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    Summary
    EudraCT Number:2021-003855-40
    Sponsor's Protocol Code Number:MOR208C115
    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:2021-12-01
    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 number2021-003855-40
    A.3Full title of the trial
    A Phase 1b/2, Open-Label, Multicenter Study to Evaluate the Safety and Pharmacokinetics of a Modified Tafasitamab IV Dosing Regimen Combined with Lenalidomide (LEN) in Patients with Relapsed or Refractory Diffuse Large B-Cell Lymphoma (R/R DLBCL) (MINDway)
    Estudio en fase Ib/II abierto y multicéntrico para evaluar la seguridad y la farmacocinética de una pauta posológica intravenosa modificada de tafasitamab en combinación con lenalidomida (LEN) en pacientes con linfoma B difuso de células grandes recidivante o refractario (LBDCG R/R) (MINDway)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Study to Evaluate the Safety and Pharmacokinetics of a Modified Tafasitamab IV Dosing Regimen Combined with Lenalidomide in Patients with Worsening (relapsed) or Unresponsive (refractory) Diffuse Large B-Cell Lymphoma (R/R DLBCL) (MINDway)
    Estudio para evaluar la seguridad y la farmacocinética de una pauta intravenosa modificada de tafasitamab en combinación con lenalidomida (LEN) en pacientes con linfoma B difuso de células grandes que ha empeorado (recidivante) o que no ha respondido al tratamiento (refractario) (LBDCG R/R) (MINDway)
    A.3.2Name or abbreviated title of the trial where available
    MINDway
    MINDway
    A.4.1Sponsor's protocol code numberMOR208C115
    A.5.4Other Identifiers
    Name:INDNumber:145,009
    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 SponsorMorphoSys AG
    B.1.3.4CountryGermany
    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 supportMorphoSys AG
    B.4.2CountryGermany
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationMorphoSys AG
    B.5.2Functional name of contact pointGlobal Program Medical Director
    B.5.3 Address:
    B.5.3.1Street AddressSemmelweisstrasse 7
    B.5.3.2Town/ cityPlanegg
    B.5.3.3Post codeD-82152
    B.5.3.4CountryGermany
    B.5.4Telephone number+34900 834 223
    B.5.6E-mailRegistroEspanolDeEstudiosClinicos@druginfo.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 MINJUVI
    D.2.1.1.2Name of the Marketing Authorisation holderIncyte Biosciences Distribution B.V.
    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 Yes
    D.2.5.1Orphan drug designation numberEMA/3/14/1424
    D.3 Description of the IMP
    D.3.1Product nameTafasitamab
    D.3.2Product code MOR00208
    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 INNTafasitamab
    D.3.9.3Other descriptive nameMOR00208
    D.3.9.4EV Substance CodeSUB91252
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number40
    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.2.1.1.1Trade name Zelvina
    D.2.1.1.2Name of the Marketing Authorisation holderADALVO LIMITED
    D.2.1.2Country which granted the Marketing AuthorisationMalta
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameLenalidomide
    D.3.4Pharmaceutical form Capsule, hard
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNLenalidomide
    D.3.9.1CAS number 191732-72-6
    D.3.9.4EV Substance CodeSUB25389
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number5
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 3
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Zelvina
    D.2.1.1.2Name of the Marketing Authorisation holderADALVO LIMITED
    D.2.1.2Country which granted the Marketing AuthorisationMalta
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameLenalidomide
    D.3.4Pharmaceutical form Capsule, hard
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNLenalidomide
    D.3.9.1CAS number 191732-72-6
    D.3.9.4EV Substance CodeSUB25389
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number10
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 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 Zelvina
    D.2.1.1.2Name of the Marketing Authorisation holderADALVO LIMITED
    D.2.1.2Country which granted the Marketing AuthorisationMalta
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameLenalidomide
    D.3.4Pharmaceutical form Capsule, hard
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNLenalidomide
    D.3.9.1CAS number 191732-72-6
    D.3.9.4EV Substance CodeSUB25389
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number25
    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
    Diffuse Large B-Cell Lymphoma (DLBCL)
    linfoma B difuso de células grandes (LBDCG)
    E.1.1.1Medical condition in easily understood language
    A cancer of B cells, a type of white blood cell responsible for producing antibodies
    Cancer de las células B, un tipo de glóbulos blancos responsables de producir anticuerpos
    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 21.0
    E.1.2Level PT
    E.1.2Classification code 10012818
    E.1.2Term Diffuse large B-cell lymphoma
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    • To evaluate the safety and tolerability of tafasitamab administered once every 2 weeks (Q2W)/once every 4 weeks (Q4W) in combination with lenalidomide in R/R DLBCL patients
    • To determine a recommended dose for tafasitamab Q2W/Q4W administration in combination with lenalidomide in R/R DLBCL patients
    • Evaluar la seguridad y la tolerabilidad de tafasitamab administrado una vez cada 2 semanas (C2S)/una vez cada 4 semanas (C4S) en combinación con lenalidomida en pacientes con LDLBG R/R.
