title: Dose-finding phase I clinical and pharmacokinetic study of orally administered irinotecan in patients with advanced solid tumors.
abstract: OBJECTIVE
  The aim of this study was to determine the daily maximum tolerated dose (MTD) and the dose-limiting toxicity for the following administration schedules: oral irinotecan given over 14 days every 3 weeks (part I) and oral irinotecan administered concomitantly with capecitabine over 14 days every 3 weeks (part II). In total, 42 patients (17 male and 25 female) with solid tumors refractory to standard therapy entered the study.
  
  
  METHODS
  Treatment in part I consisted of irinotecan administered orally as semisolid matrix capsules at doses of 25, 30, and 35 mg/m(2) once daily to confirm the MTD of our earlier study. In part II treatment, dose levels for irinotecan combined with capecitabine were 20/1,600, 25/1,600, 30/1,600, and 30/2,000 mg/m(2)/d.
  
  
  RESULTS
  The median number of cycles administered per patient was 2.0 (range, 1-12) in part I and 2.0 (range, 1-13) in study part II. Gastrointestinal toxicities (grade 3 nausea, grades 3 and 4 vomiting, and grades 3 and 4 diarrhea) were dose limiting in both parts of the study. There were no grade 3 or 4 hematologic toxicities. The MTD was 30 mg/m(2)/d for irinotecan single agent and 30/1,600 mg/m(2)/d for the combination with capecitabine. Absorption of irinotecan was rapid, and peak concentrations of irinotecan and metabolite SN-38 were reached within 0 to 3 and 1.5 to 4.0 hours, respectively.
  
  
  CONCLUSIONS
  In conclusion, oral irinotecan and capecitabine is feasible and well tolerated, and the recommended dose for phase II studies is 30/1,600 mg/m(2)/d administered daily for 14 days every 3 weeks.
authors.affiliation: Department of Medical Oncology, Antoni van Leeuwenhoek Hospital/The Netherlands Cancer Institute, Amsterdam. isa_kuppens@hotmail.com
authors.forename: Isa E L M
authors.initials: IE
authors.lastname: Kuppens
authors.forename: Eric
authors.initials: E
authors.lastname: Dansin
authors.forename: Henk
authors.initials: H
authors.lastname: Boot
authors.forename: Celine
authors.initials: C
authors.lastname: Feger
authors.forename: Sylvia
authors.initials: S
authors.lastname: Assadourian
authors.forename: Maria-Edith
authors.initials: ME
authors.lastname: Bonneterre
authors.forename: Jos H
authors.initials: JH
authors.lastname: Beijnen
authors.forename: Jan H M
authors.initials: JH
authors.lastname: Schellens
authors.forename: Jacques
authors.initials: J
authors.lastname: Bonneterre
mesh_terms: D000284:Administration, Oral; D000972:Antineoplastic Agents, Phytogenic / Q000097:blood / Q000493:pharmacokinetics / Q000633:toxicity; D019540:Area Under Curve; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D005260:Female; D041981:Gastrointestinal Tract / Q000187:drug effects / Q000473:pathology; D006207:Half-Life; D006801:Humans; D000077146:Irinotecan; D008297:Male; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D000077146:Irinotecan; D002166:Camptothecin