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dc.contributor.authorMateo, J
dc.contributor.authorGanji, G
dc.contributor.authorLemech, C
dc.contributor.authorBurris, HA
dc.contributor.authorHan, S-W
dc.contributor.authorSwales, K
dc.contributor.authorDecordova, S
dc.contributor.authorDeYoung, MP
dc.contributor.authorSmith, DA
dc.contributor.authorKalyana-Sundaram, S
dc.contributor.authorWu, J
dc.contributor.authorMotwani, M
dc.contributor.authorKumar, R
dc.contributor.authorTolson, JM
dc.contributor.authorRha, SY
dc.contributor.authorChung, HC
dc.contributor.authorEder, JP
dc.contributor.authorSharma, S
dc.contributor.authorBang, Y-J
dc.contributor.authorInfante, JR
dc.contributor.authorYan, L
dc.contributor.authorde Bono, JS
dc.contributor.authorArkenau, H-T
dc.date.accessioned2017-08-14T13:54:06Z
dc.date.issued2017-10-01
dc.identifier.citationClinical cancer research : an official journal of the American Association for Cancer Research, 2017, 23 (19), pp. 5981 - 5992
dc.identifier.issn1078-0432
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/773
dc.identifier.eissn1557-3265
dc.identifier.doi10.1158/1078-0432.ccr-17-0725
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. Clin Cancer Res; 23(19); 5981-92. ©2017 AACR.
dc.formatPrint-Electronic
dc.format.extent5981 - 5992
dc.languageeng
dc.language.isoeng
dc.publisherAMER ASSOC CANCER RESEARCH
dc.rights.urihttps://www.rioxx.net/licenses/all-rights-reserved
dc.subjectHumans
dc.subjectNeoplasms
dc.subjectImidazoles
dc.subjectMorpholines
dc.subjectProtein Kinase Inhibitors
dc.subjectNeoplasm Staging
dc.subjectDrug Administration Schedule
dc.subjectMaximum Tolerated Dose
dc.subjectDose-Response Relationship, Drug
dc.subjectAdult
dc.subjectAged
dc.subjectMiddle Aged
dc.subjectFemale
dc.subjectMale
dc.subjectPhosphatidylinositol 3-Kinases
dc.subjectPhosphoinositide-3 Kinase Inhibitors
dc.titleA First-Time-in-Human Study of GSK2636771, a Phosphoinositide 3 Kinase Beta-Selective Inhibitor, in Patients with Advanced Solid Tumors.
dc.typeJournal Article
dcterms.dateAccepted2017-06-19
rioxxterms.funderThe Institute of Cancer Research
rioxxterms.identifier.projectUnspecified
rioxxterms.versionofrecord10.1158/1078-0432.ccr-17-0725
rioxxterms.licenseref.urihttps://www.rioxx.net/licenses/all-rights-reserved
rioxxterms.licenseref.startdate2017-10
rioxxterms.typeJournal Article/Review
dc.relation.isPartOfClinical cancer research : an official journal of the American Association for Cancer Research
pubs.issue19
pubs.notesNot known
pubs.organisational-group/ICR
pubs.organisational-group/ICR/Primary Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Clinical PD Biomarker Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies/Clinical PD Biomarker Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies/Prostate Cancer Targeted Therapy Group
pubs.organisational-group/ICR/Primary Group/Royal Marsden Clinical Units
pubs.organisational-group/ICR
pubs.organisational-group/ICR/Primary Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Clinical PD Biomarker Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies/Clinical PD Biomarker Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies/Prostate Cancer Targeted Therapy Group
pubs.organisational-group/ICR/Primary Group/Royal Marsden Clinical Units
pubs.publication-statusPublished
pubs.volume23
pubs.embargo.termsNot known
icr.researchteamClinical PD Biomarker Group
icr.researchteamProstate Cancer Targeted Therapy Group
dc.contributor.icrauthorSwales, Karen
dc.contributor.icrauthorDe Bono, Johann


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