SBRT + Atezolizumab + Bevacizumab in Resectable HCC

Inclusion Criteria:

* Participants must have a diagnosis of hepatocellular carcinoma that is localized to the liver, has no radiographic evidence of macrovascular invasion, and is deemed surgically resectable. The diagnosis may be obtained radiographically (i.e. having a LiRADS or OPTN category 5 liver lesion) or by histologic diagnosis from a core biopsy or cytology specimen. Radiographic evaluation should occur within approximately 30 days prior to enrollment.
* Participants must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded for non-nodal lesions and short axis for nodal lesions) as ≥20 mm (≥2 cm) by chest x-ray or as ≥10 mm (≥1 cm) with CT scan, MRI, or calipers by clinical exam. See Section 12 (Measurement of Effect) for the evaluation of measurable disease.
* Participants must have Child-Pugh A liver function (see Appendix A).
* No prior therapy directed against the index hepatocellular carcinoma lesion is allowed
* Age ≥18 years at the time of signing the informed consent document.
* ECOG performance status ≤ 1 (Karnofsky ≥60%, see Appendix B).
* Participants must have adequate organ and marrow function as defined below:

  * leukocytes ≥3,000/mcL
  * absolute neutrophil count ≥1,500/mcL
  * platelets ≥100,000/mcL
  * total bilirubin ≤ 2 × institutional upper limit of normal (ULN)
  * AST(SGOT)/ALT(SGPT) ≤ 3 × institutional ULN
  * creatinine ≤ 1.5 × institutional ULN OR
  * estimated glomerular filtration rate (GFR) ≥50 mL/min/1.73 m2 (according to the Cockcroft-Gault formula)
* Human immunodeficiency virus (HIV)-infected participants on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial.
* Documented virology status of hepatitis, as confirmed by screening tests for HBV and HCV

  * For patients with active HBV: HBV DNA \<500 IU/mL during screening, initiation of anti-HBV treatment at least 14 days prior to randomization and willingness to continue anti-HBV treatment during the study (per local standard of care; e.g., entecavir)
  * Patients with HCV, either with resolved infection (as evidenced by detectable antibody and negative viral load) or chronic infection (as evidenced by detectable HCV RNA), are eligible.
* Participants with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial.
* Participants with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. To be eligible for this trial, participants should be class 2B or better.
* The effects of the combination of radiation and atezolizumab plus bevacizumab on the developing human fetus are unknown. For this reason, women of child-bearing potential and men must agree to either abstain from sexual intercourse or use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 3 months after completion of atezolizumab and bevacizumab administration.
* Ability to understand and the willingness to sign a written informed consent document.

Exclusion Criteria:

