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    Summary
    EudraCT Number:2015-001641-89
    Sponsor's Protocol Code Number:PM1183-C-003-14
    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:2016-06-14
    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 number2015-001641-89
    A.3Full title of the trial
    Phase III Randomized Clinical Trial of Lurbinectedin (PM01183)/Doxorubicin (DOX) versus Cyclophosphamide (CTX), Doxorubicin (DOX) and Vincristine (VCR) (CAV) or Topotecan as Treatment in Patients with Small-Cell Lung Cancer (SCLC) Who Failed One Prior Platinum-containing Line (ATLANTIS Trial)
    Ensayo clínico de fase III aleatorizado de lurbinectedin (PM01183)/doxorubicina (DOX) en comparación con ciclofosfamida (CTX), doxorubicina (DOX) y vincristina (VCR) (CAV) o topotecán como tratamiento en pacientes con carcinoma microcítico de pulmón (CMP) en quienes ha fracasado una línea de tratamiento anterior con platino (ensayo ATLANTIS)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Clinical Trial of Lurbinectedin (PM01183)/Doxorubicin (DOX) versus Cyclophosphamide (CTX), Doxorubicin (DOX) and Vincristine (VCR) (CAV) or Topotecan as Treatment in Patients with Small-Cell Lung Cancer (SCLC)
    Ensayo clínico de lurbinectedin (PM01183)/doxorubicina (DOX) en comparación con ciclofosfamida (CTX), doxorubicina (DOX) y vincristina (VCR) (CAV) o topotecán como tratamiento en pacientes con carcinoma microcítico de pulmón (CMP)
    A.3.2Name or abbreviated title of the trial where available
    ATLANTIS trial
    Ensayo clínico ATLANTIS
    A.4.1Sponsor's protocol code numberPM1183-C-003-14
    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 SponsorPharma Mar S.A.
    B.1.3.4CountrySpain
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportPharma Mar S.A.
    B.4.2CountrySpain
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationPharma Mar S.A.
    B.5.2Functional name of contact pointClinical Trials
    B.5.3 Address:
    B.5.3.1Street AddressAvd. de los Reyes,nº1. Pol. Ind. La Mina
    B.5.3.2Town/ cityColmenar Viejo (Madrid)
    B.5.3.3Post code28770
    B.5.3.4CountrySpain
    B.5.4Telephone number+3491846 60 00
    B.5.5Fax number+3491846 60 03
    B.5.6E-mailclinicaltrials@pharmamar.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 namelurbinectedin
    D.3.2Product code PM01183
    D.3.4Pharmaceutical form Powder for 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 INNlurbinectedin
    D.3.9.1CAS number 497871-47-3
    D.3.9.2Current sponsor codePM01183
    D.3.9.4EV Substance CodeSUB31196
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number4
    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 Doxorubicin-Actavis 2 mg/ml Konzentrat zur Herstellung einer Infusionslösung
    D.2.1.1.2Name of the Marketing Authorisation holderActavis Group PTC ehf.
