Arylsulfonamides for the Treatment of Primary and Metastatic Uveal Melanoma

总结： 这项II期SBIR的目标是推进OncoSpherix的HIF-1抑制剂64 B，作为联合治疗的一部分。 转移性和高风险葡萄膜黑色素瘤（UM）的治疗，这是成人中最常见的原发性眼癌。64B 是一种小分子治疗剂，通过破坏转录辅因子的募集来抑制HIF功能， p300/CBP，同时保留完整的p300/CBP与多种其他转录因子一起发挥作用的能力。作为 因此，64 B在荷瘤小鼠中长期耐受良好，无论是单独还是联合使用 与其他多种癌症治疗方法的结合。 我们已经发表了一些研究，其中几种UM细胞系被原位植入葡萄膜内， 眼睛，显示64 B抑制小鼠中的原发性肿瘤生长和转移，同时也延长存活。 我们第一阶段SBIR研究的结果建立在这一先前工作的基础上，并有力地支持了持续的开发。 64 B作为一种重要的、新颖的和创新的癌症治疗剂。64 B显示出上级治疗功效 与处于2期或3期临床试验的两种酪氨酸激酶抑制剂（TKI，舒尼替尼和司美替尼）相比， 测试UM。64 B的耐受性优于TKI。当肿瘤大得多时， 开始时，64 B与索拉非尼（UM临床试验中的另一种TKI）联合使用时显示出治疗协同作用。 我们的I期SBIR研究在推进64 B进入临床所需的化学方面取得了重大进展。 试验.选择了5步合成，其消除了微波反应器的使用， 纯化和钯催化剂的使用。总生产产率从约2%提高到> 22%， 或在五个阶段中每阶段约75%的产率。通过工艺的改进，制备了700 g 64 B。 以> 98%的纯度生产，为提议的SBIR 2期研究提供足够的64 B。我们测试了无定形 固体分散体（ASD）作为一种增强的制剂方法，将64 B的溶解度提高了40倍以上。 代谢和PK研究提供了口服递送的64 B的血浆水平不足以完全抑制的证据。 阻断HIF，最有可能是由于肝脏中的首过效应，因此我们将专注于胃肠外递送， 临床前和临床研究。 II期SBIR研究将确定最佳的64 B-TKI类组合，以推进临床试验， UM细胞直接植入眼睛的葡萄膜中。几种UM细胞系对64 B反应性的研究 靶向缺失HIF-1a、HIF-2a或两者将增加额外的机制见解。其他目的 专注于将疗效和非GLP毒理学研究转换为IV给药，包括确定 64 B的最大耐受剂量和两个物种的重复给药毒性。我们期待圆满完成 在两年内实现所有具体目标，并确保完成国家工业发展扶持研究所需的额外资金， 提交IND，并启动使用64 B与TKI治疗转移性UM的临床试验。

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.