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...
Ausführliche Beschreibung
Autor*in: |
Jean-Pascal Machiels [verfasserIn] Ramon Salazar [verfasserIn] Sylvie Rottey [verfasserIn] Ignacio Duran [verfasserIn] Luc Dirix [verfasserIn] Karen Geboes [verfasserIn] Christine Wilkinson-Blanc [verfasserIn] Gillian Pover [verfasserIn] Simon Alvis [verfasserIn] Brian Champion [verfasserIn] Kerry Fisher [verfasserIn] Hilary McElwaine-Johnn [verfasserIn] John Beadle [verfasserIn] Emiliano Calvo [verfasserIn] |
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Englisch |
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2019 |
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In: Journal for ImmunoTherapy of Cancer - BMJ Publishing Group, 2013, 7(2019), 1, Seite 15 |
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volume:7 ; year:2019 ; number:1 ; pages:15 |
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DOI / URN: |
10.1186/s40425-019-0510-7 |
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Katalog-ID: |
DOAJ047375043 |
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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 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. Trial registration (ClinicalTrials.gov Identifier: NCT02028442). Trial registration date: 07 January 2014 – Retrospectively registered. | ||
650 | 4 | |a Clinical trials | |
650 | 4 | |a Pharmacokinetics and pharmacodynamics | |
650 | 4 | |a Enadenotucirev | |
650 | 4 | |a Oncolytic adenovirus | |
650 | 4 | |a Epithelial solid tumor | |
650 | 4 | |a Intravenous | |
653 | 0 | |a Neoplasms. Tumors. Oncology. Including cancer and carcinogens | |
700 | 0 | |a Ramon Salazar |e verfasserin |4 aut | |
700 | 0 | |a Sylvie Rottey |e verfasserin |4 aut | |
700 | 0 | |a Ignacio Duran |e verfasserin |4 aut | |
700 | 0 | |a Luc Dirix |e verfasserin |4 aut | |
700 | 0 | |a Karen Geboes |e verfasserin |4 aut | |
700 | 0 | |a Christine Wilkinson-Blanc |e verfasserin |4 aut | |
700 | 0 | |a Gillian Pover |e verfasserin |4 aut | |
700 | 0 | |a Simon Alvis |e verfasserin |4 aut | |
700 | 0 | |a Brian Champion |e verfasserin |4 aut | |
700 | 0 | |a Kerry Fisher |e verfasserin |4 aut | |
700 | 0 | |a Hilary McElwaine-Johnn |e verfasserin |4 aut | |
700 | 0 | |a John Beadle |e verfasserin |4 aut | |
700 | 0 | |a Emiliano Calvo |e verfasserin |4 aut | |
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10.1186/s40425-019-0510-7 doi (DE-627)DOAJ047375043 (DE-599)DOAJ26c0983875fa4d0da5e0fc2f0a11a2aa DE-627 ger DE-627 rakwb eng RC254-282 Jean-Pascal Machiels 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 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. Trial registration (ClinicalTrials.gov Identifier: NCT02028442). Trial registration date: 07 January 2014 – Retrospectively registered. Clinical trials Pharmacokinetics and pharmacodynamics Enadenotucirev Oncolytic adenovirus Epithelial solid tumor Intravenous Neoplasms. Tumors. Oncology. Including cancer and carcinogens Ramon Salazar verfasserin aut Sylvie Rottey verfasserin aut Ignacio Duran verfasserin aut Luc Dirix verfasserin aut Karen Geboes verfasserin aut Christine Wilkinson-Blanc verfasserin aut Gillian Pover verfasserin aut Simon Alvis verfasserin aut Brian Champion verfasserin aut Kerry Fisher verfasserin aut Hilary McElwaine-Johnn verfasserin aut John Beadle verfasserin aut Emiliano Calvo verfasserin aut In Journal for ImmunoTherapy of Cancer BMJ Publishing Group, 2013 7(2019), 1, Seite 15 (DE-627)750086335 (DE-600)2719863-7 20511426 nnns volume:7 year:2019 number:1 pages:15 https://doi.org/10.1186/s40425-019-0510-7 kostenfrei https://doaj.org/article/26c0983875fa4d0da5e0fc2f0a11a2aa kostenfrei http://link.springer.com/article/10.1186/s40425-019-0510-7 kostenfrei https://doaj.org/toc/2051-1426 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ 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 15 |
