SUBJECTS WITH ADVANCED IMAGEABLE MALIGNANCIES

患有晚期可成像恶性肿瘤的受试者

• 批准号: 7376474
• 负责人: Wallace Lovell Akerley
• 金额: $ 8.1万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-01 至 2007-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7376474
• 关键词: chemotherapy; clinical trial phase I; neoplasm /cancer; neoplasm /cancer blood supply; salts

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Despite advances in the management of cancer with radiotherapy, chemotherapy and surgery, many solid tumors remain incurable. There is an urgent need for treatments with new mechanisms of action, which may act synergistically with chemotherapy and radiotherapy. Tumor vasculature has become a recent target in the development of new cancer therapies, with the focus aimed primarily on compounds that prevent the formation and growth of new blood vessels (i.e., anti-angiogenesis therapy). An alternative approach is therapy targeted against the existing vasculature of tumors (i.e., anti-vascular therapy) using vascular destructing agents (VDAs). Through this approach, tumor blood flow is impeded, leading to extensive tumor cell death as a consequence of oxygen and nutrient deprivation. Several agents have been shown in animal models to cause marked tumor vascular shutdown, but at doses that cause prohibitive toxicity. Combretastatin A-4 Phosphate (CA4P) is a novel anti-cancer agent that displays potent and selective toxicity towards tumor vasculature. CA4P is a synthetic, water soluble, phosphorylated prodrug of the natural product combretastatin A-4 (CA4), which was originally isolated from the bark of the African bush willow, Combretum caffrum. In vitro, the parent CA4 is a strong tubulin-binding agent that has potent activity in preventing tubulin polymerization. Although the exact mechanism for the anti-vascular effects of CA4P remain under investigation, preclinical evidence suggests that it may be a consequence of endothelial cell damage. Clinically, CA4P was evaluated in three Phase I trials as of January 2002, which included 96 patients with advanced malignancies. Due to the range of Phase II recommendations from these Phase I trials, it remains difficult to choose a best dose for Phase II studies with chemotherapy. Taken together, the interpreted Phase I trials suggests the real maximum tolerated dose (MTD) is approximately 67 mg/m2 (75 mg/m2 salt form) and may be even greater in subsets of patients. Points of further consideration involved in the choice of doses are the non-overlapping toxicities of CA4P and chemotherapy. Since the optimal biologic dose may not necessarily coincide with the MTD, Phase I data for changes in tumor perfusion were reviewed. It appears that doses between 47 mg/m2 and 61 mg/m2 (52 and 68 mg/m2 salt form, respectively) are effective in reducing tumor perfusion based on DCE (dynamic contrast imaging)-MRI from 20-50%, so the optimal biologic dose may be close to the MTD. There exist PET data that suggest the effects may occur at even lower doses. For these reasons, this study is evaluating doses of 45 mg/m2 (50 mg/m2 salt form) and 63 mg/m2 (70 mg/m2 salt form) in an effort to resolve the divergent recommendations made by these Phase I studies.

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得主要资金，因此可以在其他CRISP条目中表示。所列机构为中心，不一定是研究者所在机构。尽管放射治疗、化疗和手术在癌症管理方面取得了进展，但许多实体瘤仍然无法治愈。迫切需要具有新作用机制的治疗，其可以与化疗和放疗协同作用。肿瘤血管系统已成为开发新癌症疗法的最近目标，其主要关注防止新血管形成和生长的化合物（即，抗血管生成疗法）。另一种方法是靶向肿瘤现有脉管系统的治疗（即，抗血管治疗）。通过这种方法，肿瘤血流受阻，导致广泛的肿瘤细胞死亡，作为氧气和营养剥夺的结果。在动物模型中，几种药物已显示出可引起显著的肿瘤血管关闭，但剂量会引起抑制性毒性。 考布他汀A-4磷酸盐（CA 4P）是一种新型的抗癌药物，对肿瘤血管系统显示出有效的和选择性的毒性。CA 4 P是天然产物考布他汀A-4（CA 4）的合成的、水溶性的、磷酸化的前药，其最初从非洲灌木杨柳（Combretum caffrum）的树皮中分离。在体外，母体CA 4是一种强微管蛋白结合剂，其在防止微管蛋白聚合中具有有效活性。虽然CA 4P抗血管作用的确切机制仍在研究中，但临床前证据表明，它可能是内皮细胞损伤的结果。 在临床上，CA 4P在三个I期临床试验中进行了评估，截至2002年1月，其中包括96例晚期恶性肿瘤患者。由于这些I期试验的II期推荐范围，仍然难以选择II期化疗研究的最佳剂量。综合考虑，I期临床试验结果表明，真实的最大耐受剂量（MTD）约为67 mg/m2（盐形式75 mg/m2），在患者亚组中可能更高。 剂量选择中涉及的进一步考虑点是CA 4P和化疗的非重叠毒性。由于最佳生物剂量可能不一定与MTD一致，因此对肿瘤灌注变化的I期数据进行了审查。似乎47 mg/m2和61 mg/m2之间的剂量（分别为52和68 mg/m2盐形式）可有效降低基于DCE（动态对比成像）-MRI的肿瘤灌注20- 50%，因此最佳生物剂量可能接近MTD。有PET数据表明，即使在更低的剂量下也可能发生这种效应。 出于这些原因，本研究正在评估45 mg/m2（50 mg/m2盐形式）和63 mg/m2（70 mg/m2盐形式）的剂量，以解决这些I期研究提出的不同建议。