E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
B-Cell Non-Hodgkin Lymphoma (B-cell NHL) |
Linfoma no hodgkiniano (LNH) de linfocitos B |
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E.1.1.1 | Medical condition in easily understood language |
B-cell NHL is cancer that originates in your lymphatic system, the disease-fighting network spread throughout body. In NHL, tumors develop from B-lymphocytes -a type of white blood cell |
LNH de linfocitos B es cáncer que se origina en el sistema linfático, red que combate la enfermedad que extiende por el cuerpo.En el LNH, los tumores se desarrollan a partir de linf B, glóbulo blanco |
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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 | 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 | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
Phase Ib Mosunetuzumab + cyclophosphamide, doxorubicin, vincristine, prednisone (M-CHOP): •To evaluate safety, tolerability of M-CHOP in patients with relapsed or refractory (R/R) B-cell NHL including estimation of the maximum tolerated dose (MTD), determination of recommended Phase II dose (RP2D), and characterization of dose-limiting toxicities (DLTs) Mosunetuzumab + cyclophosphamide, doxorubicin, prednisone, polatuzumab vedotin (M-CHP-pola): •To evaluate the safety and tolerability of M CHP-pola in patients with relapsing/refractory (R/R) B-cell NHL, including estimation of the MTD, determination of RP2D, and characterization of DLTs Phase II To evaluate •Efficacy of M-CHP-pola compared with rituximab (R)-CHP-pola in patients with previously untreated diffuse large B-cell lymphoma (DLBCL) |
Fase Ib Mosunetuzumab + cyclophosphamida, doxorubicina, vincristina, prednisona (M-CHOP): • Evaluar la seguridad y tolerabilidad de MCHOP en pacientes con LNH de linfocitos B R/R, incluido el cálculo de la dosis máxima tolerada (DMT), la determinación de la DRF2 y la caracterización de la toxicidad limitante de la dosis (TLD). Mosunetuzumab + cyclophosphamida, doxorubicina, prednisona, polatuzumab vedotin (M-CHP-pola): • Evaluar la seguridad y tolerabilidad de MCHP-pola en pacientes con LNH de linfocitos B R/R, incluido el cálculo de la DMT, la determinación de la DRF2 y la caracterización de la TLD. Fase II: • Evaluar la eficacia de M-CHP-pola con respecto a R-CHP-pola en pacientes con un DLBCL no tratado previamente. |
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E.2.2 | Secondary objectives of the trial |
Phase Ib To evaluate •Pharmacokinetics (PK) of mosunetuzumab when administered in combination with CHOP/CHP-pola, polatuzumab vedotin when administered in combination with mosunetuzumab, CHP •Relationship between serum PK, safety, biomarkers, efficacy •Preliminary assessment of anti-tumor activity of M-CHOP and M-CHP-pola Phase II •Efficacy of M-CHP-pola compared with R-CHP-pola in patients with previously untreated DLBCL •Efficacy of M-CHOP in patients with previously untreated DLBCL Phase Ib and II •Immune response to mosunetuzumab, polatuzumab vedotin and potential effect of mosunetuzumab, polatuzumab vedotin anti-drug antibody (ADA) incidence on relevant clinical outcomes •Safety, tolerability of M-CHP-pola compared with R-CHP-pola, M-CHOP •PK of mosunetuzumab when administered by IV infusion with CHOP, CHP-pola, polatuzumab vedotin when administered by IV infusion with mosunetuzumab, CHP |
Fase Ib •Caracterizar farmacocinética de mosunetuzumab cuando se administra en combinación con CHOP o CHP-pola y cuando se administra en combinación con mosunetuzumab y CHP •Caracterizar la relación entre farmacocinética sérica,seguridad,biomarcadores y eficacia. •Efectuar valoración preliminar de actividad antitumoral de M-CHOP y de M-CHP-pola Fase II •Evaluar eficacia de M-CHP-pola respecto a R-CHP-pola en pacientes con DLBCL no tratado previamente. •Evaluar eficacia de M-CHP-pola respecto R-CHP-pola en pacientes con DLBCL no tratado previamente. Fase I_II •Evaluar respuesta inmunitaria a mosunetuzumab, polatuzumab y evaluar el efecto de la presencia de anticuerpos antifármaco (AAF) contra el mosunetuzumab ó polatuzumab en resultados clínicos pertinentes •Evaluar seguridad y tolerabilidad de M-CHP-pola respecto R-CHP-pola, M-CHOP •Describir farmacocinética de mosunetuzumab en combinación con CHOP y CHP-pola IV, polatuzumab vedotin en combinación con mosunetuzumab y CHP IV |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Phase Ib and Phase II - Age >= 18 years - At least one bi-dimensionally measurable nodal lesion - Life expectancy of at least 24 weeks - Eastern Cooperative Oncology Group Performance Status of 0, 1, or 2 - Left ventricular ejection fraction defined by multiple-gated acquisition scan or echocardiogram within the institutional limits of normal - Adequate hematologic function - Contraception use Phase Ib - Histologically confirmed B-cell NHL according to WHO 2016 classification - R/R B-cell NHL after at least one prior systemic lymphoma therapy - Treatment with at least one prior CD20-directed therapy - Group B only: no prior treatment with polatuzumab vedotin Phase II - Previously untreated, histologically confirmed DLBCL according to WHO 2016 classification - International Prognostic Index score of 2-5 |
