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

Salomon M Stemmer, Nebojsa S Manojlovic, Mihai Vasile Marinca, Petar Petrov, Nelly Cherciu, Doina Ganea, Tudor Eliade Ciuleanu, Ioana Adriana Pusca, Muhammad Shaalan Beg, William T Purcell, Adina-Emilia Croitoru, Rumyana Nedyalkova Ilieva, Sladjana Natošević, Amedeia Lavinir Nita, Dimitar Nikolaev Kalev, Zivit Harpaz, Motti Farbstein, Michael H Silverman, David Bristol, Inbal Itzhak, Pnina Fishman, Salomon M Stemmer, Nebojsa S Manojlovic, Mihai Vasile Marinca, Petar Petrov, Nelly Cherciu, Doina Ganea, Tudor Eliade Ciuleanu, Ioana Adriana Pusca, Muhammad Shaalan Beg, William T Purcell, Adina-Emilia Croitoru, Rumyana Nedyalkova Ilieva, Sladjana Natošević, Amedeia Lavinir Nita, Dimitar Nikolaev Kalev, Zivit Harpaz, Motti Farbstein, Michael H Silverman, David Bristol, Inbal Itzhak, Pnina Fishman

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.

Keywords: Child–Pugh B; hepatocellular carcinoma; namodenoson; overall survival; randomized clinical trial.

Conflict of interest statement

Salomon M. Stemmer and Michael H. Silverman are consultants and stakeholders at Can-Fite BioPharma; Zivit Harpaz, Motti Farbstein, Inbal Itzhak and Pnina Fishman are employed by and stakeholders at Can-Fite BioPharma; David Bristol is a consultant at Can-Fite BioPharma; The remaining authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
Flow chart of patient recruitment, treatment, and follow-up. F/U, follow-up; ICF, informed consent form; ITT, intention to treat; Pt, patient.
Figure 2
Figure 2
Kaplan–Meier curves by treatment group (namodenoson 25 mg/kg twice a day (BID) and placebo) for all patients and Child–Pugh B7 (CPB7) patients. (a) overall survival (OS) in all patients; (b) progression-free survival (PFS) in all patients; (c) OS in CPB7 patients; (d) PFS in CPB7 patients.
Figure 3
Figure 3
Forest plot summarizing exploratory overall survival (OS) subgroup analysis comparing patients assigned to receive namodenoson 25 mg/kg twice a day (BID) versus placebo. AFP, Alpha-fetoprotein; CI, confidence interval; ECOG PS, Eastern Cooperative Oncology Group performance status; EHS, extrahepatic spread; H, hazard ratio; PVT, portal vein thrombosis.

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