E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Mature B-Cell Neoplasm |
Neoplasma Células-B Maduras |
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E.1.1.1 | Medical condition in easily understood language |
Mature B-Cell Cancer |
Cáncer Células-B Maduras |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 19.0 |
E.1.2 | Level | HLGT |
E.1.2 | Classification code | 10025320 |
E.1.2 | Term | Lymphomas non-Hodgkin's B-cell |
E.1.2 | System Organ Class | 10005329 - Blood and lymphatic system disorders |
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E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
Part 1: Confirm that the pharmacokinetics in pediatric subjects is consistent with that in adults
Part 2: Assess efficacy (EFS) of ibrutinib in combination with RICE or RVICI background therapy compared to RICE or RVICI background therapy alone |
Parte 1: Confirmar que la farmacocinética en los sujetos pediátricos es consistente con la de adultos
Parte 2: • Evaluar la seguridad de ibrutinib combinado con (RICE) o (RVICI) como tratamiento de base en sujetos pediátricos con neoplasias malignas de células B |
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E.2.2 | Secondary objectives of the trial |
Part 1: -Evaluate the safety and tolerability of ibrutinib in combination with RICE or RVICI background therapy in pediatric subjects with B-cell malignancies -Assess anti-tumor activity of ibrutinib as add-on to RICE or RVICI regimens -Assess disease-specific biomarkers -Assess the pharmacodynamic response -Acceptability and palatability assessment of all ibrutinib formulations
Part 2: -Evaluate the safety and tolerability of ibrutinib in combination with RICE or RVICI background therapy in pediatric subjects and young adults with B-cell malignancies -Determine the ORR -Evaluate tumor volume reduction at Day 14 -Determine the number and proportion of subjects who proceed to stem cell transplantation -Evaluate the time to response -Measure the duration of response -Evaluate long-term survival (EFS at 2 and 3 years) -Evaluate overall survival -Assess disease-specific biomarkers For the remaining secondary objectives, please refer to protocol page 28. |
P1: Evaluar -La seguridad y tolerabilidad de ibrutinib combinado con (RICE) o (RVICI) como tratamiento de base en sujetos pediátricos con neoplasias malignas de células B -La actividad antitumoral de ibrutinib como tratamiento complementario a los regímenes de RICE o RVICI -Los biomarcadores específicos de la enfermedad -La respuesta farmacodinámica - Valoración de la aceptabilidad y palatabilidad de todas las formulaciones de ibrutinib P2: Evaluar -La seguridad y tolerabilidad de ibrutinib combinado con tratamiento de base con RICE o RVICI en sujetos pediátricos y adultos jóvenes con neoplasias de linfocitos B -Determinar tasa respuesta global (TRG) -Reducción del volumen tumoral el Día 14 -Determinar el número y proporción de sujetos que pasan a trasplante de células madre -El tiempo hasta la respuesta -Medir la duración de la respuesta -Supervivencia a largo plazo (SLE a 2 y 3 años) -Supervivencia global -Niomarcadores específicos de la neoplasia Otro, ref. Pág.28 |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
- Participants with 1 to less than (<) 18 years of age (Part 1 only), or 1 to 30 years of age, inclusive, if initial diagnosis of mature B-cell non-Hodgkin lymphoma (NHL) occurred at <18 years of age (Part 2 only) - Participants must be in first or later recurrence or have disease that is primarily refractory to conventional therapy - Participants must have at least 1 of the following: 1 site of measurable disease greater than (>) 1 centimeter (cm) in the longest diameter by radiological imaging; bone marrow involvement; cerebrospinal fluid with blasts present - Participants with lansky-Karnofsky score of greater than or equal to (>=) 50 - Adolescent women/young women of childbearing potential must have a negative highly sensitive serum or urine beta-human chorionic gonadotropin (beta-hCG) pregnancy test at Screening before enrollment/randomization. Adolescent/young women who are pregnant or breastfeeding are ineligible for this study |
-Participantes de 1 a <18 años (Parte 1 solo), o de 1 a 30 años, inclusive, si el diagnóstico inicial de LNH de linfocitos B maduros fue antes de los 18 años (Parte 2 solo)
-Participante debe estar en la primera recurrencia o posteriores o tener una neoplasia que sea intrínsecamente resistente al tratamiento convencional - Participante debe presentar al menos 1 de los siguientes: 1) sitio de neoplasia mensurable >1 cm de diámetro mayor en una prueba de imagen radiológica 2) Afectación de la médula ósea 3)Blastos en el líquido cefalorraquídeo -Puntuación Lansky-Karnofsky de ≥50 -Las mujeres adolescentes/jóvenes con posibilidad de concebir se realizarán una prueba de embarazo de gonadotropina corinónica humana ( hCG) de alta sensibilidad en suero u orina que debe dar negativo en la Selección antes de la inclusión/aleatorización. Las mujeres adolescentes/jóvenes embarazadas o que estén dando el pecho no son elegibles para este estudio. |
