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 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 × $ 10^{10} $ and 1 × $ 10^{13} $ 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 × $ 10^{12} $ 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 × $ 10^{12} $ vp. Trial registration (ClinicalTrials.gov Identifier: NCT02028442). Trial registration date: 07 January 2014 – Retrospectively registered. Ausführliche Beschreibung

Gespeichert in:

Autor*in:	Machiels, Jean-Pascal [verfasserIn] Salazar, Ramon 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

Format:	E-Artikel
Sprache:	Englisch

Erschienen:	2019

Schlagwörter:	Clinical trials Pharmacokinetics and pharmacodynamics Enadenotucirev Oncolytic adenovirus Epithelial solid tumor Intravenous

Anmerkung:	© The Author(s). 2019

Übergeordnetes Werk:	Enthalten in: Journal for ImmunoTherapy of Cancer - London : BioMed Central, 2013, 7(2019), 1 vom: 28. Jan.
Übergeordnetes Werk:	volume:7 ; year:2019 ; number:1 ; day:28 ; month:01

Links:	Volltext

DOI / URN:	10.1186/s40425-019-0510-7

Katalog-ID:	SPR03643857X

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100	1		\|a Machiels, Jean-Pascal \|e verfasserin \|4 aut
245	1	2	\|a A phase 1 dose escalation study of the oncolytic adenovirus enadenotucirev, administered intravenously to patients with epithelial solid tumors (EVOLVE)
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520			\|a 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 × $ 10^{10} $ and 1 × $ 10^{13} $ 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 × $ 10^{12} $ 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 × $ 10^{12} $ vp. Trial registration (ClinicalTrials.gov Identifier: NCT02028442). Trial registration date: 07 January 2014 – Retrospectively registered.
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700	1		\|a Calvo, Emiliano \|4 aut
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allfields	10.1186/s40425-019-0510-7 doi (DE-627)SPR03643857X (SPR)s40425-019-0510-7-e DE-627 ger DE-627 rakwb eng Machiels, Jean-Pascal verfasserin aut A phase 1 dose escalation study of the oncolytic adenovirus enadenotucirev, administered intravenously to patients with epithelial solid tumors (EVOLVE) 2019 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s). 2019 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 × $ 10^{10} $ and 1 × $ 10^{13} $ 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 × $ 10^{12} $ 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 × $ 10^{12} $ vp. Trial registration (ClinicalTrials.gov Identifier: NCT02028442). Trial registration date: 07 January 2014 – Retrospectively registered. Clinical trials (dpeaa)DE-He213 Pharmacokinetics and pharmacodynamics (dpeaa)DE-He213 Enadenotucirev (dpeaa)DE-He213 Oncolytic adenovirus (dpeaa)DE-He213 Epithelial solid tumor (dpeaa)DE-He213 Intravenous (dpeaa)DE-He213 Salazar, Ramon aut Rottey, Sylvie aut Duran, Ignacio aut Dirix, Luc aut Geboes, Karen aut Wilkinson-Blanc, Christine aut Pover, Gillian aut Alvis, Simon aut Champion, Brian aut Fisher, Kerry aut McElwaine-Johnn, Hilary aut Beadle, John aut Calvo, Emiliano aut Enthalten in Journal for ImmunoTherapy of Cancer London : BioMed Central, 2013 7(2019), 1 vom: 28. Jan. (DE-627)750086335 (DE-600)2719863-7 2051-1426 nnns volume:7 year:2019 number:1 day:28 month:01 https://dx.doi.org/10.1186/s40425-019-0510-7 kostenfrei Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 7 2019 1 28 01
