Therasphere® and Systemic Therapy for Patients With Hepatocellular Carcinoma That is High-risk

Inclusion Criteria:

• Patients must have a diagnosis of hepatocellular carcinoma (HCC) confirmed byAmerican Association for Study of Liver Diseases (AASLD) guidelines with aChilds-Pugh score of A or B7 NOTE: If the patient does not have histologicalconfirmation of disease by biopsy, diagnosis of HCC must be documented with approvalby a tumor board or other multidisciplinary conference. Please refer to theappropriate source documents.

• Patients must have at least 1 lesion that is measurable using RECIST guidelines.NOTE: A previously irradiated lesion can be considered a target lesion if the lesionis well defined, measurable per RECIST, and has clearly progressed.

• Patients must have advanced disease that is not amenable to transplant or resection.

• Patients may be treatment naïve or have received any number of prior therapies.NOTE:

Prior cancer targeted immunotherapy is contraindicated and not permitted.

• Patients must exhibit an ECOG performance status of 0, 1, or 2 [Appendix 1]

• Patients must have adequate organ function prior to registration as determined by:

• Adequate organ function parameters:

1. HEMATOLOGICAL (without growth factor support)

• Hemoglobin (HgB) ≥ 8.5 g/dL (without the use of growth factors) [transfusion permitted]
• Absolute Neutrophil Count (ANC) ≥1000 microliter (µL)
• Platelet Count ≥ 50 x 109/L (without use of growth factors [i.e., IL-11 ] [Transfusion permitted to achieve this value]
• Prothrombin time (PT)/ International normalized ratio (INR)
• NOTE: Subjects receiving anticoagulant therapy are eligible if their INRis stable and within the recommended range for the desired level ofanticoagulation. ≤ 2.3 or PT ≤ 6 seconds above control.

2. RENAL • Calculated creatinine clearance (*Cockcroft-Gault formula will be used tocalculate CrCl)[Appendix 2] (CrCl) or 24-hour urine CrCl > 30 mL/min

3. HEPATIC

• Serum Bilirubin ≤ 3 times the upper limit of normal (ULN)

• AST ≤ 5 times ULN

• ALT ≤ 5 times ULN Abbreviations: ALT = alanine aminotransferase; ANC =absolute neutrophil count; AST = aspartate aminotransferase; ULN = upperlimit of normal.

• For patients with a known history of Human immunodeficiency virus (HIV), infectedpatients on effective anti-retroviral therapy

• For patients with a known history of chronic hepatitis B virus (HBV) infection, theHBV viral load must be undetectable on suppressive therapy, if indicated.

• Patients with a known history of hepatitis C virus (HCV) infection must have beentreated and cured. For patients with HCV infection who are currently on treatment,they are eligibleif they have an undetectable HCV viral..

• Females of childbearing potential (FOCBP), and non-sterilized males who are sexuallyactive must agree to the use of two methods of contraception, with one method beinghighly effective and the other method being either highly effective or lesseffective. They must also refrain from egg and/or sperm cell donation andbreastfeeding for 90 days after the final dose of investigational product(s) FOCBPare defined as those who are not surgically sterile (i.e. bilateral tubal ligation,bilateral oophorectomy, or complete hysterectomy) or postmenopausal (defined as 12months with no menses without an alternative medical cause) FOCBP must agree tofollow instructions for method(s) of contraception for the duration of treatment. .

Men who are sexually active with FOCBP must agree to follow instructions for method(s) of contraception for the duration of treatment.

• FOCBP must have a negative pregnancy test (Serum or urine pregnancy test per siteinvestigator discretion) within 7 days prior to registration.

• Patients must have the ability to understand and the willingness to sign a writteninformed consent prior to registration on study.

Exclusion Criteria:

• Patients who are concurrently enrolled in another clinical study unless it is anobservational (non- interventional) clinical study or the follow-up period of aninterventional study.

• Patients who are receiving any other investigational agents within 28 days ofregistration.

• Patients who have a history of allergic reactions attributed to compounds of similarchemical or biologic composition to Y90, PD-1 &PD-L1 antagonists and TKI's.