Fase Ib y fase II -Edad >= 18 años -Como mínimo con una lesión nodal mensurable en dos dimensiones -Esperanza de vida de al menos 24 semanas -Estado funcional según el Grupo Oncológico Cooperativo de la Costa Este (ECOG) de 0, 1 o 2 -Fracción de eyección ventricular izquierda (FEVI) definida a través de una ventriculopatía isotópica (MUGA) o un ecocardiograma (ECO) dentro de los límites de la normalidad institucional. -Una función hematológica adecuada -Uno de anticonceptivos Fase Ib -LNH de linfocitos B confirmado histológicamente conforme a la clasificación de la OMS 2016 -LNH de linfocitos B R/R después de como mínimo un tratamiento del linfoma sistémico previo. -Tratamiento con al menos un tratamiento previo dirigido al antígeno CD20 -Solo el grupo B: sin tratamiento previo con polatuzumab vedotin Fase II: -Un DLBCL no tratado previamente y confirmado histológicamente de acuerdo con la clasificación de la OMS 2016 -Puntuación según el índice de pronóstico internacional (IPI) de 2-5. |
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E.4 | Principal exclusion criteria |
- Pregnant or breastfeeding, or intending to become pregnant during the study - Prior treatment with mosunetuzumab and prior stem-cell transplant - Contraindication to receive full dose of any of the individual components - Current Grade >1 peripheral neuropathy - Received systemic immunosuppressive medications - Current or past history of central nervous system (CNS) lymphoma - Current or past history of CNS disease - Prior radiotherapy to the mediastinal/pericardial region - History of other malignancy - Recent major surgery Phase Ib - Prior treatment with >250 mg/m2 doxorubicin (or equivalent anthracycline dose) - Prior treatment with chemotherapy, immunotherapy, and biologic therapy within a specified period - Prior treatment with radiotherapy within a specified period - Adverse events from prior anti-cancer therapy resolved to <= Grade 1 Phase II - Patients with transformed lymphoma - Prior therapy for B-cell NHL |
-Las mujeres embarazadas o en periodo de lactancia, o que tienen la intención de quedarse embarazadas durante el estudio -Han recibido un tratamiento previo con mosunetuzumab ó Trasplante previo de células madre -Contraindicación a recibir la dosis completa de cualquiera de los componentes individuales -Neuropatía periférica actual de grado >1 -Administración de inmunodepresores sistémicos -Linfoma del SNC actual o antecedentes de dicha afección -Enfermedad del SNC actual o antecedentes de ella -Radioterapia previa en la región pericárdica o mediastínica. -Antecedentes de otra neoplasia maligna -Cirugía mayor reciente Fase Ib -Tratamiento previo con >250 mg/m2 de doxorubicina (o dosis de antraciclinas equivalente) -Tratamiento previo con quimioterapia, inmunoterapia o biológico en un periodo especifico -Tratamiento previo con radioterapia en un periodo especifico -Acontecimientos adversos de un tratamiento contra el cáncer previo que mejoró hasta un grado ≤1 Fase II -Pacientes con un linfoma transformado -Tratamiento previo para el LNH de linfocitos B. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Phase Ib 1.Occurrence and severity of adverse events 2.Occurrence of DLT with severity determined according to NCI CTCAE v5.0 3.Change from baseline in targeted vital signs 4.Change from baseline in targeted clinical laboratory test results 5.Number of cycles received and dose density and intensity Phase II 6.Complete response (CR) rate at the time of primary response assessment (PRA) |
Fase Ib 1.La incidencia y gravedad de los acontecimientos adversos 2.TLD, siendo la gravedad determinada en función de los CTCAE del INC, versión 5.0. 3.Los cambios en constantes vitales concretas con respecto al valor basal 4.Los cambios en los resultados de análisis clínicos concretos con respecto al valor basal 5.El número de ciclos de tratamiento recibidos, así como la intensidad y la densidad de la dosis Fase II 6.La tasa de RC detectada solo en la TAC al llevar a cabo la evaluación de la respuesta principal |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
