Introduction - GNS561/Ezurpimtrostat is a first-in-class, orally bioavailable, small molecule that blocks cancer cell proliferation by inhibiting late-stage autophagy and dose-dependent build-up of enlarged lysosomes by interacting with the palmitoyl-protein thioesterase 1 (PPT1). Methods - This phase I, open-label, dose-escalation trial (3+3 design) explored two GNS561 dosing schedules: one single oral intake three times a week (Q3W) and twice daily (BID) continuous oral administration in patients with advanced hepatocellular carcinoma, cholangiocarcinoma, and pancreatic adenocarcinoma or colorectal adenocarcinomas with liver metastasis. The primary objective was to determine GNS561 recommended phase II dose (RP2D) and schedule. Secondary objectives included evaluation of the safety/tolerability, pharmacokinetics, pharmacodynamics, and antitumor activity of GNS561. Results - Dose escalation ranged from 50-400mg Q3W to 200-300mg BID. Among 26 evaluable patients for safety, 20 were evaluable for efficacy and no dose-limiting toxicity was observed. Adverse events (AEs) included gastrointestinal grade 1-2 events, primarily nausea and vomiting occurred in 13 (50%) and 14 (54%) patients respectively, and diarrhea in 11 (42%) patients. Seven (7) grade 3 adverse events were reported (diarrhea, decreased appetite, fatigue, ALT and AST increased). Q3W administration was associated with limited exposure and the BID schedule was preferred. At 200 mg BID GNS561, plasma and liver concentrations were comparable to active doses in animal models. Liver trough concentrations were much higher than in plasma a median time of 28 days of administration with a mean liver to plasma ratio of 9559 (Min 149-Max 25759), which is in accordance with rat preclinical data observed after repeated administration. PPT1 expression in cancer tissues in the liver was reduced upon GNS561 exposure. There was no complete or partial response. Five patients experienced tumor stable diseases (25%), including one minor response (-23%). Conclusion - Based on a favourable safety profile, exposure, and preliminary signal of activity, oral GNS561 RP2D was set at 200mg BID. Studies to evaluate the antitumor activity of GNS561 in HCC and iCCA are to follow. NCT 03316222


中文翻译：

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在原发性和继发性肝癌患者中使用 GNS561/Ezurpimtrostat 口服治疗 PPT1 抑制的首次人体效应

简介——GNS561/Ezurpimtrostat 是一流的口服生物利用度小分子，通过与棕榈酰蛋白硫酯酶 1 (PPT1) 相互作用，抑制晚期自噬和剂量依赖性扩大溶酶体的形成，从而阻止癌细胞增殖). 方肝细胞癌、胆管癌、胰腺癌或结直肠腺癌伴肝转移。主要目标是确定 GNS561 推荐的 II 期剂量 (RP2D) 和时间表。次要目标包括评估安全性/耐受性、药代动力学、药效学、GNS561 的抗肿瘤活性。结果 - 剂量递增范围从 50-400mg Q3W 到 200-300mg BID。在 26 名可评估安全性的患者中，20 名可评估疗效，未观察到剂量限制性毒性。不良事件 (AE) 包括胃肠道 1-2 级事件，主要分别有 13 名 (50%) 和 14 名 (54%) 患者出现恶心和呕吐，11 名 (42%) 患者出现腹泻。报告了七 (7) 个 3 级不良事件（腹泻、食欲下降、疲劳、ALT 和 AST 升高）。Q3W 管理与有限的暴露相关，并且 BID 时间表是首选。在 200 mg BID GNS561 时，血浆和肝脏浓度与动物模型中的活性剂量相当。肝谷浓度远高于血浆，中位给药时间为 28 天，平均肝血浆比为 9559（最小 149-最大 25759），这与大鼠重复给药后观察到的临床前数据一致。暴露于 GNS561 后，肝脏癌组织中的 PPT1 表达降低。没有完整或部分的回应。5 名患者经历了肿瘤稳定疾病 (25%)，包括一名轻微反应 (-23%)。结论——基于良好的安全性、暴露和初步的活动信号，口服 GNS561 RP2D 设定为 200mg BID。评估 GNS561 在 HCC 和 iCCA 中的抗肿瘤活性的研究即将进行。NCT 03316222 暴露于 GNS561 后，肝脏癌组织中的 PPT1 表达降低。没有完整或部分的回应。5 名患者经历了肿瘤稳定疾病 (25%)，包括一名轻微反应 (-23%)。结论——基于良好的安全性、暴露和初步的活动信号，口服 GNS561 RP2D 设定为 200mg BID。评估 GNS561 在 HCC 和 iCCA 中的抗肿瘤活性的研究即将进行。NCT 03316222 暴露于 GNS561 后，肝脏癌组织中的 PPT1 表达降低。没有完整或部分的回应。5 名患者经历了肿瘤稳定疾病 (25%)，包括一名轻微反应 (-23%)。结论——基于良好的安全性、暴露和初步的活动信号，口服 GNS561 RP2D 设定为 200mg BID。评估 GNS561 在 HCC 和 iCCA 中的抗肿瘤活性的研究即将进行。NCT 03316222