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    Summary
    EudraCT Number:2014-000835-17
    Sponsor's Protocol Code Number:BRESHAP-GELTAMO.LH-2013
    National Competent Authority:Spain - AEMPS
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2014-05-08
    Trial results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedSpain - AEMPS
    A.2EudraCT number2014-000835-17
    A.3Full title of the trial
    PHASE I-II CLINICAL TRIAL FOR THE EVALUATION OF THE ROLE OF BRENTUXIMAB VEDOTIN PLUS ETOPOSIDE, SOLUMODERIN, HIGH DOSE ARA-C AND CIS-PLATIN IN THE TRANSPLANT AND POST-TRANSPLANT MANAGEMENT FOR PATIENTS WITH RELAPSED OR REFRACTORY CLASSICAL HODGKIN LYMPHOMA
    ENSAYO CLÍNICO FASE I-II PARA EVALUAR EL PAPEL DE BRENTUXIMAB VEDOTIN MÁS ETOPÓSIDO, SOLUMODERIN, ALTAS DOSIS DE ARA-C Y CISPLATINO LA INDUCCIÓN PRE-TRASPLANTE Y MANEJO POST-TRASPLANTE DE PACIENTES CON LINFOMA DE HODGKIN CLÁSICO EN RECAÍDA O REFRACTARIO
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    PHASE I-II CLINICAL TRIAL FOR THE EVALUATION OF THE ROLE OF BRENTUXIMAB VEDOTIN PLUS ETOPOSIDE, SOLUMODERIN, HIGH DOSE ARA-C AND CIS-PLATIN IN THE TRANSPLANT AND POST-TRANSPLANT MANAGEMENT FOR PATIENTS WITH RELAPSED OR REFRACTORY CLASSICAL HODGKIN LYMPHOMA
    ENSAYO CLÍNICO FASE I-II PARA EVALUAR EL PAPEL DE BRENTUXIMAB VEDOTIN MÁS ETOPÓSIDO, SOLUMODERIN, ALTAS DOSIS DE ARA-C Y CISPLATINO LA INDUCCIÓN PRE-TRASPLANTE Y MANEJO POST-TRASPLANTE DE PACIENTES CON LINFOMA DE HODGKIN CLÁSICO EN RECAÍDA O REFRACTARIO
    A.4.1Sponsor's protocol code numberBRESHAP-GELTAMO.LH-2013
    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 SponsorGELTAMO (Grupo Cooperativo Español de Linfoma/Trasplante Autólogo de Médula Ósea)
    B.1.3.4CountrySpain
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportGELTAMO (Grupo Cooperativo Español de Linfoma/Trasplante Autólogo de Médula Ósea)
    B.4.2CountrySpain
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationSecretaría Científica GELTAMO
    B.5.2Functional name of contact pointÁngel Cedillo
    B.5.3 Address:
    B.5.3.1Street AddressC/ Fortuny nº51 Local 5
    B.5.3.2Town/ cityMadrid
    B.5.3.3Post code28010
    B.5.3.4CountrySpain
    B.5.4Telephone number0034913195780
    B.5.5Fax number0034913913383
    B.5.6E-mailsc@geltamo.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 ADCETRIS
    D.2.1.1.2Name of the Marketing Authorisation holderTakeda Pharma A/S
    D.2.1.2Country which granted the Marketing AuthorisationSpain
    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 nameBrentuximab vedotin
    D.3.2Product code PR-1
    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 INNBrentuximab vedotin
    D.3.9.1CAS number 914088-09-8
    D.3.9.3Other descriptive nameBRENTUXIMAB VEDOTIN
    D.3.9.4EV Substance CodeSUB32397
    D.3.10 Strength
    D.3.10.1Concentration unit mg/kg milligram(s)/kilogram
    D.3.10.2Concentration typeup to
    D.3.10.3Concentration number1.8
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product Yes
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 2
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.2Country which granted the Marketing AuthorisationSpain
    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 nameETOPOSIDO
    D.3.2Product code PR2
    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 INNETOPOSIDE
    D.3.9.3Other descriptive nameETOPOSIDE
    D.3.9.4EV Substance CodeSUB07337MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    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: 3
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.2Country which granted the Marketing AuthorisationSpain
    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 nameCISPLATINO
    D.3.2Product code PR3
    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 INNCISPLATINO
    D.3.9.3Other descriptive nameCISPLATIN
    D.3.9.4EV Substance CodeSUB07483MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typerange
    D.3.10.3Concentration number10 to 50
    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.2.1.2Country which granted the Marketing AuthorisationSpain
    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 nameMETILPREDNISOLONA
    D.3.2Product code PR4
    D.3.4Pharmaceutical form Powder and solvent 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 INNMETILPREDNISOLONA
