Phase I and pharmacokinetic study of KW-2170, a novel pyrazoloacridone compound, in patients with malignant tumors

Purpose The primary purposes of this study were to determine the dose-limiting toxicity (DLT) and maximum tolerated dose (MTD), to recommend a dose for phase II studies, and to analyze the pharmacokinetics of KW-2170. A secondary purpose was to assess tumor response to KW-2170. Experimental design KW-2170 was given as a 30-min i.v. infusion every 4 weeks. Doses were escalated from 1.0 mg/m 2 according to a modified Fibonacci method. Results A total of 45 cycles of KW-2170 were delivered to 41 patients at doses ranging from 1.0 to 53.0 mg/m 2 . The primary DLT was neutropenia which was observed in two of six patients treated at 32.0 mg/m 2 and in two of two patients treated at 53.0 mg/m 2 ; therefore, the MTD was 53.0 mg/m 2 . Although no patients showed a complete response (CR) or partial response (PR), 15 patients were evaluated as having freedom from progression at the 1-month time-point, with two demonstrating slight tumor shrinkage in their metastatic lesions. None of the patients experienced significant cardiotoxicity. The plasma concentration of KW-2170 declined in a triphasic manner. The half-life, total clearance (CL tot ) and volume of distribution (V dss ) were nearly constant and independent of dose, and showed a relatively small interpatient variability. A linear relationship was observed between dose and maximum plasma concentration (C max ) and area under the concentration–time curve (AUC 0–∞ ). In addition, there was a good correlation between neutropenia and AUC 0–∞ . This suggests that toxicity may be dependent on systemic exposure to the drug. Two oxidative metabolites were observed in the patients’ plasma and urine. Conclusions The primary DLT of KW-2170 in this study was neutropenia, with a MTD of 53 mg/m 2 . A significant linear relationship was observed between neutropenia and AUC 0–∞ . We estimate the recommended dose for phase II studies to be 41.0 mg/m 2 .