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dc.contributorVall d'Hebron Barcelona Hospital Campus
dc.contributor.authorChoudhury, Atish D.
dc.contributor.authorHigano, Celestia
dc.contributor.authorde Bono, Johann S
dc.contributor.authorCook, Natalie
dc.contributor.authorRathkopf, Dana E.
dc.contributor.authorWisinski, Kari
dc.contributor.authorMartín Liberal, Juan Jesús
dc.date.accessioned2022-09-08T11:41:04Z
dc.date.available2022-09-08T11:41:04Z
dc.date.issued2022-06-01
dc.identifier.citationChoudhury AD, Higano CS, de Bono JS, Cook N, Rathkopf DE, Wisinski KB, et al. A Phase I Study Investigating AZD8186, a Potent and Selective Inhibitor of PI3Kβ/δ, in Patients with Advanced Solid Tumors. Clin Cancer Res. 2022 Jun 1;28(11):2257–69.
dc.identifier.issn1557-3265
dc.identifier.urihttp://hdl.handle.net/11351/8076
dc.descriptionAdvanced Solid Tumors; PI3K beta/delta inhibitor
dc.description.abstractPurpose: To characterize safety and tolerability of the selective PI3Kβ inhibitor AZD8186, identify a recommended phase II dose (RP2D), and assess preliminary efficacy in combination with abiraterone acetate or vistusertib. Patients and Methods: This phase I open-label study included patients with advanced solid tumors, particularly prostate cancer, triple-negative breast cancer, and squamous non–small cell lung cancer. The study comprised four arms: (i) AZD8186 monotherapy dose finding; (ii) monotherapy dose expansion; (iii) AZD8186/abiraterone acetate (with prednisone); and (iv) AZD8186/vistusertib. The primary endpoints were safety, tolerability, and identification of the RP2D of AZD8186 monotherapy and in combination. Secondary endpoints included pharmacokinetics (PK), pharmacodynamics, and tumor and prostate-specific antigen (PSA) responses. Results: In total, 161 patients were enrolled. AZD8186 was well tolerated across all study arms, the most common adverse events being gastrointestinal symptoms. In the monotherapy dose-finding arm, four patients experienced dose-limiting toxicities (mainly rash). AZD8186 doses of 60-mg twice daily [BID; 5 days on, 2 days off (5:2)] and 120-mg BID (continuous and 5:2 dosing) were taken into subsequent arms. The PKs of AZD8186 were dose proportional, without interactions with abiraterone acetate or vistusertib, and target inhibition was observed in plasma and tumor tissue. Monotherapy and combination therapy showed preliminary evidence of limited antitumor activity by imaging and, in prostate cancer, PSA reduction. Conclusions: AZD8186 monotherapy had an acceptable safety and tolerability profile, and combination with abiraterone acetate/prednisone or vistusertib was also tolerated. There was preliminary evidence of antitumor activity, meriting further exploration of AZD8186 in subsequent studies in PI3Kβ pathway–dependent cancers.
dc.language.isoeng
dc.publisherAmerican Association for Cancer Research
dc.relation.ispartofseriesClinical Cancer Research;28(11)
dc.rightsAttribution-NonCommercial-NoDerivatives 4.0 International
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/
dc.sourceScientia
dc.subjectCàncer - Tractament
dc.subjectFosfodiesterases - Inhibidors
dc.subject.meshNeoplasms
dc.subject.mesh/drug therapy
dc.subject.meshPhosphodiesterase Inhibitors
dc.titleA Phase I Study Investigating AZD8186, a Potent and Selective Inhibitor of PI3Kβ/δ, in Patients with Advanced Solid Tumors
dc.typeinfo:eu-repo/semantics/article
dc.identifier.doi10.1158/1078-0432.CCR-21-3087
dc.subject.decsneoplasias
dc.subject.decs/farmacoterapia
dc.subject.decsinhibidores de fosfodiesterasas
dc.relation.publishversionhttps://doi.org/10.1158/1078-0432.CCR-21-3087
dc.type.versioninfo:eu-repo/semantics/publishedVersion
dc.audienceProfessionals
dc.contributor.organismesInstitut Català de la Salut
dc.contributor.authoraffiliation[Choudhury AD] Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts. [Higano CS] Department of Medical Oncology, University of Washington and Fred Hutchinson Cancer Research Center, Seattle, Washington. [de Bono JS] Drug Development Unit, The Institute of Cancer Research and Royal Marsden, London, United Kingdom. [Cook N] The Christie NHS Foundation Trust and The University of Manchester, Manchester, United Kingdom. [Rathkopf DE] Memorial Sloan Kettering Cancer Center and Weill Cornell Medicine, New York, New York. [Wisinski KB] Carbone Cancer Center, University of Wisconsin–Madison, Madison, Wisconsin. [Martin-Liberal J] Servei d’Oncologia Mèdica, Vall d’Hebron Hospital Universitari, Barcelona, Spain. Vall d’Hebron Institute of Oncology (VHIO), Barcelona, Spain
dc.identifier.pmid35247924
dc.identifier.wos000809230200001
dc.rights.accessrightsinfo:eu-repo/semantics/openAccess


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