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A phase 1 dose escalation study of the oncolytic adenovirus enadenotucirev, administered intravenously to patients with epithelial solid tumors (EVOLVE)

Authors
  • Machiels, Jean-Pascal1
  • Salazar, Ramon2
  • Rottey, Sylvie3
  • Duran, Ignacio4
  • Dirix, Luc5
  • Geboes, Karen6
  • Wilkinson-Blanc, Christine7
  • Pover, Gillian7
  • Alvis, Simon7
  • Champion, Brian7
  • Fisher, Kerry7, 8
  • McElwaine-Johnn, Hilary7
  • Beadle, John7
  • Calvo, Emiliano9
  • 1 Institut Roi Albert II, Cliniques universitaires Saint-Luc and Institut de Recherche Clinique et Expérimentale, Université catholique de Louvain, Department of Medical Oncology, Brussels, Belgium , Brussels (Belgium)
  • 2 Catalan Institute of Oncology, IDIBELL, University of Barcelona, Medical Oncology Department, Barcelona, Spain , Barcelona (Spain)
  • 3 Ghent University Hospital, Drug Research Unit Ghent, Ghent, Belgium , Ghent (Belgium)
  • 4 Instituto de Biomedicina de Sevilla, IBiS/Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Seville, Spain , Seville (Spain)
  • 5 Saint-Augustinus Hospital, Antwerp, Belgium , Antwerp (Belgium)
  • 6 Ghent University Hospital, Department of Gastroenterology and Digestive Oncology, Ghent, Belgium , Ghent (Belgium)
  • 7 PsiOxus Therapeutics Limited, 4–10 The Quadrant, Barton Lane, Abingdon, UK , Abingdon (United Kingdom)
  • 8 University of Oxford, Department of Oncology, Oxford, UK , Oxford (United Kingdom)
  • 9 START Madrid, Centro Integral Oncológico Clara Campal, Hospital Madrid Norte Sanchinarro, Madrid, Spain , Madrid (Spain)
Type
Published Article
Journal
Journal for ImmunoTherapy of Cancer
Publisher
Springer (Biomed Central Ltd.)
Publication Date
Jan 28, 2019
Volume
7
Issue
1
Identifiers
DOI: 10.1186/s40425-019-0510-7
Source
Springer Nature
Keywords
License
Green

Abstract

BackgroundEnadenotucirev is a chimeric adenovirus with demonstrated preclinical tumor-selective cytotoxicity and a short half-life. Further clinical mechanism of action data showed that enadenotucirev can gain access to and replicate within different types of epithelial tumors. This phase 1 dose escalation study assessed intravenous (IV) dose escalation with enadenotucirev to establish the maximum tolerated dose (MTD) and subsequently identify a suitable schedule for repeated cycles.MethodsSixty-one patients with advanced epithelial tumors unresponsive to conventional therapy were enrolled and received enadenotucirev monotherapy as part of this study. During the phase 1a dose escalation (n = 22) and expansion (n = 9), delivery of enadenotucirev between 1 × 1010 and 1 × 1013 viral particles (vp) on days 1, 3, and 5 (single cycle) was used to determine an appropriate MTD. Subsequent treatment cohorts (phase 1a, n = 6 and phase 1b, n = 24) examined the feasibility of repeated dosing cycles in either 3-weekly or weekly dosing regimens.ResultsEnadenotucirev displayed a predictable and manageable safety profile at doses up to the MTD of 3 × 1012 vp, irrespective of infusion time or dosing schedule. The most commonly reported treatment-emergent adverse events (TEAEs) of grade 3 or higher were hypoxia, lymphopenia, and neutropenia. The frequency of all TEAEs (notably pyrexia and chills) was highest within 24 h of the first enadenotucirev infusion and decreased upon subsequent dosing. Additionally, delivery of three doses of enadenotucirev over 5 days optimized pharmacokinetic and chemokine profiles in the circulation over time.ConclusionsThis study provides key clinical data in patients with solid epithelial tumors following treatment with IV enadenotucirev monotherapy and supports further investigation of enadenotucirev in combination with other therapeutic agents at doses up to the MTD of 3 × 1012 vp.Trial registration(ClinicalTrials.gov Identifier: NCT02028442). Trial registration date: 07 January 2014 – Retrospectively registered.

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