Background: ALKS 4230 is a fusion protein of circularly permuted IL-2 and IL-2 Receptor (IL-2R) α designed to selectively bind the intermediate-affinity (ia) IL-2R, comprised of IL-2Rβ and γ_c, for activation of CD8⁺ T cells and NK cells, which drive antitumor immune responses. In contrast, unmodified IL-2 activates high-affinity (ha) IL-2R, driving the expansion of immunosuppressive CD4⁺ regulatory T cells (T_regs) at concentrations below those that activate iaIL-2R expressing cells. Binding of IL-2 to haIL-2R on endothelial cells may contribute to capillary leak syndrome seen with high-dose IL-2. Thus, selective activation of the iaIL-2R by ALKS 4230 has the potential to enhance tumor killing and improve tolerability. ALKS 4230 has previously been shown to improve antitumor activity relative to IL-2 in murine models. In this clinical study, ALKS 4230 will be assessed as monotherapy and in combination with anti-PD-1 therapy. Methods: ALKS 4230 is being studied in adults with advanced solid tumors in a phase I first-in-human trial designed primarily to assess the safety of ALKS 4230 alone and with pembrolizumab. The study will also determine a monotherapy recommended phase 2 dose (RP2D) and characterize pharmacokinetics, pharmacodynamics (PD), immunogenicity, and evidence of anti-tumor activity. It will be conducted in 3 parts: monotherapy dose escalation (Part A), monotherapy dose expansion at the RP2D (Part B), and combination therapy with pembrolizumab (Part C). ALKS 4230 is administered as a 30 minute IV infusion once daily for five days in each 14 or 21 day cycle. Part A is inpatient. Eligibility requires ECOG PS 0-1 and adequate bone marrow, liver and kidney function. Part B will enroll 21 patients each in renal cell carcinoma and melanoma cohorts. Part C will enroll up to 79 patients total into 3 cohorts based on tumor type and prior anti-PD-1 therapy; a 4th cohort will enroll patients from Part A or B who received at least 4 cycles of ALKS 4230 or experienced disease progression on monotherapy. The primary PD endpoint is change from baseline in CD8⁺ T, NK, and T_reg cell counts. Inflammatory cytokine levels will also be measured. Parts A and C are currently enrolling. Clinical trial information: NCT02799095