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    Summary
    EudraCT Number:2018-002279-16
    Sponsor's Protocol Code Number:EOGBM1-18
    National Competent Authority:Spain - AEMPS
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2019-08-09
    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 ConcernedSpain - AEMPS
    A.2EudraCT number2018-002279-16
    A.3Full title of the trial
    A MulticenteR, Open-Label, First-in-Human, PhaSe Ib/IIa Trial of EO2401, a Novel Multipeptide Therapeutic VAccine, with and without PD-1 Check Point Inhibitor, FoLlowing Standard Treatment in PatIents with ProgrEssive Glioblastoma (Rosalie study)
    Primer ensayo clínico en el ser humano multicéntrico, abierto, de fase Ib/IIa de EO2401, una nueva vacuna terapéutica multipéptido, con y sin inhibidor de punto de control de PD-1, después del tratamiento de referencia en pacientes con glioblastoma (GB) progresivo (estudio Rosalie)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A First-in-Human, Early Phase Trial to investigate EO2401, a Novel Cancer Vaccine Therapy, with and without an Immune-Checkpoint Blocker, Following Standard Treatment in Patients with Progressive or Recurrent Glioblastoma Multiforme, a Certain Form of Brain Cancer
    Un primer ensayo en el ser humano en fase temprana para investigar el EO2401, una nueva vacuna terapéutica contra el cáncer, con y sin un bloqueador del punto de control inmunitario, después del tratamiento estándar en pacientes con glioblastoma multiforme progresivo o recurrente, una cierta forma de cáncer cerebral
    A.4.1Sponsor's protocol code numberEOGBM1-18
    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 SponsorEnterome
    B.1.3.4CountryFrance
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportEnterome
    B.4.2CountryFrance
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationCovance Clinical and Periapproval Services Limited
    B.5.2Functional name of contact pointProject Management
    B.5.3 Address:
    B.5.3.1Street AddressOsprey House, Westacott Way
    B.5.3.2Town/ cityMaidenhead
    B.5.3.3Post codeSL6 3QH
    B.5.3.4CountryUnited Kingdom
    B.5.4Telephone number+44117942 6711
    B.5.6E-mailcatrin.jones@covance.com
    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.3.2Product code EO2401
    D.3.4Pharmaceutical form Emulsion for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPSubcutaneous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNN/A
    D.3.9.1CAS number N/A
    D.3.9.2Current sponsor codeEO2316
    D.3.9.3Other descriptive nameEO2316
    D.3.10 Strength
    D.3.10.1Concentration unit µg microgram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number300
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNN/A
    D.3.9.1CAS number N/A
    D.3.9.2Current sponsor codeEO2317
    D.3.9.3Other descriptive nameEO2317
    D.3.10 Strength
    D.3.10.1Concentration unit µg microgram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number300
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNN/A
    D.3.9.1CAS number N/A
    D.3.9.2Current sponsor codeEO2318
    D.3.9.3Other descriptive nameEO2318
    D.3.10 Strength
    D.3.10.1Concentration unit µg microgram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number300
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNN/A
    D.3.9.1CAS number N/A
    D.3.9.2Current sponsor codeUCP2
    D.3.9.3Other descriptive nameUCP2
    D.3.10 Strength
    D.3.10.1Concentration unit µg microgram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number300
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNN/A
    D.3.9.1CAS number 190396-06-6
    D.3.9.3Other descriptive nameMONTANIDE ISA51
    D.3.9.4EV Substance CodeSUB33722
    D.3.10 Strength
    D.3.10.1Concentration unit µl microlitre(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number500
    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.IMP: 2
    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 10 mg/mL
    D.2.1.1.2Name of the Marketing Authorisation holderBristol-Myers Squibb Pharma EEIG
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    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.3.4Pharmaceutical 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.3.9.2Current sponsor codeN/A
    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 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.IMP: 3
    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 10 mg/mL
    D.2.1.1.2Name of the Marketing Authorisation holderBristol-Myers Squibb Pharma EEIG
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    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.3.4Pharmaceutical 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.3.9.2Current sponsor codeN/A
    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 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
    Progressive or recurrent Glioblastoma (PG)
    Glioblastoma progresivo o recurrente (GB)
    E.1.1.1Medical condition in easily understood language
    Progressive or recurrent Form of a Certain Type of Malignant Brain Cancer
    Forma progresiva o recurrente de cierto tipo de cáncer 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 20.0
    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
    The primary objective of this first-in-human (FIH) trial of EO2401 is to evaluate the safety and tolerability of EO2401 as monotherapy and in combination with nivolumab, and nivolumab/bevacizumab in patients with progressive glioblastoma (GB).
