Hamaguchi T, Kato K, Yasui H, Morizane C, Ikeda M, Ueno H, Muro K, Yamada Y, Okusaka T, Shirao K, Shimada Y, Nakahama H, Matsumura Y
Department of Medicine National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan.
Br J Cancer. 2007 Jul 16;97(2):170-6. doi: 10.1038/sj.bjc.6603855. Epub 2007 Jun 26.
This phase I study was designed to examine the maximum tolerated dose (MTD), the dose-limiting toxicities (DLTs), the recommended dose (RD) for phase II, and the pharmacokinetics of NK105, a new polymeric micelle carrier system for paclitaxel (PTX). NK105 was administered as a 1-h intravenous infusion every 3 weeks, without antiallergic premedication. The starting dose was 10 mg m(-2), and the dose was escalated according to the accelerated titration method. Nineteen patients were recruited. The tumour types treated included pancreatic (n=11), bile duct (n=5), gastric (n=2), and colonic (n=1) cancers. Neutropenia was the most common haematological toxicity. A grade 3 fever developed in one patient given 180 mg m(-2). No other grades 3 or 4 nonhaematological toxicities, including neuropathy, was observed during the entire study period. DLTs occurred in two patients given 180 mg m(-2) (grade 4 neutropenia lasting for more than 5 days). Thus, this dose was designated as the MTD. Grade 2 hypersensitivity reactions developed in only one patient given 180 mg m(-2). A partial response was observed in one patient with pancreatic cancer. The maximum concentration (C(max)) and area under the concentration (AUC) of NK105 were dose dependent. The plasma AUC of NK105 at 150 mg m(-2) was approximately 15-fold higher than that of the conventional PTX formulation. NK105 was well tolerated, and the RD for the phase II study was determined to be 150 mg m(-2) every 3 weeks. The results of this phase I study warrant further clinical evaluation.
本I期研究旨在考察NK105（一种新型紫杉醇（PTX）聚合物胶束载体系统）的最大耐受剂量（MTD）、剂量限制性毒性（DLT）、II期推荐剂量（RD）及其药代动力学。NK105每3周静脉输注1小时给药，不进行抗过敏预处理。起始剂量为10 mg m(-2)，并根据加速滴定法增加剂量。招募了19名患者。治疗的肿瘤类型包括胰腺癌（n = 11）、胆管癌（n = 5）、胃癌（n = 2）和结肠癌（n = 1）。中性粒细胞减少是最常见的血液学毒性。1例接受180 mg m(-2)的患者出现3级发热。在整个研究期间未观察到其他3级或4级非血液学毒性，包括神经病变。2例接受180 mg m(-2)的患者出现DLT（4级中性粒细胞减少持续超过5天）。因此，该剂量被指定为MTD。仅1例接受180 mg m(-2)的患者出现2级过敏反应。1例胰腺癌患者观察到部分缓解。NK105的最大浓度（C(max)）和浓度-时间曲线下面积（AUC）呈剂量依赖性。150 mg m(-2)时NK105的血浆AUC约比传统PTX制剂高15倍。NK105耐受性良好，II期研究的RD确定为每3周150 mg m(-2)。本I期研究结果值得进一步临床评估。
