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

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 e...

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Autores: Machiels, Jean-Pascal, Salazar Soler, Ramón, Rottey, Sylvie, Duran, Ignacio, Dirix, Luc, Geboes, Karen, Wilkinson-Blanc, Christine, Pover, Gillian, Alvis, Simon, Champion, Brian, Fisher, Kerry, McElwaine-Johnn, Hilary, Beadle, John, Calvo, Emiliano
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2019
País:España
Institución:Universidad de Barcelona
Repositorio:Dipòsit Digital de la UB
OAI Identifier:oai:diposit.ub.edu:2445/171998
Acceso en línea:https://hdl.handle.net/2445/171998
Access Level:acceso abierto
Palabra clave:Adenovirus
Tumors
Adenoviruses
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spelling A Phase 1 dose escalation study of the oncolytic adenovirus enadenotucirev, administered intravenously to patients with epithelial solid tumors (evolve)Machiels, Jean-PascalSalazar Soler, RamónRottey, SylvieDuran, IgnacioDirix, LucGeboes, KarenWilkinson-Blanc, ChristinePover, GillianAlvis, SimonChampion, BrianFisher, KerryMcElwaine-Johnn, HilaryBeadle, JohnCalvo, EmilianoAdenovirusTumorsAdenovirusesTumorsBackground: 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.BMJ Publishing Group2019info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfhttps://hdl.handle.net/2445/171998Articles publicats en revistes (Ciències Clíniques)reponame:Dipòsit Digital de la UBinstname:Universidad de BarcelonaInglésReproducció del document publicat a: https://doi.org/10.1186/s40425-019-0510-7Journal for ImmunoTherapy of Cancer , 2019, vol. 7https://doi.org/10.1186/s40425-019-0510-7cc-by-nc (c) Machiels, Jean-Pascal et al., 2019http://creativecommons.org/licenses/by-nc/3.0/esinfo:eu-repo/semantics/openAccessoai:diposit.ub.edu:2445/1719982026-05-27T06:46:51Z
dc.title.none.fl_str_mv A Phase 1 dose escalation study of the oncolytic adenovirus enadenotucirev, administered intravenously to patients with epithelial solid tumors (evolve)
title A Phase 1 dose escalation study of the oncolytic adenovirus enadenotucirev, administered intravenously to patients with epithelial solid tumors (evolve)
spellingShingle A Phase 1 dose escalation study of the oncolytic adenovirus enadenotucirev, administered intravenously to patients with epithelial solid tumors (evolve)
Machiels, Jean-Pascal
Adenovirus
Tumors
Adenoviruses
Tumors
title_short A Phase 1 dose escalation study of the oncolytic adenovirus enadenotucirev, administered intravenously to patients with epithelial solid tumors (evolve)
title_full A Phase 1 dose escalation study of the oncolytic adenovirus enadenotucirev, administered intravenously to patients with epithelial solid tumors (evolve)
title_fullStr A Phase 1 dose escalation study of the oncolytic adenovirus enadenotucirev, administered intravenously to patients with epithelial solid tumors (evolve)
title_full_unstemmed A Phase 1 dose escalation study of the oncolytic adenovirus enadenotucirev, administered intravenously to patients with epithelial solid tumors (evolve)
title_sort A Phase 1 dose escalation study of the oncolytic adenovirus enadenotucirev, administered intravenously to patients with epithelial solid tumors (evolve)
dc.creator.none.fl_str_mv Machiels, Jean-Pascal
Salazar Soler, Ramón
Rottey, Sylvie
Duran, Ignacio
Dirix, Luc
Geboes, Karen
Wilkinson-Blanc, Christine
Pover, Gillian
Alvis, Simon
Champion, Brian
Fisher, Kerry
McElwaine-Johnn, Hilary
Beadle, John
Calvo, Emiliano
author Machiels, Jean-Pascal
author_facet Machiels, Jean-Pascal
Salazar Soler, Ramón
Rottey, Sylvie
Duran, Ignacio
Dirix, Luc
Geboes, Karen
Wilkinson-Blanc, Christine
Pover, Gillian
Alvis, Simon
Champion, Brian
Fisher, Kerry
McElwaine-Johnn, Hilary
Beadle, John
Calvo, Emiliano
author_role author
author2 Salazar Soler, Ramón
Rottey, Sylvie
Duran, Ignacio
Dirix, Luc
Geboes, Karen
Wilkinson-Blanc, Christine
Pover, Gillian
Alvis, Simon
Champion, Brian
Fisher, Kerry
McElwaine-Johnn, Hilary
Beadle, John
Calvo, Emiliano
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Adenovirus
Tumors
Adenoviruses
Tumors
topic Adenovirus
Tumors
Adenoviruses
Tumors
description 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.
publishDate 2019
dc.date.none.fl_str_mv 2019
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv https://hdl.handle.net/2445/171998
url https://hdl.handle.net/2445/171998
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Reproducció del document publicat a: https://doi.org/10.1186/s40425-019-0510-7
Journal for ImmunoTherapy of Cancer , 2019, vol. 7
https://doi.org/10.1186/s40425-019-0510-7
dc.rights.none.fl_str_mv cc-by-nc (c) Machiels, Jean-Pascal et al., 2019
http://creativecommons.org/licenses/by-nc/3.0/es
info:eu-repo/semantics/openAccess
rights_invalid_str_mv cc-by-nc (c) Machiels, Jean-Pascal et al., 2019
http://creativecommons.org/licenses/by-nc/3.0/es
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv BMJ Publishing Group
publisher.none.fl_str_mv BMJ Publishing Group
dc.source.none.fl_str_mv Articles publicats en revistes (Ciències Clíniques)
reponame:Dipòsit Digital de la UB
instname:Universidad de Barcelona
instname_str Universidad de Barcelona
reponame_str Dipòsit Digital de la UB
collection Dipòsit Digital de la UB
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,300719

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