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    Summary
    EudraCT Number:2011-002893-21
    Sponsor's Protocol Code Number:GO27912
    National Competent Authority:Spain - AEMPS
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2012-02-24
    Trial results View results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedSpain - AEMPS
    A.2EudraCT number2011-002893-21
    A.3Full title of the trial
    A PHASE II, DOUBLE-BLIND, PLACEBO CONTROLLED, RANDOMIZED STUDY EVALUATING THE SAFETY AND EFFICACY OF CARBOPLATIN/PACLITAXEL AND CARBOPLATIN/PACLITAXEL/BEVACIZUMAB WITH AND WITHOUT GDC-0941 IN PATIENTS WITH PREVIOUSLY UNTREATED ADVANCED OR RECURRENT NON-SMALL CELL LUNG CANCER
    Estudio fase II, aleatorizado, doble ciego, controlado con placebo para evaluar la seguridad y la eficacia de carboplatino/paclitaxel y carboplatino / paclitaxel /bevacizumab con y sin GDC- 0941 en pacientes con cáncer de pulmón no microcítico avanzado o recurrente sin tratar previamente.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Study of the novel cancer drug GDC-0941 (or placebo) in combination with : a) the approved anticancer drugs carboplatin and paclitaxel; and b) the approved anticancer drugs carboplatin, paclitaxel and bevacizumab in previously untreated advance or recurrent patients with advanced non-small cell lung cancer
    Estudio de un nuevo fármaco para el cáncer GDC-0941 (o placebo) en combinación con: a) unos fármacos anticancerígenos aprobados carboplatino y paclitaxel; y b) unos fármacos anticancerígenos aprobados carboplatino , paclitaxel y bevacizumab en pacientes con cáncer de pulmón no microcítico avanzado o recurrente sin tratar previamente.
    A.4.1Sponsor's protocol code numberGO27912
    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 SponsorGenentech, Inc.
    B.1.3.4CountryUnited States
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportGenentech
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationGenentech
    B.5.2Functional name of contact pointGenentech Trial Information Support
    B.5.3 Address:
    B.5.3.1Street Address1 DNA Way
    B.5.3.2Town/ citySouth San Francisco
    B.5.3.3Post code94080
    B.5.3.4CountryUnited States
    B.5.4Telephone number+1888662 6728
    B.5.5Fax number+1866200 8133
    B.5.6E-mailglobal.rochegenentechtrials@roche.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 nameGDC-0941/RO5314482
    D.3.2Product code GDC-0941
    D.3.4Pharmaceutical form Film-coated tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.9.1CAS number 957054-33-0
    D.3.9.2Current sponsor codeGDC-0941/RO5314482
    D.3.9.3Other descriptive nameGDC-0941.180
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number20
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 2
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation 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 nameGDC-0941/RO5314482
    D.3.2Product code GDC-0941
    D.3.4Pharmaceutical form Film-coated tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.9.1CAS number 957054-33-0
    D.3.9.2Current sponsor codeGDC-0941/RO5314482
    D.3.9.3Other descriptive nameGDC-0941.180
    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: 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 Avastin
    D.2.1.1.2Name of the Marketing Authorisation holderGenentech, Inc.
    D.2.1.2Country which granted the Marketing AuthorisationUnited States
    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 nameAvastin (Bevacizumab)
    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 INNBEVACIZUMAB
    D.3.9.1CAS number 216974-75-3
    D.3.9.4EV Substance CodeSUB16402MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number25
    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: 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 Paclitaxel-GRY
    D.2.1.1.2Name of the Marketing Authorisation holderTEVA 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.3.1Product 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: 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 Carboplatin-GRY
    D.2.1.1.2Name of the Marketing Authorisation holderGRY Pharma 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.3.1Product nameCarboplatin
    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 INNCARBOPLATINO
    D.3.9.1CAS number 41575-94-4
    D.3.9.4EV Substance CodeSUB06614MIG
    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.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboFilm-coated tablet
    D.8.4Route of administration of the placeboOral use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    PREVIOUSLY UNTREATED ADVANCED OR RECURRENT NON-SMALL CELL LUNG CANCER
    Cáncer de pulmón no microcítico avanzado o recurrente no tratado.
