BACKGROUND: Epigenetic abnormalities are manifold in all solid tumors and include changes in chromatin configuration and DNA methylation. We designed a phase I study to evaluate oral DNT methyltransferase inhibitor CC-486 with the histone deacetylase inhibitor romidepsin in advanced solid tumors with dose expansion to further evaluate pharmacodynamics and possible clinical benefit of the recommended phase II dose (RP2D). METHODS: This was a phase I study with a 3+3 dose escalation design and an expansion phase for patients with virally mediated cancers. Disease control rate (DCR) was the primary outcome for the expansion cohort. Correlative studies included LINE-1 methylation and drug exposure in blood samples. Clinical Trial Registration: NCT01537744 RESULTS: Fourteen patients were enrolled in the dose escalation portion at three dose levels. Three patients experienced dose-limiting toxicities; the RP2D was CC-486 300mg orally daily days 1–14 and romidepsin 8mg/m(2) days 8 and 15. Due to slow accrual into the expansion phase, the trial was closed after 4 patients enrolled. Common toxicities of the combination included nausea (83.3%), anorexia (72.2%), fatigue (61.1%), and constipation (55.6%). There were 12 patients evaluable for response, 5 with stable disease, 2 of which were > 4 cycles; there were no responses. CC-486 and romidepsin exposure were consistent with prior data. LINE-1 methylation on C1D8 was significantly reduced (mean: −6.23; 95% CI: −12.23, −0.24; p=0.04). CONCLUSIONS: While at the RP2D the combination of CC-486 and romidepsin was tolerable, no significant anti-cancer activity was observed. Significant demethylation in post-treatment ctDNA and biopsies provided proof of target acquisition.