    • Determinar una dosis recomendada de tafasitamab C2S/C4S en combinación con lenalidomida en pacientes con LDLBG R/R
    E.2.2Secondary objectives of the trial
    • To evaluate the pharmacokinetic profile of tafasitamab after Q2W/Q4W dosing in combination with lenalidomide
    • To assess anti-tumor activity of tafasitamab after Q2W/Q4W dosing in combination with lenalidomide
    • To assess the incidence of anti-drug antibodies to tafasitamab
    • Evaluar el perfil farmacocinético de tafasitamab tras la administración C2S/C4S en combinación con lenalidomida
    • Evaluar la actividad antitumoral de tafasitamab tras la administración C2S/C4S en combinación con lenalidomida
    • Evaluar la incidencia de anticuerpos antifármaco contra tafasitamab
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Capable of giving signed informed consent as described in Appendix 2: Regulatory, Ethical, and Trial Oversight Considerations, which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol.
    2. Patient must be 18 - 80 years of age (18 – 70 for Czech republic) at the time of signing the informed consent.
    3. One of the following histologically confirmed diagnoses:
    • DLBCL not otherwise specified (NOS)
    • T cell/histiocyte-rich large B-cell lymphoma (THRLBCL)
    • Epstein-Barr virus (EBV) positive DLBCL of the elderly (EBV-positive DLBCL)
    • Grade 3b Follicular Lymphoma
    • Composite lymphoma with a DLBCL component with a subsequent DLBCL relapse, according to the Revised European American Lymphoma/World Health Organization (REAL/WHO) classification.
    Additionally, patients with the evidence of histological transformation to DLBCL from an earlier diagnosis of low-grade lymphoma (i.e., an indolent pathology such as follicular lymphoma, marginal zone lymphoma, chronic lymphocytic leukemia) into DLBCL with a subsequent DLBCL relapse are also eligible.
    4. Tumor tissue for retrospective central pathology review must be provided as an adjunct to participation in this study. If archival paraffin embedded tumor tissue acquired ≤3 years prior to screening is not available, a fresh tumor tissue sample from the patient should be obtained.
    5. Patients must have:
    a. Relapsed and/or refractory disease as defined in Appendix 3: Study Specific Definitions Appendix
    b. At least one bidimensionally measurable disease site. The lesion must have a greatest transverse diameter of ≥ 1.5 cm and greatest perpendicular diameter of ≥ 1.0 cm at baseline. The lesion must be positive on positron emission tomography (PET) scan (for definition see Juweid et al., 2007)
    c. Received at least one, but no more than three previous systemic regimens for the treatment of DLBCL and one therapy line must have included a cluster of differentiation-20 (CD20)-targeted therapy (e.g., rituximab [RTX])
    d. An Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2.
