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)
Authors: Mato Anthony R. , Wierda William G. , Pagel John M. , Davids Matthew S. , Zinzani Pier Luigi , Lu Yi , Liu Hui , Shahda Safi , Leow Ching Ching , Tam Constantine S. , Woyach Jennifer A. , Eyre Toby A. 
Published: November 2021

Abstract
Background: Covalent Bruton's Tyrosine Kinase (BTK) inhibitors (BTKi) have transformed the management of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), but these treatments are not curative and the majority of patients will require additional treatment. The MURANO study established the time-limited combination of 2 years venetoclax plus rituximab as a clinically important regimen for patients with R/R CLL/SLL. However, that trial almost exclusively enrolled patients who were never treated with a covalent BTKi, a population less relevant in the context of today's standard of care. Pirtobrutinib is a highly selective, non-covalent BTKi that inhibits both wild type (WT) and C481-mutated BTK with equal low nM potency. In a phase 1/2 BRUIN trial, pirtobrutinib achieved pharmacokinetic exposures that exceeded its BTK IC96 at trough, was well tolerated, and demonstrated promising efficacy in CLL/SLL patients regardless of prior therapy, number of prior lines of therapy, or BTK C481 mutation status (Mato et al. Lancet 2021;397,10277:892-901). Therefore, adding fixed duration pirtobrutinib to the time-limited MURANO regimen may allow for even deeper and more prolonged disease control, and generate a clinically relevant dataset in a BTK-pretreated CLL/SLL population.
Study Design and Methods: BRUIN CLL-322 is a randomized, open-label, global phase 3 study comparing fixed duration pirtobrutinib plus venetoclax and rituximab (PVR) versus venetoclax and rituximab (VR) in patients with CLL/SLL who have received prior therapy. To ensure relevance in the modern therapy context, a minimum of 80% of patients must have had a prior covalent BTKi. 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).
Eligible patients are adults with a diagnosis of CLL/SLL and requirement for therapy per iwCLL 2018 criteria who have received prior therapy that may or may not include a covalent BTKi. Unlimited number of lines of prior therapy are allowed. Key exclusion criteria include CNS involvement by CLL/SLL, Richter transformation at any time pre-enrollment, history of allogeneic stem cell transplant (SCT) or autologous SCT or chimeric antigen receptor (CAR) T-cell therapy within 60 days and prior therapy with a BCL2 inhibitor or non-covalent BTKi.
The primary endpoint is progression-free survival (PFS) per iwCLL assessed by an independent review committee (IRC). Secondary endpoints include overall response rate (ORR), overall survival (OS), time to next treatment (TTNT), event-free survival (EFS), safety and tolerability, and patient-reported outcomes. This global study is currently enrolling patients (NCT04965493).

Disclosures
Mato: MSKCC: Current Employment; AstraZeneca: Consultancy; Nurix: Research Funding; AbbVie: Consultancy, Research Funding; Sunesis: Consultancy, Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; LOXO: Consultancy, Research Funding; Adaptive Biotechnologies: Consultancy, Research Funding; BeiGene: Consultancy, Research Funding; Acerta/AstraZeneca: Consultancy, Research Funding; Genmab: Research Funding; DTRM BioPharma: Consultancy, Research Funding; Johnson and Johnson: Consultancy, Research Funding; TG Therapeutics: Consultancy, Other: DSMB, Research Funding; Genentech: Consultancy, Research Funding. Wierda: GSK/Novartis: Research Funding; Xencor: Research Funding; Genentech: Research Funding; Janssen: Research Funding; Cyclacel: Research Funding; Loxo Oncology, Inc.: Research Funding; Pharmacyclics LLC, an AbbVie Company: Research Funding; Karyopharm: Research Funding; Oncternal Therapeutics, Inc.: Research Funding; Miragen: Research Funding; Sunesis: Research Funding; KITE Pharma: Research Funding; Juno Therapeutics: Research Funding; Acerta Pharma Inc.: Research Funding; Gilead Sciences: Research Funding; Genzyme Corporation: Consultancy; AbbVie: Research Funding; AstraZeneca: Research Funding. Pagel: Pharmacyclics/AbbVie: Consultancy; Gilead: Consultancy; Epizyme: Consultancy; AstraZeneca: Consultancy; BeiGene: Consultancy; MEI Pharma: Consultancy; Kite, a Gilead Company: Consultancy; Incyte/MorphoSys: Consultancy; Actinium Pharmaceuticals: Consultancy. Davids: Astra-Zeneca: Consultancy, Research Funding; TG Therapeutics: Consultancy, Research Funding; AbbVie: Consultancy; Adaptive Biotechnologies: Consultancy; BeiGene: Consultancy; Celgene: Consultancy; Eli Lilly and Company: Consultancy; MEI Pharma: Consultancy; Merck: Consultancy; Research to Practice: Consultancy; Takeda: Consultancy; MEI Pharma: Consultancy, Research Funding; Janssen: Consultancy; Genentech: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Verastem: Consultancy, Research Funding; Ascentage Pharma: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Surface Oncology: Research Funding. Zinzani: ROCHE: Other, Speakers Bureau; KYOWA KIRIN: Other, Speakers Bureau; BMS: Other: Advisory board, Speakers Bureau; SERVIER: Other: Advisory board, Speakers Bureau; VERASTEM: Consultancy, Other: Advisory board, Speakers Bureau; SANDOZ: Other: Advisory board; NOVARTIS: Consultancy, Other, Speakers Bureau; Incyte: Other, Speakers Bureau; ADC Therap.: Other; MSD: Consultancy, Other: Advisory board, Speakers Bureau; JANSSEN-CILAG: Other: Advisory board, Speakers Bureau; TAKEDA: Other: Advisory board, Speakers Bureau; EUSAPHARMA: Consultancy, Other, Speakers Bureau; GILEAD: Other: Advisory board, Speakers Bureau; Beigene: Other, Speakers Bureau; TG Therapeutics: Other: Advisory board, Speakers Bureau; CELLTRION: Other: Advisory board, Speakers Bureau. Lu: Eli Lilly and Company: Current Employment, Current equity holder in publicly-traded company. Liu: Loxo Oncology at Lilly: Current Employment; AstraZeneca: Ended employment in the past 24 months. Shahda: Loxo Oncology at Lilly: Current Employment, Current equity holder in publicly-traded company. Leow: Loxo Oncology at Lilly: Current Employment, Current equity holder in publicly-traded company. Tam: Beigene: Honoraria; Loxo: Honoraria; Abbvie: Research Funding; Janssen: Research Funding; Beigene: Research Funding; Janssen: Honoraria; Abbvie: Honoraria. Woyach: AbbVie Inc, ArQule Inc, Janssen Biotech Inc, AstraZeneca, Beigene: Other: Advisory Committee; AbbVie Inc, ArQule Inc, AstraZeneca Pharmaceuticals LP, Janssen Biotech Inc, Pharmacyclics LLC, an AbbVie Company,: Consultancy; AbbVie Inc, Loxo Oncology Inc, a wholly owned subsidiary of Eli Lilly & Company: Research Funding; Gilead Sciences Inc: Other: Data & Safety. Eyre: Secura Bio: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria, Other: Travel to conferences; AstraZeneca: Honoraria, Research Funding; Janssen: Honoraria; Gilead/KITE: Honoraria, Other: Travel support for conferences, Research Funding, Speakers Bureau; Incyte: Consultancy; Loxo Oncology: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Honoraria; Beigene: Honoraria, Research Funding.