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E.4 | Principal exclusion criteria |
- Participants with ongoing anticoagulation treatment with warfarin or equivalent vitamin K antagonists (example phenprocoumon), or ongoing treatment with agents known to be strong CYP3A4/5 inhibitors, or has taken any disallowed therapies as noted in Section 8.2, Prohibited Medications, before the planned first dose of study drug - Participants with inherited or acquired bleeding disorders - Participants with clinically significant arrhythmias, complex congenital heart disease, or left ventricular ejection fraction (LVEF) <50 percent (%) or shortening fraction (SF) <=28% - Participants with known history of human immunodeficiency virus (HIV) or active Hepatitis B or C virus - Participants with any condition that could interfere with the absorption or metabolism of ibrutinib including malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel - Participants with known allergies, hypersensitivity, or intolerance to ibrutinib or its excipients (refer to Investigator's Brochure) |
-Tratamiento actual con anticoagulantes como warfarina o antagonistas equivalentes de la vitamina K (por ejemplo fenprocoumon), o tratamiento actual con productos que son inhibidores potentes de CYP3A4/5, o cualquier tratamiento no permitido como se indica en la Sección 8.2, Medicación prohibida, antes de la primera dosis prevista del fármaco del estudio -Trastornos de la coagulación hereditarios o adquiridos -Arritmias clínicamente significativas, cardiopatía congénita compleja o fracción de eyección ventricular izquierda (FEVI) < 50 % o fracción de acortamiento (FA) ≤ 28 % -Antecedentes conocidos de (VIH) o virus de la hepatitis B o C activos -Cualquier afección que pueda interferir con la absorción o el metabolismo de ibrutinib como síndrome de malabsorción, enfermedad que afecte significativamente a la función gastrointestinal o resección de estómago o intestino delgado -Alergias conocidas, hipersensibilidad o intolerancia a ibrutinib o a sus excipientes (ref M. del investigador) |
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E.5 End points |
E.5.1 | Primary end point(s) |
1/ Part 1: Area Under The Plasma Concentration-Time Curve (Auc) of Ibrutinib 2/ Part 1: Apparent (oral) Plasma Clearance (CL/F) of Ibrutinib 3/ Part 1: Apparent (oral) Volume of Distribution (Vd/F) of Ibrutinib 4/ Part 1: Maximum Observed Plasma Concentration (Cmax) 5/ Part 1: Relationship Between Pharmacokinetic Parameters and Age or Measure of Body Size 6/ Part 2: Event-free Survival [EFS]) of Ibrutinib |
1/Parte 1: Área bajo la concentración plasmática-tiempo de curva (AUC) de Ibrutinib 2/Parte 1: Aparente (oral) aclaramiento plasmático de Ibrutinib (CL/F) 3/Parte 1: Volumen aparente (oral) de distribución de Ibrutinib (Vd/F) 4/Part 1: Concentración plasmática máxima observada (Cmax) 5/Parte 1: Relación entre los parámetros farmacocinéticos la edad o la medida del tamaño corporal 6 / Parte 2: Evento de supervivencia libre de Ibrutinib [EFS]) |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
1-4 /Predose and at 1, 2, 4, and 6 hours postdose on Day 1 and on Day 7 or 8 of cycle 1; predose, 1, 2, 4, and 6 hours postdose on Day 1 of Cycle 2 or Cycle 3. 5/ up to three 28-day cycles 6/ Randomization to death, disease progression, or lack of CR or PR after 3 cycles of treatment (approximately 4.2 years) |
1-4 /Antes de la dosis, a las 1, 2, 4, y 6 horas después de la dosis en el día 1 y el día 7 o 8 del ciclo 1; antes de la dosis, 1, 2, 4, y 6 horas después de la dosis en el día 1 del Ciclo 2 o del Ciclo 3. 5 / Hasta tres ciclos de 28 días 6 / La asignación, al azar hasta la muerte, progresión de la enfermedad, o la falta de RC o RP después de 3 ciclos de tratamiento (aproximadamente 4.2 años) |
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E.5.2 | Secondary end point(s) |
1/ Part 1: Number of Participants with Adverse Events 2/ Part 1: Percentage of Participants Who Achieve Complete Response (CR) and Partial Response (PR) 3/ Part 1: Disease-specific Biomarkers Assessment 4/ Part 1: Bruton’s tyrosine kinase (BTK) Percent Occupancy 5/ Part 1: Visual analog Scale Score for Palatability 6/ Part 2: Number of Participants with Adverse Events 7/ Part 2: Percentage of Participants Who Achieve Complete Response (CR) and Partial Response (PR) 8/ Part 2: Tumor Volume Reduction 9/ Part 2: Percentage of Participants who Proceed to Stem Cell Transplantation 10/ Part 2: Time to Response 11/ Part 2: Duration of Response 12/ Part 2: Percentage of Participants with Long-term Survival 13/ Part 2: Overall Survival 14/ Part 2: Disease-specific Biomarkers Assessment 15/ Part 2: Bruton’s tyrosine kinase (BTK) Percent Occupancy 16/ Part 2: Visual analog Scale Score for Palatability 17/ Part 2: Area under the plasma concentration-time curve (AUC) |