    D.3.9.3Other descriptive nameMETHYLPREDNISOLONE
    D.3.9.4EV Substance CodeSUB08872MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typerange
    D.3.10.3Concentration number8 to 250
    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 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.2.1.2Country which granted the Marketing AuthorisationSpain
    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 nameCITARABINA
    D.3.2Product code PR5
    D.3.4Pharmaceutical form Powder and solvent 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 INNCITARABINA
    D.3.9.3Other descriptive nameCYTARABINE
    D.3.9.4EV Substance CodeSUB06880MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typerange
    D.3.10.3Concentration number100 to 500
    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
    CLASSICAL HODGKIN LYMPHOMA
    LINFOMA DE HODGKIN CLÁSICO
    E.1.1.1Medical condition in easily understood language
    CLASSICAL HODGKIN LYMPHOMA
    LINFOMA DE HODGKIN CLÁSICO
    E.1.1.2Therapeutic area Diseases [C] - Blood and lymphatic diseases [C15]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 17.0
    E.1.2Level HLGT
    E.1.2Classification code 10025319
    E.1.2Term Lymphomas Hodgkin's disease
    E.1.2System Organ Class 10005329 - Blood and lymphatic system disorders
    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 objectives of the study will be:
    1. Search the recommended dose (To determine the Maximum Tolerable Dose of the BV (Brentuximab vedotin) in combination with ESHAP (etoposide, methylprednisolone, high-­dose cytarabine, cisplatin) in relapsed/resistant HODGKIN LYMPHOMA patients)
    2. To evaluate the global and complete response rate after BV-ESHAP as salvage regimen prior to APBSCT (autologous peripheral blood stem cell transplant )
    Objetivo Primario Fase I:
    Busqueda de la dosis recomendada (Determinar la MTD de BV asociado a ESHAP en pacientes de LH en recaída/resistentes)
    Objetivo Primario de la fase II:
    Evaluar la tasa de respuesta global y completa después de BV-ESHAP como régimen de rescate antes del TASPE.
    E.2.2Secondary objectives of the trial
    As secondary objectives we will also try:
    1. To determine the toxicity of BV-ESHAP regimen
    2. To assess the stem cell mobilization capacity of the BV-ESHAP regimen
    3. To evaluate the final results of the whole procedure (BV-ESHAP followed by high-dose chemotherapy, APBSCT and three doses of BV): transplant-related mortality (TRM), overall survival(OS), and progression free survival (PFS)
    Como objetivos secundarios también intentaremos:
    1. Determinar la toxicidad de régimen BV-ESHAP
    2. Evaluar la capacidad de movilización de células madre de la pauta de BV ESHAP
    3. Evaluar el resultado final de todo el procedimiento (BV-ESHAP seguido de altas dosis de quimioterapia, TASPE y tres dosis de BV): mortalidad relacionada con el trasplante (TRM), en supervivencia global (SG) y supervivencia libre de progresión (SLP)
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Patients must have fully recovered from the acute toxic effects of all prior chemotherapy, immunotherapy, or radiotherapy prior to entering this study.
    Each patient must meet all of the following inclusion criteria to be enrolled in this study:
    1. Patients with histologically confirmed relapsed or refractory classical HL after first line chemotherapy. CD30 has to be positive in tumor cells based on any previous lymph node immunohistochemistry. Lymphocyte predominance (LP) Hodgkins Lymphoma with LP CD30 [neg] cells will be excluded.
    2. Age 18 to 65 years. Patient >65 years old with ECOG ≤1 and absence of comorbidities will be included in the study if considered adequate by the investigator.
    3. ECOG ≤ 2.
    4. No major organ dysfunction.
    5. Written informed consent.
    6. Biopsy at HL relapse or when refractoriness disease is diagnosed must be done prior to BV-ESHAP. If biopsy cannot be performed, tumor biopsy at initial diagnosis of HL must be available to be revised by reference pathologist if required.
    7. Absence of prior history of other malignant diseases, except:
    - Basal cell carcinoma of the skin or uterine "in situ" carcinoma adequately treated.
