Gui Lin, Cao Junning, Ji Dongmei, Zhang Huilai, Fan Qian, Zhu Jun, Song Yuqin, Jiang Shiyu, Ning Zhiqiang, Yu Jia, Shi Yuankai
Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing Key Laboratory of Clinical Study on Anticancer Molecular Targeted Drugs, Beijing 100021, China.
Department of Medical Oncology, Fudan University Shanghai Cancer Center, Shanghai Medical College, Fudan University, Shanghai 200032, China.
Chin J Cancer Res. 2021 Oct 31;33(5):616-626. doi: 10.21147/j.issn.1000-9604.2021.05.08.
Chidamide is an oral histone deacetylase subtype-selective inhibitor approved for relapsed or refractory peripheral T-cell lymphoma (PTCL). This phase 1b study evaluated the safety, pharmacokinetics, and preliminary efficacy of chidamide in combination with cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) for treatment-naïve PTCL patients.
This study was an open-label, multicenter trial composed of dose escalation and dose expansion. Patients received CHOP for six 21-d cycles and chidamide on d 1, 4, 8 and 11 in each cycle. Four dose levels of chidamide (20, 25, 30 and 35 mg) were evaluated. The primary objective was to evaluate the safety and tolerability of the combination regimen.
A total of 30 patients were evaluated in this study: 15 in the dose-escalation part and 15 in the dose-expansion part. In the dose-escalation study, three patients were enrolled in the 35 mg chidamide cohort. One had dose-limiting toxicity with grade 3 vascular access complications, and one had grade 2 neutropenia with a sustained temperature >38 °C. Dose escalation was stopped at this chidamide dose level. The most common (≥10%) grade 3 or 4 adverse events (AEs) were leukopenia (90.0%), neutropenia (83.3%), vomiting (13.3%), thrombocytopenia (10.0%) and febrile neutropenia (10.0%). No significant changes in chidamide pharmacokinetic properties were observed before and after combination treatment. The objective response rate for the 28 patients evaluable for preliminary efficacy was 89.3% (25/28), with 16 (57.1%) achieving complete response or unconfirmed complete response. The estimated median progression-free survival was 14.0 months. In summary, we chose chidamide 30 mg as the recommended dose for phase 2.
The addition of chidamide to standard CHOP chemotherapy was tolerable with promising preliminary efficacy in previously untreated PTCL patients, which supports further clinical studies with this combination regimen for the frontline treatment of PTCL.
西达本胺是一种口服的组蛋白去乙酰化酶亚型选择性抑制剂，已被批准用于复发或难治性外周T细胞淋巴瘤（PTCL）。这项1b期研究评估了西达本胺联合环磷酰胺、阿霉素、长春新碱和泼尼松（CHOP）方案用于初治PTCL患者的安全性、药代动力学及初步疗效。
本研究为开放标签、多中心试验，包括剂量爬坡和剂量扩展。患者接受CHOP方案治疗，共6个21天周期，每个周期的第1、4、8和11天给予西达本胺。评估了4个西达本胺剂量水平（20、25、30和35毫克）。主要目的是评估联合方案的安全性和耐受性。
本研究共评估了30例患者，其中剂量爬坡部分15例，剂量扩展部分15例。在剂量爬坡研究中，35毫克西达本胺队列入组了3例患者。1例出现3级血管通路并发症的剂量限制性毒性，1例出现2级中性粒细胞减少且持续体温>38°C。在此西达本胺剂量水平停止剂量爬坡。最常见的（≥10%）3级或4级不良事件（AE）为白细胞减少（90.0%）、中性粒细胞减少（83.3%）、呕吐（13.3%）、血小板减少（10.0%）和发热性中性粒细胞减少（10.0%）。联合治疗前后未观察到西达本胺药代动力学特性的显著变化。28例可评估初步疗效的患者客观缓解率为89.3%（25/28），其中16例（57.1%）达到完全缓解或未确认的完全缓解。估计的无进展生存期的中位数为14.0个月。总之，我们选择30毫克西达本胺作为2期试验的推荐剂量。
在标准CHOP化疗中加入西达本胺对既往未治疗的PTCL患者是可耐受的，且初步疗效良好，这支持进一步开展该联合方案用于PTCL一线治疗的临床研究。
