Objectives:The primary aim of this phase 1 trial is to establish the recommended phase 2 dose (RP2D) of tazemetostat given with a fixed dose of pembrolizumab in patients with recurrent or metastatic head and neck squamous cell carcinomas (RM-HNSCCs).Methods:A 3 + 3 dose-escalation phase 1 design was used to assess three dose-levels of tazemetostat (400, 600, and 800 mg orally, twice daily) with pembrolizumab (200 mg intravenously). Cycle 1 was 35 days (tazemetostat days 1–35; pembrolizumab day 15). Subsequent cycles were 21 days (tazemetostat days 1–21; pembrolizumab day 1). Dose-limiting toxicity (DLT), assessed during cycle 1, was defined as study-drug-related grade 4 neutropenia or thrombocytopenia, grade 3 febrile neutropenia, or grade 3–4 non-hematologic adverse events (AEs). Patients had to have completed cycle 1 to be evaluable for the DLT assessment; otherwise, an equal number of additional patients were enrolled. The RP2D was defined as the highest dose level in which zero of three or less than or equal to one of six patients experienced a DLT.Results:Twelve patients were enrolled: three on 400 mg, three on 600 mg, and six on the 800 mg dose level of tazemetostat. Three patients on the 800 mg dose level did not complete cycle 1 and were not evaluable for DLT. In the other nine patients, DLTs did not occur during cycle 1. In all 12 patients, the most common AEs included anemia (10 patients), fatigue (eight), and hyponatremia (seven).Conclusions:Among the patients with RM-HNSCCs, the RP2D of tazemetostat was 800 mg and administered twice daily when given with pembrolizumab.
目的：本I期试验的主要目标是在复发或转移性头颈部鳞状细胞癌（RM-HNSCC）患者中，确定他泽司他与固定剂量帕博利珠单抗联合使用的推荐II期剂量（RP2D）。 方法：采用3+3剂量递增的I期试验设计，评估他泽司他三个剂量水平（400、600和800毫克，口服，每日两次）与帕博利珠单抗（200毫克，静脉注射）的联合用药。第1周期为35天（他泽司他第1-35天；帕博利珠单抗第15天）。后续周期为21天（他泽司他第1-21天；帕博利珠单抗第1天）。剂量限制性毒性（DLT）在第1周期内评估，定义为与研究药物相关的4级中性粒细胞减少或血小板减少、3级发热性中性粒细胞减少，或3-4级非血液学不良事件（AEs）。患者必须完成第1周期才能进行DLT评估；否则，将额外入组同等数量的患者。RP2D定义为在3名患者中未出现DLT，或在6名患者中DLT发生率小于或等于1例的最高剂量水平。 结果：共入组12名患者：3名接受400毫克剂量，3名接受600毫克剂量，6名接受800毫克剂量的他泽司他。在800毫克剂量组的3名患者未完成第1周期，因此无法进行DLT评估。在其他9名患者中，第1周期内未发生DLT。在所有12名患者中，最常见的不良事件包括贫血（10名患者）、疲劳（8名）和低钠血症（7名）。 结论：在RM-HNSCC患者中，他泽司他与帕博利珠单抗联合使用时，推荐II期剂量为800毫克，每日两次给药。
肿瘤(癌症)患者之家