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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.accessioned2018-10-03T04:43:13Z
dc.date.available2018-10-03T04:43:13Z
dc.date.issued2018-09-09
dc.identifier.issn1569-8041
dc.identifier.urihttps://www.repository.cam.ac.uk/handle/1810/283015
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 (3/7days) and schedule B, vistusertib dosed bd for 2 consecutive days per week (2/7days). 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. Based on toxicity, 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.description.sponsorshipThis work was supported by AstraZeneca through Cancer Research UK’s Experimental Cancer Medicine Centre (ECMC) Combinations’ Alliance. All sites acknowledge funding from ECMC awards. In addition, The Institute of Cancer Research and The Royal Marsden, Cambridge University Hospitals NHS Foundation Trust, King’s College London, and The Christie NHS Foundation Trust, Manchester, acknowledge infrastructural funding from the National Institute for Health Research Biomedical Research Centre (NIHR BRC) and Clinical Research Facility grants. RS was supported by a fellowship from the National Medical Research Council, Singapore. U Banerji is a recipient of an NIHR Research Professorship Award [grant number RP-2016-07-028].
dc.languageeng
dc.publisherOxford University Press
dc.rightsAttribution 4.0 International
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.subjectPhase 1
dc.subjectm-TORC1/m-TORC2 inhibitor
dc.subjectcombination therapy
dc.subjectovarian cancer
dc.subjectsquamous non-small cell lung cancer
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.typeArticle
prism.publicationDate2018
prism.publicationNameAnnals of Oncology
dc.identifier.doi10.17863/CAM.30379
dcterms.dateAccepted2018-06-29
rioxxterms.versionofrecord10.1093/annonc/mdy245
rioxxterms.licenseref.urihttp://creativecommons.org/licenses/by/4.0/
rioxxterms.licenseref.startdate2018-09-09
dc.contributor.orcidBasu, Bristi [0000-0002-3562-2868]
dc.identifier.eissn1569-8041
rioxxterms.typeJournal Article/Review
cam.issuedOnline2018-07-17


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Attribution 4.0 International
Except where otherwise noted, this item's licence is described as Attribution 4.0 International