Phase Ib Study of the Oral Proteasome Inhibitor Ixazomib (MLN9708) and Fulvestrant in Advanced ER+ Breast Cancer Progressing on Fulvestrant
Mené sur 9 patientes atteintes d'un cancer du sein ER+ de stade avancé, cet essai de phase IB évalue la dose maximale tolérée de l'ixazomib (un inhibiteur du protéasome) en combinaison avec le fulvestrant, et analyse les caractéristiques pharmacocinétiques de cette combinaison, après l'échec d'un traitement par fulvestrant
Résumé en anglais
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.
