A Phase 1 Study of the Combination of Acalabrutinib and AZD9150 in Patients with Relapsed/Refractory Diffuse Large B-Cell Lymphoma

Background: Patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) after prior autologous stem cell transplant (ASCT) or chimeric antigen receptor T-cell (CAR-T) therapy have poor outcomes with limited treatment options. Bruton's tyrosine kinase (BTK) inhibitors are safe and effective agents in subsets of DLBCL with chronic active B-cell receptor (BCR) signaling, but durations of remission are short. Acalabrutinib, a highly selective, covalent, potent next-generation inhibitor of BTK (Calquence ® prescribing information [USPI]), is approved for the treatment of mantle cell lymphoma and chronic lymphocytic leukemia and is being explored in combination with other rational targeted agents in DLBCL. High levels of signal transducer and activator of transcription 3 (STAT3) expression and activation have been preferentially detected in activated B-cell DLBCL (Ding et al, 2008), and inhibition of STAT3 has suppressed DLBCL in preclinical models (Scuto et al, 2011). A phase 1b study demonstrated the safety and tolerability of AZD9150 in DLBCL with some evidence of clinical activity including 2 complete responses (CRs) and 2 partial responses (PRs) in 27 patients (Reilley et al, 2018). We report results from one of the arms of a phase 1 master protocol PRISM study (NCT03527147: A Platform Protocol for the Treatment of Relapsed/Refractory Aggressive Non-Hodgkin's Lymphoma), which evaluated combination therapy of acalabrutinib with the anti-STAT3 allele-specific oligonucleotide AZD9150 in patients with R/R DLBCL. Methods: Study participants were patients with R/R DLBCL aged ≥18 years with Eastern Cooperative Oncology Group performance status ≤2 and after ≥1 line of prior chemo-immunotherapy (including patients failing or ineligible for ASCT or CAR-T therapy). Starting on cycle 1 day 1 (C1D1), acalabrutinib was administered at 100 mg twice daily until disease progression or discontinuation. AZD9150 200 mg was administered as a 1-hour intravenous (IV) infusion on D1, D3, and D5 of C1, followed by weekly infusions (starting D8C1 and beyond). The primary endpoint was safety, and there was a dose-limiting toxicity (DLT) analysis after 6 subjects completed D28. Disease response (secondary endpoint) was assessed using Response Evaluation Criteria in Lymphoma 2017. Exploratory analyses included longitudinal peripheral blood and tumor tissue samples including immunophenotyping by flow cytometry and gene expression from total blood RNA (using the Nanostr