Novel small-molecule TNF-a modulators as chemoprotective agents

作为化学保护剂的新型小分子 TNF-a 调节剂

基本信息

批准号：
8323860
负责人：
Jiajiu Shaw
金额：
$ 54.22万
依托单位：
21ST CENTURY THERAPEUTICS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-08-01 至 2014-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8323860
关键词：
ADME Study Acute Adverse effects Affect Alanine Transaminase Amifostine Animals Aspartate Transaminase Blood Blood Urea Nitrogen Chemoprotective Agent Cisplatin Clinical Clinical Trials Creatinine Cytotoxic agent Development Dosage Forms Dose Drug Formulations FDA approved Foundations Goals Health system Hepatotoxicity Industry Injection of therapeutic agent Institutes Kidney Licensing Liver Maximum Tolerated Dose Mus Myelosuppression Nitrogen Oral Pharmacologic Substance Phase Phase I Clinical Trials Platinum Prodrugs Protocols documentation Radiation therapy Reducing Agents Regimen Science Small Business Innovation Research Grant Solid Sulfur Therapeutic Therapeutic Effect Toxic effect Tumor Necrosis Factor-alpha Universities Up-Regulation Urine analytical method base chemotherapy dosage improved in vivo meetings microbial alkaline proteinase inhibitor nephrotoxicity novel phase 1 study phase 2 study pre-clinical prevent protective effect scale up small molecule tumor

项目摘要

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.

描述（申请人提供）：顺铂是一种广泛使用的细胞毒性药物，对多种肿瘤具有治疗活性，但也具有显着的副作用，包括肾毒性、肝毒性和骨髓抑制。因此，减少顺铂副作用而不影响其疗效的化学保护剂将具有显着的临床益处。目前，氨磷汀是 FDA 唯一批准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，氨磷汀存在显着的局限性，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，表明对肾脏和肝脏有保护作用通过UTL-5g。顺铂升高的TNF-α血液水平也被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，UTL-5g的预处理实际上还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，持续的临床前开发是有必要的。本次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腹腔注射（I期使用）的化疗保护作用，确定UTL-5g的最佳口服剂量。如果 ADME 研究表明 UTL-5g 可能是前药，我们还将使用相同的方案来研究代谢物的化学保护作用。 [目标2]利用UTL-5g的最佳口服剂量（目标1中确定的）和顺铂剂量的增加剂量来研究UTL-5g是否可以增加小鼠顺铂的MTD。如果顺铂的 MTD 确实增加，则在使用或不使用 UTL-5g 的情况下以新的 MTD 进行顺铂的治疗评估。 [目标 3] 使用目标 1 中的最佳口服剂量进行 ADME 研究。 [目标 4] 扩大 API 的合成规模并制备最多 1 kg 的 UTL-5g。 [目标5]采用UTL-5g口服剂型，在GLP条件下对两个物种进行28天重复给药毒性研究。【目标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；确定口服剂型的规格并进行稳定性研究。 [目标 7] 准备适合第一个 I 期临床试验的方案草案。 [目标 8] 按照 FDA 行业指南的格式编制 IND 前包，并为与 FDA 举行的 IND 前会议做好准备。