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    Summary
    EudraCT Number:2007-005669-37
    Sponsor's Protocol Code Number:26866138LYM3002
    National Competent Authority:Italy - Italian Medicines Agency
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2008-06-30
    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 ConcernedItaly - Italian Medicines Agency
    A.2EudraCT number2007-005669-37
    A.3Full title of the trial
    A Randomised, Open-Label, Multicentre Phase 3 Study of the Combination of Rituximab, Cyclophosphamide, Doxorubicin, VELCADE, and Prednisone (VcR-CAP) or Rituximab, Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone (R-CHOP) in Patients With Newly Diagnosed Mantle Cell Lymphoma who are not Eligible for a Bone Marrow Transplant
    Uno studio multicentrico di fase III, randomizzato, in aperto sulla combinazione terapeutica di rituximab, ciclofosfamide, doxorubicina, VELCADE e prednisone (VcR-CAP) o verso la combinazione terapeutica di rituximab, ciclofosfamide, doxorubicina, vincristina e prednisone (R-CHOP) in pazienti con linfoma a cellule del mantello di recente diagnosi non idonei al trapianto di midollo osseo
    A.4.1Sponsor's protocol code number26866138LYM3002
    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 SponsorJANSSEN-CILAG INTERNATIONAL BV
    B.1.3.4CountryBelgium
    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 supportJANSSEN CILAG SPA
    B.4.2CountryItaly
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationJANSSEN CILAG INTERNATIONAL NV
    B.5.2Functional name of contact pointClinical Registry Group
    B.5.3 Address:
    B.5.3.1Street AddressClinical Registry Group
    B.5.3.2Town/ cityLeiden
    B.5.3.3Post code2333CM
    B.5.3.4CountryNetherlands
    B.5.4Telephone number+31 071 524 21 66
    B.5.5Fax number+31 071 524 21 10
    B.5.6E-mailClinicalTrialsEU@its.jnj.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 Yes
    D.2.1.1.1Trade name VELCADE*INIET 1FL 3,5MG 1MG/ML
    D.2.1.1.2Name of the Marketing Authorisation holderJANSSEN CILAG SpA
    D.2.1.2Country which granted the Marketing AuthorisationItaly
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.4Pharmaceutical form Powder for solution for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNBortezomib
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.3Concentration number3.5
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 2
    D.1.2 and D.1.3IMP RoleComparator
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name ENDOXAN BAXTER
    D.2.1.1.2Name of the Marketing Authorisation holderBAXTER SpA
    D.2.1.2Country which granted the Marketing AuthorisationItaly
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.4Pharmaceutical form Powder for solution for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNCyclophosphamide
    D.3.10 Strength
    D.3.10.1Concentration unit g gram(s)
    D.3.10.3Concentration number1
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 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 DOXORUBIN
    D.2.1.1.2Name of the Marketing Authorisation holderPHARMACHEMIE BV
    D.2.1.2Country which granted the Marketing AuthorisationNetherlands
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.4Pharmaceutical form Solution for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNDoxorubicin
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.3Concentration number50
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 4
    D.1.2 and D.1.3IMP RoleComparator
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name DECORTIN
    D.2.1.1.2Name of the Marketing Authorisation holderMERCK GmbH
    D.2.1.2Country which granted the Marketing AuthorisationGermany
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.4Pharmaceutical form 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.3.8INN - Proposed INNPrednisone
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    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: 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 MABTHERA
    D.2.1.1.2Name of the Marketing Authorisation holderROCHE SpA
    D.2.1.2Country which granted the Marketing AuthorisationItaly
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.4Pharmaceutical form Solution for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNRituximab
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.3Concentration number100
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 6
    D.1.2 and D.1.3IMP RoleComparator
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name VINCRISTINE SULPHATE
    D.2.1.1.2Name of the Marketing Authorisation holderHOSPIRA UK
    D.2.1.2Country which granted the Marketing AuthorisationUnited Kingdom
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.4Pharmaceutical form Solution for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNVincristine
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.3Concentration number1
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 7
    D.1.2 and D.1.3IMP RoleComparator
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name DECORTIN
    D.2.1.1.2Name of the Marketing Authorisation holderMERCK GmbH
    D.2.1.2Country which granted the Marketing AuthorisationGermany
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.4Pharmaceutical form 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.3.8INN - Proposed INNPrednisone
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    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: 8
    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 MABTHERA
    D.2.1.1.2Name of the Marketing Authorisation holderROCHE SpA
    D.2.1.2Country which granted the Marketing AuthorisationItaly
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.4Pharmaceutical form Solution for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNRituximab
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    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 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 Yes
    D.3.11.13.1Other medicinal product typemedicinal product of biotechnological derivation
    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 a cellule del mantello
    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 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
    To determine which regimen rituximab, cyclophosphamide, doxorubicin, VELCADE, and prednisone (VcR-CAP) or rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) provides greater benefit in patients with newly diagnosed mantle cell lymphoma (MCL), as assessed by significant prolongation of progression-free survival (PFS).
