Phase I Clinical Trials of Anti-Cancer Agents

描述（由申请人提供）：本提案题为“抗癌药物的I期临床试验”，是根据RFA No。CA-02-011，要求支持早期临床评估，特别是第一阶段，药理学和相关生物学研究，研究性抗癌治疗。癌症治疗的最大进步是由于引入了新的抗癌治疗方法及其随后的临床实践优化（即剂量，计划，排序，组合部署）。I期是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会对新疗法的权宜之计和最佳开发产生重大影响。对于选择性的、合理设计的、基于目标的代理来说尤其如此。相对于现有的发展资源，研究候选药物的绝对数量是惊人的，考虑到治疗的最终影响，这些资源的优先次序代表了必须克服的主要发展挑战。此外，与非特异性细胞毒素不同，非特异性细胞毒素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优势表明，最大生物效应将在大大低于MTD的剂量下发生。选择最大生物剂量可能会导致更高的治疗指标和更大的联合发展“呼吸空间”。临床前数据的优势也表明，靶向治疗的主要有益效果将是肿瘤生长抑制，这在非随机研究中可能没有得到重视。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。具体目的是为了识别传统的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）。鉴于许多新型抗癌药物可能没有明确的毒理学终点，并且在进一步的评估完成之前，临床应用的前景可能尚不清楚，因此后者尤其重要。因此，其他具体目标，包括在靶水平上评估相关生物活性，对于最终优化研究性癌症治疗的治疗指标至关重要。sadg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。结果将被综合，以解决治疗优化问题，确定原则的证明，并发展分析，以辨别治疗对目标的相关影响。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，以测量生物靶向和/或体内肿瘤生长抑制。除了提出应对这些挑战的方法外，该提案还将展示sadg在抗癌治疗药物综合开发方面的丰富经验、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.