    D.2.1.2Country which granted the Marketing AuthorisationGermany
    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 namedoxorubicin
    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 INNdoxorubicin
    D.3.9.1CAS number 23214-92-8
    D.3.9.4EV Substance CodeSUB06391MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number2
    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 Topotecan Hospira 4 mg/4 ml concentrate for solution for infusion
    D.2.1.1.2Name of the Marketing Authorisation holderHospira UK 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.3.4Pharmaceutical 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 INNtopotecan
    D.3.9.1CAS number 123948-87-8
    D.3.9.4EV Substance CodeSUB11191MIG
    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 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 Cyclophosphamid Trockensubstanz 1 g Baxter Oncology
    D.2.1.1.2Name of the Marketing Authorisation holderBaxter Oncology GmbH
    D.2.1.2Country which granted the Marketing AuthorisationGermany
    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.3.4Pharmaceutical form Powder 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 INNCYCLOPHOSPHAMIDE
    D.3.9.1CAS number 50-18-0
    D.3.9.4EV Substance CodeSUB06859MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number1000
    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 Vincristine Sulphate 1 mg/ml Injection
    D.2.1.1.2Name of the Marketing Authorisation holderHospira UK Limited
    D.2.1.2Country which granted the Marketing AuthorisationUnited Kingdom
    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.3.4Pharmaceutical 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 INNvincristine
    D.3.9.1CAS number 2068-78-2
    D.3.9.4EV Substance CodeSUB05101MIG
    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 Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Small-Cell Lung Cancer (SCLC)
    Cáncer de pulmón microcítico (CMP)
    E.1.1.1Medical condition in easily understood language
    Small-Cell Lung Cancer (SCLC)
    Cáncer de pulmón microcítico (CMP)
    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 10041067
    E.1.2Term Small cell lung 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 Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To determine a difference in PFS by an Independent Review Committee (IRC) between lurbinectedin (PM01183)/DOX and a control arm consisting of best Investigator’s choice between CTX, DOX and VCR (CAV) or topotecan, as treatment in SCLC patients after failure of one prior platinum-containing line
    Determinar una diferencia en la supervivencia sin progresión (SSP) por parte de un Comité de revisión independiente (CRI) entre lurbinectedina (PM01183) más doxorubicina (DOX) y un grupo de control tratado con la mejor alternativa posible a juicio del investigador entre ciclofosfamida (CTX), doxorubicina (DOX) y vincristina (VCR) (CAV) o topotecán en pacientes con CMP después del fracaso de una línea de tratamiento previa con platino.
    E.2.2Secondary objectives of the trial
    -Overall survival (OS).
    -Mid- and long-term survival (OS at 12, 18 and 24 months, respectively).
    -Efficacy and safety profiles in the subgroups of the PM01183/DOX arm vs. CAV or topotecan
    -PFS by Investigator’s Assessment (IA).
    -Antitumor activity according to the Response Evaluation Criteria in Solid Tumors (RECIST) v.1.1.
    -Safety profile.
    -Patient-reported outcomes (PRO).
    -Pharmacokinetics (PK) of the combination in patients treated in the experimental arm (PM01183/DOX)
    -PK/pharmacodynamic (PDy) correlations in the Experimental Arm, if any.
    -Pharmacogenetics of known polymorphisms in patients treated in the experimental Arm.
    - Supervivencia global (SG)
    - Supervivencia a medio y largo plazo (SG a los 12, 18 y 24 meses, respectivamente).
    - Evaluar los perfiles de la eficacia y la seguridad de los subgrupos del grupo de tratamiento PM01183/DOX en comparación con CAV o topotecán.
    - SSP según la evaluación del investigador (EI).
    - Actividad antitumoral conforme a los criterios de evaluación de la respuesta en tumores sólidos (RECIST) v. 1.1.
    - Perfil de seguridad.
    - Resultados referidos por los pacientes (RRP)
    - Farmacocinética (FC) del tratamiento en combinación de los pacientes del grupo experimental (PM01183/DOX).
    - Correlaciones farmacodinámicas FC/FD en el grupo experimental, si las hay.
    - Farmacogenética de los polimorfismos conocidos en pacientes tratados en el grupo experimental.
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    Pharmacogenetic sub-study:
    To explore factors that may help to explain individual variability in main pharmacokinetic parameters, the presence or absence of germline mutations or polymorphisms will be analyzed in leukocyte DNA extracted from a blood sample obtained at any time during the study in the experimental Arm
    Subestudio farmacogenético:
    Con el fin de estudiar los factores que podrían ayudar a explicar la variabilidad entre los individuos en cuanto a los principales parámetros farmacocinéticos, se analizará la presencia o ausencia de mutaciones o polimorfismos de la estirpe germinal en ADN de leucocitos extraído de una muestra de sangre obtenida en cualquier momento del estudio en el grupo experimental.
    E.3Principal inclusion criteria
    1) Voluntary written informed consent of the patient obtained before any study-specific procedure.
    2) Adult patients aged ≥ 18 years.
    3) Histologically or cytologically confirmed diagnosis of limited or extensive stage SCLC which failed one prior platinum-containing regimen. Small-cell carcinoma of unknown primary site with or without neuroendocrine features confirmed in histology test(s) performed on
    metastatic lesion(s) are eligible, if Ki-67/MIB-1 is expressed in >50% of tumor cells.
    4) ECOG PS ≤ 2.