    E.1.1.1Medical condition in easily understood language
    Patients with previously untreated, advanced or recurrent non-small cell lung cancer
    Pacientes con cáncer de pulmón no microcítico avanzado o recurrente no tratado
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 14.1
    E.1.2Level PT
    E.1.2Classification code 10061873
    E.1.2Term Non-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 No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    For Arms A and B (squamous NSCLC), the primary objectives are:
    - To evaluate the efficacy (as measured by PFS) of GDC-0941 + carboplatin + paclitaxel (Arm A) versus carboplatin + paclitaxel (Arm B) in all patients with squamous NSCLC
    - To evaluate the efficacy (as measured by PFS) of GDC-0941 + carboplatin + paclitaxel (Arm A) versus carboplatin + paclitaxel (Arm B) in patients with squamous NSCLC with PIK3CA amplification

    For Arms C and D (non-squamous NSCLC), the primary objectives are:
    - To evaluate the efficacy (as measured by PFS) of GDC-0941 + carboplatin + paclitaxel + bevacizumab (Arm C) versus carboplatin + paclitaxel + bevacizumab (Arm D) in all patients with non squamous NSCLC
    - To evaluate the efficacy (as measured by PFS) of GDC-094 + carboplatin + paclitaxel + bevacizumab (Arm C) versus carboplatin + paclitaxel +bevacizumab (Arm D) in patients with non squamous NSCLC with PTEN-low status
    En los grupos A y B (CPNM epidermoide)
    -Evaluar la eficacia (medida mediante la SSP) de GDC-0941 + carboplatino + paclitaxel (grupo A) frente a carboplatino + paclitaxel (grupo B) en todos los pacientes con CPNM epidermoide y lo mismo en los pacientes con CPNM epidermoide con amplificación de PIK3CA.
    -En los grupos C y D (CPNM no epidermoide.
    - Evaluar la eficacia (medida mediante la SSP) de GDC-0941 + carboplatino + paclitaxel + bevacizumab (grupo C) frente a carboplatino + paclitaxel + bevacizumab (grupo D) en todos los pacientes con CPNM no epidermoide y lo mismo en los pacientes con CPNM no epidermoide con concentraciones bajas de PTEN.
    E.2.2Secondary objectives of the trial
    For Arms A and B (squamous NSCLC):
    - To assess the clinical activity (as measured by ORR, duration of response and OS), of GDC-0941 + carboplatin + paclitaxel (Arm A) versus carboplatin + paclitaxel (Arm B) in all patients with squamous NSCLC and in patients with squamous NSCLC with PIK3CA amplification
    - To evaluate the safety and tolerability of GDC-0941 when combined with carboplatin + paclitaxel in all patients with squamous NSCLC
    For Arms C and D (non-squamous NSCLC):
    - To assess the clinical activity (as measured by ORR, duration of response and OS), of GDC-0941 + carboplatin + paclitaxel + bevacizumab (Arm C) versus carboplatin + paclitaxel + bevacizumab (Arm D) in all patients with non-squamous NSCLC and in patients with non-squamous NSCLC with PTEN-low status
    - To evaluate the safety and tolerability of GDC-0941 when combined with carboplatin + paclitaxel + bevacizumab in all patients with non-squamous NSCLC
    Please refer to protocol for additional secondary objectives.
    En los grupos A y B (CPNM epidermoide): -Evaluar la actividad clínica (medida mediante la TRO, duración de la respuesta y SG) del grupo A frente a grupo B en todos los pacientes con CPNM epidermoide y con CPNM epidermoide con amplificación de PIK3CA. -Evaluar la seguridad y la tolerabilidad de GDC-0941 cuando se combina con carboplatino + paclitaxel en todos los pacientes con CPNM epidermoide.
    En los grupos C y D (CPNM no epidermoide):- Evaluar la actividad clínica (medida mediante la TRO, duración de la respuesta y SG) del grupo C frente a gupo D en todos los pacientes con CPNM no epidermoide y en los pacientes con CPNM no epidermoide con concentraciones bajas de PTEN.-Evaluar la seguridad y la tolerabilidad de GDC-0941 cuando se combina con carboplatino + paclitaxel + bevacizumab en todos los pacientes con CPNM no epidermoide.
    Refiérase al protocolo para el resto de los objetivos secundarios
    .
