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

Abstract

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 a shaving 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 (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 (AUC 0-infinity). In addition, there was a good correlation between neutropenia and AUC 0- infinity. This suggests that toxicity may be dependent on systemic exposure to the drug. Two oxi-dative 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 AUC 0- infinity. We estimate the recommended dose for phase II studies to be 41.0 mg/m2.

• Authors: Toshiaki Saeki, Kenji Eguchi, Shigemitu Takashima, Takahiko Sugiura, Toyoaki Hida, Noboru Horikoshi, Keisuke Aiba, Takashi Kuwabara, Makoto Ogawa
• Journal: Cancer chemotherapy and pharmacology (Cancer Chemother Pharmacol) Vol. 54 Issue 5 Pg. 459-68 (Nov 2004) ISSN: 0344-5704 [Print] Germany
• PMID: 15290094 (Publication Type: Clinical Trial, Clinical Trial, Phase I, Journal Article, Multicenter Study)

Chemical References

• Acridines
• Antineoplastic Agents
• Pyrazoles
• KW 2170

Topics

• Acridines (pharmacokinetics, toxicity)
• Adult
• Aged
• Antineoplastic Agents (blood, pharmacokinetics, toxicity)
• Area Under Curve
• Dose-Response Relationship, Drug
• Female
• Humans
• Male
• Middle Aged
• Neoplasms (classification, drug therapy)
• Pyrazoles (blood, pharmacokinetics, toxicity)