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    Summary
    EudraCT Number:2017-004345-24
    Sponsor's Protocol Code Number:B9991027
    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:2018-09-17
    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 number2017-004345-24
    A.3Full title of the trial
    A PHASE 2, OPEN LABEL STUDY TO EVALUATE SAFETY AND CLINICAL ACTIVITY OF AVELUMAB (BAVENCIO) IN COMBINATION WITH AXITINIB (INLYTA) IN PATIENTS WITH ADVANCED OR METASTATIC PREVIOUSLY TREATED NON-SMALL CELL LUNG CANCER OR TREATMENT NAÏVE CISPLATIN-INELIGIBLE UROTHELIAL CANCER.
    Javelin Medley VEGF
    ESTUDIO ABIERTO EN FASE II PARA EVALUAR LA SEGURIDAD Y LA ACTIVIDAD CLÍNICA DE AVELUMAB (BAVENCIO®) EN COMBINACIÓN CON AXITINIB (INLYTA®) EN PACIENTES CON CÁNCER DE PULMÓN NO MICROCÍTICO AVANZADO O METASTÁSICO TRATADO PREVIAMENTE O CON CÁNCER UROTELIAL NO APTO PARA RECIBIR CISPLATINO SIN TRATAMIENTO PREVIO
    Javelin Medley VEGF
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Safety and clinical activity of avelumab with Axitinib in patients with advanced or metastatic previously treated non small cell lung cancer or urothelial cancer not previously treated who are unable to receive cisplatin.
    Seguridad y actividad clínica de avelumab con Axitinib en pacientes con cáncer, avanzado o metastásico, de pulmón no microcítico, tratado previamente, o urotelial, no tratado previamente y no elegible para recibir cisplatino
    A.3.2Name or abbreviated title of the trial where available
    Javelin Medley VEGF
    A.4.1Sponsor's protocol code numberB9991027
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT03472560
    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 SponsorPfizer Inc. 235 East 42nd Street, New York,NY 10017
    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 supportPfizer Inc.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationPfizer Inc.
    B.5.2Functional name of contact pointClinical Trials.gov Call Centre
    B.5.3 Address:
    B.5.3.1Street Address235 E 42nd Street
    B.5.3.2Town/ cityNew York
    B.5.3.3Post codeNY 10017
    B.5.3.4CountryUnited States
    B.5.4Telephone number+1800718 1021
    B.5.6E-mailClinicalTrials.gov_Inquiries@pfizer.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 Yes
    D.2.1.1.1Trade name Bavencio
    D.2.1.1.2Name of the Marketing Authorisation holderMerck Serono Europe Limited
    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 nameAvelumab
    D.3.2Product code MSB0010718C
    D.3.4Pharmaceutical form Concentrate for solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNAvelumab
    D.3.9.1CAS number 319460-85-0
    D.3.9.2Current sponsor codeMSB0010718C
    D.3.9.3Other descriptive nameMSB0010718C
    D.3.9.4EV Substance CodeSUB176547
    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.IMP: 2
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Inlyta 1mg
    D.2.1.1.2Name of the Marketing Authorisation holderPfizer Limited, Ramsgate Road, Sandwich, Kent, CT13 9NJ
    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 nameAxitinib
    D.3.2Product code AG-013736
    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 INNAXITINIB
    D.3.9.1CAS number 319460-85-0
    D.3.9.2Current sponsor codeAG-013736
    D.3.9.3Other descriptive nameIUPAC: N-methyl-2-[3-((E)-2-pyridin-2-yl-vinyl)-1H-indazol-6-ylsulfanyl]-benzamide
    D.3.9.4EV Substance CodeSUB25427
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number1
    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 RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Inlyta 5 mg
    D.2.1.1.2Name of the Marketing Authorisation holderPfizer Limited, Ramsgate Road, Sandwich, Kent, CT12 9NJ
    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 nameAxitinib
    D.3.2Product code AG-013736
    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 INNAXITINIB
    D.3.9.1CAS number 319460-85-0
    D.3.9.2Current sponsor codeAG-013736
    D.3.9.3Other descriptive nameIUPAC: N-methyl-2-[3-((E)-2-pyridin-2-yl-vinyl)-1H-indazol-6-ylsulfanyl]-benzamide
    D.3.9.4EV Substance CodeSUB25427
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    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 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
    Advanced or Metastatic previously treated non-small cell lung cancer or treatment naïve cisplatin-ineligible urothelial cancer.
    Cáncer, avanzado o metastásico, de pulmón no microcítico, tratado previamente, o urotelial, no tratado previamente y no elegible para recibir cisplatino
    E.1.1.1Medical condition in easily understood language
    Advanced or metastatic previously treated non-small cell lung cancer or treatment naive cisplatin-ineligible urothelial cancer
    Cáncer, avanzado o metastásico, de pulmón no microcítico, tratado previamente, o urotelial, no tratado previamente y no elegible para recibir cisplatino
    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 10061873
    E.1.2Term Non-small cell lung cancer
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10064467
    E.1.2Term Urothelial carcinoma
    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
    To evaluate the Objective Response Rate (ORR) based on Investigator assessment, per Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 of avelumab in combination with axitinib in patients with advanced or metastatic NSCLC who have received at least one prior platinum-containing therapy and in treatment naïve patients with advanced or metastatic UC, who are ineligible for cisplatin-containing chemotherapy for their advanced disease.
    Evaluar la tasa de respuesta objetiva (TRO) a partir de la evaluación del investigador según los criterios de evaluación de la respuesta al tratamiento en tumores sólidos (RECIST) v. 1.1 de avelumab combinado con axitinib en los pacientes con CPNM avanzado o metastásico que anteriormente han recibido al menos un tratamiento con platino, así como en los pacientes sin tratamiento previo con CU avanzado o metastásico que no son aptos para recibir quimioterapia con cisplatino para la enfermedad avanzada
    E.2.2Secondary objectives of the trial
    To evaluate the following in patients with advanced or metastatic NSCLC who have received at least one prior platinum-containing therapy and in treatment naïve patients with advanced or metastatic UC, who are ineligible for cisplatin-containing chemotherapy for their advanced disease:

