{"doi":"10.1002/onco.13733","title":"Phase Ib Study of the Oral Proteasome Inhibitor Ixazomib (MLN9708) and Fulvestrant in Advanced ER+ Breast Cancer Progressing on Fulvestrant","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: ) 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.","journal":"The Oncologist","year":2021,"id":199850,"datarank":0.46737840553469034,"base_score":2.1972245773362196,"endowment":2.1972245773362196,"self_citation_contribution":0.32958368660043297,"citation_network_contribution":0.1377947189342574,"self_endowment_contribution":0.32958368660043297,"citer_contribution":0.1377947189342574,"corpus_percentile":null,"corpus_rank":null,"citation_count":8,"citer_count":8,"citers_with_citation_signal":5,"citers_with_endowment":5,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.954,"is_data_producer":true,"deposit_databanks":{"ClinicalTrials.gov":["NCT02384746"]},"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":292411,"name":"Kevin Shee","orcid":"0000-0001-5378-7650","position":1,"is_corresponding":false},{"id":776881,"name":"Bianca A. Romo","orcid":"0009-0004-5340-6300","position":2,"is_corresponding":false},{"id":292416,"name":"Jonathan D. Marotti","orcid":"0000-0002-2181-3698","position":3,"is_corresponding":false},{"id":361042,"name":"Alexei F. Kisselev","orcid":"0000-0002-6503-4995","position":4,"is_corresponding":false},{"id":292414,"name":"Lionel D. Lewis","orcid":"0000-0003-1164-5157","position":5,"is_corresponding":false},{"id":292418,"name":"Todd W. Miller","orcid":"0000-0001-8912-2909","position":6,"is_corresponding":false},{"id":776880,"name":"Gary N. Schwartz","orcid":"0000-0003-2537-9531","position":0,"is_corresponding":true}],"reference_count":31,"raw_metadata":null,"created_at":"2026-07-18T23:50:44.479665Z","pmid":"33641211","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}