SBIR-STTR Award

The chemokine receptors CXCR and CXCR CXCR 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 CXCL 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 CXCR Dual CXCR blockade is thus a validated therapeutic strategy to deliver a multi pronged attack on i melanoma cells that depend on CXCR autocrine signaling for growth ii CXCR driven angiogenesis and iii CXCR driven recruitment of MDSCs SX is a new in class oral small molecule immuno oncology IO therapy directed at disrupting CXCR signaling SX has a mechanism unlike any current IO agent and unlike conventional chemotherapeutics SX is extremely well tolerated with no dose limiting toxicity DLT SX works via a novel intracellular site and exhibits durable antagonism of both receptors andgt hours SX 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 PD 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 with pembrolizumab in metastatic melanoma will afford enhanced efficacy vs historical pembrolizumab monotherapy but with no added toxicity If successful SX would be a critical new addition to the existing treatment landscape in metastatic melanoma Through execution of the Specific Aims we will advance SX through critical first in man proof of concept POC testing in human melanoma the first ever of a CXCR or CXCR inhibitor The open label escalation and expansion trial design is standard for this POC testing in oncology The primary objective is to determine the safety profile of SX alone and with pembrolizumab Secondary objectives are to evaluate SX 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 CD CD ratio Based on preclinical data we hypothesize SX 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 In the United States will die from melanoma in Through the secretion of soluble factors cancers recruit myeloid derived suppressor cells MDSCs that block the therapeutic effects of chemotherapeutics and newer immune based therapies This proposal would advance the newly discovered drug SX into clinical evaluation for melanoma with the aim that SX would allow a patientandapos s immune system to more effectively attack the tumor by disrupting cancer mediated MDSC recruitment

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.

Public Health Relevance Statement:
In the United States, 9,940 will die from melanoma in 2015. Through the secretion of soluble factors, cancers recruit myeloid-derived suppressor cells (MDSCs) that block the therapeutic effects of chemotherapeutics and newer immune-based therapies. This proposal would advance the newly discovered drug SX-682 into clinical evaluation for melanoma with the aim that SX-682 would allow a patient's immune system to more effectively attack the tumor by disrupting cancer-mediated MDSC recruitment.

Project Terms:
Adverse effects; angiogenesis; anti-PD1 therapy; Autocrine Communication; B-Lymphocytes; base; Biopsy; Blood Circulation; CD4/CD8 ratio procedure; Cell Aging; cell motility; checkpoint inhibition; chemokine; chemokine receptor; chemotherapy; Clinic; Clinical; Correlative Study; cost; CTLA4 gene; Cyclic GMP; Data; Data Analytics; Disease Progression; Disease remission; Distant; Dose; Dose-Limiting; epithelial to mesenchymal transition; Exhibits; FDA approved; fighting; first-in-human; Formulation; Genetically Engineered Mouse; Goals; Growth; Hour; Human; IL8 gene; IL8RA gene; IL8RB gene; Immune checkpoint inhibitor; Immune system; Immunologic Markers; Immunologic Surveillance; Immunooncology; Immunosuppressive Agents; Immunotherapy; inhibitor/antagonist; Interleukin 8A Receptor; Laboratories; Ligands; Lymphocyte; Malignant Neoplasms; Mediating; melanoma; Melanoma Cell; Metastatic Melanoma; Modeling; Myeloid-derived suppressor cells; Myeloproliferative disease; neoplasm immunotherapy; Neoplasm Metastasis; neoplastic cell; neutrophil; novel; oncology; open label; optimism; Oral; Organ; Outcome; Patient-Focused Outcomes; Patients; Pharmaceutical Preparations; Phase; Phase I Clinical Trials; pre-clinical; Progression-Free Survivals; Protein Isoforms; Protocols documentation; Publishing; receptor; Records; recruit; Regulatory T-Lymphocyte; research clinical testing; Rest; Role; Safety; Signal Transduction; Site; small molecule; sobriety; Solid Neoplasm; stemness; success; T-Lymphocyte; Testing; Therapeutic; Therapeutic Effect; Toxic effect; trial design; tumor; Tumor Burden; Tumor Cell Invasion; tumor microenvironment; United States; United States National Institutes of Health; Work