Background: The HR+/HER2- subtype comprises ~70% of all breast cancers. Sequential endocrine therapy with SERMS ( tamoxifen), AIs (letrozole, anastrozole, exemestane), and SERDs (fulvestrant) are recommended for pts with HR+ metastatic breast cancer (MBC). However, development of resistance to endocrine therapy poses a major problem in the use of these agents. CC-486, an oral epigenetic modifying agent, is hypothesized to potentially restore sensitivity to endocrine therapy. This Phase II study will evaluate the efficacy of CC-486 in combination with fulvestrant in pts with ER+/HER2- MBC who have progressed on an AI. Methods: Approximately 92 pts will be randomized 1:1 to receive CC-486 300 mg orally on days 1 - 21 of each 28-day cycle plus fulvestrant 500 mg IM on days 1 and 15 in the first cycle and day 1 in cycles ≥ 2 or fulvestrant 500 mg on days 1 and 15 in the first cycle and day 1 in cycles ≥ 2. Key eligibility criteria include age ≥ 18 years, postmenopausal, metastatic disease, ER+/HER2− disease refractory to treatment with an AI defined as recurrence on or ≤ 12 months after prior AI treatment in the adjuvant setting or disease progression on or ≤ 1 months of prior treatment with an AI in the metastatic setting, ECOG PS 0 – 1 and measurable disease by RECIST v1.1. The primary endpoint is progression-free survival (PFS). Secondary endpoints include overall response rate, clinical benefit rate, overall survival, duration of response, and safety. Exploratory endpoints include molecular profiling of the tumor for evaluation of predictors of clinical outcome. Efficacy will be evaluated every 8 weeks during the first 24 weeks and then every 12 weeks until disease progression, unacceptable toxicity, death, or new therapy. The primary efficacy analysis will be performed after 70 PFS events are documented. The first safety analysis will be conducted after 32 patients have completed ≥ 1 cycle of treatment. The trial is open for enrollment; 56 pts have been enrolled to date. Clinical trial information: NCT02374099