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    Summary
    EudraCT Number:2016-002453-38
    Sponsor's Protocol Code Number:15-102-14
    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:2016-12-09
    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 number2016-002453-38
    A.3Full title of the trial
    A Phase 3 Open-Label, Randomized, Multicenter Study of NKTR-102 versus Treatment of Physician’s Choice (TPC) in Patients with Metastatic Breast Cancer Who Have Stable Brain Metastases and Have Been Previously Treated with an Anthracycline, a Taxane, and Capecitabine
    Estudio En Fase III, Abierto, Aleatorizado y Multicéntrico de Nktr-102 Frente Al Tratamiento Elegido por El Médico En Pacientes Con Cáncer de Mama Metastásico que Tienen Metástasis Cerebrales Estables y Que Han Recibido Tratamiento con una Antraciclina, un Taxano y Capecitabina con Anterioridad
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A study to compare the study drug NKTR-102 with standard treatments in breast cancer patients with stable brain metastases
    Un estudio para comparar el fármaco del estudio NKTR-102 con los tratamientos estándar en pacientes con cáncer de mama metastásico que tienen metástasis cerebrales estables
    A.4.1Sponsor's protocol code number15-102-14
    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 codeCA 94158
    B.5.3.4CountryUnited States
    B.5.4Telephone number+1 855 482 8676
    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 nameetirinotecan pegol drug product
    D.3.2Product code NKTR-102
    D.3.4Pharmaceutical form Powder 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 INNetirinotecan pegol
    D.3.9.1CAS number 1193151-06-2
    D.3.9.2Current sponsor codeNKTR-102
    D.3.9.4EV Substance CodeSUB129291
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number100
    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 RoleComparator
    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 Halaven
    D.2.1.1.2Name of the Marketing Authorisation holderEisai Europe Ltd
    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 nameEribulin
    D.3.4Pharmaceutical form 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 INNEribulin
    D.3.9.1CAS number 441045-17-6
    D.3.9.3Other descriptive nameERIBULIN MESYLATE
    D.3.9.4EV Substance CodeSUB31126
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number0.44
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 3
    D.1.2 and D.1.3IMP RoleComparator
    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 Vinorelbine
    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 nameVinorelbine
    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 INNVinorelbine tartrate
    D.3.9.1CAS number 125317-39-7
    D.3.9.4EV Substance CodeSUB20777
    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 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: 4
    D.1.2 and D.1.3IMP RoleComparator
    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 Gemcitabine
    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 nameGemcitabine
    D.3.4Pharmaceutical form Powder 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 INNGemcitabine hydrochloride
    D.3.9.1CAS number 122111-03-9
    D.3.9.4EV Substance CodeSUB02324MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number38
    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: 5
    D.1.2 and D.1.3IMP RoleComparator
    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 Paclitaxel
    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 namePaclitaxel
    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 INNPACLITAXEL
    D.3.9.1CAS number 33069-62-4
    D.3.9.4EV Substance CodeSUB09583MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number6
    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: 6
    D.1.2 and D.1.3IMP RoleComparator
    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 Docetaxel
    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 nameDocetaxel
    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 INNDOCETAXEL
    D.3.9.1CAS number 114977-28-5
    D.3.9.4EV Substance CodeSUB12492MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number20
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin 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: 7
