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    Summary
    EudraCT Number:2012-002542-20
    Sponsor's Protocol Code Number:MCL-R2Elderly
    National Competent Authority:Portugal - INFARMED
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2015-01-13
    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 ConcernedPortugal - INFARMED
    A.2EudraCT number2012-002542-20
    A.3Full title of the trial
    Efficacy of alternating immunochemotherapy consisting of R-CHOP + R-HAD versus R-CHOP alone, followed by maintenance therapy consisting of additional lenalidomide with rituximab versus rituximab alone for older patients with mantle cell lymphoma
    Eficácia de imunoquimioterapia alternada de R-CHOP+R-HAD versus R-CHOP isolado, seguida de terapêutica de manutenção com lenalidomida + rituximab versus rituximab isolado adjuvante, para doentes idosos com linfoma de células do manto
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Study to evaluate the efficacy of therapy consisting of R-CHOP + R-HAD versus R-CHOP alone, followed by maintenance therapy consisting of lenalidomide + rituximab versus rituximab alone for older patients with mantle cell lymphoma
    Estudo para avaliar a eficácia de terapia consistindo em R-CHOP+ R-HAD isolado, seguida de terapêutica de manutenção com lenalidomida com lenalidomida + rituximab versus rituximab isolado para doentes idosos com linfoma de células do manto
    A.4.1Sponsor's protocol code numberMCL-R2Elderly
    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 SponsorLYSARC
    B.1.3.4CountryFrance
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportCelgene
    B.4.2CountrySwitzerland
    B.4.1Name of organisation providing supportHoffmann La Roche
    B.4.2CountrySwitzerland
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationLYSARC
    B.5.2Functional name of contact pointPascal Bilbault
    B.5.3 Address:
    B.5.3.1Street AddressLYSARC - Centre Hospitalier Lyon-Sud Secteur Sainte Eugénie - Bâtiment 2D
    B.5.3.2Town/ cityPIERRE-BÉNITE Cedex
    B.5.3.3Post code69495
    B.5.3.4CountryFrance
    B.5.4Telephone number330472 66 93 33
    B.5.5Fax number330426 07 40 13
    B.5.6E-mailpascal.bilbault@lysarc.org
    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 Yes
    D.2.1.1.1Trade name Revlimid 15 mg
    D.2.1.1.2Name of the Marketing Authorisation holderCelgene Europe Ltd
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameLenalidomide
    D.3.2Product code CC-5013
    D.3.4Pharmaceutical form Capsule
    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.3.8INN - Proposed INNLENALIDOMIDE
    D.3.9.1CAS number 191732-72-6
    D.3.9.4EV Substance CodeSUB25389
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number15
    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 Yes
    D.2.1.1.1Trade name Revlimid 10 mg
    D.2.1.1.2Name of the Marketing Authorisation holderCelgene Europe Ltd
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameLenalidomide
    D.3.2Product code CC-5013
    D.3.4Pharmaceutical form Capsule
    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.3.8INN - Proposed INNLENALIDOMIDE
    D.3.9.1CAS number 191732-72-6
    D.3.9.4EV Substance CodeSUB25389
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number10
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 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 Revlimid 5 mg
    D.2.1.1.2Name of the Marketing Authorisation holderCelgene Europe Ltd
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameLenalidomide
    D.3.2Product code CC-5013
    D.3.4Pharmaceutical form Capsule
    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.3.8INN - Proposed INNLENALIDOMIDE
    D.3.9.1CAS number 191732-72-6
    D.3.9.4EV Substance CodeSUB25389
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number5
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin 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 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
    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 nameRituximab SC
    D.3.2Product code RO 45-2294
    D.3.4Pharmaceutical form Solution for injection/infusion
    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.3.9.4EV 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 Yes
    D.3.11.13.1Other medicinal product typeContains recombinant human hyaluronidase
    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
    Mantle Cell Lymphoma
    Linfoma de Células do Manto
    E.1.1.1Medical condition in easily understood language
    Lymphoma
    Linfoma
    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 PT
