Background: Lapatinib has been previously shown to markedly decrease cancer stem cells (CSC) in HER2−positive breast cancer. In preclinical models, we have demonstrated that histone deacetylase inhibitors (HDACi) such as vorinostat can induce differentiation and decrease CSC. The combination of vorinostat and lapatinib is synergistic with a combination index of 0.32 (synergism if CI Method: Patients were eligible if they were: age ≥ 18 years with incurable solid tumors, ECOG PS 0–2, adequate organ function, and no prior exposure to HDACi. The first 3 patients received lapatinib at the dose of 1,250 mg continuous daily and vorinostat 300 mg 4 days on 3 days off. The second dose level with lapatinib 1,250 mg continuous daily and vorinostat 400 mg 4 days on 3 days off were administered in 6 patients. Cycles were repeated every 21 days until disease progression. Echocardiogram and radiologic evaluation were performed every 12 weeks. During the first cycle, pharmacokinetic (PK) evaluation was performed on days 18 and 21. Results: Nine consented patients (7 with metastatic breast cancer, 1 with non-small cell lung cancer, and 1 with thyroid cancer) have been enrolled with the median age of 52 (range 25–66). Patients received an average of 6 prior treatments (range 2–10). No dose limiting toxicity or drug related death have been observed. Grade 1–2 toxicities including diarrhea, fatigue, muscle cramps and stomatitis were observed. No grade 3 or 4 hepatic, renal or cardiac toxicity were observed (including no QTc prolongation and no significant reduction in the left ventricular ejection fraction). Patients have received the maximum of 7 cycles (median 3 cycles, range 2–7). Response: as of June 2011, 2 patients are still on treatment. Two patients achieved stable disease (triple negative metastatic breast cancer and HER2−positive breast cancer), 6 patients with progressive disease, and 1 patient is too early to evaluate for response. PK analysis will be presented at the time of the meeting. Conclusions: The combination of vorinostat and lapatinib is tolerable and has some antitumor activity in heavily pretreated advanced solid tumors. A phase II study in HER2−positive metastatic breast cancer is underway with lapatinib 1,250 mg continuous daily and vorinostat 400 mg 4 days on 3 days off. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P1-12-20.