A phase I pharmacologic and pharmacodynamic study of pyrazoloacridine given as a weekly 24-hour continuous intravenous infusion in adult cancer patients.

Abstract

Pyrazoloacridine (PZA) is an investigational nucleic acid binding agent that inhibits the activity of topoisomerases I and II through a mechanism distinct from other topoisomerase poisons. PZA shows schedule-independent cytotoxicity against tumor cells, whereas host toxicity is greater with shorter infusions. We assessed the clinical toxicities and pharmacologic effects of PZA given as a 24-h i.v. infusion weekly for 3 of 4 weeks. Thirty-two adult patients with solid tumors received PZA at five dose levels (100-351 mg/m(2)). Plasma samples were obtained at the end of the PZA infusion at all of the dose levels, with extended sampling in a cohort treated at the recommended dose. Dose-limiting granulocytopenia and mucositis occurred in 2 of 6 patients at 351 mg/m(2), but lower doses were well tolerated. No responses were seen, but 28% had stable disease for > or =3 months. Plasma levels strongly correlated with the degree of granulocytopenia. Extended pharmacokinetics in 7 patients treated with 281 mg/m(2) indicated the following averages: maximum plasma level, 1.6 microM; area under the plasma concentration-time curve, 56 microM.h; terminal half-life, 27 h; urinary recovery, 17% over 72 h. DNA fragmentation in post-PZA bone marrow mononuclear cells was seen in 9 of 28 samples (all at > or =281 mg/m(2)). Unlike other schedules of PZA, neurotoxicity and thrombocytopenia were not problematic with a weekly 24-h infusion of PZA. The recommended Phase II dose is 281 mg/m(2), which was well tolerated. Both end of infusion plasma levels and presence of DNA damage correlated with granulocyte toxicity.