Phase I trial of the cyclin-dependent kinase inhibitor and protein kinase C inhibitor 7-hydroxystaurosporine in combination with fluorouracil in patients with advanced solid tumors
Phase I trial of the cyclin-dependent kinase inhibitor and protein kinase C inhibitor 7-hydroxystaurosporine in combination with fluorouracil in patients with advanced solid tumors
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DOI：
10.1200/jco.2005.03.116
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发表时间：
2005-03-20
影响因子：
45.3
通讯作者：
Schwartz, GK
中科院分区：
文献类型：
--
作者：
Kortmansky, J;Shah, MA;Schwartz, GK
目的临床前研究表明，细胞周期蛋白依赖性激酶和蛋白激酶C抑制剂7-羟基星形孢菌素（UCN-01）可增强氟尿嘧啶（FU）的细胞毒作用。我们设计了一项FU联合JCN-01的I期临床试验。患者与方法FU每周24小时静脉滴注。根据改良的Fibonacci设计，在连续队列中递增剂量。UCN-01每4周一次给药，在断开FIJ后立即给药，第1周期剂量为135 mg/m2，持续72小时，后续周期剂量为67.5 mg/m2，持续36小时。所有患者均获得FU和UCN-01的药代动力学数据，并通过逆转录聚合酶链反应测定外周血单个核细胞中胸苷酸合成酶（TS）的活性。结果我们将每周FU剂量增加至2,600 mg/m2，同时每月输注一次UCN-01。剂量限制性毒性包括心律失常和晕厥。其他毒性包括高血糖、头痛、恶心和呕吐。UCN-01的平均最大血浆浓度为33.5 μ mol/L。有显着的患者间变异性，这与α-1酸性糖蛋白的血浆浓度。FU被迅速清除，剂量对UCN-01曲线下面积无影响。TS表达的变化在UCN-01给药后外周血单核细胞中可检测到，但与毒性或活性无关。我们没有观察到客观的反应，虽然7例患者病情稳定，其中6人已收到前fluoropyrimidines.Conclusion每周输注FU和每月UCN-01的组合可以安全地管理，并值得进一步研究在II期试验。推荐的II期FU联合每月UCN-01的剂量为2，600 mg/m（2）。(c)2005年，美国临床肿瘤学会。
Purpose Preclinical studies indicate that the cyclin-dependent kinase and protein kinase C inhibitor 7-hydroxystaurosporine (UCN-01) potentiates the cytotoxic effects of fluorouracil (FU). We designed a phase I clinical trial of FU in combination with JCN-01.Patients and Methods FU was administered as a weekly 24-hour infusion. Doses were escalated in successive cohorts according to a modified Fibonacci design. UCN-01 was administered once every 4 weeks, immediately after disconnection from FIJ, at a dose of 135 mg/m(2) over 72 hours in cycle 1 and 67.5 mg/m(2) over 36 hours in subsequent cycles. FU and UCN-01 pharmacokinetics were obtained on all patients, and thymiclylate synthetase (TS) activity was measured in peripheral-blood mononuclear cells by reverse-transcriptase polymerase chain reaction.Results We escalated the weekly FU dose to 2,600 mg/m(2) in combination with once a month infusions of UCN-01. Dose-limiting toxicity included arrhythmia and syncope. Other toxicities included hyperglycemia, headache, and nausea and vomiting. The mean maximal plasma concentration of UCN-01 was 33.5 mu mol/L. There was significant interpatient variability, which correlated with plasma concentrations of alpha-1 acid glycoprotein. FU was rapidly cleared and the dose had no effect on the area under the curve of UCN-01. Changes in TS expression were detectable in peripheral-blood mononuclear cells after administration of UCN-01 but did not correlate with toxicity or activity. We observed no objective response, although seven patients had stable disease, six of whom had received prior fluoropyrimidines.Conclusion The combination of weekly infusions of FU and monthly UCN-01 can be administered safely and warrants further study in phase II trials. The recommended phase II dose of FU in combination with monthly UCN-01 is 2,600 mg/m(2). (c) 2005 by American Society of Clinical Oncology.