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dc.contributor.authorBasu, Ben_US
dc.contributor.authorKrebs, MGen_US
dc.contributor.authorSundar, Ren_US
dc.contributor.authorWilson, RHen_US
dc.contributor.authorSpicer, Jen_US
dc.contributor.authorJones, Ren_US
dc.contributor.authorBrada, Men_US
dc.contributor.authorTalbot, DCen_US
dc.contributor.authorSteele, Nen_US
dc.contributor.authorIngles Garces, AHen_US
dc.contributor.authorBrugger, Wen_US
dc.contributor.authorHarrington, EAen_US
dc.contributor.authorEvans, Jen_US
dc.contributor.authorHall, Een_US
dc.contributor.authorTovey, Hen_US
dc.contributor.authorde Oliveira, FMen_US
dc.contributor.authorCarreira, Sen_US
dc.contributor.authorSwales, Ken_US
dc.contributor.authorRuddle, Ren_US
dc.contributor.authorRaynaud, FIen_US
dc.contributor.authorPurchase, Ben_US
dc.contributor.authorDawes, JCen_US
dc.contributor.authorParmar, Men_US
dc.contributor.authorTurner, AJen_US
dc.contributor.authorTunariu, Nen_US
dc.contributor.authorBanerjee, Sen_US
dc.contributor.authorde Bono, JSen_US
dc.contributor.authorBanerji, Uen_US
dc.date.accessioned2018-08-03T13:50:21Z
dc.date.issued2018-09en_US
dc.identifier.citationAnnals of oncology : official journal of the European Society for Medical Oncology, 2018, 29 (9), pp. 1918 - 1925en_US
dc.identifier.issn0923-7534en_US
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/2264
dc.identifier.eissn1569-8041en_US
dc.identifier.doi10.1093/annonc/mdy245en_US
dc.description.abstract<h4>Background</h4>We have previously shown that raised p-S6K levels correlate with resistance to chemotherapy in ovarian cancer. We hypothesised that inhibiting p-S6K signalling with the dual m-TORC1/2 inhibitor in patients receiving weekly paclitaxel could improve outcomes in such patients.<h4>Patients and methods</h4>In dose escalation, weekly paclitaxel (80 mg/m2) was given 6/7 weeks in combination with two intermittent schedules of vistusertib (dosing starting on the day of paclitaxel): schedule A, vistusertib dosed bd for 3 consecutive days per week (3/7 days) and schedule B, vistusertib dosed bd for 2 consecutive days per week (2/7 days). After establishing a recommended phase II dose (RP2D), expansion cohorts in high-grade serous ovarian cancer (HGSOC) and squamous non-small-cell lung cancer (sqNSCLC) were explored in 25 and 40 patients, respectively.<h4>Results</h4>The dose-escalation arms comprised 22 patients with advanced solid tumours. The dose-limiting toxicities were fatigue and mucositis in schedule A and rash in schedule B. On the basis of toxicity and pharmacokinetic (PK) and pharmacodynamic (PD) evaluations, the RP2D was established as 80 mg/m2 paclitaxel with 50 mg vistusertib bd 3/7 days for 6/7 weeks. In the HGSOC expansion, RECIST and GCIG CA125 response rates were 13/25 (52%) and 16/25 (64%), respectively, with median progression-free survival (mPFS) of 5.8 months (95% CI: 3.28-18.54). The RP2D was not well tolerated in the SqNSCLC expansion, but toxicities were manageable after the daily vistusertib dose was reduced to 25 mg bd for the following 23 patients. The RECIST response rate in this group was 8/23 (35%), and the mPFS was 5.8 months (95% CI: 2.76-21.25).<h4>Discussion</h4>In this phase I trial, we report a highly active and well-tolerated combination of vistusertib, administered as an intermittent schedule with weekly paclitaxel, in patients with HGSOC and SqNSCLC.<h4>Clinical trial registration</h4>ClinicialTrials.gov identifier: CNCT02193633.en_US
dc.formatPrinten_US
dc.format.extent1918 - 1925en_US
dc.languageengen_US
dc.language.isoengen_US
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en_US
dc.subjectHumansen_US
