Phase I/II study of bortezomib plus docetaxel in patients with advanced androgen-independent prostate cancer
Phase I/II study of bortezomib plus docetaxel in patients with advanced androgen-independent prostate cancer
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DOI：
10.1158/1078-0432.ccr-06-2046
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发表时间：
2007-02-15
影响因子：
11.5
通讯作者：
Roth, Bruce
中科院分区：
文献类型：
--
作者：
Dreicer, Robert;Petrylak, Daniel;Roth, Bruce
目的：为了确定剂量限制性毒性和最大耐受剂量，并评估硼替佐米/多西他赛联合治疗雄激素非依赖性前列腺癌的抗肿瘤活性，实验设计：两种硼替佐米剂量（1.3和1.6 mg/m2/剂量）与四种多西他赛剂量（25-40 mg/m2/剂量）联合使用。两种药物每周给药一次，共给药2/3周。使用前列腺特异性抗原（PSA）的水平和实体瘤guidelines.Results的反应评价标准的抗肿瘤活性进行了评价：83例患者接受了至少一剂研究药物。尽管递增至最高剂量水平，但未观察到剂量限制性毒性。67名可评估患者中有19名（28%）出现PSA应答（PSA水平从基线下降>= 50%），14名患者（21%）维持>= 4周。根据实体瘤指南中的反应评价标准，11%达到了部分反应，另外67%病情稳定。蛋白酶体抑制的程度与单药硼替佐米报告的相似。治疗耐受性良好;疲劳是最常见的药物相关不良事件，而腹泻是最常见的药物相关3/4级不良事件。没有临床意义的发热性中性粒细胞减少症或神经病变happened.Conclusions：这21天的方案的最大耐受剂量尚未达到。最高剂量水平（1.6 mg/m2硼替佐米+40 mg/m2多西他赛）是可行和可耐受的;硼替佐米+多西他赛显示出抗肿瘤活性。活性和耐受性结果与硼替佐米单药或与多西他赛联合给药的既往研究一致。需要进一步研究以确定硼替佐米/多西他赛在雄激素非依赖性前列腺癌中的活性并优化其治疗。
Purpose: To determine the dose-limiting toxicities and maximum tolerated dose, and evaluate the antitumor activity of bortezomib/docetaxel combination therapy in androgen-independent Prostate cancer.Experimental Design: Two bortezomib doses (1.3 and 1.6 mg/m(2) /dose) in combination with four docetaxel doses (25-40 mg/m(2) /dose) were evaluated. Both drugs were administered weekly for 2 out of 3 weeks. Antitumor activity was evaluated using prostate-specific antigen (PSA) levels and Response Evaluation Criteria in Solid Tumors guidelines.Results: Eighty-three patients received at least one dose of study drug. No dose-limiting toxicities were observed despite escalation to the highest dose level. PSA response (>= 50% decline in PSA levels from the baseline) occurred in 19 (28%) of 67 evaluable patients and was maintained for >= 4 weeks in 14 patients (21 %). According to Response Evaluation Criteria in Solid Tumors guidelines, 11% achieved a partial response, and an additional 67% had stable disease. The degree of proteasome inhibition was similar to that reported with single-agent bortezomib. Treatment was well tolerated; fatigue was the most common drug-related adverse event, whereas diarrhea was the most common drug-related grade 3/4 adverse event. No clinically significant febrile neutropenia or neuropathy occurred.Conclusions: The maximum tolerated dose of this 21-day regimen has not been reached. The highest dose level (1.6 mg/m(2) bortezomib plus 40 mg/m(2) docetaxel) was feasible and tolerable; bortezomib plus docetaxel showed antitumor activity. Activity and tolerability results were consistent with previous studies of bortezomib alone or in combination with docetaxel. Further investigations are warranted to determine activity and optimize bortezomib/docetaxel therapy in androgen-independent prostate cancers.