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    Summary
    EudraCT Number:2017-002567-17
    Sponsor's Protocol Code Number:8951-CL-0301
    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:2018-05-28
    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 number2017-002567-17
    A.3Full title of the trial
    A Phase 3, Global, Multi-Center, Double-Blind, Randomized, Efficacy Study of IMAB362 Plus mFOLFOX6 Compared with Placebo Plus mFOLFOX6 as First-line Treatment of Subjects with Claudin (CLDN)18.2-Positive, HER2-Negative, Locally Advanced Unresectable or Metastatic Gastric or Gastroesophageal Junction (GEJ) Adenocarcinoma
    Estudio de fase 3 internacional, multicéntrico, doble ciego y aleatorizado, de la eficacia de IMAB362 más mFOLFOX6, en comparación con placebo más mFOLFOX6, como tratamiento de primera línea en sujetos con adenocarcinoma gástrico o de la unión gastroesofágica localmente avanzado
    irresecable o metastásico, claudin (CLDN)18.2 positivo y HER2 negativo.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Phase 3, Global, Multi-Center, Double-Blind, Randomized, Efficacy Study of IMAB362 Plus mFOLFOX6 Compared with Placebo Plus mFOLFOX6 as First-line Treatment of Subjects with Claudin (CLDN)18.2-Positive, HER2-Negative, Locally Advanced Unresectable or Metastatic Gastric or Gastroesophageal Junction (GEJ) Adenocarcinoma
    Estudio de fase 3 internacional, multicéntrico, doble ciego y aleatorizado, de la eficacia de IMAB362 más mFOLFOX6, en comparación con placebo más mFOLFOX6, como tratamiento de primera línea en sujetos con adenocarcinoma gástrico o de la unión gastroesofágica localmente avanzado
    irresecable o metastásico, claudin (CLDN)18.2 positivo y HER2 negativo.
    A.3.2Name or abbreviated title of the trial where available
    SPOTLIGHT
    A.4.1Sponsor's protocol code number8951-CL-0301
    A.5.4Other Identifiers
    Name:INDNumber:129598
    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 SponsorAstellas Pharma Global Development, Inc. (APGD)
    B.1.3.4CountryUnited States
    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 supportAstellas Pharma Global Development, Inc. (APGD)
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationAstellas Pharma Europe B.V.
    B.5.2Functional name of contact pointService Desk - Global Clinical Dev.
    B.5.3 Address:
    B.5.3.1Street AddressSylviusweg 62
    B.5.3.2Town/ cityLeiden
    B.5.3.3Post code2333 BE
    B.5.3.4CountryNetherlands
    B.5.4Telephone number+31715455878
    B.5.5Fax number+31715455224
    B.5.6E-mailcontacts@nl.astellas.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/3/10/803
    D.3 Description of the IMP
    D.3.1Product nameIMAB362
    D.3.2Product code IMAB362
    D.3.4Pharmaceutical form Powder for 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 INNZolbetuximab (recommended)
    D.3.9.1CAS number 1496553-00-4
    D.3.9.2Current sponsor codeIMAB362
    D.3.9.3Other descriptive nameIMAB362
    D.3.9.4EV Substance CodeSUB190351
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number20
    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
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboSolution for infusion
    D.8.4Route of administration of the placeboIntravenous use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Claudin (CLDN)18.2-Positive, HER2-Negative, Locally Advanced Unresectable or Metastatic Gastric or Gastroesophageal Junction (GEJ) Adenocarcinoma
    Adenocarcinoma gástrico o de la unión gastroesofágica (GEJ) localmente avanzado irresecable o metastásico, positivo para Claudin (CLDN)18.2 y negativo para el receptor del factor de crecimiento epidérmico humano 2 (HER2)
    E.1.1.1Medical condition in easily understood language
    Metastatic Gastric or Gastroesophageal Junction (GEJ) Adenocarcinoma
    Adenocarcinoma gástrico o de la unión gastroesofágica (GEJ)
    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 10001150
    E.1.2Term Adenocarcinoma gastric
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    to evaluate the efficacy of IMAB362 plus mFOLFOX6 compared with placebo plus mFOLFOX6 (as first-line treatment) as measured by PFS in subjects with Claudin (CLDN)18.2 positive, HER2–negative locally advanced unresectable or metastatic gastric and GEJ adenocarcinoma
    Evaluar la eficacia de IMAB362 más mFOLFOX6 en comparación con placebo más mFOLFOX6 (como tratamiento de primera línea), medida mediante la supervivencia sin progresión (Progression Free Survival, PFS) en sujetos con adenocarcinoma gástrico o de la
