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dc.contributor.authorMateo, Jen_US
dc.contributor.authorOlmos, Den_US
dc.contributor.authorDumez, Hen_US
dc.contributor.authorPoondru, Sen_US
dc.contributor.authorSamberg, NLen_US
dc.contributor.authorBarr, Sen_US
dc.contributor.authorVan Tornout, JMen_US
dc.contributor.authorJie, Fen_US
dc.contributor.authorSandhu, Sen_US
dc.contributor.authorTan, DSen_US
dc.contributor.authorMoreno, Ven_US
dc.contributor.authorLoRusso, PMen_US
dc.contributor.authorKaye, SBen_US
dc.contributor.authorSchöffski, Pen_US
dc.coverage.spatialEnglanden_US
dc.date.accessioned2018-11-29T09:14:37Z
dc.date.issued2016-04-12en_US
dc.identifierhttps://www.ncbi.nlm.nih.gov/pubmed/27002938en_US
dc.identifierbjc201659en_US
dc.identifier.citationBr J Cancer, 2016, 114 (8), pp. 889 - 896en_US
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/2960
dc.identifier.eissn1532-1827en_US
dc.identifier.doi10.1038/bjc.2016.59en_US
dc.description.abstractBACKGROUND: The kinase activity of mTOR involves 2 multiprotein complexes, (mTORC1-mTORC2). Targeting mTORC1 with rapalogues induces compensatory feedback loops resulting in AKT/ERK activation, which may be abrogated by mTORC2 inhibition. A first-in-human trial evaluating tolerability, pharmacokinetics and pharmacodynamics of the dual TORC1/TORC2 inhibitor OSI-027 was conducted. METHODS: Dose escalation was pursued for three schedules of administration (three consecutive days per week (S1), once a week (S2) and daily dosing (S3)), until dose-limiting toxicities (DLT) were identified. Expansion cohorts with paired tumour biopsies were initiated based on tolerability and pharmacodynamics. RESULTS: One hundred and twenty eight patients with advanced cancer were enrolled. DLT consisted predominantly of fatigue, renal function disturbances and cardiac events. OSI-027 exposure was dose proportional, with Tmax within 4 h and a half-life of ∼14 h. Expansion cohorts were initiated for S1 and S2, as MTD for S3 was overall considered suboptimal. Target modulation in peripheral blood mononuclear cells were observed from 30 mg, but in tumour biopsies 120 mg QD were needed, which was a non-tolerable dose due to renal toxicity. No RECIST responses were recorded, with stable disease >6 months in six (5%) patients. CONCLUSIONS: OSI-027 inhibits mTORC1/2 in patients with advanced tumour s in a dose-dependent manner but doses above the tolerable levels in S1 and S3 are required for a sustained biological effect in tumour biopsies.en_US
dc.format.extent889 - 896en_US
dc.languageengen_US
dc.language.isoengen_US
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en_US
dc.subjectAdulten_US
dc.subjectAgeden_US
dc.subjectDose-Response Relationship, Drugen_US
dc.subjectFemaleen_US
dc.subjectHalf-Lifeen_US
dc.subjectHumansen_US
dc.subjectImidazolesen_US
dc.subjectLeukocytes, Mononuclearen_US
dc.subjectMaleen_US
dc.subjectMaximum Tolerated Doseen_US
dc.subjectMechanistic Target of Rapamycin Complex 1en_US
dc.subjectMechanistic Target of Rapamycin Complex 2en_US
dc.subjectMiddle Ageden_US
dc.subjectMultiprotein Complexesen_US
dc.subjectNeoplasmsen_US
dc.subjectProtein Kinase Inhibitorsen_US
dc.subjectTOR Serine-Threonine Kinasesen_US
dc.subjectTriazinesen_US
dc.subjectYoung Adulten_US
dc.titleA first in man, dose-finding study of the mTORC1/mTORC2 inhibitor OSI-027 in patients with advanced solid malignancies.en_US
dc.typeJournal Article
dcterms.dateAccepted2016-02-16en_US
rioxxterms.versionofrecord10.1038/bjc.2016.59en_US
rioxxterms.licenseref.startdate2016-04-12en_US
rioxxterms.typeJournal Article/Reviewen_US
dc.relation.isPartOfBr J Canceren_US
pubs.issue8en_US
pubs.notesNot knownen_US
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/Prostate Cancer Targeted Therapy Group
pubs.publication-statusPublisheden_US
pubs.volume114en_US
pubs.embargo.termsNot knownen_US
icr.researchteamProstate Cancer Targeted Therapy Groupen_US
dc.contributor.icrauthorMateo Valderrama, Joaquinen_US


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