Protocol of the STRIDE-X study: a multicenter, single-arm trial of single tremelimumab regular interval durvalumab followed by hepatectomy for initially unresectable hepatocellular carcinoma

Background Hepatocellular carcinoma (HCC) ranks as the fifth most common cancer globally and the third leading cause of cancer-related death. Systemic therapies such as lenvatinib or the combination of atezolizumab and bevacizumab has recently emerged as a first-line therapy for advanced HCC. The introduction of tremelimumab with durvalumab (STRIDE regimen) has shown potential in improving overall survival in unresectable cases, making them candidates for surgical intervention post-treatment. Methods The STRIDE-X study is a prospective multicenter, single-arm trial aimed at evaluating the efficacy of single dose tremelimumab combined with durvalmub followed by hepatectomy in patients with initially unresectable HCC. This non-randomized, open-label study will enroll subjects based on specific inclusion criteria such as body weight over 30 kg, life expectancy of at least 12 weeks, and no prior treatments for HCC. Key exclusion criteria include significant cardiovascular disease, other active malignancies, and recent history of severe infections. Patients will undergo initial intravenous doses of tremelimumab and durvalumab, followed by an assessment of resectability via imaging after 8 and 16 weeks. If tumors become resectable, surgery will be scheduled for 3 to 8 weeks after the last dose of treatment. The primary endpoint is the safety of surgical resection post-therapy, measured by the incidence of Clavien-Dindo grade III or higher complications. Secondary endpoints include surgical resection rates, post-hepatectomy liver failure, progression-free survival (PFS), and overall survival (OS). Exploratory endpoint analyses will be conducted to further explore the potential biological markers, including plasma cytokines, PD-L1, PD-1, CTLA-4, and circulating tumor DNA (ctDNA). Discussion This study will aim to elucidate the safety of conversion surgery with STRIDE regimen for initially unresectable HCC. In addition, efficacy (PFS and OS), the conversion rate during the treatment course, and the analysis of relevant biomarkers will also be assessed. Trial registration This study is registered in the Japan Registry of Clinical Trials (jRCTs071250043, July 14, 2025).