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    Summary
    EudraCT Number:2017-000232-34
    Sponsor's Protocol Code Number:NASIR-HCC
    National Competent Authority:Spain - AEMPS
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2017-06-09
    Trial results View 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 ConcernedSpain - AEMPS
    A.2EudraCT number2017-000232-34
    A.3Full title of the trial
    A multicenter, open-label, single-arm study of the safety and antitumoral efficacy of nivolumab in combination with selective internal radiation therapy (SIRT) using SIR-Spheres for the treatment of patients with hepatocellular carcinoma that are candidates for locoregional therapies.
    Estudio multicéntrico, abierto, de un solo brazo, sobre la seguridad y eficacia antitumoral de nivolumab en combinación con radioterapia interna selectiva (SIRT) con SIR-Spheres para el tratamiento de pacientes con carcinoma hepatocelular que son candidatos a terapias locorregionales.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Nivolumab after selective internal radiation therapy using SIR-Spheres to treat patients with primary liver cancer: a safety and efficacy study
    Nivolumab tras radioterapia interna selectiva con SIR-Spheres para tratar pacientes con cáncer primario de hígado: estudio de seguridad y eficacia
    A.4.1Sponsor's protocol code numberNASIR-HCC
    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 SponsorClínica Universidad de Navarra/Universidad de Navarra
    B.1.3.4CountrySpain
    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 supportBristol-Myers-Squibb SAU
    B.4.2CountrySpain
    B.4.1Name of organisation providing supportSirtex Technology
    B.4.2CountryAustralia
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationClinica Universidad de Navarra
    B.5.2Functional name of contact pointUCEC
    B.5.3 Address:
    B.5.3.1Street AddressAvda. Pío XII, 36
    B.5.3.2Town/ cityPamplona
    B.5.3.3Post code31008
    B.5.3.4CountrySpain
    B.5.4Telephone number349482554002724
    B.5.5Fax number34948296667
    B.5.6E-mailucicec@unav.es
    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 holderBristol-Myers Squibb Pharma EEIG
    D.2.1.2Country which granted the Marketing AuthorisationSpain
    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 nameNIVOLUMAB
    D.3.4Pharmaceutical form Concentrate for 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 nameNIVOLUMAB
    D.3.9.4EV Substance CodeSUB122750
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number10
    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 Yes
    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
    Hepatocellular carcinoma
    Carcinoma hepatocelular
    E.1.1.1Medical condition in easily understood language
    Primary liver cancer
    Cáncer primario de hígado
    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 evaluate the safety of nivolumab in combination with SIRT using SIR-Spheres
    Evaluar la seguridad de nivolumab en combinación con SIRT mediante SIR-Spheres
    E.2.2Secondary objectives of the trial
    The secondary objective is to evaluate the antitumoral activity of nivolumab in combination with SIRT using SIR-Spheres.
    Exploratory objectives are:
    • To evaluate the role of tissue biomarkers (tumor immune cell infiltrate, PD-1 and PD-L1 expression, peripheral blood markers) in determining the antitumoral activity of nivolumab in combination with SIRT using SIR-Spheres.
    • To evaluate the utility of baseline or on-treatment variables that may serve as surrogate markers of efficacy.
    El objetivo secundario es evaluar la actividad antitumoral de nivolumab en combinación con SIRT mediante SIR-Spheres.

    Son objetivos exploratorios:

    • Evaluar el papel de marcadores tisulares (infiltrado tumoral por células inmunes, expresión de PD-1 y PD-L1, marcadores en sangre periférica) en la determinación de la actividad antitumoral de nivolumab en combinación con SIRT mediante SIR-Spheres.

    • Evaluar la utilidad de variables basales o durante el tratamiento que puedan servir como marcadores surrogados de eficacia.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Age 18-years-old or above
    Diagnosis of HCC based on histology or non-invasive criteria if cirrhotics. Patients with fibrolamellar carcinoma are not excluded.
    Chronic liver disease absent, non-viral or due to hepatitis C or B virus infection. Subjects with chronic HBV infection must be on effective antiviral therapy
    Preserved liver function (without cirrhosis or with compensated cirrhosis in Child Pugh Class A).
