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    The EU Clinical Trials Register currently displays   43884   clinical trials with a EudraCT protocol, of which   7296   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:2015-000442-39
    Sponsor's Protocol Code Number:Neo-Nivo
    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:2015-04-27
    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 number2015-000442-39
    A.3Full title of the trial
    PHASE II STUDY OF NEOADJUVANT NIVOLUMAB IN PATIENTS WITH GLIOBLASTOMA MULTIFORME
    Estudio fase II con nivolumab neoadyuvante en pacientes con glioblastoma multiforme
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Nivolumab administered before surgery in patients with glioblastoma multiforme
    A.4.1Sponsor's protocol code numberNeo-Nivo
    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 SponsorClinica 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 supportClinica Universidad de Navarra
    B.4.2CountrySpain
    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. Pio XII 36
    B.5.3.2Town/ cityPamplona
    B.5.3.3Post code31008
    B.5.3.4CountrySpain
    B.5.4Telephone number349482554002723
    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 No
    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.3.2Product code BMS-936558
    D.3.4Pharmaceutical form Solution for injection/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.3.9.2Current sponsor codeBMS-936558-01
    D.3.9.3Other descriptive nameBMS936558
    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 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
    Glioblastoma multiforme
    Glioblastoma Multiforme
    E.1.1.1Medical condition in easily understood language
    Glioblastoma multiforme (malignant brain tumor)
    Glioblastoma Multiforme (tumor cerebral maligno)
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 18.0
    E.1.2Level PT
    E.1.2Classification code 10018337
    E.1.2Term Glioblastoma multiforme
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 18.0
    E.1.2Level PT
    E.1.2Classification code 10018336
    E.1.2Term Glioblastoma
    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
    2.1 Main objective.
    To assess changes in PD-L1 and CD8 expression induced by neoadjuvant nivolumab in GBM. For that purpose we will compare GBM tissue of patients before and after treatment with neoadjuvant nivolumab.
    Determinar cambios en la expresión de PD-L1 y CD8 inducidos por nivolumab neo adyuvante en GBM. Para ello compararemos tejido de pacientes con GBM antes y después de nivolumab neoadyuvante
    E.2.2Secondary objectives of the trial
    2.2 Secondary objectives.
    To determine:
    - Progression-free survival (PFS) and overall survival (OS) in all patients.
    - Safety of neoadjuvant nivolumab in patients with GBM.
    - Tumor and peripheral blood biomarkers with potential predictive of pharmacodynamic effects and clinical activity.
    - Early tumor response to the neoadjuvant dose
    Determinar:
    - Supervivencia libre de progresión (SLP) y supervivencia global en todos los pacientes.
    - Seguridad de nivolumab neoadyuvante en pacientes con GBM.
    - Biomarcadores en tumor y en sangre periférica con valor potencial predictivo de eficacia y de efectos farmacodinámicos.
    - Respuesta tumoral precoz al tratamiento neoadyuvante.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Written informed consent.
    2. Patients must be willing and able to comply with scheduled visits, treatment schedule, laboratory testing and other requirements of the study.
    3. Patients with GBM that are candidates to primary or salvage resection surgery, according to the following criteria:
    a. in patients undergoing primary surgery, diagnosis of GBM should be confirmed by previous biopsy or previous partial resection.
    b. in patients with recurrent GBM, diagnosis of progression will be confirmed either by previous biopsy or by the Revised Assessment in Neuro-Oncology (RANO) criteria, as assessed by the investigator (appendix 1).
    4. Patients may have received previous treatments for GBM. There is no limit on previous treatment lines, as long as the other inclusion criteria are met.
    5. Patients in whom surgery can be safely delayed for a minimum period of 2 weeks following the administration of the first dose of nivolumab, in the opinion of the investigator.
    6. ECOG performance status of 0-1. Patients with ECOG>1 due to neurological symptoms considered to be reversible following surgery, according to investigator´s criteria will be eligible.
    7. Life expectancy >12 weeks.
    8. Steroids should be ideally discontinued or reduced to a dose <10 mg of prednisone or its equivalence at inclusion and during treatment with nivolumab. Nevertheless, greater doses of systemic steroids are allowed for the control of cerebral edema.
