A Clinical Trial of Firsekibart, Tislelizumab, and Lenvatinib in Patients With Unresectable, TP53-Mutated Hepatocellular Carcinoma

Lab values

• Candidates suitable for local curative therapy.
  • Mixed liver tumors containing sarcomatoid or intrahepatic cholangiocarcinoma components.
  • Hematologic malignancies.
  • History of hepatic encephalopathy or prior liver transplantation.
  • Symptomatic pleural effusion, ascites, or pericardial effusion requiring drainage; asymptomatic small effusions allowed.
  • Active HBV (HBV DNA \>2000 IU/mL) or HCV (HCV RNA \>10\^3 copies/mL) infection; co-infection HBsAg+/HCV Ab+ excluded.
  • CNS metastases.
  • Significant recent variceal bleeding (within 6 months).
  • Life-threatening hemorrhagic events within 3 months.
  • Significant thromboembolic events within 6 months.
  • Use of high-dose aspirin (\>325 mg/day) or other platelet inhibitors within 2 weeks prior to first dose.
  • Unresolved grade ≥2 toxicities from prior therapies (excluding hair loss or asymptomatic lab abnormalities).
  • Symptomatic heart failure NYHA II-IV or LVEF \<50%.
  • Uncontrolled arrhythmias or congenital long QT syndrome, QTc \>500 ms.
  • Active bleeding disorders or on thrombolytic therapy.
  • Recent history of gastrointestinal perforation, fistula, obstruction, or significant bowel disease.
  • Radiotherapy within 3-7 weeks prior to first dose with residual toxicity.
  • History of pulmonary fibrosis, interstitial pneumonia, pneumoconiosis, drug-induced lung injury, or severe impaired lung function.
  • Active tuberculosis or treatment for TB within 1 year.
  • HIV infection or active, untreated syphilis.
  • Active or uncontrolled severe infection within 4 weeks prior to first dose.
  • Active autoimmune disease requiring systemic treatment within 2 years. Known primary immunodeficiency.
  • Use of systemic immunosuppressants within 4 weeks prior to first dose (nasal/inhaled steroids at physiologic dose allowed).
  • Receipt of live attenuated vaccines within 4 weeks prior to first dose.
  • Major surgery within 4 weeks prior to first dose, or unhealed wounds. Minor procedures like IV lines excluded.
  • Uncontrolled metabolic disorders or organ/systemic disease posing excess risk.
  • History of other malignancy within 5 years, except curatively treated basal cell carcinoma, squamous cell carcinoma, or in situ carcinoma.
  • Known hypersensitivity to study drugs or formulation components.
  • History of aortic dissection or visceral artery aneurysm.
  • Participation in another clinical trial within 4 weeks prior to first dose.
  • Pregnant or breastfeeding women.
  • Extensive metastatic disease (≥5 lesions) or major vascular invasion.
  • Other acute or chronic diseases, psychiatric conditions, or lab abnormalities deemed by investigator to increase risk or interfere with study.

• Ability to understand and sign written informed consent prior to any study-related procedures.
  • Age ≥18 years at the time of signing informed consent.
  • Histologically or cytologically confirmed advanced or unresectable hepatocellular carcinoma (HCC).
  • Documented disease progression after prior systemic immunotherapy, including at least one PD-(L)1 inhibitor.
  • Confirmed TP53 mutation in fresh liver tumor tissue by central laboratory testing.
  • Determined by liver tumor MDT to be unsuitable for curative surgery (R0 resection not feasible, insufficient normal liver volume, or other criteria).
  • BCLC stage B or C.
  • At least one measurable lesion per RECIST v1.1 confirmed by BICR.
  • ECOG performance status 0-1.
  • Child-Pugh class A within 7 days prior to randomization.
  • Adequate organ and bone marrow function within 7 days prior to enrollment:
  • ANC ≥1.5×10\^9/L, Platelets ≥75×10\^9/L, HGB ≥9 g/dL
  • TBIL ≤2×ULN, ALT/AST ≤5×ULN, Albumin ≥28 g/L, ALP ≤5×ULN
  • Creatinine ≤1.5×ULN or CCr ≥50 mL/min, urine protein \<2+ (or 24-h urine protein \<1 g if baseline ≥2+)
  • INR ≤2.3 or PT prolongation ≤6 sec
  • Expected survival ≥12 weeks.
  • Women of childbearing potential and male participants with partners of childbearing potential must use effective contraception during treatment and for 6 months after last dose.
  • Ability and willingness to comply with study procedures and visits.