    E.1.2Classification code 10061275
    E.1.2Term Mantle cell lymphoma
    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
    The primary objective of the trial is to evaluate whether the addition of lenalidomide to standard rituximab-maintenance improves progression free survival (PFS) compared to standard rituximab maintenance after response to induction chemotherapy in older patients with mantle cell lymphoma not suitable for autologous stem cell transplantation
    O objetivo primário do ensaio é avaliar se a adição de lenalidomida à terapêutica de manutenção com rituximab melhora a sobrevivência livre de progressão (PFS) comparativamente à terapêutica de manutenção padrão com rituximab após resposta à quimioterapia de indução em doentes idosos com linfoma de células do manto não adequado a transplante de células estaminais autólogas
    E.2.2Secondary objectives of the trial
    The secondary efficacy objectives are:
    • to compare efficacy and safety of the maintenance regimens in terms of secondary endpoints
    • to evaluate whether the introduction of cytarabine into induction improves clinical outcome compared to standard R-CHOP in older patients with mantle cell lymphoma not suitable for autologous stem cell transplantation
    Os objetivos secundários de eficácia são:
    • comparar a eficácia e segurança dos regimes de manutenção em termos de endpoints secundários
    • avaliar se a introdução de citarabina na terapêutica de indução melhora o outcome clínico comparativamente a terapêutica com R-CHOP padrão em doentes idosos com linfoma de células do manto não adequado a transplante de células estaminais autólogas
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    • signed informed consent form
    • Biopsy-proven mantle cell lymphoma according to WHO classification, including evidence of cyclin D1 overexpression or the translocation t(11;14)(q13;q32).
    • ≥ 60 years of age and ineligible for autologous transplant
    • Ann Arbor stage II-IV
    • previously untreated
    • ECOG performance status ≤ 2
    • Male subjects must:
    - agree to use a condom during sexual contact with a woman of childbearing potential, even if they have had a vasectomy, throughout lenalidomide/placebo therapy
    - agree to not donate semen during lenalidomide therapy.
    • All subjects must:
    - have an understanding that the lenalidomide could have a potential teratogenic risk.
    - agree to abstain from donating blood while taking lenalidomide therapy
    - agree not to share study medication with another person.
    - be counseled about pregnancy precautions and risks of fetal exposure.

    • Additional criteria for randomization in maintenance phase :
    - CR, CRu or PR after induction treatment, determined as per Cheson 1999 criteria by investigator
    - During the run-in period of 6 months starting from the date of the first patient randomized in the trial: in case of direct randomization into maintenance phase, patient must have been treated in first line by 6-8 cycles of R-CHOP.
    • Formulário de consentimento informado assinado
    • Linfoma de células do manto comprovado através de biópsia de acordo com a classificação da OMS, incluindo evidência de sobreexpressão de ciclina D1 ou de translocação t(11;14)(q13;q32)
    • ≥ 60 anos de idade e não elegível para transplante autólogo
    • Estadiamento Ann Arbor II-IV
    • Sem tratamento prévio
    • ECOG performance status ≤ 2
    • Os doentes do sexo masculino devem:
    - concordar em usar preservativo durante o contacto sexual com uma mulher com potencial reprodutor, mesmo que tenham feito uma vasectomia, durante a terapêutica com lenalidomida - concordar em não doar sémen durante a terapêutica com lenalidomida
    • Todos os doentes devem:
    - compreender que a lenalidomida pode ter um potencial risco teratogénico
    - concordar em abter-se de fazer doações de sangue durante a terapêutica com lenalidomida
    - concordar em não partilhar qualquer medicação do estudo com outras pessoas
    - ser aconselhado sobre precauções de gravidez e riscos de exposição fetal

    • Critérios adicionais para aleatorização na fase de manutenção:
    - Remissão Completa (CR), Remissão Completa não confirmada (Cru) ou Remissão Parcial (PR) do tumor após o tratamento de indução, determinada pelo investigador de acordo com os critérios de Cheson 1999
    - Durante o período pré-tratamento de 6 meses com início na data de aleatorização do primeiro doente no ensaio: em caso de aleatorização direta para a fase de manutenção, o doente deve ter sido tratado em primeira linha com 6-8 ciclos de R-CHOP.
