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Title: A phase 1 dose escalation study of the oncolytic adenovirus enadenotucirev, administered intravenously to patients with epithelial solid tumors (EVOLVE)
Authors: Machiels, Jean-Pascal
Salazar, Ramón
Rottey, Sylvie
Duran, Ignacio
Dirix, Luc
Geboes, Karen
Wilkinson-Blanc, Christine
Pover, Gillian
Alvis, Simon
Champion, Brian
Fisher, Kerry
McElwaine-John, Hilary
Beadle, John
Calvo, Emiiano
metadata.dc.contributor.authoraffiliation: [Machiels,JP] Department of Medical Oncology, Institut Roi Albert II, Cliniques universitaires Saint-Luc and Institut de Recherche Clinique et Expérimentale, Université catholique de Louvain, Brussels, Belgium. [Salazar,R] Medical Oncology Department, Catalan Institute of Oncology, IDIBELL, University of Barcelona, Barcelona, Spain. [Rottey,S] Drug Research Unit Ghent, Ghent University Hospital, Ghent, Belgium. [Duran,I] Instituto de Biomedicina de Sevilla, IBiS/Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Seville, Spain. [Dirix,L] Saint-Augustinus Hospital, Antwerp, Belgium. [Geboes,K] Department of Gastroenterology and Digestive Oncology, Ghent University Hospital, Ghent, Belgium. [Wilkinson-Blanc,C; Pover,G; Alvis,S; Champion,B; Fisher,K; McElwaine-Johnn,H; Beadle,J] PsiOxus Therapeutics Limited, 4-10 The Quadrant, Barton Lane, Abingdon, UK. [Fisher,K] Department of Oncology, University of Oxford, Oxford, UK. [Calvo,E] START Madrid, Centro Integral Oncológico Clara Campal, Hospital Madrid Norte Sanchinarro, Madrid, Spain.
Keywords: Clinical Trials;Pharmacokinetics and pharmacodynamics;Enadenotucirev;Oncolytic adenovirus;Epithelial solid tumor;Intravenous;Farmacocinética;Farmacología;Ensayos clínicos como asunto;Adenoviridae;Carcinoma;Inyecciones intravenosas
metadata.dc.subject.mesh: Medical Subject Headings::Analytical, Diagnostic and Therapeutic Techniques and Equipment::Therapeutics::Drug Therapy::Drug Administration Routes::Administration, Intravenous
Medical Subject Headings::Organisms::Viruses::DNA Viruses::Adenoviridae
Medical Subject Headings::Chemicals and Drugs::Amino Acids, Peptides, and Proteins::Peptides::Intercellular Signaling Peptides and Proteins::Cytokines
Medical Subject Headings::Persons::Persons::Age Groups::Adult
Medical Subject Headings::Disciplines and Occupations::Natural Science Disciplines::Biological Science Disciplines::Pharmacology
Medical Subject Headings::Phenomena and Processes::Chemical Phenomena::Biochemical Phenomena::Kinetics::Pharmacokinetics
Medical Subject Headings::Persons::Persons::Age Groups::Adult::Aged
Medical Subject Headings::Organisms::Viruses::Oncolytic Viruses
Medical Subject Headings::Analytical, Diagnostic and Therapeutic Techniques and Equipment::Therapeutics::Biological Therapy::Oncolytic Virotherapy
Issue Date: 28-Jan-2019
Publisher: BioMed Central Ltd
Citation: Machiels JP, Salazar R, Rottey S, Duran I, Dirix L, Geboes K, et al. A phase 1 dose escalation study of the oncolytic adenovirus enadenotucirev, administered intravenously to patients with epithelial solid tumors (EVOLVE). J Immunother Cancer. 2019 Jan 28;7(1):20.
Abstract: Background: Enadenotucirev 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. Methods: Sixty-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. Results: Enadenotucirev 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. Conclusions: This 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.
Description: Artículo editado por BMC en 2019. La revista "Journal for ImmunoTherapy of Cancer" pasa a ser propiedad de BMJ en 2020, quien actualmente la edita y distribuye.
metadata.dc.identifier.doi: 10.1186/s40425-019-0510-7
ISSN: 2051-1426 (Online)
Appears in Collections:01- Artículos - Hospital Virgen del Rocío
01- Artículos - IBIS. Instituto de Biomedicina de Sevilla

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