E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Newly diagnosed, treatment-naïve multiple myeloma (MM) who are ineligible for autologous stem cell transplant (auto-SCT). |
Tratamiento de pacientes con mieloma múltiple de diagnóstico reciente que no han recibido tratamiento y no son aptos para TCM autólogo. |
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E.1.1.1 | Medical condition in easily understood language |
Newly diagnosed, never treated multiple myeloma (MM) who are not eligible for his/her own stem cell transplant (auto-SCT). |
Tratamiento de pacientes con mieloma múltiple de diagnóstico reciente que no han recibido tratamiento y no son aptos para TCM autólogo. |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
MedDRA Classification |
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 |
Compare the Progression Free Survival (PFS) as assessed by independent central review according to the International Myeloma Working Group response criteria, (IMWG criteria) between treatment arms. |
Comparar la supervivencia sin progresión (SSP) evaluada mediante revisión centralizada enmascarada por un CAC con arreglo a los criterios de respuesta del International Myeloma Working Group (criterios IMWG) entre grupos de tratamiento. |
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E.2.2 | Secondary objectives of the trial |
(1) Objective: To compare the Overall Survival (OS) between treatment arms. (2) Objective: To evaluate Overall Response Rate (ORR), Disease Control Rate (DCR), Duration of Response (DOR), and second Progression Free Survival (PFS2) as assessed by CAC blinded central review using IMWG criteria [1] between treatment arms. (3) Objective: To evaluate the safety and tolerability in both treatment arms |
(1)Objetivo: comparar la supervivencia global (SG) entre los grupos de tratamiento. (2)Objetivo: evaluar la tasa de respuesta global (TRG), la tasa de control de la enfermedad TCE), la duración de la respuesta (DR) y la segunda supervivencia sin progresión (SSP2) según lo determinado por un CAC central desconocedor del tratamiento utilizando los criterios IMWG [1] entre grupos de tratamiento. (3)Objetivo: evaluar la seguridad y la tolerabilidad en los dos grupos de tratamiento |
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Merck will conduct Future Biomedical Research on DNA (blood) specimens collected during this clinical trial. Such research is for biomarker testing to address emergent questions not described elsewhere in the protocol (as part of the main trial) and will only be conducted on specimens from appropriately consented subjects. The objective of collecting specimens for Future Biomedical Research is to explore and identify biomarkers that inform the scientific understanding of diseases and/or their therapeutic treatments. The overarching goal is to use such information to develop safer, more effective drugs, and/or to ensure that subjects receive the correct dose of the correct drug at the correct time. |
Merck llevará a cabo investigaciones biomédicas futuras con las muestras obtenidas específicamente con estos fines durante este ensayo clínico. Estas investigaciones tendrán por objeto el análisis de biomarcadores para abordar aspectos nuevos que no se describen en otras partes del protocolo (como parte del ensayo principal) y solo se llevarán a cabo en muestras de los sujetos que hayan otorgado el consentimiento correspondiente. El objetivo de la obtención de muestras para investigaciones biomédicas futuras consiste en estudiar e identificar biomarcadores que proporcionen información a los científicos sobre las enfermedades y sus tratamientos. El objetivo último es utilizar tal información para desarrollar fármacos más seguros y eficaces y/o para garantizar que los pacientes reciban la dosis correcta del fármaco adecuado en el momento preciso. |
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E.3 | Principal inclusion criteria |
1.Newly diagnosed, treatment-naïve, ASCT ineligible, symptomatic MM (CRAB features). 2.Confirmed diagnosis of active MM and measurable disease defined as: -Serum monoclonal protein (M-protein) levels > or = to 0.5 g/dL or -Urine monoclonal protein (M-protein) levels > or = to 200 mg/24-hours or -Subjects without measurable serum and urine M-protein levels, an abnormal serum free light chain ratio (FLC ?/?) with involved FLC level > or = to 100 mg/L. (Normal serum FLC ?/? value: 0.26 - 1.65) -Presence of CRAB features 3.Must be ineligible to receive treatment with ASCT due to age (> or = to 65 years old) or coexisting medical condition. Subjects < 65 years old who refuse ASCT are not eligible for this study. 4.Provide, archival (< or = to 60 days) or newly obtained bone marrow biopsy or aspirate material for disease assessment and biomarker analysis. 5.Performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) Performance Scale. |
1. Sujetos con mieloma múltiple (MM), con características CRAB, de diagnóstico reciente y sin tratamiento previo no apto para trasplante de células madre autólogo. 2.Tener un diagnóstico confirmado de mieloma múltiple activo y enfermedad mensurable, definida como: a.Concentración de proteína monoclonal (proteína M) en suero ?0,5 g/dl; o b.Concentración de proteína monoclonal (proteína M) en orina ?200 mg/24 horas; o c.En sujetos sin concentraciones mensurables de proteína M en suero y en orina, proporción anómala de cadenas ligeras libres en suero (CLL ?/?) con una concentración de CLL afectadas ?100 mg/l. (Valor normal de CLL ?/? en suero: 0,26 - 1,65). d.Presencia de características CRAB 2.No ser candidatos al tratamiento con TCM autólogo debido a la edad (?65 años) o a la presencia de otras enfermedades. Los pacientes de <65 años que no quieran someterse a TCM autólogo no serán elegibles para este estudio. 3.Ser capaces de proporcionar muestras de aspirado/biopsia de médula ósea de archivo (?60 días) o recién obtenidas para realizar análisis de biomarcadores y una evaluación de la enfermedad. 4.Presentar un estado funcional del Eastern Cooperative Oncology Group (ECOG) de 0 o 1. |
