47P - Optimizing the tolerability of intravenous oncolytic viral immunotherapy administration: a sub-analysis of tolerability and cytokine data from the...

Date 08 December 2017
Event ESMO Immuno-Oncology Congress 2017
Session Lunch & Poster Display session
Topics Vulvar and Vaginal Cancers
Gynaecologic Malignancies
Presenter Hilary McElwaine-Johnn
Citation Annals of Oncology (2017) 28 (suppl_11): xi6-xi29. 10.1093/annonc/mdx711
Authors H. McElwaine-Johnn1, G. Pover2, S. Alvis3, R. Brown4, K. Fisher5, C. Morris4, B. Champion4, J. Beadle6
  • 1Clinial Development, PsiOxus Therapeutics Ltd, OX14 3YS - Abingdon/GB
  • 2Clinical, PsiOxus Therapeutics Ltd, OX14 3YS - Abingdon/GB
  • 3Clinical Assays, PsiOxus Therapeutics Ltd, OX14 3YS - Abingdon/GB
  • 4Project Management, PsiOxus Therapeutics Ltd, OX14 3YS - Abingdon/GB
  • 5Research, PsiOxus Therapeutics Ltd, OX14 3YS - Abingdon/GB
  • 6Corporate, PsiOxus Therapeutics Ltd, OX14 3YS - Abingdon/GB

Abstract

Background

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.

Methods

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.

Results

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.

Conclusions

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.

Clinical trial identification

EUDRACT: 2012-001067-79

Legal entity responsible for the study

PsiOxus Therapeutics Ltd.

Funding

PsiOxus Therapeutics Ltd.

Disclosure

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.