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Background: The aim of this phase I trial was to define the maximum tolerated dose (MTD), the dose-limiting toxicity (DLT) and the recommended dose of erlotinib combined with capecitabine and gemcitabine in the treatment of advanced pancreatic cancer (APC). Methods: Gemcitabine was administered intravenously at 1,000 mg/m2/week (days 1, 8 and 15) and oral capecitabine from day 1 to day 21 at 1,660 mg/m2/day. Oral erlotinib was administered daily continuously at escalating doses (28-day cycle). Dose levels (DLs) 1, 2, 3 and 4 were 50, 75, 100 and 125 mg/day, respectively. Pharmacokinetic analysis of the three drugs was performed in the first cycle. Results: Nineteen patients were enrolled. At the MTD (DL4; 125 mg/day erlotinib), 100% of patients developed DLT consisting of grade 4 febrile neutropenia and nonhematological grade 3 events (vomiting, diarrhea, stomatitis, rash). The most common toxicities, regardless of grade, were neutropenia, anemia, rash and diarrhea. Erlotinib systemic exposure was significantly related to the administered dose. Of note, toxicity was significantly associated with elevated systemic exposure of capecitabine anabolites. Conclusion: When combined concurrently with 1,000 mg/m2/week gemcitabine and 1,660 mg/m2/day capecitabine, erlotinib can be administered safely at a daily dose of 100 mg in APC patients. Copyright © 2012 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]