First-in-human第一阶段安全、PK和PD G1T28 CDK4/6抑制剂的研究。

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Tiessen RG,罗伯茨PJ, Sorrentino JA,白色HS, Makhuli公里,建筑师,我弹奏JC, van Hoogdalem E,马利克家乡

First-in-human第一阶段安全、PK和PD G1T28 CDK4/6抑制剂的研究。

临床肿瘤学杂志。2015年5月20日,33 (15):2527 - 2527。

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背景:G1T28是高度有效的和选择性CDK4/6抑制剂被开发成一个四剂有针对性的骨髓保护以免和口服抗肿瘤药。CDK4/6通路在调节细胞增殖的肿瘤是至关重要的。此外,造血干细胞和祖细胞(公司)是依赖于CDK4/6扩散。瞬态G1T28-induced G1细胞周期阻滞的公司呈现他们抵抗化疗的毒性效应。因此,G1T28可以用于保护以免(减少化疗所致myelosuppression) CDK4/6-independent患者肿瘤,或作为一种抗肿瘤药CDK4/6-dependent肿瘤患者。方法:本研究的目的是评估G1T28的安全性和耐受性,以及描述PK和PD (NCT02243150)。第1部分是一个双盲、安慰剂对照、单剂量升级研究两性健康的志愿者,在受试者随机(3:1)接收G1T28或安慰剂作为一个30分钟静脉输液。在第2部分中,8个主题将收到单三个剂量口服剂量的G1T28升级时间。PD评估包括评估体外刺激淋巴细胞和骨髓细胞周期分析。结果:45调查对象参加了实验。 In Part 1, G1T28 was administered at doses of 6, 12, 24, 48, 96 and 192 mg/m2. G1T28 was well tolerated, with no dose limiting toxicities or serious adverse events reported. In Part 1, G1T28 exposure (Cmax and AUC) increased proportionally with dose, while clearance was relatively constant. G1T28 at 96 and 192 mg/m2 demonstrated a robust pharmacodynamic effect with a dose-dependent decrease in phytohemagglutinin (PHA)-stimulated lymphocyte proliferation ex vivo. Conclusions: G1T28, a novel CDK4/6 inhibitor, is well tolerated and demonstrates predictable PK and robust PD activity. Based on these results, IV G1T28 will be investigated in Phase 1b/2a studies in patients with CDK4/6-independent tumors to evaluate its potential as a targeted bone marrow chemoprotectant. In addition, the oral formulation will be assessed as an antineoplastic agent in patients with CDK4/6-dependent tumors. Clinical trial information: NCT02243150.

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Trilaciclib