E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Stage II-IV follicular lymphoma grade 1-3a not previously treated |
Linfoma folicular en estadio II-IV, grado 1-3a no previamente tratado |
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E.1.1.1 | Medical condition in easily understood language |
Follicular lymphoma in need of treatment |
Linfoma folicular que requiera tratamiento |
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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 | 14.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10016908 |
E.1.2 | Term | Follicle centre lymphoma, follicular grade I, II, III stage II |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 14.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10016910 |
E.1.2 | Term | Follicle centre lymphoma, follicular grade I, II, III stage IV |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 14.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10016909 |
E.1.2 | Term | Follicle centre lymphoma, follicular grade I, II, III stage III |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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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 |
The primary objective of the study is to compare the efficacy of rituximab plus lenalidomide to rituximab plus chemotherapy followed by rituximab in patients with previously untreated follicular lymphoma. Efficacy determination will be based upon the co-primary endpoints of complete response (CR/CRu) rate at 120 weeks and PFS assessed by the IRC using the IWG (Cheson, 1999) criteria. |
El objetivo primario de este ensayo es comparar la eficacia de Rituximab asociado a Lenalidomida frente a Rituximab combinado con quimioterapia, seguido de Rituximab, en pacientes que no hayan recibido tratamiento previo para el linfoma folicular. La determinación de la eficacia se basará en las covariables primarias de la tasa de respuesta completa (RC/RCnc) a las 120 semanas y la SLP (Supervivencia libre de progresión) evaluada por el IRC (comité de revisión independiente) mediante los criterios de respuesta IWG (Cheson, 1999). |
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E.2.2 | Secondary objectives of the trial |
The secondary objectives of the study are: o To compare the efficacy of rituximab plus lenalidomide versus rituximab plus chemotherapy followed by rituximab using other parameters of efficacy: o Event Free Survival (EFS), Time to Next Anti-Lymphoma Treatment (TTNLT), and Overall Survival (OS). To compare the safety of rituximab plus lenalidomide versus rituximab plus chemotherapy followed by rituximab |
o Comparar la eficacia del Rituximab con Lenalidomida versus Rituximab y quimioterapia, seguido de Rituximab, empleando otros parámetros de eficacia como: Supervivencia Libre de Eventos (SLE), Tiempo hasta el próximo Tratamiento contra el Linfoma (TTNLT), y Supervivencia Global (SG). o Comparar la seguridad de Rituximab y Lenalidomida versus Rituximab y quimioterapia seguida de Rituximab. |
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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 |
The exploratory objectives of the study are: ? CR rate at 120 weeks and PFS by 2007 Revised Response Criteria for Malignant Lymphoma incorporating FDG-PET (Cheson, 2007) ? Time to Treatment Failure (TTF) ? Time to Next Chemotherapy Treatment (TTNCT) ? Histological transformation rate at first progression ? To explore the relationship between lenalidomide exposure and response (hematology, biomarkers, and other clinical outcomes as appropriate). ? To compare the effects of rituximab plus lenalidomide versus rituximab plus chemotherapy followed by rituximab on minimal residual disease using PCR detection of the t(14;18) translocation in peripheral blood or other MRD assays. ? To compare the effects of rituximab plus lenalidomide versus rituximab plus chemotherapy followed by rituximab on immune competence ? Evaluate Fc-gamma receptor polymorphisms in blood samples collected pre-treatment and correlate with clinical outcomes ? To investigate potential predictive biomarkers of clinical response or resistance to rituximab plus lenalidomide, including, but not limited to, gene expression, analysis of acquired chromosomal aberrations (translocations, gains, deletions, single nucleotide polymorphisms, mutations), microRNA and protein expression in archival diagnostic or fresh tumor samples ? Health related quality of life as measured by the EORTC QLQ-C30
To examine utility during the active, maintenance, and follow-up phases using the EQ-5D for the purpose of collecting information on the treatment regimens to support cost-effectiveness analyses and modeling. |
EXISTE UN SUBESTUDIO QUE NO SE VA A REALIZAR EN ESPAÑA |
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E.3 | Principal inclusion criteria |
-Histologically confirmed CD20+ follicular lymphoma grade 1, 2 or 3a -Have no prior systemic treatment for lymphoma. -Must be in need of treatment -Bi-dimensionally measurable disease with at least one mass lesion > 2 cm that was not previously irradiated. -Stage II, III or IV disease. -Must be ? 18 years and sign an informed consent. -Performance status ? 2 on the ECOG scale. -Adequate hematological function -Females of childbearing potential (FCBP) receiving lenalidomide must have two negative pregnancy tests . She must agree to ongoing pregnancy testing during the course of the study, and after end of study therapy. -Male patients receiving lenalidomide must practice complete abstinence or agree to use a condom during sexual contact with a pregnant female or a female of childbearing potential while participating in the study, during dose interruptions and for at least 28 days following study drug discontinuation -All patients receiving lenalidomide must have an understanding that the study drug could have a potential teratogenic risk. -For all patients receiving Rituximab Women must not breast feed and must use effective contraception must not be pregnant and agree not to become pregnant during participation in the trial and during the 6 months thereafter. Men must agree not to father a child during participation in the trial and during the 6 months thereafter. |
