El-Rayes Basil F, Gadgeel Shirish, Parchment Ralph, Lorusso Patricia, Philip Philip A
Karmanos Cancer Institute, Wayne State University, Detroit, Michigan 48201, USA.
Invest New Drugs. 2006 Jul;24(4):305-10. doi: 10.1007/s10637-005-4343-5.
Flavopiridol is a cyclin dependent kinase inhibitor. Preclinical models suggest a sequence dependent synergy between flavopiridol and taxanes. The primary objective of this study was to determine the maximum tolerated dose (MTD) of flavopiridol and docetaxel and the influence of flavopiridol on the pharmacokinetics of docetaxel.
The major eligibility criteria included: a diagnosis of non-hematologic cancer with no conventional effective therapy, normal organ function, and ECOG performance status of 0-2. Patients were treated with docetaxel followed 24 h later by flavopiridol given via continuous intravenous infusion over a 24-h period. The starting doses of docetaxel and flavopiridol were 60 and 60 mg/m2, respectively. Cycles were repeated every 21 days. All patients received diarrhea prophylaxis consisting of bismuth subsalicylate.
Ten patients (M:F 4:6; median age 56 years) were treated. The median number of cycles per patient was 2 (range 1-6). Two of the three patients on dose level 1 developed dose-limiting toxicities consisting of neutropenia and fever. Seven patients were subsequently enrolled on dose level -1 (docetaxel 60 mg/m2, flavopiridol 50 mg/m2). One episode of grade 3 diarrhea was reported at dose level -1.
Neutropenia complicated by infection was the major dose-limiting toxicity. The recommended doses of flavopiridol and docetaxel for phase II trials are 50 and 60 mg/m2 every three weeks, respectively.
黄酮哌啶醇是一种细胞周期蛋白依赖性激酶抑制剂。临床前模型表明黄酮哌啶醇与紫杉烷类之间存在序列依赖性协同作用。本研究的主要目的是确定黄酮哌啶醇和多西他赛的最大耐受剂量（MTD）以及黄酮哌啶醇对多西他赛药代动力学的影响。
主要入选标准包括：诊断为非血液系统癌症且无常规有效治疗方法、器官功能正常、东部肿瘤协作组（ECOG）体能状态为0 - 2。患者先接受多西他赛治疗，24小时后再接受黄酮哌啶醇治疗，通过持续静脉输注24小时给药。多西他赛和黄酮哌啶醇的起始剂量分别为60和60mg/m²。每21天重复一个周期。所有患者均接受由碱式水杨酸铋组成的腹泻预防治疗。
治疗了10名患者（男:女为4:6；中位年龄56岁）。每位患者的中位周期数为2（范围1 - 6）。1级剂量水平的3名患者中有2名出现了由中性粒细胞减少和发热组成的剂量限制性毒性。随后有7名患者进入-1级剂量水平（多西他赛60mg/m²，黄酮哌啶醇50mg/m²）。在-1级剂量水平报告了1例3级腹泻。
感染并发的中性粒细胞减少是主要的剂量限制性毒性。II期试验中黄酮哌啶醇和多西他赛的推荐剂量分别为每三周50和60mg/m²。
