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dc.contributor.authorWolin, Edward
dc.contributor.authorMita, Alain
dc.contributor.authorMahipal, Amit
dc.contributor.authorMeyer, Tim
dc.contributor.authorBendell, Johanna
dc.contributor.authorNemunaitis, John
dc.contributor.authorMunster, Pam N
dc.contributor.authorPaz Ares, Luis Gonzaga 
dc.contributor.authorFilvaroff, Ellen H
dc.contributor.authorLi, Shaoyi
dc.contributor.authorHege, Kristen
dc.contributor.authorde Haan, Hans
dc.contributor.authorMita, Monica
dc.date.accessioned2020-03-30T14:11:44Z
dc.date.available2020-03-30T14:11:44Z
dc.date.issued2019-09-17
dc.identifier.citationPLoS One. 2019 ;14(9):e0221994.es_ES
dc.identifier.issn1932-6203es_ES
dc.identifier.urihttp://hdl.handle.net/20.500.12105/9369
dc.description.abstractSecond-generation mammalian target of rapamycin (mTOR) inhibitors such as CC-223 may have theoretical advantages over first-generation drugs by inhibiting TOR kinase in mTOR complex 1 (mTORC1) and 2 (mTORC2), potentially improving clinical efficacy for well-differentiated neuroendocrine tumors (NET).Enrolled patients had metastatic, well-differentiated NET of non-pancreatic gastrointestinal or unknown origin, with/without carcinoid symptoms, had failed ≥1 systemic chemotherapy, and were taking a somatostatin analog (SSA). Oral once-daily CC-223 was administered in 28-day cycles starting at 45 mg (n = 24), with a subsequent cohort starting at 30 mg (n = 23). Objectives were to evaluate tolerability, preliminary efficacy, and pharmacokinetic and biomarker profiles of CC-223. Forty-seven patients completed the study, with mean treatment duration of 378 days and mean dose of 26 mg; 26% of patients remained on the starting dose. Most frequent grade ≥3 toxicities were diarrhea (38%), fatigue (21%), and stomatitis (11%). By investigator, 3 of 41 evaluable patients (7%) showed partial response (PR) and 34 (83%) had stable disease (SD) for a disease control rate (DCR) of 90% (95% confidence interval [CI] 76.9-97.3%). Duration of PR was 125-401 days; median SD duration was 297 days (min-max, 50-1519 days). Median progression-free survival was 19.5 months (95% CI 10.4-28.5 months). Carcinoid symptoms of flushing, diarrhea, or both improved in 50%, 41%, and 39% of affected patients, respectively. For the first time, this study describes that a second-generation mTOR pathway inhibitor can result in highly durable tumor regression and control of NET carcinoid symptoms. The manageable safety profile, high DCR, and durable response, coupled with reduction in carcinoid symptoms refractory to SSA, make CC-223 a promising agent for further development.es_ES
dc.description.sponsorshipWe thank the patients and their families, and the principal investigator study teams, for enabling this study to complete successfully. We also thank the many support staff at Celgene who were involved in the operational aspects of the study, including Angela Joubert James and Torsten Trowe, who were employees of Celgene at the time of the study. The authors received medical writing assistance from Amy Agbonbhase, PhD, of The Lockwood Group, funded by Celgene Corporation.es_ES
dc.language.isoenges_ES
dc.publisherPloses_ES
dc.relation.isversionofPublisher's versiones_ES
dc.rights.urihttp://creativecommons.org/licenses/by-nc-sa/4.0/*
dc.subject.meshAdministration, Orales_ES
dc.subject.meshAdult es_ES
dc.subject.meshAged es_ES
dc.subject.meshCarcinoid Tumor es_ES
dc.subject.meshCohort Studies es_ES
dc.subject.meshFemale es_ES
dc.subject.meshGastrointestinal Neoplasms es_ES
dc.subject.meshHumans es_ES
dc.subject.meshMale es_ES
dc.subject.meshMaximum Tolerated Dose es_ES
dc.subject.meshMechanistic Target of Rapamycin Complex 1 es_ES
dc.subject.meshMechanistic Target of Rapamycin Complex 2 es_ES
dc.subject.meshMiddle Aged es_ES
dc.subject.meshNeuroendocrine Tumors es_ES
dc.subject.meshPyrazines es_ES
dc.titleA phase 2 study of an oral mTORC1/mTORC2 kinase inhibitor (CC-223) for non-pancreatic neuroendocrine tumors with or without carcinoid symptomses_ES
dc.typeArtículoes_ES
dc.rights.licenseAtribución-NoComercial-CompartirIgual 4.0 Internacional*
dc.identifier.pubmedID31527867es_ES
dc.format.volume14es_ES
dc.format.number9es_ES
dc.format.pagee0221994es_ES
dc.identifier.doi10.1371/journal.pone.0221994es_ES
dc.description.peerreviewedes_ES
dc.identifier.e-issn1932-6203es_ES
dc.relation.publisherversionhttps://doi.org/10.1371/journal.pone.0221994.es_ES
dc.identifier.journalPloS onees_ES
dc.repisalud.institucionCNIOes_ES
dc.repisalud.orgCNIOCNIO::Unidades técnicas::Unidad de Investigación Clínica de Cáncer Pulmón H12O-CNIOes_ES
dc.rights.accessRightsinfo:eu-repo/semantics/openAccesses_ES


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Atribución-NoComercial-CompartirIgual 4.0 Internacional
This item is licensed under a: Atribución-NoComercial-CompartirIgual 4.0 Internacional