1. CD20 positivo confirmado histológicamente y linfoma folicular grados 1, 2 ó 3a
2. No haber recibido tratamiento previo para el linfoma.
3. Deben estar en necesidad de tratamiento, demostrado al menos por uno de los siguientes criterios: - Enfermedad voluminosa definida como: * nodal o extranodal (excepto en bazo) con una masa > 7cm en el mayor diámetro o, * afectación de al menos 3 sitios nodales o extranodales (cada uno con un diámetro >3 cm) - Presencia de al menos uno de los siguientes síntomas B: * fiebre (>38ºC) de etiología poco clara * sudores nocturnos * pérdida de peso superior al 10% en los 6 meses previos - Esplenomegalia sintomática - Síndrome de compresión (uretral, orbital, gastrointestinal) - Cualquiera de las siguientes citopenias debidas a linfoma: * hemoglobina < 10g/dL (6.25 mmol/L) * plaquetas <100 x 109/L , o * recuento absoluto de neutrófilos (ANC) < 1.5 x 109/L - Derrame pleural o peritoneal seroso (independientemente del contenido celular) - LDH > ULN ó ?2 microglobulina > ULN
4. Enfermedad bidimensional medible con al menos una lesión > 2 cm que no haya sido previamente irradiada.
5. Estadio de la enfermedad II, III o IV.
6. El paciente debe ser ? 18 años de edad y haber firmado el consentimiento informado.
7. Performance status ? 2 en la escala ECOG.
8. Función hematológica adecuada (excepto si las anormalidades están relacionadas con infiltración del linfoma en médula ósea) durante los 28 días previos a la firma del consentimiento informado, incluyendo: - Recuento absoluto de neutrófilos (ANC) ? 1.5 x 109/L - Recuento de plaquetas ? 75 x 109/L - Hemoglobina ? 8.0 g/dl (5 mmol/L)
9. Capacidad de cumplimiento con las visitas y otros requisitos del protocolo.
10. Las mujeres en edad fértil (FCBP)? que estén recibiendo Lenalidomida deben: Contar con 2 tests de embarazo negativos, verificados por el médico del estudio, previos al inicio de la terapia de estudio. Además deberá estar de acuerdo en realizarse más tests de embarazo durante el trascurso del ensayo y tras haber finalizado el tratamiento de estudio. Ello será aplicable aún cuando la paciente practique una abstinencia heterosexual completa. Aunque se comprometa a una completa abstinencia sexual (la cual será revisada una vez al mes) o se comprometa a utilizar, y ser capaz de cumplir con una efectiva anticoncepción sin interrupciones, 28 días antes de comenzar el medicamento de estudio, durante el período de tratamiento (incluyendo los periodos de interrupción), y durante los 28 días posteriores a la interrupción definitiva del tratamiento en estudio.
11. Los pacientes varones recibiendo Lenalidomida deberán?: Practicar una completa abstinencia sexual o aceptar el uso de condón durante el contacto sexual con una mujer embarazada o en edad fértil, mientras esté participando en el estudio, durante los periodos de interrupción del tratamiento y al menos, 28 días tras la discontinuación definitiva del medicamento, aunque le hubiera sido practicada vasectomía eficaz. Estar de acuerdo con no donar semen durante la terapia con el medicamento de estudio y por 28 días tras la discontinuación definitiva del mismo.
