A phase 1b study to assess the safety of PLX3397, a CSF-1 receptor inhibitor, and paclitaxel in patients with advanced solid tumors.

TPS3127 Background: Tumor-associated macrophages (TAMs) mediate resistance to chemotherapy and radiation therapy. Macrophages are regulated in part by colony stimulating factor -1 (CSF-1), which signals through the CSF-1 receptor (CSF-1R) expressed predominantly on TAMs. CSF-1 is expressed by several types of malignancies (including breast and prostate cancer, leiomyosarcoma and glioblastoma) and correlates with extent of TAM presence in tumor parenchyma. Preclinical studies demonstrated that tumor exposure to cytotoxic therapies such as paclitaxel, cisplatin or ionizing radiation lead to increased expression of CSF-1, IL-34 (the other ligand for CSF1R), and chemokines regulating TAM recruitments, CCL8/MCP2. This is associated with an increased presence of TAMs in residual tumors, resulting in a tumor immune microenvironment favoring malignant cell proliferation and survival. PLX3397 is an orally available small molecule inhibitor of CSF-1R with IC50 of ~17 nM. In vivo studies in transgenic MMTV-PyMT mice...