Neoadjuvant and Adjuvant Lenvatinib in HCC Patients Treated by Percutaneous Ablative

Phase

Condition

Abdominal Cancer

Digestive System Neoplasms

Liver Cancer

Treatment

Lenvatinib Pill

Clinical Study ID

NCT05113186

APHP201185

Ages 18-99
All Genders

Study Summary

Percutaneous ablation (PA) is the only non-surgical curative treatment of hepatocellular carcinoma (HCC). Due to its excellent tolerance, particularly in patients with portal hypertension or bearing comorbidities, it now represents in France nearly 70% of the first-line curative treatment of "in Milan" tumours. For HCC less than 3 cm, ideal indication for percutaneous ablations, results of monopolar radiofrequency ablation (mRFA), are excellent with only 5% of reported non-tumoral control after a first procedure. In addition to mRFA the arsenal of ablations has grown considerably with the emergence of new techniques which allow the expansion of indications for PA, especially in patients with poor prognostic tumors or relatively advanced beyond the Milan criteria. In this setting, multibipolar mode using no touch technique (mbpRFAnt) increases the tumour volume than can be ablated, allowing the removal of large tumors> 5 cm. Inadequate tumour control is then de facto greater in these situations, around 20%. Difficult-to-access tumors can furthermore be treated by percutaneous irreversible electrotroporation (IRE).

Despite a tumor burden accessible for curative ablation, a phenotype of "aggressive" HCC characterized by high rates of local recurrences is yet to be defined. Up to now, several characteristics might define this subtype with a poor-prognosis and include 1) high serum alpha-foetoprotein (AFP) levels, 2) radiological infiltrative form, and 3) histological macrotrabecular subtype. Based on these characteristics, median recurrence-free survival of these patients is usually below 10 months.

High serum AFP level is a well-known predictor of HCC recurrence following curative procedure. In patients treated by percutaneous ablation, regardless of the technique used and irrespective of tumor burden, high baseline serum AFP level has tenaciously been reported as an independent predictor or recurrence..

More recently, the radiological description of infiltrative HCC (as opposed to mass-forming) has been identified as an aggressive from of HCC with a poor prognosis even when eligible for ablation. This aspect is often associated with infra-clinical invasion of the portal veins (PV), leading to poor prognosis. Finally, a "massive macrotrabecular" (MTM) histological subtype of HCC associated with specific molecular features has recently been described. This MTM-HCC subtype, reliably observed in 12% of patients eligible for curative treatment, represents an aggressive form of HCC is an independent predictor of early and overall recurrence following PA, which is retained even after patient stratification according to common clinical, biological, and pathological features of aggressiveness.

The idea of optimizing HCC curative treatments using adjuvant biotherapy, particularly in patients with poor-prognosis tumors in curative intent, is particularly attractive. One trial in adjuvant setting was conducted, the STORM trial, that tested the benefit of sorafenib in curative intent of in Milan HCC. This negative trial included patients within Milan HCC, with an expected low rate of recurrence with only few patients treated by PA.

Lenvatinib is a multikinase inhibitor which has been recently approved as firs-line therapy for advanced HCC. The investigators assume that lenvatinib could have also a synergistic local action with PA in two ways. First, given as neoadjuvant regimen, lenvatinib by reducing tumor and liver perfusion could decrease the global heat sink effect associated with loco-regional blood microcirculation during PA. Second, by carrying on in adjuvant treatment, lenvatinib could decrease the magnitude of non-specific inflammatory angiogenesis around the treatment zone, therefore reducing the risk of locoregional (intrasegmental) cells tumor spreading or promotion.

Given the dismall prognosis of the aforementioned poor-prognosis HCC eligible for PA with an overall median recurrence-free survival below 10 months, the investigators hypothesis is that addition of Lenvatinib as neo- and adjuvant therapy might increase tumour control in these difficult-to-treat patients. Patients combining either high serum AFP levels, infiltrative form or MTM-HCC histological subtype represent 30% of BCLC A stage HCC patients in expert centers, and are the ideal candidates for such trials.

Therefore, the first aim of this proposal is to assess the benefit of lenvatinib in neo- and adjuvant setting combined with curative percutaneous ablation for BCLC A HCC patients considered at high risk of local recurrence (high AFP or infiltrative form or macrotrabecular massive subtype).

Eligibility Criteria

Inclusion

Inclusion Criteria:

Male or female patients ≥ 18 years
Histological or radiological diagnosis of HCC, whether new or recurrent following aprior 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 ormagnetic 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 followinglaboratory 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 upperlimit 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 ofcontraception until 1 month after the last lenvatinib intake and avoid pregnancy
Patients who are sexually active with WOCBP partners need to accept one effectivemethod of contraception until 1 month after lenvatinib intake and men must agree touse 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

Exclusion Criteria:

Patients with recurrence of HCC occurring less than six months after a curativetreatment regarded as successful
BCLC stage >A (1 single lesion >5cm or more than 3 lesions ore multifocal HCC >3cmor vascular invasion or extra-hepatic spread)
Patients with contraindications to PA
Pacemakers or patients who have a history of cardiac arrhythmias or irregularheartbeats (in case of electroporation procedure)
Ascites
Coagulopathy
Ongoing bacterial infection
Patients with contraindication to contrast medium intravenous injection eithergadolinium 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 beingtreated with conventional medical intervention
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 tumours.Any cancer curatively treated > 3 years prior to study entry is permitted
Major surgical procedure or significant traumatic injury within 28 days beforeenrolment
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 inspite of an optimized regimen of antihypertensive medication.
Patients with phaeochromocytoma
Refractory ascites according to EASL guidelines definition (ascites that cannot bemobilized or the early recurrence of which cannot be prevented because of a lack ofresponse 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 isallowed if no active replication is present (below 100 IU/mL). Hepatitis C isallowed if no antiviral treatment is required
Clinically significant bleeding NCI-CTCAE version 4.0 ≥ Grade 3 within 30 daysbefore enrolment
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
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

Study Design

Lenvatinib Pill

February 02, 2022

October 02, 2026

Study Description

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.

Connect with a study center

NAHON
Bobigny, 93000
France
Site Not Available
NAHON
Bobigny 3032179, 93000
France
Site Not Available

Not the study for you?

Let us help you find the best match. Sign up as a volunteer and receive email notifications when clinical trials are posted in the medical category of interest to you.