Novel agent namodenoson demonstrated tolerability in a favorable safety profile in patients with advanced hepatocellular carcinoma and severe liver dysfunction, according to the results of a randomized phase II trial.
Novel agent namodenoson (CF102) demonstrated tolerability and a favorable safety profile in patients with advanced hepatocellular carcinoma (HCC) and severe liver dysfunction, according to the results of a randomized phase II trial.
Although the primary endpoint of improved overall survival (OS) compared with placebo was not met in the intent-to-treat (ITT) population, the trial did show promising OS with the A3adenosine receptor (A3AR) agonist in patients with Child-Pugh class B7 disease in a preplanned subgroup analysis, which investigators believe warrants further analysis.
“The subgroup analysis showed a positive efficacy signal in patients with Child-Pugh B7,” said lead investigator Salomon M. Stemmer, MD, when presenting the findings at the 2019 ASCO Annual Meeting. “The favorable safety profile and lack of liver toxicity, together with the clinical activity observed in the Child-Pugh B7 subpopulation, supports further clinical development of namodenoson.”
Currently, no systemic therapies have shown a clinical benefit in patients with advanced HCC and Child-Pugh class B disease, remaining a significant unmet medical need.
The agent is being investigated as a potential treatment for patients with advanced HCC and Child-Pugh class B cirrhosis, as A3AR is highly expressed in liver tumor cells and in low frequencies in adjacent normal cells, suggesting its rationale as a drug target for HCC. Namodenoson’s mechanism of action involves the downregulation of the Wnt and NF-kB signaling pathways.
Namodenoson has demonstrated promising preliminary activity in patients with advanced HCC and Child-Pugh B disease in an open-label phase I/II trial (NCT00790218), showing a median OS of 8.1 months.
The double-blind, placebo-controlled, international, multicenter, randomized phase II trial (NCT02128958) was designed to further assess the efficacy and safety of namodenoson as a second-line therapy for patients with advanced HCC and Child-Pugh class B cirrhosis.
Investigators screened 136 patients and randomized 78 patients 2:1 to either namodenoson (n = 50) or placebo (n = 28). Patients in the namodenoson arm received 25 mg of the A3AR antagonist orally twice daily continuously.
OS was the primary endpoint of the trial and secondary endpoints included safety, progression-free survival (PFS), overall response rate (ORR), and disease control rate (DCR).
At baseline, the median patient age was 62 years (range, 24-81) in the namodenoson arm compared with 66 years in the placebo arm (range, 41-83). Between the 2 arms, 73% of all patients were male and 72% had a Child-Pugh score of 7, with the remainder having scores of 8 or 9. Thirty-eight percent of patients overall had hepatitis C virus and 22% had hepatitis B virus. Additionally, two-thirds of patients had an alpha-fetoprotein level above 400 ng/mL and one-quarter had received prior chemoembolization.
Stemmer, of the Davidoff Cancer Center, Rabin Medical Center, Petah Tikva and Sackler Faculty of Medicine, Tel-Aviv University in Israel, noted that there was an unpredicted misbalance between the 2 groups in terms of Child-Pugh scores, with all 9 patients with a Child-Pugh score of 9 randomized to the namodenoson arm.
In the ITT analysis, the median OS was 4.1 months with namodenoson compared with 4.3 months with placebo (HR, 0.82;P= .46), which was not found to be statistically significant. The median PFS was 2.6 months and 1.9 months with namodenoson and placebo, respectively (HR, 0.82;P= .46).
In the 56 patients with a Child-Pugh score of 7, however, the median OS was increased with the use of namodenoson compared with placebo (6.8 vs 4.3 months, respectively; HR, 0.77;P= .40), and the median PFS was also improved (3.5 vs 1.9 months; HR, 0.87;P= .65).
At 12 months, the rate of OS in the namodenoson arm was 44% compared with 18% in the placebo arm in patients with Child-Pugh B7 disease.
In patients with at least 1 evaluable post-baseline assessment (n = 55), the ORR was 9% in the namodenoson arm and 0% in the placebo arm; the DCRs were 26% and 10%, respectively (P= .013).
Stemmer noted that the level of A3AR expression by mRNA testing in patients’ white blood cells did not change substantially with treatment, “demonstrating that continuous treatment with namodenoson does not result in desensitization or loss of the target.”
Grade 1/2 treatment-related adverse events (TRAEs) were observed in 20% of patients in the namodenoson arm compared with 50% in the placebo arm. The grade 1/2 TRAEs that occurred in more than 1 patient included nausea and weight increase in 2 patients each in the namodenoson arm; in the placebo arm, there were 3 cases of asthenia, and 2 cases each of weight increase and increased TSH.
In the namodenoson arm, 1 patient had grade 3 hyponatremia, the only grade 3 TRAE noted in the namodenoson group, and 1 patient in the placebo arm developed both grade 3 anemia and grade 3 fatigue. Stemmer noted that the hyponatremia could have been attributed to the cirrhosis.
Stemmer SM, Manojlovic NS, Marinca MV, et al. A phase II, randomized, double-blind, placebo-controlled trial evaluating efficacy and safety of namodenoson (CF102), an A3 adenosine receptor agonist (A3AR), as a second-line treatment in patients with Child-Pugh B (CPB) advanced hepatocellular carcinoma (HCC).J Clin Oncol.2019;37(suppl; abstr 2503).