Herben V M, van Gijn R, Schellens J H, Schot M, Lieverst J, Hillebrand M J, Schoemaker N E, Porro M G, Beijnen J H, ten Bokkel Huinink W W
Department of Medical Oncology, Antoni van Leeuwenhoek Hospital/the Netherlands Cancer Institute, Amsterdam.
J Clin Oncol. 1999 Jun;17(6):1906-14. doi: 10.1200/JCO.1999.17.6.1906.
To determine the maximum-tolerated dose (MTD), dose-limiting toxicities (DLT), and pharmacokinetics of 9-aminocamptothecin (9-AC) in a colloidal dispersion (CD) formulation administered as a 30-minute intravenous (IV) infusion over 5 consecutive days every 3 weeks.
Patients with solid tumors refractory to standard therapy were entered onto the study. The starting dose was 0.4 mg/m(2)/d. The MTD was assessed on the first cycle and was defined as the dose at which > or = two of three patients or > or = two of six patients experience DLT. Pharmacokinetic measurements were performed on days 1 and 5 of the first cycle and on day 4 of subsequent cycles using high-performance liquid chromatography.
Thirty-one patients received 104+ treatment courses at seven dose levels. The DLT was hematologic. At a dose of 1.3 mg/m(2)/d, three of six patients experienced grade 3 thrombocytopenia. Grade 4 neutropenia that lasted less than 7 days was observed in four patients. At a dose of 1.1 mg/m(2)/d, four of nine patients had grade 4 neutropenia of brief duration, which was not dose limiting. Nonhematologic toxicities were relatively mild and included nausea/vomiting, diarrhea, obstipation, mucositis, fatigue, and alopecia. Maximal plasma concentrations and area under the concentration-time curve (AUC) increased linearly with dose, but interpatient variation was wide. Lactone concentrations exceeded 10 nmol/L, the threshold for activity in preclinical tumor models, at all dose levels. Sigmoidal E(max) models could be fit to the relationship between AUC and the degree of hematologic toxicity. A partial response was observed in small-cell lung cancer.
9-AC CD administered as a 30-minute IV infusion daily times 5 every three weeks is safe and feasible. The recommended phase II dose is 1. 1 mg/m(2)/d.
确定每3周连续5天静脉输注30分钟的胶体分散体（CD）制剂中9-氨基喜树碱（9-AC）的最大耐受剂量（MTD）、剂量限制性毒性（DLT）和药代动力学。
将对标准治疗难治的实体瘤患者纳入研究。起始剂量为0.4mg/m²/d。在第一个周期评估MTD，定义为三名患者中≥两名或六名患者中≥两名出现DLT的剂量。在第一个周期的第1天和第5天以及后续周期的第4天使用高效液相色谱法进行药代动力学测量。
31名患者在7个剂量水平接受了104个以上的疗程。DLT为血液学毒性。在剂量为1.3mg/m²/d时，六名患者中有三名出现3级血小板减少。四名患者观察到持续时间少于7天的4级中性粒细胞减少。在剂量为1.1mg/m²/d时，九名患者中有四名出现短暂的4级中性粒细胞减少，这不是剂量限制性的。非血液学毒性相对较轻，包括恶心/呕吐、腹泻、便秘、粘膜炎、疲劳和脱发。最大血浆浓度和浓度-时间曲线下面积（AUC）随剂量呈线性增加，但患者间差异较大。在所有剂量水平下，内酯浓度均超过10nmol/L，这是临床前肿瘤模型中的活性阈值。S形E(max)模型可拟合AUC与血液学毒性程度之间的关系。在小细胞肺癌中观察到部分缓解。
每3周每天静脉输注30分钟共5天给予9-AC CD是安全可行的。推荐的II期剂量为1.1mg/m²/d。
Zotero 插件