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    Summary
    EudraCT Number:2013-001426-26
    Sponsor's Protocol Code Number:A8471005
    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:2014-04-11
    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 number2013-001426-26
    A.3Full title of the trial
    A phase 2, randomized, open label study to evaluate the efficacy, safety, pharmacodynamics, pharmacokinetics of the anti-ALK-1 MAB PF-03446962 in combination with best supportive care vs. best supportive care alone in adult patients with advanced hepatocellular carcinoma.
    Estudio de fase II, aleatorizado y abierto para evaluar la eficacia, seguridad, farmacodinámica y farmaconética del anticuerpo monoclonal anti ALK1 PF 03446962 en combinación con el mejor tratamiento paliativo frente al mejor tratamiento paliativo sólo, en pacientes adultos con carcinoma hepatocelular avanzado.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Study To Evaluate The Efficacy And Safety of The Investigational Drug PF-03446962 (A Monoclonal Antibody With Antiangiogenic Features) In Combination With Best Supportive Care Versus Best Supportive Care Alone In Patients Affected By Recurrent Liver Cancer.
    Estudio para evaluar la eficacia y seguridad del fármaco PF 03446962 (anticuerpo monoclonal con características antiangiogénicas) en combinación con el mejor tratamiento paliativo frente al mejor tratamiento paliativo sólo, en pacientes adultos con carcinoma hepatocelular recurrente.
    A.4.1Sponsor's protocol code numberA8471005
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT01911273
    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, 235 East 42nd Street, New York, NY 10017
    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 pointClinicalTrials.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+18007181021
    B.5.5Fax number+13037391119
    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 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-03446962
    D.3.4Pharmaceutical form Solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous drip use (Noncurrent)
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNNot Applicable
    D.3.9.2Current sponsor codePF-03446962
    D.3.9.3Other descriptive nameALK-1, Anti-human ALK-1 mAb
    D.3.9.4EV Substance CodeSUB26598
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number10
    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 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 hepatocellular carcinoma (HCC)
    Carcinoma hepátocelular avanzado (CHC)
    E.1.1.1Medical condition in easily understood language
    Liver cancer
    Cáncer hepático
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 16.1
    E.1.2Level PT
    E.1.2Classification code 10073071
    E.1.2Term Hepatocellular 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 determine whether overall survival (OS) of PF-03446962 plus best supportive care (BSC) is superior to OS of BSC in patients with advanced HCC following sorafenib failure.
    Determinar si la supervivencia global de PF 03446962 más el mejor tratamiento paliativo es superior a la supervivencia global del mejor tratamiento paliativo en pacientes con CHC avanzado tras el fracaso de sorafenib.
    E.2.2Secondary objectives of the trial
    - To compare measures of tumor control between treatment arms.
    - To evaluate the safety and tolerability of PF-03446962 administered in combination with BSC.
    - To assess the potential influence on PF-03446962 efficacy of gene alterations, transcripts and proteomic profiles related to ALK-1 signaling and HCC biology in patients? tumor (pre-randomization biopsy in all patients) and blood samples.
    - To assess biomarkers associated with tumor resistance mechanisms and/or tumor progression in HCC patients treated with PF-03446962 who have experienced objective response or SD for at least 16 weeks from randomization and have then experienced disease progression on or after study treatment (in Arm A only).
    Please refer to protocol to review the rest of secondary objectives.
    -Comparar las determinaciones del control tumoral entre los grupos de tratamiento.
    -Evaluar la seguridad y tolerabilidad de PF 03446962 administrado en combinación con el mejor tratamiento paliativo.
    -Evaluar la posible influencia en la eficacia de PF 03446962 de las alteraciones genéticas, los transcritos y los perfiles proteómicos relacionados con la señalización de ALK-1 y la biología del CHC en las muestras tumorales (biopsia previa a la aleatorización en todos los pacientes) y de sangre de los pacientes.
