A phase I and pharmacokinetic study of lapatinib in combination with infusional 5-fluorouracil, leucovorin and irinotecan.

Journal article

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. PATIENTS AND 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. CONCLUSION: 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: Midgley, R; Kerr, D; Flaherty, K; Stevenson, J; Pratap, SE

• Publication status: Published
• Journal: Annals of oncology : official journal of the European Society for Medical Oncology / ESMO
• Volume: 18
• Issue: 12
• Pages: 2025-2029
• Publication date: 2007-12-01
• DOI: 10.1093/annonc/mdm366
• EISSN: 1569-8041
• ISSN: 0923-7534
• Language: English
• Keywords: Fluorouracil; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Quinazolines; Aged; Leucovorin; Female; Adult; Tandem Mass Spectrometry; Middle Aged; Neoplasms; Male; Humans