Neoadjuvant and Adjuvant Lenvatinib in HCC Patients Treated by Percutaneous Ablative

Multicenter, 20 hepatology or hepatoGastroenterology and radiology departments in 13 French hospitals (inclusion of patients in 12 centers).

A pilot interventional, prospective, multicenter study.

The design of study is summarized as follows:

• Neoadjuvant phase with lenvatinib for 21 days (rationale: compromise between expected benefit and acceptable tolerance without compromising ablation procedure)
• PA of HCC in a curative intent (radiofrequency, microwave or electroporation)
• Adjuvant phase with lenvatinib for 3 months (rationale: compromise between expected benefit and acceptable tolerance without compromising ablation procedure) Lenvatinib doses will be adapted according to SmPC.

Constitution of a biobank with :

• paraffin and frozen tumoral and non tumoral biopsy sampled at before and after one month of neoadjuvant lenvatinib (second biopsies at the time of the PA procedure)
• Serum, plasma samples before the neoadjuvant lenvatinib, before PA procedure, at 1,3 months of the adjuvant lenvatinib and at month 6.

Inclusion criteria

• Male or female patients ≥ 18 years
• Histological or radiological diagnosis of HCC, whether new or recurrent following a prior curative therapeutic management > 6 months.
• Barcelona Clinical Liver Cancer (BCLC) stage Category A
• Comprising at least one of the following the following characteristics:
• Single tumour>3 cm≤ 5cm or
• Multiple tumours (max 3 lesions ≤ 3cm) or
• Single tumour between 2 and 3 cm with at least one of the following characteristic:

• Serum AFP>100 ng/mL
• Infiltrative form
• Macro-trabecular subtype (if applicable)
• Patients with HCC amenable for PA as assessed by multidisciplinary board
• At least one uni-dimensional measurable lesion by computed tomography (CT) scan or magnetic resonance imaging (MRI) according to modified RECIST for HCC
• Absence of any portal vein thrombosis
• Liver function status Child-Pugh Class A
• Eastern Cooperative Oncology Group (ECOG) Performance Status ≤ 1
• Adequate bone marrow, liver and renal function as assessed by the following laboratory tests:

• Hemoglobin > 8.5 g/dL
• Absolute neutrophil count ≥ 1500/mm3 (≥ 1200/mm3 for black/African, American)
• Platelet count ≥ 60,000/ mm3
• Total bilirubin ≤ 2 mg/dL
• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 5 x upper limit of normal (ULN)
• Serum creatinine ≤ 1.5 x ULN
• Prothrombine time-international normalized ratio (PT-INR) < 2.3 and PTT < 1.5
• Glomerular Filtration Rate (GFR) ≥ 30 mL/min/1.73 m2
• Life expectancy ≥ 3 months
• Women of childbearing potential (WOCBP) need to accept one effective method of contraception until 1 month after the last lenvatinib intake and avoid pregnancy
• Patients who are sexually active with WOCBP partners need to accept one effective method of contraception until 1 month after lenvatinib intake and men must agree to use adequate contraception
• Patients affiliated to a Social Security System
• Written informed consent signed
• Patient under guardianship or curatorship*
• Satisfactory nutritional status (BMI>18 kg/m² for patients under 70 years old, or ≥21 kg/m² for the patients over 70 years old)
• Patient under guardianship or curatorship*

Exclusion criteria

• Patients with recurrence of HCC occurring less than six months after a curative treatment regarded as successful
• BCLC stage >A (1 single lesion >5cm or more than 3 lesions ore multifocal HCC >3cm or vascular invasion or extra-hepatic spread)
• Patients with contraindications to PA

• Pacemakers or patients who have a history of cardiac arrhythmias or irregular heartbeats (in case of electroporation procedure)
• Ascites
• Coagulopathy
• Ongoing bacterial infection
• Patients with contraindication to contrast medium intravenous injection either gadolinium or iodinate
• Prior liver transplantation
• Prior systemic treatment for HCC (chemotherapy, any other TKI, immunotherapy)
• Patients with large esophageal varices at risk of bleeding that are not being treated with conventional medical intervention
• 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 tumours. Any cancer curatively treated > 3 years prior to study entry is permitted
• Major surgical procedure or significant traumatic injury within 28 days before enrolment
• Congestive heart failure New York Heart Association (NYHA) ≥ class 2
• Unstable angina or myocardial infarction within the past 6 months before enrolment
• Uncontrolled blood pressure to systolic BP >140mmHg or diastolic BP >90 mmHg in spite of an optimized regimen of antihypertensive medication.
• Patients with phaeochromocytoma
• Refractory ascites according to EASL guidelines definition (ascites that cannot be mobilized or the early recurrence of which cannot be prevented because of a lack of response to sodium restriction and diuretic treatment)
• Persistent proteinuria of NCI-CTCAE version 4.0 ≥ Grade 3
• Ongoing infection > Grade 2 according to NCI-CTCAE version 4.0. Hepatitis B is allowed if no active replication is present (below 100 IU/mL). Hepatitis C is allowed if no antiviral treatment is required
• Clinically significant bleeding NCI-CTCAE version 4.0 ≥ Grade 3 within 30 days before enrolment
• 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
• Non-healing wound, ulcer or bone fracture
• Known hypersensitivity to the study drug or excipients in the formulation
• Any malabsorption condition
• Breast feeding
• Pregnancy
• Patient unable to swallow oral medication