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    Summary
    EudraCT Number:2012-001790-86
    Sponsor's Protocol Code Number:PIX306
    National Competent Authority:Spain - AEMPS
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2012-08-07
    Trial results View results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedSpain - AEMPS
    A.2EudraCT 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
    Estudio aleatorizado y multicéntrico de comparación de pixantrona +
    rituximab con gemcitabina + rituximab en pacientes con linfoma no Hodgkin
    de células B agresivo que hayan recidivado tras recibir tratamiento con
    CHOP-R o un régimen equivalente y que no cumplan los requisitos para
    recibir un trasplante de células madre
    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
    Estudio para comparar la combinación de pixantrona más rituximab versus gemcitabina más rituximab en pacientes con Linfoma no Hodgkin de células B agresivo que hayan recidivado tras al menos un régimen quimioterapéutico previo con Rituximab (CHOP-R) y que no cumplan los requisitos para recibir un trasplante de células madre
    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 SponsorCell Therapeutics, Inc.
    B.1.3.4CountryUnited States
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportCell Therapeutics, Inc.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationTheorem Clinical Research
    B.5.2Functional name of contact pointProject Management
    B.5.3 Address:
    B.5.3.1Street AddressMethuen Park South, Bath Road
    B.5.3.2Town/ cityChippenham, Wiltshire
    B.5.3.3Post codeSN14 0GT
    B.5.3.4CountryUnited Kingdom
    B.5.4Telephone number+441249444212
    B.5.5Fax number+441249444189
    B.5.6E-mailrebecca.thompson@theoremclinical.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 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 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 (as dimaleate)
    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 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 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 ?1-chain anti-human antigen CD 20), disulfide with human-mouse monoclonal IDEC-C2B8 ?-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 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-?-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 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 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 ?1-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-?-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
    Tratamiento de pacientes con linfoma no Hodgkin de células B agresivo que hayan recidivado tras recibir tratamiento con CHOP-R o un régimen equivalente y que no cumplan los requisitos para recibir un trasplante de células madre
    E.1.1.1Medical condition in easily understood language
    Non-Hodgkin Lymphoma
    Linfoma No Hodgkin
    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 LLT
    E.1.2Classification code 10012820
    E.1.2Term Diffuse large B-cell lymphoma NOS
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 14.1
    E.1.2Level LLT
    E.1.2Classification code 10067070
    E.1.2Term Follicular B-cell non-Hodgkin's lymphoma
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To evaluate the efficacy (as measured by overall survival) of pixantrone plus rituximab compared to gemcitabine plus rituximab in patients with a diagnosis of de novo DLBCL, DLBCL transformed from indolent lymphoma, or follicular grade 3 lymphoma who have relapsed after at least 1 prior chemotherapy regimen and who are not currently eligible for high-dose (myeloablative) chemotherapy and stem cell transplant.
    Evaluar la eficacia (determinada a partir de la supervivencia global) de la combinación de pixantrona más rituximab en comparación con gemcitabina más rituximab en pacientes diagnosticados con linfoma difuso de células B grandes (LDCBG) de novo, LDCBG trasformado a partir de un linfoma indolente, o linfoma folicular en grado 3 que hayan recidivado tras al menos un régimen quimioterapéutico previo y que actualmente no cumplan los requisitos para recibir quimioterapia (mieloablativa) en dosis alta y un trasplante de células madre.
    E.2.2Secondary objectives of the trial
    To compare the two treatment arms with regard to the following secondary endpoints:
    ? Progression-free survival
    ? Overall response rate
    ? Complete response rate
    ? Safety
    Comparar los siguientes criterios de valoración secundarios entre los dos grupos de tratamiento:
    ? Supervivencia sin progresión
    ? Tasa de respuesta global
    ? Tasa de respuesta completa
    ? Seguridad
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    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 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 multiagent regimen (e.g., R-CHOP, R-CVP, 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 109L/; 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. Serum glutamic-oxaloacetic transaminase (AST) and serum glutamic-pyruvic transaminase (ALT) ? 2 x ULN, or ? 5 x ULN if elevation is due to hepatic involvement by lymphoma
    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).
