Background: Whileparenteral hypomethylating agents (HMAs) induce hematologic response in ~50% of pts with IPSS higher-risk MDS, options are very limited for nonresponding pts who are at high risk of progression to AML and death. In a previous study of pts who had received prior HMA therapy (n = 7), extended dosing of CC-486 resulted in an overall response rate of 29%. Other promising strategies for cancer therapy are emerging, including blockade of the programmed cell death-1 (PD-1)/PD ligand-1 (PD-L1) pathway by immune checkpoint inhibitors. In early-phase studies, durvalumab (MEDI4736), an anti-PD-L1 human antibody, was well tolerated and associated with durable responses in pts with solid tumors. PD-L1 expression on myeloblasts is upregulated in MDS pts following HMA exposure. This randomized, open-label, phase II study evaluates the efficacy and safety of CC-486 ± durvalumab in pts unable to tolerate, or who fail to respond to, prior HMA therapy. Methods: This study consists of a run-in phase exploring the safety and tolerability of CC-486 ± durvalumab, followed by a randomized treatment phase (Table). Pts aged ≥ 18 years with FAB-defined MDS ( < 30% marrow blasts) who failed on prior HMA therapy are eligible. Primary endpoint is proportion of pts achieving an objective response (hematologic improvement, partial response, complete remission [CR], or marrow CR). Secondary endpoints include overall survival, time to/duration of response, progression-free survival, AML progression, and safety. Exploratory analyses include molecular biomarker assessments. Enrollment in the CC-486 arm began in July 2015. Target enrollment is 194 pts. Clinical trial information: NCT02281084

d, day; i.v., intravenous; PD, progressive disease; SD, stable disease.