Namodenoson in Advanced Hepatocellular Carcinoma and Child–Pugh B Cirrhosis: Randomized Placebo-Controlled Clinical Trial

SIMPLE SUMMARY: We conducted a phase II randomized placebo-controlled trial to investigate namodenoson, an A3 adenosine-receptor agonist, as 2nd-line treatment for advanced hepatocellular carcinoma and moderate hepatic dysfunction (Child–Pugh [CP] scores of 7–9). The study included 50 patients in the namodenoson arm and 28 patients in the placebo arm. No overall survival advantage was observed with namodenoson; however, in patients with CP score of 7 (34 namodenoson-treated, 22 placebo-treated), namodenoson was associated with a significant improvement in 12-month overall survival (44% versus 18%, p = 0.028). Response rates were determined in patients with ≥1 assessment post-baseline (34 namodenoson-treated, 21 placebo-treated). Partial response was achieved by 3 (8.8%) namodenoson-treated and 0 (0%) placebo-treated patients. Namodenoson was well-tolerated, with a safety profile comparable to that of the placebo group. No treatment-related deaths were reported. In conclusion, namodenoson demonstrated a favorable safety profile and a preliminary efficacy signal in the evaluated population. ABSTRACT: Namodenoson, an A3 adenosine-receptor agonist, showed promising results in advanced hepatocellular carcinoma (HCC) and moderate hepatic dysfunction (Child–Pugh B; CPB) in a phase I/II clinical study. This phase II study investigated namodenoson as second-line therapy in such patients. Patients were randomized 2:1 to twice a day (BID) namodenoson (25 mg; n = 50) or placebo (n = 28). The primary endpoint (overall survival [OS]) was not met. Median OS was 4.1/4.3 months for namodenoson/placebo (hazard ratio [HR], 0.82; 95% confidence interval [CI] 0.49–1.38; p = 0.46). Pre-planned subgroup analysis of CPB7 patients (34 namodenoson-treated, 22 placebo-treated) showed a nonsignificant improvement in OS/progression-free survival (PFS). OS: 6.9 versus 4.3 months; HR, 0.81; 95% CI: 0.45–1.43, p = 0.46. PFS: 3.5 versus 1.9 months; HR, 0.89; 95% CI: 0.51–1.55, p = 0.67 (log-rank test). The difference in 12-month OS was significant (44% versus 18%, p = 0.028). Response rates were determined in patients for whom ≥ 1 assessment post-baseline was available (34 namodenoson-treated, 21 placebo-treated). Partial response was achieved by 3/34 (8.8%) and 0/21 (0%) patients, respectively. Namodenoson was well-tolerated, with a safety profile comparable to that of the placebo group. No treatment-related deaths were reported; no patients withdrew due to toxicity. In conclusion, namodenoson demonstrated a favorable safety profile and a preliminary efficacy signal in HCC CPB.