    6. Patients that are not eligible, or patients unwilling to undergo intensive salvage therapy including autologous stem cell transplantation (ASCT). The reason for a patient’s ineligibility must meet one of the criteria described below and documented in the patient’s source data:
    a. Inadequate performance status (Karnofsky performance status ≤ 80%; see Appendix 5: Karnofsky Performance Status Scale)
    b. Disease not responsive to salvage chemotherapy. Responsiveness is defined as a tumor demonstrating either complete response (CR) or partial response (PR) to salvage chemotherapy
    c. Inadequate major organ function (any of the below):
    i. symptomatic congestive heart failure
    ii. lung function-forced vital capacity (FVC), forced expiratory volume in 1 second (FEV-1), and corrected diffusion capacity of the lung for carbon monoxide (DLCO) ≤ 60%
    iii. liver function-total serum bilirubin and transaminases > 2 x upper limit of normal (ULN)
    d. History or evidence of significant co-morbid medical or psychiatric illness which would significantly compromise the patient's clinical care and chances of survival
    e. Inability to collect adequate stem cell graft (e.g. < 1–2 x 106 CD34+ cells free of tumor contamination/kg recipient body weight)
    7. Patients must meet the following laboratory criteria at screening:
    a. Absolute neutrophil count (ANC) ≥ 1.5 × 109/L (unless secondary to bone marrow involvement by DLBCL as demonstrated by recent bone marrow aspiration and bone marrow biopsy)
    b. Platelet count ≥ 75 × 109/L (unless secondary to bone marrow involvement by DLBCL as demonstrated by recent bone marrow aspiration and bone marrow biopsy)
    c. Total serum bilirubin ≤ 2.5 × ULN unless secondary to Gilbert’s syndrome or documented liver involvement by lymphoma. Patients with Gilbert’s syndrome or documented liver involvement by lymphoma may be included if their total bilirubin is ≤ 5 × ULN (see exclusion criterion 6g)
    d. Alanine transaminase (ALT), aspartate transaminase (AST) and alkaline phosphatase (ALP) ≤ 3 × ULN or < 5 × ULN in cases of documented liver involvement
    e. Serum creatinine CL must be ≥ 50 mL/minute either measured or calculated using a standard Cockcroft and Gault formula (see Appendix 6: Cockcroft-Gault Formula)
    1. Capacidad para otorgar el consentimiento informado firmado según se describe en el Apéndice 2: Consideraciones normativas, éticas y de supervisión del estudio, lo que incluye el cumplimiento de los requisitos y restricciones que se recogen en el documento de consentimiento informado (DCI) y en este protocolo.
    2. El paciente debe tener entre 18 y 80 años (18-70 en República Checa) en el momento de firmar el consentimiento informado.
    3. Uno de los siguientes diagnósticos confirmados histológicamente:
    • LDLBG no especificado de otra manera (NEOM)
    • Linfoma de linfocitos B grandes rico en linfocitos T/histiocitos (LLBGRLTH)
    • LDLBG positivo para el virus de Epstein-Barr (VEB) del anciano (LDLBG VEB-positivo)
    • Linfoma folicular de grado 3b
    • Linfoma compuesto con un componente de LDLBG con una recidiva posterior del LDLBG, según la clasificación revisada de la European American Lymphoma/Organización Mundial de la Salud (REAL/OMS).
    Además, también podrán participar pacientes con signos de transformación histológica en LDLBG a partir de un diagnóstico previo de linfoma de bajo grado (es decir, una enfermedad poco activa como linfoma folicular, linfoma de la zona marginal o leucemia linfocítica crónica) con una recidiva posterior del LDLBG.
    4. Como complemento a la participación en este estudio deberá facilitarse tejido tumoral para un examen anatomopatológico centralizado retrospectivo. Si no se dispone de tejido tumoral incluido en parafina de archivo obtenido ≤ 3 años antes de la selección, deberá obtenerse una muestra de tejido tumoral reciente del paciente.
    5. Los pacientes deberán tener:
    a. Enfermedad recidivante o resistente según se define en el Apéndice 3: Definiciones específicas del estudio.
    b. Al menos un foco de enfermedad mensurable en dos dimensiones. La lesión debe tener un diámetro transversal mayor ≥ 1,5 cm y un diámetro perpendicular mayor ≥ 1,0 cm en el momento basal. La lesión debe ser positiva en la tomografía por emisión de positrones (PET) (véase la definición en Juweid y cols., 2007)
    c. Haber recibido al menos una, pero no más de tres, pautas sistémicas previas para el tratamiento del LDLBG y una línea de tratamiento debe haber incluido un tratamiento dirigido al grupo de diferenciación 20 (CD20) (p. ej., rituximab [RTX])
    d. Estado funcional del Eastern Cooperative Oncology Group (ECOG) de 0 a 2.
