Atezolizumab and Bevacizumab Pre-Liver Transplantation for Patients With Hepatocellular Carcinoma Beyond Milan Criteria

Prior treatment

• Previous systemic therapy for HCC prior to study enrollment
• Planned or prior multi-organ transplant or prior solid organ or allogeneic stem cell transplantation
• History or evidence upon physical or neurological examination of central nervous system (eg seizures) unrelated to cancer unless adequately treated with standard medical therapy. Anticonvulsants (stable dose) are allowed.
• Evidence of a Grade 2 or higher esophageal and/or gastric varices. Patients must have an esophagogastroduodenoscopy (EGD) within 6 months prior to initiating the study treatment. See Section 8.7.1.2. If the EGD shows Grade 2 or higher esophageal and/or gastric varices, patients will be excluded and will not receive study treatment but can be re-evaluated for enrollment after successful treatment of varices according to institutional guidelines.
• Significant vascular disease (eg, aortic aneurysm requiring surgical repair or recent arterial thrombosis) within 6 months prior to drug administration
• Clinically significant cardiovascular disease, such as cerebrovascular accidents within 12 months prior to randomization, myocardial infarction within 12 months prior to randomization, unstable angina, New York Heart Association (NYHA) Grade II or greater CHF, or serious cardiac arrhythmia uncontrolled by medication or potentially interfering with study treatment
• Major surgical procedure (including open biopsy, surgical resection, wound revision, or any other major surgery involving entry into a body cavity) or significant traumatic injury within 28 days prior to initiation of study treatment, or anticipation of need for major surgical procedure during the Treatment Phase of the study
  • Treatment should not be initiated within 7 days of having a core biopsy or other minor surgical procedure.
  • Treatment should not be initiated within 2 days of placement of a vascular access device.
• History of abdominal fistula, gastrointestinal (GI) perforation, intra-abdominal abscess, grade 2 or higher untreated esophageal or gastric varices or active GI bleeding within 6 months prior to treatment
• Other malignancy within 5 years prior to randomization, except for localized cancer in situ, such as basal or squamous cell skin cancer
• Active or history of autoimmune disease or immune deficiency, including, but not limited to, myasthenia gravis, myositis, autoimmune hepatitis, systemic lupus erythematosus, rheumatoid arthritis, inflammatory bowel disease, antiphospholipid antibody syndrome, Wegener granulomatosis, Sjögren syndrome, Guillain-Barré syndrome, or multiple sclerosis, 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 (eg, patients with psoriatic arthritis are excluded) are eligible for the study provided all 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
• Treatment with a live, attenuated vaccine (eg, FluMist®) within 4 weeks prior to initiation of study treatment, or anticipation of need for such a vaccine during atezolizumab treatment or within 5 months after the final dose of atezolizumab
• Treatment with investigational therapy within 28 days prior to initiation of study treatment
• Prior treatment with CD137 agonists or immune checkpoint blockade therapies, including anti-CTLA-4, anti-PD-1, and anti-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 systemic immunosuppressive medication (including, but not limited to, corticosteroids, cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-TNF-α agents) within 2 weeks prior to initiation of study treatment, or anticipation of need for systemic immunosuppressive medication during the Treatment Phase, with the following exceptions:
  • Patients who received acute, low-dose systemic immunosuppressant medication or a one-time pulse dose of systemic immunosuppressant medication (eg, 48 hours of corticosteroids for a contrast allergy) are eligible for the study after Principal Investigator confirmation has been obtained.
  • Patients who received mineralocorticoids (eg, fludrocortisone), corticosteroids for chronic obstructive pulmonary disease (COPD) or asthma, or low-dose corticosteroids for orthostatic hypotension or adrenal insufficiency are eligible for the study.
• Active infection requiring IV antibiotics within 2 weeks prior to initiation.
  • Note: Placement of a vascular access device should be at least 2 days prior to initiation of study treatment.
  • Patients receiving prophylactic antibiotics (eg, to prevent a urinary tract infection or chronic obstructive pulmonary disease exacerbation) are eligible for the study.
• 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
• Evidence of abdominal free air that is not explained by paracentesis or recent surgical procedure
• History of intra-abdominal inflammatory process within 6 months prior to initiation of study treatment, including but not limited to active peptic ulcer disease, diverticulitis, or colitis.
• Chronic daily treatment with a nonsteroidal anti-inflammatory drug (NSAID). Occasional use of NSAIDs for the symptomatic relief of medical conditions such as headache or fever is allowed
• Uncontrolled tumor-related pain
  • Patients requiring pain medication must be on a stable regimen at study entry.
  • Symptomatic lesions (eg, bone metastases or metastases causing nerve impingement) amenable to palliative radiotherapy should be treated prior to enrollment. Patients should be recovered from the effects of radiation. There is no required minimum recovery period.

