Neoadjuvant Atezo, Adjuvant Atezo + Beva Combined With RF Ablation of Small HCC: a Multicenter Randomized Phase II Trial

Inclusion Criteria:

1. Male or female patients ≥ 18 years of age
2. Diagnostic of HCC based on Imaging (EASL guidelines)
3. Patients with HCC eligible for ablation as assessed by multidisciplinary board:

   * All HCC nodules \<3cm
   * 1-3 nodules of HCC
4. At least one uni-dimensional measurable lesion by magnetic resonance imaging (MRI) according to modified RECIST criteria
5. Liver function status Child-Pugh Class A
6. Eastern Cooperative Oncology Group (ECOG) Performance Status ≤ 1
7. Adequate bone marrow, liver and renal function as assessed by the following laboratory tests:

   * Hemoglobin \> 8.5 g/dL
   * Absolute neutrophil count ≥ 1500/mm3
   * Platelet count ≥ 50,000/ mm3
   * Total bilirubin ≤ 2 mg/dL (ou ≤ 34 µmol/ L).
   * Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 5 x upper limit of normal (ULN)
   * Serum creatinine ≤ 1.5 x ULN
   * Lipase ≤ 2 x ULN
   * Prothrombin time \> 50%
   * Glomerular Filtration Rate (GFR) ≥ 35 mL/min/1.73 m2
8. Life expectancy ≥ 3 months
9. Women of childbearing potential and men must agree to use adequate contraception
10. Patients affiliated to a Social Security System

Exclusion Criteria:

1. Patients with contraindications to ablation or atezolizumab or bevacizumab
2. Patients with contraindication to contrast medium intravenous injection either gadolinium or iodinate
3. Patients with contraindication to MRI
4. Prior liver transplantation
5. Child-Pugh B or C
6. Patients with mixed histology (HCC and cholangiocarcinoma, namely hepatocholangiocarcinoma), if a biopsy is available
7. Current or recent (≤ 10 days prior to initiation of study treatment) 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 x ULN and aPTT is within normal limits within 14 days prior to initiation of study treatment. For prophylactic use of anticoagulants or thrombolytic therapies, the approved dose as described by local label may be used.
8. Current or recent (≤10 days prior to initiation of study treatment) use of aspirin (\> 325 mg/day) or treatment with clopidogrel, dipyramidole, ticlopidine, or cilostazol.
9. 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:

   1. Patients with a history of autoimmune-related hypothyroidism who are on thyroid-replacement hormone are eligible for the study.
   2. Patients with controlled Type 1 diabetes mellitus who are on an insulin regimen are eligible for the study.
   3. 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.
10. 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 forsystemic immunosuppressive medication during study treatment, with the following exceptions:

    * Patients who received acute, low-dose systemic immunosuppressant medication or a onetime pulse dose of systemic immunosuppressant medication (e.g., 48 hours of corticosteroids for a contrast allergy) are eligible for the study after Medical Monitor confirmation has been obtained.
    * Patients who received mineralocorticoids (e.g., 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.
11. Portal vein invasion, whatever its extent, shown on baseline imaging
12. Prior chemo-embolization or radio-embolization.
13. Patients with extra-hepatic metastases, either previously-treated or not. One lung nodule (\<5mm) is allowed. Calcified lung micronodules as well as typical intra-pulmonary lymph nodes are allowed. Hepatic hilum lymph node \< 10mm (short axis) is allowed.
14. Prior surgery of HCC with micro- or macro-vascular invasion demonstrated at pathology.
15. Prior systemic treatment for HCC, in particular agents targeting T-cell costimulation or checkpoint pathways (including those targeting PD-1, PD-L1 or PD-L2, cluster of differentiation 137 (CD137), or cytotoxic T-lymphocyte antigen (CTLA-4)).
16. Patients with uncontrolled HBV infection and viral load above 500 IU/mL.
17. Untreated or incompletely treated esophageal and/or gastric varices with bleeding or high risk for bleeding. Patients must undergo an esophagogastroduodenoscopy (EGD), and all size of varices (small to large) must be assessed and treated per local standard of care prior to enrollment. Patients who have undergone an EGD within 6 months of prior to initiation of study treatment do not need to repeat the procedure
18. Past or concurrent history of neoplasm other than HCC, except for in-situ carcinoma of the cervix uteri and/or non-melanoma skin cancer and superficial bladder tumors. Any cancer curatively treated \> 3 years prior to study entry is permitted
19. Known history or symptomatic meningeal tumors
20. Grade 3 (severe) hypertension ≥160 and/or ≥100 mmHG (systolic and diastolic, according to NCI-CTCAE v5.0)
21. Patients with phaeochromocytoma
22. Ongoing infection : Hepatitis B is allowed if no active replication is present (HBV replication below 500 IU/mL) or Hepatitis C is allowed if no antiviral treatment is required
23. Clinically significant bleeding NCI-CTCAE version 5.0 ≥ Grade 3 within 30 days before enrolment (transfusion indicated)
24. Arterial or venous thrombotic or embolic events such as cerebrovascular accident, deep vein thrombosis or pulmonary embolism within 6 months before enrolment
25. Any psychological, familial, sociological, geographical or illness or medical condition that could jeopardize the safety of the patient and/or his compliance with the study protocol and follow-up procedure
26. Known history of human immunodeficiency virus (HIV) infection
27. Seizure disorder requiring medication
28. Non-healing wound, ulcer or bone fracture
29. Breast feeding
30. Pregnancy
31. Legal incapacity (persons in custody or under guardianship)
32. Deprived of liberty Subject (by judicial or administrative decision)