Gastrointestinal and Lymphoma Unit, The Royal Marsden Hospital NHS Foundation Trust, London.
Oesophago-Gastric Cancer Services, The Christie NHS Foundation Trust, Manchester, UK.
ESMO Open. 2024 Apr;9(4):102971. doi: 10.1016/j.esmoop.2024.102971. Epub 2024 Mar 21.
Most oesophagogastric adenocarcinomas (OGAs) and colorectal cancers (CRCs) are mismatch repair proficient (MMRp), responding poorly to immune checkpoint inhibition. We evaluated the safety and efficacy of domatinostat (histone deacetylase inhibitor) plus avelumab (anti-PD-L1 antibody) in patients with previously treated inoperable, advanced/metastatic MMRp OGA and CRC.
Eligible patients were evaluated in a multicentre, open-label dose escalation/dose expansion phase II trial. In the escalation phase, patients received escalating doses of domatinostat [100 mg once daily (OD), 200 mg OD, 200 mg twice daily (BD)] orally for 14 days followed by continuous dosing plus avelumab 10 mg/kg administered intravenously 2-weekly (2qw) to determine the recommended phase II dose (RP2D). The trial expansion phase evaluated the best objective response rate (ORR) during 6 months by RECIST version 1.1 using a Simon two-stage optimal design with 2/9 and 1/10 responses required to proceed to stage 2 in the OGA and CRC cohorts, respectively.
Patients (n = 40) were registered between February 2019 and October 2021. Patients in the dose escalation phase (n = 12) were evaluated to confirm the RP2D of domatinostat 200 mg BD plus avelumab 10 mg/kg. No dose-limiting toxicities were observed. Twenty-one patients were treated at the RP2D, 19 (9 OGA and 10 CRC) were assessable for the best ORR; 2 patients with CRC did not receive combination treatment and were not assessable for the primary endpoint analysis. Six patients were evaluated in the dose escalation and expansion phases. In the OGA cohort, the best ORR was 22.2% (95% one-sided confidence interval lower bound 4.1) and the median duration of disease control was 11.3 months (range 9.9-12.7 months). No responses were observed in the CRC cohort. No treatment-related grade 3-4 adverse events were reported at the RP2D.
Responses in the OGA cohort met the criteria to expand to stage 2 of recruitment with an acceptable safety profile. There was insufficient signal in the CRC cohort to progress to stage 2.
NCT03812796 (registered 23 January 2019).
大多数食管胃腺癌（OGAs）和结直肠癌（CRCs）是错配修复功能完整（MMRp）的，对免疫检查点抑制反应不佳。我们评估了先前治疗过的不可切除的晚期/转移性 MMRp OGA 和 CRC 患者中应用多他赛（组蛋白去乙酰化酶抑制剂）联合avelumab（抗 PD-L1 抗体）的安全性和疗效。
在一项多中心、开放标签的剂量递增/剂量扩展的 II 期试验中对符合条件的患者进行评估。在递增阶段，患者接受多他赛 [100 mg 每日一次（OD），200 mg OD，200 mg 每日两次（BD）] 口服治疗 14 天，随后连续给药，联合avelumab 10 mg/kg 每 2 周（2qw）静脉输注，以确定 II 期推荐剂量（RP2D）。试验扩展阶段使用 RECIST 版本 1.1 通过 Simon 两阶段最优设计评估 6 个月时的最佳客观缓解率（ORR），OGA 和 CRC 队列分别需要 2/9 和 1/10 的缓解率进入 2 期。
2019 年 2 月至 2021 年 10 月期间共登记了 40 名患者。对剂量递增阶段的 12 名患者进行评估，以确认多他赛 200 mg BD 联合avelumab 10 mg/kg 的 RP2D。未观察到剂量限制毒性。21 名患者接受 RP2D 治疗，19 名（9 名 OGA 和 10 名 CRC）患者可评估最佳 ORR；2 名 CRC 患者未接受联合治疗，无法对主要终点分析进行评估。6 名患者在剂量递增和扩展阶段进行了评估。在 OGA 队列中，最佳 ORR 为 22.2%（95%单侧置信区间下限 4.1），疾病控制的中位持续时间为 11.3 个月（9.9-12.7 个月）。CRC 队列中未观察到缓解。在 RP2D 时未报告与治疗相关的 3-4 级不良事件。
OGA 队列的反应符合扩展招募阶段 2 的标准，且具有可接受的安全性。CRC 队列的信号不足，无法进入阶段 2。
NCT03812796（2019 年 1 月 23 日注册）。
