title: Phase I study of irinotecan combined with carboplatin in previously untreated solid cancers.
abstract: Irinotecan (CPT-11) and carboplatin have broad anti-tumor activities. We conducted a Phase I study of CPT-11 combined with carboplatin in previously untreated solid cancers, especially advanced lung cancer. The aim of the study was to determine the maximum tolerated dose (MTD) and the dose-limiting toxicities in this regimen. In addition, we prospectively evaluated the Chatelut formula for predicting carboplatin clearance. Patients with advanced cancer were treated with CPT-11 (days 1, 8, and 15) and carboplatin (day 1) of a fixed-target area under the concentration-time curve (AUC) of 5 mg x min/ml. Carboplatin dose was determined by multiplying the AUC by the clearance predicted using the Chatelut formula. The CPT-11 dose was escalated from 40 mg/m2 to the MTD by 10 mg/m2. A total of 27 patients, 26 lung cancer patients and 1 colon cancer patient, were enrolled in this study. Dose-limiting leukoneutropenia, thrombocytopenia, and diarrhea, including one treatment-related death, were observed at 60 mg/m2 CPT-11, indicating that this level was the MTD. In 11 patients, the actual AUCs of carboplatin almost achieved the target AUC of 5. Fifteen (60%) of 25 evaluable patients showed an objective response, with an 85% response rate [11 of 13 patients (complete response, 31%; partial response, 54%)] in small cell lung cancers and a 36% response rate (4 of 11 patients) in non-small cell lung cancers. Neutropenia, thrombocytopenia, and diarrhea were the dose-limiting toxicities in this regimen. CPT-11 (50 mg/m2) under the carboplatin target AUC of 5 using the Chatelut formula was the recommended dose for further Phase II study, and this regimen seems to be active for small cell lung cancer.
authors.affiliation: Second Department of Internal Medicine, Nagasaki University School of Medicine, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Fukuda
authors.forename: M
authors.initials: M
authors.lastname: Oka
authors.forename: H
authors.initials: H
authors.lastname: Soda
authors.forename: K
authors.initials: K
authors.lastname: Terashi
authors.forename: S
authors.initials: S
authors.lastname: Kawabata
authors.forename: K
authors.initials: K
authors.lastname: Nakatomi
authors.forename: H
authors.initials: H
authors.lastname: Takatani
authors.forename: J
authors.initials: J
authors.lastname: Tsurutani
authors.forename: K
authors.initials: K
authors.lastname: Tsukamoto
authors.forename: Y
authors.initials: Y
authors.lastname: Noguchi
authors.forename: M
authors.initials: M
authors.lastname: Fukuda
authors.forename: A
authors.initials: A
authors.lastname: Kinoshita
authors.forename: S
authors.initials: S
authors.lastname: Kohno
mesh_terms: D000328:Adult; D000368:Aged; D000972:Antineoplastic Agents, Phytogenic / Q000009:adverse effects / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects* / Q000627:therapeutic use; D019540:Area Under Curve; D002166:Camptothecin / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives; D016190:Carboplatin / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D005260:Female; D006801:Humans; D000077146:Irinotecan; D008175:Lung Neoplasms / Q000188:drug therapy / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D011446:Prospective Studies
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D000077146:Irinotecan; D016190:Carboplatin; D002166:Camptothecin