APhaseIandPharmacologicStudyofBelotecaninCombination withCisplatininPatientswithPreviouslyUntreated Extensive-StageDiseaseSmallCellLungCancer Dae Ho Lee, 1 Sang-We Kim, 1 Kyun-Seop Bae, 2 Jeong-Sook Hong, 1 Cheolwon Suh, 1 Yoon-Koo Kang, 1 andJung-Shin Lee 1 Abstract Purpose: 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 pre- liminary antitumor activity against SCLC were evaluated. ExperimentalDesign: Belotecan was administeredi.v. as intermittent 30-mininfusions on days 1to 4, starting dose of 0.40 mg/m 2 /d with increment of 0.05 mg/m 2 /d. Intrapatient dose escala- tion was not allowed. Cisplatin (60 mg/m 2 ) was given on day 1. The treatments were repeated every 3 weeks. Pharmacokinetics was determined during the first cycle using noncompartmental pharmacokinetic analysis. Results: Seventeen chemotherapy-naive patients with extensive-stage disease SCLC were trea- ted. The MTD of belotecan was 0.50 mg/m 2 /d with the dose-limiting toxicity of grade 4 neutro- penia 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 anal- ysis revealed that, at the dose of 0.50 mg/m 2 /d, plasma clearance of belotecan was 5.78 F 1.32 L/h and terminal half-life was 8.55 F 2.12 h. Fraction of excreted amount in urine was 37.36 F 5.55%. Pharmacokinetics of belotecan was not altered by administration of cisplatin compared with historical control. Conclusions: The MTD and recommended dose of belotecan for phase II studies was 0.50 mg/m 2 /d on days1to 4 in combination with 60 mg/m 2 cisplatin on day 1every 3 weeks. Combination chemotherapy remains the main treatment of patients with extensive-stage disease small cell lung cancer (SCLC). Etoposide and cisplatin combination has been used as a standard treatment. However, although initial response rates to etoposide-cisplatin combination were up to 80%, the me- dian survival time of patients treated with etoposide-cisplatin regimen was reportedly only 8 to 9 months and 2-year survival of 4% (1 – 4). Several new drugs, such as paclitaxel, topotecan, and irinotecan, were shown to be active in chemotherapy-naive or chemosensitive patients with SCLC, in which the response rates had reached 40% (5 – 7). However, except the Japanese trial (8), new regimens containing these new drugs failed to show the survival benefit compared with the standard etopo- side-cisplatin regimen (9 – 11). Irinotecan and cisplatin regimen showed survival advantage in Japan (8), but a subsequent trial in Western countries failed to confirm the survival benefit of this regimen over etoposide-cisplatin regimen (12). Belotecan [Camtobell, CKD602, 7-[2-(N -isopropylami- no)ethyl]-(20S )-camptothecin, Chong Keun Dang Corp.] is a novel camptothecin derivative, in which a water-solubilizing group is introduced at position of the B ring (13). The preclinical studies showed that belotecan was a more potent topoisomerase I inhibitor in the cleavable complex assay and had superior in vitro and in vivo antitumor activity to camptothecin and topotecan in the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetra- zolium bromide cell cytotoxicity assay and six human tumor xenografts (13, 14). Of interest, the mean ATI values of belotecan were over 2-fold higher than those of topotecan, suggesting that this drug would show encouraging antitumor activity in a clinical study. Although several in vitro and in vivo test systems developed to predicting the clinical activity have some limitations, the ATI values, defined as the area under the inhibition ratio (%) versus time curve plotted from 0 to 240 min as obtained by ex vivo pharmacodynamic assay and calculated by trapezoidal rule, showed a good clinical correlation with the clinical response (15). In a phase I study, the maximum tolerated dose (MTD) of single-agent belotecan was 0.7 mg/m 2 /d when given i.v. daily for 5 consecutive days every 3 weeks and the dose-limiting toxicity Cancer Therapy: Clinical Authors’Affiliations: 1 Division of Oncology, Department of Internal Medicine and 2 Department of Clinical Pharmacology and Therapeutics, University of Ulsan, College of Medicine, Asan Medical Center, Seoul, Korea Received 3/6/07; revised 7/3/07; accepted 8/8/07. Grantsupport: Korea Health 21R&D Project, Ministry of Health and Welfare, Republic of Korea (A060775). Belotecan was provided by Chong Keun Dang Corp., Seoul, Korea. The costs of publication of this article were defrayed in part by the payment of page charges.This article must therefore be hereby marked advertisement in accordance with18 U.S.C. Section1734 solely to indicate this fact. Requests forreprints: Jung-Shin Lee, Division of Oncology, Department of Internal Medicine, University of Ulsan, College of Medicine, Asan Medical Center, 388-1Pungnap-2 dong, Songpa-gu, Seoul 138-736, Korea. Phone: 82-2-3010- 3212; Fax: 82-2-3010-6961; E-mail: jayslee@amc.seoul.kr. F 2007 American Association for Cancer Research. doi:10.1158/1078-0432.CCR-07-0534 www.aacrjournals.org ClinCancerRes2007;13(20)October15,2007 6182