Faculty Collaboration Database

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

Date

03/01/2021

Pubmed ID

33641211

Pubmed Central ID

PMC8176977

DOI

10.1002/onco.13733

Scopus ID

2-s2.0-85103048467 (requires institutional sign-in at Scopus site)   4 Citations

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 (C_max ) of 155 (122-171) ng/mL, time of maximal concentration (T_max ) 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.

Author List

Schwartz G, Shee K, Romo B, Marotti J, Kisselev A, Lewis L, Miller T

Author

Todd W. Miller PhD Professor in the Pharmacology and Toxicology department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Antineoplastic Agents, Hormonal
Boron Compounds
Breast Neoplasms
Estradiol
Female
Glycine
Humans
Proteasome Inhibitors
Receptors, Estrogen