Department of Experimental Therapeutics, National Cancer Center Hospital, Tokyo, Japan.
Department of Breast and Medical Oncology, National Cancer Center Hospital, Tokyo, Japan.
Mol Cancer Ther. 2019 Mar;18(3):531-540. doi: 10.1158/1535-7163.MCT-18-0831. Epub 2019 Jan 24.
HSP90 is involved in stability and function of cancer-related proteins. This study was conducted to define the MTD, safety, pharmacokinetics, pharmacodynamics, and preliminary antitumor efficacy of TAS-116, a novel class, orally available, highly selective inhibitor of HSP90. Patients with advanced solid tumors received TAS-116 orally once daily (QD, step 1) or every other day (QOD, step 2) in 21-day cycles. Each step comprised a dose escalation phase to determine MTD and an expansion phase at the MTD. In the dose escalation phase, an accelerated dose-titration design and a "3+3" design were used. Sixty-one patients were enrolled in Japan and the United Kingdom. MTD was determined to be 107.5 mg/m/day for QD, and 210.7 mg/m/day for QOD. In the expansion phase of step 1, TAS-116 was administered 5 days on/2 days off per week (QD × 5). The most common treatment-related adverse events included gastrointestinal disorders, creatinine increases, AST increases, ALT increases, and eye disorders. Eye disorders have been reported with HSP90 inhibitors; however, those observed with TAS-116 in the expansion phases were limited to grade 1. The systemic exposure of TAS-116 increased dose-proportionally with QD and QOD regimens. Two patients with non-small cell lung cancer and one patient with gastrointestinal stromal tumor (GIST) achieved a confirmed partial response. TAS-116 had an acceptable safety profile with some antitumor activity, supporting further development of this HSP90 inhibitor.This is a result from a first-in-human study, in which the HSP90 inhibitor TAS-116 demonstrated preliminary antitumor efficacy in patients with advanced solid tumors, including those with heavily pretreated GIST.
HSP90 参与癌症相关蛋白的稳定性和功能。本研究旨在确定 HSP90 的新型、口服、高选择性抑制剂 TAS-116 的最大耐受剂量、安全性、药代动力学、药效学和初步抗肿瘤疗效。晚期实体瘤患者接受 TAS-116 口服，每日一次（QD，第 1 步）或每两天一次（QOD，第 2 步），21 天为一个周期。每一步包括剂量递增阶段以确定最大耐受剂量和最大耐受剂量的扩展阶段。在剂量递增阶段，采用加速剂量滴定设计和“3+3”设计。61 例患者在日本和英国入组。QD 的最大耐受剂量为 107.5mg/m/天，QOD 的最大耐受剂量为 210.7mg/m/天。在第 1 步的扩展阶段，TAS-116 每周给药 5 天/停药 2 天（QD×5）。最常见的与治疗相关的不良事件包括胃肠道疾病、肌酐升高、AST 升高、ALT 升高和眼部疾病。HSP90 抑制剂已报告眼部疾病；然而，在 TAS-116 的扩展阶段观察到的仅限于 1 级。TAS-116 的全身暴露与 QD 和 QOD 方案呈剂量比例增加。2 例非小细胞肺癌患者和 1 例胃肠道间质瘤（GIST）患者获得了确认的部分缓解。TAS-116 具有可接受的安全性特征和一定的抗肿瘤活性，支持进一步开发这种 HSP90 抑制剂。这是一项首次人体研究的结果，其中 HSP90 抑制剂 TAS-116 在包括既往大量治疗的 GIST 在内的晚期实体瘤患者中显示出初步抗肿瘤疗效。
