Dasatinib combined with docetaxel for castration-resistant prostate cancer: results from a phase 1-2 study.
Dasatinib combined with docetaxel for castration-resistant prostate cancer: results from a phase 1-2 study.
复制标题
DOI：
10.1002/cncr.26204
复制
发表时间：
2012-01-01
期刊：
影响因子：
6.2
通讯作者：
Logothetis CJ
中科院分区：
文献类型：
--
作者：
Araujo JC;Mathew P;Armstrong AJ;Braud EL;Posadas E;Lonberg M;Gallick GE;Trudel GC;Paliwal P;Agrawal S;Logothetis CJ
为了确定靶向去势抵抗性前列腺癌（CRPC）患者肿瘤和骨微环境的潜在疗效，我们进行了一项1/2期试验，将多西他赛与达沙替尼（一种口服SRC抑制剂）联合使用。在I期研究中，16例男性接受达沙替尼50-120 mg每日一次（QD）和多西他赛60-75 mg/m2每21天一次（Q21 D）。在II期研究中，另外30例男性接受达沙替尼100 mg QD/多西他赛75 mg/m2 Q21 D。疗效终点包括前列腺特异性抗原（PSA）、可测量疾病、骨扫描和骨代谢标志物的变化。还研究了安全性和药代动力学。达沙替尼和多西他赛联合治疗通常耐受良好。46例患者中有13例（28%）出现3/4级毒性。未确定药物间相互作用和最大耐受剂量。46例患者中有26例（57%）PSA持续下降50%。在30例有可测量疾病的患者中，18例（60%）有部分缓解。14例患者（30%）骨扫描病灶消失。在骨标志物评估中，33/38（87%）和26/34（76%）分别出现尿N-端肽或骨特异性碱性磷酸酶水平降低。28例患者（61%）在多西他赛停药后接受单药达沙替尼治疗，并在另外1-12个月内病情稳定。高客观缓解率和良好的毒性特征是有希望的，并证明多西他赛和达沙替尼在CRPC中的随机研究是合理的。PSA和骨标志物水平的平行下降与癌症的上皮和骨区室的共同靶向一致。多西他赛停药后单药达沙替尼治疗值得进一步研究。
To determine the potential efficacy of targeting both the tumor and bone microenvironment in patients with castration-resistant prostate cancer (CRPC), we conducted a phase 1/2 trial combining docetaxel with dasatinib, an oral SRC inhibitor. In phase 1, 16 men received dasatinib 50–120 mg once daily (QD) and docetaxel 60–75 mg/m2 every 21 days (Q21D). In phase 2, 30 additional men received dasatinib 100 mg QD/docetaxel 75 mg/m2 Q21D. Efficacy endpoints included changes in prostate-specific antigen (PSA), measurable disease, bone scans, and markers of bone metabolism. Safety and pharmacokinetics were also studied. Combination dasatinib and docetaxel therapy was generally well tolerated. Thirteen of 46 patients (28%) had a grade 3/4 toxicity. Drug–drug interactions and a maximum tolerated dose were not identified. Durable 50% PSA declines occurred in 26/46 patients (57%). Of 30 patients with measurable disease, 18 (60%) had a partial response. Fourteen patients (30%) had disappearance of a lesion on bone scan. In bone-marker assessments, 33/38 (87%) and 26/34 (76%) had decreases in urinary N-telopeptide or bone-specific alkaline phosphatase levels, respectively. Twenty-eight patients (61%) received single-agent dasatinib following docetaxel discontinuation and had stabilization of disease for an additional 1–12 months. The high objective response rate and favorable toxicity profile are promising and justify randomized studies of docetaxel and dasatinib in CRPC. Parallel declines in levels of PSA and bone markers are consistent with co-targeting of epithelial and bone compartments of the cancer. Treatment with single-agent dasatinib following docetaxel cessation warrants further study.