    9. Adequate organ function defined by:
    a. Bone Marrow Reserve: white blood cells (WBC): ?2000/ mm3 absolute neutrophil count (ANC) ?1500x 109/L; platelet count ?100000/ mm3 100 x 109/L; hemoglobin ?9.0 g/dL).
    b. Hepatic: bilirubin <1.5 times the upper limit of normality (ULN), AST and ALT <3.0 ? ULN (BR< 3 x ULN for patients with Gilbert´s Syndrome).
    c. Renal: creatinine < 1.5 x ULN or estimated creatinine clearance > 40 ml/min, using the Cokcroft-Gault formula.
    10. Women of childbearing potential (WOCBP) must use appropriate method(s) of contraception. WOCBP should use an adequate method to avoid pregnancy for 23 weeks (30 days plus the time required for nivolumab to undergo five half-lives) after the last dose of investigational drug.
    11. Women of childbearing potential must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 hours prior to the start of nivolumab
    12. Men who are sexually active with WOCBP must use any contraceptive method with a failure rate of less than 1% per year. Men receiving nivolumab and who are sexually active with WOCBP will be instructed to adhere to contraception for a period of 31 weeks after the last dose of investigational product. Women who are not of childbearing potential (ie, who are postmenopausal or surgically sterile as well as azoospermic men) do not require contraception.
    13. Patients must be at least 18 years old.
    1. Consentimiento informado por escrito.
    2. Capacidad de cumplir los procedimientos del estudio.
    3. Pacientes con GBM candidatos a resección primaria o de rescate, según los siguientes criterios:
    a. En los pacientes con tumores primarios el diagnostico de GBM debe estar confirmado por biopsia o resección parcial previa. El material previo debe estar disponible y debe ser suficiente para cumplir el objetivo principal del estudio, según el criterio de los investigadores.
    b. En los pacientes con GBM recurrente, el diagnostico de progresión se confirmará por biopsia o por los criterios RANO (Revised Assessment in Neuro-Oncology) Será necesario obtener tejido tumoral previo en cantidad suficiente para cumplir el objetivo principal, según el criterio de los investigadores.
    4. Los pacientes pueden haber recibido tratamientos previos sin límite para el GBM.
    5. Pacientes en los que se pueda retrasar 2 semanas la cirugía con seguridad para ellos, según el criterio del investigador.
    6. ECOG 0-1. Los pacientes con ECOG>1 por deficit neurológico, que se considere reversible tras la intervención, según el criterio de los investigadores, podrán ser incluidos.
    7. Esperanza de vida >12 semanas.
    8. Se deberán discontinuar los esteroides o reducirlos a dosis <10 mg de prednisona o equivalente en el momento de la inclusión o durante el tratamiento con nivolumab. No obstante, se permitirán dosis mayores de esteroides para el control del edema cerebral.
    9. Función orgánica adecuada, definida por:
    a. Hematológica: leucocitos: 2000/ mm3; neutrófilos 1500x 109/L; plaquetas100000/ mm3 100 x 109/L; hemoglobina 9.0 g/dL).
    b. Hepática: bilirrubina <1.5 x límite superior de la normalidad (LSN), AST y ALT <3.0  LSN (BR< 3 x LSN para pacientes con síndrome de Gilbert).
    c. Renal: creatinina < 1.5 x LSN o aclaramiento estimado de creatinina > 40 ml/min (Cokcroft-Gault).
    10. Las mujeres con capacidad reproductiva deberán utilizar métodos adecuados para evitar la concepción durante el tratamiento hasta al menos 23 semanas después de la última dosis de nivolumab.
    11. Las mujeres en capacidad reproductiva deberán tener una prueba negativa de embarazo en suero u orina 24 horas antes del comienzo del tratamiento con nivolumab.
    12. Los hombres sexualmente activos deberán usar un método anticonceptivo con una tasa de fallos <1% al año, durante el tratamiento hasta al menos 31 semanas después de la última dosis de nivolumab. Las mujeres u hombres sin capacidad reproductiva no requieren medidas anticonceptivas.
    13. Edad mayor o igual a 18 años
    E.4Principal exclusion criteria
    1. Presence of extracranial disease.
    2. Any serious or uncontrolled medical disorder that, in the opinion of the investigator, may increase the risk associated with study participation or study drug administration, impair the ability of the subject to receive the planned therapy (including brain surgery), or interfere with the interpretation of study results.
    3. Subjects with active, known or suspected autoimmune disease. Subjects with vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll.
    4. Previous treatment with a PD-1, PDL1 or CTLA-4 targeted therapy
    5. Treatment with any anti-cancer drug or radiation therapy within the last 14 days. A shorter interval can be approved by the principal investigator, if deemed appropriate.
