A Phase 1 Clinical Trial Evaluating the Novel Small Molecule Immuno-Oncology Antagonist SX-682 Alone and With Pembrolizumab in Metastatic Melanoma

趋化因子受体CXCR1和CXCR2(CXCR1/2)被证实在 分泌大量黑色素瘤的生长、存活、运动、侵袭和血管生成 相应的趋化因子配体，包括CXCL8。此外，异常致癌 循环中的免疫抑制髓系来源的抑制细胞与肿瘤相关 黑色素瘤分期、转移性肿瘤负担、无进展生存和对 免疫疗法。MDSCs有效抑制免疫监视，促进肿瘤细胞侵袭，血管生成 并中和肿瘤细胞的衰老。MDSCs通过激活人类趋化因子被招募到肿瘤中 受体亚型CXCR1/2。因此，双重CXCR1/2阻断是一种有效的治疗策略，可提供 多管齐下攻击(I)依赖CXCR1/2自分泌信号生长的黑色素瘤细胞，(Ii) CXCR1/2驱动的血管生成和(Iii)CXCR1/2驱动的MDSCs募集。SX-682是一款全新的口语， 旨在干扰CXCR1/2信号的小分子免疫肿瘤学(IO)疗法。SX-682有一个 与目前任何IO剂不同的是，SX-682与传统化疗药物不同，它的作用机理非常好- 耐受，无剂量限制毒性(DLT)。SX-682通过一个新的细胞内位置工作，并表现出耐用性 两种受体的拮抗作用(&gt；12小时)。SX-682在实体瘤模型中显示出显著的活性，在那里它 逆转化疗耐药，延长总生存期，以及在同基因和基因工程小鼠中 (GEM)黑色素瘤模型，与抗PD1治疗有效地协同作用并导致完全缓解。基座 根据这些数据和许多其他独立实验室发布的临床前机制数据，我们 假设SX-682与培溴利珠单抗联合治疗转移性黑色素瘤将提高疗效 与历史上的pembrolizumab单一疗法相比，但没有额外的毒性。如果成功，SX-682将是一款关键的 对转移性黑色素瘤现有治疗方案的新补充。通过执行特定的 AIMS，我们将通过对人类黑色素瘤的关键的第一人概念验证(POC)测试来推进SX-682 (首次使用CXCR1或CXCR2抑制剂)。开放标签3+3升级和扩展试验设计为 这是肿瘤学POC测试的标准。主要目标是确定SX-682的安全性 单独和培布罗利单抗一起服用。次要目标是评估SX-682的疗效并表征其特性 单剂量和多剂量PK谱。相关研究将检验疗效与免疫生物标记物：肿瘤 MDSCs、Tregs和T细胞(连续活检)和循环MDSCs、中性粒细胞、中性粒细胞/淋巴细胞比率 (NLR)、Tregs、T细胞和B细胞、CD4/CD8比值。基于临床前数据，我们假设SX-682 Plus Pembrolizumab将表现出比以往的Pembrolizumab疗效更高的疗效，但不会增加毒性。 如果成功，这将是转移性黑色素瘤治疗的重大临床进步。

The chemokine receptors CXCR1 and CXCR2 (CXCR1/2) are validated as having essential roles in the growth, survival, motility, invasion and angiogenesis of human melanoma, which secretes abundant amounts of the corresponding chemokine ligands, including CXCL8. Additionally, abnormal cancer-induced immunosuppressive myeloid-derived suppressor cells (MDSCs) in the circulation and tumor correlate with melanoma stage, metastatic tumor burden, lack of progression-free survival and non-response to immunotherapy. MDSCs potently suppress immune surveillance, promote tumor cell invasion, angiogenesis and neutralize tumor cell senescence. MDSCs are recruited to tumors through activation of human chemokine receptor isoforms CXCR1/2. Dual CXCR1/2 blockade is thus a validated therapeutic strategy to deliver a multi-pronged attack on (i) melanoma cells that depend on CXCR1/2 autocrine signaling for growth, (ii) CXCR1/2-driven angiogenesis and (iii) CXCR1/2-driven recruitment of MDSCs. SX-682 is a new-in-class oral, small-molecule, immuno-oncology (IO) therapy directed at disrupting CXCR1/2 signaling. SX-682 has a mechanism unlike any current IO agent, and unlike conventional chemotherapeutics, SX-682 is extremely well- tolerated with no dose-limiting toxicity (DLT). SX-682 works via a novel intracellular site, and exhibits durable antagonism of both receptors (> 12 hours). SX-682 exhibits significant activity in solid tumor models, where it reversed chemoresistance, extended overall survival, and in syngeneic and genetically engineered mouse (GEM) melanoma models, potently synergized with anti-PD1 therapy and caused complete remissions. Based on these data and the preclinical mechanistic data published by many other independent laboratories, we hypothesize that combining SX-682 with pembrolizumab in metastatic melanoma will afford enhanced efficacy vs. historical pembrolizumab monotherapy, but with no added toxicity. If successful, SX-682 would be a critical new addition to the existing treatment landscape in metastatic melanoma. Through execution of the Specific Aims, we will advance SX-682 through critical first-in-man proof-of-concept (POC) testing in human melanoma (the first ever of a CXCR1 or CXCR2 inhibitor). The open-label 3+3 escalation and expansion trial design is standard for this POC testing in oncology. The primary objective is to determine the safety profile of SX-682 alone and with pembrolizumab. Secondary objectives are to evaluate SX-682 efficacy and characterize its single-dose and multidose PK profile. Correlative studies will examine efficacy vs. immune biomarkers: tumor MDSCs, Tregs and T cells (serial biopsies), and circulating MDSCs, neutrophils, neutrophil-to-lymphocyte ratio (NLR), Tregs, T- and B-cells, the CD4:CD8 ratio. Based on preclinical data, we hypothesize SX-682 plus pembrolizumab will exhibit enhanced efficacy vs. historical pembrolizumab efficacy, but without added toxicity. If successful, this would be a major clinical advance in the treatment of metastatic melanoma.