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
Panoramica dello studio
Stato
Condizioni
Intervento / Trattamento
Descrizione dettagliata
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 di studio
Iscrizione (Stimato)
Fase
- Fase 2
Contatti e Sedi
Contatto studio
- Nome: Ana Bello Gamboa
- Numero di telefono: +41 31 389 91 91
- Email: trials@swisscancerinstitute.ch
Luoghi di studio
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Aarau, Svizzera, 5001
- Kantonsspital Aarau
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Contatto:
- Martina Dickenmann, MD
- Numero di telefono: +41 79 391 22 75
- Email: martina.dickenmann@ksa.ch
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Investigatore principale:
- Martina Dickenmann, MD
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Basel, Svizzera, 4056
- Universitätsspital Basel
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Contatto:
- Andreas Holbro, MD
- Numero di telefono: +41 61 265 25 25
- Email: Andreas.Holbro@usb.ch
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Investigatore principale:
- Andreas Holbro, MD
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Bellinzona, Svizzera, 6500
- Ente Ospedaliero Cantonale (EOC)-Istituto Oncologico della Svizzera Italiana (IOSI)
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Contatto:
- Georg Stüssi, Prof
- Numero di telefono: +41 91 811 87 78
- Email: Georg.Stuessi@eoc.ch
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Investigatore principale:
- Georg Stüssi, Prof
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Bern, Svizzera, 3010
- Inselspital Bern - Universitätsklinik für Medizinische Onkologie
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Contatto:
- Marc Wehrli, MD
- Numero di telefono: +41 31 632 41 11
- Email: marc.wehrli@insel.ch
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Investigatore principale:
- Marc Wehrli, MD
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Chur, Svizzera, 7000
- Kantonsspital Graubunden
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Contatto:
- Ulrich Mey, PD
- Numero di telefono: +41 81 256 71 70
- Email: ulrich.mey@ksgr.ch
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Investigatore principale:
- Ulrich Mey, MD
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Geneva, Svizzera, 1211
- Les hôpitaux universitaires de Genève
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Contatto:
- Federico Simonetta, MD
- Numero di telefono: +41 22 372 38 38
- Email: federico.simonetta@unige.ch
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Investigatore principale:
- Federico Simonetta, MD
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Lucerne, Svizzera, 6004
- Luzerner Kantonsspital
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Contatto:
- Ramona Merki, MD
- Numero di telefono: +41 41 205 51 47
- Email: ramona.merki@luks.ch
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Investigatore principale:
- Ramona Merki, MD
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Sankt Gallen, Svizzera, 9007
- HOCH Health Ostschweiz - Kantonsspital St. Gallen
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Contatto:
- Martin Fehr, MD
- Numero di telefono: +41 71 494 62 69
- Email: martin.fehr@h-och.ch
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Investigatore principale:
- Martin Fehr, MD
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Zurich, Svizzera, 8032
- Klinik für Hämatologie und Onkologie Hirslanden Zürich
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Contatto:
- Christoph Renner, Prof
- Numero di telefono: +41 43 387 37 80
- Email: christoph.renner@kho.ch
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Investigatore principale:
- Christoph Renner, Prof
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Criteri di partecipazione
Criteri di ammissibilità
Età idonea allo studio
- Adulto
- Adulto più anziano
Accetta volontari sani
Descrizione
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.
Piano di studio
Come è strutturato lo studio?
Dettagli di progettazione
- Scopo principale: Trattamento
- Assegnazione: Randomizzato
- Modello interventistico: Assegnazione parallela
- Mascheramento: Nessuno (etichetta aperta)
Armi e interventi
Gruppo di partecipanti / Arm |
Intervento / Trattamento |
|---|---|
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Sperimentale: Arm A: Experimental Arm
Bendamustine
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Comparatore attivo: Arm B: Control Arm
Fludarabine/Cyclophosphamide
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Cosa sta misurando lo studio?
Misure di risultato primarie
Misura del risultato |
Misura Descrizione |
Lasso di tempo |
|---|---|---|
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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)
Lasso di tempo: 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
Lasso di tempo: 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
|
|
Incidence of the following side effect occurring within 4 weeks (28 days) from the CAR-T infusion: Grade ≥3 Immune effector Cell-Associated Neurotoxicit
Lasso di tempo: 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
|
Misure di risultato secondarie
Misura del risultato |
Misura Descrizione |
Lasso di tempo |
|---|---|---|
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Best lymphoma response at 3 months post-CAR-T infusion
Lasso di tempo: 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)
Lasso di tempo: 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.
|
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)
Lasso di tempo: 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
|
Collaboratori e investigatori
Sponsor
Investigatori
- Cattedra di studio: Benjamin Kasenda, PD Dr. med. Dr. phil., University Hospital Basel (USB)
- Direttore dello studio: Guido Ghilardi, Ente Ospedaliero cantonale (EOC)
Studiare le date dei record
Studia le date principali
Inizio studio (Stimato)
Completamento primario (Stimato)
Completamento dello studio (Stimato)
Date di iscrizione allo studio
Primo inviato
Primo inviato che soddisfa i criteri di controllo qualità
Primo Inserito (Effettivo)
Aggiornamenti dei record di studio
Ultimo aggiornamento pubblicato (Effettivo)
Ultimo aggiornamento inviato che soddisfa i criteri QC
Ultimo verificato
Maggiori informazioni
Termini relativi a questo studio
Parole chiave
Termini MeSH pertinenti aggiuntivi
- Neoplasie
- Malattie del sistema immunitario
- Neoplasie per tipo istologico
- Malattie linfatiche
- Malattie linfoproliferative
- Disturbi immunoproliferativi
- Linfoma non Hodgkin
- Linfoma
- Malattie emiche e linfatiche
- Linfoma, cellule B
- Prodotti chimici organici
- Composti eterociclici
- Benzimidazoli
- Composti eterociclici, 2 anelli
- Composti eterociclici, anello fuso
- Idrocarburi
- Acidi, aciclici
- Acidi carbossilici
- Senape di fosforamide
- Composti di senape di azoto
- Composti di senape
- Idrocarburi, alogenati
- Fosforamidi
- Composti organofosfori
- Butirati
- Bendamustina cloridrato
- Ciclofosfamide
- fludarabina
Altri numeri di identificazione dello studio
- SCI-003_FC-BALANCE
- 2026-525792-36-00 (Ctis)
- U1111-1335-8513 (Altro identificatore: ICTRP)
Informazioni su farmaci e dispositivi, documenti di studio
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