    Stabilire quale regime di chemioterapia con rituximab , ciclofosfamide, doxorubicina, velcade e prednisione (VcR-CAP) o con rituximab , ciclofosfamide, doxorubicina, vincristina e prednisone (R-CHOP) offre maggiore beneficio a pazienti con linfoma a cellule del mantello (MCL) di recente diagnosi in termini di prolungamento significativo della sopravvivenza senza progressione (PFS).
    E.2.2Secondary objectives of the trial
    The secondary objectives are: To determine overall survival (OS) To determine time to progression (TTP) To determine the 18 month survival rate To determine overall response (CR+CRu+PR) and CR rates (CR+CRu) To determine the duration of response (DoR) and time to subsequent anti-lymphoma therapy To evaluate the safety of VcR-CAP compared to R-CHOP
    Gli obiettivi secondari sono i seguenti.`Stabilire la sopravvivenza generale (OS) `Stabilire il tempo prima della progressione (TTP) `Stabilire il tasso di sopravvivenza a 18 mesi `Stabilire il tasso di risposta generale (CR + CRu + PR) e il tasso di CR (CR + CRu) `Stabilire la durata della risposta (DoR) e il tempo prima della successiva terapia anti-linfoma `Valutare la sicurezza del regime VcR-CAP rispetto al regime R-CHOP
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Patients must satisfy all of the following criteria before entering the study: Male or female patients 18 years or older Diagnosis of MCL (Stage II, III or IV) as evidenced by histology and either expression of cyclin D1 (in association with CD20 and CD5) or evidence of t(11;14) translocation such as by cytogenetics, fluorescent in situ hybridization (FISH) or polymerase chain reaction (PCR). Patients with a diagnosis of Stage I MCL will not be permitted to enter study. `€' Paraffin embedded biopsy tissue block (preferably of lymph node origin) must be sent to the central laboratory for confirmation of MCL diagnosis prior to randomization. In China, a paraffin embedded lymph node biopsy tissue block must be sent for central confirmation of sample adequacy, prior to randomization. At least 1 measurable site of disease No prior therapies for MCL Not eligible or not considered for bone marrow transplantation as assessed by the treating physician (for example, the presence of co-morbid conditions that may have a negative impact on the tolerability to transplantation). Eastern Cooperative Oncology Group [ECOG] status `‰¤2 (Attachment 1) Absolute neutrophil count (ANC) `‰¥1500 cells/µL, Platelets `‰¥100,000 cells/µL, Alanine transaminase `‰¤3 x upper limit of normal (ULN) Aspartate transaminase `‰¤3 x upper limit of normal (ULN) Total bilirubin `‰¤1.5 x ULN, Calculated creatinine clearance `‰¥20 mL/min. Female patients must be post menopausal for at least 1 year (must not have had a natural menses for at least 12 months), surgically sterile, or practicing an effective method of birth control (e.g., prescription oral contraceptives, contraceptive injections, intrauterine device, double-barrier method, contraceptive patch, male partner sterilization) and have a negative serum βHCG or urine pregnancy test at screening. They must also be prepared to continue birth control measures for al least 6 months after terminating treatment Male patients must agree to use an acceptable method of contraception (for themselves or female partners as listed above) for the duration of the study. All patients (or their legally acceptable representatives) must have signed an informed consent document indicating that they understand the purpose of and procedures required for the study and are willing to participate in the study. In order to participate in the pharmacogenomic component of this study, patients (or their legally acceptable representative) must have signed the informed consent form for pharmacogenomic research indicating willingness to participate in the pharmacogenomic component of the study. Acquisition of tumor sample collections is required for all patients (where available); all other sample collections are optional. AMENDMENT II NR. 5 Not eligible for bone marrow transplantation as assessed by the treating physician (e.g., age or the presence of co-morbid conditions that may have a negative impact on the tolerability to transplantation). NR. 8 Platelets `‰¥100,000 cells/µL or `‰¥75,000 cells/µL if thrombocytopenia is considered by the investigator to be secondary to MCL (e.g., due to bone marrow infiltration or sequestration from splenomegaly).
