Phase I and Pharmacokinetic Study of Intravenous Irinotecan Plus Oral Ciclosporin in Patients With Fluorouracil-Refractory Metastatic Colon Cancer

• Published in: Journal of clinical oncology Vol. 21; no. 6; pp. 1125 - 1132
• Main Authors: CHESTER, John D, JOEL, Simon P, CHEESEMAN, Susan L, HALL, Geoffrey D, BRAUN, Michael S, PERRY, Jackie, DAVIS, Theresa, BUTTON, Christopher J, SEYMOUR, Matthew T
• Format: Journal Article
• Language: English
• Published: Baltimore, MD American Society of Clinical Oncology 15.03.2003; Lippincott Williams & Wilkins
• Subjects: Antineoplastic agents; Biological and medical sciences; Chemotherapy; Medical sciences; Pharmacology. Drug treatments; Human; DNA topoisomerase (ATP-hydrolysing); Drug combination; Intravenous administration; Enzyme; Maximal dose; Oral administration; Enzyme inhibitor; Malignant tumor; Colonic disease; Irinotecan; Chemotherapy; Isomerases; Treatment; Phase I trial; Digestive diseases; Intestinal disease; Advanced stage; Ciclosporin; Colon; Pharmacokinetics
• ISSN: 0732-183X; 1527-7755
• DOI: 10.1200/JCO.2003.08.049

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) 0-tn was increased 2.2-fold by the coadministration of Cs. Similar significant increases in AUC 0-24h 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.