Novel small-molecule TNF-a modulators as chemoprotective agents

描述（由申请人提供）：顺铂是一种广泛使用的细胞毒性药物，对各种肿瘤具有治疗活性，但也有明显的副作用，包括肾毒性、肝毒性和骨髓抑制。因此，减少顺铂的副作用而不影响其功效的化学保护剂将具有显著的临床益处。目前，amifostine是FDA批准的唯一用于顺铂治疗的化学保护药物。氨磷汀是一种含硫药物，可减少化疗（包括顺铂）和放疗方案引起的副作用。不幸的是，存在与氨磷汀相关的显著限制，包括其潜在的严重副作用和潜在的肿瘤保护作用。理想的化学保护剂不应干扰顺铂的治疗效果，并且本身毒性很小或没有毒性。因此，在我们最近完成的SBIR I期研究中，我们研究了肿瘤坏死因子α（TNF-α）的小分子调节剂UTL-5g作为主要的化学保护剂。基于这项SBIR I期研究，UTL-5g已被证明可降低顺铂升高的血尿素氮（BUN）、肌酐、天冬氨酸转氨酶（AST）和丙氨酸转氨酶（ALT）水平，表明UTL-5g可保护肾脏和肝脏。通过顺铂升高的TNF-α的血液水平也通过UTL-5g以剂量依赖性方式降低。一个令人兴奋的发现是，UTL-5g不仅没有降低顺铂在体内的抗肿瘤作用，而且UTL-5g的预处理实际上增加了顺铂的治疗效果。此外，UTL-5g具有非常低的急性毒性。SBIR I期研究的所有这些令人兴奋的结果表明，继续进行临床前开发是必要的。本SBIR II期研究的具体目的是：[目的1]在动物研究中比较经口灌胃和腹腔注射（I期使用）的化学保护作用，并确定UTL-5g的最佳口服剂量。如果ADME研究表明UTL-5g可能是一种前药，我们也将使用相同的方案研究代谢产物的化学保护作用。[Aim 2]采用UTL-5g的最佳口服剂量（在目标1中确定）和顺铂剂量的递增剂量来发现UTL-5g是否可以增加顺铂在小鼠中的MTD。如果顺铂的MTD确实增加，则在新的MTD下（联合或不联合UTL-5g）对顺铂进行治疗评估。[Aim 3]使用目标1中的最佳口服剂量进行ADME研究。[Aim 4]按比例放大API的合成，并制备至多1 kg UTL-5 g。[Aim 5]采用UTL-5g的口服剂型，在GLP条件下在两个物种中进行28天重复给药毒性研究。[Aim 6]开发适合首次临床试验的UTL-5g口服制剂;开发并验证口服制剂的分析方法;确定质量标准并对口服剂型进行稳定性研究。[Aim 7]准备适合第一个I期临床试验的方案草案。[Aim 8]按照FDA行业指南的格式编写IND前文件包，并准备与FDA进行IND前会议。 公共卫生相关性：这项SBIR II期研究是成功的SBIR I期研究的继续，以进行小分子TNF-α调节剂UTL-5g的临床前开发，作为化学保护剂，以预防/减少顺铂诱导的副作用，而不影响其治疗效果。

DESCRIPTION (provided by applicant): Cisplatin is a widely used cytotoxic agent with therapeutic activity against various tumors, but also with substantial side effects, including nephrotoxicity, hepatotoxicity and myelosuppression. Therefore, a chemoprotective agent which reduces the side effects of cisplatin without affecting its efficacy would have significant clinical benefit. Currently, amifostine is the only FDA approved chemoprotective drug for cisplatin therapy. Amifostine is a sulfur-containing agent that reduces side effects resulted from both chemotherapy (including cisplatin) and radiotherapy regimens. Unfortunately, there are significant limitations associated with amifostine including its potentially serious side effects and potential tumor-protective effect. An ideal chemoprotector should not interfere with cisplatin's therapeutic effect, and with little or no toxicity by itself. As such, in our recently completed SBIR Phase I study, we investigated a small-molecule modulator of tumor necrosis factor alpha (TNF-a), UTL-5g, as a leading chemoprotective agent. Based on this SBIR Phase I study, UTL-5g has been shown to reduce levels of blood urea nitrogen (BUN), creatinine, aspartate transaminase (AST), and alanine transaminase (ALT) elevated by cisplatin, indicating the protection of kidney and liver by UTL-5g. Blood levels of TNF-a elevated by cisplatin were also lowered by UTL-5g in a dose- dependent manner. An exciting finding is that not only UTL-5g did not reduce the antitumor effect of cisplatin in vivo, pre-treatment of UTL-5g actually increased the therapeutic effect of cisplatin. In addition, UTL-5g has a very low acute toxicity. All these exciting results from the SBIR Phase I study indicate that continued preclinical development is warranted. The specific aims of this SBIR Phase II study are: [Aim 1] Compare the chemoprotective effects by both oral gavage and ip injection (which was used in Phase I) in animal studies and determine the optimal oral dose of UTL-5g. If the ADME study shows that UTL-5g may be a pro-drug, we will also use the same protocol to study the chemoprotective effect of the metabolite(s). [Aim 2] Use the optimal oral dose of UTL-5g (determined in Aim 1) and increasing doses of cisplatin dose to find whether the MTD of cisplatin in mice can be increased by UTL-5g. If the MTD of cisplatin does increase, conduct a therapeutic assessment of cisplatin at the new MTD with and without UTL-5g. [Aim 3] Use the optimal oral dosage from Aim 1 to conduct the ADME study. [Aim 4] Scale up the synthesis of API and prepare up to 1 kg of UTL-5g. [Aim 5] Conduct the 28-day repeat- dose toxicity studies in two species under GLP condition, employing the oral dosage form of UTL-5g. [Aim 6] Develop an oral formulation of UTL-5g suitable for the first clinical trial; develop and validate an analytical method for the oral formulation; define the specification and conduct a stability study on the oral dosage form. [Aim 7] Prepare a draft protocol suitable for the first Phase I clinical trial. [Aim 8] Compile a pre-IND package in the format according to FDA's guidance for Industry and be ready for a pre-IND meeting with the FDA. PUBLIC HEALTH RELEVANCE: This SBIR Phase II study is the continuation of the successful SBIR Phase I study to conduct the preclinical development of a small-molecule TNF-a modulator, UTL-5g, as a chemoprotective agent to prevent/reduce side effects induced by cisplatin without compromising its therapeutic effect.