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

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