Phase I study of chidamide (CS055/HBI-8000), a new histone deacetylase inhibitor, in patients with advanced solid tumors and lymphomas
Phase I study of chidamide (CS055/HBI-8000), a new histone deacetylase inhibitor, in patients with advanced solid tumors and lymphomas
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DOI：
10.1007/s00280-012-1847-5
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发表时间：
2012-06-01
影响因子：
3
通讯作者：
Feng, Feng-Yi
中科院分区：
文献类型：
--
作者：
Dong, Mei;Ning, Zhi-Qiang;Feng, Feng-Yi
Chidamide（CS 055/HBI-8000）是一种新型苯甲酰胺类组蛋白去乙酰化酶抑制剂，具有显著的抗肿瘤活性。本研究报告了I期结果，晚期实体瘤或淋巴瘤患者接受口服剂量为5、10、17.5、25、32.5或50 mg西达米特，每周两次（BIW）或三次（TIW），连续4周，每6周一次。评价31例患者的安全性、药代动力学（PK）和药效学（PD）特征及初步疗效。在高达50 mg的BIW队列中未发现DLT。在TIW队列中，50 mg剂量组的2例患者分别发生了3级腹泻和呕吐DLT。PK分析显示t（1 - 2）为16.8-18.3 h，大多数情况下T（max）为1-2 h，C（max）和AUC呈剂量相关性增加。在单剂量西达米特后，观察到外周白色血细胞中组蛋白H3乙酰化的显著诱导。4例T细胞淋巴瘤患者和1例下颌下腺样囊性癌患者获得部分缓解。在试验方案中，晚期实体瘤或淋巴瘤患者对西达胺的耐受性一般良好。证实了有利的PK和PD特征以及令人鼓舞的初步抗肿瘤活性。
Chidamide (CS055/HBI-8000) is a new benzamide class of histone deacetylase inhibitor with marked anti-tumor activity. This study reports the phase I results.Patients with advanced solid tumors or lymphomas received oral doses of 5, 10, 17.5, 25, 32.5, or 50 mg chidamide either twice (BIW) or three times (TIW) per week for 4 consecutive weeks every 6 weeks. Safety, characteristics of pharmacokinetics (PK) and pharmacodynamics (PD), and preliminary efficacy were evaluated.A total of 31 patients were enrolled. No DLTs were identified in the BIW cohorts up to 50 mg. DLTs were grade 3 diarrhea and vomiting in two patients in the TIW cohort at 50 mg, respectively. PK analysis revealed t(1/2) of 16.8-18.3 h, T (max) of 1-2 h in most cases, and a dose-related increase in C (max) and AUC. Significant induction of histone H3 acetylation in peripheral white blood cells was observed after a single dose of chidamide. Four patients with T-cell lymphomas and 1 patient with submandibular adenoid cystic carcinoma achieved a partial response.Chidamide was generally well tolerated in patients with advanced solid tumors or lymphomas in the tested regimens. Favorable PK and PD profiles, as well as encouraging preliminary anti-tumor activity, were demonstrated.