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.

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TPS7582 Background: Covalent (c) Bruton tyrosine kinase inhibitors (BTKi) have transformed the management of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), but these agents are not curative. cBTKi share pharmacologic liabilities such as low oral bioavailability and a short half-life that may lead to suboptimal BTK target coverage, especially in rapidly proliferating tumors with high BTK protein turnover, which can manifest as acquired resistance to cBTKi. Novel therapeutic agents addressing both intolerance and resistance while also improving efficacy are needed. 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 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 objective of this study is to determine whether pirtobrutinib is superior to conventional therapy in patients previously treated with cBTKi. Methods: BRUIN CLL-321 (NCT04666038) is a randomized, open-label, global phase 3 study comparing pirtobrutinib monotherapy (200mg QD) to investigator’s choice of idelalisib plus rituximab (IdelaR) or bendamustine plus rituximab (BR). Approximately 250 CLL/SLL patients previously treated with a covalent BTKi will be randomized 1:1 and stratified by both del(17p) status (yes/no) and prior venetoclax treatment (yes/no). Patients on the control arm can crossover to pirtobrutinib monotherapy if they experience progressive disease per iwCLL 2018 as confirmed by an independent review committee (IRC). Adults with CLL/SLL who require therapy per iwCLL 2018 criteria and have received prior covalent BTKi are eligible. An unlimited number of prior lines of therapy, including venetoclax, are allowed. Key exclusion criteria include CNS involvement by CLL/SLL, a major bleeding event on prior cBTKi, Richter’s Transformation at any time, prior therapy with a non-covalent BTKi, or a history of either allogeneic or autologous stem cell transplant (SCT), or chimeric antigen receptor (CAR) T-cell therapy within 60 days prior to randomization. The primary end point is progression-free survival (PFS) per iwCLL 2018 criteria as assessed by IRC. Secondary endpoints include investigator assessed PFS, overall survival, ORR, duration of response, safety and tolerability, and patient reported outcomes. Enrollment for this study is ongoing. Clinical trial information: NCT04666038 .