EnAd is a tumor-selective oncolytic adenovirus with highly selective replication and cell killing in a broad range of carcinoma cell lines and little replication in normal and non-carcinoma cells. Following intravenous (IV) dosing in clinical studies, uptake and replication of EnAd, associated with CD8+ cell infiltration, has been shown in various carcinomas.
EVOLVE was a Phase 1 study to primarily explore the safety and efficacy of EnAd following IV administration of doses from 1e10 to 1e13 viral particles. Treatment cycles comprised IV infusions on Days (D) 1, 3 and 5, repeated every 3 weeks. Initial safety data have been reported elsewhere (ASCO 2014, abstr 3103). Here we present an analysis of the incidence and timing of adverse events (AEs) alongside the cytokine response data.
During dose escalation, DLTs of acute lung injury, dyspnoea and hypoxia were reported at the highest dose tested, occurring on Cycle 1 Day 1 (C1D1). At doses up to the maximum tolerated dose (MTD), a higher incidence of AEs was reported following dosing on C1D1 compared with D3 & D5. Following D1 administration in Cycle 2, the frequency of AEs was lower than that reported on C1D1. Dose-dependent transient increases in MCP-1 and IL-6 were observed in all patients following C1D1 dose, with lower average increases following D3 & D5 administration, or on D1 of subsequent cycles. This pattern of cytokine release tends to mirror that of reported AEs, and appears independent of the anti-EnAd antibody response.
Tolerability of EnAd is primarily determined by C1D1, correlating with the cytokine response across the patient cohort. This supports the hypothesis that tolerability of the C1D1 dose of EnAd is limited by the activation of innate immune cells (for example, Kuppfer cells in the liver) with associated cytokine release. The MTD of EnAd has been determined primarily based on AEs occurring on C1D1, however higher subsequent doses may be tolerable. Manipulation of dosing regimens may allow administration of higher doses of EnAd on D3 & D5, and/or more doses per cycle, to increase EnAd delivery to tumor and optimize its immunotherapeutic potential.
EUDRACT: 2012-001067-79
PsiOxus Therapeutics Ltd.
PsiOxus Therapeutics Ltd.
H. McElwaine-Johnn, S. Alvis, R. Brown, K. Fisher, C. Morris, B. Champion: Paid employee and stockholder of PsiOxus Therapeutics Ltd. G. Pover: Paid consultant of PsiOxus Therapeutics Ltd. J. Beadle: Paid employee, director and stockholder of PsiOxus Therapeutics Ltd.