    I pazienti devono soddisfare tutti i criteri elencati di seguito prima dell`ingresso nello studio. Uomini e donne di eta` pari o superiore a 18 anni. o Diagnosi di MCL (di stadio II, III o IV) dimostrata dall`esame istologico e dall`espressione della ciclina D1 (in associazione con CD20 e CD5) o dall`evidenza di traslocazione t(11;14), mediante citogenetica, ibridazione in situ fluorescente (FISH) o reazione a catena della polimerasi (PCR). o Un blocchetto di tessuto di biopsia (preferibilmente di origine linfonodale)deve essere inviato al laboratorio centralizzato per la conferma di diagnosi di MCL prima della randomizzazione. In Cina, e` richiesto l`invio di un blocchetto di tessuto di biopsia linfonodale, per la conferma dell`adeguatezza del campione da parte del laboratorio centralizzato, prima della randomizzazione. o Almeno una sede misurabile della malattia. o Nessuna precedente terapia per l`MCL. o Non idoneita` al trapianto di midollo osseo secondo la valutazione del medico curante (ad esempio, presenza di copatologie che potrebbero esercitare un impatto negativo sulla tollerabilita` del trapianto). o Stato ECOG (Eastern Cooperative Oncology Group) `‰¤2 (Allegato 1). o Conta assoluta dei neutrofili (ANC) `‰¥1500 cellule/mL. o Piastrine `‰¥100 000 cellule/mL. o Alanino-transaminasi `‰¤3 volte il limite superiore della norma (ULN). o Aspartato-transaminasi `‰¤3 volte il limite superiore della norma (ULN). o Bilirubina totale `‰¤1.5 x ULN. o Clearance della creatinina calcolata `‰¥20 ml/min. (Allegato 2). o Le donne devono essere in menopausa da almeno 1 anno (assenza di cicli mestruali naturali da almeno 12 mesi) o sterilizzate chirurgicamente, altrimenti devono adottare un metodo contraccettivo efficace (ad es., contraccettivi orali con obbligo di prescrizione, iniezioni contraccettive, dispositivo intrauterino, metodo a doppia barriera, cerotto contraccettivo, sterilizzazione del partner maschile) e presentare un test di gravidanza -HCG in siero o urina negativo allo screening; devono essere inoltre disponibili a proseguire le misure anticoncezionali per almeno 6 mesi dopo la fine del trattamento o Gli uomini devono accettare di adottare un metodo contraccettivo efficace (per loro stessi o per le partner femminili, secondo quanto sopra indicato) per la durata dello studio. o Tutti i pazienti (o i relativi rappresentanti legali autorizzati) devono aver firmato un modulo di consenso informato indicante che hanno compreso lo scopo dello studio e le relative procedure e che intendono prendervi parte. o Per partecipare alla parte di farmacogenomica di questo studio, i pazienti (o i relativi rappresentanti legali autorizzati) devono aver firmato il modulo di consenso informato per la ricerca di farmacogenomica indicante che intendono prendervi parte. L`acquisizione dei set di campioni di tessuto tumorale e` richiesta per tutti i pazienti (ove disponibili); tutti gli altri set di campioni sono facoltativi. EMENDAMENTO II NR. 5 Non idoneita` al trapianto di midollo osseo secondo la valutazione del medico curante (ad esempio, eta` o presenza di copatologie che potrebbero esercitare un impatto negativo sulla tollerabilita` del trapianto). NR. 8 Piastrine `‰¥100.000 cellule/L o &gt; 75.000 cellule/L se la trombocitopenia e` considerata dallo sperimentatore come secondaria al MCL (ad esempio dovuta a infiltrazione del midollo osseo o sequestro da splenomegalia)
