Y型聚乙二醇重组人粒细胞集落刺激因子随机开放、单次给药、自身对照、剂量递增Ⅰ期临床试验  

A randomized,open-label,single-dose,self-controlled,dose-escalation phase Ⅰ study of Y-pegylated recombinant human granulocyte-colony stimulating factor

作　　者：周生余[1] 石远凯[1] 桂琳[1] 韩晓红[1] 汪麟[1] 张春玲[1] 张淑香[1] 宋媛媛[1] 姚嘉瑞[1] 唐乐[1] 冯云[1] 李丹[1] 孙燕[1] 

机构地区：[1]北京协和医学院中国医学科学院肿瘤医院内科,抗肿瘤分子靶向药物临床研究北京市重点实验室,北京100021

出　　处：《中国新药杂志》2013年第8期928-936,共9页Chinese Journal of New Drugs

基　　金：国家“重大新药创制”科技重大专项“十一·五”课题资助(2008ZX09312-020;2009ZX09102-232);国家“重大新药创制”科技重大专项“十二·五”课题资助(2011ZX09101-001-13);北京市科技计划项目(Z111102071011001)

摘　　要：目的:评价试验药物Y型聚乙二醇(polyethylene glycol,PEG)重组人粒细胞集落刺激因子注射液(YPEG-rHuG-CSF)单次给药预防化疗引起的中性粒细胞减少症的安全性和初步疗效,探索其各个剂量与对照药物普通重组人粒细胞集落刺激因子(rHuG-CSF,特尔津)常用剂量预防给药的药效对应关系。方法:未经化放疗的恶性肿瘤患者,接受3个周期相同方案(紫杉醇联合卡铂或表阿霉素联合环磷酰胺)的化疗。第1周期为筛选(空白对照)周期仅单纯化疗,第2和第3周期化疗后48 h同时给予试验药物(单次)或对照药物(每天)预防给药。试验药物剂量递增设定5个剂量组(10,20,30,45和60μg.kg-1),逐组(每组3～9例)爬坡进行试验。每个试验药物剂量组患者随机进入2个对照药物剂量组(150和300μg.d-1)。结果:30例经筛选周期评估合格入组并顺利完成本研究(试验药物10μg.kg-1组3例、20μg.kg-1组6例、30μg.kg-1组6例、45μg.kg-1组9例、60μg.kg-1组6例,对照药物150和300μg.d-1组各15例),并均参与安全性和初步疗效的评价。耐受性研究显示,3个化疗周期的常见不良事件主要与化疗药物相关;YPEG-rHuG-CSF耐受性良好,主要相关不良反应与对照药物(特尔津)相似,表现为Ⅰ～Ⅱ度骨骼肌肉关节痛(14/30,46.67%)。初步药效学研究显示,预防性给予YPEG-rHuG-CSF(20～60μg.kg-1)与常规rHuG-CSF,都能显著减少Ⅲ～Ⅳ度中性粒细胞减少的发生率;中性粒细胞计数(ANC)的动态变化都呈现出明显的双峰趋势;试验药物ANC的动态变化呈一定程度的量效关系。结论:本项研究中YPEG-rHuG-CSF表现出良好的耐受性和疗效,未见到剂量限制性毒性剂量,也未达到最大耐受剂量;Ⅱ期临床推荐剂量为45μg.kg-1,每化疗周期给药一次。Objective： To assess the safety and efficacy of single-dose Y-pegylated recombinant humangranuloeyte-colony stimulating factor （YPEG-rHuG-CSF） in the prophylaxis of chemotherapy-induced neutropenia, and to explore the dose-response relationships between YPEG-rHnG-CSF and recombinant human granulocyte-colo- ny stimulating factor （rHuG-CSF, Topneuter）. Methods： Cancer patients who were chemotherapy and radiother- apy naive received chemotherapy with three cycles of the same regimen with paclitaxel and carboplatin or epirubicin and cyclophosphamide. Firstly, patients were treated just with chemotherapy in cycle 1 defined as the screening or blank control cycle. Subsequently, patients were treated with chemotherapy and 48 hours after chemotherapy a sin- gle subcutaneous injection of YPEG-rHuG-CSF in cycle 2 or daily rHuG-CSF in cycle 3. The dose-escalation study enrolled five successive cohorts of patients （3 to 9 per cohort） treated with YPEG-filgrastim at 10, 20, 30, 45 or 60μg·kg^-1. The five successive cohorts of patients were randomized to receive daily rHuG-CSF at 150μg or 300μg in the control arms. Results： Thirty patients were enrolled into the trial and assessed the safety and efficacy. There were 3, 6, 6, 9, and 6 patients to be enrolled in five successive cohorts treated with single-dose YPEG- rHuG-CSF at 10, 20, 30, 45 or 60μg·kg^-1, fifteen patients with daily rHuG-CSF at 150μg or 300 μg in the con- trol arms, respectively. The tolerability study revealed that the adverse events observed during the three cycles were most attributable to complications associated with cancer chemotherapies and YPEG-rHuG-CSF was well tolerated. The most frequently reported YPEG-rHuG-CSF-related adverse event was mild to moderate musculoskeletal pain （14/30,46.67%）, the same as rHuG-CSF （Topneuter）. The pharmacodynamics research revealed that YPEG- rHuG-CSF could decrease the incidence of Grade 3 -4 neutropenia and resulted in an ANC dynamic profile with double peaks, which was the same as r

关 键 词：恶性肿瘤 重组人粒细胞集落刺激因子 Y型聚乙二醇重组人粒细胞集落刺激因子 中性粒细胞减少症 Ⅰ期临床研究 耐受性 

分 类 号：R969.4[医药卫生—药理学] R979.1[医药卫生—药学]