A Phase 2 interventional study of Lenvatinib Pill in Hepatocellular Carcinoma, sponsored by Assistance Publique - Hôpitaux de Paris. Active, not recruiting at 1 site in France. Open to participants aged 18 Years to 99 Years. Per ClinicalTrials.gov, last updated 2026-01-29.
Sponsored by Assistance Publique - Hôpitaux de Paris · Phase 2, Interventional, and Treatment
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).
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:
Constitution of a biobank with :
3,182 studies on the registry are indexed under Carcinoma, Hepatocellular; 954 are open to participants now.
This study's enrollment of 32 is below the median of 55 across 2,298 interventional studies indexed under Carcinoma, Hepatocellular.
Browse Carcinoma, Hepatocellular studies →Assistance Publique - Hôpitaux de Paris is the lead sponsor of 3,505 studies on the registry; 1,006 are open to participants now.
Counted across the registry records on this site, refreshed daily.
Single tumour between 2 and 3 cm with at least one of the following characteristic:
Adequate bone marrow, liver and renal function as assessed by the following laboratory tests:
Exclusion Criteria:
Patients with contraindications to PA
* Neoadjuvant therapy with lenvatinib to complete a 3-week course, stopping 1 week before the planned date of PA procedure * Adjuvant therapy with lenvatinib for 3 months starting after the PA evaluation (± 14 days) The daily dose of lenvatinib will be 12 mg (≥60 kg) or 8 mg (\<60 kg). Lenvatinib will be taken within 2 hours after a light meal, preferably in the morning.
Drug: Lenvatinib Pill
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)
Also known as: percutaneous ablative procedure
One-year local recurrence-free survival
Recurrence rate local will be assessed using imaging techniques as recommended by international guidelines (3-months US and MRI during two years). Patients who will meet primary endpoint will be alive 1 year afterPA procedure without evidence of local recurrence on 3-months US/MRI evaluations.
Time frame: At one year
Per nodule assessment of early response (one month) after PA
Evaluation performed by MRI : Assessment of complete response versus incomplete response (persistence of active tumour). Evaluation performed by MRI
Time frame: At one month after a single procedure of PA
Per nodule assessment of local recurrence
Evaluation performed by MRI
Time frame: During 2 years following PA procedure
Per nodule assessment of intra segmental distant recurrence
Evaluation performed by MRI
Time frame: During 2 years following PA procedure
Per nodule assessment of extra segmental distant recurrence
Evaluation performed by MRI
Time frame: During 2 years following PA procedure
Assessment of overall recurrence-free survival at 1 and 2 years
patients will meet this endpoint if they are alive with or without HCC recurrenceat 1and 2 years after PA procedure. Causes and date of death will be specified when applicable during this timeframe.
Time frame: At 1 year and 2 years following PA procedure
Evaluation of the safety of lenvatinib administered as neo and adjuvant therapy
Adverse events related : fatigue, arterial hypertension, hand-foot skin syndrome to Lenvatinib will be monitored according to manufacturer guidelines and recommendation
Time frame: During 2 years of follow up
Assessment of tumour architecture and cytology : Histological outcome measures
Absence of tumour cells (binary scale :0/1)
Time frame: from inclusion to Percutaneous Ablation procedure; assessed up to 30 days
Assessment of tumour architecture and cytology :Histological outcome measures
Assessment of intra and extra tumoral inflammatory infiltrate (semi quantitative scale: 0=non, 1=mild, 2=intense)
Time frame: from inclusion to Percutaneous Ablation procedure; assessed up to 30 days
Assessment of tumour architecture and cytology :Genomics
change in gene expression following sequential whole exome sequencing (binary scale 0/1 with clustering analyses)
Time frame: from inclusion to Percutaneous Ablation procedure; assessed up to 30 days
Compliance to lenvatinib treatment :Number of returned capsules
Accounting for treatment returns. checking respect of scheduled lenvatinib administered
Time frame: during 3-weeks for the neodjuvant lenvatinib and 3 months starting after the PA evaluation
Absence of tumour cells (binary scale: 0/1)
Consittution of a sequential biobank comprising liver tissue : histological outcome
Time frame: At inclusion, and at the time of the PA procedure
Assessment of intra and extra tumoral inflammatory infiltrate (semi quantitative scale: 0=non, 1=mild, 2=intense)outcome
Consittution of a sequential biobank comprising liver tissue : histological
Time frame: At inclusion, and at the time of the PA procedure
Consittution of a sequential biobank comprising liver tissue : Genomics
change in gene expression following sequential whole exome sequencing (binary scale 0/1 with clustering analyses)
Time frame: At inclusion, and at the time of the PA procedure
Consittution of a sequential biobank comprising peripheral samples (serum, plasma)
Changes in PIGF (UI/mL), VEGF-A (UI/mL), VEGF-C (UI/mL), sVEGFR2 (UI/mL), sVEGFR3 (UI/mL), MET (UI/mL), sKIT (UI/mL), Ang2 (UI/mL), AFP (UI/mL), PIVKA (UI/mL) (changes expressed by median comparison)
Time frame: At inclusion,at Percutaneous Ablation ; at 1, 3 and 6 months after PA
Plan to share: No
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