3005 - 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)

Background: Covalent (c) Bruton tyrosine kinase inhibitors (BTKi) have reshaped the treatment landscape for chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) and are now often used as initial therapy. The MURANO study established 2-year fixed duration venetoclax plus rituximab as a standard of care regimen for patients with relapsed or refractory CLL/SLL. However, its efficacy has not been formally assessed in CLL/SLL patients treated with a cBTKi, a common setting where this regimen is used in contemporary practice. Pirtobrutinib, a highly selective, non-covalent (reversible) BTKi, inhibits both wildtype and C481-mutant BTK with equal low nM potency, and has favorable oral pharmacology that enables continuous BTK inhibition throughout the dosing interval regardless of intrinsic rate of BTK turnover. In the phase 1/2 BRUIN study, pirtobrutinib demonstrated promising durable overall response rates (ORR) and was well tolerated in patients with pre-treated CLL/SLL regardless of prior therapy (including cBTKi), number of prior lines of therapy, BTK C481 mutation status, or reason for prior cBTKi discontinuation. The study’s objective is to assess the superiority of adding time-limited pirtobrutinib to the MURANO regimen, hypothesized to prolong disease control in a largely BTKi-pretreated population.

Methods: BRUIN CLL-322 (NCT04965493) is a randomized, open-label, global, phase 3 study comparing time-limited pirtobrutinib (200mg QD) plus venetoclax and rituximab versus venetoclax and rituximab in previously treated CLL/SLL patients. Approximately 600 patients, 80% who have been previously treated with cBTKi, will be randomized 1:1 and stratified by del(17p) status (yes/no) and prior BTKi experience (discontinuation due to progressive disease vs due to other reasons vs no prior BTKi exposure).
Eligible patients are adults diagnosed with CLL/SLL and require therapy per iwCLL 2018 criteria who have received prior therapy that may or may not include a cBTKi. There are no restrictions on the number of lines of prior therapy. Key exclusion criteria include CNS involvement by CLL/SLL, Richter transformation at any time, prior BCL2 inhibitor or non-covalent BTK inhibitor, or a history of either allogeneic or autologous stem cell transplant, or chimeric antigen receptor T-cell therapy within 60 days prior to randomization.
The primary endpoint is progression-free survival (PFS) per iwCLL criteria assessed by an independent review committee. Secondary endpoints include investigator assessed PFS, ORR, overall survival, time to next treatment, event-free survival, safety and tolerability, and patient-reported outcomes. Enrollment is ongoing for patients previously treated with BTKi and completed for BTKi naïve patients.