Early Clinical Trials of New Anti-Cancer Agents with Phase I Emphasis

描述（由申请人提供）：本资助申请的前提是对一种系统给药的新型抗肿瘤药物的药理学和对癌症分子靶点的作用进行了无可挑剔的描述和理解，从而使该药物能够更好地用于临床。确定药物的临床毒性和最大耐受剂量（MTD）已不再足够。理想情况下，研究药物的早期临床试验应该确定药代动力学（PK）处置和代谢，并在分子、细胞和临床水平上与药效学（PD）表现相关。有了这个持久的哲学和假设，通过国家癌症研究所提供的有前途的新型抗癌药物的科学指导的I期试验的性能是有保证的。将分子靶点的作用机制和作用信息与I期临床试验中生物标志物的开发相结合，将实现以下目标：确定新型抗肿瘤药物对晚期癌症患者的毒性；重新定义（必要时）现有抗癌药物与分子靶向药物、集落刺激因子和其他可能有助于探索更有效剂量和时间表的毒性改善药物联合使用的毒性和PK；提供抗肿瘤药物的吸收、分布、代谢和消除信息；确定用于II期试验的治疗方案；根据临床和药理学特点，为特殊患者群体（如器官功能受损患者、重度预处理患者或老年患者群体）确定适当的II期剂量，探讨基于性别、种族或族裔群体的PK和PD差异；获得PK/PD相关性的初步信息，然后可以在II期试验中扩展；在可能和适当的情况下，结合基础实验室和相关科学研究，以加强对药物作用的生化和/或生物学机制的理解；利用磁共振波谱和放射性标记药物核成像等非侵入性技术研究药物对特定代谢途径和分子靶点的PK和PD影响；并结合药物基因组学研究，表征与毒性和疗效相关的相关药物代谢酶和药物靶点的差异。

DESCRIPTION (provided by applicant): The premise behind this grant application is that impeccable characterization and understanding of a systemically administered new antineoplastic agent's pharmacology and effect on molecular targets in cancer should allow better clinical utilization of that agent. Determination of clinical toxicities and maximum tolerated dose (MTD) of an agent is no longer sufficient. Ideally, early clinical trials of an investigational agent should define pharmacokinetic (PK) disposition and metabolism, with correlation to pharmacodynamic (PD) manifestations at molecular, cellular, and clinical levels. With this abiding philosophy and hypothesis, performance of scientifically directed phase I trials of promising novel anti-cancer agents available through the National Cancer Institute is warranted. Integrating information regarding the mechanism of action and effect on molecular targets with development of biomarkers in phase I trials is the strategy that will be pursued with the following objectives to : define the toxicities of new antineoplastic agents in patients with advanced cancer; re-define (as necessary)the toxicities and PK of existing anticancer agents administered in combination with molecularly targeted agents, colony stimulating factors and other toxicity-ameliorating agents that may facilitate the exploration of more effective doses and schedules; provide information on the absorption, distribution, metabolism, and elimination of antitumor agents; define treatment regimens for use in phase II trials; establish, based on clinical and pharmacologic characteristics, appropriate phase II doses in special patient populations (e.g., patients with impaired organ function; heavily pretreated patients or geriatric patient populations), explore PK and PD differences based on sex, race, or ethnic group; obtain preliminary information on PK/PD correlations that can then be extended in phase II trials; incorporate basic laboratory and correlative science studies, when possible and appropriate, to enhance the understanding of the biochemical and/or biological mechanisms of drug actions; study the PK and the PD impact of drugs on specific metabolic pathways and molecular targets using non-invasive techniques such as magnetic resonance spectroscopy and nuclear imaging with radio-labeled drugs; and integrate pharmacogenomic studies to characterize differences in relevant drug metabolizing enzymes and drug targets related to toxicity and efficacy.