dc.subjectCarcinoma, Non-Small-Cell Lungen_US
dc.subjectOvarian Neoplasmsen_US
dc.subjectLung Neoplasmsen_US
dc.subjectBenzamidesen_US
dc.subjectPaclitaxelen_US
dc.subjectMorpholinesen_US
dc.subjectPyrimidinesen_US
dc.subjectRibosomal Protein S6 Kinasesen_US
dc.subjectAntineoplastic Combined Chemotherapy Protocolsen_US
dc.subjectProtein Kinase Inhibitorsen_US
dc.subjectDrug Administration Scheduleen_US
dc.subjectMaximum Tolerated Doseen_US
dc.subjectPhosphorylationen_US
dc.subjectAdulten_US
dc.subjectMiddle Ageden_US
dc.subjectFemaleen_US
dc.subjectMaleen_US
dc.subjectResponse Evaluation Criteria in Solid Tumorsen_US
dc.subjectMechanistic Target of Rapamycin Complex 1en_US
dc.subjectMechanistic Target of Rapamycin Complex 2en_US
dc.titleVistusertib (dual m-TORC1/2 inhibitor) in combination with paclitaxel in patients with high-grade serous ovarian and squamous non-small-cell lung cancer.en_US
dc.typeJournal Article
dcterms.dateAccepted2018-06-29en_US
rioxxterms.versionofrecord10.1093/annonc/mdy245en_US
rioxxterms.licenseref.urihttps://creativecommons.org/licenses/by/4.0en_US
rioxxterms.licenseref.startdate2018-09en_US
rioxxterms.typeJournal Article/Reviewen_US
dc.relation.isPartOfAnnals of oncology : official journal of the European Society for Medical Oncologyen_US
pubs.issue9en_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/Cancer Therapeutics
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Cancer Biomarkers
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Clinical PD Biomarker Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Clinical Pharmacology & Trials (including Drug Metabolism & Pharmacokinetics Group)
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Cancer Therapeutics/Medicine Drug Development Unit (de Bono)
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies/Cancer Biomarkers
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies/Clinical PD Biomarker Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies/Clinical Pharmacology – Adaptive Therapy
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies/Clinical Trials & Statistics Unit
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies/ICR-CTSU Urology and Head and Neck Trials Team
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies/Medicine Drug Development Unit (de Bono)
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/Students
pubs.organisational-group/ICR/Students/PhD and MPhil
pubs.organisational-group/ICR/Students/PhD and MPhil/18/19 Starting Cohort
pubs.organisational-group/ICR/Students/PhD and MPhil/19/20 Starting Cohort
pubs.publication-statusPublisheden_US
pubs.volume29en_US
pubs.embargo.termsNot knownen_US
icr.researchteamClinical Pharmacology & Trials (including Drug Metabolism & Pharmacokinetics Group)en_US
icr.researchteamCancer Biomarkersen_US
icr.researchteamClinical PD Biomarker Groupen_US
icr.researchteamClinical Pharmacology – Adaptive Therapyen_US
icr.researchteamClinical Trials & Statistics Uniten_US
icr.researchteamICR-CTSU Urology and Head and Neck Trials Teamen_US
icr.researchteamMedicine Drug Development Unit (de Bono)en_US
icr.researchteamProstate Cancer Targeted Therapy Groupen_US
dc.contributor.icrauthorRaynaud, Florenceen_US
dc.contributor.icrauthorTovey, Hollyen_US
dc.contributor.icrauthorCarreira, Suzanneen_US
dc.contributor.icrauthorTunariu, Ninaen_US
dc.contributor.icrauthorBanerjee, Susanaen_US
dc.contributor.icrauthorDe Bono, Johannen_US
dc.contributor.icrauthorBanerji, Udaien_US
dc.contributor.icrauthorHall, Emmaen_US
dc.contributor.icrauthorTurner, Lydiaen_US
dc.contributor.icrauthorSwales, Karenen_US
dc.contributor.icrauthorIngles Russo, Alvaro Henriqueen_US


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