PHASE I TRIALS OF ANTICANCER AGENTS

抗癌药物的 I 期试验

• 批准号: 2466227
• 负责人: DAVID A VAN ECHO
• 金额: $ 37.07万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-05-15 至 2001-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2466227
• 关键词: acute leukemia; angiogenesis inhibitors; antineoplastics; apoptosis; butyrates; carboplatin; cell differentiation; clinical research; clinical trial phase I; colony stimulating factor; combination cancer therapy; cytotoxicity; drug administration rate /duration; drug metabolism; drug screening /evaluation; flow cytometry; gender difference; human subject; human therapy evaluation; neoplasm /cancer chemotherapy; neoplasm /cancer pharmacology; pharmacokinetics; prodrugs; racial /ethnic difference; retinoids

The premise behind this grant application if that characterization and understanding of the pharmacology of an antineoplastic agent should allow better utilization of that agent in the clinical arena. Impeccable characterization of the clinical toxicities and maximum tolerated dose of an agent is no longer sufficient. Pharmacologic characteristics of an agent that ideally would be developed in its initial clinical trials include: pharmacokinetics, metabolism and pharmacodynamic manifestations on molecular and cellular, as well as, clinical levels. With this abiding philosophy and hypothesis, it is our intent to provide scientifically directed Phase I trials of promising anti-cancer agents available through the National Cancer Institute. The agents may come from the NCI's drug screening program, or may be referred to the NCI from outside sources. In pursuit of this specific aim, we intend to apply principles well established at our institution regarding integration of drug metabolism, pharmacokinetics, and pharmacokinetic/pharmacodynamic relationships into clinical trial designs. Furthermore, we intend to extend our activities integrating information regarding the mechanism of action into clinical trial design, and interpretation of the pharmaco-dynamic consequences of drug therapy. The specific goals of the application are: a) To define the acute toxicities of new anticancer agents in patients with advanced cancer; b) to re-define the acute toxicities and pharmacokinetics of existing anticancer agents administered in combination with colony stimulating factors and other toxicity-ameliorating agents, which may facilitate the exploration of more effective doses and schedules; c) to provide information on the pharmacologic characteristics (absorption, distribution, metabolism, and elimination) of selected antitumor agents; d) to define treatment regimens for evaluation of antitumor activity in Phase II trials; e) based on pharmacologic characteristics, to establish appropriate Phase II doses in special patient populations, such as those with impaired end-organ function or with heavy pretreatment, geriatric populations, and to explore pharmacokinetic and pharmacodynamic differences based on gender, race or ethnic group; f) to obtain preliminary information on pharmacokinetic/pharmacodynamic, correlations which can then be extended in Phase II trials; g) to incorporate ancillary basic laboratory studies, when possible and appropriate, to enhance our understanding of the biochemical and/or biological mechanisms of drug actions.

本拨款申请背后的前提是，如果该特征和 了解抗肿瘤药的药理学应 允许在临床领域更好地利用该药物。 临床毒性和最大毒性的无可挑剔的表征 药物的耐受剂量不再足够。 药理作用 理想情况下将在其自身中开发的代理的特征 初步临床试验包括：药代动力学、代谢和 分子和细胞上的药效学表现，以及， 临床水平。 有了这种持久的哲学和假设，我们的 旨在提供有希望的科学指导的第一阶段试验 国家癌症研究所提供抗癌药物。 这 药物可能来自 NCI 的药物筛选计划，也可能是 从外部来源参考 NCI。 为了追求这个特定的 目标，我们打算应用我们机构既定的原则 关于药物代谢、药代动力学和 临床试验中的药代动力学/药效学关系 设计。 此外，我们打算扩展我们的活动，整合 有关临床试验作用机制的信息 药物药效学结果的设计和解释 治疗。 该应用程序的具体目标是： a) 定义 新型抗癌药物对晚期癌症患者的急性毒性 癌症; b) 重新定义急性毒性和药代动力学 与菌落联合施用的现有抗癌剂 刺激因子和其他毒性改善剂，可能 促进探索更有效的剂量和时间表； c) 到 提供有关药理学特征的信息（吸收、 选定的抗肿瘤药物的分布、代谢和消除； d) 定义用于评估抗肿瘤活性的治疗方案 二期试验； e) 根据药理学特征，建立 特殊患者群体的适当 II 期剂量，例如 终末器官功能受损或经过大量预处理、老年 人群，并探索药代动力学和药效学 基于性别、种族或族裔群体的差异； f) 获得 药代动力学/药效学、相关性的初步信息 然后可以在第二阶段试验中进行扩展； g) 合并 在可能和适当的情况下进行辅助基础实验室研究，以 增强我们对生化和/或生物的理解 药物作用机制。