Hepatocellular Carcinoma, Portal Vein Tumor Thrombus, Oligometastases, Radiotherapy, Immunotherapy, Hepatic Artery Infusion Chemotherapy
Conditions
Brief 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.
Detailed description
In recent years, first-line systemic treatment of advanced hepatocellular carcinoma (HCC) has shifted toward immunotherapy-based combinations, particularly regimens pairing immune checkpoint inhibitors (ICIs) with vascular endothelial growth factor (VEGF) or VEGF receptor (VEGFR)-targeted antiangiogenic agents, which have become the preferred options in major clinical guidelines. Nevertheless, a substantial proportion of patients with Barcelona Clinic Liver Cancer (BCLC) stage C disease complicated by portal vein tumor thrombus (PVTT) and/or extrahepatic oligometastases remain ineligible for resection despite conversion-oriented systemic or locoregional therapy. Even when hepatectomy is attempted in this subset, candidates are highly selected and the overall benefit appears limited. Accordingly, major contemporary guidelines adopt a cautious stance on resection in the presence of PVTT, which remains controversial in some respects. In parallel, recent phase III trials evaluating transarterial chemoembolization (TACE) in combination with immunotherapy and anti-VEGF agents have supported the emergence of a locoregional-systemic treatment paradigm for unresectable, non-metastatic HCC. However, patients with BCLC stage C HCC with PVTT and/or extrahepatic oligometastases were generally under-represented or excluded, leaving the applicability of these regimens to this population uncertain. By contrast, stereotactic body radiotherapy (SBRT) delivered with ablative intent can achieve high local control under stringent dose-volume constraints. Furthermore, radiotherapy (RT) may induce immunogenic cell death and reshape the tumor microenvironment, thereby amplifying systemic immune responses and providing a biological rationale for combination with ICIs and anti-VEGF therapy. Iparomlimab/tuvonralimab, a novel bispecific antibody designed to target both programmed cell death protein 1 (PD-1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), offers a promising approach to augment T-cell activation and strengthen antitumor immunity beyond what is achievable with single-agent ICIs. When combined with bevacizumab, which blocks VEGF signaling to normalize tumor vasculature, improves the tumor microenvironment, and promotes immune-cell infiltration, this dual strategy could significantly enhance treatment efficacy. Hepatic artery infusion chemotherapy (HAIC) concentrates cytotoxic exposure within the liver and induces rapid cytoreduction, facilitating downstaging in advanced HCC. For the HAIC component, we selected an FOHAIC-1-based HAIC-FO regimen because it is among the best-validated HAIC backbones in advanced HCC and significantly improved overall survival (OS) versus sorafenib in the randomized phase III FOHAIC-1 trial. This oxaliplatin-fluorouracil-leucovorin HAIC backbone has also been explored in combination studies with immunotherapy and anti-angiogenic therapy, supporting its feasibility within multimodal treatment strategies. Among patients who remain ineligible for resection despite modern conversion strategies, HAIC-mediated debulking can help render intrahepatic disease dosimetrically amenable to local ablation with SBRT. Building on this rationale, we hypothesise that a sequential regimen combining dual ICIs (iparomlimab/tuvonralimab) and bevacizumab with HAIC, followed by consolidative SBRT, will act synergistically to improve progression-free survival (PFS) in patients with BCLC stage C HCC complicated by PVTT and/or extrahepatic oligometastases, while maintaining an acceptable safety profile.
Interventions
DRUGAnti-VEGF
Drug: Bevacizumab (15 mg/kg, IV, every 3 weeks)
DRUGImmunotherapy
Iparomlimab/tuvonralimab (7.5 mg/kg, IV, every 3 weeks, administered sequentially after bevacizumab)
RADIATIONLocal 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
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.
Sponsors
Shandong Cancer Hospital and Institute
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 70 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Progression-free survival (PFS) | Two years | The time between enrollment and disease progression or death for patients in the intent-to-treat population, whichever occurred first; for those who did not progress at the time of withdrawal from the study or whose time to disease progression was not recorded, the date of the last visit was used as the endpoint date. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival (OS) | Five years | Time from initiation of treatment to death from any cause. |
| objective response rate (ORR) | Two years | The proportion of patients whose tumor size decreases (partial response) or disappears (complete response) after radiation based on RECIST 1.1. |
| Disease Control Rate (DCR) | Two years | The proportion of patients whose tumor size decreases (partial response), disappears (complete response), or is stable after radiation based on RECIST 1.1. |
| Local control rate (LCR) | Two years | The proportion of treated lesions without in-field local progression within the irradiated/target volume at prespecified time points (e.g., 6 and 12 months) per RECIST 1.1 |
| Incidence of Treatment-related adverse events | Five years | Treatment-related adverse events will be assessed and graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Specific examples of expected toxicities include, but are not limited to: Gastrointestinal disorders: Abdominal distension (visible or palpable enlargement of the abdomen); Abdominal pain; Belching; Subjective sensation of gastric bloating or fullness; Nausea (with or without retching or urge to vomit); Vomiting; Dyspepsia (characterized by burning sensation, bloating, nausea, or discomfort); Constipation; Diarrhea; Dysphagia (difficulty in swallowing); Upper gastrointestinal bleeding General disorders and administration site conditions: Fatigue; Pain, such as radiation-associated pain at sites of bone metastases or liver region pain Respiratory disorders: Dyspnea (shortness of breath); Radiation pneumonitis Skin and subcutaneous tissue disorders: Radiation dermatitis. |
| Change in Quality of Life Assessed by EORTC QLQ-C30 Questionnaire | Two years | Quality of life will be assessed using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30). Changes from baseline to follow-up time points will be analyzed across multiple domains including physical, emotional, and social functioning. |
Countries
China
Contacts
CONTACTJinbo Yue, doctor
PRINCIPAL_INVESTIGATORJinbo Yue, Doctor
Shandong Cancer Hospital and Institute
Outcome results
None listed