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

NCT07293468 | Recruiting Phase 2 DMC

• 1 other identifier: BIIRTH
• Study Type: interventional
• Target: 106
• Locations: 1 country
• Sites: 1

Brief 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.

Conditions

Hepatocellular Carcinoma (HCC)

Keywords

TACE; SBRT; Y90; SIRT; immunotherapy; combination therapy; locally advanced; unresectable HCC; RCT; liver; hepatocellular carcinoma; stereotactic body radiotherapy; transarterial chemoembolization; radioembolization

Outcome Measures

Primary Outcomes (1)

• Progression-free survival (PFS)

  defined as the period from the date of starting TACE or Y90-radioembolisation to the time of local, in-field disease progression, or the time of patient death, whichever occurring first; up to 10 years

Secondary Outcomes (11)

• Overall Survival (OS)

  defined as the period from the date of starting TACE or Y90-radioembolisation to the date of patient death; up to 10 years

• Objective response rate (ORR) per mRECIST criteria

  The percentage of patients in each study group achieving a partial response or complete response to intervention arm, from start of TACE or SIRT to date of progression or death; up to 10 years

• Local Control (LC)

  From start of TACE or SIRT to local (target lesion) progression or death, whichever occurs first; up to 10 years

• Surgical conversion rate

  From treatment to disease progression or death, up to 10 years

• Pathological response

  From treatment completion to disease progression or death; up to 10 years

Study Arms (2)

TACE-SBRT arm

EXPERIMENTAL

Combination TACE and SBRT followed by immunotherapy

Procedure: Transarterial chemoembolization (TACE); Radiation: Stereotactic Body Radiation Therapy (SBRT); Drug: Atezolizumab & Bevacizumab

Y90 SIRT arm

ACTIVE COMPARATOR

Combination Y90 SIRT followed by immunotherapy

Radiation: SIRT Yttrium-90; Drug: Atezolizumab & Bevacizumab

Interventions

Transarterial chemoembolization (TACE) PROCEDURE

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.

TACE-SBRT arm

Stereotactic Body Radiation Therapy (SBRT) RADIATION

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.

TACE-SBRT arm

SIRT Yttrium-90 RADIATION

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.

Y90 SIRT arm

Atezolizumab & Bevacizumab DRUG

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.

TACE-SBRT arm; Y90 SIRT arm

Eligibility Criteria

• Age: 18 Years - 80 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• The University of Hong Kong: collaborator
• The University of Hong Kong-Shenzhen Hospital: collaborator
• Tuen Mun Hospital: lead
• Queen Mary Hospital, Hong Kong: collaborator

Study Sites (1)

Tuen Mun Hospital

Hong Kong, Hong Kong

RECRUITING

Related Publications (9)

• Wong N, Chiang C, Ho C, Yip W, Yeung C, Chan M, et al. Prognostic Factors and Survival in Advanced Large Hepatocellular Carcinomas Treated with Combined Transarterial Chemoembolisation and Hypofractionated Image-guided Radiotherapy. Hong Kong Journal of Radiology. 2020 Sep 25;23(3):198-207.

  BACKGROUND

• Chiang CL, Chan KSK, Chiu KWH, Lee FAS, Chen W, Wong NSM, Ho RLM, Lee VWY, Man K, Kong FMS, Chan ACY. Complete Response to Locoregional Therapy Plus Immunotherapy for Hepatocellular Carcinoma. JAMA Oncol. 2024 Nov 1;10(11):1548-1553. doi: 10.1001/jamaoncol.2024.4085.

  PMID: 39325464 BACKGROUND

• Chiang CL, Lee FAS, Chan KSK, Lee VWY, Chiu KWH, Ho RLM, Fong JKS, Wong NSM, Yip WWL, Yeung CSY, Lau VWH, Man K, Kong FMS, Chan ACY. Survival Outcome Analysis of Stereotactic Body Radiotherapy and Immunotherapy (SBRT-IO) versus SBRT-Alone in Unresectable Hepatocellular Carcinoma. Liver Cancer. 2023 Oct 1;13(3):265-276. doi: 10.1159/000533425. eCollection 2024 Jun.

