Phase I Clinical Trials of Anticancer Agents

描述(申请人提供)：我们将进行新型抗癌药物或抗癌药物组合的第一阶段临床试验，目的是确定药物毒性、确定最大耐受量、进行药物遗传学分析、评估药代动力学，并将临床终点与衍生的药代动力学参数、药物遗传学和/或相关生物终点联系起来。这项建议的一个主要焦点是与新靶点相互作用的研究试剂，如信号转导途径、细胞周期调节检查点、DNA修复途径和凋亡调节因子，无论是单独使用还是与标准化疗联合使用。评估这些治疗的终点将是临床疗效(毒性和抗肿瘤反应)以及临床前模型系统中受影响的生化途径的变化。这些研究的具体目的是：在符合患者安全性的情况下，尽可能有效地确定国家癌症研究所为评估随后的第二阶段试验的治疗活性而选择的适当剂量的新抗癌药物；确定可能预测毒性的临床、药代动力学或其他实验室参数；确定药物代谢的功能多态性或与药物反应相关的其他酶的功能多态性是否会改变正在研究的药物的药代动力学、毒性和/或活性；以及评估可用作药物效果替代标记物的生物终点。药物组合的研究将根据临床前数据设计，确定合适的药物体外时间表和暴露时间。将构建新型调制剂的研究，以监测和评估预期的调制。每一种新制剂都将使用标准的修改后的斐波那契剂量递增方案或适当的新的剂量递增方法进行评估。研究将纳入适当的药代动力学和药物遗传学分析、药物分析和药效学评估。将在适当的研究中对数据进行药代动力学/药效学建模。通过以这种方式进行第一阶段研究，我们将促进将新的临床前观察结果转化为可在第二阶段和第三阶段试验中评估疗效的治疗方法。

DESCRIPTION (provided by applicant): We will conduct Phase I clinical trials of new anticancer agents or combinations of anticancer agents for the purposes of characterizing drug toxicity, determining the maximum tolerated dose, performing pharmacogenetic analysis, evaluating the pharmacokinetics, and relating clinical endpoints to the derived pharmacokinetic parameters, pharmacogenetics, and/or relevant biologic endpoints. A major focus of this proposal is the study agents that interact with novel targets such as signal transduction pathways, cell cycle regulation checkpoints, DNA repair pathways and apoptosis regulators, either alone or in combination with standard chemotherapy. The endpoints for the evaluation of such treatments will be clinical effect (toxicity and antineoplastic response) as well as alterations in biochemical pathways affected in preclinical model systems. The specific aims of these studies are: to determine as efficiently as is compatible with patient safety the appropriate dose of new anticancer agents selected by the National Cancer Institute for evaluation of therapeutic activity in subsequent Phase II trials; to identify clinical, pharmacokinetic or other laboratory parameters that may predict toxicity; to determine whether functional polymorphisms of drug metabolizing or other enzymes associated with drug response alter pharmacokinetics, toxicity and/or activity of agents being studied; and to evaluate biological endpoints that may be used as surrogate markers of drug effect. Studies of drug combinations will be designed based on preclinical data identifying the appropriate schedule and exposure duration of the agents in vitro. Studies of novel modulating agents will be constructed to monitor and evaluate the intended modulation. Each new agent will be evaluated using a standard modified Fibonacci dose escalation scheme or novel dose-escalation methods as appropriate. Studies will be designed to incorporate the appropriate pharmacokinetic and pharmacogenetic analysis, drug analysis, and pharmacodynamic assessments. Pharmacokinetic/pharmacodynamic modeling of the data will be performed in those studies in which it is appropriate. By performing Phase I studies in this fashion, we will facilitate translation of novel preclinical observations into treatments that can be assessed for efficacy in Phase II and Phase III trials.