Department of Medical Oncology, Beaujon University Hospital, Paris 7, AP-HP, Clichy, France.
Eur J Cancer. 2010 Dec;46(18):3243-50. doi: 10.1016/j.ejca.2010.08.001. Epub 2010 Sep 6.
Phase I study of seliciclib (CYC202, R-roscovitine), an inhibitor of cyclin-dependent kinases 2, 7 and 9, causing cell cycle changes and apoptosis in cancer cells.
This phase I trial aimed at defining the toxicity profile, the maximum tolerated dose (MTD), the recommended phase II dose (RD) and the main pharmacokinetic and pharmacodynamic parameters of oral seliciclib. Three schedules were evaluated: seliciclib given twice daily for 5 consecutive days every 3 weeks (schedule A), for 10 consecutive days followed by 2 weeks off (schedule B) and for 3d every 2 weeks (schedule C).
Fifty-six patients received a total of 218 cycles of seliciclib. Dose-Limiting Toxicities (DLT) consisting of nausea, vomiting, asthenia and hypokalaemia occurred at 1600 mg bid for schedule A and in schedule C, DLT of hypokalaemia and asthenia occurred at 1800 mg bid. The evaluation of longer treatment duration in schedule B was discontinued because of unacceptable toxicity at lower doses. Other adverse events included transient serum creatinine increases and liver dysfunctions. Pharmacokinetic data showed that exposure to seliciclib and its carboxylate metabolite increased with increasing dose. Soluble cytokeratin 18 fragments allowed monitoring of seliciclib-induced cell death in the blood of patients treated with seliciclib at doses above 800 mg/d. One partial response in a patient with hepatocellular carcinoma and sustained tumour stabilisations were observed.
The MTD and RD for seliciclib are 1250 mg bid for 5d every 3 weeks and 1600 mg bid for 3d every 2 weeks, respectively.
塞利昔布（CYC202，R-罗司维亭）是一种细胞周期依赖性激酶 2、7 和 9 的抑制剂，能诱导癌细胞周期改变和凋亡。本研究旨在评价塞利昔布的安全性、最大耐受剂量（MTD）、推荐的Ⅱ期剂量（RD）及主要药代动力学和药效学参数。
Ⅰ期临床试验采用塞利昔布 3 种方案：每 3 周连续 5 天，每天 2 次（A 方案）；连续 10 天，然后停药 2 周（B 方案）；每 2 周连续 3 天（C 方案）。共入组 56 例患者，接受了 218 个周期的塞利昔布治疗。A 方案和 C 方案中，1600mg bid 剂量组出现剂量限制性毒性（DLT），包括恶心、呕吐、乏力和低钾血症；C 方案中，1800mg bid 剂量组 DLT 为低钾血症和乏力。由于 B 方案中较低剂量时毒性不可接受，故停止了更长时间的治疗方案评估。其他不良反应包括短暂的血肌酐升高和肝功能异常。药代动力学研究显示，塞利昔布及其羧酸代谢物的暴露量随剂量增加而增加。在接受 800mg/d 以上剂量塞利昔布治疗的患者中，血清可溶性细胞角蛋白 18 片段的变化可监测塞利昔布诱导的细胞死亡。观察到 1 例肝细胞癌患者部分缓解和持续肿瘤稳定。
塞利昔布的 MTD 和 RD 分别为每 3 周连续 5 天，每天 2 次 1250mg；每 2 周连续 3 天，每天 2 次 1600mg。
