First in Human Trials of ProAgio, a Cytotoxin

Division Of Basic Sciences - Nci

Investigators

Abstract

AIM1 (ongoing): Test safety and pharmacokinetics (PK) of ProAgio in patients. A Phase I clinical study at the NIH Clinical Center was initiated in previously treated patients with advanced solid tumor malignancies (PI Alewine). Patient accrual began in 12/2021 and is ongoing to the dose expansion study. Patients receiving dose levels (DL) 1-3 received ProAgio infusion every 2 weeks. No significant toxicity or efficacy was observed. Pharmacokinetic studies suggested the ProAgio trough levels were insufficient to maintain activity and the study was amended in 2022 to a weekly dosing schedule for DLs 4-6. Once accrual of the dose escalation phase is completed and the recommended phase 2 dose is identified, then enrollment of patients to the dose expansion phase will begin. AIM 2 (ongoing): Identify the specific cell subsets in the PDAC TME that are targeted by ProAgio and characterize its effect on TME structure over time. Our current data indicate that short-course ProAgio treatment does not deplete PDAC TME cell subsets that express integrin alphaV-beta3 despite causing significant retardation of tumor growth in an autochthonous mouse model of PDAC. These data have been presented at the AACR Special Conference on Pancreatic Cancer. We are continuing to study the affect of ProAgio on the murine PDAC TME after longer courses of treatment. AIM 3 (ongoing): Assess bioactivity of ProAgio in patients. Tumor biopsy samples are being collected from patients on the ProAgio study. Correlative studies to assess ProAgio effect on stromal density, blood vessels and tumor cellular components will begin when all samples are collected. AIM4 (ongoing): Determine whether ProAgio co-administration can increase penetration of large molecule therapeutics. The anti-fibrotic activity of ProAgio is predicted to increase ability of large molecule therapeutics to penetrate PDAC tumors. Combination of ProAgio with the mesothelin-targeted iTox LMB-100 is being tested in novel humanized mesothelin mouse models developed in collaboration with Serguei Kozlov (NCI/ CAPR).