UCN-01联合伊立替康治疗实体瘤患者的I期及药代动力学研究。
Phase I and pharmacokinetic study of UCN-01 in combination with irinotecan in patients with solid tumors.
作者信息
Jimeno Antonio, Rudek Michelle A, Purcell Thomas, Laheru Daniel A, Messersmith Wells A, Dancey Janet, Carducci Michael A, Baker Sharyn D, Hidalgo Manuel, Donehower Ross C
机构信息
The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Cancer Research Building I, Baltimore, MD, USA.
出版信息
Cancer Chemother Pharmacol. 2008 Mar;61(3):423-33. doi: 10.1007/s00280-007-0485-9. Epub 2007 Apr 12.
PURPOSE
7-Hydroxystaurosporine (UCN-01) is a protein kinase inhibitor that inhibits several serine-threonine kinases including PKC and PDK1. Due to the preclinical synergistic effects seen with topoisomerase I inhibitors and non-overlapping toxicity, UCN-01 and irinotecan were combined in a dose-finding study designed to determine the maximum tolerated dose (MTD), toxicity profile, and pharmacokinetics (PK) of UCN-01 and irinotecan.
METHODS
Patients with incurable solid malignancies received UCN-01 intravenously (IV) as a 3-h infusion on day 1 and irinotecan IV over 90 min on days 1 and 8 of a 21-day cycle. Doses of UCN-01 for subsequent cycles were half the starting dose. Dose level 1 (DL1) consisted of UCN-01 and irinotecan doses of 50 and 60 mg/m(2), respectively. Blood samples were collected in cycle 1 for UCN-01, irinotecan, and irinotecan metabolites.
RESULTS
A total of 16 patients were enrolled on the trial at UCN-01/Irinotecan doses of 50/60 mg/m(2) (DL1; n = 1), 70/60 mg/m(2) (DL2; n = 6), 90/60 mg/m(2) (DL3; n = 4), and 70/90 mg/m(2) (DL4; n = 5). Two dose-limiting toxicities were observed each in DL3 and DL4 (2 grade 3 hypophosphatemia, 1 grade 4 hyperglycemia and grade 3 hypophosphatemia, 1 grade 4 febrile neutropenia). Fatigue, diarrhea, nausea, and anorexia were the most prevalent toxicities. No objective responses were documented, and four patients had stable disease for at least ten cycles. The long half-life (292.0 +/- 135.7 h), low clearance (0.045 +/- 0.038 l/h), and volume of distribution (14.3 +/- 5.9 l) observed for UCN-01 are consistent with prior UCN-01 data. There was a significant decrease in C(max) of APC, AUC of APC and SN-38, and AUC ratio of SN-38:irinotecan when comparing days 1 and 8 PK.
CONCLUSIONS
APC and SN-38 exposure decreased when administered in combination with UCN-01. The MTD of the combination based on protocol criteria was defined as 70 mg/m(2) of UCN-01 on day 1 and 60 mg/m(2) of irinotecan on days 1 and 8 in a 21-day cycle.
目的
7-羟基星孢菌素（UCN-01）是一种蛋白激酶抑制剂，可抑制包括蛋白激酶C（PKC）和丙酮酸脱氢酶激酶1（PDK1）在内的多种丝氨酸-苏氨酸激酶。鉴于拓扑异构酶I抑制剂在临床前研究中显示出协同作用且毒性不重叠，故开展了一项剂量探索研究，将UCN-01与伊立替康联合使用，以确定UCN-01和伊立替康的最大耐受剂量（MTD）、毒性特征及药代动力学（PK）。
方法
患有无法治愈的实体恶性肿瘤的患者在第1天接受3小时静脉输注UCN-01，并在21天周期的第1天和第8天接受90分钟静脉输注伊立替康。后续周期中UCN-01的剂量为起始剂量的一半。剂量水平1（DL1）的UCN-01和伊立替康剂量分别为50和60mg/m²。在第1周期采集血样检测UCN-01、伊立替康及其代谢产物。
结果
共有16例患者入组该试验，UCN-01/伊立替康剂量分别为50/60mg/m²（DL1；n = 1）、70/60mg/m²（DL2；n = 6）、90/60mg/m²（DL3；n = 4）和70/90mg/m²（DL4；n = 5）。在DL3和DL4中各观察到2例剂量限制毒性（2例3级低磷血症、1例4级高血糖和3级低磷血症、1例4级发热性中性粒细胞减少）。疲劳、腹泻、恶心和厌食是最常见的毒性反应。未记录到客观缓解，4例患者病情稳定至少达10个周期。观察到UCN-01的长半衰期（292.0±135.7小时）、低清除率（0.045±0.038 l/h）和分布容积（14.3±5.9 l），与既往UCN-01数据一致。比较第1天和第8天的PK时，活性代谢产物APC的Cmax、APC和SN-38的AUC以及SN-38与伊立替康的AUC比值均显著降低。
结论
与UCN-01联合给药时，APC和SN-38的暴露量降低。根据方案标准，该联合用药的MTD定义为在21天周期的第1天给予70mg/m²的UCN-01，第1天和第8天给予60mg/m²的伊立替康。
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