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    Summary
    EudraCT Number:2012-001790-86
    Sponsor's Protocol Code Number:PIX306
    National Competent Authority:Hungary - National Institute of Pharmacy
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2012-10-15
    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 ConcernedHungary - National Institute of Pharmacy
    A.2EudraCT number2012-001790-86
    A.3Full title of the trial
    A Randomized Multicenter Study Comparing Pixantrone + Rituximab with Gemcitabine + Rituximab in Patients with Aggressive B-cell Non-Hodgkin Lymphoma Who Have Relapsed after Therapy with CHOP-R or an Equivalent Regimen and are Ineligible for Stem Cell Transplant
    Randomizált multicentrikus vizsgálat pixantron + rituximab és gemcitabin + rituximab összehasonlítására agresszív B-sejtes non-Hodgkin lymphomában szenvedő, CHOP-R terápia vagy azzal egyenértékű kezelés után visszaeső, őssejt-transzplantációra nem alkalmas betegeknél
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Study to compare the combination of Pixantrone and Rituximab vs Gemcitabine and Rituximab in patients with aggressive B cell NHL, who have failed therapy with chemotherapy plus rituximab (e.g.CHOP-R) and are not eligible for stem cell transplantation
    Vizsgálat pixantron + rituximab és gemcitabin + rituximab összehasonlítására agresszív B-sejtes non-Hodgkin lymphomában szenvedő, CHOP-R terápia vagy azzal egyenértékű kezelés után visszaeső, őssejt-transzplantációra nem alkalmas betegeknél
    A.4.1Sponsor's protocol code numberPIX306
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT01321541
    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 SponsorCTI Biopharma, Corp.
    B.1.3.4CountryUnited States
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportCTI Biopharma, Corp.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationPSI Company Ltd.,
    B.5.2Functional name of contact pointEkaterina Efremova
    B.5.3 Address:
    B.5.3.1Street Address19/21, Dostoyevsky str.,
    B.5.3.2Town/ citySt.Petersburg
    B.5.3.3Post code191119
    B.5.3.4CountryRussian Federation
    B.5.4Telephone number+7 812320 3855 0032
    B.5.5Fax number+7 812320 3850
    B.5.6E-mailEkaterina.Efremova@psi-cro.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 Pixuvri
    D.2.1.1.2Name of the Marketing Authorisation holderCTI Life Sciences 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 namePixantrone
    D.3.2Product code BBR 2778
    D.3.4Pharmaceutical form Powder for concentrate for solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNPixantrone (base)
    D.3.9.1CAS number 144675-97-8
    D.3.9.2Current sponsor codeBBR 2778
    D.3.9.3Other descriptive name6,9-bis[(2-aminoethyl)amino]benzo[g]isoquinoline-5,10-dione dimaleate
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number29
    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 MabThera 500 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.3.1Product nameRituximab
    D.3.4Pharmaceutical form Concentrate for solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNRITUXIMAB
    D.3.9.1CAS number 174722-31-7
    D.3.9.3Other descriptive nameImmunoglobulin G1 (human-mouse monoclonal IDEC-C2B8 γ1-chain anti-human antigen CD 20), disulfide with human-mouse monoclonal IDEC-C2B8 κ-chain, dimer
    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 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 Gemzar 1000 mg
    D.2.1.1.2Name of the Marketing Authorisation holderEli Lilly and Company Limited
    D.2.1.2Country which granted the Marketing AuthorisationHungary
    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 nameGemcitabine
    D.3.4Pharmaceutical form Powder for solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNGEMCITABINE hydrocloride
    D.3.9.1CAS number 122111-03-9
    D.3.9.3Other descriptive name4-Amino-1-(2-deoxy-2,2-difluoro-β-d-ribofuranosyl)pyrimidin-2(1H)-one hydrochloride; 2′-Deoxy-2′,2′-difluorocytidine hydrochloride
    D.3.9.4EV Substance CodeSUB07892MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number1000
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 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 100 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.3.1Product nameRituximab
    D.3.4Pharmaceutical form Concentrate for solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNRITUXIMAB
    D.3.9.1CAS number 174722-31-7
    D.3.9.3Other descriptive nameImmunoglobulin G1 (human-mouse monoclonal IDEC-C2B8 γ1-chain anti-human
