A phase 1, first-in-human study of safimaltib, a MALT1 inhibitor, in B-lymphocytic malignancies.

IF 12.2 Q1 HEMATOLOGY

Blood Cancer Discovery Pub Date : 2026-09-30 DOI:10.1158/2643-3230.BCD-26-0179

Mark Hertzberg, Chan Y Cheah, Stephen Opat, Matko Kalac, Pau Abrisqueta, Vincent Ribrag, Emmanuel Bachy, Loïc Ysebaert, Lugui Qiu, Erel Joffe, Shuhua Yi, Pier Luigi Zinzani, Alessandra Tedeschi, Noriko Nishimura, Charlotte R Lemech, Jacqueline Bussolari, Changchun Deng, Alemu Takele Assefa, Sandy Van Hemelryck, Jan Snoeys, Brendan P Hodkinson, Nele Fourneau, Yu Cao, Srimathi Srinivasan, Yue Guo, Virginie Soete, Isabel Soriano Paradinas, Lorena Fontan, Ulrike Philippar, John F Gerecitano, Franck Morschhauser

{"title":"A phase 1, first-in-human study of safimaltib, a MALT1 inhibitor, in B-lymphocytic malignancies.","authors":"Mark Hertzberg, Chan Y Cheah, Stephen Opat, Matko Kalac, Pau Abrisqueta, Vincent Ribrag, Emmanuel Bachy, Loïc Ysebaert, Lugui Qiu, Erel Joffe, Shuhua Yi, Pier Luigi Zinzani, Alessandra Tedeschi, Noriko Nishimura, Charlotte R Lemech, Jacqueline Bussolari, Changchun Deng, Alemu Takele Assefa, Sandy Van Hemelryck, Jan Snoeys, Brendan P Hodkinson, Nele Fourneau, Yu Cao, Srimathi Srinivasan, Yue Guo, Virginie Soete, Isabel Soriano Paradinas, Lorena Fontan, Ulrike Philippar, John F Gerecitano, Franck Morschhauser","doi":"10.1158/2643-3230.BCD-26-0179","DOIUrl":null,"url":null,"abstract":"<p><p>Following preclinical findings, we evaluated safimaltib (MALT1 protease inhibitor; JNJ-67856633) in relapsed/refractory B-cell non-Hodgkin lymphomas or chronic lymphocytic leukemia in a multi-center, phase-1, dose-escalation/dose-expansion study (NCT03900598). Primary endpoints were recommended phase-2 dose (RP2D) and safety. Among 226 patients, 56.2% had diffuse large B-cell lymphoma (DLBCL); 47.3% received ≥4 prior therapy lines. RP2D was once-daily, 300-mg, oral safimaltib±loading dose. Most common adverse events (AEs) were hyperbilirubinemia (48.2%; off-target related), anemia (36.7%), neutropenia (31.4%), and thrombocytopenia (27.4%). Dose reduction mitigated safimaltib-related AEs. Objective response rate was 28.8% (95% CI: 23.0%-35.1%), including 9 (3.9%) complete responses. All patients with non-germinal-center B-cell-like DLBCL and ≥1 B-cell-receptor pathway activating mutation (n=5) responded to safimaltib. Safimaltib exhibited on-target activity in translational studies, affecting NF-κB-regulated cytokines. Proof-of-principle activity in this first MALT1-targeting study in hematologic malignanices suggest MALT1 may be a feasible target in humans and supports further investigation despite observed off-target effects.</p>","PeriodicalId":29944,"journal":{"name":"Blood Cancer Discovery","volume":" ","pages":""},"PeriodicalIF":12.2000,"publicationDate":"2026-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Blood Cancer Discovery","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.1158/2643-3230.BCD-26-0179","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"HEMATOLOGY","Score":null,"Total":0}

