Background: RGX-104 is a small-molecule LXR agonist that activates the expression of the ApoE gene. We have identified the LXR/ApoE pathway as a novel innate-immune checkpoint that stimulates antitumor immunity. LXR agonist-mediated ApoE induction depletes circulating and tumor-infiltrating myeloid derived suppressor cells (MDSCs), resulting in activation of cytotoxic lymphocytes (CTLs) in murine tumor models. Treatment with RGX-104 as monotherapy elicited significant antitumor activity in a variety of preclinical models, including B16F10, LLC, and CT26. Additionally, combining RGX-104 with a PD-1 antagonist yielded synergistic antitumor activity in PD-1 resistant models. These data motivated studies of RGX-104 in patients with refractory cancer. Methods: We are conducting a first-in-human, dose escalation and expansion phase 1 study of RGX-104 in patients with refractory solid tumors or lymphomas. Safety, PK, PD, efficacy, and immunologic activity are being assessed. Results: RGX-104 was dosed orally for 21 days with a 1-week rest (28 day cycle), at 120 mg QD (n=3) and 240 mg QD (n=4). Tumor types in cohorts 1 and 2 included colon, uterine, renal, melanoma, cholangiocarcinoma, and Ewing’s sarcoma. PK analysis demonstrated dose-proportional drug increases in AUC and a t 1/2 of ~7 hours with oral administration. Induction of ApoE gene expression in peripheral blood cells (median 3.57-fold; mean 11.61-fold at steady-state) correlated with RGX-104 drug exposure, indicating robust LXR target engagement. Monitoring of relevant immune-cell populations in peripheral blood revealed substantial MDSC depletion in 6/6 evaluable patients, with up to 95% depletion of granulocytic (CD33 + CD15 + HLA-DR -/low ; median 86% decrease; mean 85%) and up to 89% depletion of monocytic (CD14 + Lin - HLA-DR -/low ; median 33% decrease; mean 45%) MDSCs. Treatment resulted in a significant increase in activated CTLs (PD-1 + GITR + CD8 + T-cells as a proportion of all CD8+ T-cells) in 5/6 evaluable patients (median 322% increase; mean 352%). Peak effects on ApoE, MDSCs, and CTLs began ~2 weeks after RGX-104 initiation. In order to maximize the achievement of biologically relevant RGX-104 exposure, and therefore desirable immune effects throughout the treatment period, continuous dosing at 120 mg BID is being evaluated in cohort 3. One of two evaluable patients in cohort 3 experienced reversible grade 4 neutropenia and grade 2 lipid elevations, which are “on-target” adverse events. No other grade 3-4 adverse events attributable to RGX-104 have occurred. One renal cancer and one melanoma patient-both refractory to anti-PD-1 therapy–had stable disease. Conclusions: Proof of principle has been demonstrated for the immune-stimulatory action of the first-in-class LXR-agonist RGX-104 in advanced cancer patients. RGX-104 activated ApoE in peripheral blood cells in a dose-dependent fashion and was well tolerated when administered orally at 120 mg or 240 mg QD. RGX-104 selectively depleted MDSCs, leading to activation of the relevant PD-1 + CTL population in a diverse group of cancer patients harboring PD-1 inhibitor refractory disease and immune-therapy resistant cancers. Dosing of RGX-104 at 120 mg BID continues. Future plans include studying RGX-104 both as monotherapy and in combination with a PD-1 inhibitor in select malignancies. Citation Format: Monica Mita, Alain Mita, Bartosz Chmielowski, Michael Postow, Erika Hamilton, Shubham Pant, Roger Waltzman, Eric Rowinsky, Michael Szarek, Foster Gonsalves, Isabel Kurth, Celia Andreu, Ilana Pollack, Daniel Mucida, Raissa Tanqueco, Sohail Tavazoie, Masoud Tavazoie. A phase 1 trial of RGX-104, a first-in-class immunotherapy targeting the liver-X nuclear hormone receptor (LXR), in patients with refractory malignancies [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr B001.