    D.1.2 and D.1.3IMP RoleComparator
    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 Abraxane
    D.2.1.1.2Name of the Marketing Authorisation holderCelgene Europe Limited
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameNab-paclitaxel
    D.3.4Pharmaceutical form Powder for suspension 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 INNNab-paclitaxel
    D.3.9.3Other descriptive namePACLITAXEL ALBUMIN-BOUND
    D.3.9.4EV Substance CodeSUB127678
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number5
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin 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
    Metastatic breast cancer with stable brain metastases
    Cáncer de Mama Metastásico con Metástasis Cerebrales Estables
    E.1.1.1Medical condition in easily understood language
    Breast cancer which has spread to the brain
    Cáncer de mama que se ha extendido al cerebro
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 19.0
    E.1.2Level PT
    E.1.2Classification code 10055113
    E.1.2Term Breast cancer metastatic
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 19.0
    E.1.2Level PT
    E.1.2Classification code 10006198
    E.1.2Term Breast cancer recurrent
    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 compare overall survival (OS) of patients who receive 145 mg/m2 NKTR-102 given once every 21 days (q21d) with OS of patients who receive Treatment of Physician’s Choice (TPC) selected from the following list of 7 single-agent intravenous (IV) therapies: eribulin, ixabepilone, vinorelbine, gemcitabine, paclitaxel, docetaxel, or nab-paclitaxel. TPC drugs will be administered per the standard of care.
    Comparar la supervivencia global (SG) de los pacientes que reciben NKTR-102 en dosis de 145 mg/m2 una vez cada 21 días (c/ 21 d) con la SG de los pacientes que reciben el tratamiento elegido por el médico de entre los siguientes 7 tratamientos intravenosos (i.v.) en monoterapia: eribulina, ixabepilona, vinorelbina, gemcitabina, paclitaxel, docetaxel o nab-paclitaxel. Los fármacos elegidos por el médico se administrarán conforme a la posología estándar.
    E.2.2Secondary objectives of the trial
    • To compare the objective response rate (ORR) from NKTR-102 treatment with that of TPC
    • To compare progression-free survival (PFS) from NKTR-102 treatment with that of TPC
    • To compare the clinical benefit rate (CBR) from NKTR-102 treatment with that of TPC
    • To compare duration of response (DoR) from NKTR-102 treatment with that of TPC
    • To evaluate the safety profiles of NKTR-102 and TPC
    • To compare health-related quality of life from NKTR-102 treatment with that of TPC using the EORTC QLQ-C30 with the BN-20 questionnaire, the EQ-5D-5LTM questionnaire, and the Brief Fatigue Inventory (BFI)
    • To evaluate PK data (patients randomized to NKTR-102 only)
    • To correlate presence of reduced function UGT1A1 variants with NKTR-102 safety (patients randomized to NKTR-102 only)
    • To evaluate the pharmacoeconomic implications of NKTR-102 therapy using selected measures of health care utilization
    • To evaluate the magnitude of clinical benefit using ESMO-MCBS clinical benefit scale
    Comparar las tasas de respuesta objetiva del tratamiento con NKTR-102 con las del tratamiento elegido por el médico (TEM).
    Comparar la supervivencia sin progresión del tratamiento con NKTR-102 con la del TEM.
    Comparar la tasa de beneficio clínico del tratamiento con NKTR-102 con la del TEM.
    Comparar la duración de la respuesta del tratamiento con NKTR-102 con la del TEM.
    Evaluar los perfiles de seguridad de NKTR-102 y del TEM.
    Comparar la calidad de vida relacionada con la salud con la del tratamiento con NKTR-102 con la del TEM utilizando el QLQ-C30 EORTC con el cuestionario BN-20 y EQ-5D-5LTM y el Inventario breve de fatiga.
    Obtener datos FC ,solo en pacientes asignados al grupo de NKTR-102.
    Correlacionar la presencia de variantes de la UGT1A1 de funcionamiento reducido con la seguridad de NKTR-102 ,solo en pacientes asignados al grupo de NKTR-102.
    Evaluar las implicaciones FE del tratamiento con NKTR-102 utilizando medidas seleccionadas de utilización de atención sanitaria.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    - Female or male, age ≥ 18 years.

