Phase I Clinical Trials of Anti-Cancer Agents

描述（由申请人提供）：本提案标题为“抗癌药物的I期临床试验”，根据RFA编号CA-02-011编写，请求支持研究性抗癌治疗药物的早期临床评价，特别是I期药理学和相关生物学研究。癌症治疗的最大进步来自于新型抗癌治疗剂的引入及其随后的临床实践优化（即给药、时间表、测序、组合部署）。I期阶段代表了该开发过程中的关键一步，临床和支持性药理学和生物学数据的可靠性可能会对新疗法的有利和最佳开发产生重大影响。这对于选择性的合理设计的、基于目标的药剂尤其如此。相对于可用的发展资源，研究候选药物的绝对数量是惊人的，通过考虑治疗的最终影响来优先考虑这些资源代表了必须克服的主要发展挑战。此外，与非特异性细胞毒性药物不同，非特异性细胞毒性药物的抗癌活性通常与剂量相关，因此通常寻求最大耐受剂量（MTD），选择性靶向治疗的临床前数据的优势表明，在显著低于MTD的剂量下将发生最大生物学效应。最大生物剂量的选择可能会导致更大的治疗指数和更多的“喘息空间”的组合开发。临床前数据的优势还表明，靶向治疗的主要有益作用是抑制肿瘤生长，这在非随机研究中可能不受重视。本提案将描述圣安东尼奥药物开发集团（SADDG）应对这些挑战的方法。具体目标是识别传统的I期研究终点（例如MTD、毒性表征）和相关的生物学和药理学终点（例如最大有效剂量）。后者尤其重要，因为许多新型抗癌药物可能没有明确的毒理学终点，在完成进一步评价之前可能无法了解其临床应用前景。因此，其他具体目标，包括在目标水平评估相关生物活性，对于最终优化研究性癌症治疗的治疗指数至关重要。SADDG建议在早期临床试验过程中进行严格和全面的毒理学、药理学和生物学评价。将对结果进行综合，以解决治疗优化问题，确定原理证明，并开发检测方法以识别治疗对靶点的相关影响。这种检测方法的发展可能对随后的疾病导向研究更加重要，以评估体内生物靶向和/或肿瘤生长抑制。除了为应对这些挑战而提出的方法外，该提案还将展示SADDG对抗癌疗法全面发展的丰富经验、成功和奉献精神，以及强有力的机构承诺。

DESCRIPTION (provided by applicant): This proposal entitled, "Phase I Clinical Trials of Anti-Cancer Agents," prepared in response to RFA No. CA-02-011, requests support for early stage clinical evaluations, particularly phase I, pharmacological and relevant biological studies, of investigational anti-cancer therapeutics. The greatest advances in the cancer therapy have resulted from the introduction of novel anti-cancer therapeutics and their subsequent optimization (i.e. dosing, scheduling, sequencing, deployment in combination) for clinical practice. The phase I stage represents a crucial step in this developmental process, and the reliability of clinical and supportive pharmacological and biological data may significantly impact on the expedient and optimal development of new therapies. This is especially true for selective rationally-designed, target-based agents. The sheer number investigational candidates is striking relative to available developmental resources, and prioritization of these resources by considering the ultimate impact of the therapeutic represent major developmental challenges that must be overcome. Furthermore, unlike nonspecific cytotoxics, in which anti-cancer activity is often dose-related and, hence, the maximum tolerated dose (MTD) is generally sought, the preponderance of preclinical data with selective target-based therapeutics suggest that maximal biological effects will occur at doses that are substantially lower than the MTD. Selection of a maximal biological dose would likely result in greater therapeutic indices and more "breathing room" for combination development. The preponderance of preclinical data also suggests that the predominant beneficial effects of target-based therapeutics will be tumor growth inhibition, which may not be appreciated in nonrandomized studies. This proposal will describe the San Antonio Drug Development Group's (SADDG) approach to meet these challenges. The specific aims are directed at discerning both traditional phase I study endpoints (e.g. MTD, characterization of toxicity) and relevant biological and pharmacological endpoints (e.g. maximally effective dose.) The latter is particularly important in view of the expectations that many novel anti-cancer agents may not have clear toxicological endpoints, and the prospects for clinical utility may not be known until further evaluations have been completed. Therefore, other specific aims, including the assessment of relevant biological activity at the target level, are of utmost importance to ultimately optimize the therapeutic indices of investigational cancer therapies. The SADDG proposes to perform rigorous and comprehensive toxicological, pharmacological, and biological evaluations in the course of early clinical trials. The results will be synthesized to address therapeutic optimization issues, ascertain proof of principle, and develop assays to discern the relevant effects of the therapy on the target. The development of such assays may be even more crucial for subsequent disease-directed studies to gauge biological targeting and/or tumor growth inhibition in vivo. In addition to the methodology proposed to meet these challenges, the proposal will demonstrate the immense experience, success, and dedication of the SADDG to the comprehensive development of anti-cancer therapeutics, as well as the strong institutional commitment.