Characterization and phase I study of CLR457, an orally bioavailable pan-class I PI3-kinase inhibitor

CLR457; Inhibidor Pan-PI3K; Fase I

Detalles Bibliográficos
Autores: Harding, James J., Tan, Daniel S. W., Bedard, Philippe L., Rodon Ahnert, Jordi, Doi, Toshihiko, Bauer, Todd
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2018
País:España
Institución:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
Repositorio:Recercat. Dipósit de la Recerca de Catalunya
OAI Identifier:oai:recercat.cat:11351/5870
Acceso en línea:https://hdl.handle.net/11351/5870
http://hdl.handle.net/11351/5870
Access Level:acceso abierto
Palabra clave:Tumors
Inhibidors enzimàtics
CHEMICALS AND DRUGS::Chemical Actions and Uses::Pharmacologic Actions::Molecular Mechanisms of Pharmacological Action::Enzyme Inhibitors::Protein Kinase Inhibitors
DISEASES::Neoplasms
COMPUESTOS QUÍMICOS Y DROGAS::acciones y usos químicos::acciones farmacológicas::mecanismos moleculares de acción farmacológica::inhibidores enzimáticos::inhibidores de proteínas cinasas
ENFERMEDADES::neoplasias
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spelling Characterization and phase I study of CLR457, an orally bioavailable pan-class I PI3-kinase inhibitorHarding, James J.Tan, Daniel S. W.Bedard, Philippe L.Rodon Ahnert, JordiDoi, ToshihikoBauer, ToddTumorsInhibidors enzimàticsCHEMICALS AND DRUGS::Chemical Actions and Uses::Pharmacologic Actions::Molecular Mechanisms of Pharmacological Action::Enzyme Inhibitors::Protein Kinase InhibitorsDISEASES::NeoplasmsCOMPUESTOS QUÍMICOS Y DROGAS::acciones y usos químicos::acciones farmacológicas::mecanismos moleculares de acción farmacológica::inhibidores enzimáticos::inhibidores de proteínas cinasasENFERMEDADES::neoplasiasCLR457; Inhibidor Pan-PI3K; Fase ICLR457; Inhibidor Pan-PI3K; Fase ICLR457; Pan-PI3K inhibitor; Phase IBackground CLR457 is an orally bioavailable pan-phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) inhibitor. Methods CLR457 anti-tumor activity and pharmacokinetics (PK) were characterized by in vitro biochemical assays and in vivo tumor xenografts. A first-in-human study was conducted to determine the maximum tolerated dose (MTD), safety, PK, and efficacy of CLR457. Successive cohorts of patients with advanced solid tumors with PI3K pathway activation received increasing CLR457 doses according to a Bayesian escalation model based on the rate of dose limiting toxicity (DLT) in the first 28-day cycle. Results CLR457 inhibited p110α, p110β, p110δ and p110γ isoforms with an IC50 of 89 ± 29 nM, 56 ± 35 nM, 39 ± 10 nM and 230 ± 31 nM, respectively. CLR457 exhibited dose-dependent antitumor activity and interfered with glucose homeostasis in PI3K-mutant tumor xenografts. 31 patients received doses ranging from 5 to 100 mg. DLTs included grade 3 hyperglycemia and rash (3). In the 100 mg cohort (n = 11), 3 (27.3%) patients had DLTs and all patients (100%) experienced ≥ grade 3 toxicity with rash (45.5%) as the most common event. The MTD was not determined. For the entire study population, stomatitis (45.2%), diarrhea (38.7%), rash (35.5%) were the most common any grade toxicities—51.6% patients experienced ≥ Grade 3 toxicity. CLR457 was rapidly absorbed with limited accumulation and linear PK. PK modeling indicated that pharmacologically active concentrations were achieved at the highest dose tested (100 mg), though no objective responses were observed. Conclusion CLR457 clinical development was terminated due to poor tolerability and limited antitumor activity. These results emphasize the difficulty of achieving a wide therapeutic index when targeting all class I PI3K-isoforms.Novartis Pharmaceuticals Corporation.SpringerInstitut Català de la Salut[Harding JJ] Memorial Sloan Kettering Cancer Center, New York, NY, USA. [Bauer TM] Sarah Cannon Research Institute / Tennessee Oncology, PLLC, Nashville, TN, USA. [Tan DSW] National Cancer Centre, Singapore, Singapore. [Bedard PL] Princess Margaret Cancer Centre, Toronto, ON, Canada. [Rodon J] Vall d’Hebron Hospital Universitari, Barcelona, Spain. [Doi T] National Cancer Center East, Kashiwa, Chiba, JapanVall d'Hebron Barcelona Hospital Campus2021202120182019info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfhttps://hdl.handle.net/11351/5870http://hdl.handle.net/11351/5870Scientiareponame:Recercat. Dipósit de la Recerca de Catalunyainstname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)InglésInvestigational New Drugs;37(2)https://link.springer.com/article/10.1007/s10637-018-0627-4Attribution 4.0 Internationalhttp://creativecommons.org/licenses/by/4.0/info:eu-repo/semantics/openAccessoai:recercat.cat:11351/58702026-05-29T05:05:01Z
