The ABC-HCC Trial: Atezolizumab Plus Bevacizumab vs. Transarterial Chemoembolization (TACE) in Intermediate-stage HepatoCellular Carcinoma

Inclusion Criteria:

1. Signed Informed Consent Form available

2. Patients* ≥ 18 years of age at time of signing Informed Consent Form

3. Confirmed hepatocellular carcinoma diagnosis based on histopathological findingsfrom tumor tissue or typical diagnostic imaging on dynamic CT or MRI according toAASLD criteria.

4. Intermediate stage HCC as defined by the following criteria:

• Disease not amenable to curative surgery, liver transplantation or curativeablation BUT disease amenable to TACE at enrollment as judged by theinvestigator.

• No massive multinodular pattern preventing adequate TACE

• No tumor of a diffuse infiltrative HCC type (hypovascular infiltrative tumorswith ill-defined borders)

• Patent portal vein flow

• No main portal vein invasion/thrombosis on baseline/eligibility imaging.Patients with minimal invasion, (Vp1 and Vp2) may be eligible if no exclusioncriteria are violated.

• No extrahepatic disease Note: Patients with HCC beyond Milan criteria who entera downstaging protocol may be recruited into the trial if they do not presentany exclusion criteria.

5. Patients with recurrence after resection/ablation or after previous TACE areeligible, if they - according to the investigator - have an indication for (additional) TACE

6. Child-Pugh score class A or B7 without ascites requiring more than 100 mg ofspironolactone/day (see exclusion criteria) at enrollment.

7. Eastern Cooperative Oncology Group (ECOG) performance status of 0-1 at enrollment.

8. Adequate organ and bone marrow function

9. Life expectancy of ≥ 3 months

10. The following laboratory values obtained less than or equal to 7 days prior torandomization.

• Total bilirubin ≤ 3.0 x the upper limit of normal (ULN)

• Urine dipstick for proteinuria ≤ 2+ (within 7 days prior to randomization)Patients discovered to have ≥ 2+ proteinuria on dipstick urinalysis at baselineshould undergo a 24-hour urine collection and must demonstrate < 1 g of proteinin 24 hours

• The following other laboratory values measured within 7 days prior torandomization are either normal or if abnormal do not represent a medicalcontraindication for TACE and atezolizumab/bevacizumab as judged by theinvestigator: Platelet count, hemoglobin, alanine aminotransferase (ALT),aspartate aminotransferase (AST), serum creatinine, INR or aPTT, alkalinephosphatase, neutrophil count (ANC), and serum albumin.

11. Negative serum pregnancy test done lesser than or equal to 7 days prior torandomization, for females of childbearing potential only.

12. No presence of untreated or incompletely treated varices with bleeding or high-riskfor bleeding: Availability of esophagogastroduodenoscopy (not older than 6 months)in which all size of varices (small to large) had been assessed and varices weretreated per local standard of care prior to randomization.

13. Absence of other severe comorbidities

14. Resolution of any acute, clinically significant treatment-related adverse eventsfrom prior therapy/procedure to Grade ≤ 1 prior to randomization, with the exceptionof alopecia.

15. For patients with active hepatitis B virus (HBV):

• HBV DNA ≤ 2000 IU/mL obtained within 28 days prior to randomization, AND

• Anti-HBV treatment (per local standard of care; e.g., entecavir) for a minimumof 14 days prior to randomization and willingness to continue treatment for thelength of the study.

16. For patients with active hepatitis C virus (HCV):

• Patients positive for hepatitis C virus (HCV) antibody are eligible, also ifpolymerase chain reaction testing is positive for HCV ribonucleic acid (RNA).

• However, anti-viral therapy against HCV is only allowed prior to trial but notduring the trial.

• For HBV and HCV co-infection refer to exclusion criterion # 11.

17. For women of childbearing potential: agreement to remain abstinent (refrain fromheterosexual intercourse) or use contraceptive methods with a failure rate of < 1%per year during the treatment period and for at least 5 months after the last doseof atezolizumab, 6 months after the last dose of bevacizumab, or 1 month after thelast TACE procedure.

• A woman is considered to be of childbearing potential if she is postmenarcheal,has not reached a postmenopausal state (≥12 continuous months of amenorrheawith no identified cause other than menopause), and has not undergone surgicalsterilization (removal of ovaries and/or uterus).

