University Hospitals Leuven, Leuven, Belgium
Institut Gustave-Roussy, Villejuif, France.
Ann Oncol. 2015 Mar;26(3):598-607. doi: 10.1093/annonc/mdu566. Epub 2014 Dec 8.
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.
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).
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.
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.
2006-003772-35.
本多中心 II 期试验评估了泛 Aurora 激酶抑制剂盐酸丹沙替尼（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）。
同意的成年患者，具有良好的表现和器官功能，患有晚期/转移性肿瘤，在独立的、疾病特异性队列中接受丹沙替尼 500mg/m2，每 14 天静脉输注 24 小时，直至疾病进展或不可接受的毒性。采用两阶段设计。主要终点为 4 个月时的无进展率（PFR）（RECIST1.1）。
共纳入 223 例患者，219 例患者接受了积极治疗。丹沙替尼的中位相对剂量强度在所有肿瘤类型中相似（84.6%-99.6%）。每例患者每两周的治疗周期中位数为 3-4 个（每个实体的最大治疗周期为 5-40 个），每个组织类型的中位治疗持续时间为 7.6-10.0 周。丹沙替尼在任何治疗的癌症中均未达到预先规定的协议标准的临床相关活性。4 个月时的 PFR 为：BC 18.4%、OC 12.1%、PC 10.0%、NSCLC（所有组织类型）10.4%、鳞状 NSCLC 16.1%和 SCLC 和 CRC 0%。在 BC、OC、PC 和 NSCLC 中观察到一些放射学和/或生化抗肿瘤活性的迹象，包括两个确认的部分缓解。最常见的药物相关非实验室不良事件（AE）为疲劳/乏力、恶心、腹泻、厌食、呕吐、脱发、便秘和发热。常见的实验室 AE 包括血液学毒性、低白蛋白血症和肝酶升高。仅有 5.5%的患者因 AE 而停止治疗。丹沙替尼的血浆浓度与早期研究结果一致。
在先前系统治疗失败的常见实体肿瘤中，单药丹沙替尼仅显示出轻微的抗肿瘤活性。安全性和 PK 特征与既往经验一致。
2006-003772-35。
