Liu Glenn, Gandara David R, Lara Primo N, Raghavan Derek, Doroshow James H, Twardowski Przemyslaw, Kantoff Philip, Oh William, Kim KyungMann, Wilding George
Medical Oncology Section, Department of Medicine, University of Wisconsin Comprehensive Cancer Center, 600 Highland Avenue, Madison, WI 53792, USA.
Clin Cancer Res. 2004 Feb 1;10(3):924-8. doi: 10.1158/1078-0432.ccr-03-0050.
Flavopiridol is a cyclin-dependent kinase inhibitor with preclinical activity against prostate cancer cell lines. A Phase II trial was conducted to determine the activity of flavopiridol in patients with metastatic hormone-refractory prostate cancer.
A total of 36 patients was enrolled from several institutions and treated with a 72-h continuous infusion of flavopiridol every 14 days at the eventual starting dose of 40 mg/m(2)/day. Dose escalation up to 60 mg/m(2)/day was permitted if no significant toxicity was observed. Responses were assessed every 12 weeks. Only those patients completing four courses of the 72-h infusion were considered evaluable for response because the primary objective was to determine progression-free survival at 6 months given the cytostatic nature of the agent.
This study was conducted in a two-stage fashion. During the first stage, at least 20 evaluable patients needed to be enrolled to assess response. There were 22 of 36 patients evaluable for response. No objective responses were observed. Only 4 patients had stable disease for 16, 26, 29, and 48 weeks, respectively, stopping the trial by design as only 3 of 22 (14%) of the patients met the 6-month progression-free survival end point. The most common toxicities were diarrhea (grade 1 and 2) and nausea, although some grade 3 and 4 diarrhea (11 and 6%, respectively) were evident.
Flavopiridol has disappointing single-agent activity in hormone-refractory prostate cancer when administered at this dose and schedule. Its use in prostate cancer should be reserved for evaluation in combination therapies or alternative schedules.
黄酮哌啶醇是一种细胞周期蛋白依赖性激酶抑制剂，对前列腺癌细胞系具有临床前活性。开展了一项II期试验，以确定黄酮哌啶醇对转移性激素难治性前列腺癌患者的活性。
从多个机构招募了36名患者，每14天接受一次72小时连续输注黄酮哌啶醇，最终起始剂量为40mg/m²/天。如果未观察到明显毒性，则允许剂量增至60mg/m²/天。每12周评估一次反应。只有完成四个疗程72小时输注的患者才被视为可评估反应，因为鉴于该药物的细胞生长抑制性质，主要目标是确定6个月时的无进展生存期。
本研究分两个阶段进行。在第一阶段，需要至少招募20名可评估患者以评估反应。36名患者中有22名可评估反应。未观察到客观反应。只有4名患者分别有16周、26周、29周和48周的疾病稳定期，按设计停止试验，因为22名患者中只有3名（14%）达到了6个月无进展生存期终点。最常见的毒性是腹泻（1级和2级）和恶心，尽管也有一些3级和4级腹泻（分别为11%和6%）。
以这种剂量和给药方案给予黄酮哌啶醇时，其在激素难治性前列腺癌中的单药活性令人失望。其在前列腺癌中的应用应保留用于联合治疗或替代给药方案的评估。
