Phase Ib Study of the Oral Proteasome Inhibitor Ixazomib (MLN9708) and Fulvestrant in Advanced ER+ Breast Cancer Progressing on Fulvestrant.

LESSONS LEARNED Fulvestrant is a selective estrogen receptor (ER)-downregulating anti-estrogen that blocks ER transcriptional activity and is approved for ER+ breast cancer. Fulvestrant also induces accumulation of insoluble ER and activates an unfolded protein response; proteasome inhibitors have been shown to enhance these effects in preclinical models. BACKGROUND Fulvestrant is a selective estrogen receptor (ER)-downregulating anti-estrogen that blocks ER transcriptional activity and is approved for ER+ breast cancer. Fulvestrant also induces accumulation of insoluble ER and activates an unfolded protein response; proteasome inhibitors have been shown to enhance these effects in preclinical models. METHODS This is a single-center phase Ib study with a 3+3 design of fulvestrant and the proteasome inhibitor ixazomib (MLN9708) in patients with advanced ER+ breast cancer that was progressing on fulvestrant. A dose-escalation design allowed establishment of the ixazomib maximum tolerated dose (MTD). Secondary objectives included progression-free survival, pharmacokinetics, and tumor molecular analyses. RESULTS Among nine evaluable subjects, treatment was well-tolerated without dose-limiting toxicities The MTD of ixazomib was 4 mg in combination with fulvestrant. Plasma concentrations of the active form of ixazomib (MLN2238) in the 4-mg dose cohort had a median (range) Cmax of 155 (122-171) ng/mL; Tmax of 1 (1-1.5) h; terminal elimination half-life of 66.6 (57.3-102.6) hr after initial dose; AUC of 5,025 (4,160-5,345) ng*h/mL. One partial response was observed, and median progression-free survival was 51 days (range 47-137). CONCLUSION This drug combination has a favorable safety profile and anti-tumor activity in patients with fulvestrant-resistant advanced ER+ breast cancer that justifies future testing.