    - Any curable neoplasia adequately treated that has achieved complete response and has remained in such status longer than 3 years.
    8. Female patient is either post-menopausal for at least 1 year before the screening visit or surgically sterile or if of childbearing potential, agree to practice 2 effective methods of contraception, at the same time, from the time of signing the informed consent through 30 days after the last dose of study drug, or agrees to completely abstain from heterosexual intercourse.
    9. Male patients, even if surgically sterilized, (i.e., status post vasectomy) agree to practice effective barrier contraception during the entire study period and through 6 months after the last dose of study drug, or agrees to completely abstain from heterosexual intercourse.
    10. Karnofsky performance status ≥60.
    11. Life-expectancy >3 months.
    12. Baseline platelet count ≥75x109 /L (or 20 if due to Bone Marrow [BM] infiltration) absolute neutrophil count ≥1.5x109 /L (or 0.5 if due to BM infiltration), andhemoglobin must be ≥ 8g/dL.
    13. Meet the following pretreatment laboratory criteria at the Screening visit conducted within 28 days of study enrollment:
    - Total Bilirubin: <1.5 times the upper limit of institutional laboratory normal, unless clearly related to the disease (Gilbert disease will be ruled out from this point).
    - AST (SGOT):<3times the upper limit of institutional laboratory normal except liver infiltration.
    - ALT (SGPT):<3 times the upper limit of institutional laboratory normalexcept liver infiltration.
    - Serum creatinine must be < 2.0 mg/dL and/or creatinine clearance or calculated creatinine clearance > 40 mL/minute
    - Serum sodium >130 mmol/L
    14. Voluntary written informed consent before performance of any study-related procedure not part of normal medical care, with the understanding that consent may be withdrawn by the subject at any time without prejudice to future medical care.
    Los pacientes deben haberse recuperado plenamente de los efectos tóxicos agudos de toda la quimioterapia previa, inmunoterapia o radioterapia antes de entrar en este estudio.
    Para su inclusión en este estudio, cada paciente debe cumplir con todos los siguientes criterios de inclusión:
    1. Diagnóstico histológico de recaída o refractario LH clásico después de la primera línea de quimioterapia. El Ag CD30 tiene que ser positivo en las células tumorales en función de la inmunohistoquímica alguno de los ganglios afectados. El Linfoma de Hodgkin Predominio de Linfocítico Nodular (LHPLN) CD30 [neg] está expresamente excluido de este ensayo.
    2. Edad 18 a 65 años. Los pacientes >65 años con ECOG ≤ 1 y ausencia de comorbilidades pueden ser incluidos en el estudio a juicio del investigador.
    3. ECOG ≤ 2.
    4. Ausencia de disfunción de órganos vitales.
    5. Consentimiento informado por escrito.
    6. Biopsia en la recaída del LH o, si la enfermedad se diagnostica como refractaria, biopsia hecha antes del BV-ESHAP. Si la biopsia no puede llevarse a cabo, debe estar disponible la biopsia tumoral del momento del diagnóstico inicial de LH y, si es necesario, ser revisada por el patólogo de referencia.
    7. Ausencia de antecedentes de otras enfermedades malignas, excepto:
    - Carcinoma de células basales de piel o de útero "in situ" tratado adecuadamente.
    - Cualquier neoplasia curable tratada adecuadamente, que ha logrado una respuesta completa y ha permanecido en esa condición por más de 3 años.
    8. En paciente femenina, bien es menopaúsica desde hace más de 1 año antes de la visita de selección o es quirúrgicamente estéril, bien es fértil pero accede a usar 2 métodos anticonceptivos simultáneos, desde la firma del consentimiento informado hasta 30 días tras la última dosis del fármaco del estudio, o se compromete a una abstinencia heterosexual absoluta.
    9. En paciente varón, aun con esterilización quirúrgica (post vasectomía), deberán acceder al uso de anticonceptivos de barrera durante todo el estudio y hasta 6 después meses de la última dosis del fármaco en estudio, o comprometerse a abstinencia heterosexual absoluta.
    10. Estado funcional de Karnofsky ≥ 60.
    11. Esperanza de vida > 3 meses.
    12. Recuento basal de plaquetas ≥75x109 /L (o 20 si es debido a infiltración de médula ósea [MO]), recuento absoluto de neutrófilos ≥1,5x109 /L (o 0,5 si se debe a infiltración de MO) y la hemoglobina debe ser ≥8 g/dL.