    unión gastroesofágica (gastroesophageal junction, GEJ) localmente avanzado irresecable o metastásico, positivo para Claudin (CLDN)18.2 y negativo para el receptor del factor de crecimiento epidérmico humano 2 (HER2)
    E.2.2Secondary objectives of the trial
    -To evaluate efficacy as measured by Overall Survival (OS) as a key secondary objective
    -To evaluate efficacy as measured by Objective Response Rate (ORR)
    -To evaluate efficacy as measured by Duration of Response (DOR)
    -To evaluate safety and tolerability of IMAB362
    -To evaluate health related quality of life (HRQoL) using the parameters as measured by European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30, QLQ-OG25, Global Pain (GP) and the EuroQOL Five Dimensions Questionnaire 5L (EQ5D-5L) questionnaires
    -To evaluate the pharmacokinetics of IMAB362
    -To evaluate the immunogenicity profile of IMAB362
    - Evaluar la eficacia en su medición mediante la supervivencia global (Overall Survival, OS) como objetivo secundario clave
    - Evaluar la eficacia en su medición mediante la tasa de respuesta objetiva (Objective Response Rate, ORR)
    - Evaluar la eficacia en su medición mediante la duración de la respuesta (Duration of Response, DOR)
    - Evaluar la seguridad y la tolerabilidad de IMAB362
    - Evaluar la calidad de vida relacionada con la salud (health related quality of life, HRQoL) en su medición mediante los parámetros de los cuestionarios European Organization for Research y Treatment of Cancer (EORTC) QLQ-C30, QLQ-OG25, Global Pain (GP) y EuroQOL Five Dimensions Questionnaire 5L (EQ5D-5L)
    - Evaluar la farmacocinética de IMAB362
    - Evaluar el perfil de inmunogenia de IMAB362
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    General Criteria:
    1.Institutional Review Board (IRB)/Independent Ethics Committee (IEC) approved written informed consent and privacy language as per national regulations (e.g., HIPAA Authorization for US sites) must be obtained from the subject or legally authorized representative (if applicable) prior to any study-related procedures.
    2.Subject is considered an adult (e.g., ≥ 18 years of age in the US) according to local regulation at the time of signing the informed consent.
    3.Subject agrees not to participate in another interventional study while on study treatment.
    4.Female subject must either:
    Be of non-childbearing potential:
    -postmenopausal (defined as at least 1 year without any menses for which there is no other obvious pathological or physiological cause) prior to Screening, or
    -documented surgically sterile (e.g., hysterectomy, bilateral salpingectomy,
    bilateral oophorectomy)
    Or, if of childbearing potential:
    -agree not to try to become pregnant during the study and for 6 months after the final study treatment administration,
    and, have a negative serum pregnancy test at Screening, (Note: Subjects with elevated serum beta human chorionic gonadotropin (βhCG) and a demonstrated non-pregnant status through additional testing are eligible), and if heterosexually active, agree to consistently use 1 form of highly effective birth control* starting at Screening and throughout the study period and for 6 months after the final study drug administration.
    5.Female subject must agree not to breastfeed starting at Screening and throughout the study period, and for 6 months after the final study treatment administration.
    6.Female subject must not donate ova starting at Screening and throughout the study period, and for 6 months after the final study drug administration.
    7.A sexually active male subject with female partner(s) who are of childbearing potential is eligible if:
    -Agree to use a male condom starting at screening and continue throughout study treatment and for 6 months after the final study drug administration.
    -If he has not had a vasectomy or is not sterile as defined below, his female partner(s) is utilizing 1 form of highly effective birth control starting at Screening and continue throughout study treatment and for 6 months after the he receives his final study drug administration.
    8.Male subject must not donate sperm starting at Screening and throughout the study period and for 6 months after the final study drug administration.
    9.Male subject with a pregnant or breastfeeding partner(s) must agree to remain abstinent or use a condom for the duration of the pregnancy or for the time partner is breastfeeding throughout the study period and for 6 months after the final study drug administration.