    -Evaluar los biomarcadores asociados a los mecanismos de resistencia tumoral y/o de progresión del tumor en pacientes con CHC tratados con PF 03446962 que han experimentado respuesta objetiva o EE durante al menos 16 semanas desde la aleatorización y que después han presentado progresión de la enfermedad durante o después del tratamiento del estudio (solo en el grupo A).
    Por favor, remítanse a protocolo para el resto de objetivos secundarios
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Diagnosis of locally advanced or metastatic HCC, obtained by histology/cytology (on a prior tumor biopsy) or by imaging (acceptable imaging modalities include triphasic contrast-enhanced helical CT, triphasic dynamic contrast-enhanced MRI and contrast-enhanced ultrasonography); all patients must provide one archival tumor specimen (if collected at the time of primary diagnosis and still available).
    2. HCC not amenable to local therapy.
    3. Documented progression on or after treatment with sorafenib. Patients who withdrew from sorafenib due to intolerance are eligible provided that they had disease progression and did not receive any anti-cancer therapy after the last sorafenib dose. Sorafenib failure must be confirmed by the Investigator upon review of appropriate imaging documentation. Imaging documentation of sorafenib failure must be retained at the site by the Investigator for potential retrospective independent central review; before randomization, all patients must provide a de novo tumor block obtained after disease progression on sorafenib (pre-randomization de novo biopsy). Inability to obtain this biopsy will make the patient ineligible for the study
    4. Measurable or non-measurable disease according to RECIST v. 1.1.
    5. Child-Pugh Class A disease (see Appendix 1). Score for hepatic encephalopathy must be 1; ascites score must be ? 2.
    6. At least 2 weeks since completion of prior radiotherapy, or surgical procedure (4 weeks for major surgery).
    7. All prior treatment-related toxicities must have resolved to baseline severity or CTCAE Grade ?1 except for alopecia or other AEs not constituting a safety risk for the patients by investigator?s judgement.
    8. Age ?18 years (or ?20 years for Japanese patients).
    9. Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) must be 0 or 1.
    10. Adequate bone marrow function (including ANC ?1,500/mm3; Platelets ? 75,000/mm3; Hemoglobin ?9 g/dL).
    11. Adequate renal function (including serum creatinine ?1.5 x ULN, or creatinine clearance ?60 ml/min as per institution standard).
    12. INR <1.7 or prothrombin time (PT) prolongation < 4 seconds* above ULN.
    13. Adequate liver function (including AST/ALT ?5.0 x ULN; total serum bilirubin ?2 mg/dL*; and serum albumin ? 2.8 g/d**) [See Appendix 1 protocol: Child-Pugh Score ?1* or ?2**].
    14. Prior liver transplantation is permitted; immunosuppressive agents in transplanted patients are also allowed.
    15. Male and female patients of childbearing potential, must agree to use a highly effective method of contraception throughout the study and for 6 months after the last dose of assigned treatment. A subject is of childbearing potential if, in the opinion of the investigator, he/she is biologically capable of having children and is sexually active.
    16. Evidence of a personally signed and dated informed consent document indicating that the patient (or a legal representative) has been informed of all pertinent aspects of the study.
    17. Patients who are willing and able to comply with scheduled visits, treatment plans, laboratory tests and other study procedures.
    1. Diagnóstico de CHC localmente avanzado o metastásico, obtenido mediante histología/citología (en una biopsia anterior del tumor) o mediante imagen (las modalidades de imagen aceptables incluyen TC helicoidal trifásica con contraste, RMN dinámica trifásica con contraste y ecografía con contraste). Todos los pacientes deberán facilitar una muestra tumoral de archivo (si se obtuvo en el momento del primer diagnóstico y está todavía disponible).