12. Todos los pacientes que reciban Lenalidomida deberán: Tener conocimiento del potencial riesgo teratogénico de la droga de estudio. Estar de acuerdo con no donar sangre mientras se esté en tratamiento ni por los 28 días tras la discontinuación definitiva del mismo. Estar de acuerdo con no compartir su medicación con ninguna persona. Estar de acuerdo con el asesoramiento sobre las precauciones contra el embarazo y el riesgo de exposición del feto. Las mujeres deberán estar de acuerdo de no practicar la lactancia materna durante su participación y por los 28 días tras la discontinuación definitiva del tratamiento de estudio.
13. Para todos los pacientes tratados con Rituximab: Las mujeres no deberán emplear la lactancia materna y deberán hacer uso de un método anticonceptivo efectivo con el fin de evitar el embarazo y acceder a no quedarse embarazadas durante su participación en el ensayo y los 6 meses posteriores.
Los hombres deberán comprometerse a no tener hijos durante su participación en el estudio y durante los 6 meses posteriores. |
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E.4 | Principal exclusion criteria |
-Clinical evidence of transformed lymphoma by investigator assessment -Grade 3b follicular lymphoma -Patients taking corticosteroids during the last 4 weeks -Major surgery within 28 days prior to signing informed consent -Seropositive for or active viral infection with hepatitis B virus (HBV) -Known seropositive for, or active infection hepatitis C virus (HCV) -Known seropositive for, or active viral infection with HIV -Life expectancy < 6 months -Known sensitivity or allergy to murine products -Prior history of malignancies, unless the subject has been free of the disease for ? 10 years. Exceptions include a history of previously treated Localized non-melanoma skin cancer or Carcinoma in situ of the cervix -Prior use of lenalidomide -Neuropathy > Grade 1 -Presence or history of CNS involvement by lymphoma -Patients who are at a high risk for a thromboembolic event and are not willing to take venous thromboembolic (VTE) prophylaxis -Uncontrolled intercurrent illness -Any serious medical condition, laboratory abnormality, or psychiatric illness that would prevent the subject from signing the informed consent form. -Pregnant or lactating females -Any condition, including the presence of laboratory abnormalities, which places the subject at unacceptable risk if he/she were to participate in the study, or which confounds the ability to interpret data from the study. |
1. Evidencia clínica de linfoma transformado, asesorado por el investigador.
2. Linfoma folicular Grado 3b.
3. Pacientes en tratamiento con corticosteroides durante las últimas 4 semanas, excepto si administrados en una dosis equivalente a < 10 mg/día Prednisona (en estas 4 semanas).
4. Cirugía mayor (excepto para biopsia de nódulos linfáticos) en los 28 días previos a la firma del consentimiento informado.
5. Ser seropositivo para/presentar una infección vírica activa del virus de la hepatitis B (VHB): ? HBsAg positivo ? HBsAg negativo, anti-HBs positivo y/o anti-HBc positivo y DNA viral detectable Nota: ? Los pacientes que sean HBsAg negativo, anti-HBs positivo y/o anti-HBc positivo pero con DNA viral negativo serán elegibles. ? Los pacientes seropositivos debido a historial de vacunación contra la hepatitis B serán también elegibles.
6. Seropositividad conocida para/ con infección activa con el virus de la hepatitis C (VHC).
7. Seropositividad conocida para/ con infección activa con el virus de la inmunodeficiencia humana adquirida (VIH).
8. Esperanza de vida < 6 meses.
9. Sensibilidad conocida o alergia a los productos murinos.
10. Historial previo de otras enfermedades malignas distintas del linfoma folicular, exceptuando si el paciente ha estado libre de enfermedad por un tiempo ? 10 años. Otras excepciones incluyen un historial de: a. Cáncer de piel localizado tipo no-melanoma b. Carcinoma de cérvix in situ Que ya hayan sido previamente tratados
11. Uso previo de Lenalidomida.
12. Neuropatía > Grado 1.
13. Presencia o historial de infiltración del linfoma al SNC.
14. Pacientes con alto riesgo de eventos tromboembólicos que no estén dispuestos a tomar profilaxis.
15. Cualquiera de las siguientes anormalidades de laboratorio: ? Aspartato transaminasa en suero (AST/SGOT) o alanina transaminasa (ALT/SGPT) > 3x superior al límite de normalidad (ULN), excepto en pacientes con infiltración del linfoma al hígado o páncreas ? Bilirubina total > 2.0 mg/dl (34 µmol/L) excepto en los casos de Síndrome de Gilberts e infiltración del linfoma al hígado ? Aclaramiento de creatinina < 30 mL/min
16. Enfermedad intercurrente no controlada.
17. Cualquier condición médica grave, anormalidad de laboratorio o enfermedad psiquiátrica que impida al paciente la firma del consentimiento informado.
