NCI Experimental Therapeutics-Clinical Trials Network with Phase 1 Emphasis

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，以表征药物毒性，确定最大耐受剂量，评估药代动力学，进行药物遗传分析，并将临床终点与药代动力学，药物遗传学和/或生物学终点联系起来。本提案的一个主要焦点是研究与新靶点相互作用的药物，如信号转导途径、细胞周期检查点成分、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：国家癌症研究所采用新的试验设计，包括加速滴定、贝叶斯设计和其他先进的设计方案，在与患者安全兼容的情况下，有效地确定新的抗癌药物的适当剂量；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；在适当的时候获得针对新的分子癌症靶点的新药物的机理证明数据；评估研究性药物临床试验中的转译终点，例如与被研究药物调节的给定药物或途径相关的分子靶标和/或下游效应物的表达水平和/或活性；识别潜在的生物标志物（在可能的情况下特别强调基因组学和成像），这些标志物可能作为后期试验结果的预测因子；将来自rol， SPORE或其他同行评审机制的新发现转化为临床试验，利用科学界的专业知识和团队科学方法。研究将包括适当的药代动力学和药物遗传学分析、药物分析和药物对预期靶点或途径的生物学分析。

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.