    Criterios de Inclusión
    1. Formulario de consentimiento informado aprobado por el Comité Ético firmado.
    2. Edad ? 18 años.
    3. Diagnóstico de LDCBG (LDCBG de novo o LDCBG transformado a partir de linfoma indolente) o linfoma folicular en grado 3 basado en una biopsia tisular.
    4. Los informes patológicos y de inmunohistoquímica que documenten el diagnóstico histológico actual de acuerdo con la clasificación de la OMS deberán ser revisados por el promotor o por quien este designe antes de la aleatorización del paciente.
    5. Número de tratamientos previos permitidos:
    ? Los pacientes con LDCBG de novo deberán haber recibido de 1 a 3 regímenes previos para el LDCBG.
    ? Los pacientes con linfoma folicular en grado 3 deberán haber recibido de 1 a 3 regímenes previos para el linfoma folicular (cualquier grado).
    ? Los pacientes con LDCBG transformado a partir de un linfoma indolente deberán haber recibido de 1 a 4 regímenes previos para el LNH (cualquier tipo).
    6. Ha recibido un régimen combinado que contenga rituximab (ej., R-CHOP, R-CVP, bendamustina-R)
    7. Los pacientes con un LDCBG transformado a partir de un linfoma indolente deben haber obtenido una respuesta completa o parcial a un tratamiento para el LNH que dure al menos 12 semanas.
    8. No es elegible para recibir quimioterapia (mieloablativa) en dosis alta ni un TCM. Los pacientes que no cumplen los requisitos para recibir un trasplante de células madre son aquellos que:
    ? Han recidivado tras un trasplante de células madre previo
    ? No han respondido a la profilaxis anticitotóxica estándar
    ? No han movilizado un número adecuado de células madre para un TCM
    ? No son elegibles para recibir un TCM debido a otras enfermedades médicas o por su edad
    ? No desean someterse a un TCM
    ? Tienen problemas financieros que les impiden someterse a un TCM
    ? Son considerados como no elegibles por el investigador por cualquier otro motivo
    9. Han transcurrido al menos 28 días entre que terminó el último tratamiento para el LNH y la aleatorización
    10. Al menos un foco de la enfermedad medible bidimensionalmente no ha recibido radiación previamente: enfermedad nodular ? 1,5 cm o enfermedad extranodular > 1,0 cm en los ejes cortos.
    Las lesiones deben dar un resultado positivo en el PET si se realiza esta prueba.
    11. Se dispone de imágenes que confirman el diagnóstico del linfoma folicular de grado 3 o el LDCBG para la revisión histológica independiente
    12. Grado de actividad del ECOG ? 2
    13. Esperanza de vida ? 12 semanas en opinión del investigador
    14. Fracción de eyección ventricular izquierda (FEVI) ? 45 % en un ecocardiograma y troponina sérica normal
    15. Hemoglobina ? 8 g/dl (puede ser posterior a la transfusión)
    16. Recuento plaquetario ? 100 × 109/l; se permite un recuento plaquetario ? 75 × 109/l si está documentada una afectación de la médula ósea
    17. Recuento absoluto de neutrófilos (RAN) ? 1,5 × 109/l; se permite un RAN ? 1,0 × 109/l si está documentada una afectación de la médula ósea
    18. Bilirrubina sérica ? 1,5 veces el límite superior de la normalidad (LSN); puede incluirse a los pacientes con síndrome de Gilbert demostrado y con una concentración de bilirrubina ? 5 veces el
    LSN.
