Flag of the European Union EU Clinical Trials Register Help

Clinical trials

The European Union Clinical Trials Register allows you to search for protocol and results information on:
  • interventional clinical trials that are conducted in the European Union (EU) and the European Economic Area (EEA);
  • clinical trials conducted outside the EU / EEA that are linked to European paediatric-medicine development.
  • Learn   more about the EU Clinical Trials Register   including the source of the information and the legal basis.


    The EU Clinical Trials Register currently displays   40165   clinical trials with a EudraCT protocol, of which   6574   are clinical trials conducted with subjects less than 18 years old.
    The register also displays information on   18700   older paediatric trials (in scope of Article 45 of the Paediatric Regulation (EC) No 1901/2006).
     
    Examples: Cancer AND drug name. Pneumonia AND sponsor name.
    How to search [pdf]
    Search Tips: Under advanced search you can use filters for Country, Age Group, Gender, Trial Phase, Trial Status, Date Range, Rare Diseases and Orphan Designation. For these items you should use the filters and not add them to your search terms in the text field.
    Advanced Search: Search tools
     

    < Back to search results

    Print Download

    Summary
    EudraCT Number:2018-001771-21
    Sponsor's Protocol Code Number:XL184–311
    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:2019-04-11
    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 number2018-001771-21
    A.3Full title of the trial
    A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study of
    Cabozantinib (XL184) in Subjects with Radioiodine-Refractory
    Differentiated Thyroid Cancer Who Have Progressed after Prior
    VEGFR-Targeted Therapy
    Estudio de fase 3, aleatorizado, doble ciego y controlado con placebo, de cabozantinib (XL184) en pacientes con cáncer diferenciado de tiroides resistente a radioyodo que han progresado después de tratamiento dirigido previo con VEGFR
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Efficacy and safety of Cabozantinib (XL184) in subjects who have progressed after VEGFR-targeted treatment
    Eficacia y seguridad de cabozantinib (XL184) en pacientes que han progresado después de tratamiento dirigido previo con VEGFR
    A.4.1Sponsor's protocol code numberXL184–311
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT03690388
    A.5.4Other Identifiers
    Name:IND-NumberNumber:113,446
    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 SponsorExelixis, Inc.
    B.1.3.4CountryUnited States
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportExelixis, Inc.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationExelixis, Inc.
    B.5.2Functional name of contact pointExelixis Medical Affairs
    B.5.3 Address:
    B.5.3.1Street Address1851 Harbor Bay Pkwy.
    B.5.3.2Town/ cityAlameda
    B.5.3.3Post codeCA 94502
    B.5.3.4CountryUnited States
    B.5.6E-maildruginfo@exelixis.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 Cabometyx™
    D.2.1.1.2Name of the Marketing Authorisation holderIpsen Pharma
    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 nameCabozantinib
    D.3.2Product code XL184
    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 INNCABOZANTINIB
    D.3.9.1CAS number 1140909-48-3
    D.3.9.2Current sponsor codeXL184
    D.3.9.3Other descriptive nameCabozantinib
    D.3.9.4EV Substance CodeSUB93452
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    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 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: 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 Cabometyx™
    D.2.1.1.2Name of the Marketing Authorisation holderIpsen Pharma
    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 nameCarbozantinib
    D.3.2Product code XL184
    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 INNCABOZANTINIB
    D.3.9.1CAS number 1140909-48-3
    D.3.9.2Current sponsor codeXL184
    D.3.9.4EV Substance CodeSUB93452
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number60
    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
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboFilm-coated tablet
    D.8.4Route of administration of the placeboOral use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Radioiodine-Refractory Differentiated Thyroid Cancer which has progressed after prior
    VEGFR-targeted therapy
    Cáncer diferenciado de tiroides resistente a radioyodo que ha progresado después de tratamiento dirigido previo con VEGFR
    E.1.1.1Medical condition in easily understood language
    Progressed thyroid cancer
    Cáncer de tiroides que ha progresado
    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 10066474
    E.1.2Term Thyroid cancer
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    The objective of this study is to evaluate the effect of cabozantinib compared with placebo on Progression Free Survival (PFS) and Objective Response Rate (ORR) in subjects with Radioiodine (RAI)-refractory differentiated thyroid cancer (DTC) who have progressed after prior VEGFR-targeted therapy.
