重组人内皮抑素腺病毒注射液Ⅰ期临床耐受性试验

Clinical Tolerance Trial on Recombinant Human Endostatin Adenovirus

背景与目的:血管生成抑制剂在抗肿瘤新生血管生成方面显示出良好的临床应用前景,已有多个I期临床试验研究人内皮抑素重组蛋白的安全性和抗瘤活性。本试验目的是确定携带人内皮抑素基因的重组腺病毒注射液(Ad-Es)的最大耐受剂量,并推荐Ⅱ期临床试验的用量和用法。方法:设预试验组1例,1×1010病毒颗粒,单次瘤内注射。普通试验组遵循以一个自然对数级的1/2的方式递增,共14例,分三个剂量组:1×1011、5×1011、1×1012病毒颗粒/次,瘤内注射,每周1次,连续2周。结果:未观察到剂量限制性毒性,各受试者均显示出良好的耐受性。主要的不良事件为:局部反应和发热。其他不良反应有轻微的肝功能异常和流感样症状,如头痛、肌痛、乏力等。1例鼻咽癌放疗后鼻咽复发并颏下淋巴结转移的患者病情好转,12例病情稳定,2例出现进展。结论:人体对Ad-Es耐受性良好,晚期肿瘤患者使用1×1012病毒颗粒/次,瘤内注射,每周1次,连续2周,初步观察到Ad-Es的抗瘤活性。推荐Ⅱ期临床给药剂量为1.0×1012病毒颗粒/次,每周1次,连续4周。

BACKGROUND ＆ OBJECTIVE： Recently, some phase Ⅰ trials on endostatin has shown broad antitumor activity with low toxicity. This study was to determine the maximal tolerant dose （MTD） of recombinant human endostatin adenovirus Ad-Es for human. METHODS, For the sake of safety, 1 patient was treated with 1×10^10 VP Ad-Es single intratumoral injection in advance. A total of 14 patients with malignant tumors received weekly intratumoral injection of Ad-Es in a dose-escalation manner （1×10^11 VP, 5×10^11 VP, 1×10^12 VP） for 2 weeks. RESULTS： Toxicity profiles in all 15 cases were available. All patients tolerated well. No dose-limited toxicity （DLT） and serious adverse event were observed during treatment. Main adverse events were injection reaction （40.0%） and fever （53.3%）. One patient with nasopharyngeal carcinoma had a minor response, 12 patients showed stable disease and 2 patients had progressive disease. CONCLUSION： Ad-Es is well tolerated up to 1×10^12 VP. The recommended dose for phase Ⅱ trial is 1×10^12 VP intratumor injection for 4 consecutive weeks.