Biomarker Studies for Novel Anti-Cancer Agents

描述(由申请人提供)：UO1第一阶段申请的总体目标是高效和安全地进行NCI的新型抗癌药物的剂量发现、药理学和生物标志物评估临床试验。来自第一阶段研究的信息将指导进一步研究的最佳剂量和时间表的选择。大多数新的抗癌药物是基于机制的，毒性有限，单一药物活性有限，与其他治疗方法联合使用或在表达一个或多个特定分子靶点的人群中可能是最有效的。为了成功开发这种药物，在将这些药物投入全面临床开发之前，提供证据证明这些药物达到了患者预期的分子靶点是至关重要的。在临床开发的早期，更好地了解这种效应与新制剂的活性和毒性有关的生理后果也是至关重要的。我们提出了以下具体目标：1.定义和描述药物的剂量限制和非剂量限制毒性，并为临床活性提供证据。2.明确新药的药代动力学性质，包括吸收、分布、代谢和消除。我们将评估这些参数在毒性、疗效和靶向抑制或刺激方面的药效学效应。3.评估新的生物标志物和/或成像研究，这些研究将为药物在目标水平上的活性提供原则性证据，并将这些与其他临床和药代动力学/药效学终点相关联。4.根据所有可用的毒性、疗效、PK、PD、成像和生物标记物数据确定II期剂量。由于目前NCI流水线中将出现的新型药物尚不完全清楚，我们将把重点放在我们拥有科学专业知识和有效转译临床研究记录的药物类别上，包括：1)靶向肿瘤血管生成的药物；2)靶向肿瘤或肿瘤基质生长因子抑制的药物；以及3)新型疫苗和其他免疫调节剂。我们也是研究针对脑瘤患者的I期药物的专家。我们预计每年有2-3项研究。我们将强调单一药物的研究，但可以评估新药物的组合，或者与标准化疗或放射治疗的组合。我们将重点开发和使用相关的生物标志物和成像方法。我们在I期临床试验中的专业知识、庞大的患者基础、临床基础设施以及在基础和转化性癌症生物学和药理学方面的深度，将使我们能够有效地实现这项建议的目标。

DESCRIPTION (provided by applicant): The overall goal of this UO1 phase I application is to efficiently and safely conduct dose finding, pharmacological, and bio-marker evaluation clinical trials of novel anti-cancer agents from the NCI. Information from phase I studies will guide selection of optimal dose and schedule for further study. Most new anti-cancer agents are mechanism-based, have limited toxicities, limited single agent activity, and may be most effective in combination with other therapies, or in populations expressing a specific molecular target or targets. For successful development of such agents, it is essential to provide evidence that these agents hit the intended molecular targets in patients before moving these agents into full scale clinical development. It is also critical to better understand the physiological consequences of this effect in relation to the new agent's activity and toxicity early in clinical development. We propose the following specific aims: 1.To define and describe agents' dose limiting and non-dose limiting toxicities, and provide evidence of clinical activity. 2. To define the pharmacokinetic properties of novel agents, including absorption, distribution, metabolism, and elimination. We will evaluate the pharmacodynamic effect of these parameters on toxicity, efficacy, and target inhibition or stimulation. 3. To evaluate novel biomarker and/or imaging studies that will provide proof of principle for an agent's activity at the target level, and to correlate these with other clinical and pharmaco- kinetic /pharmacodynamic endpoints. 4. To define a phase II dose based upon all available toxicity, efficacy, PK, PD, imaging, and biomarker data. Since the novel agents that will become available in the NCI pipeline are not completely known at this time, we will focus our approaches on classes of agents for which we have both scientific expertise and a track record of productive translational clinical investigation, including, 1) agents targeting tumor angiogenesis; 2) agents targeting tumor or tumor-stromal growth factor inhibition; and 3) novel vaccine and other immunomodulatory agents. We are also expert in studying agents targeted to brain tumor patients for phase I agents. We anticipate 2-3 studies per year. We will emphasize single agent studies but can evaluate combinations of novel agents or with standard chemotherapeutics or radiation therapy. We will emphasize the development and use of correlative biomarker and imaging approaches. Our ex- pertise in phase I clinical trial, large patient base, clinical infrastructure, and depth in basic and translational cancer biology and pharmacology will allow us to efficiently accomplish the goals of this proposal.