Department of Oncology, Palacký University Medical School and Teaching Hospital, Olomouc, Czech Republic.
Centre Oscar Lambret, Lille, France.
Lancet Oncol. 2015 Apr;16(4):395-405. doi: 10.1016/S1470-2045(15)70051-3. Epub 2015 Feb 27.
Alisertib is an investigational, oral, selective inhibitor of aurora kinase A. We aimed to investigate the safety and activity of single-agent alisertib in patients with predefined types of advanced solid tumours.
We did a multicentre phase 1/2 study at 40 centres in four countries (Czech Republic, France, Poland, and the USA). Here, we report results from phase 2; enrolment for the study began on Feb 16, 2010, and ended on May 3, 2013. Adult patients were eligible for the study if they had either breast cancer, small-cell lung cancer, non-small-cell lung cancer, head and neck squamous-cell carcinoma, or gastro-oesophageal adenocarcinoma that had relapsed or was refractory to chemotherapy. Patients had to have undergone two or fewer previous cytotoxic regimens (four or fewer for breast cancer patients), not including adjuvant or neoadjuvant treatments. Enrolment followed a two-stage design: to proceed to the second stage, two or more objective responses were needed in the first 20 response-assessable patients in each of the five tumour cohorts. Alisertib was administered orally in 21-day cycles at the recommended phase 2 dose of 50 mg twice daily for 7 days followed by a break of 14 days. The protocol-specified primary endpoint was the proportion of patients with an objective response, assessed by Response Evaluation Criteria In Solid Tumors version 1.1 in the response-assessable population (ie, patients with measurable disease who received at least one dose of alisertib and had undergone at least one post-baseline tumour assessment). This completed trial is registered with ClinicalTrials.gov, NCT01045421.
By May 31, 2013, 249 patients had been treated, 53 with breast cancer, 60 with small-cell lung cancer, 26 with non-small-cell lung cancer, 55 with head and neck squamous-cell carcinoma, and 55 with gastro-oesophageal adenocarcinoma. Among response-assessable patients, an objective response was noted in nine (18%, 95% CI 9-32) of 49 women with breast cancer, ten (21%, 10-35) of 48 participants with small-cell lung cancer, one (4%, 0-22) of 23 patients with non-small-cell lung cancer, four (9%, 2-21) of 45 people with head and neck squamous-cell carcinoma, and four (9%, 2-20) of 47 individuals with gastro-oesophageal adenocarcinoma; all were partial responses. Adverse events were similar across tumour types. The most frequent drug-related grade 3-4 adverse events included neutropenia (n=107 [43%]), leukopenia (53 [21%]), and anaemia (26 [10%]). Serious drug-related adverse events were reported in 108 (43%) patients.
These data support further clinical assessment of alisertib in patients with solid tumours, particularly those with breast cancer and small-cell lung cancer.
Millennium Pharmaceuticals, Inc, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited.
alisertib 是一种新型、口服、选择性 Aurora 激酶 A 抑制剂。本研究旨在评估alisertib 单药治疗特定类型晚期实体瘤患者的安全性和疗效。
本研究为多中心 1/2 期研究，在四个国家（捷克共和国、法国、波兰和美国）的 40 个中心进行。本文报道的是 2 期结果。研究于 2010 年 2 月 16 日开始患者入组，2013 年 5 月 3 日结束。符合条件的患者为：复发或化疗耐药的乳腺癌、小细胞肺癌、非小细胞肺癌、头颈部鳞癌或胃食管腺癌。患者至少接受过 2 种（乳腺癌患者至少接受过 4 种）之前的细胞毒化疗方案，不包括辅助或新辅助治疗。本研究采用两阶段设计入组：在前 5 个肿瘤队列中，每个队列前 20 例可评价患者中至少有 2 例客观缓解，即可进入第 2 阶段。alisertib 推荐的 2 期剂量为 50mg，每日 2 次，口服，连续服用 7 天，停药 14 天。方案规定的主要研究终点为可评价人群（即接受至少 1 剂 alisertib 治疗且至少有 1 次基线后肿瘤评估的有可测量病灶的患者）的客观缓解率，采用实体瘤疗效评价标准 1.1 进行评估。该研究已在 ClinicalTrials.gov 注册，编号为 NCT01045421。
截至 2013 年 5 月 31 日，共入组 249 例患者，其中乳腺癌 53 例、小细胞肺癌 60 例、非小细胞肺癌 26 例、头颈部鳞癌 55 例和胃食管腺癌 55 例。在可评价疗效的患者中，乳腺癌患者中 9 例（18%，95%CI 9-32）、小细胞肺癌患者中 10 例（21%，10-35）、非小细胞肺癌患者中 1 例（4%，0-22）、头颈部鳞癌患者中 4 例（9%，2-21）和胃食管腺癌患者中 4 例（9%，2-20）患者获得客观缓解，均为部分缓解。各肿瘤类型患者的不良反应相似。最常见的与药物相关的 3-4 级不良事件包括中性粒细胞减少（107 例[43%]）、白细胞减少（53 例[21%]）和贫血（26 例[10%]）。108 例（43%）患者发生严重的药物相关不良事件。
这些数据支持进一步评估 alisertib 在实体瘤患者中的应用，尤其是乳腺癌和小细胞肺癌患者。
千禧制药公司，武田制药公司的全资子公司。