    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 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: 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 Gemzar 200 mg
    D.2.1.1.2Name of the Marketing Authorisation holderEli Lilly and Company Limited
    D.2.1.2Country which granted the Marketing AuthorisationUnited Kingdom
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameGemcitabine
    D.3.4Pharmaceutical form Powder for solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNGEMCITABINE hydrocloride
    D.3.9.1CAS number 122111-03-9
    D.3.9.3Other descriptive name4-Amino-1-(2-deoxy-2,2-difluoro-β-d-ribofuranosyl)pyrimidin-2(1H)-one hydrochloride; 2′-Deoxy-2′,2′-difluorocytidine hydrochloride
    D.3.9.4EV Substance CodeSUB07892MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number200
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Treatment of Patients with Aggressive B-cell Non-Hodgkin Lymphoma , who Have Relapsed after Therapy with CHOP-R or an Equivalent Regimen and are Ineligible for Stem Cell Transplant
    Terápia agresszív B-sejtes non-Hodgkin lymphomában szenvedő, CHOP-R terápia vagy azzal egyenértékű kezelés után visszaeső, őssejt-transzplantációra nem alkalmas betegeknél
    E.1.1.1Medical condition in easily understood language
    Non-Hodgkin Lymphoma
    Non-Hodgkin limfóma
    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 10012820
    E.1.2Term Diffuse large B-cell lymphoma NOS
    E.1.2System Organ Class 100000004864
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 19.1
    E.1.2Level LLT
    E.1.2Classification code 10067070
    E.1.2Term Follicular B-cell non-Hodgkin's lymphoma
    E.1.2System Organ Class 100000004864
    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 this study is to evaluate the efficacy (as measured by progression-free survival [PFS]) of pixantrone + rituximab (pixantrone + R) compared with gemcitabine + rituximab (gemcitabine + R) in patients with a diagnosis of de novo diffuse large B-cell lymphoma (DLBCL), DLBCL transformed from indolent lymphoma, or follicular grade 3 lymphoma who have relapsed after at least 1 prior chemotherapy regimen and who are currently ineligible for high-dose (myeloablative) chemotherapy and stem cell transplant (SCT).
    A vizsgálat elsődleges célja a pixatrone+ rituximab (pixantrone + R) kezelés hatásosságának értékelése (progressziómentes túlélés [PFS] paraméterrel mérve) összehasonlítva a gemcitabin+ rituximab (gemcitabine + R) kezeléssel olyan betegeknél akik de novo diffúz nagy B sejtes limfúmájuk (DLBCL), az indolens limfómából transzformált DLBCL-jük vagy 3-as fokú follikulásis limfómájuk kezelésére kapott kemoteráoia után már legalább egyszer visszaestek és jelenleg nem alkalmasak nagy dózisú (myeloablatív) kemoterápiára és őssejt transzplációra (SCT)
    E.2.2Secondary objectives of the trial
    To compare the two treatment arms with regard to the following secondary endpoints:
     Overall survival
     Overall response rate
     Complete response rate
     Safety

    Exploratory Objectives
     Assess the duration of overall response between treatments
     Assess the duration of complete response (CR) between treatments
     Determine the proportion of randomized patients who receive a stem cell transplant (SCT) after study treatment
    A két kezelési kar összehasonlítása a következő másodlagos végpontok tekintetében:

     Teljes túlélés (OS)
     Terápiás válasz aránya összesen (ORR)
     Teljes válasz aránya (CR)
     Biztonságosság

    Feltáró célkitűzések

     Mérni a kezelések közötti terápiás válasz időtartamát
     Mérni a kezelések közötti teljes válasz (CR) időtartamát
     Meghatározni azoknak a randomizált betegeknek az arányát, akik a kezelés után alkalmassá válnak őssejttranszplantációra
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    The objective of the PK sub-study is to characterize the PK profile of poxantrone when co-administered with rituximab.
    PK Sus-study Inclusion Criteria
    - Patient must have been randomized to the PIX306 pixantrone+rituximab arm at a participating clinical site. Patients newly randomized or already randomized in the pixantrone group can be included.
    - Patients must be willing to participate in the PK sub-study and cooperate with the PK sampling schedule, as described in the written consent for participation in the sub-study
    E.3Principal inclusion criteria
    1. Signed Institutional Review Board or Institutional Ethics Committee-approved Informed Consent Form
    2. Age ≥ 18 years old
    3. Diagnosis of DLBCL (de novo DLBCL or DLBCL transformed from indolent lymphoma) or follicular grade 3 lymphoma on the basis of a tissue biopsy.
