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）被验证为在 人类黑色素瘤的生长，生存，运动，侵袭和血管生成，分泌丰富的量 包括CXCL8在内的相应趋化因子配体中。另外，癌症引起的异常 循环中的免疫抑制髓样衍生的抑制细胞（MDSC），肿瘤与 黑色素瘤阶段，转移性肿瘤负担，缺乏无进展的生存和无反应 免疫疗法。 MDSC有效抑制免疫监测，促进肿瘤细胞侵袭，血管生成 并中和肿瘤细胞衰老。通过激活人趋化因子将MDSC募集到肿瘤 受体同工型CXCR1/2。因此，双CXCR1/2封锁是一种经过验证的治疗策略 依赖于CXCR1/2自分泌信号的（I）生长的（I）的多管齐下攻击（I） CXCR1/2驱动的血管生成和（III）CXCR1/2驱动的MDSC募集。 SX-682是一类新的口头， 小分子，免疫肿瘤学（IO）治疗，旨在破坏CXCR1/2信号传导。 SX-682有一个 与当前的IO代理不同，与常规化学治疗药不同，SX-682非常好 无剂量限制毒性（DLT）耐受。 SX-682通过新型细胞内部位工作，并表现出耐用 两个受体的对抗（> 12小时）。 SX-682在实体瘤模型中表现出显着的活性 逆转化学抗性，延长的总生存期以及合成和基因工程的小鼠 （GEM）黑色素瘤模型有效地通过抗PD1治疗协同，并导致完全缓解。基于 关于这些数据以及许多其他独立实验室发布的临床前机械数据，我们 假设将SX-682与Pembrolizumab结合在转移性黑色素瘤中将获得增强的功效 与历史pembrolizumab单一疗法相比，但没有附加的毒性。如果成功，SX-682将是关键 转移性黑色素瘤中现有治疗景观的新增加。通过执行特定 目的，我们将通过人类黑色素瘤中的关键概念验证（POC）测试提高SX-682 （CXCR1或CXCR2抑制剂的第一个）。开放标签3+3升级和扩展试验设计是 该POC测试的标准肿瘤学。主要目的是确定SX-682的安全性 单独和pembrolizumab。次要目标是评估SX-682的功效并表征其功效 单剂量和多糖PK曲线。相关研究将检查功效与免疫生物标志物：肿瘤 MDSC，Treg和T细胞（系列活检）以及循环的MDSC，中性粒细胞，中性粒细胞与淋巴细胞比例 （NLR），Tregs，T和B细胞，CD4：CD8比率。根据临床前数据，我们假设SX-682 Plus pembrolizumab与历史pembrolizumab功效相比，将表现出增强的功效，但没有增加的毒性。 如果成功，这将是治疗转移性黑色素瘤的主要临床进步。