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    For ALL Arms, patients must meet the following criteria to undergo screening procedures:
    - Signed Informed Consent Form
    - All patients must consent to the collection of an archival formalin-fixed paraffin embedded (FFPE) block or freshly cut unstained tumor slides from archival tumor tissue (10?15 preferred, minimum of 5 slides required) or a newly collected tumor sample for PIK3CA amplification testing and/or PTEN IHC, as well as for other protocol-mandated exploratory assessments.
    Availability of archival tissue for biomarker testing must be confirmed by the site prior to any study-specific screening procedures.
    Suitability of archival non-FFPE tissue must be evaluated by the local study pathologist and discussed with the Genentech Medical Monitor.
    Patients with no available archival tissue (or if the sample is difficult to obtain) may undergo a new tumor biopsy to meet eligibility criteria, as long as the patient consents to this and the biopsy can be obtained with minimal risk and discomfort to the patient as determined by the local investigator.
    Adequate tumor tissue content of the patient's archival tumor sample must be confirmed by the site's pathologist or a third-party vendor prior to randomization of the patient.
    For Arms A and B, patients must meet the following criteria to be eligible:
    - Histologically documented advanced (Stage IV) or recurrent squamous NSCLC
    Diagnoses of squamous NSCLC that are based on cytology alone are not acceptable.
    Mixed tumors should be categorized according to the predominant cell type.
    For Arms C and D, patients must meet the following criteria to be eligible:
    - Histologically documented advanced (Stage IV) or recurrent non-squamous NSCLC
    Diagnoses of non-squamous NSCLC that are based on cytology alone are not acceptable.
    Mixed tumors should be categorized according to the predominant cell type.
    For ALL Arms, patients must meet the following criteria to be eligible:
    - Age >= 18 years
    - ECO performance status of 0 or 1 (see Appendix E)
    - Disease that is measurable per RECIST v1.1 (see Appendix C)
    - Adequate hematologic and end organ function, defined by the following laboratory results obtained within 14 days prior to the first study treatment:
    Absolute neutrophil count (ANC) >= 1500 cells/microL
    Without granulocyte colony stimulating factor support within 2 weeks prior to randomization
    Platelet count >= 100,000/microL
    Without transfusion within 2 weeks prior to randomization
    Hemoglobin >= 9.0 g/dL (90 g/L)
    Patients may be transfused to meet this criterion.
    Albumin >= 3.0 g/dL (30 >=mol/L)
    Total bilirubin <= 1.5 x ULN
    AST and ALT <= 3.0 x ULN
    Serum creatinine <= 1.5 x ULN, or creatinine clearance >= 50 mL/min on the basis of the Cockcroft-Gault glomerular filtration rate estimation:
    (140-age) x (weight in kg) x (0.85 if female) / 72 x (serum creatinine in mg/dL)
    INR <= 1.5 and aPTT <= 1.5 x ULN, except for patients receiving allowed anti-coagulation therapy
    For patients without known type II diabetes, the following is required
    Fasting blood glucose < 135 mg/dL (7.49 mmol/L) and HbA1c < 7.0%
    For patients with type II diabetes receiving oral anti-hyperglycemic therapy the following is required:
    Fasting blood glucose < 160 mg/dL (8.88 mmol/L) and HbA1c < 8.5
    Stable regimen of oral anti-hyperglycemic therapy without the use of insulin for at least 3 weeks prior to randomization
    Fasting blood glucose levels < 160 mg/dL (8.88 mmol/L) and no hypoglycemia during home monitoring for at least 1 week prior to randomization
    - For female patients of childbearing potential and male patients with partners of childbearing potential, agreement (by patient and/or partner) to use two effective forms of contraception (e.g., surgical sterilization, a reliable barrier method, birth control pills, or contraceptive hormone implants)
    For females in Arms A and B, continued use for the duration of the study treatment or 6 months after discontinuation of paclitaxel, whichever is longer, is required.
    For females in Arms C and D, continued use until 6 months after study treatment discontinuation is required.
    For males in Arms A, B, C, and D, continued use until 90 days after study treatment or 6 months after discontinuation of paclitaxel, whichever is longer, is required.
    - Firma del documento de consentimiento informado.
