Department of Hematology, National Cancer Center Hospital, Tokyo, Japan.
Department of Hematology and Oncology, Tokai University School of Medicine, Isehara, Japan.
Cancer Sci. 2021 Mar;112(3):1123-1131. doi: 10.1111/cas.14822. Epub 2021 Feb 15.
Tazemetostat is a selective and orally available inhibitor of enhancer of zeste homolog 2 (EZH2), a histone methyltransferase and epigenetic regulator of cellular differentiation programs. We carried out a phase I study of tazemetostat in Japanese patients with relapsed or refractory B-cell non-Hodgkin-type lymphoma (B-NHL) to evaluate its tolerability, safety, pharmacokinetics, and preliminary antitumor activity.
Tazemetostat was given orally at a single dose of 800 mg on the first day and 800 mg twice daily (BID: total 1600 mg/d) on following days in a 28-day/cycle manner. Tazemetostat dose-limiting toxicity (DLT) was evaluated up to the end of the first treatment cycle. Archival tumor tissues were analyzed for hotspot EZH2 mutations.
As of 15 January 2018, seven patients (four follicular lymphoma [FL] and three diffuse large B-cell lymphoma [DLBCL]) were enrolled. The median age was 73 (range, 59-85) years, and the median number of prior chemotherapy regimens was three (range, one to five). No DLT was observed (one patient was not evaluable due to early disease progression). The common treatment-related adverse events (AEs) were thrombocytopenia and dysgeusia (three patients each; 42.9%). No treatment-related serious AEs were observed. The objective response rate was 57% (4/7 patients), including responses in three of four patients with FL and one of three patients with DLBCL. An EZH2 mutation was detected in one patient with FL responding to treatment.
Tazemetostat at 800 mg BID showed an acceptable safety profile and promising antitumor activity in Japanese patients with relapsed or refractory B-NHL.
他泽司他丁是一种选择性、口服有效的增强子结合锌指蛋白 2（EZH2）抑制剂，EZH2 是一种组蛋白甲基转移酶和细胞分化程序的表观遗传调节剂。我们在日本复发或难治性 B 细胞非霍奇金淋巴瘤（B-NHL）患者中进行了一项他泽司他丁的 I 期研究，以评估其耐受性、安全性、药代动力学和初步抗肿瘤活性。
他泽司他丁的给药方案为第 1 天单次口服 800mg，随后 28 天/周期内每天两次口服 800mg（BID：每日总剂量 1600mg）。评估第 1 个治疗周期结束时的他泽司他丁剂量限制毒性（DLT）。分析存档肿瘤组织中的热点 EZH2 突变。
截至 2018 年 1 月 15 日，共入组 7 例患者（滤泡淋巴瘤[FL]4 例，弥漫性大 B 细胞淋巴瘤[DLBCL]3 例）。中位年龄为 73 岁（范围，59-85 岁），中位化疗方案数为 3 个（范围，1-5 个）。未观察到 DLT（1 例患者因疾病早期进展而无法评估）。常见的治疗相关不良事件（AE）是血小板减少症和味觉障碍（各 3 例；42.9%）。未观察到与治疗相关的严重 AE。客观缓解率为 57%（7 例患者中 4 例），包括 4 例 FL 患者中的 3 例和 3 例 DLBCL 患者中的 1 例。1 例对治疗有反应的 FL 患者检测到 EZH2 突变。
在日本复发或难治性 B-NHL 患者中，BID 800mg 的他泽司他丁显示出可接受的安全性和有前景的抗肿瘤活性。
