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: 9348033
• 负责人: STUART J KAHN
• 金额: $ 62.1万
• 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 2018-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9348033
• 关键词: Adverse effects; Autocrine Communication; B-Lymphocytes; Biopsy; Blood Circulation; CD4/CD8 ratio procedure; CTLA4 gene; Cell Aging; Clinic; Clinical; Correlative Study; Cyclic GMP; Data; Data Analytics; Disease Progression; Disease remission; Distant; Dose; Dose-Limiting; Employee Strikes; Exhibits; FDA approved; Formulation; Genetically Engineered Mouse; Goals; Growth; Hour; Human; IL8 gene; IL8RA gene; IL8RB gene; Immune; Immune checkpoint inhibitor; Immune system; Immunologic Markers; Immunologic Surveillance; Immunooncology; Immunosuppressive Agents; Immunotherapy; Interleukin 8A Receptor; Laboratories; Ligands; Lymphocyte; Malignant Neoplasms; Mediating; Melanoma Cell; Metastatic Melanoma; Modeling; Myelogenous; Myeloproliferative disease; Neoplasm Metastasis; Oral; Organ; Outcome; Patient-Focused Outcomes; Patients; Pharmaceutical Preparations; Phase; Phase I Clinical Trials; Progression-Free Survivals; Protein Isoforms; Protocols documentation; Publishing; Records; Recruitment Activity; Regulatory T-Lymphocyte; Rest; Role; Safety; Signal Transduction; Site; Solid Neoplasm; Suppressor-Effector T-Lymphocytes; T-Lymphocyte; Testing; Therapeutic; Therapeutic Effect; Toxic effect; Tumor Burden; Tumor Cell Invasion; United States; United States National Institutes of Health; Work; angiogenesis; base; cell motility; chemokine; chemokine receptor; chemotherapy; cost; epithelial to mesenchymal transition; fighting; inhibitor/antagonist; man; melanoma; neoplasm immunotherapy; neoplastic cell; neutrophil; novel; oncology; open label; optimism; pre-clinical; receptor; research clinical testing; small molecule; sobriety; stemness; success; trial design; tumor; tumor microenvironment

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