-Author name in bold denotes the presenting author
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3732 BRUIN CLL-313: A Phase 3 Open-Label, Randomized Study of Pirtobrutinib Versus Bendamustine Plus Rituximab in Untreated Patients with Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (Trial in Progress)

Program: Oral and Poster Abstracts
Session: 642. Chronic Lymphocytic Leukemia: Clinical and Epidemiological: Poster III
Hematology Disease Topics & Pathways:
Lymphoid Leukemias, Clinical Trials, CLL, Clinical Research, Diseases, Lymphoid Malignancies
Monday, December 13, 2021, 6:00 PM-8:00 PM

Wojciech Jurczak, MD, PhD1*, Caroline Dartigeas, MD2*, Marta Coscia, MD, PhD3*, Peter S. Ganly, BMBCh, PhD4, Ghassan Al-Jazayrly, MD5, Chunxiao Wang6*, Katherine Bao7*, Ching Ching Leow7*, Safi Shahda, MD7* and Pier Luigi Zinzani, Prof, MD8

1Maria Sklodowska-Curie National Research Institute of Oncology, Kraków, Poland
2Centre Hospitalier Universitaire de Tours, Hôpital Bretonneau, Tours, France
3Division of Hematology, A.O.U. Città della Salute e della Scienza di Torino and Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy
4Department of Haematology, Christchurch Hospital, Christchurch, New Zealand
5Hollywood Presbyterian Medical Tower, Los Angeles, CA
6Eli Lilly and Company, Indianapolis, IN
7Loxo Oncology at Lilly, Stamford, CT
8Institute of Hematology “Seràgnoli” University of Bologna, Bologna, Italy

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. Covalent BTKi share pharmacologic liabilities (e.g. low oral bioavailability, short half-life) that collectively may lead to suboptimal BTK target coverage, for example in rapidly proliferating tumors with high BTK protein turnover such as accelerating CLL/SLL, 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 equal low nM potency was developed. In a phase 1/2 BRUIN study, 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).

Study Design and Methods: BRUIN CLL-313 is a randomized, open-label, global phase 3 study comparing pirtobrutinib monotherapy versus bendamustine plus rituximab (BR) in treatment naïve CLL/SLL patients with retained 17p. Approximately 250 patients will be randomized 1:1. Randomization will be stratified by IGHV mutation status (mutated vs unmutated), and Rai stage (low/intermediate vs high). Patients in the BR arm are eligible to crossover to pirtobrutinib monotherapy if they experience progressive disease per iwCLL 2018 and confirmed by an independent review committee (IRC).

Eligible patients are adults with confirmed diagnosis of CLL/SLL and who require therapy per iwCLL 2018 criteria. Key exclusion criteria include CNS involvement by CLL/SLL, Richter transformation to DLBCL, prolymphocytic leukemia or Hodgkin lymphoma any time pre-enrollment, presence of 17p deletion, prior systemic therapy for CLL/SLL, and significant cardiovascular disease.

The primary endpoint is progression-free survival (PFS) per iwCLL assessed by an IRC. Secondary endpoints include investigator-assessed PFS, overall survival (OS), overall response rate (ORR), duration of response (DoR), safety and tolerability, and patient reported outcomes. The global study is currently enrolling patients.

Disclosures: Jurczak: Abbvie, AstraZeneca, BeiGene, Celtrion, Celgene, Debbiopharm, Epizyme, Incyte, Janssen, Loxo Oncology, Merck, Mei Pharma, Morphosys, Novo Nordisk, Roche, Sandoz, Takeda, TG Therapeutics: Research Funding; Astra Zeneca, BeiGene, Janssen, Loxo Oncology, Sandoz, Roche,: Membership on an entity's Board of Directors or advisory committees. Dartigeas: Astra-Zeneca: Membership on an entity's Board of Directors or advisory committees, Other: travel grants/Congress; Abbvie: Membership on an entity's Board of Directors or advisory committees, Other: travel grants/Congress; Janssen: Membership on an entity's Board of Directors or advisory committees, Other: travel grants/Congress. Coscia: Gilead: Honoraria; AbbVie: Honoraria, Other; Janssen: Honoraria, Other, Research Funding; AstraZeneca: Honoraria. Wang: Eli Lilly and Company: Current Employment, Current equity holder in publicly-traded company. Bao: Loxo Oncology at Lilly: Current Employment; Genentech: Ended employment in the past 24 months. Leow: Loxo Oncology at Lilly: Current Employment, Current equity holder in publicly-traded company. Shahda: Loxo Oncology at Lilly: Current Employment, Current equity holder in publicly-traded company. Zinzani: Eusapharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kyowa Kirin: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Merck Sharp & Dohme: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; ADC Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Verastem: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen Cilag: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Immune Design: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; TG Therapeutics: Honoraria, Speakers Bureau; Celtrion: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sanofi: Consultancy; Beigene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sandoz: Membership on an entity's Board of Directors or advisory committees; Portola: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau.

*signifies non-member of ASH