    5) Adequate hematological, renal, metabolic and hepatic function in an assessment performed within 7 days (+ 3 day window) of randomization:
    a) Hemoglobin ≥ 9.0 g/dl [patients may have received priorred blood cell (RBC) transfusion, if clinically indicated]; absolute neutrophil count (ANC) ≥ 2.0 x 10^9/l and platelet count ≥ 100 x 10^9/l.
    b) Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3.0 x upper limit of normal (ULN).
    c) Total bilirubin ≤ 1.5 x ULN or direct bilirubin ≤ ULN.
    d) Albumin ≥ 3.0 g/dl.
    e) Calculated creatinine clearance (CrCL) ≥ 30 ml/minute (using Cockcroft and Gault’s formula).
    f) Left ventricular ejection fraction (LVEF) by echocardiogram (ECHO) or multiple-gated acquisition (MUGA) scan within normal range (according to institutional standards).
    g) Creatine phosphokinase (CPK) ≤ 2.5 x ULN (≤ 5.0 x ULN is acceptable if elevation is disease-related).
    6) At least three weeks since last prior anticancer treatment and recovery to grade ≤ 1 from any adverse event (AE) related to previous anticancer treatment (excluding sensory neuropathy, anemia, asthenia and alopecia, all grade ≤ 2) according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE,
    v.4).
    7) Prior radiotherapy (RT): At least four weeks since completion of whole-brain RT (WBRT), at least two weeks since completion of prophylactic cranial irradiation (PCI), and to any other site not previously specified.
    8) Evidence of non-childbearing status for women of childbearing potential (WOCBP). WOCBP must agree to use a highly effective contraceptive measure up to six weeks after treatment discontinuation. Valid methods to determine the childbearing potential, adequate contraception and requirements for WOCBP partners
    1) Consentimiento informado por escrito voluntario del paciente, obtenido antes de cualquier procedimiento específico del estudio.
    2) Pacientes adultos de ≥18 años de edad.
    3) Diagnóstico de CMP en estadio limitado o extendido confirmado mediante histología o citología en el que ha fracasado un régimen anterior con platino. Se considerará que el carcinoma microcítico de localización primaria desconocida, con o sin características neuroendocrinas confirmadas en las pruebas de histología realizadas en las lesiones metastásicas, es elegible si Ki-67/MIB-1 se expresa en >50 % de las células tumorales.
    4) EF ECOG ≤2
    5) Funciones hemática, renal, metabólica y hepática adecuadas en una evaluación efectuada en los 7 días (intervalo de +3 días)previos a la aleatorización :
    a) Hemoglobina ≥9,0 g/dl [los pacientes pueden haber recibido una transfusión de eritrocitos (ERI) previa si estaba clínicamente indicado]; cifra absoluta de neutrófilos (CAN) ≥2,0 x 109/l, y cifra de plaquetas ≥100 x 109/l.
    b) Alanina-aminotransferasa (ALAT) y aspartato-aminotransferasa (ASAT) >3,0 x límite superior de la normalidad (LSN).
    c) Bilirrubina total ≤1,5 x LSN o bilirrubina directa ≤ LSN.
    d) Albúmina ≥ 3,0 g/dl.
    e) Aclaramiento de la creatinina (ACr) calculado ≥30 ml/minuto (usando la fórmula de Cockcroft y Gault).
    f) Fracción de eyección ventricular izquierda (FEVI) mediante ecocardiograma (ECO) o ventriculografía isotópica (MUGA) dentro del intervalo normal (conforme a las normas institucionales).
    g) Creatina-cinasa (CPK) ≤2,5 x LSN (una concentración ≤5,0 x LSN es aceptable si la elevación está relacionada con la enfermedad).
    6) Al menos tres semanas desde el último tratamiento antineoplásico y recuperación hasta un grado ≤1 de cualquier acontecimiento adverso (AA) relacionado con el tratamiento antineoplásico previo (salvo la neuropatía sensitiva, la anemia, la astenia y la alopecia, todas de grado ≤2) conforme a los Criterios terminológicos comunes para los acontecimientos adversos del National Cancer Institute (CTCAE del NCI, v.4).