    E.4Principal exclusion criteria
    • Female of child-bearing potential (without natural menopause for at least 24 consecutive months, a hysterectomy or bilateral oophorectomy)
    • Any of the following laboratory abnormalities, if not related to lymphoma:
    - Absolute neutrophils count (ANC) <1,000 /mm3 (1.0 x 109/L) if not result of a BM infiltration.
    - Platelet count < 75,000/mm3 (75 x 109/L) if not result of a BM infiltration.
    - Serum aspartate transaminase (AST/SGOT) or alanine transaminase (ALT/SGPT) >3.0 x upper limit of normal.
    - Serum total bilirubin > 1.5 UNL (except if due to Gilbert’s syndrome)
    • Calculated creatinine clearance (Cockcroft-Gault formula or MDRD) < 30 mL /min.
    • Central nervous system involvement by lymphoma
    • Contraindication for medicamentous DVT prophylaxis
    • Prior history of malignancies other than MCL unless the subject has been free of the disease for ≥ 5 years (Exceptions: Basal or squamous cell carcinoma of the skin, Carcinoma in situ of the cervix or of the breast, Incidental histologic finding of prostate cancer (TNM stage of T1a or T1b).
    • Any serious medical condition, laboratory abnormality, or psychiatric illness that would prevent the patient to receive the study medication as planned.
    • Poor cardiac fuction (LVEF < 50%) on echecardiography
    • Seropositivity for human immunodeficiency virus (HIV, mandatory test)
    Seropositivity for hepatitis C virus (HCV, mandatory test),
    Active viral infection with hepatitis B virus (HBV, mandatory test):
    - HBsAg positive
    - HBsAg negative, anti-HBs positive and anti-HBc positive
    • Uncontrolled illness including, but not limited to:
    - Active infection requiring parenteral antibiotics
    - Uncontrolled diabetes mellitus
    - Chronic symptomatic congestive heart failure (Class NYHA III or IV).
    - Unstable angina pectoris, angioplasty, stenting, or myocardial infarction within 6 months
    - Clinically significant cardiac arrhythmia that is symptomatic or requires treatment, or asymptomatic sustained ventricular tachycardia.
    • Prior ≥ Grade 3 allergic hypersensitivity to thalidomide.
    • Prior ≥ Grade 3 rash or any desquamating (blistering) rash while taking thalidomide.
    • Subjects with ≥ Grade 2 neuropathy.
    • Known anti-murine antibody (HAMA) reactivity or known hypersensitivity to murine antibodies
    • Prior use of lenalidomide.
    • Participation in another clinical trial within three weeks before randomization in this study

    Additional exclusion criteria for randomization in maintenance phase:
    - SD or PD after induction treatment determined as per Cheson 1999 criteria assessed by investigator.
    - Patients who had not received at least 6 cycles of R-CHOP21 or 2 cycles of R-CHOP21 / 2 cycles of R-HAD28 (alternating).
    - Patients with serious underlying medical conditions, which could impair the ability to receive maintenance treatment.
    - Calculated creatinine clearance (Cockcroft-Gault formula or MDRD) of < 30 mL /min at screening for maintenance.
    - ANC < 1,000 cells/mm³ (1.0 X 109/L) at screening for maintenance.
    - Platelet count < 50,000 cells/mm³ (50 X 109/L) at screening for maintenance.
