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    Summary
    EudraCT Number:2020-005504-18
    Sponsor's Protocol Code Number:APHP201185
    National Competent Authority:France - ANSM
    Clinical Trial Type:EEA CTA
    Trial Status:Trial now transitioned
    Date on which this record was first entered in the EudraCT database:2021-03-11
    Trial results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedFrance - ANSM
    A.2EudraCT number2020-005504-18
    A.3Full title of the trial
    Lenvatinib in neo-adjuvant and adjuvant therapy for poor-prognosis BCLC A HepatoCellular Carcinoma treated by ablative procedure in a curative intent: multicentre phase 2 therapeutic trial
    NA
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    NA
    NA
    A.3.2Name or abbreviated title of the trial where available
    LENVABLA
    LENVABLA
    A.4.1Sponsor's protocol code numberAPHP201185
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorAssistance Publique – Hôpitaux de Paris (AP-HP)
    B.1.3.4CountryFrance
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportEISAI
    B.4.2CountryFrance
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationAPHP
    B.5.2Functional name of contact pointSEYMOUR-INAMO
    B.5.3 Address:
    B.5.3.1Street Address1 Avenue Claude VELLEFAUX
    B.5.3.2Town/ cityParis
    B.5.3.3Post code75010
    B.5.3.4CountryFrance
    B.5.4Telephone number+3301 44 84 17 42
    B.5.5Fax number+3301 44 84 17 01
    B.5.6E-mailkarine.seymour@aphp.fr
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name LENVIMA 4 mg, Capsules
    D.2.1.1.2Name of the Marketing Authorisation holderEISAI GmBH
    D.2.1.2Country which granted the Marketing AuthorisationFrance
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameLENVATINIB
    D.3.4Pharmaceutical form Capsule
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNLENVATINIB
    D.3.9.1CAS number 417716-92-8
    D.3.9.4EV Substance CodeSUB10537MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number4
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    NA
    patients atteints d’un Carcinome Hépato-Cellulaire (CHC) (BCLC A) ayant un mauvais pronostic, et traités par ablation percutanée en intention curatrice
    E.1.1.1Medical condition in easily understood language
    NA
    Carcinome Hépato-Cellulaire
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To assess local recurrence-free survival during a 1 year follow-up after PA procedure.
    Local recurrence is defined as emergence of irregular areas enhanced at arterial phase followed by washout at portal phase observed next to the ablation zone.
    Justification of 1-yr follow-up period: HCC recurrence is usually divided in the literature as time-related recurrence: “early” within the two years following the ablation and “late” after two years (reference: Imamura H, et al. Risk factors contributing to early and late phase intrahepatic recurrence of hepatocellular carcinoma after hepatectomy. Journal of hepatology 2003;38:200-207).
    Early relapse is usually related to tumour features whereas late relapse is related to de novo carcinogenesis.
    NA
    E.2.2Secondary objectives of the trial
    - To assess the changes of tumorous and non-tumorous perfusion parameters observed with MRI after of neoadjuvant treatment, and before the PA procedure
    - To assess the Per nodule rates of early response (one month) after a single procedure of PA
    - To assess the incidences of intra segmental/ extra segmental distant recurrence
    - To assess the overall survival at 1 and 2 years following PA procedure
    - To assess the compliance to neoadjuvant and adjuvant treatments
    - To assess the tolerance of lenvatinib in the setting of neo- and adjuvant therapy to PA
    NA
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Male or female patients ≥ 18 years
    - Histological 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:
    - Serum AFP>100 ng/mL
    - Infiltrative form
    - Macro-trabecular subtype
    - 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)der
    NA
    E.4Principal 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 or candidates for liver transplantation
    - Prior systemic treatment for HCC (chemotherapy, any other TKI, immunotherapy)
    - Patients with large oesophageal 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
    NA
    E.5 End points
    E.5.1Primary end point(s)
    Local recurrence-free survival during a 1-year follow-up after lenvatinib neoadjuvant/adjuvant therapy and PA procedure (see definition above).

    Recurrence rates (whether local or distant) will be assessed using imaging techniques as recommended by international guidelines (every 3-months US and CT/MRI during one year). Patients who will meet primary endpoint will be alive 1 year after PA procedure without evidence of local recurrence on 3-months MRI evaluations.
    NA
    E.5.1.1Timepoint(s) of evaluation of this end point
    1 year after PA procedure without evidence of local recurrence on 3-months MRI evaluations.
    NA
    E.5.2Secondary end point(s)
    - Changes of tumorous and non-tumorous perfusion parameters observed with MRI after one month of neoadjuvant treatments
    - Per nodule rates of early response (one month) after a single procedure of PA
    - Incidences of intra segmental/ extra segmental distant recurrence
    - Assessment of overall survival at 1 and 2 years following PA procedure: patients will meet this endpoint if they are alive with or without HCC recurrence 1 year, and 2 years after PA procedure. Causes and date of death will be specified when applicable during this timeframe.
    - Assessment of tolerance of lenvatinib: adverse events related will be monitored according to manufacturer guidelines and recommendation.
    - Compliance to neoadjuvant and adjuvant treatments
    - Frequency of SAEs and discontinuations due to AEs
    NA
    E.5.2.1Timepoint(s) of evaluation of this end point
    1 and 2 years following PA procedure
    NA
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy No
    E.6.4Safety No
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled No
    E.8.1.1Randomised No
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial1
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned11
    E.8.5The trial involves multiple Member States No
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.7Trial has a data monitoring committee No
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    LVLS
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years3
    E.8.9.1In the Member State concerned months6
    E.8.9.1In the Member State concerned days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 30
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 20
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception Information not present in EudraCT
    F.3.3.2Women of child-bearing potential using contraception No
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally Yes
    F.3.3.6.1Details of subjects incapable of giving consent
    NA
    Personnes sous protection juridique: sous tutelle ou curatelle
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state50
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    None
    Non
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2021-05-21
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2021-04-06
    P. End of Trial
    P.End of Trial StatusTrial now transitioned
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