spelling	10.1186/s40425-019-0510-7 doi (DE-627)SPR03643857X (SPR)s40425-019-0510-7-e DE-627 ger DE-627 rakwb eng Machiels, Jean-Pascal verfasserin aut A phase 1 dose escalation study of the oncolytic adenovirus enadenotucirev, administered intravenously to patients with epithelial solid tumors (EVOLVE) 2019 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s). 2019 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 × $ 10^{10} $ and 1 × $ 10^{13} $ 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 × $ 10^{12} $ 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 × $ 10^{12} $ vp. Trial registration (ClinicalTrials.gov Identifier: NCT02028442). Trial registration date: 07 January 2014 – Retrospectively registered. Clinical trials (dpeaa)DE-He213 Pharmacokinetics and pharmacodynamics (dpeaa)DE-He213 Enadenotucirev (dpeaa)DE-He213 Oncolytic adenovirus (dpeaa)DE-He213 Epithelial solid tumor (dpeaa)DE-He213 Intravenous (dpeaa)DE-He213 Salazar, Ramon aut Rottey, Sylvie aut Duran, Ignacio aut Dirix, Luc aut Geboes, Karen aut Wilkinson-Blanc, Christine aut Pover, Gillian aut Alvis, Simon aut Champion, Brian aut Fisher, Kerry aut McElwaine-Johnn, Hilary aut Beadle, John aut Calvo, Emiliano aut Enthalten in Journal for ImmunoTherapy of Cancer London : BioMed Central, 2013 7(2019), 1 vom: 28. Jan. (DE-627)750086335 (DE-600)2719863-7 2051-1426 nnns volume:7 year:2019 number:1 day:28 month:01 https://dx.doi.org/10.1186/s40425-019-0510-7 kostenfrei Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 7 2019 1 28 01
allfields_unstemmed	10.1186/s40425-019-0510-7 doi (DE-627)SPR03643857X (SPR)s40425-019-0510-7-e DE-627 ger DE-627 rakwb eng Machiels, Jean-Pascal verfasserin aut A phase 1 dose escalation study of the oncolytic adenovirus enadenotucirev, administered intravenously to patients with epithelial solid tumors (EVOLVE) 2019 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s). 2019 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 × $ 10^{10} $ and 1 × $ 10^{13} $ 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 × $ 10^{12} $ 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 × $ 10^{12} $ vp. Trial registration (ClinicalTrials.gov Identifier: NCT02028442). Trial registration date: 07 January 2014 – Retrospectively registered. Clinical trials (dpeaa)DE-He213 Pharmacokinetics and pharmacodynamics (dpeaa)DE-He213 Enadenotucirev (dpeaa)DE-He213 Oncolytic adenovirus (dpeaa)DE-He213 Epithelial solid tumor (dpeaa)DE-He213 Intravenous (dpeaa)DE-He213 Salazar, Ramon aut Rottey, Sylvie aut Duran, Ignacio aut Dirix, Luc aut Geboes, Karen aut Wilkinson-Blanc, Christine aut Pover, Gillian aut Alvis, Simon aut Champion, Brian aut Fisher, Kerry aut McElwaine-Johnn, Hilary aut Beadle, John aut Calvo, Emiliano aut Enthalten in Journal for ImmunoTherapy of Cancer London : BioMed Central, 2013 7(2019), 1 vom: 28. Jan. (DE-627)750086335 (DE-600)2719863-7 2051-1426 nnns volume:7 year:2019 number:1 day:28 month:01 https://dx.doi.org/10.1186/s40425-019-0510-7 kostenfrei Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 7 2019 1 28 01
allfieldsGer	10.1186/s40425-019-0510-7 doi (DE-627)SPR03643857X (SPR)s40425-019-0510-7-e DE-627 ger DE-627 rakwb eng Machiels, Jean-Pascal verfasserin aut A phase 1 dose escalation study of the oncolytic adenovirus enadenotucirev, administered intravenously to patients with epithelial solid tumors (EVOLVE) 2019 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s). 2019 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 × $ 10^{10} $ and 1 × $ 10^{13} $ 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 × $ 10^{12} $ 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 × $ 10^{12} $ vp. Trial registration (ClinicalTrials.gov Identifier: NCT02028442). Trial registration date: 07 January 2014 – Retrospectively registered. Clinical trials (dpeaa)DE-He213 Pharmacokinetics and pharmacodynamics (dpeaa)DE-He213 Enadenotucirev (dpeaa)DE-He213 Oncolytic adenovirus (dpeaa)DE-He213 Epithelial solid tumor (dpeaa)DE-He213 Intravenous (dpeaa)DE-He213 Salazar, Ramon aut Rottey, Sylvie aut Duran, Ignacio aut Dirix, Luc aut Geboes, Karen aut Wilkinson-Blanc, Christine aut Pover, Gillian aut Alvis, Simon aut Champion, Brian aut Fisher, Kerry aut McElwaine-Johnn, Hilary aut Beadle, John aut Calvo, Emiliano aut Enthalten in Journal for ImmunoTherapy of Cancer London : BioMed Central, 2013 7(2019), 1 vom: 28. Jan. (DE-627)750086335 (DE-600)2719863-7 2051-1426 nnns volume:7 year:2019 number:1 day:28 month:01 https://dx.doi.org/10.1186/s40425-019-0510-7 kostenfrei Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 7 2019 1 28 01
