Comparing TACE plus SBRT versus Y90 radioembolization with immunotherapy for large, unresectable liver cancer

Comparison of Stereotactic Body Radiotherapy and Selective Internal Radiation Therapy in Combination With Immunotherapy for Locally-advanced, Unresectable Hepatocellular Carcinomas: an Open-label, Randomized Controlled Trial (BIIRTH)

This trial will test whether giving TACE followed by focused radiation (SBRT) or Y90 radioembolization, each followed by immunotherapy (atezolizumab + bevacizumab), helps people with large, unresectable hepatocellular carcinoma stay progression-free longer.

Quick facts

• Phase: PHASE2; PHASE3
• Study type: Interventional
• Enrollment: 106 (estimated)
• Ages: 18 Years to 80 Years
• Sex: All
• Sponsor: Tuen Mun Hospital (other gov)
• Drugs / interventions: radiation, prednisone, Atezolizumab, bevacizumab, nivolumab, avelumab, immunotherapy
• Locations: 1 site (Hong Kong)
• Trial ID: NCT07293468 on ClinicalTrials.gov

What this trial studies

This randomized phase 2/3 trial enrolls patients with large, locally advanced unresectable hepatocellular carcinoma and randomly assigns them 1:1 to either sequential TACE followed by stereotactic body radiotherapy (SBRT) or to Y90 selective internal radiation therapy (SIRT), with both arms receiving subsequent systemic immunotherapy (atezolizumab + bevacizumab). Patients are recruited through multidisciplinary tumor boards and must meet predefined liver function, performance status, and tumor-size criteria. The main outcome is progression-free survival, with safety and toxicity compared between the two locoregional approaches. The trial seeks to determine whether intensifying local control with TACE+SBRT provides longer disease control without added harm compared with Y90 SIRT.

Who should consider this trial

Good fit: Ideal candidates are adults (18–80 years) with unresectable HCC (BCLC B2-4 or C), at least one measurable lesion ≥5 cm, ECOG 0–1, Child‑Pugh A5–B7, and adequate blood and organ function who are deemed unsuitable for curative resection or transplantation.

Not a fit: Patients with poor performance status, more advanced liver decompensation (beyond Child‑Pugh B7), those eligible for curative surgery or transplant, or those with contraindications to locoregional therapy or immunotherapy are unlikely to benefit from this protocol.

Why it matters

Potential benefit: If successful, the TACE+SBRT approach could extend progression-free survival for patients with large, unresectable HCC while keeping side effects similar to Y90 treatment.

How similar studies have performed: Early-phase and nonrandomized studies have shown promising local control with intensified locoregional approaches (TACE+SBRT or Y90) and emerging benefit when combined with immunotherapy, but direct randomized comparisons are limited.

Eligibility criteria

Inclusion Criteria:

* Patients diagnosed with HCC either by histology or by the American Association for the Study of Liver Diseases Criteria (AASLD) 2018
* Patients age 18-80 years of age with HCCs deemed unresectable at the Multidisciplinary Team Meetings (MDTs) because of the following:
* R0 resection not feasible e.g. unfavourable tumour location
* Remnant liver volume \<30% in non-cirrhotic patients or 40% in cirrhotic patients
* Indocyanine green test \>15%
* Patients with Barcelona Clinic Liver Cancer (BCLC) stage B2-4 (unresectable group) or C
* Tumour sizes of ≥5cm, of which ≥1 is a measurable lesion as defined by the mRECIST criteria
* Subjects aged 18-80 years of age
* ECOG performance status of 0-1
* Predicted life expectancy should be of ≥ 3 months
* Child Pugh (CP) score of A5-B7
* Adequate organ and marrow functions, as listed below:
* Haemoglobin ≥9 g/dL
* Absolute neutrophil count ≥1,500/uL
* Platelet count ≥100,000/L
* Total bilirubin ≤2.0 x upper limit of normal (ULN)
* Albumin ≥2.8 g/dL
* ALT ≤3 x ULN
* INR ≤1.6
* Calculated creatinine clearance (eGFR) ≥45 mL/minute as determined by Cockcroft-Gault (using actual body weight) or 24-hour urine creatinine clearance
* Liver volume minus intrahepatic gross tumour volume (GTV) with \>700cc
* Patients with concomitant HBV infection (defined as having HBsAg positive and/or detectable HBV DNA level) must be treated with antiviral therapy (per local institutional practice) to ensure adequate viral suppression (defined as HBV DNA \<2,000 IU/mL) prior to enrolment, throughout study duration and continue for at least 6 months following the last dose of local-systemic therapy
* Informed consent provided
* Females of childbearing potential or non-sterilized male who are sexually active must use a highly effective method of contraception
* Females of childbearing potential must have negative serum or urine pregnancy test

Exclusion Criteria:

* Prior invasive malignancy within 2 years except for noninvasive malignancies such as cervical carcinoma in situ, in situ prostate cancer, non-melanomatous carcinoma of the skin, lobular or ductal carcinoma in situ of the breast that has been surgically cured
* Presence of any extra-hepatic metastases
* Presence of main portal vein (PV) or inferior vena cava (IVC) involvement
* Presence of active, uncontrolled varices
* Presence of active, severe comorbidities including uncontrolled cardiovascular or cerebrovascular diseases or recent events within 6months prior to treatment
* Received prior non-curative locoregional (including TACE, RT to liver, SIRT) or systemic therapy received for HCC\\
* Prior treatment with any anti-programmed cell death protein-1 (anti-PD-1), PD Ligand-1 (PD-L1) or PD Ligand-2 (PD-L2) agent, or an antibody targeting other immune-regulatory receptor(s) or mechanism(s)
* Use of chronic systemic steroid or any other immunosuppressive medication within 14days prior to treatment initiation, except:
* Intranasal, inhaled, topical steroids, or local steroid injection;
* Systemic corticosteroids at physiologic doses ≤10mg/day of prednisone or equivalent;
* Steroids as premedication for hypersensitivity reactions
* Active or documented autoimmune or inflammatory disorders within 2years, except diabetes type I, vitiligo, psoriasis, or hypo-/hyperthyroid diseases not requiring immunosuppressant(s)
* Known history of a positive HIV test, primary/acquired immunodeficiency syndrome, or solid organ transplantation
* Receipt of live, attenuated vaccine within 28 days prior to study treatment
* Severe hypersensitivity reaction to another monoclonal antibody
* Presence of any contraindication to TACE not otherwise listed: cisplatin allergy
* Presence of any contraindication to SBRT not otherwise listed:
* Maximal size of any one HCC \>25 cm
* Direct tumour extension into gastrointestinal structures (stomach, duodenum, remaining small or large bowel)
* Presence of any contraindication to SIRT not otherwise listed:
* Pre-treatment 99mTc-MAA scan \>20% lung shunting of hepatic artery blood flow, or a demonstration of radiation exposure to the lungs potentially \>25Gy
* Pre-treatment hepatic angiogram showing potential Y90 microspheres deposition in the gastrointestinal tract or any other organ(s) which is not correctable by catheter embolization techniques.
* Pregnant or lactating females

Where this trial is running

Hong Kong

• Tuen Mun Hospital — Hong Kong, Hong Kong (RECRUITING)

Study contacts

• Study coordinator: Sean Man Natalie WONG

Conditions: Hepatocellular Carcinoma, TACE, SBRT, Y90, SIRT, immunotherapy, combination therapy, locally advanced