在具有基因组缺陷和高度炎症的肿瘤中，ceralasertib 对 ATR 抑制产生持久反应。
Durable responses to ATR inhibition with ceralasertib in tumors with genomic defects and high inflammation.
发表日期：2023 Nov 07
作者：
Magnus T Dillon, Jeane Guevara, Kabir Mohammed, Emmanuel Christian Patin, Simon A Smith, Emma Dean, Gemma N Jones, Sophie E Willis, Marcella Petrone, Carlos Silva, Khin Thway, Catey Bunce, Ioannis Roxanis, Pablo Nenclares, Anna Wilkins, Martin McLaughlin, Adoracion Jayme-Laiche, Sarah Benafif, Georgios Nintos, Vineet Kwatra, Lorna Grove, David C Mansfield, Paula Proszek, Philip Martin, Luiza Moore, Karen E Swales, Udai Banerji, Mark P Saunders, James Spicer, Martin D Forster, Kevin J Harrington
来源：
CLINICAL PHARMACOLOGY & THERAPEUTICS
摘要：
PATRIOT 是口服 ATR（共济失调毛细血管扩张和 Rad3 相关）抑制剂 ceralasertib (AZD6738) 在晚期实体瘤中的首个人体 I 期研究。主要目标是安全性。次要目标包括抗肿瘤反应评估、药代动力学 (PK) 和药效学 (PD) 研究。 67 名患者连续或间歇性接受 ceralasertib 20-240 mg BD（28 天周期中的 14 例）。间歇给药比连续给药具有更好的耐受性，这与剂量限制性血液学毒性有关。 ceralasertib 的推荐 2 期剂量为 160 mg，每日两次，持续 2 周，每 4 周为一个周期。在肿瘤和替代 PD 中发现了靶点调节和 DNA 损伤增加。有 5 例 (8%) 确诊部分缓解 (PR，40-240 mg BD)，34 例 (52%) 疾病稳定 (SD)，包括 1 例未经证实的部分缓解，以及 27 例 (41%) 疾病进展。在富含 AT 的相互作用结构域蛋白 1A (ARID1A) 丢失和 DNA 损伤反应缺陷的肿瘤中观察到持久反应。治疗调节肿瘤和全身免疫标记物，有反应的肿瘤比无反应的肿瘤更容易出现免疫炎症。Ceralasertib 单一疗法在间歇性 160 mg BD 时具有耐受性，并且与抗肿瘤活性相关。gov：NCT02223923，EudraCT：2013-003994-84。癌症英国研究中心、阿斯利康、英国卫生部（国家健康研究所）、Rosetrees Trust、实验癌症医学中心。阿斯利康为 PATRIOT 的临床实施以及药物供应和标签的组成部分提供资金。
PATRIOT was the first-in-human phase I study of the oral ATR (ataxia telangiectasia and Rad3-related) inhibitor ceralasertib (AZD6738) in advanced solid tumors.Primary objective was safety. Secondary objectives included assessment of anti-tumor responses, pharmacokinetic (PK) and pharmacodynamic (PD) studies. Sixty-seven patients received ceralasertib 20-240 mg BD continuously or intermittently (14 of a 28-day cycle).Intermittent dosing was better tolerated than continuous, which was associated with dose-limiting hematological toxicity. The recommended phase 2 dose of ceralasertib was 160 mg twice daily for 2 weeks in a 4-weekly cycle. Modulation of target and increased DNA damage were identified in tumor and surrogate PD. There were 5 (8%) confirmed partial responses (PR, 40-240 mg BD), 34 (52%) stable disease (SD) including 1 unconfirmed partial response, and 27 (41%) progressive disease. Durable responses were seen in tumors with loss of AT-rich interactive domain-containing protein 1A (ARID1A) and DNA damage response defects. Treatment modulated tumor and systemic immune markers and responding tumors were more immune-inflamed than non-responding.Ceralasertib monotherapy was tolerated at 160 mg BD intermittent and associated with anti-tumor activity.gov: NCT02223923, EudraCT: 2013-003994-84.Cancer Research UK, AstraZeneca, UK Department of Health (National Institute for Health Research), Rosetrees Trust, Experimental Cancer Medicine Centre.AstraZeneca provided funding for components of the clinical conduct of PATRIOT and drug supply and labelling.