title: A phase I and pharmacokinetic study of lapatinib in combination with infusional 5-fluorouracil, leucovorin and irinotecan.
abstract: BACKGROUND
  This study determined the optimally tolerated regimen (OTR) of oral lapatinib administered in combination with infusional 5-fluorouracil (5-FU), leucovorin and irinotecan (FOLFIRI) and assessed the safety, tolerability and pharmacokinetics of the combination.
  
  
  METHODS
  Twenty-five patients were enrolled; 12 patients were treated at three dose levels to determine OTR; then 13 patients were treated at OTR to evaluate the pharmacokinetics of the combination.
  
  
  RESULTS
  The 2-weekly OTR comprised lapatinib 1250 mg/day with irinotecan 108 mg/m(2) (day 1) and leucovorin 200 mg/m(2), 5-FU bolus 240 mg/m(2) and 5-FU infusion 360 mg/m(2) (days 1 and 2); doses of 5-FU and irinotecan represent a 40% reduction in dose compared to conventional FOLFIRI. Dose-limiting toxicities were grade 3 diarrhoea and grade 4 neutropenia. Co-administration of lapatinib increased the area under the plasma concentration-time curve of SN-38, the active metabolite of irinotecan, by an average of 41%; no other pharmacokinetic interactions were observed. Of 19 patients evaluable for disease response assessment, four patients had partial response and nine patients had stable disease.
  
  
  CONCLUSIONS
  The combination of lapatinib and FOLFIRI is safe and demonstrates clinical activity; the documented PK interaction can effectively be compensated by lowering the doses of 5-FU and irinotecan. This regime may be further tested in a phase II trial.
authors.affiliation: Department of Clinical Pharmacology, University of Oxford, Oxford, UK. Rachel.Midgley@cancer.org.uk
authors.forename: R S
authors.initials: RS
authors.lastname: Midgley
authors.forename: D J
authors.initials: DJ
authors.lastname: Kerr
authors.forename: K T
authors.initials: KT
authors.lastname: Flaherty
authors.forename: J P
authors.initials: JP
authors.lastname: Stevenson
authors.forename: S E
authors.initials: SE
authors.lastname: Pratap
authors.forename: K M
authors.initials: KM
authors.lastname: Koch
authors.forename: D A
authors.initials: DA
authors.lastname: Smith
authors.forename: M
authors.initials: M
authors.lastname: Versola
authors.forename: R A
authors.initials: RA
authors.lastname: Fleming
authors.forename: C
authors.initials: C
authors.lastname: Ward
authors.forename: P J
authors.initials: PJ
authors.lastname: O'Dwyer
authors.forename: M R
authors.initials: MR
authors.lastname: Middleton
mesh_terms: D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000627:therapeutic use*; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D006801:Humans; D000077146:Irinotecan; D000077341:Lapatinib; D002955:Leucovorin / Q000008:administration & dosage; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000188:drug therapy; D011799:Quinazolines / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D053719:Tandem Mass Spectrometry
chemical_list: D011799:Quinazolines; D000077341:Lapatinib; D000077146:Irinotecan; D002955:Leucovorin; D005472:Fluorouracil; D002166:Camptothecin