    -The safety and tolerability of avelumab in combination with axitinib;
    -The anti-tumor activity of avelumab in combination with axitinib;
    -The pharmacokinetics of avelumab and axitinib when administered in combination;
    -Candidate predictive and/or early response biomarkers in pre-treatment tumor tissue and pre-and post-treatment blood samples that may aid in the identification of a patient subpopulation most likely to benefit from treatment with avelumab in combination with axitinib. Assessments may include but are not limited to tumor mutational burden, immune repertoire and PD-L1 expression within the tumor microenvironment;
    -The immunogenicity of avelumab when combined with axitinib.
    Evaluar en pacientes con CPNM avanzado o metastásico q anteriormente han recibido al - un tratamiento con platino, así como en pacientes sin tratamiento previo con CU avanzado o metastásico q no son aptos para recibir QT con cisplatino para la enfermedad avanzada:
    -Seguridad y tolerabilidad de avelumab en combinación con axitinib
    -Actividad antitumoral de avelumab en combinación con axitinib
    -Farmacocinética de avelumab y axitinib cuando se administran combinados
    -Biomarcadores candidatos predictivos o d respuesta temprana en el tejido tumoral anterior al tratamiento y en muestras de sangre anteriores y posteriores al tratamiento que puedan contribuir a la identificación de una subpoblación de pacientes+propensa a beneficiarse del tratamiento con avelumab combinado con axitinib. Las evaluaciones incluirán la carga mutacional tumoral, la gama inmunitaria y la expresión de PD-L1 dentro del microambiente tumoral, entre otras
    -Inmunogenicidad de avelumab cuando se combina con axitinib
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Patients must meet all of the following inclusion criteria to be eligible for enrollment into the study:

