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    The EU Clinical Trials Register currently displays   43851   clinical trials with a EudraCT protocol, of which   7283   are clinical trials conducted with subjects less than 18 years old.   The register also displays information on   18700   older paediatric trials (in scope of Article 45 of the Paediatric Regulation (EC) No 1901/2006).

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    Summary
    EudraCT Number:2017-004679-29
    Sponsor's Protocol Code Number:P171001J
    National Competent Authority:France - ANSM
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2018-04-17
    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 number2017-004679-29
    A.3Full title of the trial
    Immunotherapy in neoadjuvant and adjuvant setting in patients with advanced HCC treated by electroporation in curative intent: French multicenter phase 2 therapeutic trial
    Immunothérapie en traitement néoadjuvant et adjuvant chez les patients atteints de CHC avancé traités par électroporation en intention curative: Etude française, prospective multicentrique de phase 2.
    A.3.2Name or abbreviated title of the trial where available
    NIVOLEP
    A.4.1Sponsor's protocol code numberP171001J
    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 - HOPITAUX 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 supportBMS
    B.4.2CountryFrance
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationASSISTANCE PUBLIQUE - HOPITAUX DE PARIS (AP-HP)
    B.5.2Functional name of contact pointDRCI Hôpital St Louis
    B.5.3 Address:
    B.5.3.1Street Address 1 av. Claude Vellefaux
    B.5.3.2Town/ cityPARIS
    B.5.3.3Post code75010
    B.5.3.4CountryFrance
    B.5.6E-mailhouria.mebarek@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 Opdivo
    D.2.1.1.2Name of the Marketing Authorisation holderLaboratoire BMS
    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 nameOpdivo
    D.3.4Pharmaceutical form Solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNNivolumab
    D.3.9.1CAS number 946414-94-4
    D.3.9.3Other descriptive nameanti- PD1 monoclonal antibody
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeup to
    D.3.10.3Concentration number5
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    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 Yes
    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
    Nivolumab in neoadjuvant and adjuvant setting in patients with advanced HCC treated by electroporation
    Traitement par Nivolumab chez les patients atteints de carcinime hépatocellulaire à un stade avancé.
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10073071
    E.1.2Term Hepatocellular carcinoma
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    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 2-years follow-up after Nivolumab neoadjuvant/adjuvant therapy and EP procedure.
    Évaluer la survie sans récidive locale à 2 ans après une procédure d'electroporation
    E.2.2Secondary objectives of the trial
    -To assess the changes of tumorous and non-tumorous perfusion parameters observed with CUS and MRI after one months of neoadjuvant treatments
    -To assess the Per nodule rates of early response (one month) after a single procedure of EP
    -To assess the incidences of intra segmental/ extra segmental distant recurrence
    -To assess the overall survival at 2-yrs following EP procedure
    -To assess the compliance to neoadjuvant and adjuvant treatments
    -To assess the tolerance of Nivolumab in the setting of neo- and adjuvant therapy to EP
    -Tumoral and non tumoral assessment (histological and molecular study) of the effect of nivolumab at 1 month: tumor apoptosis and lymphocyte infiltration, expression of immunity modulating genes
    -Peripheral blood approach of the effect of immunotherapy: changes in phenotypic and functional characteristic of circulating lymphocytes subpopulation, cytokine, chemokine and metabolomic profile changes under therapy
    - Evaluer les taux de réponse après traitement neo-adjuvant par Nivolumab
    -Évaluer les taux de réponse précoce par nodule (un mois) après une procédure unique de l'EP
    -Évaluer l'incidence de la récidive à distance intra segmentaire / extra segmentaire
    -Évaluer la survie globale à 2 ans après la procédure de l'EP.
    -Évaluer la compliance aux traitements néoadjuvants et adjuvants.
    -Évaluer la tolérance du Nivolumab
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Male or female patients superior or equal 18 years
    - Histological or cytological documentation of HCC or non-invasive diagnosis of HCC as per American Association for the Study of Liver Diseases (AASLD) criteria in patients with a confirmed diagnosis of cirrhosis
    - Barcelona Clinical Liver Cancer (BCLC) stage Category B or C
    - Patients with HCC amenable for EP as assessed by multidisciplinary board corresponding to the following extension:
    o Uninodular HCC >3cm and <5cm
    o Multinodular HCC
    - At least one uni-dimensional measurable lesion by computed tomography (CT) scan or magnetic resonance imaging (MRI) according to modified RECIST for HCC
    - Liver function status Child-Pugh Class A
    - Eastern Cooperative Oncology Group (ECOG) Performance Status inferior or equal 2
    - Adequate bone marrow, liver and renal function as assessed by the following laboratory tests:
    o Hemoglobin > 8.5 g/dL
    o Absolute neutrophil count superior or equal 1500/mm3
    o Platelet count superior or equal 60,000/ mm3
    o Total bilirubin inferior or equal 2 mg/dL
    o Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) inferior or equal 5 x upper limit of normal (ULN)
    o Serum creatinine inferiror or equal 1.5 x ULN
    o Lipase inferiro or equal 2 x ULN
    o Prothrombine time-international normalized ratio (PT-INR) < 2.3 x ULN and PTT < 1.5 x ULN
    o Glomerular Filtration Rate (GFR) superior or equal 30 mL/min/1.73 m2
    - Life expectancy superior or equal 3 months
    - Women of childbearing potential (WOCBP) need to accept one effective method of contraception until 5 months after the last nivolumab infusion
    - Men who are sexually active with WOCBP partners need to accept one effective method of contraceptionuntil 7 months after the nivolumab infusion
    and men must agree to use adequate contraception
    - Patients affiliated to a Social Security System
    - Written informed consent signed
    Patient homme ou femme âgé de 18 ans et plus
    -Diagnostic histologique ou cytologique du CHC.
