E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
corticosteroid refractory chronic Graft vs Host Disease |
enfermedad de injerto contra huésped crónica refractaria a corticoesteroides |
|
E.1.1.1 | Medical condition in easily understood language |
chronic Graft vs Host Disease |
enfermedad de injerto contra huésped crónica refractaria a corticoesteroides |
|
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 | PT |
E.1.2 | Classification code | 10072158 |
E.1.2 | Term | Chronic graft versus host disease in intestine |
E.1.2 | System Organ Class | 10021428 - Immune system disorders |
|
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 | 10072159 |
E.1.2 | Term | Chronic graft versus host disease in skin |
E.1.2 | System Organ Class | 10021428 - Immune system disorders |
|
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 | 10066261 |
E.1.2 | Term | Chronic graft versus host disease |
E.1.2 | System Organ Class | 10021428 - Immune system disorders |
|
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 | 10072160 |
E.1.2 | Term | Chronic graft versus host disease in liver |
E.1.2 | System Organ Class | 10021428 - Immune system disorders |
|
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 compare the efficacy of ruxolitinib versus Investigator’s choice Best Available Therapy (BAT) in patients with moderate or severe SR-cGvHD assessed by Overall Response Rate (ORR) at the Cycle 7 Day 1 visit. |
Comparar la eficacia de ruxolitinib frente a la mejor terapia de disponible (BAT) en pacientes con SR-cGvHD moderada a grave evaluada mediante la Tasa de Respuesta Global (ORR) en la visita del Ciclo 7 Día 1. |
|
E.2.2 | Secondary objectives of the trial |
Key Secondary: To compare the rate of failure free survival (FFS) and the change in the modified Lee cGvHD Symptom Scale score between treatment groups
Other secondary: -Best overall response (BOR) -Estimate ORR at the end of Cycle 3 -Duration of response -Overall survival -Non-relapse mortality (NRM) -Proportion of patients with ≥50% reduction in the daily steroid dose at Cycle 7 Day 1 -Proportion of patients who successfully tapered off all steroids at Cycle 7 Day 1 -Cumulative incidence of Malignancy Relapse/Recurrence (MR) -Change in FACT-BMT and EQ-5D -To assess pharmacokinetics of ruxolitinib -Safety and tolerability of ruxolitinib and BAT -Medical resource utilization |
-Mejor respuesta global (BOR) -ORR estimada al final del Ciclo 3 -Duración de respuesta -Supervivencia global -Mortalidad sin recaída (NRM) -Proporción de pacientes con reducción ≥ 50% en la dosis de esteroides diarios en el Ciclo 7 Día 1 -Proporción de pacientes que fueron disminuyendo hasta eliminar todos los esteroides con éxito en el Ciclo 7 Día1 -Incidencia acumulada de Recaída/Recurrencia de Neoplasia (MR) -Cambio en FACT-BMT y EQ-5D -Evaluar la farmacocinética de ruxolitinib y BAT -Seguridad y tolerabilidad de ruxolitinib y BAT -Utilización de recursos medicos |
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
For the complete list of the inclusion criteria please refer to protocol apart 5.2. Inclusion criteria include: -Male or female patients ≥12 years old at the time of signing the ICF -Have undergone alloSCT from any donor source (matched unrelated donor, sibling, haplo-identical) using bone marrow, peripheral blood stem cells, or cord blood. Recipients of non-myeloablative, myeloablative, and reduced intensity conditioning are eligible -Evident myeloid and platelet engraftment: Absolute neutrophil count (ANC) > 1000/mm3 and platelet count > 25,000/ mm3 -Patients with clinically diagnosed moderate to severe cGvHD according to NIH Consensus Criteria (Jagasia 2015) prior to randomization: -Moderate cGvHD: At least one organ (not lung) with a score of 2, 3 or more organs