Phase I Molecular and Clincal Pharmacodynamic Trials

描述（由申请人提供）：本次申请的主要目标是由来自加州癌症联盟（CCC）的分子和临床药理学家、分子生物学家和临床科学家组成，该联盟由三个nci指定的癌症中心组成，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。这些I期研究不仅将导致推荐的、生物有效的II期剂量的分配，并了解针对新分子途径的特定抗肿瘤药物的正常组织毒性谱，而且还将提供药物对关键肿瘤细胞靶点作用的机制验证，将肿瘤和宿主生物标志物的药物相关改变与临床结果联系起来。并在实验室和临床中对I期化合物的治疗作用机制产生新的见解。使用的研究方法基于希望之城综合癌症中心（COM）、南加州大学(USC)/诺里斯综合癌症中心和加州大学的特定科学和临床研究专业知识；戴维斯癌症中心（UCD）即将进行的I期试验将得到大量患者资源（每年超过10,000名新癌症患者）的支持，I期和ll-ll期癌症临床试验的良好累积记录（2006年总共有超过1250名患者加入），以及三家机构之间富有成效的临床研究互动历史（超过2000名患者进入联合I期和II期研究）。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等领域的综合专业知识，开展由CTEP和NCI支持的创新的、实验室指导的I期开发和药代动力学研究，重点关注：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)在血液系统恶性肿瘤中具有潜在活性的药物；4)通过CCC调查员发起的RAID项目开发的代理人；此外，5)在特殊的患者群体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遗传差异而改变；6)为进入CCC I期临床试验的患者确定生物活性和耐药的新的和信息丰富的实验室相关性，并探索肿瘤反应、进展和临床获益的新功能终点。

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.