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

Официальное название

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, Single- Center, Single-Arm, Phase II Study

Обзор

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.

Подробное описание

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 HAIC with dual ICIs (iparomlimab/tuvonralimab) and bevacizumab, 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.

Вмешательства

• Препарат Anti-VEGF
  Drug: Bevacizumab (15 mg/kg, IV, every 3 weeks)
• Препарат Immunotherapy
  Iparomlimab/tuvonralimab (7.5 mg/kg, IV, every 3 weeks, administered sequentially after bevacizumab)
• Лучевая терапия 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
• Процедура 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.

Первичные конечные точки

• Progression-free survival (PFS) [Срок оценки: Two years]

Вторичные конечные точки (6)

• Overall Survival (OS) [Срок оценки: Five years]
• objective response rate (ORR) [Срок оценки: Two years]
• Disease Control Rate (DCR) [Срок оценки: Two years]
• Local control rate (LCR) [Срок оценки: Two years]
• Incidence of Treatment-related adverse events [Срок оценки: Five years]
• Change in Quality of Life Assessed by EORTC QLQ-C30 Questionnaire [Срок оценки: Two years]

Критерии участия

Критерии включения

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

Критерии исключения

• Histopathological exclusions

• Mixed HCC subtypes: Fibrolamellar HCC or sarcomatoid HCC or cholangiocarcinoma components
• Curative local therapy candidacy

• Current candidacy for resection, liver transplant, or RFA
• 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
• 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
• 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
• Allergy to any component of iparomlimab/tuvonralimab or bevacizumab
• 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

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Не применимо

Модель

Одна группа

Маскирование

Открытое

Основная цель

Лечение

Центры проведения

Китай · 1 центр

• Shandong Cancer Hospital and Institute — Цзинань

Публикации

• Liu Y, Wang H, Zhu K, Jiang S, Shi F, Feng R, Dou X, Xu L, Gong Z, Wang S, Wang C, Wang P, Zhang X, Yue J. 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, single-center PMID 42502358

Идентификаторы

NCT: NCT07062055 · SDZLEC2025-152-02

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

Открыть это исследование на ClinicalTrials.gov ↗