allfieldsSound	10.1186/s40425-019-0510-7 doi (DE-627)SPR03643857X (SPR)s40425-019-0510-7-e DE-627 ger DE-627 rakwb eng Machiels, Jean-Pascal verfasserin aut A phase 1 dose escalation study of the oncolytic adenovirus enadenotucirev, administered intravenously to patients with epithelial solid tumors (EVOLVE) 2019 Text txt rdacontent Computermedien c rdamedia Online-Ressource cr rdacarrier © The Author(s). 2019 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 × $ 10^{10} $ and 1 × $ 10^{13} $ 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 × $ 10^{12} $ 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 × $ 10^{12} $ vp. Trial registration (ClinicalTrials.gov Identifier: NCT02028442). Trial registration date: 07 January 2014 – Retrospectively registered. Clinical trials (dpeaa)DE-He213 Pharmacokinetics and pharmacodynamics (dpeaa)DE-He213 Enadenotucirev (dpeaa)DE-He213 Oncolytic adenovirus (dpeaa)DE-He213 Epithelial solid tumor (dpeaa)DE-He213 Intravenous (dpeaa)DE-He213 Salazar, Ramon aut Rottey, Sylvie aut Duran, Ignacio aut Dirix, Luc aut Geboes, Karen aut Wilkinson-Blanc, Christine aut Pover, Gillian aut Alvis, Simon aut Champion, Brian aut Fisher, Kerry aut McElwaine-Johnn, Hilary aut Beadle, John aut Calvo, Emiliano aut Enthalten in Journal for ImmunoTherapy of Cancer London : BioMed Central, 2013 7(2019), 1 vom: 28. Jan. (DE-627)750086335 (DE-600)2719863-7 2051-1426 nnns volume:7 year:2019 number:1 day:28 month:01 https://dx.doi.org/10.1186/s40425-019-0510-7 kostenfrei Volltext GBV_USEFLAG_A SYSFLAG_A GBV_SPRINGER SSG-OLC-PHA GBV_ILN_11 GBV_ILN_20 GBV_ILN_22 GBV_ILN_23 GBV_ILN_24 GBV_ILN_31 GBV_ILN_39 GBV_ILN_40 GBV_ILN_60 GBV_ILN_62 GBV_ILN_63 GBV_ILN_65 GBV_ILN_69 GBV_ILN_73 GBV_ILN_74 GBV_ILN_95 GBV_ILN_105 GBV_ILN_110 GBV_ILN_151 GBV_ILN_161 GBV_ILN_170 GBV_ILN_206 GBV_ILN_213 GBV_ILN_230 GBV_ILN_285 GBV_ILN_293 GBV_ILN_602 GBV_ILN_2003 GBV_ILN_2014 GBV_ILN_4012 GBV_ILN_4037 GBV_ILN_4112 GBV_ILN_4125 GBV_ILN_4126 GBV_ILN_4249 GBV_ILN_4305 GBV_ILN_4306 GBV_ILN_4307 GBV_ILN_4313 GBV_ILN_4322 GBV_ILN_4323 GBV_ILN_4324 GBV_ILN_4325 GBV_ILN_4338 GBV_ILN_4367 GBV_ILN_4700 AR 7 2019 1 28 01
language	English
source	Enthalten in Journal for ImmunoTherapy of Cancer 7(2019), 1 vom: 28. Jan. volume:7 year:2019 number:1 day:28 month:01
sourceStr	Enthalten in Journal for ImmunoTherapy of Cancer 7(2019), 1 vom: 28. Jan. volume:7 year:2019 number:1 day:28 month:01
format_phy_str_mv	Article
institution	findex.gbv.de
topic_facet	Clinical trials Pharmacokinetics and pharmacodynamics Enadenotucirev Oncolytic adenovirus Epithelial solid tumor Intravenous
isfreeaccess_bool	true
container_title	Journal for ImmunoTherapy of Cancer
authorswithroles_txt_mv	Machiels, Jean-Pascal @@aut@@ Salazar, Ramon @@aut@@ Rottey, Sylvie @@aut@@ Duran, Ignacio @@aut@@ Dirix, Luc @@aut@@ Geboes, Karen @@aut@@ Wilkinson-Blanc, Christine @@aut@@ Pover, Gillian @@aut@@ Alvis, Simon @@aut@@ Champion, Brian @@aut@@ Fisher, Kerry @@aut@@ McElwaine-Johnn, Hilary @@aut@@ Beadle, John @@aut@@ Calvo, Emiliano @@aut@@
publishDateDaySort_date	2019-01-28T00:00:00Z
hierarchy_top_id	750086335
id	SPR03643857X
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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 × $ 10^{10} $ and 1 × $ 10^{13} $ 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 × $ 10^{12} $ 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 × $ 10^{12} $ vp. Trial registration (ClinicalTrials.gov Identifier: NCT02028442). 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author	Machiels, Jean-Pascal
spellingShingle	Machiels, Jean-Pascal misc Clinical trials misc Pharmacokinetics and pharmacodynamics misc Enadenotucirev misc Oncolytic adenovirus misc Epithelial solid tumor misc Intravenous A phase 1 dose escalation study of the oncolytic adenovirus enadenotucirev, administered intravenously to patients with epithelial solid tumors (EVOLVE)