    El objetivo de este estudio es evaluar el efecto de cabozantinib en comparación con placebo en la SSP y la TRO en pacientes con CDT resistente a RAY que han progresado después del tratamiento previo dirigido a VEGFR.
    E.2.2Secondary objectives of the trial
    Not applicable
    No aplica
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Histologically or cytologically confirmed diagnosis of DTC, including the following subtypes (Note: results of a previous biopsy will be accepted):
    a. PTC including histological variants of PTC such as follicular variant, tall cell, columnar cell, cribriform-morular, solid, oxyphil, arthin-like, trabecular, tumor with nodular fasciitis-like stroma, Hürthle cell variant of papillary carcinoma, poorly differentiated
    b. FTC including histological variants of FTC such as Hürthle cell, clear cell, insular, and poorly differentiated
    2. Measurable disease according to RECIST 1.1 on CT/MRI performed within 28 days prior to randomization
    3. Must have been previously treated with or deemed ineligible for treatment with Iodine-131 for DTC
    4. Must have been previously treated with at least one of the following VEGFR-targeting TKI agents for DTC: lenvatinib or sorafenib.
    (Note: Up to two prior VEGFR-targeting TKI agents are allowed including (but not limited to) lenvatinib and sorafenib.)
    5. Must have experienced documented radiographic progression per RECIST 1.1 per Investigator during or following treatment with a VEGFR-targeting TKI prior to starting the next anticancer therapy (which may be treatment in this study)
    6. Recovery to baseline or ≤ Grade 1 (Common Terminology Criteria for Adverse Events Version 5 [CTCAE v5]) from toxicities related to any prior treatments, unless AE(s) are clinically nonsignificant and/or stable on supportive therapy
    7. Age ≥ 16 years old on the day of consent
    8. Eastern Cooperative Oncology Group (ECOG) PS of 0 or 1
    9. Adequate organ and marrow function, based upon meeting all of the following laboratory criteria within 10 days before randomization:
    a. Absolute neutrophil count ≥ 1500/mm3 (≥ 1.5 GI/L) without receipt of granulocyte colony-stimulating factor support within 2 weeks before screening laboratory sample collection
    b. Platelets ≥ 100,000/mm3 (≥ 100 GI/L) without receipt of transfusion within 2 weeks before screening laboratory sample collection
    c. Hemoglobin ≥ 9 g/dL (≥ 90 g/L) without receipt of transfusion within 2 weeks before screening laboratory sample collection
    d. Alanine aminotransferase (ALT), AST, and alkaline phosphatase (ALP) ≤ 3 × upper limit of normal (ULN). ALP ≤ 5 × ULN if the subject has documented bone metastases
    e. Bilirubin ≤ 1.5 × the ULN. For subjects with known Gilbert’s disease ≤ 3 × ULN
    f. Serum creatinine ≤ 2.0 × ULN or calculated creatinine clearance ≥ 30 mL/min (≥ 0.5 mL/sec) using the Cockcroft-Gault (see Table 5-2 for Cockcroft-Gault formula).
    g. Urine protein/creatinine ratio (UPCR) ≤ 1 mg/mg (≤ 113.2 mg/mmol)
    10. Must be receiving thyroxine suppression therapy, and TSH must be below the lower cutoff of the reference range or less than 0.50 mIU/L (< 0.50 ╬╝IU/mL), whichever is lower, within 28 days before randomization.
    (Note: If hormone replacement therapy is tolerated a TSH level of ≤ 0.1 mIU/L should be targeted.)