    -Todos los pacientes deben otorgar su consentimiento para la obtención de un bloque fijado con formol e incluido en parafina (FFIP) de archivo o extensiones tumorales sin teñir de reciente preparación a partir de tejido tumoral archivado (preferiblemente 10-15, mínimo exigido de 5 extensiones) o una muestra tumoral recién obtenida para realizar un análisis de amplificación de PIK3CA y/o IHQ de PTEN, así como otras evaluaciones exploratorias exigidas por el protocolo.
    La disponibilidad de tejido de archivo para realizar análisis de biomarcadores debe ser confirmada por el centro antes de efectuar ningún procedimiento de selección específico del estudio.La idoneidad del tejido no FFIP de archivo debe ser evaluada por el anatomopatólogo del estudio local y comentarse con el monitor médico de Genentech.
    Los pacientes sin tejido de archivo disponible (o si la muestra es difícil de obtener) podrán someterse a una nueva biopsia tumoral para cumplir los criterios de participación, siempre que el paciente dé su consentimiento para ello y la biopsia pueda obtenerse con mínimos riesgos y molestias para el paciente según lo determinado por el investigador local. El contenido suficiente en tejido tumoral de las muestras tumorales de archivo del paciente debe ser confirmado por el anatomopatólogo del centro o por un proveedor externo antes de la aleatorización del paciente.
    En los grupos A y B, los pacientes deberán cumplir los siguientes criterios para poder participar:
    - CPNM epidermoide avanzado o recurrente (estadio IV) confirmado mediante histología.Los diagnósticos de CPNM epidermoide que se basen exclusivamente en citología no son aceptables. Los tumores mixtos han de clasificarse en función del tipo celular predominante.
    En los grupos C y D, los pacientes deberán cumplir los siguientes criterios para poder participar:
    - CPNM no epidermoide avanzado o recurrente (estadio IV) confirmado mediante histología.Los diagnósticos de CPNM no epidermoide que se basen exclusivamente en citología no son aceptables. Los tumores mixtos han de clasificarse en función del tipo celular predominante.
    En TODOS los grupos, los pacientes deberán - Edad >=18 años.
    -Estado funcional del ECOG de 0 ó 1
    - Enfermedad mensurable según los criterios RECIST, versión 1.1
    -Función hematológica y orgánica adecuada, definida por los siguientes
    resultados analíticos obtenidos en los 14 días previos al comienzo del
    tratamiento del estudio:
    -Recuento absoluto de neutrófilos (RAN) >=1500 células/microl. Sin apoyo con factor estimulador de las colonias de granulocitos durante las 2 semanas previas a la aleatorización.
    -Recuento de plaquetas >= 100.000/microl.Sin transfusiones durante las 2 semanas previas a la aleatorización.
    -Hemoglobina >= 9,0 g/dl (90 g/l).Se podrá transfundir a los pacientes para cumplir este criterio.
    -Albúmina >= 3,0 g/dl (30 micromol/l).
    -Bilirrubina total <=1,5 x LSN.
    -AST y ALT <= 3,0 x LSN.
    -Creatinina sérica <= 1,5 x LSN o aclaramiento de creatinina >= 50 ml/min calculado a partir de la fórmula de filtración glomerular de Cockroft-Gautl: (140 - edad) x (peso en kg) x (0,85 en mujeres) 72 x (creatinina sérica en mg/dl)
    INR <= 1,5 y TTPa <= 1,5 x LSN, excepto en los pacientes que estén recibiendo un tratamiento anticoagulante permitido.
    En los pacientes sin diabetes tipo 2 conocida se exigirá lo siguiente -Glucemia en ayunas < 135 mg/dl (7,49 mmol/l) y HbA1c < 7,0%.
    En los pacientes con diabetes tipo 2 que estén recibiendo tratamiento antidiabético oral se exigirá lo siguiente:
    Glucemia en ayunas < 160 mg/dl (8,88 mmol/l) y HbA1c < 8,5%. Régimen estable de tratamiento antidiabético oral sin uso de insulina durante las 3 semanas previas a la aleatorización como mínimo. Glucemia en ayunas < 160 mg/dl (8,88 mmol/l) y ausencia de hipoglucemia durante el control domiciliario durante al menos una semana antes de la aleatorización.
