Phase I Clinical Trials of Anti-Cancer Agents

描述(由申请人提供)：这份题为“抗癌药物第一阶段临床试验”的建议书，是针对RFA No.CA-02-011，请求支持抗癌研究疗法的早期临床评估，特别是第一阶段的药理学和相关生物学研究。癌症治疗的最大进展是引入了新的抗癌治疗药物，并随后对其进行了优化(即剂量、排序、排序、组合部署)用于临床实践。第一阶段代表着这一发展过程中的关键一步，临床和支持性药理学和生物学数据的可靠性可能对新疗法的权宜性和最佳开发产生重大影响。对于有选择的、合理设计的、以目标为基础的药物来说，情况尤其如此。与可用的发展资源相比，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确定这些资源的优先顺序是必须克服的主要发展挑战。此外，与非特异性细胞毒药不同，抗癌活性通常与剂量相关，因此通常寻求最大耐受剂量(MTD)，而选择性靶向治疗的临床前数据表明，在显著低于MTD的剂量时，将产生最大的生物学效应。选择一个最大的生物剂量可能会导致更大的治疗指数和更大的联合开发的“喘息空间”。临床前数据的优势也表明，靶向治疗的主要益处将是抑制肿瘤生长，这在非随机研究中可能没有被认识到。该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。具体目标是辨别传统的第一阶段研究终点(例如，MTD，毒性特征)和相关的生物和药理学终点(例如，最大有效剂量)。考虑到许多新型抗癌药物可能没有明确的毒理学终点，以及临床应用的前景可能要等到进一步的评估完成才能知道，后者尤其重要。因此，其他具体目标，包括评估目标水平上的相关生物活性，对于最终优化癌症研究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、药理学和生物学评估。这些结果将被综合起来，以解决治疗优化问题，确定原则证据，并开发分析方法，以辨别治疗对目标的相关影响。这种分析方法的发展可能对后续的疾病导向研究更加关键，以评估体内的生物靶向和/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在全面发展抗癌疗法方面的丰富经验、成功和奉献精神，以及强大的机构承诺。

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.