    4. Pathology and immunohistochemistry reports documenting the current histological diagnosis according to World Health Organization (WHO) classification must be reviewed by the sponsor or designee prior to randomization.
    5. Number of prior therapies allowed:
     Patients with de novo DLBCL must have received 1-3 prior regimens for DLBCL
     Patients with follicular grade 3 lymphoma must have received 1-3 prior regimens for follicular lymphoma (any grade)
     Patients with DLBCL transformed from indolent lymphoma must have received 1-4 prior regimens for NHL
    6. Received a rituximab-containing multi-agent regimen (eg, rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone [R-CHOP]; rituximab, cyclophosphamide, vincristine, prednisone [R-CVP]; or bendamustine-R)
    7. Patients with DLBCL transformed from indolent lymphoma must have had a complete or partial response to a therapy for NHL lasting at least 12 weeks
    8. Not eligible for high-dose (myeloablative) chemotherapy and SCT. Patients not eligible for stem cell transplant include those who:
     relapsed after previous stem cell transplant
     did not respond to a standard salvage regimen
     did not mobilize an adequate number of stem cells for SCT
     are unsuitable for SCT due to other medical conditions or age
     do not wish to undergo SCT
     have financial issues precluding SCT
     are considered by the investigator as unsuitable for SCT for any other reason
    9. At least 28 days from completion of last NHL therapy to randomization
    10. At least one bidimensionally measurable site of disease that has not been previously irradiated: nodal disease ≥ 1.5 cm or extranodal disease > 1 .0 cm in short axes. Lesion must be PET-positive if PET scan is obtained.
    11. Slides confirming diagnosis of follicular grade 3 lymphoma or DLBCL available for independent histology review
    12. ECOG performance status (PS) ≤ 2
    13. Life expectancy ≥ 12 weeks in investigator’s judgment
    14. Left ventricular ejection fraction (LVEF) ≥ 45% by echocardiogram and normal serum troponin
    15. Hemoglobin ≥ 8 g/dL (can be post transfusion)
    16. Platelet count ≥ 100 x 109/L; platelet count ≥ 75 x 109/L permitted if documented bone marrow involvement
    17. Absolute neutrophil count (ANC) ≥ 1.5 x 109/L; ANC ≥ 1.0 x 109/L permitted if documented bone marrow involvement
    18. Serum bilirubin ≤ 1.5 x upper limit of normal (ULN); patients with proven Gilbert’s syndrome and bilirubin ≤ 5 x ULN may be enrolled.
    19. Aspartate aminotransferase (AST; also called serum glutamic-oxaloacetic transaminase
    [SGOT]) and alanine aminotransferase (ALT; also called serum glutamic-pyruvic transaminase [SGPT]
    20. Serum creatinine ≤ 2 x ULN
    21. All acute toxicities related to prior treatment recovered to grade ≤ 1 except alopecia
    22. Willingness and ability to comply with the visit schedule and assessments required by the study protocol
    23. Due to the long retention time of rituximab in B cell-depleted patients, both males and females must agree to use effective birth control. Women of childbearing potential must use highly effective methods (defined as those resulting in a failure rate of <1% per year when used consistently and correctly) for the duration of study treatment and for 12 months after last dose of study drug. The contraceptive methods considered highly effective are intrauterine devices and hormonal contraceptives (contraceptive pills, implants, transdermal patches, hormonal vaginal devices, or injections with prolonged release).
    1.A hatóság és a központi etikai bizottság által jóváhagyott beleegyező nyilatkozat aláírása
    2.Betöltött18 év
    3.DLBCL diagnózis (de novo DLBCLvagy indolens limfómából transzformálódott DLBCL), vagy follikuláris 3-as fokú limfóma a szövetbiopszia alapján
    4.Randomizálás előtt a szponzor, vagy megbízottja áttekinti a patológiai és immunhisztokémiai leleteket, amelyek a WHO osztályozása szerinti jelenlegi szövettani diagnózis felállítását támasztják alá.
    5.Megengedett korábbi terápiák száma:
    a.A de novo DLBCL betegek 1-3 korábbi kezelést kellett kapjanak a DLBCL-re
    b.A follikuláris 3-as fokú limfómás betegek 1-3 korábbi kezelést kellett kapjanak a bármely fokú follikuláris limfómára.
    c.Az indolens limfómából transzformálódott DLBCL-ben szenvedőknek 1-4 korábbi kezelést kellett kapniuk a bármely típusú NHL-ra.
