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Abstract Background Preclinical studies have demonstrated that VT1021, a first-in-class therapeutic agent, inhibits tumor growth via stimulation of thrombospondin-1 (TSP-1) and reprograms the tumor microenvironment. We recently reported data from the dose escalation part of a phase I study of VT1021 in solid tumors. Here, we report findings from the dose expansion phase of the same study. Methods We analyzed the safety and tolerability, clinical response, and biomarker profile of VT1021 in the expansion portion of the phase I study (NCT03364400). Safety/tolerability is determined by adverse events related to the treatment. Clinical response is determined by RECIST v1.1 and iRECIST. Biomarkers are measured by multiplexed ion beam imaging and enzyme-linked immunoassay (ELISA). Results First, we report the safety and tolerability data as the primary outcome of this study. Adverse events (AE) suspected to be related to the study treatment (RTEAEs) are mostly grade 1–2. There are no grade 4 or 5 adverse events. VT1021 is safe and well tolerated in patients with solid tumors in this study. We report clinical responses as a secondary efficacy outcome. VT1021 demonstrates promising single-agent clinical activity in recurrent GBM (rGBM) in this study. Among 22 patients with rGBM, the overall disease control rate (DCR) is 45% (95% confidence interval, 0.24-0.67). Finally, we report the exploratory outcomes of this study. We show the clinical confirmation of TSP-1 induction and TME remodeling by VT1021. Our biomarker analysis identifies several plasmatic cytokines as potential biomarkers for future clinical studies. Conclusions VT1021 is safe and well-tolerated in patients with solid tumors in a phase I expansion study. VT1021 has advanced to a phase II/III clinical study in glioblastoma (NCT03970447).

Abstract Background VT1021 is a cyclic peptide that induces the expression of thrombospondin-1 (TSP-1) in myeloid-derived suppressor cells (MDSCs) recruited to the tumor microenvironment (TME). TSP-1 reprograms the TME via binding to CD36 and CD47 to induce tumor and endothelial cell apoptosis as well as immune modulation in the TME. Methods Study VT1021-01 (ClinicalTrials.gov ID NCT03364400) used a modified 3 + 3 design. The primary objective was to determine the recommended Phase 2 dose (RP2D) in patients with advanced solid tumors. Safety, tolerability, and pharmacokinetics (PK) were assessed. Patients were dosed twice weekly intravenously in 9 cohorts (0.5–15.6 mg/kg). Safety was evaluated using CTCAE version 5.0 and the anti-tumor activity was evaluated by RECIST version 1.1. Results The RP2D of VT1021 is established at 11.8 mg/kg. VT1021 is well tolerated with no dose-limiting toxicities reported (0/38). The most frequent drug-related adverse events are fatigue (15.8%), nausea (10.5%), and infusion-related reactions (10.5%). Exposure increases proportionally from 0.5 to 8.8 mg/kg. The disease control rate (DCR) is 42.9% with 12 of 28 patients deriving clinical benefit including a partial response (PR) in one thymoma patient (504 days). Conclusions VT1021 is safe and well-tolerated across all doses tested. RP2D has been selected for future clinical studies. PR and SD with tumor shrinkage are observed in multiple patients underscoring the single-agent potential of VT1021. Expansion studies in GBM, pancreatic cancer and other solid tumors at the RP2D have been completed and results will be communicated in a separate report.