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    Summary
    EudraCT Number:2015-003693-33
    Sponsor's Protocol Code Number:CDX011-04
    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:2015-11-12
    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 number2015-003693-33
    A.3Full title of the trial
    A Randomized Multicenter Pivotal Study of CDX-011 (CR011-vcMMAE) in Patients with Metastatic, GPNMB Over-Expressing, Triple-Negative Breast Cancer
    Estudio pivotal aleatorizado y multicéntrico de CDX-011 (CR011 vcMMAE) en pacientes con cáncer de mama triple negativo metastásico con sobreexpresión de GPNMB
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Pivotal Study of CDX-011 in Patients with Metastatic, Triple-Negative Breast Cancer (cancer that does not overexpress hormone or HER2 receptors)
    Estudio pivotal de CDX-011 en pacientes con cáncer de mama triple negativo (cáncer que no sobreexpresa receptores hormonales o receptores HER2) metastásico
    A.3.2Name or abbreviated title of the trial where available
    The METRIC Study
    Estudio METRIC
    A.4.1Sponsor's protocol code numberCDX011-04
    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 SponsorCelldex Therapeutics, Inc.
    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 supportCelldex Therapeutics, Inc.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationCelldex Therapeutics, Inc.
    B.5.2Functional name of contact pointDirector of Regulatory Affairs
    B.5.3 Address:
    B.5.3.1Street Address119 Fourth Avenue
    B.5.3.2Town/ cityNeedham, MA
    B.5.3.3Post code02494
    B.5.3.4CountryUnited States
    B.5.4Telephone number+34900834223
    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 No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameCDX-011, Glembatumumab vedotin
    D.3.2Product code CDX-011
    D.3.4Pharmaceutical form Concentrate for solution for injection
    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 INNGlembatumumab Vedotin
    D.3.9.1CAS number 1020264-78-1
    D.3.9.2Current sponsor codeCDX-011
    D.3.9.3Other descriptive nameCR011-vcMMAE, Anti-gpNMB (glycoprotein nonmetastatic melanoma protein B)?vcMMAE (monomethylauristatin E)
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number5
    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: 2
    D.1.2 and D.1.3IMP RoleComparator
    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 Capecitabine
    D.2.1.1.2Name of the Marketing Authorisation holdermedac
    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.3.1Product nameCapecitabine
    D.3.4Pharmaceutical form Film-coated tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNCapecitabine
    D.3.9.1CAS number 154361-50-9
    D.3.9.3Other descriptive nameCAPECITABINE
    D.3.9.4EV Substance CodeSUB12474MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number150
    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: 3
    D.1.2 and D.1.3IMP RoleComparator
    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 Capecitabine
    D.2.1.1.2Name of the Marketing Authorisation holdermedac
    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.3.1Product nameCapecitabine
    D.3.4Pharmaceutical form Film-coated tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNCapecitabine
    D.3.9.1CAS number 154361-50-9
    D.3.9.3Other descriptive nameCAPECITABINE
    D.3.9.4EV Substance CodeSUB12474MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number300
    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: 4
    D.1.2 and D.1.3IMP RoleComparator
    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 Capecitabine
    D.2.1.1.2Name of the Marketing Authorisation holdermedac
    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.3.1Product nameCapecitabine
    D.3.4Pharmaceutical form Film-coated tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNCapecitabine
    D.3.9.1CAS number 154361-50-9
    D.3.9.3Other descriptive nameCAPECITABINE
    D.3.9.4EV Substance CodeSUB12474MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(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.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
    Metastatic, GPNMB Over-Expressing, Triple-Negative Breast Cancer
    Cáncer de mama triple negativo metastásico con sobrexpresión de GPNMB
    E.1.1.1Medical condition in easily understood language
    Triple-Negative Breast Cancer (cancer that does not overexpress hormone (ER or PR) or HER2 receptors)
    Cáncer de mama triple negativo (cáncer que no sobreexpresa receptores hormonales (estrógenos o progesterona) o HER2
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 18.1
    E.1.2Level PT
    E.1.2Classification code 10075566
    E.1.2Term Triple negative breast cancer
    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 the study is to evaluate the anti-cancer activity of CDX-011 in metastatic, GPNMB over-expressing, triple-negative breast cancer as measured by the duration of progression-free survival (PFS).
    El objetivo del estudio es evaluar la actividad antineoplásica de CDX-011 en el cáncer de mama triple negativo metastásico con sobrexpresión de GPNMB, medida mediante la duración de la supervivencia sin progresión (SSP).