    Disease Specific Criteria:
    10.Subject has histologically confirmed diagnosis of Gastric or GEJ adenocarcinoma.
    11.Subject has radiologically confirmed locally advanced unresectable or metastatic disease within 28 days prior to the first dose of study treatment.
    12.Subject has measurable disease according to RECIST 1.1 within 28 days prior to the first dose of study treatment. For subjects with only 1 measurable lesion and prior radiotherapy, the lesion must be outside the field of prior radiotherapy or must have documented progression following radiation therapy.
    13.Subject’s tumor expresses CLDN18.2 in ? 75% of tumor cells demonstrating moderate to strong membranous staining as determined by central IHC testing.
    14.Subject has a HER2-Negative tumor as determined by local or central testing on a gastric or GEJ tumor specimen.
    Physical or Laboratory Findings
    15.Subject has ECOG performance status 0 to 1.
    16.Subject has predicted life expectancy  12 weeks in the opinion of the investigator.
    17.Subject must meet all of the following criteria based on the centrally analyzed laboratory tests within 14 days prior to the first dose of study treatment. In case of multiple laboratory data within this period, the most recent data should be used to determine eligibility.
    -Hemoglobin (Hgb) >= 9 g/dL. NOTE: subject must not have received any growth factor or blood transfusions within 14 days prior to the hematology values obtained at screening. Subjects requiring transfusions to meet eligibility criteria are not eligible.
    -Absolute neutrophil count (ANC) >= 1.5 x 109/L
    -Platelets >=100 x 109/L
    -Albumin >= 2.5 g/dL
    -Total bilirubin < 1.5 x upper limit of normal (ULN)
    -Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 x
    ULN without liver metastases (or ≤ 5 x ULN if liver metastases are present)
    -Either serum creatinine ≤ 1.5 x ULN or estimated glomerular filtration rate ? 45 mL/min/1.73 m2
    -PT/international normalized ratio (INR) and PTT ≤ 1.5 x ULN (except for subjects receiving anticoagulation therapy)
    1. Antes de la práctica de cualquier procedimiento del estudio, deberá obtenerse el C.I. por escrito aprobado por el CEIm, así como el documento de privacidad de acuerdo a las normativas locales.
    2. El sujeto es adulto en el momento de la firma del consentimiento informado.
    3. El sujeto muestra su conformidad en no participar en otro estudio intervencional mientras esté recibiendo el tratamiento (tto) del presente estudio.
    4. Si es mujer: No deberá ser potencialmente fértil, deberá: - estar en posmenopausia (definida como al menos 1 año sin menstruación, para lo que no haya ninguna otra causa patológica o fisiológica evidente) antes de la Selección, o - haber sido sometida a esterilización quirúrgica documentada
    O, si es potencialmente fértil, deberá:
    - mostrar su conformidad en no intentar quedarse embarazada durante el estudio y los 6 meses siguientes a la última administración del tto del estudio, y presentar un resultado negativo en una prueba de embarazo en suero en la Selección (nota: podrán participar las sujetos con niveles elevados en suero de βhCG que demuestren no estar embarazada mediante prueba adicional), y si mantienen actividad heterosexual, mostrar su conformidad en utilizar 1 método anticonceptivo altamente efectivo* a partir de la Selección, durante todo el periodo del estudio y hasta 6 meses después de la última administración del tto del estudio.
    5. Las mujeres deberán mostrar su conformidad en no amamantar a un niño a partir de la Selección, durante el estudio y hasta 6 meses después de la última administración del tto.
    6. Las mujeres no deberán donar óvulos a partir de la Selección, durante el estudio y hasta 6 meses después de la última administración del tto del estudio.
    7. Los varones que mantengan relaciones sexuales con mujeres potencialmente fértiles podrán participar si:
    -Están de acuerdo en utilizar preservativos masculinos a partir de la Selección, durante el tto y hasta 6 meses después de la última administración del tto del estudio.
    - En caso de no haber sido sometidos a vasectomía o esterilizados de acuerdo a la definición que se muestra más adelante, su pareja(s) femenina utiliza 1 método anticonceptivo altamente
    efectivo* a partir de la Selección, durante el tto y hasta 6 meses después de la última administración del tto del estudio.
    8. Los varones no deberán donar semen a partir de la Selección, durante todo el estudio y hasta 6 meses después de la última administración del tto.
