Necchi Andrea, Lo Vullo Salvatore, Mariani Luigi, Raggi Daniele, Giannatempo Patrizia, Calareso Giuseppina, Togliardi Elena, Crippa Flavio, Di Genova Nicola, Perrone Federica, Colecchia Maurizio, Paolini Biagio, Pelosi Giuseppe, Nicolai Nicola, Procopio Giuseppe, Salvioni Roberto, De Braud Filippo G
Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Via G. Venezian 1, 20133, Milano, Italy.
Clinical Epidemiology and Trials Organization Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy.
Invest New Drugs. 2016 Apr;34(2):236-42. doi: 10.1007/s10637-016-0328-9. Epub 2016 Feb 12.
Progress in developing effective salvage therapies for UC is warranted. Alisertib is an orally available, selective inhibitor of the aurora kinase A.
A single-group, phase 2 trial was conducted with alisertib 50 mg orally BID for 7 days, with 14d rest until disease progression (PD) (NCT02109328). The primary endpoint (EP) was RECIST 1.1 objective response-rate (ORR, H0 ≤ 5%, H1 ≥ 20%, α = 10% and β = 20%). Eligibility included failure of at least one platinum-based regimen.
From 10/2014 to 04/2015, 22 patients were enrolled (20 evaluable for response), 8 (36.4%) in second-line and 14 (63.6 %) beyond the second-line. Eight (36.4%) had an ECOG-performance status 1-2. Two partial responses (PR, ORR: 9.1%), 7 stable disease (SD) and 11 PD were obtained. Median follow-up was 8.3 months (IQR: 7-10.3), 6-month progression-free survival (PFS) was 13.6% (95%CI: 4.8-39.0). Two SD are still receiving treatment after 11.5 and 6.3 months. Median overall survival (OS) was not reached (6-month OS: 59.1%, 95%CI: 41.7-83.7). Hb < 10 g/dl was significantly associated with shorter PFS and OS multivariably (p = 0.031 and p = 0.033). Tissue of the case with 11.5 month SD harbored a missense mutation of mTOR (E1813D), the nonsense mutation Q527STOP of TSC1, HER3 and TAF1L missense mutations. Grade 3-4 adverse events (AE) were: 40.9% mucositis, 36.4% fatigue, 18.2% neutropenia (13.6% febrile neutropenia). There were 2 treatment-related deaths.
The study did not meet the primary EP, yet sustained disease control was obtained in about 14% of patients. The incidence of AE and the issue of patient selection are two major concerns.
开发有效的溃疡性结肠炎挽救疗法很有必要。阿利塞替布是一种口服可用的极光激酶A选择性抑制剂。
进行了一项单组2期试验，给予阿利塞替布50mg口服，每日两次，共7天，休息14天直至疾病进展（PD）（NCT02109328）。主要终点（EP）是实体瘤疗效评价标准（RECIST）1.1版的客观缓解率（ORR，H0≤5%，H1≥20%，α=10%，β=20%）。入选标准包括至少一种铂类方案治疗失败。
2014年10月至2015年4月，共纳入22例患者（20例可评估疗效），8例（36.4%）为二线治疗，14例（63.6%）为二线以上治疗。8例（36.4%）患者东部肿瘤协作组（ECOG）体能状态为1 - 2级。获得2例部分缓解（PR，ORR：9.1%），7例疾病稳定（SD），11例疾病进展（PD）。中位随访时间为8.3个月（四分位间距：7 - 10.3个月），6个月无进展生存期（PFS）为13.6%（95%置信区间：4.8 - 39.0）。2例SD患者在11.5个月和6.3个月后仍在接受治疗。中位总生存期（OS）未达到（6个月OS：59.1%，95%置信区间：41.7 - 83.7）。血红蛋白（Hb）<10g/dl与较短的PFS和OS在多因素分析中显著相关（p = 0.031和p = 0.033）。1例11.5个月疾病稳定患者的组织存在mTOR错义突变（E1813D）、结节性硬化症复合物1（TSC1）的无义突变Q527STOP、人表皮生长因子受体3（HER3）和TATA框结合蛋白样1（TAF1L）错义突变。3 - 4级不良事件（AE）为：40.9%的黏膜炎、36.4%的疲劳、18.2%的中性粒细胞减少（13.6%为发热性中性粒细胞减少）。有2例治疗相关死亡。
该研究未达到主要终点，但约14%的患者获得了持续的疾病控制。AE的发生率和患者选择问题是两个主要关注点。
