Background: The HDACi vorinostat (V) inhibits growth of BC cell lines and downregulates thymidylate synthase (TS), an enzyme thought to be involved in resistance to 5-fluoruracil. Methods: We designed a phase I/II clinical trial of V + capecitabine (C) for advanced BC. The primary aims are to determine the maximum tolerated dose (MTD), dose-limiting toxicities (DLT) and response by RECIST criteria. Secondary aims are pharmacodynamic (PD) measures of gene signatures and candidate transcription factors in pre/post V biopsies using RNA-seq. Cohorts (Co) of 3-6 patients (pts) were enrolled and treated with escalating doses of C (1,500/1,800/2,000 mg) + V 200 mg BID on days 1-7 and 15-21 of a 28 day cycle. Pts received V on days -10, -9, -8, -7, -6 and C on day -3 to facilitate PD studies. A DLT is defined as ≥ grade 3 non-hematologic toxicity, grade 4 thrombocytopenia, grade 4 neutropenia > 5 days, grade 4 febrile neutropenia requiring hospitalization, or treatment delay of > 2 weeks due to unresolved toxicity. Results: 13 pts enrolled on phase I study: (Co1 1,500/200 mg, n= 8), (Co2 1,800/200 mg, n=5). Median age was 59 yrs (range 46-68); median number of prior therapy was 5 (range 2-9); 10 pts had ER/PR+ BC; 1 pt had HER-2+ BC; 3 pts had prior C therapy. Nine of 13 pts were evaluable for toxicity; 3 DLTS (grade 3 fatigue) occurred in Co 1 (2) and Co 2 (1). Other grade 3/4 toxicities included: 1 pt had grade 3 neutropenia, anemia, fatigue, hyponatremia, hypoalbuminemia, ataxia, infection, muscle weakness, headache and grade 4 thrombocytopenia; 1 pt had grade 3 hand/foot syndrome; 1 pt had grade 3 syncope and grade 4 hypokalemia; 1 pt had grade 3 thrombocytopenia; 1 pt had grade 3 anemia;1 pt had grade 3 neutropenia and infection; 1 pt had grade 3 neutropenia and lymphopenia; and 1 pt had grade 3 headache. Seven pts completed > 2 cycles and were evaluable for response; 3 pt had stable disease, notably 1 pt is on treatment for 27 cycles and 1 pt completed 6 cycles. Extraction/amplification/ sequencing from core biopsies shows acceptable read-mapping (45-50 % of RefSeq genes) on Illumina GA II platform. Conclusions: The MTD and recommended dose for phase II study is C1,500 mg BID and V 200 mg BID in a biweekly schedule. PD results will be presented.