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

描述（由申请人提供）：本次拨款申请背后的前提是，对全身给药的新型抗肿瘤药物的药理学和对癌症分子靶点的影响进行无可挑剔的表征和理解，应该能够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) 已经不够了。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，并与分子、细胞和临床水平上的药效（PD）表现相关。有了这种持久的理念和假设，有必要对国家癌症研究所提供的有前景的新型抗癌药物进行科学指导的一期试验。将有关分子靶标的作用机制和影响的信息与 I 期试验中生物标志物的开发相结合，是为了实现以下目标而采取的策略：确定新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毒性改善药物联合用药的毒性和药代动力学，这可能有助于探索更有效的剂量和时间表；提供有关抗肿瘤药物的吸收、分布、代谢和消除的信息；确定用于 II 期试验的治疗方案；根据临床和药理学特征，在特殊患者群体（例如器官功能受损的患者；接受过大量治疗的患者或老年患者群体）中确定适当的 II 期剂量，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 期试验中进行扩展；在可能和适当的情况下，纳入基础实验室和相关科学研究，以增强对药物作用的生化和/或生物学机制的理解；使用核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标的 PK 和 PD 影响；并整合药物基因组学研究来表征相关药物代谢酶和与毒性和功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.