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    Summary
    EudraCT Number:2018-000572-15
    Sponsor's Protocol Code Number:GRASPANC-2018-01
    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:2018-06-21
    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 number2018-000572-15
    A.3Full title of the trial
    A Randomized, Phase 3 Study of Eryaspase in Combination with Chemotherapy versus Chemotherapy Alone as Second-Line Treatment in Patients with Pancreatic Adenocarcinoma
    Estudio de fase 3 aleatorizado para evaluar el uso de Eryaspase en combinación con quimioterapia, comparada con quimioterapia sola como tratamiento de segunda línea en pacientes con adenocarcinoma pancreático.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Clinical study in subjects with pancreatic adenocarcinoma to assess safety and efficacy of investigational product (eryaspase) when added to standard chemotherapy
    Ensayo clínico en pacientes con adenocarcinoma pancreático para valorar la seguridad y eficacia de un fármaco en investigación (Eryaspase) cuando se combina con la quimioterapia estándar.
    A.3.2Name or abbreviated title of the trial where available
    TRYbeCA-1– TRial of erYaspase in pancreatic CAncer
    TRYbeCA-1- EsTudio de eRYaspase en CAncer pancreático
    A.4.1Sponsor's protocol code numberGRASPANC-2018-01
    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 SponsorERYTECH Pharma
    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 supportERYTECH Pharma
    B.4.2CountryFrance
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationERYTECH Pharma
    B.5.2Functional name of contact pointIman El-Hariry
    B.5.3 Address:
    B.5.3.1Street Address60 avenue Rockefeller
    B.5.3.2Town/ cityLyon
    B.5.3.3Post code69008
    B.5.3.4CountryFrance
    B.5.4Telephone number34900834223
    B.5.5Fax number33478755629
    B.5.6E-mailRegistroEspanolDeEstudiosClinicos@druginfo.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 Yes
    D.2.5.1Orphan drug designation numberEU/3/09/633
    D.3 Description of the IMP
    D.3.1Product nameEryaspase
    D.3.4Pharmaceutical form Dispersion for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    Unknown use (Noncurrent)
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNL-asparaginase encapsulated in red blood cells
    D.3.9.3Other descriptive nameL-ASPARAGINASE ENCAPSULATED IN RED BLOOD CELLS
    D.3.9.4EV Substance CodeSUB181586
    D.3.10 Strength
    D.3.10.1Concentration unit IU/kg international unit(s)/kilogram
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number100
    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
    Pancreatic Adenocarcinoma
    Adenocarcinoma Pancreático
    E.1.1.1Medical condition in easily understood language
    Pancreatic Adenocarcinoma
    Adenocarcinoma Pancreático
    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 LLT
    E.1.2Classification code 10051971
    E.1.2Term Pancreatic adenocarcinoma
    E.1.2System Organ Class 100000004864
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    The primary objective of this study is to determine whether the addition of eryaspase to chemotherapy improves overall survival (OS) in second-line treatment of pancreatic
    adenocarcinoma compared to chemotherapy alone.
    El objetivo principal del estudio es detmerninar si la adición de Eryaspase a la quimioterapai mejora la tasa general de supervivencia en tratamientos de segunda linea de adenocarcioma pancreático comoparad con quimioterapai sola
    E.2.2Secondary objectives of the trial
    The secondary objectives of this study:
    To compare progression-free survival (PFS) between the 2 treatment arms.
    To compare the objective response rate (ORR) and duration of response (DoR) between the 2 treatment arms. To compare the disease control rate (DCR) between the 2 treatment arms.To evaluate the safety and tolerability of eryaspase in combination with chemotherapy versus chemotherapy alone. To assess the effect of eryaspase on quality of life using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30). To determine the pharmacokinetics of eryaspase. To assess the immunogenicity of eryaspase in terms of the induction of anti-asparaginase antibodies and neutralizing antibodies. To evaluate the relationship of clinical outcome with relevant biomarkers and genetic changes present in tumor tissues and blood and/or serum samples. To investigate the predictive relationship between the patient’s DNA sequence variation.
