Overcoming mTOR resistance: Results of a phase I study of the mTOR inhibitor ridaforolimus and the HDAC inhibitor vorinostat.

501 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 downregulation pAKT when used in combination in renal cell carcinoma (RCC). Methods: The primary objective was to determine the MTD most applicable to 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 weekly, Vori days 1-3 weekly. Results: 15 pts (10 clear cell RCC, 3 papillary RCC, 1 esophageal, 1 carcinoid) were treated at one 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 complet...