    - Histologically-confirmed carcinoma of the breast (either the primary or metastatic lesions) for whom single-agent cytotoxic chemotherapy is indicated. Patients may have either measurable or non-measurable disease according to RECIST version 1.1.

    - History of brain metastases that are non-progressing.

    - For triple-negative breast cancer, a minimum of 1 prior cytotoxic chemotherapy regimen must have been administered for the indication of metastatic disease. For HER2-positive disease, a minimum of 2 cytotoxic chemotherapy regimens must have been administered for the indication of metastatic disease as well as at least 1 hormonal therapy. For HER2-positive disease, a minimum of 2 cytotoxic chemotherapy regimens must have been administered for the indication of metastatic disease as well as at least 1 HER2 targeted therapy (ado-trastuzumab emtansine is considered a cytotoxic chemotherapy regimen).

    - Have had prior therapy (administered in the neoadjuvant, adjuvant, and/or metastatic setting) with an anthracycline, a taxane, and capecitabine (prior anthracycline can be omitted if not medically appropriate or contraindicated for the patient).

    - Last dose of anticancer therapy must have been administered within 6 months of the date of randomization into this study.

    - All anticancer- and radiation therapy-related toxicities must be completely resolved or downgraded

    - ECOG performance status of 0 or 1.

    - Adequate organ function obtained within 14 days prior to randomization and analyzed by the central laboratory as evidenced by:

    - Use highly effective methods of birth control throughout the duration of the study until 6 months following the last dose of study drug.
    - Se admitirá a pacientes adultos de sexo femenino o masculino con carcinoma de mama confirmado mediante histología.

    - Los pacientes pueden tener enfermedad metastásica tanto medible como no medible mediante los criterios RECIST.

    - Los pacientes deben tener antecedentes de metástasis cerebrales no progresivas. Las metástasis cerebrales deben haberse tratado previamente con radiación pancerebral al menos 14 días antes de la aleatorización o con radiación estereotáctica y/o resección quirúrgica al menos 7 días antes de la aleatorización. Para poder participar en el estudio, los pacientes deben encontrarse suficientemente recuperados de la radiación pancerebral y/o de la radiación estereotáctica o resección quirúrgica, con signos y síntomas estables de metástasis cerebrales a criterio del investigador. En el caso de los pacientes que se han sometido a radiación pancerebral o a radiación estereotáctica y/o resección quirúrgica al menos 28 días antes de la aleatorización, los signos o síntomas de metástasis cerebrales deben ser estables durante un mínimo de 28 días antes de la aleatorización. Se pueden utilizar corticosteroides para esta indicación siempre y cuando los pacientes reciban una dosis estable o decreciente durante al menos 7 días antes de la aleatorización.

    - El tratamiento anterior (administrado en el contexto neoadyuvante, adyuvante y/o metastásico) debe incluir una antraciclina, un taxano y capecitabina (el tratamiento previo con antraciclina puede omitirse si médicamente no es pertinente o está contraindicado en el paciente).

    - En caso de cáncer de mama triple negativo, debe haberse administrado un mínimo de 1 pauta de quimioterapia citotóxica anteriormente para la indicación de enfermedad metastásica. En caso de enfermedad con receptores hormonales positivos, deben haberse administrado un mínimo de 2 pautas de quimioterapia citotóxica para la indicación de enfermedad metastásica, así como al menos 1 tratamiento hormonal. En caso de enfermedad con receptor 2 del factor de crecimiento epidérmico humano (HER2) positivo, deben haberse administrado un mínimo de 2 pautas de quimioterapia citotóxica para la indicación de enfermedad metastásica, así como al menos 1 tratamiento para el HER2. La última dosis de quimioterapia debe haberse administrado en el plazo de 6 meses antes de la fecha de aleatorización en este estudio. Los pacientes deben presentar un estado funcional según el ECOG de 0 o 1 con demostración de funcionamiento orgánico adecuado.
    E.4Principal exclusion criteria
    - Last dose of anticancer therapy (including HER2-targeted therapy) within 14 days prior to randomization.

    - High-dose chemotherapy followed by stem cell transplantation (autologous or allogeneic).

    - Major surgery within 28 days prior to randomization.

    - Concomitant use of any anticancer therapy or use of any investigational agent(s).

    - Received prior treatment for cancer with a camptothecin-derived agent.

    - Brain metastases amenable to local therapy but without completion of such therapy

    - Lesions on imaging, by cerebrospinal fluid or with neurological findings that are consistent with leptomeningeal disease or meningeal carcinomatosis.

    - Chronic or acute GI disorders resulting in diarrhea of any severity grade.

    - Patients who are pregnant or lactating, plan to get pregnant, or have a positive serum pregnancy test prior to randomization.

    - Enzyme-inducing anti-epileptic drugs (EIAEDs) within 14 days of randomization.

    - Hepatitis B or C, tuberculosis, or HIV.

    - Cirrhosis.

    - Prior malignancy (other than breast cancer) unless diagnosed and definitively treated more than 5 years prior to randomization.

    - Severe/uncontrolled illness within the previous 28 days prior to randomization.

