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    Summary
    EudraCT Number:2016-003579-22
    Sponsor's Protocol Code Number:MO39107
    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:2017-05-29
    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 number2016-003579-22
    A.3Full title of the trial
    A PHASE II STUDY EXPLORING THE SAFETY AND EFFICACY OF ATEZOLIZUMAB ADMINISTERED IN COMBINATION WITH OBINUTUZUMAB OR RITUXIMAB ANTI-CD20 THERAPY IN PATIENTS WITH RELAPSED/REFRACTORY MANTLE CELL LYMPHOMA, MARGINAL ZONE LYMPHOMA AND WALDENSTRÖM MACROGLOBULINEMIA
    Estudio fase II de seguridad y eficacia de Atezolizumab administrado en combinación con terapia anti-CD20 Obinutuzumab o Rituximab en pacientes con linfoma de células del manto o de la zona marginal y macroglobulinemia de Waldenström refractarios o en recaída.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Study Exploring the Safety and Efficacy of Atezolizumab Administered in Combination with Obinutuzumab or Rituximab Anti-CD20 Therapy in Patients with Relapsed/Refractory Mantle Cell Lymphoma, Marginal Zone Lymphoma and Waldenström Macroglobulinemia
    Estudio fase II de seguridad y eficacia de Atezolizumab administrado en combinación con terapia anti-CD20 Obinutuzumab o Rituximab en pacientes con linfoma de células del manto o de la zona marginal y macroglobulinemia de Waldenström refractarios o en recaída.
    A.4.1Sponsor's protocol code numberMO39107
    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 SponsorRoche Farma S.A. (Soc.unipersonal)que realiza el ensayo en España y que actúa como representante de F.Hoffmann- La Roche
    B.1.3.4CountrySwitzerland
    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 supportF.Hoffman-La Roche Ltd.
    B.4.2CountrySwitzerland
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationF.Hoffmann-La Roche Ltd.
    B.5.2Functional name of contact pointTrial Information Support Line-TISL
    B.5.3 Address:
    B.5.3.1Street AddressGrenzacherstrasse 124
    B.5.3.2Town/ cityBasel
    B.5.3.3Post code4070
    B.5.3.4CountrySwitzerland
    B.5.6E-mailspain.start_up_unit@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 nameAtezolizumab
    D.3.2Product code RO5541267
    D.3.4Pharmaceutical form Solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntrauterine use
    Intravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNATEZOLIZUMAB
    D.3.9.1CAS number 1380723-44
    D.3.9.2Current sponsor codeRO5541267
    D.3.9.3Other descriptive nameTECENTRIQ
    D.3.9.4EV Substance CodeSUB178312
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number60
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product Yes
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 2
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Gazyvaro 1,000 mg
    D.2.1.1.2Name of the Marketing Authorisation holderRoche Registration 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
    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 INNObinutuzumab
    D.3.9.1CAS number 949142-50-1
    D.3.9.2Current sponsor codeRO5072759
    D.3.9.3Other descriptive nameOBINUTUZUMAB
    D.3.9.4EV Substance CodeSUB32751
    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 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: 3
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name MabThera 500 mg concentrate for solution for infusion
    D.2.1.1.2Name of the Marketing Authorisation holderRoche Registration 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 nameMabThera 500 mg concentrate for solution for infusion
    D.3.2Product code RO0452294
    D.3.4Pharmaceutical form 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 INNRITUXIMAB
    D.3.9.1CAS number 174722-31-7
    D.3.9.2Current sponsor codeRO452294
    D.3.9.3Other descriptive nameMabThera 500 mg concentrate for solution for infusion
    D.3.9.4EV Substance CodeSUB12570MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number500
    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 RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name MabThera 1400 mg solution for subcutaneous injection
    D.2.1.1.2Name of the Marketing Authorisation holderRoche Registration 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 nameMabThera 1400 mg solution for subcutaneous injection
    D.3.2Product code RO0452294
    D.3.4Pharmaceutical form Solution for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPSubcutaneous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNRITUXIMAB
    D.3.9.1CAS number 174722-31-7
    D.3.9.3Other descriptive nameMabThera 1400 mg solution for subcutaneous injection
    D.3.9.4EV Substance CodeSUB12570MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number120
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product Yes
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Relapsed/Refractory Mantle Cell Lymphoma (MCL), Marginal Zone Lymphoma (MZL) and Waldenström Macroglobulinemia (WM)
    LINFOMA DE CÉLULAS DEL MANTO, LINFOMA DE LA ZONA MARGINAL, MACROGLOBULINEMIA DE WALDENSTRÖM
    E.1.1.1Medical condition in easily understood language
    MCL is a B-cell non-Hodgkin lymphoma (lymph nodes, spleen, etc); MZL (B-cell lymphoma) arise from post-germinal center marginal zone B-cell; WM is a lymphoplasmacytic lymphoma in the bone marrow.