    • Mulheres com potencial reprodutor (sem menopausa natural durante, pelo menos, 24 meses consecutivos, uma histerectomia ou ooforectomia bilateral)
    • Qualquer uma das seguintes anomalias laboratoriais, se não relacionadas com o linfoma:
    - Contagem absoluta de neutrófilos (ANC – Absolute Neutrophil Count) <1,000/mm3 (1.0 x 109/L) se não for resultante de uma infiltração da medula óssea
    - Contagem de plaquetas <75000/mm3 (75 x 109/L) se não for resultante de uma infiltração da medula óssea
    - Aspartato transaminase (AST/SGOT) ou alanina transaminase (ALT/SGOT) séricas > 3.0 x limite superior dos valores normais (ULN – Upper Limit of Normal)
    - Bilirrubina sérica total > 1.5 ULN (exceto se for devida a síndrome de Gilbert)
    • Depuração de creatinina calculada (através da fórmula de Cockcroft-Gault ou MDRD) < 30 mL/min
    • Envolvimento do sistema nervoso central pelo linfoma
    • Contraindicação para profilaxia medicamentosa para trombose venosa profunda (DVT) para doentes com risco elevado de DVT
    • História prévia de outros eventos malignos além de linfoma de células do manto (MCL), exceto se o doente estiver sem doença há ≥ 5 anos (exceções: carcinoma basocelular ou espinocelular da pele, carcinoma in situ do colo do útero ou da mama, descoberta histológica acidental de cancro da próstata (Estadio TNM T1a ou T1b)
    • Qualquer condição médica grave, alteração laboratorial, ou doença psiquiátrica que impeça o doente de receber a medicação do estudo como planeado
    • Fraca função cardíaca (LVEF < 50%) na ecocardiografia
    • Seropositividade para vírus da imunodeficiência humana (HIV, teste obrigatório)
    • Seropositividade para vírus da hepatite C (HCV, teste obrigatório)
    • Infeção viral ativa com o vírus da hepatite B (HBV, teste obrigatório):
    - HBsAg positivo
    - HBsAg negativo, anti-HBs positivo e anti-HBc positivo
    • Doença não controlada incluindo, mas não limitada a:
    - Infeção ativa com necessidade de antibióticos parentéricos
    - Diabetes mellitus não controlada
    - Insuficiência cardíaca congestiva sintomática crónica (Classe NYHA III ou IV)
    - Angina de peito instável, angioplastia, colocação de stent, ou enfarte agudo do miocárdio no espaço de 6 meses
    - Arritmia cardíaca clinicamente significativa que seja sintomática ou que exija tratamento, ou taquicardia ventricular sustentada assintomática.
    • Antecedente de hipersensibilidade alérgica de Grau ≥ 3 à talidomida.
    • Antecedente de rash ou qualquer erupção cutânea descamativa (com formação de bolhas) de Grau ≥ 3 durante a toma de talidomida.
    • Doentes com neuropatia de Grau ≥ 2
    • Reatividade a anticorpos anti-murino (HAMA) conhecida ou hipersensibilidade a anticorpos murinos conhecida
    • Utilização prévia de lenalidomida
    • Participação em outro ensaio clínico nas 3 semanas anteriores à aleatorização para este estudo

    Critérios e exclusão adicionais para aleatorização na fase de manutenção:
    - Doença Estável (SD) ou Doença Progressiva (PD) após tratamento de indução, segundo avaliação do investigador com base nos critérios de Cheson 1999.
    - Doentes que não receberam pelo menos 6 ciclos de R-CHOP21 ou 2 ciclos de R-CHOP21 / 2 ciclos de R-HAD28 (alternados).
    - Doentes com condições médicas graves subjacentes, que possam comprometer a sua capacidade de receber tratamento de manutenção.
    - Depuração de creatinina calculada (fórmula de Cockcroft-Gault ou MDRD) < 30 mL/min no rastreio para terapêutica de manutenção.
    - ANC < 1,000 células/mm3 (1.0 x 109/L) no rastreio para terapêutica de manutenção.
    - Contagem de plaquetas < 50,000 células/mm3 (50 x 109/L) no rastreio para terapêutica de manutenção.
    E.5 End points
    E.5.1Primary end point(s)
    progression free survival (PFS).
    sobrevivência livre de progressão
    E.5.1.1Timepoint(s) of evaluation of this end point
    From randomization for maintenance to progression or death from any cause.
    Tumor assessment (clinical examination, laboratory tests, CT scan, bone marrow examination) will be performed at baseline, at the end of induction and of maintenance and every 6 months during maintenance and follow-up period.
    Desde aleatorização para manutenção até à progressão ou morte de qualquer causa. A avaliação do tumor (exame clínico, testes laboratoriais, TAC, exame da medula óssea) será realizada na baseline, no fim da indução e da manutenção e a cada 6 meses durante o período de manutenção e follow-up.
