Tislelizumab Before and After Radiation Therapy for the Treatment of Liver Cancer

Inclusion Criteria

• Written informed consent
• Primary diagnosis of HCC, planned to receive radiation, treatment naive to systemic therapy for HCC, prior transarterial chemoembolization (TACE) permitted
• Hepatocellular carcinoma diagnosis by histologic findings and/or imaging criteria of Liver Imaging Reporting and Data System (LI-RADS) 5
• Eastern Cooperative Oncology Group performance status score of 0-2
• Age >= 18 years
• Child-Pugh class A liver function or B7, Barcelona Clinic Liver Cancer (BCLC) A-C or deemed not a candidate for surgery or liver transplantation
• No extrahepatic metastasis detected on computed tomography (CT) chest with or without IV contrast, abdomen and pelvis with IV and oral contrast (triphasic-if feasible based on kidney function), or magnetic resonance imaging (MRI) abdomen/liver and chest CT
• Females of childbearing potential must be willing to use a highly effective method of birth control for the duration of the study, and >= 6 months after the last dose of tislelizumab, and have a negative urine or serum pregnancy test =< 7 days of first dose of study drug
• Non-sterile males must be willing to use a highly effective method of birth control for the duration of the study and for >= 6 months after the last dose of tislelizumab. Males must agree not to donate or bank sperm during treatment with tislelizumab and for >= 6 months after treatment stop
• Must have 1 target lesion measurable in 1 dimension according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1.
• Absolute neutrophil count (ANC) >= 1,500/mcL
• Hemoglobin > 8.5 g/dL
• Platelet count >= 75,000/mcL
• Serum creatinine =< 1.5 x upper limit of normal (ULN) OR calculated serum creatinine clearance (glomerular filtration rate [GFR] can be used in place of creatinine or creatinine clearance) >= 30 mL/min for participants with creatinine levels > 1.5 x institutional ULN * Calculate serum creatinine clearance using the standard Cockcroft-Gault formula
• Urine dipstick for proteinuria < 2+ within 7 days prior to start of study treatment * Patients with >= 2+ proteinuria on dipstick analysis at baseline should undergo a 24-hour urine collection which must demonstrate < 1 g of protein in 24 hours
• Serum total bilirubin =< 3 mg/dL
• Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 5 x ULN
• Alkaline phosphatase (ALP) =< 8 x ULN
• International normalized ratio (INR) or prothrombin time (PT) or activated partial thromboplastin time (aPTT) =< 2.0 x ULN * This applies only to patients not receiving therapeutic anticoagulation; patients receiving therapeutic anticoagulation should be on a stable dose

