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，但也有严重的副作用，包括肾毒性、肝毒性和骨髓抑制。因此，一种既能减少顺铂副作用又不影响其疗效的化学保护剂将具有显著的临床益处。目前，氨磷汀是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剂，可减少化疗（包括顺铂）和放疗方案的副作用。不幸的是，氨磷汀有很大的局限性，包括潜在的严重副作用和潜在的肿瘤保护作用。理想的化疗保护剂不应干扰顺铂的治疗效果，其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-a)的小分子调节剂UTL-5g作为主要的化学保护剂。根据这项SBIR I期研究，UTL-5g已被证明可以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对肾脏和肝脏有保护作用。顺铂升高的血液TNF-a水平也被UTL-5g以剂量依赖性的方式降低。一个令人兴奋的发现是，UTL-5g在体内不仅没有降低顺铂的抗肿瘤作用，UTL-5g的预处理实际上增加了顺铂的治疗效果。此外，UTL-5g的急性毒性非常低。所有这些来自SBIR I期研究的令人兴奋的结果表明，继续进行临床前开发是有必要的。这项SBIR II期研究的具体目的是：[目的1]在动物研究中比较口服灌胃和ip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来研究代谢物的化学保护作用。[目的2]采用UTL-5g的最佳口服剂量（在目的1中确定）和顺铂剂量的增加，观察UTL-5g是否能提高小鼠顺铂的MTD。如果顺铂的MTD确实增加，则在新的MTD下对顺铂进行治疗性评估，无论是否使用UTL-5g。[目标3]从目标1开始使用最佳口服剂量进行ADME研究。[目标4]扩大原料药的合成规模，制备高达1公斤的UTL-5g[目标5]在GLP条件下对两种物种进行28天重复剂量毒性研究，使用口服剂型UTL-5g[目标6]开发适合首次临床试验的UTL-5g口服制剂；开发和验证口服制剂的分析方法；确定规格并对口服剂型进行稳定性研究。[目标7]准备一份适合第一期临床试验的方案草案。[目标8]根据FDA的行业指南格式编写ind前的包装，并准备与FDA进行ind前会议。

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.