    2. CHC no susceptible al tratamiento local.
    3. Progresión documentada con o después del tratamiento con sorafenib. Los pacientes que interrumpiesen la administración de sorafenib debido a la intolerancia podrán ser elegidos siempre que presentasen progresión de la enfermedad y no hubiesen recibido tratamiento antineoplásico desde la última dosis de sorafenib. El investigador debe confirmar el fracaso de sorafenib al revisar la documentación pertinente de las imágenes. El investigador debe guardar la documentación de las imágenes del fracaso de sorafenib en el centro para una posible revisión central independiente retrospectiva. Antes de la aleatorización, todos los pacientes deben facilitar un bloque tumoral de novo obtenido después de la progresión de la enfermedad con sorafenib (biopsia de novo previa a la aleatorización). La imposibilidad de obtener esta biopsia supondrá que no se puede elegir al paciente para el estudio.
    4. Enfermedad medible o no medible conforme a RECIST v. 1.1.
    5. Enfermedad de clase A en Child Pugh (ver el Anexo 1). La puntuación de la encefalopatía hepática debe ser 1; la puntuación de la ascitis debe ser ?2.
    6. Al menos 2 semanas desde la finalización de la radioterapia previa, o de una intervención quirúrgica (4 semanas en el caso de cirugía mayor).
    7. Todas las toxicidades previas relacionadas con el tratamiento deben haber remitido hasta la intensidad basal o al grado ?1 de CTCAE excepto la alopecia u otro AA que en opinión del investigador no constituya un riesgo de seguridad para los pacientes.
    8. Edad ?18 años (o ?20 años en pacientes japoneses).
    9. Estado de actividad (EA) del Grupo Oncológico Cooperativo del Este (ECOG) debe ser de 0 o 1.
    10. La función de la médula ósea debe ser adecuada (incluido un recuento absoluto de neutrófilos ?1500/mm3; plaquetas ?75 000/mm3; hemoglobina ?9 g/dl).
    11. Función renal adecuada (incluida creatinina sérica ?1,5 x LSN o aclaramiento de la creatinina ?60 ml/min conforme a la normativa del centro).
    12. INR <1,7 o prolongación del tiempo de protrombina (TP) <4 segundos* por encima del LSN.
    13. Función hepática adecuada (incluida ASAT/ALAT ?5,0 x LSN; bilirrubina sérica total ?2 mg/dl*; y albúmina sérica ?2,8 g/d**) (Ver Anexo 1 protocolo: Puntuación de Child Pugh ?1* o ?2**).
    14. Se permiten el trasplante hepático previo y los inmunodepresores en pacientes trasplantados.
    15. Los hombres potencialmente fértiles y las mujeres con capacidad de gestación deben aceptar utilizar un método anticonceptivo altamente eficaz durante todo el estudio y durante 6 meses después de la última dosis del tratamiento asignado. Un sujeto es potencialmente fértil/tiene capacidad de gestación si, en opinión del investigador, es biológicamente capaz de tener hijos y es sexualmente activo.
    16. Constancia de un documento de consentimiento informado firmado y fechado en persona que indique que el paciente (o su representante legal) ha sido informado de todos los aspectos pertinentes del estudio.
    17. Pacientes que deseen y que sean capaces de cumplir con las visitas programadas, los planes de tratamiento, los análisis de laboratorio y demás procedimientos del estudio.
    E.4Principal exclusion criteria
    1. Prior systemic treatment for advanced HCC other than 1st-line sorafenib (single agent or in combination).
    2. Prior local therapy (such as hepatic arterial embolization, TACE, hepatic arterial infusion, radiofrequency ablation, percutaneous ethanol injection or cryoablation) within 2 weeks of starting the study treatment.
    3. Presence of main portal vein invasion by HCC (invasion to 1st or 2nd branch of portal vein is acceptable).
    4. 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 the start of study medication, have discontinued corticosteroid treatment for these metastases for at least 4 weeks and are radiographically and neurologically stable.
    5. Clinically significant bleeding disorders, including gastrointestinal bleeding, as evidenced by hematemesis, significant hemoptysis or melena in the past 3 months; or untreated high risk esophageal varices in patients with known portal hypertension.
