Phase I Studies of Targeted Anti-Cancer Therapies

描述(由申请人提供)：从历史上看，转移性癌症的治疗模式存在重大问题。这些问题包括宿主和癌症组织之间的药物区分不佳，对适当靶点的了解有限，以及无法选择可能有反应的患者。目前的进展，特别是将靶向药物引入临床环境，使这些关键问题得以解决。我们建议，作为药物开发基石的第一阶段试验应旨在提供有关靶标影响和选择的基本知识，以便在此基础上进行进一步的试验。在这方面，至关重要的是要认识到，分子靶向化合物的作用方式可能与细胞毒性化疗根本不同。例如，靶向药物可能是细胞抑制药物，而不是细胞毒性药物，只有携带能够被药物调节的特定蛋白质的患者才可能有反应。因此，与其利用主要基于最大耐受量(MTD)确定的标准范式来开发化疗药物，不如采用更合适的范式，包括替代标志物和功能终点。因此，我们假设，中间生物终点的整合反映了与靶点的相互作用或对靶点的功能影响，将为确定最佳生物剂量(OBD)提供关键信息，并为在随后的II期研究中进一步研究有效患者的生物标记物识别奠定基础。有了这样的承诺，除了分子成像领域的专家外，临床和实验室研究人员必须进行有效的合作，以评估靶向药物调节、相互作用或抑制特定分子和生化目标的能力。这种合作可以在M.D.安德森癌症中心(MDACC)找到，该中心非常重视临床和转化药的开发，我们庞大的基础设施证明了这一点！以及对临床试验研究的教育支持。事实上，MDACC在数据管理、质量控制、监管监督、样本获取、患者护理和翻译研究方面拥有广泛的设施和极其经验丰富的教职员工，以识别药效学和分子生物标记物。我们提出的研究的意义在于，它将促进新的癌症治疗方法的发展，为阐明反应与靶点影响的关系奠定基础，从而为成功的个体化癌症治疗奠定基础。

DESCRIPTION (provided by applicant): Historically, there have been major problems with the paradigm for the treatment of metastatic cancer. These include poor discrimation of drugs between host and cancer tissues, limited knowledge of appropriate targets, and inability to select patients who are likely to respond. Current advances, especially the introduction of targeted agents into the clinical setting, allow these critical issues to be addressed. We propose that the Phase I trial, which is the cornerstone for drug development, should be designed to provide basic knowledge regarding target impact and selection, upon which further trials can be built. In this regard, it is critical to recognize that molecularly targeted compounds may behave in a way that is fundamentally dissimilar to cytotoxic chemotherapy. For instance, targeted agents may be cytostatic, rather than cytotoxic, and only patients who bear a specific protein capable of being modulated by the drug may respond. Thus, rather than utilizing the standard paradigm for Phase I development of chemotherapeutic agents that is based predominantly on determination of maximum tolerated dose (MTD), a more suitable paradigm involving surrogate markers and functional endpoints is crucial. We, therefore, hypothesize that integration of intermediate biologic endpoints, which reflect interaction with or functional impact on the target, will provide key information for determining optimal biologic dose (OBD), as well as the foundation for further study of biomarker identification of responsive patients in subsequent Phase II studies. With such an undertaking, there must be effective cooperation between clinical and laboratory investigators, in addition to experts in the field of molecular imaging, in order to evaluate the ability of targeted drugs to modulate, interact with, or inhibit specific molecular and biochemical targets. Such cooperation is found at the M.D. Anderson Cancer Center (MDACC), where great emphasis is placed on clinical and translational drug development, as evidenced by our tremendous infrastructure! and educational support for clinical trials research. Indeed, MDACC has extensive facilties and extremely experienced faculty and personnel for data management, quality control, regulatory oversight, specimen acquisition, patient care, and translational studies to identify pharmacodynamic and molecular biomarkers. The significance of our proposed research is that it should advance the development of new cancer therapeutics by providing the groundwork for elucidating how response correlates with target impact, hence laying the foundation for successful personalized cancer treatment.