Other illness

• History of Grade ≥4 venous thromboembolism
• History of hepatic encephalopathy
• Inadequately controlled hypertension (defined as systolic blood pressure \>150 mmHg and/or diastolic blood pressure \>100 mmHg)
• History of hypertensive crisis or hypertensive encephalopathy
• History or evidence of inherited bleeding diathesis or significant coagulopathy at risk of bleeding (ie, in the absence of therapeutic anticoagulation)
• Serious, non-healing wound, active ulcer, or untreated bone fracture
• History of idiopathic pulmonary fibrosis, organizing pneumonia (eg, bronchiolitis obliterans), drug-induced pneumonitis, or idiopathic pneumonitis, or evidence of active pneumonitis on screening chest computed tomography (CT) scan. History of radiation pneumonitis in the radiation field (fibrosis) is permitted.
• Active tuberculosis
• History of severe allergic anaphylactic reactions to chimeric or humanized antibodies or fusion proteins
• Known allergy or hypersensitivity to any component of the Atezlizumab and Bevacizumab formulation, such as a known hypersensitivity to Chinese hamster ovary cell products
• History of leptomeningeal disease

Lab values

• 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 or parenteral anticoagulants for therapeutic purpose is permitted as long as the INR and/or a PTT is within therapeutic limits (according to institution standards) within 7 days prior to initiation of study treatment and the patient has been on a stable dose of anticoagulants for ≥2 weeks prior to initiation of study treatment. Prophylactic use of anticoagulants is allowed. However, the use of direct oral anticoagulant therapies such as apixaban (Eliquis®), dabigatran (Pradaxa®), and rivaroxaban (Xarelto®) is not recommended due to bleeding risk, unless approved by the treating physician and the primary investigator.
• Pregnancy (positive pregnancy test) or lactation, or intention of becoming pregnant during study treatment or within 6 months after the final dose of study drugs
  • Women of childbearing potential must have a negative serum or urine pregnancy test result within 28 days prior to initiation of study treatment.
• Uncontrolled or symptomatic hypercalcemia (ionized calcium \>1.5 mmol/L, calcium \>12 mg/dL or corrected serum calcium \>ULN)
• Any other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding that contraindicates the use of an investigational drug, may affect the interpretation of the results, or may render the patient at high risk from treatment complications

Other

• Known fibrolamellar HCC, sacromatoid HCC, or mixed cholangiocarcinoma and HCC
• Moderate or severe ascites
• Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures (once monthly or more frequently)
  • Patients with indwelling catheters (eg, PleurX®) are allowed
• Inability to comply with study and/or follow-up procedures