    6. Pacientes que no sean elegibles o pacientes que no estén dispuestos a recibir tratamiento de rescate intensivo, incluido un trasplante autólogo de células madre (TACM). El motivo de la falta de elegibilidad de un paciente deberá cumplir uno de los criterios descritos a continuación y documentados en los datos originales del paciente:
    a. Estado funcional insuficiente (Estado funcional de Karnofsky ≤ 80%; véase el Apéndice 5: Escala del estado funcional de Karnofsky).
    b. Enfermedad que no responde a la quimioterapia de rescate. La respuesta se define como un tumor que muestra una respuesta completa (RC) o parcial (RP) a la quimioterapia de rescate
    c. Función inadecuada de un órgano principal (cualquiera de las siguientes):
    i. insuficiencia cardíaca congestiva sintomática
    ii. función pulmonar: capacidad vital forzada (CVF), volumen espiratorio máximo en
    1 segundo (VEMS) y capacidad de difusión pulmonar corregida para el
    monóxido de carbono (DLCO) ≤ 60 %
    iii. función hepática: bilirrubina sérica total y transaminasas > 2 veces el límite superior de la normalidad (LSN)
    d. Antecedentes o signos de enfermedad médica o psiquiátrica concomitante importante que pueda comprometer significativamente la asistencia clínica del paciente y las posibilidades de supervivencia
    e. Incapacidad para obtener un injerto adecuado de células madre (p. ej., < 1–2 × 106 células CD34+ sin contaminación tumoral/kg de peso corporal del receptor)
    7. Los pacientes deberán cumplir los siguientes criterios analíticos en el período de selección:
    a. Recuento absoluto de neutrófilos (RAN) ≥ 1,5 × 109/l (a menos que sea secundario a afectación medular por el LDLBG, demostrada por medio de un aspirado y biopsia de médula ósea recientes).
    b. Recuento de plaquetas ≥ 75 × 109/l (a menos que sea secundario a afectación medular por el LDLBG, demostrada por medio de un aspirado y biopsia de médula ósea recientes).
    c. Bilirrubina sérica total ≤ 2,5 veces el LSN a menos que sea secundaria a un síndrome de Gilbert o a afectación hepática documentada por el linfoma. Los pacientes con síndrome de Gilbert o afectación hepática documentada por el linfoma podrán participar si su bilirrubina total es ≤ 5 veces el LSN (véase el criterio de exclusión 6g)
    d. Alanina transaminasa (ALT), aspartato transaminasa (AST) y fosfatasa alcalina (FA) ≤ 3 veces el LSN, o < 5 veces el LSN en caso de afectación hepática documentada
    e. El aclaramiento de creatinina sérica debe ser ≥ 50 ml/minuto medido o calculado con la fórmula de Cockcroft y Gault convencional (véase el Apéndice 6: Fórmula de Cockcroft y Gault)
    E.4Principal exclusion criteria
    1. General provisions:
    a. Patients who are legally institutionalized, or patients under judicial protection
    b. Concurrent enrollment in another interventional clinical study
    2. Patients who have:
    a. Any other histological type of lymphoma including primary mediastinal (thymic) large B-cell (PMBL) or Burkitt lymphoma
    b. Primary refractory DLBCL
    c. Known "double/triple hit" genetics (high grade B-cell lymphoma) characterized by simultaneous detection of MYC with BCL2 and/or BCL6 translocation(s). MYC, BCL2, BCL6 testing prior to study enrollment is not required
    3. Patients who have, within 14 days prior to Day 1 dosing:
    a. Not discontinued CD20-targeted therapy, chemotherapy, radiotherapy, investigational anticancer therapy or other lymphoma-specific therapy
    b. Undergone major surgery (within 4 wks) or suffered from significant traumatic injury
    c. Received live vaccines
    d. Required parenteral antimicrobial therapy for active, intercurrent infections
    4. Patients who:
    a. Have not recovered sufficiently from the adverse toxic effects of prior therapies
    b. Were previously treated with CD19-targeted therapy or IMiDs® (e.g., thalidomide, LEN)
    c. Have a history of hypersensitivity to compounds of similar biological or chemical composition to tafasitamab, IMiDs® and/or the excipients contained in the study treatment formulations
    d. Have undergone ASCT within the period ≤ 3 months prior to signing the ICF. Patients with distant history of ASCT must exhibit full hematological recovery before enrolment
    e. Have undergone previous allogenic stem cell transplantation
    f. Have a history of DVT/embolism, threatening thromboembolism or known thrombophilia or at high risk for a thromboembolic event & who are not willing to take VTE prophylaxis during the entire treatment period
    g. Concurrently use other anticancer or experimental treatments
    5. History of other malignancy that could affect protocol compliance or interpretation of results. Exceptions:
