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).

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 大多数临床有效的抗癌化疗药物是通过对肿瘤和正常组织细胞的相对非选择性脱氧核糖核酸(DNA)损伤来实现其药理作用的。DNA损伤包括单链和双链断裂以及对DNA复制叉功能的干扰(复制应激)。DNA损伤通常会引起细胞反应，使细胞得以修复。修复的一个重要组成部分是激活两个检查点激酶(Chk1和Chk2)。AZD7762是一种有效的、新颖的和相对选择性的Chk1和Chk2激酶的抑制剂，它可逆地结合在Chk1的5‘-三磷酸腺苷(ATP)结合口袋中，并使Chk1失活(抑制常数(Ki)=3.6 nM；&lt；10倍于有限数量的激酶的选择性)。与DNA损伤剂结合，该化合物在体外抑制肿瘤细胞的生长，其作用模式与抑制和消除G2和S阶段的检查点相关。AZD7762已被广泛分析，并已被证明在许多不同的癌细胞系中增加了对多种DNA给药药物(如吉西他滨、伊立替康和阿霉素)的反应。AZD7762在体内试验中是有效的，在体内试验中，抑制Chk1导致消除DNA损伤诱导的细胞周期停滞。在帕金森病模型中，药物暴露和检查站的取消之间已经建立了明确的关系，该数据已被用来预测人的有效剂量范围为11至30 mg/m2，尽管在低至6 mg/m2的剂量下观察到检查站的显著减少。AZD7762在一些人类肿瘤异种移植模型中以良好的耐受量增强吉西他滨和伊立替康。这项研究将是AZD7762首次用于人类。这项I期研究中的安全性、PK和生物标志物数据将支持AZD7762剂量(S)的确定，以在未来的研究中进行评估。AZD7762的初始临床计划旨在提供单药AZD7762的安全性和PK数据。它还将结合吉西他滨提供安全性、药理学和肿瘤PD和反应数据。由于所有临床前药物的不良反应在第一周都很明显，而且AZD7762打算每周服用一次吉西他滨，在这项研究中，AZD7762将作为单一药物连续两周服用(第二次服药后7天观察期)；随后将在吉西他滨之后服用AZD7762。AZD7762的剂量将不断增加，直到达到剂量限制毒性或药代动力学定义的终点。然后，另一组选择剂量的患者(剂量升级阶段或更低的MTD)将被招募，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)。