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    Summary
    EudraCT Number:2016-003543-11
    Sponsor's Protocol Code Number:16-214-02
    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:2017-06-08
    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 number2016-003543-11
    A.3Full title of the trial
    A Phase 1/2, open-label, multicenter, dose escalation and dose expansion study of NKTR-214 and Nivolumab in patients with select locally advanced or metastatic solid tumor malignancies
    Estudio en fase I/II, sin enmascaramiento, multicéntrico, de aumento progresivo y ampliación de la dosis de NKTR-214 y nivolumab en pacientes con determinadas neoplasias malignas de tumores sólidos localmente avanzadas o metastásicas
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A study to investigate the use of the study drug NKTR-214 in combination with other approved treatments for solid tumours.
    Estudio para investigar el uso de la sustancia de estudio NKTR-214 en combinación con otros tratamientos aprobados para tumores sólidos.
    A.4.1Sponsor's protocol code number16-214-02
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT02983045
    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 SponsorNektar Therapeutics
    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 supportNektar Therapeutics
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationNektar Therapeutics Contact Center
    B.5.2Functional name of contact pointClinical Trial Information Desk
    B.5.3 Address:
    B.5.3.1Street Address455 Mission Bay Boulevard South
    B.5.3.2Town/ citySan Francisco
    B.5.3.3Post codeCA94158
    B.5.3.4CountryUnited States
    B.5.6E-mailstudyinquiry@nektar.com
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameNKTR-214
    D.3.4Pharmaceutical form Lyophilisate for solution for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNNot yet assigned
    D.3.9.2Current sponsor codeNKTR-214
    D.3.9.3Other descriptive nameNKT-11135-R
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    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 No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product Yes
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 2
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Opdivo
    D.2.1.1.2Name of the Marketing Authorisation holderBristol-Myers Squibb Pharma EEIG
    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 nameNivolumab
    D.3.4Pharmaceutical form Concentrate for solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNNIVOLUMAB
    D.3.9.1CAS number 946414-94-4
    D.3.9.4EV Substance CodeSUB122750
    D.3.10 Strength
    D.3.10.1Concentration unit ml millilitre(s)
    D.3.10.2Concentration typerange
    D.3.10.3Concentration number4 to 10
    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.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
    Locally Advanced or Metastatic Solid Tumor Malignancies
    Tumores sólidos localmente avanzadas o metastásicas
    E.1.1.1Medical condition in easily understood language
    Cancer
    Cancer
    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 LLT
    E.1.2Classification code 10065143
    E.1.2Term Malignant solid tumour
    E.1.2System Organ Class 100000004864
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    - To evaluate the safety and tolerability, and define the maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D) of NKTR 214 in combination with nivolumab.
    - To evaluate the efficacy of NKTR 214 in combination with nivolumab by assessing the objective response rate (ORR) by RECIST 1.1 at the RP2D.
    - Evaluar la seguridad y la tolerabilidad, y definir la dosis tolerada máxima (DTM) o la dosis recomendada para la fase II (DRF2) de NKTR-214 en combinación con nivolumab.
    - Evaluar la eficacia de NKTR-214 en combinación con nivolumab al evaluar la tasa de respuesta objetiva (TRO) según los criterios RECIST 1.1. con la DRF2.
    E.2.2Secondary objectives of the trial
    - To evaluate the efficacy of NKTR 214 in combination with nivolumab by assessing overall survival (OS) and progression-free survival (PFS).
    - To evaluate the efficacy of NKTR 214 in combination with nivolumab by assessing immune-related RECIST (irRECIST) at the RP2D.
    - To assess the immunological effects and to accommodate disease-specific pharmacodynamics markers such as lactate dehydrogenase (LDH) (e.g., in melanoma), of NKTR 214 when administered in combination with nivolumab.
    - To characterize the pharmacokinetics (PK) of nivolumab and NKTR 214 and metabolites.
    - To assess the development of anti-drug antibodies against NKTR-214 and nivolumab when administered in combination.
    - To assess the association between efficacy measures and PD-L1 expression in tumors.
