title: A phase I study and pharmacologic evaluation of irinotecan and carboplatin for patients with advanced ovarian carcinoma who previously received platinum-containing chemotherapy.
abstract: BACKGROUND
  The objectives of the current study were to determine the maximum tolerated dose (MTD) of irinotecan and carboplatin in combination, to evaluate the efficacy and toxicity of the combination in patients with advanced ovarian carcinoma who previously received platinum-containing chemotherapy, and to examine the pharmacokinetics and pharmacodynamics of both drugs by using the Chatelut formula.
  
  
  METHODS
  Patients with advanced ovarian carcinoma who previously received platinum-containing chemotherapy were treated with a combination of irinotecan and carboplatin. Carboplatin was administered as a 60-minute intravenous infusion on Day 1 and was followed by irinotecan, which was administered as a 90-minute intravenous infusion on Days 1, 8, and 15. Six dose levels of irinotecan (in mg/m(2))/carboplatin (mg . mL/min) were planned: 50 mg/m(2)/4 mg . mL/minute, 60 mg/m(2)/4 mg . mL/minute, 50 mg/m(2)/5 mg . mL/minute, 60 mg/m(2)/5 mg . mL/minute, 50 mg/m(2)/6 mg . mL/minute, and 60 mg/m(2)/6 mg . mL/minute. The carboplatin dosage was calculated by using the Chatelut formula. Treatment was repeated at 28-day intervals.
  
  
  RESULTS
  In total, 19 patients in cohorts of 3 to 5 patients received irinotecan and carboplatin at 5 dose levels. The dose-limiting toxicities were Grade 4 neutropenia and Grade 4 thrombocytopenia. The MTD of the irinotecan/carboplatin combination was 60 mg/m(2)/5 . mg mL/minute. Partial responses were observed at higher dose levels. Pharmacologic studies demonstrated that administration of the dosage estimated with the Chatelut formula instead of the Chatelut formula with adjustment for serum creatinine resulted in a slightly excessive dose of carboplatin.
  
  
  CONCLUSIONS
  The recommended dose for the Phase II study was irinotecan 60 mg/m(2) on Days 1, 8, and 15 with carboplatin 5 mg/mL . minute on Day 1 repeated every 4 weeks.
authors.affiliation: Breast and Medical Oncology Division, National Cancer Center Hospital, Tokyo, Japan.
authors.forename: Kan
authors.initials: K
authors.lastname: Yonemori
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Katsumata
authors.forename: Noboru
authors.initials: N
authors.lastname: Yamamoto
authors.forename: Takahiro
authors.initials: T
authors.lastname: Kasamatsu
authors.forename: Takuro
authors.initials: T
authors.lastname: Yamada
authors.forename: Ryuichiro
authors.initials: R
authors.lastname: Tsunematsu
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Fujiwara
mesh_terms: D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002166:Camptothecin / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D016190:Carboplatin / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D005260:Female; D006801:Humans; D000077146:Irinotecan; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D010051:Ovarian Neoplasms / Q000188:drug therapy*
chemical_list: D000077146:Irinotecan; D016190:Carboplatin; D002166:Camptothecin