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    Summary
    EudraCT Number:2011-002190-33
    Sponsor's Protocol Code Number:B1131004
    National Competent Authority:Spain - AEMPS
    Clinical Trial Type:EEA CTA
    Trial Status:Prematurely Ended
    Date on which this record was first entered in the EudraCT database:2011-11-17
    Trial results View 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 number2011-002190-33
    A.3Full title of the trial
    A PHASE II TRIAL OF PF-04856884 (CVX-060), A SELECTIVE ANGIOPOIETIN 2 (ANG-2) INHIBITOR IN COMBINATION WITH AG-013736 (AXITINIB) IN PATIENTS WITH PREVIOUSLY TREATED METASTATIC RENAL CELL CARCINOMA
    ENSAYO DE FASE II DE PF 04856884 (CVX-060), UN INHIBIDOR SELECTIVO DE LA ANGIOPOYETINA-2 (ANG-2), EN COMBINACIÓN CON AG 013736 (AXITINIB) EN PACIENTES CON CARCINOMA DE CÉLULAS RENALES METASTÁSICO PREVIAMENTE TRATADO
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A clinical trial of axitinib plus PF-04856884 or axitinib alone for patients with metastatic renal cancer who have already been treated with an anti-VEGF agent.
    ENSAYO DE AXITINIB MAS PF 04856884, O SÓLO AXITINIB PARA PACIENTES CON CARCINOMA DE CÉLULAS RENALES METASTÁSICO PREVIAMENTE TRATADO CON UN AGENTE ANTI-VEGF
    A.4.1Sponsor's protocol code numberB1131004
    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, S.L.U.
    B.1.3.4CountrySpain
    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 Center
    B.5.3 Address:
    B.5.3.1Street Address235 East 42nd Streeat
    B.5.3.2Town/ cityNew York
    B.5.3.3Post codeNY 10017
    B.5.3.4CountryUnited States
    B.5.4Telephone number0018007181021N/A
    B.5.5Fax number0013037391119N/A
    B.5.6E-mailClinicalTrials.govCallCenter@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 No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.2Product code PF-04856884
    D.3.4Pharmaceutical form 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.3.9.2Current sponsor codePF-04856884
    D.3.9.3Other descriptive nameCVX-060
    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 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 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.3.10 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 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 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.3.10 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
    METASTATIC RENAL CELL CARCINOMA
    CARCINOMA DE CÉLULAS RENALES METASTÁSICO
    E.1.1.1Medical condition in easily understood language
    Metastatic kidney cancer
    CANCER RENAL METASTASICO
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 14.0
    E.1.2Level LLT
    E.1.2Classification code 10038407
    E.1.2Term Renal cell 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
    Part I (not applicable in Spain): To confirm that the combination of PF-04856884 and AG-013736 is safe and tolerable at the doses to be used in Part II of the study.
    Part II: To document clinical activity of the combination of PF-04856884 and AG-013736 or AG-013736 alone as measured by PFS in adult patients with previously treated mRCC.
    Parte I I (No aplica España): Confirmar que la combinación de PF 04856884 y AG 013736 es segura y tolerable en las dosis que se utilizarán en la parte II del estudio.
    Parte II: Documentar la actividad clínica de la combinación de PF 04856884 y AG 013736 o AG 013736 en monoterapia en función de la SSP en pacientes adultos con CCRm previamente tratado.
    E.2.2Secondary objectives of the trial
    ? To evaluate the safety and tolerability of the combination of PF-04856884 and AG-013736 and of AG-013736 alone.
    ? To document clinical activity as measured by overall response rate (ORR) and duration of response of the combination of PF-04856884 and AG-013736 and of AG-013736 alone in patients with mRCC.
    ? To assess the pharmacokinetics (PK) of PF-04856884 and of AG-013736.
    ? To evaluate immunogenicity in patients treated with PF-04856884.
    ? To assess pharmacodynamic (PD) effects of the combination of PF-04856884 and AG-013736 and of AG-013736 alone as measured by Ang 1, Ang 2 and VEGF A levels.
    ? Part II: To document clinical activity of the combination of PF-04856884 and AG-013736 or AG-013736 alone as measured by PFS based on an independent radiological assessment.
    ? Part II: To determine overall survival (OS) at two years in patients receiving PF-04856884 in combination with AG-013736 and AG-013736 alone.
    Evaluar la seguridad y la tolerabilidad de la combinación de PF 04856884 y AG013736 y de AG013736 en monoterapia.