    ECOG performance status 0 or 1
    Willing to have a liver biopsy pre-treatment
    Considered candidates for locoregional therapy using SIR-Spheres based on
    • the absence of extrahepatic disease.
    • unsuitability for liver resection or transplantation, or percutaneous ablation
    • considered not good candidates for TACE because they have:
    o Single tumors larger than 5 cm. Unsuitability for TACE in patients with single tumors of size between 5 and 10 cm will follow local practice in the treating center.
    o Multiple tumors that cannot be targeted superselectively. These patients should be in the BCLC-B2 substage proposed by Bolondi et al (3). In summary, they should fall within the up-to-7 rule (the sum of the number of tumors and the maximal size of the largest lesion in cm should be higher than 7) and should be in a Child-Pugh stage A. Unsuitability for TACE in patients with multiple tumors within the BCLC-B2 substage will follow local practice in the treating center.
    o Unilobar tumors with segmental or lobar portal vein thrombosis. Patients that have a small burden of disease (< 10% of the total tumor burden) in the contralateral lobe may be treated at the discretion of the site Principal Investigator
    At least one measurable lesion by RECIST 1.1 criteria.
    Adequate organ and marrow function as evidenced by:
    • WBC ≥ 2000/μL.
    • Neutrophils ≥ 1000/μL.
    • Platelets ≥ 60 x 103/μL.
    • Hemoglobin ≥ 9.0 g/dL.
    • Creatinine CrCl >40 mL/min.
    • AST and ALT ≤ 5 X ULN
    • Bilirubin ≤ 2 mg/dL
    • INR ≤ 1.8.
    • Albumin ≥ 2.8 g/dL
    Willing and able to comply with immune-monitoring sample collection and required study follow-up.
    Edad igual o superior a 18 años
    Diagnóstico de carcinoma hepatocelular basado en confirmación histológica o criterios no invasivos si el paciente es cirrótico. Los pacientes con hepatocarcinoma fibrolamelar no quedan excluidos.
    Enfermedad hepática crónica ausente, no viral o causada por los virus B o C de la hepatitis. Las personas con infección por virus B han de estar recibiendo un tratamiento antiviral eficaz.
    Función hepática preservada (sin cirrosis o con cirrosis compensada en estadio Child Pugh A).
    Performance status 0 o 1 de la clasificación ECOG
    Que acceda a la realización de una biopsia hepática.
    Que se consideren candidatos a tratamiento locorregional con SIR-Spheres en base a:
    • ausencia de enfermedad extrahepática
    • no candidatos a resección hepática, trasplante hepático o ablación percutánea
    • considerados no buenos candidatos a TACE porque tengan:
    o Tumores único de más de 5 cm. La consideración como candidato a TACE en los pacientes con tumores únicos de entre 5 y 10 cm debe ajustarse a la práctica habitual de cada centro.
    o Tumores múltiples que no puedan ser tratados de forma superselectiva. Estos pacientes habrán de estar en el subestadio B2 propuesto por Bolondi et al (3). En resumen, debe caer dentro de la regla "hasta 7" (la suma del número de tumores y el tamaño máximo en centímetros de la lesión más grande debe ser superior a 7) y debe estar en un estadio Child-Pugh A. La consideración como candidato a TACE en los pacientes con tumores múltiples en el subestadio BCLC-B2 debe ajustarse a la práctica habitual de cada centro.
    o Tumores unilobares con trombosis portal segmentaria o lobar. Los pacientes que tengan una pequeña carga de enfermedad (<10% de la carga tumoral total) en el lóbulo contralateral pueden ser tratados, a criterio del investigador principal de cada centro.
    Al menos una lesión tumoral medible según criterios RECIST 1.1.
    Funciones orgánicas adecuadas en base a:
    • Leucocitos ≥ 2000 / μL.
    • Neutrófilos ≥ 1000 / μL.
    • Plaquetas ≥ 60 x 103 / μL.
    • Hemoglobina ≥ 9,0 g / dL.
    • Aclaramiento de creatinina > 40 ml / min.
    • AST y ALT ≤ 5 veces el límite superior de la normalidad
    • Bilirrubina ≤ 2 mg / dL
    • INR ≤ 1,8.