    13. Cumple los siguientes criterios de laboratorio pre tratamiento en la visita de selección, llevada a cabo dentro de los 28 días de inscripción en el estudio:
    - Bilirrubina total: <1,5 veces el límite superior normal, salvo que esté claramente relacionado con la enfermedad o haya enfermedad de Gilbert.
    - AST (SGOT): <3 veces el límite superior normal, salvo infiltración hepática.
    - ALT (SGPT): <3 veces el límite superior normal, salvo infiltración hepática.
    - La creatinina sérica debe ser <2,0 mg/dL y/o aclaramiento de creatinina calculado o aclaramiento creatinina >40 mL/minuto
    - Sodio sérico >130 mmol/L
    14. Consentimiento informado por escrito antes de realizar cualquier procedimiento relacionado con el estudio que no sea parte de la atención médica normal, entendiéndose que el consentimiento puede ser retirado en cualquier momento sin perjuicio de la atención médica futura.
    E.4Principal exclusion criteria
    Subjects meeting any of the following criteria must not be enrolled in the study:
    1. Subjects who have current active hepatic or biliary disease (with exception of patients with Gilbert's syndrome, asymptomatic gallstones, liver metastases or stable chronic liver disease per investigator assessment).
    2. Serious medical or psychiatric illness likely to interfere with participation in this clinical study.
    3. Patients that have been treated previously with anti-CD30 monoclonal antibodies cannot be enrolled in the study.
    4. Myocardial infarction within 6 months prior to enrollment or has New York Hospital Association (NYHA) Class III or IV heart failure, uncontrolled angina, congestive heart failure (NYHA III-IV), severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities. Prior to study entry, any EKG abnormality
    at Screening has to be documented by the investigator as not medically relevant.Recent evidence (within 6 months before first dose of study drug) of a left-ventricular ejection fraction <50%.
    5. Peripheral neuropathy or neuropathic pain grade 2 or higher as defined by NCI CTCAE version 4
    6. Known cerebral or meningeal disease (HL or any other etiology), including signs or symptoms of PML
    7. Symptomatic neurologic disease compromising normal activities of daily living or requiring medications
    8. Known hypersensitivity to recombinant proteins, murine proteins, or to any excipient contained in the drug formulation of brentuximabvedotin.
    9. Women who are pregnant. Women who are breast-feeding and do not consent to discontinue breast-feeding. Women of childbearing potential, including women whose last menstrual period was less than one year prior to screening, unable or unwilling to use adequate contraception from study start to one year after the last dose of protocol therapy. Adequate contraception is defined as hormonal birth control, intrauterine device, double barrier method or total abstinence. Women of childbearing potential must have a negative pregnancy test at screening and cycle 1 day 1 prior to the first dose of brentuximabvedotin.
    10. Treatment with any known non-marketed drug substance or experimental therapy within the longer of 5 terminal half-lives or 4 weeks prior to enrollmentor currently participating in any other interventional clinical study
    11. Chronic or current infectious disease requiring systemic antibiotics, antifungal, or antiviral treatment within two weeks prior to first study drug dose such as, but not limited to, chronic renal infection, chronic chest infection with bronchiectasis, tuberculosis and active Hepatitis C.
    12. History of significant cerebrovascular disease in the past 6 months or ongoing event with active symptoms or sequelae
    13. Known HIV positive
    14. Significant concurrent, uncontrolled medical condition including, but not limited to, renal, hepatic, gastrointestinal, endocrine, pulmonary, neurological, cerebral, or psychiatric disease which in the opinion of the investigator may represent a risk for the patient.
    15. Positive serology for hepatitis B (HBV) defined as a positive test for HBsAg. In addition, if negative for HBsAg but HBcAb positive and HBsAb negative, a HB DNA test will be performed and if positive the subject will be excluded. Note: If HBcAb positive and HBsAb positive, which is indicative of a past infection, the subject can be included.
    16. Positive serology for hepatitis C virus (HCV) defined as a positive test for HCAb, in which case reflexively perform a HCV RIBA immunoblot assay on the same sample to confirm the result
    Los sujetos que cumplan cualquier criterio siguiente no pueden ser incluidos en el estudio:
    1. Enfermedad hepática o biliar activa en la actualidad (salvo pacientes con síndrome de Gilbert, cálculos biliares asintomáticos, infiltración hepática o enfermedad hepática crónica estable a juicio del investigador).