    Documentar la actividad clínica medida en función de la tasa de respuesta global (TRG) y la duración de la respuesta de la combinación de PF04856884 y AG013736 y de AG013736 en monoterapia en pacientes con CCRm.
    Evaluar la farmacocinética (FC) de PF04856884 y de AG013736.
    Evaluar la inmunogenia en los pacientes tratados con PF04856884.
    Evaluar los efectos farmacodinámicos (FD) de la combinación de PF 04856884 y AG013736 y de AG013736 en monoterapia en función de las concentraciones de Ang-1, ANG 2 y VEGF-A.
    PII: Documentar la actividad clínica de la combinación de PF 04856884 y AG013736 o AG013736 en monoterapia en función de la SSP conforme a una evaluación radiológica independiente.
    PII: Determinar la supervivencia global (SG) a los dos años en pacientes tratados con PF 04856884 en combinación con AG013736 y en pacientes tratados con AG013736 en monoterapia.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Subject eligibility should be reviewed and documented by an appropriately qualified member of the investigator?s study team before subjects are included in the study.
    ? Evidence of a personally signed and dated informed consent document indicating that the subject (or a legally acceptable representative) has been informed of all pertinent aspects of the study.
    ? Subjects who are willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures.
    Subjects must meet all of the following inclusion criteria to be eligible for enrollment into the study:
    1. Histologically or cytologically confirmed renal cell cancer (RCC) with a component of clear cell subtype and evidence of metastasis.
    2. Evidence of unidimensionally measurable disease (ie, ? malignant tumor mass that can be accurately measured in at least 1 dimension ?20 mm with conventional computerized tomography [CT] scan or magnetic resonance imaging [MRI], or ?10 mm with spiral CT scan using a 5 mm or smaller contiguous reconstruction algorithm).
    3. Prior therapy:
    ? Part I (Not applicable in Spain): Having received 1-3 prior systemic regimens for treatment of mRCC.
    ? Part II: Evidence of disease progression following 1 prior regimen administered as 1st line therapy for mRCC. The prior regimen must have contained one of the following:
    ? VEGFR2 tyrosine kinase inhibitor (TKI) such as (but not limited to) pazopanib, sunitinib, tivozanib, or sorafenib.
    ? Other anti VEGF compounds, such as bevacizumab.
    4. Adequate bone marrow as defined by the following criteria:
    ? Platelets ?75,000 cells/mm3.
    ? Absolute neutrophil count (ANC) ?1500 cells/mm3.
    ? Hemoglobin (Hb) ?9.0 g/dL.
    5. Adequate liver function as defined by the following criteria:
    ? Bilirubin ?1.5 mg/dL.
    ? AST/ALT ?2.5x upper limit of normal (ULN) or ?5.0x ULN with documented liver metastases.
    ? Partial thromboplastin time (PTT) and Prothrombin time (PT) or International Normalized Ration (INR) ?1.5x ULN.
    6. Adequate renal function as defined by:
    ? Serum creatinine ?1.5 mg/dL or calculated or measured creatinine clearance (CrCl) ?50 cc/min using the following formula: Calculated Creatinine Clearance = (140 - age) x wt (kg) x 0.85 (if female) / 72 x serum creatinine (mg/dl).
    7. Urinary dipstick <2+ protein. If ?2+ protein on urine dipstick, then urine protein to creatinine ratio (UPCR) ratio ?0.5 as characterized by spot urine sample.
    8. ECOG performance status 0 or 1.
    9. At least two weeks (prior to Day 1) since end of prior systemic treatment (four weeks for bevacizumab), radiotherapy, or surgical procedure for RCC with resolution of all treatment-related toxicity (except alopecia or hypothyroidism) to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) V. 4.0, Grade ?1 or back to baseline.
    10. Male or female, age ?18 years.
    11. Life expectancy ?12 weeks.
    12. Women of childbearing potential must have a negative serum pregnancy test within 3 days prior to treatment.
    13. Willingness and ability to comply with scheduled visits, treatment plans, laboratory tests and other study procedures, including in Part II the completion of the patient-reported outcome (PRO) measures
    Un miembro debidamente cualificado del equipo del estudio del investigador debe analizar y documentar la elegibilidad de los sujetos antes de su inclusión en el estudio.
    ?Existencia de un documento de consentimiento informado, firmado y fechado personalmente, que indique que se ha informado al sujeto (o a su representante legal) de todos los aspectos pertinentes del estudio.