    E.4Principal exclusion criteria
    Potential patients who meet any of the following criteria will be excluded from participating in the study: Prior treatment with VELCADE Prior anti-neoplastic (including unconjugated therapeutic antibodies), experimental or radiation therapy, radioimmunoconjugates or toxin immunoconjugates for the treatment of MCL. In the event that a patient has received doxorubicin for the treatment of any condition, other than MCL, the maximum dose and exposure received prior to entry into this study should not exceed 150mg/m2. Short course (maximum of 10 days; not exceeding 100 mg/day) prednisone or equivalent steroids are allowed to treat symptoms in subjects with advanced disease who enter the screening phase and are waiting to be randomized. Major surgery (at the discretion of the treating physician and in consultation with the sponsor s medical monitor) within 2 weeks before randomization Peripheral neuropathy or neuropathic pain of Grade 2 or worse (as per the investigators assessment) Diagnosed or treated for a malignancy other than MCL within 1 year of randomization, or who were previously diagnosed with a malignancy other than MCL and have any radiographic or biochemical marker evidence of malignancy. Patients with completely resected basal cell carcinoma, squamous cell carcinoma of the skin, or in situ malignancy are not excluded. Active systemic infection requiring treatment and patients with known diagnosis of HIV or active Hepatitis B (carriers ho Hepatitis B are permitted to enter study) History of allergic reaction attributable to compounds containing boron, mannitol, or hydroxybenzoates Known anaphylaxis or immunoglobulin E (IgE)-mediated hypersensitivity to murine proteins or to any component of rituximab including polysorbate 80 and sodium citrate dihydrate Female or male patients of child-bearing potential who will not use adequate contraception during the course of the study. Serious medical (eg pericardial disease or acute diffuse infiltrative pulmonary disease) or psychiatric illness likely to interfere with participation in this clinical study Concurrent treatment with another investigational agent. AMENDMENT II NR. 10 Serious medical (e.g., pericardial disease, cardiac failure [New York Heart Association; NYHA Class III or IV, Attachment 12 or left ventricular ejection fraction; LVEF <50%], active peptic ulceration, uncontrolled diabetes mellitus, or acute diffuse infiltrative pulmonary disease), or psychiatric illness likely to interfere with participation in this clinical study
    I potenziali soggetti che soddisfino uno qualsiasi dei criteri seguenti saranno esclusi dalla partecipazione allo studio. o Precedente trattamento con VELCADE. o Precedente terapia antineoplastica (inclusi gli anticorpi terapeutici non coniugati), terapia sperimentale o radioterapia, radioimmunoconiugati o immunotossine per il trattamento dell`MCL. Per i pazienti che abbiano assunto doxorubicina per il trattamento di una qualsiasi patologia diversa dall`MCL, la dose e l`esposizione massime ricevute prima dell`ingresso in questo studio non devono essere superiori a 150 mg/m2. Per trattare i sintomi dei soggetti con avanzata malattia che entrano nella fase di screening e sono in attesa della randomizzazione e` consentito un breve ciclo(max 10 gg) con dosi non superiori a 100 mg/giorno di prednisone o steroidi equivalenti. o Importante intervento chirurgico (a discrezione del medico curante e in seguito al consulto con il monitor medico dello sponsor) entro le 2 settimane precedenti alla randomizzazione. o Neuropatia o dolore neuropatico periferica/o di grado 2 o peggiore (secondo la valutazione dello sperimentatore). o Diagnosi o trattamento di una neoplasia maligna diversa dall`MCL entro l`anno precedente