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Annals of Oncology Advance Access originally published online on January 20, 2007
Annals of Oncology 2007 18(4):730-737; doi:10.1093/annonc/mdl481
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© 2007 European Society for Medical Oncology

gastrointestinal tumors

Gefitinib and irinotecan in patients with fluoropyrimidine-refractory, irinotecan-naive advanced colorectal cancer: a phase I–II study

I Chau1, D Cunningham1,*, T Hickish2, A Massey1, L Higgins1, R Osborne3, N Botwood4 and A Swaisland4

1 Department of Medicine, Royal Marsden Hospital, London and Surrey
2 Department of Oncology, Royal Bournemouth and Poole Hospital, Dorset
3 Department of Oncology, Poole Hospital, Dorset
4 AstraZeneca, Macclesfield, UK

* Correspondence to: Prof D. Cunningham, Department of Medicine, Royal Marsden Hospital, Downs Road, Sutton, Surrey SM2 5PT, UK. Tel: +44-208-661-3156; Fax: +44-208-643-9414; E-mail: david.cunningham{at}rmh.nhs.uk

Background: To establish the recommended dose level (RDL) and to evaluate the efficacy and safety of gefitinib plus irinotecan in patients with advanced fluoropyrimidine-refractory colorectal cancer (CRC).

Patients and methods: Patients with advanced CRC progressing on or within 12 weeks of fluoropyrimidine-based chemotherapy, irinotecan naive and performance status of two or less were recruited. During dose-finding phase, dose-limiting toxicity (DLT) was encountered at dose level 1, therefore subsequent dose de-escalation and pharmacokinetic (PK) studies were carried out. The RDL was then expanded in a multicentre setting to further evaluate safety and efficacy.

Results: From June 2002 to February 2005, 39 patients were treated in total with 27 at the RDL. The RDL was established at irinotecan 225 mg/m2 every 3 weeks and gefitinib 250 mg daily. The DLTs were neutropenia and diarrhoea. For the patients treated at RDL, the objective tumour response rate was 11.1% (95% confidence interval 2.4% to 29.2%) and median survival was 9.3 months. PK studies indicated that the addition of irinotecan to gefitinib resulted in an average of 50% increase in exposure to gefitinib (P < 0.05), but gefitinib did not alter the PK profiles of irinotecan or SN-38. Grade 3–4 toxic effects in all patients included diarrhoea (35.9%), lethargy (15.4%), neutropenia (15.4%), febrile neutropenia (10.3%) and skin rash (7.7%).

Conclusions: Irinotecan and gefitinib at this dose schedule was tolerable, but gefitinib did not appear to add substantial efficacy to irinotecan.

Key words: colorectal cancer, epidermal growth factor receptor, gefitinib, irinotecan

Received for publication September 6, 2006. Accepted for publication November 30, 2006.


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