Background: Elevation of pAKT levels has been shown to result from mTOR inhibition. We hypothesized that the HDAC inhibitor vorinostat (Vori) would abrogate ridaforolimus (Rida) resistance due to down-regulation of pAKT when used in combination in patients with renal cell carcinoma (RCC). Methods: The primary objective was to determine the maximum tolerated dose (MTD) for RCC patients (pts), thus while all solid tumors were allowed, prior cytotoxic chemotherapy was limited to 1 regimen. There was no limit to the number of prior targeted or immunotherapies. ECOG PS 0-1 and adequate organ and marrow function were required. A modified 3+3 dose escalation design tested 2 dose levels concurrently by escalating each drug in separate cohorts. Rida was dosed days 1-5 and Vori days 1-3, weekly. Results: 15 pts (10 clear cell RCC, 3 papillary RCC, 1 esophageal, 1 carcinoid) were treated at 1 of 3 dose levels: 1) Rida 20mg QD + Vori 100mg BID, 2) Rida 20 mg QD + Vori 200 mg BID, 3) Rida 40 mg QD + Vori 100 mg BID. Inability to complete 80% of doses during cycle 1 due to thrombocytopenia resulted in dose limiting toxicities (DLTs) in 2/6 pts at dose level 2. There were no other DLTs and no grade 4-5 toxicities. Related grade 3 toxicities were: hyperglycemia (1), anemia (2), fatigue (1), and mucositis (1). Grade 2 pneumonitis was seen in 2 pts. The MTD was Rida 20mg QD + Vori 100mg BID, however all 7 pts who received >2 cycles required dose reduction to Rida 10-20 mg QD + Vori 100 mg QD, 6 due to thrombocytopenia. Thus the recommended phase II dose (RP2D) to allow for chronic dosing is Rida 20mg QD + Vori 100mg QD. Stable disease for 19, 21, 46+ and 74+ weeks, respectively, was maintained in 4 pts with RCC. Of these, 3 had progressed on prior mTOR therapy, including 2 pts with papillary RCC and ongoing disease control at the time of data cutoff. Conclusions: Rida 20mg QD + Vori 100 mg QD is the RP2D for this combination. Prolonged, ongoing disease control was seen in 2 papillary RCC pts, both of whom had progressed on a prior mTOR inhibitor. Further study of combined mTOR and HDAC inhibition in RCC, with tumor sampling to assess for pharmacodynamics and proof of concept, is warranted to further define the toxicity, efficacy and mechanism of this combination. Clinical trial information: NCT01169532.