    19. Transaminasa glutámicooxaloacética sérica (AST) y transaminasa glutámicopirúvica sérica (ALT) ? 2 veces el LSN, o ? 5 veces el LSN si la elevación se debe a la afectación hepática provocada por el linfoma
    20. Creatinina sérica ? 2 veces el LSN
    21. Recuperación de todas las toxicidades agudas relacionadas con el tratamiento anterior hasta un grado ? 1, excepto la alopecia
    22. Voluntad y capacidad de cumplir con el calendario de visitas y las evaluaciones exigidas por el protocolo del estudio
    23. Debido al prolongado periodo de retención del rituximab en los pacientes con disminución de las células B, tanto los hombres como las mujeres deben aceptar el uso de un método anticonceptivo
    eficaz. Las mujeres potencialmente fértiles deben usar métodos muy eficaces (definidos como aquellos asociados a una tasa de fallo anual <1 % al usarse de forma constante y correcta) durante todo el tratamiento del estudio así como durante los 12 meses siguientes a la administración de la última dosis del fármaco del estudio. Los métodos anticonceptivos que se consideran muy eficaces son los dispositivos intrauterinos y los anticonceptivos hormonales (píldoras anticonceptivas, implantes, parches transdérmicos, dispositivos vaginales hormonales o inyecciones de liberación prolongada).
    E.4Principal exclusion criteria
    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 HIV
    9. Current CNS involvement by lymphoma
    ? Any past 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
    Criterios de exclusión
    1. Cualquiera de los siguientes si son focos únicos de la enfermedad: ganglios linfáticos palpables pero no visibles en pruebas de diagnóstico por imagen, lesiones cutáneas o afectación exclusiva de la médula ósea.
    2. LDCBG de novo principal refractario o linfoma folicular de grado 3 principal refractario, definido como una progresión documentada en las 12 semanas del último ciclo del régimen combinado de primera elección.
    3. Tratamiento previo con una dosis acumulada de doxorrubicina o equivalente que supere los 450 mg/m2.
    4. FEVI < 45 % demostrada mediante ecocardiograma.
    5. Infección activa de grado 3/4 de acuerdo con los CTCAE.
    6. Cirugía mayor ? 28 días antes de la aleatorización.
    7. Hepatitis B crónica o aguda o infección por el virus de la hepatitis C conocidas.
    8. Infección conocida por el VIH
    9. Afectación actual del SNC por un linfoma
    ? Antecedentes o signos de afectación leptomeníngea actual por un linfoma
    ? Se podrá elegir a pacientes con una afectación previa localizada del SNC que no hayan recidivado durante ? 12 meses y que en la actualidad tengan una RM negativa de la cabeza; deberá comentarse con el supervisor médico.
    10. Cualquier tratamiento experimental en los 28 días previos a la aleatorización
    11. Infarto de miocardio en los últimos 6 meses
    12. Cardiopatía de clase III o IV según la Asociación Cardiológica de Nueva York (sección 8.4)
    13. Otra neoplasia maligna en los últimos 5 años. Las excepciones son:
    ? Carcinoma de piel de céluas basales o escamosas tratado y curado
    ? carcinoma localizado en el cuello uterino
    ? cáncer superficial de vejiga transicional
    ? carcinoma ductal de mama localizado tras una extirpación completa
    ? se podrán elegir pacientes con cáncer de próstata localizado, extirpado y/o de bajo riesgo; deberá comentarse con el supervisor médico
    14. Cualquier contraindicación, alergia conocida o hipersensibilidad a alguno de los fármacos del estudio
    15. Embarazo o lactancia
    16. Tratamiento concomitante con medicación antineoplásica, inmunodepresores o cualquier otro tratamiento antineoplásico en investigación. Se permiten las dosis bajas de corticosteroides para el
    tratamiento de afecciones no relacionadas con el cáncer
    17. Cualquier elemento psicológico, familiar, sociológico o geográfico que pueda dificultar el cumplimiento de los procedimientos del estudio o de los calendarios de seguimiento
    18. Afección grave y/o descontrolada que pueda comprometer la participación en el estudio o cualquier afección médica o psiquiátrica que, en opinión del investigador, haga que la administración del fármaco sea peligrosa o dificulte la interpretación de los datos.
    E.5 End points
    E.5.1Primary end point(s)
    Overall Survival (OS) is the only primary endpoint of the study.
    La supervivencia global (SG) es el único criterio de valoración del estudio.
    E.5.1.1Timepoint(s) of evaluation of this end point
    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.
    SG se define como el tiempo transcurrido desde la aleatorización hasta la
    muerte por cualquier causa. En caso de que el paciente esté vivo o de que se desconozca su estado de supervivencia, se censurará la fecha de la muerte en la fecha en que se tuviese la última noticia de que seguía con vida.
