Abstract CT234: Phase I study of epacadostat added to preoperative chemoradiation in patients with locally advanced rectal cancer

Background: Epacadostat is an orally active, potent and selective inhibitor of indoleamine 2, 3-dioxygenase 1 (IDO1). IDO1 inhibition enhances cytotoxic T cell activation by dendritic cells, and significantly decreases regulatory T cell proliferation. We developed preclinical data supporting combination of epacadostat with radiation therapy in rectal cancer. In rectal cancer samples obtained from patients who received hypofractionated radiation, IDO1 was overexpressed in tumor tissue as compensatory response after radiation in both microsatellite stable and unstable cell lines. IDO1 inhibition with epacadostat selectively reduced survival of cancer cells and enhanced radiosensitivity without impacting normal epithelial cells. Epacadostat in addition to radiation showed both increased tumor cytotoxicity and enhanced immune activation in tumor microenvironment in a syngeneic mouse model of colorectal cancer. Literature also supports the choice of high dose, hypofractionated radiation to induce a more favorable anti-tumor immune response. Therefore, we hypothesized that IDO1 expression is a mechanism of radioresistance in rectal cancer and IDO1 inhibition is a safe and well-tolerated combination therapy to enhance tumor radiosensitivity. Methods: Patients with locally advanced rectal cancer who are candidates for neoadjuvant therapy using short-course radiation and chemotherapy are included in this study. Primary objective of the study is to determine the recommended phase II dose (RP2D) of epacadostat for combination with short course radiation and chemotherapy in preoperative treatment of locally advanced rectal cancer. This study includes dose-escalation part of patients receiving epacadostat with radiation and chemotherapy (n=6-18) followed by dose-expansion (n=up to 27 including those treated at RP2D during escalation). Two dose levels of epacadostat (300mg and 600mg orally twice daily) will be explored. Epacadostat will be combined with short-course radiation (5Gy x 5 fractions) followed by 6 cycles of CAPOX chemotherapy, until the day of surgery for a total of approximately 24 weeks of therapy. Research biopsies of tumor and adjacent non-tumor tissue along with blood sample collection will be performed before and after the radiation, and at the time of surgery. Tryptophan pathway metabolites, immune checkpoint biomarkers, markers of cell death, proliferation and potentially prognostic molecular biomarkers will be measured in tumor tissues before and after radiation therapy. In addition, patient-derived organoid and xenograft models from rectal biopsy samples will be used to determine the success rate of organoid generation, to evaluate treatment response and to characterize molecular changes to identify potential predictors of response and mechanisms of resistance. Enrollment began in November 2019. NCT03516708 Citation Format: Haeseong Park, Ebunoluwa Otegbeye, Hyun Kim, Matthew Mutch, Katrina Pedersen, Manik Amin, Benjamin Tan, Nikolaos Trikalinos, Kian-Huat Lim, Olivia Aranha, Rama Suresh, Shahed Badiyan, Matthew Silviera, Lauren Henke, Paul Wise, Steven Hunt, Jonathan Mitchem, Esther Lu, Andrea Wang-Gillam, Matthew Ciorba. Phase I study of epacadostat added to preoperative chemoradiation in patients with locally advanced rectal cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT234.