    El objetivo principal de este primer ensayo clínico en el ser humano (PEH) de EO2401 ensayo es evaluar la seguridad y la tolerabilidad de EO2401 como monoterapia y en combinación con nivolumab y nivolumab/bevacizumab en pacientes con glioblastoma (GB) progresivo.
    E.2.2Secondary objectives of the trial
    The secondary objectives are:
    •The evaluation of survival
    •The evaluation of tumor progression and response by magnetic resonance imaging (MRI) assessment using the Immunotherapy Response Assessment in Neuro-Oncology (iRANO) criteria
    •To assess the immunogenicity of EO2316, EO2317, EO2318, and universal cancer peptide 2 (UCP2) that compose EO2401 by interferon-gamma (IFN-γ) enzyme-linked immunospot (ELISpot), and if needed by intracellular cytokines staining, or multimers staining assays. Cross reactivities with the human tumor associated antigens (TAAs) interleukin 13 receptor alpha-2 (IL-13Rα2), survivin also called baculoviral inhibitor of apoptosis repeat-containing 5 (BIRC5), and forkhead box M1 (FOXM1) will also be tested.
    Los objetivos secundarios son:
    • La evaluación de la supervivencia
    • La evaluación de la progresión del tumor y la respuesta mediante resonancia magnética (RM) usando los criterios de valoración de la respuesta a la inmunoterapia en neurooncología(Immunotherapy Response Assessment in Neuro-Oncology, iRANO)
    • Evaluar la inmunogenicidad de EO2316, EO2317, EO2318 y el péptido contra el cáncer
    universal (UCP2) que componen EO2401 por enzimoinmunoanálisis de adsorción (enzymelinked
    immunospot, ELISpot) del interferón gamma (IFN-γ) y, si es necesario, por tinción de citoquinas intracelulares o análisis de tinción de multímeros. También se analizarán reactividades cruzadas con los antígenos asociados a tumores (AAT) humanos del receptor alfa- 2 de interleucina 13 (IL-13Rα2), survivina, también denominada inhibidor baculoviral de apoptosis con repeticiones 5 (BIRC5), y el forkhead box (dominio de cabeza de tenedor) M1 (FOXM1).
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1.Patients with unequivocal documented (including histological confirmation of GB at the primary diagnosis) evidence of progressive or first recurrent GB on MRI, as defined by RANO criteria
    2.Patients with at least 1 measurable lesion
    3.Patients with an age ≥ 18 years old
    4.Patients who are human leukocyte antigen (HLA)-A2 positive
    5.Patients with an Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2 or Karnofsky performance status ≥ 70
    6.Patients should have received standard therapy, including surgery (biopsy, incomplete or complete resection), radiation, temozolomide, if applicable
    a.Radiation therapy must have been finished 28 days before first study treatment administration
    b.Patients who received temozolomide as adjuvant therapy must have stopped the treatment and have a wash-out period of 28 days before first study treatment administration (6 weeks for nitrosoureas and 5 half lives for experimental therapies)
    c.Patients with unmethylated methylguanine-DNA-methyltransferase (MGMT) promoter can be included even if they have not received temozolomide prior to the inclusion in this clinical study)
    7.Female patients of childbearing potential must have a negative serum pregnancy test within 72 hours prior to dosing
    8.Considering the embryofetal toxicity of the nivolumab shown on animals’ models, the following recommendations for contraception must be followed:
    a.If not surgically sterile, female patients of childbearing potential age must use highly effective barrier contraception from signing the Informed Consent Form (ICF) through 6 months after the last treatment dose administered. Highly effective barrier and non barrier contraception included:
    i.Combined (estrogen and progesterone containing) hormonal contraception associated with inhibition of ovulation:
    Oral
    Intravaginal
    Transdermal
    ii.Progestogen-only hormonal contraception associated with inhibition of ovulation:
    Oral
    Injectable
    Implantable
    iii.Intrauterine device
    iv.Intrauterine hormone-releasing system
    v.Bilateral tubal occlusion
    vi.Sexual abstinence.
