TY - JOUR
T1 - A Phase I pharmacologic and pharmacodynamic study of pyrazoloacridine given as a weekly 24-hour continuous intravenous infusion in adult cancer patients
AU - Grem, Jean L.
AU - Harold, Nancy
AU - Keith, Bruce
AU - Chen, Alice P.
AU - Kao, Viven
AU - Takimoto, Chris H.
AU - Hamilton, J. Michael
AU - Pang, Janet
AU - Pace, Marie
AU - Jasser, Gada B.
AU - Quinn, Mary G.
AU - Monahan, Brian P.
PY - 2002
Y1 - 2002
N2 - 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.
AB - 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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M3 - Article
C2 - 12114415
AN - SCOPUS:0035992312
SN - 1078-0432
VL - 8
SP - 2149
EP - 2156
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 7
ER -