0629GCC: A PHASE I, OPEN-LABEL, MULTI-CENTER, DOSE-ESCALATION STUDY TO ASSESS SL

0629GCC：评估 SL 的 I 期、开放标签、多中心、剂量递增研究

• 批准号: 7608176
• 负责人: EDWARD A. SAUSVILLE
• 金额: $ 0.32万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-03-01 至 2008-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7608176
• 关键词: Adenosine; Binding; Biological Assay; Biological Markers; Biopsy; Cancer cell line; Cell Cycle Arrest; Cells; Checkpoint kinase 1; Clinical; Computer Retrieval of Information on Scientific Projects Database; DNA; Data; Dose; Dose-Limiting; Doxorubicin; Drug Exposure; End Point; Enrollment; Funding; Future; G2 Phase; Gemcitabine/Irinotecan; Grant; Human; In Vitro; Institution; Label; Normal tissue morphology; Numbers; Patients; Pharmacology; Phase; Phase I Clinical Trials; Phosphotransferases; Range; Research; Research Personnel; Resources; Safety; Source; Stress; Time; Tissues; Toxic effect; United States National Institutes of Health; Week; Xenograft Model; cell growth; chemotherapeutic agent; cohort; data modeling; day; design; gemcitabine; in vivo; inhibitor/antagonist; man; neoplastic cell; novel; pre-clinical; programs; repaired; response; tripolyphosphate; tumor; tumor xenograft

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The majority of clinically effective anticancer chemotherapeutic agents achieve their pharmacologic effects by relatively non-selective deoxyribonucleic acid (DNA) damage of both tumor and normal tissue cells. The DNA damage involves single and double strand breaks as well as interference with the function of DNA replication forks (replication stress). DNA damage typically evokes cellular responses to allow cell repair. A well-described key component of repair is the activation of two checkpoint kinases (Chk1 and Chk2). AZD7762 is a potent, novel and relatively selective inhibitor of Chk1 and Chk2 kinases that binds reversibly in the Chk1 adenosine 5'-triphosphate (ATP) binding pocket and inactivates Chk1 (inhibitory constant (Ki) = 3.6 nM; <10 fold selectivity over a limited number of kinases). In combination with DNA damaging agents, the compound inhibits tumor cell growth in vitro with a mode of action that correlates with Chk1 inhibition and abrogation of the G2- and S-phase checkpoints. AZD7762 has been profiled extensively and has been shown to increase the response to multiple DNAdamaging agents (eg, gemcitabine, irinotecan and doxorubicin) in a number of different cancer cell lines. AZD7762 is active in in vivo assays where inhibition of Chk1 results in the abrogation of DNA damage-induced cell cycle arrest. A clear relationship between drug exposure and checkpoint abrogation has been established in the PD model, and this data has been used to predict an efficacious dose range in man of 11 to 30 mg/m2 although significant abrogation of the checkpoint was observed at doses as low as 6 mg/m2. AZD7762 potentiates gemcitabine and irinotecan in a number of human tumor xenograft models at well-tolerated doses. This study will be the first time AZD7762 is administered to man. Safety, PK, and biomarker data in this Phase I study will support the determination of the dose(s) of AZD7762 to be evaluated in future studies. The initial clinical program for AZD7762 is designed to provide single agent AZD7762 safety and PK data. It will also provide safety, pharmacology, and tumor PD and response data in combination with gemcitabine. Since all AEs in pre-clinical species were evident in the first week and AZD7762 is intended to be dosed once weekly with gemcitabine, in this study AZD7762 will be administered on two successive weeks as a single agent (followed by a 7- day observation period after the second dose); subsequently AZD7762 will be administered following gemcitabine. Doses of AZD7762 will escalate until dose limiting toxicity or the pharmacokinetically defined endpoint is reached. Then, an additional cohort of patients at a selected dose (MTD from the dose escalation phase or lower), will be enrolled to obtain more safety, PK, and tumor response data, as well as tumor and surrogate tissue biopsies (for PD analyses of pChk1 and pH2AX).

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这不一定是调查员的机构。 大多数临床有效的抗癌化学治疗剂通过相对非选择性的脱氧核糖核酸（DNA）损伤来实现其药理作用。 DNA损伤涉及单链和双链断裂以及干扰DNA复制叉（复制应力）的功能。 DNA损伤通常会唤起细胞反应以允许细胞修复。修复的一个很好的关键组成部分是两个检查点激酶（CHK1和CHK2）的激活。 AZD7762是CHK1和CHK2激酶的有效，新颖且相对选择性的抑制剂，在CHK1腺苷5'-三磷酸（ATP）结合口袋中可逆地结合，并使CHK1失活（抑制性常数（ki）= 3.6 Nm; <10 fold fold fold fold fold fold fold fold fold fold fold flivitivity <10倍; <<10倍; <<10倍; <<10倍; <<10倍; <<10折叠率超过了有限的kinasase）。结合DNA损伤剂，该化合物通过与CHK1抑制和废除G2-和S相检查点相关的作用方式抑制肿瘤细胞的生长。 AZD7762已被广泛介绍，并已显示可增加对多种不同癌细胞系中多种DNADAMAGEG剂（例如，吉西他滨，伊立替康和阿霉素）的反应。 AZD7762在体内分析中有效，在体内测定中，抑制CHK1导致DNA损伤诱导的细胞周期停滞的废除。在PD模型中已经建立了药物暴露与检查点废除之间的明显关系，该数据已用于预测男子11至30 mg/m2的有效剂量范围，尽管以低至6 mg/m2的剂量观察到了检查点的显着废除。 AZD7762以耐受性良好的剂量增强了许多人类肿瘤异种移植模型中的吉西他滨和伊立替康。这项研究将是第一次对人进行AZD7762。在本I阶段研究中的安全性，PK和生物标志物数据将支持确定在未来研究中评估的AZD7762剂量。 AZD7762的初始临床计划旨在提供单位AGD AGD7762安全性和PK数据。它还将提供安全性，药理学和肿瘤PD以及与吉西他滨联合响应数据。由于在第一周，临床前物种中的所有AE都显而易见，并且AZD7762旨在每周用吉西他滨给药一次，因此在这项研究中，AZD7762将连续两周连续两周作为单个药物（随后是第二次剂量后的7天观察期）；随后，AZD7762将在吉西他滨之后进行管理。 AZD7762的剂量将升级，直到达到剂量限制毒性或达到药理定义的终点为止。然后，将在选定剂量（剂量升级阶段或较低的MTD）下进行额外的患者队列，以获得更多的安全性，PK和肿瘤反应数据，以及肿瘤和替代组织活检（用于PCHK1和PH2AX的PD分析）。