Pharmacokinetics and pharmacodynamics evaluation in phase I trial of APX-343A, selective NOX inhibitor targeting CAF-mediated immunosuppression in patients with advanced solid tumors.

Abstract

TPS2684 Background: Cancer-associated fibroblasts (CAFs) drive fibrotic remodeling and immune exclusion in solid tumors and contribute to resistance to immune checkpoint inhibitors (ICIs). CAF-mediated immune suppression is regulated by upstream oxidative signaling pathways. NADPH oxidases (NOXs) are upregulated in CAFs and promote fibrotic remodeling and myeloid cell–mediated inhibition of cytotoxic T-cell function, linking CAF activity to immune exclusion and immunotherapy resistance. APX-343A is a selective NOX1/2/4 inhibitor designed to modulate CAF-associated tumor biology. This ongoing Phase 1 study evaluates pharmacokinetic (PK) and pharmacodynamic (PD) components to assess translational biomarkers of NOX target engagement and CAF-driven immune modulation supporting dose selection and rational combination strategies with immunotherapy. Methods: This is a Phase 1, dose-escalation study (NCT07123415) evaluating the safety, tolerability, PK, PD, and preliminary antitumor activity of orally administered APX-343A as monotherapy (Part A; 100–600 mg BID) and in combination with pembrolizumab (Part B; 200–600 mg BID) in patients with advanced solid tumors. Dose escalation is conducted independently using dose-limiting toxicity–based escalation in Part A and a Bayesian Optimal Interval (BOIN) design in Part B to determine the maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D). PK assessments are conducted in Part A to evaluate dose proportionality and support RP2D determination, including Cmax, Tmax, area under the concentration–time curve (AUC), and accumulation. PD assessments use peripheral blood and tumor tissue samples to evaluate biomarkers of NOX pathway inhibition and CAF-driven immune modulation, including NOX isoforms (NOX1/2/4), CAF-associated markers, and immune-related cytokines and chemokines (e.g., interleukins, CCL2). Integrated PK/PD analyses explore exposure–biomarker relationships. This ongoing Phase 1 trial of APX-343A is actively enrolling, with Part A dose-escalation cohorts underway. Integrated PK and PD assessments are designed to establish translational evidence of NOX target engagement and CAF modulation, providing a mechanistic foundation for dose selection and rational combination strategies with ICI. Clinical trial information: NCT07123415 .