    - Evaluar la eficacia de NKTR-214 en combinación con nivolumab al evaluar la supervivencia global (SG) y la supervivencia sin progresión (SSP).
    - Evaluar la eficacia de NKTR-214 en combinación con nivolumab al evaluar los criterios RECIST relacionados con el sistema inmunitario (RECISTrsi) con la DRF2.
    - Evaluar los efectos inmunitarios y adaptar los marcadores farmacodinámicos específicos de la enfermedad, tal como la lactato deshidrogenasa (LDH) (p. ej., en el melanoma), de NKTR-214 cuando se administra en combinación con nivolumab.
    - Caracterizar la farmacocinética (FC) de nivolumab y NKTR-214 y los metabolitos.
    - Evaluar el desarrollo de anticuerpos contra los medicamentos NKTR-214 y nivolumab cuando se administran juntos.
    - Evaluar la asociación entre las medidas de eficacia y la expresión de PD-L1 en tumores.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    For Dose Escalation (Part 1) and Dose Expansion (Part 2):
    1. Willing and able to provide written informed consent
    2. Histologically confirmed diagnosis of a locally advanced (not amenable to curative therapy such as surgical resection) or metastatic melanoma, RCC, NSCLC, urothelial carcinoma, or TNBC
    3. Male or female patients, age 18 years or older at the time of signing the informed consent form (ICF)
    4. Life expectancy >12 weeks
    5. Patients must not have received prior interleukin 2 (IL 2) therapy
    6. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1
    7. Measurable disease per RECIST 1.1
    8. Demonstrated adequate organ function, as defined below, within 14 days of treatment initiation
    a. White blood cell (WBC) count ≥ 2000/μL (after at least 7 days without growth factor support or transfusion)
    b. Absolute neutrophil count (ANC) ≥ 1500/μL (after at least 7 days without growth factor support or transfusion)
    c. Platelet count ≥ 100 × 103/μL (transfusions allowed)
    d. Hemoglobin ≥ 9.0 g/dL (transfusions allowed)
    e. Serum creatinine ≤ 2 mg/dL (or glomerular filtration rate ≥ 40 mL/min)
    f. Aspartate aminotransferase (AST) and alanine transaminase (ALT) ≤ 3× upper limit of normal (ULN)
    g. Total bilirubin within normal limits unless associated with hepatobiliary metastases or Gilbert’s syndrome, in that case total bilirubin ≤ 2× ULN
    h. Lipase and amylase ≤ 1.5× ULN. Patients with pancreatic metastases and lipase and/or amylase < 3× ULN may enroll. Patients may not enroll if there are clinical or radiographic signs of pancreatitis.
    9. On stress echocardiogram, documented left ventricular ejection fraction > 45% on cardiac stress test within 60 days prior to Cycle 1 Day 1. At the discretion of the Investigator, patients who are unable to perform a stress echocardiogram may instead have a multigated acquisition (MUGA) scan or transthoracic echocardiogram (TTE).
    10. Oxygen saturation ≥ 92% on room air
    11. Clinically significant toxic effect(s) of the most recent prior chemotherapy must be resolved to Grade 1 or less (except alopecia and sensory neuropathy). If the patient received major surgery or radiation therapy of > 30 Gy, they must have recovered from the toxicity and/or complications from the intervention.
    12. Women of childbearing potential (WCBP) must agree to use highly effective methods of birth control throughout the duration of the study until 6 months following the last dose of study drug. Acceptable methods are defined as those that result, alone or in combination, in a low failure rate (i.e., less than 1% per year) when used consistently and correctly, such as surgical sterilization, an intrauterine device, or hormonal contraception in combination with a barrier method. It is currently unknown whether NKTR-214 may reduce the effectiveness of systemically acting hormonal contraceptives, and therefore women using systemically acting hormonal contraceptives should add a barrier method. In certain countries (if permitted by law), WCBP may agree to abide by heterosexual sexual abstinence during the time of participation in this study.
