Arylsulfonamides for the Treatment of Primary and Metastatic Uveal Melanoma

摘要： 这项第二阶段SBIR的目标是作为联合的一部分，促进OncoSpherix的HIF-1抑制剂64B的发展 治疗转移性和高危葡萄膜黑色素瘤(UM)，这是成人最常见的原发眼癌。64亿 是一种小分子治疗剂，通过干扰转录共刺激因子的募集来抑制HIF功能。 P300/CBP，同时保持完整的p300/CBP与多种其他转录因子结合的能力。AS 因此，64B在荷瘤小鼠身上长期耐受性良好，无论是单独还是联合使用 与多种其他癌症疗法相结合。 我们已经发表了一些研究，其中几个UM细胞系被原位植入葡萄膜内 对眼睛的研究表明，64B抑制了小鼠的原发肿瘤生长和转移，同时还延长了生存时间。 我们第一阶段SBIR研究的结果建立在先前工作的基础上，并有力地支持了继续发展 64B作为一种重要的、新颖的、创新的癌症治疗方法。64b显示出卓越的治疗效果 与两种处于临床2期或3期的酪氨酸激酶抑制剂(TKI、舒尼替尼和塞鲁米替尼)相比 正在测试UM。64B较TKI耐受性好。当治疗时肿瘤大得多的时候 开始，64B与索拉非尼联合治疗UM的临床试验中的另一种TKI显示出治疗协同作用。 我们的I期SBIR研究在推动64B进入临床所需的化学方面取得了重大进展 测试。选择了一种5步合成方法，消除了使用微波反应器， 钯催化剂的提纯和应用。总产量从2%左右提高到22%， 或者说，在五个阶段中，每个阶段的收益率约为75%。通过对工艺的改进，64B中的700g 生产的纯度为98%，为拟议的SBIR第二阶段研究提供了足够的64B。我们测试了无定形的 固体分散体(ASD)作为一种增强型配方方法，将64B的溶解度提高了40倍以上。 代谢和PK研究提供证据表明，口服64B的血浆水平不足以完全 阻断HIF，很可能是由于肝脏的首次通过效应，因此我们将重点放在肠外给药上 临床前和临床研究。 第二阶段SBIR研究将确定最佳的64B-TKI类组合，以推进临床测试 UM细胞直接植入眼睛的葡萄膜。几种UM细胞株对64B的反应性研究 有针对性地删除HIF-1a、HIF-2a或两者都将增加额外的机械性见解。其他目标是 专注于转换为静脉给药进行有效性和非GLP毒理学研究，包括确定 两个物种的最大耐受剂量64B和重复剂量毒性。我们期待着成功完成 在两年内实现所有具体目标，并确保完成支持IND的研究所需的额外资金， 申请IND，并使用64B和TKI对转移性UM进行临床测试。

Summary: The goal of this Phase II SBIR is to advance OncoSpherix’s HIF-1 inhibitor, 64B, as part of combination therapy for metastatic and high-risk uveal melanoma (UM), the most prevalent primary eye cancer in adults. 64B is a small molecule therapeutic that inhibits HIF function by disrupting the recruitment of the transcriptional co- factor, p300/CBP, while leaving intact p300/CBP’s ability to function with multiple other transcription factors. As a consequence, 64B is well-tolerated for prolonged periods in tumor bearing mice, both alone and in combination with multiple other cancer therapeutics. We’ve published studies where several UM cell lines were orthotopically implanted within the uveal of the eye, showing that 64B inhibits primary tumor growth and metastases in mice while also prolonging survival. Results from our Phase I SBIR studies built on this prior work and strongly support the continued development of 64B as an important, novel and innovative cancer therapeutic. 64B demonstrated superior therapeutic efficacy when compared to two tyrosine kinase inhibitors (TKIs, sunitinib and selumetinib) that are in phase 2 or 3 clinical testing for UM. 64B was better tolerated that the TKIs. When tumors were much larger when treatment was started, 64B showed therapeutic synergy when combined with sorafenib, another TKI in clinical testing for UM. Our Phase I SBIR studies led to significant progress in the chemistry needed to advance 64B into clinical testing. A 5-step synthesis was selected that eliminated the use of microwave reactors, chromatographic purifications and use of palladium catalysts. The overall production yield was improved from about 2 % to >22%, or about 75% yield per stage across the five stages. Through refinement of the process, 700 g of 64B were produced with >98 % purity, providing sufficient 64B for proposed SBIR phase 2 studies. We tested amorphous solid dispersion (ASD) as an enhanced formulation method that improved 64B’s solubility more than 40-fold. Metabolic and PK studies provided evidence the plasma levels of orally delivered 64B were insufficient to fully block HIF, most likely due to first pass effects in the liver, and thus we will focus on parenteral delivery for preclinical and clinical studies. Phase II SBIR studies will identify the best 64B-TKI class combination to advance for clinical testing using UM cells directly implanted in the uvea of the eye. Studies on responsiveness to 64B using several UM cell lines with targeted deletion of HIF-1a, HIF-2a or both will add additional mechanistic insights. Other objectives are focused on converting to IV dosing for both efficacy and non-GLP toxicology studies, including determining the maximum tolerated dose of 64B and repeat dosing toxicity in two species. We anticipate successful completion of all specific aims within 2 years and securing the additional funds needed for completing IND-enabling studies, filing an IND, and launching clinical testing using 64B with a TKI for metastatic UM.