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

Salomon M Stemmer,Doina Ganea,Nelly Cherciu,Ioana Adriana Pusca,Sladjana Natošević,Zivit Harpaz,Motti Farbstein,Mihai Vasile Marinca,Amedeia Lavinir Nita,Michael H Silverman,Muhammad Shaalan Beg,Pnina Fishman,Petar Petrov,Inbal Itzhak,Tudor Ciuleanu ,Rumyana Ilieva ,Dimitar Kalev ,W Thomas Purcell ,Adina Croitoru ,Nebojša Manojlović ,David R Bristol

doi:10.3390/cancers13020187

Abstract

Simple SummaryWe 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.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.

Highlights

Liver cancer is the fifth most common cancer worldwide and the second most frequent cause of cancer-related death globally, with an estimated 854,000 new cases and 810,000 deaths annually [1]
In patients with CP score of 8 (CPB8) (n = 13, 7 namodenoson-treated and 6 placebo-treated), overall survival (OS) and Progression-free survival (PFS) were similar between the treatment arms and shorter than observed in the CPB7 subgroup
The study did not meet its primary endpoint, our findings demonstrate a favorable safety profile of namodenoson and suggest a positive efficacy signal in hepatocellular carcinoma (HCC)

Summary

Introduction

Liver cancer is the fifth most common cancer worldwide and the second most frequent cause of cancer-related death globally, with an estimated 854,000 new cases and 810,000 deaths annually [1]. Hepatocellular carcinoma (HCC) accounts for approximately 90% of primary liver cancer cases and constitutes a major global health problem [1]. Patients with advanced HCC and Child–Pugh B (CPB) cirrhosis have a borderline liver function, and the benefit of any therapy might be offset by the decline in their liver function. The only curative option for these patients involves successful downstaging and liver transplantation. This approach is appropriate only for a minority of patients and is further limited by the restricted number of livers available for transplantation [2]. The most common treatment for HCC and CPB is the multikinase inhibitor sorafenib, which is approved by the US Food and Drug Administration (FDA) for advanced HCC regardless of liver function [3]

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