Clinical trial NCT05113186: Neoadjuvant and Adjuvant Lenvatinib in HCC Patients Treated by Percutaneous Ablative
Official title: Lenvatinib in Neo-adjuvant and Adjuvant Therapy for Poor-prognosis BCLC A HepatoCellular Carcinoma Treated by Percutaneous Ablation Procedure in a Curative Intent: Multicentre Pilot Therapeutic Trial
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE2
Conditions: Hepatocellular Carcinoma
Keywords: Lenvatinib
Adjuvant
Neoadjuvant
curative intent
percutaneous ablative
Lead sponsor: Assistance Publique - Hôpitaux de Paris
Sponsor class: OTHER
Collaborators: name: Eisai Inc.
First posted: 2021-11-09
Enrollment: 32
Sex: ALL
Minimum age (years): 18
Maximum age (years): 99
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: a pilot interventional study
Primary purpose: TREATMENT

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).

Detailed description: Multicenter, 19 hepatology or hepatoGastroenterology and radiology departments in 11 French hospitals (inclusion of patients in 10 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.

Eligibility criteria: 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

Primary outcomes:
measure: One-year local recurrence-free survival
timeFrame: At one year
Secondary outcomes:
measure: Per nodule assessment of early response (one month) after PA
timeFrame: At one month after a single procedure of PA
measure: Per nodule assessment of local recurrence
timeFrame: During 2 years following PA procedure
Other outcomes:
measure: Per nodule assessment of intra segmental distant recurrence
timeFrame: During 2 years following PA procedure
measure: Per nodule assessment of extra segmental distant recurrence
timeFrame: During 2 years following PA procedure
measure: Assessment of overall recurrence-free survival at 1 and 2 years
timeFrame: At 1 year and 2 years following PA procedure
measure: Evaluation of the safety of lenvatinib administered as neo and adjuvant therapy
timeFrame: During 2 years of follow up
measure: Assessment of tumour architecture and cytology : Histological outcome measures
timeFrame: from inclusion to Percutaneous Ablation procedure; assessed up to 30 days
measure: Assessment of tumour architecture and cytology :Histological outcome measures
timeFrame: from inclusion to Percutaneous Ablation procedure; assessed up to 30 days
measure: Assessment of tumour architecture and cytology :Genomics
timeFrame: from inclusion to Percutaneous Ablation procedure; assessed up to 30 days
measure: Compliance to lenvatinib treatment :Number of returned capsules
timeFrame: during 3-weeks for the neodjuvant lenvatinib and 3 months starting after the PA evaluation
measure: Absence of tumour cells (binary scale: 0/1)
timeFrame: At inclusion, and at the time of the PA procedure
measure: Assessment of intra and extra tumoral inflammatory infiltrate (semi quantitative scale: 0=non, 1=mild, 2=intense)outcome
timeFrame: At inclusion, and at the time of the PA procedure
measure: Consittution of a sequential biobank comprising liver tissue : Genomics
timeFrame: At inclusion, and at the time of the PA procedure
measure: Consittution of a sequential biobank comprising peripheral samples (serum, plasma)
timeFrame: At inclusion,at Percutaneous Ablation ; at 1, 3 and 6 months after PA
Locations:
city: Bobigny
country: France
facility: NAHON
Study officials:
affiliation: APHP-Hôpital Jean Verdier
name: Pierre NAHON, MD-PhD
role: PRINCIPAL_INVESTIGATOR
References:
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