    9. Los varones con pareja(s) embarazada o amamantando deberán mostrar su conformidad en practicar la abstinencia sexual o utilizar preservativos a lo largo del embarazo o durante el tiempo que su pareja practique la lactancia natural, durante el estudio y hasta 6 meses después de la última administración del tto.
    10. El sujeto tiene un diagnóstico de adenocarcinoma gástrico o de la unión gastroesofágica histológicamente confirmado.
    11. El sujeto presenta enfermedad localmente avanzada irresecable o metastásica, confirmada radiológicamente, en el plazo de los 28 días anteriores a la primera dosis del tto del estudio.
    12. El sujeto presenta enfermedad medible según RECIST 1.1 en el plazo de los 28 días anteriores a la 1ª dosis del tto del estudio. En los sujetos con solo 1 lesión medible y radioterapia previa, la lesión debe encontrarse fuera del campo de la radioterapia previa o haber presentado progresión documentada tras la radioterapia.
    13. El tumor del sujeto expresa CLDN18.2 en >= 75% de las células tumorales, con tinción de membrana de grado moderado o potente según la prueba de IHC en el laboratorio central.
    14. El sujeto tiene un tumor negativo para HER2, según el estudio del laboratorio local o central en una muestra del tumor gástrico o de la unión gastroesofágica.
    15. El sujeto tiene un estado funcional del ECOG 0 o 1.
    16. El sujeto tiene una esperanza de vida prevista >=12 semanas en opinión del investigador.
    17. El sujeto cumple todos los demás criterios siguientes según pruebas del laboratorio central practicadas en el plazo de los 14 días anteriores a la 1ª dosis del tto del estudio. En caso de pruebas repetidas practicadas en el laboratorio central dentro de dicho periodo, para determinar la elegibilidad se utilizarán los datos más recientes.
    -Hemoglobina (Hgb) >=9 g/dl. NOTA: El sujeto no deberá haber recibido ningún factor de crecimiento o transfusiones de sangre en el plazo de los 14 días anteriores a la obtención de los valores hematológicos de la Selección. No podrán participar los sujetos que precisen transfusiones para cumplir los criterios de elegibilidad.
    - ANC>=1,5x109 /L
    - Plaquetas >=100x109 /L
    - Albúmina >=2,5 g/dl
    - Bilirrubina total <1,5 x límite superior de la normalidad
    - AST y ALT<=2,5 x ULN si no hay metastasis hepáticas (o <=5 x ULN en caso de metástasis hepáticas)
    - Creatinina sérica <=1,5 x ULN o tasa de filtración glomerular estimada>=45 ml/min/1,73 m2
    -PT/INR y PTT<=1,5 x ULN (excepto en los sujetos con tto anticoagulante)
    E.4Principal exclusion criteria
    Prohibited Treatment or Therapies
    1.Subject has received prior systemic chemotherapy for locally advanced unresectable or metastatic gastric or GEJ adenocarcinoma. However, subject may have received either neo-adjuvant or adjuvant chemotherapy as long as it was completed at least 6 months prior to the first dose of study treatment.
    2.Subject has received radiotherapy for locally advanced unresectable or metastatic gastric or GEJ adenocarcinoma unless the radiotherapy was completed within28 days prior to start of study treatment. Subject who received palliative radiotherapy to peripheral bone metastases >=14 days prior to start of study treatment and has recovered from all acute toxicities is allowed.
    3.Subject has received systemic immunosuppressive therapy, including systemic corticosteroids within 14 days prior to first dose of study treatment. Subjects using a physiologic replacement dose of hydrocortisone or its equivalent (defined as up to 30 mg per day of hydrocortisone or up to 10 mg per day of prednisone) are allowed.
    4.Subject has received other investigational agents or devices within 28 days prior to first dose of study treatment.
    Medical History or Concurrent Disease
    5.Subject has prior severe allergic reaction or intolerance to a monoclonal antibody, including humanized or chimeric antibodies.
    6.Subject has known immediate or delayed hypersensitivity, intolerance or contraindication to any component of study treatment.
    7.Subject has prior severe allergic reaction or intolerance to any component of mFOLFOX6.
    8.Subject has known dihydropyrimidine dehydrogenase deficiency.
    9.Subject has gastric outlet syndrome or persistent/recurrent vomiting.
    10.Subject with recent gastric bleeding or symptomatic subjects with proven gastric ulcers that would exclude the subject from participation per investigator judgment.
