PHASE I TRIALS OF ANTICANCER AGENTS

这项拨款申请背后的前提是，如果该特性和 了解一种抗抑郁剂的药理学， 允许在临床竞技场中更好地利用该试剂。 临床毒性和最大 药剂的耐受剂量不再足够。 药理学 理想情况下将在其开发的代理的特性 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。 有了这个永恒的哲学和假设，这是我们的 目的是提供科学指导的I期试验， 国家癌症研究所提供的抗癌药物。 的 药物可能来自NCI的药物筛选计划，也可能来自 从外部来源提到了国家癌症研究所 在追求这个具体的 为了达到这个目的，我们打算应用我们机构确立的原则， 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 的设计. 此外，我们打算扩大我们的活动， 关于临床试验作用机制的信息 药物的药效学结果的设计和解释 疗法 应用程序的具体目标是：a）定义 新抗癌药物对晚期乳腺癌患者的急性毒性 癌症; B）重新定义急性毒性和药代动力学 现有的抗癌剂与集落联合给药 刺激因子和其它毒性改善剂，其可 促进探索更有效的剂量和时间表; c） 提供药理学特征（吸收， 分布、代谢和消除）; d）确定治疗方案，以评估在以下情况下的抗肿瘤活性： II期试验; e）基于药理学特征，建立 在特殊患者人群中使用适当的II期剂量，例如 终末器官功能受损或预处理严重，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II期试验中扩展; g）将 在可能和适当的情况下，进行辅助基础实验室研究， 提高我们对生物化学和/或生物学的理解， 药物作用机制。

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.