Multinational Phase II Trial to Compare Safety and Efficacy of SIRT (Y-90 Resin Microspheres) Followed by Atezolizumab Plus Bevacizumab, vs SIRT (SIRT-Y90) Followed by Placebo in Locally Advanced HCC Patients

Inclusion Criteria:

Patients must fulfill all of the following criteria to be eligible for this study:

1. Unequivocal diagnosis of HCC (AASLD 2010 diagnostic criteria or histology) that islocally advanced without extra-hepatic metastases but with significant tumor burden,i.e.,

• Tumor confined to the liver that is beyond the up-to-7 criteria, and/or

• Tumor with vascular invasion VP 1-3 and/or Vv 1-2 (at the discretion of siteinvestigator) Both local and central assessments are required at screening,prior to any study treatment. Sites are required to send all CT/MRI images forcentral imaging review. The central assessment result will be made known tosites and will take precedence in determining a patient's study eligibility incase of a discrepancy between local and central review.

2. Aged 21 years old and above of either gender.

3. Patient eligible for SIRT-Y90 treatment after assessment with macro-aggregatedalbumin labeled with technetium-99 (Tc-99m MAA) scan on SPECT/CT or planar imagingwith all of the following criteria prior to each SIRT-Y90 treatment:

• Lung shunting <20% on SPECT/CT or planar imaging

• Lung dose limit of <25Gy for single treatment or <30Gy for cumulative treatment (second delivery within 4-6 weeks)

4. No prior radiation to the liver.

5. No prior systemic adjuvant or neoadjuvant therapy for HCC.

6. Measurable disease, defined as at least one lesion that can be accurately measuredin at least one dimension (longest diameter to be recorded) as ≥10 mm with spiral CTscan or MRI.

7. Negative HIV test at screening, with the following exception - patients with apositive HIV test at screening are eligible provided they fulfil all of thefollowing criteria:

• Are stable on anti-retroviral therapy

• Have a CD4 count ≥ 200/μL

• Have an undetectable viral load

8. Documented virology status of hepatitis, as confirmed by screening hepatitis B virus (HBV) and hepatitis C virus (HCV) tests.

9. Patients with active HBV: HBV DNA <500 IU/mL, initiation of anti-HBV treatment atleast 14 days prior to randomization, and willingness to continue anti-HBV treatmentduring the study (per local standard of care; e.g., entecavir). For patients with HBV DNA ≥ 500 IU/mL during screening, anti-HBV treatment will beinitiated and HBV DNA levels will be re-assessed prior to randomization.

10. ECOG performance status 0 - 1.

11. Child-Pugh A (up to 6 points).

12. Adequate hematological, renal, and hepatic function as follows:

• Lymphocyte count ≥ 0.5 x 10**9/L (500/μL)

• Platelets ≥75,000/μL without transfusion

• Hemoglobin >9.5 g/dL (Patients may be transfused to meet this criterion.)

• Serum bilirubin ≤ 3 x ULN

• For patients not receiving therapeutic anticoagulation: INR and aPTT ≤ 2.0 xULN

• ALP ≤5×institutional upper limit of normal

• AST and ALT ≤5×institutional upper limit of normal

• Albumin ≥2.8 g/dL

• Serum creatinine ≤ 1.5 x ULN or creatinine clearance ≥ 30 mL/min (calculatedusing the Cockcroft-Gault formula)

• Absolute Neutrophil Count ≥1.5×10**9/L without granulocyte colony-stimulatingfactor support

• Urine dipstick for proteinuria <2+ at screening

• Patients discovered to have ≥2+ proteinuria on dipstick urinalysis atbaseline should undergo a 24-hour urine collection and must demonstrate <1g of protein in 24 hours

13. Life expectancy of at least 3 months without any active treatment.

14. Suitable for protocol treatment as determined by clinical assessment undertaken bythe site investigator.

15. Performance of an esophagogastroduodenoscopy (EGD) within 6 months prior torandomization as part of pre-procedure work-up or during screening, and assessmentand complete treatment of varices of all sizes per local standard of care prior torandomization. Patients with varices should be re-assessed prior to randomization to ensurecomplete treatment of varices of all sizes per local standard of care.

16. Willing, able and mentally competent to provide written informed consent prior toany testing undertaken for this study protocol, including screening tests andevaluations that are not considered to be part of the patient's routine care.

17. Female patients must be either postmenopausal or, if premenopausal, must have anegative pregnancy test and agree to use two forms of contraception if sexuallyactive during the treatment period, for at least 5 months after the last dose ofatezolizumab and 6 months after the last dose of bevacizumab.

18. Male patients must be surgically sterile, or if sexually active and having apre-menopausal female partner, they must be using an acceptable form ofcontraception during the treatment period and for 6 months after the last dose ofbevacizumab.

Exclusion Criteria:

The following criteria should be checked. If ANY apply, the patient must not be included in the study:

1. Patient not eligible for SIRT-Y90 treatment after assessment with macro-aggregatedalbumin labeled with technetium-99 (MAA) scan on SPECT/CT or planar imaging.

2. Patients who have SAE > grade 3 within 4 weeks after receiving SIRT-Y90. Forpatients who experience SAE > grade 3 after receiving SIRT-Y90 (1st or 2ndadministration), the duration between the SIRT-Y90 dose and randomization and/or 1stand 2nd SIRT-Y90 dose (for two-staged delivery) may be extended by an additional 4weeks to re-assess the patient's eligibility.