    a. Any malignancy treated with curative intent and malignancy in remission without treatment for > 2 years prior to enrollment are eligible
    b. Low-grade, early-stage prostate cancer (Gleason score 6 or below, Stage 1 or 2) with no requirement for therapy at any time prior to study are eligible
    6. Patients with:
    a. Positive hepatitis B and/or C serology
    b. Known seropositivity for or history of active viral infection with human immunodeficiency virus (HIV)
    c. CNS lymphoma involvement – present or past medical history
    d. History or evidence of clinically significant cardiovascular, CNS and/or other systemic disease that precludes participation in study or compromises ability to give informed consent
    e. History or evidence of rare hereditary problems of galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption
    f. GI abnormalities (absorption issues) including inability to take oral medication
    g. History or evidence of severe hepatic impairment (total serum bilirubin > 3 mg/dL), jaundice unless secondary to Gilbert’s syndrome or documented liver involvement by lymphoma (see inclusion criterion 7c)
    h. History of hypersensitivity to study treatments or excipients or to drugs of similar chemical class
    i. Any other medical condition which makes the patient unsuitable for the study
    7. Contraception provisions:
    Females: Due to the teratogenic potential of LEN, FCBP must:
    All countries except US:
    a. Not be pregnant (confirmed negative serum pregnancy test) at screening & urine pregnancy test prior to starting therapy
    b. Refrain from breast feeding and donating oocytes during study and for 3 months after last dose
    c. Agree to ongoing pregnancy testing during study & at study end (even with abstinence)
    d. Commit to continued abstinence (reviewed monthly) or agree to use highly effective contraception, no interruption, at least 4 wks prior to study start, during treatment, 3 months after the last dose*
    US:
    e. Not be pregnant - confirmed pregnancy test before treatment start, within 10–14 days & within 24 hrs of treatment (even with abstinence)
    f. Refrain from breast feeding and donating oocytes during study & for 3 months after the last dose*
    g. Agree to ongoing pregnancy testing during the study & at study end (even with abstinence)
    h. Not get pregnant while taking study treatment & at least 3 months after the last dose*. True abstinence is an acceptable method of contraception. Use of emergency contraception is permitted
    2. Males:
    All countries except US:
    a. Use an effective barrier method of contraception without interruption. Refrain from donating sperm during the study & for 3 months after the last dose*

    US:
    b. Use latex or synthetic condom. True abstinence is an acceptable method of contraception. Use of emergency contraception is permitted. Refrain from donating sperm during study & for 3 months after the last dose *

    *or according to the US guidelines for LEN, whichever is longer
    1.Disposiciones grales.:
    a.Pacientes legalmente institucionalizados o bajo protección judicial
    b.Participación simultánea en otro estudio clínico de intervención
    2. Pacientes que presenten:
    a.Otro tipo histológico de linfoma, como linfoma mediastínico primario (tímico) de linfocitos B grandes (LMPLBG) o linfoma de Burkitt
    b.LDLBG primario resistente (Apéndice 3)
    c.Genética conocida de "doble/triple impacto" (linfoma de linfocitos B de alto grado) carac. por detección simultánea de translocaciones de MYC con BCL2 o BCL6. No es necesario análisis de MYC, BCL2 o BCL6 antes de la inclusión en el estudio.
    3. Pacientes que en 14 días previos a la admini. del día 1 presentan:
    a.Ausencia de suspensión del trat. dirigido contra CD20, quimioterapia, radioterapia, trat. antineoplásico en investigación u otro trat. específico del linfoma
    b.Intervención de cirugía mayor en 4 semanas previas o traumatismo importante
    c.Recepción de vacunas de microorganismos vivos
    d.Necesidad de trar. antibiótico parenteral para infecciones intercurrentes activas
    4. Pacientes que:
    a.No se han recuperado suficientemente de los ef. tóxicos adversos de los trat. previos.
    b.Han recibido trat. previo dirigido contra CD19 o fármacos inmunomoduladores (ej.talidomida, LEN)
    c.Presentan antecedentes de hipersensibilidad a compuestos de composición biológica o química similar a la de tafasitamab, a inmunomoduladores o a los excipientes contenidos en las formulaciones del trat. del estudio
    d.Se han sometido a un TACM en los 3 meses previos a la firma del DCI. Los pacientes con antecedentes más distantes de TACM deberán presentar una recuperación hematológica completa antes de su inclusión en el estudio.
