Phase I trial and pharmacokinetic study of pyrazoloacridine in children and young adults with refractory cancers

Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
Stacey L BergFrank M Balis

Abstract

To define the maximum-tolerated dose (MTD), quantitative and qualitative toxicities, recommended phase II dose, and pharmacokinetics of pyrazoloacridine (PZA) administered as a 1- or 24-hour infusion in children and young adults with refractory cancers. Twenty-two patients received PZA as a 1-hour infusion at doses of 380 mg/m2 (n = 3), 495 mg/m2 (n = 6), 640 mg/m2 (n = 6), and 835 mg/m2 (n = 7). An additional four patients received PZA as a 24-hour infusion at the MTD (640 mg/m2) for the 1-hour infusion schedule. Plasma samples were obtained for pharmacokinetic analysis in 17 patients. PZA concentration in plasma was measured by reverse-phase high-performance liquid chromatography (HPLC). A two-compartment pharmacokinetic model was fit to the PZA plasma concentration data. On the 1-hour infusion schedule, dose-limiting myelosuppression (neutropenia more than thrombocytopenia) was observed in two of seven patients at the 835-mg/m2 dose level. Myelosuppression did not appear to be ameliorated by prolonging the infusion to 24 hours. Nonhematologic toxicities were minor. Significant neurotoxicity, which was dose-limiting in adults treated with a 1-hour infusion of PZA, was observed in one patient treated at 640 mg/m2, but was not ...Continue Reading

Citations

Jul 1, 2008·The Oncologist·Aerang KimBrigitte C Widemann
Dec 12, 2012·British Journal of Clinical Pharmacology·Johan G C van HasseltAlwin D R Huitema
Nov 19, 2005·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Debra P LeePeter C Adamson
Feb 24, 2004·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Joel M ReidMatthew M Ames

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