South Texas Accelerated Research Therapeutics LLC, San Antonio.
Sarah Cannon Research Institute/Tennessee Oncology, PLLC, Nashville.
Ann Oncol. 2015 Jan;26(1):58-64. doi: 10.1093/annonc/mdu482. Epub 2014 Oct 24.
This phase Ib trial investigated the safety, tolerability, and recommended phase II dose and schedule of the MEK inhibitor trametinib in combination with the mammalian target of rapamycin (mTOR) inhibitor everolimus. Secondary objectives included pharmacokinetic (PK) characterization and evaluation of clinical activity.
A total of 67 patients with advanced solid tumors were enrolled in this open-label, single-arm, dose-escalation study. Dose escalation followed a 3 + 3 design. Patients were assigned to one of 10 different cohorts, involving either daily dosing with both agents or daily dosing with trametinib and intermittent everolimus dosing. This included an expansion cohort comprising patients with pancreatic tumors. PKs samples were collected predose, as well as 1, 2, 4, and 6 h post-dose on day 15 of the first treatment cycle.
Concurrent treatment with trametinib and everolimus resulted in frequent treatment-related adverse events, including mucosal inflammation (40%), stomatitis (25%), fatigue (54%), and diarrhea (42%). PK assessment did not suggest drug-drug interactions between these two agents. Of the 67 enrolled patients, 5 (7%) achieved partial response (PR) to treatment and 21 (31%) displayed stable disease (SD). Among the 21 patients with pancreatic cancer, PR was observed in 1 patient (5%) and SD in 6 patients (29%).
This study was unable to identify a recommended phase II dose and schedule of trametinib in combination with everolimus that provided an acceptable tolerability and adequate drug exposure.
本 Ib 期临床试验旨在研究 MEK 抑制剂曲美替尼（trametinib）联合哺乳动物雷帕霉素靶蛋白（mTOR）抑制剂依维莫司（everolimus）的安全性、耐受性、推荐的 II 期剂量和方案。次要目标包括药代动力学（PK）特征和临床活性评估。
共纳入 67 例晚期实体瘤患者，进行开放标签、单臂、剂量递增研究。采用 3+3 设计进行剂量递增。患者被分配到 10 个不同队列中的一个，涉及两种药物的每日联合治疗或曲美替尼的每日治疗和依维莫司的间歇性治疗。其中包括一个包含胰腺肿瘤患者的扩展队列。在首个治疗周期第 15 天，在每个周期的第 1 天、第 2 天、第 4 天和第 6 天的给药前和给药后 1、2、4 和 6 小时采集 PK 样本。
曲美替尼和依维莫司联合治疗导致频繁的治疗相关不良事件，包括黏膜炎症（40%）、口腔炎（25%）、疲劳（54%）和腹泻（42%）。PK 评估未提示这两种药物之间存在药物相互作用。在纳入的 67 例患者中，5 例（7%）对治疗有部分缓解（PR），21 例（31%）显示疾病稳定（SD）。在 21 例胰腺肿瘤患者中，1 例（5%）观察到 PR，6 例（29%）显示 SD。
本研究未能确定曲美替尼联合依维莫司的推荐 II 期剂量和方案，该方案能提供可接受的耐受性和足够的药物暴露。
