Phase I Molecular and Clinical Pharmacodynamic Trials

描述（由申请人提供）：该提案的主要目标是由一组分子和临床药理学家、分子生物学家和临床科学家组成的联盟，该联盟由两个NCI指定的综合癌症中心和一家大型大学医院组成，旨在开发新的基于实验室的癌症治疗策略，用于早期治疗试验环境。这些I期研究将不仅导致分配推荐的、生物学有效的II期剂量，并且导致理解针对新分子途径的特定抗肿瘤剂的正常组织毒性谱，而且还将提供该药剂对关键肿瘤细胞靶点的作用的机制验证，将肿瘤和宿主生物标志物的药物相关改变与临床结果相关联，并在实验室和临床中对I期化合物的治疗作用机制提出新的见解。使用的研究方法基于City of Hope综合癌症中心（COH）、南加州大学（USC）/诺里斯综合癌症中心和加州大学戴维斯癌症中心（UCD）的特定科学和临床研究专业知识。I期试验将得到大量患者资源的支持（每年超过7000名新癌症患者），I期和试点/I-II期癌症临床试验的良好记录（2001年共有320多名患者登记），以及三个机构之间富有成效的临床研究互动的历史（在过去七年中，超过1500名患者参加了I期和II期联合研究）。我们建议利用COH，USC和UCD在分子药理学，药代动力学，药效学，药物基因组学，信号转导，细胞周期调控，非侵入性成像和生物信息学领域的综合专业知识进行创新，实验室指导的I期开发和药代动力学研究，由CTEP支持，NCI重点关注：1）靶向癌细胞中的特定遗传或表观遗传异常作为其独特的抑制作用或毒性机制的药剂;（二）在特殊患者人群中检查靶向癌症治疗药物的临床药理学，这些药物的处置可能会改变因为异常的器官功能或性能状态，或因为影响抗癌药物作用或毒性的遗传多态性; 3）肿瘤反应，进展或临床获益的新功能终点的验证;和4）可以应用于COH-USC-UCD联盟的早期治疗试验的治疗活性或耐药性的新的和信息性实验室相关性的鉴定。

DESCRIPTION (provided by applicant): The principal goal of this proposal by a group of molecular and clinical pharmacologists, molecular biologists, and clinical scientists from a consortium comprised of two NCI-designated Comprehensive Cancer Centers and a large University Hospital is to develop new, laboratory-based cancer treatment strategies for application in the early therapeutic trial setting. These Phase I studies will lead not only to the assignment of a recommended, biologically effective Phase II dose, and to an understanding of the spectrum of normal tissue toxicity for specific antineoplastic agents that are directed against novel molecular pathways, but will also provide a mechanistic validation of the effects of the agents on critical tumor cell targets, correlate drug-related alterations of tumor and host biologic markers with clinical outcome, and develop new insights into the therapeutic mechanism of action of Phase I compounds both in the laboratory and the clinic. The investigational methodologies to be used are based on specific areas of scientific and clinical research expertise available at the City of Hope Comprehensive Cancer Center (COH), the University of Southern California (USC)/Norris Comprehensive Cancer Center, and the University of California, Davis Cancer Center (UCD). The Phase I trials to be pursued will be supported by the availability of a large patient resource (in excess of 7000 new cancer patients per year), a strong record of accrual to Phase I and Pilot/Phase I-II cancer clinical trials (over 320 total patient accessions in 2001), and a history of productive clinical research interactions among the three institutions (over 1500 patients entered on joint Phase I and II studies over the past seven years). We propose to utilize the combined expertise of COH, USC, and UCD in the areas of molecular pharmacology, pharmacokinetics, pharmacodynamics, pharmacogenomics, signal transduction, cell cycle regulation, non-invasive imaging, and bioinformatics to conduct innovative, laboratory-directed Phase I developmental and pharmacokinetic studies supported by CTEP, NCI that focus on: 1) agents that target specific genetic or epigenetic abnormalities in cancer cells as their unique antineoplastic mechanism of action or toxicity; 2) the examination in special patient populations of the clinical pharmacology of targeted cancer therapeutic agents whose disposition may be altered because of abnormal organ function or performance status, or because of genetic polymorphisms that affect anticancer drug action or toxicity; 3) the validation of novel functional endpoints of tumor response, progression or clinical benefit; and 4) the identification of new and informative laboratory correlates of therapeutic activity or resistance that can be applied in the early therapeutic trials of the COH-USC-UCD Consortium.