Title	Maximum tolerated dose
Number of Patients Screened	9
Number of Patients Enrolled	9
Number of Patients Evaluable for Toxicity	9
Number of Patients Evaluated for Efficacy	9
Evaluation Method	Adverse events
Response Assessment PR	n = 1 (11%)
Response Assessment PD	n = 8 (88%)
(Median) Duration Assessments PFS	51 Days, CI: 20
Outcome Notes
We performed a 3+3 dose‐escalation trial to assess the safety and efficacy of fulvestrant with three dose cohorts of oral ixazomib: 2.3 mg (cohort A), 3 mg (cohort B), and 4 mg (cohort C). Subjects were treated with fulvestrant (500 mg) by intramuscular injection once every 28 days starting on day 1. Subjects were treated with ixazomib orally on days 1, 4, 8, and 11 of a 21‐day cycle based on prior clinical studies [19, 20]. The dose of ixazomib started at 2.3 mg, slightly greater than 50% of the phase III dose in another ongoing study at the time (NCT01850524). MLN2238 is the biologically active, boronic acid form of ixazomib citrate; in aqueous systems, the equilibrium shifts from ixazomib citrate to MLN2238. Plasma MLN2238 (ixazomib) concentration versus time profiles were determined [21] during cycle 1 day 1 through cycle 2 day 1. Subjects with visceral or soft‐tissue disease had a tumor biopsy prior to treatment with ixazomib to confirm ER, progesterone receptor (PR), and HER2 status and to provide a baseline specimen for molecular analysis. When safely accessible, a biopsy of the same tumor was obtained on cycle 1 day 11 after dosing with ixazomib. Treatments continued without interruption until disease progression, severe or intolerable toxicity, or participant withdrawal of consent.