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).

person Aung Naing University of Texas MD Anderson Cancer Center, Houston, TX info_outline Aung Naing, Ecaterina Elena Ileana Dumbrava, Ravi Murthy, Funda Meric-Bernstam, Andrew Fox, David Krige, Jo Carter, Brian Champion, Paul Cockle, Barbara Koetz, Hilary McElwaine-Johnn

Authors person Aung Naing University of Texas MD Anderson Cancer Center, Houston, TX info_outline Aung Naing, Ecaterina Elena Ileana Dumbrava, Ravi Murthy, Funda Meric-Bernstam, Andrew Fox, David Krige, Jo Carter, Brian Champion, Paul Cockle, Barbara Koetz, Hilary McElwaine-Johnn Organizations University of Texas MD Anderson Cancer Center, Houston, TX, The University of Texas MD Anderson Cancer Center, Houston, TX, PsiOxus Therapeutics Ltd, Abingdon, United Kingdom, PsiOxus, Abingdon, United Kingdom, PsiOxus Therapeutics Ltd., Abingdon, United Kingdom, PsiOxus Therapeutics Ltd., Oxford, United Kingdom Abstract Disclosures Research Funding Pharmaceutical/Biotech Company 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.