    LCM linfoma no Hodgkin de células B (ganglios linfáticos, bazo, etc); LZM (linfoma de células B) zona marginal del centro post-germinal de células B; MW linfoma linfoplasmocitario en la médula ósea.
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10054697
    E.1.2Term Waldenstrom's macroglobulinemia recurrent
    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 20.0
    E.1.2Level LLT
    E.1.2Classification code 10054698
    E.1.2Term Waldenstrom's macroglobulinemia refractory
    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 20.0
    E.1.2Level PT
    E.1.2Classification code 10077534
    E.1.2Term Marginal zone lymphoma refractory
    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 20.0
    E.1.2Level PT
    E.1.2Classification code 10077533
    E.1.2Term Marginal zone lymphoma recurrent
    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 20.0
    E.1.2Level PT
    E.1.2Classification code 10026801
    E.1.2Term Mantle cell lymphoma refractory
    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 20.0
    E.1.2Level PT
    E.1.2Classification code 10026800
    E.1.2Term Mantle cell lymphoma 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 evaluate the efficacy of atezolizumab in combination with obinutuzumab or rituximab
    Evaluar la eficacia de atezolizumab en combinación con obinutuzumab o rituximab.
    E.2.2Secondary objectives of the trial
    • To evaluate the efficacy of atezolizumab in combination with obinutuzumab or rituximab
    • To evaluate the safety and tolerability of atezolizumab in combination with obinutuzumab or rituximab
    • To characterize the pharmacokinetics of atezolizumab and obinutuzumab when administered in combination in MCL and WM patients
    • To characterize the pharmacokinetics of atezolizumab and rituximab when administered in combination in MZL patients
    • To evaluate the immune response to atezolizumab with obinutuzumab or rituximab
    - Evaluar la eficacia de atezolizumab en combinación con obinutuzumab o rituximab.
    - Evaluar la seguridad y tolerabilidad de atezolizumab en combinación con obinutuzumab o rituximab.
    - Definir la farmacocinética de atezolizumab y obinutuzumab cuando se administran en combinación a pacientes con LCM y MW.
    - Definir la farmacocinética de atezolizumab y rituximab cuando se administran en combinación a pacientes con LZM.
    - Evaluar la respuesta inmunitaria a atezolizumab en combinación con obinutuzumab o rituximab.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    - Ability to comply with the protocol
    - Age >= 18 years
    - Histologically documented, CD20 positive non-Hodgkin lymphoma (NHL), relapsed or refractory MCL and MZL. For WM relapse/refractory intended as reappearance of monoclonal IgM protein and/or recurrence of bone marrow involvement, lymphadenopathy/splenomegaly or symptoms attributable to active disease Patients must have failed at least 1 prior line of systemic treatment for mucosa associated lymphoid tissue patients.
    - Bone marrow biopsy and/or other sites of disease at screening for tumor staging and response evaluation
    - ECOG performance status of 0, 1 or 2
    - Life expectancy>=12 weeks
    - For mantle cell lymphoma (MCL) and nodal marginal zone lymphoma (MZL), at least one bi-dimensionally measurable lesion>=1.5 cm in its largest dimension by Computed Tomography scan or MRI, as defined by Revised Response Criteria for Malignant Lymphoma
    - Adequate hematologic and end-organ function
    - For women who are not postmenopausal or surgically sterile: agreement to remain abstinent or to use single highly effective or combined contraceptive methods that result in a failure rate of  1% per year during the treatment period for at least 18 months after the last dose of combination therapy
    - For women of childbearing potential, a negative serum pregnancy test result within 7 days prior to commencement of dosing
    - For men, agreement to remain abstinent or to use a condom plus an additional contraceptive method that together result in a failure rate of 1% per year during the treatment period and for at least 3 months after the last dose of atezolizumab
    - Tumor tissue or archival only
    - Capacidad para cumplir el protocolo
    - Edad ≥ 18 años
    - LNH documentado histologicamente, positivo para CD20 ,refractario o en recaída de tipo LCM o LZM. En el caso de la MW refractario o en recaída definida por la reaparición de proteína IgM monoclonal y/o de la afectación de la médula ósea, las adenopatías/esplenomegalia o los síntomas atribuibles a la enfermedad activa. Los pacientes deben haber recibido al menos una línea de tratamiento sistémico previo.
