A Phase I Study to Investigate the Safety, Tolerability and Pharmacokinetics of Napabucasin Combined with Sorafenib in Japanese Patients with Unresectable Hepatocellular Carcinoma

by Selleckchem | Jul 10 2023

Background and objective: For patients with advanced hepatocellular carcinoma (HCC), the standard of care for many years has been sorafenib. Preliminary data have suggested that the combination of the NAD(P)H:quinone oxidoreductase 1 bioactivatable agent napabucasin plus sorafenib may improve clinical outcomes in patients with HCC. In this phase I, multicenter, uncontrolled, open-label study, we evaluated napabucasin (480 mg/day) plus sorafenib (800 mg/day) in Japanese patients with unresectable HCC.

Methods: Adults with unresectable HCC and an Eastern Cooperative Oncology Group performance status of 0 or 1 were enrolled in a 3 + 3 trial design. The occurrence of dose-limiting toxicities was assessed through 29 days from the start of napabucasin administration. Additional endpoints included safety, pharmacokinetics, and preliminary antitumor efficacy.

Results: In the six patients who initiated treatment with napabucasin, no dose-limiting toxicities occurred. The most frequently reported adverse events were diarrhea (83.3%) and palmar-plantar erythrodysesthesia syndrome (66.7%), all of which were grade 1 or 2. The pharmacokinetic results for napabucasin were consistent with prior publications. The best overall response (per Response Evaluation Criteria in Solid Tumors [RECIST] version 1.1) was stable disease in four patients. Using Kaplan-Meier methodology, the 6-month progression-free survival rate was 16.7% per RECIST 1.1 and 20.0% per modified RECIST for HCC. The 12-month overall survival rate was 50.0%.

Conclusions: These findings confirm the viability of napabucasin plus sorafenib treatment, and there were no safety or tolerability concerns in Japanese patients with unresectable HCC.

Comments:

The study you described is a phase I clinical trial conducted in Japan, evaluating the combination of napabucasin and sorafenib in Japanese patients with unresectable hepatocellular carcinoma (HCC). The objective of the study was to assess the safety, pharmacokinetics, and preliminary antitumor efficacy of the combination therapy.

The trial enrolled adult patients with unresectable HCC and a good performance status. The treatment regimen consisted of napabucasin at a dose of 480 mg/day and sorafenib at a dose of 800 mg/day. The study followed a 3 + 3 trial design, where the occurrence of dose-limiting toxicities was assessed within 29 days of starting napabucasin administration.

The results of the study showed that none of the six patients who initiated treatment with napabucasin experienced dose-limiting toxicities. The most frequently reported adverse events were diarrhea (83.3%) and palmar-plantar erythrodysesthesia syndrome (66.7%), which were mostly of grade 1 or 2 severity. The pharmacokinetic results for napabucasin were consistent with previous publications.

In terms of antitumor efficacy, the best overall response, as per the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, was stable disease in four patients. The 6-month progression-free survival rate was 16.7% according to RECIST 1.1 and 20.0% according to modified RECIST for HCC. The 12-month overall survival rate was 50.0%.

Based on these findings, the study confirms the feasibility and safety of combining napabucasin with sorafenib in Japanese patients with unresectable HCC. The combination therapy showed acceptable tolerability, with manageable side effects. However, it's important to note that this was a phase I trial with a small number of patients, and further studies, particularly randomized controlled trials, are needed to establish the efficacy and safety of this combination in a larger patient population.