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10.1186/s40425-019-0510-7 doi (DE-627)DOAJ047375043 (DE-599)DOAJ26c0983875fa4d0da5e0fc2f0a11a2aa DE-627 ger DE-627 rakwb eng RC254-282 Jean-Pascal Machiels 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 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. Trial registration (ClinicalTrials.gov Identifier: NCT02028442). Trial registration date: 07 January 2014 – Retrospectively registered. Clinical trials Pharmacokinetics and pharmacodynamics Enadenotucirev Oncolytic adenovirus Epithelial solid tumor Intravenous Neoplasms. Tumors. Oncology. Including cancer and carcinogens Ramon Salazar verfasserin aut Sylvie Rottey verfasserin aut Ignacio Duran verfasserin aut Luc Dirix verfasserin aut Karen Geboes verfasserin aut Christine Wilkinson-Blanc verfasserin aut Gillian Pover verfasserin aut Simon Alvis verfasserin aut Brian Champion verfasserin aut Kerry Fisher verfasserin aut Hilary McElwaine-Johnn verfasserin aut John Beadle verfasserin aut Emiliano Calvo verfasserin aut In Journal for ImmunoTherapy of Cancer BMJ Publishing Group, 2013 7(2019), 1, Seite 15 (DE-627)750086335 (DE-600)2719863-7 20511426 nnns volume:7 year:2019 number:1 pages:15 https://doi.org/10.1186/s40425-019-0510-7 kostenfrei https://doaj.org/article/26c0983875fa4d0da5e0fc2f0a11a2aa kostenfrei http://link.springer.com/article/10.1186/s40425-019-0510-7 kostenfrei https://doaj.org/toc/2051-1426 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ 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 15 |
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10.1186/s40425-019-0510-7 doi (DE-627)DOAJ047375043 (DE-599)DOAJ26c0983875fa4d0da5e0fc2f0a11a2aa DE-627 ger DE-627 rakwb eng RC254-282 Jean-Pascal Machiels 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 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. Trial registration (ClinicalTrials.gov Identifier: NCT02028442). Trial registration date: 07 January 2014 – Retrospectively registered. Clinical trials Pharmacokinetics and pharmacodynamics Enadenotucirev Oncolytic adenovirus Epithelial solid tumor Intravenous Neoplasms. Tumors. Oncology. Including cancer and carcinogens Ramon Salazar verfasserin aut Sylvie Rottey verfasserin aut Ignacio Duran verfasserin aut Luc Dirix verfasserin aut Karen Geboes verfasserin aut Christine Wilkinson-Blanc verfasserin aut Gillian Pover verfasserin aut Simon Alvis verfasserin aut Brian Champion verfasserin aut Kerry Fisher verfasserin aut Hilary McElwaine-Johnn verfasserin aut John Beadle verfasserin aut Emiliano Calvo verfasserin aut In Journal for ImmunoTherapy of Cancer BMJ Publishing Group, 2013 7(2019), 1, Seite 15 (DE-627)750086335 (DE-600)2719863-7 20511426 nnns volume:7 year:2019 number:1 pages:15 https://doi.org/10.1186/s40425-019-0510-7 kostenfrei https://doaj.org/article/26c0983875fa4d0da5e0fc2f0a11a2aa kostenfrei http://link.springer.com/article/10.1186/s40425-019-0510-7 kostenfrei https://doaj.org/toc/2051-1426 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ 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 15 |
allfieldsGer |
10.1186/s40425-019-0510-7 doi (DE-627)DOAJ047375043 (DE-599)DOAJ26c0983875fa4d0da5e0fc2f0a11a2aa DE-627 ger DE-627 rakwb eng RC254-282 Jean-Pascal Machiels 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 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. Trial registration (ClinicalTrials.gov Identifier: NCT02028442). Trial registration date: 07 January 2014 – Retrospectively registered. Clinical trials Pharmacokinetics and pharmacodynamics Enadenotucirev Oncolytic adenovirus Epithelial solid tumor Intravenous Neoplasms. Tumors. Oncology. Including cancer and carcinogens Ramon Salazar verfasserin aut Sylvie Rottey verfasserin aut Ignacio Duran verfasserin aut Luc Dirix verfasserin aut Karen Geboes verfasserin aut Christine Wilkinson-Blanc verfasserin aut Gillian Pover verfasserin aut Simon Alvis verfasserin aut Brian Champion verfasserin aut Kerry Fisher verfasserin aut Hilary McElwaine-Johnn verfasserin aut John Beadle verfasserin aut Emiliano Calvo verfasserin aut In Journal for ImmunoTherapy of Cancer BMJ Publishing Group, 2013 7(2019), 1, Seite 15 (DE-627)750086335 (DE-600)2719863-7 20511426 nnns volume:7 year:2019 number:1 pages:15 https://doi.org/10.1186/s40425-019-0510-7 kostenfrei https://doaj.org/article/26c0983875fa4d0da5e0fc2f0a11a2aa kostenfrei http://link.springer.com/article/10.1186/s40425-019-0510-7 kostenfrei https://doaj.org/toc/2051-1426 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ 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 15 |
