Neoadjuvant and Adjuvant Lenvatinib in BCLC A Hepatocellular Carcinoma with Percutaneous Ablation: A Multicenter Pilot Study

Trial ID: 2024-514606-31-00
Protocol: APHP201185
Sponsor: Assistance Publique Hopitaux De Paris

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Diseases & Conditions

Hepatocellular carcinoma

Objectives

The primary objective of this study is to evaluate **local recurrence-free survival** during a 1-year follow-up period after percutaneous ablation (PA) procedure in patients with poor-prognosis BCLC A Hepatocellular Carcinoma (HCC). This objective is clinically significant as it aims to determine the effectiveness of the treatment in preventing the return of cancer in the treated area, which is crucial for improving patient outcomes and guiding future therapeutic strategies.

Secondary objectives include: - Assessing changes in tumorous and non-tumorous perfusion parameters observed with MRI after neoadjuvant treatment and before the PA procedure. - Evaluating the incidences of intra-segmental and extra-segmental distant recurrence. - Assessing overall survival at 1 and 2 years following the PA procedure. - Evaluating compliance with neoadjuvant and adjuvant treatments. - Assessing the tolerance of **lenvatinib** in the context of neo- and adjuvant therapy to PA.

Participants

The clinical trial involves **patients** diagnosed with hepatocellular carcinoma (HCC) at the Barcelona Clinical Liver Cancer (BCLC) stage A, who are eligible for percutaneous ablation (PA). The study population includes both male and female participants aged 18 years and older. Participants are required to have adequate bone marrow, liver, and renal function, as well as a life expectancy of at least three months. The trial includes individuals with a satisfactory nutritional status, defined by a body mass index (BMI) greater than 18 kg/m² for those under 70 years old, or greater than 21 kg/m² for those over 70 years old. The trial population was selected based on specific criteria, including the absence of portal vein thrombosis and a liver function status classified as Child-Pugh Class A. Participants must have an Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1. The sponsor has not provided information regarding the total number of participants. The trial includes individuals who are part of a vulnerable population, and all participants must be affiliated with a Social Security System and provide written informed consent. Lifestyle considerations such as diet and physical activity are not specified in the available data.

Plans and Procedures

The clinical trial is designed to evaluate the efficacy of **lenvatinib** as a neo-adjuvant and adjuvant therapy for patients with poor-prognosis Barcelona Clinic Liver Cancer (BCLC) stage A hepatocellular carcinoma (HCC) who are treated with percutaneous ablation (PA) in a curative intent. This is a multicenter, pilot therapeutic trial with a randomized, double-blind, and controlled design. The trial is expected to last until August 2025, with recruitment having commenced in February 2022. The primary objective is to assess local recurrence-free survival during a one-year follow-up after the PA procedure.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, liver function, and tumor characteristics. Follow-up visits will be scheduled to monitor the patient's response to treatment and to assess any adverse effects. The end-of-study visit will conclude the participant's involvement, during which final assessments will be conducted to evaluate the primary and secondary endpoints, including overall recurrence-free survival and safety of the treatment.

The expected length of participant involvement is approximately one year, with conditions for early termination including significant adverse events, withdrawal of consent, or non-compliance with the study protocol. The trial will utilize **LENVIMA 4 mg hard capsules**, administered orally, with a maximum daily dose of 12 mg and a total dose not exceeding 588 mg over a seven-day treatment period. The study aims to provide valuable insights into the potential benefits of lenvatinib in improving outcomes for patients with HCC undergoing PA.

Treatment

The clinical trial involves the administration of **Lenvatinib**, marketed under the name **LENVIMA 4 mg hard capsules**. This experimental medication is presented in the form of hard capsules, intended for oral administration. The active substance, **Lenvatinib**, is of chemical origin. The maximum daily dose is 12 mg, with a total maximum dose of 588 mg over the treatment period. The treatment duration is limited to a maximum of 7 days. The primary packaging for the study differs from the marketed authorization, utilizing a bottle instead of a blister pack. The medication is manufactured by EISAI GMBH and is not a pediatric formulation.

In this study, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are specified. The focus is solely on the administration of the experimental medication, **Lenvatinib**. Participant compliance with the dosing schedule will be monitored throughout the trial to ensure adherence to the prescribed regimen. The trial aims to assess local recurrence-free survival during a 1-year follow-up after a percutaneous ablation procedure in patients with poor-prognosis BCLC A Hepatocellular Carcinoma.

Efficacy

Efficacy in this clinical trial will be assessed primarily through the evaluation of **local recurrence-free survival** during a one-year follow-up period after the percutaneous ablation (PA) procedure. This primary endpoint will potentially be compared with historical controls to determine the effectiveness of the treatment. Secondary endpoints include a detailed per nodule assessment of early response one month after PA, local recurrence, intra-segmental distant recurrence, and extra-segmental distant recurrence. Additionally, overall recurrence-free survival will be assessed at one and two years. The safety of lenvatinib, administered as both neo-adjuvant and adjuvant therapy, will also be evaluated.

Further secondary endpoints involve the study of tumor and non-tumor histological and molecular predictors of therapeutic response and resistance, based on sequential biopsies performed before and after the neo-adjuvant phase, and in case of recurrence. Compliance with lenvatinib treatment will be monitored, and a sequential biobank comprising liver tissue and peripheral samples (serum, plasma) will be constituted if applicable. These assessments will provide comprehensive data on the efficacy and safety of lenvatinib in the treatment of poor-prognosis BCLC A Hepatocellular Carcinoma.

Inclusion and Exclusion Criteria

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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
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 corresponding to the following extension: o Uninodular HCC≥ 2 cm and ≤ 5 cm, no macroscopic vascular invasion o Multinodular maximum 3 nodules ≤ 3 cm, no macroscopic vascular invasion
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: o Hemoglobin > 8.5 g/dL o Absolute neutrophil count ≥ 1500/mm3 (≥ 1200/mm3 for black/African, American) o Platelet count ≥ 60,000/ mm3 o Total bilirubin ≤ 2 mg/dL o Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 5 x upper limit of normal (ULN) o Serum creatinine ≤ 1.5 x ULN o Prothrombine time-international normalized ratio (PT-INR) < 2.3 and PTT < 1.5 o 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)

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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
Active hepatitis B is allowed if the patient is under antiviral therapy
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