• Examples of contraceptive methods with a failure rate of < 1% per year includebilateral tubal ligation, male sterilization, hormonal contraceptives thatinhibit ovulation, hormone-releasing intrauterine devices, and copperintrauterine devices.

• The reliability of sexual abstinence should be evaluated in relation to theduration of the clinical trial and the preferred and usual lifestyle of thepatient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, orpostovulation methods) and withdrawal are not acceptable methods ofcontraception.

18. For men: agreement to remain abstinent (refrain from heterosexual intercourse) oruse contraceptive measures, and agreement to refrain from donating sperm, as definedbelow:

• With female partners of childbearing potential, men must remain abstinent oruse a condom plus an additional contraceptive method that together result in afailure rate of < 1% per year during the treatment period and for 6 monthsafter the last dose of bevacizumab or 1 month after the last TACE procedure.Men must refrain from donating sperm during this same period.

• With pregnant female partners, men must remain abstinent or use a condom duringthe treatment period and for 6 months after the last dose of bevacizumab or 1month after the last TACE procedure to avoid exposing the embryo.

• The reliability of sexual abstinence should be evaluated in relation to theduration of the clinical trial and the preferred and usual lifestyle of thepatient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, orpostovulation methods) and withdrawal are not acceptable methods ofcontraception.

• There are no data that indicate special gender distribution. Therefore,patients will be enrolled in the study gender-independently.

Exclusion Criteria:

1.

1. Known fibrolamellar HCC, sarcomatoid HCC, or mixed cholangiocarcinoma and HCC (only if proven by biopsy).

2. Previous treatment with atezolizumab or bevacizumab.

3. Previous treatment with a programmed death 1 (PD1), programmed death-ligand (PD-L1),or cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitors, or any form ofcancer immunotherapy for HCC.

4. Clinically meaningful ascites, defined as ascites requiring non-pharmacologicintervention (e.g. paracentesis) to maintain symptomatic control.

• Patients with ascites requiring pharmacologic intervention (e.g. diuretics) andstable for ≥ 2 months on low doses of diuretics (spironolactone 100 mg/d orequivalent) for ascites are eligible. Of note, diuretics for other indications suchas congestive heart failure are not considered in this regard.

5. Major surgical procedure, open biopsy, or significant traumatic injury ≤ 28 daysprior to randomization or anticipation of need for major surgical procedure duringthe course of the study or non-recovery from side effects of any such procedure.

6. Significant cardiovascular disease, such as cardiac disease (New York HeartAssociation Class II or greater), myocardial infarction or cerebrovascular accidentwithin 3 months prior to randomization, as well as unstable arrhythmias (note: betablockers or digoxin are permitted), unstable angina, new-onset angina (begun withinthe last 3 months).

7. Uncontrolled hypertension defined by a systolic blood pressure (BP) ≥ 150 mmHg ordiastolic blood pressure (BP) ≥ 100 mmHg, with or without antihypertensivemedication. Prior history of hypertensive crisis or hypertensive encephalopathy.Patients with initial blood pressure (BP) elevations are eligible if initiation oradjustment of antihypertensive medication lowers pressure to meet entry criteria.

8. Current or recent (within 10 days prior to study treatment start) use of full-doseoral or parenteral anticoagulants or thrombolytic agents for therapeutic purpose (prophylactic anticoagulation permitted, e.g. new oral anticoagulants [apixaban,dabigatran, rivaroxaban], LMW heparin, ASA up to 300 mg/qd).

9. Arterial or venous thrombotic or embolic events such as cerebro-vascular accident (including transient ischemic attacks), deep vein thrombosis or pulmonary embolism ≤6 months prior to randomization.

10. With regards to eligibility for adequate TACE, patients presenting with either ofthe following conditions are excluded:

• Past history of bilioenteric anastomosis or biliary procedure (e.g., endoscopicpapillotomy or biliary stenting) or patients with aerobilia

• Central biliary obstruction (right or left intrahepatic duct, common hepaticduct, common bile duct)

• Celiac occlusion

11. Any ongoing infection > grade 2 NCI-CTCAE version 5.0. Note on HIV, HBV, and HCVinfection: also consider inclusion criteria #s 15, 16, and exclusion criterion # 18.Patients with co-infection for HBV and HCV are excluded, unless tested negative forHCV RNA by PCR.

