Phase I Trials of Anticancer Agents

描述（由申请人提供）：该提案是对RFA CA-02-011题为“新型抗癌药物的早期临床试验与I期重点”的回应，将在nci指定的科罗拉多大学综合癌症中心进行。肿瘤学的药物开发正在迅速变化。随着实验室研究继续阐明导致恶性表型的机制，抗癌治疗的靶点出现了。过去，主要关注的是直接干扰细胞复制机制的药物，而目前的重点是针对异常生物途径的药物。尽管如此，不管具体的靶点是什么，肿瘤的I期试验对新药的成功临床开发至关重要。本提案的总体目标是开展实验性抗癌药物的早期剂量范围研究，重点是生物学相关性、药理学研究、老年人群分析和新型联合方案。这项建议的具体目的是：1)确定新药物在包括老年人群在内的癌症患者中的急性和慢性毒性特征、耐受性和最佳剂量；2)利用生物标志物和功能成像来获得靶向药物的有效剂量和时间表；3)使用标准和基于生理学的方法确定新药物的药理学特征和药效学关系。4)根据上述终点，制定和分析药物与标准化疗、放疗和其他靶向药物的合理联合策略。

DESCRIPTION (provided by applicant): This proposal is in response to the RFA CA-02-011 entitled "Early Clinical Trials of New Anti-Cancer Agents with Phase I Emphasis" to be conducted at the NCI-designated University of Colorado Comprehensive Cancer Center. Drug development in oncology is rapidly changing. As laboratory investigations continue to elucidate mechanisms that contribute to the malignant phenotype, targets for anticancer therapy emerge. In the past, the major focus was on agents that interfered directly with the cellular replication machinery, whereas the current focus is on agents that target aberrant biological pathways. Nonetheless, regardless of the specific target, phase I trials in oncology are critical to the successful clinical development of novel agents. The overall objective of this proposal is to conduct early dose-ranging studies of investigational anticancer agents with an emphasis on biological correlates, pharmacological studies, analysis in the geriatric population, and novel combination regimens. The specific aims of this proposal are to : 1) determine the acute and chronic toxicity profiles, tolerability, and optimal dose of new agents in cancer patients including the geriatric population, 2) utilize biological markers and functional imaging to derive efficacious doses and schedules of targeted agents, 3) determine the pharmacological profile and pharmacodynamic relationships of novel agents using standard and physiologically-based methods, and 4) develop and analyze rational combination strategies of agents with standard chemotherapy, radiotherapy, and other targeted agents using the endpoints described above.