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10.1186/s40425-019-0510-7 doi (DE-627)DOAJ047375043 (DE-599)DOAJ26c0983875fa4d0da5e0fc2f0a11a2aa DE-627 ger DE-627 rakwb eng RC254-282 Jean-Pascal Machiels 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 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. Trial registration (ClinicalTrials.gov Identifier: NCT02028442). Trial registration date: 07 January 2014 – Retrospectively registered. Clinical trials Pharmacokinetics and pharmacodynamics Enadenotucirev Oncolytic adenovirus Epithelial solid tumor Intravenous Neoplasms. Tumors. Oncology. Including cancer and carcinogens Ramon Salazar verfasserin aut Sylvie Rottey verfasserin aut Ignacio Duran verfasserin aut Luc Dirix verfasserin aut Karen Geboes verfasserin aut Christine Wilkinson-Blanc verfasserin aut Gillian Pover verfasserin aut Simon Alvis verfasserin aut Brian Champion verfasserin aut Kerry Fisher verfasserin aut Hilary McElwaine-Johnn verfasserin aut John Beadle verfasserin aut Emiliano Calvo verfasserin aut In Journal for ImmunoTherapy of Cancer BMJ Publishing Group, 2013 7(2019), 1, Seite 15 (DE-627)750086335 (DE-600)2719863-7 20511426 nnns volume:7 year:2019 number:1 pages:15 https://doi.org/10.1186/s40425-019-0510-7 kostenfrei https://doaj.org/article/26c0983875fa4d0da5e0fc2f0a11a2aa kostenfrei http://link.springer.com/article/10.1186/s40425-019-0510-7 kostenfrei https://doaj.org/toc/2051-1426 Journal toc kostenfrei GBV_USEFLAG_A SYSFLAG_A GBV_DOAJ 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 15 |
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Jean-Pascal Machiels @@aut@@ Ramon Salazar @@aut@@ Sylvie Rottey @@aut@@ Ignacio Duran @@aut@@ Luc Dirix @@aut@@ Karen Geboes @@aut@@ Christine Wilkinson-Blanc @@aut@@ Gillian Pover @@aut@@ Simon Alvis @@aut@@ Brian Champion @@aut@@ Kerry Fisher @@aut@@ Hilary McElwaine-Johnn @@aut@@ John Beadle @@aut@@ Emiliano Calvo @@aut@@ |
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RC254-282 A phase 1 dose escalation study of the oncolytic adenovirus enadenotucirev, administered intravenously to patients with epithelial solid tumors (EVOLVE) Clinical trials Pharmacokinetics and pharmacodynamics Enadenotucirev Oncolytic adenovirus Epithelial solid tumor Intravenous |
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misc RC254-282 misc Clinical trials misc Pharmacokinetics and pharmacodynamics misc Enadenotucirev misc Oncolytic adenovirus misc Epithelial solid tumor misc Intravenous misc Neoplasms. Tumors. Oncology. Including cancer and carcinogens |
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misc RC254-282 misc Clinical trials misc Pharmacokinetics and pharmacodynamics misc Enadenotucirev misc Oncolytic adenovirus misc Epithelial solid tumor misc Intravenous misc Neoplasms. Tumors. Oncology. Including cancer and carcinogens |
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misc RC254-282 misc Clinical trials misc Pharmacokinetics and pharmacodynamics misc Enadenotucirev misc Oncolytic adenovirus misc Epithelial solid tumor misc Intravenous misc Neoplasms. Tumors. Oncology. Including cancer and carcinogens |
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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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A phase 1 dose escalation study of the oncolytic adenovirus enadenotucirev, administered intravenously to patients with epithelial solid tumors (EVOLVE) |
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Jean-Pascal Machiels |
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Jean-Pascal Machiels Ramon Salazar Sylvie Rottey Ignacio Duran Luc Dirix Karen Geboes Christine Wilkinson-Blanc Gillian Pover Simon Alvis Brian Champion Kerry Fisher Hilary McElwaine-Johnn John Beadle Emiliano Calvo |
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phase 1 dose escalation study of the oncolytic adenovirus enadenotucirev, administered intravenously to patients with epithelial solid tumors (evolve) |
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A phase 1 dose escalation study of the oncolytic adenovirus enadenotucirev, administered intravenously to patients with epithelial solid tumors (EVOLVE) |
abstract |
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. Trial registration (ClinicalTrials.gov Identifier: NCT02028442). Trial registration date: 07 January 2014 – Retrospectively registered. |
abstractGer |
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. Trial registration (ClinicalTrials.gov Identifier: NCT02028442). Trial registration date: 07 January 2014 – Retrospectively registered. |
abstract_unstemmed |
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. Trial registration (ClinicalTrials.gov Identifier: NCT02028442). Trial registration date: 07 January 2014 – Retrospectively registered. |
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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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