DUBHE-H-308 study protocol: rationale and adaptive design of a randomized, open-label, seamless phaseII/III trial of iparomlimab and tuvonralimab (QL1706)-based regimens versus sintilimab plus bevacizumab as first-line treatment for advanced hepatocellular carcinoma

No randomized trial has compared multiple immunotherapy-based combination strategies head-to-head in first-line advanced HCC, where approved doublet regimens achieve objective responses in fewer than one-third of patients. Iparomlimab and Tuvonralimab (QL1706), a new-type bifunctional combinedantibody (anti-PD-1/anti-CTLA-4 dual checkpoint inhibitor), deepens antitumor immunity while preserving tolerability. DUBHE-H-308 evaluates whether QL1706-based regimens, including a triplet with bevacizumab and oxaliplatin-based chemotherapy, can improve first-line outcomes in advanced HCC. DUBHE-H-308 (NCT05976568) is a prospective, randomized, open-label, multicenter, inferentially seamless phase II/III trial comparing three QL1706-based regimens against sintilimab plus bevacizumab in previously untreated advanced HCC. Three adaptive elements are incorporated: arm selection after phase II; seamless integration of phase II data into the phase III overall survival analysis; and a group-sequential interim analysis. Phase II co-primary endpoints are objective response rate and safety; the phase III primary endpoint is overall survival. Phase II enrollment is complete; interim data have guided regimen selection and confirmed transition to the confirmatory phase III stage. If successful, DUBHE-H-308 would provide the first randomized evidence supporting a triplet first-line strategy combining dual-checkpoint blockade, anti-VEGF therapy, and chemotherapy in advanced HCC, potentially establishing a new treatment standard. The adaptive framework maximizes efficiency without compromising confirmatory rigor. Clinical trial registration: ClinicalTrials.gov identifier NCT05976568.