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)

Plain English Summary

Comparison of SBRT and SIRT With Combination IO for Locally-advanced, Unresectable HCCs (BIIRTH) is a Phase 3 clinical trial sponsored by Tuen Mun Hospital studying Hepatocellular Carcinoma (HCC). Compares TACE-SBRT and Y90 SIRT with immunotherapy for large, locally advanced, unresectable HCCs. For patients aged 18-80 with HCC deemed unresectable, who have specific tumor sizes and liver function. Participation involves multiple treatments over several weeks, followed by immunotherapy. Alternatives include other radiation and chemotherapy treatments. The trial aims to enroll 106 participants.

Official 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.

Who Can Participate

Here is what you need to know about eligibility for this trial. Eligible: HCC patients aged 18-80, with specific tumor sizes and liver function. Not eligible: Previous HCC treatments, extra-hepatic metastases, severe comorbidities, or immunosuppressive medications. Age: 18-80 years Health: Specific liver function and tumor size criteria This trial is studying Hepatocellular Carcinoma (HCC), so participants generally need a confirmed diagnosis. The trial is currently accepting new participants.

What They're Measuring

The primary outcome measures the time until the disease progresses or the patient dies, helping patients understand the effectiveness of the treatment. The specific primary outcome measures are: 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). These endpoints are how researchers determine whether the treatment is effective and will form the basis of any future regulatory submissions.

About This Phase

This trial is in Phase 3, the final and most rigorous stage before seeking FDA approval. Phase 3 trials involve 300-3,000+ patients across multiple sites and compare the new treatment directly against the current standard of care. These pivotal trials generate the evidence needed for regulatory review. About 58% of Phase 3 drugs receive FDA approval. Successful Phase 3 results typically lead to a New Drug Application submission.

Why This Trial Matters

This trial aims to fill the gap in treatment options for large, locally advanced HCCs, offering a potentially longer progression-free survival. As a Phase 3 trial, positive results could directly lead to FDA approval, making this treatment available to the broader patient population. This research targets Hepatocellular Carcinoma (HCC), where improved treatment options are needed.

Investor Insight

The large market size and competitive landscape highlight the potential for significant approval and market impact. Phase 3 trials have approximately a 50-60% chance of gaining FDA approval if they reach this stage.

Is This Trial Right for Me?

Ask your doctor about your eligibility and the potential risks. Participation involves multiple treatments over several weeks, followed by immunotherapy. This trial is currently recruiting participants. The trial is being conducted at 1 site. Always discuss clinical trial participation with your healthcare provider before making any decisions. This information is for educational purposes only and is not medical advice.

AI-generated analysis for educational purposes only. This is not medical advice. Discuss clinical trial participation with your doctor. Data sourced from ClinicalTrials.gov.

Study Design

• Study Type: INTERVENTIONAL
• Allocation: RANDOMIZED
• Model: PARALLEL
• Masking: NONE
• Enrollment: 106 participants

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
• 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 delivere
• 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
• 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 transi

Primary Outcomes

• 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

• 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)

Full 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

Trial Locations

• Tuen Mun Hospital, Hong Kong, Hong Kong

Frequently Asked Questions

Related Conditions

• Hepatocellular Carcinoma (HCC)
• Liver cancer
• Cancer
• Radiation therapy
• Immunotherapy
• Hepatic tumors
• Liver diseases
• Cancer treatments
• Hepatobiliary diseases
• Cancer research

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