长春新碱脂质体Ⅰ期临床多次耐受性试验

A phase Ⅰ clinical trial of vincristine sulfate liposome:tolerance and safety evaluation of successive administration

目的观察长春新碱脂质体在肿瘤患者中多次静脉给药的耐受性、不良反应及与剂量的关系,并初步观察该药的抗肿瘤作用。方法根据该剂型单次静脉给药的试验结果,设置低(1.5 mg.m-2)、中(1.8 mg.m-2)、高(2.0 mg.m-2)3个剂量组,进行剂量爬坡。每剂量组至少6例受试者,每名受试者仅接受1个剂量,长春新碱脂质体加入5%葡萄糖注射液100 mL,静脉滴注1 h。每周静脉滴注1次,1 wk为一个周期,连用4个周期,进行疗程耐受性试验。结果 19例肿瘤患者进入试验,共进行了1.5、1.8 mg.m-2两个剂量组的研究(n=7和n=12),分别有6例和7例完成4周期给药。1.5 mg.m-2剂量组1例患者用药2周期后,因出现肺部真菌感染合并应用吡咯系列抗真菌药而出组;1.8 mg.m-2剂量组3例患者用药3周期、1例用药1周期因出现不可耐受的神经毒性而出组,另1例用药2周期后患者放弃治疗而出组。主要不良反应为神经毒性,表现为神经性疼痛及肢端麻木;其次有便秘、发热、乏力、腹痛腹胀、恶心呕吐、食欲减退。血液学毒性轻微。结论长春新碱脂质体通过每周1次连续4次静脉给药,最大耐受性剂量为1.5 mg.m-2,剂量限制性毒性为神经毒性。

AIM To evaluate the tolerance and safety of vincristine sulfate liposome and it’s initial anticancer effect on patients with malignant tumor after successive administration.METHODS According to the results of single dosage vincristine sulfate liposome,dose was escalated from 1.5 mg.m-2 to 2.0 mg.m-2,with cohorts of six or more patients per dose level,once a week was a cycle,totally four cycles.Each patient only received one dose.RESULTS Nineteen patients with histologically confirmed malignancies were enrolled.Two dosage（1.5 and 1.8 mg.m-2） were studied through deeply intravenous infusion.There were thirteen patients that finished the whole study.One patient in the dose level of 1.5 mg.m-2 experienced a fungus infection and received antifungal drugs of pyrrole.There were five patients in the dose level of 1.8 mg.m-2 that didn’t finish the administration of four cycles,because four of them can’t subject the drug’s toxicity and one of them gave up voluntarily.The main toxicities are neuropathic pain and acroanesthesia,others were constipation,fever,fatigue,abdominal distension,nausea and vomit,anorexia.Hematologic toxicity was mild.CONCLUSION The maximum-tolerated dose of vincristine liposome after successive administration is 1.5 mg.m-2.Neurotoxicity is the dose-limiting toxicity.