    11. Capable of understanding and complying with the protocol requirements and signed informed consent (or informed assent and parental/guardian consent for subjects < 18 years of age)
    12. Sexually active fertile subjects and their partners must agree to use highly effective methods of contraception that alone or in combination result in a failure rate of less than 1% per year when used consistently and correctly during the course of the study and for 4 months after the last dose of study treatment. For females, such methods include combined hormonal contraception (oral, intravaginal, dermal), progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable hormonal contraception, implantable hormonal contraception), placement of an intrauterine device, or placement of an intrauterine hormone-releasing system. Males must agree to use a barrier method (eg, condom) unless they have had a vasectomy.

    For further inclusion criteria, please, see protocol section 4.2.
    1. Diagnóstico histológico o citológico confirmado de CDT, incluidos los siguientes subtipos (Nota: se aceptarán los resultados de una biopsia previa):
    a.CPT incluidas las variantes histológicas del CPT, como por ejemplo la variante folicular, la variante de células altas, la variante de células columnares, variante cribiforme-morular, variante sólida, variante oxifílica, variante similar a tumor de Warthin, variante trabecular, tumor con estroma similar a fascitis nodular, variante de células de Hürthle del carcinoma papilar, variante poco diferenciada
    b.CFT incluidas las variantes histológicas del CFT como por ejemplo variante de células de Hürthle, variante de células claras, variante insular y variante poco diferenciada
    2.Enfermedad medible según RECIST 1.1 en TAC/RM realizada en los 28 días anteriores a la aleatorización
    3.Debe haber sido tratado previamente o considerado no apto para el tratamiento con yodo-131 para CDT
    4.Debe haberse tratado previamente con al menos uno de los siguientes agentes TKI dirigidos contra el VEGFR para CDT: lenvatinib o sorafenib.
    (Nota: se permiten un máximo de dos agentes TKI dirigidos contra el VEGFR previos, incluidos, entre otros, lenvatinib y sorafenib.)
    5.Debe haber experimentado una progresión radiográfica documentada según RECIST 1.1 por el investigador durante o después del tratamiento con un TKI dirigido contra el VEGFR antes de comenzar el siguiente tratamiento antineoplásico (que puede ser el tratamiento del presente estudio)
    6.Recuperación hasta el valor inicial o ≤ Grado 1 (Criterios terminológicos comunes para acontecimientos adversos versión 5 [CTCAE v5]) de toxicidades relacionadas con cualquier tratamiento previo, a menos que los AA no sean clínicamente significativos o estables durante el tratamiento complementario
    7.Edad ≥ 16 años el día en que se obtenga el consentimiento
    8.Estado funcional del Grupo Oncológico Cooperativo del Este (ECOG) de 0 o 1
    9.Función adecuada de los órganos y la médula, con base en el cumplimiento de todos los siguientes criterios analíticos en los 10 días anteriores a la aleatorización:
    a.Recuento absoluto de neutrófilos ≥ 1500/mm3 (≥ 1,5 GI/l) sin recibir apoyo con factor estimulante de colonias de granulocitos en las 2 semanas anteriores a la recogida de la muestra analítica para la selección
    b.Plaquetas ≥ 100.000/mm3 (≥ 100 GI/l) sin recibir una transfusión en las 2 semanas anteriores a la recogida de la muestra analítica para la selección
    c.Hemoglobina ≥ 9 g/dl (≥ 90 g/l) sin recibir una transfusión en las 2 semanas anteriores a la recogida de la muestra analítica para la selección
    d.Alanina aminotransferasa (ALT), AST y fosfatasa alcalina (ALP) ≤ 3 × límite superior de la normalidad (LSN). ALP ≤ 5 × LSN si el sujeto tiene metástasis óseas documentadas
    e.Bilirrubina ≤ 1,5 × LSN. Para sujetos con síndrome de Gilbert conocido ≤ 3 × LSN
    f.Creatinina sérica ≤ 2,0 x LSN o aclaramiento de creatinina calculado ≥ 30 ml/min (≥ 0,5 ml/s) utilizando la fórmula de Cockcroft-Gault (consulte la fórmula de Cockcroft-Gault en la Tabla 5-2).
    g.Cociente proteinuria/creatininuria ≤ 1 mg/mg (o (≤ 113,2 mg/mmol)
    10.Debe estar recibiendo un tratamiento de supresión de la tiroxina, y la TSH debe estar por debajo del límite inferior del rango de referencia o ser menos de 0,50 mUI/l (< 0,50 mUI/ml), lo que sea menor, en los 28 días anteriores a la aleatorización.
