Purpose: To evaluate the safety, tolerability, and pharmacokinetics of BAY 2666605, a velcrin that induces complex formation between the phosphodiesterase PDE3A and the protein Schlafen 12 (SLFN12) leading to a cytotoxic response in cancer cells. Patients and methods: This was a first-in-human phase I study of BAY 2666605 (NCT04809805), an oral, potent first-in-class PDE3A-SLFN12 complex inducer, with reduced PDE3A inhibition. Adults with advanced solid tumors that co-express SLFN12 and PDE3A received BAY 2666605 at escalating doses starting at 5 mg once daily in 28-day cycles. Forty-seven patients were pre-screened for SLFN12 and PDE3A overexpression, and 5 biomarker-positive patients received ≥ 1 BAY 2666605 dose. Results: The most common adverse event was grade 3-4 thrombocytopenia in 3 of the 5 patients treated. The long half-life (> 360 hours) and associated accumulation of BAY 2666605 led to the selection of an alternative schedule consisting of a loading dose with QD maintenance dose. The maximum tolerated dose was not established as the highest doses of both schedules were intolerable. No objective responses were observed. Due to the high expression of PDE3A in platelets compared to tumor tissues, the ex vivo dose-dependent inhibitory effect of BAY 2666605 on megakaryocytes, and the pharmacokinetic profile of the compound, alternative schedules were not predicted to ameliorate the mechanism-based thrombocytopenia. Conclusions: Despite the decreased PDE3A enzymatic inhibition profile of BAY 2666605, the occurrence of thrombocytopenia in treated patients, an on-target effect of the compound, precluded the achievement of a therapeutic window, consequently leading to trial termination.

中文翻译：

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同类首创的 PDE3A-SLFN12 复合物诱导剂 BAY 2666605 在共表达 SLFN12 和 PDE3A 的晚期实体瘤患者中的首次人体剂量递增研究。


目的：评估 BAY 2666605 的安全性、耐受性和药代动力学，BAY 是一种 velcrin ，可诱导磷酸二酯酶 PDE3A 和蛋白 Schlafen 12 （SLFN12） 之间形成复合物，导致癌细胞中出现细胞毒反应。患者和方法： 这是 BAY 2666605 （NCT04809805） 的首次人体 I 期研究，BAY 是一种口服、有效的同类首创 PDE3A-SLFN12 复合物诱导剂，PDE3A 抑制降低。共表达 SLFN12 和 PDE3A 的晚期实体瘤成人患者接受 BAY 2666605，剂量递增，从 5 mg 开始，每天一次，周期为 28 天。47 例患者接受了 SLFN12 和 PDE3A 过表达的预筛选，5 例生物标志物阳性患者接受了 1 ≥ BAY 2666605剂量。结果： 最常见的不良事件是接受治疗的 5 例患者中有 3 例出现 3-4 级血小板减少症。BAY 2666605的长半衰期 （x3E 360 小时） 和相关的积累导致选择了由负荷剂量和 QD 维持剂量组成的替代方案。由于两种方案的最高剂量都无法耐受，因此未确定最大耐受剂量。未观察到客观反应。由于与肿瘤组织相比，PDE3A 在血小板中的高表达、BAY 2666605 对巨核细胞的离体剂量依赖性抑制作用以及化合物的药代动力学特征，未预测替代方案会改善基于机制的血小板减少症。结论：尽管 BAY 2666605 的 PDE3A 酶抑制谱降低，但接受治疗的患者发生血小板减少症，该化合物的靶向作用，排除了治疗窗的实现，从而导致试验终止。