DFMO/SULINDAC PHASE III

DFMO/SULINDAC III 期

• 批准号: 7374265
• 负责人: FRANK MEYSKENSJR
• 金额: $ 2.42万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 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 2006-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7374265
• 关键词: adenoma; adenomatous polyps; chemoprevention; colorectal neoplasms; mucosa; placebos; polyamines; prostaglandins

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. OBJECTIVES Adenomatous polyps are generally regarded as precursors to colorectal cancer and relatively late surrogates in the carcinogenic pathway to the development of these malignancies. Etiologic and experimental investigations have established the critical nature of definable molecular changes precedent to and during pathogenesis of the disease that leads to abnormal signaling pathways and defective growth control. Extensive epidemiologic studies have identified numerous dietary and non-dietary factors that affect adenoma and colorectal cancer development, including regular intake of non-steriodal anti-inflammatory drugs (NSAIDs). Experimental interventions in several animal models have demonstrated that NSAIDs as well as the polyamine synthesis inhibitor, difluoromethylornithine (DFMO), inhibit carcinogenesis including adenoma formation and colon cancer. We and others have performed Phase I, IIa and IIb clinical chemoprevention trials of DFMO and in a series of studies that have established its effectiveness in lowering the polyamine content of colorectal tissue at doses of DFMO that are almost completely free of side effects. The NSAID and sulindac has been shown to cause regression of FAP and sporadic associated polyps and its side effects profile is widely understood. The available data on these two agents and their potential role as candidate preventive agents for colorectal cancer is as comprehensive as for any agent(s) currently being considered for human use and they represent the intervention focus of this proposal. We have nearly completed accrual to our Phase IIb combination trial fo DFMO plus sulindac versus placebo in which the major goal was to study various pathobiologic markers in flat mucosa and incident adenoma recurrence. We propose to use this large group of individuals as a Vanguard for a randomized, placebo-controlled, phase III trial of DFMO plus sulindac to determine whether this combination can decrease substantially the recurrence of adenomatous polyps and do so safely. SPECIFIC AIMS 1. To conduct a randomized, double-blind, placebo-controlled phase III clinical chemoprevention trial of the combination of DFMO plus sulindac to decrease the rate of new adenomatous polyp formation. Hypothesis: This combination of candidate chemoprevention agents will lower the rate of adenomatous polyps by 50% or greater. Qualifying and recurrent adenomas will be collected, measured, and archived for future studies. Dietary parameters will be measured and family history of colorectal cancer and polyps will be determined in all randomized participants. 2. To correlate the effects of the combination on polyamine and prostaglandin contents in the flat mucosa to the rate of adenoma formation. The changes in the levels fo these biochemical parameters will also be used as one measure of compliance as well as an indication that the agent is producing the intended biochemical modulation. Hypothesis: The level of reduction of polyamine and prostaglandin contents of flat mucosa after 36 months of treatment will be correlated with the rate of adenoma recurrence. 3. To determine the side effects in patients randomized to the combination therapy over the course of the intervention. Hypothesis: Both GI and non-GI side effects, as well as drop-offs after randomization, will be no different between the treatment and placebo arms. The major objectives of this investigation are to reduce the recurrence rate of adenomatous colonic polyps without producing toxicity greater than seen in the placebo group. The overall goal of our work is to develop safe combinations of chemoprevention agents that can be used in the practice setting and complement current surveillance efforts.

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。腺瘤性息肉通常被认为是结直肠癌的前兆，并且是这些恶性肿瘤发展的致癌途径中相对较晚的替代物。病因学和实验研究已经确定了可定义的分子变化的关键性质，导致异常信号传导途径和缺陷的生长控制的疾病的发病机制之前和期间。广泛的流行病学研究已经确定了许多影响腺瘤和结直肠癌发展的饮食和非饮食因素，包括定期摄入非甾体抗炎药（NSAID）。在几种动物模型中的实验干预已经证明，NSAID以及多胺合成抑制剂二氟甲基鸟氨酸（DFMO）抑制致癌作用，包括腺瘤形成和结肠癌。我们和其他人已经进行了DFMO的I期、IIa期和IIb期临床化学预防试验，并在一系列研究中确定了DFMO在几乎完全无副作用的剂量下降低结直肠组织多胺含量的有效性。NSAID和舒林酸已被证明可导致FAP和散发性相关息肉的消退，其副作用特征已被广泛理解。关于这两种药物及其作为结直肠癌候选预防药物的潜在作用的现有数据与目前考虑用于人类的任何药物一样全面，它们代表了本提案的干预重点。 我们已经接近完成了对DFMO+舒林酸与安慰剂的IIb期联合试验的招募，该试验的主要目标是研究平坦粘膜中的各种病理生物学标志物和腺瘤复发事件。我们建议将这一大群个体作为DFMO加舒林酸的随机、安慰剂对照、III期试验的先锋，以确定这种组合是否能显著降低腺瘤性息肉的复发，并且安全。 具体目标1.进行一项随机、双盲、安慰剂对照的三期临床化学预防试验，研究DFMO联合舒林酸降低新发腺瘤性息肉形成率。假设：这种候选化学预防剂的组合将使腺瘤性息肉的发生率降低50%或更高。将收集、测量并存档合格和复发性腺瘤，以供未来研究使用。将测量所有随机化受试者的饮食参数，并确定其结肠直肠癌和息肉家族史。 2.将组合对平坦粘膜中多胺和前列腺素含量的影响与腺瘤形成率相关联。这些生化参数水平的变化也将被用作一种顺应性的量度以及试剂正在产生预期的生化调节的指示。假设：治疗36个月后，平坦粘膜中多胺和前列腺素含量的降低水平将与腺瘤复发率相关。 3.确定在干预过程中随机接受联合治疗的患者的副作用。假设：治疗组和安慰剂组之间的GI和非GI副作用以及随机化后的脱落没有差异。 本研究的主要目的是降低腺瘤性结肠息肉的复发率，而不产生比安慰剂组更大的毒性。我们工作的总体目标是开发安全的化学预防剂组合，可用于实践环境，并补充目前的监测工作。