    ?Sujetos dispuestos a cumplir las visitas programadas, el plan de tratamiento, los análisis clínicos y otros procedimientos del estudio, y capaces de hacerlo.
    Los sujetos deberán cumplir todos los criterios de inclusión siguientes para poder participar en el estudio:
    1.Cáncer de células renales (CCR) confirmado mediante histología o citología con un componente de subtipo de células claras y evidencia de metástasis.
    2. Evidencia de enfermedad mensurable unidimensionalmente (es decir, >=1 masa tumoral maligna que puede medirse de forma exacta en al menos una dimensión con un tamaño >=20 mm mediante tomografía computarizada [TC] convencional o resonancia magnética nuclear [RMN] o con un tamaño >=10 mm con TC helicoidal usando un algoritmo de reconstrucción de bloques contiguos de 5 mm o más pequeños).
    3.Tratamiento previo:
    ?Parte I I (No aplica España): Haber recibido 1-3 tratamientos sistémicos previos para el CCRm.
    ?Parte II: Evidencia de progresión de la enfermedad después de 1 tratamiento previos administrado como tratamiento de primera línea para el CCRm. El tratamiento previo debe haber contenido uno de los siguientes agentes:
    ?Inhibidor de la tirosina-kinasa (ITK) VEGFR2 como (entre otros) pazopanib, sunitinib, tivozanib o sorafenib.
    ?Otros compuestos anti-VEGF, como bevacizumab.
    4.Función adecuada de la médula ósea, conforme a los criterios siguientes:
    ?Recuento de plaquetas >=75.000 células/mm3.
    ?Recuento absoluto de neutrófilos (RAN) >=1.500 células/mm3.
    ?Hemoglobina (Hb) >=9,0 g/dl.
    5.Función hepática adecuada, conforme a los criterios siguientes:
    ?Bilirrubina <=1,5 mg/dl.
    ?AST/ALT <=2,5 x límite superior de la normalidad (LSN) o <=5,0 x LSN con metástasis hepáticas documentadas.
    ?Tiempo de tromboplastina parcial (TTP) y tiempo de protrombina (TP) o cociente internacional normalizado (CIN) <=1,5 x LSN.
    6.Función renal adecuada, conforme a los criterios siguientes:
    ?Creatinina sérica <=1,5 mg/dl o aclaramiento de creatinina (CrCl) calculado o medido >=50 ml/min utilizando la fórmula siguiente: Aclaramiento de creatinina calculado = (140 - edad) x peso (kg) x 0,85 (mujeres)/72 x creatinina sérica (mg/dl).
    7.Tira reactiva en orina con un resultado <2+ para proteínas. Si el resultado de proteínas en la tira reactiva en orina es >=2+, para ser elegible el cociente proteínas: creatinina en orina (CPCO) debe ser <=0,5 determinado en una muestra de orina aleatoria.
    8.Estado funcional del ECOG de 0 o 1 (apéndice 1).
    9.Han transcurrido al menos dos semanas (antes del día 1) desde el final del tratamiento sistémico previo (cuatro semanas para el bevacizumab), la radioterapia previa o la intervención quirúrgica previa para el CCR con resolución de todas las reacciones adversas relacionadas con el tratamiento (salvo alopecia o hipotiroidismo) a un grado <=1 de los criterios terminológicos comunes para acontecimientos adversos (CTCAE, por su nombre en inglés), v. 4.0, del National Cancer Institute (NCI) o a su valor basal.
    10.Varones o mujeres >=18 años.
    11.Esperanza de vida >=12 semanas.
    12.Las mujeres con capacidad reproductiva deberán tener un resultado negativo en una prueba de embarazo en suero en los tres días anteriores al tratamiento.
    13.Disposición y capacidad para cumplir las visitas programadas, los planes de tratamiento, las pruebas analíticas y otros procedimientos del estudio, entre ellos, la determinación de los resultados comunicados por los pacientes (RCPP) en la parte II.
    E.4Principal exclusion criteria
    Subjects presenting with any of the following will not be included in the study:
    1. Subjects who are investigational site staff members or subjects who are Pfizer employees directly involved in the conduct of the trial.
    2. Prior therapy:
    ? Part I (No applicable in Spain)
    ? Intolerant to prior AG-013736 therapy.
    ? Prior treatment with compounds which contain the core platform antibody as PF-04856884. These include CVX-045, CVX-096, and CVX-241.
    ? Part II
    ? Prior AG-013736 therapy.
