Bendamustine Versus Fludarabine/Cyclophosphamide for Lymphodepletion in Chimeric Antigen Receptor T-cell Immunotherapy (CAR-T): a Randomized Trial. (FC-BALANCE)
Bendamustine Versus Fludarabine/Cyclophosphamide for Lymphodepletion in CAR-T Therapy: a Randomized Trial
Descripción general del estudio
Estado
Condiciones
Intervención / Tratamiento
Descripción detallada
Chimeric antigen receptor (CAR) T-cell immunotherapy (CAR-T) has emerged as an effective treatment for relapsed/refractory aggressive B-cell lymphomas. Three products that demonstrate clinical activities in relapse/refractory large B-Cell Lymphoma (LBCL), axicabtagene ciloleucel, tisagenlecleucel, and lisocabtagene maraleucel are currently available. To ensure an optimal CAR-T cell expansion and proliferation inside the host once infused, lymphodepleting therapy is administered before CAR-T immunotherapy as it exerts its activities by generating the optimal cytokine and metabolites milieu to ensure engraftment and proliferation of CAR-T cells once infused, by removing anergic circulating lymphocytes responsible of the "cytokine sink effect", and by debulking immunosuppressive tumor masses by the time of CAR-T cell infusion. Nowadays, commercially approved CAR-T products use a combination of fludarabine (Flu) and cyclophosphamide (Cy), at different dosages, as the standard lymphodepletion regimen. After CAR-T cell infusion participants might experience several toxicities including hematological toxicities and resulting infective events, as a direct consequence of lymphodepleting chemotherapy infusion.
Furthermore, the participants can experience CAR-T specific toxicities such as cytokine release syndrome (CRS) and Immune effector cell-associated neurotoxicity syndrome (ICANS), which are the consequence of the CAR-T cell to tumor engagement activity. In fact, these toxicities are responsible for more than 60% of non-relapse mortalities after CAR-T cells and their treatment increase the hospitalization stay and overall costs of CAR-T cell immunotherapy.
Therefore, there is a great need to improve the current CAR-T cell immunotherapy treatment to reduce the risk of toxicity. A growing number of retrospective studies demonstrated that bendamustine lymphodepletion is an alternative lymphodepletion regimen. In all these studies, bendamustine lymphodepletion showed comparable response rate but drastically reduced toxicities, in terms of CRS, neurotoxicity, hematological toxicity and, in particular, infections. As a result, its use is steadily increasing across Swiss centers. There are no published and other randomized trials, currently ongoing, investigating this particular question. For these reasons, bendamustine should be tested against the current SoC lymphodepleting chemotherapy.
This trial aims to prospectively compare the safety and efficacy of bendamustine versus standard Flu/Cy lymphodepletion before CART cell therapy in participants with relapsed/refractory large B-cell lymphoma (LBCL).
Tipo de estudio
Inscripción (Estimado)
Fase
- Fase 2
Contactos y Ubicaciones
Estudio Contacto
- Nombre: Ana Bello Gamboa
- Número de teléfono: +41 31 389 91 91
- Correo electrónico: trials@swisscancerinstitute.ch
Ubicaciones de estudio
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Aarau, Suiza, 5001
- Kantonsspital Aarau
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Contacto:
- Martina Dickenmann, MD
- Número de teléfono: +41 79 391 22 75
- Correo electrónico: martina.dickenmann@ksa.ch
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Investigador principal:
- Martina Dickenmann, MD
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Basel, Suiza, 4056
- Universitätsspital Basel
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Contacto:
- Andreas Holbro, MD
- Número de teléfono: +41 61 265 25 25
- Correo electrónico: Andreas.Holbro@usb.ch
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Investigador principal:
- Andreas Holbro, MD
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Bellinzona, Suiza, 6500
- Ente Ospedaliero Cantonale (EOC)-Istituto Oncologico della Svizzera Italiana (IOSI)
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Contacto:
- Georg Stüssi, Prof
- Número de teléfono: +41 91 811 87 78
- Correo electrónico: Georg.Stuessi@eoc.ch
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Investigador principal:
- Georg Stüssi, Prof
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Bern, Suiza, 3010
- Inselspital Bern - Universitätsklinik für Medizinische Onkologie
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Contacto:
- Marc Wehrli, MD
- Número de teléfono: +41 31 632 41 11
- Correo electrónico: marc.wehrli@insel.ch
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Investigador principal:
- Marc Wehrli, MD
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Chur, Suiza, 7000
- Kantonsspital Graubunden
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Contacto:
- Ulrich Mey, PD
- Número de teléfono: +41 81 256 71 70
- Correo electrónico: ulrich.mey@ksgr.ch
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Investigador principal:
- Ulrich Mey, MD
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Geneva, Suiza, 1211
- Les hôpitaux universitaires de Genève
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Contacto:
- Federico Simonetta, MD
- Número de teléfono: +41 22 372 38 38
- Correo electrónico: federico.simonetta@unige.ch
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Investigador principal:
- Federico Simonetta, MD
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Lucerne, Suiza, 6004