    1. Diagnosis:
    a. NSCLC Cohort: Histologically or cytologically confirmed diagnosis of NSCLC that is locally advanced or metastatic:
    -No activating EGFR mutations, Anaplastic lymphoma kinase (ALK) translocations/rearrangements, or c-ros oncogene 1 (ROS1) translocations/rearrangements where testing is standard of care.
    -Have received at least 1 prior platinum-based chemotherapy regimen for locally advanced or metastatic NSCLC.
    -No more than 2 prior lines of systemic therapy for locally advanced or metastatic disease.
    -If disease progression occurred during or within 6 months after neoadjuvant/adjuvant chemotherapy or radiotherapy chemotherapy, the regimen is counted as 1 prior treatment regimen towards the allowed limit of prior treatment regimens.
    -Checkpoint inhibitor naïve.
    b. UC Cohort: Histologically or cytologically confirmed diagnosis of transitional cell carcinoma (TCC) of the urothelium (if mixed, more than 50% TCC component) including bladder, urethra, ureters, or renal pelvis that is locally
    advanced or metastatic:
    -No prior systemic treatment for locally advanced or metastatic disease. Prior neoadjuvant or adjuvant therapy is permitted if disease progression occurred >12 months after the completion of therapy.
    -Checkpoint inhibitor naïve.
    -Ineligible for receiving cisplatin-containing front-line chemotherapy based at least one of the following criteria:
    i. ECOG performance status (PS) 2;
    ii. Renal dysfunction (defined as creatinine-clearance <60 ml/min);
    iii. Grade 2 peripheral neuropathy;
    iv. Grade 2 hearing loss (hearing loss measured by audiometry of 25 decibels at two contiguous frequencies)
    2. Measurable disease by RECIST v1.1 with at least 1 measurable lesion that has not previously been irradiated.
    3. Availability of an archival formalin-fixed and paraffin-embedded (FFPE) tumor tissue block from primary diagnosis specimen or metastatic specimen (if available). If a FFPE tissue block cannot be provided, then 15 unstained slides (10 minimum) will be acceptable. If such an archived sample is not available, a de novo (ie, fresh) tumor sample must be obtained prior to study enrolment.
    4. ECOG PS: 0 or 1. For UC patients, ECOG PS 2 is permitted as part of cisplatin-ineligibility criteria.
    5. Age 18 years.
    6. Estimated life expectancy of at least 90 days.
    7. Adequate hepatic function defined by:
    a. Total serum bilirubin 1.5 × the upper limit of normal range (ULN);
    b. AST and ALT 2.5 × ULN; for subjects with documented metastatic disease to the liver, AST and ALT levels 5 × ULN.
    8. Adequate bone marrow function including:
    a. Absolute Neutrophil Count (ANC) 1,500/mm3 or 1.5 x 109 /L;
    b. Platelets 100,000/mm3 or 100 x 109 /L;
    c. Hemoglobin 9 g/dL (5.6 mmol/L) (may have been transfused).
    9. Adequate renal function defined by:
    a. Estimated creatinine clearance 30 mL/min as calculated using the Cockcroft-Gault (CG) equation.
    b. Urinary protein <2+ by urine dipstick. If dipstick is 2+, then 24-hour urinary protein <2 g per 24 hours.
    10. Left ventricular ejection fraction (LVEF) lower limit of normal (LLN) as assessed by multi-gated acquisition (MUGA) scan or echocardiogram (ECHO).
    11. No evidence of uncontrolled hypertension as documented by 2 baseline blood pressure readings taken at least 1 hour apart. The baseline systolic blood pressure readings must be 140 mm Hg, and the baseline diastolic blood pressure readings must be 90 mm Hg. Patients whose hypertension is controlled by antihypertensive therapies are eligible.
    12. Evidence of a personally signed and dated informed consent document indicating that the patient has been informed of all pertinent aspects of the study.
    13. Willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures.
    14. Female patients of childbearing potential must have negative serum pregnancy or urine pregnancy test at screening. Female patients of non-childbearing potential must meet at least 1 of the following criteria:
    a. Achieved postmenopausal status, defined as follows: cessation of regular menses for at least 12 consecutive months with no alternative pathological or physiological cause; status may be confirmed with a serum follicle-stimulating hormone (FSH) level confirming the postmenopausal state;
    b. Have undergone a documented hysterectomy and/or bilateral oophorectomy;
    c. Have medically confirmed ovarian failure.
    All other female patients (including female patients with tubal ligations) are considered to be of childbearing potential
    1. Diagnóstico:
    a.Cohorte de cáncer de pulmón no microcítico (NSCLC): Diagnóstico de NSCLC confirmado histológica o citológicamente que es localmente avanzado o metastásico:
    - Ausencia de mutaciones de activación del EGFR, de translocaciones/reordenaciones de la cinasa del linfoma anaplásico (ALK) o de translocaciones/reordenaciones del oncogén c-ros 1 (ROS1) si estas pruebas forman parte de la práctica habitual.
    - Haber recibido como mínimo 1 régimen previo de quimioterapia basada en el platino por NSCLC localmente avanzado o metastásico.
    -No más de dos líneas previas de terapia sistémica por enfermedad localmente avanzada o metastásica.
    -Si se hubiera producido la progresión de la enfermedad durante o en el plazo de los 6 meses siguientes a la quimioterapia o radioterapia-quimioterapia neoadyuvantes/adyuvantes, el régimen se considerará como 1 régimen de tratamiento previo a contar en cuanto al límite permitido de regímenes previos de tratamiento.
    -No haber recibido inhibidores de los puntos de control inmunitario.
    b.Cohorte de cáncer urotelial: Diagnóstico de carcinoma de células transicionales (TCC) de urotelio (si es de extirpe mixta, más de un 50% de componentes de TCC) confirmado histológica o citológicamente, incluidos vejiga, uretra, uréteres o pelvis renal, que es localmente avanzado o metastásico:
