Beer Tomasz M, Ryan Christopher W, Venner Peter M, Petrylak Daniel P, Chatta Gurkamal S, Ruether J Dean, Redfern Charles H, Fehrenbacher Louis, Saleh Mansoor N, Waterhouse David M, Carducci Michael A, Vicario Daniel, Dreicer Robert, Higano Celestia S, Ahmann Frederick R, Chi Kim N, Henner W David, Arroyo Alan, Clow Fong W
Division of Hematology and Medical Oncology, Department of Medicine, Oregon Health & Science University, Portland, OR 97239, USA.
J Clin Oncol. 2007 Feb 20;25(6):669-74. doi: 10.1200/JCO.2006.06.8197.
To compare the safety and activity of DN-101, a new high-dose oral formulation of calcitriol designed for cancer therapy, and docetaxel with placebo and docetaxel.
Patients with progressive metastatic androgen-independent prostate cancer and adequate organ function received weekly docetaxel 36 mg/m2 intravenously for 3 weeks of a 4-week cycle combined with either 45 microg DN-101 or placebo taken orally 1 day before docetaxel. The primary end point was prostate-specific antigen (PSA) response within 6 months of enrollment, defined as a 50% reduction confirmed at least 4 weeks later.
Two hundred fifty patients were randomly assigned. Baseline characteristics were similar in both arms. Within 6 months, PSA responses were seen in 58% in DN-101 patients and 49% in placebo patients (P = .16). Overall, PSA response rates were 63% (DN-101) and 52% (placebo), P = .07. Patients in the DN-101 group had a hazard ratio for death of 0.67 (P = .04) in a multivariate analysis that included baseline hemoglobin and performance status. Median survival has not been reached for the DN-101 arm and is estimated to be 24.5 months using the hazard ratio, compared with 16.4 months for placebo. Grade 3/4 adverse events occurred in 58% of DN-101 patients and in 70% of placebo-treated patients (P = .07). Most common grade 3/4 toxicities for DN-101 versus placebo were neutropenia (10% v 8%), fatigue (8% v 16%), infection (8% v 13%), and hyperglycemia (6% v 12%).
This study suggests that DN-101 treatment was associated with improved survival, but this will require confirmation because survival was not a primary end point. The addition of weekly DN-101 did not increase the toxicity of weekly docetaxel.
比较用于癌症治疗的新型高剂量口服骨化三醇制剂DN - 101与多西他赛联合安慰剂及多西他赛的安全性和活性。
患有进展性转移性雄激素非依赖性前列腺癌且器官功能良好的患者，在为期4周的周期中，每周静脉注射36 mg/m²多西他赛，共3周，同时在多西他赛给药前1天口服45微克DN - 101或安慰剂。主要终点是入组后6个月内前列腺特异性抗原（PSA）反应，定义为至少4周后确认PSA降低50%。
250例患者被随机分组。两组的基线特征相似。6个月内，DN - 101组患者的PSA反应率为58%，安慰剂组为49%（P = 0.16）。总体而言，PSA反应率分别为63%（DN - 101）和52%（安慰剂），P = 0.07。在包含基线血红蛋白和体能状态的多因素分析中，DN - 101组患者的死亡风险比为0.67（P = 0.04）。DN - 101组的中位生存期尚未达到，使用风险比估计为24.5个月，而安慰剂组为16.4个月。3/4级不良事件在58%的DN - 101组患者和70%的安慰剂治疗患者中发生（P = 0.07）。DN - 101组与安慰剂组最常见的3/4级毒性分别为中性粒细胞减少（10%对8%）、疲劳（8%对16%）、感染（8%对13%）和高血糖（6%对12%）。
本研究表明DN - 101治疗与生存期改善相关，但由于生存期并非主要终点，这需要进一步证实。每周添加DN - 101并未增加每周多西他赛的毒性。
