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 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，异常癌症诱发 循环系统中的免疫抑制性骨髓源性抑制细胞（MDSC）与肿瘤相关 黑色素瘤分期、转移性肿瘤负担、缺乏无进展生存期和无反应 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 并中和肿瘤细胞衰老。 MDSC 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 阻断是一种经过验证的治疗策略，可提供 对 (i) 依赖 CXCR1/2 自分泌信号传导生长的黑色素瘤细胞进行多管齐下的攻击，(ii) CXCR1/2 驱动的血管生成和 (iii) CXCR1/2 驱动的 MDSC 募集。 SX-682 是一款新型口服、 旨在破坏 CXCR1/2 信号传导的小分子免疫肿瘤学 (IO) 疗法。 SX-682 有一个 SX-682 的机制与任何当前的 IO 剂不同，并且与传统的化疗药物不同，SX-682 非常有效 耐受且无剂量限制毒性（DLT）。 SX-682 通过新颖的细胞内位点发挥作用，并表现出持久的 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着的活性，其中 在同基因和基因工程小鼠中逆转化疗耐药性，延长总体生存期 (GEM) 黑色素瘤模型，与抗 PD1 疗法有效协同并导致完全缓解。基于 根据这些数据以及许多其他独立实验室发布的临床前机制数据，我们 假设将 SX-682 与派姆单抗联合治疗转移性黑色素瘤将提高疗效 与历史上的派姆单抗单一疗法相比，但没有增加毒性。如果成功，SX-682 将是一个关键 转移性黑色素瘤现有治疗方案的新补充。通过具体实施 目标是，我们将通过针对人类黑色素瘤的关键首次人体概念验证 (POC) 测试来推进 SX-682 （第一个 CXCR1 或 CXCR2 抑制剂）。开放标签3+3升级和扩展试验设计是 肿瘤学 POC 测试的标准。主要目标是确定 SX-682 的安全性 单独使用或与派姆单抗联合使用。次要目标是评估 SX-682 的功效并表征其特性 单剂量和多剂量 PK 曲线。相关研究将检查疗效与免疫生物标志物：肿瘤 MDSC、Treg 和 T 细胞（连续活检）以及循环 MDSC、中性粒细胞、中性粒细胞与淋巴细胞比率 (NLR)、Treg、T 细胞和 B 细胞、CD4:CD8 比率。根据临床前数据，我们假设 SX-682 plus 与历史上的帕博利珠单抗疗效相比，帕博利珠单抗将表现出增强的疗效，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展。