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

描述(由申请人提供)：这项拨款申请背后的前提是，对系统管理的新型抗肿瘤药物的药理学和对癌症分子靶标的影响的完美描述和了解，应该能够使该药物更好地在临床上使用。一种药物的临床毒性和最大耐受量(MTD)的测定不再足够。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，并与分子、细胞和临床水平上的药效(PD)表现相关联。有了这一持久的哲学和假设，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期试验的表现是有保证的。在I期试验中，将分子靶标的作用机制和影响的信息与生物标记物的开发相结合是一项战略，将追求以下目标：确定新的抗肿瘤药物在晚期癌症患者中的毒性；(必要时)重新定义现有抗癌剂与分子靶向药物、集落刺激因子和其他毒性改善剂联合使用的毒性和PK，这些药物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；定义用于第二阶段试验的治疗方案；根据临床和药理学特征，在特殊患者群体(例如，器官功能受损患者；严重预治疗患者或老年患者群体)中确定适当的第二阶段剂量，探索基于性别、种族或民族的PK和PD差异；获得关于PK/PD相关性的初步信息，然后可在第二阶段试验中推广；在可能和适当的情况下，纳入基础实验室和相关科学研究，以加强对药物作用的生化和/或生物机制的了解；利用核磁共振波谱和放射性标记药物的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；整合药物基因组学研究，以表征与毒性和疗效相关的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.