HLS- A Phase 1 Open-Label Dose-Escalation with Expansion Study of SX-682 in MDS Patients

此SBIR快速通道提案符合NHLBI小型企业特别关注主题的目标， 2017财年代码HLS 17 -04。骨髓增生异常综合征（MDS）是遗传和形态学 由造血干细胞内的一小部分突变克隆引起的多种造血肿瘤， 祖细胞隔室。只有三种药物获得了专门用于MDS治疗的监管批准， 所有这些都具有<50%的次优响应率和有限的耐久性，通常为1-2年。一旦这些特工 不再有效，没有建立用于二线治疗的护理标准（即，在 复发/难治性环境）。此外，低甲基化剂失败后的预后令人沮丧， 高风险患者估计生存期<6个月，低风险患者估计生存期<18个月。颇为明显的一点 是对新的MDS治疗的显著未满足的需求，所述新的MDS治疗（a）根除白血病前干细胞并导致 血细胞减少症的长期缓解和正常化，以及（B）实现该目标而不需要以下的沉重代价： 副作用，特别是在低风险MDS中。 MDS患者的干细胞和早期祖细胞持续过表达趋化因子CXCL 8 （IL-8）及其受体CXCR 2。抑制CXCR 2选择性抑制MDS干细胞生长 患者而非健康对照，证明了临床前治疗原理验证并验证了CXCR 2 作为MDS的治疗靶点。此外，髓源性抑制细胞（MDSC）明显 在MDS患者的骨髓中增加，在那里它们诱导骨髓发育不良并损害免疫功能 监测和清除突变克隆。CXCR 2和CXCR 1在MDSC招募中起关键作用。双 因此，CXCR 1和CXCR 2（CXCR 1/2）抑制是一种用“一个- （i）突变型MDS细胞直接和（ii）MDSC驱动的免疫抑制骨髓 微环境 由Syndrome在NHLBI（IND开放用于黑色素瘤）的支持下，经过十年的长期发现努力开发 4/16），SX-682是一种新型口服小分子免疫肿瘤学（IO）疗法，旨在破坏 CXCR 1/2信号传导。我们假设，在MDS中，SX-682将导致长期缓解和正常化 血细胞减少症，但与其他疗法相比，只有轻微的副作用。如果成功，SX-682 将彻底改变MDS的现有治疗格局。通过执行具体目标，我们将 通过1期、开放标签剂量递增和扩展试验推进SX-682，以评估SX-682在 发生进展或对既往治疗不耐受的MDS患者。SX-682 MDS IND 131，876是 于2017年9月1日开放，本试验的入组可能开始。

This SBIR Fast-Track proposal meets the objectives of NHLBI Small Business Topic of Special Interest for Fiscal Year 2017 Code HLS17-04. Myelodysplastic syndromes (MDS) are genetically and morphologically diverse hematopoietic neoplasms that arise from a small pool of mutant clones within hematopoietic stem and progenitor compartments. Only three drugs have received regulatory approval specifically for MDS treatment, all with suboptimal response rates of <50% and of limited durability, typically 1-2 years. Once these agents are no longer effective, there is no standard of care established for second-line treatment (i.e., in the relapsed/refractory setting). Furthermore, prognosis after hypomethylating agent failure is dismal, with median survival estimated at <6 months for higher-risk patients, and <18 months for lower-risk patients. Clearly there is a significant unmet need for a new MDS treatment that both (a) eradicates preleukemic stem cells and leads to long-term remission and normalization of cytopenias, and (b) achieves this goal without the heavy cost of side effects, particularly in lower-risk MDS. Stem cells and early progenitors from MDS patients consistently overexpressed the chemokine CXCL8 (IL-8) and its receptor, CXCR2. Inhibition of CXCR2 selectively arrested the growth of stem cells from MDS patients but not healthy controls, demonstrating preclinical therapeutic proof-of-principle and validating CXCR2 as a therapeutic target in MDS. Additionally, myeloid-derived suppressor cells (MDSCs) are markedly increased in the bone marrow of MDS patients where they induce myelodysplasia and impair immune surveillance and clearance of mutant clones. CXCR2 and CXCR1 are pivotal in MDSC recruitment. Dual CXCR1 and CXCR2 (CXCR1/2) inhibition is therefore a novel therapeutic strategy to treat MDS with a “one- two punch” to (i) the mutant MDS cells directly and (ii) the MDSC-driven immunosuppressive marrow microenvironment. Developed by Syntrix in a decade's long discovery effort supported by NHLBI (IND open for melanoma 4/16), SX-682 is a new-in-class oral, small-molecule, immuno-oncology (IO) therapy directed at disrupting CXCR1/2 signaling. We hypothesize that in MDS, SX-682 will lead to long-term remissions and normalization of cytopenias, but with only a mild side-effect effect profile compared to other therapies. If successful, SX-682 would revolutionize the existing treatment landscape in MDS. Through execution of the Specific Aims, we will advance SX-682 through a Phase 1, open label dose-escalation and expansion trial to evaluate SX-682 in MDS patients who had progression or were intolerant to prior therapy. The SX-682 MDS IND 131,876 was opened on September 1, 2017, and enrollment for this trial may begin.