Background: Programmed cell death ligand 1 (PD-L1) is a cell-surface protein involved in the programmed cell death protein 1 (PD-1)/PD-L1 immune checkpoint, which inhibits T-cell activation. Elevated PD-L1 expression is observed across a broad spectrum of solid tumor types. Expression of PD-L1 in tumors can signal through PD-1 on T cells to inhibit T-cell effector function. Blockade of the PD-1/PD-L1 signaling axis may restore antitumor immunity by reactivating T-cell effector function in the tumor microenvironment. SGN-PDL1V is a novel, investigational vedotin antibody–drug conjugate directed to PD-L1 with multiple proposed mechanisms of action including monomethyl auristatin E (MMAE)-directed cytotoxicity, bystander effect, and immunogenic cell death (ICD). Even in xenograft models with low, heterogeneous PD-L1 expression, SGN-PDL1V demonstrated antitumor activity via direct cytotoxicity and the bystander effect. Cytotoxicity mediated by SGN-PDL1V also led to immune activation due to MMAE-induced ICD (Kwan et al 2021). These preclinical findings provide a rationale for evaluating SGN-PDL1V in patients (pts) with advanced solid tumors. Methods: SGNPDL1V-001 (NCT05208762) is a phase 1, first-in-human, multicenter, open-label trial designed to evaluate the safety, tolerability, pharmacokinetics (PK), and antitumor activity of SGN-PDL1V in pts with advanced solid tumors. This study includes 3 parts: dose escalation (Part A), dose and schedule optimization cohorts (Part B), and dose expansion in disease-specific cohorts and a biology cohort (Part C). Adult pts (≥18 years) with histologically/cytologically confirmed metastatic/unresectable solid tumors, including non-small cell lung cancer, head and neck squamous cell carcinoma, esophageal squamous cell carcinoma, melanoma, or ovarian cancer, will be eligible. Pts must have ECOG PS 0–1 and have failed or are unable to tolerate standard therapies. Pts must have PD-L1 expression ≥1 by tumor proportion score or combined positive score based on historical testing. Prior treatment with an MMAE-containing agent or an anti–PD-L1 agent (within 6 months) is not permitted. Primary endpoints include adverse events, laboratory abnormalities, dose-limiting toxicities, and cumulative dose-level safety. Secondary endpoints include rate and duration of objective response, progression-free survival, overall survival, PK, and incidence of antidrug antibodies. Exploratory endpoints include pharmacodynamics (PD), PK/PD relationships, and patient-reported outcomes. Safety and antitumor activity endpoints will be assessed using descriptive statistics. Objective response rate will be analyzed by tumor type, dose levels, and schedules. Enrollment for Part A is ongoing at sites in North America and is planned in Europe. Clinical trial information: NCT05208762.