A phase I study of 1,2-diamminomethyl-cyclobutane-platinum (II)-lactate (D-19466; lobaplatin) administered daily for 5 days.
A phase I study of 1,2-diamminomethyl-cyclobutane-platinum (II)-lactate (D-19466; lobaplatin) administered daily for 5 days.
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DOI：
10.1038/bjc.1993.73
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发表时间：
1993-02
影响因子：
8.8
通讯作者：
Mulder, N H
中科院分区：
文献类型：
--
作者：
Gietema, J A;de Vries, E G;Sleijfer, D T;Willemse, P H;Guchelaar, H J;Uges, D R;Aulenbacher, P;Voegeli, R;Mulder, N H
进行了一项I期试验，使用洛铂（D-19466; 1，2-二氨甲基-环丁烷-铂（II）-乳酸盐）静脉推注，每日一次，每4周一次，持续5天。进入5例患者后，毒性似乎与肾功能相关，因此根据肌酐清除率（CRCL）调整洛铂的个体剂量（5天内总剂量20-100 mg m-2），并在患者中递增。27例难治性实体瘤患者接受了72个疗程。血小板减少是剂量限制性的，其程度与给药时的剂量和CRCL相关。当CRCL为60-80 ml min-1时，最大耐受剂量为40 mg m-2，当CRCL为81-100 ml min-1时，最大耐受剂量为70 mg m-2，当CRCL > 100 ml min-1时，最大耐受剂量为85 mg m-2。在第21天左右观察到血小板和白细胞最低值。血小板百分比最低值（第1天血小板计数的百分比）与不同剂量水平下的CRCL相关，可用0.76 x CRCL（ml min-1）-（1.45 x剂量（mg m-2）+ 43.38）描述。在20例患者（28个疗程）中检验了该方程，结果显示观察到的血小板百分比最低值与预测值之间存在相关性（r = 0.82，P < 0.001）。未发生肾功能损害。在6例患者中估计了铂的尿排泄（通过A.A.S），结果显示91.5%（s.e.）+/- 7.9）的铂剂量在4小时内排泄。2例卵巢癌患者（均接受卡铂和顺铂预治疗）出现缓解（1例PR，1例CR）。II期研究中洛铂静脉推注每日一次、持续5天的推荐剂量取决于肾功能，即CRCL 60-80 ml min-1时为30 mg m-2; CRCL 81-100 ml min-1时为55 mg m-2; CRCL > 100 ml min-1时为70 mg m-2。
A phase I trial was conducted with lobaplatin (D-19466; 1,2-diamminomethyl-cyclobutane-platinum (II)-lactate) i.v. bolus daily for 5 days every 4 weeks. After entering five patients toxicity appeared to be related to renal function, therefore the individual dose (total dose 20-100 mg m-2 over 5 days) of lobaplatin was modified according to creatinine clearance (CRCL) and escalated in patients. Twenty-seven patients with refractory solid tumours received 72 courses. Thrombocytopenia was dose-limiting, its degree was related to dose and CRCL at time of drug administration. With a CRCL of 60-80 ml min-1 the maximum tolerated dose was 40 mg m-2, with a CRCL of 81-100 ml min-1 70 mg m-2, and with a CRCL > 100 ml min-1 it was 85 mg m-2. Platelet and leukocyte nadirs were observed around day 21. The percentual platelet nadir (percentage of day 1 platelet count) correlated with CRCL at different dose levels and could be described by 0.76 x CRCL (ml min-1) - (1.45 x dose (mg m-2) + 43.38. This equation tested in 20 patients (28 courses) produced a correlation between observed and predicted percentual platelet nadir (r = 0.82, P < 0.001). No renal function impairment occurred. Urinary excretion of platinum (by A.A.S) was estimated in six patients and revealed that 91.5% (s.e. +/- 7.9) of the platinum dose was excreted within 4 h. Responses (one PR, one CR) occurred in two patients with ovarian cancer (both pretreated with carboplatin and cisplatin). The recommended dose of lobaplatin i.v. bolus daily for 5 days for phase II studies depends on renal function, namely 30 mg m-2 at CRCL 60-80 ml min-1; 55 mg m-2 at CRCL 81-100 ml min-1; 70 mg m-2 at CRCL > 100 ml min-1.