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


METHODS
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.
Department of Surgery, National Shikoku Cancer Center Hospital, Matsuyama, Ehime, Japan. tsaeki@shikoku-cc.go.jp
Toshiaki
T
Saeki
Kenji
K
Eguchi
Shigemitu
S
Takashima
Takahiko
T
Sugiura
Toyoaki
T
Hida
Noboru
N
Horikoshi
Keisuke
K
Aiba
Takashi
T
Kuwabara
Makoto
M
Ogawa
D000166:Acridines / Q000493:pharmacokinetics* / Q000633:toxicity*; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000097:blood / Q000493:pharmacokinetics / Q000633:toxicity; D019540:Area Under Curve; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000145:classification / Q000188:drug therapy*; D011720:Pyrazoles / Q000097:blood / Q000493:pharmacokinetics* / Q000633:toxicity*
D000166:Acridines; D000970:Antineoplastic Agents; D011720:Pyrazoles; C113299:KW 2170