal carcinomas. Significant intraindividual variability characterized by the presence of multiple drug peaks and t roughs was observed in the pharmacologic studies, The maximal PZA conc entrations achieved in both studies exceeded drug concentrations assoc iated with significant cytotoxicity in preclinical studies and correla ted with the occurrence of CNS toxicity. Conclusion: Neutropenia is th e dose-limiting toxicity on both schedules and 750 mg/m(2) and 150 mg/ m(2)/d are the recommended starting doses of PZA on single- and multip le-dosing schedules, respectively, for minimally pretreated patients i n phase II studies; slightly lower doses are recommended for more heav ily pretreated subjects, The favorable toxicity profile of PZA and its antitumor activity in several refractory tumors warrant broad phase I I evaluations of this agent. J Clin Oncol 13:1975-1984. (C) 1995 by Am erican Society of Clinical Oncology.