    Comparar supervivencia libre de progresión (SLP). Comparar tasa respuestas objetivas (TRO) y duración de respuesta (DR) . Comparar tasa control de enfermedad (TCE). Evaluar seguridad y tolerabilidad de eriaspasa combinada con quimioterapia, comparada con quimioterapia sola. Evaluar el efecto de eriaspasa sobre calidad de vida mediante cuestionario QLQ-C30 (Cuestionario calidad de vida 30 apartados (EORTC).Determinar la farmacocinética de Eryaspase. Evaluar inmunogenicidad de eryaspase en la inducción de anticuerpos antiasparraginasa y anticuerpos neutralizantes. Evaluar relación de la evolución clínica con biomarcadores y cambios genéticos en tejidos tumorales y muestras de sangre o suero.Investigar relación predictiva entre variación de secuencia del ácido desoxirribonucleico (ADN), p. ej., genotipificación exploratoria de polimorfismos mononucleotídicos (SNP) en determinados genes y su respuesta al tratamiento combinado en cuanto a seguridad y tolerabilidad (farmacogenética [FG]).
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    A patient will be eligible for the study if all the following criteria are met:
    1. Must be 18 years of age or older.
    2. Must have histologically confirmed pancreatic ductal adenocarcinoma.
    3. Must have Stage III or IV disease (see Appendix 11.1).
    4. Must have received only one line of systemic chemotherapy with or without targeted agents, immunotherapy, or radiotherapy for treatment of advanced pancreatic
    adenocarcinoma.
    5. Must have radiological evidence of disease progression following most recent prior treatment, defined as appearance of any new lesion or increase of >20% of one or more existing lesions.
    6. Must have measurable lesion(s) per RECIST version 1.1 by CT scan with contrast (or MRI, if the patient is allergic to CT contrast media).
    - Measurable disease may be in the field of prior irradiation; however, at least 4 weeks must have elapsed between the completion of radiation therapy and the baseline scan documenting disease status.
    - Bone disease is considered radiologically measurable only if there is at least a 50% lytic component.
    NOTE: Bone disease consisting of blastic lesion only is not measurable.
    7. Archival or fresh tumor tissue must be available for evaluating relevant biomarkers. Formalin-fixed paraffin-embedded [FFPE] block preferred, or a minimum of 10 unstained FFPE slides of one archived block is required. NOTE: cytology samples
    from fine needle aspirates or brushing biopsies are not sufficient.
    8. Must have adequate performance status (see Appendix 11.2):
    - ECOG Performance Status (PS) score of 0, or
    - ECOG score 1 and score ≥80 on Karnofsky Performance Status (KPS) scale.
    9. Must have life expectancy of >12 weeks according to the Investigator’s clinical judgment.
    10. Females of childbearing potential must have a negative pregnancy test at screening and additional pregnancy test prior to first dose. Males and females of childbearing potential must agree to use a highly effective method of contraception during treatment and for at least 6 months after the last dose of study treatment.
    11. Must have adequate laboratory parameters at baseline (obtained <14 days prior to randomization:
    a. Absolute neutrophil count ≥1.5 x 109/L.
    b. Hemoglobin ≥9 g/dL.
    c. Platelet count ≥100,000/mm3 (100 x 109/L).
    d. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5 x upper limit of normal (ULN) (≤5 x ULN in presence of liver metastases).
    e. Total bilirubin ≤1.5 x institutional ULN.
    f. Serum creatinine within normal limits or calculated clearance >60 mL/min/1.73 m2 for patients with serum creatinine levels above or below the
    institutional normal range. Actual body weight should be used for calculating creatinine clearance (e.g., using the Cockcroft-Gault formula). For patients with a
    Body Mass Index (BMI) >30 Kg/m2, lean body weight should be used instead.
    g. Acceptable coagulation parameters: plasma antithrombin III >70%, fibrinogen ≥1.5 g/dL, international normalized ratio (INR) <1.5, and partial thromboplastin
    time (PTT) ≤ institutional ULN.
    h. Serum albumin ≥3.0 g/dL.
    12. Patients requiring biliary stent placement must have the biliary stent placed >7 days prior to screening and must have normalization of bilirubin level after stenting.
    13. Must not be receiving therapy in a concurrent clinical study and must agree not to participate in any other interventional clinical studies during their participation in this trial while on study treatment. Patients taking part in surveys or observational studies are eligible to participate in this study.
