A phase 1/2 study of the combination of acalabrutinib and vistusertib in patients with relapsed/refractory B-cell malignancies. Issue 11 (19th September 2021)

• Record Type: Journal Article
• Authors: 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
• Is Part Of: Leukemia & lymphoma. Volume 62:Issue 11(2021)
• Page Start: 2625
• Page End: 2636
• Publication Date: 2021-09-19
• Subjects: Bruton tyrosine kinase -- mammalian target of rapamycin -- Richter transformation -- lymphoma -- genomic segmentation -- gene expression profiling; Leukemia -- Periodicals; Lymphomas -- Periodicals; 616.99419
• DOI: 10.1080/10428194.2021.1938027
• Languages: English
• ISSNs: 1042-8194

Abstract

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.