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Annals of Oncology Advance Access originally published online on November 6, 2007
Annals of Oncology 2008 19(2):332-339; doi:10.1093/annonc/mdm452
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© 2007 European Society for Medical Oncology. For Permissions, please email: journals.permissions@oxfordjournals.org

gastrointestinal tumors

A phase Ib dose-escalation study of erlotinib, capecitabine and oxaliplatin in metastatic colorectal cancer patients

E. Van Cutsem1,*, C. Verslype1, P. Beale2, S. Clarke2, R. Bugat3, A. Rakhit4, S. H. Fettner4, U. Brennscheidt5, A. Feyereislova5 and J.-P Delord3

1 University Hospital Gasthuisberg, Leuven, Belgium
2 Sydney Cancer Centre, Sydney, Australia
3 Institut Claudius Regaud, Toulouse, France
4 F. Hoffmann-La Roche, Nutley, NJ, USA
5 F. Hoffmann-La Roche Ltd, Basel, Switzerland

* Correspondence to: Prof. E. Van Cutsem, University Hospital Gasthuisberg, Herestraat 49, BE-3000 Leuven, Belgium. Tel: +32-16-34-42-25; Fax: +32-16-34-44-19; E-mail: eric.vancutsem{at}uz.kuleuven.ac.be

Background: Dysregulation of the epidermal growth factor receptor (HER1/EGFR) has been reported in colorectal cancer (CRC). Erlotinib is a potent inhibitor of HER1/EGFR-mediated signaling. This trial of patients with metastatic CRC (MCRC) examined the safety, maximum tolerated dose (MTD) and pharmacokinetics (PK) of erlotinib in combination with capecitabine and oxaliplatin (XELOX), a regimen with established efficacy.

Patients and methods: Patients previously untreated or treated with one line of 5-fluorouracil and/or irinotecan received escalating oral doses of erlotinib (daily), capecitabine (days 1–14) and i.v. oxaliplatin (day 1 of a 21-day cycle).

Results: The first six patients in cohort 1 (erlotinib 100 mg/day, capecitabine 825 mg/m2 twice daily, oxaliplatin 130 mg/m2) had no dose-limiting toxicities (DLTs). In cohort 2 (capecitabine increased to 1000 mg/m2 twice daily), two of six patients had DLTs. When cohort 2 was expanded to 11 patients two further DLTs occurred, exceeding the definition of MTD. Cohort 1 was expanded to 12 patients, and no DLTs occurred. The most common adverse events (AEs) were diarrhea and rash. There was a trend for reduced capecitabine concentrations in the presence of erlotinib. While this was not statistically significant, the possibility of an interaction affecting capecitabine PK cannot be excluded. Antitumor activity was observed in both cohorts (one complete and four partial responses, and stable disease in 11 patients).

Conclusion: The MTD for this combination in MCRC is capecitabine 825 mg/m2 twice daily days 1–14, oxaliplatin 130 mg/m2 day 1 and erlotinib 100 mg/day of a 21-day cycle. The combination was well tolerated at the MTD, with no unexpected AEs. The use of this combination in MCRC warrants further investigation.

Key words: capecitabine, erlotinib, metastatic colorectal cancer, oxaliplatin, XELOX

Received for publication July 24, 2007. Accepted for publication August 13, 2007.


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