Background: Although immune-checkpoint inhibitors (ICIs) have shown significant survival benefits in several cancers, optimal outcomes have been limited to subsets of patients. We obtained complete regression of an engrafted solid tumor with metformin in a murine syngeneic model. This effect could not be obtained in T cell-deficient SCID mice. These findings suggested that metformin induced immune-mediated reactions. The combination of anti-PD-1 antibody (nivolumab) and metformin resulted in significant tumor regression. This combination also increased the number of tumor-infiltrating CD8 T cells producing IL-2, TNF-α, and IFN-γ, suggesting that this combination induced clinically synergistic antitumor effects. Based on these results, we initiated the following study. Objectives: To investigate the safety, efficacy, and pharmacokinetics of combined treatment with metformin and nivolumab. Methods: This was an open-label, phase Ib trial consisting of two parts (part 1 and 2). The recommended dose of metformin combined with nivolumab was determined in part 1, and the safety and efficacy at the optimal dose were examined in part 2. The inclusion criteria were as follows: histologically or cytologically diagnosed refractory/recurrent solid tumors in part 1, and non-small cell lung cancer or pancreatic cancer that was refractory to standard primary treatment in part 2; use of naïve ICIs; a performance status of 0 or 1; > 20 years of age; and adequate organ functions. The primary endpoints were safety, maximum tolerated dose (MTD), and dose limiting toxicity (DLT) in part 1, and pharmacokinetics and adverse event profiles in parts 1 and 2. The secondary endpoints were efficacy, tumor shrinkage, and progression-free survival. Nivolumab (3 mg/kg) was administered intravenously every 2 weeks. In part 1, metformin was started at 750 mg/day, and increased by 750 mg/day up to 2,250 mg/day. The MTD and recommended dose were determined by the 3+3 cohort method. The DLT evaluation period was 4 weeks from the start of administration. A total of 9–18 patients were enrolled in part 1, and 30 patients in part 2. Enrollment began in 2017 and will be complete by 2019. The UMIN registration number is 000028405. Clinical trial information: 000028405.