Niitani H, Furuse K, Fukuoka M, Hasegawa K, Taguchi T
Dept. of Internal Medicine, Nippon Medical School.
Gan To Kagaku Ryoho. 1994 Feb;21(2):177-87.
Phase I study on a new vinca alkaloid derivative, KW-2307(vinorelbine), was conducted by multiple institutions in 40 patients with a variety of malignant tumors. KW-2307 was given intravenously by single administration or by weekly repeated for 4 weeks (hereinafter as the repeated administration). The initial dose, 10 mg/m2(ln), was escalated to 35 mg/m2(3.5n) in single administration and to 30 mg/m2(3n) in the repeated administration. A total of 35 cases were eligible for evaluation, consisting of 18 cases in single administration group and 17 in the repeated group. Both of single and repeated administration caused leukopenia dose-dependently, and the dose limiting toxicity (DLT) was judged as leukopenia. The maximum tolerated dose (MTD) was 30 mg/m2 in single administration and 25 mg/m2 in the repeated administration provided that administration is made weekly for 4 consecutive weeks. As subjective and objective adverse effects, general fatigue, anorexia, constipation, phlebitis etc. were observed, but all of these symptoms were relatively mild and recoverable. Peripheral neuropathy were found in two cases and judged as Grade 1. In this phase I study, a tendency of the decrease in tumor size was seen in 3 cases; 2 of non-small cell lung cancer and 1 of breast cancer. The pharmacokinetics of KW-2307 in blood after single administration showed a triphasic disappearance pattern with half-life of about 20 to 60 hrs. The data of pharmacokinetics after repeated administration revealed no accumulation of this agent. The recommended dose for early phase II study was supposed to be 20 to 25 mg/m2/week.
多个机构对一种新的长春花生物碱衍生物KW-2307（长春瑞滨）进行了I期研究，入组了40例患有各种恶性肿瘤的患者。KW-2307通过单次静脉给药或每周重复给药4周（以下简称重复给药）。初始剂量为10mg/m²（ln），单次给药时剂量递增至35mg/m²（3.5n），重复给药时剂量递增至30mg/m²（3n）。共有35例患者符合评估条件，其中单次给药组18例，重复给药组17例。单次给药和重复给药均导致白细胞减少呈剂量依赖性，剂量限制性毒性（DLT）判定为白细胞减少。最大耐受剂量（MTD）在单次给药时为30mg/m²，在重复给药（连续4周每周给药）时为25mg/m²。作为主观和客观不良反应，观察到全身乏力、厌食、便秘、静脉炎等，但所有这些症状相对较轻且可恢复。发现2例出现周围神经病变，判定为1级。在该I期研究中，3例患者出现肿瘤大小减小的趋势；2例非小细胞肺癌患者和1例乳腺癌患者。单次给药后KW-2307在血液中的药代动力学呈现三相消除模式，半衰期约为20至60小时。重复给药后的药代动力学数据显示该药物无蓄积。II期早期研究的推荐剂量应为20至25mg/m²/周。
