(1) Background: Histone deacetylases (HDACs) play a critical role in epigenetic signaling in cancer; however, available HDAC inhibitors have limited therapeutic windows and suboptimal pharmacokinetics (PK). This first-in-human phase I dose escalation study evaluated the safety, PK, pharmacodynamics (PDx), and efficacy of the oral Class I-targeting HDAC inhibitor bocodepsin (OKI-179). (2) Patients and Methods: Patients (n= 34) with advanced solid tumors were treated with OKI-179 orally once daily in three schedules: 4 days on 3 days off (4:3), 5 days on 2 days off (5:2), or continuous in 21-day cycles until disease progression or unacceptable toxicity. Single-patient escalation cohorts followed a standard 3 + 3 design. (3) Results: The mean duration of treatment was 81.2 (range 11–447) days. The most frequent adverse events in all patients were nausea (70.6%), fatigue (47.1%), and thrombocytopenia (41.2%). The maximum tolerated dose (MTD) of OKI-179 was 450 mg with 4:3 and 200 mg with continuous dosing. Dose-limiting toxicities included decreased platelet count and nausea. Prolonged disease control was observed, including two patients with platinum-resistant ovarian cancer. Systemic exposure to the active metabolite exceeded the preclinical efficacy threshold at doses lower than the MTD and was temporally associated with increased histone acetylation in circulating T cells. (4) Conclusions: OKI-179 has a manageable safety profile at the recommended phase 2 dose (RP2D) of 300 mg daily on a 4:3 schedule with prophylactic oral antiemetics. OKI-179 is currently being investigated with the MEK inhibitor binimetinib in patients with NRAS-mutated melanoma in the phase 2 Nautilus trial.
(1) 背景：组蛋白去乙酰化酶（HDACs）在癌症表观遗传信号传导中起关键作用；然而现有HDAC抑制剂治疗窗有限且药代动力学（PK）欠佳。这项首次人体I期剂量递增研究评估了口服I类靶向HDAC抑制剂bocodepsin（OKI-179）的安全性、PK、药效学（PDx）及疗效。(2) 患者与方法：34例晚期实体瘤患者接受每日一次口服OKI-179治疗，采用三种给药方案：用药4天/停药3天（4:3）、用药5天/停药2天（5:2）或连续给药（21天为周期），直至疾病进展或出现不可耐受毒性。单患者剂量递增队列采用标准3+3设计。(3) 结果：平均治疗持续时间为81.2天（范围11-447天）。所有患者最常见不良事件为恶心（70.6%）、疲劳（47.1%）和血小板减少（41.2%）。OKI-179的最大耐受剂量（MTD）在4:3方案中为450 mg，连续给药方案中为200 mg。剂量限制性毒性包括血小板计数下降和恶心。观察到持久的疾病控制，包括两例铂类耐药卵巢癌患者。在低于MTD的剂量下，活性代谢产物的全身暴露量已超过临床前疗效阈值，且与循环T细胞中组蛋白乙酰化水平升高存在时间相关性。(4) 结论：在推荐II期剂量（RP2D）——4:3方案每日300 mg联合预防性口服止吐药时，OKI-179具有可控的安全性特征。目前正在II期Nautilus试验中联合MEK抑制剂binimetinib，用于NRAS突变黑色素瘤患者的临床研究。
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