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Annals of Oncology Advance Access originally published online on September 9, 2007
Annals of Oncology 2007 18(12):2025-2029; doi:10.1093/annonc/mdm366
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© 2007 European Society for Medical Oncology

phase I and pharmacokinetics

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

R. S. Midgley1,*, D. J. Kerr1, K. T. Flaherty2, J. P. Stevenson2, S. E. Pratap3, K. M. Koch4, D. A. Smith4, M. Versola4, R. A. Fleming4, C. Ward3, P. J. O'Dwyer2 and M. R. Middleton3

1 Department of Clinical Pharmacology, University of Oxford, Oxford, UK
2 Abramson Cancer Center, University of Pennsylvania, Philadelphia, USA
3 Department of Medical Oncology, University of Oxford, Oxford, UK
4 Clinical Pharmacology & Discovery Medicine, GlaxoSmithKline, Research Triangle Park, USA

* Correspondence to: Dr R. Midgley, Cancer Research UK Medical Oncology Unit, Churchill Hospital, Old Road, Oxford OX3 7LJ, UK. Tel: +44-1865-226054; Fax +44-1865-226179; E-mail: Rachel.Midgley{at}cancer.org.uk

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/m2 (day 1) and leucovorin 200 mg/m2, 5-FU bolus 240 mg/m2 and 5-FU infusion 360 mg/m2 (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.

Key words: colorectal cancer, FOLFIRI chemotherapy, phase I, lapatinib

Received for publication June 22, 2007. Accepted for publication June 25, 2007.


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