E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Generalized mantle cell Lymphoma |
Linfoma de Células del Manto Diseminado |
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E.1.1.1 | Medical condition in easily understood language |
Generalized mantle cell Lymphoma |
Linfoma de Células del Manto Diseminado |
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E.1.1.2 | Therapeutic area | Diseases [C] - Blood and lymphatic diseases [C15] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10026805 |
E.1.2 | Term | Mantle cell lymphoma stage IV |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10026804 |
E.1.2 | Term | Mantle cell lymphoma stage III |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10026803 |
E.1.2 | Term | Mantle cell lymphoma stage II |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To establish one of three study arms, R-CHOP/R-DHAP followed by ASCT (control arm A), R-CHOP+ibrutinib /R-DHAP followed by ASCT and ibrutinib maintenance (experimental armA+I), and R-CHOP+ibrutinib /R-DHAP followed by ibrutinib maintenance (experimental arm I) as future standard based on the comparison of the investigator-assessed failure-free survival (FFS). |
Establecer una de los tres grupos del estudio, R-CHOP/R-DHAP seguido de TASPE (grupo control A), R-CHOP+Ibrutinib /R-DHAP seguido de TASPE y mantenimiento con Ibrutinib (grupo experimental A+I), y R-CHOP+Ibrutinib /R-DHAP seguido de mantenimiento con Ibrutinib (grupo experimental I) como futuro tratamiento estándar basado en la comparación de la supervivencia libre de fracaso (SLF) evaluada por el investigador |
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E.2.2 | Secondary objectives of the trial |
To compare the efficacy of the three treatment arms in terms of secondary efficacy endpoints. To determine the safety and tolerability of ibrutinib during induction immuno-chemotherapy and during maintenance and to compare the safety profile of the three treatment arms in terms of secondary toxicity endpoints. |
Comparar la eficacia de los tres grupos de tratamiento en términos de las variables secundarias de eficaciaDeterminar la seguridad y tolerabilidad de Ibrutinib durante la inducción con inmunoquimioterapia y durante el mantenimiento y comparar el perfil de seguridad de los tres grupos de tratamiento en términos de la variable secundaria de toxicidad. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Histologically confirmed diagnosis of MCL according to WHO classification 2. suitable for high-dose treatment including high-dose AraC 3. Stage II-IV (Ann Arbor) 4. Age >= 18 years and <= 65 years 5. Previously untreated MCL 6. At least 1 measurable lesion; in case of bone marrow infiltration only, bone marrow aspiration and biopsy is mandatory for all staging evaluations. 7. ECOG/WHO performance status <= 2 8. The following laboratory values at screening (unless related to MCL): - Absolute neutrophil count (ANC) >=1000 cells/uL - Platelets >=100,000 cells/uL - Transaminases (AST and ALT) <= 3 x upper limit of normal (ULN) - Total bilirubin <= 2 x ULN unless due to known Morbus Meulengracht [Gilbert-Meulengracht-Syndrome]) - Creatinine <=2 mg/dL or calculated creatinine clearance >= 50 mL/min 9. Written informed consent form according to ICH/EU GCP and national regulations 10. Sexually active men and women of child-bearing potential must agree to use one of the highly effective contraceptive methods (combined oral contraceptives using two hormones, contraceptive implants, injectables, intrauterine devices, sterilized partner) together with one of the barrier methods (latex condoms, diaphragms, contraceptive caps) while on study; this should be maintained for 90 days after the last dose of study drug. |
1.Diagnóstico confirmado de linfoma de células del manto de acuerdo a la clasificación de la OMS. 2.Pacientes candidatos a recibir tratamiento intensivo incluidas dosis altas de Ara-C 3.Estadios clínicos de Ann Arbor II-IV. 4.Pacientes ≥ 18 años y ≤ 65 años 5.Pacientes no tratados previamente para MCL 6.Al menos una lesión medible, en caso de que solo esté infiltrada la medula ósea, el aspirado y la biopsia de médula ósea son obligatorios para todas las evaluaciones de la enfermedad 7.Estado general ECOG/OMS ≤ 2 8. Valores de laboratorio en el screening (a menos que estén relacionados con el MCL): o Recuento Absoluto de Neutrófilos (ANC) 1000 células/L o Plaquetas 100,000 células/L o Transaminasas (AST y ALT) ≤ 3 x límite superior normal (LSN) o Bilirrubina total ≤2 x LSN a menos que el aumento de bilirrubina se deba a un síndrome Morbus Meulengracht [Gilbert-Meulengracht-Syndrome]) o Creatinina ≤ 2 mg/dL o aclaramiento de creatinina calculado ≥ 50 mL/min/ 9. Consentimiento informado por escrito de acuerdo a las normas ICH/EU GCP y la regulación nacional 10.Hombres sexualmente activos y mujeres en edad fértil tendrán que utilizar uno de los método anticonceptivo altamente eficaces (ej., anticonceptivo oral combinado usando dos hormonas, implantes, inyectables, anticonceptivos orales combinados, dispositivos intrauterinos, o esterilización de la pareja) junto con un método barrera (preservativo, diafragmas, capsulas anticonceptivas) mientras dure su participación en el estudio; y mantenerse de esta forma durante 90 días después de la última dosis del fármaco en estudio. |