    -No tratamiento sistémico previo por enfermedad localmente avanzada o metastásica. Se permite el tratamiento neoadyuvante o adyuvante previo si la progresión de la enfermedad se produjo >12 meses después de finalizado dicho tratamiento.
    -No haber recibido inhibidores de los puntos de control inmunitario.
    -No elegible para recibir una quimioterapia de primera línea que contenga cisplatino, por como mínimo uno de los siguientes criterios:
    i.Estado funcional (PS) del ECOG: 2;
    ii.Disfunción renal (definida como aclaramiento de creatinina <60 ml/min);
    iii.Neuropatía periférica de Grado 2;
    iv.Pérdida auditiva de Grado 2 (pérdida auditiva medida mediante audiometría de 25 decibelios en dos frecuencias contiguas)
    2.Enfermedad medible por RECIST v1.1, con como mínimo 1 lesión medible que no haya sido radiada previamente.
    3.Disponibilidad de una muestra de tumor de archivo, fijada en formol e incluida en parafina (FFPE), del tumor primario o de una metástasis (si se dispone de dicha muestra). Si no puede aportarse un bloque de tejido FFPE, se aceptan 15 laminillas sin teñir (como mínimo, 10). Si no se dispone de una muestra de archivo, antes de la inclusión en el estudio debe obtenerse una muestra (fresca) de tumor.
    4.Estado funcional del ECOG: 0 o 1. En los pacientes con cáncer urotelial, se permite un estado funcional del ECOG de 2 (como parte de los criterios de no elegibilidad para el cisplatino).
    5.Edad ≥18 años.
    6.Esperanza de vida de como mínimo 90 días.
    7.Función hepática adecuada:
    a.Bilirrubina total ≤1,5 × límite superior de la normalidad (ULN);
    b.AST y ALT ≤2,5 × ULN; en los sujetos con metástasis hepáticas documentadas se admiten AST y ALT ≤ 5 × ULN.
    8.Función de médula ósea adecuada:
    a.Recuento absoluto de neutrófilos (ANC) ≥1.500/mm3 o ≥1,5 x 109 /L;
    b.Plaquetas ≥100.000/mm3 o ≥100 x 109 /L;
    c.Hemoglobina ≥9 g/dL (≥ 5,6 mmol/L) (se permiten las transfusiones).
    9.Función renal adecuada, definida por:
    a.Aclaramiento de creatinina estimado ≥30 mL/min (mediante la ecuación de Cockcroft-Gault, CG).
    b.Proteínas en orina <2+ mediante tira reactiva. Si el resultado de la tira reactiva es 2+, proteínas en orina de 24 horas <2 g en 24 horas.
    10.Fracción de eyección de ventrículo izquierdo (LVEF) ≥ límite inferior de la normalidad (LLN), determinada mediante ventriculografía isotópica (MUGA) o ecocardiograma (ECHO).
    11.No evidencia de hipertensión no controlada, documentada por dos mediciones de presión arterial en el basal con como mínimo 1 hora de separación. Los valores de la presión arterial basal deben ser: sistólica ≤140 mm Hg y diastólica ≤ 90 mm Hg. Podrán participar los pacientes con hipertensión controlada mediante medicación antihipertensiva.
    12.Disponibilidad del documento de consentimiento informado firmado y fechado personalmente, que evidencia que el paciente ha sido informado de todos los aspectos pertinentes del estudio.
    13.Deseo y capacidad de cumplir con las visitas programadas, el plan de tratamiento, las determinaciones de laboratorio y otros procedimientos del estudio.
    14.En las mujeres potencialmente fértiles, resultado negativo de una prueba de embarazo en suero o en orina en los exámenes de selección.
    Para más detalle referirse al protocolo criterio de inclusion 14.
    E.4Principal exclusion criteria
    Patients with any of the following characteristics/conditions will not be included in the study:
    1. Prior immunotherapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti- CD137, anti-OX-40, anti-glucocorticoid induced tumor necrosis factor (TNF) receptor (GITR), anti-lymphocyte activation gene-3 (LAG-3), anti- T cell immunoglobulin and mucin (TIM-3) domain, or anti-cytotoxic T lymphocyte-associated protein 4 (CTLA-4) antibody (including
    ipilimumab).
    2. Prior treatment with an anti-VEGF pathway TKI; prior use of anti-VEGF pathway mAb is permitted.
    3. Patients with newly diagnosed brain metastases or known symptomatic brain metastases requiring steroids. Patients with previously diagnosed brain metastases are eligible if they have completed their treatment and have recovered from the acute effects of radiation therapy or surgery prior to enrollment, have discontinued corticosteroid treatment for these metastases for at least 14 days prior to study enrollment, and are neurologically stable.
    4. Diagnosis of any other malignancy within 5 years prior to study enrollment. Adequately treated basal cell or squamous cell skin cancer, or carcinoma in situ of the bladder, breast, or cervix, or low grade (Gleason 6) prostate cancer on surveillance without any plans for treatment intervention (eg, surgery, radiation, or castration) are
    allowed.
    5. Radiologically documented evidence of major blood vessel invasion or encasement by cancer (ie, invasion into the fat plane between the vessel wall and tumor) or intratumor cavitation, regardless of tumor histology.
    6. Current use of immunosuppressive medication at the time of study enrollment, EXCEPT for the following: a. intranasal, inhaled, topical steroids, or local steroid injection (eg, intra-articular injection); b. Systemic corticosteroids at physiologic doses 10 mg/day of prednisone or equivalent; c. Steroids as premedication for hypersensitivity
    reactions.
    7. Active autoimmune disease that might deteriorate when receiving an immunostimulatory agent. Patients with diabetes type I, vitiligo, psoriasis, or hypo-or hyperthyroid disease not requiring immunosuppressive treatment are
    eligible.
    8. Prior organ transplantation including allogenic stem-cell transplantation.
    9. Active infection requiring systemic therapy.
    10. Known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome.
