E7777 in Japanese patients with relapsed/refractory peripheral and cutaneous T-cell lymphoma: A phase I study
E7777 in Japanese patients with relapsed/refractory peripheral and cutaneous T-cell lymphoma: A phase I study
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DOI：
10.1111/cas.13513
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发表时间：
2018-03-01
期刊：
影响因子：
5.7
通讯作者：
Nakanishi, Tadashi
中科院分区：
文献类型：
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作者：
Ohmachi, Ken;Ando, Kiyoshi;Nakanishi, Tadashi
E7777是一种重组细胞毒性融合蛋白，由白喉毒素片段a和B和人白细胞介素-2组成，与脱白喉毒素具有相同的氨基酸序列，但其纯度和活性蛋白单体物种的百分比有所提高。一项I期研究旨在评估E7777在日本复发/难治性外周和皮肤t细胞淋巴瘤患者中的耐受性、安全性、药代动力学和抗肿瘤活性。13例患者以21 d为周期，连续5天静脉滴注E7777（6、12、扩展9g/kg/day）。剂量限制性毒性，包括谷丙转氨酶升高、低钠血症（n=2）、低钾血症、淋巴细胞减少、疲劳、低白蛋白血症、皮疹和脂肪酶升高（n=1），在12g/kg/天组的所有3例患者中观察到，而在9g/kg/天组的6例患者中有2例出现食欲下降或疲劳。E7777的最大耐受和推荐剂量为9g/kg/天，连续5天，每21天一个周期。客观缓解率为38%(5/13)，似乎不依赖于CD25的肿瘤表达。E7777耐受性良好，在治疗过程中对不良事件进行了仔细的管理，并观察到初步但具有临床意义的抗肿瘤活性。E7777治疗t细胞淋巴瘤的后续研究是有必要的。本研究已注册（NCT1401530）。
E7777, a recombinant cytotoxic fusion protein comprising diphtheria toxin fragments A and B and human interleukin-2, shares an amino acid sequence with denileukin diftitox but has improved purity and an increased percentage of active protein monomer species. A phase I study was carried out to evaluate the tolerability, safety, pharmacokinetics, and antitumor activity of E7777 in Japanese patients with relapsed/refractory peripheral and cutaneous T-cell lymphoma. E7777 (6, 12, and expanded 9g/kg/day) was given to 13 patients by i.v. infusion on five consecutive days per 21-day cycle. Dose-limiting toxicities, including increased alanine aminotransferase, hyponatremia (n=2), hypokalemia, lymphopenia, fatigue, hypoalbuminemia, rash, and increased lipase (n=1), were observed in all three patients in the 12g/kg/day cohort, whereas two of six patients in the 9g/kg/day cohort showed decreased appetite or fatigue. The maximum tolerated and recommended dose of E7777 was 9g/kg/day for five consecutive days per 21-day cycle. The objective response rate was 38% (5/13) and did not appear to depend on tumor expression of CD25. E7777 was well tolerated, assuming careful management of adverse events during treatment, and preliminary but clinically meaningful antitumor activity was observed. Subsequent studies of E7777 for T-cell lymphomas are warranted. This study was registered with (NCT1401530).