Phase I Clinical Trials of Anticancer Agents

描述（由申请人提供）：我们将进行新的抗癌药物或抗癌药物组合的I期临床试验，目的是表征药物毒性，确定最大耐受剂量，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/或相关生物学终点相关联。本提案的主要重点是研究与新靶点相互作用的药物，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，无论是单独还是与标准化疗联合使用。评估这些治疗的终点将是临床效果（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改变。这些研究的具体目的是：在符合患者安全的前提下，确定由国家癌症研究所选择的新抗癌药物的适当剂量，以便在随后的II期试验中评估治疗活性；确定可能预测毒性的临床、药代动力学或其他实验室参数；确定与药物反应相关的药物代谢酶或其他酶的功能多态性是否会改变所研究药物的药代动力学、毒性和/或活性；并评估可作为药物效果替代标记物的生物学终点。药物组合研究将根据临床前数据设计，确定药物在体外的适当时间表和暴露时间。将建立新的调制剂的研究，以监测和评估预期的调制。每个新药物将使用标准的修正斐波那契剂量递增方案或适当的新型剂量递增方法进行评估。研究将设计纳入适当的药代动力学和药物遗传分析，药物分析和药效学评估。数据的药代动力学/药效学建模将在适当的研究中进行。通过以这种方式进行I期研究，我们将促进将新的临床前观察结果转化为可以在II期和III期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.