    In each case of delayed menstrual period (over 1 month between menstruations), confirmation of absence of pregnancy is strongly recommended. This recommendation also applies to women of childbearing potential with infrequent or irregular menstrual cycles.
    b.If not surgically sterile, male with female partner of childbearing potential must use condom from signing the ICF through 8 months after the last treatment dose administered. Males must ensure that their partners of childbearing potential use highly effective barrier contraception also.
    9.Patients having received the information sheet and who have provided written informed consent prior to any study-related procedures
    10.Patients willing and able to comply with the scheduled visits, treatment plan, laboratory tests, and other study procedures indicated in the protocol.
    Los criterios de inclusión son los siguientes:
    1. Pacientes con indicios de progresión documentada inequívoca (incluida la confirmación
    histológica del GB en el diagnóstico principal) o 1a recurrencia del GB en la RM como se define
    por los criterios iRANO.
    2. Pacientes con al menos una lesión medible.
    3. Pacientes con una edad ≥18 años.
    4. Pacientes positivos para el antígeno leucocitario humano (human leucocyte antigen, HLA) A2.
    5. Pacientes con un estado funcional del Grupo Oncológico Cooperativo del Este (ECOG) ≤2 o
    estado funcional de Karnofsky ≥70.
    6. Los pacientes deben haber recibido tratamiento estándar, incluida la intervención quirúrgica
    (biopsia, resección completa o incompleta), radioterapia y temozolomida, si procede.
    a. La radioterapia debe haber terminado 28 días antes de la primera administración del
    tratamiento del estudio.
    b. Los pacientes que recibieron temozolomida como tratamiento complementario deben haber
    interrumpido el tratamiento y haber pasado por un periodo de reposo farmacológico de 28
    días antes de la primera administración del tratamiento del estudio (6 semanas para
    nitrosoureas y 5 semividas para tratamientos experimentales).
    c. Las pacientes con promotor de metilguanina-ADN-metiltransferasa (MGMT) no metilado
    pueden incluirse aunque no haya recibido temozolomida antes de la inclusión en este estudio
    clínico.
    7. Las pacientes en edad fértil deben tener una prueba de embarazo en suero negativa en las 72
    horas previas a la administración.
    8. Teniendo en cuenta la toxicidad en embriones y fetos del nivolumab mostrada en modelos
    animales, se deben seguir las recomendaciones siguientes para la anticoncepción:
    a. Si no son quirúrgicamente estériles, las pacientes en edad fértil deben utilizar un
    método anticonceptivo de barrera muy eficaz desde la firma del formulario de
    consentimiento informado (FCI) hasta 6 meses después de la última dosis de
    tratamiento administrada. Los anticonceptivos de barrera y distintos de los de barrera
    muy eficaces incluían:
    i. Anticonceptivos hormonales combinados (con estrógenos y progestágenos)
    asociados con la inhibición de la ovulación:
    Orales
    Intravaginales
    Transdérmicos.
    ii. Anticonceptivos hormonales de progestágeno solamente asociados con la
    inhibición de la ovulación:
    Orales
    Inyectables
    Implantables
    iii. Dispositivo intrauterino
    iv. Sistema intrauterino liberador de hormonas
    v. Oclusión tubaria bilateral
    vi. Abstinencia sexual.
