Phase I Molecular and Clincal Pharmacodynamic Trials

描述（由申请人提供）：本申请的主要目标是由来自加州癌症联盟（CCC）的一组分子和临床药理学家、分子生物学家和临床科学家（由三个NCI指定的癌症中心组成）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（COM）、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）提供的特定领域的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10，000名新癌症患者），I期和II-III期癌症临床试验的强劲记录（2006年共有1250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（超过2000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，进行创新的，实验室指导的I期开发和药代动力学研究，由CTEP，NCI支持，重点是：1）靶向癌细胞遗传或表观遗传异常的药物; 2）靶向信号转导途径、细胞周期和宿主/肿瘤相互作用的药物; 3）在恶性血液病中具有潜在活性的药物; 4）通过CCC制药商发起的RAID项目开发的药物;另外，第五章）在特殊患者人群中检查靶向抗癌药物的临床药理学，这些药物的治疗效果可能因器官功能异常或控制药物处置和活性的基因的遗传差异;和6）鉴定生物活性和耐药性的新的和信息性实验室相关性，并探索进入CCC的I期临床试验的患者的肿瘤应答、进展和临床益处的新的功能终点。

DESCRIPTION (provided by applicant): The principal goal of this application by a group of molecular and clinical pharmacologists, molecular biologists, and clinical scientists from the California Cancer Consortium (CCC) comprised of three NCI-designated Cancer Centers 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 (COM), 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 10,000 new cancer patients per year), a strong record of accrual to Phase I and Phase ll-lll cancer clinical trials (over 1250 total patient accessions in 2006), and a history of productive clinical research interactions among the three institutions (over 2000 patients entered on joint Phase I and II studies). 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 genetic or epigenetic abnormalities in cancer cells; 2) agents that target signal transduction pathways, the cell cycle, and host/tumor interactions; 3) agents that are potentially active in hematologic malignancies; 4) agents developed through CCC investigator-initiated RAID projects; and additionally, 5) to examine in special patient populations the clinical pharmacology of targeted anticancer agents whose therapeutic effects may be altered because of abnormal organ function or because of inherited differences in genes controlling drug disposition and activity; and 6) to identify new and informative laboratory correlates of biologic activity and drug resistance and explore novel functional endpoints of tumor response, progression, and clinical benefit for patients entered on the Phase I clinical trials of the CCC.