A phase 1/2 study of the combination of acalabrutinib and vistusertib in patients with relapsed/refractory B-cell malignancies.
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Embargo End Date
ICR Authors
Authors
Collins, GP
Clevenger, TN
Burke, KA
Yang, B
MacDonald, A
Cunningham, D
Fox, CP
Goy, A
Gribben, J
Nowakowski, GS
Roschewski, M
Vose, JM
Vallurupalli, A
Cheung, J
Raymond, A
Nuttall, B
Stetson, D
Dougherty, BA
Schalkwijk, S
Carnevalli, LS
Willis, B
Tao, L
Harrington, EA
Hamdy, A
Izumi, R
Pease, JE
Frigault, MM
Flinn, I
Clevenger, TN
Burke, KA
Yang, B
MacDonald, A
Cunningham, D
Fox, CP
Goy, A
Gribben, J
Nowakowski, GS
Roschewski, M
Vose, JM
Vallurupalli, A
Cheung, J
Raymond, A
Nuttall, B
Stetson, D
Dougherty, BA
Schalkwijk, S
Carnevalli, LS
Willis, B
Tao, L
Harrington, EA
Hamdy, A
Izumi, R
Pease, JE
Frigault, MM
Flinn, I
Document Type
Journal Article
Date
2021-07-15
Date Accepted
2021-07-15
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
Leukemia and Lymphoma, 2021, 62 (11), pp. 2625 - 2636
Source Title
Leukemia and Lymphoma
Publisher
TAYLOR & FRANCIS LTD
ISSN
1042-8194
eISSN
1029-2403
1029-2403
1029-2403
Collections
Research Team
Medicine (RMH)