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

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.

Eligibility

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

Conditions4

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