    (Nota: si se tolera la terapia hormonal sustitutiva, debe fijarse como objetivo un nivel de TSH de ≤ 0,1 mUI/l).
    11.Ser capaz de comprender y cumplir con los requisitos del protocolo y firmar el consentimiento informado (o asentimiento informado y consentimiento de los padres/tutores para sujetos menores de 18 años)
    12.Los sujetos fértiles sexualmente activos y sus parejas deben aceptar el uso de métodos anticonceptivos altamente eficaces que, solos o en combinación, den como resultado una tasa de fallo inferior al 1% al año cuando se usan de manera consistente y correcta durante el curso del estudio y durante los 4 meses posteriores a la última dosis del tratamiento del estudio. Para las mujeres, tales métodos incluyen la anticoncepción hormonal combinada (oral, intravaginal, dérmica), la anticoncepción hormonal de solo progesterona asociada con la inhibición de la ovulación (oral, anticoncepción hormonal inyectable, implante anticonceptivo hormonal), la colocación de un dispositivo intrauterino o la colocación de un sistema intrauterino liberador de hormonas. Los varones deben aceptar el uso de un método de barrera (por ejemplo, preservativo) a menos que se hayan realizado una vasectomía.

    Para criterios de inclusion adicionales, consulte la sección 4.2 del protocolo.
    E.4Principal exclusion criteria
    1. Prior treatment with any of the following:
    a. Cabozantinib
    b. Selective small-molecule BRAF kinase inhibitor (eg, vemurafenib, dabrafenib)
    c. More than 2 VEGFR-targeting TKI agents (eg, lenvatinib, sorafenib, sunitinib, pazopanib, axitinib, vandetanib)
    d. More than 1 immune checkpoint inhibitor therapy (eg, PD-1 or PD-L1 targeting agent)
    e. More than 1 systemic chemotherapy regimen (given as single agent or in combination with another chemotherapy agent)
    2. Receipt of any type of small molecule kinase inhibitor (including investigational kinase inhibitor) within 2 weeks or 5 half-lives of the agent, whichever is longer, before randomization
    3. Receipt of any type of anticancer antibody (including investigational antibody) or systemic chemotherapy within 4 weeks before randomization
    4. Receipt of radiation therapy for bone metastasis within 2 weeks or any other radiation therapy within 4 weeks before randomization. Subjects with clinically relevant ongoing complications from prior radiation therapy that have not completely resolved are not eligible (eg, radiation esophagitis or other inflammation of the viscera).
    5. Known brain metastases or cranial epidural disease unless adequately treated with radiotherapy and/or surgery (including radiosurgery) and stable for at least 4 weeks before randomization. Eligible subjects must be neurologically asymptomatic and without corticosteroid treatment at the time of randomization.
    6. Concomitant anticoagulation with oral anticoagulants (eg, warfarin, direct thrombin and Factor Xa inhibitors) or platelet inhibitors (eg, clopidogrel), except for the following allowed anticoagulants:
    • Low-dose aspirin for cardioprotection (per local applicable guidelines) and low-dose low molecular weight heparins (LMWH)
    • Anticoagulation with therapeutic doses of LMWH in subjects without known brain metastases who are on a stable dose of LMWH for at least 6 weeks before randomization and who have had no clinically significant hemorrhagic complications from the anticoagulation regimen or the tumor
    7. The subject has uncontrolled, significant intercurrent or recent illness including, but not limited to, the following conditions:
    a. Cardiovascular disorders:
    i. Congestive heart failure class 3 or 4 as defined by the New York Heart Association, unstable angina pectoris, serious cardiac arrhythmias
    ii. Uncontrolled hypertension defined as sustained blood pressure (BP) > 150 mm Hg systolic or > 100 mm Hg diastolic despite optimal antihypertensive treatment
    iii. Stroke (including transient ischemic attack [TIA]), myocardial infarction (MI), or other ischemic event, or thromboembolic event (eg, deep venous thrombosis [DVT], pulmonary embolism) within 6 months before randomization. Subjects with a more recent diagnosis of DVT are allowed if stable, asymptomatic, and treated with LMWH for at least 6 weeks before randomization.