    -En las mujeres en edad fértil y los varones con parejas en edad fértil, compromiso (por parte del paciente o su pareja) a utilizar dos métodos anticonceptivos eficaces (por ejemplo, esterilización quirúrgica, un método de barrera fiable, anticonceptivos orales o implantes hormonales anticonceptivos).
    En las mujeres de los grupos A y B se exige un uso continuado durante todo el tratamiento del estudio o durante los 6 meses siguientes a la retirada de paclitaxel, lo que sea más prolongado.
    En las mujeres de los grupos C y D se exige un uso continuado hasta 6 meses después de la discontinuación del tratamiento del estudio.
    En los varones de los grupos A, B, C y D se exige un uso continuado hasta 90 días después del tratamiento del estudio o durante los 6 meses siguientes a la discontinuación de paclitaxel, lo que sea más prolongado.
    E.4Principal exclusion criteria
    Patients for ALL Arms who meet any of the following criteria will be excluded from study entry:
    -NSCLC with documented EGFR mutation or documented fusion gene involving the anaplastic lymphoma kinase (ALK) gene (such as EML4- ALK)
    -Prior therapy (including chemotherapy, antibody therapy, tyrosine kinase inhibitors, radiotherapy, immunotherapy, hormonal therapy, or investigational therapy) before Day 1 of Cycle 1 for the treatment of advanced (Stage IV) or recurrent NSCLC
    Patients who received prior adjuvant chemotherapy or radiotherapy for NSCLC are not excluded if the time interval from completion of adjuvant therapy until disease progression is >12 months
    Patients who received prior palliative radiotherapy for metastatic or lobar lesions (not including target lesions) are not excluded (if > 2 weeks prior to Day 1 of Cycle 1).
    Patients who receive hormone-replacement therapy or oral contraceptives are not excluded.
    Patients who received herbal therapy >2 weeks prior to Day 1 of Cycle 1 are not excluded.
    -Evidence of tumor invading major blood vessels on imaging
    The investigator or the local radiologist must exclude evidence of tumor that is fully contiguous with, surrounding, or extending into the lumen of a major blood vessel (e.g., pulmonary artery or superior vena cava).
    -Known CNS disease except for treated brain metastases
    Treated brain metastases are defined as having no evidence of progression or hemorrhage >2 weeks after treatment and no ongoing requirement for dexamethasone, as ascertained by clinical examination and brain imaging (MRI or CT) during the screening period
    Stable doses of non-enzyme inducing anti-convulsants are allowed
    Treatment for brain metastases may include whole brain radiotherapy, radiosurgery (Gamma Knife, LINAC, or equivalent) or a combination as deemed appropriate by the treating physician and if >2 weeks have passed since radiation treatment
    Patients with CNS metastases treated by neurosurgical resection or brain biopsy performed within 3 months prior to Day 1 of Cycle 1 will be excluded.
    -Leptomeningeal disease
    -Malignancies other than NSCLC successfully treated within 3 years prior to randomization, except for adequately treated carcinoma in situ of the cervix, basal or squamous cell skin cancer, localized prostate cancer treated surgically with curative intent, ductal carcinoma in situ treated surgically with curative intent
    -Type I diabetes
    -Type II diabetes requiring chronic therapy with insulin
    -Requirement for supplemental oxygen therapy to perform activities of daily living
    -Unstable angina
    -Serious cardiac arrhythmia requiring medication during the study
    -New York Heart Association (NYHA) Class II or greater congestive heart failure
    -History of malabsorption syndrome or other condition that would interfere with enteral absorption
    -Major surgical procedure, open biopsy, or significant traumatic injury within 28 days prior to Day 1 of Cycle 1, or anticipation of need for major surgical procedure during the course of the study
    Placement of vascular access device will not be considered major surgery
    -Clinically significant history of liver disease, including cirrhosis, active viral hepatitis and current alcohol abuse
    -Known HIV infection
    -Active infection requiring IV antibiotics
    -Active inflammatory diseases that require immunosuppressants, including small or large intestine inflammation such as Crohn's disease or ulcerative colitis
    -Active autoimmune disease that is not controlled by nonsteroidal antiinflammatory drugs
    -Need for current chronic corticosteroid therapy (>=10 mg of prednisone per day or an equivalent dose of other anti inflammatory corticosteroids)
    Stable use (within 3 months prior to Day 1 of Cycle 1) of inhaled corticosteroids is allowed
    -Pregnancy, lactation, or breastfeeding
    -Uncontrolled hypercalcemia, defined as values above the ULN, despite optimal management including bisphosphonate therapy
    Chronic use of bisphosphonate therapy for other reasons (e.g., bone metastasis, osteoporosis, etc.) is allowed.