    - Biopsia de médula ósea y/u otros focos de enfermedad en el momento de la selección para determinar el estadio y la respuesta del tumor
    - Estado funcional del ECOG de 0,1 o 2
    - Esperanza de vida ≥ 12 semanas.
    - En el caso del LCM y del LZM ganglionar, al menos una lesión mensurable en dos dimensiones con un diámetro mayor ≥ 1,5 cm en la tomografía computarizada (TC) o RM según los criterios de respuesta modificados para el linfoma maligno
    - Función hematológica y de los órganos afectados, adecuada
    - Las mujeres que no son postmenopáusicas o quirúrgicamente estériles deberán comprometerse a guardar abstinencia o usar un método anticonceptivo único o combinado muy eficaz, con un índice de fallos inferior al 1% al año, durante el periodo de tratamiento y al menos hasta 18 meses después de la última dosis del tratamiento combinado.
    - Las mujeres en edad fértil deberán tener un resultado negativo en la prueba de embarazo en suero realizada en los 7 días previos al comienzo de la administración del tratamiento
    - Los varones deben comprometerse a practicar abstinencia o utilizar preservativo y otro método anticonceptivo que en conjunto tengan una tasa de fallos del 1% anual durante el período de tratamiento y hasta, como mínimo, 3 meses después de la última dosis de atezolizumab.
    - Tejido tumoral o de archivo
    E.4Principal exclusion criteria
    - Any approved anticancer therapy or hormonal therapy within 3 weeks prior to initiation of study treatment. Any radiotherapy within 4 weeks prior to initiation of study treatment.
    - Treatment with any other investigational agent or participation in another clinical trial with therapeutic intent within 28 days prior to enrolment
    - Known Central nervous system lymphoma, leptomeningeal lymphoma, or histologic evidence of transformation to a high-grade or diffuse large B-cell lymphoma
    - Uncontrolled tumor-related pain
    - Uncontrolled pleural effusion, pericardial effusion, or ascites requiring recurrent drainage procedures; patients with indwelling catheters are eligible
    - Uncontrolled hypercalcemia or symptomatic hypercalcemia requiring continued use of bisphosphonate therapy or denosumab
    - History of other malignancy
    - History of severe allergic or anaphylactic or other hypersensitivity reactions to chimeric or humanized or murine monoclonal antibodies or fusion proteins or murine proteins or known sensitivity or allergy to murine products
    - Known active bacterial, viral, fungal, mycobacterial, parasitic, or other infection or any major episode of infection requiring treatment with intravenous (IV) antibiotics or hospitalization within 4 weeks of the start of Cycle (C) 1
    - Regular treatment with corticosteroids within the 4 weeks prior to the start of C1
    General Medical Exclusions
    - Pregnant and lactating women, or intending to become pregnant during the study. Women who are not postmenopausal or surgically sterile must have a negative serum pregnancy test result within 7 days prior to Day (D) 1 of C1
    - History of autoimmune disease
    - Other serious underlying medical conditions, which, in the Investigator’s judgment, could impair the ability of the patient to participate in the study
    - Significant cardiovascular disease, such as cardiac disease (New York Heart Association Class II or greater), myocardial infarction within the previous 3 months, unstable arrhythmias, or unstable angina
    - Patients with history of confirmed progressive multifocal leukoencephalopathy
    - Patients with prior allogeneic bone marrow transplantation or prior solid organ transplantation
    - History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), drug-induced pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis per chest CT scan at screening
    - Serum albumin < 2.5 g/dL
    - Positive test for HIV, human T-lymphotrophic 1 virus, and hepatitis B or C
    - Active tuberculosis
    - Received therapeutic oral or IV antibiotics within 4 weeks prior to C1D1
    - Major surgical procedure other than for diagnosis within 28 days prior to C1D1
    - Administration of a live, attenuated vaccine within 4 weeks before C1D1
    Exclusion Criteria Related to Medications
    - Hypersensitivity to obinutuzumab, rituximab or atezolizumab or their formulation excipients
    - Prior treatment with obinutuzumab or atezolizumab, or anti progressive disease (PD)-1 or programmed death-ligand 1 (PDL-1) antibodies
    - Fludarabine or Campath® within 12 months prior to study entry
    - Prior treatment with CD137 agonists or immune checkpoint blockade therapies, including anti-CTLA4 therapeutic antibodies
    - Treatment with systemic immunostimulatory agents within 6 weeks or 5 half-lives of the drug, whichever is shorter, prior to C1D1
    - Treatment with systemic immunosuppressive medications within 2 weeks prior to C1D1
    - Cualquier tratamiento antineoplásico autorizado u hormonoterapia en las 3 semanas previas al comienzo del tratamiento del estudio. Cualquier radioterapia en las 4 semanas previas al comienzo del tratamiento.