    e.Se han sometido a un trasplante alogénico de células madre previo.
    f.Antecedentes de trombosis venosa profunda/embolia, tromboembolia potencialmente mortal o trombofilia conocida o presentan un riesgo elevado de sufrir un episodio tromboembólico y no quieran/puedan de recibir profilaxis para la tromboembolia venosa (TEV) durante todo el período de trat..
    g.Uso simultáneo de otros trat. antineoplásicos o experimentales
    5. Antecedentes de otra neoplasia maligna que pueda afectar al cumplimiento del protocolo o a la interpretación de los resultados. Excepciones:
    a.Podrán participar pacientes con cualquier neoplasia maligna tratada adecuadamente con intención curativa y que haya estado en remisión sin trat. durante > 2 años antes de la inclusión
    b.Podrán participar pacientes con cáncer de próstata de bajo grado en estadio inicial (punt. Gleason de 6 o menos, estadio 1 o 2) que no hayan necesitado trat. en ningún momento antes del estudio
    6. Pacientes con:
    a.Serología positiva para hepatitis B o C
    b.Seropositividad conocida o antecedentes de infección vírica activa por VIH
    c.Afectación por linfoma del sistema nervioso central (SNC): antecedentes médicos presentes o pasados
    d.Antecedentes o signos de enfermedad cardiovascular, del SNC u otra enfermedad sistémica clínicamente significativas que impidan la participación en el estudio o alteren la capacidad del paciente para otorgar su consentimiento informado.
    e.Antecedentes o signos de problemas hereditarios raros de intolerancia a la galactosa, alactasia lapona o malabsorción de glucosa-galactosa.
    f.Anomalías digestivas (problemas con absorción), incluida la incapacidad para tomar medicación oral
    g.Antecedentes o signos de insuf. hepática grave (bilirrubina sérica total > 3 mg/dl), ictericia a menos que sea secundaria a síndrome de Gilbert o afectación hepática documentada por el linfoma ( crit. de incl. 7c)
    h.Antecedentes de hipersensibilidad a cualquiera de los trat. del estudio o sus excipientes o a fármacos de un grupo químico parecido
    i.Otra enfermedad que haga que el paciente no sea adecuado para el estudio.
    7. Anticoncepción:
    Mujeres en edad fértil deben:
    a.No estar embarazadas, confirmado mediante prueba de embarazo en suero negativa en el período de selección y una prueba de embarazo en orina supervisada médicamente antes de iniciar el trat. del estudio
    b.Abstenerse de amamantar y donar óvulos durante el estudio y hasta 3 meses después de la última dosis del fármaco del estudio o según las directrices locales para LEN.
    c.Comprometerse a someterse a pruebas periódicas de embarzo durante el estudio y una vez finalizado el trat. del estudio. Aunque practique abstinencia sexual completa.
    d.Comprometerse a practicar la abstinencia continua de rel.heterosexuales (revisable mensualmente), o a usar métodos anticonceptivos muy eficaces sin interrupción al menos 4 semanas antes del inicio del estudio, durante el estudio y durante 3 meses después de la última dosis del trat.
    8.Los participantes varones deberán:
    a.Utilizar un método anticonceptivo de barrera eficaz sin interrupción en caso de mantener rel. sexuales con MEF. Abstenerse de donar semen durante su participación en el estudio y hasta 3 meses después de la última dosis del trat. del estudio
    E.5 End points
    E.5.1Primary end point(s)
    Incidence and severity of TEAEs
    Incidencia e intensidad de los AAST
    E.5.1.1Timepoint(s) of evaluation of this end point
    All visits, all cycles.
    Todas las visitas, todos los ciclos
    E.5.2Secondary end point(s)
    1) Primary Analysis all available data up until all patients in the study have either reached C3D28 or discontinued the study prior to C3D28.
    2) Final Analysis all available data until approximately 3 years after the last patient was enrolled.

