| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Relapsed and/or Refractory Multiple Myeloma |
| Mieloma múltiple recidiva o resistente |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| 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 | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10028228 |
| E.1.2 | Term | Multiple myeloma |
| E.1.2 | System Organ Class | 100000004864 |
|
| 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 |
| To compare the effect of ixa+dex versus pom+dex on progression-free survival (PFS) in patients with relapsed and/or refractory multiple myeloma (RRMM) who have received at least 2 prior lines of therapy, including lenalidomide and a proteasome inhibitor, and are refractory to lenalidomide but not refractory to proteasome inhibitors |
| Comparar el efecto de ixa+dex con el de pom+dex en la supervivencia libre de progresión (SSP) en pacientes con mieloma múltiple recidiva o resistente (MMRR) que hayan recibido previamente al menos 2 líneas de tratamiento, como lenalidomida y un inhibidor del proteasoma, y sean resistentes a lenalidomida pero no a inhibidores del proteasoma. |
|
| E.2.2 | Secondary objectives of the trial |
To compare the effect of ixa+dex versus pom+dex on overall survival (OS).
To compare duration of response, overall response rate (ORR), time to response, and time to progression with ixa+dex versus pom+dex.
To obtain health-related QOL data related to physical functioning of patients treated with ixa+dex versus pom+dex.
To assess health-related QOL by additional function and symptom domains of the EORTC QLQ-C30 instrument and by the EORTC QLQ-MY20 and 5-level classification system of the EuroQol 5-Dimensional Health Questionnaire (EQ-5D-5L) instruments.
To evaluate health care utilization by patients receiving ixa+dex versus those receiving pom+dex.
To collect plasma concentration-time data for ixazomib to contribute to population pharmacokinetic characterization of ixazomib and to conduct exposure-response analyses for patients receiving ixa+dex.
To compare safety/tolerability of ixa+dex to that of pom+dex. |
| Comparar efecto de ixa+dex con pom+dex en supervivencia global (SG),y duración de respuesta,tasa de respuestas globales,tiempo transcurrido hasta la respuesta y hasta la progresión.Obtener datos de calidad de vida(CdV)relacionada con salud y funcionamiento físico en pacientes tratados con ixa+dex o con pom+dex.Evaluar la CdV relacionada con la salud mediante dominios adicionales de función y síntomas del Cuestionario CdV-Central 30 de la European Organization for Research and Treatment of Cancer ,el Cuestionario CdV-Módulo del mieloma múltiple de la EORTC y el sistema de clasificación de 5 niveles del Cuestionario de salud EuroQol de 5 dimensiones.Determinar el uso de asistencia sanitaria por los pacientes tratados con ixa+dex, o con pom+dex.Obtener datos de la concentración plasmática-tiempo de ixazomib para contribuir a la caracterización farmacocinética poblacional de ixazomib y hacer análisis de exposición-respuesta .Comparar la seguridad ytolerabilidad de ixa+dex y pom+dex. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Adult patients (aged ≥18 years) who have been diagnosed with multiple myeloma (MM) according to standard criteria.
All patients must have had a relapse or PD after having received 2 or more prior lines of systemic therapy. (A line of therapy is defined as 1 or more cycles of a planned treatment program; this may consist of 1 or more planned cycles of single-agent therapy or combination therapy, as well as a sequence of treatments administered in a planned manner. For example, a planned treatment approach of induction therapy followed by autologous stem-cell transplantation, followed by maintenance is considered 1 line of therapy. Typically each line of therapy is separated by PD.)
All patients must be refractory to lenalidomide, defined as having received at least 2 consecutive cycles of lenalidomide as a single agent or within a lenalidomide-containing regimen and having had PD during treatment with or within 60 days after the last dose of lenalidomide. The starting dose of lenalidomide should have been 25 mg (or as low as 10 mg in the case of renal function impairment or other safety concern), and the final dose should
have been a minimum of 10 mg.