    - Tratamiento con cualquier otro agente en investigación o participación en otro ensayo clínico con fines terapéuticos en los 28 días previos a la inclusión.
    - Linfoma del sistema nervioso central identificado, linfoma leptomeníngeo o signos histológicos de transformación a linfoma de alto grado o LDLBG.
    - Dolor relacionado con el tumor, no controlado
    - Derrame pleural incontrolado, derrame pericárdico o ascitis no controlados que requieran procedimientos de drenaje repetidos (una vez al mes o con más frecuencia); sí podrán participar los pacientes con catéteres permanentes.
    - Hipercalcemia no controlada o hipercalcemia sintomática que requiera la administración continuada de bisfosfonatos o denosumab
    - Antecedentes de otros tumores malignos
    - Antecedentes de reacciones alérgicas graves o anafilácticas u otras reacciones de hipersensibilidad a los anticuerpos monoclonales quiméricos o humanizados o murinos o a las proteínas de fusión o murinas, o sensibilidad o alergia a los productos de origen murino.
    - Infección activa conocida por bacterias, virus, hongos, micobacterias, parásitos u otra infección o cualquier episodio importante de infección que requiera tratamiento con antibióticos IV u hospitalización en las 4 semanas previas al comienzo del ciclo 1.
    - Tratamiento regular con corticoides durante las 4 semanas anteriores al inicio del ciclo 1
    Criterios de exclusión relacionados con situaciones médicas generales
    - Mujeres embarazadas o en período de lactancia, o con intención de quedarse embarazadas durante el estudio. Las mujeres que no sean posmenopáusicas (al menos 12 meses de amenorrea no inducida por tratamiento) ni quirúrgicamente estériles deben tener un resultado negativo en la prueba de embarazo en suero en los 7 días previos al día 1 del ciclo 1.
    - Antecedentes de enfermedades autoinmunitarias
    - Otros procesos médicos graves subyacentes que, en opinión del investigador, puedan afectar a la capacidad del paciente para participar en el estudio
    - Enfermedad cardiovascular importante, como insuficiencia cardíaca (clase II o superior de la New York Heart Association), infarto de miocardio en los 3 meses previos, arritmias inestables o angina inestable
    - Antecedentes de leucoencefalopatía multifocal progresiva (LMP).
    - Antecedentes de alotrasplante de médula ósea o trasplante de órganos sólidos.
    - Antecedentes de fibrosis pulmonar idiopática, neumonía organizada (p. ej., bronquiolitis obliterante), neumonitis inducida por fármacos, neumonitis idiopática o signos de neumonitis activa en la TC de tórax de la selección.
    - Albúmina sérica < 2,5 g/dl.
    - Resultado positivo en el análisis del VIH.
    - Tuberculosis activa.
    - Administración de antibióticos por vía oral o IV con fines terapéuticos en las 4 semanas previas al D1C1
    - Intervención de cirugía mayor, aparte de la diagnóstica, en los 28 días previos al D1C1 o previsión de la necesidad de una intervención de este tipo durante el estudio.
