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dc.contributor.authorBasu, B
dc.contributor.authorKrebs, MG
dc.contributor.authorSundar, R
dc.contributor.authorWilson, RH
dc.contributor.authorSpicer, J
dc.contributor.authorJones, R
dc.contributor.authorBrada, M
dc.contributor.authorTalbot, DC
dc.contributor.authorSteele, N
dc.contributor.authorIngles Garces, AH
dc.contributor.authorBrugger, W
dc.contributor.authorHarrington, EA
dc.contributor.authorEvans, J
dc.contributor.authorHall, E
dc.contributor.authorTovey, H
dc.contributor.authorde Oliveira, FM
dc.contributor.authorCarreira, S
dc.contributor.authorSwales, K
dc.contributor.authorRuddle, R
dc.contributor.authorRaynaud, FI
dc.contributor.authorPurchase, B
dc.contributor.authorDawes, JC
dc.contributor.authorParmar, M
dc.contributor.authorTurner, AJ
dc.contributor.authorTunariu, N
dc.contributor.authorBanerjee, S
dc.contributor.authorde Bono, JS
dc.contributor.authorBanerji, U
dc.date.accessioned2018-08-03T13:50:21Z
dc.date.issued2018-09
dc.identifier.citationAnnals of oncology : official journal of the European Society for Medical Oncology, 2018, 29 (9), pp. 1918 - 1925
dc.identifier.issn0923-7534
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/2264
dc.identifier.eissn1569-8041
dc.identifier.doi10.1093/annonc/mdy245
dc.description.abstractBackground 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.Patients and methods 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.Results 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).Discussion 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.Clinical trial registration ClinicialTrials.gov identifier: CNCT02193633.
dc.formatPrint
dc.format.extent1918 - 1925
dc.languageeng
dc.language.isoeng
dc.rights.urihttps://creativecommons.org/licenses/by/4.0
dc.subjectHumans
dc.subjectCarcinoma, Non-Small-Cell Lung
dc.subjectOvarian Neoplasms
dc.subjectLung Neoplasms
dc.subjectBenzamides
dc.subjectPaclitaxel
dc.subjectMorpholines
dc.subjectPyrimidines
dc.subjectRibosomal Protein S6 Kinases
dc.subjectAntineoplastic Combined Chemotherapy Protocols
dc.subjectProtein Kinase Inhibitors
dc.subjectDrug Administration Schedule
dc.subjectMaximum Tolerated Dose
dc.subjectPhosphorylation
dc.subjectAdult
dc.subjectMiddle Aged
dc.subjectFemale
dc.subjectMale
dc.subjectResponse Evaluation Criteria in Solid Tumors
dc.subjectMechanistic Target of Rapamycin Complex 1
dc.subjectMechanistic Target of Rapamycin Complex 2
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.
dc.typeJournal Article
dcterms.dateAccepted2018-06-29
rioxxterms.versionofrecord10.1093/annonc/mdy245
rioxxterms.licenseref.urihttps://creativecommons.org/licenses/by/4.0
rioxxterms.licenseref.startdate2018-09
rioxxterms.typeJournal Article/Review
dc.relation.isPartOfAnnals of oncology : official journal of the European Society for Medical Oncology
pubs.issue9
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/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.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-statusPublished
pubs.volume29
pubs.embargo.termsNot known
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
dc.contributor.icrauthorSwales, Karenen
dc.contributor.icrauthorTovey, Hollyen
dc.contributor.icrauthorCarreira, Suzanneen
dc.contributor.icrauthorTunariu, Ninaen
dc.contributor.icrauthorBanerjee, Susanaen
dc.contributor.icrauthorDe Bono, Johannen
dc.contributor.icrauthorBanerji, Udaien
dc.contributor.icrauthorHall, Emmaen
dc.contributor.icrauthorTurner, Lydiaen
dc.contributor.icrauthorIngles Russo, Alvaro Henriqueen


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