• Male or female, aged ≥18 years old at the time of signing Informed Consent Form
• Measurable or evaluable disease per RECIST v1.1 or mRECIST of unresectable HCC outside of Milan criteria
• Histologically or radiologically proven HCC, without extrahepatic disease. Patients who consent to a fresh tissue biospy, and under the discretion of the Investigators, will provide a baseline biopsy sample for diagnosis and correlative studies. Archival tumor tissue may be used to confirm HCC in patients who do not consent to a fresh tissue biopsy.
• Prior remote LRT is allowed if new lesions or local disease recurrence are present. Participants may have received one TACE or TARE treatment within 8 weeks prior to enrollment, whether or not new lesions are present.
• Must be undergoing evaluation for or waitlisted for liver transplantation
• Eligible and suited to receive TACE or TARE procedure(s)
• Child-Pugh score ≤B7
• Eastern Cooperative Oncology Group (ECOG) score 0-1
• Life expectancy of ≥ 6 months
• Adequate hematological and end-organ function, defined by the following laboratory test results obtained within 14 days prior to study initiation:
  • Absolute neutrophil count (ANC) ≥ 1.5 x 109/L
  • Lymphocyte count ≥ 0.5 x 10\^9/L (500/μL)
  • Platelet count \> 75 x 10\^9/L
  • Hemoglobin ≥ 9 g/dL
  • Total bilirubin \< 1.5 x upper limit of normal (ULN)
  • Aspartate transaminase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (ALP) \< 2.5 x ULN
  • Serum albumin \> 2.7 g/dL
  • Serum creatinine \< 1.5x ULN
  • Urine dipstick for proteinuria ≤ 2+ unless a 24-hour urine protein \< 1 g of protein is demonstrated
  • International normalized ratio (INR) ≤ 1.5 or partial thromboplastin time (PTT) ≤ 1.5 x ULN for patients not receiving anti-coagulation. The use of full-dose oral or parenteral anticoagulants is permitted as long as the INR or PTT is within therapeutic limits (according to the medical standard of the enrolling institution) and the patient has been on a stable dose of anticoagulants for at least two weeks prior to the first study treatment.
• No history of hemoptysis (≥ 1/2 teaspoon of bright red blood per episode) within 1 month of study enrollment
• Negative HIV test at screening or transplant workup
• Documentation of referral to the Transplant Hepatology team for appropriate evaluation and management of patients who have one or more of the following:
  • Positive hepatitis B surface antigen (HBsAg) test at screening
  • Positive total hepatitis B core antibody (HBcAb) test at screening followed by a positive hepatitis B virus (HBV) DNA test at screening. The HBV DNA test must be performed only for patients who have a negative HBsAg test and a positive total HBcAb test.
  • Positive hepatitis C virus (HCV) antibody test at screening followed by a positive HCV RNA test at screening. The HCV RNA test must be performed for patients who have a positive HCV antibody test.
• For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive methods, as defined below:
  • Women must remain abstinent or use contraceptive methods with a failure rate of \<1% per year during the treatment period and for 6 months after the final dose of atezolizumab/bevacizumab Females who receive a LT are required to maintain abstinence or contraception until the End of Study.
  • A woman is considered to be of childbearing potential if she is postmenarchal, has not reached a postmenopausal state (≥12 continuous months of amenorrhea with no identified cause other than menopause), and has not undergone surgical sterilization (removal of ovaries and/or uterus). The definition of childbearing potential may be adapted for alignment with local guidelines or requirements.
  • Examples of contraceptive methods with a failure rate of \<1% per year include bilateral tubal ligation, male sterilization, hormonal contraceptives that inhibit ovulation, hormone-releasing intrauterine devices, and copper intrauterine devices.
  • The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient. Periodic abstinence (eg, calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not adequate methods of contraception.
• For men: agreement to remain abstinent (refrain from heterosexual intercourse) or use a condom, and agreement to refrain from donating sperm, as defined below:
  • With a female partner of childbearing potential or pregnant female partner, men must remain abstinent or use a condom during the treatment period and for 6 months after the final dose of atezolizumab/bevacizumab to avoid exposing the embryo. Men must refrain from donating sperm during this same period. Males who receive a LT are required to maintain these criteria until the End of Study.
  • The reliability of sexual abstinence should be evaluated in relation to the duration of the clinical trial and the preferred and usual lifestyle of the patient. Periodic abstinence (eg, calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not adequate methods of preventing drug exposure.
• Stated willingness to comply with all study procedures and availability for the duration of the study
• Women of childbearing potential must have a negative serum or urine pregnancy test result within 14 days prior to initiation of study treatment.