Overview

The investigators hypothesize that the addition of Tislelizumab after definitive local therapy for locally advanced inoperable Hepatocellular carcinoma (HCC) will synergize with local therapy as well as treat micro metastatic disease and improve one year progression-free survival rates for participants and optimize local control.

Eligibility

Inclusion Criteria:

• Each patient eligible to participate in this study must meet all the following

  criteria

  1. Written informed consent
  2. Primary diagnosis of HCC, planned to receive radiation, treatment naïve to systemic therapy for HCC, prior TACE permitted
  3. Hepatocellular carcinoma diagnosis by histologic findings and/or imaging criteria of LI-RADS 5
  4. Eastern Cooperative Oncology Group performance status score of 0-2
  5. Age>/=18 years
  6. Child-Pugh class A liver function or B7, BCLC A-C or deemed not a candidate for surgery or liver transplantation
  7. No extrahepatic metastasis detected on CT chest with or without IV contrast, abdomen and pelvis with IV and oral contrast (triphasic-if feasible based on kidney function), or MRI abdomen/liver and chest CT.
  8. 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
  9. 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.
  10. Must have 1 target lesion measurable in 1 dimension according to RECIST 1.1.
  11. Demonstrate adequate bone marrow and organ function as defined below:
      1. Hematologic - Absolute neutrophil count (ANC) ≥ 1,500/mcL, Hemoglobin > 8.5 g/dL, Platelet count ≥ 75,000/mcL
      2. Renal - Serum creatinine OR calculated* serum creatinine clearance (GFR can be used in place of creatinine or creatinine clearance) ≤ 1.5x upper limit of normal (ULN) OR ≥ 30 mL/min for participants with creatinine levels > 1.5x institutional ULN
         • Calculate serum creatinine clearance using the standard Cockcroft-Gault formula.

                       Urine protein Urine dipstick for proteinuria < 2+ within 7 days prior to
                       start of study treatment *Participants with ≥ 2+ proteinuria on dipstick
                       analysis at baseline should undergo a 24-hour urine collection which must
                       demonstrate < 1g of protein in 24 hours
                    3. Hepatic - Serum total bilirubin ≤ 3 mg/dL , AST (SGOT) and ALT (SGPT) ≤ 5x
                       ULN , Alkaline phosphatase (ALP) ≤ 8x ULN Coagulation - International
                       Normalized Ratio (INR) or prothrombin time (PT) or activated partial
                       thromboplastin time (aPTT) ≤ 2.0x ULN *This applies only to participants not
                       receiving therapeutic anticoagulation; participants receiving therapeutic
                       anticoagulation should be on a stable dose.
                       Exclusion Criteria:
               1. Prior radiotherapy to the region of the liver that would result in excessive
                  doses to normal tissues due to overlap of radiation therapy fields
               2. Prior selective internal radiotherapy/hepatic arterial Yttrium therapy, at any
                  time
               3. Severe, active co-morbidity as per investigator
               4. More than five discrete intrahepatic parenchymal foci of definite HCC or
                  left/right or main portal vein thrombus
               5. Direct tumor extension into the stomach, duodenum, small bowel or large bowel
               6. Measurable common or main branch biliary duct involvement with HCC
               7. 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.
               8. Prior liver transplant
               9. HIV positive
              10. Immunodeficiency requiring chronic systemic therapy or that may relapse
              11. Participants who have received prior immunotherapy.
              12. Participants with clinically meaningful ascites, defined as ascites requiring
                  non-pharmacologic intervention (e.g. paracentesis) to maintain symptomatic
                  control
                  a. Note: Participants with ascites who require pharmacologic intervention (e.g.
                  diuretics) to maintain symptomatic control and who have been on stable doses of
                  diuretics for two months days prior to the first dose of study treatment are
                  eligible.
              13. Participants with clinically meaningful encephalopathy
              14. Participants 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.
              15. Patients must have documented hepatitis virology status.
                  a. Participants 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 fourteen days
                  prior to start of study treatment and for the length of the study. b.
                  Participants with co-infection with HBV and hepatitis C virus (HCV) are excluded.
                  c. Participants with a history of HCV infection but with negative HCV RNA by PCR
                  are considered non-infected with HCV and can enroll.
              16. Participants with a history of autoimmune hypothyroidism on a stable dose of
                  thyroid replacement hormone are eligible.
              17. Participants with controlled Type 1 diabetes mellitus on a stable insulin regimen
                  are eligible.
              18. Participants 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%).
              19. 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).
              20. Treatment with a live, attenuated vaccine within four weeks prior to initiation
                  of study treatment with Tislelizumab.
                    1. Note: Seasonal vaccines for influenza and COVID-19 are generally inactivated
                       vaccines and are allowed. Intranasal vaccines are live vaccines and are not
                       allowed.
              21. 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 a. Note: Participants who are currently or
                  have previously been on any of the following steroid regimens are not excluded:
                  i. Adrenal replacement steroid (dose ≤ 10 mg daily of prednisone or equivalent)
                  ii. Topical, ocular, intra-articular, intranasal, or inhaled corticosteroid with
                  minimal systemic absorption iii. 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)
              22. 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
              23. With history of interstitial lung disease, non-infectious pneumonitis or
                  uncontrolled diseases including pulmonary fibrosis, acute lung diseases, etc.
              24. With severe chronic or active infections requiring systemic antibacterial,
                  antifungal or antiviral therapy, including tuberculosis infection, etc.
              25. 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.
              26. Received therapeutic oral or intravenous antibiotics within two weeks before
                  first dose of study drug
              27. Any major surgical procedure requiring general anesthesia ≤ 28 days before first
                  dose of study drug
              28. Any of the following cardiovascular risk factors:
                  a. Cardiac chest pain, defined as moderate pain that limits instrumental
                  activities of daily living, ≤ 28 days before first dose of study drug b.
                  Pulmonary embolism ≤ 28 days before first dose of study drug c. Any history of
                  acute myocardial infarction ≤ 6 months before first dose of study drug d. Any
                  history of heart failure meeting New York Heart Association (NYHA) Classification
                  III or IV (Appendix 4) ≤ 6 months before first dose of study drug e .Any event of
                  ventricular arrhythmia ≥ Grade 2 in severity ≤ 6 months before first dose of
                  study drug f. Any history of cerebrovascular accident ≤ 6 months before first
                  dose of study drug
              29. Has received any herbal medicine used to control cancer within fourteen days of
                  the first study drug administration
              30. Participants with toxicities (because of prior anticancer therapy) which have not
                  recovered to baseline or stabilized, except for AEs not considered a likely
                  safety risk (e.g., alopecia, neuropathy and specific laboratory abnormalities)
              31. 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 c conduct.
              32. Concurrent participation in another therapeutic clinical study.