Gerrits C J, Creemers G J, Schellens J H, Wissel P, Planting A S, Kunka R, Selinger K, de Boer-Dennert M, Marijnen Y, Harteveld M, Verweij J
Department of Medical Oncology, Rotterdam Cancer Institute, The Netherlands.
Br J Cancer. 1996 Mar;73(6):744-50. doi: 10.1038/bjc.1996.130.
Topoisomerase I inhibitors are interesting anti-cancer agents with a novel mechanism of action. We performed a phase I study with intravenous GI147211, a new semisynthetic camptothecin analogue, using a daily x 5 schedule administered every 3 weeks, to evaluate the side-effects and pharmacokinetics of the agent. Patients with a histologically confirmed diagnosis of a solid tumour refractory to standard froms of therapy were eligible for the study. GI147211 was given as a 30 min intravenous infusion daily for 5 consecutive days, repeated every 3 weeks. In subsequent patient cohorts the dose was escalated from 0.3 to 1.5 mg m-2 day-1. Pharmacokinetics analysis was performed on days 1 and 4 of the first course using a validated high-performance liquid chromatographic assay and non-compartmental methods. A total of 19 patients were entered into the study, one patient was not evaluable for toxicity because only one drug administration was given. Eighteen patients received a total of 67 courses through four dose levels. The dose-limiting toxicities were neutropenia and thrombocytopenia at the dose of 1.5 mg m-2 day-1. Nadirs occurred on day 15 and day 15 respectively. Other toxicities were mild and infrequent and included nausea/vomiting, headache and alopecia. The maximal tolerated dose was 1.2 mg m-2 day-1. One partial response was observed in a patient with colorectal cancer. The total plasma clearance was 999+/-184 ml min-1 (range 640-1329). The volume of distribution was 190+/-461 m-2 and the terminal half-life was 3.7+/-1.2 h. The AUC increased linearly with the administered dose. A steep and significant sigmoid relationship was established between the AUC and the percent decrease of ANC. GI147211 is a new topoisomerase I inhibitor that induced dose-limiting neutropenia and thrombocytopenia in this phase I study. The recommended dose for phase II studies with this schedule is 1.2 mg m-2 x 5 every 3 weeks.
拓扑异构酶I抑制剂是一类作用机制新颖的有趣抗癌药物。我们对一种新的半合成喜树碱类似物静脉注射GI147211进行了I期研究，采用每3周每日给药5天的方案，以评估该药物的副作用和药代动力学。经组织学确诊对标准治疗形式耐药的实体瘤患者符合该研究条件。GI147211连续5天每日静脉输注30分钟，每3周重复一次。在随后的患者队列中，剂量从0.3毫克/平方米/天-1逐步增加至1.5毫克/平方米/天-1。在第一个疗程的第1天和第4天，使用经过验证的高效液相色谱法和非房室方法进行药代动力学分析。共有19名患者进入该研究，1名患者因仅给药一次而无法评估毒性。18名患者通过四个剂量水平共接受了67个疗程。剂量限制性毒性为1.5毫克/平方米/天-1剂量时的中性粒细胞减少和血小板减少。最低点分别出现在第15天和第15天。其他毒性较轻且不常见，包括恶心/呕吐、头痛和脱发。最大耐受剂量为1.2毫克/平方米/天-1。在一名结直肠癌患者中观察到部分缓解。总血浆清除率为999±184毫升/分钟（范围640-1329）。分布容积为190±461平方米，末端半衰期为3.7±1.2小时。AUC随给药剂量呈线性增加。在AUC与ANC降低百分比之间建立了陡峭且显著的S形关系。GI147211是一种新的拓扑异构酶I抑制剂，在该I期研究中诱导了剂量限制性中性粒细胞减少和血小板减少。按照该方案进行II期研究的推荐剂量为每3周1.2毫克/平方米×5天。
