TY - JOUR
T1 - A phase 1/2 study of the combination of acalabrutinib and vistusertib in patients with relapsed/refractory B-cell malignancies
AU - Collins, Graham P.
AU - Clevenger, Tracy N.
AU - Burke, Kathleen A.
AU - Yang, Buyue
AU - MacDonald, Alex
AU - Cunningham, David
AU - Fox, Christopher P.
AU - Goy, Andre
AU - Gribben, John
AU - Nowakowski, Grzegorz S.
AU - Roschewski, Mark
AU - Vose, Julie M.
AU - Vallurupalli, Anusha
AU - Cheung, Jean
AU - Raymond, Amelia
AU - Nuttall, Barrett
AU - Stetson, Dan
AU - Dougherty, Brian A.
AU - Schalkwijk, Stein
AU - Carnevalli, Larissa S.
AU - Willis, Brandon
AU - Tao, Lin
AU - Harrington, Elizabeth A.
AU - Hamdy, Ahmed
AU - Izumi, Raquel
AU - Pease, J. Elizabeth
AU - Frigault, Melanie M.
AU - Flinn, Ian
N1 - Publisher Copyright:
© 2021 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.
PY - 2021
Y1 - 2021
N2 - 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.
AB - 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.
KW - Bruton tyrosine kinase
KW - Richter transformation
KW - gene expression profiling
KW - genomic segmentation
KW - lymphoma
KW - mammalian target of rapamycin
UR - http://www.scopus.com/inward/record.url?scp=85110853150&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85110853150&partnerID=8YFLogxK
U2 - 10.1080/10428194.2021.1938027
DO - 10.1080/10428194.2021.1938027
M3 - Article
C2 - 34269152
AN - SCOPUS:85110853150
SN - 1042-8194
VL - 62
SP - 2625
EP - 2636
JO - Leukemia and Lymphoma
JF - Leukemia and Lymphoma
IS - 11
ER -