    - Administración de una vacuna de microorganismos vivos, atenuados en las 4 semanas previas al D1C1
    Criterios de exclusión relacionados con medicamentos
    - Hipersensibilidad a obinutuzumab, rituximab o atezolizumab o a los excipientes de su formulación.
    - Tratamiento previo con obinutuzumab o atezolizumab o con anticuerpos anti–PD-1 o anti–PDL-1.
    - Tratamiento con fludarabina o Campath® en los 12 meses previos a la entrada en el estudio.
    - Tratamiento previo con agonistas de CD137 o tratamientos que bloqueen puntos de control inmunitarios, como los anticuerpos terapéuticos anti-CTLA4.
    - Tratamiento con inmunoestimuladores sistémicos en las 6 semanas o el equivalente a 5 semividas del fármaco anteriores al D1C1, lo que sea más corto.
    - Tratamiento con inmunodepresores sistémicos en las 2 semanas previas al D1C1
    E.5 End points
    E.5.1Primary end point(s)
    1. For MCL and nodal and extra-nodal MZL, objective response (OR) at end of Induction, defined as a complete response (CR) or partial response (PR) based on modified Cheson 2007 criteria (excluding PET)
    2. For WM, best overall objective response (BOR), defined as a CR, very good partial response, PR, or minimum response, based on Owen 2013 criteria
    3. For gastric MZL, OR at end of Induction, defined as a CR or probable minimal residual disease or responding residual disease, based on the histological grading system of GELA 2003 criteria
    4. For splenic MZL, OR at end of Induction, defined as a CR or PR based on Matutes (2008)
    1. En el caso del LCM y el LZM ganglionar y extraganglionar, respuesta objetiva al final de la inducción (EOI), definida como RC o RP según los criterios de Cheson modificados de 2007 (excepto la PET).
    2. En el caso de la MW, mejor respuesta global objetiva (MRG), definida como RC, MBRP, RP o Rmín según los criterios de Owen de 2013.
    3. En el caso del LZM gástrico, respuesta objetiva al final de la inducción (EOI), definida como RC, EMRp o ERr según los sistemas de gradación histológica de los criterios GELA de 2003.
    4. En el caso del LZM esplénico, respuesta objetiva al final de la inducción (EOI), definida como RC o RP según los criterios de Matutes (2008).
    E.5.1.1Timepoint(s) of evaluation of this end point
    1, 3 & 4. At the end of induction
    2. Up to approximately 54 months
    1, 3 y 4. Al final de la inducción
    2. Hasta 54 meses aproximadamente
    E.5.2Secondary end point(s)
    1. Progression-free survival (PFS), defined as the time from enrolment to the first occurrence of PD or death, as determined by the investigator
    2. BOR, defined as best response seen throughout study
    3. Complete Response Rate defined as best response of CR
    4. Duration of objective response, defined for responding patients as the first occurrence of a documented objective response to the time of progression or death from any cause, whichever occurs first
    5. Time to next treatment, defined as the time from the date of enrolment to the start date of the next anti-lymphoma treatment (NALT) or death from any cause
    6. Overall survival, defined as the time from the enrolment to death from any cause
    7. Event free survival, defined as the time from enrolment to disease progression or relapse, death from any cause, as assessed by the investigator, or initiation of any NALT
    8. Disease-free survival, defined as the time from the date of the first occurrence of a documented CR to the date of disease progression, relapse or death from any cause (PFS), as assessed by the investigator, for the subgroup of patients with a BOR of CR
    9. Response rates for MCL and nodal/extranodal MZL using the assessment based on FDG-PET scans based on modified Cheson 2007
    10. Safety: Incidence, nature and severity of adverse events (AEs), graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE v4.03)
    11. Pharmacokinetic parameters of atezolizumab, obinutuzumab, and rituximab
    12. Occurrence of anti-drug antibodies of atezolizumab, obinutuzumab, and rituximab
    1. Supervivencia libre de progresión (SLP), definida como el tiempo desde la inclusión hasta la primera aparición de progresión de la enfermedad o la muerte según lo determinado por el investigador.
    2. Mejor respuesta global (MRG), definida como la mejor respuesta observada durante el estudio.
    3. Tasa de respuesta completa (TRC), definida como una mejor respuesta de RC.
    4. Duración de la respuesta objetiva (DRO), definida para los pacientes con respuesta como el tiempo transcurrido desde que se documenta por primera vez una respuesta objetiva hasta la fecha de la progresión de la enfermedad o la muerte por cualquier causa, lo que suceda antes.
