NCI Experimental Therapeutics-Clinical Trials Network with Phase 1 Emphasis

NCI 实验治疗-临床试验网络，重点为 1 期

• 批准号: 9086290
• 负责人: ALEX A. ADJEI
• 金额: $ 71.82万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-07 至 2020-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9086290
• 关键词: Affect; Aftercare; Antineoplastic Agents; Apoptosis; Apoptosis Regulation Gene; Biochemical; Biochemical Pathway; Biological; Biological Markers; Biological Models; Biopsy; CLIA certified; Cancer Center; Cell Cycle Checkpoint; Cell Survival; Clinical; Clinical Trials; Clinical Trials Network; Communities; DNA Repair Pathway; Data; Dose; Drug Combinations; Drug Kinetics; Drug Targeting; Drug toxicity; Eastern Cooperative Oncology Group; Eligibility Determination; Environment; Enzymes; Evaluation; Functional disorder; Funding; Genetic Polymorphism; Genomics; Grant; Hand; Image; Imaging Techniques; Immune system; Immunotherapeutic agent; In Vitro; Investigational Therapies; Laboratories; Malignant Neoplasms; Maryland; Maximum Tolerated Dose; Mayo Clinic Cancer Center; Measures; Molecular; Molecular Target; Monitor; National Cancer Institute; New Agents; North Central Cancer Treatment Group; Organ; Pathway interactions; Patients; Peer Review; Pharmaceutical Preparations; Pharmacogenetics; Phase; Phase I Clinical Trials; Phase II/III Trial; Population; Population Heterogeneity; Pre-Clinical Model; Regimen; Regulation; Resources; Schedule; Scheme; Science; Scientist; Signal Transduction Pathway; Testing; Therapeutic Clinical Trial; Therapeutic Effect; Therapeutic Intervention; Titrations; Toxic effect; Translating; Translations; Universities; angiogenesis; antitumor effect; base; chemotherapy; clinical effect; design; genomic biomarker; instrument; named group; novel; novel anticancer drug; outcome prediction; patient safety; pharmacodynamic model; phase 1 study; phase II trial; potential biomarker; pre-clinical; programs; response; targeted agent; therapeutic evaluation; trial design; tumor

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.

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，以确定药物毒性，确定最大耐受量，评估药代动力学，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、细胞周期检查点组件、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：使用包括加速滴定、贝叶斯设计和其他先进设计方案在内的新试验设计，以与患者安全相容的方式有效地确定国家癌症研究所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；在适当的情况下，获得针对新的分子癌症靶点的新药物的机械原理证明数据；评估临床试验和研究制剂的翻译终点，例如与研究中制剂调节的特定制剂或途径相关的分子靶标和/或下游效应物的表达和/或活性的水平；确定可能作为后期试验结果预测因子的潜在生物标志物(可能时特别强调基因组和成像)；将R01、孢子或其他同行评审机制的新发现转化为利用科学界专业知识的临床试验。研究的设计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影响分析。 相关性：梅奥诊所癌症中心和马里兰大学Greenebaum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。将把重点放在第一阶段试验上的两个中心的团队环境和专业知识将促进将新的临床前发现转化为可以在第二阶段和第三阶段试验中评估疗效的治疗方法。