    • Tafasitamab serum concentrations after 3 (Ctrough and Cmax) and 12 (Ctrough) treatment cycles
    • Best Objective Response Rate (ORR) by Investigator assessment up to treatment Cycle 12 based on Cheson et al. (2007)
    • Duration of Response (DoR) by Investigator assessment based on Cheson et al. (2007)
    • Progression-Free Survival (PFS) by Investigator assessment based on Cheson et al. (2007)
    • Number and percentage of patients developing anti- tafasitamab antibodies up to treatment Cycle 12
    1) Análisis principal cuando todos los pacientes incluidos hayan completado el D28C3 o se hayan retirado del estudio antes del D28C3
    2) Análisis final con todos los datos disponibles hasta aproximadamente 3 años después de que el último paciente haya sido incluido.

    •Concentraciones séricas de tafasitamab después de 3 (Cmín y Cmáx) y 12 (Cmín) ciclos de tratamiento.
    •Mejor tasa de respuesta objetiva (TRO) según la evaluación del investigador hasta el ciclo 12 de tratamiento basada en Cheson y cols. (2007)
    •Duración de la respuesta (DR) según la evaluación del investigador basada en Cheson y cols. (2007)
    •Supervivencia sin progresión según la evaluación del investigador basada en Cheson y cols. (2007)
    •Número y porcentaje de pacientes que presenten anticuerpos antitafasitamab hasta el ciclo 12 de tratamiento
    E.5.2.1Timepoint(s) of evaluation of this end point
    Tafasitamab: days 1, 4, 8, 15 cycle 1; day 1, 15 cycles 2 &3; days 1 & 28 cycle 4-12; EOT
    ORR: PET CT or PET-MR at screening, day 28 cycle 12; day 1 cycle 13+; EOT; bone marrow assessment at screening, day 15 cycle 3; day 1 cycle 4-12; day 1 cycle 13+
    DoR: screening; day 1 cycle 1; day 1 cycle 3, day 1 cycle 4-12; day 1 cycle 13+; EOT
    PFS: as per DoR
    ADA: day 1 cycle 1-3; day 1, cycles 4, 6, 8, 10; cycle 12; days 1 & 28; EOT

    The timing information included here (e.g., 12 treatment cycles, or cycle 13+) is referring to the Final Analysis, as that data will not be available in a Primary Analysis (except only the patients who make it to those later cycles).
    Tafasitamab: dias 1, 4, 8, 15 ciclo 1; dias 1, 15 ciclos 2 &3; dias 1 & 28 ciclos 4-12; FDT
    TRO: PET CT o PET-MR en la visita de selección, dia 28 ciclo 12; dia 1 ciclos 13+; FDT; biopsia de médula osea en la visita de seledción, día 15 cycle 3; dia 1 ciclos 4-12; dia 1 ciclo 13+
    DR: visita de selección; dia 1 ciclo 1; dia 1 ciclo3, dia 1 ciclos 4-12; dia 1 ciclo 13+; FDT
    Supervivencia sin progresión : según DR
    ACF: dia 1 ciclos 1-3; dia 1, ciclos 4, 6, 8, 10; ciclo 12; dias 1 & 28; FDT

    La información sobre los tiempos incluida aqui (ej., 12 ciclos de tratamiento, o ciclo 13+) está referida al análisis final, pues estos datos no estaran disponibles en el analisis principal (excepto solo los pacientes que llegan a esos ciclos posteriores)
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy No
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    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 Yes
    E.6.13.1Other scope of the trial description
    Immunogenicity, biomarkers, genetic analysis
    Inmunogenicidad, biomarcadores, análisis genético
    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
    Safety and preliminary efficacy
    Seguridad y eficacia preliminar
    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 Yes
    E.8.1.7.1Other trial design description
    cohortes secuenciales
    sequential cohorts
    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.8.2.4Number of treatment arms in the trial1
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned8
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA40
    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
    Czechia
    Italy
    Spain
    United States
    France
    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 end of the study is defined as the date when the last patient has completed last visit (approximately 3 years after the last patient received the first study treatment).
    El final del estudio se define como la fecha en la que el último paciente haya completado la última visita (aproximadamente 3 años después de que el último paciente haya recibido el primer tratamiento del estudio).
    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
    E.8.9.2In all countries concerned by the trial years4
    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: 45
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 6
    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 state9
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 40
    F.4.2.2In the whole clinical trial 51
    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)
    The Sponsor does not have any plans to provide study treatment to patients after the end of the study
    El promotor no tiene planes de proporcionar el tratamiento del estudio después del final de estudio
    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 Decision2022-03-09
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2021-12-29
    P. End of Trial
    P.End of Trial StatusOngoing
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