Background Immunotherapy has made relatively few inroads in pancreatic ductal adenocarcinoma (PDAC) due to its non-redundant mechanisms of resistance, underscoring the need to target alternative immune pathways using a multi-faceted approach. Transforming growth factor-beta (TGFβ) plays an important role in mediating primary resistance to programmed cell death protein/ligand 1(PD-1)/PD-(L)1 blockade. Active adenosine signaling and high basal CD73 expression (an enzyme involved in adenosine metabolism), represent another established resistance mechanism in PDAC and other solid tumors. AGEN1423 is a bifunctional humanized immunoglobulin (IgG1) antibody designed to target both CD73 and TGFβ with a unique mechanism of action featuring (1) preferential localization within the tumor microenvironment (TME) via its CD73 targeting moiety; (2) ability to reduce the concentration of adenosine in the TME by blocking CD73 enzymatic activity; and (3) inhibition the immunosuppressive effect of TGFβ via intracellular trapping. A Phase 1 dose escalation study of AGEN1423 monotherapy was already conducted in patients with advanced solid tumors. Collectively, AGEN1423 is a promising therapeutic investigational candidate designed to address two unique immunosuppressive resistance mechanisms in PDAC simultaneously.
Methods This open-label, two-cohort Phase 2 clinical trial was designed to assess the safety and efficacy of AGEN1423 plus balstilimab with or without chemotherapy in advanced PDAC. Eligible patients include individuals ≥18 years with histologically or cytologically confirmed metastatic or locally advanced PDAC, Eastern Cooperative Oncology Group performance status of 0 or 1 and adequate organ and bone marrow function. In cohort 1, twelve patients with advanced PDAC with progression after ≥1 prior lines of therapy will be enrolled to receive AGEN1423 30mg/kg plus balstilimab 3mg/kg on day 1 of a 14-day cycle. In cohort 2, twelve patients with metastatic PDAC following disease progression on fluorouracil-based therapy will be enrolled to receive AGEN1423 30mg/kg plus balstilimab 3mg/kg on days 1 and 15 of a 28-day cycle in combination with gemcitabine 1000 mg/m2 plus nab-paclitaxel 125 mg/m2 on days 1, 8 and 15 of a 28-day cycle. The primary endpoint is to assess the objective response rate (ORR) according to RECISTv1.1. Secondary endpoints include disease control rate (stable disease or a complete or partial response), overall survival and progression-free survival, and to evaluate safety and tolerability. Biopsies will be obtained at baseline and on-treatment for multiplex immunohistochemistry and additional genomic analyses to better understand changes in the tumor microenvironment following AGEN1423 and balstilimab treatment. Recruitment is anticipated to commence in Q3 2022.
Statistics from Altmetric.com
If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.