    6. History of Osler-Weber-Rendu syndrome or Hereditary Hemorrhagic Telangiectasia.
    7. Known active and clinically significant bacterial, fungal or viral infection (other than hepatitis B (HBV), hepatitis C (HCV)), known human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS)-related illness.
    8. Any one of the following currently or in the previous 6 months: myocardial infarction, congenital long QT syndrome, torsades de points, clinically significant ventricular arrhythmias (including sustained ventricular tachyarrhythmia and ventricular fibrillation), right bundle branch block and left anterior hemiblock (bifascicular block), unstable angina, coronary/peripheral artery bypass graft, symptomatic congestive heart failure (CHF NY Heart Association class III or IV), cerebrovascular accident, transient ischemic attack or symptomatic pulmonary embolism; as well as bradycardia defined as <50 bpms. Ongoing cardiac dysrrhythmias of CTCAE Grade ?2, atrial fibrillation of any grade, or QTc interval >480 msec (unless considered not clinically significant) at screening are exclusionary.
    9. Pregnant females; breastfeeding females; males and females of childbearing potential who are unwilling or unable to use a highly effective method of contraception as outlined in this protocol for the duration of the study and for 6 month after last dose of investigational product.
    10. Participation in other studies involving investigational drugs (Phases 1-4) within 1 month before the current study begins and/or during study participation.
    11. Other severe acute or chronic medical or psychiatric condition (including recent [within the past year] or active suicidal ideation or behavior) 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 patient inappropriate for entry into this study.
    12. Patients who are investigational site staff members directly involved in the conduct of the trial and their family members, site staff members otherwise supervised by the Investigator, or patients who are Pfizer employees directly involved in the conduct of the trial.
    13. History of any other malignancy in the previous 3 years (except for local cancers resected with curative intent without evidence of recurrence over the past 12 months).
    1. Tratamiento sistémico previo para el CHC avanzado que no sea sorafenib de primera línea (en monoterapia o combinado).
    2. Tratamiento local previo (como por ejemplo embolización de la arteria hepática, quimioembolización transarterial [TACE], perfusión de la arteria hepática, ablación por radiofrecuencia, inyección percutánea de etanol o crioablación) en el plazo de 2 semanas de comenzar el tratamiento del estudio.
    3. Presencia de invasión del CHC en la vena portal principal (se acepta la invasión hasta la 1.ª o 2.ª rama de la vena portal).
    4. Metástasis cerebrales sintomáticas conocidas que requieren esteroides. Los pacientes con metástasis cerebrales previamente diagnosticadas son elegibles si han finalizado el tratamiento y se han recuperado de los efectos agudos de la radioterapia o la cirugía antes de comenzar la medicación del estudio, han suspendido el tratamiento con corticoesteroides para estas metástasis durante al menos 4 semanas y están radiográfica y neurológicamente estables.
    5. Trastornos hemorrágicos clínicamente significativos, incluidas hemorragia gastrointestinal, evidenciada por hematemesis, hemoptisis significativa o melena en los últimos 3 meses; o varices esofágicas de alto riesgo sin tratar en pacientes con hipertensión portal conocida.
    6. Historia de síndrome de Osler Weber Rendu o telangiectasia hemorrágica hereditaria.
    7. Infección bacteriana, fúngica o vírica activa y clínicamente significativa conocida (que no sea por hepatitis B [VHB], hepatitis C [VHC]), virus de la inmunodeficiencia humana (VIH) conocida o enfermedad relacionada con el síndrome de inmunodeficiencia adquirida (SIDA).
    8. Cualquiera de las siguientes patologías en la actualidad o en los últimos 6 meses: infarto de miocardio, síndrome de QT prolongado congénito, taquicardia ventricular en entorchado, arritmias ventriculares clínicamente significativas (incluidas taquicardia ventricular sostenida y fibrilación ventricular), bloqueo de la rama derecha del haz de His y hemibloqueo anterior izquierdo (bloqueo bifascicular), angina inestable, derivación aortocoronaria/periférica, insuficiencia cardiaca congestiva sintomática (ICC de clase III o IV de la NY Heart Association), accidente cerebrovascular, ataque isquémico transitorio o embolia pulmonar sintomática, así como bradicardia, definida como <50 lpm. Las arritmias cardiacas en curso de grado ?2 de CTCAE, la fibrilación auricular de cualquier grado o el intervalo QTc >480 ms (a menos que no se considere clínicamente significativo) en la selección son motivos de exclusión.