    5. Tiempo hasta el siguiente tratamiento (TST), definido como el tiempo transcurrido entre la fecha de la inclusión y la fecha de inicio de un tratamiento nuevo contra el linfoma (TNL) o la muerte por cualquier causa.
    6. Supervivencia global (SG), definida como el tiempo transcurrido entre la inclusión y la muerte por cualquier causa
    7. La supervivencia libre de evento (SLE), definida como el tiempo transcurrido desde la inclusión hasta la progresión o recidiva, la muerte por cualquier causa, certificada por el investigador o el inicio de un TNL.
    8. Supervivencia sin enfermedad (SSE), definida como el tiempo transcurrido desde la fecha de la primera aparición de una RC documentada hasta la fecha de la progresión, la recidiva de la enfermedad o de la muerte por cualquier causa (SSP), evaluada por el investigador, en el subgrupo de pacientes con una mejor respuesta global (MRG) de RC.
    9. Tasas de respuesta del LCM y el LZM ganglionar o extraganglionar, evaluadas mediante FDG-PET conforme a los criterios de Cheson de 2007.
    10. Seguridad: incidencia, naturaleza e intensidad de los acontecimientos adversos (AA), graduados conforme a los criterios terminológicos comunes para la clasificación de acontecimientos adversos del National Cancer Institute (CTCAE del NCI, v4.03)
    11. Parámetros farmacocinéticos de atezolizumab, obinutuzumab y rituximab
    12. Aparición de anticuerpos contra el fármaco atezolizumab, obinutuzumab y rituximab
    E.5.2.1Timepoint(s) of evaluation of this end point
    1-10. Up to approximately 54 months
    11. C1D1, C2D1, C3D1, C4D1, C8D1, C12D1, C16D1 (atezolizumab); C1D1, C2D1, C4D1 (obinutuzumab); C1D1, C2D1, C4D1, C8D1 (rituximab), end of treatment (EOT) and at Follow-up 1 (FU1)
    12. C1D1, C2D1, C3D1, C4D1, C8D1, C12D1, C16D1 (atezolizumab); C1D1, C4D1 (obinutuzumab); C1D1, C4D1 (rituximab); EOT and at FU1
    1-10. Hasta 54 meses aproximadamente.
    11. D1C1, D1C2, D1C3, D1C4, D1C8, D1C12 (atezolizumab); D1C1, D1C2, D1C4 (obinutuzumab); D1C1, D1C2, D1C8 (rituximab), fin de tratamitento(EOT) y en la visita 1 Follow-up (FU1)
    12. D1C1, D1C2, D1C3, D1C4, D1C8, D1C12, D1C16(atezoliz fin de tratamitento(EOT) y en la visita 1 Follow-up (FU1) EOT and at FU1
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy No
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) 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 No
    E.8.1.1Randomised No
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial3
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned5
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA20
    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
    Bosnia and Herzegovina
    Korea, Republic of
    Russian Federation
    Switzerland
    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 the study is defined as the date when the last patient, last visit (LPLV) occurs. LPLV is expected to occur approximately 54 months after the first patient is enrolled.
    El estudio se considera finalizado en la fecha de la última visita del último paciente (LPLV). Se prevé que LPLV tenga lugar aproximadamente 54 meses después de la inclusión del primer paciente.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years5
    E.8.9.1In the Member State concerned months1
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years3
    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: 36
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 84
    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 No
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception No
    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 80
    F.4.2.2In the whole clinical trial 120
    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)
    The Sponsor will offer post-trial access to the study drug (atezolizumab) free of charge to eligible patients after the completion of the planned 18 cycles of study treatment in accordance with the Roche Global Policy on Continued Access to Investigational Medicinal Product.
    El Promotor ofrecerá acceso gratuito al fármaco del estudio (atezolizumab) a los pacientes que sean elegibles después de la finalización de los 18 ciclos de tratamiento del estudio, según la politica global de acceso a los productos investigacionales (Roche Global Policy on Continued Access to Investigational Medicinal Product)
    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 Decision2017-08-02
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2017-07-26
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2022-01-14
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