A Phase I and Pharmacologic Study of Belotecan in Combination with Cisplatin in Patients with Previously Untreated Extensive-Stage Disease Small Cell Lung Cancer

Abstract

Belotecan (Camtobell, CKD602) is a novel camptothecin derivative. This study was designed to determine the maximum tolerated dose (MTD), toxicity profile, and dose-limiting toxicity of belotecan in combination with cisplatin in patients with previously untreated extensive-stage disease small cell lung cancer (SCLC). Furthermore, pharmacokinetics and preliminary antitumor activity against SCLC were evaluated. Belotecan was administered i.v. as intermittent 30-min infusions on days 1 to 4, starting dose of 0.40 mg/m2/d with increment of 0.05 mg/m2/d. Intrapatient dose escalation was not allowed. Cisplatin (60 mg/m2) was given on day 1. The treatments were repeated every 3 weeks. Pharmacokinetics was determined during the first cycle using noncompartmental pharmacokinetic analysis. Seventeen chemotherapy-naive patients with extensive-stage disease SCLC were treated. The MTD of belotecan was 0.50 mg/m2/d with the dose-limiting toxicity of grade 4 neutropenia with fever. A partial response was seen in 13 of 17 patients (76.5%). The most common toxicity was neutropenia but nonhematologic toxicity was very favorable. Pharmacokinetic analysis revealed that, at the dose of 0.50 mg/m2/d, plasma clearance of belotecan was 5.78 +/- 1.32 L/h and terminal half-life was 8.55 +/- 2.12 h. Fraction of excreted amount in urine was 37.36 +/- 5.55%. Pharmacokinetics of belotecan was not altered by administration of cisplatin compared with historical control. The MTD and recommended dose of belotecan for phase II studies was 0.50 mg/m2/d on days 1 to 4 in combination with 60 mg/m2 cisplatin on day 1 every 3 weeks.