    11.Subject has a known history of a positive test for human immunodeficiency virus (HIV) infection or known active hepatitis B (positive HBs Ag) or C infection. For subjects who are negative for HBs Ag, but HBc Ab positive, an HB DNA test will be performed and if positive the subject will be excluded. Subjects with positive serology but negative HCV RNA test results are eligible.
    12.Subject has an active autoimmune disease that has required systemic treatment within the past 2 years.
    13.Subject has active infection requiring systemic therapy that has not completely resolved within 14 days prior to start of study treatment.
    14.Subject has significant cardiovascular disease, including:
    -Congestive heart failure (defined as New York Heart Association Class III or IV), myocardial infarction, unstable angina, coronary angioplasty, stenting, coronary artery bypass graft, cerebrovascular accident or hypertensive crisis within 6 months prior to administration of first dose of study drug.
    -History of clinically significant ventricular arrhythmias (i.e., sustained ventricular tachycardia, ventricular fibrillation or Torsades de Pointes);
    -QTc interval > 450 msec
    -Cardiac arrhythmias requiring anti-arrhythmic medications (Subject with rate controlled atrial fibrillation for > 1 month prior to first dose of study drugs are eligible)
    15.Subject has known active central nervous system metastases and/or carcinomatous meningitis.
    16.Subject has known peripheral sensory neuropathy > Grade 1 unless the absence of deep tendon reflexes is the sole neurological abnormality.
    17.Subject has had a major surgical procedure and has not completely recovered within 28 days prior to the start of study treatment.
    18.Subject has psychiatric illness or social situations that would preclude study compliance, per investigator judgment.
    19.Subject has another malignancy for which treatment is required per investigator’s clinical judgment.
    20.Subject has any concurrent disease, infection or comorbid condition that interferes with the ability of the subject to participate in the study, which places the subject at undue risk or complicates the interpretation of data in the opinion of the investigator.
    1. El sujeto ha recibido quimioterapia sistémica previa por adenocarcinoma gástrico o de la union gastroesofágica localmente avanzado irresecable o metastásico. No obstante, el sujeto podrá haber recibido quimioterapia neoadyuvante o adyuvante si se ha completado como mínimo 6 meses antes de la primera dosis del tratamiento del estudio.
    2. El sujeto ha recibido radioterapia por adenocarcinoma gástrico o de la unión gastroesofágica localmente avanzado irresecable o metastásico, salvo si la radioterapia hubiera finalizado como
    mínimo 28 días antes del inicio del tratamiento del estudio. Podrán participar los sujetos que hayan recibido radioterapia paliativa por metástasis óseas periféricas >=14 días antes del inicio tratamiento del estudio y se hayan recuperado de la eventual toxicidad aguda.
    3. El sujeto ha recibido inmunosupresores sistémicos, incluidos corticosteroides sistémicos, en el plazo de los 14 días anteriores a la primera dosis del tratamiento del estudio. Podrán participar los
    sujetos que estén recibiendo dosis de sustitución fisiológicas de hidrocortisona o su equivalente (lo que se define como un máximo de 30 mg al día de hidrocortisona o un máximo de 10 mg al día de prednisona).
    4. El sujeto ha recibido otros agentes o productos sanitarios en fase de investigación en el plazo de los 28 días anteriores a la primera dosis del tratamiento del estudio.
    5. El sujeto ha presentado anteriormente una reacción alérgica o intolerancia severas a un anticuerpo monoclonal, incluidos los anticuerpos humanizados o quiméricos.
    6. El sujeto tiene diagnóstico de hipersensibilidad inmediata o tardía, intolerancia o contraindicación a cualquiera de los componentes del tratamiento del estudio.
    7. El sujeto ha presentado anteriormente una reacción alérgica o intolerancia severas a cualquier componente de mFOLFOX6.
    8. El sujeto tiene diagnóstico de deficiencia de dihidropirimidina deshidrogenasa.
    9. El sujeto tiene un síndrome del tracto de salida gástrico o vómitos persistentes/recurrentes.
    10. El sujeto ha padecido recientemente una hemorragia gástrica o se trata de sujeto sintomático con úlceras gástricas demostradas que, a criterio del investigador, no le permitirían de participar en el
    estudio.