    E.2.2Secondary objectives of the trial
    Secondary objectives are:
    -To further assess the anti-cancer activity of CDX-011 in metastatic, GPNMB over-expressing, triple-negative breast cancer, as assessed by the objective response rate (ORR), duration of response (DOR) and overall survival (OS).
    -To further characterize the safety of CDX-011 in metastatic, GPNMB over-expressing, triple-negative breast cancer.
    - To obtain pharmacokinetic parameters and to explore the relationships between patient-specific measures of exposure and safety and activity parameters
    -Evaluar también la actividad antineoplásica de CDX-011 en el cáncer de mama triple negativo metastásico con sobrexpresión de GPNMB según la tasa de respuestas objetivas (TRO), la duración de la respuesta (DR) y la supervivencia global (SG)
    -Caracterizar con más detalle la seguridad de CDX-011 en el cáncer de mama triple negativo metastásico con sobrexpresión de GPNMB
    -Obtener parámetros farmacocinéticos e investigar las relaciones entre las mediciones de la exposición y la seguridad específicas de los pacientes y los parámetros de la actividad
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Patients may be included in the study only if they meet all of the following inclusion criteria at the time of randomization:
    1. Female or male subjects with metastatic, histologically or cytologically confirmed carcinoma of the breast.
    2. Documented progression of disease, based on radiographic, clinical or pathologic assessment showing increased tumor burden or new site(s) of disease during or subsequent to the last anticancer regimen received.
    3. Overexpression of GPNMB (>= 25% of malignant epithelial cells expressing GPNMB, as determined by a central laboratory using IHC methods) in at least one tumor sample obtained in the advanced setting.
    4. Triple-negative status determined in a tumor sample obtained in the advanced setting, according to the following criteria:
    a. Minimal or no expression of estrogen and progesterone receptors (<10% of cells positive by immunohistochemistry (IHC)). Patients with low hormone receptor expression (ER and/or PR 1-9%) must be deemed appropriate candidates for cytotoxic chemotherapy by the investigator.
    b. Minimal or no expression of HER2 (IHC staining of 0 or 1+; ISH single-probe average HER2 copy number < 4.0 signals/cell; or ISH dual-probe HER2/CEP17a ratio < 2.0 with an average HER2 copy number < 4.0 signals/cell). (Wolff, Hammond et al. 2014):
    NOTE: laboratory reports will be required to provide quantitative results of sufficient detail to verify the above eligibility for all patients enrolled.
    5. 0 to 2 prior chemotherapy-containing regimens for advanced breast cancer. For the purpose of this criterion, a regimen is defined as any combination of therapy, including sequential therapy, received before progression.
    6. Prior receipt of anthracycline-containing chemotherapy in any setting, unless anthracycline therapy is not clinically indicated, in the opinion of the treating investigator
    7. Prior receipt of taxane-containing chemotherapy, in any setting
    8. Age >= 18 years
    9. Eastern Cooperative Oncology Group (ECOG) Performance Status 0 to 1 (Appendix 4).
    10. Life expectancy of >= 3 months
    11. Measurable (target) disease by RECIST 1.1 criteria (Eisenhauer, Therasse et al. 2009) (Appendix 3). Target lesions selected for tumor measurements should be those where surgical resection or radiation are not indicated or anticipated.
    12. Resolution of all chemotherapy or radiation-related toxicities <= CTCAE v. 4.0 Grade 1 severity, except for alopecia.
    13. Adequate bone marrow function as assessed by absolute neutrophil count (ANC) >=1500/mm3; hemoglobin >= 9.0 g/dL, and platelet count >= 100,000/mm3.
    14. Adequate renal function as assessed by serum creatinine <= 2.0 mg/dL or calculated creatinine clearance > 40 mL/min per the Cockcroft and Gault formula (Appendix 5).
    15. Adequate liver function as assessed by total bilirubin <= 1.5 x upper limit of normal (ULN), and alanine transaminase (ALT) and aspartate transaminase (AST) <= 3.0 x ULN (<= 5.0 x ULN in the case of liver metastases). Patients with known Gilbert s syndrome may be enrolled with total bilirubin <= 3.0 mg/dL.
    16. Read, understood, and provided written informed consent and, if applicable, HIPAA authorization.
    Únicamente podrán participar en el estudio pacientes que cumplan todos los criterios de inclusión siguientes en el momento de la aleatorización:
    1.Pacientes de ambos sexos con carcinoma de mama metastásico confirmado de manera histológica o citológica.
    2.Progresión documentada de la enfermedad, basándose en una evaluación radiológica, clínica o anatomopatológica que demuestre un aumento de la masa tumoral o nuevas zonas de enfermedad durante o después de la última pauta antineoplásica recibida.
