PHASE-I TRIAL AND PHARMACOKINETIC STUDY OF PYRAZOLOACRIDINE IN CHILDREN AND YOUNG-ADULTS WITH REFRACTORY CANCERS

Purpose: To define the maximum-tolerated dose (MTD), quantitative and qualitative toxicities, recommended phase II dose, and pharmacokinetic s of pyrazoloacridine (PZA) administered as a 1- or 24-hour infusion i n children and young adults with refractory cancers. Patients and Meth ods: Twenty-two patients received PZA as a 1-hour infusion at doses of 380 mg/m(2) (n = 3), 495 mg/m(2) (n = 6), 640 mg/m(2) (n = 6), and 83 5 mg/m(2) (n = 7). An additional four patients received PZA as a 24-ho ur infusion at the MTD (640 mg/m(2)) for the 1-hour infusion schedule. Plasma samples were obtained for pharmacokinetic analysis in 17 patie nts. PZA concentration in plasma was measured by reverse-phase highper formance liquid chromatography (HPLC). A two-compartment pharmacokinet ic model was fit to the PZA plasma concentration data. Results: On the 1-hour infusion schedule, dose-limiting myelosuppression (neutropenia more than thrombocytopenia) was observed in two of seven patients at the 835-mg/m(2) dose level. Myelosuppression did not appear to be amel iorated by prolonging the infusion to 24 hours. Nonhematologic toxicit ies were minor. Significant neurotoxicity, which was dose-limiting in adults treated with a 1-hour infusion of PZA, was observed in one pati ent treated at 640 mg/m(2), but was not dose-limiting. There was marke d interpatient variability in plasma PZA concentrations at all dose le vels. The pharmacokinetic profile of PZA was characterized by an initi al rapid decline (alpha half-life [t(1/2)alpha], 0.5 hours) followed b y a prolonged elimination phase (t(1/2)beta, 30 hours). The volume of distribution at steady-state (Vd(ss)) was 700 L/m(2) and the clearance was 300 ml/min/m(2). There was no evidence of dose-dependent clearanc e. The area under the PZA concentration-time curve (AUC) correlated po orly with dose and was more predictive of the degree of myelosuppressi on than was PZA dose. Conclusion: PZA administered as 1- or 24-hour in fusion is well tolerated by children and young adults. The dose-limiti ng toxicity (DLT) is myelosuppression. Neurotoxicity is not prominent in this age group. There was marked interpatient variation in plasma c oncentrations of PZA. The recommended dose for phase II studies is 640 mg/m(2). (C) 1998 by American Society of Clinical Oncology.