Purpose: TAK-659 is an investigational, dual SYK/FLT3 inhibitor with preclinical activity in B-cell malignancy models. This first-in-human, dose-escalation/expansion study aimed to determine the safety, tolerability, MTD/recommended phase II dose (RP2D), and preliminary efficacy of TAK-659 in relapsed/refractory solid tumors and B-cell lymphomas. Patients and Methods: Patients received continuous, once-daily oral TAK-659, 60–120 mg in 28-day cycles, until disease progression or unacceptable toxicity. The study applied an accelerated dose-escalation design to determine the MTD and RP2D. In the expansion phase, patients with lymphoma were enrolled in five disease cohorts at the MTD. Results: Overall, 105 patients were enrolled [dose escalation, n = 36 (solid tumors, n = 19; lymphoma, n = 17); expansion, n = 69]. The MTD was 100 mg once daily. TAK-659 absorption was fast ( T max ∼2 hours) with a long terminal half-life (∼37 hours). Exposure generally increased with dose (60–120 mg), with moderate variability. The most common treatment-related adverse events were generally asymptomatic and reversible elevations in clinical laboratory values. Among 43 response-evaluable patients with diffuse large B-cell lymphoma, 8 (19%) achieved a complete response (CR) with an overall response rate (ORR) of 28% [23% intent-to-treat (ITT)]. Responses were seen in both de novo and transformed disease and appeared independent of cell-of-origin classification. Among 9 response-evaluable patients with follicular lymphoma, 2 (22%) achieved CR with an ORR of 89% (57% ITT). Conclusions: TAK-659 has single-agent activity in patients with B-cell lymphoma. Further studies of the drug in combination, including an evaluation of the biologically optimal and safest long-term dose and schedule, are warranted.

中文翻译：

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TAK-659（一种研究性双重 SYK/FLT3 抑制剂）在 B 细胞淋巴瘤患者中的 I 期研究。

目的：TAK-659 是一种研究性的 SYK/FLT3 双重抑制剂，在 B 细胞恶性肿瘤模型中具有临床前活性。这项首次人体剂量递增/扩展研究旨在确定 TAK-659 在复发/难治性实体瘤和 B 细胞淋巴瘤中的安全性、耐受性、MTD/推荐 II 期剂量（RP2D）和初步疗效。患者和方法：患者接受连续、每日一次的口服 TAK-659，60-120 毫克，28 天为一个周期，直到疾病进展或出现不可接受的毒性。该研究应用加速剂量递增设计来确定 MTD 和 RP2D。在扩展阶段，淋巴瘤患者被纳入 MTD 的五个疾病队列。结果：总共有 105 名患者入组 [剂量递增，n = 36（实体瘤，n = 19；淋巴瘤，n = 17）；扩展，n = 69]。MTD 为 100 毫克，每天一次。TAK-659 吸收快（T max ～2 小时），终末半衰期长（～37 小时）。暴露量通常随剂量（60-120 毫克）而增加，具有适度的变异性。最常见的治疗相关不良事件通常是临床实验室值无症状且可逆的升高。在 43 名可评估缓解的弥漫性大 B 细胞淋巴瘤患者中，8 名 (19%) 达到了完全缓解 (CR)，总缓解率 (ORR) 为 28% [23% 的意向治疗 (ITT)]。在新发疾病和转化疾病中都观察到了反应，并且似乎与细胞源分类无关。在 9 名可评估反应的滤泡性淋巴瘤患者中，2 名 (22%) 达到 CR，ORR 为 89% (57% ITT)。结论：TAK-659 在 B 细胞淋巴瘤患者中具有单药活性。联合用药的进一步研究，