    A salvage kombinált terápia, amellyel az esetleges SCT előkészítésére próbálnak válaszreakciót kiváltani (pl. R-ICE, R-ESHAP, or R-DHAP) az azt követő nagy dózisú myeloablációs terápiával (pl. BEAM) együtt az egyetlen kezelési protokollnak számít.
    A rituximabbal, vagy hasonló szerekkel, kortikosteroidos monoterápiával végzett fenntartó terápia és a helyi sugárterápia nem számít kezelési protokollnak.

    6.A beteg egy rituximab tartalmú kombinált kezelést-kapott (pl. rituximab, ciklofoszfamid, doxorubicin, vincristin, prednizon protokollt [R-CHOP]; rituximab, ciklofoszfamid, vincristin, prednizon protokollt [R-CVP]; vagy bendamustin-e-R-t)
    7.Az indolens limfómából transzformálódott DLBCL-es beteg legalább 12 hétig tartó teljes, vagy részleges válaszreakciót mutat az NHL-re kapott egyik kezelésre.
    8.Nem alkalmas a magas dózisú (myeloablációs) kemoterápiára, vagy SCT-re Az SCT-re alkalmatlan betegek azok, akik:
    a.Visszaestek korábbi SCT után
    b.Nem reagáltak a szokásos salvage kezelésre
    c.Nem mobilizálódott megfelelő számú őssejtet az SCT-hez
    d.Koruk, vagy egyéb orvosi probléma miatt nem alkalmasak SCT-re
    e.Nem egyeznek bele SCT végzésébe
    f.Anyagilag nem tudnak SCT beavatkozást vállalni
    g.A vizsgáló megítélése szerint nem alkalmasak az SCT –re valami miatt
    9.Legalább 28 nap telt el az utolsó NHL terápiától a randomizálásig
    10.Legalább egy olyan két dimenzióban mérhető lézió van, amit még nem sugároztak be: nodális limfóma esetén a rövid átmérő ≥ 1.5 cm, extranodális limfóma esetén pedig> 1.0 cm. Amennyiben készült PET scan, a léziónak PET pozitívnak kell lennie.
    11.Független szövettani értékeléshez rendelkezésre állnak a 3-as fokú follikuláris limfóma, vagy DLBCL diagnózisát igazoló metszetek
    12.Az ECOG skála: ≤ 2 (PS) (8.2 bekezdés)
    13.A várható élettartam ≥ 12 hét a vizsgáló megítélése szerint
    14.Bal kamra ejekciós frakció (LVEF) ≥ 45% echokardiogrammal és normál szérum troponin T
    15.Hemoglobin ≥ 8 g/dl (transzfúzió utáni is mérhető)
    16.Vérlemezke szám ≥ 100 × 109/l; igazolt csontvelő érintettség esetén megengedhető vérlelmezke szám ≥ 75 × 109/l
    17.Abszolút neutrofil szám (ANC) ≥ 1.5 × 109/l; csontvelő érintettség esetén megengedhető ANC ≥ 1.0 × 109/l
    18.Szérum bilirubin ≤ 1.5 × a normál érték felső határa (ULN); bevonhatók az igazoltan Gilbert szindrómás és ≤ 5 × ULN bilirubin értéket mutató betegek.
    19.Az aspartate aminotransferase (AST; más néven szérum glutamic-oxaloacetic transaminase [SGOT]) és az alanin aminotransferase (ALT; más néven szérum glutamic-pyruvic transaminase [SGPT]) ≤ 2 × ULN, vagy limfóma okozta máj érintettség esetén ≤ 5 × ULN
    20.Szérum kreatinin ≤ 2 × ULN
    21.Alopécián kívül minden akut toxicitás, ami az előző kezelés következtében alakult ki 1-es, vagy attól kisebb fokú.
    22.A beteg hajlandó és képes betartani a vizitek tervezett időpontját és részt venni a vizsgálati terv szerint szükséges vizsgálatokon
    23.A csökkent B sejt számú betegeknél, a rituximab hosszú retenciója miatt mind a férfi, mind a nőbetegek kötelesek beleegyezni, hogy hatékony fogamzásgátlást alkalmaznak. A fogamzóképes nőknek nagyon megbízható módszert kell alkalmazniuk (a módszer legalább 99 % -os biztonságot garantáljon következetes és helyes használat esetén) a vizsgálati kezelés teljes ideje alatt, és a vizsgálati készítmény utolsó dózisát követően 12 hónapig. Nagyon megbízható módszernek számítanak a méhen belüli eszközök és a hormontartalmú fogamzásgátlók: tabletta, implantátum, tapasz, hormontartalmú hüvelyi fogamzásgátló, vagy retard injekció. .
