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Rituximab Maintenance Versus Observation After First-line Immunochemotherapy by FCR in Older Patients With Chronic Lymphocytic Leukemia (LLC2007SA)

27 de julio de 2017 actualizado por: University Hospital, Tours

Single-agent Rituximab as Maintenance Treatment Versus Observation After Combined Induction Immunochemotherapy With Fludarabine, Cyclophosphamide and Rituximab in Patients Older Than 65 Years With Previously Untreated Chronic Lymphocytic Leukemia: a Phase III Trial of FILO

RATIONALE: Classical chemotherapy does not cure advanced chronic lymphocytic leukemia (CLL) despite new drugs. Rituximab is a monoclonal antibody directed against CD20 surface antigen on B lymphocytes and leads to apoptosis of CD20 positive B lymphocytes. The highest response rate yet published in the treatment of first-line CLL has been obtained by the association of fludarabine, cyclophosphamide and rituximab (FCR). Now, the question is whether this response can be improved, as some trials showed that eradication of minimal residual disease (MRD) in CLL is associated with a longer treatment-free and overall survival. Maintenance therapy using rituximab has been recently approved as a means of prolonging remission in patients with indolent non Hodgkin's lymphoma. Maintenance therapy with rituximab could be of interest in treatment of MRD in CLL and prolonging remission and survival times.

PURPOSE: The overall purpose of the study is to determine the value of immunotherapy maintenance with single agent rituximab in comparison with no further treatment (observation ) for previously untreated chronic lymphocytic leukaemia in elderly (>65 years) patients who respond to induction immunochemotherapy with FCR.

Descripción general del estudio

Estado

Terminado

Condiciones

Intervención / Tratamiento

Descripción detallada

OBJECTIVES:

Primary

  • To demonstrate superiority, in terms of 3-year progression-free survival (PFS), of rituximab maintenance over observation in patients who are in complete or partial response (CR or PR) after induction therapy comprising fludarabine, cyclophosphamide, and rituximab.

Secondary

  • To determine event-free survival, disease-free survival, overall survival, and time to next treatment, all from time of randomization.
  • To determine overall response rate (CR and PR) according to NCI and iwCLL criteria
  • To assess the rate of phenotypic response (minimal residual disease).
  • To assess duration of phenotypic and NCI and iwCLL clinical responses.
  • To determine response rates and time-related parameters in biological subgroups.
  • To determine rates of treatment-related adverse events.
  • To evaluate CD4/CD8 counts, immunoglobulin levels, and incidence of Coombs-positive hemolytic anemia.
  • To study pharmacokinetics of rituximab during induction and maintenance.
  • To evaluate the prognostic impact of the immunoglobulin FcγRIIIA genotype.
  • To assess quality of life.
  • To study pharmacoeconomics.

OUTLINE: This is a multicenter study. Randomization is stratified according to response to induction therapy (complete response [CR] vs partial response [PR]), IGHV mutational status, and 11q deletion.

Patients receive rituximab IV on days 1 and 14 of courses 1-2 and on day 1 of courses 3 and 4. Patients also receive oral fludarabine and oral cyclophosphamide once daily on days 2-4 of course 1 and on days 1-3 of courses 2-4. Courses are administered every 28 days. Patients achieving CR or PR are randomized 1:1 to maintenance arm or observation arm.

  • Arm A: Patients receive rituximab IV every 2 months in the absence of disease progression or unacceptable toxicity for a maximum duration of 24 months (12 infusions).
  • Arm B: Patients undergo observation only.

After completion of study therapy, patients are followed every 3 months for 1 year and then every 6 months for 2 years.

Tipo de estudio

Intervencionista

Inscripción (Actual)

542

Fase

  • Fase 3

Contactos y Ubicaciones

Esta sección proporciona los datos de contacto de quienes realizan el estudio e información sobre dónde se lleva a cabo este estudio.

Ubicaciones de estudio

  • Francia
      • TOURS Cedex, Francia, 37044
        • French Innovative Leukemia Organization

Criterios de participación

Los investigadores buscan personas que se ajusten a una determinada descripción, denominada criterio de elegibilidad. Algunos ejemplos de estos criterios son el estado de salud general de una persona o tratamientos previos.

