X4P-001 and Pembrolizumab in Patients With Advanced Melanoma

X4P-001 is an orally bioavailable CXCR4 antagonist that has demonstrated activity in various tumor models. CXCR4 (C-X-C chemokine receptor type 4) is the receptor for CXCL12 (C-X-C chemokine ligand type 12). CXCL12 has potent chemotactic activity for lymphocytes and MDSCs (myeloid-derived suppressor cells), and is important in homing of hematopoietic stem cells to the bone marrow. CXCR4 is also expressed and active on multiple types of human cancers, including melanoma, ccRCC, and ovarian cancer. Additionally, increased expression of CXCR4 on tumor cells has been associated with significantly decreased overall participant survival. In animal cancer models, interference with CXCR4 function has been demonstrated to disrupt the tumor microenvironment (TME) and unmask the tumor to immune attack by multiple mechanisms, including: * Decreasing the infiltration of MDSCs * Increasing the ratio of CD8+ T cells to Treg cells * Eliminating tumor re-vascularization Pembrolizumab is a humanized IgG4 kappa monoclonal antibody that blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2. Pembrolizumab is currently approved for the treatment of unresectable or metastatic melanoma. Analysis of tumor samples before and during treatment in an earlier study demonstrated that a clinical response was associated with an increase in the density of CD8+ T cells in the tumor parenchyma (center), while disease progression was associated with persistent low levels of those cells. In an autochthonous murine model of pancreatic adenocarcinoma, persistent tumor growth despite administration of anti-PD-L1 was similarly associated with failure of tumor-specific cytotoxic T cells to enter the TME despite their presence in the peripheral circulation. This immunosuppressed phenotype was associated with CXCL12 production by cancer-associated fibroblasts. Moreover, administration of a CXCR4 antagonist (AMD3100) induced rapid T-cell accumulation among the cancer cells and, in combination with anti-PD-L1, synergistically decreased tumor growth. Based on these observations, the hypothesis is that effective CXCR4 antagonism by X4P-001 would be of potential benefit in participants with advanced melanoma and other cancers by multiple mechanisms, resulting in increased anti-tumor immune attack.