    6. Patients should be excluded if they have a condition requiring systemic treatment with either corticosteroids (>10 mg daily prednisone equivalents), with the exception of control of cerebral edema, or other immunosuppressive medications within 14 days of study drug administration. Inhaled or topical steroids and adrenal replacement doses > 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease.
    7. Pregnant or breastfeeding patients.
    8. Known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS). Routine testing is not required.
    9. Positive tests for hepatitis B virus surface antigen (HBV sAg) or hepatitis C virus ribonucleic acid (HCV RNA) indicating active or chronic infection.
    10. History of allergy to study drug components or of severe hypersensitivity reactions to any monoclonal antibodies.
    11. Prisoners or subjects who are involuntarily incarcerated or who are compulsorily detained for treatment of either a psychiatric or physical (eg, infectious disease) illness.
    12. Subjects unable (due to existent medical condition, e.g, pacemaker or implantable cardioverter defibrillator device) or unwilling to have a head contrast enhanced MRI and/or a CT scan of the brain.
    13. Concomitant or prior malignancy that, in the opinion of the investigator contraindicates GBM surgery or can interfere with the results of the study, in the opinion of the investigator.
    14. Known drug or alcohol abuse.
    1. Enfermedad extracraneal.
    2. Alteraciones médicas serias o no controladas que en opinión de los investigadores aumenten el riesgo del sujeto al participar en el estudio, impidan que reciba el tratamiento del estudio (incluyendo la cirugía) o interfiera con la interpretación de los resultados.
    3. Enfermedad autoinmune activa, con la excepción de vitiligo, diabetes mellitus tipo I, hipotiroidismo residual autoinmune que solo precise tratamiento hormonal sustitutivo, psoriasis que no requiera tratamiento sistémico o enfermedades que no se sospeche que recurran.
    4. Tratamiento previo con anti PD-1, PDL1 o CTLA-4.
    5. Tratamiento con fármacos antitumorales o radioterapia en los 15 días previos.
    6. Necesidad de recibir tratamiento con esteroides (>10 mg de prednisona diaria o equivalentes), con la excepción del control del edema cerebral
    7. Lactancia o embarazo.
    8. Positividad conocida para VIH. No es obligatorio realizar la prueba.
    9. Positividad conocida para HBsAg o HCV RNA que indique infección activa o crónica.
    10. Historia de alergias al fármaco del estudio o hipersensibilidad grave a los anticuerpos monoclonales.
    11. Presos o sujetos recluidos para el tratamiento de una enfermedad psiquiátrica o física.
    12. Incapacidad de realizar RNM o TAC del cerebro.
    13. Enfermedad tumoral concomitante que pueda interferir con el resultado del estudio o impedir la cirugía.
    14. Abuso conocido de alcohol o drogas.
    E.5 End points
    E.5.1Primary end point(s)
    Changes in CD8 and PDL1 expression after one dose of nivolumab
    Cambios en expresión de CD8 y PDL1 tras una dosis de nivolumab
    E.5.1.1Timepoint(s) of evaluation of this end point
    Day 15 of the trial (after one neoadjuvant dose)
    Dia 15 del ensayo (tras una dosis neoadyuvante)
    E.5.2Secondary end point(s)
    Progression-free survival (PFS) and overall survival (OS) in all patients.
    - Safety of neoadjuvant nivolumab in patients with GBM.
    - Tumor and peripheral blood biomarkers with potential predictive of pharmacodynamic effects and clinical activity.
    - Early tumor response to the neoadjuvant dose
    - Supervivencia libre de progresión (SLP) y supervivencia global en todos los pacientes.
    - Seguridad de nivolumab neoadyuvante en pacientes con GBM.
    - Biomarcadores en tumor y en sangre periférica con valor potencial predictivo de eficacia y de efectos farmacodinámicos.
    - Respuesta tumoral precoz al tratamiento neoadyuvante.
    E.5.2.1Timepoint(s) of evaluation of this end point
    All throughout the trial
    Durante toda la duración del ensayo
    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 No
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic Yes
    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 years3
    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: 29
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 29
    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 No
    F.3.3.1Women of childbearing potential not using contraception No
    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 No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state29
    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. Patients may undergo any treatment they need.
    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 Decision2015-08-17
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2015-07-03
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2017-03-01
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