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

Exclusion Criteria

• •The following criteria should be checked. If ANY apply, the patient must not be included in the study:
• •2. Patients who have SAE \> grade 3 within 4 weeks after receiving SIRT-Y90. For patients who experience SAE \> grade 3 after receiving SIRT-Y90 (1st or 2nd administration), the duration between the SIRT-Y90 dose and randomization and/or 1st and 2nd SIRT-Y90 dose (for two-staged delivery) may be extended by an additional 4 weeks 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 of ICF 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, peginterferon alfa-2a, peginterferon alfa-2b, thymosin-α1, etc.) within 30 days prior to randomization, is currently receiving immunotherapy or is planned to start immunotherapy during the study (e.g., for the management of active CHB or CHC according 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 their cancer.
• •10. Has intractable clinical ascites (in spite of optimal diuretic treatment) or any other clinical signs of liver failure, on physical examination.
• •11. Untreated or incompletely treated esophageal and/or gastric varices prior to randomization.
• •12. Presence of tumor thrombus in the main trunk of the portal vein or a portal vein branch contralateral to the primarily involved lobe (or both) i.e. beyond VP3 and/or tumor 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 or squamous cell skin cancer, in situ cervical cancer, or other cancer for which the patient has been disease-free for at least five years.
• •15. Presence of clinical signs of CNS metastases due to their poor prognosis and because progressive neurologic dysfunction would confound the evaluation of neurologic and other adverse events.
• •16. Uncontrolled inter-current illness including, but not limited to, ongoing or active infection (except viral hepatitis), symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would 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 three BP readings on separate occasions.
• •• Anti-hypertensive therapy to achieve these parameters is allowed.
• •18. Any of the following contraindications to angiography and selective visceral catheterization:
• •* Bleeding diathesis, not correctable by the standard forms of therapy.
• •* Severe peripheral vascular disease that would preclude arterial catheterization.
• •19. Significant cardiovascular disease (such as cardiac disease, myocardial infarction, or cerebrovascular accident within 3 months prior to randomization), unstable arrhythmia, or unstable angina.
• •20. History of congenital long QT syndrome or corrected QT interval \> 500 ms (calculated with 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 use (within 10 days prior to angiogram) of aspirin (\>325 mg/day) or current or recent treatment with dipyridamole, ticlopidine, clopidogrel, and cilostazol.
• •• Use of dipyridamole, ticlopidine, clopidogrel, and cilostazol is allowed for patients who do not have any active bleeding for the past 6 months after review with attending physician.
• •23. Current or recent (within 10 days prior to angiogram) 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 is allowed provided the activity of the agent results in an INR \<1.5×ULN and aPTT is within normal limits (according to institutional standards) within 14 days prior 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 as dabigatran (Pradaxa®) and rivaroxaban (Xarelto®) is not recommended due to bleeding risk.
• •24. History of allergic reactions attributed to compounds of similar chemical or biologic composition to SIRT-Y90 or atezolizumab or bevacizumab.
• •25. The patient has active or history of autoimmune disease or immune deficiency such as, but not limited to, multiple sclerosis, systemic lupus erythematosus, and inflammatory bowel disease, 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 prior to screening.
• •26. The patient requires concomitant treatment with any immunosuppressive or immunostimulant agent, or with systemic corticosteroids prescribed for chronic treatment (more than 7 consecutive days).
• •27. Inability or unwillingness to understand or sign a written informed consent document.
• •28. Female patients who are pregnant or currently breastfeeding.
• •29. Current enrolment in any other investigational therapeutic drug or device study.