Atezolizumab and Bevacizumab in Combination With TACE for Patients With BCLC B HCC

Inclusion Criteria:

• At least 18 years old

• Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 or 1 within 28days prior to registration

• No cirrhosis or Child-Pugh A cirrhosis

• Diagnosis of HCC either by imaging or biopsy

• Evidence of HCC that meets BCLC B criteria

• Patients must have adequate hepatic, bone marrow, and renal function. All screeninglabs should be performed within 14 days of treatment initiation.

• Patients must be candidates for TACE treatment that can be treated in up to 4sessions

• Patients who are positive for Hepatitis B (HBc), regardless of HBs status, and havean undetectable Hepatitis B virus (HBV) viral load do not require HBV antiviralprophylaxis

• Patients who are not on HBV therapy, but positive for Hepatitis B surface antigen (HBsAg) and have an undetectable viral load are eligible for the study as long asthey begin anti-viral prophylaxis prior to the start of study treatment

• Patients can have untreated hepatitis C

• At least one unidimensional tumor measurable by RECIST v1.1 criteria

• Hg ≥ 9 g/dL

• Creatinine less than 1.5 x ULN

• Serum bilirubin < 2.5 mg/dl

• Aspartate Transferase (AST) < 5X upper limit of normal (ULN)

• Alanine Transaminase (ALT) < 5X ULN

• Platelet count > 100 x 10^9/L

• Patients must have an EGD within 6 months with no evidence of esophageal and/orgastric varices with bleeding or high risk of bleeding. Patients with varices mustbe assessed and treated per local standard-of-care prior to enrollment.

• Ability to comply with the study protocol, in the investigator's judgment

• Life expectancy ≥ 6 months

• Adequate hematologic and end-organ function, defined by the following laboratorytest results, obtained within 14 days prior to initiation of study treatment:

• Absolute Neutrophil Count (ANC) ≥1.5 · 10^9/L (1500/ÍL) without granulocytecolony-stimulating factor support

• Lymphocyte count ≥ 0.5 ∙ 10^9/L (500/ÍL)

• Serum albumin ≥ 25 g/L (2.5 g/dL)

• For patients not receiving therapeutic anticoagulation: International NormalizedRatio (INR) or activated partial thromboplastin time (aPTT) ≤ 1.5 ∙ ULN

• For patients receiving therapeutic anticoagulation: stable anticoagulant regimenallowed for both Atezo and Avastin. Please note the most current guidelines forAvastin are: Exclusionary: Current or recent (< 10 days prior to initiation of studytreatment) use of aspirin (> 325 mg/day), or clopidogrel (> 75 mg/day) Allowed:Note: The use of full-dose oral or parenteral anticoagulants for therapeutic purposeis permitted as long as the INR and/or aPTT is within therapeutic limits (accordingto institution standards) within 7 days prior to initiation of study treatment andthe patient has been on a stable dose of anticoagulants for ≥ 2 weeks prior toinitiation of study treatment. Prophylactic use of anticoagulants is allowed.However, the use of direct oral anticoagulant therapies such as dabigatran (Pradaxa®) and rivaroxaban (Xarelto®) is not recommended due to bleeding risk.

• For women of childbearing potential: agreement to remain abstinent (refrain fromheterosexual intercourse) or use contraceptive methods, and agreement to refrainfrom donating eggs, as defined below. Women of child-bearing potential must remainabstinent or use contraceptive methods with a failure rate of < 1% per year duringthe treatment period and for 6 months after the final dose of atezolizumab andbevacizumab. Women must refrain from donating eggs during this same period.

1. A woman is considered to be of childbearing potential if she is postmenarchal,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).

2. 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.

3. 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 adequate methods ofcontraception.

• For men of childbearing potential: With a female partner of childbearing potentialor pregnant female partner, men must remain abstinent or use a condom during thetreatment period and for 6 months after the final dose of atezolizumab andbevacizumab to avoid exposing the embryo. Men must refrain from donating spermduring this same period.