    11. Hepatitis B virus (HBV) or hepatitis C virus (HCV) infection at screening (positive HBV surface antigen or HCV RNA if anti-HCV antibody screening test positive).
    12. Administration of a live vaccine within 28 days prior to study enrollment.
    13. Known prior severe hypersensitivity to the investigational products or any component in their formulations, including known severe hypersensitivity reactions to monoclonal antibodies (NCI CTCAE v4.03
    Grade 3).
    14. Persisting toxicity related to prior therapy (NCI CTCAE v4.03 Grade >1); however, alopecia, sensory neuropathy Grade 2, or other Grade 2 AEs not constituting a safety risk based on Investigator's judgment are
    acceptable. For UC patients, Grade 2 peripheral neuropathy is permitted as part of cisplatin-ineligibility criteria.
    15. NCI CTCAE Grade 3 hemorrhage within 28 days prior to study enrollment.
    16. Hemoptysis (1/2 teaspoon of bright red blood episode with cough) within 28 days prior to enrolment.
    17. Evidence of inadequate wound healing.
    18. History of abdominal fistula, gastrointestinal perforation, or intraabdominal abscess within 28 days prior to enrollment.
    19. Any of the following in the previous 6 months prior to study enrollment: deep vein thrombosis or symptomatic pulmonary embolism.
    20. Any of the following within the 12 months prior to study enrollment: myocardial infarction, severe/unstable angina, coronary/peripheral artery bypass graft, symptomatic congestive heart failure, LVEF less than LLN, clinically significant
    pericardial effusion, cerebrovascular accident, transient ischemic attack.
    21. Ongoing cardiac dysrhythmias of NCI CTCAE Grade 2 or prolongation of the QTc interval to >500 msec.
    22. Evidence of tumor involvement of the myocardium or pericardium or tumor thrombus extending to the heart.
    23. Spinal cord compression unless the patient has good pain control attained through therapy, and there is stabilization or recovery of neurological function for the 4 weeks prior to first dose of study drug.
    24. Known history of immune-mediated colitis, inflammatory bowel disease, immune-mediated pneumonitis, pulmonary fibrosis.
    For Exclusion criteria 25 to 33 please see the protocol
    No podrán participar en el estudio los pacientes con cualquiera de las siguientes características/enfermedades:
    1. Inmunoterapia previa con un anticuerpo anti-PD-1, anti-PD-L1, anti-PD-L2, anti- CD137, anti-OX-40, anti-receptor del factor de necrosis tumoral (TNF) inducido por glucocorticoides (GITR), anti-gen de activación linfocitaria 3 (LAG-3), anti- dominio de inmunoglobulina y mucina de células T (TIM-3) o anti-proteína asociada a los linfocitos T citotóxicos 4 (CTLA-4) (incluido el ipilimumab).
    2. Tratamiento previo con un inhibidor de la tirosina cinasa anti-vía del VEGF; se permite el uso previo de anticuerpos monoclonales anti-vía del VEGF.
    3. Pacientes con diagnóstico reciente de metástasis cerebrales o con metástasis cerebrales sintomáticas conocidas que precisan corticosteroides. Se permiten los pacientes con diagnóstico previo de metástasis cerebrales si han finalizado su tratamiento y se han recuperado de los efectos agudos de la radioterapia o de la cirugía antes de su entrada en este estudio, han suspendido los corticosteroides para las metástasis como mínimo 14 días antes de la entrada en este estudio y se encuentran estables neurológicamente.
    4. Diagnóstico de otra neoplasia maligna en el plazo de los 5 años anteriores a la entrada en este estudio. Se permiten el cáncer cutáneo de células basales o escamosas, el carcinoma in situ de vejiga, mama o cuello uterino adecuadamente tratados o el cáncer de próstata de bajo grado (Gleason ≤6) sometido a vigilancia sin planificación de intervención terapéutica (esto es, cirugía, radioterapia o castración).
    5. Evidencia radiológica de invasión o atropamiento de grandes vasos por el tumor (esto es, invasión del plano graso entre la pared del vaso y el tumor) o de cavitación intratumoral, independientemente de la histología del tumor.
    6. Empleo actual de inmunosupresores en el momento de entrada en el estudio, EXCEPTO lo siguiente: a. Corticosteroides intranasales, inhalados, tópicos o en inyección local (por ejemplo, inyección intra-articular); b. Corticosteroides sistémicos a dosis fisiológicas (≤ 10 mg/día de prednisona o equivalente); c. Corticosteroides como premedicación frente a reacciones de hipersensibilidad.
    7. Enfermedad autoinmunitaria activa que pudiera empeorar al recibirse un agente inmunoestimulador.
    8. Transplante de órgano previo, incluido el alotransplante de células madre.
    9. Infección activa que precisa tratamiento sistémico.
    10. Conocimiento de resultado positivo del virus de la inmunodeficiencia humana o del síndrome de inmunodeficiencia adquirida.
    11. Infección por los virus de las hepatitis B (HBV) o C (HCV) en la selección (positividad del antígeno de superficie de la HBV o del RNA del HCV en caso de positividad del anticuerpo anti-HCV en la selección).
    12. Administración de una vacuna con gérmenes vivos en el plazo de los 28 días anteriores a la entrada en el estudio.
    13. Conocimiento de hipersensibilidad severa previa a los medicamentos en investigación o a cualquiera de los componentes de sus formulaciones, incluidas las reacciones de hipersensibilidad severa a anticuerpos monoclonales (Grado ≥ 3 de los NCI CTCAE v4.03).
    14. Persistencia de toxicidad del tratamiento previo (Grado >1 de los NCI CTCAE v4.03); sin embargo, se permiten: alopecia, neuropatía sensitiva de Grado ≤2 u otros acontecimientos adversos de Grado ≤2 que no supongan un riesgo de seguridad en opinión del Investigador. En el caso de los pacientes con cáncer urotelial, se permite la neuropatía periférica de Grado ≥2 (como parte de los criterios de no elegibilidad para el cisplatino)

