Background: PAZ is a tyrosine kinase inhibitor of VEGFR, PDGFR, and C-KIT approved for use in renal cell carcinoma (RCC) and soft tissue sarcoma (STS). ABX is a potent pan-HDAC inhibitor (HDACi). Pre-clinical models suggest that HDACi-mediated epigenetic modulation of VEGF expression potentiates PAZ’s efficacy and may reverse therapeutic resistance. We therefore designed a Phase I clinical trial combining ABX with PAZ in pts with advanced solid tumors. Methods: The primary objective was to determine the maximal tolerated dose (MTD) of PAZ plus ABX. Secondary objectives included pharmacokinetics (PK) and efficacy. Altered histone acetylation post treatment denoted HDACi activity and served as a pharmacodynamic (PD) marker in peripheral blood mononuclear cells. PAZ was dosed days 1-28 and ABX days 1-5, 8-12, and 15-19 of 28-day cycle (schedule A) at a starting dose of 400 mg/day and 45 mg/m²orally twice daily respectively. An alternate ABX dosing schedule of days 1-4, 8-11, and 15-18 was also investigated (schedule B). Results: 36 patients with advanced solid tumors were enrolled (N = 22 schedule A; N = 14 schedule B). There were six dose-limiting toxicities (DLTs) (5 on schedule A, 1 on schedule B), including fatigue (N = 2), thrombocytopenia (N = 2), and elevated AST/ALT (N = 2). The most common grade ≥ 3 related adverse events observed include thrombocytopenia (8%), fatigue (8%), and diarrhea (6%), the majority of which occurred with schedule A. The MTD was PAZ 800 mg/day + ABX 45 mg/m² BID on schedule B. 5 of 29 evaluable pts (17%) (including 2 RCC pts) experienced a partial tumor response (PR). All 6 pts with prior disease progression on PAZ monotherapy had reduction in tumor burden on study. 12 out of 29 evaluable pts (41%) experienced stable disease or better for ≥ 6 months, and two pts with PRs remain on study for > 2 years. PK and PD analyses are ongoing. Conclusions: In the first trial to explore the combination of ABX with PAZ in RCC and other solid tumor malignancies, the combination was well tolerated, particularly with schedule B ABX dosing. Preliminary evidence of anti-tumor activity was observed, notably in pts with progression on prior PAZ monotherapy. The promising efficacy in RCC is being further evaluated. Clinical trial information: NCT01543763