Phase I trial of the cyclin-dependent kinase inhibitor flavopiridol in combination with docetaxel in patients with metastatic breast cancer
Phase I trial of the cyclin-dependent kinase inhibitor flavopiridol in combination with docetaxel in patients with metastatic breast cancer
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DOI：
10.1158/1078-0432.ccr-04-0025
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发表时间：
2004-08-01
影响因子：
11.5
通讯作者：
Swain, SM
中科院分区：
文献类型：
--
作者：
Tan, AR;Yang, XW;Swain, SM
目的：本研究的目的是确定多西紫杉醇和黄吡醇在转移性乳腺癌患者中的毒性并表征其药代动力学。实验设计：多西紫杉醇初始剂量为 60 mg/m(2)，随后在 24 小时内输注黄吡醇 50 mg/m(2)/d，每 3 周 72 小时。由于发生了剂量限制性骨髓抑制，治疗方案修改为多西紫杉醇，50 mg/m(2)，随后逐渐增加黄吡醇剂量（起始剂量，26 mg/m(2)/d），每天输注 1 小时，持续 3 天。进行了药代动力学研究。通过免疫组织化学检查配对肿瘤和颊粘膜活检（治疗前和治疗后获得）中的 Ki67、p53 和磷酸化视网膜母细胞瘤蛋白（磷酸化 Rb）。 结果：11 名患者入组。 5 名患者接受了多西紫杉醇和 72 小时黄吡醇治疗。剂量限制性毒性为 4 级中性粒细胞减少症。 6 名患者接受多西他赛和 1 小时黄吡醇治疗，剂量限制性毒性为 3 级低血压。黄吡醇和多西紫杉醇的药代动力学与历史数据一致。治疗后 10 对颊粘膜活检组织中 p53 的核染色增加，磷酸化 Rb 减少（分别为 P = 0.002 和 P = 0.04）。在六对肿瘤中未检测到 Ki67、p53 或磷酸化 Rb 的显着变化。两名患者病情稳定持续>3个月（72小时黄吡多），一名患者观察到部分缓解（1小时黄吡多）。结论：由于剂量限制性中性粒细胞减少症，多西紫杉醇联合72小时黄吡多不可行。黄吡醇与多西紫杉醇输注 1 小时的剂量递增也是不可能的。颊粘膜中 p53 和磷酸化 Rb 的变化表明黄酮吡醇已实现生物学效应。
Purpose: The purpose of this study was to determine the toxicities and characterize the pharmacokinetics of docetaxel and flavopiridol in patients with metastatic breast cancer.Experimental Design: Docetaxel was administered at an initial dose of 60 mg/m(2) followed in 24 hours by a 72-hour infusion of flavopiridol at 50 mg/m(2)/d every 3 weeks. Because dose-limiting myelosuppression occurred, the schedule was amended to docetaxel, 50 mg/m(2), followed by escalating doses of flavopiridol (starting dose, 26 mg/m(2)/d) as a 1-hour infusion daily for 3 days. Pharmacokinetic studies were performed. Ki67, p53, and phosphorylated retinoblastoma protein (phospho-Rb) in paired tumor and buccal mucosa biopsies (obtained pre- and posttreatment) were examined by immunohistochemistry.Results: Eleven patients were enrolled. Five patients received docetaxel and 72-hour flavopiridol. Dose-limiting toxicity was grade 4 neutropenia. Six patients received docetaxel and 1-hour flavopiridol, and the dose-limiting toxicity was grade 3 hypotension. Pharmacokinetics of flavopiridol and docetaxel were consistent with historical data. Nuclear staining with p53 increased and phospho-Rb decreased in 10 pairs of buccal mucosa biopsies posttreatment (P = 0.002 and P = 0.04, respectively). No significant changes in Ki67, p53, or phospho-Rb were detected in six paired tumors. Two patients sustained stable disease for >3 months (72-hour flavopiridol), and one partial response was observed (1-hour flavopiridol).Conclusions: Docetaxel combined with 72-hour flavopiridol was not feasible because of dose-limiting neutropenia. Dose escalation of a 1-hour infusion of flavopiridol with docetaxel was also not possible. The changes in p53 and phospho-Rb in buccal mucosa suggest that a biological effect with flavopiridol was achieved.