    b. Gastrointestinal disorders (GI; eg, malabsorption syndrome or gastric outlet obstruction) including those associated with a high risk of perforation or fistula formulation:
    i. Tumors invading the GI tract, active peptic ulcer disease, inflammatory bowel disease, ulcerative colitis, diverticulitis, cholecystitis, symptomatic cholangitis or appendicitis, acute pancreatitis or acute obstruction of the pancreatic or biliary duct, or gastric outlet obstruction
    ii. Abdominal fistula, GI perforation, bowel obstruction, or intra-abdominal abscess within 6 months before randomization
    Note: Complete healing of an intra-abdominal abscess must be confirmed prior to randomization
    c. Clinically significant hematemesis or hemoptysis of > 0.5 teaspoon (> 2.5 mL) of red blood or history of other significant bleeding within 3 months before randomization
    d. Cavitating pulmonary lesion(s) or known endobronchial disease manifestation
    e. Lesions invading major pulmonary blood vessels
    f. Other clinically significant disorders such as:
    • Active infection requiring systemic treatment, infection with human immunodeficiency virus or acquired immunodeficiency syndrome-related illness, or chronic hepatitis B or C infection
    • Serious non-healing wound/ulcer/bone fracture

    For further exclusion criteria, please, see protocol section 4.3
    1.Tratamiento previo con alguno de los siguientes:
    a.Cabozantinib
    b.Inhibidor selectivo de molécula pequeña de la quinasa BRAF (por ejemplo, vemurafenib, dabrafenib)
    c.Más de 2 agentes TKI dirigidos contra VEGFR (por ejemplo, lenvatinib, sorafenib, sunitinib, pazopanib, axitinib, vandetanib)
    d.Más de 1 tratamiento con inhibidores del punto de control inmunitario (por ejemplo, agente dirigido contra PD-1 o PD-L1)
    e.Más de 1 pauta de quimioterapia sistémica (administrada como agente único o en combinación con otro agente de quimioterapia)
    2.Recibir cualquier tipo de inhibidor de molécula pequeña de la quinasa (incluido un inhibidor de la quinasa en investigación) en el plazo de 2 semanas o 5 semividas del agente, lo que sea más largo, antes de la aleatorización
    3.Recibir cualquier tipo de anticuerpo contra el cáncer (incluido un anticuerpo en investigación) o quimioterapia sistémica en las 4 semanas anteriores a la aleatorización
    4.Recibir radioterapia para metástasis óseas en el plazo de 2 semanas o cualquier otra radioterapia en el plazo de las 4 semanas anteriores a la aleatorización. Los sujetos con complicaciones en curso clínicamente relevantes derivadas de la radioterapia previa que no se hayan resuelto completamente no son aptos (por ejemplo, esofagitis por radiación u otra inflamación de las vísceras).
    5.Metástasis cerebrales conocidas o enfermedad epidural craneal, a menos que se traten adecuadamente con radioterapia o cirugía (incluida la radiocirugía) y se mantengan estables durante al menos 4 semanas antes de la aleatorización. Los sujetos aptos deben ser neurológicamente asintomáticos y no estar recibiendo tratamiento con corticosteroides en el momento de la aleatorización.