alla randomizzazione oppure precedente diagnosi di neoplasia maligna diversa dall`MCL ed evidenza radiografica o di marcatore biologico di neoplasia maligna. Non sono esclusi i pazienti con carcinoma basocellulare, carcinoma a cellule squamose della pelle o neoplasia maligna in situ completamente asportati. o Infezione sistemica attiva che richieda il trattamento e pazienti con nota diagnosi di HIV o Epatite B attiva (i portatori di Epatite B possono partecipare allo studio) o Storia di reazione allergica imputabile a composti contenenti boro, mannitolo o idrossibenzoati. o Anafilassi o ipersensibilita` mediata dall`immunoglobulina E (IgE) nota alle proteine murine o a qualsiasi componente del rituximab, inclusi polisorbato 80 e sodio citrato diidrato. o Donne o uomini in eta` fertile che non adottino un metodo contraccettivo adeguato durante lo svolgimento dello studio. o Patologie mediche (per esempio malattie pericardiache o infiltrati polmonari diffusi) o psichiatriche serie, inclini ad interferire con la partecipazione a questo studio clinico. o Trattamento concomitante con un altra sostanza sperimentale. EMENDAMENTO II NR. 10 Patologie mediche serie (ad esempio, malattie del pericardio, insufficienza cardiaca [NewYork Association; NYHA claase III o IV, Allegato 12 o frazione di eiezione ventricolare; LVEF &lt; 50%], ulcera peptica attiva, diabete mellito non controllato, o malattia polmonare infiltrativa diffusa acuta), o psichiatriche inclini ad interferire con la partecipazione a questo studio clinico.
    E.5 End points
    E.5.1Primary end point(s)
    The primary endpoint is the Progression Free Survival (PFS) which is defined as the interval between the date of randomisation and the date of PD or death, whichever is first reported, in the intent to treat (ITT) population. The death due to PD will be considered as an event if the date of death is within 6 month after last disease aseessment (or within one disease assessment period) otherwise death will be censored at the date of last disease assessment.
    L'endpoint primario e' la sopravvivenza senza progressione (PFS), definita come l'intervallo tra la data della randomizzazione e la data della PD o del decesso, a seconda dell'evento segnalato per primo, nella popolazione ITT (Intent To Treat). Il decesso dovuto a PD sara' considerato un evento in caso di data di decesso compresa nei 6 mesi successivi all'ultima valutazione della malattia (o compresa entro un periodo di valutazione della malattia); in caso contrario, il decesso sara' censurato alla data dell'ultima valutazione della malattia.
    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 No
    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) 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 Yes
    E.8.2.3.1Comparator description
    VINCRISTINA
    E.8.2.4Number of treatment arms in the trial2
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned8
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA63
    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
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years0
    E.8.9.1In the Member State concerned months42
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years0
    E.8.9.2In all countries concerned by the trial months42
    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.1.1Number of subjects for this age range: 0
    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.1.3Elderly (>=65 years) Yes
    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 state10
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 150
    F.4.2.2In the whole clinical trial 486
    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 Decision2008-06-17
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2008-06-03
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2017-06-30
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