An open-label, single-arm, phase 2 trial of the Polo-like kinase inhibitor volasertib (BI 6727) in patients with locally advanced or metastatic urothelial cancer.
An open-label, single-arm, phase 2 trial of the Polo-like kinase inhibitor volasertib (BI 6727) in patients with locally advanced or metastatic urothelial cancer.
复制标题
DOI：
10.1002/cncr.28519
复制
发表时间：
2014-04-01
期刊：
影响因子：
6.2
通讯作者：
Carducci MA
中科院分区：
文献类型：
--
作者：
Stadler WM;Vaughn DJ;Sonpavde G;Vogelzang NJ;Tagawa ST;Petrylak DP;Rosen P;Lin CC;Mahoney J;Modi S;Lee P;Ernstoff MS;Su WC;Spira A;Pilz K;Vinisko R;Schloss C;Fritsch H;Zhao C;Carducci MA
Polo 样激酶 (Plk) 控制细胞周期中的多个步骤，Plk1 在尿路上皮癌 (UC) 中过度表达。 Volasertib (BI 6727) 是一种 Plk 抑制剂，已证明对包括 UC 在内的多种恶性肿瘤具有抗肿瘤活性。在这项 2 期试验中，作者研究了 volasertib 作为晚期/转移性 UC 的二线治疗。先前 1 种化疗方案 2 年内病情进展的患者每 3 周在第 1 天接受 300 mg volasertib 治疗。如果 volasertib 在第 1 周期中耐受，则在第 2 周期中剂量增加至 350 mg。主要终点是肿瘤反应，每 6 周评估一次；次要终点是无进展生存期、总生存期、缓解持续时间、安全性和药代动力学。入组了 50 名患者，患者中位年龄为 68.5 岁（范围：52-83 岁）。所有患者均先前接受过铂类治疗，94%的患者在先前治疗后≤2年内复发，36%有肝转移，54%有肺转移。治疗周期中位数为 2 个（范围为 1-27 个治疗周期），23 名患者在第 2 个周期增加剂量。7 名患者 (14%) 出现部分缓解，13 名患者 (26%) 病情稳定，30 名患者 (60%) 在 6 周内病情进展。中位缓解持续时间为 41 周（范围：29.1-77.3 周）。中位无进展生存期为 1.4 个月，中位总生存期为 8.5 个月。最常见的 3 级和 4 级不良事件是中性粒细胞减少症 (28%)、血小板减少症 (20%) 和贫血 (16%)。没有观察到累积毒性。 Volasertib 作为晚期/转移性 UC 的二线治疗具有可接受的安全性，但其抗肿瘤活性不足以作为单一疗法进行进一步评估。
Polo-like kinases (Plks) control multiple steps during the cell cycle, and Plk1 is overexpressed in urothelial cancer (UC). Volasertib (BI 6727), a Plk inhibitor, has demonstrated antitumor activity in several malignancies, including UC. In this phase 2 trial, the authors investigated volasertib as a second-line treatment in advanced/metastatic UC. Patients who progressed within 2 years of 1 prior chemotherapy regimen received 300 mg volasertib on day 1 every 3 weeks. The dose was escalated to 350 mg in cycle 2 if volasertib was tolerated in cycle 1. The primary endpoint was tumor response, which was assessed every 6 weeks; secondary endpoints were progression-free survival, overall survival, duration of response, safety, and pharmacokinetics. Fifty patients were enrolled, and the median patient age was 68.5 years (range, 52-83 years). All patients had received prior platinum, 94% of patients had relapsed ≤2 years after prior therapy, 36% had liver metastases, and 54% had lung metastases. The median number of treatment cycles was 2 (range, 1-27 treatment cycles), and 23 patients were dose escalated at cycle 2. Seven patients (14%) had a partial response, 13 (26%) had stable disease, and 30 (60%) progressed within 6 weeks. The median response duration was 41 weeks (range, 29.1-77.3 weeks). The median progression-free survival was 1.4 months, and the median overall survival was 8.5 months. The most frequent grade 3 and 4 adverse events were neutropenia (28%), thrombocytopenia (20%), and anemia (16%). No cumulative toxicity was observed. Volasertib as second-line treatment for advanced/metastatic UC had an acceptable safety profile but demonstrated insufficient antitumor activity for further evaluation as a monotherapy.