CLL-114 BRUIN CLL-321: A Phase 3 Open-Label, Randomized Study of Pirtobrutinib Versus Investigator's Choice of Idelalisib Plus Rituximab or Bendamustine Plus Rituximab in BTK Inhibitor–Pretreated Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (Trial in Progress)

Context: Covalent Bruton tyrosine kinase (BTK) inhibitors (BTKi) have transformed the management of patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), but these treatments are not curative. Covalent BTKi share pharmacologic liabilities (e.g., low oral bioavailability, short half-life) that collectively may lead to suboptimal BTK target coverage, ultimately manifesting as acquired resistance in some patients. To address these limitations, pirtobrutinib, a highly selective, non-covalent BTKi that inhibits both wild-type (WT) and C481-mutated BTK with equally low nM potency, was developed. Objective: Demonstrate the superiority of continued BTK pathway inhibition with pirtobrutinib compared with other available therapies in patients with BTKi-treated CLL/SLL. Design: BRUIN CLL-321 is a randomized, open-label, global phase 3 study comparing pirtobrutinib monotherapy versus the investigator's choice of idelalisib plus rituximab or bendamustine plus rituximab in patients with CLL/SLL who have been treated with a prior covalent BTKi. Approximately 250 patients will be randomized 1:1. Randomization will be stratified by 17p deletion (yes/no) and prior venetoclax (yes/no). Patients receiving the investigator's choice are eligible to cross over to pirtobrutinib monotherapy if they experience progressive disease per iwCLL 2018 (determined by an independent review committee [IRC]). Setting: Global; community hospitals, academic medical centers. Patients: Eligible patients are adults aged ≥18 years with a diagnosis of CLL/SLL who require therapy per iwCLL 2018 criteria and who have received prior covalent BTKi. An unlimited number of lines of prior therapy is allowed. Key exclusion criteria include CNS involvement by CLL/SLL, Richter transformation at any time pre-enrollment, a major bleeding event on prior covalent BTKi, and a history of allogeneic or autologous stem cell transplant or chimeric antigen receptor (CAR) T-cell therapy within 60 days of randomization. Intervention: Pirtobrutinib monotherapy versus investigator's choice of idelalisib plus rituximab or bendamustine plus rituximab. Main Outcome Measures: The primary endpoint is progression-free survival (PFS) per iwCLL assessed by an IRC. Secondary endpoints include overall survival, overall response rate, duration of response, safety and tolerability, and patient-reported outcomes. The global study is currently enrolling patients (NCT04666038). Results: This study is a trial in progress. Conclusions: This study is a trial in progress.