12. Patients with seizure disorder requiring medication.

13. Prior allogeneic bone marrow transplantation or prior solid organ transplantation.

14. Evidence or history of bleeding diathesis or any hemorrhage or bleeding event >CTCAE grade 3 within 4 weeks prior to randomization.

15. Non-healing wound, ulcer, or bone fracture.

16. Renal failure requiring hemo- or peritoneal dialysis.

17. Known hypersensitivity to any of the study drugs, study drug classes, or excipientsin the formulation including a history of severe allergic, anaphylactic, or otherhypersensitivity reactions to chimeric or humanized antibodies or fusion protein;known hypersensitivity to Chinese hamster ovary cell products or to any component ofthe atezolizumab or bevacizumab formulation.

18. Positive test for human immunodeficiency virus (HIV) or acquired immunodeficiencysyndrome (AIDS), with the following exception: patients with a positive HIV test atscreening are eligible, provided they are stable on anti-retroviral therapy, have aCD4 count > 200 cells/µL, and have an undetectable viral load.

19. Active tuberculosis

20. Interstitial lung disease with ongoing signs and symptoms at the time of informedconsent.

21. History of idiopathic pulmonary fibrosis (including pneumonitis), drug-inducedpneumonitis, idiopathic pneumonitis, organizing pneumonia (i.e., bronchiolitisobliterans, cryptogenic organizing pneumonia), or evidence of active pneumonitis onscreening chest computed tomography (CT) scan Note: History of radiation pneumonitiswithin the radiation field (fibrosis) is permitted.

22. Persistent proteinuria of CTCAE Grade 3 or higher (> 3.5 g/24 hrs, measured by urineprotein: creatinine ratio on a random urine sample).

23. Pregnant or nursing women

24. Comorbid systemic illnesses or other severe concurrent disease which, in thejudgment of the investigator, would make the patient inappropriate for entry intothis study or interfere significantly with the proper assessment of safety andtoxicity of the prescribed regimens.

25. Active or history of autoimmune disease including, but not limited to, myastheniagravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoidarthritis, inflammatory bowel disease, antiphospholipid antibody syndrome, Wegener'sgranulomatosis, Sjögren syndrome, Guillain-Barré syndrome, multiple sclerosis,vasculitis, or glomerulonephritis. Note: History of autoimmune-mediated hypothyroidism on a stable dose of thyroidreplacement hormone, or controlled Type 1 diabetes mellitus on a stable insulinregimen may be eligible based on consultation with the sponsor's medical monitor.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 are met:

• Rash must cover < 10% of body surface area

• Disease is well controlled at baseline and requires only low-potency topicalcorticosteroids

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

26. Treatment with systemic immunosuppressive medication (including, but not limited to,corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, andanti-TNF-α agents) within 2 weeks prior to initiation of study treatment, oranticipation of need for systemic immunosuppressive medication during studytreatment, with the following exceptions:

• Patients who received acute, low-dose systemic immunosuppressant medication ora one-time pulse dose of systemic immunosuppressant medication (e.g., 48 hoursof corticosteroids for a contrast allergy) are eligible for the study.

• Patients who received mineralocorticoids (e.g., fludrocortisone),corticosteroids for chronic obstructive pulmonary disease (COPD) or asthma, orlow-dose corticosteroids for orthostatic hypotension or adrenal insufficiencyare eligible for the study.

27. Use of any herbal remedies known to interfere with the liver or other major organfunctions. Patients must notify the investigator of all herbal remedies used duringthe study.

28. Administration of a live, attenuated vaccine within four weeks prior to start ofenrollment, or anticipation that such a live attenuated vaccine will be requiredduring the study or within 5 months after the last dose of atezolizumab, 6 monthsafter the last dose of bevacizumab, or 1 month after the last TACE procedure.

29. History of malignancy other than HCC within 3 years prior to screening, with theexception of malignancies with a negligible risk of metastasis or death (e.g. 5-yearOS rate > 90%), such as adequately treated carcinoma in situ of the cervix,non-melanoma skin carcinoma, localized prostate cancer, ductal carcinoma in situ, orStage I uterine cancer. Other similar cases can be considered after discussion withlead investigators and sponsor.

30. Receipt of an investigational drug within 28 days prior to initiation of study drug

31. Patient with any significant history of non-compliance to medical regimens or withinability to grant reliable informed consent or patients with substance abuse,medical, psychological or social conditions that may interfere with the patient'sparticipation in the study or evaluation of the study results.