This study is evaluating the safety and tolerability of neoadjuvant stereotactic body
radiation therapy (SBRT) with atezolizumab and bevacizumab for treating resectable
This study involves the following study interventions:
- Stereotactic Beam Radiation Therapy (SBRT)
- 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
- 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
- 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.,
- 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
- Ability to understand and the willingness to sign a written informed consent document.
- Known fibrolamellar HCC, sarcomatoid HCC, or mixed/biphenotypic
- 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
- 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
- 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,
- 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
- 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
- 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
- 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
- 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
- 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
- Prior allogeneic stem cell or solid organ transplantation or on the wait list for
- 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
- Known allergy or hypersensitivity to any of the study drugs or any of their
- 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
- Participants with uncontrolled intercurrent illness.
- Participants with psychiatric illness/social situations that would limit compliance
with study requirements.