    13. Males with female partners of child-bearing potential must agree to use a barrier contraception (e.g., condom with spermicidal foam/gel/film/cream/suppository) throughout the duration of the study until 6 months following the last dose of study drug; in addition to their female partner using either an intrauterine device or hormonal contraception and continuing until 6 months following the last dose of study drug. This criterion may be waived for male subjects who have had a vasectomy > 6 months before signing the informed consent form (ICF).
    14. Patients with stable brain metastases may be enrolled, provided:
    a. No prior brain metastasis lesion greater than 2 cm
    b. No new or progressing brain metastasis of any size
    c. No stereotactic radiation or craniotomy within 4 weeks of Cycle 1 Day 1
    d. No new central nervous system lesions on repeat radiographic imaging 4 weeks or more from last treatment
    e. No treatment with systemic steroids (> 10 mg of prednisone daily or equivalent) within 2 weeks of Cycle 1 Day 1
    f. No clinically significant symptoms secondary to brain metastases
    15. Sample of fresh baseline tumor biopsies (fresh baseline biopsy is defined as a biopsy specimen taken during screening) is required, except if inaccessible and with Medical Monitor approval. Patients must also consent to allow acquisition of existing formalin-fixed paraffin-embedded (FFPE) material (archival tumor tissue), either a block or unstained slides for performance of correlative studies.

    Please refer to the protocol for a detailed list of the inclusion criteria
    Para el aumento progresivo (parte 1) y la ampliación de la dosis (parte 2):
    1. Pacientes dispuestos y capaces de proporcionar el consentimiento informado por escrito.
    2. Diagnóstico con confirmación histológica de melanoma, CCR, CPAM, carcinoma urotelial o CMTN localmente avanzado (no susceptible de tratamiento curativo como resección quirúrgica) o metastásico.
    3. Pacientes de ambos sexos de al menos 18 años de edad en el momento de la firma del formulario de consentimiento informado (FCI).
    4. Esperanza de vida > 12 semanas.
    5. Los pacientes no deben haber recibido tratamiento anterior con interleucina-2 (IL-2).
    6. Estado funcional de 0 o 1 según el Eastern Cooperative Oncology Group (ECOG).
    7. Enfermedad mensurable según los criterios RECIST 1.1.
    8. Función orgánica adecuada demostrada, como se define a continuación, en los 14 días previos al inicio del tratamiento.
    a. Recuento de glóbulos blancos (GB) ≥ 2000/μl (después de al menos 7 días sin recibir transfusión o respaldo de factor de crecimiento).
    b. Recuento absoluto de neutrófilos (RAN) ≥ 1500/μl (después de al menos 7 días sin recibir transfusión o respaldo de factor de crecimiento).
    c. Recuento de plaquetas ≥ 100 × 103/μl (se permiten transfusiones).
    d. Hemoglobina ≥ 9,0 g/dl (se permiten transfusiones).
    e. Creatinina sérica ≤ 2 mg/dl ( o velocidad de filtración glomerular ≥ 40 ml/min).
    f. Aspartato aminotransferasa (AST) y alanina transaminasa (ALT) ≤ 3 veces el límite superior de la normalidad (LSN).
    g. Bilirrubina total dentro de los límites normales, salvo que se asocie con metástasis hepatobiliares o el síndrome de Gilbert, en cuyo caso la bilirrubina total ≤ 2 veces el LSN.
    h. Lipasa y amilasa ≤ 1,5 veces el LSN. Los pacientes con metástasis pancreáticas y concentraciones de lipasa y/o amilasa < 3 veces el LSN pueden inscribirse. No pueden inscribirse si hay signos clínicos o radiográficos de pancreatitis.
    9. En la ecocardiografía de esfuerzo, fracción de eyección ventricular izquierda documentada > 45 % en la prueba de esfuerzo cardíaco en los 60 días previos al día 1 del ciclo 1. Según criterio del investigador, a los pacientes a los que no se les pueda hacer una ecocardiografía de esfuerzo se les puede realizar una ventriculografía nuclear (MUGA) o una ecocardiografía transtorácica (ETT).