    14. Must be able to understand and comply with the conditions of the protocol and must have read and understood the consent form and provided written informed consent.
    Criterios de inclusión:
    Podrán participar en este estudio los pacientes que cumplan todos los criterios siguientes:
    1. Edad mínima de 18 años.
    2. Adenocarcinoma canalicular de páncreas confirmado histológicamente.
    3. Enfermedad en estadio III o IV (véase el apéndice 11.1).
    4. Recepción previa de tan solo una línea de quimioterapia sistémica con o sin fármacos dirigidos, inmunoterapia o radioterapia como tratamiento del adenocarcinoma pancreático avanzado.
    5. Signos radiológicos de progresión de la enfermedad después del tratamiento previo más reciente, definido como la aparición de cualquier lesión nueva o un aumento > 20% de una o más lesiones existentes.
    6. Presencia de lesiones mensurables conforme a los criterios RECIST, versión 1.1, en la TC con contraste (o RM, si el paciente es alérgico a los medios de contraste para TC).
    o La enfermedad mensurable puede encontrarse en el campo de irradiación previa; sin embargo, deberá haber transcurrido un mínimo de cuatro semanas entre la finalización de la radioterapia y el estudio de imagen basal que documente el estado de la enfermedad.
    o La enfermedad ósea solo se considera mensurable desde el punto de vista radiológico si existe un componente lítico del 50%, como mínimo.
    NOTA: La enfermedad ósea consistente exclusivamente en lesiones blásticas no se considera mensurable.
    7. Disponibilidad de tejido tumoral de archivo o reciente para evaluar biomarcadores pertinentes. Se prefiere un bloque fijado en formol e incluido en parafina (FFIP) o un mínimo de 10 extensiones FFIP sin teñir de un bloque archivado. NOTA: Las muestras de citología procedentes de aspirados con aguja fina o de biopsias por cepillado no son suficientes.
    8. Estado funcional adecuado (véase el apéndice 11.2):
    o Puntuación de estado funcional (EF) del ECOG de 0, o
    o Puntuación de estado funcional del ECOG de 1 y puntuación ≥ 80 en la escala de estado funcional de Karnofsky (KPS).
    9. Esperanza de vida superior a 12 semanas según el criterio clínico del investigador.
    10. Las mujeres en edad fértil deberán tener una prueba de embarazo negativa en la fase de selección y otra antes de recibir la primera dosis. Los varones y las mujeres en edad fértil deberán comprometerse a utilizar un método anticonceptivo muy eficaz durante el tratamiento y hasta al menos seis meses después de la última dosis del tratamiento del estudio.
    11. Parámetros analíticos adecuados en el momento basal (obtenidos < 14 días antes de la aleatorización):
    a. Recuento absoluto de neutrófilos ≥ 1,5 x 109/l
    b. Hemoglobina ≥ 9 g/dl.
    c. Recuento de plaquetas ≥ 100.000/mm3 (100 x 109/l).
    d. Aspartato aminotransferasa (AST) y alanina aminotransferasa (ALT) ≤ 2,5 veces el límite superior de la normalidad (LSN) (≤ 5 veces el LSN en presencia de metástasis hepáticas).
    e. Bilirrubina total ≤ 1,5 veces el LSN del centro.
    f. Creatinina sérica dentro de los límites normales o aclaramiento calculado > 60 ml/min/1,73 m2 en pacientes con cifras de creatinina sérica por encima o por debajo del intervalo normal del centro. Se utilizará el peso corporal real para calcular el aclaramiento de creatinina (por ejemplo, con la fórmula de Cockcroft-Gault). En los pacientes con un índice de masa corporal (IMC) > 30 kg/m2 deberá utilizarse en su lugar el peso corporal magro.
    g. Parámetros de coagulación aceptables: antitrombina III en plasma > 70%, fibrinógeno ≥ 1,5 g/dl, índice normalizado internacional (INR) < 1,5 y tiempo de tromboplastina parcial (TTP) ≤ LSN del centro.
    h. Albúmina sérica ≥ 3,0 g/dl.
