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RECRUITING

NCT07293468

PHASE2/PHASE3

Comparison of SBRT and SIRT With Combination IO for Locally-advanced, Unresectable HCCs (BIIRTH)

Sponsor: Tuen Mun Hospital

View on ClinicalTrials.gov

Summary

The goal of this clinical trial is to compare the safety and efficacy of sequential Transarterial Chemoembolization (TACE) and Stereotactic body radiation therapy (SBRT) versus Y90-radioembolisation (SIRT), followed by systemic therapy in patients with large, locally advanced, unresectable Hepatocellular carcinoma (HCC). The main question it aims to answer is whether Sequential TACE-SBRT potentially gives longer Progression-free survival (PFS) benefit with similar toxicities as compared with Y90 SIRT. Participants will be recruited via multidisciplinary meetings (MDTs) with hepatobiliary surgeons, medical hepatologists and radiologists with consistent, strict considerations on eligibility and treatment alternatives. Eligible patients will be randomized in 1:1 ratio to received one of the two treatment arms.

Official title: 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)

Key Details

Gender

All

Age Range

18 Years - 80 Years

Study Type

INTERVENTIONAL

Enrollment

106

Start Date

2024-04-01

Completion Date

2034-12-31

Last Updated

2026-04-09

Healthy Volunteers

Conditions

Hepatocellular Carcinoma (HCC)

Interventions

PROCEDURE

Transarterial chemoembolization (TACE)

One dose of TACE would be performed as per standardized procedure at 21-35 days preceding SBRT. Celiac and superior mesenteric arterial and porto-venogram would be performed to exclude main portal vein occlusion and to delineate the size(s) and number(s) of tumour nodule(s). Supra-selective cannulation of the supplying tumour artery would follow. The 1:1 lipiodol-cisplatin emulsion prepared by pumping would be slowly injected under fluoroscopic guidance according to the tumour size and arterial blood flow.

RADIATION

Stereotactic Body Radiation Therapy (SBRT)

Patients are immobilized with customized device and abdominal compression or active breathing control. Four-dimensional computed tomography (4D-CT) was phase-sorted into 10 image-sets. A radiation dose of 27.5-50.0 Gy in five fractions, delivered in alternate days, is allowed. The prescription dose is individualized based on normal tissue constraints. This should be based on delivering a maximal tumoricidal dose while respecting the tolerance dose of neighbouring organs-at-risk. SBRT is delivered by dynamic conformal arc therapy, intensity-modulated RT, or volumetric modulated arc RT.

RADIATION

SIRT Yttrium-90

Patients undergo intrahepatic arterial Y90-radioembolisation (TheraSphere glass microspheres; MDS Nordion, Ottawa, Canada or SIR-Spheres, Sirtex Medical Pty Limited; St. Leonards, NSW, Australia). The administered activity of Y90-glass microspheres was determined by the nuclear medicine physician, medical physicist, radiologist and clinical oncologist using the artery-specific partition model within the limits of radiation safety, taking into account treatment variables including patient's body surface area, tumour-to-normal liver ratio, and liver tumour size. Where possible, personalized dosimetry using the partition model was the default methodology to facilitate selective administration of Y90-radioembolisation avoiding toxicities to the normal liver parenchyma.

DRUG

Atezolizumab & Bevacizumab

Patients will start Atezolizumab-bevacizumab 14days upon completion of SBRT or SIRT. Atezolizumab, if given, is administered via IV infusion at a fixed dose of 1200mg, together with Bevacizumab (start 28days after SBRT/SIRT) via IV infusion at a fixed dose of 15mg/kg, on Day 1 of each 21-day cycle until unacceptable toxicity or loss of clinical benefit as determined by the investigator, or after curative surgical intervention is performed with no evidence of residual disease. Patients who transiently or permanently discontinued either atezolizumab or bevacizumab due to an adverse event are allowed to continue with single-agent therapy provided there is ongoing clinical benefit as determined by the investigator.

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

Locations (1)

Tuen Mun Hospital

Hong Kong, Hong Kong