A first-in-human phase I clinical trial evaluating the safety, tolerability, and preliminary efficacy of the novel fas ligand (FasL) inhibitor M3T01 in adults with advanced solid tumors.

Abstract

TPS2670 Background: Tumor-specific T cells undergo apoptotic cell death following FasL binding to the fas (CD95) receptor. FasL is upregulated in many advanced cancers and is expressed by tumor endothelial cells, macrophages, and activated T and natural killer (NK) cells. Consequently, FasL contributes to tumor progression through deletion of tumor-specific T cells and impaired T cell tumor infiltration. Preclinical studies demonstrate that FasL blockade facilitates increased T cell tumor infiltration and enhances efficacy of immune checkpoint inhibitors and adoptive cell therapies. M3T01 is a fully human IgG4/kappa monoclonal antibody that potently inhibits FasL. This is an ongoing first-in-human phase I clinical trial (NCT06719362) evaluating the safety, tolerability and preliminary antitumor efficacy of M3T01 as monotherapy and in combination with pembrolizumab in adults with advanced solid tumors. Methods: The primary objectives are to evaluate the safety/tolerability, dose-limiting toxicity (DLT), and maximum tolerated dose (MTD) of M3T01. Secondary objectives are to characterize the pharmacokinetics, pharmacodynamics, immunogenicity, and preliminary antitumor efficacy of M3T01 as monotherapy and in combination with pembrolizumab. A sub-study will evaluate paired tumor biopsies (pre-treatment and cycle 2 day 8) to evaluate for changes in the tumor microenvironment induced by FasL inhibition. Eligible patients have unresectable or metastatic solid tumors that are refractory to standard systemic therapy. Patients must have adequate organ function, measureable disease per RECIST v1.1 or RANO 2.0, and an ECOG performance status of 0-1. Dose escalation through a 3 + 3 design will evaluate M3T01 as monotherapy and in combination with pembrolizumab (administered intravenously every 3 weeks). Monotherapy cohorts 1-4 (100 to 600 mg) have been completed without DLT. After completion of the dose escalation portion of the trial, dose expansion cohorts will open to evaluate M3T01 in combination with standard systemic therapies in the treatment of patients with glioblastoma, gastric/esophageal adenocarcinoma, and head and neck squamous cell carcinoma. Clinical trial information: NCT06719362 .