    -Indication de traitement par electroporation posée en réunion de concertation pluridisciplinaire et répondant aux critères suivants :
    o CHC uninodulaire> 3cm et <5cm
    o CHC multinodulaire
    - Cirrhose compensée Child-Pugh Classe A.
    - ECOG État de performance ? 2.
    - Bilan bilogique répondant aux critères ci-dessous:
    o Hémoglobine> 8,5 g / dL
    o Nombre absolu de neutrophiles ? 1500 / mm3
    o Nombre de plaquettes ? 60 000 / mm3
    o Bilirubine totale ? 2 mg / dL
    o Alanine aminotransférase (ALT) et aspartate aminotransférase (AST) ? 5 x limite supérieure de la normale (LSN)
    o Créatinine sérique ? 1,5 x LSN
    o Lipase ? 2 x ULN
    o Temps de Prothrombine (PT-INR) <2,3 x LSN et PTT <1,5 x ULN
    oTaux de filtration glomérulaire (GFR) ? 30 mL / min / 1,73 m2
    - Espérance de vie ? 3 mois
    - Femmes en âge de procréer et hommes acceptant d'utiliser une contraception adéquate
    - Patients affiliés à un système de sécurité sociale
    - Signature du consentement éclairé écrit
    E.4Principal exclusion criteria
    Patients with past history of HCC
    - Patients with contraindications to EP
    - 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
    - Patients with autoimmune disease and patients requiring chronic systemic treatment with corticosteroids (>10 mg daily prednisone equivalent) or other immunosuppressive medications.
    - 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 tumors. Any cancer curatively treated > 3 years prior to study entry is permitted
    - Known history or symptomatic metastatic brain or meningeal tumors
    - Major surgical procedure or significant traumatic injury within 28 days before enrolment
    - Congestive heart failure New York Heart Association superior or equal class 2
    - Unstable angina or myocardial infarction within the past 6 months before enrolment
    - Cardiac arrhythmias requiring anti-arrhythmic therapy
    - Grade 3 (severe) hypertension superior or equal 180 and/or superior or equal 110 mmHG (systolic and diastolic, according to National Heart Foundation 2016)
    - 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 superior or equal 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 superior or equal Grade 3 within 30 days before enrolment
    - Arterial or venous thrombotic or embolic events such as cerebrovascular accident, deep vein thrombosis or pulmonary embolism within 6 months 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
    - Known history of human immunodeficiency virus (HIV) infection
    - Seizure disorder requiring medication
    - 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
    - Antécédent de CHC
    - Patients ayant une contre-indication à l'electroporation
    - Impossibilité de réaliser une TDM ou une IRM avec injection de produit de contraste
    - Patients candidats à la transplantation hépatique en situation " activée "
    - Antécedent de traitement par immunomothérapie
    - Patients atteints d'une infection non contrôlée par le virus de l'hépatite B, ayant une charge virale supérieure à 100 UI / mL.
    - Patients ayant des varices œsophagiennes importantes ayant un risque de saignement et qui ne sont pas traités par une intervention médicale conventionnelle.
    - Antécédents antérieurs ou simultanés de néoplasmes autres que le CHC, à l'exception du carcinome in situ du cancer de la peau, de l'utérus et / ou du non-mélanome et des tumeurs superficielles de la vessie. Un traitement curatif par cancer supérieur à 3 ans avant l'entrée à l'étude est autorisé.
    - Insuffisance cardiaque congestive New York Heart Association (NYHA) ? classe 2.
    - Angor instable ou infarctus du myocarde au cours des 6 derniers mois avant l'inclusion
    - Arythmies cardiaques nécessitant un traitement
    - Hypertension artérielle non contrôlée supérieure à 18 mm Hg (systolique) ou 10 mm Hg (diastolique)
    - Ascite abondante nécessitant des ponctions itératives
    - Thrombopathie ou coagulopathie congénitale
    -Antécédents connus d'infection par le virus de l'immunodéficience humaine (VIH).
    - Trouble épileptique nécessitant un traitement
    - Fracture non cicatrisée, ulcère ou fracture osseuse.
    - Hypersensibilité connue au médicament de l'étude ou aux excipients
    - Grossesse ou allaitement
    E.5 End points
    E.5.1Primary end point(s)
    Efficacy endpoint is remission of treated nodules. At M1 post EP, a tumor will be considered completely ablated if no nodular or irregular enhancement is visible next to the ablation zone during the arterial phase, with washout within the portal phase. After the ablation will be considered complete, local tumor progression will be defined as the emergence of irregular areas enhanced at the arterial phase followed by washout at the portal phase next to the ablation zone. Local tumor progression will also include cases of failure of initial IRE treatment course, reported per nodule.

    As a consequence:
    1- Primary endpoint is achieved if a given patient is alive without local recurrence as defined in the above criteria
    2- All secondary endpoints will be assessed as defined in the above criteria
    Survie sans récidive locale à 2 ans
    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 Yes
    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.8.3 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
    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 months5
    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: 25
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 25
    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 For clinical trials recorded in the database before the 10th March 2011 this question read: "Women of childbearing potential" and did not include the words "not using contraception". An answer of yes could have included women of child bearing potential whether or not they would be using contraception. The answer should therefore be understood in that context. This trial was recorded in the database on 2018-04-17. Yes
    F.3.3.2Women of child-bearing potential using contraception Yes
    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 No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state50
    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 Decision2018-06-13
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2018-06-12
    P. End of Trial
    P.End of Trial StatusOngoing
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