TK216:第一代EWS::FLI1融合蛋白拮抗剂治疗尤文肉瘤。

IF 42.1 1区 医学 Q1 ONCOLOGY Journal of Clinical Oncology Pub Date : 2024-11-01 Epub Date: 2024-07-02 DOI:10.1200/JCO.24.00020
Paul A Meyers, Noah Federman, Najat Daw, Peter M Anderson, Lara E Davis, AeRang Kim, Margaret E Macy, Angela Pietrofeso, Ravin Ratan, Richard F Riedel, Matteo Trucco, James B Breitmeyer, Jeffrey A Toretsky, Joseph A Ludwig
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引用次数: 0

摘要

目的:尤文肉瘤(ES)是一种罕见的癌症,其病理标志性易位导致尤文肉瘤基因(EWS)::FLI1 肿瘤蛋白,在复发/难治(R/R)情况下预后较差。Tokalas (TK)216旨在直接结合EWS::FLI1蛋白,破坏蛋白与蛋白之间的相互作用,抑制转录因子的功能。TK216 加长春新碱在临床前肿瘤模型中显示出协同活性。据我们所知,我们报告了TK216在R/R ES中的首次同类、首次人体I/II期试验结果:TK216以连续输注的方式静脉给药给11组R/R ES患者。用药时间从 7 天延长至 10 天、14 天和 28 天。根据研究者的选择,长春新碱可在第2周期后的第1天加入。试验采用3+3设计,并按II期推荐剂量(RP2D)扩增队列:共有85名患者入组,中位年龄为27岁(11-77岁)。第9队列确定了14天输注TK216的最大耐受剂量(200 mg/m2,每日一次),并将其选定为RP2D。既往接受过全身治疗方案的中位数为3次(1-10次不等)。在RP2D治疗的患者中,最常见的相关不良事件包括中性粒细胞减少(44.7%)、贫血(29.4%)、白细胞减少(29.4%)、发热性中性粒细胞减少(15.3%)、血小板减少(11.8%)和感染(17.6%)。在第9组和第10组中,2名患者完全应答,1名患者部分应答,14名患者病情稳定;6个月无进展生存率为11.9%。第11组的8名患者没有应答:结论:TK216与长春新碱或不与长春新碱一起连续输注14天,耐受性良好,在R/R ES的RP2D显示出有限的活性。
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Open-Label, Multicenter, Phase I/II, First-in-Human Trial of TK216: A First-Generation EWS::FLI1 Fusion Protein Antagonist in Ewing Sarcoma.

Purpose: Ewing Sarcoma (ES), a rare cancer with a pathognomonic translocation resulting in the Ewing sarcoma gene (EWS)::FLI1 oncoprotein, has a poor prognosis in the relapsed/refractory (R/R) setting. Tokalas (TK)216 was designed to bind EWS::FLI1 proteins directly, disrupt protein-protein interactions, and inhibit transcription factor function. TK216 plus vincristine showed synergistic activity in preclinical tumor models. To our knowledge, we report the results of a first-in-class, first-in-human phase I/II trial of TK216 in R/R ES.

Patients and methods: TK216 was administered intravenously as a continuous infusion to patients with R/R ES in 11 cohorts. The dosing duration of 7 days was later extended to 10, 14, and 28 days. Vincristine could be added on day 1 after cycle 2, per investigators' choice. The trial used a 3 + 3 design with an expansion cohort at the recommended phase II dose (RP2D).

Results: A total of 85 patients with a median age of 27 years (range, 11-77) were enrolled. The maximum tolerated dose for the 14-day infusion of TK216, 200 mg/m2 once daily, was determined in cohort 9 and selected as the RP2D. The median previous number of systemic therapies regimens was three (range, 1-10). The most frequent-related adverse events in patients treated at the RP2D included neutropenia (44.7%), anemia (29.4%), leukopenia (29.4%), febrile neutropenia (15.3%), thrombocytopenia (11.8%), and infections (17.6%). In cohorts 9 and 10, two patients had a complete response, one had a partial response, and 14 had stable disease; the 6-month progression-free survival was 11.9%. There were no responses among the eight patients in cohort 11.

Conclusion: TK216 administered as 14-day continuous infusion with or without vincristine was well tolerated and showed limited activity at the RP2D in R/R ES.

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来源期刊
Journal of Clinical Oncology
Journal of Clinical Oncology 医学-肿瘤学
CiteScore
41.20
自引率
2.20%
发文量
8215
审稿时长
2 months
期刊介绍: The Journal of Clinical Oncology serves its readers as the single most credible, authoritative resource for disseminating significant clinical oncology research. In print and in electronic format, JCO strives to publish the highest quality articles dedicated to clinical research. Original Reports remain the focus of JCO, but this scientific communication is enhanced by appropriately selected Editorials, Commentaries, Reviews, and other work that relate to the care of patients with cancer.
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