Note: Patients must not have a history of severe allergic reactions (i.e., Grade 4 allergy, anaphylactic reaction from which the subject did not recover within 6 hours of institution of supportive care) to any unknown allergens or any components of the systemic therapy

• Patients must not have had prior treatment any PDL1 or PD-1 antagonists

• Patients who have known additional malignancy that progressed or required treatmentwithin the last 3 years. Exceptions include adequately treated basal cell orsquamous cell skin cancer, in situ cervical cancer, adequately treated Stage I or IIcancer from which the patient is currently in complete remission, or any othercancer from which the patient has been disease free for at least three years.

• Patients with active autoimmune disease or history of autoimmune disease that mightrecur, which may affect vital organ function or require immune suppressive treatmentincluding chronic prolonged systemic corticosteroids (defined as corticosteroid useof duration one month or greater), should be excluded. These include but are notlimited to patients with a history of: immune related neurologic disease

• multiple sclerosis

• autoimmune (demyelinating) neuropathy NU22I07 10.25.22 initial 19

• Guillain-Barre syndrome

• myasthenia gravis

• systemic autoimmune disease such as SLE

• connective tissue diseases

• scleroderma

• inflammatory bowel disease (IBD)

• Crohn's

• ulcerative colitis

• patients with a history of toxic epidermal necrolysis (TEN)

• Stevens-Johnson syndrome

• anti-phospholipid syndrome NOTE: Subjects with vitiligo, type I diabetesmellitus, residual hypothyroidism due to autoimmune condition only requiringhormone replacement, psoriasis not requiring systemic treatment, or conditionsnot expected to recur in the absence of an external trigger are permitted toenroll

• Patients with renal failure currently requiring dialysis of any kind .

• Patients with untreated central nervous system (CNS) metastatic disease (includingspinal cord and leptomeningeal disease) are excluded.

Note: Subjects with previously treated CNS metastases that are radiographically and neurologically stable for at least 6 weeks and do not require corticosteroids (of any dose) for symptomatic management are permitted to enroll

• Patients receiving any concurrent chemotherapy, biologic or hormonal therapy forcancer treatment within 28 days of registration. Note: Prior cancer immunotherapy isnot permitted. Note: Concurrent use of hormones for non-cancer-related conditions (e.g., insulin for diabetes and hormone replacement therapy) is acceptable.

• Patients who have unresolved toxicities from prior anticancer therapy, defined ashaving not resolved to NCI CTCAE v 5 [Appendix 6] Grade 0 or 1 with the exception ofalopecia and laboratory values listed per the inclusion criteria. Note: Subjectswith irreversible toxicity that is not reasonably expected to be exacerbated by anyof the investigational products may be included (e.g., hearing loss) afterconsultation with the PI and NU QAM.

• Patients receiving radiation therapy within 14 days of registration.

• Patients receiving live vaccines within 28 days of study registration.

• No systemic glucocorticoids will be permitted within 48 hours prior to studyregistration.

Note: Topical steroids, bronchodilators and local steroid injections are permitted if clinically required.

• Patients with cardiac disease defined as one of the following are not eligible:

• Congestive heart failure > class II NYHA.[Appendix 4]

• Unstable angina (anginal symptoms at rest) or new onset angina (began withinthe last 90 days )

• Myocardial infarction within the past 180 days.

• Patients with cardiac ventricular arrhythmias requiring anti-arrhythmic therapy .

• Patients having elevated lung shunting precluding treatment with Y-90.

• Patients who have had major surgery within 4 weeks prior to registration.

• Patients with a history of gastrointestinal bleeding (GIB) within 6 weeks prior toregistration.

• Patients with prior transplant of any kind

• Patients who are pregnant or nursing .

• Patients who have an uncontrolled intercurrent illness including, but not limited toany of the following, are not eligible:

• Hypertension that is not controlled on medication

• Patients who have active clinically serious infection > CTCAEv 5 Grade 2 .Psychiatric illness/social situations that would limit compliance with studyrequirements

• Any other illness or condition that the treating investigator feels wouldinterfere with study compliance or would compromise the patient's safety orstudy endpoints

• Active alcohol use, drug use, or a psychiatric disease that would, in theopinion of the PI or a sub-investigator (sub-I), prevent the subject fromcomplying with the study protocol and/or endanger the subject during theirparticipation in the study