Randomized Phase II Trial of Custirsen (OGX-011) in Combination with Docetaxel or Mitoxantrone as Second-line Therapy in Patients with Metastatic Castrate-Resistant Prostate Cancer Progressing after First-line Docetaxel: CUOG Trial P-06c
Randomized Phase II Trial of Custirsen (OGX-011) in Combination with Docetaxel or Mitoxantrone as Second-line Therapy in Patients with Metastatic Castrate-Resistant Prostate Cancer Progressing after First-line Docetaxel: CUOG Trial P-06c
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DOI：
10.1158/1078-0432.ccr-11-0859
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发表时间：
2011-09-01
影响因子：
11.5
通讯作者：
Winquist, Eric
中科院分区：
文献类型：
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作者：
Saad, Fred;Hotte, Sebastien;Winquist, Eric
目的：异丙肾上腺素（CLU）是一种抗凋亡的应激诱导蛋白，当过表达时赋予治疗抗性。本研究测试custirsen，CLU抑制剂，在转移性去势抵抗性前列腺癌（mCRPC）进展期间或6个月内的初始多西他赛therapeutic. Patients和方法：男性随机接受多西他赛+泼尼松+custirsen（DPC）或米托蒽醌+泼尼松+custirsen（MPC）。两组的毒性相似。20例接受DPC治疗的患者接受了中位8个周期的治疗，总生存期（OS）为15.8个月。至疼痛进展的中位时间（TTPP）为10.0个月; 13例可评价患者中有10例（77%）出现疼痛缓解。13例可评价患者中有3例（23%）客观部分缓解。前列腺特异性抗原（PSA）下降≥ 90%者4例（20%），≥ 50%者8例（40%），≥ 30%者11例（55%）。中位TTPP为5.2个月; 13例可评价患者中有6例（46%）出现疼痛缓解。未观察到客观缓解。PSA下降50%或以上的患者分别为6例（27%）和7例（32%）。基于时间依赖协变量和不同标志的比例风险回归模型，治疗期间低血清CLU水平显示患者的上级生存率。在一线多西他赛治疗后进行性mCRPC患者中，Custirsen联合多西他赛或米托蒽醌是可行的。疼痛缓解高于预期，血清CLU和生存率之间存在有趣的相关性。一项III期临床试验正在评估custirsen与紫杉烷治疗的疼痛缓解益处。临床癌症研究; 17（17）; 5765 - 73。（c）2011年《非洲标准化评论》。
Purpose: Clusterin (CLU) is an antiapoptotic, stress-induced protein conferring treatment resistance when overexpressed. This study tested custirsen, a CLU inhibitor, in patients with metastatic castration-resistant prostate cancer (mCRPC) progressing during or within 6 months of initial docetaxel therapy.Patients and Methods: Men were randomized to receive either docetaxel + prednisone + custirsen (DPC) or mitoxantrone + prednisone + custirsen (MPC).Results: Forty-two patients received study treatment. Toxicity was similar in both arms. Twenty patients treated with DPC received a median of 8 cycles; overall survival (OS) was 15.8 months. Median time to pain progression (TTPP) was 10.0 months; 10 of 13 (77%) evaluable patients had pain responses. Three of 13 (23%) evaluable patients had objective partial responses. Prostate-specific antigen (PSA) declines of 90% or more, 50% or more, and 30% or more occurred in 4 (20%), 8 (40%), and 11 (55%) patients, respectively.Twenty-two patients treated with MPC received a median of 6 cycles; OS was 11.5 months. The median TTPP was 5.2 months; 6 of 13 (46%) evaluable patients had pain responses. No objective responses were observed. PSA declines of 50% or more and 30% or more occurred in 6 (27%) and 7 (32%) patients, respectively.Low serum CLU levels during treatment showed superior survival for patients based on modeling with proportional hazard regression with a time-dependent covariate and different landmarks.Conclusions: Custirsen plus either docetaxel or mitoxantrone was feasible in patients with progressive mCRPC following first-line docetaxel therapy. Pain relief was higher than expected, with interesting correlations between serum CLU and survival. A phase III trial evaluating the pain palliation benefit of custirsen with taxane therapy is ongoing. Clin Cancer Res; 17(17); 5765-73. (C)2011 AACR.