BITS-TO-HCC Study: HAIC+Iparomlimab/Tuvonralimab + Bevacizumab + SBRT for BCLC-C HCC With PVTT and/or Oligometastases

Summary

This single-center, prospective, single-arm Phase II clinical trial is designed to evaluate the efficacy and safety of combining hepatic artery infusion chemotherapy (HAIC, for up to 4 cycles) with iparomlimab/tuvonralimab plus bevacizumab followed by stereotactic body radiotherapy (SBRT) in patients with Barcelona Clinic Liver Cancer (BCLC) stage C hepatocellular carcinoma (HCC) who present with portal vein tumor thrombus (PVTT) or extrahepatic oligometastatic disease. The study aims to determine whether this combination strategy can prolong progression-free survival (PFS), while also improving overall survival (OS), objective response rate (ORR), disease control rate (DCR), and local control rate (LCR), as well as maintaining quality of life (QoL). In addition, the trial will systematically evaluate the safety profile and treatment-related toxicities associated with this regimen.

Eligibility

Inclusion Criteria:

1. Male or female patients aged between 18 and 70 years.
2. Unresectable HCC, BCLC Stage C according to the BCLC strategy-2025 update, with staging established via biopsy pathology and/or clinical diagnosis.
3. Child-Pugh class A without clinically significant hepatic decompensation; Eastern Cooperative Oncology Group (ECOG) performance status 0-1
4. Metastatic burden and SBRT eligibility

   * Extrahepatic oligometastatic disease defined as ≤3 involved organs with ≤5 total metastatic lesions
   * All intended intrahepatic and/or extrahepatic SBRT targets must satisfy protocol-specified target-coverage, liver reserve, and organ-at-risk (OAR) constraints within a composite 5-fraction plan
5. Prognosis \& measurable disease

   * Life expectancy ≥3 months
   * ≥1 measurable lesion (per RECIST 1.1):
   * Tumor: ≥10 mm (CT long axis)
   * Lymph node: ≥15 mm (CT short axis)
6. Prior therapy

   * Prior locoregional therapy permitted：radiofrequency ablation (RFA), TACE, or HAIC, provided that:
   * Documented radiographic progression or intolerance after the prior therapy
   * Washout ≥28 days
   * Treatment-related toxicities recovered to ≤Grade 1 (alopecia and peripheral neuropathy ≤Grade 2 allowed)
7. Laboratory and virologic requirements

   * Aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (ALP) ≤5 × upper limit of normal (ULN); total bilirubin ≤3 × ULN; serum albumin ≥28 g/L
   * Serum creatinine ≤1.5 × ULN or creatinine clearance ≥50 mL/min
   * Urine dipstick protein \<2+; if baseline dipstick proteinuria is ≥2+, 24-hour urinary protein must be \<1 g
   * International normalized ratio (INR) and activated partial thromboplastin time (aPTT) ≤1.5 × ULN

Exclusion Criteria:

1. Histopathological exclusions

   * Mixed HCC subtypes: Fibrolamellar HCC or sarcomatoid HCC or cholangiocarcinoma components
2. Curative local therapy candidacy

   * Current candidacy for resection, liver transplant, or RFA
3. RT infeasibility

   * Prior radioembolization
   * Single liver tumor ≥15 cm or total intrahepatic tumor diameter ≥20 cm
   * more than 5 discrete intrahepatic parenchymal foci are present
   * direct tumor extension into the stomach, duodenum, small bowel, or large bowel
   * measurable common or main-branch biliary duct involvement
   * Prior liver radiotherapy that would result in excessive overlap with the planned treatment fields
4. Prior systemic therapies

   * Received targeted-immunotherapy for HCC (e.g., PD-(L)1 inhibitors + tyrosine kinase inhibitors (TKIs))
   * Prior immunotherapy: anti-PD-(L)1/CTLA-4 or chimeric antigen receptor T-cell therapy
5. Hemorrhage/portal hypertension and hepatic decompensation risk

   * Variceal bleeding within 6 months.
   * Untreated or high-risk esophagogastric varices (e.g., grade ≥2 on endoscopy within 3 months) or other clinical evidence of portal hypertension with high bleeding risk per investigator.
   * Moderate or severe ascites
   * History of or active hepatic encephalopathy
   * History of hemoptysis (≥2.5 mL of bright red blood per episode) within 28 days before study treatment
   * Evidence of bleeding diathesis or significant coagulopathy
   * Current or recent (within 10 days before study treatment) use of aspirin (≥325 mg/day), dipyridamole, ticlopidine, clopidogrel, cilostazol, or therapeutic-dose oral/parenteral anticoagulants or thrombolytic agents
6. Allergy to any component of iparomlimab/tuvonralimab or bevacizumab
7. Comorbidities

   * Active autoimmune disease or a history of autoimmune or inflammatory disease that may relapse; exceptions include hypothyroidism controlled with hormone replacement only, controlled celiac disease, and skin disorders not requiring systemic treatment (e.g., vitiligo, psoriasis, or alopecia)
   * Any condition requiring systemic corticosteroids (\>10 mg/day prednisone or equivalent) or other immunosuppressive medication within 14 days before study treatment
   * Active or uncontrolled infection, including tuberculosis, or known HIV infection
   * Prior allogeneic stem cell transplantation or organ transplantation
   * Inadequately controlled hypertension, defined as systolic blood pressure ≥150 mmHg and/or diastolic blood pressure \>90 mmHg despite optimal medical management, or a history of hypertensive crisis or hypertensive encephalopathy
   * History within 6 months before study treatment of myocardial infarction, unstable angina, symptomatic heart failure (New York Heart Association class ≥II), cerebrovascular accident, transient ischemic attack, pulmonary embolism, deep vein thrombosis, or other serious thromboembolic events
   * Major surgical procedure within 28 days before study treatment, or serious, non-healing or dehiscing wound, active ulcer, or untreated bone fracture
   * History within 6 months before study treatment of gastrointestinal perforation, abdominal or tracheoesophageal fistula, or intra-abdominal abscess

Conditions10

Interventions2

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