dc.contributor.author | Collins, GP | |
dc.contributor.author | Clevenger, TN | |
dc.contributor.author | Burke, KA | |
dc.contributor.author | Yang, B | |
dc.contributor.author | MacDonald, A | |
dc.contributor.author | Cunningham, D | |
dc.contributor.author | Fox, CP | |
dc.contributor.author | Goy, A | |
dc.contributor.author | Gribben, J | |
dc.contributor.author | Nowakowski, GS | |
dc.contributor.author | Roschewski, M | |
dc.contributor.author | Vose, JM | |
dc.contributor.author | Vallurupalli, A | |
dc.contributor.author | Cheung, J | |
dc.contributor.author | Raymond, A | |
dc.contributor.author | Nuttall, B | |
dc.contributor.author | Stetson, D | |
dc.contributor.author | Dougherty, BA | |
dc.contributor.author | Schalkwijk, S | |
dc.contributor.author | Carnevalli, LS | |
dc.contributor.author | Willis, B | |
dc.contributor.author | Tao, L | |
dc.contributor.author | Harrington, EA | |
dc.contributor.author | Hamdy, A | |
dc.contributor.author | Izumi, R | |
dc.contributor.author | Pease, JE | |
dc.contributor.author | Frigault, MM | |
dc.contributor.author | Flinn, I | |
dc.coverage.spatial | United States | |
dc.date.accessioned | 2022-09-16T08:37:53Z | |
dc.date.available | 2022-09-16T08:37:53Z | |
dc.date.issued | 2021-07-15 | |
dc.identifier.citation | Leukemia and Lymphoma, 2021, 62 (11), pp. 2625 - 2636 | en_US |
dc.identifier.issn | 1042-8194 | |
dc.identifier.uri | https://repository.icr.ac.uk/handle/internal/5491 | |
dc.identifier.eissn | 1029-2403 | |
dc.identifier.eissn | 1029-2403 | |
dc.identifier.doi | 10.1080/10428194.2021.1938027 | |
dc.description.abstract | In 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.format | Print-Electronic | |
dc.format.extent | 2625 - 2636 | |
dc.language | eng | |
dc.language.iso | eng | en_US |
dc.publisher | TAYLOR & FRANCIS LTD | en_US |
dc.relation.ispartof | Leukemia and Lymphoma | |
dc.rights.uri | https://creativecommons.org/licenses/by-nc-nd/4.0/ | en_US |
dc.subject | Bruton tyrosine kinase | |
dc.subject | Richter transformation | |
dc.subject | gene expression profiling | |
dc.subject | genomic segmentation | |
dc.subject | lymphoma | |
dc.subject | mammalian target of rapamycin | |
dc.subject | B-Lymphocytes | |
dc.subject | Benzamides | |
dc.subject | Humans | |
dc.subject | Morpholines | |
dc.subject | Neoplasm Recurrence, Local | |
dc.subject | Protein Kinase Inhibitors | |
dc.subject | Pyrazines | |
dc.subject | Pyrimidines | |
dc.title | A phase 1/2 study of the combination of acalabrutinib and vistusertib in patients with relapsed/refractory B-cell malignancies. | en_US |
dc.type | Journal Article | |
dcterms.dateAccepted | 2021-07-15 | |
dc.date.updated | 2022-09-16T08:36:59Z | |
rioxxterms.version | VoR | en_US |
rioxxterms.versionofrecord | 10.1080/10428194.2021.1938027 | en_US |
rioxxterms.licenseref.startdate | 2021-07-15 | |
rioxxterms.type | Journal Article/Review | en_US |
pubs.author-url | https://www.ncbi.nlm.nih.gov/pubmed/34269152 | |
pubs.issue | 11 | |
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-status | Published | |
pubs.publisher-url | http://dx.doi.org/10.1080/10428194.2021.1938027 | |
pubs.volume | 62 | |
icr.researchteam | Medicine (RMH) | en_US |
dc.contributor.icrauthor | Cunningham, David | |
icr.provenance | Deposited 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 | |