18. Mujeres embarazadas o lactantes.
19. Cualquier condición, incluyendo la presencia de anormalidades de laboratorio, que pongan al paciente en un riesgo inaceptable al participar en el estudio o que pueda confundir la capacidad de interpretación de los resultados del estudio. |
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E.5 End points |
E.5.1 | Primary end point(s) |
The tumor response data will be assessed by the IRC using the IWG (Cheson 1999) criteria. Based on the CT/MRI schedule, any assessments in a time window of 120 weeks ± 4 weeks are qualified as the 120 weeks assessments. If two or more assessments are performed in this time window, the assessment with the least favorable response will be used. PFS is an accepted endpoint of clinical benefit for previously untreated FL patient and was the basis for the recent approval of rituximab maintenance in this population (Salles 2011). The disease progression status will be assessed by IRC using the IWG (Cheson 1999) criteria. PFS is defined as the time from randomization into the study to the first observation of documented disease progression or death due to any cause. If a patient has not progressed or died, PFS will be censored at the time of last visit with adequate assessment. If a patient received other anti-cancer treatment for follicular lymphoma before progression, the CT/MRI assessments should continue as scheduled until disease progression or death which will be counted as events. |
Las covariables de eficacia primarias son la tasa de respuesta completa (RC / RCnc) y SLP (supervivencia libre de progresión). |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
For the co-primary endpoint of the complete response (CR/CRu) rate at 120 weeks, one interim analysis and one primary analysis is pre-planned. The interim analysis will be performed for the first 200 patients, and the primary analysis for co-primary endpoint of complete response (CR/CRu) will be performed for the total of 644 patients. The purpose of the interim analysis is to check for futility to see if the trial needs to stop early.
Moreover, a first futility analysis will be done to evaluate the complete response (CR/CRu) rate as determined by IRC at 6 months of treatment for the first 200 patients. PFS will be compared between the two treatment arms when the required 456 progress/relapse/death events are observed |
La covariable tasa de respuesta completa (RC/RCno confirmada) se medirá a las 120 semanas; (realizándose un análisis intermedio cuando se hayan alcanzado los 200 primeros pacientes y un segundo análisis intermedio a los 644 pacientes) |
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E.5.2 | Secondary end point(s) |
?Event Free Survival (EFS) ?Time to Next Anti-Lymphoma Treatment (TTNLT), ?Overall Survival (OS) |
- Supervivencia Libre de Eventos (SLE) - Tiempo hasta el próximo tratamiento contra el linfoma (TTNLT) - Supervivencia Global (SG) |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
(EFS) will be measured from the date of randomization to the date of first documented progression, relapse, and initiation of a new anti-lymphoma treatment or death by any cause. (TTNLT) will be measured from the date of randomization to the date of first documented administration of any new anti-lymphoma treatment (chemotherapy, radiotherapy, radio-immunotherapy, immunotherapy). (OS) will be measured from date of randomization to the date of death. Patients who die, regardless of the cause of death, will be considered to have had an event. Patients who withdraw consent for the study will be considered censored at the time of withdrawal. |
SLE se medirá desde la fecha de randomización a la fecha en que se haya reportado progresión, relapso, inicio de un nuevo tratamiento para el linfoma o muerte por cualquier causa.
TTNLT se medirá desde la fecha de randomización hasta la fecha de la primera administración de terapia contra linfoma (quimioterapia, radioterapia, inmunoterapia, radio-inmunoterapia)
SG se medirá desde la fecha de randomización hasta la fecha de muerte. |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | Yes |
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 | Yes |
E.6.13.1 | Other scope of the trial description |
Quality of life |
Calidad de vida |
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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 | 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 | 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 | 15 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 120 |
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 |
France |
Germany |
Italy |
New Zealand |
Portugal |
Spain |
|
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
|
Last visit of the last subject undergoing the trial |
Última visita de estudio del último paciente participante |
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 13 |
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 | 13 |
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 |