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
Department of Internal Medicine, University Hospital, Groningen, The Netherlands.
Br J Cancer. 1993 Feb;67(2):396-401. doi: 10.1038/bjc.1993.73.
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.
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4周连续5天每日给药。纳入5例患者后，毒性似乎与肾功能有关，因此根据肌酐清除率（CRCL）调整了洛铂的个体剂量（5天内总剂量为20 - 100 mg/m²），并在患者中逐步增加剂量。27例难治性实体瘤患者接受了72个疗程的治疗。血小板减少是剂量限制性毒性，其程度与给药时的剂量和CRCL有关。当CRCL为60 - 80 ml/min时，最大耐受剂量为40 mg/m²；当CRCL为81 - 100 ml/min时，为70 mg/m²；当CRCL > 100 ml/min时，为85 mg/m²。血小板和白细胞最低点出现在第21天左右。不同剂量水平下血小板最低点百分比（第1天血小板计数的百分比）与CRCL相关，可用公式0.76×CRCL（ml/min） - （1.45×剂量（mg/m²） + 43.38）描述。在20例患者（28个疗程）中进行验证，该公式得出观察到的和预测的血小板最低点百分比之间具有相关性（r = 0.82，P < 0.001）。未发生肾功能损害。对6例患者进行了铂的尿排泄（通过原子吸收光谱法）评估，结果显示91.5%（标准误±7.9）的铂剂量在4小时内排出。2例卵巢癌患者出现反应（1例部分缓解，1例完全缓解）（均曾接受卡铂和顺铂预处理）。II期研究中洛铂静脉推注每日5天的推荐剂量取决于肾功能，即CRCL为60 - 80 ml/min时为30 mg/m²；CRCL为81 - 100 ml/min时为55 mg/m²；CRCL > 100 ml/min时为70 mg/m²。