involved with a score of 1 in each organ, or lung score of 1 -Severe cGvHD: at least 1 organ with a score of 3, or lung score of 2 or 3 -Patients currently receiving systemic or topical corticosteroids for the treatment of cGvHD for a duration of < 6 months prior to Cycle 1 Day 1 (if applicable), and have a confirmed diagnosis of steroid refractory cGvHD defined per 2014 NIH consensus criteria (Martin 2015) irrespective of the concomitant use of a calcineurin inhibitor, as follows: -A lack of response or disease progression after administration of minimum prednisone 1 mg/kg/day for at least 1 week, OR -Disease persistence without improvement despite continued treatment with prednisone at >0.5 mg/kg/day or 1 mg/kg/every other day for at least 4 weeks, OR -Increase to prednisolone dose to >0.25 mg/kg/day after two unsuccessful attempts to taper the dose -Patient must accept to be treated with only one of the following BAT options on Cycle 1 Day 1. (Additions and changes are allowed during the course of the study, but only with BAT from the following BAT options): extracorporeal photopheresis (ECP), low-dose methotrexate (MTX), mycophenolate mofetil (MMF), mTOR inhibitors (everolimus or sirolimus), infliximab, rituximab, pentostatin, imatinib |
Para una lista completa de criterios de inclusión, ver el apartado 5.2. Los criterios de inclusión clave incluyen: -Pacientes hombres o mujeres ≥ 12 años en el momento de la firma del HIP+CI -A quienes se haya realizado trasplante alogénico de células madre (alloSCT) de cualquier donante (donante no familiar compatible, hermano, donante haploidéntico) utilizando médula ósea, células madre de sangre periférica, o sangre de cordón umbilical. Son elegibles los receptores de acondicionamiento no mieloablativos, mieloablativos, y de intensidad reducida. -Evidencia de injerto mieloide y plaquetario: Recuento absoluto de neutrófilos (ANC) > 1.000/mm3 y recuento de plaquetas > 25.000/mm3 -Pacientes con cGvHD moderada a grave clínicamente diagnosticada según los Criterios de Consenso NIH (Jagasia 2015) antes de la aleatorización: -cGvHD moderada: Al menos un órgano (excepto pulmón) con una puntuación de 2, 3 o más órganos afectados con una puntuación de 1 en cada órgano, o puntuación pulmonar de 1 -cGvHD grave: al menos 1 órgano con una puntuación de 3, o puntuación pulmonar de 2 o 3 -Pacientes actualmente recibiendo corticosteroides sistémicos o tópicos para el tratamiento de cGvHD con una duración < 6 meses antes del Ciclo 1 Día 1 (si procede), y que tengan un diagnóstico confirmado de cGvHD refractaria a esteroides definida según los criterios de consenso NIH 2014 (Martin 2015) independientemente del uso concomitante de un inhibidor de calcineurina, como sigue: - Una falta de respuesta o progresión de la enfermedad tras administración mínima de prednisona 1 mg/kg/día durante al menos 1 semana, O - Persistencia de la enfermedad sin mejoría a pesar de tratamiento continuado con prednisona > 0,5 mg/kg/día o 1 mg/kg/cada dos días durante al menos 4 semanas, O - Aumento de la dosis de prednisolona a > 0,25 mg/kg/día tras dos intentos sin éxito de disminuir la dosis - El paciente debe aceptar recibir tratamiento con solo una de las siguientes opciones de BAT en el Ciclo 1 Día 1. (Se permiten adiciones y cambios durante el transcurso del estudio, pero solo con BAT de las siguientes opciones de BAT): fotoféresis extracorpórea (ECP), metotrexato (MTX) a dosis bajas, micofenolato mofetil (MMF), inhibidores mTOR (everolimus o sirolimus), infliximab, rituximab, pentostatina, imatinib |
|
E.4 | Principal exclusion criteria |
