Phase I Study of the Combination of MLN9708 and Fulvestrant

Subjects with metastatic ER+/HER2- breast cancer with disease progression on Fulvestrant, for whom continuation of endocrine therapy would be an appropriate treatment, will be treated with the combination of MLN9708 (proteasome inhibitor) and Fulvestrant (anti-estrogen). Subjects with visceral or soft tissue disease will have a tumor biopsy while on treatment with Fulvestrant but prior to initiation of MLN9708 to confirm ER/PR/HER2 status, and to provide a baseline specimen for molecular analysis. A biopsy of the same tumor will be obtained after 2 days of treatment with MLN9708 plus Fulvestrant (i.e. on day 3). Patients with bone-only disease will be eligible for the study, but will not be biopsied. The Investigators propose a 3x3 dose-escalation trial to assess the safety and efficacy of Fulvestrant and three dose levels of MLN9708 (2.3, 3, and 4mg) Subjects will be treated with Fulvestrant (500mg) once every four weeks on day 1. The dose of MLN9708 will start at 2.3mg, which is about 50% of the phase 3 dose in another ongoing study. If 2.3mg MLN9708 does not induce any grade 3 non-hematologic toxicity, or any grade 4 hematologic toxicity by CTCAE v4.0 (Common Terminology Criteria for Adverse Events, version 4.0) in any of the 3 subjects treated for 1 cycle, the Investigators will treat another 3 subjects with the combination of Fulvestrant and MLN9708 (3mg); and if no grade 3 non-hematologic toxicity, or any grade 4 hematologic toxicity by CTCAE v4.0 is seen over the first cycle, the Investigators will treat another 3 subjects with Fulvestrant and MLN9708 (4mg, which is the phase 3 dose). If dose-limiting toxicity is observed in 1/3 subjects, the Investigators will treat an additional 3 subjects at that same dose. If dose-limiting toxicity is seen in 2 of 6 subjects at any dose level, that dose level will be considered the maximum tolerated dose, and a total of 6 subjects will be treated at the prior dose. Plasma pharmacokinetic profiles of MLN9708 will be determined over 21 days after the first dose of the combination. Pre- and post- treatment tumor biopsies will be formalin-fixed and paraffin-embedded. Tissue sections will be analyzed by H\&E (Hematoxylin and eosin) staining and immunohistochemistry using antibodies against markers of proliferation, apoptosis, estrogen receptor alpha activation, endoplasmic reticulum stress, and polyubiquitin. Proteasome activity of whole blood will be determined using samples acquired prior to treatment initiation, and on day 3. Tumor-specific plasma DNA will also be measured prior to treatment initiation and after the first two doses of MLN9708.