    9. Mujeres embarazadas; mujeres en periodo de lactancia; hombres potencialmente fértiles y mujeres con capacidad de gestación que no quieran o no puedan utilizar un método anticonceptivo altamente eficaz según la descripción de este protocolo durante todo el estudio y durante 6 meses después de la última dosis del producto en investigación.
    10. Participación en otros estudios con medicamentos en fase de investigación (fases 1 4) en el mes anterior al comienzo de este estudio y/o durante la participación en el estudio.
    11. Otra patología médica o psiquiátrica grave, aguda o crónica (incluye la ideación o la conducta suicida reciente [en el último año] o activa) o una anomalía de laboratorio que pueda aumentar el riesgo asociado a la participación en el estudio o a la administración del producto en fase de investigación o que pueda interferir en la interpretación de los resultados del estudio y, en opinión del investigador, haría que el paciente no fuera apto para entrar en este estudio.
    12. Pacientes que sean miembros del personal del centro de investigación directamente implicados en la realización del ensayo y sus familiares, miembros del personal del centro que sean supervisados por el investigador o pacientes que sean empleados de Pfizer directamente implicados en la realización del ensayo.
    13. Antecedentes de cualquier otra neoplasia maligna en los últimos 3 años (excepto en el caso de los cánceres localizados resecados con intención de curar sin indicios de recaída durante los últimos 12 meses).
    E.5 End points
    E.5.1Primary end point(s)
    - Overall Survival (OS).
    -Supervivencia global (SG).
    E.5.1.1Timepoint(s) of evaluation of this end point
    Time Frame: From 1st randomization to about 30 months
    Período: desde la primera randomización hasta aproximadamente 30 meses.
    E.5.2Secondary end point(s)
    - Time to Progression (TTP), Progression Free Survival (PFS), Objective Response Rate (ORR), Duration of Response (DR) and Disease Control Rate (DCR) at 16 weeks [by Response Evaluation Criteria in Solid Tumor (RECIST 1.1)].
    - Adverse Events as characterized by type, frequency, severity (as graded by NCI CTCAE v.4.0), timing, seriousness and relationship to study therapy.
    - Laboratory abnormalities as characterized by type, frequency, severity (as graded by NCI CTCAE v. 4.0) and timing.
    - Tumor molecular characteristics including but not limited to transcriptomic (RNA) signatures of efficacy. Gene alterations studied may include but are not limited to TGF-?. Somatic DNA mutations, and expression of proteins associating with sensitivity and resistance may also be assessed.
    - Levels of circulating proteins including but not limited to angiogenesis and HCC biology.
    - Observed maximum serum concentration (Cmax) and serum trough concentrations (Ctrough).
    - Human Anti-Human Antibodies (HAHA).
    - Functional Assessment of Cancer Therapy ? Hepatobiliary questionnaire (FACT-Hep).
    -Tiempo hasta la progresión (TTP), supervivencia libre de progresión (PFS), tasa de respuesta objetiva (ORR), duración de la respuesta (DR) y la tasa de control de la enfermedad (DCR)a las 16 semanas (según los Criterios de Evaluación de la Respuesta en Tumores Sólidos [RECIST 1.1]).
    -Acontecimientos adversos caracterizados por tipo, frecuencia, intensidad (clasificada conforme a NCI CTCAE v.4.0), momento de aparición, gravedad y relación con el tratamiento del estudio.
    -Anomalías de laboratorio caracterizadas por tipo, frecuencia, intensidad (clasificada conforme a NCI CTCAE v.4.0) y momento de aparición.