    E.4Principal exclusion criteria
    1. Any of the following as the only site(s) of disease: palpable lymph nodes not visible on imaging studies, skin lesions, or bone marrow involvement only
    2. Primary refractory de novo DLBCL or primary refractory follicular grade 3 lymphoma, defined as documented progression within 12 weeks of the last cycle of the first-line multiagent regimen
    3. Prior treatment with a cumulative dose of doxorubicin or equivalent exceeding 450 mg/m²
    4. LVEF < 45% by echocardiogram
    5. Active CTCAE grade 3/4 infection
    6. Major surgery ≤ 28 days prior to randomization
    7. Known acute or chronic hepatitis B or hepatitis C infection
    8. Known seropositivity for human immunodeficiency virus (HIV)
    9. Current CNS involvement by lymphoma
     Any history or evidence of current leptomeningeal involvement by lymphoma is prohibited.
     Patients with prior localized CNS involvement who have been without recurrence for ≥ 12 months and currently have a negative head MRI may be eligible; please discuss with the medical monitor.
    10. Any experimental therapy ≤ 28 days prior to randomization
    11. Myocardial infarction within the past 6 months
    12. New York Heart Association class III or IV heart disease
    13. Other malignancy within last 5 years. Exceptions are:
     curatively treated basal cell/squamous cell skin cancer
     carcinoma in situ of the cervix
     superficial transitional cell bladder carcinoma
     in situ ductal carcinoma of the breast after complete resection
     localized, resected and/or low-risk prostate cancer may be eligible; please discuss with the medical monitor
    14. Any contraindication or known allergy or hypersensitivity to any study drugs
    15. Pregnant or lactating
    16. Concomitant therapy with any anticancer agents, immunosuppressive agents, other investigational anticancer therapies. Low-dose corticosteroids for the treatment of non cancer-related illnesses are permitted
    17. Any psychological, familial, sociological or geographical condition potentially hampering compliance with the study procedures or follow-up schedules
    18. Severe and/or uncontrolled medical disease that could compromise participation in the study, or any medical or psychiatric condition that in the opinion of the investigator would make study drug administration hazardous or obscure the interpretation of data
    1.Az alábbiak bármelyike, mint a betegség manifesztálódásának egyedüli helye: tapintható, de képalkotó módszerrel nem kimutatható nyirokcsomók, bőr léziók, vagy kizárólag csontvelő érintettség
    2.Elsődleges, refrakter, de novo DLBCL, vagy elsődleges, refrakter follikulásris 3-as fokú limfóma, ami a meghatározás szerint az elsővonalbeli kombinált kezelés utolsó ciklusától számított 12 héten belüli, igazolt progresszió
    3.Korábban alkalmazott doxorubicin, vagy azzal egyenértékű készítmény kummulatív dózisa meghaladja a 450 mg/m² -t (képlet a 8.5 pontban)
    4.LVEF < 45% echokardiogrammmal
    5.3/4 fokú fertőzés az NCI CTCAE beosztása szerint (Active National Cancer Institute (Common Terminology Criteria for Adverse Events)
    6.Nagyműtét ≤ 28 nappal a randomizálás előtt
    7.Ismert akut, vagy krónikus hepatitis B, vagy C vírusfertőzés
    8.Ismert szeropozitív HIV fertőzés (humán immundeficiencia vírus)
    9.Limfóma következtében fennálló központi idegrendszeri érintettség
    a.Tilos beválasztani azt, akinek a kórtörténetében előfordult, vagy jelenleg van bármiféle leptomeningeális érintettsége lymphoma miatt.
    b.Alkalmas lehet az a beteg, akinek korábban lokalizált központi idegrendszeri léziója volt, de az nem tért vissza már 12 hónapja vagy még régebben, és jelenleg is negatív a koponya MR felvétele; az orvos monitorral kell konzultálni.