    10. Saturación de oxígeno >= 92 % sin oxigenoterapia.
    11. Los efectos tóxicos clínicamente importantes de la quimioterapia previa más reciente se deben haber resuelto hasta grado 1 o menos (excepto la alopecia y la neuropatía sensorial). Si al paciente se le realizó una cirugía mayor o recibió radioterapia de > 30 Gy, se debe haber recuperado de la toxicidad y/o de las complicaciones de la intervención.
    12. Las mujeres con capacidad para procrear (Women of childbearing potential, WCBP) deben aceptar el uso de métodos anticonceptivos altamente eficaces durante todo el estudio hasta 6 meses después de la última dosis del medicamento del estudio. Los métodos aceptables se definen como aquellos que dan lugar, solos o en combinación, a una tasa de fracaso baja (es decir, menor del 1 % por año) cuando se usan de manera sistemática y correcta, como la esterilización quirúrgica, un dispositivo intrauterino, anticonceptivos hormonales en combinación con un método de barrera. Se desconoce en la actualidad si NKTR-214 puede reducir la eficacia de los anticonceptivos hormonales de acción sistémica y, por tanto, las mujeres que usen este tipo de anticonceptivos deben usar también un método de barrera. En determinados países (si lo permite la ley), las mujeres con capacidad para procrear deben aceptar no mantener relaciones sexuales con hombres durante su participación en este estudio.
    13. Los varones con parejas de sexo femenino con capacidad para procrear deben aceptar el uso de un método anticonceptivo de barrera (pej preservativo con espuma, gel, película, crema o supositorio espermicida) durante el estudio y hasta 6 meses después de la última dosis del medicamento del estudio. Además, su pareja femenina tendrá que usar un dispositivo intrauterino o un anticonceptivo hormonal, y prolongar su uso hasta 6 meses después de la última dosis del medicamento del estudio. Este criterio se puede obviar en el caso de varones que se hayan sometido a una vasectomía más de 6 meses antes de firmar el formulario de consentimiento informado (FCI).
    14. Los pacientes que tengan metástasis cerebrales estables pueden inscribirse si:
    a. No tenían lesiones metastásicas cerebrales previas mayores de 2 cm.
    b. No hay metástasis cerebrales nuevas o progresivas de cualquier tamaño.
    c. No han recibido radiación estereotáctica ni una craneotomía en las 4 semanas previas al día 1 del ciclo 1.
    d. No hay lesiones nuevas en el sistema nervioso central en los estudios radiográficos repetidos en las 4 semanas posteriores o más desde el último tratamiento.

    Véase el protocolo para una descripción detallada de los criterios de inclusión.
    E.4Principal exclusion criteria
    1. Use of an investigational agent or an investigational device within 28 days before administration of first dose of study drug
    2. Females who are pregnant or breastfeeding
    3. Patients who have an active, known or suspected autoimmune disease. Patients requiring systemic treatment within the past 3 months or a documented history of clinically severe autoimmune disease that requires systemic steroids or immunosuppressive agents. (Exceptions include any patient on 10 mg or less of prednisone or equivalent, patients with vitiligo, hypothyroidism stable on hormone replacement, Type I diabetes, Graves’ disease, Hashimoto's disease, alopecia areata, eczema, or with Medical Monitor approval)
    4. History of allergy or hypersensitivity to study drug components
    5. Active malignancy not related to the current diagnosed malignancy
    6. History of organ transplant that requires use of immune suppressive agents
    7. Use of warfarin within 14 days of initiating study drug (Note: Low molecular weight heparin is allowed on the study)
    8. Evidence of clinically significant interstitial lung disease or active, noninfectious pneumonitis
    9. Prior surgery or radiotherapy within 14 days of therapy. Patients must have recovered from all radiation-related toxicities, not required corticosteroids and have not had radiation pneumonitis.
    10. Patients who have had < 28 days since the last chemotherapy, biological therapy, or < 14 days from approved tyrosine kinase inhibitor (TKI) therapy (sunitinib, sorafenib, vemurafenib, dabrafenib, cobimetinib), or systemic or inhaled steroid therapy at doses greater than 10 mg of prednisone or equivalent before administration of the first dose of study drug.
