Bevacizumab Plus Iparomlimab/Tuvonralimab With Hepatic Artery Infusion Chemotherapy Followed by Stereotactic Body Radiotherapy in Patients With BCLC Stage C Hepatocellular Carcinoma With Thrombus and/or Extrahepatic Oligometastases (BITS-TO-HCC): Study Protocol of a Prospective, Multicenter, Single-Arm, Phase II Study

Plain English Summary

BITS-TO-HCC Study: HAIC+Iparomlimab/Tuvonralimab + Bevacizumab + SBRT for BCLC-C HCC With PVTT and/or Oligometastases is a Phase 2 clinical trial sponsored by Shandong Cancer Hospital and Institute studying Hepatocellular Carcinoma, Portal Vein Tumor Thrombus, Oligometastases, Radiotherapy, Immunotherapy, Hepatic Artery Infusion Chemotherapy. This trial tests a new treatment combination for a specific type of advanced liver cancer. It is for patients with BCLC stage C liver cancer that has spread to a blood vessel in the liver or to a few other parts of the body. Participants will receive a combination of chemotherapy delivered directly to the liver, immunotherapy drugs, a targeted drug, and focused radiation therapy. Alternative treatments for this stage of liver cancer may include other systemic therapies, radiation, or supportive care, depending on the patient's specific situation. The trial aims to enroll 54 participants.

Official Summary

This multicenter, prospective, single-arm Phase II clinical trial is designed to evaluate the efficacy and safety of combining bevacizumab plus iparomlimab/tuvonralimab with hepatic artery infusion chemotherapy (HAIC) 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.

Who Can Participate

Here is what you need to know about eligibility for this trial. Patients aged 18-70 with advanced liver cancer (BCLC stage C) that has spread to the portal vein or to a few other organs (up to 3 organs, 5 lesions total). Patients must have good liver function (Child-Pugh A) and be able to perform daily activities (ECOG 0-1). Patients cannot have other types of liver cancer, be candidates for surgery or transplant, or have had certain prior treatments like other immunotherapies or liver radiation. Individuals with significant bleeding risks, uncontrolled high blood pressure, recent heart problems, or active infections are also excluded. This trial is studying Hepatocellular Carcinoma, Portal Vein Tumor Thrombus, Oligometastases, Radiotherapy, Immunotherapy, Hepatic Artery Infusion Chemotherapy, so participants generally need a confirmed diagnosis. The trial is currently accepting new participants.

What They're Measuring

The primary goal is to see if the new treatment combination helps patients live longer without their cancer getting worse, measured over two years. The specific primary outcome measures are: Progression-free survival (PFS) (Two years). These endpoints are how researchers determine whether the treatment is effective and will form the basis of any future regulatory submissions.

About This Phase

This trial is in Phase 2, which tests whether the treatment actually works against the target condition. Phase 2 trials involve 100-300 patients and continue to monitor safety while evaluating effectiveness. This phase often tests different dosages to find the optimal amount. About 33% of Phase 2 drugs advance to Phase 3. If successful, the treatment will move to large-scale Phase 3 trials needed for FDA approval.

Why This Trial Matters

This trial addresses a critical need for more effective treatments for advanced liver cancer that has spread, aiming to improve survival and control for patients with limited options. Phase 2 success would typically lead to larger Phase 3 trials needed for regulatory approval. This research targets Hepatocellular Carcinoma, Portal Vein Tumor Thrombus, Oligometastases, Radiotherapy, Immunotherapy, Hepatic Artery Infusion Chemotherapy, where improved treatment options are needed.

Investor Insight

This trial targets a significant unmet need in advanced liver cancer, a disease with a large patient population and a growing market for innovative therapies, suggesting potential for future drug deve Phase 2 trials have approximately a 15-20% chance of eventually gaining FDA approval.

Is This Trial Right for Me?

Ask your doctor about the specific chemotherapy drugs, immunotherapy drugs, and radiation plan used in this trial. Participation involves regular clinic visits for infusions, radiation sessions, and monitoring for side effects, which may include blood tests, scans, and check-ups. Be prepared for potential side effects from the combination therapy and discuss any new or worsening symptoms with your medical team promptly. This trial is currently recruiting participants. The trial is being conducted at 1 site. Always discuss clinical trial participation with your healthcare provider before making any decisions. This information is for educational purposes only and is not medical advice.

AI-generated analysis for educational purposes only. This is not medical advice. Discuss clinical trial participation with your doctor. Data sourced from ClinicalTrials.gov.

Study Design

• Study Type: INTERVENTIONAL
• Allocation: NA
• Model: SINGLE_GROUP
• Masking: NONE
• Enrollment: 54 participants

Interventions

• DRUG: Anti-VEGF — Drug: Bevacizumab (15 mg/kg, IV, every 3 weeks)
• DRUG: Immunotherapy — Iparomlimab/tuvonralimab (7.5 mg/kg, IV, every 3 weeks, administered sequentially after bevacizumab)
• RADIATION: Local Therapy — Stereotactic Body Radiotherapy (SBRT), total dose of 25-40 Gy in 5 fractions over 1-2 weeks, targeting intrahepatic tumors, portal vein tumor, and/or limited extrahepatic oligometastatic lesions
• PROCEDURE: hepatic arterial infusion chemotherapy (HAIC) — On Day 1 of each cycle, HAIC using the HAIC-FO regimen will be initiated via a hepatic arterial catheter or pump and completed over 2-3 days, as follows: oxaliplatin 130 mg/m², leucovorin 200 mg/m², fluorouracil 400 mg/m² as a bolus, followed by fluorouracil 2,400 mg/m² by continuous infusion over 46 h. HAIC may be administered every 3 weeks for up to four cycles.

Primary Outcomes

• Progression-free survival (PFS) (Two years)

Secondary Outcomes

• Overall Survival (OS) (Five years)
• objective response rate (ORR) (Two years)
• Disease Control Rate (DCR) (Two years)
• Local control rate (LCR) (Two years)
• Incidence of Treatment-related adverse events (Five years)

Full Eligibility Criteria

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

Trial Locations

• Shandong Cancer Hospital and Institute, Jinan, Shandong, China

Frequently Asked Questions

Related Conditions

• Hepatocellular Carcinoma
• Liver Cancer
• Portal Vein Tumor Thrombus
• Extrahepatic Metastases
• Oligometastatic Disease
• Advanced Liver Cancer
• BCLC Stage C Liver Cancer
• Hepatoma
• Oncology
• Cancer Treatment

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