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