    15. Hemorragia de Grado ≥3 de los NCI CTCAE en el plazo de los 28 días anteriores a la entrada en el estudio.
    16. Hemoptisis (episodio de expectoración de ≥ 2,5 ml de sangre fresca) en el plazo de los 28 días anteriores a la entrada en el estudio.
    17. Evidencia de cicatrización de heridas inadecuada.
    18. Antecedente de fístula abdominal, perforación gastrointestinal o absceso intraabdominal en el plazo de los 28 días anteriores a la entrada en el estudio.
    19. Cualquiera de lo siguiente en el plazo de los 6 meses anteriores a la entrada en el estudio: trombosis venosa profunda o embolismo pulmonar sintomático.
    20. Cualquiera de lo siguiente en el plazo de los 12 meses anteriores a la entrada en el estudio: infarto de miocardio, angina severa/inestable, cirugía de bypass coronario/ de arterias periféricas, insuficiencia cardiaca congestiva, fracción de eyección de ventrículo izquierdo por debajo del límite inferior de la normalidad, derrame pericárdico clínicamente importante, accidente cerebrovascular, ataque isquémico transitorio.
    21. Arritmia cardiaca actual de Grado ≥2 de los NCI CTCAE o prolongación del intervalo QTc a >500 mseg.
    22. Evidencia de tumor que invade miocardio o pericardio o de trombo tumoral que se extiende al corazón.
    Para el resto de criterios de exclusion refierase al protocolo.
    E.5 End points
    E.5.1Primary end point(s)
    Confirmed Objective Response (OR) based on Investigator assessment per RECIST v1.1
    Confirmada la respuesta objetiva (OR) basada en la evaluación del investigador de acuerdo a los RECIST v1.1
    E.5.1.1Timepoint(s) of evaluation of this end point
    Throughout the study.
    A lo largo del estudio
    E.5.2Secondary end point(s)
    Adverse events (AEs) as characterized by type, severity as graded by National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE] v.4.03, timing, seriousness, and relationship to study treatments;