引用次数: 0

Abstract

Following preclinical findings, we evaluated safimaltib (MALT1 protease inhibitor; JNJ-67856633) in relapsed/refractory B-cell non-Hodgkin lymphomas or chronic lymphocytic leukemia in a multi-center, phase-1, dose-escalation/dose-expansion study (NCT03900598). Primary endpoints were recommended phase-2 dose (RP2D) and safety. Among 226 patients, 56.2% had diffuse large B-cell lymphoma (DLBCL); 47.3% received ≥4 prior therapy lines. RP2D was once-daily, 300-mg, oral safimaltib±loading dose. Most common adverse events (AEs) were hyperbilirubinemia (48.2%; off-target related), anemia (36.7%), neutropenia (31.4%), and thrombocytopenia (27.4%). Dose reduction mitigated safimaltib-related AEs. Objective response rate was 28.8% (95% CI: 23.0%-35.1%), including 9 (3.9%) complete responses. All patients with non-germinal-center B-cell-like DLBCL and ≥1 B-cell-receptor pathway activating mutation (n=5) responded to safimaltib. Safimaltib exhibited on-target activity in translational studies, affecting NF-κB-regulated cytokines. Proof-of-principle activity in this first MALT1-targeting study in hematologic malignanices suggest MALT1 may be a feasible target in humans and supports further investigation despite observed off-target effects.

查看原文本刊更多论文

MALT1抑制剂safimaltib治疗b淋巴细胞恶性肿瘤的i期临床研究

根据临床前研究结果，我们在一项多中心、剂量递增/剂量扩大研究（NCT03900598）中评估了safimaltib （MALT1蛋白酶抑制剂；JNJ-67856633）在复发/难治性b细胞非霍奇金淋巴瘤或慢性淋巴细胞白血病中的治疗效果。主要终点是推荐的2期剂量（RP2D）和安全性。226例患者中，弥漫大b细胞淋巴瘤（DLBCL）占56.2%；47.3%接受过≥4个既往治疗线。RP2D为每日1次，300 mg，口服萨菲莫替±负荷剂量。最常见的不良事件（ae）是高胆红素血症（48.2%；脱靶相关）、贫血（36.7%）、中性粒细胞减少（31.4%）和血小板减少（27.4%）。剂量减少减轻了萨莫替布相关的不良反应。客观有效率为28.8% (95% CI: 23.0% ~ 35.1%)，其中完全缓解9例（3.9%）。所有非生发中心b细胞样DLBCL和≥1个b细胞受体途径激活突变（n=5）的患者对萨菲莫替有应答。在翻译研究中，Safimaltib表现出靶向活性，影响NF-κ b调节的细胞因子。这项首次针对血液恶性肿瘤的MALT1靶向研究的原理证明表明，尽管观察到脱靶效应，MALT1可能是一种可行的人类靶点，并支持进一步的研究。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

求助全文

约1分钟内获得全文求助全文

来源期刊

Blood Cancer Discovery Multiple-

CiteScore

12.70

自引率

1.80%

发文量

139

期刊介绍： The journal Blood Cancer Discovery publishes high-quality Research Articles and Briefs that focus on major advances in basic, translational, and clinical research of leukemia, lymphoma, myeloma, and associated diseases. The topics covered include molecular and cellular features of pathogenesis, therapy response and relapse, transcriptional circuits, stem cells, differentiation, microenvironment, metabolism, immunity, mutagenesis, and clonal evolution. These subjects are investigated in both animal disease models and high-dimensional clinical data landscapes. The journal also welcomes submissions on new pharmacological, biological, and living cell therapies, as well as new diagnostic tools. They are interested in prognostic, diagnostic, and pharmacodynamic biomarkers, and computational and machine learning approaches to personalized medicine. The scope of submissions ranges from preclinical proof of concept to clinical trials and real-world evidence. Blood Cancer Discovery serves as a forum for diverse ideas that shape future research directions in hematooncology. In addition to Research Articles and Briefs, the journal also publishes Reviews, Perspectives, and Commentaries on topics of broad interest in the field.