3068 Background: Multiple lines of evidence indicate that histone deacetylase inhibitors (HDACi) potentiate topoisomerase (topo) inhibitors. The HDACi-induced histone acetylation and chromatin modulation facilitates DNA access and target recruitment for topo II inhibitors. Methods: This Phase I trial explored a sequence-specific combination of VPA and epirubicin in solid tumors. A VPA loading dose and 6 oral doses (q12h) were given prior to epirubicin in 3-week cycles. Histone acetylation and topo II expression were evaluated in pre-and post-VPA peripheral blood mononuclear cells and tumor samples. Results: To date, 42 patients [median age 53 (39–78)] have been treated in 12 cohorts: IV VPA loading (mg/kg)/epirubicin (mg/m2): 15/75, 30/75, 45/75, 60/75, 75/75 and 75/100, oral loading: 75/100, 90/100, 100/100, 120/100, 140/100 and 160/100. Tumor types included: breast (10), melanoma (11), lung (6), sarcoma (2), GYN (2), GI (5) and others (6). Dose-limiting toxicities included somnolence (1) and neutropenia (1). No exacerbation of epirubicin-related toxicities was observed. Objective responses were seen across different tumor types in anthracycline-resistant and -refractory tumors, despite a median number of 3 (0–6) prior regimens: Partial response; 7/37 (19%), stable disease/minor response: 16/37 (43%). Patients received a median number of 4 (1–10) treatment cycles. Study treatment was stopped despite a clinical benefit or response in 4/33 patients after reaching maximal epirubicin doses (≤750 mg/m2). VPA peak and trough plasma concentrations increased linearly up to 120 mg/m2. MTD is being defined at 160/100 mg/kg/d VPA. H3 and H4 histone acetylation and topo II expression have been correlated with VPA dose, plasma concentration and response. Conclusion: A sequence-specific combination of VPA and epirubicin is active without exacerbation of epirubicin toxicity. VPA plasma peak and trough levels exceeding concentrations needed for biological effects and in vitro synergy are easily achievable with minimal toxicity. The noteworthy anti-tumor activity seen in this heavily pretreated Phase I population warrants further exploration. [Table: see text]