    11. El sujeto tiene un resultado positivo para la infección por el virus de la inmunodeficiencia humana o presenta infección activa conocida por hepatitis B (positividad de HBs Ag) o C. En los sujetos
    negativos para HBs Ag pero positivos para HBc Ab, se practicará un test HB DNA que, si fuera positivo, no permitiría la participación del sujeto. Podrán participar los sujetos con serología positiva pero resultado negativo del test HCV RNA.
    12. El sujeto tiene una enfermedad autoinmunitaria activa que ha precisado tratamiento sistémico en los 2 últimos años.
    13. El sujeto tiene una infección activa que precisa tratamiento sistémico y que no se ha resuelto por completo dentro de los 14 días anteriores al inicio del tratamiento del estudio.
    14. El sujeto tiene una enfermedad cardiovascular importante, tal como:
    - Insuficiencia cardíaca congestiva (definida como Clase III o IV de la New York Heart Association), infarto de miocardio, angina inestable, angioplastia coronaria, colocación de stent, cirugía de bypass coronario, accidente cerebrovascular o crisis hipertensiva, en el plazo
    de los 6 meses anteriores a la primera administración del fármaco del estudio.
    - Antecedente de arritmia ventricular clínicamente importante (por ej., taquicardia ventricular mantenida, fibrilación ventricular o Torsades de Pointes);
    - Intervalo QTc > 450 ms
    - Arritmias cardíacas que precisan medicación antiarrítmica (podrán participar los sujetos con fibrilación auricular controlada durante > 1 mes antes de la primera dosis de los medicamentos del estudio).
    15. El sujeto tiene diagnóstico de metástasis activas en sistema nervioso central y/o meningitis carcinomatosa.
    16. El sujeto tiene diagnóstico de neuropatía sensitiva periférica de Grado > 1, salvo si la única anomalía neurológica fuera la ausencia de reflejos tendinosos profundos.
    17. El sujeto ha sido sometido a una intervención quirúrgica mayor y no se ha recuperado por completo dentro de los 28 días anteriores al inicio del tratamiento del estudio.
    18. El sujeto tiene un trastorno psiquiátrico o una situación social que, en opinión del investigador, obstaculizaría su cumplimiento del estudio.
    19. El sujeto presenta otra neoplasia maligna que, en opinión del investigador, precisa tratamiento.
    20. El sujeto tiene una enfermedad, infección o trastorno concomitantes que, en opinión del investigador, pudiera afectar a su capacidad de participar en el estudio, someterle a un riesgo
    excesivo o complicar la interpretación de los datos.
    E.5 End points
    E.5.1Primary end point(s)
    The primary endpoint is PFS, which is defined as the time from the date of randomization until the date of radiological PD (per Response Evaluation Criteria In Solid Tumors [RECIST] 1.1 by independent review committee [IRC]) or death from any cause, whichever is earliest.
    El criterio de evaluación primario es el PFS, definido como el tiempo transcurrido desde la fecha de aleatorización hasta la fecha de PD
    radiológica (según RECIST 1.1 por el IRC) o la muerte (por cualquier causa), eligiéndose la primera de estas situaciones que tenga lugar
    E.5.1.1Timepoint(s) of evaluation of this end point
    The primary analysis will be performed when the protocol-defined number of PFS events have been observed.
    El análisis primario se realizará cuando se haya observado el número preestablecido de acontecimientos de la PFS definidos en el protocolo
    E.5.2Secondary end point(s)
    The secondary endpoints are:
    -OS, defined as the time from the date of randomization until the date of death from any cause
    -ORR, defined as the proportion of subjects who have a best overall response (BOR) of CR or PR as assessed by IRC per RECIST 1.1
    -DOR, defined as the time from the date of the first response (CR/PR) until the date of PD as assessed by IRC per RECIST 1.1 or date of death from any cause, whichever is earliest
    -Safety and tolerability, as measured by AEs, laboratory test results, vital signs, electrocardiograms (ECGs) and Eastern Cooperative Oncology Group (ECOG) performance status
    -HRQoL, as collected via EORTC QLQ-C30, QLQ-OG25, GP and EQ5D-5L questionnaires
    -Pharmacokinetics of IMAB362, Cmax and Ctrough
    -Immunogenicity of IMAB362 as measured by the frequency of anti-drug antibody (ADA) positive subjects.