    ? More than one systemic first-line regimen for the treatment of mRCC.
    ? Prior treatment with compounds which contain the core platform antibody as PF-04856884. These include CVX-045, CVX-096, and CVX-241.
    3. Major surgery <4 weeks or radiation therapy <2 weeks prior to start of therapy.
    4. Clinically significant gastrointestinal abnormalities including any of the following:
    ? Inability to take oral medications.
    ? Requiring intravenous alimentation.
    ? Malabsorption syndromes.
    ? Requiring treatment of active ulcer disease in prior six months.
    ? Prior gastric resection.
    ? Active gastrointestinal bleeding, related or unrelated to cancer, as evidenced by either hematemesis, hematochezia, or melena in prior 3 months.
    5. Current use or anticipated need for drugs that are known potent CYP3A4 inhibitors (ie, grapefruit juice, verapamil, ketoconazole, miconazole, itraconazole, erythromycin, clarithromycin, ergot derivatives, indinavir, saquinavir, ritonavir, nelfinavir, lopinavir, and delavirdine) during the course of the study.
    6. Current use or anticipated need for drugs that are known CYP3A4 or CYP1A2 inducers (ie, carbamazapine, dexamethasone, felbamate, omeprazole, Phenobarbital, phenytoin, primidone, rifabutin, rifampin, and St. John?s wort) during the course of the study.
    7. Requirement for therapeutic anticoagulant therapy including daily aspirin (>325 mg/day) or non steroidal anti inflammatory agents known to inhibit platelet function. Low dose anti coagulants such as low dose heparin or 1-2 mg/day of warfarin for prevention of deep vein thrombosis or maintenance of patency of central venous devices is permitted.
    8. Active seizure disorder or evidence of brain metastases, spinal cord compression, or carcinomatous meningitis.
    ? Patients with clinical evidence suggestive of new brain metastases are excluded if brain metastases have not been ruled out using CT or MRI imaging.
    ? Patients with previously diagnosed brain metastases are eligible if they have completed their radiation therapy to the central nervous system (CNS) and have recovered from the acute effects of that treatment prior to enrollment, have discontinued corticosteroid treatment for these metastases for at least 2 weeks, and are neurologically stable.
    9. History of bleeding diathesis or coagulopathy.
    10. NCI CTCAE Grade 3 or greater hemorrhage from any cause <4 weeks prior to screening.
    11. Hemoptysis >½ teaspoon of blood per day within 2 weeks prior to screening.
    12. History of allergic or anaphylactic reaction to any therapeutic or diagnostic monoclonal antibody or IgG fusion protein.
    13. Any of the following in the preceding 12 months to receiving study drug: myocardial infarction, uncontrolled angina, coronary/peripheral artery bypass graft, symptomatic congestive heart failure, cerebrovascular accident or transient ischemic attack. Deep vein thrombosis or pulmonary embolism in the preceding six months to receiving study drug.
    14. Evidence of pre-existing uncontrolled hypertension as documented by 2 baseline blood pressure readings taken at least 1 hour apart. The baseline systolic blood pressure must be ?140 mm Hg, and baseline diastolic blood pressure must be ?90 mm Hg. Patients whose hypertension is controlled by medications are eligible.
    15. Known human immunodeficiency virus (HIV) seropositivity.
    16. Female patients who are pregnant or lactating, or men or women of reproductive potential not willing or not able to employ effective method of birth control/contraception to prevent pregnancy during treatment and for six months after discontinuing study therapy.
    17. Participation in other studies within 14 days prior to screening and/or during study participation.
    18. Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the subject inappropriate for entry into this study.
    1.Sujetos que sean miembros del personal del centro de investigación o empleados de Pfizer directamente implicados en la realización del ensayo.
    2.Tratamiento previo:
    ?Parte I (No aplica en España)
    ?Intolerancia al tratamiento previo con AG-013736.
    ?Tratamiento previo con compuestos que contengan el anticuerpo de plataforma principal como PF-04856884. Entre ellos se encuentran CVX 045, CVX-096 y CVX-241.
    ?Parte II
    ?Tratamiento previo con AG-013736.
    ?Más de un tratamiento sistémico de primera línea para el CCRm.
    ?Tratamiento previo con compuestos que contengan el anticuerpo de plataforma principal como PF-04856884. Entre ellos se encuentran CVX 045, CVX-096 y CVX-241.
    3.Cirugía mayor <4 semanas o radioterapia <2 semanas antes del día 1.
