ESCALADE: A PHASE 3 STUDY OF ACALABRUTINIB IN COMBINATION WITH R‐CHOP FOR PATIENTS ≤65Y WITH UNTREATED NON‐GERMINAL CENTER B‐CELL–LIKE DIFFUSE LARGE B‐CELL LYMPHOMA

Background: Rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) remains the standard of care for diffuse large B-cell lymphoma (DLBCL). Although most patients (pts) can be cured, 35–40% will experience relapsed/refractory disease, leading to poor outcomes in the majority of pts. Covalent irreversible Bruton tyrosine kinase inhibitors (BTKi) have shown higher responses in pts with non-germinal center B-cell–like (non-GCB) DLBCL than with GCB DLBCL. In untreated non-GCB DLBCL pts, the phase 3 PHOENIX study (Younes et al. J Clin Oncol. 2019;37:1285-95) showed that addition of the BTKi ibrutinib to R-CHOP (R-CHOP-I) did not improve outcomes in the intent-to-treat population. However, pts age <60y treated with R-CHOP-I had significantly improved progression-free survival (PFS) and overall survival (OS) compared with those receiving R-CHOP alone. Acalabrutinib (A) is a second-generation BTKi with enhanced kinase selectivity and potential for better efficacy and tolerability than first-generation BTKis. There is a strong rationale for combining A with R-CHOP in pts with untreated DLBCL, and safety of A + R-CHOP has been shown in a phase 1b/2 study (Davies et al. ASH 2020). The aim of this study is to determine if the addition of A to R-CHOP leads to improved PFS in pts age ≤65y with untreated non-GCB DLBCL. Methods: ESCALADE (ACE-LY-312; NCT04529772) is a phase 3, randomized, global, double-blind study of A vs placebo in combination with R-CHOP for treatment of newly diagnosed non-GCB DLBCL. The study is recruiting adults ≥18y and ≤65y with previously untreated DLBCL stage II–IV disease with a Revised International Prognostic Index (R-IPI) score of 2–5. Prior to randomization, all pts will receive an initial R-CHOP cycle (cycle 1) as standard-of-care treatment to prevent delays in therapy initiation. Based on central Gene Expression Profile (GEP) testing performed after enrollment, pts with non-GCB DLBCL (activated B-cell like or unclassified) will be randomized into 2 arms to receive A 100 mg twice daily plus R-CHOP or placebo plus R-CHOP from cycle 2 to cycle 6 followed by 2 additional cycles of rituximab + A or placebo (cycles 7 and 8). All pts will receive primary prophylaxis with granulocyte colony-stimulating factors accompanying all R-CHOP cycles. The study aims to randomize 600 pts (∼300 per arm). The primary objective is to evaluate whether the addition of A to R-CHOP will prolong PFS. Secondary endpoints include event-free survival, complete response rate, OS, pharmacokinetics, and safety. Key exclusion criteria are central nervous system involvement, primary mediastinal lymphoma, high-grade B-cell lymphoma, diagnosis or treatment of malignancy other than DLBCL, and history of indolent lymphoma. Approximately 250 sites globally will enroll pts. Enrollment began in Q3 of 2020. EA – previously submitted to ASCO and EHA 2021. The research was funded by: Acerta Pharm, a member of the AstraZeneca Group Keywords: Aggressive B-cell non-Hodgkin lymphoma, Molecular Targeted Therapies, Ongoing Trials Conflicts of interests pertinent to the abstract L. H. Sehn Consultant or advisory role: Celgene, AbbVie, Seattle Genetics, TG Therapeutics, Janssen, Amgen, Roche/Genentech, Gilead Sciences, Lundbeck, Amgen, Apobiologix, Karyopharm Therapeutics, Kite Pharma, Merck, Takeda, Teva, AstraZeneca, Acerta Pharma, Morphosys, Incyte, Debiopharm Group, Sandoz-Novartis, Genmab, Verastem Honoraria: Amgen, Apobiologix, AbbVie, Celgene, Gilead Sciences, Janssen-Ortho, Karyopharm Therapeutics, Kite Pharma, Lundbeck, Merck, Roche/Genentech, Seattle Genetics, Takeda, Teva, TG Therapeutics, AstraZeneca, Acerta Pharma, Morphosys, Incyte, Debiopharm Group, Sandoz-Novartis, Verastem, Genmab, AstraZeneca Research funding: Roche/Genentech, Teva B. Kahl Consultant or advisory role: Celgene, AbbVie, Pharmacyclics, Acerta Pharma, ADC Therapeutics, Genentech, Roche, BeiGene, Bayer, MEI Pharma, Kite/Gilead, MorphoSys, Janssen, Karyopharm Therapeutics, Teva, BMS, Molecular Templates, Incyte Research funding: Genentech, Acerta Pharma, ADC Therapeutics, Celgene Educational grants: Celgene, Juno Therapeutics, Genentech/Roche, AbbVie, Millenium, Seattle Genetics M. Matasar Consultant or advisory role: Genentech, Bayer, Merck, Juno Therapeutics, Roche, Teva, Rocket Medical, Seattle Genetics, Daiichi Sankyo, Takeda; Stock ownership: Merck Honoraria: Genentech, Roche, Glaxosmithkline, Bayer, Pharmacyclics, Janssen, Seattle Genetics, Immunovaccine Technologies, Takeda Research funding: Genentech, Roche, Glaxosmithkline, IGM Biosciences, Bayer, Pharmacyclis, Janssen, Rocket Medical, Seattle GEnetics, Immunovaccine Tech Educational grants: Genentech, Roche, Seattle Genetics, Bayer Other remuneration: Expert Testimony: Bayer G. Lentz Consultant or advisory role: Roche/Genentech, Janssen-Cilag, Bristol-Myers Squibb, Bayer, Novartis, Celgene, MorphoSys, AstraZeneca, Gilead Sciences Honoraria: Janssen-Cilag, Bayer, Celgene, Roche/Genentech, AstraZeneca, BMS, MorphoSys, Gilead Sciences, Novartis, AbbVie Research funding: Janssen-Cilag, Roche/Genentech, AstraZeneca, Aquinox Pharmaceuticals, Bayer, MorphoSys, Gilead Sciences, Verastem, AGIOS Educational grants: Janssen-Cilag, Celegene, AstraZeneca, Roche/Genentech, Other remuneration: Expert Testimony: MorphoSys K. Izutsu Consultant or advisory role: Bayer, Celgene, AstraZeneca, Ono Pharmaceutical, Kyowa Kirin Honoraria: Takeda, Chugai Pharma, Eisai, Janssen, AbbVie, Novartis, MSD, Sumitomo Dainippon Pharma, Ono Pharmaceutical, Mundipharma, HUYA Bioscience International, AstraZeneca, Bayer, BMS, Kyowa Kirin, Fujifilm, Celgene, Daiichi Sankyo, Allergan Research funding: Eisai, Chugai Pharma L. Tao Employment or leadership position: AstraZeneca R. Calvo Employment or leadership position: AstraZeneca Stock ownership: AstraZeneca P. L. Zinzani Consultant or advisory role: Verastem, Celltrion, Gilead, Janseen-Cilag, BMS, Servier, Sandoz, MSD, TG Therapeutics, Takeda, Roche, Eusapharma, Kwoya Kirin, Sanofi, ADC Therapteutics Other remuneration: Speakers’ Bureau - Verastem, Celltrion, Gilead, Janseen-Cilag, BMS, Servier, MSD, TG Therapeutics, Takeda, Roche, Eusapharma, Kyowa Kirin

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