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
Visão geral do estudo
Status
Condições
Intervenção / Tratamento
Descrição detalhada
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 estudo
Inscrição (Estimado)
Estágio
- Fase 2
Contactos e Locais
Contato de estudo
- Nome: Ana Bello Gamboa
- Número de telefone: +41 31 389 91 91
- E-mail: trials@swisscancerinstitute.ch
Locais de estudo
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Aarau, Suíça, 5001
- Kantonsspital Aarau
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Contato:
- Martina Dickenmann, MD
- Número de telefone: +41 79 391 22 75
- E-mail: martina.dickenmann@ksa.ch
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Investigador principal:
- Martina Dickenmann, MD
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Basel, Suíça, 4056
- Universitätsspital Basel
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Contato:
- Andreas Holbro, MD
- Número de telefone: +41 61 265 25 25
- E-mail: Andreas.Holbro@usb.ch
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Investigador principal:
- Andreas Holbro, MD
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Bellinzona, Suíça, 6500
- Ente Ospedaliero Cantonale (EOC)-Istituto Oncologico della Svizzera Italiana (IOSI)
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Contato:
- Georg Stüssi, Prof
- Número de telefone: +41 91 811 87 78
- E-mail: Georg.Stuessi@eoc.ch
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Investigador principal:
- Georg Stüssi, Prof
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Bern, Suíça, 3010
- Inselspital Bern - Universitätsklinik für Medizinische Onkologie
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Contato:
- Marc Wehrli, MD
- Número de telefone: +41 31 632 41 11
- E-mail: marc.wehrli@insel.ch
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Investigador principal:
- Marc Wehrli, MD
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Chur, Suíça, 7000
- Kantonsspital Graubunden
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Contato:
- Ulrich Mey, PD
- Número de telefone: +41 81 256 71 70
- E-mail: ulrich.mey@ksgr.ch
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Investigador principal:
- Ulrich Mey, MD
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Geneva, Suíça, 1211
- Les hôpitaux universitaires de Genève
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Contato:
- Federico Simonetta, MD
- Número de telefone: +41 22 372 38 38
- E-mail: federico.simonetta@unige.ch
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Investigador principal:
- Federico Simonetta, MD
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Lucerne, Suíça, 6004
- Luzerner Kantonsspital
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Contato:
- Ramona Merki, MD
- Número de telefone: +41 41 205 51 47
- E-mail: ramona.merki@luks.ch
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Investigador principal:
- Ramona Merki, MD
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Sankt Gallen, Suíça, 9007
- HOCH Health Ostschweiz - Kantonsspital St. Gallen
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Contato:
- Martin Fehr, MD
- Número de telefone: +41 71 494 62 69
- E-mail: martin.fehr@h-och.ch
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Investigador principal:
- Martin Fehr, MD
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Zurich, Suíça, 8032
- Klinik für Hämatologie und Onkologie Hirslanden Zürich
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Contato:
- Christoph Renner, Prof
- Número de telefone: +41 43 387 37 80
- E-mail: christoph.renner@kho.ch
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Investigador principal:
- Christoph Renner, Prof
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Critérios de participação
Critérios de elegibilidade
Idades elegíveis para estudo
- Adulto
- Adulto mais velho
Aceita Voluntários Saudáveis
Descrição
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.
Plano de estudo
Como o estudo é projetado?
Detalhes do projeto
- Finalidade Principal: Tratamento
- Alocação: Randomizado
- Modelo Intervencional: Atribuição Paralela
- Mascaramento: Nenhum (rótulo aberto)
Armas e Intervenções
Grupo de Participantes / Braço |
Intervenção / Tratamento |
|---|---|
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Experimental: Arm A: Experimental Arm
Bendamustine
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Comparador Ativo: Arm B: Control Arm
Fludarabine/Cyclophosphamide
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O que o estudo está medindo?
Medidas de resultados primários
Medida de resultado |
Descrição da medida |
Prazo |
|---|---|---|
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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)
Prazo: From the start of lymphodepletion therapy until 4 weeks (day 28) after the CAR-T cell Infusion
|
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
Prazo: From the start of lymphodepletion therapy until 4 weeks (day 28) after the CAR-T cell Infusion
|
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
Prazo: 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
|
Medidas de resultados secundários
Medida de resultado |
Descrição da medida |
Prazo |
|---|---|---|
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Best lymphoma response at 3 months post-CAR-T infusion
Prazo: 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)
Prazo: 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)
Prazo: 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
- Cadeira de estudo: Benjamin Kasenda, PD Dr. med. Dr. phil., University Hospital Basel (USB)
- Diretor de estudo: Guido Ghilardi, Ente Ospedaliero cantonale (EOC)
Datas de registro do estudo
Datas Principais do Estudo
Início do estudo (Estimado)
Conclusão Primária (Estimado)
Conclusão do estudo (Estimado)
Datas de inscrição no estudo
Enviado pela primeira vez
Enviado pela primeira vez que atendeu aos critérios de CQ
Primeira postagem (Real)
Atualizações de registro de estudo
Última Atualização Postada (Real)
Última atualização enviada que atendeu aos critérios de controle de qualidade
Última verificação
Mais Informações
Termos relacionados a este estudo
Palavras-chave
Termos MeSH relevantes adicionais
- Neoplasias
- Doenças do sistema imunológico
- Neoplasias por Tipo Histológico
- Doenças Linfáticas
- Distúrbios Linfoproliferativos
- Distúrbios imunoproliferativos
- Linfoma Não-Hodgkin
- Linfoma
- Doenças hemic e linfáticas
- Linfoma de Células B
- Produtos químicos orgânicos
- Compostos heterocíclicos
- Benzimidazóis
- Compostos heterocíclicos, 2 anel
- Compostos heterocíclicos, anel fundido
- Hidrocarbonetos
- Ácidos, acíclico
- Ácidos carboxílicos
- Mustarazas de fosforamida
- Compostos de mostarda de nitrogênio
- Compostos de mostarda
- Hidrocarbonetos, halogenados
- Fosforamidas
- Compostos organofosforos
- Butyrates
- Cloridrato de Bendamustina
- Ciclofosfamida
- fludarabina
Outros números de identificação do estudo
- SCI-003_FC-BALANCE
- 2026-525792-36-00 (Ctis)
- U1111-1335-8513 (Outro identificador: ICTRP)
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