A phase 1 study of the CD40 agonist MEDI5083 in combination with durvalumab in patients with advanced solid tumors

<b>Aim:</b> This first-in-human study evaluated safety and efficacy of CD40 agonist MEDI5083 with durvalumab in patients with advanced solid tumors. <b>Methods:</b> Patients received MEDI5083 (3–7.5 mg subcutaneously every 2 weeks × 4 doses) and durvalumab (1500 mg every 4 weeks) either sequentially (N = 29) or concurrently (N = 9). Primary end point was safety; secondary end points included efficacy. <b>Results:</b> Thirty-eight patients received treatment. Most common adverse events (AEs) were injection-site reaction (ISR; sequential: 86%; concurrent: 100%), fatigue (41%; 33%), nausea (20.7%; 55.6%) and decreased appetite (24.1%; 33.3%). Nine patients had MEDI5083-related grade ≥3 AEs with ISR being the most common. Two patients experienced dose limiting toxicities (ISR). One death occurred due to a MEDI5083-related AE. MEDI5083 maximum tolerated dose was 5 mg. Objective response rate was 2.8% (1 partial response and 11 stable disease). <b>Conclusion:</b> MEDI5083 toxicity profile limits its further development. MEDI5083 is a molecule that was designed as a potential anticancer medication. Once inside the body, MEDI5083 connects to specific proteins found on the surface of immune cells and cancer cells. It can boost the immune system of the body in multiple ways to help kill cancer cells. In this clinical study, 38 patients with various types of cancers (bladder, breast, colon, head and neck, kidney, lung, and pancreas) were treated with MEDI5083 together with another anticancer medicine called durvalumab. MEDI5083 was given to patients as an injection under the skin once every 2 weeks. Durvalumab was given to patients as an infusion once every 4 weeks. The study monitored whether treatment caused unwanted side effects and whether MEDI5083 was able to shrink the size of tumors. A total of 34 of 38 patients who received treatment experienced unwanted reactions at the site of MEDI5083 treatment injection. These symptoms were long lasting and did not go away with an applied steroid treatment. A total of 5 of 38 patients experienced extreme tiredness and 4 of 38 patients experienced fever. Of 38 patients enrolled, 6 discontinued treatment because of a MEDI5083-related side effect. Only one patient had a decrease in the size of their cancer mass with treatment. Because of safety concerns, this study was not completed. The injectable form of MEDI5083 is not being further tested in patients with cancer. CD40 is widely expressed in multiple solid tumor types and activation of the CD40 pathway is an attractive approach to boost antitumor immune responses. MEDI5083 is a homodimeric fusion protein composed of a single chain fusion of three single-chain CD40L domains and an IgG4P domain fragment crystallizable linked by 9-glycine-serine linker regions, containing a mutated residue 194 (unpaired cysteine). MEDI5083 was designed to have better potency with prolonged exposure and less systemic toxicities. This multicenter, open-label, phase 1 study evaluated the safety and clinical activity of MEDI5083, administered sequentially or concurrently with durvalumab in adult patients with advanced solid tumors. Limited efficacy has been observed with the combination across cancer types evaluated. The most common MEDI5083-related adverse events were injection-site reaction, fatigue, and pyrexia. MEDI5083 demonstrated mobilization of B-cells and increased proliferating T-cell in peripheral blood. The toxicity profile of MEDI5083, when administered subcutaneously alone or in combination with durvalumab, did not support further development of this formulation.