    6.Anticoagulación concomitante con anticoagulantes orales (por ejemplo, warfarina, inhibidores directos de la trombina e inhibidores del factor Xa) o inhibidores de plaquetas (por ejemplo, clopidogrel), excepto los siguientes anticoagulantes permitidos:
    •Ácido acetilsalicílico en bajas dosis para cardioprotección (según las directrices locales aplicables) y heparinas de bajo peso molecular (HBPM) en dosis bajas
    •Anticoagulación con dosis terapéuticas de HBPM en sujetos sin metástasis cerebrales conocidas que reciban una dosis estable de HBPM durante al menos 6 semanas antes de la aleatorización y que no hayan tenido complicaciones hemorrágicas clínicamente significativas de la pauta de anticoagulación o del tumor
    7.El sujeto tiene una enfermedad intercurrente o reciente significativa y no controlada, incluyendo, entre otras, las siguientes afecciones:
    a.Afecciones cardiovasculares:
    i.Insuficiencia cardíaca congestiva de clase 3 o 4 según la definición de la New York Heart Association, angina de pecho inestable, arritmias cardíacas graves
    ii.Hipertensión no controlada definida como un presión arterial (PA) sostenida > 150 mmHg sistólica o > 100 mmHg diastólica a pesar del tratamiento antihipertensivo óptimo
    iii.Accidente cerebrovascular (incluido el accidente isquémico transitorio (AIT), infarto de miocardio (IM) u otro acontecimiento isquémico, o acontecimiento tromboembólico (por ejemplo, trombosis venosa profunda [TVP], embolia pulmonar) en los 6 meses anteriores a la aleatorización. Los sujetos con un diagnóstico más reciente de TVP se permiten si están estables, son asintomáticos y están a tratamiento con HBPM durante al menos 6 semanas antes de la aleatorización.
    b.Trastornos gastrointestinales (GI; por ejemplo, síndrome de malabsorción u obstrucción del tracto de salida gástrica), incluidos aquellos asociados con un alto riesgo de perforación o formación de fístulas:
    i.Tumores que invadan el tracto GI, úlcera péptica activa, enfermedad inflamatoria intestinal, colitis ulcerosa, diverticulitis, colecistitis, colangitis sintomática o apendicitis, pancreatitis aguda u obstrucción aguda del conducto pancreático o biliar, u obstrucción del tracto de salida gástrica
    ii.Fístula abdominal, perforación GI, obstrucción intestinal o absceso intraabdominal en los 6 meses anteriores a la aleatorización
    Nota: la curación completa de un absceso intraabdominal debe confirmarse antes de la aleatorización
    c.Hematemesis o hemoptisis clínicamente significativa de > una cucharadita de 0,5 (> 2,5 ml) de sangre roja o antecedentes de otro sangrado significativo en los 3 meses anteriores a la aleatorización
    d.Lesión(es) pulmonar(es) que formen cavidades o manifestación conocida de enfermedad endobronquial
    e.Lesiones que invadan los principales vasos sanguíneos pulmonares
    f.Otros trastornos clínicamente significativos como, por ejemplo:
    •Infección activa que requiera tratamiento sistémico, infección por el virus de la inmunodeficiencia humana o enfermedad relacionada con el síndrome de inmunodeficiencia adquirida o infección crónica por hepatitis B o C
    •Herida/úlcera/fractura ósea grave que no cicatriza

    Para criterios de exclusión adicionales, consulte la sección 4.3 del protocolo.
    E.5 End points
    E.5.1Primary end point(s)
    • Progression-free survival (PFS) per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 by blinded independent radiology committee (BIRC)
    • Objective response rate (ORR) per RECIST 1.1 by BIRC
    •Supervivencia sin progresión (SSP) según los criterios de evaluación de la respuesta en tumores sólidos (RECIST) 1.1 por comité de radiología independiente enmascarado (BIRC)

    •Tasa de respuesta objetiva (TRO) según RECIST 1.1 por BIRC
    E.5.1.1Timepoint(s) of evaluation of this end point
    Throughout the study and based on study assessments and procedures as stated in the protocol section 5
    A lo largo del estudio y basado en evaluaciones del estudio y procedimientos tal y como se describen en la sección 5 del protocolo.