    12. En los pacientes que requieran la colocación de una endoprótesis biliar, esta deberá colocarse más de 7 días antes de la selección y deberán mostrar una normalización de la concentración de bilirrubina tras la implantación de la endoprótesis.
    13. No estar recibiendo tratamiento en un estudio clínico concurrente y comprometerse a no participar en ningún otro estudio clínico intervencionista durante la participación en este ensayo mientras se reciba el tratamiento del estudio. En este estudio podrán participar pacientes que estén participando en encuestas o estudios observacionales.
    14. Capacidad de comprender y cumplir las condiciones del protocolo, así como haber leído y comprendido el documento de consentimiento y otorgado el consentimiento informado por escrito.
    E.4Principal exclusion criteria
    A patient is not eligible to participate in the study if any of the following criteria are met:
    1. Resectable or borderline resectable pancreatic adenocarcinoma.
    2. Histology other than pancreatic ductal adenocarcinoma (for example, but not inclusive: neuroendocrine, adenosquamous).
    3. More than 1 line of prior treatment in advanced or metastatic setting.
    4. Patient has experienced medically significant acute decline in clinical status including
    a. Decline in ECOG PS to >1 (or KPS <70) between baseline visit and within 72 hours prior to randomization.
    b. Weight loss of ≥10% during screening.
    5. Presence of active or symptomatic untreated central nervous system (CNS) metastases.
    NOTE: Patients with asymptomatic or stable CNS metastases are eligible, provided that the CNS metastases are radiologically and clinically stable, and the patient is off steroids for at least 1 month prior to randomization.
    6. Prior radiotherapy to the only area of measurable disease, unless there is documented disease progression, defined as an increase of at least 1 cm in the longest diameter compared to the nadir scan.
    NOTE: Patients must have completed treatment and recovered from all acute treatmentrelated toxicities prior to administration of the first dose of eryaspase or chemotherapy.
    7. Bone as the only site of metastatic disease from pancreatic cancer (bone-only disease).
    8. History of recent clinical pancreatitis, according to revised Atlanta criteria, within 3 months of randomization.
    NOTE: The revised Atlanta classification [1] requires that two or more of the following criteria be met for the diagnosis of acute pancreatitis: (a) abdominal pain suggestive of
    pancreatitis, (b) serum amylase or lipase level ≥3 x ULN, or (c) characteristic imaging findings using CT or MRI.
    9. Neurosensory neuropathy >Grade 1 at baseline.
    10. Pregnancy or breastfeeding.
    11. History of infection with human immunodeficiency virus (HIV) and/or active infection with hepatitis B or hepatitis C.
    12. Hypersensitivity to any of the components of the chemotherapy or asparaginase.
    NOTE: Patients known to be homozygous for UGT1A1*28 who are assigned to an irinotecan-containing regimen must have the initial irinotecan dose reduced. Subjects whose UGT1A1 status is not known but are being considered for irinotecan-based
    chemotherapy must be screened for UGT1A1*28 allele before enrollment into the trial and must have the initial irinotecan dose reduced if demonstrated to be homozygous for the UGT1A1*28 allele.
    13. Patients being treated with warfarin are not eligible. Warfarin must be replaced with low molecular weight heparin.
    14. History of other malignancies except: adequately treated non-melanoma skin cancer, curatively treated in-situ cancer of the cervix, or other solid tumors curatively treated by
    surgery alone or surgery plus radiotherapy with no evidence of disease for >5 years.
    15. Any other severe acute or chronic condition that may increase the risk of study participation including:
    a. History of abdominal fistula, gastrointestinal perforation, peptic ulcer, or intraabdominal abscess within 6 months prior to randomization.
    b. Current or history within 6 months prior to randomization of medically significant cardiovascular disease including symptomatic congestive heart failure >New York Heart Association (NYHA) Class II, unstable angina pectoris, clinically significant cardiac arrhythmia.
    c. Psychiatric illness/social situations or any other serious uncontrolled medical disorders in the opinion of the Investigator that would limit compliance with study requirements.
    Criterios de exclusión:
    No podrán participar en el estudio los pacientes que cumplan alguno de los criterios siguientes:
    1. Adenocarcinoma pancreático resecable o con resecabilidad limítrofe.
    2. Histología distinta de un adenocarcinoma canalicular de páncreas (por ejemplo: neuroendocrino, adenoepidermoide, etc.).
