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

Autor: Saeki, Toshiaki, Eguchi, Kenji, Takashima, Shigemitu, Sugiura, Takahiko, Hida, Toyoaki, Horikoshi, Noboru, Aiba, Keisuke, Kuwabara, Takashi, Ogawa, Makoto
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Zdroj: Cancer Chemotherapy & Pharmacology; Nov2004, Vol. 54 Issue 5, p459-468, 10p
Abstrakt: 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/m2 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/m2. The primary DLT was neutropenia which was observed in two of six patients treated at 32.0 mg/m2 and in two of two patients treated at 53.0 mg/m2; therefore, the MTD was 53.0 mg/m2. 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 timepoint, 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 (CLtot) and volume of distribution (Vdss) 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 (Cmax) and area under the concentration-time curve (AUC0-∞). In addition, there was a good correlation between neutropenia and AUC0-∞. 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/m2. A significant linear relationship was observed between neutropenia and AUC0-∞. We estimate the recommended dose for phase II studies to be 41.0 mg/m2. [ABSTRACT FROM AUTHOR]
Databáze: Complementary Index
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