    7) Radioterapia previa (RT): Al menos cuatro semanas desde la finalización de la RT cerebral completa (RTCC), al menos dos semanas desde la finalización de la radiación profiláctica craneal (RPC) y de cualquier otra localización no especificada previamente.
    8) Pruebas de ausencia de embarazo para las mujeres fértiles. Las mujeres fértiles deben acceder a utilizar un método anticonceptivo de gran eficacia hasta seis semanas después de la suspensión del tratamiento. En el APPENDIX 2 se exponen los métodos válidos para determinar si una mujer es fértil, los métodos anticonceptivos adecuados y los requisitos para las parejas de mujeres fértiles.
    E.4Principal exclusion criteria
    1) More than one prior CHT-containing regimen (including patients re-challenged with same initial regimen).
    2) Patients who never received any platinum-containing regimen for SCLC treatment.
    3) Prior treatment with PM01183, topotecan or anthracyclines.
    4) Limited-stage patients who are candidates for local or regional therapy, including PCI, thoracic RT or both, must have been offered that option and completed treatment or refused it prior to randomization.
    5) Impending need for palliative RT or surgery for pathological fractures and/or for medullary compression within four weeks prior to randomization.
    6) Symptomatic, or steroid-requiring, or progressing CNSdisease involvement during at least four weeks prior to randomization (asymptomatic, non-progressing patients taking steroids in the process of already being tapered within two weeks prior to randomization are allowed).
    7) Concomitant diseases/conditions:
    a) History (within one year prior to randomization) or presence of unstable angina, myocardial infarction, congestive heart failure or clinically significant valvular heart disease.
    b) Symptomatic or uncontrolled arrhythmia despite ongoing treatment.
    c) Patients with any immunodeficiency, including those known to be or have been infected by human immunodeficiency virus (HIV).
    d) Ongoing, treatment-requiring, non-neoplastic chronic liver disease of any origin. For hepatitis B, this includes positive tests for both Hepatitis B surface antigen (HBsAg) and quantitative Hepatitis B polymerase chain reaction (PCR). For hepatitis C, this includes positive tests for both Hepatitis C antibody and quantitative Hepatitis C PCR.
    e) Active infection or increased risk due to external drainages.
    f) Intermittent or continuous oxygen requirement within two weeks prior to randomization. Patients with confirmed or suspected diagnosis of diffuse interstitial lung disease (ILD) or pulmonary fibrosis.
    g) Patients with a second invasive malignancy treated with CHT and/or RT. Patients with a previous malignancy that was completely resected with curative intention three or more years prior to randomization, and who has been continuously in remission since then will be permitted.
    h) Limitation of the patient’s ability to comply with the treatment or to follow the protocol.
    i) Documented or suspected invasive fungal infections requiring systemic treatment within 12 weeks of randomization.
    8) Pregnant or breast feeding women.
    1) Más de un régimen previo con quimioterapéuticos (incluidos los pacien es reexpuestos al mismo régimen inicial).
    2) Los pacientes que nunca recibieron un régimen con platino para el tratamiento del CMP.
    3) Tratamiento previo con PM01183, topotecán o antraciclinas.
    4) A los pacientes en estadio limitado que son candidatos para tratamiento local o regional, incluidas la RPC, la RT torácica o ambas, se les debe haber ofrecido esa opción y deben haber finalizado el tratamiento o haberlo rechazado antes de la aleatorización.
    5) Necesidad imperiosa de RT paliativa o cirugía por fracturas patológicas o por compresión medular en las cuatro semanas anteriores a la aleatorización.
    6) Afectación patológica del SNC sintomática, que requiere esteroides o en progresión durante al menos cuatro semanas antes de la aleatorización (se admite a los pacientes asintomáticos y sin progresión que reciben esteroides en proceso de disminución en las dos semanas anteriores a la aleatorización).
