Glucocorticoid-induced TNF receptor-related protein (GITR) is the target of the monoclonal antibody TRX518. In advanced solid tumors, the safety and effectiveness of TRX518 monotherapy and in combination with gemcitabine, pembrolizumab, or nivolumab was tested in this open-label, phase I research (TRX518-003). The maximum safe dose of TRX518 monotherapy was 4 mg/kg loading, with further doses of 1 mg/kg every 3 weeks (Part A) and up to 8 mg/kg loading (Part B). Gemcitabine (Part C), pembrolizumab (Part D), or nivolumab (Part E) were used throughout the dose-escalation (2 and 4 mg/kg loading followed by 1 mg/kg) and dose-expansion (4 mg/kg loading) phases (Part E). Dose-limiting toxicities (DLTs), severe adverse events (SAEs), and pharmacokinetics were the primary objectives. Both effectiveness and pharmacodynamics were considered secondary endpoints. Out of a total of 109 patients, 43 were given TRX518 as part of Parts A+B, 30 were given it as part of C, 26 were given it as part D, and 10 were given it as part E. Patients in Groups D+E were more likely to have received anti-PD(L)1 or anti-CTLA-4 on previous visits (67% vs. 33%). When TRX518 has used alone, no treatment-related serious adverse events (SAEs), no deaths, and no AEs of grade 4 or 5. There were no DLTs reported in Parts C-E, but 3.35% of participants (Part C) and 10.0% of participants (Part E) reported experiencing side effects while taking TRX518. In Parts A+B, C+D, and E, the objective response rates were 3.2%, 3.8%, 4%, and 12.5%, respectively. Depending on the treatment plan, TRX518 had varying times of effect on both peripheral and intratumoral regulatory T cells (Treg). In patients who responded to TRX518 monotherapy plus an anti-PD1 combo, decreased intratumoral Tregs and increased CD8 levels and activation were seen. The pharmacodynamic activity and safety profile of TRX518 were found to be satisfactory. In both monotherapy and combination settings, repeated dosing with TRX518 led to modest clinical responses associated with immune activation.