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We report the results from a phase I study of buparlisib, an oral pan-class I phosphotidyinositol-3-kinase inhibitor, combined with capecitabine in patients with metastatic breast cancer. The maximum tolerated dose of the combination was buparlisib 100 mg daily and capecitabine 1000 mg/m2 twice daily. A complete response was seen in 1 patient with a basal-like tumor. Pharmacokinetic analysis suggested that a pharmacokinetic interaction might exist between the 2 agents.Buparlisib is an oral pan-class I phosphotidyinositol-3-kinase (PI3K) inhibitor. The present phase I study evaluated the safety, pharmacokinetics, and efficacy of buparlisib with capecitabine in patients with metastatic breast cancer.Patients received buparlisib once daily (range, 50 to 100 mg) for 3 weeks with capecitabine twice daily (range, 1000 to 1250 mg/m2) for 2 weeks with a 1-week break. Dose escalation used a traditional “3 + 3” design with standard definitions of dose-limiting toxicity (DLT) and maximum tolerated dose.Of the 25 patients enrolled, 23 were evaluable for DLT and 17 were evaluable for response. The maximum tolerated dose of the combination was buparlisib 100 mg daily and capecitabine 1000 mg/m2 twice daily. DLTs included grade 3 hyperglycemia and grade 3 confusion. The most common grade 3 toxicities were diarrhea and elevation of aspartate aminotransferase and alanine transaminase. One patient exhibited a complete response to treatment and four had a confirmed partial response. In cohorts 3 and 4, in which the buparlisib dose remained constant but the capecitabine dose was increased, significant increases in the buparlisib plasma concentration were noted.The combination of buparlisib with capecitabine in patients with metastatic breast cancer was generally well-tolerated, with several patients demonstrating prolonged responses. Unexpectedly low rates of PIK3CA mutations (3 of 17) were seen, and only 2 of 7 tumors with subtyping were luminal, making exploration of these putative predictive markers impossible. Further study of the combination is not unreasonable, with expanded pharmacokinetics and sequencing analysis to better elucidate potential drug–drug interactions and more accurate predictive biomarkers of response.