Chen E X, Hotte S, Hirte H, Siu L L, Lyons J, Squires M, Lovell S, Turner S, McIntosh L, Seymour L
Princess Margaret Cancer Centre, University Health Network, Room 5-719, 610 University Avenue, Toronto, Ontario, Canada.
Juravinski Cancer Centre, Hamilton Health Sciences, Hamilton, Ontario, Canada.
Br J Cancer. 2014 Dec 9;111(12):2262-7. doi: 10.1038/bjc.2014.565. Epub 2014 Nov 13.
AT7519 is a small-molecular inhibitor of multiple cyclin-dependent kinases (CDKs). It shows encouraging anti-cancer activity against multiple cell lines and in tumour xenografts. This phase I study was conducted to evaluate the safety and tolerability of AT7519 given as 1-h intravenous infusion on days 1, 4, 8 and 11 every 3 weeks.
Patients with advanced refractory solid tumours or non-Hodgkin's lymphoma were enroled. Dose escalation occurred in a 3+3 manner based on toxicity assessment. Pharmacokinetic samples were collected after first AT7519 infusion, whereas pharmacodynamics (PD) samples were obtained in selected patients.
Thirty-four patients were enroled, and 32 received study treatments over 4 dose levels. Dose-limiting toxicities included mucositis, febrile neutropenia, rash, fatigue and hypokalemia. The recommended phase II dose (RP2D) was 27.0 mg m(-2). Ten of 19 patients evaluable for efficacy had stable disease as the best response (median duration: 3.3 months; range: 2.5 to 11.1 months). There was no clinically significant QTc prolongation. There was an apparent dose proportional increase in AT7519 exposure. The PD studies showed reduction in markers of CDK activity in selected patients' skin biopsies post treatment.
AT7519, when administered as an intravenous infusion on days 1, 4, 8 and 11, was well tolerated. The RP2D is 27.0 mg m(-2). At this dose level, plasma AT7519 concentrations were above the biologically active concentrations, and preliminary anti-cancer activity was observed in patients. This dosing schedule is being further evaluated in multiple phase II studies.
AT7519是一种多种细胞周期蛋白依赖性激酶（CDK）的小分子抑制剂。它在多种细胞系和肿瘤异种移植模型中显示出令人鼓舞的抗癌活性。本I期研究旨在评估每3周的第1、4、8和11天静脉输注1小时AT7519的安全性和耐受性。
纳入晚期难治性实体瘤或非霍奇金淋巴瘤患者。根据毒性评估以3+3方式进行剂量递增。首次输注AT7519后采集药代动力学样本，而在选定患者中获取药效学（PD）样本。
34例患者入组，32例在4个剂量水平接受了研究治疗。剂量限制性毒性包括粘膜炎、发热性中性粒细胞减少、皮疹、疲劳和低钾血症。推荐的II期剂量（RP2D）为27.0mg m(-2)。19例可评估疗效的患者中有10例病情稳定为最佳反应（中位持续时间：3.3个月；范围：2.5至11.1个月）。没有临床上显著的QTc延长。AT7519暴露量有明显的剂量比例增加。PD研究显示治疗后选定患者皮肤活检中CDK活性标志物降低。
AT7519在第1、4、8和11天静脉输注时耐受性良好。RP2D为27.0mg m(-2)。在此剂量水平下，血浆AT7519浓度高于生物活性浓度，并在患者中观察到初步抗癌活性。这种给药方案正在多项II期研究中进一步评估。
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