Data from Phase I Study of Acalabrutinib Plus Danvatirsen (AZD9150) in Relapsed/Refractory Diffuse Large B-Cell Lymphoma Including Circulating Tumor DNA Biomarker Assessment
Year: 2023
Type: other
Abstract: Background: Novel targeted and immunotherapies have improved outcomes in relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL), but toxicities limit widespread use. The selective Bruton tyrosine kinase (BTK) inhibitor acalabrutinib has activity in patients with R/R DLBCL but durable responses are uncommon. STAT3 inhibition has demonstrated clinical activity in DLBCL. Methods: Final results of the phase I study of acalabrutinib plus STAT3 inhibitor (danvatirsen; AZD9150) in patients with R/R DLBCL are reported. Danvatirsen 200 mg intravenous infusion [Days 1, 3, 5 (Cycle 1); weekly infusions starting Day 8, Cycle 1] was administered in combination with oral acalabrutinib 100 mg twice daily until progressive disease (PD) or unacceptable toxicity. Primary endpoints were safety and tolerability. Secondary endpoints included efficacy, pharmacokinetics, and immunogenicity. Results: Seventeen patients received combination treatment. One dose-limiting toxicity (Grade 3 liver transaminase) occurred in 1 patient. The most common reason for treatment discontinuation was PD (65%). In evaluable patients (n = 17), objective response rate was 24%; median duration of response was 1.9 months. All responders with available DLBCL cell-of-origin data were either activated B-cell or nongerminal center B-cell like subtype. Genetic subtype did not correlate with response. Baseline and longitudinal plasma cell-free DNA (cfDNA) concentrations were mostly higher in nonresponding patients. cfDNA changes were generally concordant with imaging. Pretreatment circulating B-cell levels were higher in responders versus nonresponders. Conclusions: Targeting both STAT3 and BTK in combination is safe and tolerable but efficacy is limited in R/R DLBCL. Results support evaluation of circulating tumor DNA as a biomarker for clinical response.
Authors: Mark Roschewski, Manish R. Patel, Patrick M. Reagan, Nakhle S. Saba, Graham P. Collins, Hendrik-Tobias Arkenau, Sven de Vos, Barrett Nuttall, Melih Acar, Kathleen Burke, Rafael D. White, Maria Udriste, Shringi Sharma, Brian Dougherty, Daniel Stetson, David Jenkins, Andrew Mortlock, Alessandra Forcina, Veerendra Munugalavadla, Ian Flinn
Institutions: National Institutes of Health, National Cancer Institute, National Cancer Institute, Center for Cancer Research, University of Rochester Medicine, Tulane University, Churchill Hospital, National Institute for Health and Care Research, NIHR Oxford Biomedical Research Centre, Sarah Cannon Research Institute, University College London, University of California, Los Angeles, AstraZeneca (United States), AstraZeneca (United Kingdom), Sarah Cannon
Language: English
Subfield: Pathology and Forensic Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Funder: AstraZeneca
OpenAlex ID: W4385359704