    2. Enfermedad médica o psiquiátrica grave que pueda interferir en la participación en el ensayo.
    3. Pacientes tratados previamente con anticuerpos monoclonales anti-CD30.
    4. Infarto de miocardio en los 6 meses previos a la inscripción, insuficiencia cardíaca clase III o IV de la NYHA (Asociación de Hospitales de Nueva York), angina no controlada, arritmias ventriculares graves no controladas, o evidencia electrocardiográfica de isquemia aguda o anomalías activos del sistema de conducción. Antes de la entrada en el estudio, ninguna anormalidad ECG en la selección tiene que ser documentado por el investigador como no médicamente relevante. Recientes evidencias (dentro de 6 meses antes de la primera dosis
    del fármaco del estudio) de una fracción de eyección del ventrículo izquierdo < 50 %.
    5. Neuropatía periférica o dolor neuropático de grado 2 o superior tal como se define por el NCI CTCAE versión 4
    6. Enfermedad cerebral o meníngea conocida (por LH o cualquier otra etiología), incluidos signos o síntomas de PML
    7. Enfermedad neurológica sintomático que comprometa las actividades normales de la vida diaria o que requiera medicación
    8. Hipersensibilidad conocida a proteínas recombinantes, proteínas murinos o cualquier excipiente contenido en la formulación del fármaco de Brentuximab Vedotin.
    9. Mujeres embarazadas y mujeres que estén dando el pecho y no accedan a interrumpir la lactancia. Las mujeres en edad fértil, incluidas las mujeres cuyo último menstrual período tuvo lugar menos de un año antes de la selección que no puedan o no consientan en usar anticoncepción adecuada desde el comienzo del estudio hasta de un año después de la última dosis
    del tratamiento. Se define anticoncepción adecuada a control hormonal, uso de dispositivo intrauterino, método de doble barrera o abstinencia total. Las mujeres en edad fértil deben hacerse una prueba de embarazo en el escrutinio que debe ser negativa, repitiéndose día 1 del ciclo 1 antes de la primera dosis de Brentuximab Vedotin.
    10. Tratamiento con cualquier fármaco no comercializado conocido o terapia experimental dentro de un período 5 semividas del producto (el más prolongado que haya), en 4 semanas antes de la inscripción, o participación actual en otro estudio clínico intervencionista
    11. Enfermedad infecciosa crónica o actual, que requiere antibióticos sistémicos, antifúngicos, o tratamiento antiviral dentro de dos semanas antes de la primera dosis del fármaco del estudio, tales como (pero no limitado a) la infección renal crónica, infección de pecho crónica con bronquiectasias, tuberculosis y hepatitis C activa
    12. VIH positivo conocido
    13. Antecedentes de enfermedad cerebrovascular significativa en los 6 meses previos o problema en curso con síntomas activos o secuelas
    14. Problema médico concurrente y significativo, no controlado, incluyendo (pero no limitado a)enfermedad renal, hepática, gastrointestinal, endocrina, pulmonar, neurológica, cerebral, o psiquiátrica que en opinión del investigador puede representar un riesgo para el paciente.
    15. Serología positiva para hepatitis B (VHB), definida como prueba positiva para el HBsAg. Además, si es HBsAg [neg] pero HBcAb [pos] y HBsAb [neg], se realizará una prueba de ADN de VHB y si es positivo se excluirá al sujeto. Nota: Si HBcAb [pos] y anti-HBs [pos], indicativo de infección pasada, el sujeto puede ser incluido.
    16. Serología positiva para el virus de la hepatitis C (VHC) definida como prueba positiva para HCAb; en tal caso se realizará un ensayo de inmunotransferencia RIBA VHC en la misma muestra para confirmar el resultado
    E.5 End points
    E.5.1Primary end point(s)
    1. Number of TLD in different cohorts.
    2. Global response rate and complete response.
    1. Número de TLD en diferentes cohortes.
    2. Tasa respuesta global y completas.
    E.5.1.1Timepoint(s) of evaluation of this end point
    1. we will evaluate three groups of patients with the standardscheme in 3-patient cohorts. It will be based on the assumption of a stable shape of the dose-toxicity curve with no cumulative toxicity for the four plus three doses of BV. Therefore the decision to escalate to the next dose level will be based solely on toxicity results from the first course administration of the current level. To determine the MDT is based on an observation period of 21 days, assessing the toxicity results of the administration of the first treatment cycle.