Exclusion Criteria

• Prior radiotherapy to the region of the liver that would result in excessive doses to normal tissues due to overlap of radiation therapy fields
• Prior selective internal radiotherapy/hepatic arterial Yttrium therapy, at any time
• Severe, active co-morbidity as per investigator
• More than 5 discrete intrahepatic parenchymal foci of definite HCC or left/right or main portal vein thrombus
• Direct tumor extension into the stomach, duodenum, small bowel or large bowel
• Measurable common or main branch biliary duct involvement with HCC
• Extrahepatic metastases or malignant nodes (that enhance with typical features of HCC) > 3.0 cm, in sum of maximal diameters (e.g. presence of one 3.4 cm metastatic lymph node or two 2 cm lung lesions) * Note: benign non-enhancing periportal lymphadenopathy is not unusual in the presence of hepatitis and is permitted, even if the sum of enlarged nodes is > 2.0 cm
• Prior liver transplant
• Human immunodeficiency virus (HIV) positive
• Immunodeficiency requiring chronic systemic therapy or that may relapse
• Patients who have received prior immunotherapy
• Patients with clinically meaningful ascites, defined as ascites requiring non-pharmacologic intervention (e.g. paracentesis) to maintain symptomatic control * Note: Patients with ascites who require pharmacologic intervention (e.g. diuretics) to maintain symptomatic control and who have been on stable doses of diuretics for 2 months days prior to the first dose of study treatment are eligible
• Patients with clinically meaningful encephalopathy
• Patients who have undergone prior solid organ or bone marrow transplant except for patients with prior renal transplant for whom dialysis may be employed in the event of graft rejection
• Patients must have documented hepatitis virology status * Patients with active hepatitis B virus (HBV) infection must have a viral load < 500 IU/mL within 28 days prior to start of tislelizumab and be on suppressive therapy (per local standard of care) for a minimum of 14 days prior to start of study treatment and for the length of the study * Patients with co-infection with HBV and hepatitis C virus (HCV) are excluded * Patients with a history of HCV infection but with negative HCV ribonucleic acid (RNA) by polymerase chain reaction (PCR) are considered non-infected with HCV and can enroll
• Patients with a history of autoimmune hypothyroidism on a stable dose of thyroid replacement hormone are eligible
• Patients with controlled Type 1 diabetes mellitus on a stable insulin regimen are eligible
• Patients with eczema, psoriasis, lichen simplex chronicus of vitiligo with dermatologic manifestations only are eligible provided: 1) rash covers < 10% of body surface area (BSA), disease is well controlled at baseline and requires only low potency topical steroids (e.g., hydrocortisone 2.5%, hydrocortisone butyrate 0.1%, flucinolone 0.01%, desonide 0.05%, aclometasone dipropionate 0.05%)
• Any malignancy =< 5 years before first dose of study drug except for the specific cancer under investigation in this study and any locally recurring cancer that has been treated curatively (e.g. resected basal or squamous cell skin cancer, superficial bladder cancer, carcinoma in situ of the cervix or breast)
• Treatment with a live, attenuated vaccine within 4 weeks prior to initiation of study treatment with tislelizumab * Note: Seasonal vaccines for influenza and coronavirus disease 2019 (COVID-19) are generally inactivated vaccines and are allowed. Intranasal vaccines are live vaccines and are not allowed
• Any condition that required systemic treatment with either corticosteroids (> 10 mg daily of prednisone or equivalent) or other immunosuppressive medication =< 14 days before first dose of study drug * Note: Patients who are currently or have previously been on any of the following steroid regimens are not excluded: ** Adrenal replacement steroid (dose =< 10 mg daily of prednisone or equivalent) ** Topical, ocular, intra-articular, intranasal, or inhaled corticosteroid with minimal systemic absorption ** Short course (=< 7 days) of corticosteroid prescribed prophylactically (e.g., for contrast dye allergy) or for the treatment of a non-autoimmune condition (e.g., delayed-type hypersensitivity reaction caused by contact allergen)
• With uncontrolled diabetes or > grade 1 laboratory test abnormalities in potassium, sodium, or corrected calcium despite standard medical management or >= grade 3 hypoalbuminemia =< 14 days before first dose of study drug
• With history of interstitial lung disease, non-infectious pneumonitis or uncontrolled diseases including pulmonary fibrosis, acute lung diseases, etc.
• With severe chronic or active infections requiring systemic antibacterial, antifungal or antiviral therapy, including tuberculosis infection, etc.
• Severe infections within 4 weeks before first dose of study drug, including but not limited to hospitalization for complications of infection, bacteremia, or severe pneumonia
• Received therapeutic oral or intravenous antibiotics within 2 weeks before first dose of study drug
• Any major surgical procedure requiring general anesthesia =< 28 days before first dose of study drug
• Any of the following cardiovascular risk factors: * Cardiac chest pain, defined as moderate pain that limits instrumental activities of daily living, =< 28 days before first dose of study drug * Pulmonary embolism =< 28 days before first dose of study drug * Any history of acute myocardial infarction =< 6 months before first dose of study drug * Any history of heart failure meeting New York Heart Association (NYHA) classification III or IV =< 6 months before first dose of study drug * Any event of ventricular arrhythmia >= grade 2 in severity =< 6 months before first dose of study drug * Any history of cerebrovascular accident =< 6 months before first dose of study drug
• Has received any herbal medicine used to control cancer within 14 days of the first study drug administration
• Patients with toxicities (because of prior anticancer therapy) which have not recovered to baseline or stabilized, except for adverse events (AEs) not considered a likely safety risk (e.g., alopecia, neuropathy and specific laboratory abnormalities)
• Underlying medical conditions (including laboratory abnormalities) or alcohol or drug abuse or dependence that, will be unfavorable for the administration of study drug or affect the explanation of drug toxicity or AEs or result in insufficient or might impair compliance with study conduct
• Concurrent participation in another therapeutic clinical study