    -Uncontrolled hypomagnesemia or hypokalemia, defined as values below the LLN despite optimal electrolyte supplementation or management
    -Grade >=2 peripheral neuropathy
    -Known severe hypersensitivity to taxanes or platinums or any of their excipients (including mannitol and macroglycol ricinoleate)
    -Inability or unwillingness to swallow pills
    -Inability to comply with study and follow up procedures
    -Current severe, uncontrolled systemic disease (e.g., clinically significant cardiovascular, pulmonary, or metabolic disease)
    -Any other diseases, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug or that may affect the interpretation of the results or render the patient at high risk for treatment complications
    Refer to section 4.1.3.2 of the protocol for Bevacizumab-Specific Exclusion Criteria for Arms C & D
    CPNM con mutación de EGFR documentada o gen de fusión documentado que afecte al gen de la cinasa del linfoma anaplásico (ALK) (como EML4-ALK).
    -Tratamiento previo (quimioterapia, terapia con anticuerpos, inhibidores de la tirosina cinasa, radioterapia, inmunoterapia, tratamiento hormonal o tratamiento en investigación) antes del día 1 del ciclo 1 para el tratamiento del CPNM avanzado ó recurrente (estadio IV).
    -Presencia de invasión tumoral de vasos sanguíneos importantes en los
    estudios de imagen.
    -Enfermedad conocida del SNC, salvo metástasis cerebrales tratadas.
    -Afectación leptomeníngea.
    -Tumores malignos distintos del CPNM tratados con éxito en los 3 años previos a la aleatorización, excepto carcinoma in situ de cuello uterino debidamente tratado, cáncer basocelular o espinocelular de piel, cáncer de próstata localizado tratado mediante cirugía con fines curativos y carcinoma canalicular in situ tratado mediante cirugía con fines curativos.
    - Diabetes tipo 1.
    -Diabetes tipo 2 que precisa tratamiento crónico con insulina.
    -Necesidad de oxigenoterapia complementaria para realizar las actividades cotidianas.
    -Angina de pecho inestable.
    -Arritmia cardíaca grave que precise medicación durante el estudio.
    -Insuficiencia cardíaca congestiva en clase II o superior de la New York Heart Association.
    -Antecedentes de síndrome de malabsorción u otro trastorno que pudiera interferir en la absorción intestinal.
    -Intervención de cirugía mayor, biopsia abierta o traumatismo importante en los 28 días previos al día 1 del ciclo 1 o previsión de la necesidad de una intervención de cirugía mayor durante el estudio. La colocación de un dispositivo de acceso vascular no se considerará cirugía mayor.
    -Antecedentes clínicamente significativos de hepatopatía, como cirrosis, hepatitis viral activa y alcoholismo activo.
    -Infección por el VIH conocida.
    -Infección activa que precisa antibióticos intravenosos.
    - Enfermedades inflamatorias activas que exijan inmunosupresores, incluidas las que afectan al intestino delgado o grueso, como la enfermedad de Crohn o la colitis ulcerosa.
    -Enfermedad autoinmunitaria activa que no se controla con antiinflamatorios no esteroideos.
    -Necesidad de tratamiento crónico activo con corticoides (>= 10 mg de prednisona al día o una dosis equivalente de otros corticoides antiinflamatorios). Se permite el uso estable (en los 3 meses previos al día 1 del ciclo 1) de corticoides inhalados.
    -Embarazo o período de lactancia.
    -Hipercalcemia no controlada, definida como valores por encima del LSN, a pesar de un tratamiento óptimo que incluya el uso de bisfosfonatos. Se permite el uso crónico de bisfosfonatos por otros motivos (como metástasis óseas, osteoporosis, etc.).
    -Hipomagnesemia o hipopotasemia no controlada, definida como valores por debajo del LIN a pesar de la administración de suplementos de electrólitos o intervención adecuada.
    -Neuropatía periférica de grado >= 2.
    -Hipersensibilidad intensa conocida a taxanos o derivados del platino o a cualesquiera otros excipientes (incluidos el manitol y el ricinoleato de macroglicol).