    En cada caso de retraso del período menstrual (más de un mes entre menstruaciones) se
    recomienda encarecidamente la confirmación de la ausencia de embarazo. Esta recomendación
    también es aplicable a las mujeres en edad fértil con ciclos menstruales irregulares o
    infrecuentes.
    b. Si no son quirúrgicamente estériles, los pacientes con pareja mujer en edad fértil deben
    utilizar preservativo desde la firma del FCI hasta 8 meses después de la última dosis de
    tratamiento administrada. Los varones deben garantizar que sus parejas en edad fértil
    usen también un método anticonceptivo de barrera muy eficaz.
    9. Pacientes que hayan recibido la hoja de información y que hayan proporcionado su
    consentimiento informado por escrito antes de cualquier procedimiento relacionado con el
    estudio.
    10. Pacientes dispuestos y capaces de cumplir con las visitas programadas, el plan de tratamiento,
    las pruebas analíticas y otros procedimientos indicados en el protocolo.
    E.4Principal exclusion criteria
    1.Patients treated with dexamethasone > 2 mg/day or equivalent (i.e., 13 mg/day of prednisone) within 14 days before the first EO2401 administration, unless required to treat an adverse event (AE)
    Note: The criterion is applicable at the time of screening and also at the time of study treatment start (i.e. the patient should not have received treatment with dexamethasone > 2 mg/day or equivalent in the time between screening and study treatment start; this should be checked at the time of treatment start).
    2.Patients treated with PD(L)-1 immunotherapy, radiotherapy, and cytoreductive therapy within 28 days before the first EO2401 administration
    3.Patients with tumors primarily located in the infra-tentorial segment
    4.Patients with known radiological evidence of extracranial metastases
    5.Patients with presence of new hemorrhage (excluding, stable Grade 1) or uncontrolled seizure
    6.Patients with significant leptomeningeal disease
    7.Patients with abnormal (≥ Grade 2 National Cancer Institute-Common Terminology Criteria for AEs [NCI-CTCAE] version 5.0) laboratory values for hematology, liver, and renal function (serum creatinine).
    8.For patients who are planned to receive bevacizumab:
    a.Patients with nephrotic syndrome
    b.Patients with proteinuria ≥ 2g/24 hours
    c.Patients with history or active gastrointestinal perforation and fistula
    d.Significant surgical procedure in the 4 weeks preceding the start of treatment or planned surgery
    e.Unhealed wound
    f.Patient with recent (4 weeks) history of hemoptysis of ½ teaspoon or more of red blood
    g.Thrombotic episode within 6 months
    h.Uncontrolled diabetes mellitus or hypertension
    i.Posterior reversible encephalopathy syndrome
    9.Patients with persistent Grade 3 or 4 toxicities (according to NCI-CTCAE v5.0). Toxicities must be resolved since at least 2 weeks to Grade 1 or less. However, alopecia or other persisting toxicities Grade ≤ 2 not constituting a safety risk based on Investigator’s judgment is acceptable
    10.Patients with contraindication to contrast-enhanced MRI
    11.Other malignancy or prior malignancy with a disease-free interval of less than 3 years except those treated with surgical intervention and an expected low likelihood of recurrence such as basal cell or squamous cell skin cancer, or carcinoma in situ. Patients with adequately treated basal cell or squamous cell skin cancer, or carcinoma in situ are eligible
    12.Patients with clinically significant cardiac disease, significant medical or psychiatric disease/condition that, in the opinion of the Investigator, would interfere with the evaluation of EO2401 or interpretation of patient safety or study results or that would prohibit the understanding or rendering of informed consent and compliance with the requirements of the protocol
    13.Patients with suspected autoimmune or active autoimmune disorder or known history of an autoimmune neurologic condition (e.g., Guillain-Barré syndrome)
    14.Patients with vitiligo, type I diabetes mellitus, hypothyroidism due to autoimmune condition only requiring hormone replacement therapy, psoriasis not requiring systemic therapy, or conditions not expected to recur in the absence of an external trigger are permitted to enroll
    15.Patients with history of solid organ transplantation or hematopoietic stem cell transplantation
    16.Patients with history or known presence of tuberculosis
    17.Pregnant and breastfeeding patients
    18.Patients with history or presence of human immunodeficiency virus and/or hepatitis B virus/hepatitis C virus
    19.Patients who have received live or attenuated vaccine therapy used for prevention of infectious diseases including seasonal (influenza) vaccinations within 4 weeks of the first dose of study drug
    20.Patients with a history of hypersensitivity to any excipient present in the pharmaceutical form of investigational medicinal product
    21.Patients treated with herbal remedies with immunostimulating properties or known to potentially interfere with major organ function
    22.Patients with known drug and alcohol abuse
    23.Patients with known or underlying medical or psychiatric condition that, in the Investigator’s opinion, would make the administration of study drug hazardous to the patient or obscure the interpretation of toxicity determination or AEs
    24.Patients who have received treatment with any other investigational agent, or participation in another clinical trial within 28 days prior to enrollment and during the treatment period
    25.Patients deprived of their liberty or under protective custody or guardianship.
