Eligibility |
Inclusion Criteria:
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.
Exclusion Criteria
Subjects meeting any of the criteria below may not participate in the study:
- Have signs of liver failure, e.g. clinically significant ascites, encephalopathy, or
variceal bleeding within six months from enrollment.
- Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent
drainage procedures (once monthly or more frequently). Patients with indwelling
catheters (e.g., PleurX® are allowed.
- Untreated or incompletely treated esophageal and/or gastric varices with bleeding or
high-risk for bleeding.
- Prior bleeding event due to esophageal and/or gastric varices within 6 months prior to
initiation of study treatment. NOTE: 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.
- Have evidence of excessive hepatopulmonary shunting (> 20% in 99mTc macro-aggregated
albumin scan for resin and 30 Gy per treatment for glass) or angiographically
demonstrable and non-occludable gastrointestinal shunting, precluding from Y-90
treatment.
- Inadequately controlled arterial hypertension (defined as systolic blood pressure (BP)
= 150 mmHg and/or diastolic blood pressure > 100 mmHg), based on an average of = 3 BP
readings on = 2 sessions. NOTE: Anti-hypertensive therapy to achieve these parameters
is allowable.
- Prior history of hypertensive crisis or hypertensive encephalopathy.
- 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.
- Known fibrolamellar HCC, sarcomatoid HCC, or mixed cholangiocarcinoma and HCC.
- Major surgery within 4 weeks prior to registration or anticipation of a major surgical
procedure during study.
- Have had prior transplant of any kind (stem cell or solid organ).
- Have active autoimmune disease that has required systemic treatment in the past 2
years (i.e. with use of disease modifying agents, corticosteroids, or
immunosuppressive drugs). including, but not limited to, myasthenia gravis, myositis,
autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory
bowel disease, antiphospholipid antibody syndrome, Wegener granulomatosis, Sjögren
syndrome, Guillain-Barré syndrome, or multiple sclerosis with the following
exceptions:
- Patients with a history of autoimmune-related hypothyroidism who are on
thyroid-replacement hormone are eligible for the study.
- Patients with controlled Type 1 diabetes mellitus who are on an insulin regimen
are eligible for the study.
- Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo with
dermatologic manifestations only (e.g., patients with psoriatic arthritis are
excluded) are eligible for the study provided all of 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 of 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
- Have history of idiopathic pulmonary fibrosis (including bronchiolitis obliterans with
organizing pneumonia) drug-induced pneumonitis, or idiopathic pneumonitis, or evidence
of active pneumonitis on screening chest CT scan. NOTE: History of radiation
pneumonitis in the radiation field (fibrosis) is permitted.
- Treatment with CD137 agonists or immune checkpoint blockade therapies, including
anti-CTLA-4, anti-PD-1 and anti-PD-L1 therapeutic antibodies.
- Treatment with systemic immunostimulatory agents (including, but not limited to,
interferon and interleukin 2 [IL-2]) within 4 weeks or 5 half-lives of the drug
(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-a 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
sponsor-investigator 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
- Uncontrolled tumor-related pain
- Patients requiring pain medication must be on a stable regimen at study entry.
- Symptomatic lesions (e.g., bone metastases or metastases causing nerve
impingement) amenable to palliative radiotherapy should be treated prior to
enrollment. Patients should be recovered from the effects of radiation. There is
no required minimum recovery period.
- Asymptomatic metastatic lesions that would likely cause functional deficits or
intractable pain with further growth (e.g., epidural metastasis that is not
currently associated with spinal cord compression) should be considered for
loco-regional therapy if appropriate prior to enrollment.
- Patients with brain metastases.
- Have unresolved toxicities from prior anticancer therapy, defined as having not
resolved to National Cancer Institute (NCI) CTCAE v5 grade 0 or 1 with the exception
of alopecia and laboratory values listed per the inclusion criteria. NOTE: Subjects
with irreversible toxicity that is not reasonably expected to be exacerbated by any of
the investigational products may be included (e.g., hearing loss) after consultation
with the sponsor-investigator.
- Diagnosed or treated for malignancy other than HCC, unless they meet one of the
following exceptions:
- Malignancy treated with curative intent and with no known active disease present
for = 2 years before registration and felt to be at low risk for recurrence by
the treating physician.
- Adequately treated non-melanoma skin cancer or lentigo maligna without evidence
of disease.
- Adequately treated cervical carcinoma in situ without evidence of disease.
- Have a known or suspected allergy to bevacizumab or atezolizumab or known
hypersensitivity to Chinese hamster ovary cell products or to any component of the
atezolizumab or bevacizumab formulation.
- 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 (within 10 days of first dose of study treatment) use of aspirin
(=325 mg/day) or treatment with dipyramidole, ticlopidine, clopidogrel, and
cilostazol.
- Current or recent (within 10 days prior to study treatment start) use of full-dose
oral or parenteral anticoagulants or thrombolytic agents for therapeutic (as opposed
to prophylactic) purpose. NOTE: Prophylactic anticoagulation for the patency of venous
access devices is allowed provided the activity of the agent results in an INR =1.5 x
ULN and aPTT is within normal limits within 14 days prior to initiation of study
treatment.
- Have an uncontrolled intercurrent illness including, but not limited to any of the
following:
- Psychiatric illness/social situations that would limit compliance with study
requirements
- Have any other disease, metabolic dysfunction, physical examination finding, or
clinical laboratory finding giving reasonable suspicion of a disease or condition
that contraindicates the use of an investigational drug or that may affect the
interpretation of the results or render the patient at high risk from treatment
complications.
- Active alcohol use, drug use, or a psychiatric disease that would, in the opinion
of the sponsor-investigator or a sub-investigator (sub-I), prevent the subject
from complying with the study protocol and/or endanger the subject during their
participation in the study.
- 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. NOTE: 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.
- Active tuberculosis.
- Pregnant or breastfeeding (NOTE: breast milk cannot be stored for future use while the
mother is being treated on study).
- Have received a live attenuated vaccine (e.g., FluMist®) within 30 days of the planned
start of study therapy and 180 days after the last dose of the study treatment. NOTE:
Seasonal influenza vaccines for injection are generally inactivated flu vaccines and
are allowed; however, intranasal influenza vaccines (e.g., Flu-Mist®) are live
attenuated vaccines, and are not allowed.
- Have received or are receiving any investigational therapy within 28 days prior to the
first dose of bevacizumab and atezolizumab. NOTE: Subjects may be enrolled in an
observational (non-interventional) clinical study or in the follow-up period of an
interventional study.
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