For the complete list of the exclusion criteria please refer to protocol apart 5.3. Exclusion criteria include: -Patients who have received systemic treatment for cGvHD in addition to corticosteroids ± CNI for cGvHD -Patients with overlap syndrome defined as presence of simultaneous features of both chronic and acute GvHD, or patients that transition from aGvHD to cGvHD without tapering off corticosteroids ± CNI and any systemic treatment -Patients who were treated with prior JAK inhibitors for aGvHD; except when the patient achieved complete or partial response and has been off JAK inhibitor treatment for at least 8 weeks prior to Cycle 1 Day 1 -Failed prior alloSCT within the past 6 months from Cycle 1 Day 1 -Patients with relapsed primary malignancy, or who have been treated for relapse after the alloSCT was performed -SR-cGvHD occurring after a non-scheduled donor lymphocyte infusion (DLI) administered for pre-emptive treatment of malignancy recurrence. Patients who have received a scheduled DLI as part of their transplant procedure and not for management of malignancy relapse are eligible -Any corticosteroid therapy for indications other than cGvHD at doses >1 mg/kg/day methylprednisolone or equivalent within 7 days of Cycle 1 Day 1 |
Para una lista completa de criterios de exclusión, ver el apartado 5.3. Los criterios de exclusión clave incluyen: - Pacientes que hayan recibido tratamiento sistémico para cGVHD además de corticosteroides ± CNI para cGvHD -Pacientes con síndrome solapado definido como presencia de rasgos simultáneos de GvHD crónica y aguda, o pacientes en que hay una transición de aGvHD a cGvHD sin disminución paulatina hasta eliminación de corticosteroides ± CNI y cualquier tratamiento sistémico -Pacientes que recibieron tratamiento previo con inhibidores JAK para aGvHD; excepto cuando el paciente alcanzó respuesta completa o parcial y haya estado sin tratamiento con inhibidores JAK durante al menos 8 semanas antes del Ciclo 1 Día 1 -Fallo de alloSCT previo durante los 6 meses anteriores al Ciclo 1 Día 1 -Pacientes con neoplasia primaria recidivante, o que hayan recibido tratamiento para recidiva tras la realización del alloSCT -Presencia de SR-cGvHD tras administración no programada de infusión de linfocitos de donante (DLI) para tratamiento preventivo de recurrencia de neoplasia. Son elegibles los pacientes que han recibido una DLI programada como parte del procedimiento de su trasplante y no para el control de recaída de la neoplasia -Cualquier terapia con corticosteroides para otras indicaciones distintas de cGvHD a dosis > 1 mg/kg/día de metilprednisolona o equivalente en los 7 días previos al Ciclo 1 Día1 |
|
E.5 End points |
E.5.1 | Primary end point(s) |
overall response rate (ORR) on Cycle 7 Day 1 after randomization, defined as the proportion of patients in each arm demonstrating a complete response (CR) or partial response (PR) without the requirement of additional systemic therapies for an earlier progression, mixed response or non-response. Scoring of response will be relative to the organ score at randomization. |
La variable para este objetivo es ORR definida como la proporción de pacientes en cada brazo que demuestren una respuesta completa (CR) o respuesta parcial (PR) sin necesidad de terapias sistémicas adicionales por progresión prematura, respuesta mixta o sin respuesta. La puntuación de respuesta será en relación a la puntuación del órgano en el momento de la aleatorización. |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
Cycle 7 Day 1 |
Ciclo 7 día 1 |
|
E.5.2 | Secondary end point(s) |
Key secondary: Composite time to event endpoint incorporating the following FFS events: i) relapse or recurrence of underlying disease or death due to underlying disease, ii) non-relapse mortality, or iii) addition or initiation of another systemic therapy for cGvHD
Rate of patients with clinically relevant improvement of the modified Lee symptoms score at Cycle 7 Day 1.