    3.Sobrexpresión de GPNMB (>= 25% de células epiteliales malignas que expresan GPNMB, según lo determinado por un laboratorio central mediante métodos de IHQ) en al menos una muestra tumoral obtenida en la enfermedad avanzada.
    4.Estado triple negativo confirmado en una muestra tumoral obtenida en la enfermedad avanzada, según los criterios siguientes:
    a.Expresión mínima o nula de receptores de estrógenos y progesterona (< 10% de células positivas mediante inmunohistoquímica (IHQ)). El investigador debe considerar candidatos adecuados para quimioterapia citotóxica a los pacientes con escasa expresión de receptores hormonales (RE o RP 1%-9%).
    b.Expresión mínima o nula de HER2 (tinción por IHQ de 0 o 1+; Promedio del número de copias de HER2 con sonda única de ISH < 4,0 señales/célula o cociente HER2/CEP17 con doble sonda de ISH < 2,0 con un promedio de número de copias de HER2 < 4,0 señales/célula). (Wolff, Hammond y cols. 2014)
    NOTA: Se exigirá que los informes de laboratorio proporcionen resultados cuantitativos de suficiente detalle para verificar la elegibilidad de todos los pacientes inscritos.
    5. 0 a 2 pautas de quimioterapia previas para cáncer de mama avanzado. A efectos de este criterio, una pauta se define como cualquier combinación de tratamiento, incluido el tratamiento secuencial, recibida antes de la progresión.
    6.Quimioterapia previa con antraciclinas en cualquier contexto, a menos que este tratamiento no esté indicado clínicamente en opinión del investigador responsable del tratamiento.
    7.Quimioterapia previa con taxanos, en cualquier contexto
    8.Edad >= 18 años.
    9.Estado funcional del Eastern Cooperative Oncology Group (ECOG) de 0 o 1 (Apéndice 4).
    10.Esperanza de vida >=3 meses.
    11.Enfermedad mensurable (diana) según los criterios RECIST 1.1 (Eisenhauer, Therasse y cols. 2009) (Apéndice 3). Las lesiones diana seleccionadas para las mediciones del tumor deben ser aquellas en que no esté indicada o prevista la resección quirúrgica o la radioterapia.
    12.Resolución de todas las toxicidades relacionadas con la quimioterapia o la radioterapia a <= de intensidad de grado 1 de los CTCAE v. 4.0, excepto la alopecia.
    13.Función adecuada de la médula ósea, según un recuento absoluto de neutrófilos (RAN) >= 1500/mm3, una hemoglobina >= 9,0 g/dl y un recuento de plaquetas>= 100.000/mm3.
    14.Función renal adecuada, evaluada según una creatinina sérica <= 2,0 mg/dl o un aclaramiento de creatinina calculado > 40 ml/min conforme a la fórmula de Cockcroft y Gault (Apéndice 5).
    15.Función hepática adecuada, evaluada según una bilirrubina total <= 1,5 x límite superior de la normalidad (LSN) y una alanina aminotransferasa (ALT) y aspartato aminotransferasa (AST) <= 3,0 x LSN (<= 5,0 x LSN si hay metástasis hepáticas). Podrán participar pacientes con síndrome de Gilbert confirmado y una bilirrubina total<=3,0 mg/dl.
    16. Consentimiento informado por escrito leído, entendido y otorgado y, si procede, autorización de la HIPAA.
    E.4Principal exclusion criteria
    Patients will be excluded from the study for any of the following reasons:
    1. Progression/recurrence of breast cancer during or within 3 months of completion of neoadjuvant or adjuvant chemotherapy.
    2. Investigational therapy within four weeks before planned start of study treatment.
    3. Persistent neuropathy > NCI-CTCAE v. 4.0 Grade 1 (at randomization).
    4. History of allergic reactions attributed to compounds of similar composition to dolastatin or auristatin. Compounds of similar composition include Auristatin PHE as an anti-fungal agent, Auristatin PE (TZT-1027, Soblidotin, NSC-654663) as an anti-tumor agent and symplostatin 1 as an anti-tumor agent.
    5. Known hypersensitivity to 5-flourouracil, capecitabine or any of its components.
    6. Known dihydropyrimidine dehydrogenase (DPD) deficiency.
    7. Known brain metastases, unless previously treated and asymptomatic for 2 months and not progressive in size or number for 2 months prior to randomization. Continued use of steroids and/or anticonvulsants (in the absence of any suspicion of progressive brain metastases) is acceptable.