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E.4 | Principal exclusion criteria |
1.Subjects with non-secretory or oligo-secretory myeloma, smoldering multiple myeloma (SMM), monoclonal gammopathy of undetermined significance (MGUS), plasma cell leukemia or Waldenström's macroglobulinemia. 2.History of repeated infections, primary amyloidosis, hyperviscosity or POEMS syndrome. 3.Has had prior anti-myeloma therapy including but not limited to dexamethasone, IMiDs, proteasome inhibitors, chemotherapy, monoclonal antibody, ASCT or radiation therapy. 4.Has undergone prior allogeneic hematopoetic stem cell transplantation (HSCT) within the last 5 years. 5.Has known hypersensitivity to dexamethasone. 6.Subjects with peripheral neuropathy ? Grade 2. 7.Has evidence of active, non-infectious pneumonitis. 8.Has received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody. |
1.Tener mieloma no secretor u oligosecretor, mieloma múltiple latente (MML), gammapatía monoclonal de significado indeterminado (GMSI), leucemia de células plasmáticas o macroglobulinemia de Waldenström 2.Antecedentes de infecciones repetidas, amiloidosis primaria, hiperviscosidad o síndrome POEGA. 3.Haber recibido tratamiento previo del mieloma con, por ejemplo, dexametasona en dosis bajas, IMiD, inhibidores del proteasoma, quimioterapia, anticuerpos monoclonales, TCM autólogo o radioterapia antes de incorporarse al estudio. 4.Haber recibido un alotrasplante de células madre hematopoyéticas en los 5 años precedentes 5.Tener hipersensibilidad documentada a la dexametasona 6.Tener neuropatía periférica de grado ?2. 7.Tener indicios de neumonitis no infecciosa activa. 8.Haber recibido tratamiento previo con un anticuerpo anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137 o anti-CTLA-4 |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary end point of the study is Progression-free survival (PFS): International Myeloma Working Group response criteria (IMWG 2006) by blinded central review. PFS is defined as the time from randomization to the first documented disease progression per IMWG 2006 based on blinded central review or death due to any cause, whichever occurs first. |
La variable principal de este estudio es la supervivencia sin progresión (SSP): criterios de respuesta del International Myeloma Working Group (IMWG 2006) mediante revisión central enmascarada por el CAC La SSP se define como el tiempo transcurrido entre la aleatorización y la primera progresión de la enfermedad documentada conforme a los criterios IMWG 2006 según una revisión centralizada por un CAC enmascarado o la muerte por cualquier causa, lo que ocurra antes. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
1.Interim PFS Analysis: ~ 20 months after trial starts (when all subjects enrolled and ~ 115 PFS events are observed). 2.Final PFS Analysis: ~ 20 months after interim PFS analysis and ~227 PFS events are observed. |
1. Análisis intermedio SSP : Aprox. 20 meses después de que comience el ensayo (cuando todos los sujetos se hayan reclutado y cuando se observen 115 eventos de PFS) 2. Análisis final de PFS: Aprox. 20 meses después del análisis intermedio de PFS y aprox. cuando se hayan observado 227 eventos de PFS. |
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E.5.2 | Secondary end point(s) |
1.Overall Survival (OS): OS is defined as the time from randomization to death due to any cause. 2.Overall Response Rate (ORR): ORR is defined as the proportion of the subjects in the analysis population who have a complete response (CR) or partial response (PR). 3.Duration of Response (DOR): For subjects who demonstrated CR or PR, response duration is defined as the time from first documented evidence of CR or PR until disease progression or death. 4.Second Progression Free Survival (PFS2): PFS2 is the time from randomization to subsequent disease progression after initiation of new anti-cancer therapy, or death from any cause, whichever comes first. |
1.Supervivencia global (SG): La SG se define como el tiempo transcurrido entre la aleatorización y la muerte por cualquier causa. 2.Tasa de respuesta global (TRG): La TRG se define como la proporción de sujetos del análisis poblacional que alcanzan al menos una respuesta parcial (RC + RPMB + RP) 3.Duración de la respuesta (DR): En los sujetos que demuestren al menos una respuesta parcial, la duración de la respuesta se define como el tiempo transcurrido desde la primera prueba documentada de respuesta al menos parcial hasta la progresión de la enfermedad o la muerte. 4.SSP2: tiempo transcurrido entre la aleatorización y la siguiente progresión de la enfermedad tras el comienzo de un nuevo tratamiento antineoplásico o la muerte por cualquier causa, lo que suceda antes. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
~ 41 months after trial starts (when last subject completes its last phone call follow-up). |
Aprox. 41 meses después del comienzo del ensayo ( cuando el ultimo sujeto haya completado la llamada de seguimiento) |
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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 | Yes |
E.6.12 | Pharmacoeconomic | Yes |
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) | Yes |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
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 | 3 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 42 |
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 |
Australia |
Brazil |
Canada |
France |
Germany |
Israel |
Italy |
Japan |
Norway |
Russian Federation |
South Africa |
Spain |
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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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 3 |
E.8.9.1 | In the Member State concerned months | 5 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial months | 5 |
E.8.9.2 | In all countries concerned by the trial days | 0 |