Phase I Trials of Anticancer Agents

描述(由申请人提供)：本提案是对将在美国国立卫生研究院指定的科罗拉多大学综合癌症中心进行的题为“第一阶段重点的新型抗癌药物的早期临床试验”的RFA CA-02-011的回应。肿瘤学中的药物开发正在迅速变化。随着实验室研究不断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，而现在的重点是针对异常生物途径的药物。尽管如此，无论具体目标如何，肿瘤学I期试验对新药的成功临床开发至关重要。这项建议的总体目标是对研究中的抗癌药物进行早期剂量范围研究，重点是生物相关性、药理学研究、老年人群分析和新的联合疗法。这项建议的具体目的是：1)确定新药物在癌症患者(包括老年人群)中的急性和慢性毒性、耐受性和最佳剂量；2)利用生物标志物和功能成像来推导靶向药物的有效剂量和时间表；3)使用标准的和基于生理的方法确定新药物的药理学特征和药效学关系；4)使用上述终点开发和分析药物与标准化疗、放射治疗和其他靶向药物的合理组合策略。

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.