    1. Pacientes tratados con dexametasona> 2 mg / día o equivalente (es decir, 13 mg / día de prednisona) dentro de los 14 días anteriores a la primera administración de EO2401, a menos que sea necesario para tratar un evento adverso (EA)
    Nota: El criterio es aplicable en el momento de la selección y en el momento del inicio del tratamiento (es decir, el paciente no debería haber recibido tratamiento con dexametasona> 2 mg / día o equivalente en el tiempo entre la selección y el inicio ; ser revisado en el momento del inicio del tratamiento).
    2. Pacientes tratados con PD (L) -1 inmunoterapia, radioterapia y terapia citorreductora dentro de los 28 días anteriores a la primera administración de EO2401
    3. Pacientes con tumores localizados principalmente en el segmento infra-tentorial.
    4. Pacientes con evidencia radiológica conocida de metástasis extracraneales.
    5. Pacientes con presencia de hemorragia nueva (excluyendo, grado estable 1) o convulsiones no controladas
    6. Pacientes con enfermedad leptomeníngea significativa.
    7. Pacientes con valores de laboratorio anormales (≥ Grado 2 del Instituto Nacional del Cáncer y Criterios de Terminología Comunes para EA [NCI-CTCAE] versión 5.0) para hematología, hígado y función renal (creatinina sérica).
    8. Para los pacientes que están planeados para recibir bevacizumab:
    a.Pacientes con síndrome nefrótico
    b.Pacientes con proteinuria ≥ 2g / 24 horas
    Pacientes con historia o perforación gastrointestinal activa y fístula.
    d. Cirugía significativa en las 4 semanas anteriores al inicio o cirugía planificada
    e. Herida no curada
    Paciente con antecedentes recientes (4 semanas) de hemoptisis de ½ cucharadita o más de sangre roja
    Episodio trombótico g. dentro de los 6 meses
    h. Diabetes mellitus no controlada o hipertensión
    Síndrome de encefalopatía reversible posterior.
    9. Pacientes con toxicidades persistentes de Grado 3 o 4 (según NCI-CTCAE v5.0). Las toxicidades deben resolverse desde 2 semanas hasta el grado 1 o menos. Sin embargo, la alopecia u otras toxicidades persistentes de grado ≤ 2 que no constituyan un riesgo de seguridad de acuerdo con el criterio del investigador es aceptable
    10. Pacientes con contraindicación para la RM con contraste
    11.Otros tumores malignos o tumores malignos anteriores con un intervalo libre de enfermedad de menos de 3 años, excepto aquellos tratados con cirugía y una probabilidad de recurrencia baja, como cáncer de piel de células basales o de células escamosas, o carcinoma in situ. Los pacientes con cáncer de piel de células basales o células escamosas adecuadamente tratados o carcinoma in situ son elegibles
    12. Pacientes con enfermedad cardíaca clínicamente significativa, enfermedad / condición médica o psiquiátrica significativa que, en opinión del IP, interferiría con la evaluación de EO2401 o la interpretación de la seguridad del paciente o los resultados del estudio o que prohibiría la comprensión o la prestación de información Consentimiento y cumplimiento de los requisitos del protocolo.