    3. Más de una línea de tratamiento previo en el contexto avanzado o metastásico.
    4. El paciente ha experimentado un deterioro agudo y médicamente significativo de su estado clínico, lo que comprende:
    a. Deterioro del EF del ECOG a > 1 (o KPS < 70) entre la visita basal y las 72 horas previas a la aleatorización.
    b. Pérdida de peso ≥ 10% durante la selección.
    5. Presencia de metástasis activas o sintomáticas no tratadas en el sistema nervioso central (SNC).
    NOTA: Podrán participar pacientes con metástasis asintomáticas o estables en el SNC, siempre que las metástasis se encuentren radiológica y clínicamente estables y que el paciente no haya recibido esteroides durante al menos un mes antes de la aleatorización.
    6. Radioterapia previa sobre el único área de enfermedad mensurable, a menos que exista progresión documentada de la enfermedad, definida como un aumento en al menos 1 cm del diámetro mayor en comparación con el estudio de imagen nadir.
    NOTA: Los pacientes deberán haber completado el tratamiento y haberse recuperado de todos los efectos tóxicos agudos relacionados con el tratamiento antes de la administración de la primera dosis de Eryaspase o quimioterapia.
    7. Hueso como único foco de enfermedad metastásica del cáncer de páncreas (enfermedad exclusivamente ósea).
    8. Antecedentes de pancreatitis clínica reciente, según los criterios de Atlanta revisados, en los 3 meses previos a la aleatorización.
    NOTA: La clasificación de Atlanta revisada [1] exige que se cumplan dos o más de los criterios siguientes para el diagnóstico de pancreatitis aguda: (a) dolor abdominal indicativo de pancreatitis, (b) concentración sérica de amilasa o lipasa ≥ 3 veces el LSN o (c) signos de imagen característicos mediante TC o RM.
    9. Neuropatía neurosensorial de grado > 1 en el momento basal.
    10. Embarazo o lactancia.
    11. Antecedentes de infección por el virus de la inmunodeficiencia humana (VIH) o infección activa por el virus de la hepatitis B o C.
    12. Hipersensibilidad a cualquiera de los componentes de la quimioterapia o a asparraginasa.
    NOTA: En los pacientes homocigotos para el alelo UGT1A1*28 que sean asignados a una pauta con irinotecán deberá reducirse la dosis inicial de irinotecán. En los pacientes cuyo estado relativo a UGT1A1 sea desconocido, pero en los que se considere la administración de quimioterapia basada en irinotecán, deberá efectuarse un análisis del alelo UGT1A1*28 antes de su inclusión en el ensayo y deberá reducirse la dosis inicial de irinotecán si se demuestra que son homocigotos para dicho alelo.
    13. No podrán participar pacientes tratados con warfarina. La warfarina deberá sustituirse por una heparina de bajo peso molecular.
    14. Antecedentes de otras neoplasias malignas, excepto cáncer de piel distinto del melanoma debidamente tratado, cáncer in situ de cuello uterino tratado con intención curativa u otros tumores sólidos tratados con intención curativa mediante cirugía sola o cirugía más radioterapia sin signos de enfermedad durante más de cinco años.
    15. Cualquier otra enfermedad aguda o crónica grave que pueda aumentar el riesgo de la participación en el estudio, por ejemplo:
    a. Antecedentes de fístula abdominal, perforación gastrointestinal, úlcera péptica o absceso intraabdominal en los seis meses previos a la aleatorización.
    b. Presencia o antecedentes en los seis meses previos a la aleatorización de una enfermedad cardiovascular médicamente significativa, como insuficiencia cardíaca congestiva sintomática en clase > II de la New York Heart Association (NYHA), angina de pecho inestable o arritmia cardíaca clínicamente significativa.
    c. Enfermedad psiquiátrica, situaciones sociales o cualquier otro trastorno médico grave no controlado que, en opinión del investigador, pueda limitar el cumplimiento de los requisitos del estudio.
    E.5 End points
    E.5.1Primary end point(s)
    The primary objective of this study is to determine whether the addition of eryaspase to chemotherapy improves overall survival (OS) in second-line treatment of pancreatic
    adenocarcinoma compared to chemotherapy alone.
