注射用紫杉肽治疗晚期恶性肿瘤Ⅰ期临床耐受性研究

Phase Ⅰ clinical tolerance trial of paclitaxtide in patients with advanced cancer

目的:观察注射用紫杉肽(paclitaxtide)在人体的安全性,确定紫杉肽静脉给药对晚期恶性肿瘤患者的最大耐受剂量(MTD)及剂量限制性毒性(DLT),为Ⅱ期临床研究提供安全有效的给药剂量及方案。方法:选择符合病例入选标准的受试者,采用改良的Fibonacci法进行剂量爬坡,起始剂量60 mg.m-2,每剂量组3例,逐渐爬升,出现DLT增至6例,一个剂量组出现2例DLT,终止试验。患者接受单次静脉给药,观察不良反应,给药d 21进行疗效评价。结果:入组晚期恶性肿瘤患者33例,剂量自60 mg.m-2升至420mg.m-2,共10个剂量组。紫杉肽最常见的毒性是骨髓抑制,白细胞、中性粒细胞、血红蛋白、血小板减少,DLT为IV度中性粒细胞减少;其他不良反应包括转氨酶升高、恶心、呕吐、疲乏、食欲下降,高剂量组出现周围神经毒性,主要是I度和II度。疗效评价部分缓解1例,稳定17例,进展15例。结论:IV度中性粒细胞减少为紫杉肽主要剂量限制性毒性,最大耐受剂量390 mg.m-2,推荐给II期临床研究的安全剂量为360mg.m-2,d1,21 d为1个周期。

Objective： To assess the safety, the maximum tolerated dose （MTD） and dose-limiting toxicity （DLT） of intravenously injected paclitaxtide in advanced cancer patient. Methods： The eligible subjects with advanced cancers were intravenously injected with a single-dose of paelitaxtide. The starting dose was 60 mg·m^-2 and doses were escalated by a modified Fibonacci series. A cohort of three patients was treated at each dose level and the dose escalation to the next level was continued until DLT reached. The trial finished when one dose level got two patients with DLT. Safety and efficacy were evaluated in 21 days after the injection. Results： 33 patients entered at dose levels ranging from 60 to 420 mg·m^-2（ 10 dose levels）. The major toxicity was myelosuppression and grade 4 neutropenia was the dose limiting toxicity of paclitaxtide. Other toxicities included nausea, vomiting, fatigue, anorexy, and abnormal ALT/AST. The grade 1 neuropathies were seen at the high dose level. A patient with breast cancer （420 mg·m^-2） had partial response and 17 patients had stable disease. Conclusion： The maximum tolerated dose of paclitaxtide is 390mg·m^-2 and dose-limiting toxicity is grade 4 neutropenia. The recommended regimen is 360 mg·m^-2 dayl every 3 weeks in phase Ⅱ clinical trial.