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E.4 | Principal exclusion criteria |
1. Major surgery within 4 weeks prior to randomization. 2. Requires anticoagulation with warfarin or equivalent vitamin K antagonists (e.g. phenprocoumon). 3. History of stroke or intracranial hemorrhage within 6 months prior to randomization. 4. Requires treatment with strong CYP3A4/5 inhibitors. 5. Any life-threatening illness, medical condition, or organ system dysfunction which, in the investigator's opinion, could compromise the subject's safety, interfere with the absorption or metabolism of ibrutinib capsules, or put the study outcomes at undue risk. 6. Vaccinated with live, attenuated vaccines within 4 weeks prior to randomization. 7. Known CNS involvement of MCL. 8. Clinically significant hypersensitivity (e.g., anaphylactic or anaphylactoid reactions to the compound of ibrutinib itself or to the excipients in its formulation). 9. Known anti-murine antibody (HAMA) reactivity or known hypersensitivity to murine antibodies. 10. Previous lymphoma therapy with radiation, cytostatic drugs, anti- CD20 antibody or interferon except prephase therapy according to trial protocol. 11. Serious concomitant disease interfering with a regular therapy according to the study protocol: - Cardiac (Clinically significant cardiovascular disease such as uncontrolled or symptomatic arrhythmias, congestive heart failure, or myocardial infarction within 6 months of Screening, or any Class 3 (moderate) or Class 4 (severe) cardiac disease as defined by the New York Heart Association Functional Classification or LVEF below LLN), - Pulmonary (e.g. chronic lung disease with hypoxemia), - Endocrinological (e.g. severe, not sufficiently controlled diabetes mellitus), - Renal insufficiency (unless caused by the lymphoma): creatinine > 2x normal value and/or creatinin clearance < 50 ml/min), - Impairment of liver function (unless caused by the lymphoma): transaminases > 3x normal or bilirubin > 2,0 mg/dl unless due to Morbus Meulengracht (Gilbert-Meulengracht-Syndrome). 12. Patients with unresolved hepatitis B or C infection or known HIV positive infection (mandatory test). 13.Prior organ, bone marrow or peripheral blood stem cell transplantation. 14. Concomitant or previous malignancies within the last 3 years other than basal cell skin cancer or in situ uterine cervix cancer. 15.Pregnancy or lactation. 16. Any psychological, familiar, sociological, or geographical condition potentially hampering compliance with the study protocol and follow up schedule. 17. Subjects not able to give consent. 18. Subjects without legal capacity who are unable to understand the nature, scope, significance and consequences of this clinical trial. 19. Participation in another clinical trial within 30 days before randomization in this study |
1.Cirugía mayor en las 4 semanas previas a la aleatorización. 2.Necesidad de anticoagulación con antagonistas de la vitamina K.(ej. acenocumarol, phenprocoumon). 3.Historia de ictus o hemorragia intracraneal en los 6 meses previos a la inclusión. 4.Necesidad de tratamiento con inhibidores potentes de CYP3A4/5. 5.Cualquier enfermedad, condición clínica o disfunción de órganos que, a criterio del investigador, pueda comprometer la seguridad del paciente, interferir con la absorción o metabolismo de las cápsulas de Ibrutinib, o ponga en riesgo los resultados del estudio. 6.Vacunación con vacunas vivas atenuadas en las 4 semanas previas a la aleatorización. 7.Infiltración de SNC conocida de MCL 8.Hipersensibilidad clínicamente significativa (ej., reacciones anafilácticas o anafilactoides al propio compuesto de Ibrutinib o a los excipientes de su formulación) 9.Reactividad conocida al anticuerpo anti-murino (HAMA) o hipersensibilidad a anticuerpos murinos. 10.Terapia previa para el linfoma con radiación, medicación citostática, anticuerpos anti-CD20 o interferón excepto la terapia de prefase contemplada en el protocolo del estudio 11.Enfermedad grave concomitante que interfiera con el tratamiento de acuerdo al protocolo del estudio: o Enfermedades cardiovasculares significativas como arritmias no controladas o sintomáticas, insuficiencia cardiaca congestiva, infarto de miocardio en los 6 meses previos al screening, o cualquier enfermedad cardiaca clase 3 (moderada) o clase 4 (severa) como se define por la NYHA o disminución de la fracción de eyección por debajo de la normalidad o Enfermedad pulmonar (ej. Enfermedad pulmonar crónica con hipoxemia) o Endocrinopatía (ej. grave, diabetes mellitus no suficientemente controlada) o Insuficiencia renal (a menos que este causada por el linfoma): creatinina > 2x valor normal y/o aclaramiento de creatinina < 50 ml/min) o Alteración de la función hepática (a menos que este causada por el linfoma): transaminasas > 3x valor normal o bilirrubina > 2,0 mg/dl a menos que sea debida a un síndrome de Gilbert 12. Pacientes con hepatitis B o C activas o infección por VIH (test obligatorio) 13.Trasplante previo de órgano, medula ósea o sangre periférica 14.Neoplasias previas o concomitantes en los últimos 3 años, que no sean cáncer de piel (carcinoma basocelular) o cáncer de cuello uterino in situ. 15.Mujeres embarazadas o en periodo de lactancia 16.Cualquier condición psicológica, familiar, sociológica o geográfica que potencialmente pueda interferir con el cumplimiento del protocolo y del seguimiento. 17.Pacientes incapaces de dar consentimiento 18..Pacientes con capacidades legales reducidas incapaces de comprender la naturaleza, objetivo, significado y consecuencias de este ensayo clínico. 19.Pacientes que hayan participado en otro ensayo clínico en los 30 días previos a la aleatorización del estudio. |
