PHASE I TRIALS OF ANTICANCER AGENTS

这项赠款申请背后前提是，如果 了解抗肿瘤药物的药理学应该 使该制剂在临床领域得到更好的利用。 无懈可击的临床毒性和最大 一种制剂的耐受量不再足够。药理学 理想情况下将在其 初步临床试验包括：药代动力学、代谢和 分子和细胞的药效学表现，以及， 临床水平。有了这个永恒的哲学和假设，它是我们的 意在提供有希望的科学指导的第一阶段试验 抗癌药物可通过国家癌症研究所获得。这个 代理人可能来自NCI的药物筛查计划，也可能是 已从外部来源向NCI提交。在追求这一特定的 AIM，我们打算应用在我们机构中确立的原则 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 设计。此外，我们打算扩大我们的活动整合 关于进入临床试验的作用机制的信息 设计和解释药物的药效学后果 心理治疗。应用程序的具体目标是：a)定义 新型抗癌药物对晚期肺癌患者的急性毒性反应 癌症；b)重新定义药物的急性毒性和药代动力学 现有抗癌药物联合菌落给药 刺激因子和其他毒性改良剂，它们可能 促进探索更有效的剂量和时间表；c) 提供有关药理特性的信息(吸收， 分布、代谢和消除)选定的抗肿瘤药物； D)确定评价#年抗肿瘤活性的治疗方案 第二阶段试验；e)根据药理学特征，建立 特殊患者人群的适当II期剂量，如 终末器官功能受损或严重预适应，老年性 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 关于药代动力学/药效学、相关性的初步信息 然后可在第二阶段试验中扩展；g)纳入 在可能和适当的情况下，辅助基础实验室研究，以 加强我们对生物化学和/或生物化学的了解 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.