{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,20]],"date-time":"2026-05-20T03:07:11Z","timestamp":1779246431586,"version":"3.51.4"},"reference-count":48,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2022,1,14]],"date-time":"2022-01-14T00:00:00Z","timestamp":1642118400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["eJHaem"],"published-print":{"date-parts":[[2022,2]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>There is a need for additional treatment options for patients with relapsed or refractory diffuse large B\u2010cell lymphoma (DLBCL) who do not benefit from available therapies. We examined combinations of the cereblon E3 ligase modulator (CELMoD) agent avadomide (CC\u2010122), the selective, ATP\u2010competitive mammalian target of rapamycin kinase inhibitor CC\u2010223, and the potent, selective, covalent Bruton tyrosine kinase inhibitor CC\u2010292 in patients with relapsed\/refractory (R\/R) DLBCL.<\/jats:p><jats:p>In the multicenter, phase Ib CC\u2010122\u2010DLBCL\u2010001 study (NCT02031419), the dose\u2010escalation portion explored combinations of CC\u2010122, CC\u2010223, and CC\u2010292 administered as doublets or triplets with rituximab in patients with chemorefractory DLBCL. Primary endpoints were safety, tolerability, and dose\u2010limiting toxicities; additional endpoints included pharmacokinetics, pharmacodynamics, biomarkers, and preliminary efficacy.<\/jats:p><jats:p>As of December 1, 2017, 106 patients were enrolled across four cohorts. The median age was 65 years (range 24\u201384 years), and patients had a median of 3 (range 1\u201310) prior to regimens. A total of 101 patients (95.3%) discontinued, most commonly due to disease progression (49.1%). The most common any\u2010grade adverse events (AEs) across treatment arms were gastrointestinal and hematologic; the most common grade 3\/4 AEs were hematologic. CC\u2010122 was well tolerated, with no unexpected safety concerns. Preliminary efficacy was observed in three of four treatment arms. CC\u2010122 plus rituximab was considered suitable for dose expansion, whereas CC\u2010223 and CC\u2010292 combinations were associated with enhanced toxicity and\/or insufficient improvement in responses.<\/jats:p><jats:p>CC\u2010122 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\u2010arm dose\u2010finding design.<\/jats:p>","DOI":"10.1002\/jha2.375","type":"journal-article","created":{"date-parts":[[2022,1,14]],"date-time":"2022-01-14T11:49:24Z","timestamp":1642160964000},"page":"139-153","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Phase Ib study of combinations of avadomide (CC\u2010122), CC\u2010223, CC\u2010292, and rituximab in patients with relapsed\/refractory diffuse large B\u2010cell lymphoma"],"prefix":"10.1002","volume":"3","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5221-353X","authenticated-orcid":false,"given":"Vincent","family":"Ribrag","sequence":"first","affiliation":[{"name":"Institut Gustave Roussy  Villejuif France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Julio C.","family":"Chavez","sequence":"additional","affiliation":[{"name":"H. 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