dc.title.none.fl_str_mv Characterization and phase I study of CLR457, an orally bioavailable pan-class I PI3-kinase inhibitor
title Characterization and phase I study of CLR457, an orally bioavailable pan-class I PI3-kinase inhibitor
spellingShingle Characterization and phase I study of CLR457, an orally bioavailable pan-class I PI3-kinase inhibitor
Harding, James J.
Tumors
Inhibidors enzimàtics
CHEMICALS AND DRUGS::Chemical Actions and Uses::Pharmacologic Actions::Molecular Mechanisms of Pharmacological Action::Enzyme Inhibitors::Protein Kinase Inhibitors
DISEASES::Neoplasms
COMPUESTOS QUÍMICOS Y DROGAS::acciones y usos químicos::acciones farmacológicas::mecanismos moleculares de acción farmacológica::inhibidores enzimáticos::inhibidores de proteínas cinasas
ENFERMEDADES::neoplasias
title_short Characterization and phase I study of CLR457, an orally bioavailable pan-class I PI3-kinase inhibitor
title_full Characterization and phase I study of CLR457, an orally bioavailable pan-class I PI3-kinase inhibitor
title_fullStr Characterization and phase I study of CLR457, an orally bioavailable pan-class I PI3-kinase inhibitor
title_full_unstemmed Characterization and phase I study of CLR457, an orally bioavailable pan-class I PI3-kinase inhibitor
title_sort Characterization and phase I study of CLR457, an orally bioavailable pan-class I PI3-kinase inhibitor
dc.creator.none.fl_str_mv Harding, James J.
Tan, Daniel S. W.
Bedard, Philippe L.
Rodon Ahnert, Jordi
Doi, Toshihiko
Bauer, Todd
author Harding, James J.
author_facet Harding, James J.
Tan, Daniel S. W.
Bedard, Philippe L.
Rodon Ahnert, Jordi
Doi, Toshihiko
Bauer, Todd
author_role author
author2 Tan, Daniel S. W.
Bedard, Philippe L.
Rodon Ahnert, Jordi
Doi, Toshihiko
Bauer, Todd
author2_role author
author
author
author
author
dc.contributor.none.fl_str_mv Institut Català de la Salut
[Harding JJ] Memorial Sloan Kettering Cancer Center, New York, NY, USA. [Bauer TM] Sarah Cannon Research Institute / Tennessee Oncology, PLLC, Nashville, TN, USA. [Tan DSW] National Cancer Centre, Singapore, Singapore. [Bedard PL] Princess Margaret Cancer Centre, Toronto, ON, Canada. [Rodon J] Vall d’Hebron Hospital Universitari, Barcelona, Spain. [Doi T] National Cancer Center East, Kashiwa, Chiba, Japan
Vall d'Hebron Barcelona Hospital Campus
dc.subject.none.fl_str_mv Tumors
Inhibidors enzimàtics
CHEMICALS AND DRUGS::Chemical Actions and Uses::Pharmacologic Actions::Molecular Mechanisms of Pharmacological Action::Enzyme Inhibitors::Protein Kinase Inhibitors
DISEASES::Neoplasms
COMPUESTOS QUÍMICOS Y DROGAS::acciones y usos químicos::acciones farmacológicas::mecanismos moleculares de acción farmacológica::inhibidores enzimáticos::inhibidores de proteínas cinasas
ENFERMEDADES::neoplasias
topic Tumors
Inhibidors enzimàtics
CHEMICALS AND DRUGS::Chemical Actions and Uses::Pharmacologic Actions::Molecular Mechanisms of Pharmacological Action::Enzyme Inhibitors::Protein Kinase Inhibitors
DISEASES::Neoplasms
COMPUESTOS QUÍMICOS Y DROGAS::acciones y usos químicos::acciones farmacológicas::mecanismos moleculares de acción farmacológica::inhibidores enzimáticos::inhibidores de proteínas cinasas
ENFERMEDADES::neoplasias
description CLR457; Inhibidor Pan-PI3K; Fase I
publishDate 2018
dc.date.none.fl_str_mv 2018
2019
2021
2021
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/11351/5870
http://hdl.handle.net/11351/5870
url https://hdl.handle.net/11351/5870
http://hdl.handle.net/11351/5870
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Investigational New Drugs;37(2)
https://link.springer.com/article/10.1007/s10637-018-0627-4
dc.rights.none.fl_str_mv Attribution 4.0 International
http://creativecommons.org/licenses/by/4.0/
info:eu-repo/semantics/openAccess
rights_invalid_str_mv Attribution 4.0 International
http://creativecommons.org/licenses/by/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv Springer
publisher.none.fl_str_mv Springer
dc.source.none.fl_str_mv Scientia
reponame:Recercat. Dipósit de la Recerca de Catalunya
instname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
instname_str Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
reponame_str Recercat. Dipósit de la Recerca de Catalunya
collection Recercat. Dipósit de la Recerca de Catalunya
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,812429

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