FFS will be used as the first key secondary endpoint for all regions except the US (ROW). The modified Lee symptom score will be used as the first key secondary endpoint for the US
Other secondary: - Proportion of patients who achieved OR (CR+PR) at any time point (up Cycle 7 day 1 or the start of additional systemic therapy for cGvHD) - To estimate ORR at end of Cycle 3 Proportion of patients who achieved OR (CR+PR) at Cycle 4 Day 1. - Duration of Response Duration of response (DOR) is assessed for responders only - Overall survival, defined as the time from the date of randomization to the date of death due to any cause - Non-relapse mortality (NRM), defined as the time from date of randomization to date of death not preceded by underlying disease relapse/recurrence - Malignancy Relapse/Recurrence (MR) is defined as the time from date of randomization to hematologic malignancy relapse/recurrence - Change in FACT-BMT from baseline to each visit where measured. - Change in EQ-5D from baseline to each visit where measured - Pharmacokinetic parameters of ruxolitinib after a single dose and at steady state. Cmax, AUClast, and AUCinf. Other PK parameters are CL/F, Vz/F, Tmax and T1/2 - Safety and tolerability including myelosuppression, infections, and bleeding will be assessed by monitoring the frequency, duration, and severity of Adverse Events including occurrence of any second primary malignancies, infections, by performing physical exams, and evaluating changes in vital signs from baseline, routine serum chemistry, hematology results and coagulation profile - Resources including duration and frequency of hospitalization, emergency room visits, additional outpatient office visits to general practitioner, specialist, and urgent care visits |
Comparar la tasa de supervivencia libre de fallos (FFS) y el cambio en la puntuación de la Escala de Síntomas de cGvHD de Lee modificada entre grupos de tratamiento. SLF se utilizará como la primera variable secundaria clave para todas las regiones excepto en EEUU y el cambio en la puntuación de la Escala de Síntomas de cGvHD de Lee modificada se comparará posteriormente. En EEUU, el orden será al revés. Las variables de este objetivo son (1) la variable compuesta tiempo hasta acontecimiento incorporará los siguientes acontecimientos FFS: i) recaída o recurrencia de enfermedad subyacente o muerte debida a enfermedad subyacente, ii) mortalidad sin recaída, o iii) adición o inicio de otra terapia sistémica para cGvHD, y (2) tasa de pacientes con mejoría clínicamente significativa en el Ciclo 7 Día 1 de la Escala de Síntomas de cGvHD de Lee modificada respecto a la basal. -Mejor respuesta global (BOR) -ORR estimada al final del Ciclo 3 -Duración de respuesta -Supervivencia global -Mortalidad sin recaída (NRM) -Proporción de pacientes con reducción ≥ 50% en la dosis de esteroides diarios en el Ciclo 7 Día 1 -Proporción de pacientes que fueron disminuyendo hasta eliminar todos los esteroides con éxito en el Ciclo 7 Día1 -Incidencia acumulada de Recaída/Recurrencia de Neoplasia (MR) -Cambio en FACT-BMT y EQ-5D -Evaluar la farmacocinética de ruxolitinib y BAT -Seguridad y tolerabilidad de ruxolitinib y BAT -Utilización de recursos medicos |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
for all: Cycle 7 Day 1 |
Para todos: Ciclo 7 día 1. |
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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 | No |
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 | Yes |
E.6.13.1 | Other scope of the trial description |
medical resource utilization |
Utilización de recursos médicos |
|
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 | Yes |
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 |
mejor terapia de disponible (BAT) |
Best Available Therapy (BAT) |
|
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 | 13 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 86 |
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 |
Austria |
Belgium |
Canada |
China |
Czech Republic |
Denmark |
France |
Germany |
India |
Israel |
Italy |
Japan |
Korea, Republic of |
Netherlands |
Norway |
Russian Federation |
Saudi Arabia |
Spain |
Sweden |
Switzerland |
Turkey |
United Kingdom |
United States |
Jordan |
|
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
|
The end of study is defined as the earliest occurrence of one of the following: All patients have completed 39 cycles OR discontinued from the study OR died |
El fin de estudio tundra lugar cuando ocurra uno de los siguientes eventos: todos los pacientes hayan completado el ciclo 39 o discontinuado del studio o muerto |
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 4 |
E.8.9.1 | In the Member State concerned months | 7 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 4 |
E.8.9.2 | In all countries concerned by the trial months | 9 |