Hyman David M, Sill Michael W, Lankes Heather A, Piekarz Richard, Shahin Mark S, Ridgway Mildred R, Backes Floor, Tenney Meaghen E, Mathews Cara A, Hoffman James S, Aghajanian Carol, Hensley Martee L
Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
NRG Oncology Statistics and Data Management Center, Buffalo, NY 14263, USA.
Gynecol Oncol. 2017 Jan;144(1):96-100. doi: 10.1016/j.ygyno.2016.10.036. Epub 2016 Oct 27.
This two-stage Phase II study assessed the activity of single agent alisertib in patients with recurrent/persistent uterine leiomyosarcoma (uLMS).
Eligibility criteria included histologically-confirmed, recurrent or persistent uLMS, age≥18, 1-2 prior cytotoxic regimens, and RECIST version 1.1 measurable disease. The primary objective of the study was to evaluate the efficacy of alisertib through the frequency of patients with objective tumor responses and the frequency who survived event-free for at least 6months (EFS6). The endpoints for EFS were RECIST progression, death, or beginning a subsequent therapy. The null hypothesis jointly specified the probability of a patient experiencing a tumor response to less than or equal to 5% and the probability of a patient surviving event-free for at least 6months to less than or equal to 20%. A two-stage design was used with a target accrual of 23 patients for stage 1 and 47 pts. cumulative for stage 2. Confidence intervals do not correct for multiplicity.
Twenty-three patients were enrolled with two patients excluded on central histology review, yielding 21 eligible patients. Median age was 61years. Prior treatment was either 1 cytotoxic regimen (71.4%) or 2 (28.6%). The most common treatment related AEs (grade 3 or worse) were anemia Hensley et al. (2008a) , leukopenia Hensley et al. (2008b) , neutropenia Maki et al. (2007) , thrombocytopenia Huang et al. (2012) , mucositis Hensley et al. (2008a) , diarrhea Huang et al. (2012) , and palmer-planter syndrome Zivanovic et al. (2012) . There were no objective responses (0%; 90% CI: 0-10.4%). Best response was stable disease (38.1%); 12 patients had progressive disease (57.1%). EFS6 was 0% (90% CI: 0-10.4%). Median PFS and OS were 1.7 (90% CI: 1.4-3.2) and 14.5months (90% CI: 7.6 - NA), respectively.
Alisertib did not demonstrate clinically meaningful single agent activity in previously treated uLMS.
本两阶段II期研究评估了单药阿利西替尼对复发/持续性子宫平滑肌肉瘤（uLMS）患者的活性。
纳入标准包括组织学确诊的复发或持续性uLMS、年龄≥18岁、既往接受过1 - 2种细胞毒性方案治疗以及根据实体瘤疗效评价标准（RECIST）1.1版可测量的疾病。本研究的主要目的是通过客观肿瘤反应患者的频率以及无事件生存至少6个月（EFS6）的患者频率来评估阿利西替尼的疗效。EFS的终点为RECIST进展、死亡或开始后续治疗。原假设共同规定患者出现肿瘤反应的概率小于或等于5%以及患者无事件生存至少6个月的概率小于或等于20%。采用两阶段设计，第1阶段目标入组23例患者，第2阶段累计入组47例患者。置信区间未进行多重性校正。
共入组23例患者，经中心组织学复查后排除2例，最终有21例符合条件的患者。中位年龄为61岁。既往治疗为1种细胞毒性方案的患者占71.4%，2种的占28.6%。最常见的与治疗相关（3级或更严重）的不良事件有贫血（Hensley等人，2008a）、白细胞减少（Hensley等人，2008b）、中性粒细胞减少（Maki等人，2007）、血小板减少（Huang等人，2012）、粘膜炎（Hensley等人，2起；8a）、腹泻（Huang等人，2012）和掌跖综合征（Zivanovic等人，2012）。未观察到客观反应（0%；90%置信区间：0 - 10.4%）。最佳反应为疾病稳定（38.1%）；12例患者疾病进展（57.1%）。EFS6为0%（90%置信区间：0 - 10.4%）。中位无进展生存期（PFS）和总生存期（OS）分别为1.7（90%置信区间：1.4 - 3.2）个月和14.5个月（90%置信区间：7.6 - 未达到）。
阿利西替尼在既往接受过治疗的uLMS患者中未显示出具有临床意义的单药活性。
