Novel small-molecule TNF-a modulators as chemoprotective agents

描述(申请人提供)：顺铂是一种广泛使用的细胞毒剂，对各种肿瘤具有治疗活性，但也有很大的副作用，包括肾毒性、肝毒性和骨髓抑制。因此，一种在不影响顺铂疗效的情况下减少顺铂副作用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性药物。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，氨磷汀有很大的局限性，包括它潜在的严重副作用和潜在的肿瘤保护作用。一个理想的化学保护剂不应该干扰顺铂的治疗效果，而且本身毒性很小或没有毒性。因此，在我们最近完成的SBIR第一阶段研究中，我们研究了一种肿瘤坏死因子α的小分子调节剂UTL-5G，作为主要的化学保护剂。在这项SBIR I期研究的基础上，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对肾脏和肝脏具有保护作用。UTL-5g还能剂量依赖性地降低顺铂升高的血中肿瘤坏死因子-α水平。一个令人振奋的发现是，UTL-5G不仅没有降低顺铂在体内的抗肿瘤作用，而且预先处理UTL-5G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。SBIR第一阶段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]在动物实验中比较口服和IP注射(I期使用)的化学保护作用，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(S)的化学保护作用。[目的2]采用UTL-5g的最佳口服剂量和顺铂递增剂量，观察UTL-5g能否增加顺铂在小鼠体内的MTD。如果顺铂的MTD确实增加，在使用和不使用UTL-5G的新MTD进行顺铂的疗效评估。[目的3]使用目标1中的最佳口服剂量进行ADME研究。[目的4]放大合成原料药，制备最多1公斤的UTL-5G。[目的5]采用UTL-5G口服剂型，在GLP条件下对两种动物进行28天重复给药毒性研究。[目的6]研制适合首次临床试验的UTL-5G口服制剂；建立和验证口服制剂的分析方法；确定规格并进行口服剂型的稳定性研究。[目的7]准备一份适用于第一阶段临床试验的草案方案。[目标8]按照FDA行业指南的格式编写IND前程序包，并准备好与FDA召开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.