    The exploratory endpoints are:
    -TTP, defined as the time from the date of randomization until the date of PD as assessed by IRC per RECIST 1.1.
    -PFS2, defined as the time from the date of randomization until the date of PD (per investigator) following subsequent anti-cancer therapy, death from any cause or start of any other anti-cancer therapy, whichever is earliest.
    -DCR, defined as the proportion of subjects who have a BOR of SD, CR or PR as assessed by IRC per RECIST 1.1.
    -Potential genomic and/or other exploratory biomarkers that may be related to treatment outcome of IMAB362
    -HRU
    Los criterios de evaluación secundarios son:
    - OS, definida como el tiempo transcurrido desde la fecha de aleatorización hasta la fecha de la muerte (por cualquier causa)
    - ORR, definida como el porcentaje de sujetos que alcanzan una mejor respuesta global (best overall response, BOR) de respuesta completa (complete response, CR) o respuesta parcial (partial response, PR) en su evaluación por el IRC según RECIST 1.1
    - DOR, definida como el tiempo transcurrido desde la fecha de la primera respuesta (CR/PR) hasta la fecha de PD en su evaluación por el IRC según RECIST 1.1 o la fecha de la muerte (por cualquier causa), eligiéndose la primera de estas situaciones que tenga lugar
    - Seguridad y tolerabilidad, en su determinación mediante acontecimientos adversos, resultados de laboratorio, constantes vitales, ECG y estado funcional del ECOG
    - HRQoL, en su evaluación mediante los cuestionarios EORTC QLQ-C30, QLQ-OG25, GP y EQ5D-5L
    - Farmacocinética de IMAB362, Cmax y Ctrough
    - Inmunogenia de IMAB362, en su medición mediante la frecuencia de sujetos con positividad de anticuerpos antifármaco (anti-drug antibodies, ADA)
    - TTP, definido como el tiempo transcurrido desde la fecha de aleatorización hasta la fecha de PD en su evaluación por el IRC según RECIST 1.1
    - Supervivencia sin progresión 2 (Progression Free Survival 2, PFS2), definida como el tiempo transcurrido desde la fecha de aleatorización hasta la fecha de PD (según el investigador) después del tratamiento antineoplásico posterior, la muerte (por cualquier causa) o el inicio de otro tratamiento antineoplásico, eligiéndose la primera de estas situaciones que tenga lugar
    - DCR, definida como el porcentaje de sujetos con una BOR de enfermedad estable (stable disease, SD), CR o PR en su evaluación por el IRC según RECIST 1.1
    - Posibles biomarcadores genómicos y/o exploratorios de otro tipo que puedan estar relacionados con el resultado del tratamiento con IMAB362
    - HRU
    E.5.2.1Timepoint(s) of evaluation of this end point
    The secondary endpoint analysis will be performed at the protocol defined primary PFS analysis and at the final OS analysis after 100% of the planned death events have been observed.
    El análisis de los criterios de evaluación secundarios se realizará según definición del analisis primario PFS del protocolo y el análisis final de la OS cuando se hayan observado el 100% de los acontecimientos de fallecimiento previstos.
    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 Yes
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic Yes
    E.6.12Pharmacoeconomic Yes
    E.6.13Others Yes
    E.6.13.1Other scope of the trial description
    Immunogenicity
    Inmunogenia
    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 Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group Yes
    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 Yes
    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 concerned12
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA60
    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
    Australia
    Belgium
    Brazil
    Canada
    Chile
    China
    Colombia
    Costa Rica
    France
    Germany
    Israel
    Italy
    Japan
    Korea, Republic of
    Mexico
    Peru
    Poland
    Spain
    Taiwan
    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
    The end of study in all participating countries is defined as the last subject's last visit, or last contact.
    El final del estudio en todos los paises participantes se define como la ultima visita del ultimo paciente o el ultimo contacto
    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 months1
    E.8.9.1In the Member State concerned days14
    E.8.9.2In all countries concerned by the trial years3
    E.8.9.2In all countries concerned by the trial months8
    E.8.9.2In all countries concerned by the trial days14
    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: 385
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 165
    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 state25
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 156
    F.4.2.2In the whole clinical trial 550
    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)
    After the end of participation in the trial, patients will receive treatment according to current local medical practice.
    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 Decision2018-07-26
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2018-07-24
    P. End of Trial
    P.End of Trial StatusOngoing
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