    E.5.2Secondary end point(s)
    • Overall survival (OS)
    • Duration of objective tumor response
    • Safety and tolerability
    • Pharmacokinetics (PK) of cabozantinib
    • Relationship of baseline and postbaseline changes in biomarkers, serum thyroglobulin (Tg), and circulating tumor cells (CTCs) and/or circulating DNA (ctDNA) with treatment and/or clinical outcome assessments may be performed
    • Change in mobility, self-care, usual activities, pain/discomfort, anxiety/depression, and global health as assessed by the EuroQol Health questionnaire instrument (EQ-5D-5L)
    • Health care resource utilization
    •Supervivencia global (SG)
    •Duración de la respuesta tumoral objetiva
    •Seguridad y tolerabilidad
    •Farmacocinética (FC) de cabozantinib
    •Relación de los cambios basales y postbasales en los biomarcadores, tiroglobulina (Tg) sérica y células tumorales circulantes (CTC) y/o ADN circulante (ADNtc) con el tratamiento y/o pueden realizarse evaluaciones de resultados clínicos
    •Cambio en movilidad, cuidado personal, actividades habituales, dolor/molestias, ansiedad/depresión y salud global evaluados mediante el cuestionario de salud EuroQol (EQ-5D-5L)
    •Utilización de recursos sanitarios
    E.5.2.1Timepoint(s) of evaluation of this end point
    Throughout the study and based on study assessments and procedures as stated in the protocol section 5
    A lo largo del estudio y basado en evaluaciones del estudio y procedimientos tal y como se describen en la sección 5 del protocolo.
    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 Yes
    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) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group No
    E.8.1.6Cross over Yes
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned8
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA99
    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
    Argentina
    Australia
    Austria
    Belgium
    Brazil
    Canada
    Chile
    Croatia
    Czech Republic
    France
    Georgia
    Germany
    Hong Kong
    Hungary
    Israel
    Italy
    Korea, Republic of
    Netherlands
    New Zealand
    Poland
    Portugal
    Romania
    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
    For each country, the trial is considered complete after all study objectives have been met and the Maintenance Phase has been implemented, and after all subjects within the country have discontinued.
    En cada país el ensayo se considera completado después de que todos los objectivos del estudio hayan sido alcanzados y haya empezado la fase de mantenimiento, y después de que todos los sujetos en el país hayan dejado el tratamiento.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years3
    E.8.9.1In the Member State concerned months1
    E.8.9.1In the Member State concerned days17
    E.8.9.2In all countries concerned by the trial years4
    E.8.9.2In all countries concerned by the trial months2
    E.8.9.2In all countries concerned by the trial days30
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 Yes
    F.1.1Number of subjects for this age range: 15
    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) Yes
    F.1.1.6.1Number of subjects for this age range: 15
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 135
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 150
    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 Yes
    F.3.3.7.1Details of other specific vulnerable populations
    Minors aged ≥ 16 years old can be included in the trial
    Se pueden incluir en el ensayo sujetos de edad igual o mayor a 16 años
    F.4 Planned number of subjects to be included
    F.4.1In the member state17
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 109
    F.4.2.2In the whole clinical trial 300
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    In the Maintenance Phase subjects will continue to receive study treatment until a criterion for protocol-defined discontinuation has been met (protocol Section 5.5).
    Subjects are to undergo periodic safety assessments (including local laboratory tests) and tumor assessments; the nature and frequency of these assessments are to be performed per standard
    of care.
    En la fase de mantenimiento los pacientes seguiran recibiendo el tratamiento del estudio hasta que se cumpla algún criterio para la suspensión definido en el protocolo (sección 5.5).
    Los pacientes deben someterse a evaluaciones de seguridad periódicas (incluidas pruebas analíticas locales) y evaluaciones del tumor; la naturaleza y frecuencia de estas evaluaciones dependerá de la atención médica habitual.
    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 Decision2019-05-14
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2019-05-09
    P. End of Trial
    P.End of Trial StatusOngoing
    The status of studies in GB is no longer updated from 1.1.2021
    For the UK, as from 1.1.2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI
    EU Clinical Trials Register Service Desk: https://servicedesk.ema.europa.eu
    European Medicines Agency © 1995-2021 | Domenico Scarlattilaan 6, 1083 HS Amsterdam, The Netherlands
    Legal notice
    EMA HMA