Phase I and pharmacokinetic study of intravenous irinotecan plus oral ciclosporin in patients with fluorouracil-refractory metastatic colon cancer

被引:36
作者
Chester, JD
Joel, SP
Cheeseman, SL
Hall, GD
Braun, MS
Perry, J
Davis, T
Button, CJ
Seymour, MT [1 ]
机构
[1] Cookridge Hosp, Canc Res UK Clin Res Leeds, Leeds LS16 6QB, W Yorkshire, England
[2] St Bartholomews Hosp, Dept Med Oncol, London EC1A 7BE, England
关键词
D O I
10.1200/JCO.2003.08.049
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Purpose : To assess the safety and toxicity profile of escalating doses of intravenous irinotecan, in combination with a fixed dose of oral ciclosporin (Cs) and to determine the pharmacokinetic profile of irinotecan and its metabolites. Patients and Methods: Patients with fluorouracil-refractory metastatic colorectal cancer received escalating doses of intravenous irinotecan from 40 to 125 mg/m(2) every 2 weeks in combination with a fixed dose of oral Cs (5 mg/kg bid for 3 days). Pharmacokinetic analysis of plasma irinotecan and its metabolites SN38 and SN38G was performed during paired cycles with and without Cs. Results: Thirty-seven patients were treated. Dose-limiting toxicity of grade 4 neutropenia was seen at an irinotecan dose of 125 mg/m(2). There was no grade 4 diarrhea, and only one patient experienced grade 3 diarrhea. Toxicities caused by Cs were generally mild. Pharmacokinetic studies demonstrated that irinotecan clearance was reduced from 13.4 to 5.8 L/h/m(2) and area under the curve (AUC)(O-tn) was increased 2.2-fold by the coadministration of Cs. Similar significant increases in AUC(O-24h) were seen for both SN38 and SN38G (2.2-fold and 2.3-fold, respectively) in the presence of Cs. Antitumor activity was seen at every irinotecan dose level. Conclusion: The maximum tolerated irinotecan dose and recommended dose for phase II studies is 100 mg/m(2) every 2 weeks. Dose-limiting diarrhea was not seen during this study, supporting the hypothesis that pharmacokinetic modulation of irinotecan by Cs may improve its therapeutic index. Further studies using this combination are warranted.
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收藏
页码:1125 / 1132
页数:8
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