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

Oncologist. 2021 Jun;26(6):467-e924. doi: 10.1002/onco.13733. Epub 2021 Mar 18.

Abstract

Lessons learned: 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.

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 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) 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 fulvestrant-resistant advanced ER+ breast cancer that justifies future testing.

Trial registration: ClinicalTrials.gov NCT02384746.

Keywords: Anti-estrogen; Breast cancer; Endocrine therapy; Proteasome inhibitor.

Publication types

  • Clinical Trial, Phase I
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents, Hormonal / pharmacology
  • Antineoplastic Agents, Hormonal / therapeutic use
  • Boron Compounds
  • Breast Neoplasms* / drug therapy
  • Breast Neoplasms* / genetics
  • Estradiol / pharmacology
  • Estradiol / therapeutic use
  • Female
  • Fulvestrant / pharmacology
  • Fulvestrant / therapeutic use
  • Glycine / analogs & derivatives
  • Humans
  • Proteasome Inhibitors* / pharmacology
  • Proteasome Inhibitors* / therapeutic use
  • Receptors, Estrogen

Substances

  • Antineoplastic Agents, Hormonal
  • Boron Compounds
  • Proteasome Inhibitors
  • Receptors, Estrogen
  • Fulvestrant
  • Estradiol
  • ixazomib
  • Glycine

Associated data

  • ClinicalTrials.gov/NCT02384746