title: Phase I and pharmacokinetic study of two different schedules of oxaliplatin, irinotecan, Fluorouracil, and leucovorin in patients with solid tumors.
abstract: OBJECTIVE
  We sought to determine the maximum-tolerated dose (MTD) and evaluate the toxicities and clinical activity of two irinotecan (CPT-11), fluorouracil (FU), leucovorin (LV), and oxaliplatin schedules in patients with advanced solid tumors. Additionally, we investigated the effect of CPT-11 on oxaliplatin pharmacokinetics.
  
  
  METHODS
  Thirteen patients (cohort 1) received intravenous CPT-11 (infusion) and FU/LV (bolus) on days 1, 8, 15, and 22 and oxaliplatin (infusion) on days 1 and 15 every 6 weeks for a total 37 courses (median, three courses) at three dose levels. Twenty-two cohort 2 patients received intravenous CPT-11/oxaliplatin (infusion, day 1) and FU/LV (90-minute bolus infusion, days 2 to 5) every 3 weeks for a total of 122 courses (median, four courses) at three dose levels. Pharmacokinetic and neurotoxicity assessments were performed at the cohort 2 MTD.
  
  
  RESULTS
  Dose-limiting toxicity (DLT) seen in both cohorts at the starting dose required dose de-escalation. Cohort 1 DLT included diarrhea and neutropenia. In cohort 2, diarrhea, vomiting, dehydration, neutropenia, febrile neutropenia, and paresthesias were DLTs. Antitumor activity was seen in both cohorts. In cohort 2, the total platinum area under the curve of patients increased 17% in cycle 2 (P =.048), but objective neurotoxicity was not seen.
  
  
  CONCLUSIONS
  The toxicities resulting from the addition of oxaliplatin to CPT-11/FU/LV are significant but manageable. The MTDs for the weekly schedule are CPT-11 (75 mg/m2), oxaliplatin (50 mg/m2), FU (320 mg/m2), and LV (20 mg/m2); and, for the 3-weekly schedule, the MTDs are CPT-11 (175 mg/m2), oxaliplatin (85 mg/m2), FU (240 mg/m2), and LV (20 mg/m2). Second-cycle platinum accumulation raises the possibility for enhanced cumulative neurotoxicity with CPT-11/oxaliplatin combinations.
authors.affiliation: Department of Neurology, Mayo Clinic, Rochester, MN 55905, USA. goetz.matther@mayo.edu
authors.forename: Matthew P
authors.initials: MP
authors.lastname: Goetz
authors.forename: Charles
authors.initials: C
authors.lastname: Erlichman
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Windebank
authors.forename: Joel M
authors.initials: JM
authors.lastname: Reid
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Sloan
authors.forename: Pamela
authors.initials: P
authors.lastname: Atherton
authors.forename: Alex A
authors.initials: AA
authors.lastname: Adjei
authors.forename: Joseph
authors.initials: J
authors.lastname: Rubin
authors.forename: Henry
authors.initials: H
authors.lastname: Pitot
authors.forename: Evanthia
authors.initials: E
authors.lastname: Galanis
authors.forename: Matthew M
authors.initials: MM
authors.lastname: Ames
authors.forename: Richard M
authors.initials: RM
authors.lastname: Goldberg
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002166:Camptothecin / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives*; D004334:Drug Administration Schedule; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage / Q000009:adverse effects; D006801:Humans; D000077146:Irinotecan; D002955:Leucovorin / Q000008:administration & dosage / Q000009:adverse effects; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy*; D009503:Neutropenia / Q000139:chemically induced; D009944:Organoplatinum Compounds / Q000008:administration & dosage / Q000009:adverse effects; D000077150:Oxaliplatin; D010523:Peripheral Nervous System Diseases / Q000139:chemically induced
chemical_list: D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D000077146:Irinotecan; D002955:Leucovorin; D005472:Fluorouracil; D002166:Camptothecin