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E.5 End points |
E.5.1 | Primary end point(s) |
FFS defined as time from start of treatment to stable disease at end of immuno-chemotherapy, progressive disease, or death from any cause. |
SLF definida como el tiempo desde el inicio del tratamiento hasta enfermedad estable al final de la inmunoquimioterapia, progresión de la enfermedad, o fallecimiento por cualquier causa |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
End of immuno-chemotherapy, progressive disease, or death from any cause |
Final de la inmunoquimioterapia, progresión de la enfermedad, o fallecimiento por cualquier causa |
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E.5.2 | Secondary end point(s) |
Secondary Efficacy Endpoints: 1. Overall survival (OS). 2. Progression-free survival (PFS) from randomization, from end of induction immuno-chemotherapy in patients with CR or PR at end of induction immuno-chemotherapy, and from the staging 6 weeks after end of induction assessment (at month 6). 3. Overall response and complete remission rates at midterm, at end of induction, 3 months after end of induction immunochemotherapy (at month 6). 4. PR to CR conversion rate during follow-up after end of induction immuno-chemotherapy. Secondary Toxicity Endpoints: 1. Rates of AEs, SAEs, and SUSARs by CTC grade (Version 4.03) during induction immuno-chemotherapy and during periods of follow-up after response to immune-chemotherapy. 2. Cumulative incidence rates of SPMs. |
Variables secundarias de eficacia: 1. Supervivencia global (SG) 2. Supervivencia libre de progresión (SLP) desde la aleatorización, desde el final de la inducción con inmunoquimioterapia en pacientes que alcanzan RC o RP y tras el periodo de 6 semanas después de finalizar las evaluaciones de la inducción (en el mes 6). 3. Respuesta global y tasa de remisión completa en la mitad, al final de la inducción, y 3 meses después de la inmunoquimioterapia de inducción (en el mes 6) 4. Tasa de conversión de RP a RC durante el seguimiento después de finalizar la inducción con inmunoquimioterapia. Variables secundarias de toxicidad: 1.Tasas AEs, SAEs, y SUSARs mediante clasificación CTC (Versión 4.03) durante la inducción con inmunoquimioterapia y durante los periodos de seguimiento después de la respuesta a la inmunoquimioterapia 2.Incidencia acumulada de segundas neoplasias |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Overall survival (OS) Progression-free survival (PFS) from randomization, from end of induction immuno-chemotherapy in patients with CR or PR at end of induction immuno-chemotherapy, and from the staging 6 weeks after end of induction assessment (at month 6) Overall response and complete remission rates at midterm, at end of induction, 3 months after end of induction immunochemotherapy (at month 6) PR to CR conversion rate during follow-up after end of induction immuno-chemotherapy |
Supervivencia global (SG) Supervivencia libre de progresión (SLP) desde la aleatorización, desde el final de la inducción con inmunoquimioterapia en pacientes que alcanzan RC o RP y tras el periodo de 6 semanas después de finalizar las evaluaciones de la inducción (en el mes 6). Respuesta global y tasa de remisión completa en la mitad, al final de la inducción, y 3 meses después de la inmunoquimioterapia de inducción (en el mes 6) Tasa de conversión de RP a RC durante el seguimiento después de finalizar la inducción con inmunoquimioterapia
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | Yes |
E.8.2.3.1 | Comparator description |
Seis ciclos alternos de R-CHOP/RDHAP segudios de TASPE |
Six alternating courses of R-CHOP/RDHAP followed by ASCT |
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E.8.2.4 | Number of treatment arms in the trial | 3 |
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.8.4.1 | Number of sites anticipated in Member State concerned | 14 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 230 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Belgium |
Croatia |
Czech Republic |
Denmark |
Finland |
Germany |
Israel |
Italy |
Netherlands |
Norway |
Poland |
Portugal |
Spain |
Sweden |
Switzerland |
United Kingdom |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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LVLS |
Ultima visita del ultimo paciente |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 10 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 10 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |