Background: VT1021 is a cyclic pentapeptide that functions as a potent inducer of thrombospondin-1 (Tsp-1) expression in the tumor microenvironment (TME). By triggering the production of Tsp-1, VT1021 reprograms the TME from one that is immune-suppressive and tumor-promoting, to one that activates the adaptive immune system and is tumor-inhibiting. Tsp-1 reprograms the TME to: (i) induce apoptosis in tumor cells that express CD36 on their cell surface, (ii) convert macrophages from M2 to M1 polarization, which promotes phagocytosis and blunts immunosuppression and (iii) inhibit angiogenesis. Preclinical studies have shown robust anti-tumor activities of VT1021 in animal models of ovarian, pancreatic and breast cancer, including complete tumor regression and reprogramming of the immune TME. These observations led to the initiation of the first-in-human study of VT1021. Methods: This study is a first-in-human, Phase 1, open-label, multicenter, dose escalation (Part 1) study with dose expansion (Part 2) in advanced solid tumors. The primary objectives are to assess the safety and tolerability of VT1021, to assess dose-limiting toxicities (DLT), and to determine the maximum tolerated dose (MTD) and the recommended Phase 2 dose (RP2D). Secondary objectives include the evaluation of pharmacokinetics (PK) and pharmacodynamic (PD) effects of VT1021 in tumor and tumor microenvironment, and assessment of preliminary antitumor activity. VT1021 is administered intravenously twice weekly. DLTs will be assessed in the first cycle (Days 1-28) of the dose escalation cohort and are defined as grade 3 adverse events related to VT1021. In Part 1 of the study, 24-30 patients will be enrolled to determine the MTD and RP2D for expansion. In Part 2 of the study, 80-100 patients will be enrolled, grouped into cohorts based on disease subtypes (ovarian, pancreatic, Triple-negative breast cancers, and glioblastoma). Blood samples and biopsy samples from patients will be collected to assess PK properties and PD responses systemically as well as in the TME. No formal statistical hypothesis testing will be conducted in this study. This study is currently open for enrollment in the US. Clinical trial information: NCT03364400