尤文肉瘤 (ES) 是一种罕见的癌症，其特征性易位导致尤文肉瘤基因 (EWS)::FLI1 癌蛋白，在复发/难治性 (R/R) 情况下预后较差。 Tokalas (TK)216 旨在直接结合 EWS::FLI1 蛋白，破坏蛋白质间相互作用，并抑制转录因子功能。 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 治疗 R/R ES 的一流、首次人体 I/II 期试验的结果。TK216 以连续输注的方式静脉注射给 R/R ES 患者11个队列。 7天的给药持续时间后来延长至10、14和28天。根据研究人员的选择，长春新碱可以在第 2 周期后的第 1 天添加。该试验采用 3 3 设计，并以推荐的 II 期剂量 (RP2D) 进行扩展队列。总共入组了 85 名中位年龄为 27 岁（范围为 11-77 岁）的患者。 TK216 输注 14 天的最大耐受剂量为每天一次 200 mg/m2，在队列 9 中确定并选择为 RP2D。既往全身治疗方案的中位数为 3（范围，1-10）。 RP2D 治疗患者中最常见的相关不良事件包括中性粒细胞减少症 (44.7%)、贫血 (29.4%)、白细胞减少症 (29.4%)、发热性中性粒细胞减少症 (15.3%)、血小板减少症 (11.8%) 和感染 (17.6%) ）。在队列 9 和队列 10 中，两名患者获得完全缓解，一名患者获得部分缓解，14 名患者病情稳定； 6 个月无进展生存率为 11.9%。第 11 组中的 8 名患者没有出现反应。连续 14 天输注（含或不含长春新碱）的 TK216 耐受性良好，并且在 R/R ES 中的 RP2D 处表现出有限的活性。

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.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).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.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.