This is an open-label, multi-center, randomized phase II study comparing the Y90 TARE
followed by bevacizumab and atezolizumab treatment to the Y90 TARE treatment alone in
unresectable intermediate stage HCC.
Subjects will be randomized to Y-90 TARE alone (Arm A) or Y-90 TARE followed by the
combination of atezolizumab and bevacizumab (Arm B). The first 10 subjects randomized to Arm
B (Y-90 TARE + bevacizumab + atezolizumab) will be assessed for safety after two cycles. If
there are no Grade ≥ 3 unexpected toxicities; possibly, probably or definitely related to
TARE in combination with bevacizumab and atezolizumab the combination will be deemed safe and
accrual will continue.
Subjects randomized to receive bevacizumab and atezolizumab (Arm B) will start the
combination of bevacizumab and atezolizumab 4 weeks (± 1 week) after TARE treatment. Full
recovery from the procedure is required prior to systemic treatment:
- AST and ALT ≤ 5 x upper limit of normal (ULN) and total bilirubin ≤ 3 mg/dL
- Manifestations of post-embolization syndrome (e.g., fever, nausea, vomiting, and
abdominal pain) have resolved to National Cancer Institute Common Terminology Criteria
for Adverse Events, Version 5.0 Grade 1
- No significant medical events (e.g., gastrointestinal [GI] bleeding, cardiac events,
hepatorenal syndrome) during or after the TARE procedure.
These subjects will continue the study drugs for a total of 24 months from the TARE
treatment, until intolerable toxicity or disease progression occur.
1. 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.
2. Age ≥ 18 years at the time of consent.
3. ECOG Performance Status of 0-1 at screening
4. Histological or cytological evidence/confirmation per AJCC, 8th edition, of
hepatocellular carcinoma (HCC).
5. Measurable disease by RECIST 1.1.
6. Patients must have a Child-Pugh score of A.
7. Patients must have at least Barcelona Clinic Liver Cancer (BCLC) stage B HCC and must
be outside of downstaging criteria (downstaging criteria are defined as: one lesion >
5 cm and </= 8 cm; two to three lesions each </= 5 cm; four to five lesions </= 3 cm
with a total tumor diameter of </= 8 cm); six lesions or more regardless of size;
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
8. Archival tissue obtained within 6 months of registration is required. If archival
tissue is not available, subjects are not eligible.
9. Patients must not be suitable for or amenable to transplant or resection.
10. Patients may be treatment naive or have received any number of prior therapies except
systemic therapy. 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) 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%.
11. Patients must demonstrate adequate hepatic, bone marrow, and renal function as defined
in Table below. All screening labs should be performed within 14 days of treatment
- Absolute Neutrophil Count (ANC) ≥ 1,500 /μL
- Hemoglobin (Hgb) ≥ 9 g/dL without transfusion or EPO dependency (within 7 days of
- Platelet count (Plt) ≥ 50,000 / μL
- Serum creatinine OR Measured or calculated CrCl ≤ 1.5 X upper limit of normal
(ULN) OR ≥ 60 mL/min for subject with creatinine levels > 1.5 x institutional ULN
- Bilirubin ≤ 3.0 X ULN upper limit of normal (ULN)
- 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 ≤ 2 g
- International Normalized Ratio (INR) or Prothrombin Time (PT) or Activated
Partial Thromboplastin Time (aPTT) ≤ 1.5 X ULN unless subject is receiving
anticoagulant therapy, in which case PT/aPTT must be within therapeutic range for
intended use of anticoagulants
12. Negative HIV test at screening; 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.
13. Urine dipstick for proteinuria < 2+ (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.
14. 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.
15. Co-infection of HBV and HCV is an exclusion. Patients with a history of HCV infection
but who are negative for HCV RNA by PCR will be considered non-infected with HCV.
16. Prior cancer treatment must be completed at least six months prior to registration and
the subject must have recovered from all reversible acute toxic effects of the regimen
(other than alopecia) to Grade ≤ 1 or baseline.
17. Females of childbearing potential must have a negative serum pregnancy test within 14
days prior to registration. 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.
18. Females of childbearing potential must be willing to abstain from heterosexual
activity or to use 2 forms of effective methods of contraception from the time of
informed consent until 150 days after treatment discontinuation (Arm B). Males of
childbearing potential must be willing to abstain from heterosexual activity or to use
2 forms of effective methods of contraception from the time of informed consent until
210 days after treatment discontinuation (Arm B). The timeframe for female and male
subjects that randomize to Arm A is from the time of informed consent until 60 days
after treatment discontinuation.
19. 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.
1. Have signs of liver failure, e.g. clinically significant ascites, encephalopathy, or
variceal bleeding within six months from enrollment.
2. 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.
3. Untreated or incompletely treated esophageal and/or gastric varices with bleeding or
high-risk for bleeding.
4. Have evidence of excessive hepatopulmonary shunting (> 20% in 99mTc macro-aggregated
albumin scan) or angiographically demonstrable and non-occludable gastrointestinal
shunting, precluding from Y-90 treatment).
5. Prior history of TACE or transarterial treatment via hepatic artery.
6. Subject not 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.
7. 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
8. Prior history of hypertensive crisis or hypertensive encephalopathy.
9. 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
10. Known fibrolamellar HCC, sarcomatoid HCC, or mixed cholangiocarcinoma and HCC.
11. Major surgery within 4 weeks prior to registration or anticipation of a major surgical
procedure during study.
12. Have had prior transplant of any kind.
13. 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). Replacement therapy (e.g., thyroxine, insulin, or
physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency,
etc.) is not considered a form of systemic treatment. Have history of idiopathic
pulmonary fibrosis (including bronchiolitis obliterans with organizing pneumonia) or
evidence of active pneumonitis on screening chest CT scan.
14. Have untreated central nervous system (CNS) metastatic disease (including spinal cord
and leptomeningeal disease). 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
15. 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.
16. Diagnosed or treated for malignancy other than HCC, unless they meet one of the
- 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
- Adequately treated cervical carcinoma in situ without evidence of disease.
17. 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.
18. Significant vascular disease (e.g., aortic aneurysm requiring surgical repair or
recent peripheral arterial thrombosis) within 6 months prior to initiation of study
19. History of hemoptysis (≥ 2.5 mL of bright red blood per episode) within 1 month prior
to initiation of study treatment.
20. Evidence of bleeding diathesis or significant coagulopathy (in the absence of
21. 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.
22. 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
23. Have an uncontrolled intercurrent illness including, but not limited to any of the
- Psychiatric illness/social situations that would limit compliance with study
- 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
- 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.
24. 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.
25. Pregnant or breastfeeding (NOTE: breast milk cannot be stored for future use while the
mother is being treated on study).
26. ave received a live vaccine within 30 days of the planned start of study therapy.
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.
27. 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