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

评估新型小分子免疫肿瘤拮抗剂 SX-682 单独使用以及与 Pembrolizumab 联合治疗转移性黑色素瘤的 1 期临床试验

• 批准号: 10189528
• 负责人: STUART J KAHN
• 金额: $ 65.14万
• 依托单位: SYNTRIX BIOSYSTEMS, INC.
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-05-04 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10189528
• 关键词: Autocrine Communication; B-Lymphocytes; Biopsy; Blood Circulation; CD4/CD8 ratio procedure; CTLA4 gene; Cell Aging; Chemoresistance; Clinic; Clinical; Correlative Study; Cyclic GMP; Data; Data Analytics; Disease Progression; Disease remission; Distant; Dose; Dose-Limiting; Exhibits; FDA approved; Formulation; Genetically Engineered Mouse; Goals; Growth; Hour; Human; IL8 gene; IL8RA gene; IL8RB gene; Immune checkpoint inhibitor; Immune system; Immunologic Markers; Immunologic Surveillance; Immunooncology; Immunotherapy; Interleukin 8A Receptor; Laboratories; Ligands; Lymphocyte; Malignant Neoplasms; Mediating; Melanoma Cell; Metastatic Melanoma; Modeling; Myeloid-derived suppressor cells; Myeloproliferative disease; Neoplasm Metastasis; Nivolumab; Oncology; Oral; Organ; Outcome; Patient-Focused Outcomes; Patients; Pharmaceutical Preparations; Phase; Phase I Clinical Trials; Progression-Free Survivals; Protein Isoforms; Protocols documentation; Publishing; Records; Regulatory T-Lymphocyte; Rest; Role; Safety; Signal Transduction; Site; Solid Neoplasm; T-Lymphocyte; Testing; Therapeutic; Therapeutic Effect; Toxic effect; Tumor Burden; Tumor Cell Invasion; United States; United States National Institutes of Health; Work; angiogenesis; anti-CTLA-4 therapy; anti-CTLA4; anti-PD-1; anti-PD1 therapy; base; cell motility; checkpoint inhibition; chemokine; chemokine receptor; chemotherapy; cost; efficacy evaluation; epithelial to mesenchymal transition; fighting; first-in-human; inhibitor/antagonist; ipilimumab; melanoma; neoplasm immunotherapy; neoplastic cell; neutrophil; novel; open label; optimism; pembrolizumab; phase I trial; pre-clinical; receptor; recruit; research clinical testing; side effect; small molecule; stemness; success; trial design; tumor; tumor-immune system interactions

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.

趋化因子受体CXCR 1和CXCR 2（CXCR 1/2）被证实在免疫调节中具有重要作用。 人黑色素瘤的生长、存活、运动、侵袭和血管生成，其分泌大量 相应的趋化因子配体，包括CXCL 8。此外，异常的癌症诱导 循环和肿瘤中的免疫抑制性髓源性抑制细胞（MDSC）与 黑色素瘤分期、转移性肿瘤负荷、无进展生存期缺乏和对 免疫疗法。MDSC有效抑制免疫监视，促进肿瘤细胞侵袭，血管生成 中和肿瘤细胞衰老。MDSC通过激活人趋化因子被募集到肿瘤中 受体亚型CXCR 1/2。因此，双重CXCR 1/2阻断是一种有效的治疗策略， 对（i）依赖CXCR 1/2自分泌信号传导生长的黑素瘤细胞的多管齐下的攻击，（ii） CXCR 1/2驱动的血管生成和（iii）CXCR 1/2驱动的MDSC募集。SX-682是一种新型的口腔， 小分子，免疫肿瘤学（IO）治疗，旨在破坏CXCR 1/2信号传导。SX-682具有 与目前任何IO剂不同的机制，也与传统的化疗药物不同，SX-682非常好- 耐受，无剂量限制性毒性（DLT）。SX-682通过一个新的细胞内位点发挥作用，并表现出耐用性 两种受体的拮抗作用（> 12小时）。SX-682在实体瘤模型中表现出显著的活性， 逆转化疗耐药性，延长总生存期，并在同基因和基因工程小鼠中 (GEM)黑色素瘤模型，与抗PD 1治疗有效协同并引起完全缓解。基于 根据这些数据和许多其他独立实验室发表的临床前机制数据，我们 假设SX-682与帕博利珠单抗联合治疗转移性黑色素瘤将提高疗效 vs.历史上的派姆单抗单药治疗，但没有增加毒性。如果成功，SX-682将是一个关键的 转移性黑色素瘤现有治疗前景的新补充。通过执行具体的 目的是，我们将推进SX-682在人类黑色素瘤中通过关键的首次人体概念验证（POC）测试 (the首次使用CXCR 1或CXCR 2抑制剂）。开放标签3+3递增和扩展试验设计是 肿瘤学POC测试的标准。主要目的是确定SX-682的安全性 单独和与派姆单抗一起。次要目的是评价SX-682的疗效，并表征其 单次给药和多次给药PK特征。相关研究将检查疗效与免疫生物标志物：肿瘤 MDSC、TCF 3和T细胞（连续活检）以及循环MDSC、中性粒细胞、嗜中性粒细胞与淋巴细胞比率 (NLR)T细胞、T细胞和B细胞、CD 4：CD 8比值。基于临床前数据，我们假设SX-682加 派姆单抗将表现出与历史派姆单抗功效相比增强的功效，但没有增加的毒性。 如果成功，这将是转移性黑色素瘤治疗的一个重大临床进展。