    11. Patients in whom prior checkpoint inhibitor therapy was intolerable and required discontinuation of treatment
    12. NSCLC patients who require supplemental oxygen
    13. Active infection requiring systemic therapy
    14. Has known hepatitis B virus (HBV) infection (e.g., HBsAg reactive) or hepatitis C virus (HCV) infection (e.g., HCV RNA qualitative is detected)
    15. Has known immunodeficiency or active human immunodeficiency virus (HIV 1/2 antibodies)
    16. Prolonged QTcF > 450 ms for men and > 470 ms for women at Screening
    17. History of unstable or deteriorating cardiac disease within the previous 6 months prior to screening including but not limited to the following:
    a. Unstable angina or myocardial infarction
    b. Congestive heart failure (New York Heart Association [NYHA] Class III or IV)
    c. Uncontrolled clinically significant arrhythmias
    18. Need for > 2 antihypertensive medications for management of hypertension (including diuretics)
    19. Known current drug or alcohol abuse
    20. Any condition including medical, emotional, psychiatric, or logistical that, in the opinion of the Investigator, would preclude the patient from adhering to the protocol
    1. Uso de un medicamento experimental o un dispositivo en fase de investigación en los 28 días previos a la administración de la primera dosis del medicamento del estudio.
    2. Mujeres que están embarazadas o amamantando.
    3. Pacientes que tienen sospecha de una enfermedad autoinmunitaria activa o que tienen una enfermedad autoinmunitaria activa conocida. Pacientes que han requerido tratamiento sistémico en los últimos 3 meses o tienen antecedentes documentados de enfermedad autoinmunitaria grave médicamente que requiere esteroides sistémicos o medicamentos inmunodepresores. (Las excepciones incluyen cualquier paciente que reciba 10 mg o menos de prednisona o equivalente, pacientes con vitíligo, hipotiroidismo estable con hormonoterapia sustitutiva, diabetes tipo I, enfermedad de Graves, enfermedad de Hashimoto, alopecia areata, eccema o si el supervisor médico lo aprueba).
    4. Antecedentes de alergia o hipersensibilidad a los componentes del medicamento del estudio.
    5. Neoplasia maligna activa no relacionada con la neoplasia diagnosticada en la actualidad.
    6. Antecedentes de trasplante de órganos que requiere el uso de medicamentos inmunodepresores.
    7. Uso de warfarina en los 14 días previos a iniciar el medicamento del estudio (Nota: la heparina de bajo peso molecular está permitida en el estudio).
    8. Evidencia de enfermedad pulmonar intersticial clínicamente importante o neumonitis no infecciosa activa.
    9. Cirugía o radioterapia previa en los 14 días anteriores al tratamiento. Los pacientes se deben haber recuperado de todas las toxicidades relacionadas con la radiación, sin necesidad de corticosteroides y no han tenido neumonitis por radiación.
    10. Pacientes que hayan recibido hace menos de 28 días la última quimioterapia o terapia biológica, o cuando hayan pasado menos de 14 días desde un tratamiento aprobado con un inhibidor de la tirosina cinasa (TKI) (sunitinib, sorafenib, vemurafenib, dabrafenib, cobimetinib) o un tratamiento esteroideo sistémico o inhalado a dosis superiores a 10 mg de prednisona o equivalente antes de la administración de la primera dosis de medicamento del estudio.
    11. Los pacientes que no hayan tolerado un tratamiento previo con inhibidores de los puntos de control y requieran la suspensión del mismo.
    12. Pacientes con CPAM que necesiten oxigenoterapia.
    13. Infección activa que precise tratamiento sistémico.
    14. Tiene infección conocida por el virus de la hepatitis B (VHB) (p. ej., reactivo para el antígeno de superficie del virus de la hepatitis B [HBsAg]) o infección por el virus de la hepatitis C (VHC) (p. ej., detección cualitativa de ARN del VHC).
