Phase II, Randomized, Controlled, Double-Blinded Trial of Weekly Elesclomol Plus Paclitaxel Versus Paclitaxel Alone for Stage IV Metastatic Melanoma
Phase II, Randomized, Controlled, Double-Blinded Trial of Weekly Elesclomol Plus Paclitaxel Versus Paclitaxel Alone for Stage IV Metastatic Melanoma
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DOI：
10.1200/jco.2008.17.1579
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发表时间：
2009-11-10
影响因子：
45.3
通讯作者：
Jacobson, Eric
中科院分区：
文献类型：
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作者：
O'Day, Steven;Gonzalez, Rene;Jacobson, Eric
目的
依斯氯莫是一种新型小分子氧化应激诱导剂，据信可通过增加细胞内活性氧物质的浓度发挥选择性细胞毒性作用，从而通过线粒体凋亡导致细胞死亡。我们评估了在每周使用紫杉醇的基础上添加依斯氯莫是否能提高IV期转移性黑色素瘤患者的疗效。
患者与方法
我们将患有转移性黑色素瘤、有可测量病灶且既往接受过一种或无化疗方案的患者按2∶1的比例随机分配至接受依斯氯莫213 mg/m²加紫杉醇80 mg/m²（E + P）组或单独使用紫杉醇80 mg/m²组；方案为每周静脉输注1小时，每4周中的3周给药，直至根据实体瘤疗效评价标准出现疾病进展或死亡。出现进展的患者揭盲，单独使用紫杉醇的患者可交叉至E + P组。主要疗效终点是无进展生存期（PFS）；次要终点是缓解率（RR）、毒性和总生存期（OS；事后分析）。
结果
在美国的21个研究中心，53名患者被随机分配至E + P组，28名患者被随机分配至紫杉醇组。在紫杉醇中添加依斯氯莫使中位PFS翻倍（112天对56天），疾病进展/死亡风险降低41.7%（风险比，0.583；P = 0.035）。E + P组和紫杉醇组的缓解率分别为15%和3%；中位OS分别为11.9个月和7.8个月。在单独使用紫杉醇的28名患者中，有19名（68%）在出现进展后交叉至E + P组。每周E + P的耐受性良好。
结论
E + P导致中位PFS在统计学上显著翻倍，具有可接受的毒性特征和令人鼓舞的OS。一项关于E + P与单独使用紫杉醇治疗转移性黑色素瘤的多国III期试验（SYMMETRY）已结束。
Purpose Elesclomol is a novel, small-molecule, oxidative stress inducer believed to exert selective cytotoxicity by increasing intracellular concentrations of reactive oxygen species, which results in cell death via mitochondrial apoptosis. We evaluated whether the addition of elesclomol to weekly paclitaxel could improve efficacy in patients with stage IV metastatic melanoma.Patients and Methods We randomly assigned patients with metastatic melanoma, measurable disease, and one or fewer prior chemotherapy regimens to elesclomol 213 mg/m(2) plus paclitaxel 80 mg/m(2) (E + P) or to paclitaxel 80 mg/m(2) alone at a 2: 1 ratio; regimens were given as a 1-hour intravenous infusion weekly, during 3 of every 4 weeks until disease progression per Response Evaluation Criteria in Solid Tumors or death occurred. Patients who experienced progression were unblended, and patients on paclitaxel alone were permitted to cross over to E + P. The primary efficacy end point was progression-free survival (PFS); secondary end points were response rate (RR), toxicity, and overall survival (OS; analyzed post hoc).Results At 21 US sites, 53 patients were randomly assigned to E + P, and 28 patients were randomly assigned to paclitaxel. The addition of elesclomol to paclitaxel yielded a doubling of median PFS (112 v 56 days) and a 41.7% risk reduction for disease progression/death (hazard ratio, 0.583; P = .035). Respective RRs for the E + P and paclitaxel groups were 15% and 3%; median OS was 11.9 v 7.8 months. Of patients on paclitaxel alone, 19 (68%) of 28 crossed over to E + P after they experienced progression. Weekly E + P was well tolerated.Conclusion E + P resulted in a statistically significant doubling of median PFS, with an acceptable toxicity profile and encouraging OS. A multinational, phase III trial (SYMMETRY) of E + P compared with paclitaxel alone in metastatic melanoma has closed.