PHASE I MOLECULAR AND CLINICAL PHARMACODYNAMIC TRIALS

I 期分子和临床药效试验

• 批准号: 6350154
• 负责人: JAMES H DOROSHOW
• 金额: $ 40.67万
• 依托单位: BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-03-14 至 2003-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6350154
• 关键词: DNA damage; DNA methylation; DNA repair; DNA topoisomerases; antineoplastics; biopsy; cancer registry /resource; cell cycle; chemical kinetics; clinical research; clinical trials; cooperative study; cytotoxicity; drug adverse effect; drug screening /evaluation; gene expression; human subject; human therapy evaluation; neoplasm /cancer chemotherapy; neoplasm /cancer pharmacology; paclitaxel; pharmacokinetics; platinum; tissue resource /registry

DESCRIPTION: (Applicant's Description) The objective of this proposal is to develop new, laboratory-based chemotherapeutic treatment strategies for application in the phase I setting. These phase I studies will lead not only to the assignment of a maximum tolerated dose and to an understanding of the spectrum of normal tissue toxicity for specific antineoplastic agents that target novel molecular pathways, but will also provide a mechanistic evaluation of the effects of the agents on critical tumor cell functions. This objective will be pursued by a group of molecular pharmacologists and clinical scientists from two NCI-designated Cancer Centers and a large University Hospital who will use the extensive laboratory and patient resources of the City of Hope National Medical Center (COH), the Kenneth Norris, Jr. Comprehensive Cancer Center at the University of Southern California (USC), and the University of California, Davis Cancer Center to perform phase I molecular pharmacodynamic studies that focus on: 1) novel compounds which significantly modify patterns of DNA methylation or directly inhibit the activity of DNA methyltransferase as a unique antineoplastic activity; 2) new agents which produce critical alterations in cell cycle checkpoint control or cell cycle progression as their mechanism of action; 3) the role of antineoplastic drug concentration (rather than dose) in the efficacy and toxicity of dose-intensive chemotherapy, as well as the effects of abnormal organ function on the pharmacokinetics and pharmacodynamics of new antineoplastic agents available from the Cancer Therapy Evaluation Program of the NCI; and 4) the identification of new antineoplastic agents available from the Cancer Therapy Evaluation Program of the NCI; and 4) the identification of new molecular correlates of therapeutic activity and drug resistance, including new markers of DNA damage, repair, and methylation, for compounds with novel mechanisms of action, as well as for the taxane, platinum, antimetabolite, and topoisomerase I drug classes. Based on a significant record of patient accrual, as well as substantive clinical, biostatistical, and laboratory interactions during the past three years which have provided the rationale for a novel set of proposed phase I trials, the investigators at COH, USC, and UCD are well suited to rapidly complete pharmacologically-driven phase I trials of anticancer agents targeting critical new intracellular pathways.

描述：（申请人的描述）该提案的目标是 开发新的、基于实验室的化疗治疗策略 在第一阶段设置中的应用。 这些第一阶段研究不会导致 仅指定最大耐受剂量并了解 特定抗肿瘤药物的正常组织毒性谱 其目标是新颖的分子途径，但也将提供一种机制 评估药物对关键肿瘤细胞功能的影响。 这一目标将由一组分子药理学家和 来自两个 NCI 指定癌症中心和一个大型癌症中心的临床科学家 大学医院将使用广泛的实验室和患者 希望之城国家医疗中心 (COH)、肯尼思医院的资源 南方大学 Norris, Jr. 综合癌症中心 加利福尼亚州 (USC) 和加利福尼亚大学戴维斯分校癌症中心 进行 I 期分子药效学研究，重点关注：1) 新颖 显着改变 DNA 甲基化模式或直接 作为一种独特的抗肿瘤药物，抑制 DNA 甲基转移酶的活性 活动; 2）对细胞周期产生关键改变的新药物 检查点控制或细胞周期进程作为其作用机制； 3）抗肿瘤药物浓度（而不是剂量）在 剂量密集化疗的疗效和毒性以及效果 器官功能异常对药代动力学和药效学的影响 癌症治疗评估提供新的抗肿瘤药物 NCI 计划； 4）新抗肿瘤药物的鉴定 可从 NCI 癌症治疗评估计划获取； 4） 鉴定治疗活性和药物的新分子相关性 抗性，包括 DNA 损伤、修复和甲基化的新标记， 对于具有新颖作用机制的化合物以及紫杉烷， 铂类、抗代谢类药物和拓扑异构酶 I 类药物。 基于一个 患者累积的重要记录以及实质性临床， 过去三年的生物统计和实验室相互作用 这为提出的一组新颖的第一阶段提供了基本原理 试验中，COH、USC 和 UCD 的研究人员非常适合快速 完整的药理学驱动的抗癌药物 I 期试验 针对关键的新细胞内途径。