Efficacy and safety of biweekly i.v. administrations of the Aurora kinase inhibitor danusertib hydrochloride in independent cohorts of patients with advanced or metastatic breast, ovarian, colorectal, pancreatic, small-cell and non-small-cell lung cancer: a multi-tumour, multi-institutional phase II study
Efficacy and safety of biweekly i.v. administrations of the Aurora kinase inhibitor danusertib hydrochloride in independent cohorts of patients with advanced or metastatic breast, ovarian, colorectal, pancreatic, small-cell and non-small-cell lung cancer: a multi-tumour, multi-institutional phase II study
复制标题
DOI：
10.1093/annonc/mdu566
复制
发表时间：
2015-03-01
影响因子：
50.5
通讯作者：
Delord, J. -P.
中科院分区：
文献类型：
--
作者：
Schoffski, P.;Besse, B.;Delord, J. -P.
背景：这项多中心II期试验评估了泛aurora激酶抑制剂danusertib hydrochloride （PHA-739358）在乳腺癌（BC）、卵巢癌（OC）、胰腺癌（PC）、结直肠癌（CRC）、小细胞肺癌（SCLC）和非小细胞肺癌（NSCLC）中的活性、安全性（CTCAE 3.0）和药代动力学（PK）。方法：在独立的疾病特异性队列中，经全身治疗失败的晚期/转移性肿瘤的表现良好和器官功能良好的成年患者接受danusertib 500 mg/m(2)，每14天24小时静脉输注，直到进展或不可接受的毒性。采用两阶段设计。主要终点是4个月时的无进展率（PFR） （RECIST1.1）。结果：共纳入223例患者，其中219例积极治疗。danusertib的中位相对剂量强度在所有肿瘤类型中相似（84.6%-99.6%）。双周治疗周期的中位数为3至4个/患者（最多5-40个/实体），每个组织型的中位数治疗持续时间为7.6至10.0周。Danusertib在任何治疗的癌症中都没有达到预先指定的临床相关活性的协议标准。4个月时的PFR在BC为18.4%，OC为12.1%，PC为10.0%，NSCLC为10.4%（所有组织类型），鳞状NSCLC为16.1%，SCLC和CRC为0%。在BC， OC， PC和NSCLC中发现了一些放射学和/或生化指标的抗肿瘤活性，包括两个确认的部分反应。最常见的药物相关非实验室不良事件（ae）是疲劳/虚弱、恶心、腹泻、厌食、呕吐、脱发、便秘和发热。常见的实验室不良反应包括血液学毒性、低白蛋白血症和肝酶升高。只有5.5%的患者因不良事件而停止治疗。丹usertib的血浆浓度与早期研究的结果一致。结论：单药danusertib在既往全身治疗失败后的常见实体瘤中仅显示出边际抗肿瘤活性。安全性和PK资料与以前的经验一致。
Background: This multi-centre phase II trial assessed the activity, safety (CTCAE 3.0) and pharmacokinetics (PK) of the pan-Aurora kinase inhibitor danusertib hydrochloride (PHA-739358) in breast (BC), ovarian (OC), pancreatic (PC), colorectal (CRC), small-cell (SCLC) and non-small-cell lung (NSCLC) cancers.Methods: Consenting adult patients with good performance and organ function with advanced/metastatic tumours who had failed systemic therapy were treated in independent, disease-specific cohorts with danusertib 500 mg/m(2) given as 24-h i.v. infusion every 14 days with until progression or unacceptable toxicity. A two-stage design was applied. Primary end point was the progression-free rate (PFR) at 4 months (RECIST1.1).Results: A total of 223 patients were enrolled with 219 actively treated. The median relative dose intensity of danusertib was similar for all tumour types (84.6%-99.6%). The median number of biweekly treatment cycles ranged from 3 to 4/patient (maximum 5-40 cycles/entity) and the median treatment duration varied between 7.6 and 10.0 weeks per histotype. Danusertib did not meet pre-specified protocol criteria for clinically relevant activity in any of the treated cancers. The PFR at 4 months was 18.4% in BC, 12.1% in OC, 10.0% in PC, 10.4% in NSCLC (all histotypes), 16.1% in squamous NSCLC and 0% in SCLC and CRC. Some radiological and/or biochemical indication of antitumor activity was seen in BC, OC, PC and NSCLC, including two confirmed partial responses. The most frequent drug-related non-laboratory adverse events (AEs) were fatigue/asthenia, nausea, diarrhoea, anorexia, vomiting, alopecia, constipation and pyrexia. Common laboratory AEs included haematological toxicity, hypalbuminaemia and increases in liver enzymes. Treatment was discontinued due to AEs in only 5.5% of patients. Plasma concentrations of danusertib were in line with results from earlier studies.Conclusion: Single-agent danusertib did show only marginal anti-tumour activity in common solid tumours after failure of prior systemic therapies. The safety and PK profile was consistent with previous experience.