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 epigenetic modulation with an HDACi potentiates PAZ’s efficacy and prevents the outgrowth of a resistant phenotype. 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 in pts with advanced solid tumor malignancies. Secondary objectives included pharmacokinetics (PK) and efficacy. Altered histone acetylation post treatment denoted HDACi activity and served as pharmacodynamic (PD) markers in peripheral blood mononuclear cells. PAZ was dosed daily and ABX on days 1-5, 8-12, 15-19 of a 28-day cycle, at a starting dose of 400 mg/day and 45 mg/m² orally twice daily for PAZ and ABX respectively. Results: 22 patients with advanced solid tumors were enrolled. There were five dose-limiting toxicities (DLTs) (fatigue: N = 2, thrombocytopenia: N = 2; grade 2 elevated AST with fever: N = 1). The MTD was PAZ 600 mg/day + ABX 30 mg/m² BID. The most common grade ≥ 3 drug regimen-related adverse events observed include thrombocytopenia (12%), fatigue (12%), and diarrhea (8%). 3 of 15 evaluable pts (20%) (including 2 RCC pts) had a confirmed objective partial tumor response, including one pt with prior progression in single agent PAZ. 5 out of 17 evaluable pts (29%) have experienced disease stabilization or better for ≥ 6 months. PK and PD analyses are ongoing. An alternate dosing schedule is being explored with ABX administered on D1-4, 8-11,15-18 of a 28-day cycle. The current dose level is 45 mg/m² BID and PAZ at 600 mg/day with no DLTs observed thus far (N = 2). Conclusions: This is the first trial to explore the combination of ABX with PAZ in RCC and other solid tumor malignancies. The optimal dosing schedule may be ABX taken 4 days/week but requires further investigation. Encouraging preliminary evidence of anti-tumor activity was observed including in a pt with prior disease resistance to PAZ monotherapy. An expansion cohort with 20 pts in RCC and sarcoma is planned. Clinical trial information: NCT01543763.