Abstract Background: LIV-1 is a highly prevalent transmembrane protein in breast cancer cells. Ladiratuzumab vedotin (LV), SGN-LIV1A, is an investigational antibody-drug conjugate (ADC) that targets LIV-1 via a humanized IgG1 monoclonal antibody conjugated to monomethyl auristatin E (MMAE) by a protease-cleavable linker. LV is internalized when it binds LIV-1 on cell surfaces and MMAE is released, which binds tubulin and induces apoptosis. LV has been shown to be active and tolerable in metastatic breast cancer (mBC) at a recommended dose of 2.5 mg/kg every 21 days (Modi 2017). More frequent, fractionated dosing has improved the activity and/or safety of other ADCs. Thus, this study is actively accruing subjects with metastatic triple negative breast cancer (mTNBC; estrogen receptor (ER)/progesterone receptor (PR)/human epidermal growth factor receptor 2 (HER2) receptor-negative) and endocrine-resistant ER+ or PR+ (hormone receptor [HR+])/HER2-negative mBC to test weekly dosing of LV (Days 1, 8, and 15 of every 3-week cycle). Methods: This study is enrolling up to 82 subjects (42 HR+/HER2-negative and 40 mTNBC) into dose escalation and dose expansion cohorts (NCT01969643). Eligible subjects are females ≥18 years old with pathologically and radiologically confirmed metastatic HR+/HER2-negative or mTNBC with at least 1 measurable lesion per RECIST v1.1. Subjects with HR+/HER2-negative disease must have received no more than 1 prior line of cytotoxic chemotherapy in the locally advanced (LA)/mBC setting, either as single agent or combination therapy. Subjects with mTNBC must have received 1 prior line of cytotoxic chemotherapy in the LA/mBC setting. Progression within 6 months of completion of neoadjuvant or adjuvant therapy is considered an LA/mBC regimen. Subjects must have adequate organ function, ECOG status of ≤1, and no ≥ Grade 2 peripheral neuropathy. Subjects with brain lesions must have received definitive treatment of the lesions. Prior therapy with MMAE-containing agents is not allowed. Dose escalation follows the modified toxicity probability interval method (Ji 2010). Dose expansion cohorts will provide data about activity and tolerability. Tumor assessments will be conducted every 2 cycles per RECIST v1.1 and all subjects will be followed for safety. Pharmacokinetics and markers of pharmacodynamics will be assessed. Primary safety endpoint is the incidence of adverse events and dose-limiting toxicities. Key efficacy endpoints include confirmed overall response rate, duration of response, and progression-free survival. Citation Format: Heather C Beckwith, Diana C Medgyesy, Jame Abraham, Rita Nanda, Katherine HR Tkaczuk, Ian E Krop, Lajos Pusztai, Shanu Modi, Monica M Mita, Jennifer M Specht, Sara A Hurvitz, Hyo S Han, Kevin Kalinsky, Sharon Wilks, Joyce O’Shaughnessy, Lowell L Hart, Hope S Rugo, Zahi I Mitri, Phillip M Garfin, Howard A Burris III. SGNLVA-001: A phase 1 open-label dose escalation and expansion study of SGN-LIV1A administered weekly in breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr OT-03-03.