    7) Enfermedades/afecciones concomitantes:
    a) Antecedentes (en el año anterior a la aleatorización) o presencia de angina inestable, infarto de miocardio, insuficiencia cardíaca congestiva o valvulopatía cardíaca clínicamente significativa.
    b) Arritmia sintomática o no controlada a pesar del tratamiento continuado.
    c) Pacientes con inmunodeficiencia, incluidos los que se sabe que están o han estado infectados por el virus de la inmunodeficiencia humana (VIH).
    d) Hepatopatía crónica no neoplásica en curso, que requiere tratamiento, de cualquier etiología. En el caso de la hepatitis B, incluye pruebas positivas tanto para el antígeno de superficie del virus de la hepatitis B (HBsAg) como para la reacción en cadena de la polimerasa (RCP) cuantitativa de la hepatitis B. En el caso de la hepatitis C, incluye pruebas positivas tanto para el anticuerpo de la hepatitis C como para la RCP cuantitativa de la hepatitis C.
    e) Infección activa o mayor riesgo de infección debido a drenajes externos.
    f) Necesidad intermitente o continua de oxígeno en las dos semanas anteriores a la aleatorización. Pacientes con diagnóstico presunto o confirmado de neumopatía intersticial difusa (NID) o fibrosis pulmonar.
    g) Pacientes con una segunda neoplasia maligna invasiva tratada con quimioterapia y/o RT. Se admitirá a los pacientes con una neoplasia maligna previa que se resecó por completo con intención curativa tres o más años antes de la aleatorización y que han estado continuamente en remisión desde entonces.
    h) Limitación de la capacidad del paciente para cumplir con el tratamiento o para seguir el protocolo.
    i) Infecciones micóticas invasivas documentadas o presuntas que requieren tratamiento sistémico en las 12 semanas previas a la aleatorización.
    8) Mujeres embarazadas o en período de lactancia.
    E.5 End points
    E.5.1Primary end point(s)
    Progression-free survival (PFS) by IRC defined as the time from the date of randomization to the date of documented progression per RECIST v.1.1 or death (regardless of the cause of death). If the patient receives further antitumor therapy or is lost to follow-up before PD, PFS will be censored at the date of last tumor assessment before the date of subsequent tumor assessment.
    Supervivencia sin progresión (SSP) evaluada por el CRI, se define como el tiempo desde la fecha de la aleatorización hasta la fecha de la progresión documentada conforme a los criterios RECIST v.1.1 o la muerte (con independencia de la causa de la muerte). Si el paciente recibe tratamiento antineoplásico adicional o se pierde durante el seguimiento antes de la PE, la SSP se censurará en la fecha de la última evaluación tumoral antes de la fecha de la siguiente evaluación tumoral.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Along the study
    A lo largo del estudio
    E.5.2Secondary end point(s)
    -Overall survival (OS) calculated from the date of randomization to the date of death (death event) or last contact.
    -OS at 12/18/24 months
    -Subgroup analyses
    - Progression-free survival (PFS)
    - Best antitumor response by Independent Review Committee (IRC)/ Investigator's Assessment (IA)
    - Duration of response (DR) by IRC/IA
    - Treatment safety profile
    - Patient-reported outcomes (PRO)
    - Plasma pharmacokinetics (PK) of PM01183 and DOX
    - PK/PDy correlation
    - Pharmacogenetics
    - Supervivencia global (SG), se calculará desde la fecha de la aleatorización hasta la fecha de la muerte (acontecimiento de fallecimiento) o el último contacto.
    - SG a los 12/18/24 meses
    - Análisis en subgrupos
    - Supervivencia sin progresión (SSP)
    - Mejor respuesta antitumoral según el CRI/EI
    - Duración de la respuesta (DDR) según el CRI/EI
    - Perfil de seguridad del tratamiento
    - Resultados referidos por los pacientes (RRP)
    - Farmacocinética (FC) plasmática de PM01183 y DOX
    - Correlación FC/FD
    - Farmacogenética
    E.5.2.1Timepoint(s) of evaluation of this end point
    Along the study
    A lo largo del estudio
    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 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 concerned15
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA113
    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
    Austria
    Belgium
    Brazil
    Bulgaria
    Canada
    Czech Republic
    France
    Germany
    Greece
    Hungary
    Italy
    Lebanon
    Mexico
    Netherlands
    Poland
    Portugal
    Romania
    Spain
    Turkey
    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
    18 months after the last patient is randomized
    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 months11
    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 months11
    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: 200
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 400
    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 state60
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 377
    F.4.2.2In the whole clinical trial 600
    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 Decision2016-08-11
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2016-08-11
    P. End of Trial
    P.End of Trial StatusOngoing
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