A multicenter phase 1a/b study of NG-350A, a tumor-selective anti-CD40-antibody expressing adenoviral vector, and pembrolizumab in patients with metastatic or advanced epithelial tumors (FORTIFY).

Abstract Background: The efficacy of immune checkpoint inhibitors is often limited by immunosuppressive tumor microenvironments (TME) and novel combination therapies are required to overcome resistance. NG-350A is a novel T-SIGn (Tumor-Specific Immuno Gene) adenoviral vector that expresses a fully human agonistic IgG anti-CD40 antibody to promote innate and adaptive immune responses. Additionally, NG-350A selectively replicates in tumor cells, allowing IV dosing to be coupled with local transgene expression in the TME, thereby targeting all tumor lesions while limiting systemic exposure. Through these immunostimulatory effects the vector is designed to re-program ‘cold’ TMEs to allow functional anti-cancer immune responses. Data from an ongoing study with IV NG-350A monotherapy have shown promising tolerability, as well as prominent and sustained elevations in inflammatory cytokines (IL-2, IFNγ, IL-17A, IL-2 and IFNα2) consistent with the mechanism of action of anti-CD40 in stimulating TME re-programming [Naing 2021]. Based on these promising initial data, we designed a study to further assess the safety, tolerability and preliminary efficacy of NG-350A + pembrolizumab. Methods: FORTIFY (NCT05165433) is an open-label, dose-escalating, phase 1a/b study of NG-350A + pembrolizumab. Eligible patients have advanced/metastatic epithelial tumors that have progressed after ≥1 line of systemic therapy and are incurable by local therapy. Patients eligible for phase 1a must have experienced failure of prior PD-1/PD-L1 inhibition as part of any prior line of therapy; patients eligible for phase 1b must have primary resistance to PD-1/PD-L1 inhibition. During phase 1a, up to 30 patients will receive escalating doses of IV NG-350A (Bayesian Optimal Interval design) to a maximum of 1 × 1012 viral particles (vp) on Day 1 and 1 × 1013 vp on Days 3 and 5 (1 cycle). Patients will receive a fixed-dose of pembrolizumab (200 mg IV) on Day 15 and then every 3 weeks thereafter for up to 35 cycles. Phase 1b will further investigate the efficacy/safety of the selected regimen in up to 3 tumor-specific cohorts using a Simon 2-stage design. Co-primary objectives are to characterize the safety and tolerability of NG-350A + pembrolizumab and to identify a recommended dose. Preliminary efficacy and immunogenicity are secondary endpoints. Pharmacodynamic outcomes will be assessed using tumor tissues and blood. Analyses of tumor tissue (serial biopsies at baseline and Day 15 of cycles 1-3 [cycles 1-2 only in Phase 1b]) will explore virus replication, transgene expression and immune/inflammatory responses. Analyses of serial blood samples will explore cytokine production and changes in peripheral immune cell subsets. Recruitment is expected to begin in Q1 2022. Citation Format: Tom Lillie, Mark O'Hara, Christian Ottensmeier, Eileen Parkes, Lee Rosen, David Krige, Marya Chaney, Jo Carter, Vladimir Evilevitch, Matthew Thomas, Aung Naing. A multicenter phase 1a/b study of NG-350A, a tumor-selective anti-CD40-antibody expressing adenoviral vector, and pembrolizumab in patients with metastatic or advanced epithelial tumors (FORTIFY) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT213.