    4.Anomalías digestivas clínicamente significativas tales como:
    ?Imposibilidad de tomar medicamentos por vía oral.
    ?Necesidad de nutrición intravenosa.
    ?Síndromes de malabsorción.
    ?Necesidad de tratamiento por enfermedad ulcerosa activa en los seis meses anteriores.
    ?Resección gástrica previa.
    ?Hemorragia digestiva activa, relacionada o no con el cáncer, demostrada por hematemesis, hematoquecia o melena, en los tres meses anteriores.
    5.Uso actual o necesidad prevista de fármacos que son potentes inhibidores de la enzima CYP3A4 (p. ej., zumo de pomelo, verapamilo, ketoconazol, miconazol, itraconazol, eritromicina, claritromicina, derivados ergotamínicos, indinavir, saquinavir, ritonavir, nelfinavir, lopinavir y delavirdina) durante el curso del estudio.
    6.Uso actual o necesidad prevista de fármacos que son inductores de las enzimas CYP3A4 o CYP1A2 (p. ej., carbamazepina, dexametasona, felbamato, omeprazol, fenobarbital, fenitoína, primidona, rifabutina, rifampicina e hipérico) durante el curso del estudio.
    7.Necesidad de tratamiento anticoagulante terapéutico, tal como tratamiento diario con ácido acetilsalicílico (> 325 mg/día) o antiinflamatorios no esteroideos que inhiben la función plaquetaria. Se permite el uso de anticoagulantes en dosis bajas, tal como heparina en dosis bajas o 1-2 mg/día de warfarina para la prevención de la trombosis venosa profunda o el mantenimiento de la permeabilidad de los dispositivos venosos centrales.
    8.Trastorno convulsivo activo o evidencia de metástasis cerebrales, compresión de la médula espinal o meningitis carcinomatosa.
    ?Se excluye a los pacientes con signos clínicos indicativos de metástasis cerebrales nuevas, si no se ha descartado la presencia de metástasis cerebrales mediante TC o RMN.
    ?Los pacientes con metástasis cerebrales diagnosticadas previamente son elegibles si han completado la radioterapia del SNC y se han recuperado de los efectos agudos del tratamiento antes del reclutamiento en el estudio, han interrumpido el tratamiento con corticosteroides para estas metástasis durante al menos 2 semanas y están neurológicamente estables.
    9.Antecedentes de diátesis hemorrágica o coagulopatía.
    10.Hemorragia de grado >=3 conforme a los CTCAE del NCI por cualquier causa <4 semanas antes de la selección.
    11.Hemoptisis > ½ cucharadita de sangre al día en las dos semanas previas a la selección.
    12.Antecedentes de reacción alérgica o anafiláctica a un anticuerpo monoclonal terapéutico o diagnóstico o a una proteína de fusión basada en IgG.
    13.Cualquiera de los trastornos siguientes en los 12 meses previos a la administración del tratamiento del estudio: infarto de miocardio, angina no controlada, injerto de derivación de arterias coronarias o periféricas, insuficiencia cardíaca congestiva sintomática, accidente cerebrovascular o accidente isquémico transitorio. Trombosis venosa profunda o embolia pulmonar en los seis meses anteriores a la administración del tratamiento del estudio.
    14.Signos de hipertensión no controlada preexistente, documentada por dos mediciones basales de la presión arterial tomadas con una separación de al menos 1 hora. La presión arterial sistólica basal debe ser <=140 mm Hg y la presión arterial diastólica basal debe ser <=90 mm Hg. Son elegibles los pacientes cuya hipertensión está controlada con tratamiento farmacológico.
    15.Seropositividad conocida para el virus de la inmunodeficiencia humana (VIH).
    16.Mujeres embarazadas o lactantes, o varones y mujeres con capacidad reproductiva que no sean capaces o no estén dispuestos a emplear métodos anticonceptivos eficaces para evitar el embarazo durante el tratamiento del estudio y durante los seis meses posteriores a su conclusión.
    17.Participación en cualquier otro estudio en los 14 días previos a la selección y/ o durante la participación en el estudio.
    18.Otro proceso médico o psiquiátrico agudo o crónico grave o anomalía analítica que pueda aumentar el riesgo asociado a la participación en el estudio o a la administración del producto en investigación o que pueda interferir en la interpretación de los resultados del estudio y que, en opinión del investigador, haga inadecuada la inclusión del sujeto en este estudio.
