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 pharmacokinetics of pyrazoloacridine (PZA) administered as a 1- or 24-hour infusion in children and young adults with refractory cancers. Patients and Methods: 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. 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/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 dose-limiting. There was marked interpatient variability in plasma PZA concentrations at all dose levels. The pharmacokinetic profile of PZA was characterized by an initial rapid decline (alpha half-life [t( 1/4 )α], 0.5 hours) followed by a prolonged elimination phase (t( 1/4 )β, 30 hours). The volume of distribution at steady- state (Vd(ss),) was 700 L/m² and the clearance was 300 mL/min/m². There was no evidence of dose-dependent clearance. The area under the PZA concentration-time curve (AUC) correlated poorly with dose and was more predictive of the degree of myelosuppression than was PZA dose. Conclusion: PZA administered as 1-or 24-hour infusion is well tolerated by children and young adults. The dose-limiting toxicity (DLT) is myelosuppression. Neurotoxicity is not prominent in this age group. There was marked interpatient variation in plasma concentrations of PZA. The recommended dose far phase II studies is 640 mg/m².