A phase 1/2 study of the combination of acalabrutinib and vistusertib in patients with relapsed/refractory B-cell malignancies

Graham P. Collins, Tracy N. Clevenger, Kathleen A. Burke, Buyue Yang, Alex MacDonald, David Cunningham, Christopher P. Fox, Andre Goy, John Gribben, Grzegorz S. Nowakowski, Mark Roschewski, Julie M. Vose, Anusha Vallurupalli, Jean Cheung, Amelia Raymond, Barrett Nuttall, Dan Stetson, Brian A. Dougherty, Stein Schalkwijk, Larissa S. CarnevalliBrandon Willis, Lin Tao, Elizabeth A. Harrington, Ahmed Hamdy, Raquel Izumi, J. Elizabeth Pease, Melanie M. Frigault, Ian Flinn

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)2625-2636
Number of pages12
JournalLeukemia and Lymphoma
Volume62
Issue number11
DOIs
StatePublished - 2021
Externally publishedYes

Keywords

  • Bruton tyrosine kinase
  • Richter transformation
  • gene expression profiling
  • genomic segmentation
  • lymphoma
  • mammalian target of rapamycin

ASJC Scopus subject areas

  • Hematology
  • Oncology
  • Cancer Research

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