Criterio de elegibilidad

Edades elegibles para estudiar

65 años y mayores (Adulto Mayor)

Acepta Voluntarios Saludables

No

Géneros elegibles para el estudio

Todos

Descripción

Inclusion criteria

  • B-CLL
  • Matutes score 4 or 5
  • Binet stages B or C
  • Age > 65 years old
  • No previous treatment of CLL by chemotherapy, radiotherapy or immunotherapy, except glucocorticoids < 1 month
  • Patient's written informed consent
  • Life expectancy > 6 months

Exclusion criteria

  • Binet stage A
  • ECOG performance status 2 or more
  • Presence of a 17p deletion by FISH (> 10% positive cores)
  • Clinically significant auto-immune cytopenia, Coombs-positive hemolytic anemia as judged by the treating physician
  • Patients with a history of another malignancy in complete remission less than 5 years, except basal cell skin cancer or tumor treated curatively by surgery
  • Concomitant disease requiring prolonged use of corticosteroids (> 1 month)
  • Any severe co-morbidities such as NYHA Class III or IV heart failure, myocardial infarction within 6 months, unstable angina, ventricular tachyarrhythmias requiring ongoing treatment, severe uncontrolled myocardiopathy, uncontrolled hypertension, severe chronic obstructive pulmonary disease with hypoxemia, or uncontrolled diabetes mellitus.
  • CIRS (Cumulative Illness rating Scale) > 6
  • Known hypersensitivity to murine proteins or to any of the study drugs or to their components
  • Transformation into an aggressive B-cell malignancy (e.g. diffuse large cell lymphoma, Hodgkin lymphoma) or prolymphocytic leukemia
  • Active bacterial, viral or fungal infection
  • Seropositivity HIV, hepatitis C or hepatitis B (unless clearly due to vaccination)
  • Total bilirubin, alkaline phosphatases and aminotransferases > 2 x ULN
  • Creatinine clearance < 60 ml/min calculated according to the formula of Cockcroft and Gault
  • Any coexisting medical or psychological condition that would preclude participation to the required study procedures
  • Patient with mental deficiency preventing proper understanding of the requirements of treatment

Inclusion criteria at randomization

  • Patients having received the full induction phase with 4 FC and 6 rituximab courses (with/without dose adjustments as per protocol)
  • Complete or partial response according to NCI and iwCLL criteria at the end of induction phase
  • Recovery from FCR toxicities
  • Patient willingness to continue on protocol

Plan de estudios

Esta sección proporciona detalles del plan de estudio, incluido cómo está diseñado el estudio y qué mide el estudio.

¿Cómo está diseñado el estudio?

Detalles de diseño

  • Propósito principal: Tratamiento
  • Asignación: Aleatorizado
  • Modelo Intervencionista: Asignación paralela
  • Enmascaramiento: Ninguno (etiqueta abierta)

Armas e Intervenciones

Grupo de participantes/brazo
Intervención / Tratamiento
Sin intervención: Observation
Observation every 8 weeks during 2 years
Experimental: rituximab arm
rituximab :500 mg/m² every 8 weeks during 2 years
Biológico: Rituximab
rituximab :500 mg/m² every 8 weeks during 2 years
Otros nombres:
  • Mabthera

¿Qué mide el estudio?

Medidas de resultado primarias

Medida de resultado
Medida Descripción
Periodo de tiempo
Progression-free survival
Periodo de tiempo: randomization until disease progression or death
Progression-free survival is defined as the time from randomization to the first occurrence of disease progression, relapse or death from any cause; using iwCLL criteria
randomization until disease progression or death

