A multicenter, open label, first-in-human study of an oncolytic viral vector expressing an agonistic anti-CD40 antibody (NG-350A) in patients with epithelial tumors (FORTITUDE).

Abstract

TPS2668 Background: NG-350A is a transgene modified variant of the oncolytic platform virus enadenotucirev (EnAd) which expresses a fully human agonist anti-cluster of differentiation 40 (anti-CD40) antibody. The principal advantage of encoding anti-CD40 within an oncolytic virus is the ability to potentially achieve very high levels within the tumor coupled with direct cytotoxicity due to viral lysis and stimulation of the immune-system. NG-350A infects and selectively replicates in tumor cells. The anti-CD40 antibodies are expected to activate the patient’s own dendritic cells, macrophages and B-cells to drive CD4+ and CD8+ T-cell immuno-inflammatory responses and immune mediated tumor cell killing. EnAd is a tumor-selective chimeric Ad11/Ad3 group B oncolytic adenovirus developed using directed evolution. Phase I clinical studies have identified a well-tolerated systemic dose and regimen for EnAd monotherapy. EnAd shows a high level of selective replication and cell killing for a broad range of carcinoma cell lines (of epithelial origin) with little replication in normal and non-carcinoma cells. Methods: This first in human study will evaluate the safety, tolerability and preliminary efficacy of NG-350A together with virus kinetics, immunogenicity and other pharmacodynamic effects to elucidate the mechanism of action of NG-350A in patients with advanced or metastatic epithelial tumours. In the dose escalation phase up to 33 patients evaluable for dose-limiting toxicity will receive NG-350A by IV infusion on Day 1, 3 and 5 at 6 US sites. The first IV cohort in the dose-escalation phase will utilize the conventional ‘3+3’ design; thereafter dose recommendations will be based on a continual reassessment method. Following determination of the recommended phase 2 dose up to 20 patients will be treated in a dose-expansion cohort. In a parallel cohort, up to 12 patients will receive a single dose of NG-350A by intratumoural (IT) injection on Day 1 for direct delivery of high viral titres to tumor. Up to six patients are planned to undergo surgical resection of a tumor lesion to optimize translational research. Clinical conduct of the study was initiated in February 2019.