Phase I Studies of Targeted Anti-Cancer Therapies

描述（由申请人提供）：对于许多恶性肿瘤，主要发生在癌细胞中的分子畸变已经被阐明。针对这些异常的药物的发现引起了相当大的兴趣，其中一些化合物已经进入临床评估，并显示出很大的希望。许多这些新型靶向药物的行为方式与细胞毒性化疗完全不同。例如，新药本质上可能是细胞抑制剂，而不是细胞毒性，或者可能需要长期给药。这些差异要求对临床试验的设计进行修改。事实上，与主要基于最大耐受剂量（MTD）确定的经典化疗药物I期开发的标准范例相反，替代标记物和功能终点可能是靶向药物开发的基本参数。因此，我们假设整合反映与靶点相互作用或对靶点功能影响的中间生物终点，将为确定后续II期研究的最佳生物剂量（OBD）提供关键信息。评估靶向药物调节、相互作用或抑制特定分子和生化靶标的能力需要临床和实验室研究者之间的有效合作。在像德克萨斯大学安德森癌症中心这样的大型机构中，非常重视临床和转化药物的开发。整个机构的研究人员都可以访问对这项工作至关重要的所有组成部分，包括分析化学，临床药理学，功能成像，生物统计学，以及许多具有最先进专业知识的基础研究实验室，以评估测试剂与特定细胞和分子端点的相互作用以及对肿瘤细胞生长和凋亡的影响。这种广泛的临床和转化研究基础设施将使我们能够安全有效地评估临床活性和毒性、药代动力学参数和药效学关系，并为单独或联合使用的新型靶向药物开发临床相关的相关性和替代终点，从而允许这些化合物通过早期临床研究快速推进。

DESCRIPTION (provided by applicant): For many malignancies, the molecular aberrations that occur predominantly in cancer cells have been elucidated. Considerable interest has been generated by the discovery of agents which specifically target these aberrations, and several of these compounds have entered into clinical evaluation and are showing great promise. Many of these novel targeted agents behave in ways that are fundamentally different from cytotoxic chemotherapy. For example, new agents may be cytostatic in nature, rather than cytotoxic, or may require long-term administration. These differences call for modifications in the design of clinical trials. Indeed, in contrast to the standard paradigm for Phase I development of classic chemotherapeutic agents based predominantly on determination of maximum tolerated dose (MTD), surrogate markers and functional endpoints may be fundamental parameters for development of targeted agents. We therefore hypothesize that integration of intermediate biologic endpoints which reflect interaction with or functional impact on the target, will provide critical information for determining the optimal biologic dose (OBD) for subsequent Phase II studies. Evaluation of the ability of targeted drugs to modulate, interact with, or inhibit specific molecular and biochemical targets requires effective cooperation between clinical and laboratory investigators. In a large institution such as The University of Texas M.D. Anderson Cancer Center, a strong emphasis on clinical and translational drug development exists. Investigators across the institution have access to all of the many components critical to this endeavor, including analytic chemistry, clinical pharmacology, functional imaging, biostatistics, and numerous basic research laboratories with state-of-the-art expertise in evaluating interactions of the test agents with specific cellular and molecular endpoints and effects on tumor cell growth and apoptosis. This extensive infrastructure for clinical and translational studies will allow us to safely and efficiently evaluate clinical activity and toxicity, pharmacokinetic parameters and pharmacodynamic relationships, and develop clinically-relevant correlates and surrogate endpoints for novel targeted agents given alone or in combination, hence permitting rapid advance of these compounds through early clinical studies.