    8. Subjects unable to provide informed consent and/or unable to comply with the study procedures.
    9. Pregnant or breast-feeding women, and women or men who are not willing to use effective contraception during the time from signing of informed consent through two months after the last dose of study treatment. Effective contraception is defined as double barrier contraception (e.g., condom plus spermicide in combination with a female condom, diaphragm, cervical cap, contraceptive sponge or vaginal ring), intra-uterine device (IUD), implants, injectables, combined oral contraceptives, sexual abstinence (total abstinence from sexual intercourse as the preferred lifestyle of the subject; periodic abstinence is not acceptable), or sexual intercourse with only a vasectomized partner. Patients and/or partners who are surgically sterile or postmenopausal are exempt from this requirement.
    10. Previously received capecitabine and discontinued due to progressive disease or intolerance; previously received CDX-011 (CR011-vcMMAE; glematumumab vedotin) or other MMAE-containing agents.
    11. Active systemic infection requiring treatment. Infection controlled by oral therapy will not be exclusionary. Note: microscopic examination of urinalysis is required during screening. If urinary infection is suspected, then a negative urine culture is required prior to enrollment.
    12. Chronic use of systemic corticosteroids above the physiologic dose (5 mg per day prednisone or equivalent) within 7 days of enrollment, except for premedication.
    13. Significant cardiovascular disease including unstable angina pectoris, uncontrolled hypertension, and congestive heart failure (New York Heart Association class 3 or 4), a history of a serious uncontrollable arrhythmia despite treatment, ischemic or severe valvular heart disease, or a myocardial infarction within 6 months prior to the trial entry.
    14. Any underlying medical condition that, in the investigator?s opinion, will make the administration of study treatment (CDX-011 or capecitabine) hazardous to the patient, or would obscure the interpretation of adverse events.
    15. Other malignancy except for adequately treated and cured basal or squamous cell skin cancer, curatively treated in situ disease, or any other cancer from which the patient has been disease-free for >= 5 years.
    Se excluirá del estudio a los pacientes por cualquiera de los motivos siguientes:
    1.Progresión o recidiva del cáncer de mama durante la quimioterapia neoadyuvante o adyuvante o en los 3 meses siguientes.
    2.Tratamiento en investigación en las cuatro semanas previas al inicio previsto del tratamiento del estudio.
    3.Neuropatía persistente > grado 1 de los CTCAE del NCI v. 4.0 (en la aleatorización).
    4.Antecedentes de reacciones alérgicas atribuidas a compuestos de composición similar a dolastatina o auristatina. Los compuestos de composición similar son auristatina PHE como antifúngico, auristatina PE (TZT-1027, Soblidotin, NSC-654663) como antineoplásico y simplostatina 1 como antineoplásico.
    5.Hipersensibilidad conocida a 5-flourouracilo, capecitabina o cualquiera de sus componentes.
    6.Carencia conocida de dihidropirimidina deshidrogenasa (DPD).
    7.Metástasis cerebrales conocidas, a menos que se les haya tratado previamente y no produzcan síntomas durante 2 meses y no aumenten de tamaño o número durante 2 meses antes de la aleatorización. Se admite el uso continuo de esteroides o antipilépticos (si no se sospecha la presencia de metástasis cerebrales progresivas).
    8.Incapacidad para otorgar el consentimiento informado y para cumplir los procedimientos del estudio.
    9.Mujeres embarazadas o lactantes y mujeres o varones que no quieran utilizar una anticoncepción eficaz desde el momento de la firma del consentimiento informado hasta dos meses después de la última dosis del tratamiento del estudio. La anticoncepción eficaz se define como anticoncepción de doble barrera (p. ej., preservativo más espermicida en combinación con preservativo femenino, diafragma, capuchón cervical, esponja anticonceptiva o anillo vaginal), dispositivo intrauterino (DIU), implantes, inyectables, anticonceptivos orales combinados, abstinencia sexual (abstinencia total de relaciones sexuales como modo de vida preferido de la paciente; no es aceptable la abstinencia periódica) o relaciones sexuales solo con una pareja vasectomizada. Están exentas de este requisito las pacientes o parejas que sean quirúrgicamente estériles o posmenopáusicas.
    10.Tratamiento previo con capecitabina suspendido por progresión de la enfermedad o intolerancia; tratamiento previo con CDX-011 (CR011-vcMMAE; glembatumumab vedotina) u otros fármacos con MMAE.
    11.Infección sistémica activa con necesidad de tratamiento. La infección controlada con tratamiento oral no será excluyente. Nota: Se precisa un examen microscópico del análisis de orina durante la selección. Si se sospecha una infección urinaria, es necesario un cultivo de orina negativo antes de la aleatorización.