- Luzerner Kantonsspital
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Contacto:
- Ramona Merki, MD
- Número de teléfono: +41 41 205 51 47
- Correo electrónico: ramona.merki@luks.ch
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Investigador principal:
- Ramona Merki, MD
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Sankt Gallen, Suiza, 9007
- HOCH Health Ostschweiz - Kantonsspital St. Gallen
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Contacto:
- Martin Fehr, MD
- Número de teléfono: +41 71 494 62 69
- Correo electrónico: martin.fehr@h-och.ch
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Investigador principal:
- Martin Fehr, MD
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Zurich, Suiza, 8032
- Klinik für Hämatologie und Onkologie Hirslanden Zürich
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Contacto:
- Christoph Renner, Prof
- Número de teléfono: +41 43 387 37 80
- Correo electrónico: christoph.renner@kho.ch
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Investigador principal:
- Christoph Renner, Prof
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Criterios de participación
Criterio de elegibilidad
Edades elegibles para estudiar
- Adulto
- Adulto Mayor
Acepta Voluntarios Saludables
Descripción
Inclusion Criteria:
- Diagnosis of large B-cell lymphoma (LBCL) with at least one line of previous treatment and indication for commercial CAR-T cell therapy as determined by the treating physician. This includes: Diffuse large B-cell lymphoma (DLBCL) not otherwise specified (NOS) and all specific DLBCL subtypes, high-grade B-cell lymphoma, primary mediastinal B-cell lymphoma, transformed follicular lymphoma, and other transformed indolent B-cell lymphomas (including transformed marginal zone lymphoma and Richter's transformation). Patients with primary or secondary central nervous system (CNS) involvement are eligible.
- Planned treatment with commercially available CAR-T cell product
- Age ≥18 years
- Ability to provide written informed consent
Exclusion Criteria:
- Administration of any other experimental drug within 5 half-lives or ≤ 4 weeks prior to lymphodepletion therapy starts.
- Bendamustine 3 months before leukapheresis. After leukapheresis, bendamustine use is allowed as bridging therapy according to physician decision.
- Previous administration of anti-CD19 CAR-T products within the last 12 months from lymphodepletion therapy start.
- Known history of hypersensitivity to the active substance or any of the excipients found in the composition of bendamustine, fludarabine, or cyclophosphamide.
Plan de estudios
¿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 |
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Experimental: Arm A: Experimental Arm
Bendamustine
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Comparador activo: Arm B: Control Arm
Fludarabine/Cyclophosphamide
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¿Qué mide el estudio?
Medidas de resultado primarias
Medida de resultado |
Medida Descripción |
Periodo de tiempo |
|---|---|---|
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Incidence of the following side effect occurring within 4 weeks (28 days) from the CAR-T infusion: Occurrence of grade ≥3 cytokine release syndrome (CRS)
Periodo de tiempo: From the start of lymphodepletion therapy until 4 weeks (day 28) after the CAR-T cell Infusion
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Primary Outcome measure consists of 3 side effects: Incidence of at least one of the following side effects occurring within 4 weeks (28 days) from the CAR-T infusion: • Occurrence of grade ≥3 cytokine release syndrome (CRS) • Febrile neutropenia • Grade ≥3 Immune effector Cell-Associated Neurotoxicit. All infections, including those that result in febrile neutropenia, and the CRS and ICANS will be graded according to Common Terminology Criteria for Adverse Events (CTCAE) version 6.0. Febrile neutropenia is defined as absolute neutrophil count <1000/mm³ with fever ≥38.3°C (single measurement) or ≥38.0°C sustained for >1 hour. Participants who remain free of any of the above listed symptoms at least 28 days from the CAR-T cell infusion AND did not stop the trial treatment will be counted as a success for this endpoint, otherwise they will be counted as a failure for the primary endpoint. |
From the start of lymphodepletion therapy until 4 weeks (day 28) after the CAR-T cell Infusion
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Incidence of the following side effect occurring within 4 weeks (28 days) from the CAR-T infusion: Febrile neutropenia
Periodo de tiempo: From the start of lymphodepletion therapy until 4 weeks (day 28) after the CAR-T cell Infusion
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Primary Outcome measure consists of 3 side effects: Incidence of at least one of the following side effects occurring within 4 weeks (28 days) from the CAR-T infusion: • Occurrence of grade ≥3 cytokine release syndrome (CRS) • Febrile neutropenia • Grade ≥3 Immune effector Cell-Associated Neurotoxicit. All infections, including those that result in febrile neutropenia, and the CRS and ICANS will be graded according to Common Terminology Criteria for Adverse Events (CTCAE) version 6.0. Febrile neutropenia is defined as absolute neutrophil count <1000/mm³ with fever ≥38.3°C (single measurement) or ≥38.0°C sustained for >1 hour. Participants who remain free of any of the above listed symptoms at least 28 days from the CAR-T cell infusion AND did not stop the trial treatment will be counted as a success for this endpoint, otherwise they will be counted as a failure for the primary endpoint. |