    13. Pacientes con sospecha de un trastorno autoinmune activo o autoinmune o historia conocida de una afección neurológica autoinmune (p.e., síndrome de Guillain-Barré)
    14.Patientes con vitiligo, diabetes mellitus tipo I, hipotiroidismo debido a una afección autoinmune que solo requiere terapia de reemplazo hormonal, psoriasis que no requiere terapia sistémica o afecciones que no se espera que se repitan en ausencia de un activador externo pueden inscribirse
    15. Pacientes con antecedentes de trasplante de órganos sólidos o trasplante de células madre hematopoyéticas
    16. Pacientes con antecedentes o presencia de tuberculosis.
    17. Pacientes embarazadas y lactantes.
    18. Pacientes con antecedentes o presencia de VIH y / o virus de la hepatitis B / virus de la hepatitis C
    19. Pacientes que han recibido una terapia de vacunación viva o atenuada utilizada para la prevención de enfermedades infecciosas, incluidas las vacunas estacionales (influenza) dentro de las 4 semanas posteriores a la primera dosis del medicamento del estudio.
    20. Pacientes con antecedentes de hipersensibilidad a cualquier excipiente presente en la forma farmacéutica del medicamento en investigación.
    21. Pacientes tratados con remedios herbales con propiedades inmunoestimulantes o que se sabe que interfieren con la función importante de los órganos
    22. Pacientes con abuso conocido de drogas y alcohol.
    23. Pacientes con afección médica o psiquiátrica conocida o subyacente que, en opinión del investigador, harían que la administración del fármaco del estudio fuera peligrosa para el paciente u obstaculizaría la interpretación de la determinación de toxicidad o EA.
    24. Pacientes que han recibido tratamiento con cualquier otro agente de investigación o participación en otro ensayo clínico dentro de los 28 días anteriores a la inscripción y durante el período de tratamiento
    25. Pacientes privados de libertad o bajo custodia o tutela protectora.
    E.5 End points
    E.5.1Primary end point(s)
    The primary endpoint includes the incidences of AEs, treatment-emergent AEs (TEAEs), serious AEs (SAEs), deaths, and laboratory abnormalities using the NCI-CTCAE v5.0.
    Safety endpoints will be assessed by review of summaries of AEs (or TEAEs)/SAEs, unless otherwise stated. Adverse events will be categorized by system organ class and preferred term using the current Medical Dictionary for Regulatory Activities version and will be graded according to NCI-CTCAE v5.0.
    El criterio de valoración principal incluye las incidencias de AA, AA surgidos durante el tratamiento
    (AAST), AA graves (AAG), muertes y anomalías analíticas, utilizando los criterios CTCAE del NCI,
    v5.0.
    Los criterios de valoración de la seguridad se evaluarán mediante la revisión de los resúmenes de AA
    (o de los AAST)/AAG, a menos que se indique lo contrario. Los acontecimientos adversos se
    clasificarán por clase de órgano o sistema y término preferido utilizando la versión actual del
    Diccionario médico para actividades reguladoras, y se clasificarán de acuerdo con los CTCAE del NCI,
    v5.0.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Adverse events will be monitored throughout the study. Adverse events will be collected from the time informed consent is signed and continue until 30 days after the last study treatment is administered, until all serious or study treatment-related toxicities have resolved or are determined to be “chronic” or “stable,” completion of the patient’s participation, study termination (e.g., patient lost to follow-up), or the Investigator or designee and Sponsor agree that follow-up is no longer necessary, whichever occurs first.
