biostudies-literatureUnknown17(1)Hamilton EAC699 is a novel, orally bioavailable chimeric estrogen receptor-α (ERα) degrader that induces proteasome-dependent ERα degradation via cereblon E3 ligase recruitment. Here we report findings from a first-in-human, phase 1, dose-escalation study of once-daily AC699 (100-600 mg) in patients with heavily-pretreated, locally-advanced/metastatic ER-positive/HER2-negative breast cancer (ClinicalTrials.gov Identifier: NCT05654532). Primary objectives are to assess dose-limiting toxicities and treatment-emergent adverse events (TEAEs). Secondary objectives are to evaluate pharmacokinetics, objective response rate (ORR), clinical benefit rate (CBR, including stable disease ≥24 weeks), duration of response (DOR), and progression-free survival (PFS). Among 37 treated patients, TEAEs occurred in 78% Nature communications796https://www.ebi.ac.uk/biostudies/studies/S-EPMC12824232biostudies-literatureER degradation for ER<sup>+</sup>/HER2- advanced or metastatic breast cancer: a phase 1 trial.PMC12824232Kim SYFan JHe WPatel MRHamilton EZhang HCosgrove DLayman RMDanso MfalseER degradation for ER<sup>+</sup>/HER2- advanced or metastatic breast cancer: a phase 1 trial.AC699 is a novel, orally bioavailable chimeric estrogen receptor-α (ERα) degrader that induces proteasome-dependent ERα degradation via cereblon E3 ligase recruitment. Here we report findings from a first-in-human, phase 1, dose-escalation study of once-daily AC699 (100-600 mg) in patients with heavily-pretreated, locally-advanced/metastatic ER-positive/HER2-negative breast cancer (ClinicalTrials.gov Identifier: NCT05654532). Primary objectives are to assess dose-limiting toxicities and treatment-emergent adverse events (TEAEs). Secondary objectives are to evaluate pharmacokinetics, objective response rate (ORR), clinical benefit rate (CBR, including stable disease ≥24 weeks), duration of response (DOR), and progression-free survival (PFS). Among 37 treated patients, TEAEs occurred in 78% 2025-01-01T00:00:00Z2025 Dec2026-07-15T07:45:37.603Z2026-07-01T03:08:03.364ZS-EPMC128242324140771010.1038/s41467-025-67485-y