Abstract CT214: A multicenter phase 1a/b study of NG-641, a tumor-selective transgene-expressing adenoviral vector, and nivolumab in patients with metastatic or advanced epithelial tumors (NEBULA)
Authors: Lillie Tom , Parkes Eileen , Ottensmeier Christian , Krige David , Ravanfar Behnaz , Evilevitch Vladimir , Thomas Matthew , Rosen Lee 
Published: June 2022

Abstract
Background: T-SIGn (Tumor-Specific Immuno Gene Therapy) vectors are transgene-expressing variants of the blood-stable adenovirus enadenotucirev. Through a novel multimodal combination of immunostimulatory effects the vectors are designed to re-program ‘cold’ tumor microenvironments (TME) to allow functional anti-cancer immune responses. T-SIGn vectors selectively replicate in tumor cells, allowing IV delivery to be coupled with local transgene expression in the TME, thereby targeting all tumor lesions while limiting systemic exposure. NG-641 is a T-SIGn vector that expresses a fibroblast activation protein-directed bi-specific T-cell activator antibody to target cancer-associated fibroblasts (CAFs) and an immune-enhancer module (CXCL9/CXCL10/IFNα2) to recruit and activate immune cells. In an ongoing study (NCT04053283), NG-641 monotherapy has been successfully dose-escalated to 1 × 1012 viral particles (vp) on Day 1 and 3 × 1012 vp on Days 3 and 5; initial results from this study have shown a manageable tolerability profile and elevations in serum cytokines indicative of T-cell activation. Based on these promising initial data with NG-641 monotherapy, we designed a new study to assess NG-641 + nivolumab.
Methods: NEBULA (NCT05043714) is an open-label, dose-escalating, phase 1a/b study of NG-641 + nivolumab. Eligible patients (pts) have advanced/metastatic epithelial tumors that have progressed after ≥1 line of systemic therapy and are incurable by local therapy. Pts eligible for phase 1a must have received prior PD-1/PD-L1 inhibition as part of any line of therapy; pts eligible for phase 1b must have primary resistance to PD-1/PD-L1 inhibition. During phase 1a, up to 30 pts will receive escalating doses of IV NG-641 (Bayesian Optimal Interval design) to a maximum dose of 1 × 1012 viral particles (vp) on Day 1 and 1 × 1013 vp on Days 3 and 5 (1 cycle). Pts will receive a fixed-dose of nivolumab (480 mg IV) on Day 15 and then every 4 weeks thereafter for up to 8 cycles. Phase 1b will further investigate the selected dose regimen in up to 3 tumor-specific cohorts (Cohorts A, B and C) using a Simon 2-stage design. Co-primary objectives are to characterize the safety and tolerability of NG-641 + nivolumab 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, immune/inflammatory responses and effects on CAFs by immunohistochemistry and gene expression analysis. Analyses of serial blood samples will explore cytokine production and changes in peripheral immune cell subsets. Enrollment to the first dose-escalation cohort is ongoing.
Citation Format: Tom Lillie, Eileen Parkes, Christian Ottensmeier, David Krige, Behnaz Ravanfar, Vladimir Evilevitch, Matthew Thomas, Lee Rosen. A multicenter phase 1a/b study of NG-641, a tumor-selective transgene-expressing adenoviral vector, and nivolumab in patients with metastatic or advanced epithelial tumors (NEBULA) [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 CT214.