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A Phase I Pharmacologic and Pharmacodynamic Study of Pyrazoloacridine Given as a Weekly 24-Hour Continuous Intravenous Infusion in Adult Cancer Patients

National Cancer Institute-Navy Hematology/Oncology [J. L. G., N. H., B. K., A. P. C., V. K., C. H. T., J. M. H., J. P., G. B. J., M. G. Q.], Department of Internal Medicine [B. P. M.], and Department of Radiology [M. P.], National Naval Medical Center, Bethesda, Maryland 20889

Purpose: 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.

Experimental Design: Thirty-two adult patients with solid tumors received PZA at five dose levels (100–351 mg/m²). 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.

Results: Dose-limiting granulocytopenia and mucositis occurred in 2 of 6 patients at 351 mg/m², but lower doses were well tolerated. No responses were seen, but 28% had stable disease for 3 months. Plasma levels strongly correlated with the degree of granulocytopenia. Extended pharmacokinetics in 7 patients treated with 281 mg/m² indicated the following averages: maximum plasma level, 1.6 µM; area under the plasma concentration-time curve, 56 µM·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 281 mg/m²).

Conclusions: 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/m², which was well tolerated. Both end of infusion plasma levels and presence of DNA damage correlated with granulocyte toxicity.

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