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 followinglaboratory 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 upperlimit 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 eithergadolinium 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, namelyhepatocholangiocarcinoma), if a biopsy is available

7. Current or recent (≤ 10 days prior to initiation of study treatment) use offull-dose oral or parenteral anticoagulants or thrombolytic agents for therapeutic (as opposed to prophylactic) purpose. Prophylactic anticoagulation for the patencyof venous access devices is allowed provided the activity of the agent results in anINR < 1.5 x ULN and aPTT is within normal limits within 14 days prior to initiationof study treatment. For prophylactic use of anticoagulants or thrombolytictherapies, 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, orcilostazol.

9. 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, with the following exceptions:

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

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

12. 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:

• Rash must cover < 10% of body surface area.
• Disease is well controlled at baseline and requires only low-potencytopical corticosteroids.
• No occurrence of acute exacerbations of the underlying condition requiringpsoralen plus ultraviolet A radiation, methotrexate, retinoids, biologicagents, oral calcineurin inhibitors, or high-potency or oralcorticosteroids.

10. 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 forsystemic immunosuppressive medication during studytreatment, with the following exceptions:

• Patients who received acute, low-dose systemic immunosuppressant medication ora onetime pulse dose of systemic immunosuppressant medication (e.g., 48 hoursof corticosteroids for a contrast allergy) are eligible for the study afterMedical Monitor confirmation has been obtained.

• 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.

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 lungnodule (<5mm) is allowed. Calcified lung micronodules as well as typicalintra-pulmonary lymph nodes are allowed. Hepatic hilum lymph node < 10mm (shortaxis) is allowed.

14. Prior surgery of HCC with micro- or macro-vascular invasion demonstrated atpathology.

15. Prior systemic treatment for HCC, in particular agents targeting T-cellcostimulation or checkpoint pathways (including those targeting PD-1, PD-L1 orPD-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 orhigh risk for bleeding. Patients must undergo an esophagogastroduodenoscopy (EGD),and all size of varices (small to large) must be assessed and treated per localstandard of care prior to enrollment. Patients who have undergone an EGD within 6months 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 carcinomaof 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 (HBVreplication below 500 IU/mL) or Hepatitis C is allowed if no antiviral treatment isrequired

23. Clinically significant bleeding NCI-CTCAE version 5.0 ≥ Grade 3 within 30 daysbefore 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 medicalcondition that could jeopardize the safety of the patient and/or his compliance withthe 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)