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This phase I study was designed to determine the maximum tolerated dose (MTD) and toxicity profile of the combination of gefitinib, capecitabine, and celecoxib in patients with advanced solid tumors. Patients were treated with escalating doses of gefitinib once daily, capecitabine twice daily (14 of 28 days), and celecoxib twice daily. Plasma samples for biomarkers were obtained at baseline and weekly for the first 2 cycles. Pharmacokinetic variables were correlated with toxicity and presence of biological effect. Tumor biopsies from 5 patients were analyzed for changes in tumor metabolic activity by nuclear magnetic resonance spectroscopy. [18F]fluorodeoxyglucose positron emission tomography was done as a correlate in 6 patients at the MTD. Thirty-nine patients received 168 cycles of therapy. The dose-limiting toxicities observed included nausea, dehydration and nausea, diarrhea, and stomatitis. The MTD was 250 mg/d gefitinib (days 1-14) and 2,000 mg/m2/d capecitabine divided twice daily (days 8-21) every 28 days. Celecoxib was eliminated due to concerns of increased risk for cardiovascular toxicity, although no patients in this study had cardiac events. One patient with cholangiocarcinoma had a confirmed partial response. Fourteen of 39 (36%) patients maintained prolonged stable disease for a median of 4 months (range, 3-24 months). [18F]fluorodeoxyglucose positron emission tomography scan and metabolomic analyses revealed differences in metabolic response to gefitinib versus capecitabine. The combination of gefitinib and capecitabine is well tolerated and appears to have activity against certain advanced solid tumors, providing a rationale for further evaluation in advanced solid malignancies.