    Laboratory abnormalities as characterized by type, severity (as graded by NCI CTCAE v.4.03) and timing;

    Time-to-event endpoints including time to tumor response (TTR), duration of response (DR), progression-free survival (PFS) based on Investigator assessment per RECIST v1.1, and overall survival (OS);

    Pharmacokinetic parameters including trough and maximum concentrations (Ctrough, Cmax) of avelumab and axitinib;

    Tumor tissue biomarker status (ie, positive or negative based on, for example, PD-L1 expression and/or quantitation of tumor mutational burden as well as characterization of the immune repertoire in peripheral blood and/or tumor);

    Anti-drug antibody (ADA) titers and neutralizing antibodies (NAb) against avelumab.
    Acontecimientos adversos (AA) caracterizados por tipo, intensidad según la clasificación de los Criterios de terminología común para acontecimientos adversos [CTCAE] del Instituto Nacional del Cáncer (NCI) de EE. UU. versión 4.03, cronología, gravedad y relación con los tratamientos del estudio;

    anomalías de laboratorio caracterizadas por tipo, intensidad (según la clasificación de los CTCAE del NCI versión 4.03) y su cronología;

    criterios de valoración de tiempo hasta el acontecimiento, incluidos el tiempo hasta la respuesta tumoral (TRT), duración de la respuesta (DR), supervivencia sin progresión (SSP) con base en la evaluación del investigador mediante los criterios RECIST versión 1.1. y supervivencia general (SG);

    parámetros farmacocinéticos, incluidas concentraciones mínimas y máximas (Cmín, Cmáx) de avelumab y axitinib;

    estado de los biomarcadores del tejido tumoral (es decir, resultado positivo o negativo con base en, por ejemplo, la expresión de PD-L1 y/o la cuantificación de la carga mutacional tumoral así como la caracterización del repertorio inmunológico en la sangre periférica y/o en el tumor);

    valores de los anticuerpos contra el fármaco (ACF) y anticuerpos neutralizantes (AcN) contra avelumab.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Throughout the study.
    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 No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled No
    E.8.1.1Randomised No
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) Information not present in EudraCT
    E.8.2.2Placebo Information not present in EudraCT
    E.8.2.3Other Information not present in EudraCT
    E.8.2.4Number of treatment arms in the trial1
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned4
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA20
    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
    Hungary
    Italy
    Korea, Republic of
    Poland
    Romania
    Russian Federation
    Spain
    Taiwan
    United States
    E.8.7Trial has a data monitoring committee No
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    Last subject Last visit
    Ultima visita del ultimo paciente
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years1
    E.8.9.1In the Member State concerned months6
    E.8.9.1In the Member State concerned days7
    E.8.9.2In all countries concerned by the trial years2
    E.8.9.2In all countries concerned by the trial months2
    E.8.9.2In all countries concerned by the trial days29
    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: 24
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 56
    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 state8
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 38
    F.4.2.2In the whole clinical trial 80
    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
    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 Decision2018-11-15
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2018-10-25
    P. End of Trial
    P.End of Trial StatusOngoing
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