* Known fibrolamellar HCC, sarcomatoid HCC, or mixed/biphenotypic cholangiocarcinoma-HCC.
* Radiographic evidence of metastasis to lymph nodes or other extra-hepatic sites.
* History of hepatic encephalopathy, moderate or severe ascites.
* Coinfection with HBV and HCV. Patients with a history of HCV infection but who are negative for HCV RNA by PCR will be considered non-infected with HCV.
* Untreated or incompletely treated esophageal and/or gastric varices with bleeding or that are at high risk for bleeding Patients must undergo an esophagogastroduodenoscopy (EGD), and all size of varices (small to large) must be assessed and treated per local standard of care prior to enrollment. Patients who have undergone an EGD within 6 months of prior to initiation of study treatment do not need to repeat the procedure.
* A prior bleeding event due to esophageal and/or gastric varices within 6 months prior to initiation of study treatment
* Inadequately controlled hypertension, defined as systolic blood pressure (BP) \<150 mmHg and/or diastolic BP \< 100 mmHg (average of at least three readings at two or more sessions). Anti-hypertensive therapy to achieve these parameters is allowed.
* History of hypertensive crisis or hypertensive encephalopathy.
* Significant vascular disease (e.g., aortic aneurysm requiring surgical repair or recent peripheral arterial thrombosis) within 6 months prior to initiation of study treatment
* History of hemoptysis (\> 2.5 mL of bright red blood per episode) within 1 month prior to initiation of study treatment
* Evidence of bleeding diathesis or significant coagulopathy (in the absence of therapeutic anticoagulation)
* Current or recent (\< 10 days prior to initiation of study treatment) use of full-dose oral or parenteral anticoagulants or thrombolytic agents for therapeutic (as opposed to prophylactic) purpose. Prophylactic anticoagulation for the patency of venous access devices allowed, provided the activity of the agent results in an INR \< 1.5 x ULN and aPPT is within normal limits within 14 days prior to initiation of study treatment. For prophylactic use of anticoagulants or thrombolytic therapies, the approved dose as described on the local label may be used.
* Current or recent (\< 10 days prior to initiation of study treatment) use of aspirin (\> 325 mg/day) or treatment with clopidogrel, dipyramidole, ticlopidine, or cilostazol.
* Participants who are receiving any other investigational agents.
* Core biopsy or other minor surgical procedure, excluding placement of a vascular access device, within 3 days prior to initiation of study systemic therapy.
* History of abdominal or tracheoesophageal fistula, gastrointestinal (GI) perforation, or intra-abdominal abscess within 6 months prior to initiation of study treatment.
* History of intestinal obstruction and/orclinical signs or symptoms of GI obstruction, including subocclusive or occlusive syndrome related to the underlying disease, or requirement for routine parenteral hydration, parenteral nutrition, or tube feeding prior to initiation of study systemic therapy. Patients with signs or symptoms of subocclusive or occlusive syndrome or with intestinal obstruction at the time of initial diagnosis may be enrolled if they had received definitive (surgical) treatment for symptom resolution.
* Evidence of abdominal free air that is not explained by paracentesis or other recent surgical or interventional procedure.
* Serious, non-healing or dehiscing wound, active ulcer, or untreated bone fracture.
* Grade 2 proteinuria, as demonstrated by 2+ protein on dipstick urinalysis and 1.0 g of protein on a 24-hour urine collection. All patients with 2+ protein on dipstick urinalysis at screening must undergo a 24-hour urine collection for protein. Patients with 2+ protein on dipstick urinalysis are eligible for the study.
* Patients with vascular invasion of the portal veins may NOT be enrolled, with the exceptions of patients with vp1 tumor thrombus (involvement distal to the second-order branches of the portal vein).
* History of intra-abdominal inflammatory process within 6 months prior to initiation of study treatment, including but not limited to: peptic ulcer disease, diverticulitis, or colitis.
* Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to initiation of study treatment; or abdominal surgery, abdominal interventions, or significant abdominal traumatic injury within 60 days prior to initiation of study treatment.
* Chronic daily treatment with a nonsteroidal anti-inflammatory drug (NSAID). The occasional use of NSAIDs for the symptomatic relief of medical conditions such as headache or fever is allowed.
* Active or history of autoimmune disease or immune deficiency, inclusing but not limited to: myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel diseae, antiphospholipid antibody syndrome, Wegener granulomatosis, Sjogren syndrome, Guillain-Barre syndrome, or multiple sclerosis. Patients with a history of autoimmune-related hypothyroidism who are on thyroid replacement hormone are eligible for this study. Patients with type I diabetes mellitus are eligible for this study. Patients with eczema, psoriasis,lichen simplex chronicus, or vitiligo with dermatologic manifestations (e.g. patients with psoriatic arthritis are exluded) are eligible for the study provided that all of the following conditions are met:

  * Rash must cover \<10% of body surface area
  * Disease is well-controlled at baseline and requires only low-potency topical corticosteroids.
  * No occurrence or acute exacerbations of the underlying condition requiring psoralen plus ultraviolet A radiation, methotrexate, retinoids, biologic agents, oral calcineurin inhibitors, or high-potency or oral corticosteroids within the previous 12 months.
* History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g. bronchiolitis obliterans), drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis on screen chest computed tomography (CT) scan.
* Active tuberculosis (TB) as documented by a positive purified protein derivative (PPD) skin test or TB blood test and confirmed by a positive chest radiograph within 3 months prior to initiation of study treatment. Patients with a positive PPD skin test or TB blood test followed by a negative chest radiograph may be eligible for the study.
* Significant cardiovascular disease (such as New York Heart Association Class II or greater cardiac disease, myocardial infarction, or cerebrovascular accident) within 3 months prior to initiation of study treatment, unstable arrhythmia, or unstable angina.
* Major surgical procedure, other than for diagnosis, within 4 weeks prior to initiation of study treatment, or anticipation of need for a major surgical procedure during the study.
* History of malignancy other than HCC within 5 years prior to screening, with the exception of malignancies with a negligible risk of metastasis or death (e.g., 5-year OS rate \>90%), such as adequately treated carcinoma in situ of the cervix, non-melanoma skin carcinoma, localized prostate cancer, ductal carcinoma in situ, or Stage I uterine cancer.
* Severe infection within 4 weeks prior to initiation of study treatment, including, but not limited to, hospitalization for complications of infection, bacteremia, or severe pneumonia. Treatment with therapeutic oral or IV antibiotics within 2 weeks prior to initiation of study treatment. Patients receiving prophylactic antibiotics (e.g., to prevent a urinary tract infection or chronic obstructive pulmonary disease exacerbation) are eligible for the study.
* Any other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding that contraindicates the use of an investigational drug, may affect the interpretation of the results, or may render the patient at high risk from treatment complications.
* Prior allogeneic stem cell or solid organ transplantation or on the wait list for liver transplantation.
* Pregnancy or breastfeeding, or intending to become pregnant during the study. Women of childbearing potential must have a negative serum pregnancy test result within 14 days prior to initiation of study treatment. The rationale for this exclusion is the unknown toxicities of immune checkpoint inhibitors on developing fetuses and the known placental risk conferred by treatment with vascular endothelial growth factor inhibitors (such as bevacizumab).
* Treatment with a live, attenuated vaccine within 4 weeks prior to initiation of study treatment, or anticipation of need for such a vaccine during atezolizumab treatment or within 5 months after the final dose of atezolizumab.
* History of severe allergic anaphylactic reactions to chimeric or humanized antibodies or fusion proteins.
* Known hypersensitivity to Chinese hamster ovary cell products or recombinant human antibodies.
* Known allergy or hypersensitivity to any of the study drugs or any of their excipients.
* Treatment with systemic immunostimulatory agents (including, but not limited to, interferon and interleukin 2 \[IL-2\]) within 4 weeks or 5 drug-elimination half-lives (whichever is longer) prior to initiation of study treatment.
* Treatment with systemic immunosuppressive medication (including, but not limited to, corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-TNF-alpha agents) within 2 weeks prior to initiation of study treatment, or anticipation of need for systemic immunosuppressive medication during study treatment, with the following exceptions:

  * Patients who received acute, low-dose systemic immunosuppressant medication or a one-time pulse dose of systemic immunosuppressant medication (e.g., 48 hours of corticosteroids for a contrast allergy) are eligible for the study after Medical Monitor confirmation has been obtained.
  * Patients who received mineralocorticoids (e.g., fludrocortisone), corticosteroids for chronic obstructive pulmonary disease (COPD) or asthma, or low-dose corticosteroids for orthostatic hypotension or adrenal insufficiency are eligible for the study.
* Since this study aims to enroll only resectable (with curative intent) hepatocellular carcinoma subjects, patients with brain (or other sites of distant) metastases are excluded.
* Participants with uncontrolled intercurrent illness.
* Participants with psychiatric illness/social situations that would limit compliance with study requirements.