NCI Experimental Therapeutics-Clinical Trials Network with Phase 1 Emphasis

描述（由申请人提供）：我们将进行新型抗癌药或抗癌药联合用药的I期临床试验，以表征药物毒性，确定最大耐受剂量，评价药代动力学，进行药物遗传学分析，并将临床终点与药代动力学、药物遗传学和/或生物学终点相关联。该提案的一个主要重点是与新靶点相互作用的研究药物，如信号转导途径、细胞周期检查点组分、DNA修复途径和凋亡调节剂，无论是单独使用还是与标准化疗联合使用。评价此类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：确定美国国家癌症研究所使用新的试验设计（包括加速滴定、贝叶斯设计和其他先进设计方案）选择的新抗癌药物的适当剂量，以确保患者安全;确定可能预测毒性的临床、药代动力学或其他实验室参数;确定药物代谢或与药物反应相关的其他酶的功能多态性是否改变所研究的药物的药代动力学、毒性和/或活性;在适当时获得针对新分子癌症靶点的新药物的机理原理验证数据;评价临床试验中研究药物的转化终点，例如与给定药物或受研究药物调节的途径相关的分子靶标和/或下游效应物的表达和/或活性水平;鉴定潜在的生物标志物（在可能的情况下特别强调基因组学和成像），可作为后期试验结果的预测因子;将来自R 01、SPORE或其他同行评审机制的新发现转化为临床试验，这些临床试验以团队科学方法利用科学界的专业知识。研究设计将纳入适当的药代动力学和药物遗传学分析、药物分析以及药物对预期靶点或途径影响的生物学分析。 相关性：马约诊所癌症中心和马里兰州大学格林鲍姆癌症中心为在不同人群中进行早期试验提供了一个特殊的环境。将专注于1期试验的2家中心的团队环境和专业知识将有助于将新的临床前发现转化为治疗方法，从而可以在II期和III期试验中评估疗效。

DESCRIPTION (provided by applicant): We will conduct Phase I clinical trials of new anticancer agents or combinations of anticancer agents to characterize drug toxicity, determine the maximum tolerated dose, evaluate the pharmacokinetics, perform pharmacogenetic analysis, and relating clinical endpoints to pharmacokinetics, pharmacogenetics, and/or biologic endpoints. A major focus of this proposal is the study agents that interact with novel targets such as signal transduction pathways, cell cycle checkpoint components, 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 antineoplasti 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 compatible with patient safety the appropriate dose of new anticancer agents selected by the National Cancer Institute using novel trial designs including accelerated titration, Bayesian design, and other advanced design schemes; 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; to obtain mechanistic proof-of-principle data for new agents directed at novel molecular cancer targets when appropriate; to evaluate translational endpoints in clinical trials o investigational agents such as, levels of expression and/or activity of molecular targets and/or downstream effectors pertinent to a given agent or pathway modulated by the agent under study; to identify potential biomarkers (with particular emphasis where possible on genomics and imaging) that may serve as predictors of outcome in later phase trials; to translate novel discoveries from R0l, SPORE, or other peer reviewed mechanisms into clinical trials that leverage the scientific community expertise with a team science approach. Studies will be designed to incorporate the appropriate pharmacokinetic and pharmacogenetic analysis, drug analysis, and biological analysis of drug effects on the intended target or pathway. RELEVANCE: The Mayo Clinic Cancer Center and University of Maryland Greenebaum Cancer Center provides an exceptional environment to perform early phase trials in a diverse population. The team environment and expertise of the 2 centers that will be brought to focus on phase 1 trials will facilitate translation of novel preclinical discoveries into treatments that ca be assessed for efficacy in Phase II and Phase III trials.