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A First-Time-in-Human Study of GSK2636771, a Phosphoinositide 3 Kinase Beta-Selective Inhibitor, in Patients with Advanced Solid Tumors

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dc.contributor.author라선영-
dc.contributor.author정현철-
dc.date.accessioned2018-07-20T08:48:32Z-
dc.date.available2018-07-20T08:48:32Z-
dc.date.issued2017-
dc.identifier.issn1078-0432-
dc.identifier.urihttps://ir.ymlib.yonsei.ac.kr/handle/22282913/161400-
dc.description.abstractBackground: The PI3K/protein kinase B (AKT) pathway is commonly activated in several tumor types. Selective targeting of p110β could result in successful pathway inhibition while avoiding the on- and off-target effects of pan-PI3K inhibitors. GSK2636771 is a potent, orally bioavailable, adenosine triphosphate-competitive, selective inhibitor of PI3Kβ.Methods: We evaluated the safety, pharmacokinetics, pharmacodynamics and antitumor activity of GSK2636771 to define the recommended phase II dose (RP2D). During the dose-selection and dose-escalation stages (parts 1 and 2), patients with PTEN-deficient advanced solid tumors received escalating doses of GSK2636771 (25-500 mg once daily) using a modified 3+3 design to determine the RP2D; tumor type-specific expansion cohorts (part 3) were implemented to further assess tumor responses at the RP2D.Results: A total of 65 patients were enrolled; dose-limiting toxicities were hypophosphatemia and hypocalcemia. Adverse events included diarrhea (48%), nausea (40%), and vomiting (31%). Single- and repeat-dose exposure increased generally dose proportionally. GSK2636771 400 mg once daily was the RP2D. Phospho/total AKT ratio decreased with GSK2636771 in tumor and surrogate tissue. A castrate-resistant prostate cancer (CRPC) patient harboring PIK3CB amplification had a partial response for over a year; an additional 10 patients derived durable (≥24 weeks) clinical benefit, including two other patients with CRPC with PIK3CB alterations (≥34 weeks). GSK2636771 400 mg once daily orally induced sufficient exposure and target inhibition with a manageable safety profile.Conclusions: Genomic aberrations of PIK3CB may be associated with clinical benefit from GSK2636771.-
dc.description.statementOfResponsibilityrestriction-
dc.languageEnglish-
dc.publisherAmerican Association for Cancer Research-
dc.relation.isPartOfCLINICAL CANCER RESEARCH-
dc.rightsCC BY-NC-ND 2.0 KR-
dc.rightshttps://creativecommons.org/licenses/by-nc-nd/2.0/kr/-
dc.titleA First-Time-in-Human Study of GSK2636771, a Phosphoinositide 3 Kinase Beta-Selective Inhibitor, in Patients with Advanced Solid Tumors-
dc.typeArticle-
dc.contributor.collegeCollege of Medicine-
dc.contributor.departmentDept. of Internal Medicine-
dc.contributor.googleauthorJoaquin Mateo-
dc.contributor.googleauthorGopinath Ganji-
dc.contributor.googleauthorCharlotte Lemech-
dc.contributor.googleauthorHoward A. Burris-
dc.contributor.googleauthorSae-Won Han-
dc.contributor.googleauthorKaren Swales-
dc.contributor.googleauthorShaun Decordova-
dc.contributor.googleauthorM. Phillip DeYoung-
dc.contributor.googleauthorDeborah A. Smith-
dc.contributor.googleauthorShanker Kalyana-Sundaram-
dc.contributor.googleauthorJiuhua Wu-
dc.contributor.googleauthorMonica Motwani-
dc.contributor.googleauthorRakesh Kumar-
dc.contributor.googleauthorJerry M. Tolson-
dc.contributor.googleauthorSun Young Rha-
dc.contributor.googleauthorHyun Cheol Chung-
dc.contributor.googleauthorJoseph P. Eder-
dc.contributor.googleauthorSunil Sharma-
dc.contributor.googleauthorYung-Jue Bang-
dc.contributor.googleauthorJeffrey R. Infante-
dc.contributor.googleauthorLi Yan-
dc.contributor.googleauthorJohann S. de Bono-
dc.contributor.googleauthorHendrik-Tobias Arkenau-
dc.identifier.doi10.1158/1078-0432.CCR-17-0725-
dc.contributor.localIdA01316-
dc.contributor.localIdA03773-
dc.relation.journalcodeJ00564-
dc.identifier.pmid28645941-
dc.identifier.urlhttp://clincancerres.aacrjournals.org/content/23/19/5981.long-
dc.contributor.alternativeNameRha, Sun Young-
dc.contributor.alternativeNameChung, Hyun Cheol-
dc.contributor.affiliatedAuthorRha, Sun Young-
dc.contributor.affiliatedAuthorChung, Hyun Cheol-
dc.citation.volume23-
dc.citation.number19-
dc.citation.startPage5981-
dc.citation.endPage5992-
dc.identifier.bibliographicCitationCLINICAL CANCER RESEARCH, Vol.23(19) : 5981-5992, 2017-
Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers

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