1. Up to 60 months 2. C1D1 through C1D21 3-4. From baseline to 60 months 5. Up to 60 weeks 6. Up to 60 months |
1.Hasta 60 meses 2.C1D1 hasta C1D21 3- 4 Desde basal hasta 60 meses 5.hasta 60 meses 6.Hasta 60meses |
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E.5.2 | Secondary end point(s) |
1.Maximum serum concentration (Cmax) of mosunetuzumab 2.Minimum serum concentration (Cmin) of mosunetuzumab 3.Total exposure (AUC) of mosunetuzumab 4.Clearance of mosunetuzumab 5.Volume of distribution of mosunetuzumab at steady state 6.Relationship between serum pharmacokinetics and safety, biomarkers, or efficacy endpoints 7.Complete response rate at the time of primary response assessment 8.Best overall response rate and ORR 9.Duration of response 10.Progression free survival 11.Progression free survival at 1 year 12.Event-free survival 13.Time to deterioration 14.Occurrence and severity of adverse events including DLTs 15.Incidence of ADAs to mosunetuzumab 16.Incidence of ADAs to polatuzumab vedotin 17.Relationship between ADAs and PK, safety, efficacy, and biomarkers 18.Occurrence and severity of adverse events 19.Change from baseline in targeted vital signs 20.Change from baseline in targeted clinical laboratory test results and clinical assessments 21.Number of cycles received and dose density and intensity |
1.Concentración máxima sérica (Cmax) de mosunetuzumab 2.Concentración mínima sérica (Cmin) de mosunetuzumab 3.La exposición total (ABC) de mosunetuzumab 4.Aclaramiento de mosunetuzumab 5.Volumen de distribución en estado de equilibrio de mosunetuzumab 6.Relación entre la farmacocinética sérica y la seguridad, los biomarcadores y los criterios de valoración de la eficacia, según sea apropiado 7.La tasa de RC detectada al llevar a cabo la evaluación de la respuesta principal 8. Mejor tasa de respuesta general y tasa de respuesta general 9.La duración de la respuesta (DdR) 10.La supervivencia libre de progresión (SSP) 11.La Supervivencia libre de progresión a un año 12.La supervivencia sin acontecimientos (SSA) 13.El tiempo transcurrido hasta el deterioro 14.La incidencia y gravedad de los acontecimientos adversos, TLD incluidas 15.La presencia de AAF contra el mosunetuzumab 16.La presencia de AAF contra el polatuzumab vedotin 17.Relación entre los AAF y la farmacocinética, la seguridad, la eficacia y los biomarcadores. 18. Ocurrencia y severidad de los Acontecimientos adversos 19. Cambios en constantes vitales concretas con respecto al valor basal 20. Cambios en los resultados de análisis clínicos concretos y evaluaciones clínicas 21.Número de ciclos de tratamiento recibidos, así como la intensidad y la densidad de la dosis |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
1-6. Up to 60 weeks 7-10. Up to 60 months 11. At 1 year 12-13. Up to 60 months 14. C1D1 through C1D21 15-16. Up to 60 weeks 17-19. Up to 60 months 20. From baseline (-14 days) to up to 60 months 21. Up to 60 weeks |
1-6 Hsta 60 semanas 7-10 Hasta 60 meses 11 a 1 año 12-13. Hasta 60 meses 14. C1D1 hasta C1D21 15-16 Hasta 60 semanas 17-19 Hasta 60 meses |
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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 | Yes |
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 |
Tolerability, immunogenicity, biomarkers |
Tolerabilidad, inmunogenicidad y biomarcadores |
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E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | Yes |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | Yes |
E.7.1.3.1 | Other trial type description |
Phase Ib - Dose-Finding |
Fase IB_ Busqueda de dosis |
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E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
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 | Yes |
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) | Yes |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
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 | 5 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 19 |
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 |
Austria |
France |
Korea, Republic of |
Poland |
Spain |
United States |
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E.8.7 | Trial 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
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The end of this study is defined as the date when the last patient, last visit occurs. |
El fin del estudio se define como la fecha en la que ocurra la 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 | 5 |
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 | 5 |
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 |