    15. Tiene una inmunodeficiencia conocida o el virus de inmunodeficiencia humano activo (anticuerpos contra el VIH 1/2).
    16. Prolongación del intervalo QTcF > 450 ms en hombres y > 470 ms en mujeres en la selección.
    17. Antecedentes de cardiopatía inestable o deteriorante en los 6 meses previos a la selección, incluidas entre otras las siguientes:
    a. Angina de pecho inestable o infarto de miocardio.
    b. Insuficiencia cardíaca congestiva de las clases III o IV según la Asociación de Cardiología de Nueva York (New York Heart Association, NYHA).
    c. Arritmias clínicamente importantes no controladas.
    18. Necesidad de más de 2 medicamentos antihipertensivos para controlar la hipertensión (incluidos diuréticos).
    19. Drogadicción o alcoholismo actuales conocidos.
    20. Cualquier afección ya sea médica, emocional, psiquiátrica o logística que, según criterio del investigador, impida al paciente cumplir el protocolo.
    E.5 End points
    E.5.1Primary end point(s)
    The primary endpoints of the study are to determine the MTD of NKTR-214 in combination with nivolumab.

    The primary efficacy measurement is the ORR per RECIST 1.1 based on data provided by the Investigator’s assessment using the response evaluable population.
    El objetivo principal del estudio es determinar la MTD de NKTR-214 en combinación con nivolumab.

    La medida de eficacia primaria es el ORR por RECIST 1.1 basado en los datos proporcionados por la evaluación del investigador usando la población evaluable de respuesta.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Safety assessments will be monitored throughout the study

    Efficacy assessments - tumour assessents: screening, every 8 weeks ± 7 days from cycle 2 onwards
    La evaluación de seguridad será monitoreada a lo largo del estudio

    Evaluación de eficacia - evaluaciones tumorales: screening, cada 8 semanas ± 7 días a partir del ciclo 2 en adelante
    E.5.2Secondary end point(s)
    ORR using RECIST 1.1
    BOR using RECIST 1.1
    TTR using RECIST 1.1
    DOR using RECIST 1.1
    CBR using RECIST 1.1
    Overall Survival (OS)
    PFS using RECIST 1.1
    ORR usando RECIST 1.1
    BOR usando RECIST 1.1
    TTR usando RECIST 1.1
    DOR usando RECIST 1.1
    CBR usando RECIST 1.1
    Superviencia general (SG)
    PFS usando RECIST 1.1
    E.5.2.1Timepoint(s) of evaluation of this end point
    Tumour assessents: screening, every 8 weeks ± 7 days from cycle 2 onwards, end of treatment, at follow up

    Immunogenicity: screening, Day 1 of every cycle, end of treatment, at follow up
    Evaluación de tumores: screening, cada 8 semanas ± 7 días a partir del ciclo 2 en adelante, final del tratamiento, en el seguimiento.

    Inmunogenicidad: screening, Día 1 de cada ciclo, final del tratamiento, en el seguimiento
    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) Yes
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other Yes
    E.7.1.3.1Other trial type description
    Safety, tolerability, efficacy
    Seguridad, tolerabilidad, eficacia
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled No
    E.8.1.1Randomised No
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial1
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned5
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA25
    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
    Belgium
    Canada
    Denmark
    France
    Italy
    Poland
    Spain
    Sweden
    Ukraine
    United Kingdom
    United States
    E.8.7Trial has a data monitoring committee No
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    End of study is defined as no more than 3 years after the last patient received their first dose of NKTR-214 or Sponsor decision to terminate the study, whichever comes first.
    Fin del estudio se define como no más de 3 años después de que el último paciente recibiera su primera dosis de NKTR-214 o la decisión del promotor de terminar el estudio, lo que ocurra primero.
    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 months0
    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 months0
    E.8.9.2In all countries concerned by the trial days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 174
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 116
    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 125
    F.4.2.2In the whole clinical trial 290
    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)
    Treatment may continue beyond progression if there is clinical benefit as determined by the Investigator.
    El tratamiento puede continuar más allá de la progresión si hay un beneficio clínico determinado por el investigador.
    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 Decision2017-10-19
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2017-10-13
    P. End of Trial
    P.End of Trial StatusOngoing
    As of 1.2.2020, the UK is no longer an EU Member State. However, EU law still applies to the UK during the transition period
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