  PMID: 38756147 BACKGROUND

• Chiang CL, Chiu KWH, Chan KSK, Lee FAS, Li JCB, Wan CWS, Dai WC, Lam TC, Chen W, Wong NSM, Cheung ALY, Lee VWY, Lau VWH, El Helali A, Man K, Kong FMS, Lo CM, Chan AC. Sequential transarterial chemoembolisation and stereotactic body radiotherapy followed by immunotherapy as conversion therapy for patients with locally advanced, unresectable hepatocellular carcinoma (START-FIT): a single-arm, phase 2 trial. Lancet Gastroenterol Hepatol. 2023 Feb;8(2):169-178. doi: 10.1016/S2468-1253(22)00339-9. Epub 2022 Dec 15.

  PMID: 36529152 BACKGROUND

• de la Torre-Alaez M, Matilla A, Varela M, Inarrairaegui M, Reig M, Lledo JL, Arenas JI, Lorente S, Testillano M, Marquez L, Da Fonseca L, Argemi J, Gomez-Martin C, Rodriguez-Fraile M, Bilbao JI, Sangro B. Nivolumab after selective internal radiation therapy for the treatment of hepatocellular carcinoma: a phase 2, single-arm study. J Immunother Cancer. 2022 Nov;10(11):e005457. doi: 10.1136/jitc-2022-005457.

  PMID: 36450386 BACKGROUND

• Dawson LA, Winter K, Knox J, Zhu AX, Krishnan S, Guha C, et al. NRG/RTOG 1112: Randomized Phase III Study of Sorafenib vs. Stereotactic Body Radiation Therapy (SBRT) Followed by Sorafenib in Hepatocellular Carcinoma (HCC) (NCT01730937). Int J Radiat Oncol. 2022 Dec;114(5):1057.

  BACKGROUND

• Apisarnthanarax S, Barry A, Cao M, Czito B, DeMatteo R, Drinane M, Hallemeier CL, Koay EJ, Lasley F, Meyer J, Owen D, Pursley J, Schaub SK, Smith G, Venepalli NK, Zibari G, Cardenes H. External Beam Radiation Therapy for Primary Liver Cancers: An ASTRO Clinical Practice Guideline. Pract Radiat Oncol. 2022 Jan-Feb;12(1):28-51. doi: 10.1016/j.prro.2021.09.004. Epub 2021 Oct 21.

  PMID: 34688956 BACKGROUND

• Wong SS, Wong WH, Ngar DY, Ma VW, Cheung C, Lee FA. NTWC Guideline for Transarterial Radioembolization using Yttrium-90 Microspheres (Y90-TARE). Hong Kong; 2020 Sep. (1).

  BACKGROUND

• Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, Bray F. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin. 2021 May;71(3):209-249. doi: 10.3322/caac.21660. Epub 2021 Feb 4.

  PMID: 33538338 BACKGROUND

MeSH Terms

Conditions

Carcinoma, Hepatocellular

Interventions

Radiosurgery; atezolizumab; Bevacizumab

Condition Hierarchy (Ancestors)

Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Liver Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Digestive System Diseases; Liver Diseases

Intervention Hierarchy (Ancestors)

Radiotherapy; Therapeutics; Stereotaxic Techniques; Neurosurgical Procedures; Surgical Procedures, Operative; Investigative Techniques; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Central Study Contacts

Sean Man Natalie WONG

CONTACT

852-24685088; wsm011@ha.org.hk

Man TONG

CONTACT

852-24685086; tm326@ha.org.hk

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER GOV
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Model Details: This is an investigator-initiated, phase III, prospective, open-label, multi-institutional randomized controlled trial.

Study Record Dates

• First Submitted: December 5, 2024
• First Posted: December 19, 2025
• Study Start: April 1, 2024
• Primary Completion (Estimated): March 31, 2034
• Study Completion (Estimated): December 31, 2034
• Last Updated: April 9, 2026

Record last verified: 2026-04

Locations

HK (1)