BRUIN CLL-322: A Phase 3 Open-Label, Randomized Study of Fixed-Duration Pirtobrutinib Plus Venetoclax and Rituximab Versus Venetoclax and Rituximab in Previously Treated Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (Trial in Progress)

Context: Currently, the majority of patients with chronic lymphocytic leukemia (CLL) who require treatment receive a covalent Bruton's tyrosine kinase inhibitor (BTKi) as their first standard of care targeted therapy. The MURANO study established the time-limited combination of venetoclax plus rituximab (2 years) as a standard of care regimen for patients with relapsed/refractory (R/R) CLL or small lymphocytic lymphoma (SLL). MURANO enrolled very few patients who were previously treated with a covalent BTKi. Pirtobrutinib is a highly selective, non-covalent (reversible) BTKi that inhibits both wild-type and C481-mutated BTK with equally low nM potency. Objective: Adding fixed-duration pirtobrutinib to the MURANO regimen may allow for deeper remissions and longer disease control and generate a clinically relevant dataset in a population of patients with BTKi-pretreated R/R CLL/SLL. Design: BRUIN CLL-322 is a randomized, open-label, global phase 3 trial comparing fixed duration pirtobrutinib plus venetoclax and rituximab with standard venetoclax and rituximab in patients with R/R CLL/SLL. Approximately 600 patients will be randomized 1:1. Randomization will be stratified by 17p deletion (yes/no) and prior BTKi experience (discontinuation due to progressive disease vs. due to other reasons vs. no prior BTKi exposure). Setting: Global; community hospitals, academic medical centers. Patients: Eligible patients are adults with a diagnosis of CLL/SLL who require therapy per iwCLL 2018 criteria and who received prior therapy that may or may not include a covalent BTKi. Key exclusion criteria include CNS involvement by CLL/SLL, Richter transformation at any time pre-enrollment, history of allogeneic or autologous stem cell transplant or chimeric antigen receptor (CAR) T-cell therapy within 60 days, and prior therapy with a BCL2 inhibitor or non-covalent BTKi. There will be no exclusion based on the number of lines of prior therapy. Intervention: Fixed-duration pirtobrutinib plus venetoclax and rituximab versus venetoclax and rituximab. Main Outcome Measures: The primary endpoint is progression-free survival per iwCLL criteria assessed by an independent review committee. Secondary endpoints include overall response rate, overall survival, time to next treatment, event-free survival, safety and tolerability, and patient-reported outcomes. This global study is currently enrolling patients (NCT04965493). Results: This study is a trial in progress. Conclusions: This study is a trial in progress.