Phase Ib study of combinations of avadomide (CC-122), CC-223, CC-292, and rituximab in patients with relapsed/refractory diffuse large B-cell lymphoma.

There is a need for additional treatment options for patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) who do not benefit from available therapies. We examined combinations of the cereblon E3 ligase modulator (CELMoD) agent avadomide (CC-122), the selective, ATP-competitive mammalian target of rapamycin kinase inhibitor CC-223, and the potent, selective, covalent Bruton tyrosine kinase inhibitor CC-292 in patients with relapsed/refractory (R/R) DLBCL. In the multicenter, phase Ib CC-122-DLBCL-001 study (NCT02031419), the dose-escalation portion explored combinations of CC-122, CC-223, and CC-292 administered as doublets or triplets with rituximab in patients with chemorefractory DLBCL. Primary endpoints were safety, tolerability, and dose-limiting toxicities; additional endpoints included pharmacokinetics, pharmacodynamics, biomarkers, and preliminary efficacy. As of December 1, 2017, 106 patients were enrolled across four cohorts. The median age was 65 years (range 24-84 years), and patients had a median of 3 (range 1-10) prior to regimens. A total of 101 patients (95.3%) discontinued, most commonly due to disease progression (49.1%). The most common any-grade adverse events (AEs) across treatment arms were gastrointestinal and hematologic; the most common grade 3/4 AEs were hematologic. CC-122 was well tolerated, with no unexpected safety concerns. Preliminary efficacy was observed in three of four treatment arms. CC-122 plus rituximab was considered suitable for dose expansion, whereas CC-223 and CC-292 combinations were associated with enhanced toxicity and/or insufficient improvement in responses. CC-122 plus rituximab was well tolerated, with preliminary antitumor activity in patients with R/R DLBCL. This innovative study demonstrates the feasibility of assessing the tolerability and preliminary efficacy of novel combinations utilizing a multi-arm dose-finding design.

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© 2022 The Authors. eJHaem published by British Society for Haematology and John Wiley & Sons Ltd.

Déclaration de conflit d'intérêts

Vincent Ribrag received honoraria from Gilead, Infinity, ArgenX, Merck Sharp & Dohme, Bristol Myers Squibb, Epizyme, Nanostring, Incyte, Roche, and AstraZeneca; served as a consultant or advisor for Servier; and received research funding from ArgenX. Julio C. Chavez served as a consultant or advisor for Novartis, Celgene, a Bristol‐Myers Squibb Company, Bayer, Morphosys, Karyopharm, AstraZeneca, Verastem, Pfizer, and Genentech; received research funding from Merck; and served on the speaker's bureau for Genentech and AstraZeneca. Jason Kaplan served as a consultant or advisor for and received research funding from Seattle Genetics, and received travel funding from Curis. Jason C. Chandler served as a consultant or advisor for Janssen and Axess Oncology. Armando Santoro served as a consultant or advisor for ArQule, Sanofi, Bristol Myers Squibb, Servier, Gilead, Pfizer, Eisai, Bayer, and Merck Sharpe and Dohme; and served on the speaker's bureau for Takeda, Bristol Myers Squibb, Roche, AbbVie, Amgen, Celgene, a Bristol‐Myers Squibb company, Servier, Gilead, AstraZeneca, Pfizer, ArQule, Lilly, Sandoz, Eisai, Novartis, Bayer, and Merck Sharpe and Dohme. Paolo Corradini received honoraria from Janssen, Gilead, AbbVie, Takeda, Roche, Novartis, and Celgene, a Bristol‐Myers Squibb Company; served as a consultant or advisor for Novartis, Janssen, Celgene, a Bristol‐Myers Squibb company, and Gilead; received travel funding from Novartis, AbbVie, and Gilead; and served on the speaker's bureau for Novartis. Ian W. Flinn received research funding from AbbVie, Acerta, Agios, ArQule, BeiGene, Calithera, Celgene, a Bristol‐Myers Squibb Company, Constellation, Curis, Forma, Forty‐Seven Inc, Genentech, Gilead, Incyte, Infinity, Janssen, Karyopharm, Kite, Merck, Novartis, Pfizer, Portola, Roche, Seattle Genetics, Takeda, Teva, TG Therapeutics, Trillium, and Verastem. Ranjana Advani served as a consultant or advisor for AstraZeneca, Bayer Healthcare Pharmaceuticals, Cell Medica, Genentech/Roche, Gilead Kite Pharma, Kyowa, Seattle Genetics, and Takeda; and received research funding from Agensys, Celgene, a Bristol‐Myers Squibb company, Forty‐Seven Inc., Genentech/Roche, Janssen Pharmaceutical, Kura, Merck, Millenium, Pharmacyclics, Regeneron, and Seattle Genetics. Philippe A. Cassier received honoraria from Amgen, AstraZeneca, Blueprint Medicines, Novartis, and Roche/Genentech; received research funding from AbbVie, AstraZeneca, Bayer, Blueprint Medicines, Bristol Myers Squibb, Celgene, a Bristol‐Myers Squibb Company, GlaxoSmithKline, Innate Pharma, Janssen, Lilly, Loxo, Merck Serono, Merck Sharp & Dohme, Novartis, Plexxikon, Roche/Genentech, Taiho Pharmaceutical, Toray Industries, and Transgene; and received travel funding from Amgen, Bristol Myers Squibb, Merck Sharp & Dohme, Netris Pharma, Novartis, and Roche. Randeep Sangha received honoraria from Pfizer, Boehringer Ingelheim, AstraZeneca, Roche, Lundbeck, Bristol Myers Squibb, Merck, AbbVie, and Takeda; served as a consultant or advisor for Boehringer Ingelheim, Roche, Lundbeck, Bristol Myers Squibb, Merck, AbbVie, Takeda, and Teva; and received research funding from Bristol Myers Squibb, AbbVie, Takeda, Pharmacyclics, Morphosys, Roche, Merck, Celgene, a Bristol‐Myers Squibb company, and Novartis. Iris Isufi served as a consultant or advisor for AstraZeneca, Celgene, a Bristol‐Myers Squibb company/Jazz Pharmaceuticals, and Kite Pharma; and received travel funding from Celgene, a Bristol‐Myers Squibb company, and Kite Pharma. Shailaja Uttamsingh, Patrick R. Hagner, Anita K. Gandhi, and Michael Pourdehnad are employed by and have equity ownership with Bristol Myers Squibb. Harald Haeske has equity ownership with Pieris AG and served as a consultant or advisor for Celgene, a Bristol‐Myers Squibb company, and 4SC AG. Kristen Hege is employed by and holds patents with Bristol Myers Squibb; has equity ownership with Bristol Myers Squibb, Arcus Biosciences, and Mersana Therapeutics; and served on the Board of Directors for Arcus Biosciences, Mersana Therapeutics, and the Society for Immunotherapy of Cancer. John Kuruvilla received honoraria from Amgen, AstraZeneca, Bristol Myers Squibb, Celgene, a Bristol‐Myers Squibb Company, Gilead, Janssen, Karyopharm Therapeutics, Merck, Novartis, Roche, and Seattle Genetics; and served as a consultant or advisor for AbbVie, Bristol Myers Squibb, Gilead Sciences, Karyopharm Therapeutics, Merck, Roche, and Seattle Genetics; and received research funding from Janssen and Roche. All other authors declare no conflict of interest.