title: A phase I pharmacologic and pharmacogenetic trial of sequential 24-hour infusion of irinotecan followed by leucovorin and a 48-hour infusion of fluorouracil in adult patients with solid tumors.
abstract: OBJECTIVE
  In preclinical studies, sequential exposure to irinotecan (CPT-11) then fluorouracil (5-FU) is superior to concurrent exposure or the reverse sequence; a 24-hour infusion of CPT-11 may be better tolerated than shorter infusions.
  
  
  METHODS
  CPT-11 was first given at four levels (70-140 mg/m(2)/24 hours), followed by leucovorin 500 mg/m(2)/0.5 hours and 5-FU 2,000 mg/m(2)/48 hours on days 1 and 15 of a 4-week cycle. 5-FU was then increased in three cohorts up to 3,900 mg/m(2)/48 hours.
  
  
  RESULTS
  Two patients had dose-limiting toxicity during cycle 1 at 140/3,900 of CPT-11/5-FU (2-week delay for neutrophil recovery; grade 3 nausea despite antiemetics); one of six patients at 140/3,120 had dose-limiting toxicity (grade 3 diarrhea, grade 4 neutropenia). Four of 22 patients with colorectal cancer had partial responses, two of which had prior bolus CPT-11/5-FU. The mean 5-FU plasma concentration was 5.1 micromol/L at 3,900 mg/m(2)/48 hours. The end of infusion CPT-11 plasma concentration averaged 519 nmol/L at 140 mg/m(2)/24 hours. Patients with UDP-glucuronosyltransferase (UGT1A1; TA)6/6 promoter genotype had a lower ratio of free to glucuronide form of SN-38 than in patients with >/=1 (TA)7 allele. Thymidylate synthase genotypes for the 28-base promoter repeat were 2/2 (13%), 2/3 (74%), 3/3 (13%); all four responders had a 2/3 genotype.
  
  
  CONCLUSIONS
  Doses (mg/m(2)) of CPT-11 140/24 hours, leucovorin 500/0.5 hours and 5-FU 3,120/48 hours were well tolerated.
authors.affiliation: Medical Oncology Clinical Research Unit, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA.
authors.forename: Maurice A
authors.initials: MA
authors.lastname: Wright
authors.forename: Geraldine
authors.initials: G
authors.lastname: Morrison
authors.forename: Pengxin
authors.initials: P
authors.lastname: Lin
authors.forename: Gregory D
authors.initials: GD
authors.lastname: Leonard
authors.forename: Dat
authors.initials: D
authors.lastname: Nguyen
authors.forename: Xaiodu
authors.initials: X
authors.lastname: Guo
authors.forename: Eva
authors.initials: E
authors.lastname: Szabo
authors.forename: Jon L
authors.initials: JL
authors.lastname: Hopkins
authors.forename: Jorge P
authors.initials: JP
authors.lastname: Leguizamo
authors.forename: Nancy
authors.initials: N
authors.lastname: Harold
authors.forename: Suzanne
authors.initials: S
authors.lastname: Fioravanti
authors.forename: Barbara
authors.initials: B
authors.lastname: Schuler
authors.forename: Brian P
authors.initials: BP
authors.lastname: Monahan
authors.forename: M Wasif
authors.initials: MW
authors.lastname: Saif
authors.forename: Mary G
authors.initials: MG
authors.lastname: Quinn
authors.forename: Janet
authors.initials: J
authors.lastname: Pang
authors.forename: Jean L
authors.initials: JL
authors.lastname: Grem
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D019540:Area Under Curve; D002166:Camptothecin / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives / Q000493:pharmacokinetics; D003967:Diarrhea / Q000139:chemically induced; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D005838:Genotype; D014453:Glucuronosyltransferase / Q000235:genetics; D006801:Humans; D007260:Infusion Pumps; D000077146:Irinotecan; D002955:Leucovorin / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics; D008297:Male; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics; D009503:Neutropenia / Q000139:chemically induced; D010597:Pharmacogenetics; D011401:Promoter Regions, Genetic / Q000235:genetics; D013940:Thymidylate Synthase / Q000235:genetics; D016896:Treatment Outcome; D000099148:UGT1A1 Enzyme
chemical_list: D002166:Camptothecin; D005472:Fluorouracil; D014453:Glucuronosyltransferase; D000077146:Irinotecan; D002955:Leucovorin; D013940:Thymidylate Synthase; D000099148:UGT1A1 Enzyme