    - Daily use of oxygen supplementation

    - Significant known cardiovascular impairment

    - Prior treatment with NKTR-102.

    - Psychiatric illness, social situation, or geographical situation that precludes informed consent or limit compliance.
    - Última dosis de terapia anticancerígena (incluyendo terapia dirigida a HER2) dentro de los 14 días previos a la aleatorización.

    - Alta dosis de quimioterapia seguida de trasplante de células madre (Autólogo o alogénico).

    - Cirugía mayor dentro de 28 días antes de la aleatorización.

    - El uso concomitante de cualquier terapia contra el cáncer o el uso de cualquier
    Agente(s) en investigación.

    - Haber recibido tratamiento previo para el cáncer con un derivado de camptotecina
    agente.

    - Metástasis cerebrales susceptibles de tratamiento local pero sin tal terapia.

    - Lesiones en la imagen, por líquido cefalorraquídeo o con hallazgos neurológicos que son compatibles con la enfermedad leptomeníngea o meníngea carcinomatosis.

    - Trastornos gastrointestinales crónicos o agudos que resultan en diarrea de cualquier grado de gravedad.

    - Pacientes que están embarazada o en período de lactancia, que planean quedar embarazadas o que tienen prueba positiva de embarazo en suero antes de la aleatorización.

    - Fármacos antiepilépticos inductores de enzimas (EIAED) dentro de los 14 días de aleatorización.

    - Hepatitis B o C, tuberculosis o VIH.

    - Cirrosis.

    - Malignidad previa (excepto cáncer de mama), a menos que se diagnostique y se trate definitivamente más de 5 años antes de la aleatorización.

    - Enfermedad grave / incontrolada en los 28 días previos a la aleatorización.

    - Uso diario de suplementos de oxígeno.

    - Insuficiencia cardiovascular conocida.

    - Tratamiento previo con NKTR-102.

    - Enfermedad psiquiátrica, situación social o situación geográfica que Impide el consentimiento informado o limitar el cumplimiento.
    E.5 End points
    E.5.1Primary end point(s)
    Overall survival
    Superviviencia global
    E.5.1.1Timepoint(s) of evaluation of this end point
    Monitored throughout the study
    Monitorizado durante todo el estudio
    E.5.2Secondary end point(s)
    Progression-free survival (outside the CNS)
    Progression-free survival in brain metastases
    Objective response rate
    Clinical benefit rate
    Duration of response
    HRQoL
    Magnitude of Clinical Benefit
    Supervivencia sin progresión (fuera del SNC)
    Supervivencia sin progresión en metástasis cerebral
    Tasa de respuesta objetiva
    Duración de la respuesta
    CdVRS
    Magnitud del beneficio clínico
    E.5.2.1Timepoint(s) of evaluation of this end point
    PFS outside the CNS, PFS in brain metastases, CBR and DoR - monitored throughout the study

    ORR - Screening, every 8 weeks through Week 24, then every 12 weeks thereafter

    HRQoL - Day 1 of each treatment Cycle prior to infusion and at End of Treatment visit
    SSP fuera del SNC, la SSP en las metástasis cerebrales, TBC y DR - monitorizados durante todo el estudio

    TRO - Pruebas de detección, cada 8 semanas hasta la semana 24, luego cada 12 semanas

    CdVRS - Día 1 de cada ciclo de tratamiento antes de la infusión y al final de la visita de Tratamiento
    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 Yes
    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 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 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 concerned4
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA116
    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
    Australia
    Austria
    Belgium
    Canada
    Czech Republic
    France
    Germany
    Ireland
    Israel
    Italy
    Netherlands
    New Zealand
    Poland
    Spain
    Switzerland
    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
    The end of study is defined as the date of database lock for all patients.
    El final del estudio se define como la fecha del cierre de base de datos para todos los pacientes.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years
    E.8.9.1In the Member State concerned months36
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years3
    E.8.9.2In all countries concerned by the trial months3
    E.8.9.2In all countries concerned by the trial days2
    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: 280
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 70
    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 state20
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 200
    F.4.2.2In the whole clinical trial 350
    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 Decision2017-02-03
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2017-01-16
    P. End of Trial
    P.End of Trial StatusOngoing
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