Medidas de resultado secundarias

Medida de resultado
Medida Descripción
Periodo de tiempo
Event-free survival
Periodo de tiempo: randomization until disease progression, death, new CLL treatment, and secondary cancer
Event-free survival is defined as the time from randomization to the occurrence of one of the following events, whichever occurs first: disease progression or relapse, death from any cause, initiation of any new anti-CLL therapy, and secondary malignancy
randomization until disease progression, death, new CLL treatment, and secondary cancer
Disease-free survival
Periodo de tiempo: first documented CR until relapse
Disease-free survival is defined as the time from first documented CR to relapse
first documented CR until relapse
Overall survival
Periodo de tiempo: randomization until death
Overall survival is defined as the time from randomization to death from any cause
randomization until death
Time to next treatment
Periodo de tiempo: randomization until new CLL treatment
Time to next treatment is defined as the time from randomization to initiation of a new CLL-related treatment
randomization until new CLL treatment
Overall response rate
Periodo de tiempo: baseline up to approximately 66 months
Overall response rate is defined by the percentage of participants with an overall response; CR or PR according to NCI criteria and CR, CRi or PR according to iwCLL
baseline up to approximately 66 months
Phenotypic response rate
Periodo de tiempo: randomization up to approximately 60 months
Phenotypic response rate is defined by the percentage of participants with minimal residual disease negativity as measured by six-colour flow cytometry with a sensitivity of 0.7 x 10-5. MRD is considered as undetectable when the positivity criteria, defined as the presence of at least 20 CLL cells, is not reached
randomization up to approximately 60 months
Rates of treatment-related adverse events
Periodo de tiempo: safety since baseline
Rate of treatment-related adverse events (plus adverse events of particular interest) is defined as the percentage of participants with adverse events assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 3.0 and version 2.0. for hematological toxicity
safety since baseline
Pharmacokinetics of rituximab
Periodo de tiempo: baseline up to approximately 36 months
Pharmacokinetics of rituximab during induction and rituximab maintenance
baseline up to approximately 36 months
Quality of life
Periodo de tiempo: baseline up to approximately 30 months
Change from baseline in EORTC Quality of Life Questionnaire Core 30
baseline up to approximately 30 months

Colaboradores e Investigadores

Aquí es donde encontrará personas y organizaciones involucradas en este estudio.

Patrocinador

University Hospital, Tours

Colaboradores

Roche Pharma AG
French Innovative Leukemia Organisation

Investigadores

  • Investigador principal: Caroline Dartigeas, MD, Hématologie et Thérapie Cellulaire Hôpital Bretonneau CHU Tours FRANCE
  • Investigador principal: Eric VAN DEN NESTE, MD PhD, Département d'hématologie Cliniques Universitaires Saint Luc BRUSSELS BELGIUM

Publicaciones y enlaces útiles

La persona responsable de ingresar información sobre el estudio proporciona voluntariamente estas publicaciones. Estos pueden ser sobre cualquier cosa relacionada con el estudio.

Publicaciones Generales

Fechas de registro del estudio

Estas fechas rastrean el progreso del registro del estudio y los envíos de resultados resumidos a ClinicalTrials.gov. Los registros del estudio y los resultados informados son revisados ​​por la Biblioteca Nacional de Medicina (NLM) para asegurarse de que cumplan con los estándares de control de calidad específicos antes de publicarlos en el sitio web público.

Fechas importantes del estudio

Inicio del estudio

1 de diciembre de 2007

Finalización primaria (Actual)

1 de febrero de 2014

Finalización del estudio (Actual)

1 de julio de 2017

Fechas de registro del estudio

Enviado por primera vez

26 de marzo de 2008

Primero enviado que cumplió con los criterios de control de calidad

26 de marzo de 2008

Publicado por primera vez (Estimar)

27 de marzo de 2008

Actualizaciones de registros de estudio

Última actualización publicada (Actual)

1 de agosto de 2017

Última actualización enviada que cumplió con los criterios de control de calidad

27 de julio de 2017

Última verificación

1 de julio de 2017

Más información

Términos relacionados con este estudio

Palabras clave

Términos MeSH relevantes adicionales

Otros números de identificación del estudio

  • CDR0000589684
  • CHRUT-LLC-2007-SA (Otro identificador: CHU Tours)
  • CHRUT-PHRN05-CD (Otro identificador: CHU Tours)
  • INCA-RECF0497 (Otro identificador: INCA)
  • 2007-001015-28 (Número EudraCT)

Plan de datos de participantes individuales (IPD)

¿Planea compartir datos de participantes individuales (IPD)?

No

Información sobre medicamentos y dispositivos, documentos del estudio

Estudia un producto farmacéutico regulado por la FDA de EE. UU.

No

Estudia un producto de dispositivo regulado por la FDA de EE. UU.

No

producto fabricado y exportado desde los EE. UU.

No

Esta información se obtuvo directamente del sitio web clinicaltrials.gov sin cambios. Si tiene alguna solicitud para cambiar, eliminar o actualizar los detalles de su estudio, comuníquese con register@clinicaltrials.gov. Tan pronto como se implemente un cambio en clinicaltrials.gov, también se actualizará automáticamente en nuestro sitio web. .

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