authorStr	Machiels, Jean-Pascal
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topic_title	A phase 1 dose escalation study of the oncolytic adenovirus enadenotucirev, administered intravenously to patients with epithelial solid tumors (EVOLVE) Clinical trials (dpeaa)DE-He213 Pharmacokinetics and pharmacodynamics (dpeaa)DE-He213 Enadenotucirev (dpeaa)DE-He213 Oncolytic adenovirus (dpeaa)DE-He213 Epithelial solid tumor (dpeaa)DE-He213 Intravenous (dpeaa)DE-He213
topic	misc Clinical trials misc Pharmacokinetics and pharmacodynamics misc Enadenotucirev misc Oncolytic adenovirus misc Epithelial solid tumor misc Intravenous
topic_unstemmed	misc Clinical trials misc Pharmacokinetics and pharmacodynamics misc Enadenotucirev misc Oncolytic adenovirus misc Epithelial solid tumor misc Intravenous
topic_browse	misc Clinical trials misc Pharmacokinetics and pharmacodynamics misc Enadenotucirev misc Oncolytic adenovirus misc Epithelial solid tumor misc Intravenous
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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)
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title_full	A phase 1 dose escalation study of the oncolytic adenovirus enadenotucirev, administered intravenously to patients with epithelial solid tumors (EVOLVE)
author_sort	Machiels, Jean-Pascal
journal	Journal for ImmunoTherapy of Cancer
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author_browse	Machiels, Jean-Pascal Salazar, Ramon 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
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author-letter	Machiels, Jean-Pascal
doi_str_mv	10.1186/s40425-019-0510-7
title_sort	phase 1 dose escalation study of the oncolytic adenovirus enadenotucirev, administered intravenously to patients with epithelial solid tumors (evolve)
title_auth	A phase 1 dose escalation study of the oncolytic adenovirus enadenotucirev, administered intravenously to patients with epithelial solid tumors (EVOLVE)
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 × $ 10^{10} $ and 1 × $ 10^{13} $ 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 × $ 10^{12} $ 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 × $ 10^{12} $ vp. Trial registration (ClinicalTrials.gov Identifier: NCT02028442). Trial registration date: 07 January 2014 – Retrospectively registered. © The Author(s). 2019
abstractGer	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 × $ 10^{10} $ and 1 × $ 10^{13} $ 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 × $ 10^{12} $ 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 × $ 10^{12} $ vp. Trial registration (ClinicalTrials.gov Identifier: NCT02028442). Trial registration date: 07 January 2014 – Retrospectively registered. © The Author(s). 2019
abstract_unstemmed	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 × $ 10^{10} $ and 1 × $ 10^{13} $ 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 × $ 10^{12} $ 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 × $ 10^{12} $ vp. Trial registration (ClinicalTrials.gov Identifier: NCT02028442). Trial registration date: 07 January 2014 – Retrospectively registered. © The Author(s). 2019
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title_short	A phase 1 dose escalation study of the oncolytic adenovirus enadenotucirev, administered intravenously to patients with epithelial solid tumors (EVOLVE)
url	https://dx.doi.org/10.1186/s40425-019-0510-7
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author2	Salazar, Ramon 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
author2Str	Salazar, Ramon 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
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A phase 1 dose escalation study of the oncolytic adenovirus enadenotucirev, administered intravenously to patients with epithelial solid tumors (EVOLVE)

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