A Phase 2 interventional study of Anti-VEGF and Immunotherapy in Hepatocellular Carcinoma, Portal Vein Tumor Thrombus and Oligometastases, sponsored by Shandong Cancer Hospital and Institute. Recruiting at 1 site in China. Open to participants aged 18 Years to 70 Years. Per ClinicalTrials.gov, last updated 2026-09-04.
Sponsored by Shandong Cancer Hospital and Institute · Phase 2, Interventional, and Treatment
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 multidisciplinary team (MDT) evaluation for surgical resection or 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), and evaluate the conversion rate to surgical resectability, 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.
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. By achieving substantial tumor debulking, this intensive locoregional-systemic approach aims to convert initially unresectable disease into resectable status for select patients. Furthermore, for 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 HAIC with dual ICIs (iparomlimab/tuvonralimab) and bevacizumab, followed by a multidisciplinary team (MDT) evaluation for subsequent surgical resection or consolidative SBRT, will act synergistically to improve progression-free survival (PFS) and conversion resectability rates in patients with BCLC stage C HCC complicated by PVTT and/or extrahepatic oligometastases, while maintaining an acceptable safety profile.
Metastatic burden and local therapy eligibility
Prognosis \& measurable disease
Prior therapy
Laboratory and virologic requirements
Exclusion Criteria:
Histopathological exclusions
Curative local therapy candidacy
RT infeasibility
Prior systemic therapies
Hemorrhage/portal hypertension and hepatic decompensation risk
Comorbidities
Hepatic artery infusion chemotherapy (HAIC): On Day 1 of each cycle, 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 (every 3 weeks for up to four cycles) Drug: Bevacizumab (15 mg/kg, IV, every 3 weeks) Drug: Iparomlimab/tuvonralimab (7.5 mg/kg, IV, every 3 weeks, administered sequentially after bevacizumab) Procedure: Following induction therapy, patients will undergo a multidisciplinary team (MDT) evaluation. Patients who meet the criteria for resectability will undergo Surgical Resection. Radiation: For patients deemed unresectable, 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 will be administered.
Drug: Anti-VEGF · Drug: Immunotherapy · Radiation: Local Therapy · Procedure: hepatic arterial infusion chemotherapy (HAIC) · Procedure: Surgical Resection
Drug: Bevacizumab (15 mg/kg, IV, every 3 weeks)
Iparomlimab/tuvonralimab (7.5 mg/kg, IV, every 3 weeks, administered sequentially after bevacizumab)
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.
Consolidative surgical resection performed on patients whose tumors are converted to resectable status, as determined by a multidisciplinary team (MDT) evaluation following the induction therapy of HAIC, bevacizumab, and iparomlimab/tuvonralimab.
Progression-free survival (PFS)
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.
Time frame: Two years
Overall Survival (OS)
Time from initiation of treatment to death from any cause.
Time frame: Five years
objective response rate (ORR)
The proportion of patients whose tumor size decreases (partial response) or disappears (complete response) after induction therapy and/or consolidative local therapy (surgery or SBRT) based on RECIST 1.1.
Time frame: Two years
Disease Control Rate (DCR)
The proportion of patients whose tumor size decreases (partial response), disappears (complete response), or is stable after induction therapy and/or consolidative local therapy (surgery or SBRT) based on RECIST 1.1.
Time frame: Two years
Local control rate (LCR)
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
Time frame: Two years
Conversion to Resectability Rate
The proportion of initially unresectable patients who are successfully converted to a resectable status and undergo surgical resection following induction therapy, as determined by a multidisciplinary team (MDT) evaluation.
Time frame: Two years
Incidence of Treatment-related adverse events
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.
Time frame: Five years
Change in Quality of Life Assessed by EORTC QLQ-C30 Questionnaire
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.
Time frame: Two years
Plan to share: No
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Shandong Cancer Hospital and Institute