From the start of lymphodepletion therapy until 4 weeks (day 28) after the CAR-T cell Infusion
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Incidence of the following side effect occurring within 4 weeks (28 days) from the CAR-T infusion: Grade ≥3 Immune effector Cell-Associated Neurotoxicit
Periodo de tiempo: From the start of lymphodepletion therapy until 4 weeks (day 28) after the CAR-T cell Infusion
|
All infections, including those that result in febrile neutropenia, and the CRS and ICANS will be graded according to Common Terminology Criteria for Adverse Events (CTCAE) version 6.0. Febrile neutropenia is defined as absolute neutrophil count <1000/mm³ with fever ≥38.3°C (single measurement) or ≥38.0°C sustained for >1 hour. Participants who remain free of any of the above listed symptoms at least 28 days from the CAR-T cell infusion AND did not stop the trial treatment will be counted as a success for this endpoint, otherwise they will be counted as a failure for the primary endpoint. |
From the start of lymphodepletion therapy until 4 weeks (day 28) after the CAR-T cell Infusion
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Medidas de resultado secundarias
Medida de resultado |
Medida Descripción |
Periodo de tiempo |
|---|---|---|
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Best lymphoma response at 3 months post-CAR-T infusion
Periodo de tiempo: From the CAR-T infusion until week 15 (inclusive) post-CAR-T infusion
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Best lymphoma response at 3 months is defined as the best response assessment in the following descending order: complete response (CR), partial response (PR), stable disease (SD), progressive disease (PD) or not evaluable (NE), measured as indicated on local guidelines (e.g., Lugano 2014 classification) based on PET/CT imaging.
Any assessment up to week 15 (inclusive) will be considered for determining the best response.
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From the CAR-T infusion until week 15 (inclusive) post-CAR-T infusion
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Progression-free survival (PFS)
Periodo de tiempo: from CAR-T infusion to lymphoma progression or death, up to 3.25 years after CAR-T infusion of the first patient]
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PFS is defined as time from CAR-T infusion to lymphoma progression or death from any cause.
Participants not experiencing an event, including participants receiving a subsequent anti-lymphoma therapy without documented disease progression or relapse, will be censored at the last time they were known to be without progression (i.e. last date of tumor assessment without progression) and before the start of a new anti-lymphoma treatment, if any.
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from CAR-T infusion to lymphoma progression or death, up to 3.25 years after CAR-T infusion of the first patient]
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Overall survival (OS)
Periodo de tiempo: From CAR-T infusion to death, up to 3.25 years after CAR-T infusion of the first patient
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Time from CAR-T infusion to death from any cause.
Participants not experiencing an event will be censored at the last date they were known to be alive.
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From CAR-T infusion to death, up to 3.25 years after CAR-T infusion of the first patient
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Colaboradores e Investigadores
Patrocinador
Investigadores
- Silla de estudio: Benjamin Kasenda, PD Dr. med. Dr. phil., University Hospital Basel (USB)
- Director de estudio: Guido Ghilardi, Ente Ospedaliero cantonale (EOC)
Fechas de registro del estudio
Fechas importantes del estudio
Inicio del estudio (Estimado)
Finalización primaria (Estimado)
Finalización del estudio (Estimado)
Fechas de registro del estudio
Enviado por primera vez
Primero enviado que cumplió con los criterios de control de calidad
Publicado por primera vez (Actual)
Actualizaciones de registros de estudio
Última actualización publicada (Actual)
Última actualización enviada que cumplió con los criterios de control de calidad
Última verificación
Más información
Términos relacionados con este estudio
Palabras clave
Términos MeSH relevantes adicionales
- Neoplasias
- Enfermedades del sistema inmunológico
- Neoplasias por tipo histológico
- Enfermedades linfáticas
- Trastornos linfoproliferativos
- Trastornos inmunoproliferativos
- Linfoma No Hodgkin
- Linfoma
- Enfermedades hemic y linfáticas
- Linfoma de células B
- Químicos orgánicos
- Compuestos heterocíclicos
- Benzimidazoles
- Compuestos heterocíclicos, 2 anillos
- Compuestos heterocíclicos, anillo fusionado
- Hidrocarburos
- Ácidos, acíclico
- Ácidos carboxílicos
- Mostaza de fosforamida
- Compuestos de mostaza de nitrógeno
- Compuestos de mostaza
- Hidrocarburos, halogenados
- Fosforamidas
- Compuestos organofosforados
- Butiratos
- Clorhidrato de bendamustina
- Ciclofosfamida
- fludarabina
Otros números de identificación del estudio
- SCI-003_FC-BALANCE
- 2026-525792-36-00 (Ctis)
- U1111-1335-8513 (Otro identificador: ICTRP)
Información sobre medicamentos y dispositivos, documentos del estudio
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Estudia un producto de dispositivo regulado por la FDA de EE. UU.
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