Background: Alkaline phosphatase placental (ALPP) and ALPP-like 2 (ALPPL2) are proteins with 98% sequence similarity that are highly expressed in ovarian, endometrial, gastric, and testicular cancers. Restricted normal tissue expression and efficient lysosomal trafficking of ALPP and ALPPL2 highlight their potential as anticancer targets. SGN-ALPV is a novel investigational vedotin antibody–drug conjugate composed of a humanized anti-ALPP/ALPPL2 monoclonal antibody, a protease-cleavable linker, and the microtubule disrupting agent monomethyl auristatin E (MMAE). The proposed mechanism of action of SGN-ALPV is binding to ALPP/ALPPL2 on the cell surface, where it is internalized and trafficked to the lysosome. Lysosomal proteases cleave the linker to release MMAE into the cytoplasm, where it binds and disrupts the microtubule network, causing cell cycle arrest and apoptosis. Additional mechanisms of action of SGN-ALPV include immunogenic cell death and apoptosis of neighboring cells via the bystander effect. Promising preclinical data support the evaluation of SGN-ALPV in a clinical trial. Methods: SGNALPV-001 (NCT05229900) is a phase 1, open-label, multicenter study designed to evaluate the safety, tolerability, pharmacokinetics (PK), and antitumor activity of SGN-ALPV in patients (pts) with select advanced solid tumors. This study consists of 3 parts: dose escalation (Part A), dose and schedule optimization (Part B), and dose-expansion in disease-specific cohorts and a biology cohort (Part C). Adult pts (≥18 years) with confirmed ovarian, endometrial, non-small cell lung, gastric, cervical cancer, or testicular germ-cell tumors, relapsed or refractory to approved therapies, with measurable disease per RECIST v1.1 and an ECOG PS 0–1 are eligible. Primary endpoints include incidence of adverse events, laboratory abnormalities, dose-limiting toxicities, and cumulative safety. Secondary endpoints include estimates of antidrug antibodies, PK parameters, objective response rate, duration of response, progression-free survival, and overall survival. Exploratory endpoints are pharmacodynamic and biomarker measurements. Safety and antitumor activity endpoints will be summarized using descriptive statistics. Enrollment for Part A is ongoing in sites in North America and Europe. Enrollment for Parts B and C will be opened upon completion of Part A. Clinical trial information: NCT05229900.