    Determinar si la adición de Eryaspase a la quimioterapia mejora la supervivencia global (SG) en el tratamiento de segunda línea del adenocarcinoma pancreático en comparación con la quimioterapia sola.
    E.5.1.1Timepoint(s) of evaluation of this end point
    To be measured from the date of randomization to the date of death from any cause. Patients who are not known to have died will be censored at the date of last contact, and this will apply as of the date of data cut-off for any particular analysis.
    Se medirá desde la fecha de aleatorización del paciente hasta la fecha de muerte por cualquier causa. Los pacientes de los que se desconozca si han muerto, se censarán en la fecha del ultimo contacto y esta fecha se utilizará como fecha de corte para cualquier análisis particular.
    E.5.2Secondary end point(s)
    The secondary objectives of this study are:
    - To compare progression-free survival (PFS) between the 2 treatment arms.
    - To compare the objective response rate (ORR) and duration of response (DoR) between the 2 treatment arms.
    - To compare the disease control rate (DCR) between the 2 treatment arms.
    - To evaluate the safety and tolerability of eryaspase in combination with chemotherapy versus chemotherapy alone.
    - To assess the effect of eryaspase on quality of life using the European Organization for
    Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30).
    - To determine the pharmacokinetics of eryaspase.
    - To assess the immunogenicity of eryaspase in terms of the induction of anti-asparaginase antibodies and neutralizing antibodies.
    - To evaluate the relationship of clinical outcome with relevant biomarkers and genetic changes present in tumor tissues and blood and/or serum samples.
    - To investigate the predictive relationship between the patient’s DNA sequence variation, e.g. exploratory SNP genotyping and their response to combination treatment in terms of safety and tolerability (pharmacogenetics [PGx]).
    • Comparar la supervivencia libre de progresión (SLP) entre los dos grupos de tratamiento.
    • Comparar la tasa de respuestas objetivas (TRO) y la duración de la respuesta (DR) entre los dos grupos de tratamiento.
    • Comparar la tasa de control de la enfermedad (TCE) entre los dos grupos de tratamiento.
    • Evaluar la seguridad y la tolerabilidad de Eryaspase en combinación con quimioterapia en comparación con la quimioterapia sola.
    • Evaluar el efecto de Eryaspase sobre la calidad de vida mediante el cuestionario QLQ-C30 (Cuestionario de calidad de vida-módulo básico de 30 apartados) de la Organización Europea para la Investigación y el Tratamiento del Cáncer (EORTC).
    • Determinar la farmacocinética de Eryaspase.
    • Evaluar la inmunogenicidad de Eryaspase en cuanto a la inducción de anticuerpos antiasparraginasa y anticuerpos neutralizantes.
    • Evaluar la relación de la evolución clínica con biomarcadores pertinentes y cambios genéticos presentes en tejidos tumorales y en muestras de sangre o suero.
    • Investigar la relación predictiva entre la variación de la secuencia del ácido desoxirribonucleico (ADN) del paciente, por ejemplo, genotipificación exploratoria de polimorfismos mononucleotídicos (SNP) en determinados genes candidatos y su respuesta al tratamiento combinado en cuanto a seguridad y tolerabilidad (farmacogenética [FG]).
    E.5.2.1Timepoint(s) of evaluation of this end point
    PFS will be compared between the 2 treatment arms using the same methods of analysis as for OS.
    La supervivencia libre de progresión (SLP) se comparará entre los dos grupos de tratamiento con el mismo método de análisis que en el caso de la SG.
    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 Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic Yes
    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) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled No
    E.8.1.1Randomised Yes
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    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 concerned7
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA100
    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
    Austria
    Belgium
    Czech Republic
    Denmark
    Finland
    France
    Germany
    Italy
    Netherlands
    Spain
    Sweden
    United Kingdom
    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 Patient Last Visit
    la visita del último paciente
    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 months0
    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 months0
    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: 420
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 182
    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 state53
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 416
    F.4.2.2In the whole clinical trial 602
    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 Decision2018-07-19
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2018-07-13
    P. End of Trial
    P.End of Trial StatusOngoing
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