Drug Development Unit, Royal Marsden NHS Foundation Trust, Surrey, London.
Northern Centre for Cancer Treatment, Newcastle upon Tyne.
Ann Oncol. 2012 May;23(5):1307-1313. doi: 10.1093/annonc/mdr451. Epub 2011 Oct 19.
AT9283 is an inhibitor of aurora kinases A and B with antitumor activity in preclinical models. This a First in Human phase I study assessed the safety, tolerability, pharmacokinetic and pharmacodynamic properties and preliminary efficacy of AT9283.
Patients with advanced tumors received AT9283 as a continuous central venous infusion over 3 days in cohorts of three to six patients starting at 1.5 mg/m(2)/day (equivalent to 4.5 mg/m(2)/72 h). The oral bioavailability of AT9283 was assessed in a cohort of seven patients. Pharmacodynamic analysis of biomarkers included phosphorylation of histone H3 on serine 10, proliferating cell nuclear antigen, Ki67, M30 and M65 in skin and plasma.
Forty patients were included in all analyses. AT9283 was generally well tolerated with main toxic effects of reversible dose-related myelosuppression, gastrointestinal disturbance, fatigue and alopecia. The dose-limiting toxicity of AT9283 was grade 3 febrile neutropenia in two patients at 36 mg/m(2)/72 h and the maximum tolerated dose (MTD) was established at 27 mg/m(2)/72 h. Systemic exposure was dose proportional. The mean oral bioavailability of a 0.9 mg/m(2) dose was 29.4% (range 11.2%-36.7%). Pharmacodynamic analyses indicated antiproliferative and apoptotic activity of AT9283. Four patients with esophageal, non-small-cell lung cancer (n = 2) and colorectal cancer demonstrated RECIST stable disease ≥ 6 months.
AT9283 was well tolerated up to the MTD of 27 mg/m(2)/72 h. AT9283 is currently assessed in phase II trials.
AT9283 是一种 Aurora 激酶 A 和 B 的抑制剂，在临床前模型中具有抗肿瘤活性。这是一项首次人体 I 期研究，评估了 AT9283 的安全性、耐受性、药代动力学和药效学特性以及初步疗效。
患有晚期肿瘤的患者接受 AT9283 连续 3 天静脉输注，每 3 至 6 名患者为一组，起始剂量为 1.5 mg/m²/天（相当于 4.5 mg/m²/72 h）。在一组 7 名患者中评估了 AT9283 的口服生物利用度。生物标志物的药效学分析包括组蛋白 H3 丝氨酸 10 的磷酸化、增殖细胞核抗原、Ki67、皮肤和血浆中的 M30 和 M65。
所有分析均纳入 40 名患者。AT9283 通常耐受性良好，主要毒性作用为可逆剂量相关的骨髓抑制、胃肠道紊乱、疲劳和脱发。AT9283 的剂量限制性毒性为 2 名患者在 36 mg/m²/72 h 时出现 3 级发热性中性粒细胞减少症，最大耐受剂量（MTD）确定为 27 mg/m²/72 h。全身暴露与剂量成正比。0.9 mg/m²剂量的平均口服生物利用度为 29.4%（范围为 11.2%-36.7%）。药效学分析表明 AT9283 具有抗增殖和凋亡活性。4 名患有食管癌、非小细胞肺癌（n=2）和结直肠癌的患者，RECIST 稳定疾病持续时间≥6 个月。
AT9283 耐受良好，最大耐受剂量为 27 mg/m²/72 h。AT9283 目前正在进行 II 期临床试验。
