Background: VIP236, a first-in-class SMDC, consists of an αvβ3 integrin small molecule binder, a peptide linker cleaved by neutrophil elastase (NE) in the tumor microenvironment (TME), and a camptothecin (CPT) payload VIP126 which was optimized for high permeability and low efflux. The overall drug design strategy for VIP236 is targeted delivery to the TME and tumors expressing α_Vβ₃ integrin on their cell surface with release of the optimized CPT derivative by NE also present in the TME. VIP126, when delivered as a component of VIP236, is anticipated to kill tumor cells while reducing effects to normal tissue. VIP236 exhibits convincing single agent in vivo antitumor efficacy and acceptable tolerability in multiple human tumor cell line- and patient- derived xenograft models in mice, including breast, colorectal, small cell lung, gastric, metastatic breast and metastatic colon cancer. In three gastric cancer xenograft models, VIP236 caused statistically significant tumor growth inhibition across the models independent of HER2 status. VIP236 outperformed an anti-HER2 ADC, trastuzumab deruxtecan, in all three models. Methods: This trial in progress is an open-label, global, multicenter Phase 1 study to characterize safety, tolerability, preliminary antitumor activity and pharmacokinetics of VIP236 monotherapy in subjects with advanced cancer. Enrollment includes all comer patients with histologically confirmed advanced or metastatic solid tumors that are relapsed or refractory to standard of care. Subjects must have exhausted all available standard therapies or be deemed ineligible for potential available therapies. Frequency, severity, and relationship to study drug of any treatment-emergent adverse events or abnormalities of laboratory tests will be studied. Tumor response will be assessed using RECIST 1.1 criteria. The following dose schedules are being evaluated: 1) Cohorts 1, 2a, and 3a: A cycle is 21 days 1-hour intravenous (IV) infusions on a 2 days on/5 days off schedule with no pause between cycles. 2) Cohorts 2b, 3b, 4b, 5b, 6b, 7b, and 8b: A cycle is 21 days of VIP236 given as a 1-hour IV infusion once every three weeks (Q3W) with no pause between cycles. 3) Cohorts 1, 2a, 3a, 2b, 3b and 4b have been completed. Enrollment continues in the Q3W cohorts. Clinical trial information: NTC05371054.