Phase I trial of poly-L-glutamate camptothecin (CT-2106) administered weekly in patients with advanced solid malignancies
Phase I trial of poly-L-glutamate camptothecin (CT-2106) administered weekly in patients with advanced solid malignancies
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DOI：
10.1158/1078-0432.ccr-06-2821
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发表时间：
2007-10-01
影响因子：
11.5
通讯作者：
Daud, Adil I.
中科院分区：
文献类型：
--
作者：
Homsi, Jade;Simon, George R.;Daud, Adil I.
目的：CT-2106是一种20（S）-喜树碱多聚谷氨酸结合物.这种连接稳定了喜树碱的活性内酯形式并提高了水溶性。此外，假定聚-L-谷氨酸盐通过增强肿瘤中的渗透性和保留效应来增加活性化合物的肿瘤递送。我们研究了CT-2106每周一次的时间表在难治性实体瘤malignances.Experimental设计：CT-2106输注（10分钟静脉输注）的第1天，第8和第15天，每个28天的周期。通过配备荧光检测器的高效液相色谱法分析血浆和尿液中的总喜树碱和未结合喜树碱。毒性和反应进行评估与不良事件的通用毒性标准第3版和实体瘤反应评价标准，分别。结果：26例患者入组。中位年龄为58岁（范围：36-83岁），中位给药次数为6次（范围：1-9次）。最常见的肿瘤类型（50%）是黑色素瘤。剂量限制性毒性为血小板减少和疲乏。最大耐受剂量为每周25 μ g/m2，每3/4周给药一次。大多数3级和4级毒性为血液学毒性。结合和非结合喜树碱的药代动力学曲线显示多指数下降，具有相似的终末半衰期（结合和非结合的t（1/2）范围分别为44-63和31-48 h）。在试验剂量范围内，结合型和非结合型喜树碱的药代动力学具有剂量和时间依赖性。尿排泄的共轭和非共轭喜树碱占约30%和4%的管理dose.Conclusions：CT-2106具有更易于管理的毒性档案相比，非共轭喜树碱。最大耐受剂量为每周25 Mg/m2，给药3/4周。该化合物导致未缀合的喜树碱的延长释放。
Purpose: CT-2106 is a 20(S) -camptothecin poly- L- glutamate conjugate. This linkage stabilizes the active lactone form of camptothecin and enhances aqueous solubility. In addition, poly-L-glutamate is postulated to increase tumor delivery of the active compound through enhanced permeability and retention effect in tumor. We studied a weekly schedule of CT-2106 in patients with refractory solid tumor malignancies.Experimental Design: CT-2106 was infused (10 min i.v. infusion) on days 1, 8, and 15 of each 28-day cycle. Plasma and urine were analyzed for total and unconjugated camptothecin by high performance liquid chromatography equipped with a fluorescence detector. Toxicity and response assessments were done with Common Toxicity Criteria for Adverse Events version 3 and Response Evaluation Criteria in Solid Tumors, respectively.Results: Twenty-six patients were enrolled. Median age was 58 years (range, 36-83) and median number of doses was 6 (range, 1-9). The most frequent tumor type (50%) was melanoma. Dose limiting toxicities were thrombocytopenia and fatigue. A weekly dose of 25 Mg/m(2) given every 3 of 4 weeks was the maximum tolerated dose. The majority of grade 3 and 4 toxicities were hematologic. The pharmacokinetic profile of conjugated and unconjugated camptothecin showed a polyexponential decline with similar terminal half life (t(1/2) range was 44-63 and 31-48 h for conjugated and unconjugated, respectively). Pharmacokinetics of conjugated and unconjugated camptothecin were dose and time independent in the tested dose range. Urinary excretion of conjugated and unconjugated camptothecin accounted for about 30% and 4% of the administered dose, respectively.Conclusions: CT-2106 has a more manageable toxicity profile compared with unconjugated camptothecin. The maximum tolerated dose is 25 Mg/m(2) weekly given 3 of 4 weeks. This compound results in prolonged release of unconjugated camptothecin.