【作者】 周生余； 陈闪闪； 刘鹏； 罗扬； 邢谱元； 何静； 刘骁； 李端； 冯奉仪；

【Author】 ZHOU sheng-yu, CHENG shan-shan, LIU peng, LUO yang, XING pu-yuan, HE jing, LIU lao, LI duan, FENG feng-yi Department of Medical Oncology, Cancer Hospital, Chinese Academy of Medical Sciences &Peking Union Medical College, Beijing 100021, P.R. China. Laboratory of Pharmacy, College of Pharmacy, Fudan University, Shanghai, 200032, P.R. China.

【机构】 中国医学科学院中国协和医科大学肿瘤医院内科； 复旦大学药学院药理教研室；

【摘要】 目的:观察肿瘤病人对重组人凋亡素2配体(rh-Apo2L)静脉滴注后的耐受性;进行人体药代动力学研究、测定该药在人体的药代动力学主要参数; 初步观察其抗肿瘤疗效;提出II期临床研究合理的剂量及方案。方法:按抗癌药物I期临床研究要求,选择经病理组织学或细胞学证实的晚期恶性肿瘤患者,签署书面知情同意书。试验药品rh-Apo2L由上海恰尔生物技术有限公司提供。志愿者首先接受rh-Apo2L皮试,皮试阴性者按入组顺序接受待试药品。研究方案为,待试药品溶于250毫升0．9％生理盐水中,匀速静脉滴注2小时,每日一次, 连用14同,观察14同,为一周期。参照小鼠移植瘤最低起效剂量的1／2,换算成人体剂量为10 μg／kg／d作为初试剂量,按“3+3”原则进行剂量爬坡,逐渐从低剂量组爬坡到高剂量组,直至得到最大耐受剂量(MTD)或剂量已相当于动物长期毒性高剂量组剂量,每组3～6例。整个研究期间应严密观察及详细记录各种不良反应,判断与试验药物之间的关系。考虑生物制剂的特性,如给本药前一天出现38度以上发热,第二天给药前30分钟预处理,预处理方案:苯海拉明 40mg,肌注;消炎痛拴50mg,置肛。预处理后不出现38度以上发热,可停药观察。不良反应按WHO抗癌药物常见毒副反应分级标准分为0～IV级。受试者如有可测量的肿瘤病灶,要同时观察疗效;根据WHO肿瘤疗效评价标准进行疗效评价。选择由低到高共四个剂量组的患者,取血清采用“Sandwich ELISA”方法,进行单次或连续给药的药代动力学研究。结果:入组晚期复治恶性肿瘤患者 22例,2例皮试阳性退出研究,20例完成剂量爬坡和耐受性研究。其中男性11 例,女性9例;年龄18～68岁,中位值54．5岁;KPS评分80～100分:体重53～ 87公斤,中位值66．5公斤:既往化疗周期数2～30个周期,中位值为8．5个。 rh-Apo2L爬坡过程为10ug／kg／d、30ug／kg／d、1 00ug／kg／d、150ug／kg／d、200ug／kg／d、 300ug／kg／d,共6个剂量组。耐受性研究显示,rh-Apo2L的毒性反应轻微,除 300ug／kg／d剂量组出现Ⅲ度全身炎性反应综合征,其余均为Ⅰ～Ⅱ度不良反应, 包括发热、疲劳、乏力、皮肤粘膜改变、消化道反应、心血管系统毒性、骨髓抑制和肝肾功能损伤。所有毒副反应均在停药2周内恢复。未出现过敏性休克和药物相关死亡。19例可评价疗效, 13例(68％)为稳定,6例(32％)为进展。18 例次进行单次或连续给药的药代动力学研究并获得主要药动学参数。结论: rh-Apo2L静脉滴注后的耐受性良好,剂量限制性毒性(DLT)是全身炎性反应综合征;最大耐受剂量(MTD)为200 μ g／kg／d×14d。rh-Apo2L静脉滴注符合二室模型药动学分布特性和线性动力学特性。II期临床研究推荐方案为 150 μg／kg／d×10d,21天为一周期。更多还原

【Abstract】 Objective: To assess the feasibility and toleration of recombinant human Apo-2 ligand (rh-Apo2L) in patients with advanced cancer, perform the pharmacokinetic study and characterize the pertinent pharmacokinetic parameters, seek evidence of antitumor activity, and recommend the reasonable dose and regimen in phase II clinical trial. Methods: Patients with advanced cancer diagnosed by pathology or cytology were selected according to the principle of phase I clinical trial of antitumor drug, and signed informed consent. The research drug was rh-Apo2L provided by Shanghai TRAIL Biotechnology Limited Company. Patients underwent intradermal allergy test of rh-Apo2L firstly, who were negative to intradermal allergy test were treated with escalating doses of rh-Apo2L intravenously over 2 hours on days 1 to 14, every 28 days, according to "3 plus 3 principle of escalating doses". The initial dose was 10ug/kg/d calculated as the half lowest effective dose of mice. The dose levels were gradually escalated from low to high up to maximally tolerated dose (MTD) or the dose equivalent with the high dose of animal in the long-term toxicity study. Each group included 3~6 patients. The adverse reactions were observed and recorded, and the relationships between the adverse reaction and the study drug were judged. Allowing for the characters of biological agent, if the patient had a fever over 38℃ in the first day, he should be pretreated 30 minutes before the drug given in the next day. The pretreatment regimen was 40mg intramuscular benzhydramine and 50mg indometacin turunda. If the patient didn’t have a fever over 38℃ again, the pretreatment could be discontinued. The single dose or multiple doses pharmacokinetic study was performed by "Sandwich ELISA" using the pretreated blood serum. Results: Twenty two patients were recruited, two patients exited due to positive to intradermal allergy test. The other twenty patients, whose general characters included: 11 males and 9 females, the median age 54.5 years-old ranged from 18 to 68, Karnofsky Performance Status 80~100 scores, the median BW 66.5 kg ranged from 53 to 87, the median chemotherapy cycles 8.5 cycles ranged from 2 to 30 they had received before, received rh-Apo2L treatment at doses ranging from 10ug/kg/d to 300ug/kg/d grouped 6 dose levels. The results revealed adverse reaction of rh-Apo2L were mild and tolerated. All but grade III system inflammatory reaction symptoms at 300ug/kg/d dose level were grade I / II adverse reactions including fever, fatigue, debility, skin or mucosa alter, GI dysfunction, cardiovascular system toxicity, myelosuppression, hepatic or renal dysfunction, and so on. But all adverse reactions could recovery in 2 weeks after last dose. No allergic shock and drug related death. Therapeutic effect could be evaluated in 19 patients, 13 cases were evaluated as stable disease (SD), 6 cases were evaluated as progress disease (PD). Eighteen cases were characterized the pertinent更多还原