    E.5 End points
    E.5.1Primary end point(s)
    Part I (Not applicable in Spain):The highest dose level at which first cycle dose limiting toxicities (DLTs) occur in <33% of patients.
    Part II: Median progression free survival (PFS) based on investigator assessments.
    ?Parte I (No aplica en España): El nivel de dosis más alto en el que se producen reacciones adversas limitantes de la dosis (RALD) en el primer ciclo en <33% de los pacientes.
    ?Parte II: Mediana de la supervivencia sin progresión (SSP) según las evaluaciones del investigador.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Part I (Establish dose for Part II) (Not applicable in Spain): February 2012
    Part II (PFS): March 2014
    Pate I (establece dosis para Parte II) (No aplica en España): Febrero 2010
    Parte II (SSP): Marzo 2014
    E.5.2Secondary end point(s)
    1. Incidence of adverse events (AE) and serious AE (SAE).
    2. Objective response rate (ORR) and duration of response based on Response Evaluation Criteria in Solid Tumors (RECIST) criteria.
    3. Pharmacokinetics of PF-04856884 and AG-013736.
    4. Immunogenicity based on the presence of anti drug antibody (ADA).
    5. Levels of circulating Ang 1, Ang 2 and VEGF A.
    6. Part II: Median progression free survival (PFS) based on an independent radiological assessment.
    7. Part II: Two year overall survival rate (OS).
    1.Incidencia de acontecimientos adversos (AA) y AA graves (AAG).
    2.Tasa de respuesta objetiva (TRO) y duración de la respuesta conforme a los criterios de evaluación de la respuesta en tumores sólidos (RECIST, por su nombre en inglés).
    3.Farmacocinética de PF 04856884 y de AG-013736.
    4.Inmunogenia basada en la presencia de anticuerpos contra el fármaco (ADA).
    5.Concentraciones circulantes de Ang-1, ANG 2 y VEGF-A.
    6.Parte II: Mediana de la supervivencia sin progresión (SSP) según una evaluación radiológica independiente.
    7.Parte II: Tasa de supervivencia global (SG) a los dos años.
    E.5.2.1Timepoint(s) of evaluation of this end point
    1. Safety and Tolerability: March 2014
    2. Overall Response Rate: March 2014
    3. Pharmacokinetics: March 2014
    4. Immunogenicity: March 2014
    5. Pharmacodynamics: March 2014
    6. Part II/Progression Free Survival by independent review: March 2014
    7. Part II/Overall Survival: March 2015
    1. Seguridad y tolerabilidad: Marzo 2014
    2. Tasa de respuesta objetiva: Marzo 2014
    3. Farmacocinética: Marzo 2014
    4. Inmunogenia: Marzo 2014
    5. Farmacodinamica: Marzo 2014
    6. Parte II/Sin progresión según una evaluación radiológica independiente: Marzo 2014
    7. Parte II/Tasa de supervivencia global: Marzo 2015
    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 No
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.3 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 concerned9
    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
    Brazil
    Canada
    Croatia
    Czech Republic
    Germany
    India
    Poland
    Russian Federation
    Singapore
    Spain
    Taiwan
    Thailand
    Ukraine
    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
    End of Trial is defined as as the date that all patients have completed the follow-up period for overall survival. (As specified in the protocol.)
    El final del estudio se define como la fecha en la que todos los pacientes han completado el período de seguimiento de la supervivencia (como especifica el protocolo)
    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 months6
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years3
    E.8.9.2In all countries concerned by the trial months6
    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.1.1Number of subjects for this age range: 0
    F.1.1.1In Utero No
    F.1.1.1.1Number of subjects for this age range: 0
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.2.1Number of subjects for this age range: 0
    F.1.1.3Newborns (0-27 days) No
    F.1.1.3.1Number of subjects for this age range: 0
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.4.1Number of subjects for this age range: 0
    F.1.1.5Children (2-11years) No
    F.1.1.5.1Number of subjects for this age range: 0
    F.1.1.6Adolescents (12-17 years) No
    F.1.1.6.1Number of subjects for this age range: 0
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 82
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 83
    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 state30
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 58
    F.4.2.2In the whole clinical trial 165
    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)
    Patients will be treated on study until disease progression or intolerable toxicity to the study drugs. Treatment or care after participation has ended will be per the patient/phycisian decision.
    El tratamiento o cuidados médicos una vez finalizada la participación en el ensayo, será por decisión del paciente / medico
    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 Decision2012-02-02
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2012-01-13
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
    P.Date of the global end of the trial2014-03-27
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