A Phase 1, First-in-Human, Open-Label Study Evaluating the Safety, Tolerability, Pharmacokinetics, and Efficacy of AMG 562 in Subjects With Relapsed / Refractory Diffuse Large B-cell Lymphoma, Mantle Cell Lymphoma, or Follicular Lymphoma

Evaluate the safety and tolerability of AMG 562 in adult subjects with DLBCL, MCL, or FL. Estimate the maximum tolerated dose (MTD) and/or a biologically active dose (e.g., recommended phase 2 dose [RP2D])

开始日期2018-10-29

申办/合作机构

Amgen, Inc.

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项与 Surovatamig 相关的文献（医药）

2022-09-08·Blood

T-cell exhaustion induced by continuous bispecific molecule exposure is ameliorated by treatment-free intervals

Article

作者: Theurich, Sebastian ; Vick, Binje ; Straub, Tobias ; Bücklein, Veit ; Sponheimer, Monika ; Leutbecher, Alexandra ; Kazerani, Maryam ; von Bergwelt-Baildon, Michael ; Kischel, Roman ; Weigert, Oliver ; Marcinek, Anetta ; Scheurer, Michaela ; Nixdorf, Daniel ; Philipp, Nora ; Wulf, Jan ; Rejeski, Kai ; Nicholls, Alyssa ; Subklewe, Marion ; Brauchle, Bettina ; Lacher, Sonja M. ; Muth, Amelie ; Jeremias, Irmela ; Ohlmeyer, Malte ; Rohrbacher, Lisa ; Hänel, Gerulf

AbstractT-cell–recruiting bispecific molecule therapy has yielded promising results in patients with hematologic malignancies; however, resistance and subsequent relapse remains a major challenge. T-cell exhaustion induced by persistent antigen stimulation or tonic receptor signaling has been reported to compromise outcomes of T-cell–based immunotherapies. The impact of continuous exposure to bispecifics on T-cell function, however, remains poorly understood. In relapsed/refractory B-cell precursor acute lymphoblastic leukemia patients, 28-day continuous infusion with the CD19xCD3 bispecific molecule blinatumomab led to declining T-cell function. In an in vitro model system, mimicking 28-day continuous infusion with the half-life–extended CD19xCD3 bispecific AMG 562, we identified hallmark features of exhaustion arising over time. Continuous AMG 562 exposure induced progressive loss of T-cell function (day 7 vs day 28 mean specific lysis: 88.4% vs 8.6%; n = 6; P = .0003). Treatment-free intervals (TFIs), achieved by AMG 562 withdrawal, were identified as a powerful strategy for counteracting exhaustion. TFIs induced strong functional reinvigoration of T cells (continuous vs TFI-specific lysis on day 14: 34.9% vs 93.4%; n = 6; P < .0001) and transcriptional reprogramming. Furthermore, use of a TFI led to improved T-cell expansion and tumor control in vivo. Our data demonstrate the relevance of T-cell exhaustion in bispecific antibody therapy and highlight that T cells can be functionally and transcriptionally rejuvenated with TFIs. In view of the growing number of bispecific molecules being evaluated in clinical trials, our findings emphasize the need to consider and evaluate TFIs in application schedules to improve clinical outcomes.

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研发状态

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适应症	最高研发状态	国家/地区	公司	日期
复发性弥漫性大B细胞淋巴瘤	临床1期	美国	Amgen, Inc.	2018-10-29
复发性弥漫性大B细胞淋巴瘤	临床1期	德国	Amgen, Inc.	2018-10-29
复发性弥漫性大B细胞淋巴瘤	临床1期	加拿大	Amgen, Inc.	2018-10-29
复发性弥漫性大B细胞淋巴瘤	临床1期	比利时	Amgen, Inc.	2018-10-29
滤泡性淋巴瘤	临床1期	美国	Amgen, Inc.	2018-10-29
滤泡性淋巴瘤	临床1期	比利时	Amgen, Inc.	2018-10-29
滤泡性淋巴瘤	临床1期	加拿大	Amgen, Inc.	2018-10-29
滤泡性淋巴瘤	临床1期	德国	Amgen, Inc.	2018-10-29
套细胞淋巴瘤	临床1期	美国	Amgen, Inc.	2018-10-29
套细胞淋巴瘤	临床1期	加拿大	Amgen, Inc.	2018-10-29

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


NCT03571828 (Phase I study of AMG 562, CTgov)	临床1期	套细胞淋巴瘤 \| 滤泡性淋巴瘤 \| 复发性弥漫性大B细胞淋巴瘤	10	AMG 562 (Cohort 1: AMG 562 0.1 μg)	鏇鬱顧積遞齋淵鑰夢鑰(積網衊簾廠衊獵壓繭顧) = 鑰獵壓簾範淵衊餘網遞醖簾願壓壓夢遞醖獵築 (遞鹹簾窪繭夢鑰網艱窪, 鑰窪鑰衊窪繭築構糧襯 ~ 築繭繭觸衊廠窪積廠鏇) 更多	-	2024-03-22
NCT03571828 (Phase I study of AMG 562, CTgov)	临床1期	套细胞淋巴瘤 \| 滤泡性淋巴瘤 \| 复发性弥漫性大B细胞淋巴瘤	10	AMG 562 (Cohort 2: AMG 562 0.3 μg)	鏇鬱顧積遞齋淵鑰夢鑰(積網衊簾廠衊獵壓繭顧) = 構壓觸繭觸簾鑰顧觸醖醖簾願壓壓夢遞醖獵築 (遞鹹簾窪繭夢鑰網艱窪, 顧艱鬱鑰廠壓觸鏇觸鬱 ~ 廠醖鏇餘遞築艱鏇選蓋) 更多	-	2024-03-22
NCT03571828 (Phase I study of AMG 562, ICML2021)	临床1期	套细胞淋巴瘤 \| 滤泡性淋巴瘤 \| 复发性弥漫性大B细胞淋巴瘤 CD19 \| CD3	9	AMG 562 0.1mg	(醖觸鬱構壓範淵獵製膚) = n = 1, Gr 4 廠鬱繭鑰顧積簾構構蓋 (蓋鹹鬱積範鑰壓淵觸淵 ) 更多	不佳	2021-06-17