• The reliability of sexual abstinence should be evaluated in relation to the durationof the clinical trial and the preferred and usual lifestyle of the patient. Periodicabstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) andwithdrawal are not adequate methods of preventing drug exposure.

Patients receiving prophylactic antibiotics (e.g., for prevention of a urinary tract infection or chronic obstructive pulmonary disease) are eligible

Exclusion Criteria:

• Patients must not have signs of liver failure or history of liver failure e.g. -encephalopathy or variceal bleeding

• Uncontrolled hepatitis B infection with viral load >500 IU/ml

• History of hypertensive crisis or hypertensive encephalopathy

• Patients who are candidates for curative intent therapy (transplant, resection, orthermal ablation) or liver transplant

• Patients who are on the transplant list

• Ascites requiring therapeutic paracentesis in the last 12 months

• Episode of hepatic encephalopathy in the last 12 months

• Extrahepatic spread: borderline portal lymph nodes deemed to be of indeterminatenature and measuring less than 2 cm are allowed

• Prior local or systemic therapy for HCC or prior TACE, excluding prior use ofRadiofrequency Ablation (RFA)

• Patients cannot have known fibrolamellar HCC, sarcomatoid HCC, or mixedcholangiocarcinoma and HCC

• Occlusion of the hepatic artery or main portal vein

• Pregnant or lactating, or intending to become pregnant during the study

• Known hypersensitivity to biopharmaceuticals produced in Chinese hamster ovary cellsor other recombinant human antibodies

• Known history of Human Immunodeficiency virus (HIV) infection. No HIV testing isrequired.

• Active or history of autoimmune disease or immune deficiency, including, but notlimited to, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupuserythematosus, rheumatoid arthritis, inflammatory bowel disease, antiphospholipidantibody syndrome, Wegener granulomatosis, Sjögren syndrome, Guillain-Barrésyndrome, or multiple sclerosis (see Appendix 8 for a more comprehensive list ofautoimmune diseases and immune deficiencies), with the following exceptions:

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

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

3. 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: i. Rash must cover < 10% of body surface area ii. Disease is well controlled atbaseline and requires only low-potency topical corticosteroids iii. No occurrence ofacute exacerbations of the underlying condition requiring psoralen plus ultravioletA radiation, methotrexate, retinoids, biologic agents, oral calcineurin inhibitors,or high-potency or oral corticosteroids within the previous 12 months

• History of leptomeningeal disease

• Active tuberculosis

• Uncontrolled tumor-related pain a. Patients requiring pain medication must be on a stable regimen at study entry.

• Uncontrolled or symptomatic hypercalcemia (ionized calcium > 1.5 mmol/L, calcium > 12 mg/dL or corrected serum calcium > ULN)

• Signs or symptoms of significant infection within 2 weeks prior to Day 1

• Severe infection within 4 weeks prior to initiation of study treatment, includingbut not limited hospitalization for complications of infection, bacteremia, orsevere pneumonia.

• Received therapeutic oral or intravenous (IV) antibiotics within 2 weeks prior toCycle 1, Day 1

• Significant cardiovascular disease, (such as New York Heart Association cardiacdisease Class II or greater, myocardial infarction, or cerebrovascular accident)within 3 months prior to prior to Day 1, unstable arrhythmias, or unstable angina

• Patients with a known left ventricular ejection fraction (LVEF) < 40% will beexcluded. Patients with known coronary artery disease, congestive heart failure notmeeting the above criteria, or LVEF < 50% must be on a stable medical regimen thatis optimized in the opinion of the treating physician, in consultation with acardiologist if appropriate.

• History of stroke, prolonged reversible ischemic neurological deficit or transientischemic attack within 6 months prior to Day 1

• Major surgical procedure within 28 days prior to Day 1 or anticipation of need for amajor surgical procedure during the course of the study

• Live, attenuated vaccines (e.g., FluMist®) are prohibited within 4 weeks prior toinitiation of study treatment, during treatment with atezolizumab, and for 5 monthsafter the last dose of atezolizumab.

