Graham P. Collins
A phase 1/2 study of the combination of acalabrutinib and vistusertib in patients with relapsed/refractory B-cell malignancies
Collins, Graham P.; Clevenger, Tracy N.; Burke, Kathleen A.; Yang, Buyue; MacDonald, Alex; Cunningham, David; Fox, Christopher P.; Goy, Andre; Gribben, John; Nowakowski, Grzegorz S.; Roschewski, Mark; Vose, Julie M.; Vallurupalli, Anusha; Cheung, Jean; Raymond, Amelia; Nuttall, Barrett; Stetson, Dan; Dougherty, Brian A.; Schalkwijk, Stein; Carnevalli, Larissa S.; Willis, Brandon; Tao, Lin; Harrington, Elizabeth A.; Hamdy, Ahmed; Izumi, Raquel; Pease, J. Elizabeth; Frigault, Melanie M.; Flinn, Ian
Authors
Tracy N. Clevenger
Kathleen A. Burke
Buyue Yang
Alex MacDonald
David Cunningham
Professor CHRIS FOX Christopher.Fox@nottingham.ac.uk
Clinical Professor in Haematology
Andre Goy
John Gribben
Grzegorz S. Nowakowski
Mark Roschewski
Julie M. Vose
Anusha Vallurupalli
Jean Cheung
Amelia Raymond
Barrett Nuttall
Dan Stetson
Brian A. Dougherty
Stein Schalkwijk
Larissa S. Carnevalli
Brandon Willis
Lin Tao
Elizabeth A. Harrington
Ahmed Hamdy
Raquel Izumi
J. Elizabeth Pease
Melanie M. Frigault
Ian Flinn
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.
Citation
Collins, G. P., Clevenger, T. N., Burke, K. A., Yang, B., MacDonald, A., Cunningham, D., …Flinn, I. (2021). A phase 1/2 study of the combination of acalabrutinib and vistusertib in patients with relapsed/refractory B-cell malignancies. Leukemia & Lymphoma, 62(11), 2625-2636. https://doi.org/10.1080/10428194.2021.1938027
Journal Article Type | Article |
---|---|
Acceptance Date | May 22, 2021 |
Online Publication Date | Jul 16, 2021 |
Publication Date | Jan 1, 2021 |
Deposit Date | Feb 8, 2023 |
Publicly Available Date | Feb 8, 2023 |
Journal | Leukemia & Lymphoma |
Print ISSN | 1042-8194 |
Electronic ISSN | 1029-2403 |
Publisher | Taylor and Francis |
Peer Reviewed | Peer Reviewed |
Volume | 62 |
Issue | 11 |
Pages | 2625-2636 |
DOI | https://doi.org/10.1080/10428194.2021.1938027 |
Keywords | Cancer Research; Oncology; Hematology |
Public URL | https://nottingham-repository.worktribe.com/output/17078875 |
Publisher URL | https://www.tandfonline.com/doi/full/10.1080/10428194.2021.1938027 |
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A phase 1/2 study of the combination of acalabrutinib and vistusertib in patients with relapsed/refractory B-cell malignancies
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https://creativecommons.org/licenses/by-nc-nd/4.0/
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