A phase I biological and pharmacologic study of the heparanase inhibitor PI-88 in patients with advanced solid tumors
A phase I biological and pharmacologic study of the heparanase inhibitor PI-88 in patients with advanced solid tumors
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DOI：
10.1158/1078-0432.ccr-05-2423
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发表时间：
2006-09-15
影响因子：
11.5
通讯作者：
Eckhardt, S. Gail
中科院分区：
文献类型：
--
作者：
Basche, Michele;Gustafson, Daniel L.;Eckhardt, S. Gail
目的：PI-88是高度硫酸化寡糖的混合物，其抑制乙酰肝素酶、细胞外基质内切糖苷酶和血管生成生长因子与硫酸乙酰肝素的结合。实验设计：本研究评价了PI-88（80-315 mg）在皮下给药时的毒性和药代动力学，并对PI-88（80-315 mg）在皮下给药时的毒性和药代动力学进行了评价。结果：42例晚期实体瘤患者[中位年龄53岁（范围19-78岁），中位体能状态1分]共接受232个疗程。最大耐受剂量为250 mg/d。剂量限制性毒性包括血小板减少和肺栓塞。其他毒性通常为轻度，包括活化部分凝血活酶时间延长和注射部位瘀斑。药代动力学与剂量呈线性关系。患者内变异性较低，患者间变异性中等。AUC和C-max均与活化部分凝血活酶时间的增加百分比相关，表明该药效学终点可用作药物暴露的替代物。未观察到PI-88给药与血管内皮生长因子或碱性成纤维细胞生长因子水平之间的相关性。结论：PI-88的推荐剂量为250 mg/d，连续4 d，每2个月或每周给药一次。PI-88通常耐受良好。在黑色素瘤中的疗效证据支持在II期试验中进一步评价PI-88。
Purpose: PI-88 is a mixture of highly sulfated oligosaccharides that inhibits heparanase, an extracellular matrix endoglycosidase, and the binding of angiogenic growth factors to heparan sulfate. This agent showed potent inhibition of placental blood vessel angiogenesis as well as growth inhibition in multiple xenograft models, thus forming the basis for this study.Experimental Design: This study evaluated the toxicity and pharmacokinetics of PI-88 (80-315 mg) when administered s.c. daily for 4 consecutive days bimonthly (part 1) or weekly (part 2).Results: Forty-two patients [median age, 53 years (range, 19-78 years); median performance status, 1] with a range of advanced solid tumors received a total of 232 courses. The maximum tolerated dose was 250 mg/d. Dose-limiting toxicity consisted of thrombocytopenia and pulmonary embolism. Other toxicity was generally mild and included prolongation of the activated partial thromboplastin time and injection site echymosis. The pharmacokinetics were linear with dose. Intrapatient variability was low and interpatient variability was moderate. Both AUC and C-max correlated with the percent increase in activated partial thromboplastin time, showing that this pharmacodynamic end point can be used as a surrogate for drug exposure, No association between PI-88 administration and vascular endothelial growth factor or basic fibroblast growth factor levels was observed. One patient with melanoma had a partial response, which was maintained for >50 months, and 9 patients had stable disease for >= 6 months.Conclusion: The recommended dose of PI-88 administered for 4 consecutive days bimonthly or weekly is 250 mg/d. PI-88 was generally well tolerated. Evidence of efficacy in melanoma supports further evaluation of PI-88 in phase II trials.