    2. Global and Complete response will be evaluated after the fourth dose of Brentuximab Vedotin
    1. Se evaluarán tres grupos de pacientes con el esquema estándar en cohortes de 3 pacientes. Se basa en el supuesto de que la curva dosis-toxicidad tiene forma estable y no hay toxicidad acumulada del las cuatro más tres dosis de BV. Por tanto, la decisión de intensificar al siguiente nivel de dosis se basará únicamente en los resultados de toxicidad de la administración del primer ciclo de tratamiento. Para determinar la MDT se basará en un período de observación de 21 días, valorando los resultados de toxicidad de la administración del primer ciclo de tratamiento.


    2. La respuesta global y la completa se evaluarán después de la cuarta dosis de Brentuximab Vedotin.
    E.5.2Secondary end point(s)
    As secondary objectives we will also try:
    - To determine the toxicity of BV-ESHAP regimen
    - To assess the stem cell mobilization capacity of the BV-ESHAP regimen
    - To evaluate the final results of the whole procedure (BV-ESHAP followed by high-dose chemotherapy, APBSCT and three doses of BV): transplant-related mortality (TRM), overall survival (OS), and progression free survival (PFS)


    (Overall Survival, PFS, Event-Free Survival, Time to HL
    Progression, Disease-Free Survival, Response Duration, Lymphoma-Specific Survival, and Time to Next Treatment)
    Como objetivos secundarios también intentaremos:
    - Determinar la toxicidad de régimen BV-ESHAP
    - Evaluar la capacidad de movilización de células madre de la pauta de BV-ESHAP
    - Evaluar el resultado final de todo el procedimiento (BV-ESHAP seguido de altas dosis de quimioterapia, TASPE y tres dosis de BV): mortalidad relacionada con el trasplante (TRM), en supervivencia global (SG) y supervivencia libre de progresión (SLP)

    (supervivencia global (SG), supervivencia libre de progresión (SLP), supervivencia libre de evento (SLE), Tiempo hasta la progresión del linfoma (TLP), supervivencia libre de enfermedad DFS), Duración de Respuesta (RD), Supervivencia Específica de Linfoma(LSS) y Tiempo hasta el siguiente Tratamiento (TNT)).
    E.5.2.1Timepoint(s) of evaluation of this end point
    Visits should be done prior every cycle, the day 14th of the first three cycles, pre and post trasplant visits, Final Protocol Treatment Visit aproximately at day +120; follow-up visits for a minimum of 2 years (the follow-up visits per protocol will be done at weeks(approximately) 31 , 48 , 65 , 91 and 117). After this point, follow-up visits will be done at the discretion of the investigator in order to have a minimum of 5 years of follow-up per patient
    Una vez se inicie el tratamiento del ensayo, se realizarán visitas previas al inicio de cada ciclo, el día 14 de los tres primeros ciclos, visita previa y tras el trasplante; visita tras el final del tratamiento (en el día 120 aproximadamente) y visitas de seguimiento durante un mínimo de dos años en las semanas (aproximadamente) 31, 48, 65, 91 y 117. Después de este punto, el seguimiento se realizará a discreción del investigador con el fin de tener un mínimo de 5 años de seguimiento por paciente.
    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 Yes
    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) Yes
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other Yes
    E.7.1.3.1Other trial type description
    Determine the Maximum Tolerable Dose and carry out the fase II
    Evaluar la máxima dosis tolerada del tratamiento y realización de la fase II
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled No
    E.8.1.1Randomised No
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.3 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 concerned14
    E.8.5The trial involves multiple Member States No
    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 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
    The trial will be considered closed when the data of primary and secondary endpoints will be sufficiently prepared for their initial publication.
    El ensayo se considerará cerrado desde el punto de vista normativo después de que los datos sobre las variables primarias y secundarias estén lo suficientemente preparados para su publicación inicial.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years4
    E.8.9.1In the Member State concerned months
    E.8.9.1In the Member State concerned days
    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: 66
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 66
    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 state66
    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)
    Expected normal treatment of that condition
    Tratamiento habitual previsto para esta patología
    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 Decision2014-08-18
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2014-07-14
    P. End of Trial
    P.End of Trial StatusOngoing
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