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

[摘要] Background. Fulvestrant is a selective estrogen receptor (ER)-downregulating antiestrogen that blocks ER transcriptional activity and is approved for ER-positive (+) 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 welltolerated 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) maximal concentration (Cmax) of 155 (122–171) ng/mL, time of maximal concentration (Tmax) of 1 (1–1.5) hour, terminal elimination half-life of 66.6 (57.3–102.6) hour after initial dose, and area under the curve (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 antitumor activity in patients with fulvestrantresistant advanced ER+ breast cancer that justifies future testing.

[学科分类] 地质学

[关键词] Breast cancer;Anti-estrogen;Endocrine therapy;Proteasome inhibitor