Double-Blind, Placebo-Controlled, Randomized Phase 2 Study of the Proapoptotic Agent AT-101 Plus Docetaxel, in Second-Line Non-small Cell Lung Cancer
Double-Blind, Placebo-Controlled, Randomized Phase 2 Study of the Proapoptotic Agent AT-101 Plus Docetaxel, in Second-Line Non-small Cell Lung Cancer
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DOI：
10.1097/jto.0b013e31820a0ea6
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发表时间：
2011-04-01
影响因子：
20.4
通讯作者：
Leopold, Lance
中科院分区：
文献类型：
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作者：
Ready, Neal;Karaseva, Nina A.;Leopold, Lance
背景：AT-101是Bcl-2家族蛋白的抑制剂，包括Bcl-2、Bcl-xL、Mcl-1和Bcl-w。在体内和体外研究显示AT-101的广泛活性，包括与多西他赛在非小细胞肺癌肿瘤models.Methods协同作用：我们进行了一项前瞻性，随机（1：1），双盲，安慰剂对照的2期研究。合格患者必须既往接受过一种晚期或转移性非小细胞肺癌化疗方案，也可能接受过表皮生长因子受体抑制剂治疗。患者接受AT-101（40 mg b.i.d. x 3天）或安慰剂联合多西他赛（第1天75 mg/m2）每21天给药。主要终点是通过独立审查确定的无进展生存期（PFS）;其他终点包括总生存期和研究者确定的PFS。约102例患者计划提供70起事件（80%功效，风险比[HR]为0.6，单侧α为0.1）。结果：106例患者被分配至治疗组，105例患者接受至少一剂AT-101或安慰剂。治疗组之间的基线因素平衡：中位年龄59岁; 77%男性，79%当前或既往吸烟者。93%的患者在随机分组时有远处转移性疾病，56%的患者为鳞状细胞癌。最常报告的不良事件是疲劳（18%）、贫血（18%）和呼吸困难（18%）。AT-101组和安慰剂组的严重不良事件无统计学显著性差异;与多西他赛+AT-101组相比，AT-101组1/2级头痛的发生率更高（9% vs 0%），多西他赛+安慰剂组中性粒细胞减少的报告率更高（17% vs 8%）。与AT-101连续每日给药的试验不同，未报告小肠梗阻病例。通过独立审查，两组之间的缓解率和中位PFS无差异，多西他赛+AT-101组PFS为7.5周，多西他赛+安慰剂组为7.1周（HR，1.04; p = 0.57）。多西他赛联合AT-101的中位总生存期为7.8个月，多西他赛联合安慰剂的中位总生存期为5.9个月（HR，0.82; p = 0.21）。AT-101加多西他赛耐受性良好，不良事件特征与基础多西他赛方案无区别。AT-101是第一个口服的，泛Bcl-2家族抑制剂，在一项随机研究中显示出可能的生存益处。
Background: AT-101 is an inhibitor of Bcl-2 family proteins including Bcl-2, Bcl-xL, Mcl-1, and Bcl-w. In vivo and in vitro studies have exhibited broad activity of AT-101, including synergy with docetaxel in non-small cell lung cancer tumor models.Methods: We conducted a prospective, randomized (1:1), double-blind, placebo-controlled phase 2 study. Eligible patients must have received one prior chemotherapeutic regimen for advanced or metastatic non-small cell lung cancer and may also have received therapy with an epidermal growth factor receptor inhibitor. Patients received AT-101 (40 mg b.i.d. x 3 days) or placebo in combination with docetaxel (75 mg/m(2) on day 1) every 21 days. The primary endpoint was progression-free survival (PFS) as determined by independent review; other endpoints include overall survival and PFS by investigator determination. Approximately 102 patients were planned to provide 70 events (80% power, hazard ratio [HR] of 0.6, one-sided alpha of 0.1).Results: One hundred six patients were assigned to treatment and 105 patients received at least one dose of AT-101 or placebo. Baseline factors were balanced between treatment groups: median age 59 years; 77% men, and 79% current or former smokers. Ninety-three percent of patients had distant metastatic disease at randomization and 56% squamous histology. The most frequently reported adverse events were fatigue (18%), anemia (18%), and dyspnea (18%). No statistically significant differences in serious adverse events were observed between AT-101 and placebo; grade 1/2 headaches appeared more frequently with AT-101 (9% versus 0%) and neutropenia was reported more frequently in the docetaxel plus placebo arm compared with docetaxel plus AT-101 (17% versus 8%). Unlike trials with continuous daily dosing of AT-101, no cases of small bowel obstruction were reported. The response rate and median PFS were not different between the arms by independent review, PFS 7.5 weeks for docetaxel plus AT-101 and 7.1 weeks for docetaxel plus placebo arms (HR, 1.04; p = 0.57). The median overall survival was 7.8 months for docetaxel plus AT-101 versus 5.9 months for docetaxel plus placebo (HR, 0.82; p = 0.21).Conclusions: The primary endpoint of improved PFS for AT-101 plus docetaxel was not met. AT-101 plus docetaxel was well tolerated with an adverse event profile indistinguishable from the base docetaxel regimen. AT-101 is the first oral, pan Bcl-2 family inhibitor to exhibit a possible survival benefit in a randomized study.