    12.Uso crónico de corticosteroides sistémicos por encima de la dosis fisiológica (5 mg al día de prednisona o equivalente) en los 7 días previos a la aleatorización, salvo para premedicación.
    13. Enfermedad cardiovascular importante, como angina de pecho inestable, hipertensión no controlada e insuficiencia cardiaca congestiva (clase 3 o 4 de la New York Heart Association), antecedente de arritmia no controlable grave a pesar del tratamiento, cardiopatía valvular isquémica o grave o infarto de miocardio en los 6 meses previos a la inclusión en el ensayo.
    14.Cualquier trastorno médico subyacente que, en opinión del investigador, suponga un peligro al administrar el tratamiento del estudio (CDX-011 o capecitabina) al paciente o dificulte la interpretación de los acontecimientos adversos.
    15. Otra neoplasia maligna, salvo cáncer basocelular o espinocelular de la piel tratado adecuadamente y curado, tumor in situ tratado de forma curativa o cualquier otro cáncer que no haya afectado al paciente durante >= 5 años
    E.5 End points
    E.5.1Primary end point(s)
    Primary end point:
    -Duration of progression-free survival (PFS)
    Objetivo Principal:
    - Duración de la supervivencia sin progresión (SSP).
    E.5.1.1Timepoint(s) of evaluation of this end point
    Under the assumption of exponential distribution for each arm and uniform enrollment over 2 years, and 10% drop out rate (PFS events cannot be observed), 300 patients (200 in the CDX-011 arm and 100 in the capecitabine arm) are needed, and it is anticipated that 203 PFS events will be observed in approximately 26 months from the date the first patient is randomized.
    Bajo la suposición de una distribución exponencial en cada grupo y una inscripción uniforme durante 2 años, así como una tasa de abandonos del 10% (no se pueden observar episodios de SSP), se precisan 300 pacientes (200 en el grupo de CDX-011 y 100 en el grupo de capecitabina), y se prevé que se observarán 203 episodios de SSP en 26 meses aproximadamente desde la fecha de la aleatorización del primer paciente
    E.5.2Secondary end point(s)
    Secondary end points:
    - Objective response rate (ORR)
    - Duration of response (DOR)
    - Overall survival (OS)
    Objetivos secundarios:
    -Tasa de respuestas objetivas (TRO)
    - Duración de la respuesta (DR)
    - Supervivencia global (SG)
    E.5.2.1Timepoint(s) of evaluation of this end point
    Objective response rate (ORR) is defined as the proportion of patients who achieve a best overall response of complete or partial response according to RECIST 1.1. The primary analysis of ORR will be based upon evaluations by the IRC.

    Duration of objective response is defined as the number of months from the time criteria are first met for either CR or PR, until the first date that PD is objectively documented. The duration of objective response will be summarized descriptively using the Kaplan-Meier method.

    Overall survival (OS) is defined as the number of months from randomization to the date of death due to any cause.
    La TRO se define como el porcentaje de pacientes que consigan una respuesta completa o parcial (RC o RP) como mejor respuesta global según los criterios RECIST 1.1. El análisis principal de la TRO se basará en evaluaciones por el CRI.
    La duración de la respuesta objetiva se define como el número de meses desde el momento en que se cumplan por primera vez los criterios para la RC o la RP hasta la primera fecha de documentación objetiva de PE. Se hará un resumen descriptivo de la duración de la respuesta objetiva con el método de Kaplan-Meier.
    La supervivencia global (SG) se define como el número de meses desde la aleatorización hasta la fecha de la muerte por cualquier causa.
    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 No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    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 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) Yes
    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 EEA50
    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
    Canada
    France
    Germany
    Italy
    Spain
    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
    LVLS
    Ultima Visita Ultimo Paciente
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years5
    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 years5
    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: 220
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 80
    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 state20
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 150
    F.4.2.2In the whole clinical trial 300
    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)
    Upon discontinuation of study treatment, patients will be permitted to receive appropriate alternate anti-cancer therapies and will be followed for progression-free survival (if progression is not yet documented) and overall survival.
    Después de la suspensión del tratamiento del estudio, los pacientes podrán recibir adecuadas terapias antineoplásicas alternativas y serán seguidos para evaluar la supervivencia libre de progresión (si la progresión no ha sido todavía documentada) y la supervivencia global.
    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 Decision2016-01-19
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2015-12-04
    P. End of Trial
    P.End of Trial StatusOngoing
    EU Clinical Trials Register Service Desk: https://servicedesk.ema.europa.eu
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