    • Albúmina ≥ 2,8 g / dL
    Estar dispuesto y ser capaz de cumplir con la recogida de muestras de monitorización inmune y seguimiento requerido por el estudio.
    E.4Principal exclusion criteria
    Any history of hepatic encephalopathy
    Any prior (within 1 year) or current clinically significant ascites.
    Any history of clinically meaningful variceal bleeding within the last three months.
    Active coinfection with both hepatitis B and C or hepatitis D infection in subjects with hepatitis B
    Occlusive main trunk portal vein thrombosis or absence of intrahepatic portal blood flow if patient carries a portocaval shunt.
    Prior malignancy active within the previous 3 years except for locally curable cancers that have been apparently cured.
    Any active autoimmune disease.
    Any severe organ disease
    Prior therapy with any drug specifically targeting T-cell costimulation or checkpoint pathways.
    Prior organ allograft or allogeneic bone marrow transplantation
    Recent active bacterial or fungal infections.
    Any condition requiring systemic treatment with corticosteroids or other immunosuppressive medications within 14 days of study drug administration.
    Cualquier antecedente de encefalopatía hepática
    Cualquier antecedente de ascitis clínicamente significativa previa (en el último año) o actual.
    Cualquier historia de hemorragia varicosa clínicamente significativa en los últimos tres meses.
    Co-infección activa con hepatitis B y C o hepatitis D en personas con hepatitis B
    Trombosis oclusiva del tronco portal principal o ausencia de flujo sanguíneo portal intrahepático si el paciente porta una derivación portocava.
    Enfermedad maligna previa en los 3 años previos excepto para cánceres curables localmente que aparentemente hayan sido curados.
    Cualquier enfermedad autoinmune activa.
    Cualquier enfermedad grave de un órgano
    Tratamiento previo con cualquier fármaco dirigido específicamente a la coestimulación de las células T o vías de control (checkpoints).
    Trasplante de órgano o trasplante alogénico de médula ósea previos.
    Infecciones bacterianas o fúngicas recientes activas.
    Cualquier proceso que requiera tratamiento sistémico con corticosteroides u otros medicamentos inmunosupresores en los 14 días anteriores a la administración del fármaco del estudio.
    E.5 End points
    E.5.1Primary end point(s)
    The primary endpoint is the rate and type of adverse events (AEs), serious AEs, liver decompensation, and transient and permanent drug discontinuations due to toxicity
    El criterio de valoración primario es la tasa y el tipo de eventos adversos (EA), EA graves, descompensación hepática e interrupción transitoria y permanente del tratamiento debido a toxicidad.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Up to 100 days after the last dose of nivolumab
    Hasta 100 días después de la última administración de nivolumab
    E.5.2Secondary end point(s)
    The secondary endpoints are the rate of objective response, disease control, duration of response and time to progression based on RECIST criteria v 1.1, as well as the pattern of progression and overall survival (OS).
    Exploratory endpoints are:
    • PD-1 and PD-L1 expression in tumor samples, TILs density, inflammatory blood markers.
    • ALBI score at baseline and time to progression untreatable by locoregional therapies.
    Los criterios de valoración secundarios son la tasa de respuesta objetiva y control de la enfermedad, la duración de la respuesta y el tiempo hasta la progresión basados en criterios RECIST v 1.1, así como el patrón de progresión y la supervivencia global.
    Los criterios de valoración exploratorios son:
    • la expresión de PD-1 y PD-L1 en muestras tumorales, densidad de linfocitos infiltrantes de tumor (TIL), y marcadores sanguíneos de inflamación.
    • la puntuación ALBI al inicio y el tiempo hasta la progresión intratable mediante terapias locorregionales.
    E.5.2.1Timepoint(s) of evaluation of this end point
    For the entire duration of the study
    Durante todo el periodo de estudio
    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 Yes
    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 Yes
    E.8.4 The trial involves multiple sites in the Member State concerned No
    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 years4
    E.8.9.1In the Member State concerned months0
    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: 20
    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 No
    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 state40
    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
    Ninguno
    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 Decision2017-09-11
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2017-06-27
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2020-04-30
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