    Los eventos adversos serán monitoreados durante todo el estudio. Los eventos adversos se recopilarán a partir del momento en que se firme el consentimiento informado y continúen hasta 30 días después de la administración del último tratamiento del estudio, hasta que se hayan resuelto todas las toxicidades graves o relacionadas con el tratamiento del estudio o se haya determinado que sean "crónicas" o "estables". de la participación del paciente, la finalización del estudio (p. ej., paciente perdido durante el seguimiento), o el investigador o su designado y el patrocinador acuerdan que el seguimiento ya no es necesario, lo que ocurra primero.
    E.5.2Secondary end point(s)
    The secondary endpoints are:
    •Overall survival (OS), defined as the time interval from the date of first study treatment administration to the date of death due to any cause
    •The tumor progression and response by MRI measurements every 8 weeks using the iRANO criteria evaluated by:
    o Progression-free Survival (PFS), using the iRANO criteria and defined as the time interval from the date of first study treatment administration to the date of first occurrence of progression or death from any cause, whichever occurs first
    o Objective Response Rate (ORR), defined as the proportion of patients with complete response (CR) and partial response (PR) according to the iRANO criteria
    o Duration of Response (DoR), defined as the time interval from the date of first occurrence of CR or PR to the date of first documentation of disease progression or death from any cause, whichever occurs first.
    •The immunogenicity of EO2316, EO2317, EO2318, and UCP2 that compose EO2401, by IFN γ ELISpot, and if needed by intracellular cytokines staining, or multimers staining assays. Cross reactivities with the human TAAs IL-13Rα2, BIRC5 (survivin), and FOXM1 will also be tested.
    Los criterios de valoración secundarios son:
    • Supervivencia global (SG), definida como el intervalo de tiempo desde la fecha de la primera
    administración del tratamiento del estudio hasta la fecha de la muerte por cualquier causa
    • La progresión del tumor y la respuesta según las mediciones de la lectura central de la RM cada
    8 semanas utilizando los criterios de iRANO, evaluada mediante:
    - La supervivencia sin progresión (SSP), utilizando los criterios de iRANO y definida
    como el intervalo de tiempo desde la fecha de la primera administración del tratamiento
    del estudio hasta la fecha de la primera aparición de progresión o la muerte por
    cualquier causa, lo que ocurra primero
    - La tasa de respuesta global (TRG), definida como la proporción de pacientes con
    respuesta completa (RC) o respuesta parcial (RP) según los criterios de iRANO
    - La duración de la respuesta (DR), definida como el intervalo de tiempo desde la fecha
    de la primera aparición de RC o RP hasta la fecha de la primera documentación de la
    progresión de la enfermedad o la muerte por cualquier causa, lo que ocurra primero.
    • La inmunogenicidad de EO2316, EO2317, EO2318 y UCP2 que componen EO2401 mediante
    ensayos ELISpot de IFN-γ y si es necesario por tinción de citoquinas intracelulares, o análisis
    de tinción de multímeros. También se analizarán reactividades cruzadas con los AAT humanos
    IL-13Rα2, BIRC5 (survivina) y FOXM1.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Please see the above
    Por favor vea texto anterior
    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 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 Yes
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others Yes
    E.6.13.1Other scope of the trial description
    Immunogenicity
    Inmunogenicidad
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) Yes
    E.7.1.1First administration to humans Yes
    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 Yes
    E.8.1.7.1Other trial design description
    Estudio de tres cohortes
    Three-Cohort study
    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 concerned2
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA9
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    France
    Germany
    Spain
    United States
    E.8.7Trial has a data monitoring committee Yes
    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
    Last Visit Last Patient (LVLP)
    Última visita último paciente (LVLP)
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years2
    E.8.9.1In the Member State concerned months1
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years2
    E.8.9.2In all countries concerned by the trial months1
    E.8.9.2In all countries concerned by the trial 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: 16
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 16
    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 state6
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 19
    F.4.2.2In the whole clinical trial 32
    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)
    The investigator will ensure that patients receive appropriate standard of care to treat the condition under the study
    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 Decision2020-01-16
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2019-10-08
    P. End of Trial
    P.End of Trial StatusOngoing
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