Background: Immune checkpoint inhibitors (CPIs) have shown promising efficacies in several types of malignancies. However, still around half of patients with most tumor types experienced disease progression at the initial tumor assessment. One possible reason for resistance to CPIs is suspected to be based on interaction with cancer niche which include suppressive immune cells such as myeloid-derived suppressor cells (MDSC), regulatory T cells (Tregs) and tumor-associated macrophages (TAMs). Previous in vivo study showed that selective inhibition of VEGF pathway with anti-VEGF antibody or anti-VEGF tyrosine kinase inhibitors (TKIs) suppress tumor growth and decrease MDSC, Tregs and TAMs. In addition, suppression of stem cell factor (SCF)-mediated signaling though c-Kit also decreases MDSC expansion and tumor angiogenesis, which may overcome resistance to CPIs. Therefore, we initiated phase I study to assess efficacy and safety for the combination of nivolumab and regorafenib as a multi-kinase inhibitor targeting both VEGF and SCF signaling. Methods: The main eligibility criteria is patients with unresectable recurrent solid tumors who are refractory or intolerant to standard chemotherapy. Primary objective is to examine the safety and tolerability of repeated dosing of regorafenib and nivolumab and to investigate the maximum tolerated dose (MTD) and recommended dose (RD). Dose escalation cohort was designed to determine the recommended expansion cohort dose in a “3+3” cohort-based dose escalation design of regorafenib (80 mg once dairy for 21 days on 7 days off on level 1, 120 mg on level 2 and 160 mg on level 3) with nivolumab (3.0 mg/kg q2w). In expansion cohort, approximately 30 patients with selected solid tumors such as gastric, coloretcal, hepatocellular cancer will be enrolled at the RD. We also investigate several biomarkers using pre- and post-treatment samples from both biopsied tumor and blood. First three patients were enrolled and treated in level 1 as of January 2018. Clinical trial information: NCT03406871.