1/Parte 1: Número de participantes con eventos adversos 2/Parte 1: Porcentaje de participantes que lograr una respuesta completa (RC) y respuesta parcial (RP) 3/Parte 1: Evaluación de biomarcadores de la enfermedad-específica 4/Part 1: Tirosina quinasa de Bruton (BTK) Porcentaje de ocupación 5/Parte 1: Escala visual analógica de puntuación para palatabilidad 6/Parte 2: Número de participantes con eventos adversos 7/Parte 2: Porcentaje de participantes que logran una respuesta completa (RC) y respuesta parcial (RP) 8/Parte 2: Reducción del volumen tumoral 9/Parte 2: Porcentaje de participantes que progresan al trasplante de células madre 10/Parte 2: Tiempo hasta la respuesta 11/Parte 2: Duración de la respuesta 12/Parte 2: Porcentaje de participantes con la supervivencia a largo plazo 13/Parte 2: La supervivencia global 14/Parte 2: Evaluación de biomarcadores de la enfermedad-específica 15/ Parte 2: Tirosina quinasa de Bruton (BTK) Porcentaje de ocupación 16/Parte 2: Escala visual analógica de puntuación para palatabilidad 17/Parte 2: El área bajo la curva de concentración plasmática-tiempo (AUC) |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
1/ Throughout the study duration (approx up to 4.2yrs) 2/ Treatment Phase:D14 (Cy1),end of Cy2,EOT visit;Post treatment phase:every 12wks for first 12m,every 6m until PD/clinical cutoff for primary endpoint/or upto 2yrs after last subject enrolled,whichever occurs first 3/ Cy1 D1, Cy2 D1, Cy3 D1&EOT visit 4/ 4 hrs postdose on D1 and D7 or 8 of Cy1, predose on Cy2 D1 or Cy3 D1, and the EOT visit 5/ Cy1 D1&y3 D1 6/ Throughout the study duration (approx up to 4.2yrs) 7/ idem timepoint nbr 2 8/ D14 9/ Cy2 (D28) 10-11/ Up to 4.2yrs 12/ 2, 3yrs 13/ Randomization to the date of death (maximum up to 4.2yrs) 14/ Cy1 D1, Cy2 D1, Cy3 D1 and EOT visit 15-16/ Cy1 D1 & Cy3 D1 17/ Predose; 1, 2, and 4 hrs postdose, either on D7 or 8 of Cy1 or on D1 of Cy2 (or Cy3) |
1/A lo largo de la dur. del estud. (aprox. hasta 4.2a.) 2/Fase de Trat.: D14 (Cy1), final de Cy2, visita EOT; fase de trat. post: cada 12s. dur. los 12 primeros m, cada 6m. hasta corte clinico de la 1ª variable, hasta 2 a. desp. últ. pac. inscrito, lo que ocurra primero 3/Cy1 D1, D1 Cy2, Cy3 D1 y EOT visita 4/4 h. desp. de la dosis en D1 y D7 u 8 de Cy1, antes de la dosis en Cy2 D1 o D1 Cy3, y la visita EOT 5/Cy1 D1 y D1 y3 6/A lo largo de la dur. del estud. (aprox hasta 4.2a) 7/Idem punto de tiempo de 2 NBR 8/D14 9/Cy2 (D28) 10-11/Hasta 4.2a. 12/2,3 a. 13/La aleatorización hasta la fecha de la muerte (máx. hasta 4.2a.) 14/Cy1 D1, D1 Cy2, Cy3 D1 y EOT vis 15-16/Cy1 D1 y D1 Cy3 17/antes de la dosis; 1, 2, y 4 h. desp. de la dosis, ya sea en D7 o 8 de Cy1 o en D1 de Cy2 (o Cy3) |
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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 | Yes |
E.6.7 | Pharmacodynamic | Yes |
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 | Yes |
E.6.13.1 | Other scope of the trial description |
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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 |
Background Chemoimmunotherapy |
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E.8.2.4 | Number of treatment arms in the trial | 2 |
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 | 5 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 54 |
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 |
Argentina |
Belgium |
Brazil |
Bulgaria |
Canada |
China |
Czech Republic |
France |
Germany |
Hungary |
Italy |
Japan |
Mexico |
Netherlands |
Poland |
Romania |
Russian Federation |
Spain |
Switzerland |
Taiwan |
Turkey |
Ukraine |
United Kingdom |
United States |
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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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The end of study is defined as when approximately 60 EFS events have occurred in Part 2 (death, disease progression, or lack of CR or PR after 3 cycles of treatment based on blinded independent event review), or the sponsor terminates the study, whichever comes first. |
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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 | 7 |
E.8.9.1 | In the Member State concerned months | 9 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 7 |
E.8.9.2 | In all countries concerned by the trial months | 9 |
E.8.9.2 | In all countries concerned by the trial days | 0 |