    E.5.2Secondary end point(s)
    • Time to event:
    - overall survival from induction randomization to death from any cause
    - overall survival from maintenance randomization to death from any cause
    - time to treatment failure, progression-free survival from induction randomization, remission duration
    • PR/CRu to CR and PR to CRu conversion during maintenance
    • Minimal residual disease (MRD) levels in peripheral blood and bone marrow at midterm and at the end of induction, after one and two years from end of induction and during follow-up until progression or 2.5 years of follow-up whichever comes first
    • complete and overall response rates (based on Cheson 1999 criteria) at midterm and end of induction
    • secondary primary malignancies rates after lenalidomide vs. no lenalidomide
    • safety according to NCI CTCAE (v 4.0)
    • Exploratory : response assessment according to Cheson 2007 criteria including FDG-PET evaluation
    • Tempo até evento:
    - sobrevivência global desde a aleatorização de indução até à morte por qualquer causa
    - sobrevivência global desde a aleatorização de manutenção até à morte por qualquer causa
    - tempo até falência terapêutica, sobrevivência sem progressão da doença, duração da remissão
    • conversão das seguintes respostas tumorais durante a terapêutica de manutenção: remissão parcial (PR)/resposta completa não confirmada (Cru) para remissão completa (CR) e PR para CRu
    • Níveis de Doença Residual Mínima (MRD) no sangue periférico e medula óssea a meio e no final da terapêutica de indução, após um e dois anos de terapêutica de manutenção e durante o follow-up até progressão, ou 2.5 anos após a seguimento, em função do que se verificar primeiro
    • Taxas de resposta completas e global (com base nos critérios de Cheson 1999) a meio e no final da terapêutica de indução
    • segurança de acordo com os Critérios Comuns de Toxicidade para Eventos Adversos do Instituto Nacional de Cancro Americano (National Cancer Institute, NCI) (v 4.0), a meio e no fim do período de indução
    • taxas de eventos malignos primários e secundários (SPM) registados após lenalidomida vs. sem lenalidomida
    • Exploratório: avaliação da resposta de acordo com os critérios de Cheson 2007, incluindo avaliação com Tomografia por Emissão de Positrões (PET) com Fluorodesoxiglicose (FDG), PET-FDG
    E.5.2.1Timepoint(s) of evaluation of this end point
    • investigator-assessed progression free survival: from randomization for maintenance
    • overall survival: from induction randomization to death from any cause
    • overall survival: from maintenance randomization to death from any cause
    • remission rates, time to treatment failure, remission duration: all duration of the study
    • minimal residual disease (MRD) levels: at end of induction, after one and two years of maintenance and during follow-up until progression or 2.5 years of follow-up, whichever comer first
    • safety according to NCI CTCAE (v 4.0): all duration of the study
    • PR to CR conversion: during maintenance
    • the rates of secondary neoplasias after lenalidomide vs. no lenalidomide: after starting maintenance treatment
    • sobrevivênvia livre de progressão avaliada pelo investigador: desde a aleatorização para a manutenção
    • sobrevivência global: desde a aleatorização de indução até à morte por qualquer causa
    • sobrevivência global: desde a aleatorização de manutenção até à morte por qualquer causa
    • taxas de remissão, tempo até falência terapêutica, duração da remissão: toda a duração do estudo
    • níveis de Doença Residual Mínima (MRD): no final da terapêutica de indução, após um e dois anos de terapêutica de manutenção e durante seguimento
    • segurança de acordo com NCI CTCAE (v 4.0): toda a duração do estudo
    • conversão de PR para CR : duriante a terapêutica de manutenção
    • taxas de neoplasias secundárias registadas após lenalidomida vs. sem lenalidomida: após início da terapêutica de manutenção
    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 No
    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) 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 trial4
    E.8.3 The trial involves single site in the Member State concerned Yes
    E.8.4 The trial involves multiple sites in the Member State concerned No
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA180
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    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
    Last visit of the last subject undergoing the trial
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years8
    E.8.9.1In the Member State concerned months
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years8
    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: 183
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 450
    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 633
    F.4.2.2In the whole clinical trial 633
    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)
    no difference
    sem diferença
    G. Investigator Networks to be involved in the Trial
    G.4 Investigator Network to be involved in the Trial: 1
    G.4.1Name of Organisation MCL Network
    G.4.3.4Network Country Germany
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2015-03-31
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2015-03-13
    P. End of Trial
    P.End of Trial StatusOngoing
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