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
Обзор исследования
Статус
Условия
Вмешательство/лечение
Подробное описание
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).
Тип исследования
Регистрация (Оцененный)
Фаза
- Фаза 2
Контакты и местонахождение
Контакты исследования
- Имя: Ana Bello Gamboa
- Номер телефона: +41 31 389 91 91
- Электронная почта: trials@swisscancerinstitute.ch
Места учебы
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Aarau, Швейцария, 5001
- Kantonsspital Aarau
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Контакт:
- Martina Dickenmann, MD
- Номер телефона: +41 79 391 22 75
- Электронная почта: martina.dickenmann@ksa.ch
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Главный следователь:
- Martina Dickenmann, MD
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Basel, Швейцария, 4056
- Universitätsspital Basel
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Контакт:
- Andreas Holbro, MD
- Номер телефона: +41 61 265 25 25
- Электронная почта: Andreas.Holbro@usb.ch
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Главный следователь:
- Andreas Holbro, MD
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Bellinzona, Швейцария, 6500
- Ente Ospedaliero Cantonale (EOC)-Istituto Oncologico della Svizzera Italiana (IOSI)
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Контакт:
- Georg Stüssi, Prof
- Номер телефона: +41 91 811 87 78
- Электронная почта: Georg.Stuessi@eoc.ch
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Главный следователь:
- Georg Stüssi, Prof
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Bern, Швейцария, 3010
- Inselspital Bern - Universitätsklinik für Medizinische Onkologie
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Контакт:
- Marc Wehrli, MD
- Номер телефона: +41 31 632 41 11
- Электронная почта: marc.wehrli@insel.ch
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Главный следователь:
- Marc Wehrli, MD
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Chur, Швейцария, 7000
- Kantonsspital Graubunden
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Контакт:
- Ulrich Mey, PD
- Номер телефона: +41 81 256 71 70
- Электронная почта: ulrich.mey@ksgr.ch
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Главный следователь:
- Ulrich Mey, MD
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Geneva, Швейцария, 1211
- Les hôpitaux universitaires de Genève
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Контакт:
- Federico Simonetta, MD
- Номер телефона: +41 22 372 38 38
- Электронная почта: federico.simonetta@unige.ch
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Главный следователь:
- Federico Simonetta, MD
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Lucerne, Швейцария, 6004
- Luzerner Kantonsspital
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Контакт:
- Ramona Merki, MD
- Номер телефона: +41 41 205 51 47
- Электронная почта: ramona.merki@luks.ch
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Главный следователь:
- Ramona Merki, MD
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Sankt Gallen, Швейцария, 9007
- HOCH Health Ostschweiz - Kantonsspital St. Gallen
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Контакт:
- Martin Fehr, MD
- Номер телефона: +41 71 494 62 69
- Электронная почта: martin.fehr@h-och.ch
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Главный следователь:
- Martin Fehr, MD
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Zurich, Швейцария, 8032
- Klinik für Hämatologie und Onkologie Hirslanden Zürich
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Контакт:
- Christoph Renner, Prof
- Номер телефона: +41 43 387 37 80
- Электронная почта: christoph.renner@kho.ch
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Главный следователь:
- Christoph Renner, Prof
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Критерии участия
Критерии приемлемости
Возраст, подходящий для обучения
- Взрослый
- Пожилой взрослый
Принимает здоровых добровольцев
Описание
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.
Учебный план
Как устроено исследование?
Детали дизайна
- Основная цель: Уход
- Распределение: Рандомизированный
- Интервенционная модель: Параллельное назначение
- Маскировка: Нет (открытая этикетка)
Оружие и интервенции
Группа участников / Армия |
Вмешательство/лечение |
|---|---|
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Экспериментальный: Arm A: Experimental Arm
Bendamustine
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Активный компаратор: Arm B: Control Arm
Fludarabine/Cyclophosphamide
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Что измеряет исследование?
Первичные показатели результатов
Мера результата |
Мера Описание |
Временное ограничение |
|---|---|---|
|
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)
Временное ограничение: 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
Временное ограничение: 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
Временное ограничение: 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
|
Вторичные показатели результатов
Мера результата |
Мера Описание |
Временное ограничение |
|---|---|---|
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Best lymphoma response at 3 months post-CAR-T infusion
Временное ограничение: 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)
Временное ограничение: 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)
Временное ограничение: 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
|
Соавторы и исследователи
Спонсор
Следователи
- Учебный стул: Benjamin Kasenda, PD Dr. med. Dr. phil., University Hospital Basel (USB)
- Директор по исследованиям: Guido Ghilardi, Ente Ospedaliero cantonale (EOC)
Даты записи исследования
Изучение основных дат
Начало исследования (Оцененный)
Первичное завершение (Оцененный)
Завершение исследования (Оцененный)
Даты регистрации исследования
Первый отправленный
Впервые представлено, что соответствует критериям контроля качества
Первый опубликованный (Действительный)
Обновления учебных записей
Последнее опубликованное обновление (Действительный)
Последнее отправленное обновление, отвечающее критериям контроля качества
Последняя проверка
Дополнительная информация
Термины, связанные с этим исследованием
Ключевые слова
Дополнительные соответствующие термины MeSH
- Новообразования
- Заболевания иммунной системы
- Новообразования по гистологическому типу
- Лимфатические заболевания
- Лимфопролиферативные заболевания
- Иммунопролиферативные заболевания
- Лимфома, неходжкинская
- Лимфома
- Гемики и лимфатические заболевания
- Лимфома, В-клеточная
- Органические химические вещества
- Гетероциклические соединения
- Бензимидазолы
- Гетероциклические соединения, 2-кольцо
- Гетероциклические соединения, слитое кольцо
- Углеводороды
- Кислоты, ациклические
- Карбоновые кислоты
- Фосфорамид горчицы
- Азотные соединения горчицы
- Горчичные соединения
- Углеводороды, галогенированные
- Фосфорамиды
- Соединения органофосфора
- Бутират
- Бендамустин гидрохлорид
- Циклофосфамид
- флударабин
Другие идентификационные номера исследования
- SCI-003_FC-BALANCE
- 2026-525792-36-00 (Ктис)
- U1111-1335-8513 (Другой идентификатор: ICTRP)
Информация о лекарствах и устройствах, исследовательские документы
Изучает лекарственный продукт, регулируемый FDA США.
Изучает продукт устройства, регулируемый Управлением по санитарному надзору за качеством пищевых продуктов и медикаментов США.
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