All patients must have received at least 2 consecutive cycles of a bortezomib- or carfilzomib-containing regimen, and either:
– Achieved at least a partial response (PR) and did not have PD during treatment with or within 60 days after the last dose of bortezomib or carfilzomib, OR
– Had bortezomib and/or carfilzomib intolerance (defined as discontinuation because of drug-related adverse events (AEs) before completion of the planned treatment course) without PD upon the start of the next regimen.
All patients must have an Eastern Cooperative Oncology Group score of 0 to 2.
All patients must have measurable disease defined by serum M-protein ≥1 g/dL (≥10 g/L) or urine M-protein ≥200 mg/24 hours and must have documented MM isotype by immunofixation (central laboratory). |
Pacientes adultos (≥ 18 años) diagnosticados de mieloma múltiple (MM) según los criterios habituales.
Todos los pacientes deben haber experimentado una recidiva o PE después de haber recibido anteriormente dos o más líneas de tratamiento sistémico.
(Una línea de tratamiento se define como uno o más ciclos de un programa de tratamiento previsto; este puede consistir en 1 o más ciclos programados de monoterapia o tratamiento combinado, así como una secuencia de tratamientos administrados de forma programada. Por ejemplo, una estrategia de tratamiento programada de tratamiento de inducción seguido de un autotrasplante de células progenitoras seguido de tratamiento mantenimiento se considera una línea de tratamiento. Característicamente, cada línea de tratamiento está separada por PE.)
Todos los pacientes deben ser resistentes a lenalidomida, definiendo la resistencia como el hecho de haber recibido al menos 2 ciclos consecutivos de lenalidomida en monoterapia o en una pauta que contuviese lenalidomida y haber experimentado PE durante el tratamiento con lenalidomida o en los 60 días siguientes a la última dosis de este medicamento. La dosis inicial del lenalidomida debe haber sido de 25 mg (o de tan solo 10 mg en el caso de insuficiencia renal u otro problema de seguridad), mientras que la dosis final debe haber sido como mínimo de 10 mg.
Todos los pacientes deben haber recibido al menos 2 ciclos consecutivos de una pauta con bortezomib o carfilzomib y:
–Deben haber conseguido al menos una respuesta parcial (RP) y no haber experimentado PE durante el tratamiento con bortezomib o carfilzomib ni en los 60 días siguientes a la última dosis de estos medicamentos, O
–Deben haber presentado intolerancia a bortezomib o carfilzomib (definida como suspensión del tratamiento por acontecimientos adversos (AA) relacionados con la medicación antes de finalizar el ciclo de tratamiento previsto) sin PE al principio de la pauta siguiente.
Todos los pacientes deben tener una puntuación de 0 a 2 del Eastern Cooperative Oncology Group.
Todos los pacientes deben presentar enfermedad medible, definida por una proteína M en suero ≥ 1 g/dl (≥ 10 g/l) o una proteína M en orina ≥ 200 mg/24 horas, y un isotipo de MM documentado mediante inmunofijación (laboratorio central). |
|
| E.4 | Principal exclusion criteria |
| Patients must not have received prior ixazomib or pomalidomide and must not have participated in a previous ixazomib clinical study. |
| Los pacientes no deben haber recibido anteriormente ixazomib o pomalidomida y no deben haber participado en un estudio clínico previo de ixazomib. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Progression-free survival (PFS), defined as the time from randomization to the first occurrence of confirmed progressive disease (PD), as evaluated by an independent review committee (IRC), according to International Myeloma Working Group (IMWG) criteria, or death from any cause, whichever occurs first. |
| El criterio de valoración principal es la SSP ( supervivencia sin Progresion) , definida como el tiempo transcurrido desde la aleatorización hasta el primer episodio de PE confirmada, evaluada por un comité de revisión independiente (CRI) aplicando los criterios del International Myeloma Working Group (IMWG) o la muerte por cualquier causa, lo que ocurra antes |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
During study treatment: weekly (Days 1 and 15) for 2 cycles and then once a cycle (on Day 1) for the remainder of the treatment period, until PD or discontinuation. In addition, in Arm B only, on Day 22 of Cycles 1 and 2, hematologic laboratory assessments will be performed.
