Graff Julie N, Higano Celestia S, Hahn Noah M, Taylor Matthew H, Zhang Bin, Zhou Xiaofei, Venkatakrishnan Karthik, Leonard E Jane, Sarantopoulos John
Knight Cancer Institute, Oregon Health & Science University, Portland, Oregon.
Fred Hutchinson Cancer Research Center, Seattle, Washington.
Cancer. 2016 Aug 15;122(16):2524-33. doi: 10.1002/cncr.30073. Epub 2016 May 18.
This study was designed to determine the safety, tolerability, and pharmacokinetics (PK) of alisertib (MLN8237) in combination with docetaxel and to identify a recommended dose for the combination.
Adults with metastatic cancer were treated on 21-day cycles with alisertib (10, 20, 30, or 40 mg) twice daily on days 1 to 7 or days 1 to 5 and with docetaxel (75 or 60 mg/m(2) ) on day 1. The primary objectives were to assess the safety and tolerability of the combination and to determine the recommended phase 2 dose (RP2D) for future studies. Secondary objectives included an efficacy assessment and PK analyses of docetaxel and alisertib.
Forty-one patients participated. Eight dose levels were explored with various doses of alisertib and docetaxel. The dose-limiting toxicities were neutropenic fever, neutropenia without fever, stomatitis, and urinary tract infection. The RP2D of this combination was 20 mg of alisertib twice daily on days 1 to 7 and intravenous docetaxel at 75 mg/m(2) on day 1 in 21-day cycles. Eight of the 28 patients (29%) who were efficacy-evaluable had objective responses. These included 1 complete response in a patient with bladder cancer, 6 partial responses in patients with castration-resistant prostate cancer, and 1 partial response in a patient with angiosarcoma. Concomitant administration of alisertib did not produce any clinically meaningful change in docetaxel PK.
Alisertib at 20 mg twice daily on days 1 to 7 with intravenous docetaxel at 75 mg/m(2) on day 1 in a 21-day cycle was well tolerated, and the combination demonstrated antitumor activity. Cancer 2016;122:2524-33. © 2016 American Cancer Society.
本研究旨在确定阿利西替尼（MLN8237）联合多西他赛的安全性、耐受性和药代动力学（PK），并确定该联合用药的推荐剂量。
转移性癌症成人患者接受为期21天的周期治疗，在第1至7天或第1至5天每天两次服用阿利西替尼（10、20、30或40毫克），并在第1天服用多西他赛（75或60毫克/平方米）。主要目的是评估联合用药的安全性和耐受性，并确定未来研究的推荐2期剂量（RP2D）。次要目的包括多西他赛和阿利西替尼的疗效评估及PK分析。
41名患者参与研究。探索了8种阿利西替尼和多西他赛不同剂量组合的给药水平。剂量限制性毒性为中性粒细胞减少性发热、无发热的中性粒细胞减少、口腔炎和尿路感染。该联合用药的RP2D为在21天周期中，第1至7天每天两次服用20毫克阿利西替尼，第1天静脉注射75毫克/平方米多西他赛。28名可评估疗效的患者中有8名（29%）出现客观缓解。其中包括1例膀胱癌患者完全缓解，6例去势抵抗性前列腺癌患者部分缓解，1例血管肉瘤患者部分缓解。同时服用阿利西替尼对多西他赛的PK未产生任何具有临床意义的变化。
在21天周期中，第1至7天每天两次服用20毫克阿利西替尼，第1天静脉注射75毫克/平方米多西他赛，耐受性良好，且联合用药显示出抗肿瘤活性。《癌症》2016年；122：2524 - 33。©2016美国癌症协会。