    -Características moleculares del tumor, que incluye entre otras las firmas transcriptómicas (ARN) de eficacia. Las alteraciones genéticas estudiadas podrán incluir entre otros el TGF ?. Se podrán analizar asimismo las mutaciones somáticas del ADN y la expresión de proteínas relacionadas con la sensibilidad y la resistencia.
    -Niveles de proteínas circulantes, entre otras la angiogénesis y la biología del CHC.
    -Concentración sérica máxima (Cmáx) y concentraciones séricas mínimas (Cmín) observadas.
    -Anticuerpos humanos antihumanos (HAHA).
    -Evaluación funcional del tratamiento antineoplásico: cuestionario hepatobiliar (FACT Hep).
    E.5.2.1Timepoint(s) of evaluation of this end point
    From 1st randomization to about 18 months:
    - TTP
    - ORR
    - DR
    - DCR at 12 weeks
    - Change From Baseline in Functional Assessment of Cancer Therapy-Hepatobiliary questionnaire (FACT-Hep)

    From 1st randomization to about 30 months:
    - PFS
    - Cmax
    - Ctrough of PF-03446962
    - Ratio to baseline of serum circulating protein concentration. Protein involved would be TGFB1, VEGF-A, VEGF-C, PIGF, Endoglin, BMP-9, VEGFR1, VEGFR2, VEGFr3, Ang-2, VEGF-D, CD54, CD106, CCL2.
    - Ratio to baseline of tumor mRNA transcript

    Baseline: Observed serum concentration of circulating protein

    Adverse Events: From Screening to End of Treatment/Withdrawal
    For SAEs, from the time that the patient provides informed consent to 28 calendar days after the last administration of the investigational product
    Desde primera aleatorización hasta aprox. 18 meses:
    - TTP, ORR, DR, DCR a 12 semanas
    -Cambio desde la basal en cuestionario hepatobiliar de eval. funcional de la terapia oncológica (FACT Hep)

    Desde primera aleatorización hasta aprox. 18 meses:
    - PFS
    - Cmax
    - Cmin de PF-03446962
    -Relación a basal de las proteínas circulantes. Las proteínas serían: TGFB1, VEGF-A, VEGF-C, PIGF, Endoglin, BMP-9, VEGFR1, VEGFR2, VEGFr3, Ang-2, VEGF-D, CD54, CD106, CCL2.
    - Relación respecto a basal de transcripción de ARNm en tumor
    Basal: concentración sérica de proteína circulante
    Acontecimientos adversos: Desde la selección a Fin tratamiento/retirada
    Para SAEs, desde el momento de firma consentimiento informado a 28 días naturales tras la última administración deol producto en investigación
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic Yes
    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 Yes
    E.8.2.3.1Comparator description
    Best supportive care
    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 concerned5
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA16
    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
    France
    Italy
    Japan
    Germany
    Hong Kong
    Korea, Republic of
    Spain
    Taiwan
    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:
    - (in a Member State of the EU), the time at which it is deemed that sufficient patients have been recruited and completed the study as stated in the regulatory application and ethics application in the Member State. Poor recruitment by a Member State is not a reason for premature termination but is considered a normal conclusion to the study in that Member State.
    - (in all other participating countries), at least 2 years after the randomization of the last patient
    La finalización del estudio se define como:
    -En un Estado Miembro de la Unión Europea se define como el momento en que se considere que se han incluido a suficientes pacientes y han finalizado el estudio de la forma descrita en la solicitud a las autoridades reguladoras (es decir, Solicitud de Ensayo Clínico [CTA]) y la solicitud al CEIC en el Estado Miembro.

    Para más información remítanse al protocolo, sección 13.1
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years2
    E.8.9.1In the Member State concerned months6
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years2
    E.8.9.2In all countries concerned by the trial 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.1.1.1In 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: 160
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 20
    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 state15
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 48
    F.4.2.2In the whole clinical trial 180
    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 Decision2014-04-16
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2014-03-13
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
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