• Any serious medical condition or abnormality in clinical laboratory tests that, inthe investigator's judgment, precludes the patient's safe participation in andcompletion of the study

• Malignancies within 2 years prior to study start, with the exception of those with anegligible risk of metastasis or death (e.g., expected 5-year Overall Survival (OS) > 90%) treated with expected curative outcome (such as adequately treated carcinomain situ of the cervix, basal or squamous cell skin cancer, localized prostate cancertreated surgically with curative intent, ductal carcinoma in situ treated surgicallywith curative intent)

• Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrentdrainage procedures (once monthly or more frequently) a. Patients with indwelling catheters (e.g., PleurX®) are allowed.

• Inadequately controlled arterial hypertension (defined as systolic blood pressure [BP] ≥150 mmHg and/or diastolic BP >100 mmHg), based on an average of ≥ 3 BPreadings on ≥ 2 sessions. Anti-hypertensive therapy to achieve these parameters isallowable

• Significant vascular disease (e.g., aortic aneurysm requiring surgical repair orrecent peripheral arterial thrombosis) within 6 months prior to Day 1

• History of hemoptysis (≥ 2.5 mL of bright red blood per episode) within 1 monthprior to Day 1

• Evidence of bleeding diathesis or significant coagulopathy

• Current or recent (within 10 days of first dose of study treatment) use of aspirin (>325 mg/day) or treatment with dipyramidole, ticlopidine, clopidogrel, andcilostazol

• Current or recent (< 10 days prior to initiation of study treatment) use of aspirin (> 325 mg/day), or clopidogrel (> 75 mg/day) Note: The use of full-dose oral orparenteral anticoagulants for therapeutic purpose is permitted as long as the INRand/or aPTT is within therapeutic limits (according to institution standards) within 7 days prior to initiation of study treatment and the patient has been on a stabledose of anticoagulants for ≥ 2 weeks prior to initiation of study treatment.Prophylactic use of anticoagulants is allowed. However, the use of direct oralanticoagulant therapies such as dabigatran (Pradaxa®) and rivaroxaban (Xarelto®) isnot recommended due to bleeding risk.

• Core biopsy or other minor surgical procedure, excluding placement of a vascularaccess device, within 3 days of treatment start

• Proteinuria, as demonstrated by urine dipstick or ≥1.0 g of protein in a 24-hoururine collection. All patients with ≥2+ protein on dipstick urinalysis at baselinemust undergo a 24-hour urine collection for protein.

• Chronic daily treatment with a nonsteroidal anti-inflammatory drug (occasional usefor the symptomatic relief of medical conditions such as headache or fever isallowed)

• History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitisobliterans), drug-induced pneumonitis, or idiopathic pneumonitis, or evidence ofactive pneumonitis on screening chest computed tomography (CT) scan. History ofradiation pneumonitis in the radiation field (fibrosis) is permitted.

• Prior allogeneic stem cell or solid organ transplantation

• Any other disease, metabolic dysfunction, physical examination finding, or clinicallaboratory finding that contraindicates the use of an investigational drug, mayaffect the interpretation of the results, or may render the patient at high riskfrom treatment complications

• Prior treatment with CD137 agonists or immune checkpoint blockade therapies,including anti- cytotoxic T-lymphocyte associated protein 4 (CTLA-4), anti-Programmed cell death protein 1 (PD-1), and anti- Programmed death-ligand 1 (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 investigational therapy within 28 days prior to initiation of studytreatment

• Known hypersensitivity to Chinese hamster ovary cell products or to any component ofthe atezolizumab formulation

• Known allergy or hypersensitivity to any component of the bevacizumab oratezolizumab formulation

• History of Grade ≥ 4 venous thromboembolism

• History of abdominal fistula, gastrointestinal (GI) perforation, intra-abdominalabscess, or active GI bleeding within 6 months prior to randomization

• Serious, non-healing wound, active ulcer, or untreated bone fracture