Phase I and pharmacokinetic study of edotecarin, a novel topoisomerase I inhibitor, administered once every 3 weeks in patients with solid tumors
Phase I and pharmacokinetic study of edotecarin, a novel topoisomerase I inhibitor, administered once every 3 weeks in patients with solid tumors
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DOI：
10.1007/s00280-005-0149-6
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发表时间：
2006-08-01
影响因子：
3
通讯作者：
Natsumeda, Y
中科院分区：
文献类型：
--
作者：
Yamada, Y;Tamura, T;Natsumeda, Y
目的：Edotecarin （J-107088）是一种有效的吲哚咔唑型拓扑异构酶I抑制剂，其结构与喜树碱不同。本研究旨在确定edotecarin在晚期实体瘤患者群体中的最大耐受剂量（MTD）、未来II期研究的推荐剂量以及安全性、药代动力学特征和初步抗肿瘤活性。实验设计：Edotecarin在晚期实体瘤患者中以单剂量静脉输注，每21天输注2小时（如果需要，允许毒性恢复1周）。剂量范围为8至15mg /m(2)。在第一次给药期间和之后进行药代动力学评估。结果：24例患者共接受61个疗程的治疗。剂量限制性毒性（感染、发热性中性粒细胞减少症、便秘、肠梗阻和延长的4级粒细胞减少症）在5名可评估的患者中观察到，剂量为15mg /m(2)，定义MTD。最常见的非血液学毒性是厌食、恶心、不适和便秘。腹泻既不频繁也不严重。中性粒细胞减少是最常见的血液学毒性（21/23例患者中3-4级）。edotecarin血药浓度在开始给药2小时后迅速升高，在13 mg/m(2)剂量时达到最大c值103 +/- 17 ng/ml，在给药结束后急剧下降。在开始输注后26小时，即最后一个PK采样时间点，血浆浓度下降至约1-2 ng/ml。该药物的平均表观血浆半衰期为20小时，这应被视为初步估计，直到有更长的血浆采样时间的研究结果可用。48小时内，平均1.4-3.6%的剂量在尿中恢复为不变药。2例患者未证实肿瘤消退>= 50%，其中1例为转移性胃癌，1例为食管癌。结论：edotecarin静脉给药2 h， MTD为15 mg/m(2)。对于为期3周的II期研究（如果需要，允许毒性恢复1周），推荐剂量为13mg /m(2)。观察到的安全性和抗肿瘤活性的初步证据证明了该药物在实体肿瘤中的进一步研究。
Purpose: Edotecarin (J-107088) is a potent indolocarbazole topoisomerase I inhibitor which is structurally distinct from the camptothecins. This study aimed to determine the maximum tolerated dose (MTD), the recommended dose for future Phase II studies and the safety, pharmacokinetic profile, and preliminary antitumor activity of edotecarin in a population of patients with advanced solid tumors. Experimental design: Edotecarin was administered as a single dose by IV infusion over 2 h every 21 days (with 1 week permitted for recovery from toxicities, if needed) in patients with advanced solid tumors. Doses ranged from 8 to 15 mg/m(2). Pharmacokinetic assessments were performed during and after the first administration. Results: Twenty-four patients received 61 cycles of therapy. Dose-limiting toxicities (infection, febrile neutropenia, constipation, ileus, and prolonged grade 4 granulocytopenia) were observed in 3 of 5 evaluable patients at the 15 mg/m(2) dose, defining the MTD. The most commonly reported non-hematologic toxicities were anorexia, nausea, malaise, and constipation. Diarrhea was neither frequent nor severe. Neutropenia was the most common hematologic toxicity (grade 3-4 in 21/23 patients during cycle 1). Plasma concentrations of edotecarin rose rapidly following the start of the 2-hour infusion, reaching C-max values of 103 +/- 17 ng/ml at the 13 mg/m(2) dose, and decreased steeply after the end of the infusion. Plasma concentrations declined to approximately 1-2 ng/ml at 26 h post start of infusion, the last PK sampling time point. The mean apparent plasma half-life of the drug was 20 h, which should be considered a preliminary estimate until results from studies with a longer duration of plasma sampling are available. A mean of 1.4-3.6% of the dose was recovered as unchanged drug in the urine over 48 h. Unconfirmed tumor regression >= 50% was observed in 2 patients, 1 with metastatic gastric carcinoma and 1 with esophageal cancer. Conclusions: The MTD of edotecarin administered IV over 2 h every 21 days was 15 mg/m(2). The recommended dose for Phase II studies with a 3-week schedule (with 1 week permitted for recovery from toxicities, if needed) is 13 mg/m(2). The observed safety profile and preliminary evidence of antitumor activity warrant further investigation of this drug in solid tumors.