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首页> 外文期刊>Journal of Clinical Oncology >Phase I clinical trial of recombinant human endostatin administered as a short intravenous infusion repeated daily.
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Phase I clinical trial of recombinant human endostatin administered as a short intravenous infusion repeated daily.

机译：重组人血管内皮抑制素的I期临床试验，每天重复一次简短的静脉输液。

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PURPOSE: To perform a phase I trial of recombinant human endostatin (rhEndostatin; EntreMed, Rockville, MD) given as a daily 20-minute intravenous (IV) injection in adult patients with refractory solid tumors. PATIENTS AND METHODS: The daily dose was increased from 15 to 240 mg/m(2) by a factor of 100% in cohorts of three patients. In the absence of dose-limiting toxicity, uninterrupted treatment was continued until the tumor burden increased by more than 50% from baseline. Correlative studies included dynamic contrast-enhanced magnetic resonance imaging of tumor blood flow, urinary vascular endothelial growth factor and basic fibroblast growth factor levels, rhEndostatin serum pharmacokinetics, and monitoring of circulating antibodies to rhEndostatin. RESULTS: There were no notable treatment related toxicities among 15 patients receiving a total of 50 monthly cycles of rhEndostatin. One patient with a pancreatic neuroendocrine tumor had a minor response and two patients showed disease stabilization. Linearity in the pharmacokinetics of rhEndostatin was indicated by dose-proportionate increases in the area under the curve for the first dose and the peak serum concentration at steady state. Daily systemic exposure to rhEndostatin in patients receiving 240 mg/m(2)/d was approximately 50% lower than that provided by the therapeutically optimal dose in preclinical studies. CONCLUSION: rhEndostatin administered as a 20-minute daily IV injection at doses up to 240 mg/m(2) showed no significant toxicities. Evidence of clinical benefit was observed in three patients. Due to high variability between the peak and trough serum concentrations associated with the repeated short IV infusion schedule, daily serum drug levels only briefly exceeded concentrations necessary for in vitro antiangiogenic effects.
机译：目的：进行重组人内皮抑素（rhEndostatin; EntreMed，罗克维尔，马里兰州）的I期试验，每天对成人难治性实体瘤患者进行静脉内（IV）注射，每次20分钟。患者与方法：在三名患者的队列中，每日剂量从15毫克/米2增加到240毫克/米2。在没有剂量限制性毒性的情况下，继续不间断的治疗，直到肿瘤负荷比基线增加超过50％。相关研究包括肿瘤血流动态对比增强磁共振成像，尿血管内皮生长因子和碱性成纤维细胞生长因子水平，rhEndostatin血清药代动力学，以及监测针对rhEndostatin的循环抗体。结果：15名接受rhEndostatin治疗，共50个月周期的患者中，没有明显的与治疗有关的毒性反应。一名患有胰腺神经内分泌肿瘤的患者反应较轻，而两名患者显示疾病稳定。 rhEndostatin药代动力学的线性由第一剂量曲线下面积和稳态血药浓度峰值的剂量成比例增加表示。接受240 mg / m（2）/ d的患者每日全身暴露于rhEndostatin的剂量比临床前研究中最佳治疗剂量所提供的剂量低约50％。结论：rhEndostatin每天静脉注射20分钟，剂量高达240 mg / m（2），无明显毒性。在三名患者中观察到临床获益的证据。由于峰值和谷值血清浓度之间的差异很大，与静脉输注时间短有关，因此每日血清药物水平仅短暂超过了体外抗血管生成作用所需的浓度。

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