3. Patients who have had >2 administrations of hepatic artery directed therapy.

4. Patients who have had hepatic artery directed therapy done <4 weeks prior to date ofICF signing.

5. Patients who have had systemic adjuvant or neoadjuvant therapy for HCC.

6. Prior hepatic radiation therapy for HCC or other malignancy.

7. Patient who has received any immunotherapy (including interferon-alfa, peginterferonalfa-2a, peginterferon alfa-2b, thymosin-α1, etc.) within 30 days prior torandomization, is currently receiving immunotherapy or is planned to startimmunotherapy during the study (e.g., for the management of active CHB or CHCaccording to local guidelines).

8. Has evidence that <30% of the total liver volume is disease-free.

9. Currently receiving any other investigational agents for the treatment of theircancer.

10. Has intractable clinical ascites (in spite of optimal diuretic treatment) or anyother clinical signs of liver failure, on physical examination.

11. Untreated or incompletely treated esophageal and/or gastric varices prior torandomization.

12. Presence of tumor thrombus in the main trunk of the portal vein or a portal veinbranch contralateral to the primarily involved lobe (or both) i.e. beyond VP3 and/ortumor thrombus in the inferior vena cava or right atrium i.e. beyond Vv2.

13. Any metastatic disease i.e. lymph node ≥15 mm in short axis or distant metastasis.

14. Any other concurrent malignancy, except for adequately treated basal cell orsquamous cell skin cancer, in situ cervical cancer, or other cancer for which thepatient has been disease-free for at least five years.

15. Presence of clinical signs of CNS metastases due to their poor prognosis and becauseprogressive neurologic dysfunction would confound the evaluation of neurologic andother adverse events.

16. Uncontrolled inter-current illness including, but not limited to, ongoing or activeinfection (except viral hepatitis), symptomatic congestive heart failure, unstableangina pectoris, cardiac arrhythmia, or psychiatric illness/social situations thatwould limit compliance with study requirements.

17. Inadequately controlled arterial hypertension (defined as systolic blood pressure [BP]>150 mmHg and/or diastolic BP >100 mmHg), based on an average of at least threeBP readings at two or more sessions.

• Anti-hypertensive therapy to achieve these parameters is allowed.

18. Any of the following contraindications to angiography and selective visceralcatheterization:

• Bleeding diathesis, not correctable by the standard forms of therapy.

• Severe peripheral vascular disease that would preclude arterialcatheterization.

19. Significant cardiovascular disease (such as cardiac disease, myocardial infarction,or cerebrovascular accident within 3 months prior to randomization), unstablearrhythmia, or unstable angina.

20. History of congenital long QT syndrome or corrected QT interval > 500 ms (calculatedwith use of the Fridericia method) at screening

21. History of uncorrectable electrolyte disorder affecting serum levels of potassium,calcium, or magnesium

22. Current or recent (within 10 days prior to angiogram) use of aspirin (>325 mg/day)or current or recent treatment with dipyramidole, ticlopidine, clopidogrel, andcilostazol.

23. Current or recent (within 10 days prior to angiogram) use of full-dose oralorparenteral anticoagulants or thrombolytic agents for therapeutic (as opposed toprophylactic) purpose.

• Prophylactic anticoagulation for the patency of venous access devices isallowed provided the activity of the agent results in an INR <1.5×ULN and aPTTis within normal limits (according to institutional standards) within 14 daysprior to Day 1 of Cycle 1.

• Prophylactic use of low-molecular-weight heparin (i.e., enoxaparin 40 mg/day)is allowed. However, the use of direct oral anticoagulant therapies such asdabigatran (Pradaxa®) and rivaroxaban (Xarelto®) is not recommended due tobleeding risk.

24. History of allergic reactions attributed to compounds of similar chemical orbiologic composition to SIRT-Y90 or atezolizumab or bevacizumab.

25. The patient has active or history of autoimmune disease or immune deficiency suchas, but not limited to, multiple sclerosis, systemic lupus erythematosus, andinflammatory bowel disease, with the following exceptions:

• Patients with a history of autoimmune-related hypothyroidism who are onthyroid-replacement hormone are eligible for the study.

• Patients with controlled Type 1 diabetes mellitus who are on an insulin regimenare eligible for the study.

• Patients with eczema, psoriasis, lichen simplex chronicus, or vitiligo withdermatologic manifestations only (e.g., patients with psoriatic arthritis areexcluded) are eligible for the study provided all of following conditions aremet:

• Rash must cover < 10% of body surface area

• Disease is well controlled at baseline and requires only low-potencytopical corticosteroids

• No occurrence of acute exacerbations of the underlying condition requiringpsoralen plus ultraviolet A radiation, methotrexate, retinoids, biologicagents, oral calcineurin inhibitors, or high-potency or oralcorticosteroids within the previous 12 months prior to screening.

26. The patient requires concomitant treatment with any immunosuppressive orimmunostimulant agent, or with systemic corticosteroids prescribed for chronictreatment (more than 7 consecutive days).

27. Inability or unwillingness to understand or sign a written informed consentdocument.

28. Female patients who are pregnant or currently breastfeeding.

29. Current enrolment in any other investigational therapeutic drug or device study.