Armstrong Andrew J, Creel Patricia, Turnbull James, Moore Cassandra, Jaffe Tracy A, Haley Sherri, Petros William, Yenser Sarah, Gockerman Jon P, Sleep Darryl, Hurwitz Herbert, George Daniel J
Duke Prostate Center, 2424 Erwin Road, Durham, NC 27705, USA.
Clin Cancer Res. 2008 Oct 1;14(19):6270-6. doi: 10.1158/1078-0432.CCR-08-1085.
The primary aims of this phase I-II study were to determine the maximum tolerated dose, dose-limiting toxicity, pharmacokinetics, and preliminary efficacy of the combination of docetaxel and the endothelin A receptor antagonist atrasentan as first-line treatment for men with metastatic castration-resistant prostate cancer.
Patients were treated with docetaxel at doses ranging from 60 to 75 mg/m(2) every 21 days, with daily oral atrasentan 10 mg starting on day 3. Patients were treated until evidence of disease progression or unacceptable toxicity.
Thirty-one patients were enrolled over three docetaxel dose levels (8 at 60 mg/m(2), 19 at 70 mg/m(2), and 4 at 75 mg/m(2)) including dose expansion at 70 mg/m(2). The maximum tolerated dose of docetaxel was 70 to 75 mg/m(2). Drug-related grade 3-4 toxicities included neutropenia (50-63%) and febrile neutropenia (16-25%); other grade 1-2 toxicities included fatigue, peripheral edema, diarrhea, headache, rhinitis, anorexia, and nausea. Confirmed prostate-specific antigen (PSA) responses were observed in 23% [95% confidence interval (95% CI), 10-41%]; the rate of >30% declines in PSA was 35% (95% CI, 19-55%). Median overall survival was 17.6 months (95% CI, 13.0-23.2) and median progression-free survival was 4.2 months (95% CI, 2.3-5.8). Significant declines in bone alkaline phosphatase and serum N-telopeptides were observed with therapy.
The maximum tolerated dose of every-3-week docetaxel with 10 mg atrasentan is 70 to 75 mg/m(2). Overall survival and progression-free survival are comparable to that seen with docetaxel and prednisone, whereas the rates of PSA decline are slightly lower than expected. A phase III study of this combination with prednisone has been initiated and is ongoing.
本I-II期研究的主要目的是确定多西他赛与内皮素A受体拮抗剂阿曲生坦联合用于转移性去势抵抗性前列腺癌男性患者一线治疗时的最大耐受剂量、剂量限制性毒性、药代动力学和初步疗效。
患者接受多西他赛治疗，剂量范围为每21天60至75mg/m²，从第3天开始每日口服10mg阿曲生坦。患者持续接受治疗，直至出现疾病进展证据或不可接受的毒性。
在三个多西他赛剂量水平（60mg/m²组8例、70mg/m²组19例、75mg/m²组4例）共纳入31例患者，包括70mg/m²剂量水平的剂量扩展。多西他赛的最大耐受剂量为70至75mg/m²。与药物相关的3-4级毒性包括中性粒细胞减少（50-63%）和发热性中性粒细胞减少（16-25%）；其他1-2级毒性包括疲劳、外周水肿、腹泻、头痛、鼻炎、厌食和恶心。观察到确诊前列腺特异性抗原（PSA）反应的比例为23%[95%置信区间（95%CI），10-41%]；PSA下降>30%的比例为35%（95%CI，19-55%）。总生存期的中位数为17.6个月（95%CI，13.0-23.2），无进展生存期的中位数为4.2个月（95%CI，2.3-5.8）。治疗后观察到骨碱性磷酸酶和血清N-端肽显著下降。
每3周使用10mg阿曲生坦的多西他赛的最大耐受剂量为70至75mg/m²。总生存期和无进展生存期与多西他赛和泼尼松治疗时相当，而PSA下降率略低于预期。已启动并正在进行该联合方案与泼尼松的III期研究。