During follow-up period: very 4 weeks until the occurrence of PD (if treatment discontinued for any reason other than PD) or every 12 weeks until death or termination of the study by the sponsor |
Durante el tratamiento de estudio: semanal (días 1 y 15) en 2 ciclos y luego un ciclo (el día 1) dpara el resto del tratamiento, hasta progresión de la enfermedad o discontinuación. Además, en el brazo B, el día 22 de los ciclos 1 y 2, se realizarán análisis hematológicos.
Durante el período de seguimiento: cada 4 semanas hasta la aparición de Progresion de la enfermedad ( PE) (si el tratamientose suspendido por cualquier motivo que no sea PE) o cada 12 semanas hasta terminación del estudio por parte del sponsor o la muerte |
|
| E.5.2 | Secondary end point(s) |
The key secondary endpoint is OS, measured as the time from randomization to death from any cause.
Other secondary endpoints are:
- ORR, defined as PR, very good partial response (VGPR), or complete response (CR), as
evaluated by an IRC according to IMWG criteria.
- Duration of response, defined as the time from the first documentation of PR or better to first documentation of PD.
- Time to response, defined as the time from randomization to the first documentation of PR or better.
- TTP, defined as the time from randomization to first documentation of PD.
- Health-related QOL as measured by the physical functioning domain of the EORTC
QLQ-C30.
- Health-related QOL as measured by other domains of the EORTC QLQ-C30, by the EORTC
QLQ-MY20, and by the EQ-5D-5L.
- HU as measured by the number and duration of medical encounters.
The safety endpoint is the safety/tolerability of ixa+dex versus pom+dex. |
El criterio de valoración secundario fundamental es la SG, definida como el tiempo transcurrido desde la aleatorización hasta la muerte por cualquier causa.
Otros criterios de valoración secundarios son:
TRG, definida como RP, respuesta parcial muy buena (RPMB) o respuesta completa (RC), según la evaluación de un CRI aplicando los criterios del IMWG [55].
Duración de la respuesta, definida como el tiempo transcurrido desde la primera documentación de RP o una respuesta mejor hasta la primera documentación de PE.
Tiempo hasta la respuesta, definido como el tiempo transcurrido desde la aleatorización hasta la primera documentación de RP o una respuesta mejor.
TTP, definido como el tiempo transcurrido desde la aleatorización hasta la primera documentación de PE.
CdV relacionada con la salud, medida mediante el dominio de funcionamiento físico del QLQ-C30 de la EORTC.
CdV relacionada con la salud, medida mediante otros dominios del QLQ-C30 de la EORTC, mediante el QLQ-MY20 de la EORTC y mediante el EQ-5D-5L.
UAS, medida mediante el número y la duración de contactos médicos. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| every 12 weeks until death or termination of the study by the sponsor |
| Cada 12 semanas hasta fallecimiento o finalizacion del estudio. |
|
| 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 | 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) | Yes |
| 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 | 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 | Yes |
| E.8.2.3.1 | Comparator description |
| Pomalidomida |
| Pomalidomide |
|
| 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 | 71 |
| 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 |
| Belgium |
| Canada |
| Czech Republic |
| Denmark |
| France |
| Germany |
| Greece |
| Israel |
| Italy |
| Netherlands |
| Norway |
| Spain |
| Sweden |
| Turkey |
| United Kingdom |
| United States |
|
| 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
|
| The study will be considered complete after the final analysis for OS has been completed . The estimated time frame for study completion is up to 63 months if the phase 3 portion of the study is completed. Alternatively, if the no-go criteria are met during the phase 2 portion, the study will be completed approximately 22 to 29 months after the first patient enters the study. |
| El estudio se considerará terminado después de haber completado el análisis de supervivencia global. El plazo estimado para la terminación del estudio es hasta 63 meses si la fase 3 del estudio se ha completado. Por otra parte, si se cumplen los criterios prohibidos durante la fase 2, el estudio se completará aproximadamente de 22 a 29 meses después de que el primer paciente entra en el estudio. |
|
| 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 | 3 |
| E.8.9.1 | In the Member State concerned days | |
| 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 | 3 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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