    E.5.2Secondary end point(s)
    The secondary efficacy endpoints are Progression-Free Survival (PFS) , Overall response rate (ORR), and Complete response rate (CR), safety

    Progression-Free Survival (PFS) is defined as the time from the date of randomization to the date of PD or death due to any cause (whichever is first reported) in the intent-to-treat (ITT) population. Patients who withdraw from study (ie. withdrawal of consent, lost to follow-up) without documented progression will be censored at the time of the last adequate disease assessment. Patients who complete the study, have not progressed, and are still alive at the cut-off date of the analysis will be censored at the last adequate disease assessment.
    Patients who receive high-dose therapy and stem cell transplant or other subsequent therapy without evidence for relapse will be censored for the PFS analysis at the last radiologic assessment date prior to the start of a new therapy.
    Overall Response Rate (ORR) is defined as the proportion of patients who achieve a CR or PR without additional therapy.
    Complete Response (CR) is defined as the proportion of patients who achieve a CR without additional therapy.
    Los criterios de valoración de la eficacia secundarios son la Supervivencia Sin Progresión (SSP), la Tasa de Respuesta Global (TRG) y la Respuesta Completa(RC).
    La supervivencia sin progresión (SSP) se define como el tiempo transcurrido desde la fecha de la aleatorización hasta la fecha de la EP o la muerte por cualquier causa (lo que se notifique primero) en la
    población con intención de tratar (ITT). Los pacientes que abandonen el estudio (es decir, retiren su consentimiento o se pierdan para el seguimiento) sin una progresión documentada serán censurados en el
    momento de la última evaluación adecuada de la enfermedad. Los pacientes que completen el estudio, no hayan experimentado progresión y sigan vivos en la fecha de corte del análisis serán censurados en la última evaluación adecuada de la enfermedad.
    Los pacientes que reciban tratamiento con altas dosis y un trasplante de células madre o cualquier otro tratamiento posterior sin pruebas de recidiva serán censurados para el análisis de la SSP en la fecha de la
    última evaluación radiológica antes del inicio de un nuevo tratamiento.
    La tasa de respuesta global (TRG) se define como la proporción de pacientes que obtuvieron una RC o una RP sin tratamiento adicional.
    La respuesta completa (RC) se define como la proporción de pacientes que logra una RC sin un tratamiento adicional.
    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 tratment,
    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
    Las evaluaciones de la enfermedad se programan al inicio, semana 8, 16, 24 y fin de tratamiento,
    en el seguimiento inicial:
    Semanas 8, 16 y 24,
    en el seguimiento intermedio:
    Semanas 36, 48, 60, 72, 84 y 96,
    en el seguimiento de la supervivencia:
    cada 12 semanas hasta la muerte o determinación del estudio
    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 No
    E.8.1.3Single blind Yes
    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
    Argentina
    Brazil
    Canada
    Ukraine
    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.
    El fin del estudio (FDE) se define como la fecha en que se produzca el número necesario de acontecimientos estadísticos (muertes) para el análisis de la supervivencia global.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years6
    E.8.9.1In the Member State concerned months2
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years6
    E.8.9.2In all countries concerned by the trial months2
    E.8.9.2In all countries concerned by the trial days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 340
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 10
    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 state30
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 176
    F.4.2.2In the whole clinical trial 350
    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
    Pacientes que discontinuen pixantrona o gemcitabina por toxicidad podrán seguir recibiendo rituximab hasta 6 ciclos.
    Pacientes que discontinuen rituximab por toxicidad podrán seguir recibiendo gemcitabina o pixantrona hasta 6 ciclos.
    Pacientes que abandonen el tratamiento por progresión o recidiva de la enfermedad pasarán al período de seguimiento de la supervivencia. Los pacientes que completen o que abandonen por cualquier otro motivo el tratamiento entrarán en los periodos de seguimiento.
    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 Decision2012-12-19
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2012-12-12
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2018-08-15
    The status of studies in GB is no longer updated from 1.1.2021
    For the UK, as from 1.1.2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI
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