Alisertib in Combination With Weekly Paclitaxel in Patients With Advanced Breast Cancer or Recurrent Ovarian Cancer A Randomized Clinical Trial
Alisertib in Combination With Weekly Paclitaxel in Patients With Advanced Breast Cancer or Recurrent Ovarian Cancer A Randomized Clinical Trial
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DOI：
10.1001/jamaoncol.2018.3773
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发表时间：
2019-01-01
期刊：
影响因子：
28.4
通讯作者：
Schilder, Russell J.
中科院分区：
文献类型：
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作者：
Falchook, Gerald;Coleman, Robert L.;Schilder, Russell J.
重要性 治疗复发性卵巢癌的医疗需求尚未得到满足，需要新的方法来改善无进展生存期 (PFS) 和总生存期。 目的 这项 1/2 期研究评估了 alisertib 与每周一次紫杉醇联合治疗乳腺癌（1 期）和卵巢癌（1 期和 2 期）患者的活性。 设计、环境和参与者 这是一项开放标签 1 期和随机 2 期临床试验，第一阶段于2010年4月16日，第二阶段于2012年3月28日至2013年8月12日在33个地点（美国、法国和波兰）进行。数据报告截止日期为 2014 年 8 月 12 日，alisertib 加紫杉醇组的中位随访时间为 7.2 个月，紫杉醇组为 4.6 个月。共有 191 名晚期乳腺癌（仅限 1 期）或复发性卵巢癌女性入组，其中 142 名患者在 2 期研究中随机接受 alisertib 加紫杉醇治疗（n = 73）或单独接受紫杉醇治疗（n = 69）。 干预措施 患者按无铂间隔（难治性、0-6 个月、6-12 个月）和之前每周接受紫杉烷治疗按 1:1 随机分层（是，否）接受阿利司替布 40 mg 每天两次口服，连续 3 天，停药 4 天，持续 3 周，加紫杉醇（静脉注射 60 mg/m(2)，第 1、8 和 15 天），或每周静脉注射紫杉醇 80 mg/m(2)，28 天为一个周期。主要疗效分析和安全性分析使用改良意向治疗 (mITT) 人群（所有接受 >= 1 剂量研究药物的随机患者）。 结果 1 期入组的 191 名患者的中位年龄为 59 岁（范围为 29-75）岁。入组第 2 期的 142 名患者的中位年龄为 63 岁（范围为 30-81）岁，接受 alisertib 加紫杉醇治疗的患者为 61 岁（范围为 41-81）岁。截至数据截止时，107 名 (75%) 患者有记录的 PFS 事件； alisertib 加紫杉醇组中有 52 例 (71%)，紫杉醇组有 55 例 (80%)。 alisertib 加紫杉醇组的中位 PFS 为 6.7 个月，而紫杉醇组为 4.7 个月（HR，0.75；80% CI，0.58-0.96；P = 0.14；双边 P 值截止值 = 0.20 被认为值得进一步研究）。在 alisertib 加紫杉醇组和紫杉醇组中，分别有 63 例 (86%) 例和 14 例 (20%) 例患者报告了与药物相关的 3 级或以上不良事件，其中包括 56 例 (77%) 例和 7 例 (10%) 中性粒细胞减少症、18 例 (25%) 例和 0 例口腔炎以及 10 例 (14%) 例和 2 例 (3%) 贫血； 54 名 (74%) 与 17 名 (25%) 发生不良事件导致剂量减少。两名患者在研究期间死亡（每组各 1 名）；两种死亡均不被认为与研究药物相关。 结论和相关性 主要终点 PFS 明显优于单独使用紫杉醇。需要进一步调查。
IMPORTANCE There is an unmet medical need for the treatment of recurrent ovarian cancer, and new approaches are needed to improve progression-free survival (PFS) and overall survival.OBJECTIVE This phase 1/2 study evaluated the activity of alisertib in combination with weekly paclitaxel in patients with breast (phase 1) and ovarian cancer (phase 1 and phase 2).DESIGN, SETTING, AND PARTICIPANTS An open-label phase 1 and randomized phase 2 clinical trial conducted from April 16, 2010, for phase 1 and March 28, 2012, to August 12, 2013, for phase 2 was conducted at 33 sites (United States, France, and Poland). Data are reported from a cutoff date of August 12, 2014, with a median duration of follow-up of 7.2 months in the alisertib plus paclitaxel arm and 4.6 months in the paclitaxel arm. A total of 191 women with advanced breast (phase 1 only) or recurrent ovarian cancer were enrolled, including 142 patients randomized to alisertib plus paclitaxel (n = 73) or paclitaxel alone (n = 69) in the phase 2 study.INTERVENTIONS Patients were randomized 1: 1 stratified by platinum-free interval (refractory, 0-6 months, 6-12 months) and prior weekly taxane treatment (yes, no) to receive alisertib 40 mg twice per day orally and 3 days on and 4 days off for 3 weeks, plus paclitaxel (60 mg/m(2) intravenously, days 1, 8, and 15), or weekly paclitaxel 80 mg/m(2) intravenously in 28-day cycles.MAIN OUTCOMES AND MEASURES Primary endpoint was PFS; primary efficacy analysis and safety analysis used modified intention to treat (mITT) population (all randomized patients who received >= 1 dose of study drug).RESULTS The median age for the 191 patients enrolled in phase 1 was 59 (range, 29-75) years. The median age for the 142 patients enrolled in phase 2 was 63 (range, 30-81) years for patients receiving alisertib plus paclitaxel and 61 (range, 41-81) years for patients receiving paclitaxel. At data cutoff, 107 (75%) patients had a documented PFS event; 52 (71%) in the alisertib plus paclitaxel arm, and 55 (80%) in the paclitaxel arm. Median PFS was 6.7 months with alisertib plus paclitaxel vs 4.7 months with paclitaxel (HR, 0.75; 80% CI, 0.58-0.96; P = .14; 2-sided P value cutoff = .20 to be considered worthy of further investigation). Drug-related grade 3 or higher adverse events were reported in 63 (86%) vs 14 (20%) patients in the alisertib plus paclitaxel and paclitaxel arms, including 56 (77%) vs 7 (10%) neutropenia, 18 (25%) vs 0 stomatitis, and 10 (14%) vs 2 (3%) anemia; 54 (74%) vs 17 (25%) had adverse events leading to dose reductions. Two patients died during the study (1 in each arm); neither death was considered related to study drug.CONCLUSIONS AND RELEVANCE The primary endpoint, PFS, significantly favored alisertib plus paclitaxel over paclitaxel alone. Further investigation is warranted.