    -Incapacidad o falta de disposición para tragar pastillas.
    -Incapacidad para cumplir los procedimientos del estudio o del seguimiento.
    -Enfermedad sistémica incontrolada y grave activa (p.e, enfermedad cardiovascular, pulmonar o metabólica clínicamente importante).
    -Cualquier otra enfermedad, disfunción metabólica, hallazgo en la exploración física o dato analítico que suscite sospechas razonables de una enfermedad o proceso que contraindique el uso de un fármaco en investigación o que pueda afectar a la interpretación de los resultados o suponer un riesgo elevado de complicaciones del tratamiento para el paciente.
    Para los criterios de exclusión relacionados específicamente con bevacizumab en los grupos C y D refiérase al protocolo sección 4.1.3.2
    E.5 End points
    E.5.1Primary end point(s)
    For ALL Arms and all predefined study populations (see Section 3.5), the
    primary efficacy outcome measure is:
    - PFS, defined as the time from randomization to disease progression as assessed by the investigator per RECIST v1.1 (Appendix C) or death from any cause on study (<= 30 days after the last dose of study treatment) whichever occurs first
    En TODOS los grupos y todas las poblaciones del estudio predefinidas (véase la sección 3.5), el criterio de valoración principal de la eficacia es:
    -Supervivencia sin progresión (SSP), definida como el tiempo transcurrido entre la aleatorización y la progresión de la enfermedad evaluada por el investigador mediante los criterios RECIST, versión 1.1 (apéndice C) o la muerte por cualquier causa durante el estudio (<= 30 días después de la última dosis del tratamiento del estudio), lo que suceda primero.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Please see E.5.1
    Por favor refiérase a la sección E.5.1
    E.5.2Secondary end point(s)
    For ALL Arms and all predefined study populations (see Section 3.3.5), the secondary efficacy outcome measures are:
    - Objective tumor response as assessed by the investigator using RECIST v1.1 (Appendix C); objective responses must be confirmed >= 28 days after initial response
    - Duration of objective response, defined as the time from first observation of an objective tumor response until first observation of disease progression as assessed by the investigator using RECIST v1.1 (Appendix C)
    - OS, defined as the time from randomization until death from any cause
    En TODOS los grupos y todas las poblaciones del estudio predefinidas (véase la sección 3.3.5), los criterios de valoración secundarios de la eficacia son:
    -Respuesta tumoral objetiva evaluada por el investigador mediante los criterios los RECIST, versión 1.1 (apéndice C); las respuestas objetivas deben confirmarse >= 28 días después de la respuesta inicial
    E.5.2.1Timepoint(s) of evaluation of this end point
    Please see E.5.1
    Por favor refiérase a la sección E.5.2
    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 No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic Yes
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over Yes
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial4
    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 EEA45
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Argentina
    Australia
    Brazil
    Canada
    Chile
    France
    Germany
    Hungary
    Israel
    Italy
    Netherlands
    Russian Federation
    Spain
    Ukraine
    United Kingdom
    United States
    E.8.7Trial has a data monitoring committee Yes
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    When last patient reaches overall survival (OS) or is lost to follow up.
    Cuando el último paciente alcance la supervivencia global (SG) o sea pérdida de seguimiento.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years3
    E.8.9.1In the Member State concerned months7
    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 months7
    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: 226
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 76
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state15
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 175
    F.4.2.2In the whole clinical trial 302
    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)
    Following study completion or discontinuation, patients who continue to benefit from study treatment may be given the
    opportunity to continue treatment as part of an extension study. In circumstances when the study drug used during the study continues to be available, Genentech will work closely with the site to assess each patient's eligibility on a case-by-case basis. Depending on the reasons for study discontinuation, however, the study drug may not be offered after study discontinuation.
    Tras la finalización o suspensión del estudio, los pacientes que sigan beneficiándose del tratamiento podrán participar en un estudio de extensión. Si el fármaco sigue estando disponible, Genentech evaluará con el centro la elegibilidad de cada paciente de forma individual. En función de los motivos de suspensión del estudio es posible que no pueda ofrecerse el fármaco después de la suspensión del estudio.
    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 Decision2012-04-03
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2012-03-15
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2016-03-30
    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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