重组人血管内皮抑制素Ⅰ期临床研究

A phase Ⅰ clinical trial for recombinant human endostatin

目的:确定重组人血管内皮抑制素(rh-endostatin,YH-16)的最大耐受剂量(MTD)并进行药动学研究。方法:将12例健康受试者分为4组,每组3例,分别单次静脉(滴注)YH-16 30,60,120和210mg·m-2;10例晚期肿瘤患者分为3组,各组分别为4,3,3例,分别静脉滴注7.5,15和30mg·m-2·d-1,连续28d。22例受试者均用ELISA法测定血清YH-16浓度,进行药动学研究。结果:剂量限制性毒性(DLT)为各种心脏不良反应,包括窦性心律不齐、阵发性室上性心动过速、室性期前收缩及心电图表现T波改变。其他不良反应有发热、皮疹、轻度头晕、头痛、疲劳、心悸、胸闷、腹泻,但均很轻微。1例恶性黑色素瘤患者病变好转(MR),5例病变稳定(SD)。健康受试者中药动学呈近似线性,肿瘤患者个体间药物浓度-时间曲线差异很大。结论:人体对YH-16耐受性良好,健康受试者单次给药的MTD为120mg·m-2,晚期肿瘤患者连续给药MTD为15mg·m-2·d-1。初步观察治疗肿瘤有一定疗效。推荐Ⅱ期临床给药剂量为每天12mg·m-2·d-1,连续28d。

Objective:To determine the maximum tolerated dose (MTD) and the pharmacoki-netics of the endostatin (rh-endostatin, YH-16) injection in human. Methods: 12 healthy volunteers were equally divided into 4 groups. Each group was intravenously administrated with a single dose of YH-16 infusion at 30,60,120 and 210mg·m-2,respectively. 10 patients with advanced solid tumors were categorized into 3 groups (4,3 and 3 patients per group). Each group was intravenously given with a dose of YH-16 infusion at 7.5,15 and 30mg·m-2 once daily for 28 days, respectively. The YH-16 concentration in serum sampes from all subjects was analyzed by ELISA,so as to determine the pharmacokinetic profile. Results:The dose limiting toxicities (DLT) were measured as varieties of car-diac adverse reactions, including sinus arrhythmia, supraventricular tachycardia, ventricular premature beat and T wave changes shown in electrocardiogram. The other mild adverse events were found to be fever,rash, minor dizziness, headache, fatigue, palpitation, chest discomfort and diarrhea. One patient with malignant melanoma had a minor response and 5 patients showed stable disease.The pharmacokinetic disposition was almost linear in healthy volunteers. However,the individual difference on concentration vs. time was observed in patients with advanced solid tumors. Conclusion:The YH-16 was clini-cally tolerated well.The MTD was 120mg·m-2 in healthy volunteers with a single dose, and 15mg· m-2 in the tumor patients with a daily dose for 28 days. The efficacy of anti-tumor with YH-16 was evident.The clinical dosage of 12mg·m-2 daily for 28 days in phase Ⅱ study is recommended.