Division of Medical Oncology, Mayo Clinic, 200 First Street S.W., Rochester, MN, 55905, USA.
Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN, USA.
Breast Cancer Res Treat. 2018 Apr;168(3):639-647. doi: 10.1007/s10549-017-4616-7. Epub 2017 Dec 30.
In estrogen receptor-positive (ER+) breast cancer models, activation of Aurora A kinase (AURKA) is associated with downregulation of ERα expression and resistance to endocrine therapy. Alisertib is an oral selective inhibitor of AURKA. The primary objectives of this phase I trial were to determine the recommended phase II dose (RP2D) and evaluate the toxicities and clinical activity of alisertib combined with fulvestrant in patients with ER+ metastatic breast cancer (MBC).
In this standard 3 + 3 dose-escalation phase I study, postmenopausal patients with endocrine-resistant, ER+ MBC previously treated with endocrine therapy were assigned to one of two dose levels of alisertib (40 or 50 mg) in combination with fixed-dose fulvestrant.
Ten patients enrolled, of which nine were evaluable for the primary endpoint. The median patient age was 59. All patients had secondary (acquired) endocrine resistance, and all had received prior aromatase inhibitor. Six had experienced disease progression on fulvestrant. There were no severe (grade 3+) toxicities reported during cycle 1 at either dose level. The median progression-free survival time was 12.4 months (95% CI 5.3-not met), and the 6-month clinical benefit rate was 77.8% (95% CI 40.0-87.2%).
In patients with endocrine-resistant, ER+ MBC, alisertib in combination with fulvestrant was well tolerated. A favorable safety profile was observed. The RP2D is 50 mg twice daily on days 1-3, 8-10, and 15-17 of a 28-day cycle with standard dose fulvestrant. Promising antitumor activity was observed, including activity among patients with prior progression on fulvestrant.
在雌激素受体阳性（ER+）乳腺癌模型中，Aurora A 激酶（AURKA）的激活与 ERα 表达下调和内分泌治疗耐药有关。alisertib 是一种口服的 AURKA 选择性抑制剂。本 I 期试验的主要目的是确定 II 期推荐剂量（RP2D），并评估 alisertib 联合氟维司群治疗 ER+转移性乳腺癌（MBC）患者的毒性和临床活性。
在这项标准的 3+3 剂量递增 I 期研究中，绝经后、内分泌治疗耐药、ER+MBC 患者以前接受过内分泌治疗，被分配到 alisertib（40 或 50mg）联合固定剂量氟维司群的两个剂量水平之一。
10 名患者入组，其中 9 名可评估主要终点。中位患者年龄为 59 岁。所有患者均有继发性（获得性）内分泌耐药，且均接受过芳香化酶抑制剂治疗。6 例患者在氟维司群治疗期间出现疾病进展。在两个剂量水平的第 1 周期均未报告严重（3 级）毒性。中位无进展生存期为 12.4 个月（95%CI 5.3-未达到），6 个月临床获益率为 77.8%（95%CI 40.0-87.2%）。
在内分泌治疗耐药、ER+MBC 患者中，alisertib 联合氟维司群耐受性良好。观察到有利的安全性特征。RP2D 为每日 2 次、每次 50mg，第 1-3、8-10 和 15-17 天给药，联合标准剂量氟维司群，28 天为 1 个周期。观察到有前景的抗肿瘤活性，包括在氟维司群治疗后进展的患者中。
