Phase I Molecular and Clincal Pharmacodynamic Trials

描述(由申请人提供)：由三个NCI指定的癌症中心组成的加州癌症联盟(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的小组提出这项申请的主要目标是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期研究不仅将导致分配推荐的生物有效的II期剂量，并了解针对新的分子途径的特定抗肿瘤药物的正常组织毒性谱，而且还将提供对这些药物对关键肿瘤细胞靶点的影响的机械验证，将与药物相关的肿瘤和宿主生物标记物的变化与临床结果相关联，并在实验室和临床对I期化合物的治疗作用机制发展新的见解。将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戴维斯癌症中心(UCD)现有的特定领域的科学和临床研究专业知识。将进行的第一阶段试验将得到以下支持：可获得大量的患者资源(每年超过10,000名新癌症患者)，第一阶段和11阶段癌症临床试验的良好记录(2006年超过1250名患者入选)，以及三家机构之间富有成效的临床研究互动历史(超过2000名患者进入第一阶段和第二阶段联合研究)。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、细胞周期调节、非侵入性成像和生物信息学等领域的综合专业知识，进行由CTEP、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，重点放在：1)针对癌细胞遗传或表观遗传异常的药物；2)针对信号转导途径、细胞周期和宿主/肿瘤相互作用的药物；3)对血液系统恶性肿瘤具有潜在活性的药物；4)通过研究人员发起的RAID项目开发的CCC药物；此外，5)在特殊患者群体中检查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的目标抗癌药物的临床药理学；以及6)确定生物活性和耐药性的新的和信息丰富的实验室相关性，并为进入CCC第一阶段临床试验的患者探索肿瘤反应、进展和临床受益的新功能终点。

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.