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dc.contributor.authorCollins, GP
dc.contributor.authorClevenger, TN
dc.contributor.authorBurke, KA
dc.contributor.authorYang, B
dc.contributor.authorMacDonald, A
dc.contributor.authorCunningham, D
dc.contributor.authorFox, CP
dc.contributor.authorGoy, A
dc.contributor.authorGribben, J
dc.contributor.authorNowakowski, GS
dc.contributor.authorRoschewski, M
dc.contributor.authorVose, JM
dc.contributor.authorVallurupalli, A
dc.contributor.authorCheung, J
dc.contributor.authorRaymond, A
dc.contributor.authorNuttall, B
dc.contributor.authorStetson, D
dc.contributor.authorDougherty, BA
dc.contributor.authorSchalkwijk, S
dc.contributor.authorCarnevalli, LS
dc.contributor.authorWillis, B
dc.contributor.authorTao, L
dc.contributor.authorHarrington, EA
dc.contributor.authorHamdy, A
dc.contributor.authorIzumi, R
dc.contributor.authorPease, JE
dc.contributor.authorFrigault, MM
dc.contributor.authorFlinn, I
dc.coverage.spatialUnited States
dc.date.accessioned2022-09-16T08:37:53Z
dc.date.available2022-09-16T08:37:53Z
dc.date.issued2021-07-15
dc.identifier.citationLeukemia and Lymphoma, 2021, 62 (11), pp. 2625 - 2636en_US
dc.identifier.issn1042-8194
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/5491
dc.identifier.eissn1029-2403
dc.identifier.eissn1029-2403
dc.identifier.doi10.1080/10428194.2021.1938027
dc.description.abstractIn a phase 1b study of acalabrutinib (a covalent Bruton tyrosine kinase (BTK) inhibitor) in combination with vistusertib (a dual mTORC1/2 inhibitor) in patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL), multiple ascending doses of the combination as intermittent or continuous schedules of vistusertib were evaluated. The overall response rate was 12% (3/25). The pharmacodynamic (PD) profile for acalabrutinib showed that BTK occupancy in all patients was >95%. In contrast, PD analysis for vistusertib showed variable inhibition of phosphorylated 4EBP1 (p4EBP1) without modulation of AKT phosphorylation (pAKT). The pharmacokinetic (PK)/PD relationship of vistusertib was direct for TORC1 inhibition (p4EBP1) but did not correlate with TORC2 inhibition (pAKT). Cell-of-origin subtyping or next-generation sequencing did not identify a subset of DLBCL patients with clinical benefit; however, circulating tumor DNA dynamics correlated with radiographic response. These data suggest that vistusertib does not modulate targets sufficiently to add to the clinical activity of acalabrutinib monotherapy. Clinicaltrials.gov identifier: NCT03205046.
dc.formatPrint-Electronic
dc.format.extent2625 - 2636
dc.languageeng
dc.language.isoengen_US
dc.publisherTAYLOR & FRANCIS LTDen_US
dc.relation.ispartofLeukemia and Lymphoma
dc.rights.urihttps://creativecommons.org/licenses/by-nc-nd/4.0/en_US
dc.subjectBruton tyrosine kinase
dc.subjectRichter transformation
dc.subjectgene expression profiling
dc.subjectgenomic segmentation
dc.subjectlymphoma
dc.subjectmammalian target of rapamycin
dc.subjectB-Lymphocytes
dc.subjectBenzamides
dc.subjectHumans
dc.subjectMorpholines
dc.subjectNeoplasm Recurrence, Local
dc.subjectProtein Kinase Inhibitors
dc.subjectPyrazines
dc.subjectPyrimidines
dc.titleA phase 1/2 study of the combination of acalabrutinib and vistusertib in patients with relapsed/refractory B-cell malignancies.en_US
dc.typeJournal Article
dcterms.dateAccepted2021-07-15
dc.date.updated2022-09-16T08:36:59Z
rioxxterms.versionVoRen_US
rioxxterms.versionofrecord10.1080/10428194.2021.1938027en_US
rioxxterms.licenseref.startdate2021-07-15
rioxxterms.typeJournal Article/Reviewen_US
pubs.author-urlhttps://www.ncbi.nlm.nih.gov/pubmed/34269152
pubs.issue11
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/Medicine (RMH Smith Cunningham)
pubs.organisational-group/ICR/Primary Group/Royal Marsden Clinical Units
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Clinical Studies/Medicine (RMH Smith Cunningham)/Medicine (RMH Smith Cunningham) (hon.)
pubs.publication-statusPublished
pubs.publisher-urlhttp://dx.doi.org/10.1080/10428194.2021.1938027
pubs.volume62
icr.researchteamMedicine (RMH)en_US
dc.contributor.icrauthorCunningham, David
icr.provenanceDeposited by Mr Arek Surman on 2022-09-16. Deposit type is initial. No. of files: 1. Files: A phase 1 2 study of the combination of acalabrutinib and vistusertib in patients with relapsed refractory B cell malignancies.pdf


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