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dc.contributor.authorYap, TA
dc.contributor.authorWinter, JN
dc.contributor.authorGiulino-Roth, L
dc.contributor.authorLongley, J
dc.contributor.authorLopez, J
dc.contributor.authorMichot, J-M
dc.contributor.authorLeonard, JP
dc.contributor.authorRibrag, V
dc.contributor.authorMcCabe, MT
dc.contributor.authorCreasy, CL
dc.contributor.authorStern, M
dc.contributor.authorPene Dumitrescu, T
dc.contributor.authorWang, X
dc.contributor.authorFrey, S
dc.contributor.authorCarver, J
dc.contributor.authorHorner, T
dc.contributor.authorOh, C
dc.contributor.authorKhaled, A
dc.contributor.authorDhar, A
dc.contributor.authorJohnson, PWM
dc.coverage.spatialUnited States
dc.date.accessioned2023-05-24T15:08:43Z
dc.date.available2023-05-24T15:08:43Z
dc.date.issued2019-12-15
dc.identifier1078-0432.CCR-18-4121
dc.identifier.citationClinical Cancer Research, 2019, 25 (24), pp. 7331 - 7339en_US
dc.identifier.issn1078-0432
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/5805
dc.identifier.eissn1557-3265
dc.identifier.eissn1557-3265
dc.identifier.doi10.1158/1078-0432.CCR-18-4121
dc.description.abstractPURPOSE: Enhancer of zeste homolog 2 (EZH2) activity is dysregulated in many cancers. PATIENTS AND METHODS: This phase I study determined the safety, maximum-tolerated dose (MTD), pharmacokinetics, and pharmacodynamics of the intravenously administered, highly selective EZH2 inhibitor, GSK2816126, (NCT02082977). Doses of GSK2816126 ranged from 50 to 3,000 mg twice weekly, and GSK2816126 was given 3-weeks-on/1-week-off in 28-day cycles. Eligible patients had solid tumors or B-cell lymphomas with no available standard treatment regimen. RESULTS: Forty-one patients (21 solid tumors, 20 lymphoma) received treatment. All patients experienced ≥1 adverse event (AE). Fatigue [22 of 41 (53.7%)] and nausea [20 of 41 (48.8%)] were the most common toxicity. Twelve (32%) patients experienced a serious AE. Dose-limiting elevated liver transaminases occurred in 2 of 7 patients receiving 3,000 mg of GSK2816126; 2,400 mg was therefore established as the MTD. Following intravenous administration of 50 to 3,000 mg twice weekly, plasma GSK2816126 levels decreased biexponentially, with a mean terminal elimination half-life of approximately 27 hours. GSK2816126 exposure (maximum observed plasma concentration and area under the plasma-time curve) increased in a dose-proportional manner. No change from baseline in H3K27me3 was seen in peripheral blood mononuclear cells. Fourteen of 41 (34%) patients had radiological best response of stable disease, 1 patient with lymphoma achieved a partial response, 21 of 41 (51%) patients had progressive disease, and 5 patients were unevaluable for antitumor response. CONCLUSIONS: The MTD of GSK2816126 was established at 2,400 mg, but the dosing method and relatively short half-life limited effective exposure, and modest anticancer activity was observed at tolerable doses.
dc.formatPrint-Electronic
dc.format.extent7331 - 7339
dc.languageeng
dc.language.isoengen_US
dc.publisherAMER ASSOC CANCER RESEARCHen_US
dc.relation.ispartofClinical Cancer Research
dc.rights.urihttp://www.rioxx.net/licenses/all-rights-reserveden_US
dc.subjectAdult
dc.subjectAged
dc.subjectAged, 80 and over
dc.subjectAntineoplastic Agents
dc.subjectEnhancer of Zeste Homolog 2 Protein
dc.subjectFemale
dc.subjectHumans
dc.subjectIndoles
dc.subjectLymphoma, B-Cell
dc.subjectMale
dc.subjectMaximum Tolerated Dose
dc.subjectMiddle Aged
dc.subjectNeoplasms
dc.subjectPatient Safety
dc.subjectPrognosis
dc.subjectPyridones
dc.subjectTissue Distribution
dc.subjectYoung Adult
dc.titlePhase I Study of the Novel Enhancer of Zeste Homolog 2 (EZH2) Inhibitor GSK2816126 in Patients with Advanced Hematologic and Solid Tumors.en_US
dc.typeJournal Article
dcterms.dateAccepted2019-08-27
dc.date.updated2023-05-24T14:36:05Z
rioxxterms.versionAMen_US
rioxxterms.versionofrecord10.1158/1078-0432.CCR-18-4121en_US
rioxxterms.licenseref.startdate2019-12-15
rioxxterms.typeJournal Article/Reviewen_US
pubs.author-urlhttps://www.ncbi.nlm.nih.gov/pubmed/31471312
pubs.issue24
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/Clinical Studies
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies/Early Phase Drug Development
pubs.publication-statusPublished
pubs.publisher-urlhttp://dx.doi.org/10.1158/1078-0432.ccr-18-4121
pubs.volume25
icr.researchteamEarly Phase Drug Developen_US
dc.contributor.icrauthorLopez, Juanita
icr.provenanceDeposited by Ms Hilary Dent (impersonating Dr Juanita Lopez) on 2023-05-24. Deposit type is initial. No. of files: 1. Files: Phase I Study of the Novel Enhancer of Zeste Homolog 2 (EZH2) Inhibitor GSK2816126 in Patients with Advanced Hematologic and.pdf


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