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

描述（由申请人提供）：本资助申请背后的前提是，对全身给药的新抗癌剂的药理学和对癌症分子靶点的影响的无可挑剔的表征和理解应该允许更好地临床利用该药物。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确定药代动力学（PK）分布和代谢，以及与分子、细胞和临床水平的药效学（PD）表现的相关性。有了这一永恒的哲学和假设，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期试验的性能是有必要的。在I期试验中，将关于作用机制和对分子靶点的影响的信息与生物标志物的开发相结合是将追求的策略，其目标如下：确定新的抗癌药物在晚期癌症患者中的毒性;重新定义（必要时）与分子靶向药物联合给药的现有抗癌药物的毒性和PK，集落刺激因子和其他毒性改善剂，可能有助于探索更有效的剂量和时间表;提供关于抗肿瘤药物的吸收、分布、代谢和消除的信息;定义用于II期试验的治疗方案;根据临床和药理学特征，在特殊患者人群中确定适当的II期剂量（例如，器官功能受损的患者;接受过大量预治疗的患者或老年患者人群），探索基于性别、种族或民族的PK和PD差异;获得有关PK/PD相关性的初步信息，然后可以在II期试验中扩展;在可能且适当的情况下，纳入基础实验室和相关科学研究，以增强对药物作用的生化和/或生物学机制的理解;使用非侵入性技术（如磁共振光谱和放射性标记药物的核成像）研究药物对特定代谢途径和分子靶点的PK和PD影响;并整合药物基因组学研究，以表征相关药物代谢酶和与毒性和疗效相关的药物靶点的差异。

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.