    10.A randomizálást megelőző 28 napon belül valamilyen vizsgálati terápiát kapott
    11.Myokardiális infarktus az elmúlt 6 hónapban
    12.A New York Heart Association beosztás szerint III-as, vagy IV-es szívbetegség (8.4-es bekezdés)
    13.Más rosszindulatú elváltozás 5 éven belül. Kivételek:
    a.Jelenleg kezelt bazálsejtes/laphámsejtes bőrrák
    b.A méhnyak in situ karcinómája
    c.Felületes urothelsejtes hólyag karcinóma
    d.Teljes reszekciót követő in situ duktális emlőkarcinóma
    e.Lokalizált, reszekált és/vagy alacsony kockázatú prosztata karcinómás beteg beválasztható; konzultálni szükséges az orvos monitorral
    14.Ismert allergia, vagy túlérzékenység, vagy kontraindikáció a vizsgálati készítményre
    15.Terhesség, vagy szoptatás
    16.Egyidejűleg alkalmazott rákellenes szerek, immunszuppresszív készítmények, más vizsgálati rákellenes terápiák. Megengedettek viszont az alacsony dózisú kortikosteroidok a malignus kórképpel nem összefüggő betegségek kezelésére
    17.Bármiféle pszichés, családi, szociális, vagy földrajzi helyzet, amely esetleg akadályozza, hogy a beteg eleget tudjon tenni a vizsgálati eljárásoknak, vagy a tervezett utánkövetésnek
    18.Súlyos és/vagy nem kezelt betegség, amely veszélyeztetheti a vizsgálati alany részvételét a vizsgálatban, vagy bármely egészségügyi, vagy pszichiátriai állapot, amely a vizsgáló megítélése szerint veszélyeztetné a vizsgálati készítmény beadását, vagy az adatok értékelhetőségét
    E.5 End points
    E.5.1Primary end point(s)
    Progression-Free Survival (PFS) is the only primary endpoint of the study.
    Progresszió-mentes túlélés az egyetlen elsődleges végpontja a vizsgálatnak.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Progression-free survival (PFS) is defined as the time from the date of randomization to the date of disease progression or death due to any cause (whichever occurs first). The progression date is the earliest time any progression is observed. Patients with no documented progression or death before the data cut off will be censored at the date of the last adequate radiological assessment.
    A vizsgálat elsődleges hatásossági végpontja a PFS, ami a randomizálástól a betegség progressziójáig, vagy a bármilyen okból bekövetkező halálig eltelt idő (amelyik a kettő közül hamarabb bekövetkezik). A PFS elsődleges elemzéséhez az IRC értékelése szerint bekövetkezett progressziót vesszük alapul.
    E.5.2Secondary end point(s)
    The secondary efficacy endpoints are Overall Survival (OS) , Overall response rate (ORR), Complete response rate (CR), and safety


    Overall survival (OS) is defined as the time from randomization until death due to any cause. If the patient is alive or the survival status is unknown, the date of death will be censored on the date the patient was last known to be alive.
    Overall Response Rate (ORR) is defined as the proportion of patients who achieve a CR or PR without additional therapy.
    Complete Response (CR) rate is defined as the proportion of patients who achieve a CR without additional therapy.

    Safety will be assessed by monitoring and recording adverse events, serious adverse events (SAEs), cardiac, hematologic and blood chemistry parameters, vital signs, performance status (PS), and any abnormal findings observed on physical examinations.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Disease assessments are scheduled at baseline and week 8, 16, 24 and end of treatment,
    in the early follow-up:
    FU week 8,16 and 24,
    in the intermediate follow-up:
    FU week 36, 48, 60, 72, 84 and 96,
    in the survival follow up:
    every 12 weeks until death or study determination
    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 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 concerned6
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA46
    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
    Austria
    Belgium
    Bulgaria
    Canada
    Czech Republic
    Denmark
    France
    Germany
    Hungary
    Italy
    Poland
    Romania
    Russian Federation
    Slovakia
    Spain
    Ukraine
    United Kingdom
    United States
    E.8.7Trial has a data monitoring committee No
    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
    End of Study (EOS) is defined as the date when the required number of statistical events (deaths) for the overall survival analysis has occurred.
    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 months2
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years8
    E.8.9.2In all countries concerned by the trial months1
    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: 64
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 256
    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 220
    F.4.2.2In the whole clinical trial 320
    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)
    Patients who discontinue pixantrone or gemcitabine due to toxicity will receive rituximab up to 6 cycles. Patients who discontinue rituximab due to toxicity remain on gemcitabine or pixantrone for up to 6 cycles. Patients who discontinue study treatment for progressive disease or relapse enter the Survival Follow-up Period. Patients who complete study treatment or discontinue study treatment for any other reason will participate in the follow-up periods
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2012-11-29
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2012-11-20
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2018-08-15
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