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 - Funding Information:
Dr. Collins acknowledges support from the Haematology and Stem Cell Theme of the NIHR Oxford Biomedical Research Centre and CRUK Experimental Cancer Medicines Centre. Editorial assistance was provided by Peloton Advantage, an OPEN Health company, Parsippany, NJ, and funded by Acerta Pharma, South San Francisco, CA, a member of the AstraZeneca Group.
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
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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 -