First-in-human study of the dual A2A/A2B adenosine receptor antagonist muvadenant (M1069) in patients with advanced solid tumors

Background Adenosine is a key driver of an immunosuppressive tumor microenvironment. Elevated extracellular adenosine levels in the tumor microenvironment contribute to therapeutic resistance via A₂A and A₂B adenosine receptor signaling on T cells. Dual A₂A/A₂B antagonism may provide a therapeutic advantage compared with selective inhibition of either receptor alone. Muvadenant (M1069), a small molecule dual antagonist of A₂A and A₂B receptors, showed encouraging preclinical activity. Patients and methods This phase I, open-label, first-in-human study (NCT05198349) evaluated muvadenant in adult patients with advanced solid malignancies (Eastern Cooperative Oncology Group performance status ≤1). Primary objectives were determination of maximum tolerated dose and recommended dose for expansion of muvadenant. Additional objectives included pharmacokinetics, pharmacodynamics and early signs of efficacy. Results Overall, 15 patients were evaluated across four dose levels (DLs) of muvadenant monotherapy provided twice daily (bd): 150 mg (n = 3), 300 mg (n = 3), 450 mg (n = 6), and 600 mg (n = 3). Dose-limiting toxicities were reported in two patients [grade 4 blood creatinine phosphokinase increased (450-mg DL, n = 1) and grade 3 lipase increased (600-mg DL, n = 1)]. Fatigue and nausea were the most common adverse events (n = 5 each, 33.3% each), while nausea was the most common muvadenant-related adverse event (n = 4, 26.7%). Two deaths were reported, both attributed to disease progression >30 days after treatment end. Best overall response of stable disease was recorded in three patients, including one patient with a stable disease of 12.6 months at the 150-mg DL. Median progression-free survival was 1.3 months (95% confidence interval 1.2-2.6). The potential recommended dose for expansion was 450-mg bd, and the maximum tolerated dose was not established due to early closure of the study. Conclusions Muvadenant was generally well tolerated; however, no antitumor activity was observed. A potential dose–response could not be determined due to limited number of patients per DL.