A Randomized Phase II Study of Atezolizumab and Bevacizumab With Y-90 TARE in Patients With Unresectable Hepatocellular Carcinoma (HCC)

⁃ Subject must meet all of the following applicable inclusion criteria to participate in this study:

• Written informed consent and HIPAA authorization for release of personal health information prior to registration. NOTE: HIPAA authorization may be included in the informed consent or obtained separately. Patients must be willing and able to provide written informed consent for this trial.

• Age ≥ 18 years at the time of consent.

• ECOG Performance Status of 0-1 at screening

• Histological or cytological evidence/confirmation per AJCC, 8th edition, of hepatocellular carcinoma (HCC).

• Measurable disease by RECIST 1.1.

• Patients must have a Child-Pugh score of A. or selected B7. NOTE: Definition of the selected B7 patients: Child Pugh B7 patients are allowed if they meet the inclusion criteria 11 and they do not have hepatic encephalopathy or more than a moderate amount of ascites.

• Patients must have at least Barcelona Clinic Liver Cancer (BCLC) stage B HCC and must be outside of Milan Criteria; and/or HCC peripheral vascular involvement of any size or number of tumor (segment peripheral, vp1 and vp2 are allowed, but vp3 and vp4 are excluded). NOTE: absence of extrahepatic spread, must be confirmed by computed tomography (CT) or magnetic resonance imaging (MRI) scan of the chest, abdomen, and pelvis.

• Patient must either (1) not be a candidate for liver transplantation as determined by the liver transplant service or (2) refuse evaluation for transplantation.

• Archival tissue obtained within 6 months of registration is required. If archival tissue is not available, subjects are not eligible.

• No prior systemic therapy is permitted. NOTE: Patients who received prior local therapy (e.g., radiofrequency ablation, percutaneous ethanol or acetic acid injection, cryoablation, high-intensity focused ultrasound or TACE) are eligible provided the target lesion(s) have not been previously treated with local therapy or the target lesion(s) within the field of local therapy have subsequently progressed in accordance with RECIST 1.1. Prior TACE is allowed if FLR is ≥ 40%.

• Patient must be a TARE candidate, as defined by a lung dose threshold for Y-90 of 30Gy and an estimated (future liver remnants) FLR of ≥ 40% at the time of forming the comprehensive treatment plan. Both the lung dose threshold and FLR values must be obtained and available in source documentation.

• Patients must demonstrate adequate hepatic, bone marrow, and renal function as defined below. All screening labs should be performed within 14 days of treatment initiation.

‣ Hematological

• Lymphocyte Count: 500/μL

∙ Absolute Neutrophil Count (ANC): ≥ 1,500 /μL

∙ Hemoglobin (Hgb): ≥ 9 g/dL without transfusion or EPO dependency (within 7 days of assessment)

∙ Platelet count (Plt): ≥ 75,000 / μL

⁃ Renal

∙ --Serum creatinine OR Measured or calculated CrCl (GFR can also be used in place of creatinine or CrCl): ≤ 1.5 X upper limit of normal (ULN) OR ≥ 60 mL/min for subject with creatinine levels \> 1.5 x institutional ULN

⁃ Hepatic

• Bilirubin: ≤ 3.0

∙ Aspartate aminotransferase (AST): ≤ 5 X ULN for subjects with cancer in liver

∙ Alanine aminotransferase (ALT): ≤ 5 X ULN for subjects with cancer in liver

∙ Albumin: \> 2.5 mg/dL

∙ Urine Protein: Urine dipstick for proteinuria ≤ 2 g (within 14 days prior to initiation of study treatment). Patients discovered to have \>2+ proteinuria on dipstick urinalysis at baseline should undergo a 24-hour urine collection and must demonstrate \< 1 g of protein in 24 hours.

⁃ Coagulation

∙ --International Normalized Ratio (INR) or Prothrombin Time (PT) Activated Partial Thromboplastin Time (aPTT): ≤ 1.5 X ULN

⁃ Calcium-Subjects with uncontrolled or symptomatic hypercalcemia are NOT eligible

• Ionized Calcium: \< 1.5 mmol/L

∙ Serum Calcium OR Corrected serum calcium: \< 12 mg/dL OR \< ULN

• Documented virology status of HIV; NOTE: Patients with a positive HIV test at screening are eligible provided they are stable on anti-retroviral therapy, have a CD4 count ≥ 200/µL, and have an undetectable viral load.

• Documented virology status of hepatitis, as confirmed by screening HBV and HCV serology test: For patients with active hepatitis B virus (HBV): HBV DNA \<500 IU/mL obtained within 28 days prior to initiation of study treatment, and Anti-HBV treatment (per local standard of care; e.g., entecavir) for a minimum of 14 days prior to study entry and willingness to continue treatment for the length of the study.

• Subjects with chronic infection by HCV who are untreated or who failed previous therapies for HCV are allowed on study. In addition, subjects with successful HCV treatment (defined as sustained virologic response \[SVR\] 12 or SVR 24) are allowed as long as patients are not actively receiving anti-HCV treatment at the time of study enrollment. Investigators can stop anti-HCV treatment at their discretion prior to enrolling patients on study.

• Females of childbearing potential must have a negative serum pregnancy test within 14 days prior to study treatment. NOTE: Females are considered of child bearing potential unless they are surgically sterile (have undergone a hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or they are naturally postmenopausal for at least 12 consecutive months.

• Female participants of childbearing potential must be willing to abstain from heterosexual intercourse or to use contraception as outlined in Section 5.6. Male participants capable of fathering children must be willing to abstain from heterosexual intercourse or to use contraception as outlined in Section 5.6.

• As determined by the enrolling physician or protocol designee, ability of the subject to understand and comply with study procedures for the entire length of the study.