Neoadjuvant and Adjuvant Lenvatinib in HCC Patients Treated by Percutaneous Ablative

NCT05113186 | Active Not Recruiting Phase 2 DMC

• 1 other identifier: APHP201185
• Study Type: interventional
• Target: 32
• Locations: 1 country
• Sites: 1

Brief 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).

Conditions

Hepatocellular Carcinoma

Keywords

Lenvatinib; Adjuvant; Neoadjuvant; curative intent; percutaneous ablative

Outcome Measures

Primary Outcomes (1)

• 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.

  At one year

Secondary Outcomes (2)

• Per nodule assessment of early response (one month) after PA

  At one month after a single procedure of PA

• Per nodule assessment of local recurrence

  During 2 years following PA procedure

Other Outcomes (12)

• Per nodule assessment of intra segmental distant recurrence

  During 2 years following PA procedure

• Per nodule assessment of extra segmental distant recurrence

  During 2 years following PA procedure

• Assessment of overall recurrence-free survival at 1 and 2 years

  At 1 year and 2 years following PA procedure

Study Arms (1)

Neoadjuvant and adjuvant therapy with lenvatinib

EXPERIMENTAL

* 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

Interventions

Lenvatinib Pill DRUG

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

Neoadjuvant and adjuvant therapy with lenvatinib

Eligibility Criteria

• Age: 18 Years - 99 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Assistance Publique - Hôpitaux de Paris: lead
• Eisai Inc.: collaborator

Study Sites (1)

NAHON

Bobigny, 93000, France

Location

Related Publications (6)

• Nault JC, Sutter O, Nahon P, Ganne-Carrie N, Seror O. Percutaneous treatment of hepatocellular carcinoma: State of the art and innovations. J Hepatol. 2018 Apr;68(4):783-797. doi: 10.1016/j.jhep.2017.10.004. Epub 2017 Oct 13.

  PMID: 29031662 BACKGROUND

• N'Kontchou G, Nault JC, Sutter O, Bourcier V, Coderc E, Grando V, Nahon P, Ganne-Carrie N, Diallo A, Sellier N, Seror O. Multibipolar Radiofrequency Ablation for the Treatment of Mass-Forming and Infiltrative Hepatocellular Carcinomas > 5 cm: Long-Term Results. Liver Cancer. 2019 May;8(3):172-185. doi: 10.1159/000489319. Epub 2018 Jun 28.

  PMID: 31192154 BACKGROUND

• Sutter O, Calvo J, N'Kontchou G, Nault JC, Ourabia R, Nahon P, Ganne-Carrie N, Bourcier V, Zentar N, Bouhafs F, Sellier N, Diallo A, Seror O. Safety and Efficacy of Irreversible Electroporation for the Treatment of Hepatocellular Carcinoma Not Amenable to Thermal Ablation Techniques: A Retrospective Single-Center Case Series. Radiology. 2017 Sep;284(3):877-886. doi: 10.1148/radiol.2017161413. Epub 2017 Apr 28.

  PMID: 28453431 BACKGROUND

• Ziol M, Pote N, Amaddeo G, Laurent A, Nault JC, Oberti F, Costentin C, Michalak S, Bouattour M, Francoz C, Pageaux GP, Ramos J, Decaens T, Luciani A, Guiu B, Vilgrain V, Aube C, Derman J, Charpy C, Zucman-Rossi J, Barget N, Seror O, Ganne-Carrie N, Paradis V, Calderaro J. Macrotrabecular-massive hepatocellular carcinoma: A distinctive histological subtype with clinical relevance. Hepatology. 2018 Jul;68(1):103-112. doi: 10.1002/hep.29762. Epub 2018 May 9.

  PMID: 29281854 BACKGROUND

• Bruix J, Takayama T, Mazzaferro V, Chau GY, Yang J, Kudo M, Cai J, Poon RT, Han KH, Tak WY, Lee HC, Song T, Roayaie S, Bolondi L, Lee KS, Makuuchi M, Souza F, Berre MA, Meinhardt G, Llovet JM; STORM investigators. Adjuvant sorafenib for hepatocellular carcinoma after resection or ablation (STORM): a phase 3, randomised, double-blind, placebo-controlled trial. Lancet Oncol. 2015 Oct;16(13):1344-54. doi: 10.1016/S1470-2045(15)00198-9. Epub 2015 Sep 8.

  PMID: 26361969 BACKGROUND

• Kudo M, Finn RS, Qin S, Han KH, Ikeda K, Piscaglia F, Baron A, Park JW, Han G, Jassem J, Blanc JF, Vogel A, Komov D, Evans TRJ, Lopez C, Dutcus C, Guo M, Saito K, Kraljevic S, Tamai T, Ren M, Cheng AL. Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial. Lancet. 2018 Mar 24;391(10126):1163-1173. doi: 10.1016/S0140-6736(18)30207-1.

  PMID: 29433850 BACKGROUND

MeSH Terms

Conditions

Carcinoma, Hepatocellular

Interventions

lenvatinib

Condition Hierarchy (Ancestors)

Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Liver Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Digestive System Diseases; Liver Diseases

Study Officials

• Pierre NAHON, MD-PhD

  APHP-Hôpital Jean Verdier

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: a pilot interventional study

Study Record Dates

• First Submitted: July 31, 2021
• First Posted: November 9, 2021
• Study Start: February 2, 2022
• Primary Completion: June 19, 2025
• Study Completion (Estimated): October 2, 2026
• Last Updated: January 29, 2026

Record last verified: 2026-01

Data Sharing

• IPD Sharing: Will not share

Locations

FR (1)