GSK2879552 在复发/难治性小细胞肺癌中的安全性、药代动力学、药效学和疗效的 I 期、开放标签、剂量递增研究,Journal of Thoracic Oncology

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GSK2879552 在复发/难治性小细胞肺癌中的安全性、药代动力学、药效学和疗效的 I 期、开放标签、剂量递增研究
Journal of Thoracic Oncology ( IF 21.0 ) Pub Date : 2019-10-01 , DOI: 10.1016/j.jtho.2019.06.021
Todd M Bauer ₁ , Benjamin Besse ₂ , Alex Martinez-Marti ₃ , Jose Manuel Trigo ₄ , Victor Moreno ₅ , Pilar Garrido ₆ , Geraldine Ferron-Brady ₇ , Yuehui Wu ₇ , Jennifer Park ₇ , Therese Collingwood ₇ , Ryan G Kruger ₇ , Helai P Mohammad ₇ , Marc S Ballas ₇ , Arindam Dhar ₇ , Ramaswamy Govindan ₈

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引言这项首次人体研究评估了 GSK2879552 在复发/难治性小细胞肺癌 (SCLC) 患者中的安全性、药代动力学 (PK)、药效学 (PD) 和临床活性。方法这项 I 期、多中心、开放标签研究 (NCT02034123) 纳入了复发/难治性 SCLC（在≥1 次含铂化疗或拒绝标准治疗后）患者（≥18 岁）。第 1 部分是剂量递增研究；第 2 部分是剂量扩展研究。剂量递增基于安全性、PK 和 PD。主要终点（第 1 部分）是确定 GSK2879552 的安全性、耐受性和推荐剂量/方案。次要终点是在第 16 周表征 PK 和 PD 参数并测量疾病控制率。第 2 部分未进行。结果 2014 年 2 月 4 日至 2017 年 4 月 18 日期间，29 名患者被分配到九个剂量组中的一个（0.25 mg-3 mg 每天一次，3 mg 或 4 mg 间歇给药）。22 名患者完成了研究；7 人退出，主要是由于不良事件 (AE)。大多数患者（24/29；83%）有≥1次治疗相关AE，最常见的是血小板减少症（12/29；41%）。9 名患者报告了 12 种严重 AE (SAE)；6 种被认为与治疗相关，其中最常见的是脑病 (4 SAE)。三名患者死亡；一种与 SAE 相关。PK 的特点是快速吸收、缓慢消除和剂量成比例的暴露增加。结论 GSK2879552 是一种有效的 LSD1 选择性抑制剂，显示出良好的 PK 特性，但在 SCLC 患者中疾病控制不佳，AE 率高。

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Phase I, Open-Label, Dose-Escalation Study of the Safety, Pharmacokinetics, Pharmacodynamics, and Efficacy of GSK2879552 in Relapsed/Refractory Small Cell Lung Cancer

INTRODUCTION This first-time-in-human study assessed the safety, pharmacokinetics (PK), pharmacodynamics (PD), and clinical activity of GSK2879552 in patients with relapsed/refractory small cell lung carcinoma (SCLC). METHODS This Phase I, multicenter, open-label study (NCT02034123) enrolled patients (≥18 years old) with relapsed/refractory SCLC (after ≥1 platinum-containing chemotherapy, or refusal of standard therapy). Part 1 was a dose-escalation study; Part 2 was a dose-expansion study. Dose escalations were based on safety, PK, and PD. The primary endpoint (Part 1) was to determine the safety, tolerability, and recommended dose/regimen of GSK2879552. Secondary endpoints were to characterize PK and PD parameters and measure disease control rate at Week 16. Part 2 was not conducted. RESULTS Between 4 February 2014 and 18 April 2017, 29 patients were allocated to one of nine dose cohorts (0.25 mg-3 mg once-daily, and 3 mg or 4 mg intermittent dosing). Twenty-two patients completed the study; 7 withdrew, primarily due to adverse events (AEs). Most patients (24/29; 83%) had ≥1 treatment-related AE, most commonly thrombocytopenia (12/29; 41%). Twelve serious AEs (SAEs) were reported by 9 patients; 6 were considered treatment-related, the most common of which was encephalopathy (4 SAEs). Three patients died; one related to SAEs. PK was characterized by rapid absorption, slow elimination, and dose-proportional increase in exposure. CONCLUSIONS GSK2879552 is a potent, selective inhibitor of LSD1 and demonstrated favorable PK properties but provided poor disease control and a high AE rate in patients with SCLC. The study was terminated as the risk-benefit profile did not favor continuation.

更新日期：2019-10-01

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