一项高剂量酮康唑联合每周多西他赛治疗转移性去势抵抗性前列腺癌的 I 期临床研究。
A phase I clinical study of high dose ketoconazole plus weekly docetaxel for metastatic castration resistant prostate cancer.
机构信息
Clinical Pharmacology Program, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
出版信息
J Urol. 2010 Jun;183(6):2219-26. doi: 10.1016/j.juro.2010.02.020.
PURPOSE
This phase I study of high dose ketoconazole and docetaxel was designed against castration resistant prostate cancer to determine the maximum tolerated doses, side effects, and pharmacokinetic interaction of co-administered docetaxel and ketoconazole.
MATERIALS AND METHODS
Patients with metastatic castration resistant prostate cancer received weekly docetaxel for 3 of every 4 weeks plus daily ketoconazole. Pharmacokinetic studies were performed on day 1 (docetaxel alone) and day 16 (after ketoconazole).
RESULTS
The study enrolled 42 patients at 9 different dose levels. The combination regimens investigated included docetaxel weekly, increasing from 5 to 43 mg/m(2), with starting doses of 600, 800 or 1,200 mg ketoconazole daily. Decreases in prostate specific antigen of 50% or greater were seen in 62% of patients. Of 25 patients with soft tissue disease 7 (28%) had a partial response. Median overall survival was 22.8 months and was significantly greater in docetaxel naïve patients than in patients pretreated with docetaxel (36.8 vs 10.3 months, p = 0.0001). The most frequently observed adverse events were anemia, edema, fatigue, diarrhea, nausea, sensory neuropathy and elevated liver function tests. The fractional change in docetaxel clearance correlated significantly with ketoconazole exposure (p <0.01). Concomitant ketoconazole increased docetaxel exposure 2.6-fold with 1,200 mg daily, 1.6-fold with 800 mg daily and approximately 1.3 to 1.5-fold with 600 mg daily.
CONCLUSIONS
Combination regimens using 600 mg ketoconazole daily were fairly well tolerated and the maximum tolerated dose of docetaxel was 32 mg/m(2). Results suggest that the combination has significant antitumor activity in castration resistant prostate cancer. The long survival in the docetaxel naïve cohort warrants additional, larger trials of docetaxel with ketoconazole or possibly CYP17A1 inhibitors such as abiraterone.
目的
本研究为针对去势抵抗性前列腺癌的高剂量酮康唑和多西他赛的 I 期研究，旨在确定最大耐受剂量、副作用和联合应用多西他赛和酮康唑的药代动力学相互作用。
材料和方法
转移性去势抵抗性前列腺癌患者每 4 周的 3 周接受每周多西他赛治疗，同时每天服用酮康唑。在第 1 天（单独使用多西他赛）和第 16 天（使用酮康唑后）进行药代动力学研究。
结果
该研究共纳入 42 例患者，分为 9 个不同剂量水平。研究方案包括每周多西他赛，剂量从 5 至 43mg/m²，起始剂量为酮康唑 600、800 或 1200mg/d。62%的患者前列腺特异性抗原下降 50%或以上。25 例软组织疾病患者中，7 例（28%）有部分缓解。中位总生存期为 22.8 个月，在未接受多西他赛治疗的患者中明显长于接受过多西他赛治疗的患者（36.8 与 10.3 个月，p=0.0001）。最常见的不良反应是贫血、水肿、疲劳、腹泻、恶心、感觉神经病变和肝功能试验升高。多西他赛清除率的分数变化与酮康唑暴露呈显著相关（p<0.01）。同时应用酮康唑使多西他赛暴露增加 2.6 倍（每日 1200mg）、1.6 倍（每日 800mg）和 1.3 至 1.5 倍（每日 600mg）。
结论
联合应用酮康唑 600mg/d 方案具有较好的耐受性，多西他赛的最大耐受剂量为 32mg/m²。结果表明，该联合方案在去势抵抗性前列腺癌中具有显著的抗肿瘤活性。在未接受多西他赛治疗的患者中生存时间较长，这提示需要进行更大规模的多西他赛联合酮康唑或可能的 CYP17A1 抑制剂（如阿比特龙）的临床试验。
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